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Good day, and thank you for standing by. Welcome to Moderna's Third Quarter 2026 Conference Call. [Operator Instructions] Please be advised, today's conference is being recorded.

I would now like to hand the conference over to your speaker today, Lavina Talukdar. Please go ahead.

Thank you, Kevin. Good morning, everyone, and thank you for joining us on today's call to discuss Moderna's third quarter 2026 financial results and business update. You can access the press release issued this morning as well as the slides that we'll be reviewing by going to the Investors section of our website.

On today's call are Stephane Bancel, our Chief Executive Officer; Stephen Hoge, our President; Jamey Mock, our Chief Financial Officer; and David Berman, our Chief Development Officer.

Before we begin, please note that this call will include forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Please see Slide 2 of the accompanying presentation and our SEC filings for important risk factors that could cause our actual performance and results to differ materially from those expressed or implied in these forward-looking statements.

With that, I will turn the call over to Stephane.

Thank you, Lavina. Good morning or good afternoon, everyone. Thank you for joining us. I will start today with a review of our third quarter. Jamey will then cover our financial results and outlook, followed by Stephen with our current business updates in infectious disease. David will then review our clinical progress in oncology and rare diseases. And I will come back quickly for close on our key value drivers before Q&A.

The Moderna team delivered a great third quarter, generating $1.3 billion in revenues, representing 29% growth year-over-year. Importantly, this strong commercial performance translated into $200 million in net income for the quarter. We also ended the quarter with a strong balance sheet with $8 billion in cash and investments, reflecting a combination of solid operational and commercial execution, along with a highly successful convertible debt financing. And we continue to demonstrate financial discipline across the company, reducing cash cost by 10% compared to the third quarter of last year. Together, these strong results underscore our ability to deliver strong commercial performance while maintaining financial discipline and strengthening our financial position.

During the quarter, we achieved several important milestones across our pipeline and our business. U.S. FDA approval of mFLUSIVA, making Moderna's fifth approved product and the first mRNA-based influenza vaccine to reach the market. In Canada, we secured approvals of both mFLUSIVA and mCOFLU yesterday, the local brand name for mCOMBRIAX, further expanding our respiratory portfolio internationally.

In oncology, we are very proud to present positive Phase III data for intismeran autogene, our individualized cancer therapy being developed in partnership with Merck. The results demonstrated a significant clinical benefit with a 42% reduction in the risk of recurrence or death in patients with resected melanoma, and additional analysis suggesting an even greater benefit of 49% reduction in the risk of recurrence or death in patients who received at least 1 dose of intismeran as planned. Importantly, this marks the first combination immunotherapy regimen to demonstrate additional benefits of a KEYTRUDA alone in the adjuvant melanoma setting, representing a significant milestone for melanoma patients and their families around the world. David will discuss these results in greater details.

We also took an important step to further strengthen our financial position. During the quarter, we raised $3 billion for a 0% convertible note debt, securing long-term capital on highly attractive terms. After accounting for the purchase of capped call, designed to mitigate potential future dilution and fees, we raised approximately $2.6 billion in net proceeds. This financing strengthens our ability to invest in the growth of our oncology business, a key strategic priority for Moderna as we approach candidate important clinical milestones.

In Global Health, our Ebola vaccine candidate, mRNA-1469, developed in collaboration with CEPI, was selected to advance into a [ Phase II/III ] following a recommendation from the WHO Technical Advisory Group.

I am extremely proud of our performance delivered by the team in Q3. Strong sales growth, profitability, approval and quick launch of flu in the U.S., intismeran positive Phase III and the convertible debt financing.

I'm also very pleased and happy to welcome back Juan Andres to Moderna Executive Committee. Many of you will remember Juan for his previous time at Moderna, where he played a critical role in building and scaling our global manufacturing network during the pandemic. He also led the scale-out of individualized manufacturing for intismeran autogene. He knows our company, our technology and our culture extremely well.

As we enter this next phase of Moderna's growth with an expanded commercial portfolio and important opportunities ahead in oncology, having Juan back on the team will be invaluable. I am personally very excited to be working with him again. And I know the entire Moderna team is delighted to welcome him back.

With that, I'll turn to Jamey.

Thanks, Stephane, and hello, everyone. Today I'll begin with a review of our third quarter financial performance, followed by an update on our 2026 financial framework. Let me start with our commercial performance on Slide 8.

We delivered a strong third quarter with revenue of $1.3 billion, bringing our year-to-date revenue to $1.8 billion. Our geographic mix for the quarter was approximately 60% U.S. and 40% international. Both the U.S. and international markets delivered stronger-than-expected revenue in 3Q, driven by a mix of increased demand, operational execution and timing of shipments between the third and fourth quarters.

As mentioned in prior calls, we forecasted 2 primary growth drivers in 2026: increased mNEXSPIKE adoption and growth in our strategic partnerships in the U.K., Canada and Australia. In the U.S., while the vaccination season is still ongoing, we have seen increased uptake of mNEXSPIKE, and vaccination rates have been relatively stable versus the prior year.

Internationally, our teams have executed well, particularly in the U.K. and Canada. Year-to-date, international revenue of $900 million is already $200 million ahead of the full year we delivered in 2025.

Based on the strong start to the season combined with the visibility we have into the fourth quarter, we are increasing our full year revenue framework to a range of 15% to 25% growth, which exceeds our prior framework of up to 10% growth. We continue to expect an approximately even split between U.S. and international revenue for the full year.

Now let me turn to our third quarter financial performance on Slide 9. As I just mentioned, total revenue was $1.3 billion for the quarter, up 29% from last year, primarily driven by higher COVID sales.

Cost of sales for the quarter was $318 million, representing 24% of total revenue for the quarter. This was a 54% increase in our cost of sales from Q3 last year, primarily driven by higher product sales volume and other manufacturing-related costs. We remain on track to drive significant gross margin improvements in 2026, excluding the $900 million litigation charge.

R&D expenses for the quarter were $583 million, down 27% from last year, driven by completion and wind-down of studies in our infectious disease portfolio as well as efficiency gains across the organization. SG&A expenses for the quarter were $282 million, a 5% increase year-over-year. We continue to maintain cost discipline across the organization while investing for growth.

Our income tax provision was immaterial in both periods. Net income for the quarter was $160 million, an improvement of $362 million compared to last year. Diluted earnings per share was $0.38, compared to a loss per share of $0.51 last year.

We ended the quarter with cash and investments of $8 billion, up from $6.9 billion at the end of the second quarter. The increase was primarily driven by $2.6 billion of net proceeds from our convertible note issuance and capped call transaction, partially offset by a $950 million litigation settlement payment as well as the seasonal impact to working capital.

Now let's turn to our financial framework for 2026. For total revenue, as I mentioned in my earlier remarks, we are improving our revenue outlook to a range of 15% to 25% growth, which exceeds our prior framework of up to 10% growth. Cost of sales is unchanged at $1.7 billion, which includes $0.9 billion of expense related to the previously announced litigation settlement charge.

We are lowering our R&D expense by $200 million to $2.7 billion due to further wind-down of studies and continued operational efficiencies. SG&A expenses are still expected to be approximately $1 billion, flat versus the prior year. Similar to last year, we expect higher SG&A expenses in the fourth quarter primarily due to commercial related activity.

In aggregate, excluding the $0.9 billion litigation charge, we are expecting total GAAP operating expenses of $4.5 billion and $3.8 billion of cash costs, which excludes stock-based compensation, depreciation and amortization. Each reflects a $200 million improvement compared to our previous framework. We expect taxes to be negligible in 2026. And we are lowering our capital expenditure estimate to $200 million from our previous range of $200 million to $300 million.

Cash and investments are now projected to be between $8.1 billion and $8.3 billion at the end of 2026. Excluding the $2.6 billion net proceeds from the convertible note and capped call transaction, our cash projection would be $5.5 billion to $5.7 billion, which is an improvement from our previous framework of $4.7 billion to $5.2 billion. The increase in our cash projection is due to our improved revenue outlook and reductions in both our cash cost and CapEx projections. Our cash cost framework does not assume any additional drawdown from our remaining $0.9 million undrawn credit facility.

With that, I will now turn the call over to Stephen.

Thank you, Jamey, and good morning or good afternoon, everyone. I'll now take you through our recent business updates. As a reminder, Slide 12 outlines our multiyear revenue growth strategy, which continues to be anchored in 2 key drivers: geographic expansion and portfolio expansion through continued pipeline advancement. We are building a more diversified portfolio with new opportunities across respiratory vaccines, oncology and rare diseases, while expanding our commercial footprint in markets around the world.

We're making tangible progress against this strategy with several important milestones achieved during the quarter. Starting with mFLUSIVA, we recently received FDA approval for adult age 50 to 64 and accelerated approval for adults age 65 and older in the U.S. In Canada, we secured approvals for both mFLUSIVA and mCOFLU, the local brand name for mCOMBRIAX, for adults aged 60 and older. For our mNEXSIPKE, we saw approvals for the annual strain updates in the United States, Canada, Japan and Taiwan for the 2026, 2027 vaccination season. And for mRESVIA, we continue to make progress in the U.S. and international markets.

We expanded our international presence with a 5-year agreement signed with a local manufacturer in Mexico to support COVID-19 vaccine supply. And finally, in oncology, we presented positive Phase III data for intismeran in adjuvant melanoma at the ESMO Presidential Symposium, as highlighted earlier. These milestones demonstrate continued execution against our strategy to drive revenue growth.

Turning to our approved infectious disease portfolio. We continue to make progress across our 5 commercial products. starting with our COVID vaccine. As I mentioned earlier, mNEXSPIKE received approval for the updated [ XFG strain ] for this coming vaccination season in the United States, Canada, Japan and Taiwan, with additional regulatory reviews and filings underway. Spikevax has also received approval for the updated strain in these markets and also in the European Union. Deliveries of our updated COVID-19 vaccines are now underway globally.

Turning to RSV, mRESVIA is approved in 44 countries. We also received published results from a Phase III study evaluating revaccination with mRESVIA in adults aged 60 and older who had previously received a protein-based RSV vaccine. This study demonstrated robust immune responses comparable to those seen following the initial vaccination with mRESVIA, with no new safety concerns identified, highlighting the potential for mRESVIA in revaccination. A link to the study can be found on this slide.

For mFLUSIVA, our seasonal influenza vaccine, we have approvals in the United States and now Canada with reviews ongoing in the European Union, Australia and Taiwan. In the U.S. the American Academy of Family Physicians has recommended mFLUSIVA for adults aged 65 and older as an enhanced influenza vaccine.

And finally, for mCOMBRIAX, our combination influenza and COVID-19 vaccine, we now have approvals in Europe and Canada. The product remains under review in Japan, the United Kingdom, Australia and Switzerland, with a decision on filing in the United States subject to further discussion with the FDA.

Turning to U.S. respiratory vaccination trends. Overall demand remains strong, as I said before. Through late October, approximately 44.1 million flu, COVID-19 and RSV vaccinations have been administered in the retail and long-term care channels, a 3% increase over the comparable period last year. Flu vaccinations are trending slightly ahead of last year, and COVID-19 vaccinations are trending slightly behind, but momentum in October suggests vaccinations may end up flat year-over-year in the channel. These trends demonstrate the healthy demand for seasonal respiratory vaccines in the United States.

Turning to our late-stage infectious disease pipeline and our norovirus vaccine program, mRNA-1403. As a reminder, as previously disclosed, the Phase III study did not meet the statistical criteria for early success at its interim analysis. Following a review of the program, we have decided not to enroll an additional cohort this coming winter season. Instead we are engaging with health authorities to determine the next steps for the program. And we'll provide further updates following those discussions.

With that, I'll now turn the call over to David to review our oncology and rare disease pipeline.

Thank you, Stephen. Hello, everyone. I will review the progress across our oncology and rare disease pipeline, starting with intismeran autogene, our individualized cancer therapy, which is being developed in partnership with Merck.

Last month, we presented the positive Phase III INTerpath-001 melanoma results at the Presidential Symposium at ESMO, and I'll discuss these in greater detail shortly. A link to the ESMO presentation can be found at the bottom of the slide.

Beyond melanoma, our intismeran development program continues to advance across multiple tumor types and stages of disease. In non-small cell lung cancer, the adjuvant Phase III study is fully enrolled. Two additional Phase III studies in non-small cell lung cancer continue to enroll patients. One, Phase III, is in patients who did not have a pathologic complete response following neoadjuvant therapy. And the other Phase III is in Stage 1 disease evaluating intismeran both as a monotherapy and in combination with KEYTRUDA [ QLEX ]. Phase II studies in adjuvant renal cell carcinoma and muscle invasive bladder cancer are fully enrolled. Both of these studies are randomized against KEYTRUDA and are event-driven studies.

We continue to enroll Phase II clinical studies in non-muscle invasive bladder cancer, metastatic melanoma and metastatic squamous non-small cell lung cancer. Phase I studies in pancreatic and gastric cancer are fully enrolled.

At ESMO, we presented a poster highlighting encouraging translational data from the Phase I pancreatic cancer study. Despite the low tumor mutational burden typically seen in pancreatic cancer, we were able to generate neoantigen-specific T cell responses in all 19 evaluable patients. A link to the poster is at the bottom of the slide.

Now let's review the Phase III melanoma results. In the INTerpath-001 trial, the primary endpoint was relapse-free survival. Intismeran plus pembrolizumab demonstrated a significant 42% reduction in the risk of recurrence or death, compared with pembrolizumab alone. The hazard ratio was 0.58 and P value below 0.001. These remarkable results were observed at the first interim analysis of this large randomized Phase III trial enrolling more than 1,100 patients with resected Stage IIb through IV melanoma. At 2 years, recurrence-free survival was 82.2% in the combination arm, compared with 70% for pembrolizumab alone, representing a 12 percentage point absolute improvement.

These results represent 2 important firsts. The first positive Phase III trial for an individualized cancer vaccine and the first positive Phase III trial demonstrating benefit over anti-PD-1 therapy in adjuvant melanoma.

This is a summary of the Phase II results at 3 different follow-ups. That study also tested intismeran plus pembrolizumab versus pembrolizumab monotherapy and also had an RFS primary endpoint. What's particularly remarkable is the consistency between the Phase II hazard ratio of 0.56 and the Phase III hazard ratio of 0.58 at the primary analysis where both had similar follow-up. In our Phase II study, the RFS hazard ratio improved, from 0.56 to 0.51% at 3 years. And that benefit was maintained through 5 years of follow-up. We are optimistic about the potential to see similar strengthening of the treatment benefit in Phase III as the data matures.

This optimism is further supported by sensitivity analyses from the Phase III trial. In the Phase III trial, we conducted prespecified sensitivity analyses that provide additional insights into the treatment to benefit. One of these analyses evaluated the modified intent to treat or MITT population, which evaluates only patients who received the intended intismeran or placebo injection. Patients were randomized and received pembrolizumab but either relapsed or withdrew prior to the first dose of intismeran or placebo as planned were excluded.

In other words, while the ITT analysis shows the results of a Phase III clinical trial, the MITT analysis, by limiting to patients actually treated with the blinded vaccine, shows the true treatment effect of intismeran. In this MITT analysis, we observed an even greater treatment benefit with a 49% reduction in the risk of recurrence or death, compared with a 42% reduction observed in the primary ITT. Notably, the hazard ratio of 0.51 is consistent with what we observed in Phase II at the 3 and 5-year follow-ups.

At 2 years, the recurrence-free survival was 84.2% with the combination, compared with 70.4% for pembrolizumab alone, representing nearly a 14 percentage point absolute improvement. Together, the ITT and MITT analyses reinforce the strength and consistency of the efficacy between Phase III and Phase II.

The degree of benefit for the combination over pembrolizumab monotherapy, which itself is a great drug, is one reason that I am optimistic intismeran will work in other tumor types.

The combination of intismeran plus pembrolizumab was generally well tolerated with findings consistent with the known safety profiles of the individual therapies. Adding intismeran did not meaningfully increase pembrolizumab associated adverse events of interest, which occurred in 36% of patients receiving the combination, compared to 35% of patients receiving pembrolizumab alone. And adverse events associated with intismeran were also consistent with its expected safety profile. The most common adverse events in the combination arm were pyrexia, injection site pain and fatigue. These events were generally low-grade, transient and were managed with standard supportive care. These findings are encouraging, particularly in the context of the significant improvement in relapse-free survival demonstrated in the study.

I'll now turn to our broader oncology portfolio. Outside of intismeran we continue to advance a diversified portfolio of oncology programs across cancer antigen therapies, T-cell engagers and cell therapy enhancement.

Starting with mRNA-4359, our cancer antigen therapy. We have an ongoing Phase II study in first-line metastatic melanoma, second-line or later metastatic melanoma and first-line metastatic non-small cell lung cancer. Our mRNA-4194 program is progressing in a Phase I/II study in Lynch syndrome with Phase I dose escalation ongoing. We all continue to advance mRNA-4106 and mRNA-4200 with Phase I studies dosing patients currently.

Turning to our T-cell engager program, mRNA-2808, is in a Phase I study in multiple myeloma. The initial clinical results have been selected for an oral presentation at the upcoming ASH Annual Meeting in December, and we look forward to presenting the data and advancing this program.

Finally, in collaboration with Immatics, we continue dosing in the Phase I study of our cell therapy enhancer, mRNA-4203 in combination with anzu-cel. Across these programs, we're evaluating several distinct therapeutic approaches and continue to generate clinical evidence to guide further development.

Turning briefly to our rare disease pipeline, our registrational trial in propionic acidemia, or PA, is on track. And we look forward to the results later this year. For methylmalonic acidemia, or MMA, we've deferred the decision to initiate a pivotal trial until after the PA readout.

With that, I'll hand the call back to Stephane.

Thank you, David, Stephen and Jamey. Looking ahead, we continue to see important value drivers across our commercial business, financial performance and pipeline. We have raised our full year 2026 revenue growth expectations to between 15% and 20% growth, exceeding our previous revenue growth expectation of up to 10%. We also continue to execute with financial discipline, lowering our adjusted cash cost target by another $200 million to approximately $3.8 billion for fiscal year '26. And we have raised our year-end cash and investment outlook to between $8.1 billion and $8.3 billion. On the commercial side, we continue to pursue additional regulatory approvals to expand the global reach of our respiratory vaccine portfolio.

Turning to our pipeline. 2026 has been a landmark year for oncology, highlighted by our positive Phase III melanoma result for intismeran and the presentation of encouraging early pancreatic cancer data at ESMO. Looking ahead, key milestone includes our events-driven Phase II renal cancer readout, the intismeran BLA submission, the presentation of mRNA-2808 at ASH and our registrational readout in propionic acidemia, or PA, our most advanced regenerative disease program.

Our priorities remain clear: grow our commercial business, maintain financial discipline and advance our pipeline towards important clinical and regulatory milestones. I'm very proud of what our team has accomplished this year and excited about the opportunities ahead for Moderna.

We look forward to hosting the investment community next week at our upcoming Analyst Day on November 12. The event will be held in person at our intismeran manufacturing site in Marlborough, Massachusetts, where attendees will have also the opportunity to tour the site. A webcast of our presentation will be available for those joining remotely.

I want to close thanking our teams around the world for their dedication and execution. This has been an important year for Moderna and our progress reinforce what we can accomplish when we combine both science with disciplined execution. Our platform is delivering. Five approved infectious disease vaccines around the world, positive Phase III for intismeran and the new modality with mRNA-2808 proof of concept in multiple myeloma T-cell engagers. Our mission remains at the heart of everything we do: to deliver the greatest possible impact to people for mRNA medicine.

With that, we'll be happy to take your questions.

[Operator Instructions] Our first question comes from Salveen Richter with Goldman Sachs.

Two questions for me. One is, could you frame your confidence into the interim data in renal cell carcinoma, particularly as we think about the statistical plan with regard to a number of events that needs to be hit around that interim? And then if you could also touch on the fact that there've been some questions in the contribution of the [ LNP ] to immunogenicity with regard to the melanoma trial, and maybe just help frame that for us as well?

In terms of the timing, it's event driven for the RCC trial, so it could be end of this year or early next year. In terms of the confidence of that, why I'm confident, I would say probably a couple of reasons. First is that we know that RCC is an anti-PD-1 sensitive tumor, anti-PD-1s work by T cells, by reactivating T cells. We work by generating novel T cells. And so it's a T cell sensitive disease, and so that's confidence number one.

Confidence number two derives from the fact that in our Phase II trial, we saw efficacy in the melanoma population at both that was equivalent for high-TMB and for low-TMB patients. And if you overlap the low-TMB spectrum in the melanoma, it actually does overlap with RCC.

And then finally, the treatment benefits that we saw in the primary analysis has a ratio of 0.58 versus pembrolizumab alone, that was the same treatment effect that pembrolizumab alone saw versus placebo in their [ KEYNOTE 54 ], and then we know KEYTRUDA went on to be positive in RCC as well. So those are the reasons why I have confidence or believe that we are likely potentially to have a positive result. I don't say anything more about the statistical analysis plan.

In terms of the LNP immunogenicity question, this is a question that's been going on for a while just [indiscernible] that came up a few years ago when MD Anderson published a retrospective analysis. And it wasn't a randomized trial. It was just observation. And they suggested that patients who got the mRNA LNP vaccine had better outcomes to immunotherapy. That has -- that data from MD Anderson has subsequently been repeated and not been repeated by different groups.

And in fact, most recently, Memorial Sloan Kettering, which is the other large cancer center in the U.S., came out with their own analysis showing that actually there was no treatment effect by the addition of mRNA LNP. So I don't think that that answer is clear. I don't think the evidence is strong enough to claim it. And I don't think LNP T can generate such an incredibly strong hazard ratio in the adjuvant setting.

Our next question comes from Terence Flynn with Morgan Stanley.

Great. I was just wondering, I know you're not going to guide on price at this point for INT, but I was just wondering if you could talk through some of the inputs that you and Merck are considering as you think about pricing that therapy? And then the second question I had is just on the Phase II RCC study, if those data are positive, do you think that can support a registration in that setting?

Look, this is Stephen, I'll take the first part of it on price and then I think hand it over to David. On price, look, it's premature at this point. We're working on getting a submission done this year and obviously working towards approval. We will always look to price our products to represent the value they create in health care systems. And obviously, we're thrilled by the data, but it is premature at this point to say anything more. And we'll work closely with Merck on that process.

Terence, in regard to your second question, look, it's a pretty large randomized, well-controlled Phase II with 282 patients. But it is a Phase II. So at a base case, I would say it can be practice-informing, especially with compendium listing, if it's positive. In an upside, if the results are very strong, I think we can consider taking it to FDA. But it will be data dependent.

Our next question comes from Ellie Merle with Barclays.

On the back of the pancreatic data at ESMO, can you elaborate on how you're thinking about potential next development steps here? Would you study in combo with PD-1, with chemo or both? And then just a quick one on RCC. If the study is not successful in the first interim, is that something you'd disclose if it moves on to additional analyses?

Ellie, so with regard to the PDAC, look, the good news is that in this low-TMB tumor, we were able to generate cassettes from the patients. And in all of the evaluable patients, we were able to see T cell reacting to those neoantigens. So I think that's a really good sign. And we did it in combination with the standard of care, which is FOLFIRINOX. So it informed us that it can safely be given with chemotherapy, which I think we probably assumed it could, and that we can still generate T cell reactivity in the face of the addition of chemotherapy.

I think for next steps, we're actively discussing that with Merck right now. I think it could be in the same regimen that we studied, it could be in combination with the RAS inhibitor. I think we need to do a little more thinking about that because the standard of care is changing.

And in terms of the disclosure, I don't think we've decided yet how we're going to handle that.

Our next question comes from Edward Tenthoff with Piper Sandler.

Great. And congrats on all the progress. My questions are just on the BLA for intismeran. What still has to happen? And are you working collaboratively with Merck on that? Are they driving the bus? And then just trying to get a sense for when we might get data from the lung cancer studies. And maybe you can kind of break out sort of how those different studies might read out.

Ted, it's Stephen. I'll take the first part of that and then hand it over to David to speak through the lung cancer work. So we're working intensely with our partner, Merck. As we said earlier, as Stephane mentioned a moment ago, we are working to make sure that submission with the BLA happens this year. And if everything goes well, as has been said before, we would hope to see approval next year.

There are lots of steps, as you know, pulling those things together, including getting ready for pre-approval inspections and everything. And I can assure you, working around the clock to make sure that not only the submission happens on time, but the review is facilitated with the FDA. Because our goal here ultimately is approval. But working very closely with Merck together on that as we speak. David?

Thanks, Stephen. The lung cancer adjuvant program is actually really comprehensive. We announced that we have just about completed. We have completed enrollment in the intismeran -- in the INTerpath-002, which is adjuvant after chemotherapy, with no neoadjuvant therapy. In fact, this was the fastest enrolling -- one of Merck's fastest enrolling trials, just to give you a sense of the excitement.

We are still ongoing in enrollment in patients who had neoadjuvant pembro chemo and did not have pathologic complete response. That's still enrolling. So it's too soon to know what's going to happen in terms of timing there. And then we have the really exciting high-risk Stage I lung cancer Phase III, where the first time we're testing intismeran monotherapy in one of the arms, also still enrolling there.

In terms of readouts and timings, I think it's a little too soon. We just finished [ PREDICT ]. We just finished enrolling. And so now we need to start monitoring events and then we'll have a better idea about timing.

Our next question comes from Alec Stranahan with Bank of America.

Two from us, one on 2808 and one financial question. Looking forward to the data at ASH, I guess, what will the update add beyond the first 11 response available patients in terms of more patients, higher dose, durability? And I guess, how does this program maybe reflect the broader oncology opportunity you see for the platform?

And quickly on your 2026 growth guidance increase, how much of this came from timing, meaning deliveries moved into 2026? And does any of it, I guess, pull revenue forward from 2027?

Alec, with regard to program, thanks for highlighting 2808, it is actually one of the exciting early-stage programs we have. There have been, obviously, lots of T-cell engagers in myeloma. There have been some that are targeting 2 antigens. This, of course, is the first time ever that 3 antigens have been targeted, and that's why we're excited this is going to be an oral presentation.

The data cut is later for the oral than it was the abstract, so you can expect more patients, longer follow-up and evaluation of what -- whether we can get a deeper response and activity in patients who had prior BCMA and [ GPCR 5D ].

In terms of the broader implications, this is testing a hypothesis we have that one of the benefits of our platform is that we can multiplex. And so we're multiplexing care against different tumor antigens in the form of 3 T-cell engagers. But it can also show that we can multiplex on the other side, going after different T cell stimulation approaches as well. So the fact that this works shows that we can multiplex, we can generate systemic proteins to treat cancer. And I think that's been a very important proof of principle.

Thanks, David. Yes. And Alec, thanks for the question. So we're encouraged that this is really broad-based growth this year. It is both U.S. and international. And I'll just go back to some of my prepared remarks, which was we came into the year with 2 key growth drivers, mNEXSPIKE is performing extremely well in the U.S. But in addition to that, in the U.S., vaccination rates are stable, which Stephen walked through on his chart.

Internationally, we came in thinking about the strategic partnerships, and those have all performed extremely well also. So when we look to 2027, I go back to what Stephen presented in terms of there are still 4 growth drivers out there. Flu is relatively immaterial right now for us in 2026, and we expect to grow next year. Europe opens up for us, Latin America partnerships, hopefully, we will have INT approved. So we're quite encouraged. So again, it was a broad-based growth in 2026, and the 2 primary growth drivers are going well for us.

Our next question comes from Myles Minter with William Blair.

Congrats on the quarter and all of the updates for the INTerpath-001. I actually had just a question on norovirus. I think at your last quarterly update, you indicated you were going to enroll another cohort. Now you're not and you're going to the regulators. Just wondering what changed there and what you're hoping to get out of those regulatory discussions.

Yes, Myles. At this point, I don't have much more to say than we already did. You're correct, we did not meet the criteria for early success, and we were going forward with a cohort initially. But as we reviewed the program, we think the most appropriate next step is not to go forward with that cohort, but instead consult with regulators. And at this point, it's premature for me to guide any further on that. But once we've had those discussions with them about the potential next steps of the program, we'll be able to provide an update more broadly. So for now, we'll have to have those conversations before I can offer anything more.

Our next question comes from Tyler Van Buren TD Cowen.

Congrats on the quarterly results. So the melanoma INT results are clearly stellar. But regarding the next readout in RCC, some KOLs have brought up research suggesting that RCC immunogens may be driven in part by [ HIF-regulated ] endogenous retroviral elements. So can the current INT antigen selection process, identify and incorporate those types of noncanonical antigens? And how might that impact the probability of success?

Yes, it's an interesting hypothesis that has been put out there. I think it's a hypothesis and it's a question whether endogenous retrovirals play a role or not. What I do know is that our algorithm does include insertion deletions, indels, which are actually strongly demonstrated to be important in RCC, as well as neoantigens, and single-point neoantigens that is.

And then I'll also point you out to a publication recently from Dana-Farber, where they did their own personalized cancer vaccine, and were able to identify sufficient neoantigens without the addition of endogenous retroviral. So the ERVs are interesting, they're speculative, and I think more research needs to be made before we include them.

Our next question comes from Andrew Tsai with Jefferies.

As we think about the BLA submission for melanoma with INT, can you talk about whether you would need some kind of special FDA approval on the algorithm side on top of the drug side? And secondly, if the power of AI continues to improve rapidly, can you just maybe talk about why competitors, hypothetically speaking, can't catch up to you on the algorithm side? Why do you think you have a protective moat?

So first of all, yes, obviously, the algorithm for selection and, in fact, the entire front-end process for designing an INT for an individual patient, is a part of the drug. Effectively, there is software in it. And that is a proprietary feature of our platform, our technology. It's not something that will be readily available.

The important question maybe is the one -- the second part of yours, which is then, how does that play forward? And we're incredibly excited by what we've learned in our clinical trials. And bear in mind, the randomized data we have on immunogenicity from Phase II was in about 150 people, about 100 people who received INT. They've now been followed through 5 years. And at ASCO this year, we presented some of the update data, recent ESMO event, we presented some of that. We learned a tremendous amount the 34 neoantigens that we put into those people in that study.

What is remarkable is with the melanoma study that just read out, we've taken the number of patients up that we have that experience with by almost a factor of 10. And if you look across the other 9 studies that are up and running, we'll go another factor of 5 again. So we're starting to develop a tremendous amount of real experience with what sorts of neoantigens are generating T cell clones, what are the features of that T cell clonality that we think is really valuable for a neoantigen vaccine and individualized neoantigen vaccine. And we are constantly looking to bring that back into how we predict and design INTs for individuals going forward.

That data is a gold mine. We had -- I think we presented this, 5,000 neoantigens across the 100-plus participants in that first study, in the Phase II, it's gone up by a factor of 10. And we will be, with our partner, Merck, we're deeply going through that data and continuing to treat that proprietary information as one of the really special sauces, as we continue to try and make INTs more and more effective going forward in the -- really in the decades ahead. So we think we're at the very beginning of scientific revolution, and we're excited to be in the lead and to have that proprietary information.

Our next question comes from Michael Yee with UBS.

Two questions. On INT, the clinical trial protocols are available for renal cell and bladder cancer, and we understand that they are an alpha spend -- one-sided alpha of 0.10, very much like you nicely designed your Phase II melanoma study and very much the same assumptions. Do you stand by that protocol and can confirm that those assumptions are correct?

And the second question is as it relates to filing in melanoma, is there a general timing guidance for that just so we can think about the gating steps and all the things that need to be done there in terms of the filing?

Michael, we're not aware of the protocols that you cite, and I obviously can't comment on it, so I'm going to have to pass on that. In terms of the BLA, we're obviously working closely with Merck on that, and stay tuned for our next message on that.

Our next question comes from Courtney Breen with Bernstein.

A couple for me. I did want to zoom back to the pancreatic cancer study, the Phase I data that you presented at ESMO this year. Obviously, we saw the neoantigen generation, the T cell expansion, et cetera, that you've spoken to. There was also a small swimmer plot of kind of performance for these patients and recurrent details for these patients. Can you just help us understand what you're taking from that efficacy data so far? We see it as relatively early compared to kind of what performance can be generated with FOLFIRINOX on its own. But just want to understand kind of what you're already able to take from those insights and the potential to move forward. Or do you need more time to assess that data before you would move forward?

And then just the second question, just a really practical one on the revenue generation. Can you just talk a little bit about the ex U.S. components here and how much of that is coming from kind of commitments, how much of that is coming from pure demand? And we're just trying to figure out how we kind of appropriately carry some of this forward.

Courtney, this is David. Thank you for the pancreatic question. It was very exciting data because we can generate T cells reactive to neoantigens that are present in the PDAC patients, which is something that actually was not really necessarily given.

In terms of the swimmer plot that you noticed, yes, I think I agree that it's probably too early, point number one. And point number two, this was a mix of patients. Some of them had neoadjuvant treatments, some of them didn't. And so it's really hard for us to discern an efficacy signal. I'm always careful about discerning efficacy signals in single-arm trial time-to-event analyses. I think the immunogenicity is data great, the safety is great, and we'll have to figure out the next step.

Question on international. So I would say a significant portion is very durable. We've talked about the strategic partnerships, and it comprises over 50% of our revenue for sure. And then -- but I think what's also great about our international growth is, one, we're playing in a lot of other markets outside of these strategic partnerships, that we have been for some time. And we are increasing share, to some degree, as well as, I think as I mentioned earlier, the vaccination rates are improving in a lot of these markets as well. So I think we are seeing a shift year-over-year globally that vaccination rates have become more stable. So we hope that that is pretty durable moving forward.

Our next question comes from Alexandria Hammond, Wolfe Research.

So on INT, what learnings have you guys been able to take in regard to the optimal number of neoantigens coated? Do you think 34 is a sweet spot? Or do you think essentially next-generation assets or of your internal kind of platform could encompass more? I guess what kind of has the data demonstrated about how much of the breadth of these neoantigen payload matters. Is more always better or could a smaller number of newly highly immunogenic [indiscernible] be more favorable?

I love the science question, and I'm happy to take it and expand on it. You're asking the exact question, right, which is what makes an optimal neoantigen, how many you need. These are things that we are now looking into because we have a randomized Phase III trial. And you need the efficacy in order to decode, go back to how many neoantigens you actually need.

So in melanoma, which has several hundred neoantigen [indiscernible] we know that 34 selected is enough. We can see that roughly 1 out of 3 of them generate a T cell response, although that may be higher. Actually, we're learning that we may actually have more immunogenicity than we actually thought we did.

So I'm not sure more is better because I'm not sure a hazard ratio of 0.58 or 0.51 in MITT is pretty good, against KEYTRUDA is really, really good. So would more have been better? It's hard to imagine more would have been better, but I don't know. These are things we now need to decode with our Phase III data.

Our next question comes from Jess Fye with JPMorgan.

Just following up on Alex's question there, you mentioned now you have this sort treasure trove of Phase III data. If I recall from the Phase II of the translational work we saw at ASCO, there were like 7 patients to work with, and it was like maybe a little hard to draw conclusions based on the small sample size. Do you have the actual like samples and data that you need to run that analysis to figure out those answers about sort of optimal number of neoantigens?

Jess, so the 7 patients that you talk about is correct, the n=7. Because in order to do very deep immunological monitoring, you have to withdraw a decent amount of blood, and not all patients are willing to do that. And in this case, there were 7 patients willing to do that.

We do have more patients available from across the trials. So that's point number one. And secondly, we have developed really exciting novel ways to decode T cell reactivity from gene -- from just looking at the expression data from the cold blood gene analysis TCR beta. We have a way that we're beginning to learn to try to decode back neoantigen specificity. I mean that's part of the Holy Grail. So I am hopeful that we will be able to get insights from the Phase III that we didn't have in the Phase II. I think that it remains to be seen how far we can go, but that is certainly the goal.

Our next question comes from Luca Issi with RBC.

Congrats on all the progress. Maybe, David, one more on RCC and the upcoming Phase II. Can you just maybe talk about the stratification strategy there? It looks like you're stratifying patients by either clear cell versus [ populari ] histology as well as by high versus low-disease risk. I guess what I'm trying to ask is, are there any specific subpopulations within RCC that are maybe more immunologically active that you're more optimistic that this approach can work? Or do you think this can work kind of across the board? And then maybe related to it, are you tracking the blinded event [indiscernible] and death? And are they on track with internal expectations or not?

And then maybe separately, Steve, any update on the ongoing conversations with the FDA and the time line for COVID plus flu in the U.S.?

Yes. In terms of the tracking of the events, we don't comment on that. In terms of the what subpopulations, I think we believe this can work in multiple subpopulations. I think that was one of the insights we made from the Phase II and the Phase III studies, that pretty much all of the subsets we looked at have had a trend or a point estimate in favor of intismeran, including high-stage versus low-stage, high-TMB versus low-TMB. Some subtypes, papillary renal cell, obviously, is different than clear-cell RCC, but that's why we're stratifying against that. But as long as they have neoantigens we think that can generate novel T cell clones, and that can potentially have a benefit. So I don't think I would narrow down to a population right now.

Just on the question on the flu/COVID combo vaccine for the U.S. We, as we said before, we are waiting for the approval in August. That was just 2 months ago, and then the launch of the flu and COVID vaccines in the U.S. And that was our key to then start the process of engaging with the FDA, that will take some time, there's a lot going on right now across our whole portfolio. And so we will, in the next number of months, be able to sit down and understand better what the U.S. FDA expects in terms of submission of the 1083 program. And once we have that information, we'll obviously provide an update.

Ladies and gentlemen, this does conclude the Q&A portion of today's program. I'd like to turn the call back over to Stephane for any further remarks.

Well, thank you, everybody, for joining us today. We really appreciate it. We're looking forward to seeing many of you in person next week for our Annual Analyst Day, November 12. And we are very excited for you to tour and to discover the intismeran manufacturing site. Have a nice weekend.

Thank you. Ladies and gentlemen, this does conclude today's presentation. We thank you for your participation. You may now disconnect, and have a wonderful day.

Good evening, and thank you for joining us today. This is a very exciting day for cancer patients, it's an exciting day for cancer immunologists, and it's an exciting day for Moderna. Here's our forward-looking statement.

Today, I'm going to start by giving just some brief contextual statements on Intismeran. I'll then invite up Dr. Georgina Long, who was the lead investigator for INTerpath-001 and gave a fantastic presentation today to give a reprise of that presentation. I'll conclude with concluding statements. And then we're very fortunate to have 2 world experts in melanoma, Professor Ascierto, who was the senior author of INTerpath-001 and Professor Ribas, who is a melanoma expert and a world leader in cancer immunotherapy as well.

Immune surveillance controls emerging cancer cells. And it does this by detecting neoantigens that form in cancer cells. These neoantigens drain or are carried to regional lymph nodes. They are processed in antigen presenting cells and then brought to the surface of the antigen-presenting cell and present it to T cells. T cells that recognize these neoantigens are activated, they circulate throughout the body, looking for the cancer and they eliminate the cancer. However, as we know, cancer can escape immune surveillance, when either the cancer lacks sufficient neoantigens. The neoantigens aren't released or aren't transported to the lymph node. The antigen presenting cells don't process them or present them on the surface. The T cell is insufficiently activated or the T cells become exhausted. Checkpoints act on T cells, anti-PD-1, PD-L1, reverse T cell exhaustion and anti-CTLA-4 lowers the threshold for T cell activation. However, they act only on T cells and are limited by whatever available neoantigens are present in that lymph node.

Intismeran, as shown today by the Phase III data, has an entirely different mechanism. It optimizes neoantigen presentation. And how does it do this? Well, first, we take the tumor out of the patient and use an algorithm to select the most promising neoantigens. We package those neoantigens into an mRNA lipid nanoparticle, and that's used to inject into the muscle of the patient. Now we know from nonhuman primate studies and from rodent studies that when an mRNA-LNP is injected into muscle, it drains into the regional lymph node is taken up by antigen-presenting cells and dendritic cells. The RNA is produced into protein, and that protein in the case of neo -- in the case of our neoantigen Intismeran can be presented on the surface.

So there are 3 important points to take away about why we think Intismeran is so potent: First, high neoantigen expression in the cells where it's required in the antigen presenting cells and in the dendritic cells. Number two, this is in an optimal environment. It's far away from the immunosuppressive microenvironment of the tumor. And number three, because CD4 and CD8 T cells are activated, dendritic cells are activated, and cytokines are released, there's a perfect milieu to create polyfunctional CD4 and CD8 T cells. And we have translational data to support some of these.

Let me take you to ASCO 2026 just a few months ago, where we presented the Phase II data. I'd first like to draw your attention to the initial Phase II data that was presented a few years ago. Recall the hazard ratio at the primary analysis, which had the same follow-up as INTerpath-001 today, the hazard ratio was 0.561 at the primary analysis. With longer follow-up, as we showed a few months ago, the hazard ratio improved to [ 0.510 ]. Now why did the hazard ratio improve? This can be seen looking at the art of the Kaplan-Meier curve. For the first 6 months, on the left-hand side, the hazard -- the Kaplan-Meiers are overlapping. And as you heard today from Dr. Long, this is in part due to the weeks required to produce Intismeran and then weeks or a month for the immune system to be activated.

At month 6, the curve separate, and we know they'll eventually remain separated. However, in the primary analysis, that first 6 months takes up about 1/4 of the entire Kaplan-Meier curve that hazard ratio 1 for the first 6 months takes up a 1/4 of that curve. In the longer 5-year follow-up, that 6-month hazard ratio 1 is still there, but now we have follow-up up to 60 months. And therefore, that initial 6 months takes up better fraction of the entire hazard ratio. And this is why we prespecified to conduct a piece-wise analysis at 6 months, and you'll hear that from Dr. Long during her presentation.

But it's very important, I think, to recall that the primary hazard ratio was essentially identical to what you'll hear today, 0.561 in this analysis. And we do believe the Phase III data for this reason will continue to improve. Intismeran, as I mentioned, activates T cells, and we should expect to see novel T cell clones in the peripheral blood. This is a figure. The y-axis is the sum of novel T cells that we detect in the blood. And the x-axis is 4 different time points, baseline, post the pembrolizumab lead-in and just prior to Intismeran at cycle 5, so in the middle of the Intismeran regimen and then at a follow-up. And this is the Phase II Intismeran plus pembro -- versus pembro. The first portion notice the 2 arms are overlapping because patient -- both groups of patients are receiving pembrolizumab, exactly what you would expect to see. However, once Intismeran is administered, the combination curve continues to go up, more novel T cell clones are generated compared to the control arm.

This leads to the question we asked, would high levels of novel T cell clones be associated with clinical benefit? And in theory, this should be most evident in the combination arm. And that's exactly what we see. So the same y-axis is the number of unique clones. X-axis is the same. On the left-hand side is the combination arm. And on the right-hand side is the pembrolizumab arm. Now we've separated the patients into 2 groups. Those who had benefits, i.e., never had a recurrence and those who had, let's say, no benefit, those who had a recurrence. We did that for both arms. And you'll notice for the combination arm, patients who had no recurrence, which is the top, their novel T cell clones continue to increase during treatment, whereas the ones who had recurrence plateaued. For the pembrolizumab arm, there's an initial increase, and then there is a plateau. So this is evidence that there's an association mechanistically between the number of novel T cell clones and clinical benefit.

Now these are novel T cell clones, and we don't know if they are related to the Intismeran drug product. And it is a little more complex to match T cells to neoantigens, but we were able to do it in 7 patients, which requires a lot more blood than is typically taken during the routine blood assessment. So we had -- so we consented 7 patients, and we matched their T cells to the 34 neoantigens they received in their cassette. And what we found is, on average, one out of every 3 neoantigens in the 34 cassette is immunogenic. That is it induces a T cell that is novel in the blood that reacts specifically to that neoantigen peptide. And it ranges from about 1 to 18. And interestingly, it includes both CD4 and CD8 T cells.

We then sought to further characterize the phenotype of these T cells. And we find -- this is an example. It's a CD8 T cell that recognizes neoantigen 14 from patient 3 and the CD4 T cell that recognizes neoantigen 27. And when we phenotype it using flow cytometry, what we see is that both T cell clones are polyfunctional. They make different types of cytokines, and they also have markers of a cytotoxic phenotype, meaning that they're ready to go out and kill the cancer cell.

Because we were able to clone out those T cells that recognize those neoantigens, we had the TCR sequences, and we could go back to whole blood and we could follow the frequency or the prevalence of those T cells during treatment. So it's the same time frame on the bottom screening, leading with pembrolizumab in the middle of the Intismeran regimen, and then at the end. And what you'll see in these 3 examples that all T cell clones only appear after Intismeran, not during pembrolizumab and most of them remain elevated for the entirety of the treatment. As a side note for the -- for those who are immunologists, one of the interesting features, which is known is that there are usually multiple T cell clones that can recognize the same neoantigen peptide.

So at this point, I'd like to invite up Dr. Long to give the presentation of INTerpath-001, and then I'll return to give a few closing comments.

Thank you. It's a pleasure to present these data again to a smaller, more cozy audience. So -- and it is a true honor to be able to present results on something so transformational for cancer. So this is a Phase III randomized clinical of Intismeran combined with pembrolizumab.

We refer to Intismeran as an type of INT therapy versus pembrolizumab alone for the adjuvant treatment of Stage IIB up to Stage IV melanoma. Now I don't have my glasses, but I can see this slide I'm not that blind, but so -- and I do present this on behalf of my co-investigators, there are 157 global sites and all of their teams. These are my disclosures. So we know that there is a clinical benefit for the adjuvant treatment of melanoma patients with anti-PD-1 monotherapy alone, that's clear. But shown here are the 2 curves for Stage III resected melanoma and Stage II resected melanoma Stage IIB. The red curve is placebo. The blue curve is pembrolizumab alone. And yet, despite their significant clinical benefit and absolutely changing the field, we still have 44% and 33% of patients recurring or dying at 5 years. So in the melanoma field, we see that there is a big -- a lot more work to do in terms of getting to 0 deaths and to curing cancer.

Now it's not that we haven't been working at it. These are 3 landmark Phase III clinical trials combining anti-PD-1 with 3 different checkpoints, CTLA-4, LAG-3 and anti-TIGIT all negative. And so we have not had any improvement in the adjuvant setting over and above anti-PD-1. Sorry, go back again. And what I presented today was really asking the oncology world, how did we get here to reflect on how we got here in 2026. And there really is over 100 years of work in immunology, cancer biology and the technological innovation that's happened, particularly in the last 60 years. And so if you're looking at where we are today with Intismeran, there are 3 really important scientific advances. First of all, the discovery that neoantigens exist back in the 1980s. These are unique mutations that are only found in an individual's tumor. They are not found in their normal cells, and they are not found in anyone else's cancer. And that begs the question if they're so unique, could they be seen as foreign to that patient's immune system.

Then the second biggest scientific advance is really built on next-generation sequencing, and that's the ability to rapidly sequence the tumor and also use the computational algorithms to identify and rank which neoantigens we think or we predict will give us the most robust antitumor response. And then the third is a platform that really is built for speed, and that's the fact that mRNA, you can include many multiple antigens in a single strand of mRNA. And there's a demonstrated robust CD4 and CD8 tumor response or responses to these proteins. That's wrapped in a lipid nanoparticle, injected into the patient. So altogether, that is a very rapid individualized manufacturing process, giving us Intismeran. Intismeran, as you heard before, encodes up to 34 neoantigens, and this is based on the patient's individual what we call, tumor mutanome and their HLA type.

The workflow for Intismeran is standardized from collecting the tumor tissue and blood right around to administration of -- to the patient takes 6 to 8 weeks. In terms of the mechanism of action, this is now a busy slide without the animations. But -- so it's injected intramuscularly. The mRNA is then taken up by nearby cells, all sorts of cells. Antigen-presenting cells take this up as well. They process the protein, present the protein as neoantigens in this case and elicit a T cell response, clonal expansion, migration to the tumor and then tumor cell kill. And it is hypothesized that with the release of more epitopes as the tumor is killed, but this enhances that cycle of immune activation.

You've just seen the data for the Phase 2b trial. Just to reiterate that the clinical benefit is durable out to 5 years. Left is relapse-free survival. So this was the proof of concept. Right is distant metastasis-free survival, hazard ratio of 0.41 at the last analysis and 0.51 and 0.41. But most importantly is that there is translational data, which you've just seen, which linked the T cell clonal increase to the lack of relapse and that, that was mapped precisely to the neoantigens in the Intismeran. So I won't go through that in any more detail than -- as we've already heard. So this is the design. This is a standard adjuvant trial design in terms of eligibility, resected cutaneous melanoma, AJCC 8th edition. Stage IIB right up to Stage IV, these are high-risk patients of recurrence.

Each patient had to have formal and fixed paraffin-embedded tissue that was of sufficient quality and quantity for Intismeran manufacturer, which required next-generation sequencing and then no price systemic therapy. Patients were randomized 2:1 to the active arm of Intismeran 1 milligram intramuscular every 3 weeks for 9 doses plus standard dosing of pembrolizumab every 6 weeks versus placebo and standard pembrolizumab. The pembrolizumab was started first at randomization within 13 weeks of resection. The Intismeran was started as soon as it was available to the site, the earliest was cycle 1, day 22 and the latest was cycle 4, day 1. The primary endpoint was the relapse-free survival as per the investigator. The secondary endpoints are shown here, the key one for today is a distant metastasis-free survival.

The statistical considerations are very important because, first of all, we had hierarchical testing, which is pretty standard for these large Phase III trials. If the relapse-free survival is positive, you then move on with power to the distant metastasis-free survival than to the overall survival. The treatment differences, just to see if they are significant was tested by the log-rank test. That doesn't tell you the size. It just tells you that it's statistically significantly different. The size or the magnitude of the treatment difference is measured using the hazard ratio for the primary end point. It was the Cox model, which is a standard approach in the intent-to-treat population. However, because of that delay in the separation that we saw in the Phase II, there were preplanned sensitivity analysis to look at the robustness of these results.

And one is called the piece-wise hazard ratios. And I really do think that this trial will be the first to sort of set this as one of the first standards for immuno-oncology because this is not a new phenomenon that you may have a little bit of a later separation. And then the other thing is the modified intent to treat. And that is all people who actually got the placebo or the Intismeran. The interim analysis was conducted when we reached at least 240 recurrence events and at least 18 months since the last patient was randomized, and this is 24.6 months of median follow-up at the data cut. So 1,749 patients were randomized -- sorry, were screened, 1,137 randomized. The biggest reason, the most common reason for screen failure was due to inadequate tissue supplied by the site. And I can talk about that in a minute because I was one of the sites, how did we learn from that experience so that we became very efficient at getting the right amount of tissue. 757 patients were randomized to the combination, 380 to pembrolizumab alone.

In both arms, one patient didn't receive treatment, the rest all did. Then when you move to the addition of the placebo Intismeran that was equal in both arms, 96% of patients received placebo or their Intismeran in each arm. 70% completed treatment, similar in both arms, but the reason was different for discontinuation in the combination arm, it was adverse events. But in the pembrolizumab arm, it was due to recurrence that they didn't continue to treatment. So 91% of all patients in the trial had the maximum of 34 neoantigens identified for the Intismeran design. Over 99% of those randomized to the combination. We were able to, when I say we, Moderna, we're able to successfully manufacture the Intismeran. The median time, and this is really important to describe those curves, the median time to first dose of Intismeran with 64 days.

Baseline characteristics is what we would expect for this population and similar in both arms. The most common stage with Stage III, which is what we would expect and the least common Stage IV, which is also what we would expect. So this is the Kaplan-Meier analysis for the recurrence-free survival. In the green is the combination. The combination of pembrolizumab with Intismeran significantly improved the recurrence-free survival over pembrolizumab alone. And the hazard ratio overall was 0.58 with a P value of less than 0.001. So this represents an overall 42% reduction in the risk of recurrence or death with the combination of a single agent. I've also got the 2-year landmark relapse-free survival with [ 82.2% ] and 70%.

Now looking at the piece-wise hazard ratios. As expected, in the first 6 months, the hazard ratio was 0.99. And then after 6 months, the hazard ratio was at 0.42. So a 58% reduction in risk of recurrence or death after 6 months. And the reason this was done, as I'll reiterate, I said it before, is the mechanism of action. I know David said it as well, the mechanism of action of Intismeran is at the early stage of antigen presentation. So that requires time for the T cells to get activated. But secondly, the median time to injection of Intismeran was 9 weeks. This is the modified intent to treat. So this is all patients who actually received placebo or the vaccine or Intismeran, and the hazard ratio was 0.51, so a 49% reduction in the risk of recurrence or death. Now looking at the distant metastasis free survival. One of the key secondary endpoints. This was the second in the hierarchy. It was significant as well with the combination hazard ratio of 0.62 and a P-value of 0.002. So a 38% reduction in the risk of distant metastases or death with the combination.

Similar sensitivity analysis, hazard ratio in the first 6 months, 1.01, hazard ratio after 6 months, 0.50, so a 50% reduction in the risk of distant metastases or death. And the confidence intervals after 6 months do not cross 1. The sensitivity and the modified intent-to-treat population hazard ratio of 0.55, that's a 45% reduction in the risk of distant metastases or death in the 2-year landmarks for distant metastases are showing there. In the prespecified subgroups, nearly all of them favored the combination over pembrolizumab alone. There are some groups that are very small numbers when you have very small numbers and you have very small numbers of events, the confidence interval is very wide, but it also means the estimate, so the diamond can switch like this with one patient. So you really have to be careful at looking any information with wide confidence intervals, we don't at this early juncture at this first interim analysis. Also, what was really very nice to see was in the risk stratification by stage. So it's risk based. We saw both groups benefit from the combination.

In terms of adverse events, the left of what we call all-cause adverse events. So as per trial protocols, there are a lot of things that we call adverse events that have nothing to do with the actual treatment. And then on the right are the treatment-related adverse events. And so I'm going to focus in on those. There was a slight higher rate of all-grade treatment-related adverse events in the combination, which is what we'd expect. Intismeran does cause local adverse events. But importantly, when we look at Grade 3 to 5 or serious adverse events, they were broadly similar in both arms.

In terms of adverse events that led to discontinuation, this was higher in the combination arm compared to pembrolizumab. And the deaths, the 2 deaths due to treatment in the combination arm all occurred before Intismeran was commenced, so they were due to pembrolizumab. The 8 deaths due to all cause adverse events, not related to treatment, only the 2 I just explained, 5 of them occurred before the Intismeran started and 3 after and were not related to either treatment. These parts are really nice because they quickly visualize where you're seeing the adverse events. So this is all cause adverse events in more than 10%. And what we've boxed there are those that are greater 10% incidents in the combination because that's what we want to know, well, what is this doing.

Well, what was really interesting is they're very low grade, they all grade 1 or 2. They're very transient injection site pain, chills, pyrexia or fever, injection site reaction. And these were of no concern to the investigators looking after these patients. When we look at the pembrolizumab or checkpoint inhibitor adverse events, you can see they're broadly similar in both groups. So what we can say is that it does not appear that Intismeran is potentiating pembrolizumab adverse events. So the conclusions focusing in on the efficacy first. The primary endpoint and the key secondary endpoints demonstrated that the combination did reduce the risk of recurrence or death over pembrolizumab alone by 42% overall and 38% for distant metastases in death.

If we look at the sensitivity analysis, the combination reduced the risk of recurrence or death by 58% after month 6. The benefit was observed in almost every prespecified subgroup. The overall survival is immature, and so a follow-up. This trial is ongoing. We are continuing to collect data on our patients who continue to remain blinded as are we. Safety was consistent with what we've seen before in the Stage II, no potentiation of pembrolizumab toxicities or adverse events. Intismeran was reliably delivered at a global scale. The trial is evidence of that. And there are ongoing trials in many cancers in the neoadjuvant, adjuvant and metastatic setting. So this is not as bold as it could be, but INTerpath-001 really does set the new benchmark for melanoma. But critically, it is a huge advantage. It is a landmark for the advance in personalized cancer medicine. Thank you.

I just want to also make note of all of the people, all the work that goes into this trial, lots of sites, a data safety monitoring board, the support from the sponsors. And as well, Jeff Weber, we always mention him, he was a huge supporter, had a leading role in the Phase II. And he actually contributed patients and enrolled them right up to his death in '24, and this will be published in the New England Journal of Medicine. Thank you.

Thank you very much, Dr. Long. One group I also want to thank and note is Merck. I've been at 2 large pharma companies that have had intense competition with Merck. And I can say it's been absolutely fantastic to be collaborating with Merck for once rather than competing with them. They're absolutely excellent partners.

So just a couple of words in conclusion. Beyond melanoma, there still remains an unmet need across many different adjuvant settings, as you can see here. And we have Intismeran clinical trials in all of these tumor types. Now one of the common questions that is frequently asked is will Intismeran work outside of melanoma. And we have the trials ongoing. But here are the reasons why I walk away believing that it does work. First, there's the science. All of these tumors, except for pancreatic cancer are PD-1 sensitive, PD-1, anti-PD-1s activate T cells and T cells kill cancer. Intismeran also activates T cells, but it does it on the front end. And in fact, we know, based on the T cell clones that Intismeran activates different T cells against different neoantigens than pembrolizumab dose.

Second is the data. So you heard from Dr. Long today, the ITT, the hazard ratio of 0.58. If you remember, the famous KEYNOTE-054, which was KEYTRUDA versus placebo their hazard ratio was 0.57. So the fact that KEYTRUDA then went on to have success in many other tumors, I think, bodes very well for Intismeran. You heard about the modified intent to treat which means this is the ideal clinical trial setting limited to only the patients who received placebo or who received Intismeran. So it excludes 46 patients who never made it to receive an injection. When you look at that comparison, which is the ideal clinical trial, the hazard ratio is 0.51. And finally, you heard about the piecewise. So this is patients who are 6 months and longer, this treatment effect, this hazard ratio of 0.42 tells you what is possible for Intismeran. It's not the top line, it's not the ITT, but it tells you scientifically what treatment effect is possible with this drug.

I really do believe Intismeran will work, but of course, we need to run the trials. There's one more reason why I have belief in Intismeran will work outside of melanoma. And that's the tumor mutational burden analysis. And by the way, in case you're going to ask, we don't have that data yet for the Phase III trial, but hopefully soon. In the Phase II trial, we analyzed RFS by high TMB and non-high TMB or low TMB. And interestingly, the RFS was identical in the Intismeran plus -- or the hazard ratio was identical in both the high TMB and the low TMB. If you draw an imaginary box on the right for low TMB melanoma, you see it does cross most of the tumors that we're studying.

One of the tumors, of course, I'd like to draw your attention to is pancreatic cancer, pancreatic ductal adenocarcinoma because we do have a poster tomorrow, and I just want to share data in the abstract because I don't like to leak data before it's presented. So this is a Phase I study of 20 patients who had resection of their pancreatic tumor. And the goal was really to see feasibility can we actually create an Intismeran drug product from a pancreatic tumor sample, which is low TMB. And then we also were curious how does Intismeran interact with chemotherapy. And here's the key data from the abstract once again, full data tomorrow, 20 patients, they had low TMB, 65% had KRAS mutation. The median number of neoantigens per Intismeran concept was actually 34. So we actually did pretty well. Of the 19 of the 20 were immunogenicity evaluable and all 19 had neoantigen-specific T cell response are seen. It's very promising that we can induce T cell responses.

In the subset who were evaluable, we could see polyfunctional T cell responses. And interestingly, the T cell response increased over time as we had seen. But there does seem to be an interaction with chemotherapy and the Intismeran-induced T cells go up even further after the FOLFIRINOX is complete. So it is feasible and possible to do this and full poster to be presented tomorrow.

Now I'd like to invite up our experts to come and join here, and we certainly open this up for questions and answers. Actually, before I do, sorry. Before I do -- sorry, just let me close on this. And then actually, I want to invite up our 2 experts to give some thoughts and comments. So you saw the melanoma today. The 3 lung cancer trials, one of them should be finished randomizing soon. The non-pathologic complete response, post-neoadjuvant is still enrolling as is the Stage I. RCC in was the first to complete enrolling and the data readout, the interim analysis will be event-driven. Bladder cancer is fully enrolled, and we expect to have an event-driven readout as well. And then nonmuscle invasive bladder cancer, it's still enrolling as is first-line melanoma and first-line lung cancer, and then we have solid tumors.

Now I'm going to invite up our 2 experts, Professor Ascierto, who I have had the pleasure of collaborating with across 4 different companies. And then Professor Ribas, who is one of the world's experts in immunotherapy. So maybe you can...

We have got the pleasure of completing [indiscernible] 4 different companies and we're still friends.

Yes. Actually, just as an interesting side note, the first investigator I ever visited -- when I joined BMS was Jeff Weber on an ipilimumab trial. And Dr. Ribas here was the lead of the tremelimumab trial, and the science was always better for tremelimumab. It's a big program. They did a great job. So maybe I could ask Professor Ascierto just to give some clinical context. And then maybe you could just give some of your immunotherapy expert context as well. And then we'll open up for questions.

Yes. So how many time I have. So just to set 5, 10 minutes, good. Okay. Take some notes. So first of all, good evening, everybody. My name is Paolo Ascierto. I'm a medical oncologist. I work in Naples, Italy. And the daily practice, before to speak about daily practice, the first question that probably discussed on should discuss was it will be Intismeran, the new standard of care, Intismeran plus pembrolizumab because this is an important question. And if it will be for the Stage IIB and IV because this is the patient's population enroll it, and have Georgina showed you in the forest plot, this is effective for all the groups at the moment. So if we look at the data from anti-PD-1 BRAF/MEK in Stage III, Stage IIB, IIC we have only anti-PD-1. The data in terms of relapse-free survival at 5 years looks similar with double trauma and anti-PD-1. So we cannot say that there is one better than another one.

So if we have in terms of relapse-free survival, a treatment better than anti-PD-1, I guess that this will be the new standard of care in the high-risk patient population. Now the discussion about adjuvant and neoadjuvant that was the topic that was discussed by the discussion. So in clinical practice in real life, I see my institution per month, 60 patients, high-risk melanoma patients, Stage IIB, IV resected that could be treated with adjuvant. So among these 60 patients, I see probably 10 patients Stage III with clinical palpable lymph node. That is the population that can be treated with neoadjuvant or perioperative approach. So in the daily practice, that population is a population where we can treat with the neoadjuvant. I strongly support neoadjuvant as Georgina knows, but it's a limited number of patients.

The big group are the patients with sentiment node positive, that we cannot treat with neoadjuvant. We need to treat with adjuvant. So it's probably surely the higher number of patients that we will treat with adjuvant. And now with this new data, surely more patients will be treated with this regimen because we have seen the data. What is really important with this data was pointed out by Dave, the consistency of the data, Phase II, Phase III, I have seen consistency of data with ipilimumab, you remember. If you look at the survival curve of CTL4, it's always the same in the different clinical trial. If you look at the survival curve of the sequence, BRAF/MEK and CTL4, PD-1 is the same in [Indiscernible]. So consistency is the key to better understand. And I believe you will see in the future interim analysis by interim analysis, the data will improve like we have seen for the KEYNOTE-942.

Second, what is really exciting with this new treatment is that after 3 trial that failed and Georgina show it, the combination of PD-1, CTLA-4, the combination PD-1 LAG-3, the combination of PDL, anti-TIGIT. Why? Because in the field of adjuvant, what is important is the minimal residual disease. We don't have the tumor from an immunological point of view is totally different from the condition where you have the tumor, metastatic disease and neoadjuvant. So with the minimum residual disease, we don't need to add Checkpoint, checkpoint. We need to improve the priming and mRNA vaccine is able to improve the priming. This is the key in the mechanism of action for the results that we have seen. I believe that I said about everything that I wanted to tell.

So it's perfect to build up on what Paolo was just finished on, which is the reason why are these curves separated? Why do we have a hazard ratio of 0.58. And the difference is because you stimulate more immune cells against what the immune system uses to differentiate between cancer cells from normal cells. That's the key to all kinds of therapies. Can you get a therapy that attacks the cancer cells specifically spares the normal cells? By doing the process that Georgina has explained and David about sequencing the tumor, knowing the sequences that are different from the cancer cells from the normal cells making an mRNA vaccine like for every patient, you then are able to stimulate to turn on more T cells that recognize the cancer.

And then with pembrolizumab, they get unleashed. If we get pembrolizumab alone, which is the control group, you're only relying on the immune cells that the cancer has turned on by itself. Cancers are not -- they don't want to be turning on T cells. They want to hide them. So this is a way to use those neoantigen sequences and turn on much more T cells. I'm excited to have Georgina present the data today. I'm excited to see that big room and overflow rooms of all these people coming to see -- to look at a melanoma presentation. This is a landmark in cancer drug development, which is we've been -- as Georgina said, for over 100 years, people have tried to inject somebody to patients with cancer to increase the immune response against it. Now we have a rational design platform that make feasible, validated by the billions of people who received the COVID-19 vaccines and personalized to this level of precision and then positive clinical data.

Great. So Georgina, can we invite you up now, sorry. And we're happy to take questions online or in person.

[Operator Instructions].

Salveen Richter, Goldman Sachs. Could you put the data in the context of the competitor regimens, including the neoadjuvant and the pros and cons that were laid out by the discussant? And maybe walk us through how INT really is positioned based on that totality to become standard of care.

Yes. Well, it is not unusual that you have multiple tools in the toolkit that are developed together. That's not -- we see this all the time in cancer. So the next steps are how do we integrate the 2 tools that are doing really well.

The one thing about neoadjuvant is we get a very early readout at 6 weeks as to those who are not doing well with neoadjuvant treatment and checkpoint inhibitors, I refer to that group as the third space. My colleagues have heard me say that, but that's the group of people who are dying of cancer. In melanoma, it's those who resistant to all the checkpoints and checkpoint combinations. So neoadjuvant gives us an early readout. There are still people in the third space. So one natural question is, well, Intismeran in that group, we know from the Phase II study, for example, that the group that benefited the most based on biomarkers at baseline. So lower tumor mutation no PD-L1 expression, they actually had the greatest benefit by the addition of Intismeran.

So the next few years are about us sorting that out in this field, how we're going to combine 2 excellent treatments. We are not worried about that. We were not worried about integrating and doing this work. They work very differently. The Intismeran is completely different from the checkpoints. They're very complement, so it's about working out what we give it to which patients. However, as Paolo beautifully explained is that not a lot of patients in that Stage IIb to Stage IV resectable, the population in INTerpath-001 fit than the DNA population exactly.

If I can add something? Just coming back to the discussion the right study for a formal comparison is not DNA, it's the SWOG because in the SWOG, we have the pembrolizumab, we have the perioperative, okay? Probably if I was discussed and to discuss this aspect, I would have been used the SWOG trial, more than NADENA.

Terence Flynn, Morgan Stanley. I guess a couple of questions. One is just for the physicians. Maybe the likelihood that these data translate to an OS benefit. I think we're still waiting to for KEYTRUDA, but just confidence level there? And then maybe for Dr. Long, one question we've gotten is just investigator versus central review. So I know in a lot studies you typically central review, but here it was investigator review? And how to think about that in the context of functional unblinding, that's another question we've got.

Okay. So about the overall survival, we'll see, as Georgina showed, there is a hierarchical concept in the study, study design, RFS, these are metastasis-free survival, and we'll see overall survival. In general, we consider the distant metastasis-free survival, a very interesting endpoint because it's close to the overall survival. We have seen that it's positive. And if we consider the Phase II improved year-by-year and probably, I believe and I feel the overall survival will be positive as well. It's my personal feeling, of course.

Can I add just one other point on that, and then we can go to Dr. Long. One of the things also to keep in mind is for all of the anti-PD-1 adjuvant trials, there was a rescue anti-PD-1 at time of catastases. There's no rescue Intismeran at time of progression, just as a small point. Do you want to talk about the -- was there a functional blinding you actually you and Paolo probably 2 largest enrollers.

We just had a discussion about this because we are finding that independent blinded review can be very problematic, particularly with immunotherapies and immunotherapies is a big -- it's a big umbrella of many treatments, but checkpoint is one type. Now we have individualized neoantigen therapy, of which Intismeran is one. In that the radiologists that do the blinded central review have to be very well trained and have to understand these drugs.

And so recently, there have been trials which would have been positive had the radiologist being trained appropriately to interpret, "Oh, everything shrinking but the lymph nodes are growing or that's progression." No, these are immune stimulated lymph nodes that don't actually have cancer. So I even proposed yesterday or the day before, can we just get rid of blinded independent view. So that's just that point.

So in this, it does not bother me at all. I don't know if it's a concern that you're expressing, I think the relapse-free survival. It was done in 157 global sites. So you're going to -- everything is going to come out in the wash anyway. We were blinded. So we didn't know what patients were receiving. And I think that speaks most highly. And the other thing is this is an adjuvant trial. So it's not like you need the radiologist to watch and see how things are shrinking and growing. They just need to pick up a recurrence. And that technically is much easier than monitoring multiple metastases in the setting of immuno-oncology. So I don't know if that was your question, but it doesn't worry us, put it that way, in terms of the strength of these results, one IOTA.

I want to add to what Georgina is saying, the local radiologists have more [Indiscernible] ability to query it's a questionable finding. And sometimes they have more parts of the body, more higher resolution than the central radiologists. Also in some of our centers, our radiologists read are the local radiologists and the central radiologists at night. And I would query how they report or differently.

This is [ Dina ] from UBS on for behalf of Mike Yee. I guess just 2 quick questions. You reminded us kindly that in the Phase II, we saw a really great benefit in the PD-1-negative population BRAF and also in the low tumor mutation burden. How do you think about that benefit translating into the Phase III? I'm sure we'll see that subgroup data if you do have it or have any color on that. But how do you see the right population to treat first and foremost, based on those biomarkers. And then on the back of the conversation for neoadjuvant, is there maybe a scenario in the real-world practice where if there are patients that do get neoadjuvant checkpoint could they go on to adjuvant therapy and do get INT and KEYTRUDA? Yes. And so I just wanted to kind of get your thoughts about that.

Sorry. The first question is about biomarker. So at the moment, we don't have biomarker. No PD-1, no TMB. In the field of adjuvant, the only biomarker that was explored, but in the target therapy was interferon gamma signature that Georgina reported years ago, but it's not for the clinical practice. It's still something in the science. So at the moment, we cannot predict patients who can get adjuvant and benefit from another patient. The second was -- the second question?

Can Intismeran eventually be administered after neoadjuvant therapy?

So again, the neoadjuvant patient is just 20% of the patients, okay? Having said that, now with this data, of course, there will be a clinical study in order to explore all the several things even in the new adjuvant and of course, in the adjuvant, which will be the patients that should receive adjuvant. Pathological complete response, No, but all the other probably, yes, and now if the standard of care is this combination, this will be the best option for patient.

I was just going to add to your very first question. And I think what you were asking is since we were seeing a greater benefit, is that going to -- no, we see a benefit in all groups. The point I was making with that is it would be easy for some people to say, "Oh, it's higher tumor mutation burden, easy to identify neoantigens, also that's who's going to benefit". My point there was not necessarily, they do benefit. We know that. The data shows that. But hey, we've got patients with lower tumor mutation burden in the pancreatic and we've got patients with no PD-L1 that are benefiting. So that was the point. It's not to pick out a population.

At this point, as Paolo said, there is no population. It's -- every subgroup we've looked at seems to be benefiting. So that's that answer.

And again, we're increasing the priming. So the priming is something different from the effector phase.

Okay. So before we go to the next live question, I'm going to take a question from online what's the best way to rationalize why the hazard ratio was much more impressive for RFS versus DMFS at this interim? That's usually standard. So if you look at most trials, you will always see that trend, Phase III landmark trials. You see relapse-free survival is often a greater hazard ratio at very interim analysis than distant metastasis free survival. so what we saw in the Phase II, it was actually a little unusual. So it is standard that that's what we see. We are not surprised by this data. It's exactly as we expected. Well, we were actually super impressed by this data is what I should say. Would you support that?

No, yes, I agree with you. We need time because we need the event at the moment. So I'm sure that in the next follow-up, we will see an improvement.

Yes. And just to add, this trial, of course, included Stage 2 patients who have a slower time to distant metastasis, and the additional point is if you look at the modified intent to treat, which is patients who got placebo or INT injection -- so people actually received something there, the hazard ratio was 0.55. So I think those are the 2 things to keep in mind. Next question.

Luisa Hector from Berenberg. I'm wonderful to see this data. So thank you. So I have a question on the tissue sampling, the 17% of the samples that were small. I think Dr. Long, you implied that you were sort of learning through the trial how to do that better. So how much could that be reduced? And anything you can add on that?

Yes. I can't tell you how much that will be reduced, but it will be reduced. My own experience, and I'd love to hear the other investigators was the first few patients we screened some got on, but some we didn't supply enough tissue. So we had to go back to the blocks and give more tissue. So what I did is I got the team together in our pathologists, and we had that a protocol that worked for our site because of the way our site works in our pathology.

And then we didn't have screen failures after that. We were able to pick patients so that we had enough tissue upfront because it's not fun for a patient to consent and then we send the tissue, it's not enough and then have to wait longer. And so we really wanted to get that right upfront. This is not new to oncology. You probably remember 15 years ago when EGFR inhibitors in lung cancer, tissue was the issue. It's not an issue anymore because we've got infrastructure and resolved those issues.

And then it may be too early to comment. I don't know how much data you have. But in the patients who are recurring, is there anything about the T cell clones or any pattern you can see from that? I don't know if I explained it [indiscernible].

But they're blind still. They're blinded the patients. So I won't know.

But we did look at recurrence in the Phase II, and I thought we presented that. I can't remember. But anyway, we did, didn't, yes, yes. So there is some data in the phase II.

Ellie Merle from Barclays. Just on a similar vein, I mean, you mentioned that there were some new antigens that are more promising and inducing T cell responses, any learning so far from the data on which ones might be. And then you've also shown that the patients with more novel T cells have greater clinical benefit. Any thoughts or early hypotheses on which patients might be more likely to have more novel T cell clones versus others? And the reason for these questions is how you interpret this data in terms of what it could mean for success in other tumor types?

I'm going to answer that question, and then I'm going to invite Tony to maybe give a scientific answer. That's an area -- both of those are areas of active investigation what makes a good neoantigen. Now that we have clinical efficacy outcome, we can go back. We actually have neoantigen prediction for both the control arm and for the experimental arm. And which and how you can understand -- and your question was about which patients do get novel T cells, so one is on antigens and on the patient level question. Is that the -- yes, that's another great question.

Tony, you've been doing this for a couple of decades. What are your thoughts?

Yes. I have trouble trying to answer the question directly because we do not have the way to measure, count how many T cells to neoantigen HLA presented peptides. It's -- these are the most polygenic areas of our genome between the T cell receptor. It's like an antibody that recombines and then the HLA Class 1, which there's 1 more common HLA 2.1, but there's 24,000 HLA Class I alleles in the human population so far. There's -- the TCRs are up to 10 to the 15, the potential sequences. A long explanation to say that the measurements that we have are associations with what the real thing is happening and that I don't think in any realistic time point, we'll be able to answer your question directly, which is the key question on any neoantigen therapy.

[indiscernible] said this, the efforts that have been made are very substantial at Moderna and Merck to be able to study from the Phase II trial and see that the vaccine, the personalized therapy and new antigen therapy can turn on T cell receptor prototypes that were not there. And you would assume that some of them will be to the mRNA because that's the protein made from the mRNA will be the most immunogenic part. So could we then decide which -- what's the best algorithm to get those T cells that work the best? I think that's a question that in clinical trials, I don't think -- large clinical trials may not be realistic about.

This is Greg Torres, representing Tyler Van Buren from TD Cowen. Congrats on this outcome. So given the apparent INT specific T cell responses you've shown, how seriously should we think about the potential for INT monotherapy? And could removing pembro ultimately expand the addressable population more than adding INT onto pembro or particularly in Stage II patients?

I'm going to take that one. And then, of course, I invite Toni and the others. I personally believe -- there's been a belief out there that in immunotherapy -- for a novel immunotherapy, you have to add on to an anti-PD-1 to work. And a lot of that has come from the fact that a lot of novel immunotherapies have not had any significant monotherapy activity and therefore, that's that belief.

I don't really think that's case. I personally believe that Intismeran should have monotherapy activity. And as you know, we are studying it in Stage I lung cancer. And part of the reason is that first slide I showed, which is evolutionary speaking, the immune system evolved to detect and eliminate viruses, but it can also detect and elate cancer. It doesn't require an anti-PD-1 to do that. We don't walk around with anti-PD-1 antibodies. And so if we can stimulate those T cells, they should be able to do what T cells normally do. So this is hypothetical speaking. We do have some Intismeran monotherapy data showing that we can induce T cells.

But Toni, what are your thoughts? And we're in the speculation phase now because we don't have the data, but what are your thoughts? Intismeran monotherapy.

So if you have more -- the field has realized that if you have more T cells for cancer, those patients do better. And that is, again, by very crude measurements. But we know from studies in colon cancer from 20 years ago that the colon cancers that have more T cells that was like being a stage lower in the HHCC staging. So more T cells is better independent if you block any checkpoint.

Prognostically.

But that tells us that if you stimulate them with INT as you're saying, you're probably going to do better. In the earlier stage, you're right that you start worrying about the pembro side effects and hypothyroidism that can be long term and adrenal insufficiency or we the rare patient that has really, really bad side effects, you don't want to reach that. So it's great that you're testing on Stage I lung cancer. I think it's a great study.

Yes. I was going to say the same thing, I think, hypothetically, given the mode of action where it's acting the algorithm, what we've seen so far, it should have some activity in earlier stages and in single agent. The issue is in something like melanoma, Stage I, which is very common Stage I melanoma is only about 5% will recur. So we need to team things like that up with tests that tell us who's going to recur and then give them these sorts of treatments to stimulate their T cells. But theoretically, it should work.

So a few other questions coming from those who are listening online. And apologies if these are basic questions. But to the physicians, are you concerned about the KM curves crossing at 33 months for DMFS? That's one question. Of course, Georgina, please do speak to it, and then I have a few others.

It means it's nothing. It's you'll see there were several Kaplan markers today in other trials where you see that. It is a phenomenon of the follow-up and the fact that when you get out to 33 months, when you go to a median follow-up of 24 months, you don't have any patients at risk. So the curves are not to be looked at. A rule of thumb for those who are not in oncology, if you've got less than 10% of patients at the number at risk, you cannot judge the shape of the curve. It will change at next analysis, guaranteed. So that does not worry us. We see this all the time at these sorts of follow-up early on. It's nothing to be concerned about.

But maybe let me know. Could we put the slide back? Because I think this is one experiment that took many years. I think it's important to get the figure right. Otherwise, you have it in your handouts. So does the curves don't separate the first 6 months, as Georgina well explained. Then they start separating. And if you look at the bottom of the Kaplan-Meier has 2 rows of numbers. So here the patients at risk and then the tick marks are the sensor patients. So can we go to the primary analysis, go to the one that says, backwards more, backwards more...

The RFS.

Here...

They're the same curves as...

So they don't separate for 6 months. They start separating, there's 600 patients at risk in one group, 200 on the other. And then you get to 24 months, you see all these stick marks. And then at the end, there's only 35 -- there's 10 patients followed them one or the other. That's when it's not reliable. But we're here trying -- we're trying to interpret this and interpret the future or anticipate what will happen in the future. Somebody asked about overall survival. All these curves are separating until there's not enough patients at risk. You would assume they'll continue to separate it. That's just logical.

A lot of enthusiasm on this. And actually, we have this exact example from the primary analysis on Slide 10 of the Phase II. Remember the curves come together in the primary analysis because there's too few patients. In the longer follow-up, that disappears exactly what they said.

All of those tick marks are patients who are alive and well, who have not had an event, but they're just alive and well and they've got to 24 months. So they've all got to come through the curve, so to speak. So it is completely unstable from, as I said, 10% of the starting number. So 757, basically, once you get up below 75 patients, ignore it. It's going to change. It's going to do this. And it doesn't tell you anything about the science or the patients. It's not reliable.

Great. Can we ran that any other way?

Thank you for education. One last question on RFS as a primary end point versus OS in the adjuvant setting, is OS required for approval here?

This is a question that it's usual when we talk about adjuvant. So it's clear now after a long discussion that relapse-free survival, it's an important endpoint that we should consider when we discuss with patients.

Now [ Christian Blank ] is almost Italian. And during the meeting, we have a funny fight about neoadjuvant and adjuvant. And the question is, of course, about relapse-free survival and overall survival. The point is if we assume a regulatory agency assume the relapse-free survival, it's a good end point. And for me and colleagues, it's a good and the point, stop. Overall survival is important. We know from a scientific point of view. But when we discuss with the patients, the patients won't be relapse-free.

Great. Thank you very much. I'd like to thank 3 experts. It's been a busy day, and thank you for taking the time. Thank you all for attending today. Thank you. Toni, thank you so much. I really appreciate you coming here. Thank you so much.

Wonderful. Hi, everyone. Thank you so much for being with us here today. My name is Courtney Breen. I am the pharma analyst here at Bernstein. And I have the privilege of sharing the stage today with Stéphane Bancel, CEO of Moderna; as well as David Berman, recently joined Chief Development Officer at Moderna as well. It is -- I'm looking forward to a fun conversation. There's lots going on with the company at the moment. Stock price is moving a huge amount at the moment as well. So there's lots of news ahead and kind of we're certainly excited for ESMO.

Perhaps just to start really big and broad for those who haven't been following the company as closely, although I don't imagine that's many. Some may know Moderna as kind of a COVID or vaccines company. In a couple of minutes, what's Moderna today and what is the most material things that have changed in the last 12 months?

All right. Good morning. It's a great question. Actually, Moderna has never been a COVID-19 vaccine company.

Exactly.

I know most people think of a company like this. Moderna has been, since day 1, an mRNA platform company, as you know. And we've always built the company in terms of how do we maximize the value of the company by developing the most exciting medicine for patients, doing things that cannot be done with other technologies across many, many therapeutic areas. That was our vision since the beginning. And I would say people who know us well, I think in the IPO S-1, anybody who is interested in doing research, go and read the IPO S-1, the intro. I mean, I think 10 pages or whatever. It described what we set as a company strategy since the beginning. We reinforced it during the IPO process.

And then COVID happened. Of course, we never planned for COVID. We thought it was a company responsibility because we had done 9 vaccines in the clinic before to try to get a COVID-19 vaccine in case this was going to become a pandemic to help as many people as we could, and we are very thankful for what the team has achieved with all of our partners, to help protect so many people during the pandemic. But that was an off plan -- it was off strategy. So it was not the strategy. It was a huge distraction, but it was the right thing to do for the world. And so what we have been doing since, there was enough vaccine available kind of end of 2021 in the world, is to kind of go back on strategy. But because it takes a long time in this industry to get moving, we are now starting to get to a place where I think people are -- we're doing the work.

Because it's a platform company, so it's complicated. It's not a one product company. But people who are doing the work, I think, are starting to realize more and more in the last 12 months, since our Analyst Day in November of last year, where people, I think, start to say, "Okay, this is not a COVID-19 company. It's really a platform company." And what actually is so interesting is that we're actually the only mRNA platform company left. Because if you think about it, CureVac was the first mRNA company. Their vaccine failed in Phase III during the pandemic, in the spring of 2021, I think, because they made a big scientific mistake of an insight we had because of all the research we did and all the investment we did in science. We took a very different scientific route, which I think paid off nicely. They are gone.

BioNTech just announced the splitting of the company, keeping the late-stage assets in the company and starting a new company. Translate Bio was bought by Sanofi, who recently announced they're stopping the mRNA vaccine programs. So we have de facto, because of what happened, the only mRNA company standing up, and the breadth of our company is very exciting because, basically, today, we have a vaccine business with 5 approved products and launch is happening as we speak. We're launching 2 products this year, so think about the growth over the next few years. We have an oncology business, and we talk I'm sure a lot about Intismeran, but that's only our first oncology product.

As Dr. David will tell you, there's many more coming that are as exciting as Intismeran, and we own all of these because Intismeran, of course, is a 50-50 with a great partner, Merck. We have a rare disease business that we should know by the end of the year, pivotal data. But those kids have been on study, and this is for years, and we've already shared the data many times, the drug is working. And because it's a genetic disease, there's no genetic biology risk. And so -- and because it's time-bound Phase III, we know we're going to have data this year. And then if you look at what we've presented at Science Day in June, in liquid tumor multiple myeloma, shared antigen cancer vaccine, autoimmune diseases, what, at least 3 programs, including CAR-T in autoimmune disease.

The company is actually becoming a very broad mRNA platform and its core from a therapeutic standpoint today, a very, very important, I think, if you look at the next 20 years, immunology company, infectious disease, oncology, autoimmune disease. So I think what the team has already done an amazing job in the science and the labs is to figure out how can you exquisitely use mRNA technology and lipid delivery technology to interact with the immune system of humans. And that, I think, if you think about the number of disease in an aging world, this is very, very powerful. So I think people who are doing the work over the last years are starting to realize that COVID was just our first product, not the company.

Absolutely. No, I think this platform basis is an incredibly important part of the story, and I'm sure we'll continue to discuss it as well as spending a decent amount of time on Intismeran, which is incredibly exciting.

David, you joined the company in March. There has been a bit going on. There was kind of some late-stage disappointments with CMV, norovirus is being pushed out, some really exciting data with Intismeran and some challenges with the FDA in terms of some of the filing strategies as well. Can you tell us a little bit about your background, first of all, and kind of why kind of this was the right opportunity for you to come into and kind of the critical things on your to-do list at Moderna.

Courtney, thank you for that. So I began my industry experience about 20 years ago at Bristol-Myers Squibb right when it was starting to work on ipilimumab, and I helped to develop ipilimumab. And that launched, of course, the checkpoint revolution. After about 10 years at BMS, I moved to AstraZeneca, where I led the immuno-oncology franchise and helped to launch IMFINZI there. And then 3 years after that, I joined a small biotech called Immunocore to launch the world's first TCR therapeutic called KIMMTRAK. So I've always been attracted to innovative immunotherapy programs. And if you look at the arc of my career and in fact, it mirrors the arc of the excitement of immunotherapy, it has really been an arc.

It's almost been a bell-shaped curve, unfortunately, because there was a lot of enthusiasm for the PD-1 field, a lot of investment. And then it sort of seemed to plateau when the field came to believe PD-1s were the ceiling that there was nothing really you could maneuver on the immune system to really improve above PD-1s. And so enthusiasm has tailed off. The Phase II data that was presented by Moderna and Merck a few years ago, to me, radically rearranged that belief. And when I saw that data, and I tore apart that Phase II trial backwards and forwards to try to find the flaws in it. And I -- and actually, when I joined, and Stéphane remembers, I said this will be a landmark Phase II trial because it's the most rigorous, beautiful Phase II immunotherapy cancer trial that I've seen. Most times, people go straight to Phase III.

And so that's why I joined because I believed at the time that if Intismeran is positive, it will herald a new wave of enthusiasm. And it's been borne out, in my opinion. And we can talk more about Intismeran and my enthusiasm for it. In terms of what I'm doing here or what I'm doing in the first couple of months, it's really threefold. The first is to build a therapeutics development group. There's a superb infectious disease development group, obviously, from COVID and beyond 5 products. We need to equal that on the development side. So developing expertise in development therapeutics, number 1.

Number 2 is Intismeran. It was to bring it -- help bring it over the finish line and help it get launched. And then what else do we need to do with Intismeran? And then number 3 was what we are calling mRED, Moderna Research and Early Development, which is to rapidly move forward those early-stage therapeutics programs that should be moved forward and rapidly stop those that shouldn't, to make rapid decisions. And I think that's where maybe my effect might initially be seen is making rigorous decisions on Phase I and II trials.

Fantastic. Really, really helpful. And maybe just to spend a couple of moments on Intismeran purely from the perspective of we're going to get some new data presented soon. You already have it in hand.

It seems like it. [indiscernible]

And we've got a big conference coming up. Without kind of giving numbers ahead of that medical meeting, how should we be thinking about what clinically meaningful means? How should we be thinking about this Phase III relative to the Phase II and that path to getting this drug approved, especially given there was a potential with the Phase II and kind of it wasn't able to be delivered against?

Right. So I'll take the first stab and Stéphane, please add anything. So if you remember, the initial approvals of pembrolizumab and nivolumab in adjuvant melanoma were against placebo, first initially in Stage III and then eventually also moving earlier into Stage II. Those are both fantastic drugs. They beat placebo, and they are widely used and standard of care. This trial adds on to KEYTRUDA versus KEYTRUDA. So it's not a very easy control arm to beat. And the fact that it hit its primary endpoint at the first interim analysis, I think, tells you one thing. Secondly, it also hit distant metastasis-free survival at the first endpoint. That was the secondary endpoint.

It's the first adjuvant trial to hit both primary and secondary endpoints at the interim. It's the first Phase III adjuvant trial to beat a PD-1 monotherapy as an add-on. And then I think the fact that it combined both Stage II and Stage III into a single population because Stage II is even harder to beat than Stage III, and the fact that it still had a statistically significant endpoint tells you about the strength of this data. I think this -- the Phase II was a Phase II trial and Phase II adjuvant trials, of course, are not controlled well enough usually for FDA approval. This is an 1,100-patient trial, rigorously controlled, blinded Phase III trial. So I'm very confident that we have a strong case for approval.

Fantastic. And maybe just one of the big questions and debates around Intismeran at the moment is where else might it work. You've obviously got a development plan that spans different tumor types, predominantly, to your point, adding on to IO where it exists today. However, it's not just early stage indications. You've got some metastatic indications. You've also got some indications that are perhaps not traditionally as immunogenic as others. How should we think about kind of that repeatability of this melanoma data in less hot tumors, but also in patients where their immune systems might not necessarily be as intact? And I know you've got some Phase I pancreatic data anticipated later this year as well. Kind of how informative will that be for helping to unlock and answer those questions?

Yes. So there's a couple of ways that I think about it. One is if you look at the Phase II trial and you look at the subset analysis by tumor mutational burden, high TMB and low TMB, it's very interesting to see that the efficacy was the same, whether the patients had high or low TMB. So what you can do then is you can take that famous TMB figure plot, which plots every tumor by the distribution of tumor mutational burden, and you can put a line or a bar where low TMB cutaneous melanoma is. And you can roughly assume that, that bar is going to cover tumors where Intismeran is going to work. Because at the end of the day, we need 34 neoantigens in a cassette. We don't need 1,000 neoantigens. We need 34 good neoantigens. And we know usually only 1/3 of those are going to be immunogenic.

So if you create that bar, essentially RCC, which is one of the next readouts that we're going to have, covers that lower TMB and cutaneous melanoma. So in essence, I believe that everywhere checkpoints work, Intismeran should be able to work. It acts upstream of PD-1s. It's actually the first step. It's alerting the immune system. So our initial approach has been in adjuvant melanoma, which is the right place, and then looking in adjuvant lung cancer. And by the way, we've stopped screening on our leading Phase III adjuvant trial in patients who had no prior neoadjuvant therapy. We should expect to have randomization complete later this year. So that was posted on ct.gov.

We have 3 Phase III trials in lung cancer. And then what we want to do is look in earlier-stage disease also. And this is something both Stéphane and I believe. Intismeran does not need, I believe, a PD-1 to be active, okay? You can combine it, the strategic reasons...

Can you say that again, slowly?

Yes. Intismeran does not need a PD-1 to be active. I'll pause there for a second because this is a really important point. There was a belief in immunotherapy that everything had to be added on to a PD-1, and I don't believe that's the case. And if you take that to be the belief, which I do, Intismeran should be able to work in very early stages of disease where PD-1s don't -- or aren't used. So we have a Stage I lung cancer trial ongoing, a Phase III. We have a non-muscle invasive bladder cancer, essentially Stage I Intismeran trial with BCG that's ongoing, randomized Phase II. And so there is our belief that Intismeran can go into very, very early stages, and the risk-benefit profile is very favorable also.

After lung cancer, of course, we have RCC. We have kidney cancer and bladder cancer, which should read out hopefully over the next 12 months or so. And then we are studying metastatic disease. And now that's a higher risk because in this case, you are getting a sample of the tumor from 1 lesion. The patient may have multiple lesions. So there is a higher risk there, but it deserves to be studied. And then finally, we're moving into tumors where either the TMB is very low, pancreatic cancer exploring, or we're looking at tumors where PD-1s haven't been as successful, although some are, and that's gastric cancer. So we are studying the entire spectrum of opportunities for Intismeran.

Maybe just to add a couple of things and to step back. If you think about Intismeran, we are basically coding an mRNA molecule, as David said, 34 mutations specific to the patient's cancer. And we know for a fact now, we showed at ASCO in the spring, the translational medicine data was presented by the MGH group and our team showing that we know for sure now, we believe it for the last 10 years, now we know for a fact, that when you inject our mRNA with our lipid in somebody's arm -- I cannot talk about any other mRNA approach I don't know, with our mRNA algorithm, because we need to talk about data as well. That's very important for the selection. We know for a fact now, we can create de novo T cells in the patients, and we can expand T cells.

So based on that mechanism, as David is saying, I think our strategy is pretty simple on Intismeran is, one, we believe, we have to prove it in the clinic, obviously, that everywhere a checkpoint works, we should add value to patients. We have to do a clinical experiment, is it -- like we saw a hazard ratio of 0.5 in the Phase II study in melanoma or more or less, we're going to have to do that work, and we are doing. One of the things we're going to do now with our colleagues at Merck is to look at how do we accelerate new studies because we have 9 studies ongoing right now. But the plan cannot be the same from when you believe something to when you know something. And now we know Intismeran is working in Phase III. I think people will get a good sense of the data soon.

And we know the mechanism. And we've always been a very mechanistic company. We don't believe in black magic. We believe in science. And so based on that, what we want to do is to add to IO very quickly, and we have a lot of tumors where we know KEYTRUDA works for the great work Merck has done over the years. We want to test that in the clinic with Intismeran. The second piece, which is also very important, as David mentioned, is going early because in early disease, checkpoints have so long-term side effect, autoimmune disease, as we all know, that they are not used in Stage I disease.

But if you think about where the world is going, and again, I'm talking about the next 5, 10 years, not the next 2 weeks, where the world is going is better and better diagnostic, earlier and earlier diagnostic. Think about the world where you could have potentially Intismeran as a monotherapy on a Stage I lung cancer that is in Phase III study right now or any other cancer, and you can get your vaccine at your local CVS because it's an IM. You have to go to a hospital. You can't do it on your way to work for 9 doses every 3 weeks. How big that would be a deal for cancer patients? And we think lung is a great place to start because former smoker and X-ray, very easy diagnostic, you can catch Stage I patient. So we're going to investigate that as strategy #2 pillar for Intismeran.

And the third one is to combine it with other agents that are helping patients because Intismeran is an orthogonal mechanism. We believe that adding to the tolerance mechanism will help patients. That's where we're going to go so aggressively, look at that.

Fantastic. It's very, very exciting. And obviously, there's a personalized element to this that you've both highlighted that is critically important. And I have 2 questions kind of on that personalized element. The first is kind of there are partners that are involved in terms of sequencing and all the steps that occur here. I would love to understand, first, kind of how much of the proprietary work is within Moderna versus relying on any of those other players?

And then the second is, when you think about personalization, scale-up is also really important. And so can you just help us understand where will be the most likely bottlenecks as we think about the scale-up? Is it going to be in the healthcare systems themselves? Is it going to be in manufacturing? How do we think about kind of the path to expansion for this product?

So that's a lot of questions. I'm going to try to give it a shot, and if I miss anything, I'm sure you'll keep me honest. The first one is very easy, all the proprietary information is with Moderna. What we get from our partners, who are doing great work and very important partners, is sequence of a healthy DNA of a patient, healthy cells, and the cancer cell. That's what we get from them, the raw data. Then everything that happens after in terms of selection of 34 is ours. And we keep it in a very tight wrap because I believe another piece that most investors do not appreciate yet is the tail that Intismeran is going to have. How do you copy Intismeran? How do you go to FDA and say, "Approve this as a generic, it's the same." How can you do that if you don't know what's in the product, and every product is individualized?

So manufacturing. So manufacturing, a few observations. First, this is a product where we only use from the patient the information of their genes, right? We don't use any biological sample from a patient. So it's very different from other technology that are individualized that people can think about. The other piece, it's a liquid manufacturing process with enzyme. So it's not like making CHO cells or whatever in biotech. This is actually a process you can compress. And I speak as a chemical engineer by training. You can squeeze things down, make things very, very tiny, which is what we have to do because we have to make product for one human. And so it's not a scale-up like you have in traditional medicine, it's a scale-out, which is the key of the game, how you scale this, is make machines that are smaller and smaller footprint.

Why? Because our biggest cost is depreciation of the clean room. So if I can do 1,000 machines versus 10 machines in this room, just you can do the math on my cost, right? And the second piece is cycle time. Because if I take 5 weeks or if I take a week to make the products, you can do the math as well, it's basic math, my output has a massive impact in terms of what happens economically. So on manufacturing, I think we're in a very good place because it's all synthetic, cell-free manufacturing process. And by the way, it's the team who did COVID. And just as an important, little piece, we scaled by ourselves as a start-up company, we had never done a Phase III, never launched a commercial product.

In 2019, we made less than 100,000 doses across all our clinical trial studies. And we got 1 billion doses out of the system 18 months after. And we had to build everything, everything. And that team, when we got the Phase II data of Intismeran, I told Scott, who was the site head of Norwood, "Scott, go take a month or 2 off. In the meantime, I'm going to look for a site to buy, to build Intismeran because when you come back, I need you to do the same thing on COVID for Intismeran and do what you did to help some people with COVID with cancer." So I think the biggest bottleneck is going to be the hospital. I think the payers and so on -- Merck is an amazing commercial machine. They have great relationships. They know how to do this in their sleep.

It's going to be the hospital, and we saw it in clinical trial in the Phase II, which is why in the Phase III, we did a much better job, is you have to help the hospital, move your hands off and getting the muscles, of how do you get the biopsy very quickly from the lab, all the data, the patient, all the piece we need to be able to do our work as fast as we can with high integrity in terms of data and quality. And so we have now teams that Merck and us are setting up as we speak to basically to set up hospital by hospital. We're ranking the hospitals across the country in terms of the importance. And we're just going hospital after hospital. With that team going around and making sure everything works well in the system, we built a great digital platform behind, so we can track everything, of course, anonymous, respecting all the patient privacy, obviously.

So all this is a thing we didn't even have in the Phase III. We didn't even dream of having in the Phase II. So we're just getting stronger, going faster, reducing cycle time. So is there a lot of work ahead of us in manufacturing? For sure. Do I worry about manufacturing? Not a minute.

Got it. Super, super helpful. You mentioned, obviously, the scale is very different to the vaccine scale. The cost and the pricing is likely also going to be very different relative to the vaccines. Can you just help us think through kind of the economics of this? And particularly with the collaboration with Merck, how does this commercial structure work?

Sure. The commercial structure, you want to think about it as a JV, as a virtual JV, like there's no legal JV. But basically, we are 50-50 cost in for everything, the sales rep, the clinical study, manufacturing CapEx, OpEx, just cash, 50-50 cost in. And at the end, 50% profit left goes to each company. We wanted to align the 2 companies, to be totally aligned that there's no funny games or whatever. And that's working extremely well. I have to give a lot of credit to the Merck leadership and to all our colleagues at Merck that are working with our teams.

I think at this stage, we want to focus on the data at ESMO because once -- it's tough to talk about anything, about value, talking about data, right? So let's wait for the data to talk about pricing and other things. And then we're focusing extremely on filing the BLA as fast as we can.

Fantastic. Intismeran is not the only oncology product, and I think you've both touched on that. David, can you kind of help us think through some of the next legs of innovation and kind of where the opportunity lies in the application of this platform beyond the personalized cancer vaccine or INT?

Yes. So I think, Courtney, with Intismeran demonstrating that cancer vaccines or cancer antigen therapies do work, the next logical question for us is, can you have a cancer antigen therapy, cancer vaccine that's off the shelf? And that's where our Lynch syndrome first comes in. So this is a fascinating -- it's a terrible disease to have. It's a high risk of developing cancer. But one of the fascinating aspects is patients share neoantigen mutations, these frameshifts. So it actually lends itself perfectly to developing an off-the-shelf vaccine for neoantigens. And we have an ongoing Phase I/II trial in the U.K. with the ultimate goal of being cancer interception. This is Stéphane's vision, he kind of articulates, which is can you -- in patients or people, there are people, they're not patients, who are high risk for developing cancer, can you prevent them from getting cancer, which is an incredible vision. So that's number 1.

Can I just add 1 or 2...

Please.

Because I'm as excited as this doctor on Lynch. So Lynch is basically a genetic disease. It's 1 in 300 people. Think about the math again, 1 in 300 people have Lynch syndrome. As soon as I learned about it, I went to get tested. It increased for some tumors by up to 10x your chance of having cancer. When you see a lot of time a 35-year-old having colon cancer, most probably you have Lynch syndrome. They might have added a lot of factors like the food and lack of sport and other things that we all know, if you look at the data. And I had so many e-mails from friends, I had no idea of Lynch syndrome, who knows about it [indiscernible] or our employees.

So it's a big, big issue, and it's literally Myriad has a test. You can go do it for a couple of hundred bucks. It's once in a lifetime because of genetics. And the idea here is a prevention vaccine. So if you're positive, you go to your pharmacy. We don't know if it's once a year, once every 2 years, David and his team and Oxford will have to figure this in the clinic. But the idea, you get this regularly so that you don't develop cancer. So think about it in 1 in 300 people, and it's exactly -- and David, it will be good to have your thoughts -- essentially the most derisked application based on Intismeran as a read-across is Lynch.

Yes, that's exactly right because these are neoantigens that the body has not -- that the thymus hasn't eliminated T cells that are reactive to. So to me, it's a high probability of success. Of course, we have to do the clinical experiment, but that's one that we're very enthusiastic about.

And by the way, we own this 100%. And think how it could help our vaccine business with retail pharmacies if we could bring such a product into retail pharmacies.

So that's our Lynch syndrome program. Then we have a series of off-the-shelf cancer vaccines, cancer antigen therapies, which are targeting antigens that are -- proteins that are expressed and shared broadly across major cancers. These are in Phase I testing. And part of what we're trying to do now is to accelerate these to try and determine do these work. There's a higher scientific risk because these are proteins that, in theory, the thymus may try to eliminate T cells that are reactive to, although we do see, interestingly, T cells being activated when we give the vaccine. So there's hope and reason to believe it can work. But those are the ones that I think are next on the horizon for us.

Behind that, one of the benefits of our platform is multiplexing. And although there are T-cell engagers being studied in myeloma targeting single targets and now there are T-cell engagers targeting 2 targets, we are the first company ever to multiplex 3 T-cell engagers into 1 single drug. And we have this ongoing Phase I in multiple myeloma and heavily pretreated patients, many of them who've received multiple T-cell engagers or multiple different CAR-Ts. So a completely unmet need population, and that trial is progressing well, and we'll share that data later this year. And this is a sentinel program for us, this multiplexing T-cell engagers, because like Intismeran, sentinel program, if that works, it derisks potentially other cancer antigen vaccines. If this T cell -- multiplexing T-cell engager works, it leads us to further invest in other programs for other -- for solid tumors in that case.

And then we have what I'd like to highlight also is our autoimmune program because in essence, this started as an mRNA company/platform, but it's an immunology company with viruses, immunotherapy for cancer and now for autoimmune diseases. And at our Science Day in June, we talked about our in vivo CAR-T program, which is heading to the clinic. And then we have several other programs for autoimmune diseases as well. So I think over the next maybe 12 to 18 months, we'll be able to share additional progress on where we're going with these other exciting programs.

Fantastic. I have perhaps a quick question on PA, which is one of your rare diseases indications that will read out in Q4, and you've got MMA as well. What does the good result look like? And does this unlock a broader rare disease platform? Or is this a 2-program franchise?

It's a great question. So like everything we do at Moderna, we don't like onesies. I'm not interested in onesies. Too much risk, too much money. We like broad platforms, within the big mRNA platform. And so the way we've always thought about rare disease in the liver is if we get into the liver, given the liver is most probably the organ in our body that makes the most protein. And what we do with mRNA is to give instructions to your liver to make a protein to give gain of function, that if you look at just the list of disease that unfortunately many people have around the world, that it is going to be a very, very large opportunity, even to the point that at some stage, not for today, for some disease because they are N of 10 or 20, do you do an Intismeran-like approach and go deal with that tail, but that's more of a public health standpoint, and bring the right thing for patients in the world.

The financial opportunity is going to be on the front of the curve, obviously. And PA being one of them. And so PA for us is just a derisking like we've always done with capital being very disciplined because we have to manage technology risk. It was the first of another family of lipid, injected IV, not IM, like Intismeran and so on. So we have a lot of new things that we wanted to carefully manage and understand in the clinic to then have a lot of assets going forward. For anybody who does work -- as I said, to understand Moderna, you have to do work, I'm sorry. But if you do work and you can use AI to help you do work faster, you can see we have published more than 12 different models of rare genetic disease in the liver. They're all published.

Some have been out there for 5 or 6 years, where they are ready to go into the clinic. It's just a financial discipline. We use the same lipid as PA. It's the same as PA. Some manufacturing think about the manufacturing leverage in terms of P&L because we can do all of this off-season because today, our cost of goods don't look great. Why? Because for half of the year, we do nothing because we're in a seasonal business with vaccines. But what if you can start loading the factory in a month where you do nothing, we're making a rare disease product and just use your fixed cost, and you can do the math yourself. So rare disease is going to be important for the patient first, important for us.

In terms of outcome, look, I'm a pretty pragmatic guy. Look at the Phase I/II data and how you looked at 1 year, 2 year, 3 year, we've showed those swimlanes, and I don't expect anything different. Those swimlanes include the kids who had the lowest dose because it was a Phase I/II study. Despite the kids at the lowest dose, of course, we think being undertreated therapeutically. If you take the kids at the dose that is in the pivotal study, like the data is wow. So I expect great data when we get -- because again, it's not black magic, it's a rare disease. So that's going to be really interesting for us. It will help, of course, in terms of top line growth. Again, talking about long, long runways as an owner and front runner.

I've been here since the beginning at this company. I don't care about the EPS next quarter. We manage the EPS for next quarter, and the team has shown great discipline. I care about how do I create a 10x return over the next 5, 10 years for all of the decisions that we do. I've done it since day 1. I'm still doing it now 15 years after. And so the way we think about this opportunity for us is we can help patients. We can have very long duration. Because if you look at our 3 business today, as we said, vaccine has massive long term because the barrier to entry is so high. $1 billion of Phase III is not for faint of heart, right? And so we have a great franchise there for a long time. And as we know, for all the vaccine companies, the sales keep on going for a really, really long time.

We talk about Intismeran that maybe is going to be really hard to copy. And then rare disease, same thing, how do you get a kid on another PA drug? Once if it's approved, our PA drug approves. How do you convince a KOL and parent to take their kids off a drug that is working to try a new drug that might work? How do you do that, which is why, as we all know, the rare disease business for those companies and rare disease business, as Henri showed us with Genzyme, have also very long tail. And so that's how we think about PA. PA is just the first -- a bit like COVID -- was the first product of the company, the first vaccine of the company. PA is just the first rare disease in the liver. There going to be a lot.

Fantastic. That's really, really helpful to understand the potential breadth of this opportunity. Perhaps just to pivot to -- you mentioned a couple of things. One on kind of trade-offs you're making internally. And you also mentioned on that long-term direction. So I want to ask these 2 questions and then you can use the remainder of the time to answer. The first is you raised recently. You raised another $2.6 billion in convertible notes only a few weeks ago off the back of the Intismeran excitement. What does this money do? What does this afford you in terms of the trade-offs that you otherwise would have been making or can make now? And then finally, long-term direction, kind of you spoke about it's not about EPS next quarter, it's over the next 10 years. So let's project 10 years into the future. What does Moderna look like to you?

It's going to be much more of the same, that faster cycle time. As Mike and I just talked, before me, about what Generate is doing. We are doing a lot of AI. We don't have time to even talk about AI so far. I could spend a day talking about AI because I'm so excited about what it's going to do to the field and to us as a company, not only in science, but also in probably to process things much faster, to reduce cost, to have a much more agile company. As I've told, when we -- to our team, David was in the room and Lavina was in the room. When we announced to our team that morning Intismeran data, I told them, watch my lips. This is not our best product. And I believe it, every cell in my body. This is not our best product. It's an amazing first oncology product.

And I say that because we are living in this very exciting time in biology and AI is accelerating things so fast, which is we don't know how our body works. We know parts. But the next 5, 10 years are going to be an amazing time in human history to be able to learn that in the field. But then what we have is a platform that is an information molecule platform. And COVID was the best example for people who want to connect the dots. The virus was put online -- sorry, its sequence was put online. My guys developed in 10 minutes a vaccine in silico in a computer. It took 2 days to validate everything because I told them, "It's going to be in the clinic in 60 days. Are you sure?"

And they look at me, say, "What do you mean in the clinic in 60 days?" We don't do -- "in 60 days in the clinic. So are you sure?" So it took 2 days to check and do models and 3D simulation and so on, and they came back, "Yes, we're sure." And by the way, that same sequence they designed in 10 minutes on the computer, and I'm not exaggerating, it was a copy and paste of a sequence online, literally. I mean on pull-down menus in our system, choosing which chemistry for the mRNA, which manufacturing process, which lipid, but it was a copy and paste from a computer online. That's how we develop medicine now. Think about people doing small molecule or large molecule in big pharma.

So think about that, why do I use that example, because if tomorrow, there's a paper from Harvard or China or Australia about a new gene doing XYZ, my guys can get on a computer and in 10 minutes, I have new medicine. Think about that tailwind we have on top of aging population with vaccines and cancer and autoimmune disease, which are all #1 risk factor, age. So when you think about where Moderna is going, I don't know precisely, but I know it's going to be really fun. And I know we're just warming up, the last few years have been hard and I'm so thankful for the team that have worked with so much headwind. It's not fun when your sales go down 90%. We had the patent expiry on the company.

Pharma always complains they lose 1 product. We had the patent expiry experience, minus 90% on the entire company. And we restructured. The team worked really hard, and we kept our eyes on the long term, which is focus on patients, focus on science, focus on execute, collaborate together because this platform is stronger than before the pandemic because it has been proven. And we raised a lot of capital through supplying the vaccine. So now we're just executing, and the world doesn't understand yet where we're going because most people are not doing the work. If you do the work, if you look at all the data we have, and Lavina and our team can help you connect the dots, if you do the work, where we're going is really exciting.

Fantastic. Thank you so much, Stéphane. Thank you, David. I really appreciate your time.

Thank you, Courtney.

Thank you.

Thanks, David.

Thanks for joining us, everybody. I'm Terence Flynn, Morgan Stanley's U.S. biopharma analyst. For important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. Very pleased to be hosting Moderna this morning.

From the company, we have Stephen Hoge, the company's President. Stephen, thanks so much for being here. Really enjoy an opportunity to get to speak with you today. I guess, first, what I wanted to start off with is the INT program is front and center. Congratulations on the positive Phase III adjuvant melanoma data.

So maybe just talk to us about the implications of that data for the broader strategy at Moderna in terms of what does this mean for additional indications? What does this mean for leaning in on the program? Just high level before we dig into some of the data questions that I have.

Of course. Well, first, thank you again for having us. Always a pleasure to be here. So look, we're obviously thrilled by the results that were announced. It's the idea of a T-cell priming approach, a vaccine, if you will, approach to treating cancer has been long promised, but this is the first time that we've been able to see a statistically significant and clinically meaningful result, as we said in our press release. It was also the first time we've ever -- anybody has ever achieved that kind of benefit over KEYTRUDA in the adjuvant setting in melanoma. And that's not because there wasn't a lot of attempts.

And so we think it bodes really well for the hypothesis, the scientific hypothesis that we've been working on ourselves for over 10 years, which is if you can prime T cells to see the tumor, are they able to mobilize a substantial response and not just in combination with KEYTRUDA, which helps with T-cell exhaustion, but actually against new and more diverse sets of tumors. And so the Phase II results that we had from 5 years ago were exciting. We recently provided some scientific updates at ASCO, and we're looking forward to sharing more. And we're quite optimistic about the large book of work we've got with ongoing studies right now.

Great. Do these data at all change the investment opportunity? So as you ramp investments, are you guys going to lean in? Does that change the breakeven target at all? Because I imagine you have a certain number of indications you're already looking at, but how do you think about a broader rollout of this in the future?

Yes. Look, I think we are still targeting breakeven in 2028, and that has been based on the strength of our infectious disease vaccines business. We now have 5 products approved, and I'm sure we'll talk more about it. But with approval of our flu product in the United States, our combination product outside the United States and Europe. So we're looking forward to building that franchise. And we have been investing in [ INT, Intismeran ] underneath that. And so we currently have a very large book of work with our partner, Merck. That includes 9 ongoing clinical trials, multiple Phase IIIs, in fact, 3 randomized Phase IIIs in lung cancer as well as melanoma as well as studies we may talk about in renal cell carcinoma and bladder cancer, both muscle invasive and non-muscle invasive.

So all of that is actually investments we've really made over the last 2 years and is baked into that perspective. The caveat becomes then, well, as this data comes out from INT, how do we respond to it? And in particular, where are the places we might go next. And those include looking at monotherapy opportunities, earlier-stage disease, Stage I. And of course, where the data directs us, we'll want to be in a position to make those investments. And we're in a strong financial position, thanks to the convertible debt we recently put in that we'll have more than enough on our balance sheet if the data directs us to make those investments, but we want to be responsible about it. So we're going to wait and look for data and then respond to that as we go forward.

Okay. Makes sense. Maybe we'll dig into the melanoma data a little bit here. But just wondering, I think there's an expectation we could see the full Phase III data at ESMO. Do you think that's a fair venue for this type of data?

You know how these things go. We look forward to sharing at an upcoming medical meeting, and that medical meeting will determine when they want to announce.

Okay. We hosted a KOL a couple of weeks ago, and he stated that he'd consider a hazard ratio of less than 0.5 -- 0.75 is exciting, but ideally looking for 0.65. And so as we think about that, do you think that's a fair characterization from what clinically meaningful is for this data set?

We would agree with that. I think those are reasonable. Again, I'd kind of come back to -- this is -- KEYTRUDA itself in the adjuvant melanoma setting is a very effective drug. And obviously, Nobel Prize-winning innovation, but a product that has had a huge impact on how we treat cancer. And so that standard is really what we compare ourselves against in this Phase III trial. And so you -- it's a very active comparator. We would want to provide a meaningful benefit. And as ourselves and Merck put out in the press release, we think we have provided a clinically meaningful benefit based on this first interim analysis.

But ultimately, we look for the field to sort of look at that data and make their own determinations. We also hope that, that data matures. We look forward to it over time. If you think about that Phase II result, from 5 years ago, we saw continued maturation over the full 5 years. And so we'll look forward to that. But can't wait to get the first round of this data out there so that people can start responding to that directly.

Okay. We're looking forward to it. The other question we get a lot is just read-through potential from this trial to other tumor types. And so I know you and Merck have a broad program, as you mentioned. But what are some of the other data points we should look for in this Phase III presentation that will give us insights into likelihood of success in these other tumor types that you're conducting right now?

Yes. So look, when we share the data, the things that people want to look at is to what extent do they reproduce or look like what's happening in the Phase II? And to what extent do the things that we looked at new populations look similar or different. So stage of disease. We have some Stage II population in the Phase III trial, what does that look like? How does that compare against later stage metastatic or otherwise? The shape of those curves, we will look forward to understanding what's the -- at what point do the curves separate. You know they separate because it was a significant result. And how does that separation shape look like over time, a median follow-up of a couple of years now, you can start to get a sense, but really maybe try to predict the future.

And then obviously, all the subgroup analysis and just understanding what we can take from it. We're -- based on the totality of clinical data we put out there as well as what we understand of the Phase III so far, we think it's a really exciting new space to do T-cell priming that really creating T-cell populations that can see tumors, can see these mutations specifically, does look like something that is powerful and incremental to the checkpoint inhibitors like PD-1 like KEYTRUDA. And that's exciting because I don't think we've ever really been there. There are lots of combinations that were tried, lots of IO/IO combinations tried in the adjuvant setting around T-cell exhaustion. I think of all the other checkpoint inhibitors we saw. And we never got to something like this, even just in the top line press release we already put out.

So we're looking forward to exploring all the ways in which that translates across other indications. So lung cancer is a big one. We talked about bladder and renal cell. And then for me, personally, I get very excited about the Stage I and early-stage disease because one of the features of the product that we're proudest of, again, think about the publication that's already out on the Phase II is its safety profile. Any cancer drug is a benefit-risk calculation, but when your safety profile really isn't adding significant grade 3 events -- grade 3 to 5 events, it really speaks to an opportunity to treat a much broader population much earlier.

Yes. And how do we think about hot versus cold tumor types? I know that's another debate. There's some -- another competitor of yours who kind of had focused more on some of the colder tumor types like pancreatic and colorectal. You guys have seemed to lean more into kind of the hotter tumor types. So how do you think about the read-through from hot to maybe colder medium tumors?

Yes. So I think first, what I can speak to is the data that we've already put out there, which is in melanoma, when we looked at that Phase II result, all the translational data and the subsequent analyses, again, posters at ASCO and other publications, a few things jumped out. We saw a favorable hazard ratio regardless of tumor mutational burden, regardless of PD-1 status. And so favorable hazard ratios in both situations. And then there was a tumor inflammation scoring version of the same, again, where we saw an opportunity to improve upon KEYTRUDA regardless of the background tumor inflammatory status. I think it was a couple of years ago in poster at ASCO.

And so if you take the totality of those, you kind of have to pull back and say, it doesn't feel like it's following the rules of a checkpoint inhibitor. That would make sense. It's not a checkpoint inhibitor. This is a T-cell priming, not T-cell exhaustion. It should be pioneering its own rules. I just don't know how far that goes, Terence. Like does it -- do we see that many of the other features about the tumor inflammation don't matter? Possibly. We've got to go explore the stage of disease clearly will matter. I think we feel strongly that adjuvant and earlier are places that are the most fruitful to look because you want to get down to really minimally residual disease. And then what you're trying to do is prevent a recurrence or relapse and ultimately lead to long-term survival. And so that's where we're focusing our energy.

But I think the rules are to be discovered and the limits around it are to be discovered. As far as other experience with BioNTech or others, we do such different things technologically, including the way that we're delivering in the dosing regimen and the lipid nanoparticle that we use versus their approaches and algorithmically that I'm not sure how to compare them. I don't -- I understand that it's worthwhile looking at them, but I don't think I know yet how to read through.

Okay. The next 2 readouts, I think, are Phase II for bladder cancer, kidney cancer. So maybe just remind us kind of design features of those studies. You mentioned going early. So these are adjuvant combo with KEYTRUDA, but any other design features that you think are important? And then frame for us, I know you're not going to put a number on it, but just likelihood of success, like, where is your confidence highest amongst these next set of readouts?

Yes. Look, so I think across the -- there's this -- what I would describe as the Phase IIIs in lung, which are going to take a little bit more time to read out, but we're quite enthusiastic to see, obviously, for all the reasons, non-small cell lung cancer, there's a huge opportunity there to continue to improve, but PD-1s have shown a great benefit. And I would highlight those as ones that we're actively working hard to enroll those Phase IIIs, then will be event-driven analyses. But we've really covered the gamut from a couple of adjuvant studies, looking at adjuvant and neoadjuvant interventions, a Stage I study, which is really going early and I think is a place even looking at monotherapy. And then we have a Phase II study looking at metastatic at frontline, which will be interesting, but that's only a Phase II.

So we're all clearly long on lung when you look across those 3 Phase IIIs and a large randomized Phase II. I think if you're looking more proximally in terms of coming readouts, which I think was your question, we've highlighted RCC, renal cell carcinoma and muscle-invasive bladder cancer as ones that are fully enrolled in event-driven trials. There is also a non-muscle-invasive bladder cancer study that's not yet fully enrolled, but all 3 of them are essentially approximately 300 patients randomized 1:1 against the standard of care and particularly the muscle-invasive bladder cancer and the renal cell carcinoma, that's against KEYTRUDA. You mentioned it, but just to underscore, it's the adjuvant setting. And those are both places where PD-1, KEYTRUDA, particularly has shown a meaningful benefit.

And so we know an immune therapy can work -- the real question is just like we have shown in melanoma, can an alternative approach to immunotherapy in cancer, not checkpoint combinations, but something completely different, add again on top of that. And I think those are the 2 that I wouldn't want to characterize optimism or pessimism, but I'm most scientifically curious about because they are essentially fully enrolled, randomized against the gold standard of care. MIBC has had some evolution in that standard of care since we've completed the study. But the readout, the value of that will still be there.

And I think on both, I'm keen to understand do we continue to add a benefit. RCC has a lower tumor mutational burden. And so many folks point to that one as the other extreme from melanoma in the current portfolio and book of work. And so we're hopeful for that. But I think we'll learn a lot from the MIBC study as well. And then I wouldn't lose sight of the non-muscle invasive bladder cancer study. That's a monotherapy study. It really gets to this idea of can you intervene early and with INT alone, which will also be event-driven and also a Phase II that could read out in the near term.

So lots of data coming. And I just would tip of the hat to our team, but also Merck as a partner, the approach they've taken -- we've taken for the last 4 or 5 years to set this up is not a melanoma and then we get started, but a melanoma and then every 6 months, you're seeing waves of clinical data, first RCC, MIBC, non-muscle invasive bladder cancer, several lung cancer studies and other things coming. So it's many years of looking forward to clinical data in the program right now.

Great. Definitely going to be an exciting period of readouts. One follow-up on RCC before I go to some commercial questions is just, I think there's been this debate about you said lower tumor mutational burden, but maybe a higher rate of indel mutations. So is that the counterpoint to that where that maybe puts a higher likelihood of success potentially?

Yes. I mean they all present neoantigens, right? They all will be non-native antigens that your immune system or a patient's immune system will be able to use to specifically identify the cancer. And so frameshift, indels, all those sorts of things create novel opportunities for presentation. We know that PD-1 antibodies work in the RCC context. And so you kind of know the immune system is ready. The question is, can we get it more focused on those things and the right things. So there's -- yes, it's an interesting tumor in many respects. And then frameshifts are something that we're obviously curious about more broadly.

Okay. Great. These 2 trials, the Phase II MIBC and RCC, if, let's say, the melanoma data support an approval, does that increase the likelihood that you think FDA will be more willing to lean in on these Phase II trials as registration enabling and some kind of accelerated approval pathway? I know you guys were optimistic back in the day around the Phase II original melanoma data, obviously, need to generate the Phase III. But how do you think about registration enablement of these Phase IIs in light of, let's say, you do get approval on the Phase III melanoma data?

Yes. So many of the aspects -- so the core technology and manufacturing, and if you think of it as sort of the modules of the BLA, it's common between them, right? So if melanoma is approved, you have worked out a lot of the CMC and manufacturing questions and ultimately, also the safety profile of the product in large respect because it's, again, the same combination partners. And so what you're left with is clinical evidence of substantial evidence of effectiveness. I think that will boil down to the data and any good regulator, but also any company should sit here and say that, right, which is if there's a strong benefit, hopefully, one that's even statistically significant, then there's really no reason why the studies can and shouldn't be registrational. They're adequate, they're well controlled. They're against the standard of care. If they're statistically significant in terms of benefit, you've got all this other safety and manufacturing data, it can and should be.

Now the question is if there's -- if it's taking more time for those events to accrue, if there's some reason why the study doesn't quite get to a statistical threshold. And at that point, I think it's probably harder to believe it's registrational, but there are other pathways forward that obviously putting the data out there might allow practice to sort of begin to adopt it. But these are all data dependent. And so I think we're all just waiting for these event-driven studies to hit their analyses.

Okay. Great. Maybe just moving over to the commercial side. A question we get a lot from investors is just manufacturer readiness, turnaround time, scalability. A lot of chatter out there like, oh, this is going to be, like, CAR-T therapy. It's so individualized. It's going to be very complicated. I know you guys have done a ton of work here over the last years to kind of improve that vein-to-vein time. So maybe just talk to us about where you stand from a commercial readiness standpoint and your view on scalability in the event that more indications read out positive and there's greater demand for this product.

So I think we are extremely -- we think we are extremely well positioned for it. We have not broken out a lot of the investment we were doing over the last few years. But so -- and obviously, there was questions about breakeven along the way, you know that we face. But a huge portion of that investment was building capability in INT and then running these 9 global trials. As a reference point, we've treated about 3,000 patients. In the last 18 months alone, it's probably close to 1,500 to 2,000, all delivered from a purpose-built manufacturing system, and that's in 40-odd countries. That is commercial scale because we're enrolling 3 Phase IIIs in lung cancer and running the melanoma and 5 other studies in Phase IIbs that we were just talking about.

So we're already, kind of, operating at commercial scale across histologies and globally. And that's because we built in Marlborough, and I think we're going to host folks there at some point, would love to have you there, a completely new manufacturing system. We have -- it's highly automated. It is unlike anything else that maybe people have seen in the manufacturing space. And it has actually already been supplying into the clinical trials.

So that facility that we have there, we are confident can supply launch. And as we bring people in, you'll see within about 12 months of lead time, we can take that facility's capacity up another sevenfold. In fact, 1 of 7 ballrooms is built out. All the technology is licensed, all of it's built out. It's sitting in that facility. It's being used in clinical trials now. And within 12 months, we can essentially double that every time we need to.

So we're very confident that we don't need more certainly for the first few years of launch. If things really take off on us, then we'll want to talk about a second facility at some point. But this isn't -- we believe we can get there. We are already operating at commercial scales globally in our large global clinical trial program. And I think it's where people are different than CAR-T. And you were talking about treating 100 patients in a clinical trial versus 3,000 globally in 42 countries. I mean we're already kind of having to do something very different.

Yes. Is that 1,500 to 2,000, is that kind of the steady-state number for that Suite 1 or there's more room -- there's more room...

Much more room. We think that Suite 1 of 7, and we'll figure out when we -- what we're comfortable disclosing in the future. But we actually don't think we need Suite 2 for launch and still supporting the clinical trials. So we have capacity. And what you'll see when you get there is it's -- there's a beautiful automation that's been built into the system. So we work -- we took everything, all of the pain difficulties that we had, all the engineering know-how that we learned from scaling COVID from -- we never sold a dose to 1 billion doses a year in '21, '22. We then pivoted in '23, '24, '25 into establishing something completely opposite in some ways, but equally technologically a marvel and that's now paid for. It's been established. And so again, coming from that breakeven question that you asked at the beginning, we've already, kind of, built it all. We were doing that over the last few years.

Okay. Great. The -- I know Stéphane has made some comments about potential price points of INT. So maybe just anything you can elaborate on there? And then what does that mean for, kind of, the margins of this, kind of, product? Because that's another question that we get from investors is just, again, going back to the individualized nature of this therapy, does that necessarily mean a lower gross margin profile for the product?

Yes. So we -- it's premature to talk about pricing notwithstanding anything Stéphane might have said, because ultimately, we're going to price to value, and we need to get the data out there and then have conversations with payers about that value. Obviously, the stronger the impact, the more value you create for a health care system and obviously, that impacts pricing. So let's get the data out, and we'll sort of talk through the specifics of it. But suffice it to say, we do believe that there's a clinically meaningful benefit here. And we have already -- again, I would come back to -- you've seen our operations on top of everything we've been doing, scaling a respiratory vaccines business has been baked into our P&L over the last few years.

So what people probably don't fully conceptualize is the degree to which we are already doing all of this and paying for that in terms of the P&L perspective. And so as we move forward, we're pretty confident about that margin profile. Now everything will be scale dependent and pacing the -- when we build out capacity and bring it online versus when there's demand there will sort of be a bit of an art in the first few years of launch as it is for any product. But if you want to talk about steady state for INT, yes, it is individualized. But the actual manufacturing technology and the actual chemical matter that goes in the vial at the end of the day is essentially the same across all of the patients. The sequence, the information is different, but that isn't the biggest driver of cost for us.

And so we -- it is not taking cells from a patient and engineering them and all the things that, kind of, went into CAR-T. It is much more like a traditional complex biologic, but not a cell therapy. And so -- we hope over time that the margins are very competitive with other complex biologics, but not cell therapy.

Okay. Great. The other one, it goes to -- it's a good segue to one of the other ones we get is just the antigen selection process. I know that's something proprietary. You guys have spent a lot of time perfecting that. Talk to us about if you do make changes to that down the road because of additional learnings, let's say, in other tumor types, what that means from a kind of FDA approval process? Is this something where it's kind of like a flu-like change where you can just kind of like roll that out? Or do you need a whole clinical program? So that's kind of the first part.

And then somewhat related is retreatment potential. You talked about metastatic. Obviously, the field has focused more on adjuvant given some of the data, but you guys still do have some metastatic trials. So let's say, theoretically, in a future use scenario, you have a patient that received 1 INT for an adjuvant setting, but then unfortunately, the disease relapses and metastasizes down the road, is there some reason to think that they could get retreated with a different INT product or something like that? So again, kind of a somewhat related but 2-part question.

Yes. So maybe I'll take the second part first because we -- I think so. We don't have any data on it. So I don't want to create expectations. But if you ask me from a hypothesis perspective or us from a hypothesis perspective, if you have a relapse and it's because the mutations that went into your INT were essentially removed from the tumor. The cells that express those mutations were killed by your immune system, then there's no reason why you shouldn't then take the new mutations and create a new product against it. And so retreatment with the exact same product, probably not, but retreatment with a product that reflects your tumor as it has changed to relapse, for sure.

And, in fact, you could almost just argue that's a different cancer, even if it, kind of, came clonally in its distance pass. And in that sense, we would -- I look forward to the day when we have that data. I really can't come up with a reason why it wouldn't actually benefit. Again, this is about unmasking your tumor. And if it puts on a mask or loses those features that your INT was targeting, it should be valid. The first part about, I forgot, Terence...

So the FDA approval process for a tumor. If you make -- let's put it in 2 categories. Like one is like minor changes to the antigen selection process, but the other would be, again, I'm assuming if you're making major changes, it's definitely a totally new product.

This is the most exciting part of the field. And so we -- if I -- again, scientifically, we have put out at ASCO some of the data on T-cell clonality and actually showing in individual patients, what are the T-cell clones that are really associated with their -- not having a relapse or not. And then across the population, I think there was like 7 patients we went very deep on that. But more broadly, across the population, can we start to show what's the mechanism of action, what's the root cause. Now what you start to be able to do is say, now how do I predict that clonality and how do I -- that was on a Phase II where we had 100 patients treated. We've got several thousand now. And in the melanoma study, about 800 patients. You're going to massively expand your ability to, say, at a population level, what are the features of these T-cell clones that predict survival. And we're in the early stages of looking at that.

But if you got to the ability to say, well, no, actually, among these 100 options, there are a few here that are going to have a higher propensity to predict survival, which is something we'll look very closely at with our partner, Merck, then you might want to do maybe a more substantive update, right? At that point, the real question, and we've been working with the FDA closely with EMA and other regulators because software is a part of the drug to define what kinds of software updates constitute a major change and require an sBLA versus more just, kind of, a process change, a prior approval supplement type approach.

And the basic answer won't surprise you. The more you expect a meaningful improvement in clinical outcomes, the more it starts to look like a new product, a new version of a product. That doesn't necessarily mean that you need a new clinical trial, right? And you can imagine how you use the flu example, how there's lots of instances where you change a product to make it more relevant for today, but where you don't have to go back because your product is still -- you're able to look at translational biomarkers and data like what I was just describing and say, look, I'm going to get you all that benefit and then some. And so we're pretty excited about that because it's a space where we think with continued improvement and ultimately, the flywheel we have with more data coming in from our translational data and more opportunities to drive those improvements that we're going to have an opportunity again, with that proprietary data set to really advance the field pretty dramatically and maybe even ultimately advance the label.

Okay. Great. Maybe just in the last few minutes and pretty amazing we've gone half an hour without talking about your vaccines portfolio. But again, obviously, a key part of the commercial business, the breakeven plans. You guys now have 3 vaccines in the portfolio. So just talk through what that scale means as we think about the forward outlook for this? Like how much of an advantage does that give you versus when you were, kind of, a single product vaccine company?

It's transformational. We've come a long way. So we -- you go back sort of 3 years ago, we were pursuing our first approval. We had a COVID vaccine and dreaming of a day where we would have a more diverse portfolio because flu and RSV are the other sort of big respiratory threats and then opportunities for combination that could be differentiating. So you said 3 products. It's actually 5 now product approvals that we've achieved. Obviously, COVID, flu and RSV, the first combination product and then a second-generation COVID that has really shown in the real world as well as in its clinical trials, Phase III trial, mNEXSPIKE, we think superior performance. And so we're excited by that.

And so that just gives us -- it's a completely different conversation. Most respiratory vaccines contracting is at a portfolio level. Portfolio of 1 is substantially inferior to portfolio of 5. That -- internationally, we've established through strategic partnerships with U.K., Canada, Australia, other governments coming online, the ability to offer them flexibility across that portfolio. It's a big flu year, you can buy more flu. It's a big COVID year, if you want some combo. And that allows a completely different conversation with those governments. And then within the United States, with health care systems, with pharmacies, portfolio-based contracting is obviously an advantage for us. So we're having our first taste of that in some ways this year. And in the years ahead, we look forward to taking full advantage of it.

Yes. Any early insights you can give us as we think through to next year in terms of how -- you said you've had some early learnings from that scalability. So just any insight in terms of how that's going or how to think about it? It seems like we should be more optimistic for, kind of, a growth -- more meaningful growth inflection.

I don't want to raise expectations anymore. So our guidance for now is up to 10% growth on the top line for this year. And as we look forward towards breakeven, we, kind of, have retained that. We think that's the right sort of mental model for us. I think we're across the board, what we're seeing is enthusiasm for that portfolio. What's great for us is we don't need more commercial infrastructure. We don't need different manufacturing infrastructure. It's all basically diversification of our sources of revenue and gives us new products to sell into customers that are already familiar with us from COVID.

I do think there are a couple of features that we're really excited to bring to the market. So flu is one, mFlusiva, our approved product in the United States. It is the first really enhanced efficacy profile for seniors that comes without egg-based manufacturing. And that 95% of flu vaccines are currently made in eggs. That matters because eggs lead to antigen drift and mismatch in more than half of years. So about half the time, you'll have 1 of the 3 strains with an egg adaptation mismatch. And that was talked about at the FDA and VRBPAC, it's been talked about for decades in CDC and WHO.

And we finally have a solution to that because mRNA allows us to make a perfect match to what they're targeting. So we're excited to bring that innovation into flu because we think it will add a lot of value. In Europe this year, we're launching combo, a flu/COVID combo. So one shot more protection. And so we're pretty excited to bring that as a way for health care systems to improve their public health outcomes without adding the cost of having store 2 shots of paying for 2 administration fees. So there are lots of places where we think we are positively disrupting the system, and hopefully, it will add a lot of value.

Great. Well, I think we're up against time. But thank you so much, Stephen. Always a pleasure. All right.

Thanks, Terence.

Good day, and thank you for standing by. Welcome to the Moderna Second Quarter 2026 Conference Call. [Operator Instructions] Please be advised today's conference is being recorded.

I would now like to hand the conference over to your speaker today, Lavina Talukdar. Please go ahead.

Thank you, Kevin. Good morning, everyone, and thank you for joining us on today's call to discuss Moderna's Second Quarter 2026 Financial Results and Business Update. You can access the press release issued this morning as well as the slides that we'll be reviewing by going to the Investors section of our website. On today's call are Stephane Bancel, our Chief Executive Officer; Stephen Hoge, our President; Jamey Mock, our Chief Financial Officer; and David Berman, our Chief Development Officer.

Before we begin, please note that this conference call will include forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Please see Slide 2 of the accompanying presentation and our SEC filings for important risk factors that could cause our actual performance and results to differ materially from those expressed or implied in these forward-looking statements.

With that, I will now turn the call over to Stephane.

Thank you, Lavina. Good morning or good afternoon, everyone. Thank you for joining us. After my review of the second quarter, Jamey will present our financial results and outlook, followed by Stephen with recent business updates. And David will review our clinical progress in oncology and rare diseases. And then I will close by discussing our key value drivers.

As you know, the second quarter is always light for seasonal vaccines. We generated revenue of EUR 0.1 billion, which exceeded the top of our range. Our focus on financial discipline continued. We reduced cash cost by 10% in Q2 compared to the second quarter of 2025. We reported a net loss of EUR 0.8 billion. We ended the quarter with $6.9 billion in cash and investments, maintaining a strong balance sheet while continuing to invest in our pipeline. Overall, I am pleased with our continued execution across the business. This team has done a great job to get us ready for the '26, '27 vaccination season, and our pipeline is progressing well.

During the quarter, we delivered several important updates across our pipeline. In our respiratory portfolio, our seasonal flu vaccine, mRNA-1010, received a positive recommendation from the U.S. VRBPAC. This represents another important milestone ahead of our August 5 PDUFA date and brings us one step closer to potentially making out flu vaccine available to patients.

For norovirus vaccine, mRNA-1403, following an interim analysis, we are preparing to enroll an additional cohort in its Phase III trial. In oncology, we are very pleased to present the 5-year Phase II update of incismiran autogene in combination with KEYTRUDA in adjuvant melanoma at ASCO 2026, highlighting the continued durability of the clinical benefit observed of this program. We also presented important translation data that provides additional confidence in the mechanism of action of our individualized neoantigen therapy.

And finally, we're excited to announce that dosing has begun in 2 cancer antigen therapy programs. The Phase I/II study of mRNA-4194 in Lynch syndrome and the Phase I study of mRNA-4200 in solid tumors. Beyond our pipeline, we also had several notable corporate achievements during the quarter. We are pleased to expand our partnership with CEPI to explore the development of an Ebola vaccine, reinforcing our long-standing commitment to global health security and pandemic preparedness.

We were also honored to be named the World's Most Impactful Company by Time Magazine, recognizing our pioneering work in mRNA science. This recognition reflects both the global impact we made during the pandemic and our continued effort to advance a broad pipeline of innovative medicine and expand access to mRNA technology worldwide.

Turning now to our leadership team. I'd like to highlight 2 important appointments we announced this quarter. As we continue to strengthen Moderna for the next phase of growth, I'm very pleased to welcome Ester Banque as our new Chief Commercial Officer. Ester joined us with more than 30 years of commercial leadership experience and an outstanding track record of leading high-performing organization across the health care industry. More recently, she led U.S. operation at Zoetis and before that, held several commercial leadership role at BMS and Novartis, where she helped bring important medicines to patients around the world. Ester now leads our global commercial organization as we prepare for multiple launches and continue expanding into new markets. We are delighted to have Esther join Moderna and have been enjoying working closely with her.

I'm also pleased to welcome Michael McDonald to Moderna's Board of Directors. Michael is familiar to many of you as most recently, he served as Executive Vice President and Chief Financial Officer of Biogen. Michael brings more than 2 decades of public company CFO experience and deep expertise across finance, capital markets, Investor Relations and corporate governance. His experience across the life science and technology sectors will be a valuable addition to our Board as we continue to execute our strategy and create long-term value. We are delighted to welcome Michael to Moderna's Board.

With that, I will now turn to Jamey.

Thanks, Stephane, and hello, everyone. Today, I'll start with our second quarter financial results and then review our updated financial framework for 2026. Let me start with our commercial performance. For the second quarter, total revenue was $145 million, above the guidance range we provided on the first quarter call. Our geographic mix for the quarter was 60% U.S. and 40% international.

For the first half of the year, total revenue was $0.5 billion with 31% from the U.S. and 69% from international markets. Our long-term strategic partnerships drove the strong international contribution during the first half. Overall, we are pleased with our first half performance and are reiterating our expectation for revenue growth of up to 10% in 2026. We continue to expect a roughly 50-50 split between U.S. and international revenue for the full year, and we expect third quarter revenue will represent approximately 55% of our second half revenue.

Now let me turn to our second quarter financial performance on Slide 10. As I just mentioned, revenue was $145 million in the quarter, up 2% from the prior year. Cost of sales for the quarter was $93 million, a 22% decrease compared to the prior year, primarily driven by lower unutilized manufacturing capacity costs as we continue to improve our manufacturing efficiency. R&D expenses for the quarter were $651 million, a 7% decrease compared to last year. The decline was driven by lower clinical development costs following the wind down of several late-stage programs.

SG&A expenses for the quarter were $216 million, down 6% from last year, reflecting continued cost discipline across the organization. Our income tax provision was immaterial in both periods as we continue to maintain a global valuation allowance, which limits our ability to recognize tax benefits from losses.

Net loss for the quarter was $782 million, improving by $43 million or 5% compared to last year. Loss per share was $1.97, and for the quarter compared to $2.13 last year. We ended the quarter with cash and investments of $6.9 billion compared to $7.5 billion at the end of the first quarter. The decrease primarily reflected cash used to fund operations as we continue to invest in R&D and advance our pipeline. In July, we paid $950 million related to the litigation settlement announced earlier this year, which will be reflected in our third quarter cash balance.

Now let's turn to our financial framework for 2026. We still expect total revenue to grow up to 10% in 2026 with the geographic mix and quarterly phasing I previously mentioned. Our 2026 revenue guidance factors in potential future declines in COVID vaccination rates and continues to assume no revenue from mFlusiva and mCombriax. We are lowering our cost of sales projection by $0.1 billion to $1.7 billion, reflecting additional manufacturing efficiency gains. The $1.7 billion estimate includes $0.9 billion of expense related to the previously announced litigation settlement charge.

We are also lowering our R&D expense estimate by $0.1 billion to $2.9 billion due to operational efficiencies and SG&A expenses are still expected to be approximately $1 billion, flat versus the prior year. Similar to 2025, our commercial spend will be more heavily weighted to the second half of the year due to the seasonality of our business. In aggregate, excluding the $0.9 billion litigation charge, we are expecting total GAAP operating expenses of $4.7 billion and $4 billion of cash costs which excludes stock-based compensation, depreciation and amortization, each reflect a $0.2 billion improvement compared to our previous guidance.

We expect taxes to be negligible in 2026. Capital expenditures are still projected to be between $0.2 billion and $0.3 billion. Cash and investments are now projected to be between $4.7 billion and $5.2 billion at the end of 2026 which reflect the improvement in our cash cost guidance. As a reminder, our cash guidance does not assume any additional drawdown from our remaining $0.9 billion undrawn credit facility.

With that, I will now turn the call over to Stephen.

Thank you, Jamey, and good morning or good afternoon, everyone. Today, I'll take you through our recent business updates. Slide 13 outlines our multiyear revenue growth strategy, anchored in geographic expansion and portfolio expansion from the continued advancement of our product pipeline. For 2026, we continue to expect revenue growth of up to 10%, driven by our long-term strategic partnerships in the United Kingdom, Canada and Australia and supported by the continued growth of mNEXSPIKE.

Looking across the 3-year horizon, we are building toward a broader and more diversified portfolio, including flu, our combination flu in COVID vaccine and norovirus as well as late-stage programs in oncology and rare disease, while continuing to expand our global commercial footprint. We're making tangible progress against this strategy, and mNEXSPIKE is now approved in Japan and Taiwan.

Our flu program received a unanimous recommendation from the Verpac FDA Advisory Committee, and we signed a joint procurement contract with the European Commission for up to 24 million doses of mRESVIA across 6 countries. We also received approval for mRESVIA in Mexico and a label expansion for the product in Australia. In Latin America, we advanced our strategic partnership in Brazil by signing an agreement with a local manufacturer to support our multiyear COVID vaccine supply agreement with the government. Finally, as our commercial portfolio expands, emerging real-world evidence strengthens the support for our respiratory portfolio.

Slide 14 highlights our approved infectious disease portfolio and several recent updates across the products. Starting with COVID, health authorities in the United States and Europe have selected the XFG strain for the '26, '27 season, and we are updating both Spikevax and mNEXSPIKE to target this strain for the upcoming vaccination season. For Spikevax, we also recently published a real-world evidence study. A link to the study is included on this slide.

And mNEXSPIKE is now approved in the United States, Europe, Canada, Australia and as mentioned earlier, now in Japan and Taiwan. Additional filings are planned for the second half of 2026. We also published a real-world evidence study evaluating the adjusted vaccine effectiveness against COVID-related hospitalization during the most recent 2025, 2026 season, which I will discuss in more detail shortly.

Turning to America, which is approved in 44 countries. Most recently, it was approved in Mexico for all adults aged 60 and older as well as high-risk adults age 18 to 59. We also received a label expansion in Australia to include high-risk adults aged 18 to 59. In addition, a real-world evidence study evaluating vaccine effectiveness against hospitalization and associated with RSV-related acute respiratory illness was published for mRESVIA.

Finally, mCombriax is now approved in the European Union is under review in Canada, Australia and most recently, Japan. In the United States. We are awaiting approval of our stand-alone flu vaccine before seeking further guidance from the FDA on next steps for refiling the combo here.

Slide 15 highlights the emerging real-world evidence supporting mNEXSPIKE's clinical profile. As a reminder, during its first season on the market in 2025, 2026, mNEXSPIKE captured approximately 24% of the total U.S. retail covid vaccine market. Uptake was particularly strong among older adults with mNEXSPIKE bike accounting for approximately 34% of the retail market among individuals aged 65 and older. This market uptake was supported in part by the Phase III head-to-head data of mNEXSPIKE versus Spikevax.

The subsequent real-world analysis evaluated adjusted vaccine effectiveness against hospitalization with documented COVID-19 during the 2025, 2026 season. Among adult age 65 and older, vaccine effectiveness was approximately 59% for mNEXSPIKE compared with a matched unvaccinated cohort. Among adults age 75 and older, it was approximately 67%. These estimates were numerically higher than those observed for a competitor vaccine and separately matched analysis.

While this real-world study was not designed as a head-to-head comparison, the numerical differences are encouraging, particularly when considered alongside the vaccine efficacy observed for mNEXSPIKE versus Spikevax in the Phase III head-to-head trial. Taken together, the strong initial market uptake and the emerging real world evidence highlight mNEXSPIKE's potential, particularly among older adults.

Turning now to our late-stage infectious disease pipeline. And starting with flu, we are grateful for the unanimous VRBPAC recommendation for mRNA-1010 and look forward to the potential for approval with the PDUFA date of August 5 in the United States. mRNA-1010 is also under review in the European Union, Canada and Australia. The efficacy and safety results from our Phase III study were recently published in the New England Journal of Medicine. A link to the publication is included at the bottom of the slide.

For our neurovirus vaccine, mRNA-1403, the Phase III study did not meet the statistical criteria for early success at its interim analysis. The study remains blinded as we now prepare to enroll an additional fourth cohort.

With that, I will now turn the call over to David, who will provide a more detailed update on our oncology and rare disease pipelines.

Thank you, Stephen. Before I begin the review of our oncology and rare disease pipeline, I want to take a moment to say how excited I am to be here. Before joining Moderna, I followed the company's oncology portfolio and Intismeran, in particular, very closely. The strength and potential of the pipeline were an important part of what attracted me to the Chief Development official role.

Since joining the company and spending time with the teams, I have become even more impressed by the quality of the science, the depth of the programs and the opportunities ahead of us. With that, let me take you through the progress we are making across our oncology and rare disease pipeline.

Starting with Intismeran, our individualized cancer therapy developed in partnership with Merck, the program continues to advance across a broad portfolio of 9 Phase II and Phase III studies. In adjuvant melanoma, the Phase III study is fully enrolled and we look forward to the interim analysis in 2026. At ASCO, we presented the 5-year update from the Phase II study of Intismeran in combination with KEYTRUDA in the adjuvant melanoma setting as well as translational data demonstrating the induction of de novo neoantigen-specific T cells following treatment. A link to our ASCO investor event presentation is on the bottom of this slide.

Our Phase III development program also includes studies in adjuvant non-small cell lung cancer, including a Phase III study in patients without a pathologic complete response following neoadjuvant therapy as well as the recently initiated Stage I study evaluating Intismeran, both as monotherapy and in combination with KEYTRUDA Fulin.

Across the Phase II portfolio, the adjuvant renal cell carcinoma and muscle invasive bladder cancer studies are fully enrolled and continue to accrue events. We are often asked when we expect these studies to read out. Because both studies are event driven, it is difficult to predict the timing with precision. The renal cell carcinoma study has been fully enrolled since the second quarter of 2025. So it is possible that the threshold for the analysis could be reached this year. However, it is also possible that this occurs next year. It depends on the pace of event accrual.

The muscle invasive bladder cancer study completed enrollment earlier this year, and we currently expect the readout to be more likely in 2027, again, subject to the timing of event accrual. Non-muscle invasive bladder cancer study continues to enroll. As a reminder, this trial is evaluating both Intismeran with BCG in combination as well as Intismeran monotherapy.

Beyond the late-stage portfolio, our Phase I studies in adjuvant pancreatic cancer and perioperative gastric cancer are also fully enrolled, and we look forward to sharing data from these programs as they mature. Taken together, the breadth and continued execution across the Intismeran program reflect our commitment to evaluating this therapy across multiple tumor types and stages of disease.

Outside of Intismeran, we continue to advance a broad portfolio of oncology programs across cancer antigen therapies, T-cell engagers and cell therapy enhancement. mRN-4359 is in a Phase II program in first-line metastatic melanoma and second-line or later metastatic melanoma. It is also being evaluated in first-line metastatic non-small cell lung cancer. We are also advancing 2 additional cancer antigen therapies. mRNA-4106 and mRNA-4200 in a Phase I study in patients with advanced solid tumors. I'm pleased to report that dosing has now begun with mRNA-4200 alongside the ongoing evaluation of mRNA-4106.

In addition, mRNA-4194 has entered clinical development with dosing now underway in a Phase I/II study in individuals with Lynch syndrome. This program is designed to evaluate the potential of our technology in an earlier cancer interception setting. Our T cell engager, mRNa-2808 also continues to advance in a Phase I/II study in multiple myeloma with patients actively dosing.

Finally, in collaboration with Immatics, dosing continues in the Phase I study of mRNA-4203 in combination with the anzu-cel therapy. These programs demonstrate the breadth of our oncology pipeline and the continued progress we are making across several distinct therapeutic approaches.

Moving now to Slide 20. In rare diseases, our propionic acidemia, or PA program is fully enrolled in its registrational study, and we expect data from the study in 2026. For our methylmalonic acidemia or MMA program, as mentioned last quarter, we have deferred our decision on a pivotal trial until the PA readouts.

With this review, I will now hand it over to Stephane.

Thank you, David, Stephen and Jamey. Looking at the second half of the year. On the commercial and financial side, we remain on track for up to 10% revenue growth this year and also remain committed to improving our operational efficiency and achieving our new lowered cash cost guidance of approximately $4 billion. We also expect to build on last year's success, mNEXSPIKE launch and to continue expanding across the COVID patients around the world.

We look forward to approvals for mCombriax in Canada and Japan. And following the positive recommendation from the U.S. VRBPAC, we now look forward to the August 5 PDUFA date and potential approval of our seasonal flu vaccine in the U.S. We also anticipate approval for flu in Canada and Europe. From a pipeline perspective, oncology remains a key focus with important milestones ahead for Intismeran in multiple tumor types. As David said, a [indiscernible] study in PA, we expect data this year.

We have a busy second half of the year ahead of us. Success will come from disciplined execution across our key priorities, and I'm confident in our team's ability to deliver. We will be happy to host you in Cambridge or online for Analyst Day on November 12. Finally, I would like to thank our employees around the world for their continued commitment to our mission and for everything they have accomplished this quarter.

With that, operator, we'll be happy to take questions.

[Operator Instructions] Our first question comes from Salveen Richter with Goldman Sachs.

Two questions for me. One is in the case that the Phase III Intismeran melanoma study passes the first interim and progresses to a second and/or final analysis, how should we interpret that in the context of powering an event accrual? And how detailed will your disclosure be?

And the second question for me. If the trial is indeed positive here, how do we think about read through to other tumor types like lung in the context of tumor mutational burden but also the fact that you're talking about different neoantigens that play the key role there as you think about the cassette.

A lot of questions in there. I think with regard to the phase -- to your first question, if the Phase III INT study in melanoma continues it continues. We haven't disclosed the statistical powering or the thresholds for early interim efficacy. So I think I won't really address any more about that. With regard to the press release, I think it's too early. Let's see what the data is, and then we'll figure out what exactly the wording will be in the press release.

I think with your other question, if Intismeran is positive, what's the read through, I think it's a very important question, one I've given a lot of thought to. I think there are several important things we need to see here. One is what is the degree of efficacy that we see. Number two, are we confident that the mechanism that we see can be validated. And I think with regard to that, the answer that -- the data that we've shown at ASCO confirms that we do -- when we give the neoantigen vaccine, we do see neoantigen-specific T cells, and we know those T cells can kill the tumor.

So I think that we have move to other tumors where checkpoints do work, and we know that this mechanism that I just talked about is the mechanism by which other checkpoints do work. And so since checkpoints work in lung cancer, and bladder, I think that gives us increased reason to believe in bladder. I think the big question comes out in tumors where checkpoints don't work and that's pancreatic cancer into a lesser degree, gastric. So that's why we're conducting Phase II trials and Phase I expanded trials in those other tumors.

And Salveen, maybe on your first question, just to fill in a little bit. As David said, we haven't disclosed statistical analysis plan. But suffice it to say, it's an interim analysis, and there are still subsequent planned analyses. And ourselves with our partner, Merck designed the overall study to evaluate the full commercial profile of the product. And so we do think that there's a commercially valuable product that could emerge maybe only in the final analysis, but that wouldn't meet the criteria for early efficacy at the interim. And obviously, we'll move forward with the study accruing events to characterize that, but we do still see there is an opportunity there.

Our next question comes from Tyler Van Buren with TD Cowen.

Another one on the Phase III melanoma INT readout. Forgive me, but I have to ask for more granularity on timing. How close are you to achieving all the events required for the first analysis? What percentage of events for the first analysis have been observed? And what's your level of confidence that we'll get the data readout this year.

Tyler, good to hear from you. So we're not going to disclose any more details around the specific timing aside from that second half in terms of powering. I think in terms of confidence, the fact that we had this very strong randomized Phase II data that had consistent efficacy in all the subsets was very promising to me. And the fact, as I mentioned, that the translational data confirms the mechanism of action. I don't think that there's anything else that can be done ahead of a randomized Phase II. And so that's what we're conducting.

Got it. And if it succeeds in the Phase III, do you expect standard review? Or is a priority review possible? And can you remind us what your capacity to treat patients would be on approval?

So priority review will always be subject to the data, but we certainly hope, certainly, if we're successful that it will be under consideration and then an accelerated review process is possible. As David said, we are we're highly confident we'll get that data in the second half of this year or at least that interim analysis will be conducted. And if that is positive, again, we don't have the data yet. Then we would obviously make the case for an accelerated review, and we think it'll be supported by any profile that looked like the Phase II.

Now as to commercial capabilities, we have been establishing the manufacturing in Massachusetts and a dedicated facility that will be able to support launch. We believe that facility can support our commercial profile that ourselves and our partner, Merck, have articulated for several years to come. We hope we have to build more in the future if there's more demand, if all goes well. But we do believe we can satisfy the initial indication out of that facility and that we'd be ready to go next year if all went perfectly to plan.

Our next question comes from Ellie Merle with Barclays.

Just 2 for me, 1 on flu and then 1 on INT. Just in terms of flu, I guess curious if you've had any discussions with the FDA regarding strain selection for 2027, specifically, if there's a mismatch in the selected strains in the beginning of the year with the circulating streams later in the year, would you be able to update your strains the other flu vaccines wouldn't be able to. Basically, just curious if this came up at all in the discussions and how you're thinking about this as a potential possibility in 2027.

And then just a second question, INT interesting analysis on the immunogenicity that you presented at ASCO, curious if there's any learnings in terms of how you think about the algorithm for the selection of the neoantigen since there seems to be variability between patients in terms of the number of neoantigens that patients had immune responses for. So curious how you're thinking about that and potential ways that you could theoretically optimize the selection of the neoantigens.

Thank you for both questions. So I'll take the flu one and obviously have David take INT. So first, in terms of discussions with U.S. FDA. The answer is yes. Those have happened. In fact, they even happened at the advisory committee. And so there was active discussion both between the agency and the committee members as well as the company on how we would address a potential mismatch or a late strain selection.

Our demonstrated capability in the COVID context is less than 2 months, and so strain selections have happened as late as early July in the history of COVID, and we've been able to make a full vaccination season to work with millions of doses. And that was discussed at the Vera and obviously had been part of the basis for pursuing accelerated approval in our discussions with the agency.

Now the process by which that would happen would ultimately fall to public health to articulate. And so FDA, CDC, WHO, others would need to accommodate a late strain selection if they wanted to. And those discussions, I would describe as in the early stage. The first step is to get the product approved. So there's a potential to address such a situation. And then the second step was to work closely public health to define how we would do that and under what circumstances they would want us to do that.

Ellie, with regard to your second question, it's a very interesting question. So we see that about 29% of our neoantigens that go into our cassettes in general, in general are immunogenic. And the data that we showed is that for the patients that we showed, there were between 1 to 18 neoantigens that were reactive in each patient. So the good news is you only need 1 neoantigen reactive T cell in order for there to be activity. Of course, the more the -- in theory, at least be more the better.

In terms of what we're doing, to improve. We do have an ongoing program to try and improve this algorithm. In fact, we're using artificial intelligence to try to develop the next algorithm. I think the key thing will be when we get an efficacy readout linking our algorithm to efficacy. I think that will be the next important step here.

Our next question comes from Terence Flynn with Morgan Stanley..

Great. Maybe just on your flu vaccine, I was wondering if you could provide any update in terms of your thoughts on potential pricing either some of the inputs or how you're thinking about analogs there? And then on the norovirus interim, just any insight in terms of what that means for potential effect size.

Great. Thank you for both questions. So first on flu pricing, look, it's a little premature. Those conversations are ongoing, but it's all subject to us getting the product approved, obviously. When we think about the positioning of that product, at least on our own with the data, we feel confident about that profile given the relative vaccine efficacy demonstrated in the Phase III trial. It's been published in the New England Journal relative to standard dose that it really is in the enhanced category from our perspective and importantly, offer some features, for instance, the lack of egg adaptation that are even more specialized than some of the available therapies.

And so we will be assessing from a health economic perspective, the potential value of those and in discussions with payers and other bodies, making sure that we characterize those potential benefits as we think about pricing in the future. But again, first step is let's get the product approved, which we're working on right now.

As it relates to norovirus, there will not be much more I can say than what we have right now because we are still -- the study is blinded and continuing. We have not previously disclosed the statistical analysis plan associated with it, so it would be inappropriate to do that now. Suffice it to say what we are doing is we know we will need additional cases from a further cohort to strengthen that statistical analysis and we're working hard on preparing to stand up that part of the study.

Our next question comes from Cory Kasimov with Evercore ISI.

I wanted to also ask on Intismeran but on the RCC front. And can you speak to the immunicity data that you have that and it gives you confidence that Intismeran works as well in low TMB RCC as what you've seen so far in melanoma and non-small cell lung cancer.

So that trial is still ongoing. So we don't actually have that data yet. But we will be showing some data later this year on other tumors that are hard to treat. And I think the fact that we can demonstrate immunogenicity in, for example, pancreatic cancer, I think, leads us to believe that we can identify neoantigens and creates a neoantigen vaccine for RCC as well. I think we have confidence in that.

And I think the one thing I'd add is at least in the context of our Phase II melanoma study, which is through 5 years, we had previously published that or presented that TMB did not correlate with a difference. In fact, low TMB melanoma -- adjuvant melanoma patients had a consistent hazard ratio as those with high. So it gives us some reason to believe that, that will translate, but to be fair, that is in the melanoma context. And as David said, we're still waiting for data in other histologies.

Yes. And I guess to be clear, I was wondering kind of where the confidence came from recognizing you don't -- we're waiting on that data later this year or next.

And I think it comes from the lack of a role of TMB high versus low in driving the effect size that we saw in the Phase II and the totality of data we have around that.

Our next question comes from Andrew Tsai with Jefferies.

So just thinking about your Horizon 2 wave of assets coming. First, for the IDO compound, sounds like that could have pivotal data in 2027 since you mentioned it as a revenue contributor in 2028. So can you talk about what the approvable bar in first-line, second-line melanoma is? And then you also have a T cell engager program that you announced at the Science Day that I believe could have data at year-end. And so I'd be curious to know in a seemingly refractory population, would a positive data look like in myeloma? And is there a strategy for you to go upstream.

Andrew. So Horizon 2, so I'm glad you picked up on that. 4359, which is the IDO, PD-L1, is a very interesting program. There was proof of confidence from a randomized study from another company, which was very interesting. For us, we saw very intriguing data, which we showed last year, and we had a follow-up first-line data set earlier this year.

What we're doing now in the expanded -- in the ongoing Phase II expansion is to confirm that signal is the signal that we saw real, and is there a path forward based on that signal. And I think I don't want to get ahead of whether it's a pivotal or not. I think let's first confirm the signal. And identify what is the best opportunity in melanoma? Is it to go first line? Or is it to go second line plus.

I think as we all know, the bar in second -- in terms of your question about what is the bar for approval in second line for single-arm trials, it's a moving target as we see. I think suffice it to say that you have to show sufficiently high response rates that have sufficient durability. And I think no one really exactly knows what that definition of sufficiently high is.

In terms of first line, we do have an ongoing combination with nivo/ipi. We showed data earlier with pembro plus 359, which was very intriguing. But we have to remember also that in single-arm trials, especially in the first-line setting, the combination of 2 active agents may sometimes be hard to disentangle what the activity is through.

So we're looking for, can you safely combine them in first line? Do we see some signal of increased activity. And in second line in the PD-1 relapsed refractory, we're looking, do we see sufficiently increased signal of activity above what we would expect to see. And in particular, in patients who progressed on prior PD-1s are we seeing durable responses. So more to come on that next year.

With regard to 2008, which is the T cell engager program, this is something that's very interesting. So multiple myeloma, obviously, has a number of T cell engagers, and we recently heard this week from J&J, very exciting news about the first combination of 2 targets. That's the first time ever T cell engagers have been combined.

And so for us, the reason we're excited is we have the first 3 T cell engagers in a single product ever being studied. And as you mentioned, we're setting this in relapsed/refractory myeloma in patients who progressed on multiple CAR Ts on multiple T cell engagers, essentially patients who have no other options available.

And so we're going to be looking -- first of all, can we produce 3 T cell engagers, number one? Is it safe and well tolerated number two, -- and is there evidence of complete responses and partial responses and how durable they are. That's, I think, what we're looking for. But I'm quite intrigued and excited about both of these programs.

Our next question comes from Courtney Breen with Bernstein.

Just a couple of others want to push a little bit further on norovirus and the update there. Obviously, the question that I think many of us are asking is, is this enrollment? Is this an efficacy? Or is this an event situation. And so perhaps if you can help us understand kind of the overall event rate relative to expectations and what might be driving that.

And then the second question is a little different. You obviously just announced a new Chief Commercial Officer into the company. And you've obviously got kind of a broadening business, particularly as we look at the pipeline and the number of readouts over the next couple of years. Can you just help us understand what are the top priorities for the Chief Commercial Officer over the next 6 months? And what might be the changes or the evolution required longer term with -- in the commercial structure to support this evolving business.

I'll take the first question and then obviously turn it over to Stephane to handle the second. The first on the question of Noroagain, limited in what I can say because the trial remains blinded, but suffice today, we have -- we are going forward with another season this year. We have been able to enroll the trial, which I think was your question in the cohorts. But the epidemiology of the primary endpoint cases has been a little bit slower coming.

As we had previously discussed, some of that in the first season for that trial, was the result of a unique outbreak of a different set of strains of norovirus that were not contributing to that primary endpoint. And so cases have came a little bit slower in that season. And for that reason, we were a little bit slower to achieve the interim analysis than we intended. We ultimately did though power the study for a final analysis, a full number of cases. And really, what we're doing now is we've kind of gone through that second season, been able to conduct the interim analysis is we're preparing for that third, which will be the third winter this year.

This has happened with other vaccines in the past. If you think about flu vaccines, they often have to do multiple season studies to accrue sufficient cases and did ultimately happen to us here or at least appears to have happened to us here. And so for that reason, we're getting ready to stand up that new case accrual. It's unique and that we have to enroll new patients to get new cases because it's a seasonal vaccine, a seasonal infection. And ultimately, we will go one more season we expect this winter for norovirus 1403.

Thank you, Stephen. Courtney, so in terms of context, as we talked about in the press release when we announced the position of Ester, basically, if you look at the business, as you know, we have 3 products on the market today. We have since the spring of fourth product approved and mCombriax, the Fuco/vit combo, which we are preparing the launch for 2027, potentially a fifth product approved in H2, which, of course, flow as we talked about before. So as you can see, just what is just in front of us is a very, very large growing ID pipeline of product.

And the other piece, as you know, is Europe, as you know, we have not been able to participate in UPI market because of an exclusive partnership that the set up during the pandemic, but this partnership expires, as we've said before in 2026. So we really see Europe as a very important growth driver for us. And as you in Europe, the markets are all very, very different. So there's a lot of complexity there.

And then, of course, there is INT. As we said, we expect Phase III data potentially in the second half of the year, given the trend. And so as you can imagine, Moderna and Merck colleague have been very active. Stephen talked about manufacturing a minute ago, but we have been very active on the commercial side of the house in terms of medical affairs, marketing, commercial. And so that's another piece where steals going to be helping and leading working hand in hand with Merck. And of course, there's also a rare disease with PA.

As you know, we've said PA because it's a time-driven Phase III, we should have data this year. Of course, it's partner [indiscernible], but we're going to be, of course, working with a partner to ensure a great launch. So if you look at the next few years, Stephen has a good slide earlier in the presentation, looking at the geographic expansion including also in Asia and Latin America, the product expansion. So there's a lot to do.

And so as we are gearing for the growth stage of a company coming ahead of us, we thought that this role was important. And also the new role for Stephen, who is really overseeing ID, INT and rare from kind of general management to make sure that all the functions are integrated together. So it's just us getting ready for the next stage of growth of companying.

Our next question comes from Michael Yee with UBS.

We have 2 questions. First is on INT for David or Stephen, at the interim analysis, while you're not going to disclose the powering, if you go back to your Phase IIb, it was statistically significant, but you were using a 1 site in alpha of 0.1. And so that's a much different hurdle rate than, say, traditional interims that you might be using here. So to what extent that people have too high expectations for the interim versus the final where you could have a nonproportional hazard ratio where the effect size gets better over time due to the way the drug works. That's question number one, is the thought around the FX side is getting better over time in a nonproportional hazard ratio.

The second question is on the COVID flu combo in Europe. Can you just remind us at what point you engage in conversations to you contracting for that? Because I guess you could have actually revenues for that in '27 and when we get visibility on that?

Michael, I'll take the first question. So we are not going to disclose anything on the statistical analysis plan. But I do think there is maybe 2 key points to highlight. The first is if you remember back to the Phase II study, of course, updated at ASCO. There was, as you said, somewhat of a nonproportional hazard with about 12 months for really strong separation to occur. The good news in the Phase III study, which was designed with Merck, who has a lot of expertise in melanoma is that it requires also a minimum of 18 months follow up.

And so every patient has been followed way beyond where they where there was before -- after -- before -- after the separation occurred. So I think that with regard to that, that gives us increased confidence.

Stephen, the second question?

Yes. On the question of combo in Europe and negotiations, so with approval, we can start the pricing negotiations with many governments where that is a separate process. And so in most cases, we have then submitted those HTA documents as health technology assessments or the supporting pricing negotiations are underway. In some cases, you need recommending body, sort of analogous to CDC recommending body recommendations before you engage in that process. And in all those cases, we've been supporting those. Some of that has been happening publicly.

And so you'll see recommending bodies in countries like Germany, which [ SICO ] others have begun to contemplate the combo vaccine and then as I said, in other countries. We're -- we've begun that pricing negotiations. There are first instances of pricing being issued in a couple of countries, and we'll continue that process through this year. Once that's there, we will have achieved market access, and then we'll be in the process of engaging in tenders or in countries that are not tender countries in Europe in commercialization and straightforward commercialization. About half of those markets will be more tender related.

Some of those tenders will deal with 2027. Some of those tenders will deal with 2028 because the timing of their flu or COVID tenders or maybe a year forward. And we'll provide more clarity on that as we get into that year. So we would expect some contribution from traditional commercialization markets as well as tender markets beginning in 2027. But the full effect really probably not felt until 2028 and maybe a little bit beyond, depending upon what individual countries require from real-world effectiveness data or other things post approval to support market access.

So we're excited to be approved. We have a lot of work to do in Europe to drive that growth. We think that there's real enthusiasm for the product. Obviously, we have it ourselves. And we're working hard to start impacting as early as '27, but really build the business over the couple of years thereafter.

Our next question comes from Geoff Meacham with Citigroup.

I just had a couple of quick ones. I guess for Jamey, the 10% revenue growth guidance for the balance of the year. Maybe just give us a reminder of the puts and takes of that when it comes to different geographies? Are there still more contracts or more sources of potential new pockets of demand.

And then on the rare disease portfolio, you guys have completed enrollment in 39 27. Just wanted to get a sense for what determines the timing, maybe the regulatory usability of the readout, I wasn't sure what you guys are looking for from an effect size or from clinical meaningful standpoint.

Yes. Thanks, Jeff, for the question. I'll take the first one on revenue. So we're sitting pretty good after the first half year in terms of $0.5 billion in revenue, roughly 70% international, 30% in the U.S.. And your question is getting at, where is the upside? Where is the variables to the second half. So I just want to start by saying, if you look at our first half, we are up almost $300 million versus the prior year. So if we are flat in the second half, that would actually be above 10% growth for the year.

So now what are the variables to the second half. If you look at the -- what we said is we're basically 50-50 for the entire year, U.S. versus international. So obviously, having a higher percentage in the first half international, that means we have a higher percentage in the U.S. And that's really where the biggest variable is. So across the globe, we've basically contracted. We have to execute. There are some countries that have minor vaccination rate. Some shipments could happen into the year or some could go into the first quarter of the following year, but I would call that relatively small.

I think the biggest variable comes down to the U.S. And we've provided for, as I mentioned in my prepared remarks that we have provided for a vaccination rate decline, particularly in the U.S. And so the biggest upside swing is if it is not as big a decline as we projected, then we should have upside in the U.S. If it's worse than we projected, then obviously, there would be a downside to that. And so if you just kind of think about the second half in terms of broad pictures, and I kind of said this on the last call, is in the second half international, last year, we had no U.K. volume and not some of the strategic partnerships volume.

This year, we will supply some of the strategic partnerships that we have, and it's quite material. And that's basically the upside that is offsetting the provision that we put in to the U.S. in terms of vaccination rate declines. So for the most part, we're really confident we've got a substantial growth through the first half year. If we are flat to last year with international growing and offsetting the U.S. decline, then we should be above our 10% guidance. and the biggest variable at this point is just what is the size of the U.S. market.

With regards to the question on PA, the time -- it's around 20 patients were enrolled and the primary endpoint, which is metabolic decompensation events on treatment relative to pretreatment so each patient serves as their own control is based on a 12-month follow-up. And so that should happen sometime in fourth quarter. And just as a reminder, in our prior releases, we showed about a 60% to 80% efficacy with our therapy. And so that's why we have confidence or hope for this trial.

Our next question comes from Myles Minter with William Blair.

My question is just one on clarification. I think Dr. Colino at ASCO mentioned in PAT001 that approximately 2/3 of patients would have micrometastatic disease. It's a little bit confusing to me as to whether that was just restricted in the Stage III patients. So that was the overall trial. So just wondering whether you can confirm or adjust his comments that are set on record. And then secondly, just the potential impact of going from a third micrometastatic in the Phase I/II study to 2/3 into PAT001 and any sort of impact that we could see there.

So I don't recall exactly what he was referring to in that statement. But the trial -- we haven't released the baseline demographics of the trial. So essentially to say that it's Stage Ib to fully resected Stage IV. And in terms of why we believe we can go to that broad eligibility based on the Phase II data, it's because when you look at the subsets of -- from an efficacy standpoint, they were all consistent. And secondly, we know that the earlier you go, i.e., Stage IIIa and then Stage IIb and IIc.

The immune system should be healthier, the tumor burden should be even lower. And so the ability to induce a T cell response and to have those T cells kill, whether it's micrometastatic or still even before it's micrometastatic should still be there. So I think that's what I would say. I'm not -- I don't remember exactly the point about 2/3 micro metastatic.

The last question comes from Jessica Fye with JPMorgan.

Just wanted to confirm 2 things on INT. First, if the interim in the Phase III adjuvant melanoma trial passes without stopping for efficacy. How will the Street learn about that? I guess, is the study simply continuing a material event that we would hear about right away? Or would we just hear about that maybe later in normal course updates.

And then the second one on INT. Is the translational poster at ASCO had a relatively small number of patients relative to the number who were in the Phase II? I'm curious if you know what the data looks like in the broader study population.

So we will be issuing a press release on that data, Jess for the interim. And with regard to the second question, the reason that the data set on the translational was only 7 patients is because that in-depth T-cell antigenicity required leukophoresis, which is a little bit more burdensome to the patients than just collecting a tube of blood. And so the patients have to consent to that.

And we do hope to expand that because we do think that, that degree of biomarker analysis is important for understanding the mechanism of the drug. And actually, we're also looking at ways and we're exploring ways to try and disentangle T cell immunogenicity without having to do leukophoresis. So that's still exploratory, but more to come on that. That's the reason why there were only 7 patients.

This concludes our Q&A session. I'd like to turn the call back to Stephane for any remarks.

Thank you very much, everybody, for joining. We look forward to speaking to many of you in the coming days and weeks, and have a great day and weekend. Bye.

Ladies and gentlemen, this does conclude today's presentation. We thank you for your participation. You may now disconnect, and have a wonderful day.

Good morning, and good afternoon for those of you that are following us from overseas. Thank you so much for joining us today. On behalf of my colleagues and I, welcome to Moderna's Science Day 2026. Before I start, let me remind you that we'll be making forward-looking statements. You can find those online at your discretion. Moderna's mission is to deliver the greatest possible impact to people through mRNA medicine.

And since the beginning, we built an mRNA platform based on 3 key pillars of science: mRNA science, which is the mRNA molecule itself, delivery system, how we get the mRNA molecule into cells and very importantly, also manufacturing processes where there's a lot of know-how that we developed over the years. But because mRNA is an information molecule, what is very exciting about this platform is we can create modalities, families of medicine that use exactly the same technology features so that we can replicate very quickly.

As you can see on the pictogram on the right? We basically start with a leading product to go into the clinic as a sentinel programs to learn about the modalities. And when we have clinical signals, we can scale very quickly because we use exactly the same technology components. And that's what is exciting about the platform. And of course, you are all very familiar with 3 established modalities that we built over the years, an Infectious Disease Vaccine modality with approved products, products under review and also products that are in the clinic.

Intismeran modality going after cancer and a rare liver disease therapeutics modality, all coming from the same mRNA platform. That established modalities is what we consider horizon #1, is driving the business today and in the coming years. But of course, we're working hard with the team to invent the future. And today, we want to talk to you about Horizon 2, the modalities that are today in the clinic, dosing patients that we want to share with you some of those programs and what's coming next.

And the other piece we want to talk about as well is Horizon #3. The future modalities that the team is working hard at that we believe should be testing in human by the end of 2027 in the next 18 months. But we're not stopping there. David will also spend time talking to you later this morning about what we're doing with AI to keep learning faster and faster to invent the next generation and the next generation of modalities.

And our AI strategy in science is based on basically 2 vectors. One is an mRNA technology vector that we will describe and talk about. And of course, there's a biology vector where we can leverage models that exist outside in the industry. So in a minute, David and Rose will come up to talk to you about mRED. And then Kristine, Professor Church and Sarah will talk to you about the cancer-antigen therapy modality. We'll take a small break, and then we will come back. Lin will talk to you about our T-cell engager modality. Then Sumana will talk to you about our EBV therapeutics in multiple sclerosis.

Lin will come back to talk about in vivo CAR-T for autoimmune disease. And then David will try to wrap it up to talk about what are the exciting science he and his team are doing to invent the future modalities. I'll come back with a few slides to close and then David, Rose and I will take your questions.

So with this, let me turn over to David and Rose.

Thank you very much, Stephane. So I joined about 3 or 4 months ago. And I think today, you'll begin to see why I joined the company, why I'm really excited about the potentials here at Moderna. But first, why are we creating an mRED, Moderna Research Early Development? The riskiest stage in the drug development continuum is the early clinical phase. And why? It's because we need to adapt to data that emerges quickly, number one.

And number two, teams need to be able to stop drugs that are not going to work to accelerate drugs that have potential. And it's very hard in the traditional scheme for teams to do that on their own. And this is compounded when you have multiple layers of governance and levels between them and senior leadership. So based on my tenure of working at 4 companies, 2 large pharmas and now 2 biotechs, I think there are 2 major levers that can be done structurally to enhance rapid innovation.

And number one here is creating an mRED leadership team, which is comprised of research, development and CMC. And by the way, we include CMC because mRNA and lipid nanoparticle science is evolving as rapidly as our biology understanding, and we need to have CMC at the table as well. But we're having this mRED leadership team with no barriers or connections, the teams directly report into the senior leadership.

And what this will do, as you see here, is it connects the senior leaders to the data directly. It allows us to accelerate decision-making that is fast, data triggered, and very clear with no guesswork by the teams involved. It ensures that we have a dedicated focus on bringing innovation in this next generation and very importantly, it enables us to make science-driven decisions to accelerate where necessary, but also to stop drugs that are not going to be promising.

The second major structural element that should be done is to marry early clinical research, early clinical trial development with research. And I think there are 2 major reasons why it's important to do this. First, early clinical research is actually closer to basic science research. We're getting data based on patients. We need to interrogate the data, and we need to adapt based on what the data is telling us as well as external data.

In late phase, you don't want to do that. You design a Phase III trial and you do not want to react and change rapidly in a rapid fashion. The second reason, and I think this is inherent to the modality discussion that you heard is -- we have these modalities with sentinel programs. And these sentinel programs are in the clinic, and you'll hear about them today. And these sentinel programs inform the other programs that share the same modality, whether it's T-cell engagers, cancer-antigen therapy, you'll hear about it today.

And so it's very important to make sure that the science that the clinical insights we're making in early phase are rapidly translated into the research and vice versa. The new insights we're making in research are embedded into the early clinical stage. So I think this mRED structure, which we are now rolling out will help Moderna accelerate where necessary, but also stop programs that are not going to be promising.

And with that, I'd like to call up Rose, who will talk more about the mRED portfolio.

Thank you, David. So we wanted to share a little bit of insight into how we actually craft this early portfolio. And so the first thing to say is that we want every asset in our pipeline to start out with a competitive advantage. So we, as a portfolio strategy, look for applications where the use of mRNA and LNP platform technology offers a competitive advantage to start. That helps us advance differentiated programs. So for example, you'll see that we utilize multiplexing in our pipeline.

And we specifically say multiplexing and not combination because from a regulatory perspective, we are able to encode and deliver multiple proteins in one therapeutic, and it's not considered a combination. It's considered one potential drug product. You'll see this in the Infectious Disease vaccines that we already have licensed, and you'll see it in our early pipeline today in the form of our T-cell engagers. We also have an advantage in being able to express intracellular and transmembrane proteins, which, of course, are not truly accessible, for example, if you have a recombinant protein platform.

Now you'll see demonstration of this already in our rare disease pipeline, which has advanced all the way through pivotal studies, but you'll also see it applied today for our in vivo CAR-T program. And then, for example, on the T-cell response front, we know that our platform can generate very robust CD8 and CD4 T-cell responses. That's been well demonstrated through our INT, our individualized neoantigen therapy program.

And you'll also see it today in multiple applications, both in oncology and now in autoimmune therapeutic space. So that's the first pillar of how we think about crafting the portfolio. We also think about how we're going to get the most leverage out of the investment that we make in R&D. And so we look for modalities where we can see multiple follow-on programs where the learnings that David mentioned that we're generating in the clinic can help derisk those follow-on programs. That lets us get the best return on our investment.

So what you'll see is we'll start a modality. We'll bring an initial program into the clinic. We often use the term sentinel program for that first program. We learn about how our technology performs and whether the biology that we were hoping to access is performing the way we anticipated. When we see that, we feel like that modality is more derisked, and we're willing to advance more programs behind it at a faster pace.

And then finally, this is the pretty early part of the funnel for our pipeline. So we like to keep quite a bit of diversity and balance. So you'll notice that we have multiple different modalities that utilize different types of our platform technology and are also looking at different therapeutic applications. And this is somewhat intentional. We want the very early part of the pipeline to also have uncorrelated risk in many ways so that we have multiple independent shots on goal as we're building the pipeline through that funnel.

So we won't talk through all of these modalities today, but to give you a sense, Horizon 2, these are the modalities where we have a program already in the clinic, generating that clinical data and moving toward clinical proof of concept. Horizon 3 that you'll see here is earlier. These are the programs that we're looking to take to first in human by the end of next year. And then while we don't talk about programs that are earlier than that, you will hear some about the technology that we're continuing to advance, and that's critical to make sure that Horizon 3 stays robust and diverse. You can also see across Horizon 2 and Horizon 3, how we gate our investment.

So in Horizon 2, in some areas where we've seen early encouraging clinical signal, we're willing to advance multiple programs in that same strategy, whereas in Horizon 3, we're typically looking at one sentinel program to move into the clinic, generate data, give us that confidence, and then we will bring in more programs behind it. So with that, I'm going to hand it over to the brilliant, Dr. Kristine McKinney, who's going to talk about our cancer-antigen therapies.

Thank you so much, Rose. And yes, I'm delighted to be here today to share with you a little bit about the emerging cancer portfolio, including our Horizon 2 that are entering and in clinic. So yes, my name is Kristine McKinney. I lead the Cancer Vaccines and Bioinformatics Research team here. And I'm going to walk you through a few of these cancer-antigen therapies. Sarah will also walk you through another one. First 2 that we are developing in solid tumors, mRNA-4106 and mRNA-4200 as well as our first foray into the preventative space with mRNA-4194.

Okay. So as Rose has been highlighted, we're very excited about the data coming out of the Intismeran program. We were really happy to share those -- the 5-year update of the Phase II at ASCO recently as well as showcase some of the data demonstrating the depth and breadth of the immune response that this drug is able to inspire in the form of a translational poster.

And as Rose highlighted, this means that we've de-risked this concept, and we're investing very steadily behind it to make sure that we bring this technology to the greatest impact in patients. And so just to orient you to how we're thinking about developing the next-generation cancer antigen therapies, I wanted to highlight that there are different opportunities in different tumors in terms of targets.

And here in the red boxes are the ones we're going to talk about today. I'm going to first start with the tumor-associated antigens. And just to reinforce that these -- this class of antigens are actually non-mutated, they're shared, and they are either misexpressed or overexpressed in malignancies. And so yes, again, these constitute Horizon 2.

So to start off, let's talk about mRNA-4106 and mRNA-4200. And you'll see these design principles flowing through the entire portfolio. So I wanted to take a second to double-click on those, how we're designing these cancer antigen therapies. So first of all, we are optimizing for population as well as individual level efficacy. Here, we're leaning into the aforementioned ability of our platform to multiplex. This really allows us to inspire the broadest immune response across broad populations.

Second of all, we're managing the biology risk. As I highlighted, there are different classes of tumor antigens, and we're really thinking about prioritizing validated antigens and optimizing for immunogenicity. Third, of course, safety is first and foremost in our mind. We're making sure that we're safely exploring that design space, again, in a data-driven manner. And fourth, in order to enable the portfolio strategy that Rose walked through, we are enabling optionality. So we are including targets that are also expressed -- that are expressed in a wide variety of tumors that allows us the ability to expand into different malignancies should the data indicate that would be wise.

Okay. So now -- sorry. Okay. So just to talk again about the design and mechanism of action for mRNA-4106 and mRNA-4200. On the left, you'll see the hypothesized mechanism of action, which is the mRNA encoding the antigens that we select, these are multiplexed, are formulated into LNPs, which are then administered intramuscularly just like in intismeran. Those LNPs are taken up by antigen-presenting cells, translated, processed and presented on MHC Class Is, which you see the little Y-shaped molecule that's sitting on the surface of the APC there. That serves as a signal to activate T cells in an antigen-specific way.

So those are now armed to go find and kill tumor cells anywhere in the body. Okay. So in particular, how do those design principles I just highlighted play out in mRNA-4106, so and mRNA-4200. So the targets are validated across many human tumors, as well as we look at both expression in tumor tissues and normal tissues in humans. That is RNA protein as well as peptide presentation using immunopeptidomics mass spectroscopy technology.

In addition, we generate preclinical data that confirm successful antigen processing and HLA presentation as well as immunogenicity in the particular -- once the antigen is formatted. And we -- and just to reinforce that we're using whole antigens here. So these are entire protein sequences that gives us many, many possible peptides that can bind across many HLAs across populations. Also, these are multiplexed products. So we -- this, again, reduces the risk of tumor escape through single antigen loss as well as improves the coverage in case of intratumoral and/or inter-patient heterogeneity, really trying to cover a really broad space here.

In addition, they are applicable across multiple tumor types. So we have selected targets that are expressed in multiple tumor types. Again, as we de-risk and prove immunogenicity in humans as well as efficacy, we will be able to expand these rapidly into other histotypes. So to show you how we're entering clinic with these. So mRNA-4106 entered clinic last year in a single monotherapy dose escalation. It's been progressing very well and without any safety findings.

And mRNA-4200 is coming close behind. We are developing these 2 in tandem. So mRNA-4200 will enter and importantly, we'll leverage the data that we've generated in mRNA-4106 to start the monotherapy dose at a safe and efficacious dose. So we don't have to go through the whole dose escalation. After the first dose, we will then combine with pembrolizumab in cycle 2 and continue dosing the combination. And of course, as all Phase I, safety and tolerability are first and foremost, but we will also be exploring, of course, efficacy as well as immunogenicity in these studies.

Okay. Now to switch gears and talk a little bit about mRNA-4194, which again is our first foray into the prevention space. And in this case, these antigens are actually exquisitely tumor-specific, very much like Intismeran, but they are derived from frame shift mutations. And I'm going to talk a little bit more about the provenance of those antigens and why they come into play in the following slides, maybe.

Okay. And like mRNA-4106 and mRNA-4200, this has a similar mechanism of action. So the only difference here is that the mRNA is encoding frame shift antigens, right? So that the T cells that it activates are then activated to kill any cell that expresses a frame shift peptide. So that could be a tumor cell or importantly, a premalignant cell. And that really is the biggest difference for mRNA-4106, right? Is that it's opening up the prevention setting.

So in order to help you understand the context of Lynch syndrome as well as the patient journey and what patients live through, we have the opportunity to hear Dr. Church explain that to you all. David Church is an esteemed collaborator. We're so lucky to have him on this program. He's really a world-renowned expert in this field. He's a physician scientist with numerous titles at Oxford, which you can see listed here. But I think I really want to reinforce that he is a person who's not only pushing the technology and the science, but he's also making sure that those are integrated into clinical practice in NHS and has multiple appointments to do that in a regional way. So without further ado...

Thank you, Kristine, for the kind introduction and the invitation to present on Lynch syndrome. My name is David Church. I'm a Professor of Precision Oncology at the University of Oxford, and I'm a Cancer Research U.K. senior Cancer Research fellow. In the next several minutes, what I'd like to do is talk you through Lynch syndrome, give you an overview, update you on epidemiology, how we diagnose it in the U.K. and its management and then cover the trial that we're really excited to be starting in partnership with Moderna.

So Lynch syndrome, is a condition that many of us have not heard of, but in fact, is a common condition. It affects more than 300 people globally. That's 175,000 people in the U.K., more than 1 million people in the U.S. And at the molecular level, Lynch syndrome is caused by germline defects and inherited defects in one of several genes which are responsible for DNA mismatch repair. This is a process that ensures our DNA is copied accurately when our cells divide.

And the failure of that due to the defects in Lynch syndrome causes error-prone DNA replication. And errors in genes that regulate cell growth, cell death can lead to cancer. And so people with Lynch syndrome have a grossly increased risk of colorectal, endometrial, and other cancers, as you see in the schematic here on the right. And also, as a consequence of that error-prone DNA replication, they're also prone to getting these stereotypical frame shift mutations. So mutations that change the sequence cause insertion of [indiscernible] encoding DNA and cause a frameshift and novel open reading frame, which is important as we'll come to in a second.

Management for Lynch syndrome relies primarily on surveillance with aspirin used by some people after the CAPP2 study to reduce the risk of colorectal cancer and possibly other cancers. But coming back to those frame shift mutations, these are important, particularly as we talk about the clinical trial that we're starting because they can create potentially targetable source of cancer-specific antigens. These are predictable alterations, which are present only in pre-cancers and cancers and people with Lynch syndrome other mismatch repair deficient tumors.

So to focus on the epidemiology of Lynch syndrome, there are 4 main mismatch repair genes that are defective causing Lynch syndrome, MLH1, MSH2, MSH6, and to a lesser extent, PMS2 and then rarely deletions in EPCAM, which cause silencing of MSH2. The cancer risk varies according to gene. As you see here, the risk of cancer is highest in MLH1 and MSH2 carriers. This is reflected in surveillance guidelines. MSH6 carriers have a lower risk of these tumors and overall, but a particularly high risk of endometrial cancers for women that carry these variants.

And you see here at the bottom, the takeaway, the lifetime risk of cancer very high in these individuals. And clearly, despite surveillance, despite aspirin, a huge unmet need for reducing cancer burden in this at-risk and common population. So recognizing the need to identify Lynch syndrome to reduce that cancer burden in this population over the last decade, we've put a number of steps in place in the U.K. to identify Lynch syndrome from cancer diagnosis and then more broadly.

Going back to 2017, NICE, the National Institute for Health and Care Excellence in the U.K. recommended that all colorectal cancers were tested for Lynch syndrome using either immunohistochemistry, so protein staining for the proteins where the genes are defective in Lynch syndrome, or microsatellite instability. This is a genomic readout of mismatch repair deficiency and consequently potentially of Lynch syndrome. And so we've been doing that to identify the 4% of colorectal and endometrial cancers or colorectal cancers that are caused by Lynch syndrome.

In 2020, the guidelines were updated to also cover endometrial cancer. So here, the testing is only immunohistochemistry because mismatch repair deficiency caused by Lynch syndrome doesn't always cause microsatellite instability in endometrial cancer. And in 2021, NHS England published guidelines to help clinicians streamline Lynch syndrome testing pathways as follows: So we do reflex testing on all colorectal and endometrial cancers where the testing suggests that it could be caused by Lynch syndrome. The follow-on step is to do germline testing to see if there's a pathogenic variant present in the germline.

And then if that's confirmed, the index case is managed by putting them on a national registry. We now have more than 13,000 people on our U.K. registry of Lynch syndrome. They're registered for surveillance to reduce their colorectal cancer risk. And then after discussion with the index case, a cascade testing of at-risk family members with the intention of identifying them, hopefully before they ever get a cancer and preventing cancer in these at-risk family members.

Management of Lynch syndrome, we've covered some of it already, covers both colorectal and extracolonic cancers. It should be noted that at the moment, there's no evidence -- high-level evidence for screening for extracolonic cancers for people with Lynch syndrome. So we focus on colonoscopy, reflecting the different risk of cancer, colorectal cancer, MLH1, MSH2 carriers compared to MSH6 carriers have a different age of onset or recommend starting surveillance.

But the recommendation in the U.K. is it's done every 2 years. Aspirin based on John Burn's CAPP2 data shows that high-dose aspirin reduces the risk of colorectal cancer. The unpublished CAPP3 study, which is just about to be published, shows that actually the reduction in cancer risk is the same as low-dose aspirin, so opening up to more people with Lynch syndrome to take this and reduce their cancer burden.

For some people, risk-reducing surgery, both colorectal, both the colon and also women who have completed their family may consider removal of the uterus tubes and ovaries. H. pylori eradication reduces the risk of gastric cancer and also lifestyle changes to reduce cancer-causing dietary and lifestyle factors. So despite all of those steps, as we said, there's a huge unmet need to reduce cancer risk and cancer burden in people with Lynch syndrome. It's a common condition.

And so we're delighted to be able to announce that in partnership with Moderna, we've developed and about to start this INTERCEPT-Lynch study. So a Phase I/II study of novel Moderna vaccine for Lynch syndrome. This vaccine leverages the fact that Lynch syndrome causes predictable frameshift mutations, which are recurrent across cancers, colorectal, endometrial, gastric, ovarian cancers caused by Lynch syndrome share these potential vaccine targets.

So Moderna developed a vaccine and was going to be opening the study to test it. The study is divided into 2 parts. First part will test safety, tolerability, and define immunogenicity of the vaccine to identify 2 doses to take forward into the second part, which will focus on identifying whether the vaccine has evidence of activity in the tissues in which we want to see it. So just to look at the first part in a little bit more detail. This is a fairly standard dose escalation study with endpoints of safety and tolerability. It will define 2 doses to take forward into Part 2.

And then Part 2, people with Lynch syndrome who are scheduled for colonoscopies will be identified. And the final stage of the screening is to do the colonoscopy. And what we're going to do here is we're going to leave small polyps, adenomatous polyps, which we know are the subtype of polyps that become microsatellite unstable and develop the target frameshift that we're looking to target with the vaccine. We'll be leaving those in situ, measuring them very carefully at baseline and then vaccinating at 2 doses defined by Part 1.

And after 28 weeks, we repeat the colonoscopy, we remeasure the polyps to see if there's evidence of response to the vaccine and then the polyps are removed. And then the standard of care colonoscopy at 2 years will be done, and we'll also be looking for polyp burden at that time point. So endpoint of the study, safety, and tolerability and then the secondary endpoint in Part 2 of the study is a percentage change in the MSI-high, the microsatellite-unstable adenomatous polyps post-vaccination.

We'll be looking at immunology, both circulating and in tissue. And we're really excited to be starting the study imminently in Oxford with the second part of the study recruiting from additional U.K. sites. And what's really motivating about this is not just the clinician engagement. We've had a huge interest from clinicians, but also directly from patients. I've presented the work leading up this study over the last 3 years to Lynch syndrome carriers at Lynch syndrome U.K. Annual Meeting.

And since we released the press release putting out the study, there's been a huge amount of interest and had many e-mails from people keen to recruit, keen to participate in the study and also just commending us on the effort that we're making to reduce the cancer burden in this common condition. So thank you very much for your attention. I'm really excited to take this study forward and look forward to updating you at a future meeting.

Okay. So David, obviously, I would just like to underscore a couple of different pieces that he mentioned as well as tell you a little bit about the design of this vaccine. So as we've discussed and David highlighted, Lynch syndrome carriers have polyps over time. And those polyps over the course of their lifetime can develop into microsatellite unstable cancer. So to design this product, what we did was take precancerous polyps and look with all of the same technologies I already highlighted. So protein expression all the way through presentation at the MHC level of the peptides from the frameshifts.

And we've also looked at MSI-high cancers from sporadic cases. So as the same genes that cause the germline defect and the germline sensitivity to developing frameshift mutations. Those mutations can be acquired sporadically as well. And so we do find them in cancers that have no -- like did not have any germline susceptibility here. Those have a lot more samples. So a lot more samples from the MSI-high cancers across different malignancies and across broad populations. And we compared the frames shift peptides that we saw expressed and presented in those cases.

And we were able to find many, many that overlapped. We selected specifically from that overlap to make sure that the cancer -- sorry, that the -- that mRNA-4194 would address all the relevant stages of disease, everything from polyp to frank malignancy. And in particular, we actually were able to incorporate 194, hence, the name, mRNA-4194, 194 different frameshift peptides into this vaccine. So we really have extremely broad coverage, again, not only intertumoral heterogeneity across disease, across histologies, and across populations.

Yes, I think that's -- and then I also just wanted to take a second to pause. I know Dr. Church reviewed the Part 2 of the Phase I and how it's constructed in great detail. So I won't take you through all of the steps. But I just want to highlight that this is quite an innovative design. And the goal here is really to make sure that we are learning fast, right? And that we are de-risking upstream of pivotal investments and that we can iterate in data-driven ways.

This sort of mindset is taken through all of the [indiscernible] trials, and we're leveraging these ideas across the [indiscernible] trials more and more leaning into the translational data because we know that if we can get this to patients, as Dr. Church said, they're hungry for it and they -- and this could transform their lives.

So with that, I'm going to pass off to Sarah, who's going to walk you through mRNA-4359. Thank you.

Hello. My name is Dr. Sarah Keidel. I'm the program lead for mRNA-4359. And it's my pleasure today to walk you through our program, including the exciting data that we presented over the last year at ESMO and earlier this year at AACR. So going back to this cancer-antigen therapy schema that Kristine talked us through earlier, we're now going to be focused on the top right-hand side of the figure at the tumor-associated antigen therapies. So mRNA-4359 employs the same mRNA and LNP technology base as the other cancer antigen therapies, but applies it to immune evasion proteins.

And importantly, mRNA-4359 is the first of our cancer antigen therapies for which we'll have the opportunity to really unpick that product concept, looking at the scientific and clinical data as they emerge. So what is mRNA-4359? It is a lipid encapsulated mRNA-based cancer antigen therapy, encoding antigens of PD-L1 and IDO1. And these are proteins that are intimately involved with immune invasion by tumor. And we know that PD-L1 and IDO1 can be expressed by tumor cells, but importantly, they can also be expressed by immunosuppressive cells.

And this gives mRNA-4359 a dual concept. So not only can it have the potential to induce T cell responses to direct tumor cell killing, but it can also direct immunodepletion of the immunosuppressive cells that are protecting the tumor. And because this immune evasion mechanism is common to many solid tumors, it is possible that this product can be applicable across multiple tumor types, although we're starting with melanoma as a very rational first place to test the mechanism given the intended backbone of IO.

So you'll recognize this schema, this mechanism of action from the talk that Kristine gave earlier on the cancer-antigen therapies. And broadly, we have the same mechanism, but there is one point of difference due to the specific antigens that are encoded by the mRNA, the PD-L1 and IDO. So kind of skipping through, you know that the protein is translated and they get expressed. The T cells that are specific to IDO1 and PD-L1 then get activated.

These mature, they expand, they go into the circulation and then they enter the tumor microenvironment. And it's at this point where you get that potential of that dual mechanism. So those T cell -- those tumor antigen-directed T cells will then look to destroy the tumor cells expressing these antigens and also those immunosuppressive cells also expressing these antigens. And so over time, we would expect a rebalancing of that tumor microenvironment to a more immune-permissive state.

Now this also gives us that impetus for the idea of the backbone of the checkpoint inhibition. So the idea of mRNA-4359 is that it really works as a target to induce those target-directed T cells. However, the idea of the checkpoint backbone is to release further brakes on the immune system to maximize the potential of the mRNA-encoded product. So now to the data. On this slide, you've got our Phase I/II study design.

We started off pretty typically with dose escalation and confirmation cohorts. And at the moment, we're in the Phase II portion of the study at dose expansion. We'll come back to that in a minute because what I'd like to focus on the next few slides is on arm 1b, which is our dose confirmation cohort in patients who are treated with mRNA-4359 in combination with pembrolizumab and who had checkpoint refractory advanced melanoma. So starting with the ESMO presentation here.

We've got here listed the patient disposition and the baseline characteristics for the 29 patients who are included in this cohort. They were treated at 2 different doses, but the main takeaway from this slide is that these were refractory patients. All of them were checkpoint refractory, and there's a median of 3 prior therapies with a maximum of 8 prior therapies in this group of patients. Now first and foremost, in this Phase I study, safety. So mRNA-4359 in combination with pembrolizumab demonstrated a manageable safety profile.

The majority of adverse events considered related to mRNA-4359 by the investigator were low grade, and they comprise of injection site reactions and localized self-limited systemic adverse events such as fever, fatigue and also chills. There were no dose-limiting toxicities or grade 4 or 5 adverse events considered related to mRNA-4359. Now switching to the pembro-related adverse events. These were very typical for the adverse events seen in the checkpoint inhibitors with irAEs.

But the overall, what we saw from this cohort is that it looks possible to combine mRNA-4359 plus pembrolizumab without getting unexpected safety signals. And this is something that, of course, we're watching out for as we expand our Phase I/II study. So here, we have the efficacy, and this is the part that really started to get us very excited. So what you'll see here on the left side of the slide is the efficacy table, and we're going to focus on all patients pooled across the dose levels. So you'll see that we had 25 patients who are valuable for their tumor responses and 6 of these patients responded, giving us an objective response rate of 24%.

We even had one complete response. The median duration of response was not reached for these patients, and our disease control rate was 60%. So we're encouraged by these results already. As we mentioned, this is a heavily pretreated population, but we were really interested in understanding, are there any signals or any biomarkers that could help us point to which patients have a higher chance of response. So on this slide, you'll see the spider plot looking at the tumor responses over time.

And what we've done here is color through the patients by their tumor PD-L1 expression. So in the red, we've got the PD-L1-positive and in the blue, we've got the PD-L1-negatives. And what you can see really clearly here is that all the responses occurred in patients who were PD-L1-positive. And indeed, these responses were enriched in that PD-L1-expressing population. So 6 out of our 9 patients responded, giving us an ORR in this subgroup of 67%, which we were very encouraged by.

But of course, we wanted to understand a little bit more who are these patients? Are they on the lighter end of the treatment spectrum? What's going on with them and what treatments have they had before? So on this slide, we've got the 6 patients treated who responded on the -- in each row. And we've got their prior treatments listed in chronological order and including the disease setting as well as their best overall response to that drug. In addition, on the right for reference, you'll also see the results that they had on our drug in the combination of mRNA-4359 plus pembrolizumab once they came on to our study.

But I'd really like to focus on the middle part of this slide because looking at it to me, what I take from this is that these were a heavily pretreated group of patients genuinely. So almost all of the patients were treated previously with anti-PD-L1 monotherapy as well as IO combinations with nivo/rela or nivo/ipi. And half of them had prior exposure to TILs or TCR therapies.

In addition, when you look at the best overall response to each of these therapies, the majority of patients had the best response of disease progression to the majority of these prior therapies. And so again, these are patients that in the real world would have exceptionally poor prognosis and see any responses in this group of patients to us was encouraging, but particularly important when you look back at that spider plot that we had in the previous slide of the durability of those responses that we saw. So for us, again, very, very promising.

Last but not least, for this checkpoint-refractory cohort, we have the translational data. We are very interested in understanding, is there a proof of biology for this drug based on its mechanism of action. So on the left-hand side there, you'll see some ELISpot analysis looking at for the development of antigen-specific T cell responses between baseline and after treatment. And what you'll see here is that indeed, there was an increase in the PD-L1 and IDO-specific T cell responses in the periphery for the evaluated patients and that this was seen across best overall response categories.

On the right, we are then interested in looking at whether the patients develop novel expanded TCR clones once they're exposed to therapy. So again, looking from baseline and across the treatment cycles and as we go through the diagram, you can see that there, again, there is an increase in these novel expanded TCR clones after starting mRNA-4359 and pembrolizumab. And this does seem to be directionally higher in those patients with responses versus those patients with either stable disease or progressive disease.

So together, these data were important for us because it really helps to underpin mechanism of action. We see that proof of biology, and it helps us to understand some of the data that we're seeing clinically as well. So based on these data, we expanded into another multiple treatment expansion cohorts. And so we're looking at a couple of first-line melanoma cohorts with combinations of checkpoint inhibitors. We have further expanded our second-line and beyond melanoma cohort, looking at those patients specifically for good reason, who are PD-L1-positive.

We've also added a first-line non-small cell lung cohort in high PD-L1 expressers. But I'm going to focus at the top at our Arm 1/2a. And this was a small cohort treated with mRNA-4359 in combination with pembrolizumab in the first-line melanoma setting. And this is fully enrolled. We had results and these results were presented at the oral plenary for AACR a couple of months ago. So here, we have treatment disposition at a median follow-up of 54 weeks. 7 of the 12 patients had discontinued treatment by that point, 2 because of progressive disease and 4 because of adverse events.

Five patients continued on therapy at this point, 4 had completed their mRNA-4359, but continued their pembrolizumab. One patient remained on the combination side of the therapy because they were pretty early in these treatment cycles. Here, we have the baseline characteristics, nothing particularly unexpected. The majority of patients had an ECOG performance status of 0. The disease stage of the majority of patients was 4. About half of the patients had BRAF-mutated disease. And this is a small, but important clinically relevant cohort for us, which we'll come back to in a few slides' time.

We had 4 patients who had prior exposure to neoadjuvant therapies, 3 of whom had immunotherapy exposure in the form of nivolumab. So again, first, the safety. Here, you'll find nothing unexpected. These are, I think a slide has gone missing, but yes, needless to say, the mRNA-4359 related adverse events, they were all low grade in these 12 patients. The most common were those fevers, chills, pyrexia and fatigue, as you'd expect from innate immune activation after administration of an mRNA product.

Pembrolizumab-related adverse events, as determined by the investigators, were predominantly low grade. Most common -- I think that's just going to -- I'm so sorry. It looks like that's pembrolizumab, but that's the mRNA-4359. This is now the pembrolizumab. So the majority of the most common adverse events were fatigue, nausea, increased amylase, diarrhea and pruritus as expected for anti-PD-1 monotherapies.

About 1/3 of patients had high-grade events, and these were pretty typical for immune-related adverse events that occur with checkpoint inhibitors. So again, based on a small number of patients, we're not seeing any signals that there are unexpected safety events occurring with the combination. But again, we continue to monitor carefully. Now to the efficacy. Here on this efficacy table, we've got all the participants on the right-hand side. And in the middle, we've also looked at the subgroups by PD-L1 expression because based on the checkpoint-refractory data, we were very interested in understanding what happened by PD-L1.

So looking at all participants first, you'll see that 10 out of those 12 patients responded, including 2 patients with CRs, Median duration of response was not yet reached. Now looking at the small subgroup of patients with PD-L1 positive and negative expression, you'll see that we were very encouraged to see that there were responses across PD-L1 expression. So we had 2 out of the 3 patients who are PD-L1 negative who responded to therapy.

On this slide, we've got the swimmer plot showing the patient journey as they came on to the study. So we've got those 12 patients on the Y-axis. And just to orient you a little bit to the plot, the blue, dark shade is the treatment duration. The lighter shade is the period of follow-up. The blue and white triangles are the complete and partial responses the patients had and the red circles are the progression events.

And what you'll see here visually is that the majority of patients remain disease-free and in follow-up on the study at the time of the data cutoff. We had 3 progression events, 2 of which contributed to the PFS results because one of them, per the prespecified statistical analysis plan, was censored because of multiple missing tumor scans. The median duration -- the median PFS was not reached. Now going back to that important small subgroup of patients who had prior neoadjuvant therapies.

And these are the patients that are denoted by the asterisks on the right-hand side of the swimmer plot. There's those 4 patients. So what you'll see here is that 3 of those 4 patients had a response of either CR or PR, and these patients remain progression-free through the duration of the follow-up. Now the reason this is important despite the fact that it is a small cohort is it starts to give us a sense that it may be possible to give mRNA-4359 in combination with pembrolizumab in the first-line setting with efficacy despite prior exposure to IO.

Now on this slide, it looks, in some ways, very similar to the one we saw in the checkpoint refractory disease with that spider plot. We've got the reduction in tumor target lesions over time. On the right-hand side and on the left, we've got the waterfall plot, again, colored by PD-L1 expression with the positives being in red. But the main point of difference that is quite striking on that spider plot compared to the one we saw earlier is just that the majority of patients here are responding. And again, that you do see those responses in the patients with PD-L1 negative disease.

What looks similar is the translational data. So here, we have the translational data from the first-line cohort. And again, we see biological activity demonstrated both by the development of IDO1 and PD-L1 specific T cell responses as well as the novo clonal expansion of those T cells. So again, very nice to see this based on the mechanism of action of the drug. So in conclusion, we were very heartened by these data. We now have data that the combination of mRNA-4359 plus pembrolizumab may have a manageable safety profile and also may have evidence of biological activity in these patients with both refractory melanoma as well as treatment-naive advanced melanoma.

In terms of efficacy, we saw durable responses in both. Of course, it was higher in the first-line setting, where we actually saw that it was regardless of PD-L1 expression, while the responses were enriched in the PD-L1 positive patients in our checkpoint-refractory disease. So based on these data, as we mentioned, our Phase II expansion cohorts are ongoing, and they should help us to elucidate our strategy in terms of ideal treatment setting, in terms of our preferred combination partner and also in terms of our biomarker strategy. And we also are eagerly anticipating the results in the non-small cell lung cohort.

So with that, you've bear with me through a lot of data, but thank you so much for your attention, and we now break. Thank you.

[Break]

Hi, everyone. Welcome back. I have the distinct pleasure of telling you about a new modality we are creating within Horizon 2, specifically mRNA-encoded T-cell engagers against surface antigens. And so T-cell engagers, as you know, are a well-established class of medicines with 10 FDA-approved products. T-cell engagers are a great demonstration of how we use mRED principles to build modalities.

And so I'm going to walk you through our platform differentiation within those modalities, walk you through also about how we think about our sentinel, our first application and how that de-risks follow-on programs. And then also about how we think about the depth of the well, follow-on programs and diversification of the follow-on programs thereof. Now unlike cancer vaccines, cancer antigen therapies, therapeutic vaccines, where we use our platform technology to train the immune system, specifically T cells to go and hunt their target.

T-cell engagers, as you know, are bispecific antibodies that physically direct T cells to tumor cells to unleash killing activity of those T cells on tumor cells. Now you probably know that T-cell engagers are conventionally recombinant antibodies. And you're probably wondering, well, what's our differentiation there. And so I'm going to come back to a point Rose and Kristine made, which is on multiplexing. And so here for T-cell engagers, we really lean into our ability to multiplex. So in a single drug product, we have multiple messenger RNAs encapsulated in lipid nanoparticles.

Again, that is considered a single-drug product. And we can encode, we can produce multiple T-cell engagers all at the same time. Why that becomes advantageous is because we can go after multiple tumor targets and thereby overcome some known resistance mechanisms for given histotypes. So inter- and intratumor heterogeneity specifically and also antigen escape, which is a well-described phenomenon for certain histotypes.

On top of that, for T-cell engagers, we can think about tumor biology and really, again, resistance mechanisms and also include T-cell engagers that encode co-stimulatory molecules. So not only directing T cells to kill tumors, but also providing molecules to improve the fitness of T cells. Now we're going to talk about the modality with respect to surface antigens, but we also are working on this modality beyond surface antigens against intracellular antigens as well.

So for our Sentinel application, we always try to minimize biology risk because this is the first time we're taking our platform technology into a new area. And so when we looked at T-cell engagers, the optimal sentinel application from our perspective was going after multiple myeloma, where you already have a bunch of clinically approved T-cell engagers and other T-cell engagers showing great antitumor activity in clinical development.

And so there, the thesis was we could encode multiple T-cell engagers all at the same time against clinically validated tumor-associated antigens, we use our technology. So we use our systemic lipid nanoparticle where we had a ton of repeat dosing clinical experience in patients with devastating rare diseases over 80-plus patient years. And we leverage that technology for oncology. And I'm going to walk you through that sentinel application momentarily. Beyond that, once we get an encouraging clinical signal from our Sentinel application, we can learn and we've ungated and de-risked follow-on programs.

And so here, our follow-on program, we wanted to move from multiple myeloma, a hematologic malignancy and really go towards solid tumors. You probably know that the 10 FDA-approved T-cell engagers 8 of them are for heme malignancies and 2 are for solids. Solids have certainly been far more challenging. And we're up to that challenge. And we're excited about using our technology to encode not only the kill T-cell engager, but also provide that co-stimulatory signal to enhance T-cell function to have greater antitumor activity against solid tumors.

Now coming back to diversification within a modality and then broadly across the portfolio. I already touched upon our first application, we go after kind of what we know the signal should look like in myeloma in a liquid tumor and then venturing into ovarian cancer, where there are clinically validated tumor-associated antigens, and we understand some of the tumor biology resistance mechanisms, particularly around the tumor microenvironment and its hostile immunosuppressive environment.

Okay. So the Sentinel application is mRNA-2808. And this sentinel application is a multiplex product. It encapsulates 4 different messenger RNAs that encodes 3 distinct T-cell engagers against clinically validated tumor-associated antigens. You recognize those antigens, I'm sure, BCMA, GPRC5D, and FcRH5. Now our differentiation with respect to multiplexing also is because it's a single drug product, we don't have to show contribution of components for each of the T-cell engagers.

And so if we were working on this with recombinant antibodies, we would have to follow a more traditional drug development path where for each specific recombinant bispecific antibody, we would have to conduct a nonclinical program, manufacturability assessment, clinical development program for each T-cell engager and then combine them. Because mRNA-2808 is a single drug product, we can advance this as a multiplex product, as Rose was saying, it's not a combination. It's a multiplex product, and we can advance it through preclinical, nonclinical, and currently, we're dosing in Phase I/II.

By the way, we haven't been asked a single question about contribution of components from the FDA. And I think that's incredibly exciting as you think about the multiplexing potential for T-cell engagers as a class of medicines for messenger RNA. Now as I said, by multiplexing, we can overcome known disease biology and resistance mechanisms. And so for myeloma, we know that there is significant both inter-and intra-tumor heterogeneity. But also very importantly, we know that these antigens upon treatment can escape. They'll mutate and they will escape patients will stop responding.

And so by going after multiple targets, we should be able to overcome both the tumor heterogeneity, but also the antigen escape. And in fact, the investigators that we're working with are really excited about the potential here of going after these clinically validated tumor-associated antigens all at the same time. Okay. So as you know, the first generation of T-cell engagers are really focused on what we call monoplex. So single target, single T-cell engagers. Of course, you have actually approved BCMA T-cell engagers and approved GPRC5D T-cell engager for multiple myeloma, and they are effective.

The second generation companies are starting to combine those T-cell engagers together. Sometimes they are separate T-cell engagers. Sometimes they are novel multi-specific antibody formats that can be difficult to manufacture. And you have a variety in clinical development and also preclinical development, mRNA-2808 to our knowledge, represents the first time any drug product encodes 3 T-cell engagers all at the same time. And so the multispecifics that others are working on typically are focused on 2 tumor-associated antigens.

Here, we don't have to resort to a fancy multi-specific antibody format. We can use actually an antibody format that we designed specifically for ourselves, for our technology, and we multiplex. We can include multiple messenger RNAs so that we can encode very functional, very well-behaved molecules, all at the same time. And so I'm going to walk you through some of the preclinical data that we showed at ASH about 1.5 years ago.

First showing you that the mRNA-2808 encoded T-cell engager proteins are all incredibly potent. And so what I'm showing you here is in vitro data when we look at binding of the T-cell engagers to their respective targets. They are in nanomolar binding affinity. So these are very potent binders. When we look at killing activity, cytotoxicity against the respective tumor cells that express their respective targets, we are in the picomolar range, so very, very potent.

And then when we do a mix and match of the various tumor cells that have their respective tumor targets, as you can imagine, by multiplexing, by including multiple of these T-cell engagers, we achieved greater killing than simply going after one of these targets by itself. Now importantly, for us, monkeys represent a highly translationally relevant species. And that's based on all of our platform experience in advancing different medicines from preclinical from monkeys to patients.

And what we showed in monkeys was definitively preclinical proof of concept. where we took mRNA-2808 and we evaluated both single and repeat dose administration studies in monkeys, both to assess pharmacology, but also we conducted repeat-dose GLP toxicology studies as well. And what we're showing you on the left-hand side is that after a single dose administration, both intravenous administration and subcutaneous administration that we see really nice dose-dependent expression of the T-cell engager protein.

Now I'm just showing you one of the exemplary T-cell engagers. This is against GPRC5D. By the way, you can note the EC50 dashed line, that's from the cytotoxicity. That's how potent the molecule is. So we are well above what is therapeutically relevant even at these very, very low doses. But what you'll notice from the protein expression kinetics is we actually don't hit the Cmax until about 1 to 2 days later.

And that's exciting for us because if you think about how the T-cell engager field has evolved, as you probably know, they have shifted from IV administration to subcu. And that really was to flatten out the protein exposure curve because you were having CRS cytokine release syndrome that was a Cmax-driven event. So they flatten out the curve. Well, we're excited because actually, our IV administration looks much more like a subcu curve from a recombinant protein.

We're also excited because you can see from this plot, we can subcu administer mRNA-2808 as well. And in fact, we actually included subcu administration as part of our nonclinical program, and we intend to evaluate subcu administration in the ongoing Phase I/II study. Okay. So on the left is we can make TCE protein at very therapeutically relevant levels. Now we know it's functional also because when we look at on-target pharmacology, specifically depletion of target expressing cells, specifically we're showing you here memory B cells.

Again, these T-cell engagers are very, very potent. And so what you'll see is after a single dose administration, we have very significant depletion of target cells. This is only a single dose and the rebound is approximately 2 weeks later. And so in monkeys, we've shown that we achieved good tolerability to enable the first-in-human study. We actually had a massive safety margin heading into the first-in-human study, that we can encode functional and therapeutically relevant levels of T-cell engager proteins of all 3 of them. And we've demonstrated on-target pharmacology.

And so with that, we have an ongoing Phase I/II study in advanced multiple myeloma. And so the patient population is relapsed and refractory multiple myeloma. They're triple-class-refractory, and so they've been exposed to proteasome inhibitors, immunomodulatories and anti-CD38. We are currently in dose escalation, where the primary endpoint, of course, is safety and tolerability. And our secondary endpoints include PK, pharmacodynamics and also antitumor activity, specifically response, duration of response, and progression-free survival.

And so we are really encouraged with the ongoing Phase I/II study, and we look forward to presenting findings and results at an upcoming medical conference. So with that, based on the encouraging signal that we've seen to date in mRNA-2808, we've actually ungated advancing our follow-on program, which is mRNA-2151 for ovarian cancer. And here, again, we diversify, we take more biology risk as we advance the follow-on program. And actually, the follow-on program, mRNA-2151, uses the same T-cell engager antibody format is mRNA-2808.

And so with mRNA-2808 having that encouraging signal and being able to show repeat visibility, et cetera, safety, we can apply those learnings to mRNA-2151. For mRNA-2151 is a similar idea to mRNA-2808. So it's a multiplex T-cell engager product, single-drug product. It encodes in this case, 2 T-cell engagers that kill the so-called Signal 1. And these are against 2 clinically validated tumor-associated antigens for ovarian cancer.

Now when we looked at ovarian and solids in general, we thought it would be a good idea to include a co-stimulatory molecule as well, again, because of the hostile, immunosuppressive tumor microenvironment and also that many of these patients, unfortunately, as a consequence of that tumor microenvironment can have poor T-cell fitness and function. And so in the drug product, we also included for the first time ever, a T-cell engager, a co-stimulatory signal, a Signal 2. And so mRNA-2151 combines the Signal 1, the kill, but also includes the Signal 2, the co-stimulatory.

And I'm going to show you some preclinical proof-of-concept data that gets us really excited about the addition of the co-stimulatory molecule to enhance antitumor activity. Now finally, I'll just note that by design, the antibody format, the molecules we're encoding, of course, messenger RNA being an information molecule. It's a very plug-and-play format. And so we're excited because we actually have a whole host of binders against other high unmet medical need tumor types where we can envision different Signal 1 and Signal 2 combinations going into higher unmet medical need tumor types and overcoming known resistance mechanisms and tumor biology.

Okay. So I'm going to show you some of the in vitro data first. So similar to mRNA-2808, these T-cell engagers for Signal 1, the kill T-cell engager are very, very potent. So we're talking about picomolar, killing activity, cytotoxicity, and this has been shown in a variety of tumor cells that express high antigen levels, mid and low. Importantly, the green is the Signal 2. And the Signal 2 molecule similarly is incredibly potent.

So here, I'm showing you sub-nanomolar affinity for T-cell activation. Now in vitro, when we look at both the Signal 1 cell and the Signal 2 co-stimulatory T-cell engager, we see enhancement of killing activity. And so the EC50 for the Signal 1 alone is shown on that dashed line on the upper right-hand side. And as we add concentrations of the Signal 2 co-stimulatory molecule, we can improve the potency, we can improve the killing activity for the drug product.

Now importantly, when we look in vitro, and we do repeat simulation studies of the T cells with tumor cells. So we stimulate the tumor cells day after day. If you focus on the blue line there, that's just a Signal 1 T-cell engager. And day after day, stimulating those T cells, those T cells get more tired, more exhausted, more terminally differentiated, and they lose their ability to kill, which is what you see in the blue. When we add the co-stimulatory Signal 2 molecule, you can see that we retain its ability to kill over time upon repeat stimulation. And that's because what we're showing on the other 2 plots is that those T cells have enhanced function.

And so they proliferate better, they have better survival markers. They're just overall more happy. And so we're excited with that in vitro data, but of course, we've taken this in vivo to various humanized xenograft tumor-bearing mice. Here, I'm showing you the OVCAR-3 model, which is one of the kind of workhorses in the field. The black line shows you just vehicle control. You can appreciate that these tumors grow out of control if these mice are not treated. The blue lines show you Signal 1 T-cell engager that kill T-cell engager alone.

And so you have significant control of the tumor with the Signal 1 T-cell engager alone. But when we add Signal 2 in addition to Signal 1, that's exemplified in the pink and red there, that's when we start to see complete responses and really significant and durable control of tumor. And so similar to mRNA-2808, we are administering this product intravenously, but we're excited about enabling subcutaneous administration as well. And so for mRNA-2151, the next steps are to complete the IND-enabling studies and also to initiate a Phase I study in 2027.

We've had excellent pre-IND meetings to date, and we're excited to advance this to patients. And so as I said, this is our T-cell engager modality against surface antigens. As part of Horizon 3, we're actually working on T-cell engagers against intracellular antigens. So these are antigens I get to that process and displayed on the surface of tumor cells with little parts, and they are HLA restricted. But there, again, we lean into our platform differentiation to multiplex. And we're excited because we should achieve broader patient coverage and also enhanced antitumor activity for that class of targets as well.

Okay. So with that, Sumana is going to walk you through our EBV therapeutic vaccine for MS.

Good morning, everyone. It's a pleasure to be here. My name is Sumana Chandramouli, and I'll be walking you through our mRNA-1195 EBV therapeutic for multiple sclerosis. Epstein-Barr virus or EBV is a very prevalent human herpes virus. It is associated with many serious diseases. And this starts with infectious mononucleosis when EBV is contracted in early adolescents or young adulthood.

And then it can -- it is -- EBV is one of the first human oncogenic viruses that was identified. So it is positively linked to several cancers such as lymphomas Hodgkin's, Burkitt lymphoma, nasopharyngeal carcinoma, and also certain forms of gastric cancer. On top of that, there is emerging evidence and strong evidence that links EBV to several autoimmune conditions, including multiple sclerosis or MS. That will be the focus of the talk today. And in immunocompromised patients and persons, it can also cause several diseases such as post-transplant lymphoproliferative disorder or PTLD, in transplant patients and chronic active EBV.

The underlying complexity of the virus and these diseases and the diversity of the biological mechanisms require not only prophylactic intervention, but also therapeutic intervention to address all of these. And we believe that the unique advantages and attributes of the mRNA platform allow us to address these from all angles. So taking a deeper look at EBV and multiple sclerosis. Multiple sclerosis or MS is a devastating neurodegenerative disease that affects predominantly women in the prime of their life. It can then lead to decades of progressive physical and cognitive disability that can be crippling in every sense of the world.

For many, many decades, people have been looking at the causative agents behind MS. There's nearly 1 million people with MS living in the U.S. today and many millions more worldwide. And the emerging evidence from looking at the data over many decades is that EBV seropositivity and a prior infection with EBV seem to be very strongly linked to a risk of developing MS later in life. This translates to an almost negligible risk of developing MS if someone is not ever exposed to EBV.

All of this was recently summarized in a landmark study that was published a few years ago now in science that showed that quantified this risk to be a staggering 26 to 32-fold increase in risk of developing MS following EBV exposure. That is shown in the graph on the left. The graph on the right shows something additionally interesting, which is that on top of the risk that comes from just having EBV infection, there is an additional two to threefold increase in risk of developing MS if there is a history of infectious model.

So this indicates that the virus starts manipulating the immune system quite early on as soon as it encounters -- so EBV is a tricky virus. It's a herpes virus. So as soon as it enters the body, it stays there for the rest of the life of the host. It bounces between forming active viral particles, which is known as lytic replication and going into a very quiet immune evasive state known as latency. And it goes into a latent state in the B cells of the immune system.

So what we understand from seeing healthy people because EBV is so seroprevalent around the world and most of the exposed people are still healthy is that the immune system uses both arms and antibody response that actively prevents EBV replication and infection of new cells and a very strong T cell control to maintain control over the latently infected EBV cells. So from that was born the concept of mRNA-1195. The composition of mRNA-1195 consists of 6 mRNAs 4 of them, gHgL, gp42, and gp220 are glycoproteins that are known to be the primary targets of neutralizing antibodies on the surface of the virus. These will prevent the virus from infecting naive B cells and epithelial cells.

Then we've also added in engineered forms of 2 latent antigens. These are a group of proteins that the virus uses to maintain its latency and to remain latent in the B cell compartment of the body. So we've included engineered forms of EBNA3A and LMP2B, which are key latent proteins that the virus uses to propagate latency. We are starting out with testing this in multiple sclerosis because we believe that immune dysregulation, often by EBV, may be one of the underlying mechanisms that EBV uses to not only trigger the disease, but also to drive it forward.

We also envision that other conditions like PTLD that might require a combination of antibody and T cell responses in order to prevent the condition from occurring might also benefit from this composition. So we started out by testing mRNA-1195 in healthy seropositive adults, and we wanted to de-risk the immunogenicity of the product before going into the vulnerable patient population.

So the Phase I Part A was designed as a randomized observer-blind, placebo-controlled study. We tested different ratios of the antigens in order to get the ratio right. So we have 2 different compositions of mRNA-1195 in this trial. We also included our mRNA-1189, which is a prophylactic vaccine for EBV against infectious mono that we are developing. We use that as a comparator to understand the interplay between the different antigens between the latent and the lytic antigens we've added in, and there was a placebo group as well.

We -- of course, the primary objective of the study was to look at the safety and the reactogenicity of this candidate. And then we were also going -- we also looked at the humoral and cell-mediated immunity and the impact on EBV shedding. So to share some of the early data we have here, this is the reactogenicity profile of mRNA-1195. As we can see from -- as we can see, the top panels show the local reactogenicity and the bottom panels show systemic reactogenicity. The shades of blue are grade 1 and grade 2, very fast resolving reactive symptoms and very, very low levels of grade 3 were detected.

So overall, mRNA-1195 was well tolerated with an acceptable safety profile. We then looked at the immunogenicity of this candidate. So here, we are looking at the binding antibodies to the glycoprotein components in the -- in this composition. So that's gHgL, gp42, and gp220. Just to orient ourselves, the gray bars that go through the middle of these graphs are the baseline responses to natural infections seen in these seropositive individuals as they come into the trial.

The line in black is the comparator mRNA-1189 that contains these glycoprotein antigens as well. And then in the shades of yellow and red are the different dose levels of mRNA-1195. So a few things are immediately obvious when you look at the curves here. The first is that compared to the placebo, there is a significant boost in the binding antibodies following just a single or 2 doses of mRNA-1195 in this population. This is then sustained by the third dose, and we can see these responses maintained well above baseline out to 6 months after the last dose, which is the last time point in the study.

There was no pronounced dose response as we can see all of the yellow curve -- yellow and red curves are overlapping with each other as well. They're looking at the functional antibodies. So the B cell neutralizing antibodies would be preventing the infection of EBV into B cells and the epithelial neutralizing antibodies are doing the same, protecting epithelial cells from incoming EBV. So here, what we see is that both -- all of the tested dose levels of mRNA-1195 and mRNA-1189 are able to boost significantly the neutralizing antibody response to both B cells and to epithelial cells.

The B cell nABs are considered the more relevant ones here because we are primarily studying B-cell biology-related diseases. And we did measure that all the way out to Day 337, which is 6 months after the last dose, and we can see that the neutralizing response is well sustained above baseline. This is an exciting piece of data we would -- we are also excited to share here, which is looking at EBV shedding and saliva of these seropositive individuals.

So as EBV bounces between lytic and latent replication over a lifetime, any given moment, multiple -- majority of the EBV-infected people will be shedding EBV in their saliva. And this is shown in the gray bars in the top panel that is the average -- the genome copies of EBV DNA in saliva in placebo recipients. And what becomes apparent is that as soon as a single dose of mRNA-1195 is given, we can see that this drops in that group and is sustained all the way through the end of the study.

This is similar to what we had presented previously with mRNA-1189 as well, where we see this rapid and sustained suppression of EBV shedding in saliva. The bottom graph is a different way to look at the data, which is to look at, at any given time, what is the percentage of individuals with detectable DNA in their saliva. This gray bar is, again, represents the placebo group and the black and the orange are mRNA-1189 and mRNA-1195. And again, we can see that as soon as either of the mRNA compositions is given, there is a rapid and sustained reduction in the frequency of individuals that are shedding over time.

As we mentioned earlier, the T cell responses are just as important in this case because the surveilling T cells are what keeps the latently infected B cells in check. So we looked at 2 different types of T cell responses induced by mRNA-1195. These are the CD8 T cell responses. And what we observed is that unlike the placebo group, we can see a nice boost and sustained increase in CD8 T cell responses to the 2 latent antigens, which are shown in the top panels, EBNA3A and LMP2B. And in the bottom, we also observed that there were very strong CD8 T cell responses to the glycoprotein antigens -- antigen gH.

Again, we didn't see much of a dose-specific response, and we also see that these responses were sustained through the end of the study. This panel here now shows the other type of helper T cells, CD8 T cells -- sorry, CD4 positive T cells. And again, we observed a nice boost in sustained response to both EBNA3A and gH following mRNA-1195. And this is sustained through the last time point in the study.

We are now continuing our Phase I, knowing what we know about mRNA-1195. We are now continuing with a second part to the Phase I. Now we are testing it both in seropositives with additional dose levels and also in seronegatives, trying to plan for the future for indication expansion as we go forward. And we also have mRNA-1195 now actively dosing in our proof-of-concept multiple sclerosis study, P201. This is a randomized, observer-blind, placebo-controlled study, where we are again looking at the potential impact that mRNA-1195 might have in people that are living with MS -- and we are looking at various time points.

In addition to safety and reactogenicity, we are also looking at the impact of mRNA-1195 on MRI markers of MS disease activity and other clinical markers as well and also looking at the humoral and cell-mediated immunogenicity in this population. I'm very happy to share an update on this study, which is that we fully enrolled our sentinel cohort of 12 patients. And the DSMB has reviewed the safety data and has given the recommendation to proceed with the dose escalation phase in this study.

So in conclusion, we have learned through our Phase I data so far that mRNA-1195 is generally well tolerated and we are continuing with our Phase I and Phase II studies. In the immunogenicity realm, we see that mRNA-1195 is able to strongly boost both B-cell and epithelial cell neutralizing antibodies, binding antibodies, CD8 positive and CD4 positive T cells. We find this very encouraging and the immune responses are sustained for well over 6 months after the last dose.

And we also, again, were able to demonstrate that mRNA-1195 is able to reduce measurable viral shedding in saliva, similar to our mRNA-1189 composition. We are continuing with our Phase I data. We expect data -- sorry, we are continuing with our Phase I trial. We expect data coming up soon, and we'll also have data from our proof-of-concept MS study in the future.

With that, I'll hand back to Lin to talk through our in vivo CAR-T program.

Thanks so much, Sumana. So I have the pleasure of walking us through an emerging modality we are advancing as part of Horizon 3, which is in vivo CAR-T more broadly in vivo T cell therapy. And so in contrast to the modalities that you've heard about today with our therapeutic vaccines, again, intravascular administration, we encode in antigen-presenting cells, and we train the immune system to go and hunt and find their target.

In contrast to T-cell engagers, where we encode multiple T-cell engagers to physically direct T cells to their tumor targets and also provide co-stimulatory signals. Here, we are directly engineering T cells in a person's body in vivo. And so the technology here, our messenger RNA encapsulated in targeted LNPs targeted to direct preferential uptake into those T cells. And the sentinel application here is focused on deep B-cell immunity reset for autoimmune diseases.

And so you probably know that many autoimmune diseases have B cells playing a central and pathophysiologic role with respect to pathogenesis. And the unmet medical need remains high. And so you often have patients cycling through various standard of care, broad immunosuppressants, sometimes targeted biologics, specifically anti-CD20 monoclonal antibodies as an example. Those targeted biologics, as you probably know, do not deplete B cells in tissues as well as they do certainly in the blood.

And the emerging ex vivo CAR-T, autologous CAR-T experience for various late autoimmune conditions has been incredibly exciting, showing that those patients can achieve durable remission and deep B-cell depletion along with an immune reset. And so the ex vivo autologous CAR-T field for autoimmune is emerging with over 400 patients dosed to date and about 270 total years of clinical experience. What we're really excited about for ex vivo CAR-T as well is by going after deep B-cell depletion in blood and tissues to achieve that immune reset, what we deem are encouraging signals across a variety of autoimmune conditions.

So you can see here for lupus, for myasthenia gravis, for scleroderma, myositis and so on and really encouraging rates of durable remission. Now the durability in particular, remains to be seen. The data is still emerging. But so far, it appears that the results are quite durable, about half year to a year plus. And importantly, the dose, as you probably know, is lower than what is typically required for oncology ex vivo CAR-T. The persistence of those T cells, in particular, seem drastically shorter for autoimmune patients than what's observed for oncology.

And so in autoimmune patients, they typically persist for several weeks versus in oncology, you will typically see them last for months up to several years and correlated with clinical outcomes. Now what's been incredibly exciting as well as the tolerability with low-grade CRS and neurotoxicity observed across patients and really manageable tolerability, particularly with respect to infection risk, which is an on-target pharmacology consequence.

Now for ex vivo CAR-T, as you know, that whole process is complicated and costly. And so the manufacturing is incredibly complex. You have to take blood out of a person's body, engineer them ex vivo with a virus. And then to get them back in, you have to make space with harsh preconditioning. There are only specialized academic centers that can really realize this entire process for patients and the entire process is not scalable and quite costly.

Compare and contrast that to in vivo, which is an off-the-shelf approach to engineer T cells directly in a person's body. You do not need to lymphodeplete. You do not need to do the harsh preconditioning regimen. The field has been showing that quite definitively, which is really exciting. And because it is off-the-shelf, you're doing this in a person's body, it is scalable. And additionally, it is transient, which confers tolerability aspects, attributes for this drug product.

And so in vivo CAR-T, in contrast to ex vivo CAR-T, where you have a single dose administration and those T cells kind of persist for several weeks. We think with in vivo CAR-T with transient expression of those CARs in T cells, we can give a limited number of repeat dose administrations. And with a concomitant deep B-cell depletion in blood and tissues, we should see a concomitant decrease in disease activity, hopefully resulting in durable remission.

Now when those B cells reconstitute or rebound, as you know, the immune system has been reset, and so they will reconstitute with a naive phenotype. And so this modality exemplifies another area in which we take mRED principles to build not only the sentinel application, which has huge value for patients across many different autoimmune conditions, as I just showed you, but also take the same technology and apply it in other aspects that we can go into such as oncology and T cell reprogramming.

So we are advancing our lead nominated candidate, mRNA-6007 that we affectionately call 007. And we selected this based on comprehensive screening of various targeted LNPs, optimization, and preclinical evaluation. It's built on the foundation of our platform, which we have extensive experience, both from a clinical perspective and manufacturing. And the LNP, the base particle that we use for the targeted LNP is actually the same LNP that we use for T-cell engagers for our rare disease programs as well.

Now we actually had screened multiple base particles to evaluate them actually in monkeys before selecting this base particle. But just to reiterate, this is an LNP where we have 80-plus patient years of repeat dose clinical experience in patients. We understand the safety profile. We understand the repeat disability. And importantly, we know how to manufacture and scale this particle. Now the LNP has to be decorated with a targeting moiety to really facilitate and preferentially drive its uptake into T cells.

And here, the targeting moiety is a single domain antibody binder that was internally discovered and humanized, and it is decorated on the surface of the particle using a validated linker chemistry. The payload itself, we lean here again into our platform differentiation to multiplex. So we have a dual CAR approach, but we use clinically validated CAR architecture. And here again, we can encapsulate multiple mRNAs without having to show contribution of components.

Now 007 is our sentinel application, as I said, I'll walk you through some of our really encouraging preclinical data, and we are advancing this rapidly into the clinic, where we will evaluate a basket of B-cell-mediated autoimmune conditions, including lupus, but other autoimmune conditions as well. But beyond that, we're taking the same targeted LNP because it gets into T cells, and we want to explore applications for oncology as well, using both mRNA transient payload, but also working on gene insertion so that we can have integrating technology as well.

Beyond that, the team is kicking around clever ideas with respect to T cell reprogramming and what we can do broader with this targeted lipid nanoparticle. Now our points on differentiation for in vivo CAR-T are twofold. Number one is on the platform in manufacturing; and number two is on the product. On the product -- on the platform in manufacturing, the platform is built on validated technology. So we have extensive experience, of course, with the messenger RNA.

I will note that the messenger RNA includes a chemical modification on the 3 prime ends of the molecule to extend the half-life of messenger RNA. So we have greater exposure, greater half-life of the encoded CAR. The base particles, as I already mentioned, has tons of clinical repeat dose experience, and we have extensive manufacturing experience of that base particle. We have a proven global health authority regulatory strategy where we know how to take platform nonclinical studies and apply them across the board for our portfolio, including this program.

And as I already highlighted, we have extensive know-how and knowledge on manufacturing. And this includes both scale-up processes, phase appropriate control strategies and an infrastructure that enables end-to-end manufacturing with the long game with getting this to patients in mind. Okay. So that was point number one on differentiation with respect to platform and manufacturing. Point number two on differentiation of the product. And so 007 actually targets CD7 on T cells.

Now the rest of the field really primarily focuses on getting into CD8 T cells. We think we're differentiated because CD7 gets you into CD8s. They get you into CD4 T cells, which we know are important for oncology, and they also get you into NK cells, which have cytolytic potential. And so we think because CD8s are not necessarily a sync for us, we can get into CD8. I'm going to show you that data momentarily, but we also get into other immune effectors. We think that is advantageous for this product.

The other differentiation on the product, again, comes back to multiplexing, where we are not encoding a single CAR, we are encoding 2 CARs. And so it's a dual-CAR approach. And by targeting 2 different antigens, we can cover not only the entire B-cell lineage, but also plasma cells, which are implicated in many autoimmune conditions. Specifically, they are responsible for the generation of pathogenic autoantibodies for many of these diseases.

And so -- but we think by targeting a broader immune effector cell population, in addition to the dual-CAR strategy, we should achieve greater biological performance, greater reset and hopefully, durable remission in patients. Okay. I'm going to walk you through some of our preclinical data, starting with humanized mice. And so this is a CD19 CAR messenger RNA encapsulated in that targeted LNP. Here, we are doing IV administration once every few days, 3 times.

And I'm showing you data in spleen after the second dose, but the data are very similar after the third dose. And what you'll see on the left-hand side is we see really nice dose-dependent expression of the CAR in both CD8 T cells, but also CD4 T cells. And we know those CAR-Ts are functional because if you look at the B cells on the right-hand side, they're completely gone. And they're completely gone at all dose levels evaluated.

Now importantly, we have taken the product into monkey studies, several monkey studies, where for us, again, monkeys are a highly translationally relevant species. Again, that's based on our experience in advancing different medicines from monkeys to patients. But also the field has shown translatability as well using monkeys. Here, we do use a surrogate CAR CD20 and not simply because the binder is cross-reactive with monkeys. And we have demonstrated reproducibility and consistency across lots in these monkey studies.

And so what I'm showing you here is first, the safety and tolerability of the CD20 CAR messenger RNA packaged in the targeted LNP. These monkeys received 3 IV dose administrations every 3 days and importantly, received no pre-treatment. So no dexamethasone, no diphenhydramine. We wanted to understand the safety and tolerability profile of the targeted LNP by itself. And the dose levels we evaluated were 0.5 and 1 milligram per kilogram. And so with respect to safety and tolerability, we've been really encouraged.

As you can see here by the liver enzymes, the gray shows you what's normal for monkeys. So we are well within normal. By the way, we have 2 controls, a vehicle and another messenger RNA control, which is simply a reporter messenger RNA control. Beyond that, the clinical pathology also looks very clean, uneventful, clinical observations great. Again, these monkeys were not pretreated. So again, happy with the safety and tolerability profile.

Let's come to delivery. So we focus on our reporter messenger RNA here, which is Green Lantern -- it's essentially GFP. And I'm showing you data from Green Lantern versus the CAR because Green Lantern is a more stable protein, and with CAR, you have trafficking and kind of the kinetics of CAR pharmacology. And what I hope you can appreciate from all these immune effector populations is we get great delivery. This is 2 days after the last dose administration in blood and various lymphoid tissues. You can see in blood, we are in the approximate 80% plus range in CD7-positive immune cells.

And in the various lymphoid tissues, we see really great uptake in various immune effectors in these lymphoid tissues as well. Now when we look at pharmacology, so first, I'm going to show you blood, but then I'll show you B-cell depletion in lymphoid tissues. When we look at blood, I hope you can appreciate, so the vertical gray lines show you the dose administrations. We see rapid depletion of B cells in blood in comparison to the control groups that you can see in gray and green.

And we wanted to show you exemplary flow cytometry plots here just to show you how comprehensive the gating is for capturing the B cells. And I hope you can appreciate the CAR-treated animals, again, in the pink and red, B cells are completely gone, not detectable in the FACS plots, and when we look at counts completely gone and remain gone after each dose administration. Now as we talked about, okay, blood is great, but it's all about lymphoid tissues. So 2 days after the last dose administration, we look at lymphoid tissues.

So starting with spleen, I'm going to show you immunohistochemistry against CD20 in these various tissues. And you can see in the control arms, you see really nice staining of CD20. You see nice follicles, you see really pronounced staining. And in all of the treated animals at both dose levels of 0.5 and 1 milligram per kilogram, in spleen, we see complete B-cell depletion. So not detectable at all, no brown spots whatsoever. In lymph nodes and here, we looked at a variety of lymph nodes. In the control again, really nice staining of CD20.

And in the treated animals, we see substantial B-cell depletion across the various animals across the various lymph nodes. In bone marrow, similarly, we see CD20 staining and upon treatment, complete B-cell depletion in bone marrow. And so with that, we've demonstrated proof of concept, pronounced B-cell depletion in blood, lymphoid tissues, excellent delivery and uptake into NK cells and T cells, and acceptable safety and tolerability to advance this asset forward.

Now I'm also going to show you some cytokine data as well. So we evaluated really the full cytokine and chemokine panel. And what you can see here is the usual suspects for CAR-mediated cytokine induction do spike up transiently after the first dose that is on-target pharmacology that attenuates upon subsequent doses. And just to remind you, these monkeys are not pretreated. And so interferon-gamma, IL-6, TNF-alpha definitely spike as a result of on-target pharmacology.

Again, we looked at the full panel of cytokines and chemokines, saw nothing concerning, very consistent with our platform, data and knowledge of repeat dosing LNPs.

And so again, we get really excited when we see data like this in monkeys because of our experience in translating these products from monkeys to patients. And we're also really excited here because that binder that I told you about that decorates the base particle, our anti-CD7 single-domain VHH binder is actually a very weak binder for monkeys.

And so actually, by monovalent format, it is not detectable for binding to monkey CD7. We can only detect it weak binding when it's in a multivalent format. It has been optimized and was selected for human performance. And so it is a very tight binder to human CD7. It binds at sub-nanomolar binding affinity. And when we look at T cell uptake in vitro, so in PBMCs from human versus [indiscernible] , we see an 18-fold increase in the potency and the uptake into T cells in humans versus humans.

Moreover, when we look at the expression pattern of CD7 on sino immune cells versus human immune cells, we see far greater expression of CD7 on normal healthy donors in addition to PBMCs from autoimmune patients as well.

And finally, as you probably know, monkeys tend to be more CD8 skewed than patients. And so with our targeting approach getting into CD8, CD4s and NK cells, we are excited about the potential of the pharmacology we may observe in human patients that have been likely underestimated from our monkey studies.

And so with that, we are completing our IND-enabling studies. We are conducting a series of pre-submission health authority engagements, and we plan to advance this program into the clinic in 2027. And we're super excited about this modality. So with that, I'm going to pass it over to David Huss, Chief Technology Officer of Research, who's going to walk through platform innovation.

Thank you very much, Lin. As Lin mentioned, my name is David Huss. I am responsible for our platform science organization. So I hope that you can appreciate through all of the talks we heard this morning on our therapeutic programs that there's really a common thread that goes through all of them.

And that is that they are each built on a unique combination of Moderna's platform technologies. Now one of the reasons that I'm standing in front of you today is because I firmly believe that our best technological innovations are still ahead of us. And so one of the things that we think about is how can we really innovate the technologies of the future to build the medicines of the future.

And today, I'm actually really excited to be able to give you the first glimpse into Moderna's scientific intelligence engine and where we are taking the future of our platform technologies. So I think it's safe to say that we are truly entering a completely new era of scientific exploration. If you think back to the days of scientists in the lab doing an experiment, looking at the data, reformulating their hypothesis, going back and performing another experiment, this serial way of experimentation, while incredibly important can be very slow at generating data that can be scaled.

And so we're now in an era where the advance of new AI technologies and automation are really eliminating this slow traditional limit on hypothesis generation and experimentation. And so we truly believe that now scientific advantage really belongs to those that can learn the fastest. And so how do we set ourselves up to be that company that can learn the fastest. This really requires fundamentally changing the way that we do experimentation and also the data infrastructure that is required to take the data in and make it usable for all of our modern AI tools.

And so what I'm going to share with you is how we really think about this concept of learning at scale and positioning ourselves to be able to do that better than anyone. And so today, I'm really excited to introduce Lucy. So Lucy is at the heart of Moderna's scientific intelligence engine. Lucy connects everything that we've built in AI, automation, experimentation and data into a continuously improving learning system.

So if we think now that experimentation is no longer done one experiment at a time, we really are conducting iterative learning cycles. And these learning cycles allow us to find that next discovery in a faster, smarter and more predictable way. Now importantly, if we think about all of the data that exists in people's lab notebooks, it's very disconnected. And so the way that we use Lucy is to be able to pull that all into connected data sets and so over time, with every learning cycle, Lucy becomes a strategic advantage that compounds across all of Moderna.

Now one of the really important elements is how do we teach Lucy. So a number of years ago, we made a really important investment into a digital-first automation platform that is able to teach Lucy. And so if you think about being able to do experimentation in a closed-loop cycle where we can go from mRNA synthesis, LNP formulation, we can look at the biophysical properties of that LNP.

We can then take that LNP and put it into a cell-based assay so that we can learn about its biological performance. And then imagine being able to take all of the data that's generated at every step along the way and without needing human intervention, we can go back to the next round of experimentation based on what Lucy has learned from that first round of experimentation. And this isn't done with one mRNA or one LNP at a time.

This is done in a scalable format so that we can be testing hundreds to thousands of iterations with every single iterative learning cycle. And so this takes that concept of a single scientist in the lab doing an experiment and really just expands it to a level that we've never before seen possible.

And what we're looking at in the video here is an example of our automation platform that is running right now up in our labs where we're able to really generate data at scale, importantly, that is connected from the initial mRNA design all the way through how that LNP mRNA performs in a biological system. So this combination of the automation that we looked at and Lucy really creates this ultimate scientific flywheel.

And the way we think about this is we're transforming the data that we generate truly into intelligence. And so I talked a little bit about this concept, but it's really allowing us to go from an AI-driven hypothesis generation. We can go through mRNA production, formulation of that mRNA into our lipid nanoparticles.

We learn from about the biophysical properties of those LNPs, going through a series of in vitro based assays and that is what we do within a closed-loop platform. And you can envision that why this matters is because if I want to test 1,000 different LNP formulations or one LNP formulation and 1,000 different mRNA designs or I can do a combinatorial approach.

And so you just start to generate data at a scale that we've never been able to do before. And now that we have the AI tools available to make sense of that, it really is able to generate new hypotheses to learn in a faster way and to make better decisions about the candidates that we move forward. Now importantly, we don't stop just at primary human cell data. We've built platforms that allow us to do in vivo multiplex screening in mice and in nonhuman primates.

And what I mean by that is instead of taking one candidate into one animal, we are able to use current barcoding systems so we can take 100 or 1,000 different candidates into a single animal and then deconvolute on the back end to understand the performance of each individual candidate.

Now of course, we view human clinical data as our ultimate ground truth. And it's probably fair to say that Moderna has more human clinical data than anybody else on the planet. And so important in our scientific flywheel is the incorporation of the volumes of human clinical data that we already have and all of the data that's emerging from our ongoing clinical trials.

So when we think about the totality here, I always think about Lucy as kind of the heart of the scientific intelligence engine. But it's not just the data that we're generating today or our internal data that we've generated over the last 15 years. We also have an ability now to look at the public domain. And with our collaboration with OpenAI, with other large language models, with emerging AI tools that are coming today, we are able to pull in publicly available data sets.

And so that allows us to kind of supercharge our existing proprietary internal data that we have and that we are generating to ultimately allow us to make better, faster decisions, not just about the therapeutic candidates that we move forward, but the diseases that are applicable if we think about the biology and pulling that in. And it allows us to continually do this cycle where we learn, make better decisions and are able to create better drugs. So with that, I'm going to turn it over to Stephane.

Thank you, David. Before I close, I would like just to thank my colleagues, not only those that presented today, but the literally hundreds and hundreds of colleagues that are working within the Emirates world trying to invent the future of medicine.

So just to close, I think you've got a good sense today of how we are trying to make sure that we both deliver for the short term through Horizon 1 initiatives, but also how we prepare the future and how we have a dedicated team within the [indiscernible] community within Moderna, working on Horizon 2 and Horizon 3.

And you just saw for David, we think we're just getting started, and we're very excited about what we can do in the future by investing in science to invent even newer modalities. As we shared at Analyst Day in November of '25, for the next few years, the plan is very clear. We're going to grow through diversification of geography, as you already saw in Q1 and through diversification of products. We are very excited with the launch across the world of mNEXSPIKE happening this year.

It was a start last year, as you know. We're very encouraged by the [indiscernible] meeting both last week, give us good hope about the approval of flu moving forward. And of course, the other products that are on the slide that we talked about.

If you look at this year, it's going to be a very exciting year because not only we're getting back into sales growth, we continue to make progress on the cost structure of the company, a lot of products approval across geographies. We are very, very pleased and proud with mCOMBRIAX to get the first approval in the world of a flu and COVID combo.

And as you know, the COVID component is actually mNEXSPIKE with much higher performance than Spikevax as we totally reengineered the product. It's a totally different product.

And so with flu, you saw the data, it was published in New England Journal of Medicine recently, showing great performance, especially for people at high risk. And those 2 products are in single dose. It's already approved in Europe and many more countries are going to follow.

Of course, we have very important clinical data ahead of us with intismeran. We had very good reception at ASCO of the 5-year data, not only the data and how all the subgroups look really strong, but also the transactional medicine that we understand the mechanism of action. That is how we decide intismeran and it is doing as advertise in terms of T cells, both expansion and programming of de novo T cells.

You heard today from the team about 459. We are also expecting norovirus data, of course, depending on case accruals and PA because it's a time-based pivotal study should read out this year as well.

So it could be very, very exciting in 2026. But as you saw today through a few examples of a few modalities, we don't have time to show you everything. Just looking at the cancer antigen therapy, looking at the T cell engagers, looking at [ 007 ], just getting a sense of all the exciting new medicines that are either in the clinic for which we are waiting for human proof-of-concept data and the new medicines that are entering the clinic in the next 6, 12 to 18 months to basically expand and expand the possibility of what we do with mRNA.

And as you just saw with David, what is so exciting is we have been doing mRNA for 15 years, and we feel that we're just getting started. The ability that we have to just change totally the pace of our learning is so exciting. We've always said as a motor of a company that we don't have to be the smartest, but we have to learn the fastest. We used to do it one experiment at a time, one lipid at a time, one chemistry at a time.

But as David showed you, the team is really changing the scale of what we are doing. And what is really exciting for me is we're really best positioned, I believe, in the world to do that. If you look at the scale that we have in science, in process engineering, in early clinical, the capability we're putting together on mRNA, the AI, the automation, all those pieces coming together.

I don't believe there's a company in the world that has the scale that we have in mRNA. And that is exciting for what we can do for patients. So if you think about where we stand today, I truly believe that we have not invented our best molecule yet. I'm very proud of what the team has accomplished.

During the pandemic, obviously, the mNEXSPIKE, [indiscernible] , the flu product, cannot wait to see the NRO data. [ Intismeran ] is looking very exciting, what we can do in rare disease.

But what we're doing also now with mRNA-1195, EBV and MS, 007 with autoimmune disease. If you think about it, we're really expanding the domain of what we can do for patients in infectious disease, in oncology, in autoimmune disease and in rare disease, which is why I'm really excited about the future. I'm so thankful for our team and all of our partners around the world, including the clinical trial sites, the participants in the studies.

And I really look forward for the next few years, it's going to be really exciting. So with this, I would love to ask Rose and David to join me, and we'll be happy to take your questions. And Lavina, you'll be moderating online and in the room. Thank you.

Please introduce yourself before your question.

This is Ted Tenthoff from Piper Sandler. So firstly, just recent things. Congrats on the flu AdCom, excited for [ intismeran ] data, really cool new in vivo CAR-T program. I have 2 quick ones.

First one is kind of high level. So when it comes to really evaluating all these different new oncology products, how do you sort of prioritize and/or sequence, obviously, data-driven, but there's some overlap between [ intismeran ] and some of the shared or tumor-associated antigen products. So how are you going to really kind of select when one is appropriate or maybe better than another one?

Yes, happy to take that. So I think it's a scientific question and a strategic question. I think the [ intismeran ] represents probably the defining clinical trial on whether cancer vaccines can work or not. It's been tested in the ideal population in the adjuvant setting.

And so we are planning for that to be a success, obviously. And that's why we are moving forward the off-the-shelf cancer antigen therapies that you heard about before.

So those are moving in parallel behind intismeran, but intismeran will be the gatekeeper for those trials because the cancer antigen therapies, the cancer vaccines will probably require randomized trials, large investments and we don't want to do that until we know that intismeran is positive, which I expect it to be, but I think that's the defining moment.

I think just to your other question about how do we prioritize, part of what I've seen successful over my career is a rigorous application of does the science work? Does the drug do what pharmacodynamically intended to do? And then does it clinically have a strong enough impact to be developed? And I think both of those questions need to be answered separately for us to move something forward.

Andrew Tsai, Jefferies. Thank you for sharing your vision today. Bigger picture question as well is that as you're developing these Horizon 2, Horizon 3 products and should they succeed in the clinic and so forth, can you maybe remind us the latest and greatest about your cash breakeven guidance for 2028? Does that incorporate an increased R&D spending over the next couple of years? And then maybe a second follow-up question is there's a lot of things going on. Would it be possible to give us a brief summary of the time lines of the data readouts actually for your Horizon 2 and 3 products that you've guided to today?

Sure. Thanks for the question. So in terms of cash guidance, there is no change. Those budgets have been all along through our long-range planning and annual budgeting process. We have not just set them apart in terms of disclosure, but those investments are in the budget. What we'll have to do as we see in human proof of concept is to figure out what's the best strategy for the product. And we'll be looking at this on an asset-by-asset basis based on the asset performance, but also where the portfolio is, what makes sense for the company. Some assets we're going to develop ourselves, some assets might be better in the hands of partners. So we'll just do what is practical and for the portfolio of the company, both upside and risk.

And for your second question in terms of the horizon for data readout. So 4359 was data we just shared at ASCO and at AACR. So we're now in the confirmation stage of that signal. We have a larger expansion. And so that should be data, I imagine, next year to be shared. 2808, which is the myeloma program that you heard about, we hope to share initial data later this year on that. And then I think the other two -- the other programs, the cancer antigen therapy and the multiple sclerosis 1195, 1195 will probably have data not until '28 just because it's a randomized trial. The cancer antigen therapy could be data next year.

Mark Allen of Goldman Sachs. A couple of mechanistic questions for the in vivo CAR-T. I was just wondering, because you're targeting T and NK cells and you're combining, I guess, both B cell and plasma cell targeting, is there any risk for a greater toxicity profile? Maybe these patients be at greater risk for infection? And also, would you -- do you plan to reimmunize patients afterwards?

I can take that one. Sure. So I think a lot of these things have to be done empirically. Obviously, we're pretty comfortable with the results that we have in NHP, but you have to use surrogate programs for some of those studies. And so we're also building off our understanding of those potential targets from oncology where they've been used extensively. So we're pretty comfortable proceeding with the plan that we have today. If the depth of depletion is such that patients do need to be revaccinated for your like standard vaccination routines, that's certainly an option, and we would look to provide that for them certainly.

I think -- I'd just add, I think part of the advantages of our RNA platform is we can hit the B cells extremely hard with CD19 and BCMA, but do it in a pulsatile short-term fashion without the need for gene integration and potential risk down the line there.

This is Greg representing Tyler Van Buren from TD Cowen. So on 4106 and 4200, how should we think about the undisclosed antigen targets? Are these well characterized from existing literature? Or does their novelty represent a key differentiator? And following on that, in the absence of robust in vivo data, what underpins your confidence that these will translate into meaningful efficacy, particularly in advanced solid tumors where the biology is more challenging than the adjuvant setting?

Yes. I'm happy to take both of those. So these are antigens that are known. So that's, I think, question number one. Question number two is a great question. I mean it's probably one of the -- it's the biggest cancer vaccine scientific question, which is cancer vaccines actually work. It's been decades, as you know, where they haven't worked. And we think mostly that's because they've been tried in late-stage patients. And I think also the vaccine technology was not the ideal one.

I think the RNP -- the RNA LNP is probably the best vaccine technology. So we don't know whether it will work. We will need to do randomized trials, but we are set up. I mean this is the company that's set up to answer that question. So if intismeran is positive, if neoantigen cancer vaccines do work, we are poised to have an off-the-shelf version. And it could be complementary. It could be in adjuvant setting, and it could also be in -- we'll try it in the metastatic setting. I think that's a question which we don't yet know.

And I might just add on the validation of antigens. This has actually been an important part of our collaboration with Immatics, where, as you mentioned, in vivo models are not particularly relevant for many cancer vaccines, but we can actually access patient samples and look at what antigens were both present in those tumor types and presented on those cancer cells.

This is Matt for Mike Yee from UBS. Maybe on the ovarian cancer program, could you talk a little bit about the target you chose, how it maybe fits into the standard of care already in ovarian cancer into the competitive landscape, the TCE modality, especially? And would this be a novel target relative to the other ADCs out there? I'm just going to speak to how you see this fitting in the landscape here.

I'll handle the landscape and you can address the target. So obviously, ovarian cancer is becoming incredibly complex and crowded and it's generally divided into the platinum-resistant setting where response rate is very important and where, of course, the ADC landscape -- the ADCs are really radically transforming the landscape. The other setting is the platinum-sensitive setting.

And here, probably the maintenance setting is the right place. And this is where probably you don't want -- this is after patients have a response to platinum-based therapy. They're in the intervening period. They probably don't want to have chronic toxicity with chemotherapies or ADCs. And this is the ideal setting for where a T cell engager can work. It's also an earlier setting where the T cell fitness is better.

So the general approach would need to be study this initially in platinum-resistant setting because those -- that's where the biggest unmet need is, and we can demonstrate, hopefully, as a monotherapy signal and then decide whether it can be developed as a monotherapy approach and then study it in a platinum-sensitive maintenance, which would be a longer trial and which you would do once you validate it in the PROC setting.

I would just add that mRNA-2151, much like 2808 is actually multiplex. So it's pursuing multiple targets for Signal 1 and also includes a targeting moiety for Signal 2 co-stimulation. So that is part of our strategy for, yes, using clinically validated targets, but being able to add on to anyone who might have been exposed to a treatment targeted at one of those same proteins.

This is [ Tejas ] from Ellie Merle's team at Barclays. Maybe I'll ask on your program in multiple myeloma. Can you expand on your target product profile in terms of safety and ease of administration as T cell engagers start to move out of the academic and community settings?

Yes. So the current formulation is administered intravenously, but we have the ability and plans to also test it subcutaneously. In terms of the safety profile, it's actually potentially better. And for the reasons that you heard, that when you administer a biologic T cell engager immediately, there's very rapid high Cmax that occurs very rapidly, and that results in very -- in high cytokine release syndrome. When you use an RNA approach, the RNA has to be first translated into protein and then secreted. And so you get a gentle ramp-up in the T cell engager release.

And what we know from the field is that there is a tachyphylaxis that occurs with repeated dosing or repeated exposure. And so we hypothesized actually that the safety might be better because you get a delayed and a blunted Cmax. Of course, that needs to be validated. I believe, especially in myeloma, that T cell engagers are going to be able to be moved into the community setting. And I think our three targets we have will be acceptable for a community setting. So right now, we're focused on demonstrating, of course, activity in heavily pretreated patients, and we'll be sharing that with safety later this year.

Alexandria Hammond from Bank of America. Thanks for hosting us here in your headquarters. A couple of pricing questions. ICER is holding a meeting today to talk about cost effectiveness of COVID-19 vaccines. I guess, do you anticipate any price changes for your COVID products this fall? When might we hear about the price that gets set? And how do you expect price will feed into coverage and availability this season? I guess a related follow-up, when you think about pricing for the flu/COVID combo opportunity, how do you expect this could shake out maybe using your early discussions in the EU as an indicator?

Yes. So we're having discussions with payers like we always do. We are following what's going on, but we are not commenting on pricing at this stage.

Myles Minter from William Blair. Two for me, one on the science. Just for 1195, the EBV vaccine, great healthy volunteer seropositive data that you showed there. My question is, as you move into an MS patient population that's going to be treated, I would think with CD20 therapy prior. How does the latent portion of that vaccine work in patients that theoretically have B-cell depletion? That's the first one.

Second one, just to confirm on capital allocation, is the potential trial that you have to run if you do get approval for your flu vaccine, that, I think, was 800,000 patients over two seasons, is that in the budget? And if you do have to run that trial, that won't impact anything that we're seeing from Horizon 2 and 3 today?

I'm happy to take the 1185 (sic) [ 1195 ]. So the initial proof-of-concept trial that you heard about today is going to be run in recently diagnosed patients who are not on any biologics. So that's the proof-of-concept trial. After that, we'll determine based on the strength of the data, do we need to add on to an anti-CD20 or can we try and replace it, of course. And then finally, anti-CD20s, of course, work well, but they don't completely reset the B-cell immunity because they probably don't eliminate all those residual B cells. And so I think that's where our approach can help.

And on your second question, yes, the discussion that we had with the FDA that was discussed are in the budget.

This is Shelby here for Luca Issi from RBC. Maybe on the 1L metastatic melanoma data that you shared earlier, do you think that 33% Grade 3/4 AEs are attributed to just pembro? Or do you see some kind of additive toxicity since that rate does seem higher than pembro alone? And then maybe on Lynch syndrome, how should we think about the TAM? I think you said 1 million patients in the U.S., but I guess, what proportion of those patients do you plan on targeting initially? And then do you expect that number to kind of increase going forward?

It's a really great observation. It's something that's occurred to us as well. And when we -- it's a small number to begin with. But when we spoke with investigators on the trial, they said potentially, it might be slightly higher than what we would expect, that they are traditional immune-mediated adverse events. Some pointed out that this is using the 600 milligram, so -- which they sometimes feel does have a slightly higher toxicity profile than the every 3-week version. But on the other hand, I wouldn't be surprised or necessarily upset if there is a higher rate of severe immune-mediated because it means that we are activating T cells.

Yes. And on the Lynch syndrome, I mean, as we said, it's around 1 in 300 people. As you know, genetic tests are available for blood work today. A lot of people are not aware of Lynch syndrome. There are some geographies where there's a bit more awareness and a bit more advocacy. So definitely, this is not the right time to do anything about it for us. But as we get more data, if we think we have a product and we have in situ approval, you will see us engaging with payers, with patient associations, with governments and so on because that will be a beautiful thing to do in terms of preventing cancer and also, of course, reducing health care costs. So we will do all that if we have a product.

This is [ Adam ] on for Jess, JPMorgan. I apologize if I missed this. But for the in vivo CAR-T, how did you decide to pursue autoimmune? And should we expect Moderna to advance in vivo CAR-T for oncology?

Okay. So the ex vivo CAR-T results that have emerged over the last few years in the autoimmune space have been really eye-opening and started to tease out some of the important biology that some of these very rare B-cell populations are bringing to autoimmune diseases, including autoimmune diseases that we would have previously characterized as more T cell driven. These are showing responses to those ex vivo cell therapies.

Now, we think as you're going forward and thinking about patients and accessibility of that therapy, that in vivo CAR-T is the way to go. So from that perspective, with the ability with a few doses to truly put an autoimmune patient into remission, we think the platform is actually the ideal approach there. We are pretty excited about continuing down the road into oncology, either thinking about CAR-T or TCR-T, which is similar to CAR-T, but lets you also pursue intracellular antigens.

Yes. And I just add one other reason I think, is important in that if you think about autoimmune diseases, the confirmatory trials and Phase III trials are, of course, going to be very large. The commercial opportunity is very large. And there's no other company in the world who can really manufacture on that scale than Moderna for mRNA-LNP. So it makes sense scientifically and it makes sense also commercially for us.

Chris Yu from Morgan Stanley on behalf of Terence Flynn. We have two questions. One is, do you have any update on the pace of event accrual for the Phase III INT adjuvant melanoma study? And the second question is, the treatment landscape for multiple myeloma is rapidly shifting due to bispecifics and CAR-Ts, and you have presented multiple programs here on multiple myeloma. Just how do you think about your approaches and how that fit into the treatment landscape?

Yes. So for intismeran, we have not disclosed events, and so we're not going to start today, but we are confirming again that 2026 is the right time frame.

Yes. In terms of multiple myeloma, it's great for patients. I started working in myeloma 15 years ago, before all of the recent changes were available. It really is phenomenal. From a drug developer standpoint, it makes it extremely hard, as you point out, because the bar keeps on getting raised. For us, it made sense for this to be our initial pilot of a modality because it is derisked biologically, and we can do it. And so the question is, can we generate sufficient response rates and a differentiated product, right? This is the first time ever three T cell engager targets have ever been administered to a patient. So we'll generate the data to see if this platform works.

And number two, is it clinically differentiated enough to develop into earlier lines? I think for us, it provides also important positive control for our modality system. You heard about the ovarian cancer T cell engagers that we're going to be moving into clinic. But behind there as well, this is a company, I think, that could be on the forefront of not only multiplexing different targets for T cell engagers, but also figuring out how to manipulate the tumor microenvironment because, as you know, T cell engagers have had a difficult time or more difficult time in solid tumors and hematologic cancers. And I think the science is beginning to catch up to where we have the technical ability to multiplex. And so that's sort of the background here.

Lili Nsongo from Leerink Partners. Thanks for the great overview of the pipeline. I just wanted to backtrack a little bit. So we talked about how Horizon 2 and 3 fit into the R&D guidance. And then on the other side of that, could you maybe give us a little more color in terms of the commercial performance assumptions that kind of support the development of the second and third wave of assets?

So obviously, a lot of the Horizon 2 assets are currently in early clinical stage and then a couple of INDs are expected in 2027. So how should we think about the revenue mix that supports it in terms of the contribution from the COVID vaccine, the flu vaccine, the combo, as well as the rare disease and the oncology pipeline?

Sure. So what we're doing at this stage is developing those assets to get to human proof of concept to validate both the assets and the modality, because that's really how we've scaled the company historically. And then we will look at where the company is at that stage in terms of what do we do for the assets moving forward of the modality in terms of does it become something that we commercialize ourselves worldwide, in the U.S., and we have a partner? Does it go through a partner for global rights? So we just look at the portfolio. So what we've always done with the company is to look at how do we maximize the value of a portfolio of products and manage risk at the same time.

So it will depend on when some of those products get launched, what is their ramp. So we don't have to make those decisions now. The Horizon 2, Horizon 3 right now generate the human data to know do we have a new modality or not? If we have a new modality, then we'll assess at that time the entire portfolio. And it doesn't necessarily have to be Moderna alone. Look at intismeran, it was a great example. Years ago, when intismeran was a great scientific idea, it was clear to us at the time that doing it alone was going to be very expensive and much harder than partnering with best-in-class company in oncology, which is why we partnered with Merck.

We're very happy about that partnership. I think being with Merck, we're able to execute things we could not have done alone. So you always see us being very pragmatic. But where is the company at the time we have to make a decision? We will always look at how to maximize the value of the asset. And sometimes it might not be in our hands, sometimes it will be in our hands.

Great. I'll take some questions from the webcast. The first question is you've previously spoken about the intention to out-license or find a partner for EBV. Is this, first, still in play? And what demonstration of data do you think a partnership becomes more relevant for that asset?

I'm happy to take it. So 1195, as David said and the team presented, we are running the clinical studies to figure out the signal we have. And again, as I just answered right now, when we have the data, we look at the totality of the Moderna portfolio, the investment opportunities, the portfolio upside, the risk, and then we'll make a decision at that time.

Great. Similar question on the CAR-T assets in oncology potentially also likely to be partnered? Or what is the strategy with Horizon 2 and Horizon 3 assets?

So those assets, initially, is really to get a confirmation in the clinic, do we have a modality or not? And you're going to see us being very consistent like we've done historically with infectious disease vaccine and we're doing [indiscernible] and then we're doing with rare disease. You're going to see us doing the same thing, which is we think we have a very interesting way to address medical need using mRNA as a platform. Let's take it to the clinic. Let's look out through one or two or three programs, do we have a modality or not? And at that time, it will graduate out of MRD, and we have to figure out, as I just described, what's the best home for that modality, either internally or externally.

Okay. With that, it looks like we have exhausted questions. Thank you very much to everyone who came in person and to all our presenters.

Thank you. Have a great day.

Thank you.

Good afternoon, everyone. Thank you so much for joining us. It's my pleasure to introduce Moderna. And with us, we have Jamey Mock, CFO. Jamey, thanks for joining us.

Thanks for having me.

So to start here, maybe frame for us how you see the company positioned today. There's been an evolution, I think, with regard to the growth outlook for the commercial business with COVID and combination flu plus COVID vaccines, where you've gone to the point, I think, here of kind of returning to this positive revenue growth cycle and you have an opportunity set with your late-stage pipeline. So what are you most focused on when you look at this from a strategy and execution standpoint as we head into second half and beyond?

Yes. Great. Well, again, thanks for having me. Good to see you, Salveen. So yes, we're super excited. The last 3 years have been hard, but we've been hard at work, really trying to build the next chapter of Moderna. And so that chapter, I think, is defined by growth, diversification and really an improving financial profile as well. And so from the growth and diversity perspective, if you look at -- we're going to have market expansion across the globe with our commercial products, as you just mentioned. We will grow from a product diversity perspective, and I'll kind of walk through some of these. So I think we're really set up, and I -- we think we started that at the beginning of this year. And I'm sure we'll get into some of the financials and that kind of thing. But we laid out 10 growth drivers a handful of months ago, and over the course of 2026 through 2028, we think could be pretty substantial.

And so in 2026, we think that mNEXSPIKE, which is more -- have better relative vaccine efficacy versus Spikevax had tremendous share last year for its first year, was approved in June, had 24% share in retail. So we were excited by that, and we hope to grow on that. And then our international partnerships in the U.K., Canada, Australia, in 2027, and we can talk about it more. Europe opens up for us. We have a flu PDUFA date this year that we hope to sell in 2027. We've announced some other market expansion opportunities, particularly in Latin America, but we're working across the globe as well.

And then 2028, additional product expansion, hopefully, with norovirus, which I'm sure we'll get into, as well as the combination vaccine in the U.S. And that's just infectious disease. Then we have INT, which I'm sure we'll talk about, 4359 as well as rare disease. So we're really set up for growth.

I think underpinning that really, though, is really financial -- is disciplined execution. And that's commercial, that's R&D, that's CMC. And I think that's really starting to show up in the financial profile, and I'll just mention a couple of things. So first, over the last 2 years, we took out nearly $5 billion in cost and investment. So in 2023, we were at $8.9 billion. Last year, we were $4.3 billion, so over 50%. And we've been trying to really make sure we navigate this so that we can grow in this next chapter that we still are investing. So that's the tricky balance. Of course, you can find efficiencies, but we also wanted to make sure we were making the right investments for this next chapter, which is here, which is what we're so excited about.

And we ended the year with $9 billion in cash and liquidity, which was ahead of our profile. So I think the execution has been terrific. We've set up this next chapter. We're in the midst of it right now. So -- and I think big picture strategy, what we're trying to do is build an infectious disease business that is leading in its space with various vaccines that is a cash cow, generates a lot of cash and has a lot of growth over the next few years and then invest that into oncology. And so we hope to diversify and have additional therapeutic areas in the next couple of years and really a vastly improving financial profile. So that is what we are focused on. That's what we've been focused on for the last [ 3 ] years, and we're in the midst of it.

Great. On the 1Q earnings report, you reiterated expectations for up to 10% year-over-year revenue growth on the -- with guidance accounting for potential decline in U.S. COVID vaccinations. Now that the winter respiratory virus season has ended, do you have any more granularity on expectations around next season? And what are the puts and takes on the revenue guidance and where there could be upside?

Yes. So I think it's important to start with 2025. And in 2025, we had $1.2 billion of revenue in the U.S. and $700 million of revenue in OUS. And we said we were going to grow -- we will grow up to 10%. We hope to beat that, but that's what our guidance is, so that's $2 billion to $2.1 billion. And we said that we are going to be 50-50 geographically split U.S. versus OUS. So roughly $1 billion each. And [Technical Difficulty] thinking in the U.S. and then what are we thinking outside the United States.

So in the United States [Technical Difficulty] $1 billion this year at some kind of midpoint here. That really takes into account a couple of things. One is vaccination rate decline. And so you were just mentioning what happened in the winter season. So if you look at fall last year, it was down 27%, but fall was a wild time. There was many different reasons, I'm sure we can get into them if we want to. But -- if you look at the spring booster, it's actually improved quite a bit. So it's encouraging the trend in terms, but it's a small sample size. But -- so nonetheless, we've provided for vaccination rate declines again in the fall of 2026 and winter of 2027. So we kind of sized that in to be prudent.

What could offset that though is everything I talked about in terms of mNEXSPIKE. So if we can grow share, particularly in retail, we were 24% share overall last year. If we can grow that, that's great, number one. Number two, it comes at a higher value. So that's the U.S. dynamics. If it really comes down to the upside question, what happens to vaccination rates? We plan for a sizable decline relatively speaking. And what happens to mNEXSPIKE share and how much penetration can we have?

Outside the United States, we were $700 million last year. And you really -- and I talked about these international strategic partnerships. And you saw that in the first half already this year. So in the first quarter, we had $400 million in revenue. We said there was $200 million in the U.K. That's just for the spring booster. We're going to have another fall campaign as well that we'll supply for. So that's substantial growth. Last year, we had next to no revenue in the U.K. and now all of a sudden, we have $200 million in the first half alone.

So when you step back, if we -- if I just -- I just want to really simplify the math for people. So we guided to $450 million to $500 million in the first half. And last year, we did $250 million. So that's up $200 million to $250 million. On $1.9 billion, that's 10% plus by itself, if we're just flat in the second half. So if you're just flat in the second half and how do you get to flat, that's if the U.S. comes down a couple of hundred million dollars and U.K. backfills [indiscernible] really simplify it. That's why we're so confident in growth this year, of up to 10%, and we hope to do better.

Great. You're also still guiding to cash flow breakeven in 2028. Can you walk through what's needed from an OpEx and revenue standpoint to achieve it. Moderna's ability to be flexible on the spend side and your confidence in meeting this goal?

Yes. So I've always -- we -- I've always said that this is both a revenue increase story and a cost decline story. And so I'll start with revenue. I already kind of laid out all the variables. But just to maybe emphasize just how big these are because I said substantial. I mean there's 10 variables for several hundred million dollars each. So if we have a 50% hit rate, it's a couple of hundred million each, that's a $3 billion-plus business. And so that's kind of the revenue side. You have to assume what do you think these 10 things are going to do. If you got a 50% hit rate, you can be at least a $3 billion business. If you hit on all of them, it could be much more than that. And that's kind of the revenue side. We've kind of got to obviously got to grow over the next 2 years.

On the cost side, we've already guided to 2027 because we have such clarity of what we want to do, and we guided to $3.5 billion to $3.9 billion of cash cost. So that's down another $400 million to $800 million from last year ending point. And so we're trying to manage what is that growth line and what is that cost line. And let me say one more thing about 2027, we know what we're going to take out. There's efficiencies that we were going to go have. There's Phase III trials that are going to run off. So that's obvious to us.

Then it comes down to this choice of, okay, how are we growing? How much are we going to invest? We're building the next chapter? How are the readouts happening? What investment level do you want to make? And of course, you can always drive efficiency to some degree. But that becomes more of a choice come 2028, and that's why we haven't guided 2028, which is let's see where the revenue line is. Let's do the things that we know will happen on the cost side. And then let's make a choice based upon the data that we're seeing on readouts, the execution on commercial sales. So that kind of paints the picture of what has to happen on both sides.

Perfect. Perhaps we can pivot over to your pipeline. So Intismeran data, you recently presented 5-year follow-up data in adjuvant melanoma at ASCO. Just to level set, remind us the high-level takeaways here and the importance of the translational data that was presented.

Yes, I'm glad, yes. It's quite an exciting year for Intismeran -- for both Merck and Moderna this year. And so I think the key -- there's two punch lines, but the headline, I would say, is that Intismeran continues to be a strong benefit, a meaningful benefit, a durable benefit. So we've now have 5 years data that we're seeing the same recurrence-free survival rate at 49% improvement. We saw it at 3 years. We saw it at 5 years. So we're really encouraged by the consistency of that, point number one.

You mentioned translational data, point number two. So now this is the first time we actually try to show what is the underlying biology and how is it affecting the clinical outcome here that we're seeing. And what we saw is that tumor-targeted immune responses are better with Intismeran versus KEYTRUDA alone. And that's largely due to T cell clonal expansion as well as the number of T cell clonal types that you have. And we saw like a 2x fold improvement on those patients that survive until 5 years or recurrence free to survive for 5 years versus just KEYTRUDA alone. So that gives us a lot of confidence in the underlying mechanism of action behind this overall program. And that's why Merck and ourselves have invested so much behind this program in various indications, and we're pretty excited about it.

Great. What is your confidence level for success on the Phase III interim study that's reading out in the second half? And maybe in the context of the Phase II results translating to Phase III, but being able to get it on an interim versus the final analysis?

Yes. I won't assign a probability to it. I'll just say a few things. One is, obviously, we're super encouraged by the Phase II results. We're super encouraged by seeing some amount of translational data that supports the program. And I think this isn't a transient response now. This is now 5 years that we're seeing this kind of impact. That's a very long time. So it's a Phase II. It's 107 patients on the -- on INT versus just KEYTRUDA alone. But that gives us a lot of confidence in what's going on. And again, we've continued to invest -- both Merck and ourselves have continued to invest. So I won't assign a probability to it, but we are quite encouraged.

On the interim point, I mean we've set up the Phase III to have numerous readouts. So I don't want to dwell on just the first interim analysis. Of course, we are hopeful and optimistic that it will be just as successful as what we've seen on the Phase II. But there will be other data points, and we will look at the totality of the data in terms of DMFS and RFS and how long from a durability standpoint. So there's other things to look at, but hopefully, the first interim analysis will be strong as well.

If you had to speculate what are the key risks here to the first interim the Phase III not working?

I'm probably not the best person to speculate on the risk of why it wouldn't read out well. But I mean, we always talk about it that you never know in clinical development until you actually get the data. So -- what we've seen is very strong, very durable and very consistent. And so that gives us a lot of confidence, but you never know. So clinical development being one. And then -- it's the first interim, like I just said. But if I step back, this trial was enrolled in very quickly. So I think that speaks to investigators and patients and just how encouraged they are and optimistic they are by this therapy. So -- but we'll see when it comes out.

Can you frame for us the commercial opportunity here for this drug in adjuvant melanoma, but also lung and RCC or where we have the best sight, I guess, line of sight to data this so far?

Sure. So all three of those are going to be multibillion-dollar opportunities. Merck and ourselves have not yet released what we think the addressable size will be, but they're quite sizable, and we're really excited. And so we think, overall, if this works across a lot of indications, it can be a very large product and a platform that is and very meaningful from a revenue standpoint, but we haven't given specific estimates yet.

How are you accounting for this asset with Merck? Will you recognize it as top line revenue? And how will commercialization expenses be split?

Yes, it's a great question. So -- first, yes, it will be top line revenue for us. I'll come back to that because that's a little bit more complicated. But broadly, it is an overall, we shared the economics 50-50 split down the middle. So at the end of the day, the cash is reconciled to make sure that both partners are in on it or benefiting from it from a 50-50 standpoint. So the expenses -- commercialization expenses are actually much easier. It will be 50% on Merck's P&L, 50% on our P&L. The reason why revenue and gross profit is a little bit more complicated is because we're manufacturing the products. We are selling it to Merck because they are the market authorization holder, and then they will sell it on to the end customer. And so we'll recognize whatever our COGS are with revenue because Merck will pay us for the COGS. And then that gross profit split, split 50-50 will be added on top of our COGS and revenue for extra revenue. So it won't be 100% of the revenue on behalf of Moderna. Merck will recognize 100% of the revenue. We will not recognize 100% of the revenue. We will have something in between, and we will recognize the full COGS as well.

Is there any commercialization effort from your side? Or is the sales force fully on the Merck side here?

There's an agreement to jointly commercialize in some areas to a small degree. But I would say the lion's share is certainly on the Merck side.

Got it. At your Analyst Day, you discussed a line-by-line expansion strategy for manufacturing. Can you touch on what this means and how it leads to efficiencies over time?

Yes. We're super excited and the team did an amazing job. We have a facility just outside of Boston in Marlboro, Massachusetts, that is a stand-alone facility only for INT and it was purchased and built in a matter of 2 years. It's just incredible. And what -- to your point, we said it's a line-by-line strategy. So the facility has the ability to have 7 lines. We have only built one of those lines, and that was very intentional for two reasons.

The first reason is why invest if you don't have -- if you don't have the demand for the second, third, fourth, fifth, sixth line, don't spend the money yet. So that makes sense. It just keeps our overall cost down and a better return. But then more importantly is the ability to drive additional productivity. So we are continuously -- we already have 3 phases of how we are going to manufacture this product from inception that we've been doing for our clinical trials. We have a second phase that is already in Marlboro right now, and then we already have a vision for a third phase. And what do I mean by that? So what I mean by that is think the footprint of the boxes to manufacture these are much more automated, so therefore, less labor and much smaller footprint. So you can get a lot more throughput through the lines, and therefore, your cost comes down as well.

So as we have the demand, hopefully, for a second, third, fourth line, we'll be able to put in the latest technology. And therefore, the overall cost of goods sold will come down because it will be the latest technology on the second line. And we have already started to envision a fourth line, frankly. And so that's the key to making this as efficient as possible and most importantly, to give it as much market access as possible across the globe to drive our COGS down.

And could you discuss the cost component here of manufacturing, noting it's a personalized product. How should we think about margins initially and longer term?

Yes. So we're very confident that the initial margins will be solid, and the long-term margins we have -- based on what I just said, we have a lot of productivity roadway here. And I think that's natural in a product like this, and I've seen it in other industries as well that you will continuously automate, take labor out, make it simpler, make it smaller. And so therefore, the cost of goods sold should go down.

To step back and just think on behalf of Moderna, in terms of margins, they will start on from a rate perspective, smaller but a revenue perspective higher because you're selling at a cost of goods sold that's higher. So if you have to do that and then you split the gross profit on top of that, you actually have more revenue but less margin. Then as costs come down, you don't sell as much from that initial transaction with Merck, but then you get a greater portion of the gross profit split so your margin rate goes up, but the revenue per patient comes down a little bit over time. So that's the way to think about it. But as the patient ramp goes up, that will more than offset the small decline on a revenue per patient basis, and the margins will improve over time.

What is the view from Moderna at this point on the read-through from INT in adjuvant melanoma to other distal tumors, like lung, among others. And the confidence that this is going to translate beyond?

Yes, we get that question a lot, rightfully so. So INT wasn't really made just for melanoma. So that's how we think about it. It wasn't designed for melanoma. It was designed for cancer, and it was designed to target specific neoantigens on a tumor cell and train the immune system to attack it. And so we're hopefully seeing that already in our Phase II with melanoma. Should that work and if the biology is different to some degree, but at the same premise should be there for other indications, albeit that biology can change and maybe you have different neoantigens and that kind of thing. But -- so we are optimistic that, that mechanism of action and what we just showed in terms of translational data at ASCO can apply to numerous indications. And again, that's why I think we have 10 trials going on right now [indiscernible] and maybe 5 Phase IIs [indiscernible] and us are confident that this could work and starting to invest aggressively behind it.

And we're on track to see Phase II data in renal cell carcinoma and non-muscle invasive bladder cancer this year, too?

I don't think we've given an exact date. There is a chance, I mean, if you look at events and that kind of thing, but we have not said that specifically that we would have renal cell data in 2026.

Got it. Perfect. Norovirus here. So -- can you discuss the commercial opportunity for the Phase III asset here and when -- where you'll likely have data this year and your confidence here that this could be successful?

Yes. This is an important product for us. And so as we -- as I said earlier in my prepared remarks or my initial remarks, we want to build a leading vaccine franchise in infectious disease, and we want to have various products to bring to patients and customers. And so having two COVID products, one RSV flu hopefully later this year, our combination vaccine was approved in Europe. Adding norovirus to it, where there is no other vaccine is really a competitive advantage. And so we're quite encouraged by that. So maybe to speak to the commercial opportunity. The burden is pretty severe with norovirus. And I think there's 20 million cases a year. There's nearly 1,000 deaths. There's maybe 100,000 hospitalization. So it's severe and anybody that's had it, I think, knows that. And so the burden is obviously substantial. We think the patient population that we would target is a little over 150 million individuals in the United States.

I think older adults that get dehydrated and it really impacts -- if you're in a hospital, it really impacts you even further. So older adults think occupational therapy, health care workers, where it might spread. So -- but if we even got a fraction of that, a fraction of $150 million from a vaccination perspective, that would be a very sizable opportunity to which there is no competition. So I say it's an important product. I think it's very meaningful from a revenue perspective. And so that's that. The second part was on the trial and our confidence around it. So we'll see. We'll see this year. We've -- we know that. We believe it will happen this year that there will be enough events that it will read out. And from an approval perspective, what we see is where there is no other standard of care, anything that has relative vaccine efficacy of 50% above versus placebo normally is encouraged and approved. So that's kind of the limit that we're looking for is to be above that, and we hope to bring it to market in the not-too-distant future and we've said, hopefully, by 2028.

On the forward trajectory here for the COVID vaccine, given Pfizer's pandemic era contract in the EU will expire this year, that geography could meaningfully contribute to your growth in 2027 plus, as you mentioned. Can you discuss the size of the market and your strategy here to gain greater share and what steps you can take now for success?

For sure. There is a lot of active work going on right there. So to size the market, the flu market is about $1 billion. These are our estimates in Europe in the year 2027. COVID market, again, in the year 2027, from an actual demand perspective, there might be greater sales going into it right now, but we think it's a $700 million market and RSV is like a $100 million market. So a $1.8 billion market, pretty substantial to which we have less than $100 million is what we've said. So even 20%, 30% share across that would be pretty substantial for us. So that's kind of the market size.

In terms of where we are, so number one, I mentioned earlier, we got our flu plus COVID vaccine approved in Europe. So we're excited to bring that to market next year. We got mNEXSPIKE approved as well. So we're kind of ready to go. And so what are the actions we're taking now? Europe is normally a single payer system where you go tender by tender with countries that are the decision-makers, so we are working with them right now to shape tenders. The second thing is you need to work with health authorities and NITAGs to make sure that you have the right recommendation as well as reimbursement. So we're working with various countries across Europe to make sure that when the tenders come out at the beginning of 2027 or maybe even some of them come out late 2026, we are -- we have market access, and we have two products approved that we can go compete in.

So -- yes, I mean, 20%, $360 million versus less than $100 million, it's another couple of hundred million dollar growth, maybe $300 million growth driver for us. So that's why I keep going back to you have to believe that if we get 50% of these hits, we could be about $3 billion, and we've already mentioned that where our cost could go at least in 2027.

And your flu, COVID combo vaccine mCOMBRIAX was approved in April by the European Commission as the first COVID/flu combination, while not included in revenue guidance for '26. Can you speak to the commercial launch preparation underway, the kind of education and patient access efforts needed and your expectations for top line contribution in 2027 plus and expectations on timing for approval in the U.S.

Yes. I kind of size the market in Europe already, flu being $1 billion, COVID being $700 million, so call it $1.7 billion. So first, you got to shape tenders to actually allow for a combination vaccine as opposed to discretely COVID or discretely flu. So whether that is large in the first year or it takes time to develop and maybe have additional competitors also, we'll see, but that's number one. And then it's the same things I just talked about in terms reimbursement and getting recommendations and that kind of thing. So that's kind of the size and the tender process.

I think what's unique though and what we're trying to educate on is it brings a lot of simplicity. It brings simplicity to the health care system because they don't have to run 2 campaigns. They don't have to run a flu and a COVID campaign. You can run one campaign so that should simplify things and increase compliance, frankly, as well. And it's better for patients as well. So that instead of going and having two vaccination appointments, you can have one vaccination. So that's really what we're trying to educate every country and every health authority in Europe right now. And I think it's resonating well. We'll see how much it can grow over time, but it could be a very substantial opportunity over time.

Great. And for flu itself, you have an August PDUFA date for the seasonal flu monotherapy vaccine. Would you expect to start contributing to revenue in 2027? How big is the U.S. market for an mRNA flu vaccine? We know how big the flu market is, but what is the willingness to take an mRNA version?

Well, that remains to be seen. Yes. So it's a sizable enhanced dose market. That's where we'll play. What we think we're bringing is a lot of innovation to this space. And I think actually, we got quite a bit of education on that over the recent history because of everything that transpired around this. So the fact that -- and why do I say we're bringing innovation to the space. So we're bringing innovation to the space because the current flu vaccines take a long time to produce. And since they take a long time to produce, you have to pick the strain well in advance of the actual season. Whereas with mRNA, the innovation is you can be ready in 60 days. And so you can pick a strain that is more likely to circulate during the actual season and perhaps have a better impact and a better clinically meaningful impact to patients because it could be more effective.

So I don't know exactly the consumer angle on that. But I mean, I think people recognize that a better strain matched vaccine, if allowed could be much more effective. And the burden of flu is still in the tens of millions of people in the United States. The hospitalizations are in the hundreds of thousands. The deaths are in the tens of thousands. So it's very meaningful. And so -- but we have to continue to educate on what that can mean, and we're excited to bring the innovation to the flu market.

On the education front, in the context of just the use of mRNA during COVID. And to the period now, how much education do you need to do on side effects and safety just to have people recalibrated to real-world data as it exists today?

Yes. So we've done a lot of that. We publish everything. We're super transparent on our website to make sure every single, in our view, myth that is out there. [indiscernible] I think there is [indiscernible] I say, look, last year, we had 40% to 45% market share. So that tells you 40% to 45% of the people that are willing to get vaccinated are willing to get our vaccine, I get that our competitors also mRNA. But maybe then the better metric is look at COVID to flu. I mean there's still over 30 million people that are getting a COVID vaccine that is mRNA right now.

So hard to say we try to debunk, it what will come with that. It's a journey, I would say, but we're -- we stand tall behind our science, and we put it out there transparently. And there's still at least 30 million individuals that are willing to get an mRNA vaccine at this point. And hopefully, if the flu vaccine is better or a combination vaccine is more effective, then maybe that will grow over time and maybe the sentiment will change over time in the country and the world.

Jamey, as the last question, anything we didn't touch on that you want to highlight?

I think we touched on all the really pertinent stuff for the next 3 years, which is our next chapter, and that is what I know is on investors' mind. And rightfully so, particularly since the journey we've been through. That said, there is a lot going on behind the scenes for the chapter after that, so to speak, which is why we are having a Science Day on June 25. But there's been a conscious and disciplined investment around our science, around our platform and around programs. We announced one this morning or last night, I think. So there's more to come beyond this chapter, but we got to get this chapter right, for sure. That's what we're focused on. The only thing we didn't touch on is there still is a lot of great work going on for the next chapter as well.

Great. Well, with that, thank you so much. We appreciate the time.

Yes. Thank you, Salveen.

Hi, I'm David Berman, and I'd like to welcome you to the Moderna ASCO Oncology event. Here are forward-looking statements, and you can read them at your leisure.

Here's the agenda for today. I'm going to review the -- give you an overview of intismeran, then Michelle Brown from Moderna is going to highlight the neoantigen selection and the mechanistic foundations of intismeran.

We're very honored to be a jointed by Dr. Matt Carlino, who will give a reprise of the Phase II KEYNOTE-942 study that he presented today. Dr. Ryan Sullivan will then join us. He presented translational data on intismeran yesterday at ASCO and say we'll be sharing that data. And then I'll conclude and we'll have some questions and answers.

So for those of you I haven't met, I'm the Chief Development Officer, and I joined Moderna about 3 months ago. About 20 years ago, I had the honor to participate in the world's first checkpoint antibody for cancer that was ipilimumab. And over the past 7 years, I've had the honor to participate in the world's first TCR therapy for cancer. And I joined Moderna 3 months ago because I believe intismeran has the potential to be the world's first RNA immunotherapy for cancer. And you'll see why I'm so enthusiastic today.

Intismeran is the most advanced individualized neoantigen therapy in development. And in brief, a tumor and blood samples are taken. They are sent to a lab for sequencing to identify neoantigen mutations. These neoantigen mutations are then designed into a neutralized mRNA. We manufacture 1 lot per patient individualized. This is then shipped back to the investigator and the investigator then administer this. And you'll hear more about this from Michelle in a few minutes.

We've begun to develop a stepwise experimental framework for understanding how intismeran works. First, of course, is the production of intismeran. And as mentioned, Michelle will walk you through this in detail.

Once intismeran is produced and injected into the muscle, the lipid nanoparticle and intismeran migrates to the regional lymph node where it's picked up by dendritic cells, converted into peptides, which are presented on the surface of the dendritic cells and then the dendritic cells activate neoantigen reactive T cells. So T cells that are specific for the neoantigens encoded by intismeran.

These neoantigen T cells then circulate in the blood and hence, there is an increased clonality in the blood. And the T cells then migrate to where the tumor is and identify those neoantigens and kill the tumor. This is the theoretical framework.

Now personalized or individualized vaccines have been studied for several decades, predominantly as peptide adjuvanted peptides and as DNA. And it has been shown that novel T-cell clones in the blood can be produced or induced as a result of personalized vaccine. However, until intismeran, no one has ever demonstrated efficacy and especially not in a randomized trial. And so today, as mentioned, Dr. Carlino will present the 5-year updated efficacy of RFS, DMFS overall survival, from our randomized Phase II trial.

Now he will also take a step to the left and show you that we do see an increased level of novel clones in the blood. And he will show that on the intismeran randomized arm that patients who are relapse-free who don't relapse have higher levels of T-cell clones in the blood than patients who do relapse. So this provides a link between intismeran and the efficacy.

Now the outstanding question to date has been what are these novel T-cell clones you'll see in Dr. Carlino's presentation. What exactly are they? And this is where Dr. Sullivan's presentation will come in, and he will complete this loop showing that these novel that appear in the blood are in fact, T cells that react to specific neoantigens encoded by the intismeran product. Therefore, we have this complete circle. And to me, someone who has worked in immunotherapy for several decades, this is the strongest proof of confidence for any immunotherapy, of course, prior to a randomized Phase III trial.

Now why have prior therapies not worked? Why have prior individualized vaccines not produce the results? And why do we -- do I think intismeran works? First, of course, is the intismeran drug product. It's a modified mRNA in a lipid nanoparticle. And we know that this type of product is highly [indiscernible] to induced T cells. We've known this for COVID, for flu and for RSV, and we now know it as well for intismeran.

But the second is where intismeran was studied. If you think about it, prior studies were in heavily pretreated patients with metastases, usually multiple lesions and 1 lesion of many is usually biopsy to make the individualized product. However, in this late stage, there's probably intralesional variability. So producing a neoantigen vaccine from 1 tumor may not represent other tumors in the patient. Second, of course, the T-cell fitness in heavily pretreated patients is not good. And finally, patients with metastatic disease usually have somewhat rapid progression and this limits the time for the vaccine to take effect.

All of these are eliminated in the adjuvant setting. There is 1 single dominant lesion that is sequenced for the vaccine. That's removed allowing maximal T-cell fitness as good as you're going to get, and there's enough of a runway to produce the intismeran drug product.

Even, in the successful -- despite the successful development of anti-PD-1s in the high-risk adjuvant setting, there is an unmet need. For example, bladder cancer, 64% of patients treated with anti-PD-1 will still recur. And up to half of patients with adjuvant high-risk melanoma will also recur. And you can see even in other tumors, there is a significant high risk of recurrence. So unmet need still remains. Pancreatic cancer is here in gray because, of course, anti-PD-1s are not approved here, but this remains in the adjuvant setting, an area of high unmet need. And this is why intismeran was initially focused in the adjuvant setting, and in tumors that are known to be IO sensitive because IO sensitive means that checkpoints work here and checkpoints unleash he sells to target neoantigens. And therefore, it makes sense to study intismeran in adjuvant settings that are IO-sensitive melanoma, lung and genitourinary tumors.

We also have trials recently initiated, for example, the Stage 1 Phase III non-small cell lung cancer, which is the first time that we're actually getting a intismeran arm that's monotherapy, and then we have our Phase II non-muscle invasive bladder cancer. We decided to also study this in the metastatic setting. Now this is a higher risk for the reasons I articulated, but it is certainly worth studying in a Phase II trial.

We have also decided to explore intismeran in tumors that are generally less sensitive to immune therapy, gastric cancer and pancreatic cancer as well. And these are single-arm trials that we hope to share results for soon.

I'm now going to call Michelle up to talk about neoantigen selection and the development, how we make intismeran..

Thank you, David. So hi, everyone. It is nice to see you on feedback Okay. It is nice to see you at the end of ASCO, and we're really excited to have this as one of our third type of conference events around an intismeran dataset. And so we're very excited to see Dr. Carlino and Dr. Sullivan showcase the data that was planned over the weekend.

As David alluded to, he highlighted the unmet need that still remains in adjuvant melanoma and the adjuvant setting and tumors overall and also the basic principle behind why we think intismeran can be extended into the type of clinical portfolio we have today. But one of the things that we think about, and I think it's important to highlight with intismeran is that it is not just a traditional clinical product. It really is a process, and it's a process that sits at the culmination of mRNA LNP advancements on genomic medicine, next generations with next-generation sequencing, digital [indiscernible] small scale manufacturing, and really, it is because of all of that, that we're able to generate a personalized approach that we think has brought applicability to a number of tumor types.

So my intent here is to double click on some of the technologies that funnel in to intismeran to be able to make it as applicable and where we're advancing and making learnings. So as you see here, one of the starting point, as David alluded to, is that with intismeran, it starts and ends with the patient. And so this is very true with the leverage of the patient's tumor tissue and their blood sample and then the use of next-generation sequencing to understand the wide variety of mutations that are actually present in a patient's tumor.

And using that litany of information, we can understand what mutations that tumor is using to generate these neoantigens. And what neoantigens are, are those aberrant tumor mutations that are recognized by the immune system. But it's not enough for a mutation just to be present. It also has to be expressed. And so we use RNA seq to understand or pick the expression profile of these mutations and then also HLA typing to understand how the immune system is going to recognize these aberrant proteins.

So then when we take all of the genomic information, the RNA seq information and the data analysis, we leverage all of that data inputs into integration and interpretation with our bioinformatics algorithm to actually manufacture intismeran. So it's a different way of looking at the little cycle that you guys are used to seeing. But as you see here, one of the foundations building on all of the inputs for the next-generation sequencing is the algorithm itself.

And the algorithm, you have to think about it as a node for this technology. Because what it does is it takes all of that input, we use the litany of mutations that are present and basically says, which out of these are going to be the ones that are most able to mobilize the immune system. It then rank orders the amount of neoantigens and puts them in and selects the top 34 that we think will activate the immune system to generate de novo T-cell clones and increase endogenous T-cell responses. And this type of mechanistic hypothesis is the foundation of what Dr. Sullivan will be presenting today.

So if you believe this, what it means is that right now, the current algorithm is well controlled, and is essentially applying the same basic rules and principles for every intismeran patient that we have. But what we know is that science advances and technology advances, and we have a litany of clinical studies, as David alluded to, that are going to drive learnings. And so while the algorithm itself right now is fixed, it doesn't mean that we don't have an approach where we could adapt to those learnings and have it iterate on itself. And in fact, we're in conversations with the agencies to understand how we could adapt the algorithm based off of learnings today.

Now a lot of you ask, this seems like a relatively complicated process. There's a lot of steps, there's a lot of arrows. Do we really have to do this? And the answer was presented back in SITC in '24 where we essentially looked at the patients in KEYNOTE-942, so the Phase II study that Dr. Carlino will be discussing and looked at their intismeran antigen cassette. And what we found in that was that the majority of intismeran plus pembrolizumab patients had a full 34 cassette. So 91% of the patients that were treated had 34 neoantigens, but you can see that there's a span. It goes from 9 up to the 34. And that's not surprising because melanoma tends to have a lot of tumor mutations and so we have a lot to choose from and select from.

But what was interesting was that 99.1%, so over 99% of the neoantigens that were selected were unique. So they did not overlap between patients. And for that, less than 1% of patients that did have overlapping neoantigens, these were BRAF mutations and NRAS mutations. So what we know is that the algorithm is actually accounting for your traditional biological relevant mutations and then selecting hotspots that are relevant for those specific patients.

But it's important to note that even though some of these were overlapping neoantigens, the actual neoantigen itself, like the cassette frame, was different because it's based off the patient's biology, it's based off their HLA type, and it's based off the specific sequence for themselves. So even though they're targeting, let's say, BRAF, it's different parts of that BRAF that are tailored to that patient. So really, what this tells you is that we do have to go through all of the steps to generate an individualized neoantigen therapy because no 2 patients and now 2 tumors are the same.

So that funnels into the mechanism, which I think you've seen before. But the idea here, as David alluded to, is that we use all of the digital infrastructure in the next-generation sequencing to program and select these 34 neoantigens, which then integrate seamlessly to our manufacturing site to generate an mRNA cassette and encapsulate that into an LNP, which is then administered IM. Once the intismeran enters into the body, it tends to go to the lymph node, where it uses natural cellular processing to generate peptides that are expressed on MHC I and MHC II to activate CD8, CD4 cells, which then generate effector immune memory phenotypes.

So essentially, this was our hypothesis for how intismeran should work. And it's essentially saying that we're training and activating the immune system in a targeted way. And then the thought was that if we combine this with a PD-1 inhibitor, you're essentially taking the brakes off the immune system and mobilizing and maintaining activity of these targeted T cells. And again, one of the things we've been so excited about is not only the clinical data that's being presented, but the translational story that's following this mechanism.

And I think it's important to double-click on that translational story because, what we talk about a lot of the time is the clinical data set, the clinical portfolio. But one of the foundations with this type of technology is, again, the amount of learning that we are going to be able to have. So it is important to note that because of the litany of clinical studies we have in collaboration with Merck, we do have a lot of translational learnings to guide our future states. So we do have across the studies, multiple sample collections basically from every patient that comes on. We have a tumor sample for sequencing. We have a blood sample, and this gives us baselines, but it also can give us baseline about their biology, their sort of biological state in the blood.

And then within each study, we have a number of samples that are being collected to generate additional earnings. So that can teach us on the mechanisms of recurrence or progression. It can also to us about the use of ctDNA or really how the neoantigen and the immune system are interacting and interfacing. And all of these learnings can then be put back into the platform to help us with either future clinical trial designs or again, future intismeran design.

And right now, if you take a look at the totality of the clinical seats that we have, what it would mean is that we would have a repository of over 5,000 patients that we would have samples for to help us learn, which represents the largest portfolio that for a neoantigen approach to really drive those learnings.

And I think it's important to know, as David alluded to, that we do have a very large portfolio of studies, and each one is addressing different questions, where we started in this immune-sensitive foundational tumor, as Dr. Carlino will talk about with adjuvant melanoma for the highest probability of success. We then expanded to tumor types that had biological adjacencies that would make sense with the mechanism that we talked about. But after that, we started exploring the bookends because really, this type of approach is tumor specific. So we wanted to test how early can we go, especially with the safety profile we see, and that's one of the reasons we're so excited for the Stage 1 study but also for the NMIBC study. And then how late can we go because maybe we really do have the ability to activate that immune system in a metastatic way.

And then lastly, we're able to do this with multiple combinations. So we aren't just combining with the PD-1. We are combining with standard of care where it makes sense because, again, the mechanism is distinct and the safety profile is distinct.

And all of this really started with the Phase II P201 study that we presented back in '23 at AACR with the primary analysis and what Dr. Carlino is going to talk about today with the 5-year analysis, which represents the longest duration we have for follow-up for this type of technology. Thank you.

Thanks, Michelle. So if I [indiscernible]. It was exciting then and to sort of think about the concept, but the last few weeks have sort of closed the loop both presenting this data, but also visiting the production facility at Moderna and seeing the change from a trial that we were, I think, we put 15 or 20 patients on at our site and 107 patients collectively to now an infrastructure that's ready to make thousands, hopefully, for commercial products very, very soon.

So this is a slide deck I presented this morning. I'm happy for people to interrupt. Also presented slightly differently, given that some of the information overlaps with David and Michelle and maybe have some commentary as I go.

So ASCO makes you do your key findings first. And the key finding of the study was intis and pembrolizumab really works. So it reduces the risk of recurrence by 49% or 59% for distant metastasis-free survival.

To put those numbers in perspective, I think the benefit of pembrolizumab over placebo is smaller than that. And one of the things I was taught when I was reading papers as a trainee was the easiest study to do was when your study is of an active drug versus nothing or an active drug versus an inactive drug, right? So a study of placebo versus an active drug, placebo versus pembro or an active drug versus an inactive drug dacarbazine versus nivolumab. It's actually harder to get a big benefit when you're comparing yourself again something that's effective. So I think those numbers are more effective when you -- when the comparators actually pembro, not placebo or we weren't silly enough to give adjuvant to dacarbazine.

The second point is the safety profile. I'll touch on when I get to the safety slide. But I think when it comes to adjuvant treatments, there's really important safety factors that this does that other adjuvant trials hasn't done. And the last point I'll come to David and Michelle touched on, is the translational data that really links how intismeran is designed to what we're seeing. So this is clearly on-target benefit in these patients. So I think the translational data that's sort of, for want of a better word, a little bit superficial from this that I'll show you to the really deep dive that Ryan will show you. It closes the loop of the story.

So this is -- I'm sure you saw my slide or maybe I saw your slide. Anyway, so look, just reminding you of the mechanism of action, the goal is to expand existing and create new T-cell clones, targeting those up to 34 neoantigens that's in the intismeran. And we'll show you that, that's actually what's happened. And the theory is by giving the pembrolizumab, you're potentiating that response. So you're, if you like, getting that response and then driving it forward with the pembro.

So as I said, background, nivo and pembro both work. In the adjuvant setting in stage 2, stage 3 and stage 4, they reduce the risk of recurrence by 40% to 50%. So that's how I -- and I'm sure Ryan's the same describer of patients. If your risk of recurrence started at 60% roughly, we're making at 30% with pembro.

But that means whatever we're doing a significant proportion of patients still develop metastatic disease and still die. So an improvement on this matters because someone who gets adjuvant pembro or nivo and subsequently occurs has a very high chance of coming from their disease.

I think the other thing to remember is no trial has improved on this. And there's been -- I've been involved in 4 studies that have tried to improve on pembro or nivo. One of them stopped early. The drug was so bad. 3 of them were negative, including 2 agents that were positive in the metastatic setting. So the addition of ipilimumab and the addition of [indiscernible] don't improve nivo. I think the other thing about those 2 studies is both of those agents increased tox. So in the adjuvant setting, the thing I don't like is permanent toxicity. And so pembrolizumab, relation ipilimumab, all drive permanent toxicity, and the one that bothers me the most is patients who make diabetic or patients that give quarters old efficiency, too.

So I guess the alternative trials that we filed and failed had the added negative causing the toxicities we don't want in the adjuvant setting. And the previous analysis were positive. So the job today was to update the 5-year data and then give that beginning of translation data.

So here's the study design. There was a question today from the audience or maybe a comment from the audience, which was a compliment to me, but really a compliment to Moderna and a slap in the face to everyone else. So Jeff Soman is the most famous question ask in melanoma. And he made the point that this study was so important to be a randomized Phase II. And the other 2 people I shared the stage we've had single-arm studies. So I think that's right.

So if Moderna had done 200 patients with intismeran and pembro, and then try to compare it to some historical control. Rightly, we wouldn't -- we would be more skeptical or you should be more skeptical -- you should be most acceptable than a randomized Phase II. So I think this is a perfect example of the power of randomized Phase II trials, not to get a drug approved but to say it's worth and it's likely to win in Phase III, it's worth going forward with.

It was quite a high-risk population, which I also think was another smart move. Although we enrolled stage IIIb patients, they had to have recurred first. And actually, there's no stage IIIb patients in the study. So by going for a high-risk population, you can get away with a 150-patient study, and you get an answer early. There's nothing biologically different between stage II melanoma and Stage III. It's just you can get an answer with a small study, and I guess from a major point of view, a quick answer with a relatively small investment.

Patients needed to have tissue available to make or design a intismeran. That's something we were really worried about early on. We are -- the investigators thought, "Gee, we're going to need large chunks of tumor to get to make this thing," but we learned in this study in the subsequent Phase III study, that's not necessarily the case. 1/3 of the patients on this study actually had micrometastatic disease. So they didn't have big lungs of tumor. It was microscopic.

And certainly, when we all see the results from the Phase III study, probably 2/3 of patients had microscopic stage 3 disease. So you don't need big lumps, but you do need tissue but patients have tissue, easing 2 patients will have blocks of tissue available. Am I going too slow?

Okay. So this was a primary endpoint, relapse-free survival. A couple of things what I touched on before, a hazard ratio of 0.51 is really impressive against an active drug. So I imagine -- and I like to do this, so I'll do it. But if you put the placebo curve from the 054 study down there, and you looked at the equivalent patients. So not the whole 054 study, the 054 is pembro versus placebo. If you put in the placebo curve, I think I calculated that it probably sits at about 30. So you're going from 30 to 50 to 72. And so that really -- it's an additive benefit. And not many drugs do this.

So I was going talk when we developed on it, it was well before my time. But when people got hormone therapy for breast cancer, tamoxifen versus nothing, tamoxifen nothing was really impressive, but arimidex versus tamoxifen wasn't that much better. Same with Herceptin. Herceptin versus nothing is fantastic. Adding in Perjeta, a small benefit. So this tells you unlimmab, unlike relatlimab, this is a new class of drug and that's why you're getting that significant delta.

The other thing to say is a delta of 23%, so an absolute benefit of 23%. Or if you put the placebo curve in an absolute benefit above 40%, 40% absolute is kind of huge.

This slide really just shows that the benefit is durable and maintained. So first analysis, the hazard ratio actually gets better. Often with trials that have transient the first ASCO presentation, the hazard ratio is as good as it's going to get, and then it gets worse. So typically, what happens is ASCO presentation, one, best data you'll get post #2 because you don't get a second oral presentation, the hazard ratio gets worse. And then you don't even bother with the third presentation. This is the opposite, improves and then maintain benefit in terms of relapse.

Acknowledging this is a small study. I think this gives us confidence that it's not just 1 small group of patients we're helping. So, the collection was better if you had stage III disease, stage IV disease, PD-L1 status, BRAF status, left-handed, right-handed, high tumor mutation burden, et cetera. And so I think it's really promising going into the Phase III study that we're unlikely, I think, to have a population of melanoma patients that aren't going to benefit from the incremental benefit of intismeran, pembro.

Just a metastasis-free survival. So this has a ratio of 0.41. Got a lot of talk, I think, probably the first presentation. So another thing that you often see if you look at an adjuvant study, the relapse-free survival hazard ratio is typically better than the distant metastasis-free survival ratio. So there aren't many studies where distant metastasis-free survival is better. And in some ways, if it's a patient, what do you want, right? You said you can -- you have to have a recurrence, Certainly, I choose a local one.

So a drug that shows a bit a great benefit when it comes to the stuff that matters liver mets, brain mets, lung mets in some ways. So I'm really interested to see if this pans out. And certainly, biologically, there's an argument why this immune surveillance may be helping with distant metastasis. And once again, an absolute benefit of, I think this is 18% is huge in terms of distant metastasis-free survival. And incrementally, that's bigger than the benefit of pembro over nothing.

Overall survival is a really high benchmark. So to give you an idea, KEYNOTE-054, pembro versus nothing, there's still no overall survival available. It's at 9 years, right? So to see even a hint of an improvement in overall survival hazard ratio of 0.47, the reason this crosses one is the lack of events. But if this pans out, we may be getting an improvement of overall survival with intismeran versus pembro when pembro versus placebo has done, which will kind of be interesting for -- we won't be allowed to use pembro unless it's given with intismeran.

Okay, side effects. So A couple of things about side effects for me. So I'm not particularly concerned that any treatment-related AE in some ways there's an incremental slightly higher number with the combination versus a single agent. That doesn't bother me in the slides. So these incremental increases relate to pretty predictable side effects, and these will be better manageable today than they were on the study.

Remember, when we were enrolling these patients, it was either no patient had ever been an mRNA vaccine because it was pre-COVID or it was post-COVID, everyone who got febrile made us panic and we had to lock them up if they were febrile. So I think having slightly higher treatment-related is not a lot of consequence, particularly when we know what they are.

The most important point to me is this, the red box, immune-related AEs being equal or at least numerically, potentially lower. So give adjuvant treatment, how I describe it to patients in the wording I use is if you get in certain side effect here and it makes you run well for a week, but your melanoma doesn't come back, you should still thank me.

If I give you type 1 diabetes, if I give you cortisol deficiency, you still have to thank me, but you're allowed to be angry at me. And there's no increase in those type of immune toxicities with this. So this, in some ways, for us, it's a relief that we're not talking about giving adjuvant ipi/nivo and giving people a 10% to 15% chance of cortisol deficiency because when this is approved, we'll be able to say a risk of quarter efficiency remains 1% to 2%.

The intismeran side effects are pretty predictable. It's interesting now that we've got a placebo control trial. I've got two. We're currently running the metastatic trial of pembro plus intismeran for Stage IV melanoma, and either I'm very lucky at getting my patients randomized to the combination or a lot of my patients/myself have the placebo effect because everyone gets chills and a sore arm, but it doesn't seem to be too bad. So they are really manageable. And I don't think of, now that we know what we're doing with the current trial in the previous Phase III trial, it was responsive really to NSAIDs, paracetamol, a little bit of fluids.

So this is the translational data that Michelle touched on, which I actually think was the best part of this presentation rather than the uptake. So I'll just talk you through it and because this took me a while, and I think Moderna immunologists had to slow it down for me.

So what this is [indiscernible] clonality. And so clonality means have you got a large amount of T cells attacking 1 clone and up is more clonality and down is more diversity. So a spread T cells targeting lots of different targets or not targeting for that matter. And they're sort of inverse relation, the more clonality, the less diversity. And the more diversity, the less clonality.

So at baseline, and the time point to baseline. So this is before they get the drug. We have sign consent. Moderna is busily making the product. They haven't yet got any pembro. We give everyone 2 doses of pembro, and they haven't yet got the intismeran, which is often given with the third dose. This is after 2 potentially with the third intismeran at this time, point. And this, for most patients, is a year after starting, but importantly, 6 months after the intismeran dose for the vast majority.

And so I'm going to talk this backwards to what I did today. I'm going to talk about the blue line first. So pembro alone does not increase clonality. And the way I think about that is pembro is activating your immune system, but it's not specific to any one thing really because otherwise, if it was specific to certain targets, you would expect clones to could have come out. And that's certainly how I describe pembro tox to patients. I say I'm trying to activate your immune system to attack melanoma because I'm not smart enough to point it towards the melanoma, you're going to get a side effect that ataxia thyroid. What intismeran is the opposite. We're getting an increase in clonality, right? So we're getting our immune response directed. This does not tell us -- well, this curve doesn't tell us that we're directing the immune response towards those 34 neoantigens. But the question is, well, if it's not directing it to those 3 neoantigens, what are you directing it to? But also, Ryan is going to show you that we are, in fact, directing it towards those 34 neoantigens.

But this also tells you why you don't get immune-related toxicities additively because your immune response from intismeran is directed at those 34 neoantigens. And hopefully, the algorithm is choosing neoantigens that are novel to the tumor, not host neoantigens.

Similarly, this is the new clones now. So the -- what they've done here is forget about any line that existed before the patient walked into the study. Same thing. We are getting new clones coming out. And at the early time point, because the 2 arms of the study are identical, as many new clone pembro as you get for pembro because both arms are getting pembro. But you get a greater number of clones with intismeran. And once again, the suggestion or the hypothesis confirmed by Ryan or whoever did the work Ryan presents is this delta, this extra number of clones is due to clones directed at those 34 neoantigens in the product.

Okay. closing the loop is this. So just for a moment, forget about that curve, this is now just the patients who got combination. So intismeran, pembrolizumab, everyone in this curve, it's the same time point. Red patients did not recur. So these are the patients who, if you like, can't hasn't come back [indiscernible] patients, unfortunately, did recur. And it's really linking the mechanism to outcome, the patients who didn't recur got more novel clones than the patients who did recur.

Closing the loop. That association between novel clones and outcome wasn't seen with pembro alone. So once again, really strongly suggesting a mechanistic link between intismeran and the improved outcome. So as I said, I think the support for this data that Ryan's data gives is huge [indiscernible]. So I think the ratios of 0.41, hard to look aside, but when you see the data that proves how it happened really does close that loop, even based on 157 patients.

So this is essentially a return to the things. It works. It reduces the risk of staff coming back a lot. The safety and tolerability is fantastic. Really, the side effects you see are pembro side effects. So there, I don't -- I cannot think of a patient that I am willing to give adjuvant pembrolizumab to that I'm not willing to give adjuvant intismeran and pembrolizumab. There are many patients I could consider giving intismeran to that perhaps wouldn't have pembro, but it's that good a safety profile.

The translational data, yes, the superficial translational data I showed to you really does, I guess, suggest the link metastatically. And Ryan's data is going to take that suggested link to a kind of uncertainty in a moment.

I think like always, I think finding so much information from a randomized phase to is a positive, not a negative. But ASCO e-mail me said I had to have some study limitations. So I actually think the ability to make such a strong scientific argument based on a randomized Phase II is a strength, not a weakness. But the job of this study, and it did it in Spain, not only to lead to a registration Phase III in melanoma but to lead to multiple registration studies. So I think when we -- I'm glad that the first registration positive study will be melanoma and like always, all the other cancer types can follow. I think when we see the study -- the registration study soon, I think, at least I'll remember and it kind of started with 157 patients 5 years ago. Okay. Thank you.

Okay. So I get to take us home. So one of the joys I've had with working with Moderna and with Matt and the other investigators is having the opportunity to present some of the translational data with this study over a few years. And when we were presenting that data that Matt just showed with the expanded clones, people said, well, are they, what are they against, and he said, "I don't know."

And we just, there was initial collection of large numbers of patients with leukapheresis to do very sophisticated analysis, and to type these T-cell clones and see if they were neoantigen specific. And we've ultimately gone to the point where we have some of that analysis. And so that's what I'm going to share.

We've seen much of this. I will say that KEYNOTE-603, which is the Phase II study of intismeran did show in their -- in the publication that came out last year that all of the patients that they had T cells collected and analyzed, they could show that there was neoantigen-specific T-cell clonal generation. 30% of those neoantigens elicited immune responses, and you could see both expansion of CD8 and CD4 positive T cells.

At KEYNOTE-942, again, intismeran shows higher new clonality. And those were sustained over the course of the study, in fact, in those patients that didn't recur, it seemed to be going up. And the novel T-cell clonal type expansion associated with better outcomes.

So what I'm going to do over the next few minutes is talk to you about how the efforts that have been done to link the de novo T-cell clonotypes to intismeran-encoded neoantigens and to characterize the resulting neoantigen-specific T-cell responses in patients who received the combination.

So importantly, this study looked at some patients worth samples. Samples were collected. I wish I had that little the figure that had each of the time points. But baseline after starting pembrolizumab after starting intismeran and then a long-term follow-up, which is usually a year after therapy started, in about 6 months after intismeran ended.

From these 7 patients, 3 were actually from the Phase I study and 4 were from the 942 study. And what this figure shows is that using a really cool assay where you can essentially load the peptide and have a reporter assay that has a T-cell receptor that can recognize that peptide, you can begin to see -- or you have the T-cell receptor that are on these T cells, you can see whether or not there was a target agent which essentially means that it was a neoepitope-specific TCR.

So this is a patient, and just showing the example that you can identify a number of different TCRs against the same neoantigen. So remember, up to 34 neoantigens are in the cassette. So this was looking at neoantigen 14. And so these were all generated for neoantigen 14 in [indiscernible]. These happen to only be CD8. So this patient generated CD8 T-cell clonal clones against neoantigen 14, against neoantigen 27 and 28 similarly, just CD8, but also CD4. And so proving the sort of proving the point that when you create a neoantigen therapy, you may get both CD4 and CD8, and we think that's probably a good thing.

Now this is taking that same patient and then looking at all the T-cell clones that were generated against those specific neoepitopes. So again, 14, 27, 28. So this is only CD8 positive T cells against 14, but as I mentioned, CD4 and CD8 against 27 and 28.

And the ones that are in color are the ones that have been characterized to date. It turns out it takes a lot of time to do this. And really, the point of doing this was just to show, yes, we can do this, we can follow this, but there's a ton more that were generated. And I think it's important to note this straight line is when patients are getting pembro. And then the steep upward sloping lines are after intismeran. So dozens of different neoepitopes for specific TCRs were mapped to each neoantigen.

And the other point to make is that, some of these are going down, but most of these are sticking around. And it's been 6 months since this person received intismeran and yet they still have at least the same, if not higher, numbers of T-cell clones against, for example, neoantigen 14.

When we look at all 7 patients, we were able to identify at least 1 T-cell clone that are T-cell neoantigen-specific T cell. This was this patient. The highest of the 7 was 18 out of the 34. Importantly, and I think it was mentioned earlier that there is rare shared neoantigens, but those that are shared are either BRAF or NRAS neoantigens. And that intismeran, again, elicits CD4 positive and CD8 positive and combined CD4 and CD8 positive to different neoepitopes.

When you begin to look and say, okay, that's cool. You have T cells that can recognize the neoepitope, what are those T cells doing? And so in this, we're looking at staining of the T cells. What you can see when these T cells are engaging the antigen is that they're making granzyme B, which is a good thing if you want T cells to kill things, and they're making interferon gamma. And so this is different patient still patient 3 and looking at the responses against neoantigen 14 and neoantigen 27. So not only are they there and we can identify them, but they seem to be acting like the type of T-cell we want to generate cancer cells.

In addition, you can then begin to look and say, okay, what type sort of bucket would you put these T cells in? Are these the cytotoxic T cells that are terminally differentiated and killing and then dying are these memory cells that may not be as close to the action, but can stick around a while? Or they T effector memory cells. And you can characterize that, what's happening here is you're doing a [indiscernible] stain of the neoepitope, and then you can see which actually buy into the [indiscernible] and then you can see where they are. So this is a control against viral antigens.

And so what you're seeing that these T cells when exposed to viral antigens are terminally differentiated. These are ready to go. They're trying to get rid of those virally infected cells that they thought they got exposed to. And when we look at the intismeran-treated T cells, these are falling more into the T effector memory. So they functionally active. They're positioned to do rapid surveillance and they can also potentially leave and go to other sales, other areas of the body.

So to conclude, we saw durable dovo neoantigen-specific T-cell responses in patients who are treated with intismeran and pembrolizumab. The team at Moderna was able to functionally validate and directly map the intismeran encoded individualized neoantigens. They've validated the neoantigen-specific TCR clonotypes and expanded during intismeran therapy. And most importantly, they persist over time. We could see both CD4 and CD8 T-cell responses.

And the nice thing about this is if I'm standing in front of somebody talking about intismeran and they say that was [indiscernible] you showed about those TCR clones, but do you even know that those things are going after neoepitopes? I can say, yes, I think we do know, what's next, Dave?

Okay. Thank you very, very much. Wonderful presentations. We appreciate you both taking time out from your busy schedules. So today, you heard about intismeran, and that's frankly, why I came to the company. But since joining the company, I have also discovered quite an exciting oncology pipeline, including our 4359, which we presented, we had an oral presentation at AACR, 4106 and 4200, which are off-the-shelf cancer antigen therapies. A T-cell engager, in vivo T-cell engager program, which is really, really interesting, 2808 and then cell -- in vivo cell therapy enhancers. These 3 programs as well as our emerging oncology research programs, which will enter the clinic will be highlighted at our Moderna Science Day later this month, and I encourage you to attend that.

So now I'd like to invite up our speakers, and we're happy to take questions and answers. So guys -- if Michelle.

Great. Thank you, everyone, for fantastic presentations. We're going to start the Q&A session. When you do take the mic, please introduce yourself and then ask your question.

Ted Tenthoff from Piper Solar. If I may, I have two for Michelle. And if you permit me, I have one for Ryan. So it was very interesting to see in melanoma that a small percentage of the antigens albeit unique to the patient were kind of what I would call shared or known driver mutation, i.e, respin. In other cancers, are you seeing more of these shared ones? And the one that jumps to mind right away would maybe be a Phase II for CRC. Are you seeing more KRAS or things like that? So are you seeing different patients depending on the tumor type, a different flavor and/or number of these shared antigens?

And kind of the second part where the question is going is, how do we know these neoantigens are actually better than shared antigens? And I guess it's kind of impossible to prove that out until maybe we do like intismeran versus one of your shared antigen [indiscernible], I don't know. But how do we actually know that these are better?

Yes. So maybe I'll start and then phone a friend if anyone else wants to answer. So I think the key is that in the bioinformatics algorithm, all it weighs out all the mutations and that includes hotspot mutation irrespective of the tumor type we're going into, which is why you see the type of clinical trial portfolio we have. So in melanoma, you would expect BRAF and RAS mutations pop up and be within the ranking system. For non-small cell lung cancer, I would expect EGFR, ALK, ROS. The question becomes when we rank them based off HLA presentation, expression level and sort of a prediction to engage the immune system, do those shared mutations actually link to the way the neoantigens or the novel clones? And in some patients, that's the case where you see it for the less than 1% in some patients, you don't see it. So the answer is in all tumor types that we have, there is the potential to have some of those shared incorporated into the neoantigen asset.

Now the question becomes, do we have data yet across the rest of the studies to start showing this? And the answer is, we did see this the P101 study back from some of the older papers where we were mapping the different neoantigens, but we haven't accessed the Phase II studies yet that are ongoing or any of the new Phase III studies and the rest of the tumor type. So that is one of the things that we are really looking forward to as the data sets there to see exactly how those neoantigens map. Do you want to add.

Yes. I was going to add, it's highly likely. The answer is going to be yes. And that's, there's a long literature on this, going back to Steve Rosenberg's interrogation, that shared neoantigens are just not a, and that probably has to do with the fact that there's evolutionary immune pressure, even in hotspot mutations, they tend not to be presented or they're presented at very low levels. So I think that's to be the case. And then the answer to your second question, which was -- what was the...

How do you compare the share?

Oh, yes. Yes. So shared antigens versus neoantigen, of course, we won't know but scientifically neoantigens have not gone through thymic selection. And so there are T cells that are going to recognize it with sufficient [indiscernible], whereas shared antigens by definition, have gone even shared antigens, such cancer tests that are not usually present in adult tissues, they're present in the testes or the placenta, so they have gone through some timing selection, that's the scientific hypothesis, but of course, we won't know until we test.

That's a great point. And I really do appreciate the comment that you're making, but it's really about how the patient is going to respond to these neoantigens. And my quick question for Ryan was, and maybe I misunderstood this really cool presentation. But on Slide 39, where you showed the 3 antigens that were activated in expanding the T-cells, does this mean that only 3 of the neoantigens were kind of taken up and activated that way? Or were these just the top 3 that you had across analyzed.

Yes. So when characterized each of the 7 patients were characterized and they were tested against each of their 34 new epitopes, and the range was 1 TCR expanded 1 TCR expansion against the 1 neoepitope to 18, neoepitopes that generated TCR expansion. So I think it's why does 1 happen or 18 happen, why do you get a dozen or 2 dozen or 3 dozen against TCRs against 1 neoepitope, I think these are questions that are hard to answer from a small data set. But maybe areas of study is particularly if we can, I mean, all these patients that I showed, none of them had recurrence. So it's not like I can say, "Oh, the 1 had 1 recurred, but the one 18 that had a gain didn't recur." And of course, because it's an adjuvant study, you can't look at response or PFS or other endpoints that sort of make you feel more certain about what's clinically happening from an anticancer standpoint.

I think the other thing with the one, my understanding is that, that patient had 1 neoantigen with a response. It wasn't 1 TCR.

Correct, [indiscernible] TCR.

Even for a given HLA, you may have more of the CR, some neoantiwill be presented in different HLA. So I think there was an illustration when one of them had multiple T-cell clones against 1 antigen. That was the norm rather than exception. The norm is multiple different T-cell clones against 1 antigen.

And what we didn't show here showed in the poster, there was an example of a patient who had across HLA and HLAB that would generate against the same neoantigen.

It sort of gives this sort of innate biological redundancy. So it's not HLA 02, 01 limited or the -- and so I think I was surprised by the number of different T-cell loans against a given neoantigen.

Yes, that was clearly the most interesting, what I would not have guessed before seeing the day.

Particular when you go, we've chosen that clone because it binds well to HLA. And in your head, the carton new drawers student was 1 T-cell finds that HLA with that neon.But clearly, there is so much redundancy in the immune response.

Alec Stranahan from Bank of America. Really great discussion. Just two questions from me. Maybe first, I believe that the Phase III is enrolling Stage II disease as well. I guess what percent this sort of within the Phase III data set? And I think we saw, I guess, directionally higher hazard ratio in the Stage IIIc versus the Stage IV in the 5-year follow-up, small end, but how does that maybe bode for even earlier patients?

And then maybe one quick one for Dr. Sullivan, in the poster yesterday, it looked like there was maybe some variability in terms of the number of immunogenic neoantigens sort of within that 34% total delivered between patients. Could you maybe speak to the variability and if there's maybe a minimum threshold of truly immunogenic neoantigens?

So I'll take the first one, which is we wouldn't disclose the number right now, but an ongoing trial. But I would say it's likely to be sufficient labeling negotiations. And in terms of efficacy, I think you're right. I think the lesson we're learning is that the earlier you go, the more likely you're going to have a treatment effect. Of course, that's balanced the early go the less treatment events or the less events you're going to have. So it will be a balance between that.

So my feet that is that the benefit the same. But I think there's some chance the benefit will be greater. So when you look at -- so when you develop a hazard ratio of a curve, the hazard ratio is a reference to the whole curve compared to the whole curve with sound intuitive, the higher risk of your population, the earlier you get recurrences. So in adjuvant studies, you get a group of patients who recur within weeks. And they're the absolute highest risk patients. So if a treatment starts at week 6, I predict the hazard ratio in the slightly lower risk patients, not the risk because Stage IIc is still a high-risk population, but they're less likely to recur 3 weeks after you start the pembro.

So if the hazard ratio instead of being 0.51 is 0.45, my hypothesis is it's that by having a more, if you like, typical adjuvant population, paradoxically, we get a better hazard ratio because when the curves run together, that feeds into the hazard ratio of the whole curve. So I actually think it's going to be a positive that we've balanced the population because really, we have -- this has got an artificially early recurrence population, not necessarily a risk, but microscopies has those early recurrences, whereas the IIIbs, the Ias and the IIcs, IIbs, don't get that, they recurred at first scan often, so I predict we might get a better number, a typical population.

And then your question about the number of neoantigens that you get T-cell responses to -- we said again, we can't answer that in this population because it's, one, we don't have enough patients and we don't have a splay between patients who recurred in patients who didn't recur. There is 2 pieces of information that speak to this, both is with a competitor called autogene [indiscernible]. One is in the pancreatic cancer data set, the initial data set that came out of MSKCC where they treat patients in the adjuvant setting with their new epitope and new epitope therapy.

The patients that generated responses against the neoepitopes didn't recur in the patients who didn't generate new epitope responses did recur. And that's very clean data. In another trial with that drug, we did a Phase II randomized study in frontline melanoma, previously untreated. This actually was launched around the same time. So weren't a lot of patients who got adjuvant therapy on that study was mostly just first time of being exposed to checkpoint inhibitors. And very similarly to that, we could see that patients who generated more new epitope and more responses to more neoepitopes had better outcomes than the patients who didn't. So it's not a specific answer to intismeran, but presumably, these things work together, and that biology is biology if you're having sort of an immune responsiveness to a therapy like this.

The one other piece I'd add on to what Dr. Sullivan saying is, at least in the poster, right? So you had that splay between 1 and 18. So we know one can be sufficient, at least for disease control in that 1 patient. And this is one of the reasons we're so excited for the 5,000-plus samples that I highlighted because these are the types of sizes. I think we're going to need to understand how many neoantigens do you need, what makes features of a neoantigen, how do we start parsing that out, I don't think we can do it with just the.

Yes. You basically need all the samples from all the patients or nearly all samples from all the patients that you can really get a good look at how core it outcomes.

Cory Kasimov with Evercore ISI. Probably for Dr. Carlino, but anybody can chime in. Curious as to your thoughts about how the upstream migration of immunotherapy to the neoadjuvant setting could impact -- eventually impact intismeran? And once available, how would you choose which patients get neoadjuvant therapy versus an intismeran-based adjuvant therapy.

Yes. So that's a good question. So, the one question I asked expecting to that get that question this morning, but not getting it was on this study, even though they're IIIc, remember, a lot of IIIc patients are microscopic IIIc, so even on this study, 1/3 of patients have micrometastatic disease, right? So by definition, those people can't get neoadjuvant.

When you look at the registration trial, the prediction or the estimation is 2/3 of those patients have micrometastatic disease. So the micrometastatic population is a significant proportion of the Stage II. And by definition, the Stage II, despite the presentation this morning, Stage II don't really have an option of neoadjuvant because the definite the biopsy removes all the tumor. So you've got all the Stage IIs. And most of the Stage IIIs, neoadjuvant isn't even on the cards for us. So I think that's the first thing. So this is the dominant much, if you will.

I think clearly, I guess the question, the provocative is at the moment, if someone walks in with macroscopic nodal disease, they're getting neoadjuvant, not adjuvant, right? And I think that will remain the standard unless the hazard ratio on the registration trial is so good where you'd actually say to someone, look, I could give you neoadjuvant pembro, same toxicity. I think intismeran outdoes the neoadjuvant benefit hypothetically. But when you're saying I'm going to give you neoadjuvant, ipi/nivo, a different question. So I think the short answer is there's a huge market or a huge group of patients that need adjuvant and can't have neoadjuvant. That's the easy population.

If the hazard ratio is spectacular, it becomes quite a complex discussion because the lack of increased tax compared to adena because adena right adds permanent tox. And then I think the most interesting question and the next study is for the can intismeran add to the neoadjuvant therapy, so if you give intismeran presurgery, can you improve on the adena or the SWOG result, and that's an important study to do. So we have to do that study. We start SWOG or start adena and you start intismeran before the operation. But the easier group patients to study is the patients to get neoadjuvant whichever one. And then post neoadjuvant if they don't have a complete response, they get their adjuvant would be typically nivo or pembro plus intismeran. So that's a very easy study to run.

Some may argue you don't need the study. But certainly, once you've got the positive Phase III study, I've just given you an idea of 2 other studies and the post-neoadjuvant one, I'm confident we could design a study with 200 patients because those patients have such a high risk of recurrence. They're technically already on label. So we could do another quick study with 200 patients and get that answer relatively quickly expanding the population.

So I think my main answer in summary is that the microscopic population is still the bulk of the patient/Stage II. And this will be tested in the adjuvant. Those 2 studies have to happen. The lung cancer guys have already got those studies going on. So we saw on that first slide, the neo -- post-neoadjuvant study already happening in the equivalent lung cancer, and we, lung cancer is not allowed to beat melanoma, so we'll get there quickly.

Myles Minter from William Blair. Congrats on running a controlled study here if you deserve that comment earlier today. My question is actually very much coming from investors and that is Dr. Carlino, I was interested you were kind of inferring where the placebo curve would be on the RFS that 5-year data, investors bring up where the pembro curve from 054 would have fitted on that. Do you think that pembro performed as expected in this trial? Did it underperform?

Exactly. So I think I think, so if you go to the 054 papers right, you can't use the whole 054 population. So the best way to capture the prediction is just look at the IIIc group. So that one of the 054 papers, we sort of update 054 every 2 years, but one of the 054 has the IIIa, IIIbs and IIIc. And that IIIc group is the best approximation to this. And I think it's smack on 50 at 4 years. So it's very, very close. And so that's what I was using in my head. I was remembering that. I think it's actually, there's 1 figure because there's, or these III, it's a, b, c in the middle. I can't remember which paper it is, but it's, I'm pretty confident it's smack on.

This is Greg Torres representing Tyler from TD Cowen. So how confident are you that the high rate of INT manufacturing you've achieved in clinical trials will be replicable in the real world? And are there any considerations related to feasibility of this in the Stage II and III versus Stage IV patients?

Yes. So maybe I'll take that one. So I'll start with the Stage II and III. So obviously, we've done it for the 001 study. And then on top of it, one of the things that we're so excited about with some of the other studies is that, especially for like NMIBC, the amount of tumor is actually even smaller than what you could get into the Stage II. So not only are we expanding the hypotheses within the clinical studies, but we're also testing the bounds for the tissue requirements as well. So for that, I think we've been able to showcase that based off the enrollment that we've had.

And then as far as the global expansion, you have to remember that this study for KEYNOTE-942 ran from 2017 to 2019. And in that time frame, we manufactured the 157 right or 107 intismeran doses over a 3-year span. The 001 study started in '23. And since then, we have the litany of the pipeline. And to date, we've dosed over 2,000 intismeran patients. So you're talking a tenfold range in the past 3 years.

So again, that ability to scale that we saw with the COVID era is what we are able to scale with intismeran, actually, a miniaturization of the process and then a scale out across the globe. So what we saw with KEYNOTE-942 was that we had a U.S. and Australia footprint. And now our global studies with Merck are in over 46 countries. And again, that turnaround time is really maintained [indiscernible]. So even with that up of the tenfold that scale out globally, we're still able to actually maintain the distribution time in the manufacturing chain. And that gives us confidence that if we enter into the commercial sphere, that we'll be able to deliver the way we expect.

When we visited, I visited the Moderna plant. And I think you really got the feel having visited that it was set up to do 50,000, and it almost felt like if it wasn't doing tens of thousands you could see the sort of the exponential of the processes where it felt very impressive to see how it's sort of this process had turned down to one thing and then you can -- it would just repeat it. And if you wanted to double it, your times it by 4. So I think probably of the ASCO week, the visit to that plant was up there with the sort of how much thought have been put into the scalability. I think as a none -- someone doesn't make things, but it seemed to be ready and raring where it's almost felt like it was built and sitting there ready to go.

Lili Nsongo from Leerink Partners. So maybe a quick question going back to the piping and then linking that to the epitope selection. So up to 34 neoantigen [indiscernible] selection, I think it was down to 9, between 9 and 34. And then 1 to 18 that are immunogenic. Can you maybe give us a sense of how much do we know in terms of whether there is any correlation between any baseline characteristic of those patients, namely P1 status stage and what you're able to do in terms of [indiscernible] selection and then what you see in the context?

Yes, I think, I mean it's an excellent question and an important one. I think with 7 patients across 2 trials we don't have -- it doesn't matter what they were in terms of like the PD-L1 status or TMB and things like that. I think we need to look at more patients and to be able to answer that question with any certainty.

But I guess, intuitively, it's unlikely to be a simple thing like stage in my mind. It's the biology of both the immune response and the tumor. And if we look at TMB, we don't have a huge difference in TMB between Stage IIIc and Stage II melanoma. Certainly, actually in Australia, you probably had a higher TMB in Stage II because they're slightly older and we get these group of patients who have Stage II melanoma and older people, which goes with chronic sun damage and TMB. But I don't think it's going to be something like stage or PD-L1 or something simple.

I guess the only thing, and I think this is where this could only get better is hypothetically, you could imagine an analysis in 5,000 patients where you run the algorithm and say, actually, this type of neoantigens isn't as good, so you no longer make the cut of the 34. And so I think the exciting thing for me is you're choosing the 34 best, right? So I think it's impressive that they chose the 34 best not having ever treated a patient, and that's worked out pretty good.

If you can feed the positive and negative feedback into the algorithm, could you improve it? I guess the question is, do you need to improve it? Until the curve is flat, you can always try. And so I actually think that if there was an opportunity to evolve the algorithm. And I know that's complicated and we'll need discussions. But certainly, the algorithm is pretty impressive. But theoretically, I think that was where the difference might come not something about the stage of the patients or...

True. But who knows, right? Like somebody with a big bulky tumor may be different than somebody with microscopic disease. So I think it's valid to look into that, but we also have to just get many more, need to get data from many more patients.

Matt Hagood for Mike Yee from UBS. Maybe one for Dr. Carlino. I just wanted to ask if you could expand a bit on the safety profile here. Compared to IO, I'm curious your thoughts on whether this kind of expands the population of patients who would get treated in the adjuvant setting with an agent.

And then if I can just squeeze one more in on the earlier stage pipeline, I wanted to ask when we might start seeing some days on updates from those programs, too?

So look, a couple of things about the safety. So I think the decision to use intismeran and pembro from a safety point of view is completely driven by the toxicity, right? So am I using intismeran and pembro and soon with a kidney transplant adjuvantly? No, but nothing to do with intismeran. It's because of pembro.

The only area, I guess, that may expand the population theoretically is I gave a second talk at ASCO this afternoon about tox. And my first slide was about risk benefit, right? So every patient has a risk profile, which can alter based on their comorbidities, and every patient has a risk appetite, right? So as a patient, a Stage II patient may say, look, for an absolute benefit of 10%, I'm unwilling to take the risk of a 1% risk of cortisol deficiency. Whether you would make that decision or I would make that division, that individual patient may decide not to take a given risk. Because intismeran doubles the benefit, right, and does nothing to the tox the risk/benefit discussion in some ways becomes easier. And so certainly, that's how I discuss adjuvant, risk/benefit, ex benefit, ex risk and you as an individual have to decide, but we're not touching the risk side of that equation. But if we're doubling the benefit side of the equation, you may expand the population.

The thing that we haven't touched on in melanoma, but the lung cancer guys get to is single-agent intismeran completely different conversation because it's probably safe to give a kidney transplant patient in single agent intismeran or a person with rheumatoid arthritis or ulcerative colitis, et cetera. So I think the summary answer to me is the combination, you probably have a slightly bigger population because of the risk benefit, but if the population was going to expand hugely, it would be single agent.

I guess a question for Ryan, when the drug is approved, if you had a patient who was contraindicated to pembro, theoretically, you could. There would be a temptation to use intismeran.

Probably wouldn't do it, but that's generally because I like some data before I make a decision. I don't need all the data. I do want to come back to your point, Matt, I think not only is the risk/benefit -- I mean, ultimately, the decision is to patients', but the way that the physician talks to the patient really can influence the decision. And right now, I don't know about you, Matt, but if somebody has a Stage IIIa melanoma. They have a 1.1 millimeter thick melanoma on their leg, and they have microscopic deposits in their node. I'm not going to recommend pembrolizumab for that patient. I'll talk to them about it. I'd say absolutely like to say, I have to have this, otherwise, I'm not going to be live. I'll entertain it. It's on label, but it's -- I think, to Matt's point about what a patient's threshold might be our threshold, just kind of our biases about how we think about risks and benefits, we might actually be more supportive of making such a recommendation.

Just to answer your second question. The 4359 we just updated at AACR, and we now are expanding the data set to confirm the signal. So that's ongoing. And I would estimate probably next year would be an update 4359. For the other 3 or 4 clinical programs, they're still mostly in dose escalation. And so we will share when we plan to update, I think, as we get closer. And then I'll just put plug in for the Science Day we have later this month.

And then the only one other part since we're talking ASCO is we did have the 2808 tip actually as a poster session here. So it does showcase that we're beginning to actually One, have the trials in progress and two, there's some preclinical papers that are out for that one as well as 4106 and 4200.

Ellie Merle at Barclays. Maybe first just for the physicians. Obviously, really impressive hazard ratio on Phase II. What would be the minimum effect size that you would want to see in Phase III to adopt this and say, widely added on to all your PD-1 adjuvant patients, given the risk-benefit comment that you make around the safety?

And then just a question for the company. obviously, really impressive hazard ratio in Phase II. As we think about the interim analysis, any color on sort of what the minimum hazard ratio would be needed to be successful on the first interim? And then just based on the curves that we've seen in the IO trials, how we should think about the likelihood that if it misses the first interim, it could be successful at the final analysis.

So just quickly on the statistics, we have we've said nothing on the interim analysis on the statistics. And with that, I'll hand it over to one of the physicians, please, to speak to what they consider a good hazard ratio in the Phase III.

Yes. I guess the first thing is that there, in my mind, is in Australia, I think there are 2 thresholds. So as a patient, as a clinician, because there's no, so when I think of tox, all I care is serious to permanent tox is the big one for me. There's permanent tox or tox that bothers the patient's quality of life is what we don't want.

So because the cost from the patient perspective, not financial, the cost from the patient's perspective is negligible, the benefit to consider doing it is lower in my mind. So hypothetically, if I had 2 trials that had the same hazard ratio, intismeran/pembro versus pembro or ipi/pembro versus pembro in the adjuvant setting, and they were identical hazard ratios, ipi doesn't meet the bar intismeran does. So from a patient and a clinician, I think the bar actually is quite low.

Acknowledging that there's another part to cost, right? And so the hazard ratio that is required to make it financially worth and it's hard as a clinician, we're not great making financial decisions, me personally. I'm also Australian, so therefore, I've come from a health system that has a central payer and has those complexities. So I don't know what number.

I think certainly -- and the other way to look at it is actually not hazard ratio, it's absolute benefits and numbers needed to treat. So we've got an absolute benefit in that study of 22%. So a number needed to treat of 25. Would I do this for a number needed to treat of 10? Yes. The pay a bit is something I don't think I'm don't have the knowledge to answer on. But from the patient point of view, the benefit could be really tiny because the patient's cost is not measured in dollars and cents. The patient cost is measured in tox. So with the calculation being tox versus benefit, the benefit could be smaller than.

Yes. And I think the answer to your question about what hazard ratio, whatever the hazard ratio where the p-value is significant and the FDA can approve it, I'll use it.

Okay. And we'll take our last question.

This is Morgan Lamberti, representing Salveen Richter at Goldman Sachs. For the physicians, how does the translational clonality data impact how you think about success in non-small cell lung cancer and indications beyond this?

I'll just start and then I don't know, I mean, if you didn't have the translational data, but you had an amazingly positive Phase III trial, it doesn't matter that you had, didn't have the translational data. it kind of matters and from a sort of scientific interest standpoint, like did it actually do what we think it can do. But I think from a proof-of-concept and as you're also rolling out potential ways that you can monitor patients. It's way easier and cheaper to do TCR sequencing than it is to do all of that really sophisticated experiments to get that reporter assay and characterize all the TCRs.

So on some level, I think seeing that there is a likely explanation of that in TCR clonality that correlates with actual expansion of neoepitope-specific clones, it will make us feel better about any of the trials if we just followed TCR clonality instead of through TCR sequencing instead of doing these deep characterizations of all these. As a scientist, it also makes me feel good that we are saying, we designed something to do something. We did it, and then we've actually shown that we were able to do the thing that we were trying to do. There's a lot of dos in there.

But ultimately, I think it feels good when you can say this works and we actually are doing what we think the drug is supposed to do, and we might even have a surrogate biomarker that can be reflective of the more sophisticated TCR characterization that can be rolled out into all of the trials.

Yes. So look, I agree Ryan. I think when you've got a randomized Phase III trial that's positive, it almost doesn't matter what the drug does, right? And by the same token, if I can give you the coolest drug ever and the best preclinical data, if properly designed and run Phase III trial is negative, it doesn't matter how cool, the net -- the science is, it's negative. So the Phase III trial thing.

I think the big thing this does for me is, one, it gives you huge confidence that the Phase II data is real certainly. So when you've got less than Phase III evidence, predicting your drug works because of x and then showing that it actually happened gives you confidence I think with the reference to non-small cell lung cancer.

The other positive is this mechanism of immune response is not melanoma specific. So it actually gives you the confidence that this is likely not just to be a melanoma, right? And so I think at the point now where we're going, what's the likelihood of the register melanoma study being positive, the translational data increases that of the scale. To be honest, once you've got the Phase III data and you just get Phase III positive trial after Phase III positive trial, the translational data is really important about working out if there is a subgroup of patients you're not helping, what do we have to tweak to have them and what's next? But it's more about the confidence today about what's coming next year, really, which is, that's the most important thing. Yes, it's cool, but it makes us way more confident than we otherwise would be.

Yes. Maybe I'll just add in the final minutes is the most validated immune therapy, of course, are anti-PD-1s. And we know that anti-PD-1s work by releasing the brake carb reversing exhaustion on tumor reactive T cells which then go on to kill the cancer. That's the most validated clinically immune therapy. We know now that our therapy roughly does the same thing. We give the intismeran. It activates neoantigen-specific T cells. And from the randomized data, we see evidence in this Phase II that the T-cell are doing their job. I think to me, that's the reason that gives me reason to believe that this is not just a melanoma specific melanoma because anti-PD-1s are not just melanoma drugs. Of course, we'll have to wait for the randomized trial, to find out.

But with that, let me thank our investigators who joined us, and thank you all for joining us tonight. Thank you, guys. Appreciate you. Thank you so much for spending the evening.

My pleasure. Thank you, guys.

Welcome, everyone. Thank you so much for joining us for this conversation about Moderna. My name is Courtney Breen. I am the U.S. pharma analyst here at Bernstein. And it is my privilege to have Stéphane Bancel here with me, the CEO and Chairman of Moderna. He's been in this role for a decent amount of time as well and has seen Moderna through the ages and through the different areas of the company. So I'm really excited to kind of have an opportunity to dive into kind of Moderna today, where Moderna has come from and where Moderna might be going in the future.

I also know that AI is a super important topic for all investors these days. So we'll be hoping to touch on kind of the impact and potential of AI and drug discovery and kind of in operating some of these businesses. But I do also want to remind you that if there are other topics that I'm not planning on covering that you'd love to have covered in this conversation, please do send them through the Pigeonhole app. You'll find a QR code to be able to send them through. I'll receive them up here and can integrate them into the conversation. So we want to make this as relevant and as impactful for everyone's here.

But without further ado, Stéphane, again, thank you so much for joining us here today. As I mentioned, you've been leading Moderna for a while, I think, since 2011. It was back kind of before there were any products in the market. Before we knew about COVID. Back before then we had the COVID vaccine. A lot has changed between then and now. What has fundamentally changed in how you're thinking about the opportunity for Moderna and how you're running the business of Moderna today?

That's a great question. Good morning, everybody. Thank you, Courtney and the team for having us here today. So yes, I've been CEO since the beginning. I was employee #2 technically. There was a scientist at Flagship VC whom the founders had recruited and I joined and we started to have the team. So of course, the job has changed a lot.

If I look maybe pre-pandemic, we were really a research and early development company. We have quite a number of products in the clinic.

I think my belief in mRNA has increased tremendously for a few reasons. First, nobody has got the mRNA product approved in 2018. If we take the IPO time frame, pre-pandemic, whereas now we have four products that have been approved by FDA, another one being under review right now and a lot of readouts for Phase III in cancer and in rare disease this year. So it's kind of quite a different world.

And the team keeps on pushing the boundaries of the science of the platform. And so I think we're still in the very early days of what mRNA can do for patients. I've always taken a very long view on things, which is when we started the company, I used the biotech technology as kind of what I was trying to achieve with mRNA, which is if you think about Amgen and Genentech when they started in the '70s, which is like more than 50 years ago now. They had no idea they could do antibodies. They're working on human protein. And it was not working well in the early days, and then they made the first growth hormone insulin and then they made more and then made first antibodies. And if you look at the biggest set of products as we know in pharma today, it's mostly antibodies and proteins, right?

And so we've always taken that arch to say, okay, if we invest in science, if you can scale the company, you can be the true platform we should be able to get a lot of medicine over time into many therapeutic areas. And so I used to spend a lot of my time before COVID on just research and early development because that's where we were. If you look at where we are today, we are very different companies present around the world. So I would say spend maybe 25% of my time on the commercial business. Which is sales, marketing, manufacturing, cost of goods, scalability, prelaunch of products like Intismeran, right now in the thick of Intismeran pre-launch activity, marketing, medical, pricing, sales. Same thing for PA, we record that on rare disease because the Phase IIIs are reading this year.

That's maybe around 1/4 of my time on research and early development because, again, as I just said, I believe we're still in the early days of mRNA. I believe we are the only company at scale today because the landscape has changed a lot. CureVac used to be an independent company. It was the first mRNA company. They're gone. They have been acquired by BioNtech. BioNtech is spitting in two. They just announced as closing down their manufacturing facilities in Germany. And so Sanofi bought Translate Bio. Translate Bio, they just announced they're not working on the flu program anymore, Sanofi on mRNA. So the world has changed a lot. And I think we are the only company today at scale to be able to keep inventing new technologies. So I need to spend a lot of time helping the team find the next IND.

And then I spend around maybe 25% of my time on AI today because I think it's an amazing opportunity to reinvent the business of its science or it's just how we do work. And then the rest is around talent and a bit of time with investors.

Fantastic. Super helpful. You touched on so many things that we're going to dive into in this conversation. Perhaps one thing that didn't necessarily come up as where you're spending time with some of the policy pressures.

Last year was a year where I think every single biotech and pharma company perhaps spent an inordinate amount of time kind of dealing with the potential risks, policy risks that might have landed at the doorsteps of the sector. We're still seeing changes play out of the FDA, particularly. We no longer have an FDA Director of Commissioner. We've got an acting individual in that role. He's come from the food side.

How are you thinking about the changes occurring in the regulator kind of impact of vaccine skepticism, but also is there going to be consistency? And therefore, how does that influence how you're making decisions in R&D and kind of the choices you have to make upfront that perhaps then don't land in front of the regulator for a couple of years?

Sure. That's a big question. So I would say, obviously, for the industry, it is really important to have predictability. I mean, every CEO said the same thing over the last couple of years because of a very long life cycle of our industry in terms of investment and returns, we need predictability. We need to know when we invest in something, is that what's going to be reviewed ? Is it going to be reviewed in the right way and so on. So that's, of course, really important.

The good news, I would say, is that most of the teams do the work. So I think it's important to differentiate at an agency like the FDA, what the commissioner and the head of the divisions do, which is around the policy about the future. So of course, that is really important for the agency to prepare for the future. So not having roles filled is, of course, a problem for the country, for Americans and the health, if you think about 5, 10 years from now.

But if you look at the product reviews we're having, whether it's a vaccine, whether it's a rare disease or Intismeran. It's a working team that are in constant discussion with our working team. And those teams are pretty stable. There's been a bit of changes early last year. But thankfully, for our programs, they have not been really impacted. The key players in all our key programs have stayed through since early 2025.

And so I'm, of course, like anybody else anxious to see stability in the agency. To be able to have people in a leadership position to talk about for example AI. How do we use AI to file for approval? How do we use AI to do science? How do we use AI to enroll clinical trial faster, to get site faster? There's a lot of things that we can decide ourselves as how we run the business. But because we are a regulated industry, there are a lot of things we need the regulatory approval, and so we need policy clarity on those topics.

So I'm hopeful because I'm not optimistic. I'm an entrepreneur also. I have to be optimistic. or I will be in different lines of business. I think those things are going to get resolved. And again, they don't impact us short term, they impact us on more long term.

Yes, absolutely. So per super helpful. I do want to get back to AI, but maybe I'll dive into some important data, particularly as we've got ASCO on the horizon and a big oncology conference and more data anticipated later this year for your Intismeran program. And just for those in the audience that don't know, this is what previously might have been called a personalized vaccine is now being turned over as an individualized neoantigen therapy that can be used to reduce the likelihood of progression or disease in cancer states.

You've obviously got programs ongoing for melanoma. We've seen some very long-term Phase II data. Demonstrating durability of the outcomes and outperformance relative to standards of care like KEYTRUDA, which previously were big step-ups. How do you think about kind of what we might see later this year? What is the goal in terms of what could be demonstrated for this product? How different might it be to what we've seen in the Phase II for the product so far? And perhaps just a broader question, what could be the potential future for something like Intismeran, if you were we're thinking a few years further out?

Wow, that's a lot of questions. So I would take them in order. If I forget anything I'm sure you keep me honest. So we shared the top line of the 5-year data in January of this year with a hazard ratio of around 0.5, which we are very pleased about because it was the same as what we saw at 3 years.

And so as you said, the durability of a response was extremely exciting to us, what it can mean for patients and what it can mean for the company. And what also was really exciting to us as we looked at the data in detail is the p-value. The p-value improved as well. Which when you see a study where you have duration in oncology and improvement in p-value, this is really a good sign. Again, does that mean it's going to be a great outcome, but it's a really, really important key enablers to a great outcome in Phase III.

We're excited about this weekend. So there are two things that ASCOs, of course, the full data set of the 5-year data Monday morning, scheduled as a plenary session oral session at ASCO. We have an Investor Day at the end of the day to walk people through the data. We don't have direct access to ASCO. And this weekend, against public information, there is a poster about the translational medicine of Intismeran, which is really at the cell level, a very detailed work is being presented this weekend ahead of the clinical data to explain how Intismeran works.

We've already shared a little bit at ASCO before including, I remember in 2018, showing in lung cancer, how we could take the blood from people -- from patients, sorry, before we inject them the product, we had sequenced the DNA of the tumor cell. So we knew exactly what antigen we coded in our product. But we took the blood before we had the first injection of Intismeran. We look at the T-cell for those new antigen. And then we do the same thing after [ four ] those, and we show that T-cells we are starting to recognize the new antigen that we knew we coded in our product. Yes we knew the patient T-cell did not recognized before starting Intismeran. So that's a great proof of mechanism. The question we all had, which is when we saw the clinical data 2 years, 3 years and now 5 years, we are very pleased to say, do you have any clinical impact because you could have T-cell activation, but have no clinical impact, and that's not the drug.

But we saw the mechanism, you're going to get more detail on Saturday, and then we saw the data and now the duration of the data. So like anybody else, I'm binded to the data, when we have the data, you have unit of data pretty quickly. As we always do at Moderna, we never keep data wrapped that are important for obvious reasons. And so we're looking forward to the data.

I think the piece that is exciting is that we just announced recently with Merck, a new Phase III study in lung disease. It's our second one, Phase III in lung, just to tell you, Merck's and our beliefs in the science and the mechanism. It's in Stage I lung cancer patients. If you're diagnosed with lung cancer in stage I you do not get a checkpoint today because of a side effect of checkpoints. As you know the checkpoints when they work are wonderful medicine, but they come with a heavy side effect profile. And so the standard of care today is surgery. Sometimes chemo, sometimes no chemo and monitoring the situation. But here, the idea is to try Intismeran as a monotherapy because whether in the study, we're also going to try Intismeran plus KEYTRUDA. But we are very, very excited. Personally, I'm very excited about trying Intismeran on monotherapy because we know from the Phase I study of Intismeran, we showed had at ASCO several years ago that we had response in several tumor types, including lung, because of what we understand the mechanism, partly was going to be presented on Saturday at ASCO on melanoma.

We really believe that if you go earlier in disease, you have first less burden of disease. And two, you have a stronger immune system. And what is very clear to us is that this drug works by teaching your immune system, what to look for or your T-cell to go eat your cancer. And so we believe that having a very healthy immune system is very important. Earlier in disease, we believe, is going to increase the odds of our medicines working well.

Fantastic. That's super exciting. And I think the there's one question of, does it work in melanoma? And then the next question immediately is how well is it going to work in other cancer? And do they have to be highly immune-sensitive cancers? Or can they be kind of a broader set of heading towards your gastrics and other cancers and other immune sensitive.

Yes. So like in science, we have to run the experiment because you cannot know a priority. But we are deploying a lot of capital and so is Merck. Again, for those of you that are not close to the partnership, it's a 50-50 cost share now and profit share. So every time you see a study going, you know that Merck is paying half of it and the capital allocation they're making compared to a lot of other assets we have in the pipeline, of course.

Look, as I just shared, we have shown earlier response of Intismeran as a monotherapy without even KEYTRUDA in melanoma, lung, head and neck. So with what we know of melanoma and the mechanism of action, we believe, I personally believe -- strongly believe. It's not the we don't deploy capital either that where KEYTRUDA works, Intismeran should help improve the response from KEYTRUDA.

How much is it? Is it a 0.5 hazard ratio like melanoma? I don't know. We have to run the clinical experiment to know. Could it be better in some, worse in other, most probably. The piece that I'm excited about, as I said a minute ago, with our lung Stage1 disease is to go earlier in disease. For example, I learn talking to key opinion leaders, world key opinion leaders in melanoma that some patient Stage 2 melanoma do not want a checkpoint because of the side effect. So could 1 day we go earlier in disease, assuming the Phase III is successful of melanoma later this year, do we want to go earlier in disease because that could be interesting and could Intismeran monotherapy. We actually could become standard of care because you don't have a safety profile. I think what most people are missing about it is Intismeran, and you have to do the work because it's a different asset, it's different technology. Its the safety profile.

The safety profile of Intismeran is similar as an infectious disease vaccine. So I think if you have a cancer and you're diagnosed by cancer or a loved one, and you are told you can try this drug, and it's like you might spike a fever tonight or you might have chills tonight and that's it. If you have a cancer and that's a side effect profile, like yes, sign me in.

We've said it several times, but -- the Phase III Intismeran plus KEYTRUDA drug melanoma study was a fastest study Phase III of KEYTRUDA that Merck ever enrolled. And I cannot say we did it better than Merck. It's not true. Merck run the study. And they are pretty good at running clinical study in oncology last time I checked. And this was a fastest study ever enroll in Phase III. And you asked the investigators why, and I have done that myself, and they tell you Stéphane was an easy call. We had very exciting data in Phase II, 0.5 hazard ratio, one in two people benefiting and the safety profile is like our vaccine.

Every patient that I told that, that they have one in two chance that this is better than what I'm going to give them anyway, KEYTRUDA. And there's no downside in safety in the like mine, which is why the PIs sometimes will tell me, I signed up everybody. Because I recommend it to everybody and when I explain it to them, they all signed up. So that's I think the interesting thing about Intismeran is its safety profile. It's unlike anything I think we have seen as a field in oncology.

Absolutely because you usually in some ways trying to...

It's always the trade-off. And when you see sometimes a lot of time, you have two checkpoints together and then you have a lot of talks.

Absolutely. So the core of your business today, though, is still very vaccines, very COVID oriented. And we've obviously been through a lot of evolutions of the COVID market. It seems like we're getting to perhaps a more stable level, predictable level of what does cover vaccine utilization look like going forward? Perhaps you can make a comment on that, but also norovirus, this is different to COVID in so many ways as you think about this opportunity. Can you talk about the market opportunity here? And what will it take for this to become a really meaningful contributor to Moderna's revenue profile?

Sure. So again, a lot of good questions, Courtney, as I want to try to unpack everything. So yes, today, we're [indiscernible] vaccine business. We have now four vaccine approved around the world. We should get through this year. And if Noro Phase III is positive later this year, we'll file it very quickly, and it could be approved next year.

And if that happens, we'll be, I believe, with the largest respiratory portfolio of any company, which will be very helpful to us as we negotiate with customers because in the U.S., most people want to realize, we sell directly to pharmacies whether it's a CVS or Walmart local pharmacies. And there's no PBM in the middle. So we are direct in a B2B setting and be able to bundle product is really important. And for one of the reason we have struggled with RSV, in my opinion, is two things. One has been the market has decreased in size tremendously. Because of a lack of a recommendation by [indiscernible] for boosting people. So basically you got the first class of people who all went in. He was a great first year for GSK and Pfizer with the [indiscernible] year 2 and year 3 with no recombination yet. I believe there will be a vaccination recommendation because if you look at the epidemiology, natural infection after a couple of years, you start to be infected and seek again.

And so what we've done over the last capital years is a few things. First, we've become much better at predicting the business because it was tough to model coming down from the pandemic. Because if you think about Moderna, we went from too big roller coaster, [indiscernible]. One was first going up from $0 to $18 billion of sales in the year. I don't think the company has ever done that before. That's at least what [indiscernible], let's say at a time. And then we went down from $18 billion to around $1.9 billion last year. So it's down 90%. No pharma company has ever done that because when they lose patent expiry on one product, it's one product. This was the company.

So we did everything we have to do in terms of processing manufacturing. We sign the company and so on. So I think that we're in a very good place. We still have work to on costs and opportunities that I think we're in a very good place. And so what is interesting for me is last year, we were in our guidance of sales for the first time because the year before were not.

And this year, we're predicting growth. And if you look at how good our Q1 was based on our outside the U.S. strategy, especially U.K. was a big driver in Q1. Even if we are flat in Q2, Q3, Q4, you will have sales growth compared to last year as you can run the math.

So I'm quite excited about where we're going. I think we stabilized. We're going to back this year and sales growth and with a very diversified product portfolio now. So four products approved, maybe five by customers, maybe six by next year. and a great geographic diversification, which is, of course, very helpful.

So I'm very excited about Noro because Noro has no vaccine on the market. Everybody in the room, I'm sure, knows of Noro from personal experience, it's not a fun experience to go through. I know doctors that have told me, when you have a Noro vaccine, I'm sure you're going to get every year, even though I don't get through every year, and I know I should. I get no way very because I would rather have a flow that we can be having no from doctors working hospitals, protecting all of us.

And so if you think about Noro the market is clearly people at high risk, age, obviously, comorbidity, usual, cancer, cardiac comorbidity, autoimmune disease, allergy and other things that I would know those infections are very bad for.

Development is going to be interesting is health care workers. Like I just mentioned the doctor to have heard it from nurses, nursing home with the elderly and then teachers, because same go talk to kindergarten teachers or lower school teachers, and they tell you, yes, I would like a Noro virus vaccine. They might not be at the full shot of a COVID shot, they take the Noro vaccine because they get Noro regularly because of just all the little kids that take off every year. And that's how we parents get Noro going back from school.

So I think Noro was going to be quite an interesting opportunity from a marine standpoint. I think is going to be very interesting opportunity for product building with customers because if you look at the margin the retailers are making on vaccines.

Again, for people who don't know they make profit from a discount they get from us and our competitors compared to list price. They get reimbursed by the payers, but to get an administration fee. So when you add those two numbers, it's actually a very large number. And if you do the math, you need to sell a lot of [ Kitkats ] to the same EBIT margin are selling one vaccine, which is where you get text from CVS and Walmart over time to get more vaccines and so on, that's why. So when you go to a pharmacy, pharmacist will ask you, are you here for food, you want COVID, are you for COVID, you want RSV or you on [indiscernible] because they get cash bonus, the pharmacist. So I think the bit to bundle products is really important for us in terms of share.

And if you think about the growth of our customers, we arcane for product. We are the only one with combo approved at IDS, but Phase III data in the U.S., Noro. So we're going to be at a stage that was really handicapping us before where we didn't have a lot of unique products. Moderna is literally in '26, '27, '28 going to flip to a company that has not one, but several products that you're going to want for your growth, that I'm going to be the only one we're able to provide to you.

So it's going to be quite interesting what happens to us in the next couple of years. The good news for us from a P&L standpoint is I don't need to add on a rep. So think about the cost leverage because I still have the same team going to CVS and the same team going to Walmart. I don't need to get the ones crop in U.S. and the manufacturing is all [ gravy ] because it's volume. I have a platform company able to spend $1 of CapEx to launch Noro or the combo. It's the same manufacturing equipment, the same people in the same factory. So what we're going to see -- and by the way, the cost of good infectious disease -- sorry, the R&D cost of infectious disease is going to come down because those Phase III studies, sunset. And so I'm going to have a very interesting P&L leverage at every line because of good R&D and SG&A.

So a I love the vaccine business. And by the way, I love a [ tale ] as well of a vaccine business. Those products last forever. I mean, you used to work for Merck, those products are in the market forever. Because the buy to entry is a $1 billion Phase III.

Absolutely. And some of those products can grow for 40 years.

And plus, as we update them all the time because the COVID is different from core last year and core 2 years ago. And so there's also that aspect to it. So I love [indiscernible]. I know what everybody does, I love it.

You touched some a few things that sparked my interest and I do want to get to cut some of the cost cutting you've been through and where there still is areas to cut in, I think you made some comments about not needing to add to generate some of this revenue, which I think is interesting as well.

There's also a question that's come in from the audience that builds on some of the vaccines topics. So I'll hit that first. which is we've seen an announcement on Tuesday this week that [ Eli Lilly ] has become a vaccines company again three acquisitions in one morning. Can you perhaps tell us how does this sit with your strategy? How does -- how do you see them now as a competitive set?

I think there was actually some commentary from Lilly that actually echo some of the things that Moderna commented on in terms of EBV and the potential for [ Sequele ] and long-term health impacts. But it would be great to hear how are you internalizing kind of this new news.

So I think it's great news. I think first, it's a great news for the world because we need more vaccines. They are more than hardware barriers that helps human. There is vaccine for less than [ 30 ]. So having a couple of serious vaccine players is a good thing for humanity, number one. Number two, I think for everybody was running away from vaccine 2 years ago and we stuck to it because we believe there's a medical need. If you add just the depth of COVID RSV, flu and Noro, it stacks in the top 5 deaths in this country. Will you take a vaccine to not have cancer. We will take a vaccine to not a hard attack. Yes and yes, I'll take both. We see why every year, I take my true shot, my COVID shot, I got in my first [indiscernible] because I'm more than 50 in the fall.

Like table stake, you want to go for sleep and run and it's healthy and you don't think of vaccines at rally. Okay. And then as you said on EBV, we believe so deeply about EBV. We believe EBV is one of the nastiest virus that hurts human. Of course, we know it mononucleosis. But it's most probably the #1 cause of [ MS ]. Many cancers are caused by EBV.

A virus that stays in your body forever. It is not a good thing. It is not a good thing. Look at the new data coming on [ Shingrix ] with [indiscernible] and potentially slowing down dementia. It's only observational now. GSK is running a study, a prospective study. It's not surprising that virus stays in your brain. It inflames your brand. It's a piece of the. It was a DNA virus. It's a piece of DNA in your human cells. We does it do it creates inflammation. If anybody likes inflammation, I don't think you're feeling hard about biology.

And so the one is an EBV vaccine. We have one right now. Actually, we have two, sorry. When in Phase II has a [ prophylactic ] vaccine, we're going to necrosis. And hopefully, we'll have to prove when they proven [ MS ]. Think about the nickel impact of that. And then we have an EBV vaccine as a treatment for MS patients. It's in the clinic right now in MS patients as we speak, and it's trying to manage the viral load of EBV, the quantity of copy of EBV virus, like people have managed beautifully HIV. If you think about HIV, you try to manage your copies of the viral load of HIV to keep it undetectable. So the virus doesn't do damage in your body, same EBV.

And so I'm delighted that Lilly is going after EBV. And I think Lilly coming at this moment after what has happened over the last couple of years around the vaccine hesitancy post-COVID and what has happened around some vaccine misinformation the biggest pharma company in the world that is saying, "I want to deploy capital, not in one, not in two, not in three companies, I want to be a vaccine business, like, alleluia.

And I'm waiting for [indiscernible] for the patients are on the product.

Absolutely. Absolutely. Prevention is one of the best interventions that we can have. Perhaps diving into that kind of costs and scaling side of the equation. I think in 2025, you took something like $2.2 billion of costs out of your business year-on-year. You're tracking to, I think, $4.2 billion in cash costs for this year.

And kind of laid out a target for that even being lower by 2027, somewhere, I think [ $3.5 billion to $3.9 billion ] is the goal. Can you talk a little bit about where have you taken out cash costs? Where are you planning to continue to take out cash costs? And most importantly, where are you cautious when it comes to risking cutting too close to the bone ensuring that, that revenue content.

A lot of questions in one, Courtney. I am going to take them in pieces. So first, we came from $9 billion of cash cost. Last year, we had [ $4.3 billion ]So the first wave was really cutting down manufacturing because we need less volume. So we've had built a very large partner networks for filling. We closed most -- we stopped most of them, but [ Rovi ] in Spain now. And we had a big partnership with [ Lonza ], which did roughly half of the drug substance for the mRNA and the lipid product during the pandemic, and we also ended up a partnership with a big write-off for all those costs. And the raw material that we had purchased because we didn't know the shape of the curve, we want to make sure we can provide vaccine to protect people.

And then it went down to prioritization of a portfolio of R&D. So we cut in R&D. What also helped us is some of the, as I say, infectiously studies tailed off because a lot of people don't appreciate that for regulatory reason our Phase III study in infectious disease failed, last longer than the end of your Phase III. Because for safety reason, and it's a good thing for the world, we have to monitor people in the studies several years after launch. But when those costs are to tail off, of course, it helps you in terms of R&D cost.

And then we took cost across the business. We restructure the whole business to rightsize it for the work, which was a streamlined portfolio. And then -- so we worked a lot with suppliers on cost because during the pandemic, as you can imagine, given we had no time, we didn't go every time we throw an [ RFP ] process because in process takes time. And sometimes suppliers will tell you, yes, if you on this, you to sign now, this needs to sign now for 3 years or you don't get product because I want to go to say to AstraZeneca, [ Myviles ] or to Lilly to somebody else.

And so we knew as we went into the pandemic that there's a lot of work that unwind that cost structure that made no sense, but was the pandemic price of doing business. Because nobody of a supplier, I'm not trying too many rocks at the suppliers just for.

But nobody if you are running a supplier company, whether you make vials or anything else, you add in your business plan for 2020 that there was going to be a pandemic. So of course, in no manufacturing infrastructure, you have not -- do not have people, you own the raw material to make those products. So it was ready. That's what I can do and the capital system, right? And so we structured a lot of that cost and we're still doing it because I was just with the procurement team a couple of years ago, and they're looking at the work they are doing for '26 savings into '27 for contracts that are expiring in '26. So we still have contracts that we have work to do to improve the construction.

I say cost across the whole P&L, whether it's material cost or with some consultant or other things. So cost across the whole P&L, the R&D cost, as we talked about as our RSV comes out. So this will help as well. And then the AI impact is going to be very profound because like most companies, we still have a lot of what we call AI gaps, meaning base data in e-mails and in PowerPoint and our smart sheet and in an [ ERP ] system. Sometimes it's not the same data and sometimes humans have to check out what's true.

It's happening in every company I worked for. And it's even more acute in Moderna because we built the company so fast. If you think about Moderna in 2020, January 2020, we had no late-stage clinical capability 0. We had 0 commercial employees, 0. So what we have to build in 2020 is all those functions, and we build them a lot in stacks parallel to each other right? Because I heard the head of safety of Merck Rose as a safety system in 3 months. So just through one body is, great expertise, we went to still to the industry, hired those people. We paid some suppliers for some [ ITSM ] we needed that we didn't have, [indiscernible] and other companies.

And so all that now we are using actually AI to go and to fit if you could start everything from scratch and do it with today's technology, even last year technology or 2 years ago technology, how will you design the business process? And we're doing it in business process by business sales. I'm personally sponsoring several business process in the company. And we are a business process across the enterprise and some business process within functions for [ Jamie ] in finance, our CFO, he is working with his finance team on things within finance, how can they use technology to streamline how they do work in finance.

I'm also challenging a lot of people about how we organize across functions. So moving things also between functions, consolidating work. So there's still work to be done. I would not surprise if there's still a couple of years of work to be done. I'm not thinking you're going to see everything in cost because I'm going to reinvest some of it into product of science that you will not see at the P&L level because this work reinvention that we're doing right now is, of course, massively enabled by AI and by vibe coding, obviously.

And it's going to impact every business process of the company. Like I cannot think of a business process, and you think about, please, [indiscernible], that is not going to be impacted by our ability to reinvent it with much more digital capabilities, not only AI, I mean software that we can write ourselves with an LLM for vibe coding, that we can plug to our system like SAP and so on. And then if we need a layer of LLM [indiscernible] it to use AI on that data. But to do things even in accounting. I think we can improve accounting tremendously. I think we can improve [indiscernible] in, we can improve [indiscernible]. There's not one business process at I cannot think of I've not spent time with the team that I think we can improve in the next 2 or 4 years.

So because I want to pace things because if I do everything at the same time, we're not going to get a good outcome. And we need a good outcome because we're launching so many products. And we have so many good things happening at the company. So we are just doing waves of business process, and we are very senior people sponsoring them, including me, as I said, for some of them to make sure that the work gets done and that we really challenge more junior people about what really drives the value.

Because like in any company, I still have people doing work that is interesting. That doesn't drive value. So I'm using that also as the moment was okay. Let's really think about everything to build more than half or tomorrow because we have a platform company in terms of the science, the manufacturing. I don't think yet I have platformized the company in all the functions of the company. That's what we are doing there.

And to that point, I mean, just continuing this AI part of the conversation, you're obviously embedding kind of this way of working and perhaps this operational lens to deployment of AI, how can we do things more efficiently. There's also a lot of talk around drug discovery and kind of can we kind of crack new problems in biology. Can we design targets or interventions that are much more likely to succeed in Phase II and Phase III? What's your kind of philosophy or thesis when it comes to the potential for the industry at large, but especially from Moderna comes to?

I want to talk about Moderna because I think the industry will depend how quickly people adopt it, how we are able to change how we do business. So can you talk about the industry with [indiscernible].

I'm extremely excited about AI for science, but I want to be realistic, investors want it next year in the sales, right? Because when the business we need to do our product and take it to [indiscernible] so for context, we have done machine learning in biology since 2016, '17. So this is not new to Moderna. We have actually invented enzymes, which are protein enzymes that we use in our factory, in our reactors that came out of silicon. And when this happened, the first time I remember vividly, the team put it. You're okay in the computer covenant we have not thought about there's going to be better than the one that exists in nature. Somebody was crazy enough to make it with their bare hands and tested. And he was doing exactly as advertised by the computer and he was optimizing the feature that the scientist that coded in the machine learning system.

We've had the time data scientists because my scientist is had no ability to write the machine on algorithm. And but they had achieve what they wanted. They have improved enzyme that exist in today by basically in my own view accelerating time. In just mutating amino acid on the enzyme solving for the chemistry they were looking for, while preserving a part of the enzyme that was doing the job they need to evolving another part of the enzyme that was doing something that didn't want happening in the reactors.

And that was a huge AHA moment for me because then as an engineer, I have heard about AI since encouraged, which is a long time ago. And it was this type of thing will never happen always later. And that moment was a huge AHA moment for me. I was lucky it happened before, COVID because at the time I set up on a academy with in Moderna to start earth one. Half my team for that was nuts.

Then, of course, COVID was a bit of a distraction to us. And then, of course, OpenAI happened, with Chat GPT. And when Chat GPT came out, I read about it a little bit, but a good friend of mine with a software guy, told me early December, you have to try the thing. [indiscernible], you have to try this thing. So as Christmas calmly we had a bit of time. I went hiding somewhere of a computer for a couple hours and [indiscernible] because I was doing science and biology and then physics and then engineering and then [ French ] port tree and then in [indiscernible], this is insane.

And again, I think led the story of Moderna, where I leave the S curve of mRNA technology from day 1. And the piece that shocked me and it was a use so for me because I've read in business book when I went to business school, I read about S curve. But I never lived the one because when I was at Lilly or at [ Boer ] that year, I was on the top of the S curve. So 3% improvement per year was great.

But I've never leave the steep curve myself. I've read [indiscernible] in books. But I was a modern and my scientist will come and say, we have a 5x improvement. Like what? You have what? A 5x improvement. You really show me the data, go redo the experiment, take back 5x, I said, okay.

And then after another team will come, we have 2x improvement. But that's uncorrelated to the 5x. No, it's not. So that's an exit those 2 pieces of science. So we have AHA [indiscernible]. And this had never seen before. And the piece for me about AI, and now we know because we're a bit of a few years behind us, if you talk to people the hyperscalers and so on and people at OpenAI or Entropic or [ DeepMind ], they'll tell you, as you've read doubling of compute every 6 months. Well, I can do math. You guys can do math, right, you can compound on your computer, right? So I have that moment that December when Chat GPT came out, oh geez, this is going to be a big deal. Not necessarily now, but this is the worst version I will ever see in my lifetime. And it has been true every time I've got a new version.

And so when we did that, I reached out to some Sam Altman say, "We need your thing, but I cannot teach everybody else with my data". So we did something which basically we've got a license for our product on AWS, but only for more than I use. And then we help them develop GPT Enterprise, which is now the product we use for all the employees of the company.

And in science now, I think it's going to change two big things for us. One is, let's talk about the field. I think we are going to accelerate the pace of learning about biology. Keeping about immunotherapy that changed the life of so many created so much value but what we do with Intismeran and so many of the biology insights, we have -- we are accelerating as a field, the pace of biology insights. And we can now do because barges very complex systems with negative feedback loop in very complex biology.

If you knit the biology we have done a human so far in the last 50-plus years is one gene, one target. Most of the biology in our bodies don't work like that. Which is why I'm excited about MRNA-2808, one of our products in the clinic, multiple myeloma, for mRNA in the drug going after full target in one chart. That's the future of medicine. You cannot do that if we're not [indiscernible]. But you can know that by mRNA. We've done already the mRNA with 11 mRNA in monkeys.

So I think the [indiscernible] tailwind we're all going to get is going to be amazing. And those are going to be able to catch it, which will go back to comment but the industry, the company is going to be able to catch it. And change how they work and have the workforce to change how they work and be humble to sometimes say to stop this job it will structure a job differently. I need a different skill, I need to upgrade people. So it's going to be a very painful process to adapt the workforce it's really like when you work into the factory when you went from people looking at from by hand and having machines 100 years ago. It was a huge change. It's a huge change management test. So people are going to have the courage to do it and the skills to do it are going to benefit it tremendously.

The second piece that's unique to Moderna is mRNA technology know-how. So what we're building now is a huge flywheel where AI generated hypothesis on M&E technology. I'm not talking biology, mRNA technology, build the mRNA, build the lipid, we can do fazed at the same time, a fatality time, we take me several years before. [indiscernible] in 1 run. Do the in vitro testing, go in animals, go in humans, feedback learn and keep going.

I would argue there's no company in the world that has -- or public institution that has as much human data as Moderna. Same thing for monkeys. Why not scale Moderna to go run a 100 monkey experiment when we have to. With six or seven arms in the study too long. We're obsessed about learning about mRNA. It's one thing that has been since day 1. We believe this is a very long game over several days. We want to be the company we know the most about the mRNA on the planet. And we want to use data we have now an AI to learn even faster because I want nobody to be able to catch up with us.

And to bring that accelerated learning to patients from new medicine. And my goal is to be able to combine two things. So we're developing internal AI machine learning on mRNA, partnering with the best on the biology, whether it's Anthropic or an OpenAI or DeepMind, Google, the best biology and access to all the platforms, I'm not abated to any platform in biology on the best platform. And within the platform of changing each other. We have already processing in a company where you ask the system, the same questions, and you haven't debate the same question in front of your eyes. It's fascinating. About very complex biology and sometimes scientists I didn't think about it.

A bit like remember we [indiscernible] came and people are protonated you, the competitor made a move had no human that they were recorded, we [indiscernible] in biology. We sent to see insights that no human scientists that we're aware of published on or documented.

And so combining those two things to design drugs. So the scientist of Moderna starting today because I have pieces of those two vectors. I don't have the full vectors yet. But getting those two vectors to be able to design your medicine is going to be fascinating.

So then, of course, we have to take them to a clinic. The piece I think the development process will be accelerated is like all my peers from GLP talks to filing an IND to Phase I and Phase II, Phase III data BLA, it's all a business process, sorry. It's all hundreds of business poses all of them, you can apply AI vibe coding to shrink and shrink and shrink.

The ultimate thing which most will take here is, can you start doing some clinical trial simulation in silicon I think it's for tomorrow, we need the FDA stability as described and so on. But given there's a finalized number of cells in the human body, given we have 20,000 genes, given we have 40,000 metabolites. It's a very big math problem. -- but it's not an infinite math problem.

That's why you see us partnering with IBM in quantum 2 or 4 years ago? Because quantum is going to happen. I don't know precisely, it's happened in '29, in '30, '40, it doesn't change anything for our trajectory. But when it starts working, when I can buy compute IBM or Google or Amazon on quantum, I want my team to know about quantum to understand quantum to have very for how do we use quantum that we're doing. We've already had several problems that the team solved with quantum that we couldn't absorb before -- that has really happened. But I want to be ready for when we do run with quantum because I don't want to discover, we need to do quantum now. It's not how we think about technology. I told you AI 2018, AI academy at Moderna for all the employees, 2016, first machine learning. So I'll do the same thing on quantum because I cannot even understand but my brain cannot understand what quantum and will do together. Put on compute quantum I want to be able to solve a very big science for. So I think 1 day will look clinical trial, not necessarily a full thing, but we do negotiate in [indiscernible].

Much better prediction.

Yes. You can predict all the biology. It's just -- it's all science and math. What happened in our body is not black magic. A lot of things we don't happen, but it's not black market. It's chemical interaction. It's molecule binding to which, it's all physics and chemistry.

Sometimes it's quantum physics. We've done quantum Moderna to sort some problems. Sometimes you have to go there science bigger is solvable. You just need enough compute. That is why I am more excited.

It's a very exciting future and kind of particularly when you sit here and think, and I think others have said maybe it's 1%, maybe it's 5% of biology that we understand the amount of potential unlocks that exist in the future.

And maybe just a side note because it's public information. I'm on the board of General Bio. General Bio has a Phase III drug that came out of a computer. The team designed it with some features they wanted on half-life. The computer design the antibodies. You went into the clinic. It's in Phase III now, and it's working in patients in Phase II as advertised. It's in Phase III now. So the notion that can we make a drug using AI, I think, is a question already answered, yes. The question is what type of innovative drug, but you cannot even think about today, you can make with that.

I mean we had a town hall after an earning call, and I told the team because I spent 2 days deep in science before that, as [ Levina ] was preparing the call and everything. And that's sort I'm convinced we have not invented our best drug yet. I'm deeply convinced, I believe in this brand should be amazing for patients. [ PA ] already the patient stories we're getting from parents for where these are unbelievable the Christmas stories and so on that they never had a Christmas story like this. All the isolation and deaths were preventing with vaccines, but I'm convinced in every set in my body, we have not yet invented besides.

That's an amazing place to end this conversation, perfect timing and a very exciting kind of path towards innovation for the industry as a whole, but also kind of Moderna's journey within that industry. So thank you so much.

And today, they're a great privilege to have Moderna as part of our 2026 Global Healthcare Conference. Representing the company, we have Lavina Talukdar as Head of Investor Relationship here. Lavina, thanks so much for joining us. How are you doing today?

Great. Thank you so much for having us.

That's awesome. Yes. We have a long list of questions here. But maybe before we go into the individual programs, let's start big picture. Can you maybe talk about what progress has Moderna made over the last few months? And maybe most importantly, what's ahead here for Moderna?

Sure. Great question. So I'll start with like the foundations that have been laid in 2025. So we entered that year with a little bit of uncertainty given the change in administration and the transition that was taking place. However, we try to control what we can control and costs came out of the infrastructure pretty significantly. We set a goal to take out $1 billion in cash costs, and we took out $2 billion.

And we also ended the year at the high end of our revenue guidance of $1.9 billion in sales, which I think, again, makes a really good foundation or establishes what we did in the first quarter of this year, also continuing on cost containment and beating sales expectations, mainly driven by where we see growth drivers this year, the ex U.S. strategic partnerships as well as mNEXSPIKE later in the fall to be continuing to drive growth for us.

Got you. Got you. Super helpful. Maybe given this is obviously been some headlines around Hantavirus, -- we continue to see those headlines kind of daily. However, it looks like the risk to the general public remains relatively low. What has Moderna disclosed around what kind of effort you guys are doing around Hantavirus?

So we do have preclinical programs that we're working on with the U.S. Army Medical Research as well as a program that we've had with the Korean Institute of Innovation at Korea University. But again, it's preclinical data, preclinical efforts that are going on there. But as you said, we're watching Hantavirus. It doesn't seem to be posing too much of a risk at this point in time. But the good news is with mRNA technology, should there be an issue, we can spring into action pretty quickly.

Yes. That's helpful. Let's pivot to INT. You're going to obviously have some data at ASCO. Maybe just walk us through -- this is the Phase II data, melanoma. I think you're going to have the 5-year data. I think we already have seen the hazard ratio for progression-free survival. However, I'm assuming you're going to present some data for OS. What should be the expectations for OS into ASCO?

Again, I think you presented data a couple of years ago. There was only 9 events at that time. I'm assuming we have more events now. But do we have enough events to have a meaningful OS Kaplan-Meier curve here? Or how should we think about that?

So you're right, we will be presenting data at ASCO, and it is the 5-year follow-up data to the Phase II study where we're testing intismeran plus KEYTRUDA versus KEYTRUDA alone. And the big news is really that the recurrence-free survival hazard ratio has remained the same. So we're really seeing a durable effect there.

And -- good question on OS. I do want to talk about the significance of recurrence-free survival as well as OS. And so with recurrence-free survival, it is a higher bar than OS is, in terms of you're asking 2 questions with recurrence-free survival, you're asking, did the cancer come back? And is the patient alive?

And so that bar is a little bit more stringent and higher, which is why recurrence-free survival is the gold standard. And as you just mentioned, the fact that it held at a hazard ratio of 0.51 is very impressive. On OS, we are following OS as well. It still may be immature data. However, we will potentially have a full data set at ASCO, which will include OS as well as DMFS.

Got you. Got you. That's helpful. Maybe just a quick follow-up on recurrence-free survival, which to your point is obviously the primary endpoint in the Phase III trial, right? So are you going to show us the p-value, both one-sided and 2-sided? I think in the press release, you have showed the p-value of one-sided. Is there -- are we going to share both at ASCO or still TBD?

I think you'll see the p-value and the one-sided versus 2-sided is literally, you can just multiply it by 2.

Okay. Okay. That's helpful. Maybe let's talk about the Phase III interim for melanoma. The company is obviously not committing to whether data is going to come this year or next year. It's possible this year, obviously it depends on the number of events and how those events will accumulate. Just maybe walk us through what's your latest thinking there? And how are you spending the alpha between the Phase III versus the Phase II?

So in a scenario where the trial failed the interim look at Phase III, does that mean that the data is worse than the Phase II? Or are you spending the alpha differently so we can't compare one to the other? Any thoughts there?

So we -- you are correct that this study is event-driven. And we do expect that 2026 is a pretty good estimate of when we will see that data set. However, we haven't commented at all on any of the statistics. So I'm afraid I can't answer any of the questions around the statistics.

Got you. But the 2 scenario at this point is that either the trial continues to the next interim or it hits on efficacy. Is that the way to think about it?

If there was an interim analysis, yes, the SMB will be looking at the results of that analysis, and it can either go on to the next analysis or we can stop the study for efficacy.

Is there a look for futility as well? Or is it just for efficacy for Phase II?

The Phase II study was very strong, as we just talked about. And so there isn't just a futility analysis.

Got you. Got you. That's helpful. We've seen this move in oncology over and over again with some time the standard of care evolves when you're kind of mid-trial, if you will. And obviously, the NADINA trial suggests that maybe PD-1 and CTLA-4 should be used in the neoadjuvant settings instead of the adjuvant settings of your trial is in the adjuvant setting.

So is there a scenario where by the time you read out your trial, maybe the standard of care has moved and everybody has moved to the neoadjuvant setting and your trial is less relevant? Or is that maybe not the right way to think about it?

So my understanding is that the NADINA study was an investigator-run study and the results were impressive. It may take some time for it to actually become more of a standard of care. In any case, having an armamentarium of medicines and products that physicians can prescribe for their patients is important. And the other thing that I'd like to point out around the combination so far with intismeran and KEYTRUDA is the remarkable safety profile there. We don't see any overlapping safety, which makes it a pretty powerful offering should this be a positive Phase III trial and make it to market.

Got it. Got it. That's actually helpful. Moderna commented on price should that drug ultimately become a reality? We're all obviously rooting for patients here. How should we think about pricing in the context of where IO is today, in the context of where CAR-T is today? Like any big picture thoughts on that side?

So it's a little premature to talk about price. We'd like to see the data first. And so unfortunately, we won't have any comments on price. But as you pointed out, there are IO-IO programs and products on the market that can give you somewhat of a proxy of what pricing may look like, but it will also be data dependent as well.

Okay. That makes sense. You also have 2 additional Phase II trials that are fully enrolled for INT, obviously, both renal cell carcinoma as well as bladder. Maybe just talk about timing of when those data sets could come out. Again, my understanding is that the melanoma Phase III trial enrolled, finished enrollment before the renal cell carcinoma trial. And I think if I look at the Kaplan-Meier curve for the PD-1 monotherapy, it looks like events are accumulating faster in melanoma than RCC. So would it be fair for us to assume that no matter what, the melanoma trial will come before RCC?

A couple of points for you. You're right that the melanoma study was fully enrolled in September of 2024. So there has been more time with that study being fully enrolled and events accruing. The RCC trial was fully enrolled as of the second quarter of 2025. So less time with that study being fully enrolled.

And if you were to compare the Kaplan-Meier curves of IO programs or checkpoint inhibitors by themselves, you would probably see that melanoma patients recover quicker than RCC. So when we say that 2026, we feel pretty good about the melanoma readout despite it still being event-driven, there is a possibility maybe RCC could read out, but it is event-driven, but we haven't committed to a readout in 2026 at all.

Got you. Got you. That's helpful. We also have seen some interesting data published in Nature Biotech, where essentially patients that received -- that were on PD-1 and actually received COVID actually had better responses than patients that did not receive COVID. So in your Phase III for melanoma, are you stratifying in any capacity, the number of patients that are going to receive COVID on both arms? Should we -- or is there a scenario where maybe you have more patients that receive COVID in one arm versus the other and that imbalance can kind of skew the statistics, if you will? How should we think about that?

So we -- I don't believe we are stratifying for COVID vaccination. What I can say is that we are very keen on seeing the mechanism of action really shine through in intismeran with intismeran plus KEYTRUDA. And there is some data that's been presented on the neoantigen selection at AACR earlier this year. We hope to have additional data on the neoantigens in our intismeran product, where we're seeing an effect of the selected neoantigens and recurrence.

And so very much in line with the mechanism of action that we expect to see. Whereas with the COVID vaccine, it's really hard to pinpoint what exactly is happening there. That study that was published, I believe, in Nature, also could have many confounding issues there in terms of the type of patients that would get COVID vaccines are likely to be more healthier. So a lot to be kind of still serrated out from that study. But we will have our data, the Phase III data, hopefully, at some point in the future that should give us a good answer on the mechanism of action that's happening with intismeran plus KEYTRUDA.

Got you. Got you. That's very helpful. What about the metastatic settings? I mean, so far, obviously, the data that we've seen is primarily in the adjuvant setting. We have seen some data in the metastatic settings from basket studies from back in the days, ASCO, I think maybe 18 or something.

Just however, I believe that you and Merck have yet to commit to run a registrational trial in the metastatic settings. What's holding you back? Is there anything in the biology that makes you believe that this is much more likely to work in the adjuvant settings versus the metastatic settings?

So we do have a study, a Phase II study that's running in metastatic frontline melanoma as well as metastatic squamous cell carcinoma of the lung, so non-small cell lung cancer squamous. And those studies have just recently been up and running. And so we are eager to see what the data there looks like. But you're right, the vast majority of the program with partner Merck has been really focused on the earlier settings in the adjuvant setting as well as potentially going even earlier as we just announced our non-small cell lung cancer study in Stage 1 patients.

So yet to be determined if it is something the mechanism of action is really the driver of that selection. We want to see the data both in the metastatic setting as well as the adjuvant setting before we rule out any area where intismeran plus KEYTRUDA doesn't show a benefit.

Got you. Got you. That's helpful. I think in non-small cell lung cancer, which is obviously the largest potential commercial opportunity in the metastatic settings, I think the only trial that you have started is actually in the squamous histology, not in the non-squamous histology.

In the metastatic setting.

Metastatic setting, the squamous histology, not non-squamous. Can you just maybe talk about why that's the case? Is that because squamous is more driven by smoking? And so patients have higher tumor mutational burden. And so this mechanism of action is more likely to respond in that histology or what?

I'm sure there's multiple reasons why we selected going into the squamous cell setting. I'll just remind you that there is a joint steering committee with both the Merck scientists and the Moderna scientists when we agree and move forward in the development and in the different areas of development. So there are probably multiple reasons why they decided to go with squamous in the metastatic setting.

Got you. Got you. That's helpful. Maybe pivoting to flu, never a boring day with the FDA these days, right? Maybe at a high level, is the fact that Makary and Prasad are no longer at the FDA, a good thing or a bad thing for Moderna?

I would just really think about how Moderna has worked with the FDA and the review staff, the scientific -- career scientists that are there all throughout 2025 and remind folks that the relationship that we've built with the FDA based on the science and the products that we take through is a really strong one. And that's really evidenced in 3 different programs that were approved by the FDA last year.

And that includes our new COVID vaccine, an expansion of the RSV label for high-risk individuals 18 to 59 years old as well as the pediatric vaccine that was approved, a full approval on the pediatric vaccine. And we are the only ones that have a COVID pediatric vaccine in the setting of 6 months to 5 years old. And so I think that shows that strong relationship rooted in the science, and we expect that to continue given that it's really started and it is with the review staff and the career scientists that are at the FDA.

Sure. That's helpful. I think PDUFA date for flu is the upcoming, right, August 5, if I recall it correctly. What's the latest thinking there? Have you had any back and forth with the FDA? Are you already in label discussions? Like how should we think about that?

So that review is ongoing. And you're right, August 5 is our PDUFA date. We typically don't talk about back and forth with FDA, but we are looking forward to a decision on that date.

Got you. Got you. That's helpful. How should we think about the commercial opportunity for flu? Obviously, it's an established market. There's a lot of players out there. Probably the most intuitive competitor here will be Fluzone HD from Sanofi, which is obviously doing pretty well commercially. Like just walk us through how should we think about the ramp of the flu vaccine from here in the United States? And are there any lessons learned from RSV? Obviously, the launch of RSV hasn't been maybe what some of us were hoping for. So what are some of the key lessons learned from RSV that you're hoping to apply here for flu? And how should we think about the trajectory of this market going forward?

Sure. So the flu market versus the RSV market, there are some marked differences there. Flu is a very established market with players competitive. But RSV was a relatively new market when we entered that market. And it also had a number of recommendations that actually didn't happen for that RSV market.

So I would characterize RSV as a competitive market. And so we entered a very competitive market where the market wasn't established as well as the lack of having a revaccination schedule that really impacted the market. Whereas with flu, again, a very established market, we'll be entering that market with a strong product profile should we get approved. And I'll just remind you that the head-to-head study that we did with standard flu vaccine showed a 27% relative vaccine efficacy. And so we think we're entering that market with a very strong profile despite the fact that it's a competitive market. We would like to position it as one for that enhanced market that Sanofi is in as well, as you mentioned, for the older adult population.

Got it. Helpful. What about the combo? Obviously, you filed in Europe, and hopefully, there will be a combination of flu and COVID available in Europe soon. However, what's the latest thinking on filing in the U.S.? It's my understanding that for a period of time, you guys were hoping to file them together versus now the FDA has come back and says like, hey, we want to first approve flu before we consider the combo. Where do we stand in the conversations with the regulators to get the combo over the finish line here?

All right. So a couple of corrections there in your question. We are approved in Europe with mCombriax. That approval came through pretty recently in this past quarter. So we're looking forward to starting discussions with NITAGs and getting it ready for the fall of 2027. In the U.S., we first filed for the combination last year, and we were asked to withdraw that filing so that we can add in the flu filing. And now that the flu filing is on track, we're still awaiting guidance from the FDA for the next steps on the combination in the U.S.

Okay. Okay. That's helpful. Maybe COVID and the guide for the year. Again, you're still guiding for potential revenues up to 10% for the year. Obviously, your competitor, Pfizer, has a little bit of a different outlook, they're actually guiding, I think, their COVID franchise more broadly. This is both the vaccine as well as their therapeutics approach, I think, down 23%.

So like what's kind of the best way to rationalize that dichotomy? And maybe just talk us through what are your expectations for vaccination rate in the U.S. I know you guys have guided that vaccination rate is expected to further decline. However, there's got to be some other dynamics that are more than offsetting that vaccination rate coming down. You already mentioned ex U.S. But yes, how should we think about the outlook for COVID for the rest of the year?

Sure. So you're right, we guided to up to 10% growth for 2026. And that growth is going to be driven by our strategic partnerships that are outside of the U.S. in the U.K., Canada and Australia as well as growth of mNEXSPIKE, our new COVID vaccine, which also showed a better relative vaccine efficacy, so higher vaccine efficacy by 13% versus Spikevax. Those 2 drivers are what will be contributing to that growth. And so while I can speak to our growth coming predominantly from the ex-U.S. strategic partnerships as well as continued growth of mNEXSPIKE, it's hard for me to say what Pfizer was thinking about their own guidance.

The visibility we have with those strategic partnerships is pretty strong. And so most of our growth is coming from that -- the international markets. In the U.S., as you pointed out, our guide of up to 10% growth, if you took the midpoint of that instead 5% off of the $1.94 billion of sales last year, you get to roughly $2 billion. And we said that ex U.S. versus U.S. would be a 50-50 split. which would then mean that our U.S. outlook would look for a 20% decline. And there could be multiple factors that go into why we see that U.S. declining.

One of them is vaccination rates, anticipating another potential decline in the number of people getting vaccinations, but it could also be additional competition, for instance. We wanted to be -- take that into account just in case, but still we see growth. And so if we are flat on vaccination rates or flat to the U.S. versus last year, then we would see growth closer to the high end of that up to 10%.

Got you. Got you. That's helpful. Maybe related to it, how should we think about the long-term floor for COVID? Obviously, numbers have come down. And however, there is now some stability, especially ex U.S., to your point. However, again, the timing of the ex U.S. orders and whatnot can be lumpy, and it's kind of hard to fully model that. So what do you think is the floor here? Is it fair for us to think that maybe $1 billion to $1.5 billion floor going forward is the right number here? Or would you guide us against that?

So COVID specifically, last year was, again, on access was a pretty tough year with the transition in leadership at HHS, for instance. And so last year could serve as a pretty good proxy in terms of what we're looking for on the go forward, particularly since those folks who wanted to get their COVID vaccine showed up and got their COVID vaccine. But as you know, we'll just have to kind of go through the years to see if, in fact, last year's rate of vaccination is somewhere in the floor.

But again, these strategic partnerships that we have that do give us visibility into international markets does provide a good sense and visibility on what the COVID and vaccines market will look like, which just gives us confidence in our projections going forward.

Got it. Super helpful. Last question. I know we're already out of time here. But what's the latest on the IP dispute with Roivant and Genevant. Obviously, you settled for a big chunk of money upfront. However, you're still in the hook for $1.3 billion potentially. You're obviously appealing that decision. Maybe just remind us what are the timelines? And I think in your press release, you mentioned that you believe that, that $1.3 billion additional payment is not probable. Why did the legal team concluded that, that $1.3 billion was not probable?

Yes. So a couple of points there. On the appealing, this is actually -- it's going to the court. We do not believe it is probable, and there isn't much more than I can say other than it is not probable in the eyes of our legal team, which is why there isn't a reservation or any kind of reserve on the cash.

Got you. Lavina, I have a lot more questions, but no more time. So I appreciate you joining us here at RBC. Thanks, everyone, for joining, and we'll talk soon. Thanks again.

Thank you.

All right. I guess it's quiet, so we'll probably get going then. Thanks for joining the session with Moderna Therapeutics, and thanks for attending the 2026 Bank of America Healthcare Conference. My name is Alex Stranahan. I'm a senior biotech analyst at Bank of America covering Moderna. And I'm pleased to be joined by Lavina Talukdar, Head of Investor Relations. Lavina, thanks for being here.

Thank you so much for having me. That was the best pronunciation of my last name.

Been practicing. But just for this.

But maybe just to start, you've got 4 approved products. You've guided to revenue growth for 2026. You've already beaten your own reduction targets ahead of schedule. I guess, is 2028 still the breakeven target? And is this now maybe conservative? And I guess what are the key variables that could accelerate or delay this?

Yes, great question. Thank you for asking it. we did guide to up to 10% growth in 2026. And there are 2 contributors to that growth that I would focus you guys on. There's increased growth of mNEXSPIKE, which was approved last year and participated in the fall 2026 -- 2025, 2026 season as well as our strategic partnerships in the U.K., Canada and Australia, where we have very good visibility to the growth coming from those 3 markets, owing to the fact that we've built facilities there, and those facilities have been online since 2025.

So the full year effect of those contracts or those strategic partnerships come into play in 2026. We've also, as you just highlighted, beaten our cost guidance that we gave for 2025. The beginning of the year, we guided to taking $1 billion out of our infrastructure costs within Moderna, and we came in at taking out $2 billion in cash costs. So already ahead of the game. 1Q we are on track to meet our cash cost guidance of $4.3 billion for the remainder all of 2026. And so what we can control, we've been really controlling. And there are factors that aren't necessarily fully under our control that will contribute to growth in '27 and '28 to ultimately get us to that breakeven. Those include approvals. I mean we do have a flu PDUFA date coming up later this year, which I'm sure we're going to talk about.

The data there looks great. We're working very well with the FDA, so there are approvals that will also play into that growth, reaching that growth as well as continued cost containment. So for 2027, we've guided to $3.5 billion to $3.9 billion in cash costs, so another reduction in 2027. So those are the things we'll control and make sure that we do get to that breakeven in 2028.

Okay. And I believe intismeran is not contemplated in the breakeven. That would be an additive.

Intismeran, we're expecting to hopefully see data from the Phase III study there are approval time lines that go into effect as well, as you know. We do think there's a possibility we'll see the approval there in 2027, but the first year of launch won't be a meaningful contributor in '27 to get us to the '28 breakeven. But there will be -- hopefully will be some sales from intismeran as well.

Okay. Maybe circling back on flu that you mentioned. So you've got your PDUFA date later this summer. It got an RTF and then that was pulled back. Now Makary is resigning not saying that there's a direct line to be drawn there, but it did create, I guess, some uncertainty around the U.S. revenue build here. I guess what are your expectations around when this could become available in the U.S.? And how do you sort of see this playing out in terms of approval sequentially thinking about a combo in the U.S. as well?

So you're right, there was some uncertainty with a change in administration every year. Any time there is a change in administration and changes at regulatory bodies, one should expect some uncertainty. And I think 2025, when we entered 2025, there was a tremendous amount of uncertainty that we had to deal with, and yet we got through 2025 pretty well. We have 3 products that were approved, and we came in at the higher end of our guidance that we gave on the third quarter earnings call. So I would characterize that as Moderna really having a strong collaboration with reviewers and scientists at the FDA, including higher -- those that are higher up as well.

And so to see some more of that continue in 2026 is something that we will try and stay ahead of, but going back to that very strong relationship with FDA, the career FDA folks that are there, I think, is testament to us navigating through some of this uncertainty. Coming back to flu, as you mentioned, we do have an August 5 PDUFA date. We're on track to hopefully see what that result is in terms of a thumbs up or thumbs down on the approval. The data speaks for itself. We showed 27% better vaccine efficacy versus the standard of care there, so we're hopeful that August 5 is when we'll see that PDUFA date go positively for us. And that will be another data point that suggests that our relationship with the regulator is pretty strong.

Okay. I guess how have your interactions with the agency evolved over the past year? And I guess, are there any near-term PDUFA time lines or review interactions that are being affected in practice?

So as I just mentioned, it's been a pretty collaborative 2-way street with the FDA. And other than to say that we have that PDUFA date on August 5, will -- there isn't much more to say on that. I think the collaboration is something that I just talked about is one that we're pretty proud of.

Okay. And in terms of, I guess, sentiment, and this is going to be a Hantavirus question, Moderna's technology has always been or has had the capabilities to be kind of first mover for any emerging pandemic. I feel like that's just being reiterated with Hantavirus. Obviously, you had something in the works, I think since 2024 I believe. Maybe you can just speak about that program and sort of what we're seeing, understanding that it's still sort of an evolving situation.

Yes. So you're right. We do have an early program. It's preclinical and that's in collaboration with the U.S. Army Medical Research as well as through our mRNA access program, we've allowed for access to our technology to major institutions around the world. In the case of Hantavirus, it's with the University of Korea, they have an innovation center. And Hantavirus is one of those viruses that the WHO ranks as potential for becoming an epidemic pandemic. So the whole realm of pandemic preparedness is what mRNA access is also trying to accomplish through that program. And so this early stage program that we have, I think, could be something that gives us a leg up should Hantavirus turn into something a little bit more serious than what we're all reading about in the headlines.

I mean we see a lot of things in the headlines about Hantavirus. Is this another COVID? I mean it's a fundamentally different virus in terms of the RNA and spreadability and how it's transmitted. I guess, how are you thinking about this as being a potential public disaster like COVID was? Or is it maybe something that's a little bit more isolated?

So that's a great question. I think we're still learning a lot about Hantavirus. There is some speculation that there is human-to-human transmission once somebody does have or is infected with Hantavirus. It is particularly from rodents is my understanding because they are the carriers of the virus. And once you have exposure to their experiment, then it could be something that you have to worry about. But then we have heard from the recent headlines that there is a possibility of human-to-human transmission. So all of those things, I think, are going to be what regulators and health agencies around the world monitor, and we'll continue to monitor that as well. But the key point you brought up, which is being ready for something like this is what the -- where the world is today, owing to what happened with COVID. And having a technology like mRNA technology as well as an early program in development, again, preclinical that gives the world a leg up on potentially avoiding something like a major pandemic in COVID.

Well put. I want to circle back sort of on the European combo approval. That was a recent positive update for the company. And the European market does have the potential to be a large growth driver with the pandemic era contracts expiring. I guess with mNEXSPIKE and mCOMBRIAX approved in the EU, how are you sort of seeing the European market evolving in terms of your up to 10% revenue guidance this year? And then when does the combo kind of add to that top line growth?

Yes. Great question again. So for 2026, we do not have mCOMBRIAX contributing to -- or even mNEXSPIKE from the EU contributing to the 2026 top line. And so you shouldn't expect any contribution from the EU for 2026 growth, that up to 0%. You did mention the competitor contract that lapses later this year. And so it will make 2027 an open opportunity for us. And it's a fairly large respiratory vaccines market in the EU. So based off of demand, we believe the COVID market is $700 million in sales for the EU, $1 billion for flu and roughly $100 million or so for RSV. We'll be entering 2027.

As you just mentioned, mNEXSPIKE is approved in the EU and mCOMBRIAX, the first approval in the world for a combination flu plus COVID vaccine is also approved in the EU. We have RSV approved. And the flu standalone program is actually being reviewed by the EU regulators. So we may be in a position to have that product approved as well, and that would be our fifth product that's approved globally. And so it gives us 2 things. One, the competitor contract lapses, so the market opens up for us. And then we'll have a full portfolio to offer the EU territories. And so we're looking forward to competing in that market. As of the end of 2025, sales from the EU was less than $100 million. So even if you assumed a fairly modest penetration or market share in the EU, you would see still meaningful growth coming from the EU once 2027 hits, and we're competing in that respiratory market.

Okay. Great. And I appreciate the color on the timing piece. I guess when we think about the launch preparedness in flu, this feels like kind of bread and butter for you guys, but it's is kind of an established market, right, whereas RSV was like you're building that out. COVID was like the pandemic funneling into an established market, but flu feels kind of like the first established market launch. How should we sort of think about the trajectory there? And how does this get positioned versus, say, some of the approved flu vaccines?

Yes. So you're right, flu is a competitive market. We feel we're entering that market with a very strong profile in our vaccine. So I'll remind everyone, we showed roughly a 27% relative vaccine efficacy relative to standard flu vaccines that are on the market. So that already positions us pretty well for that enhanced market for that highly vulnerable population, older adults and people who have medical issues that might want a little bit better coverage in their flu vaccines. And so we'll be entering that market, which wouldn't include the standard flu vaccines and so a little bit more limited in terms of who's competing there.

And given the profile of this vaccine, plus having it be part of a portfolio of vaccines that we'll be selling to our customers, I think, will position us well for that market. It's a fairly large market, the flu vaccine market. It's $6 billion worldwide with the U.S. making up roughly half of that. And so we look forward to the launch. But you're right, it's competitive. So we'll see what we can do there.

Okay. Okay. Great. I do want to shift gears and ask about oncology now. We're all eagerly awaiting the intismeran adjuvant melanoma update. The 5-year data look pretty compelling, roughly a 50% reduction in relapse or death. I think this is kind of the context for the ASCO presentation later this month. For the Phase III interim expected later this year, I guess, what is the sort of statistical framework? What are the hazard ratios that give you early success versus continued finding?

Yes. So our partners, Merck and Moderna have not discussed the statistical plan for the trial. So unfortunately, I'm not going to be able to say anything about that. We do think on timing, it's going to be in 2026, and that's been the guidance all along. So we look forward. We're just as anticipatory and anxious about that data and want to see that data as all of our investors are as well.

Okay. And I think the Phase IIb showed a median RFS of like 19.4 months, if I'm remembering correctly. Would that be kind of a win?

The Phase II data was an absolute home run. And so that would definitely be a win. Is it the hurdle you need to have in a product that could be successful on the market at the end of the day, probably not. And so I would like say, if you looked in the sea of other oncology products that are approved, you'd often find hazard ratios of 0.8 as products that are approved. And that's oftentimes in relation or with a control arm with a placebo. So not an active comparator, which hazard 0.8 means there's a 20% reduction in an event or death happening.

And in the case of our Phase III at the end of the day, if we had a 0.8 hazard ratio, would it still be a meaningful clinical impact for patients, we believe so because it's on top of a very good active comparator in KEYTRUDA. So that would still be a meaningful result for patients.

Okay. That's helpful. I guess, in a few weeks at ASCO you'll have, like I said, a 5-year data, I believe. Anything specifically that you think bodes well or sort of informs what we should be looking at from the Phase III.

So we've already released the top line data of RFS, and we said the hazard ratio was sustained at the 5-year mark as well. So a 49% reduction in having a recurrence or dying if you get the combination of intismeran and KEYTRUDA. So that already kind of tells you. When I get that question, Alec, I often think to myself, other than the durability now out to 5 years, continuing to see that hazard ratio, which we all know and it is going to be presented at ASCO as well. Do you -- can you glean any more from that Phase II? I feel like the Phase II results in of itself at 3 years and the top line at 5 years kind of tells you a lot of why we're and our partners, Merck, are excited about potentially having that Phase III readout.

Is there anything more you'll learn? I know that outside of the Kaplan-Meier curves, and this has already been released with the abstracts, there will be some translational data. So this is speaking to the mechanism we've announced is fully enrolled and has been now fully enrolled since the second quarter of 2025. And it is one, as you mentioned, where KEYTRUDA also works. So a lot of the development programs that are under this broad development program within intismeran is to really exploit that synergy, if you will, with INT plus KEYTRUDA because we do believe there's that synergism in terms of how the 2 act together or behave together. And so KEYTRUDA has shown positive results in RCC as well. So it felt low risk to go after that type of a tumor because KEYTRUDA has shown a benefit already.

And if this is true synergism with intismeran, then we would expect to see that follow through in RCC and all the other cancers that we're developing this intismeran program in. And so despite being less tumor mutation -- having less tumor mutational burden, we do think that's one that could be interesting. It's a Phase II randomized study, as you pointed out, an end that is nearly twice the end of the Phase II in adjuvant melanoma. In terms of whether or not it serves as a registrational study depends on the strength of the data and also conversations we have with regulators. But we're looking forward to that data readout as well at some point in the future.

Okay. And on your 1Q call, you disclosed that your partner, Merck recently launched a new study in Stage I lung cancer. That's basically the very earliest population in combination with KEYTRUDA. I guess does this, in your view, kind of signal confidence from Merck in the program or continued confidence? Obviously, they've been confident in it. But how should we be thinking about this new study start in the context of all the other studies you have ongoing?

Definitely continued confidence because it already was a very broad development program. As you know, we have -- this is our third non-small cell lung cancer study that we've started. I think it does speak to how committed Merck is to this intismeran program. It is a 50-50 joint venture with Moderna. And so they're splitting the costs and resources, all of that evenly with us. The other thing I'd say from -- personally, I'm actually super excited about this study because it gives intismeran 2 opportunities to win. And so what do I mean by that? This is a 3-arm study where you've got in one arm, intismeran plus KEYTRUDA, in arm intismeran monotherapy and then the final arm, the control arm of placebo because in Stage 1 nonsmall cell lung cancer, the standard of care is watchful waiting.

So after you've resected the cancer, you're just waiting for a recurrence -- hopefully, it doesn't happen, but if it does happen. And so you've got now 2 active arms with intismeran in it. So 2 opportunities to win in that study. So I'm super excited to have the ability through this study to offer patients active and proven through at least the Phase II studies that we've conducted in adjuvant melanoma to show meaningful clinical benefit with intismeran plus KEYTRUDA as well as intismeran by itself. And it also speaks to another thing that both Merck and ourselves have been pointing out, which is the safety profile of intismeran and the combination of the 2, intismeran and KEYTRUDA.

There isn't any overlapping toxicity that you see oftentimes with other IO/IO combinations. You just don't see that with intismeran plus KEYTRUDA. And so that offers us this ability to move earlier into the earliest stages of disease in the case of non-small cell lung cancer in Stage 1 setting. And so the risk benefit there is something also that I think is another reason why Merck and ourselves felt very comfortable moving as early as we did.

Okay. That's helpful. I want to ask about mRNA-4359. This is your 100% owned cancer antigen therapy going after IDO and PD-L1. The IDO component of that, we haven't seen for a little while, but it showed some pretty encouraging, I guess, initial activity at AACR earlier this year. I guess, -- maybe you could walk us through sort of the emerging profile for that therapy. And I guess what sort of efficacy signal would be sufficient to move this into pivotal study?

Yes. Great question. So you're right. This is wholly owned by Moderna, off-the-shelf antigen therapy, cancer antigen therapy. And we are targeting epitopes of both PD-L1 protein as well as epitopes of IDO1. So the mechanism that we're using, I know when I speak to investors about IDO, they recall the small molecule approach back several years ago that did not actually have a successful readout. Here, we are teaching your T cells to look for epitopes of IDO1 as well as PD-L1. And we've learned a lot from INT and how we can teach your T cells to look for neoantigens in the case of INT, here it's epitopes of those 2 proteins.

And so the data we've seen so far, and we've now turned over the cards from the Phase I study at ESMO last year, we showed some pretty compelling early -- still early data in highly refractory patients. So people who have had multiple rounds of therapy, some 3 lines plus. And there, we were able to show close to 2/3 overall response rates in a highly refractory patient population. Most recently at AACR, which is what you asked about, in the Phase II portion of that study in frontline melanoma patients, we've seen the ORR now of 83%. So 11 out of the 12 patients or 10 out of the 12 patients have now had a meaningful response rate.

So again, very encouraging. But this is still a handful of patients of data. I think if David Berman, who just joined us here at Moderna were here, he'd say he'd want to see a little bit more quantum of data in a few more -- many more patients to actually then move this forward. And so we're running the Phase II. So let's see if this data consistently holds up as we've been finding with this program, then it will be ripe to move into the later stages.

Okay. Great. And maybe in the last minute that we have, I want to ask -- in terms of the burn vis-a-vis investing today in the Moderna of the future, do you feel like you've rounded a corner on that kind of seesaw of trimming expenses to a point where now you feel confident in building out the pipeline further, doing external BD or additional partnerships? I guess, what are sort of -- where are we in that continuum leading up to 2028? And I guess what are the investments that you're comfortable making today to build Moderna for the future?

Yes. What a great question, and I'm going to probably take more than a minute to even answer it. But the key thing to note that on that kind of rounding out on the cost side, many of the Phase IIIs that we ran up until the last one that we'll be doing in the infectious disease arena is the norovirus vaccine study that also has a readout in 2026, by the way. Once those Phase IIIs are done, that cost is largely behind you because the maintenance cost for infectious disease vaccines is probably 10%, maybe 15% of sales. And so a lot more manageable. And that large cost that you needed to make in order to get the product on the market is behind you.

In oncology, the cost of a late-stage development program pales in comparison to infectious disease vaccines, Phase III studies costs. And that's largely driven by the end, the number of people you have to have in your studies. In infectious diseases is tens of thousands of patients. A Phase III in INT is 1,000 patients. So even though the cost per patient might be a little bit higher, the number of the N in those Phase III studies are so much lower that you can handle the cost. And so if the future for us is now going into cancer as a big therapeutic area and other therapeutic areas that don't require large clinical studies like infectious diseases do, and now we have this commercial portfolio that's coming to market, all of the R&D costs associated with that is behind us. And so we still can now invest without the quantum of investing being as large as it should be for infectious diseases and have a plethora of opportunity from oncology and other therapeutic areas going forward.

Okay. Very good. Well, with that, I know we're over time. So I really want to thank you, Lavina, for the great conversation, and thanks, everyone, for attending.

Thank you.

Good day, and thank you for standing by. Welcome to Moderna's First Quarter 2026 Conference Call. [Operator Instructions] Please be advised, today's conference is being recorded. I would now like to hand the conference over to your speaker today, Lavina Talukdar, Head of IR. Please go ahead.

Thank you, Kevin. Good morning, everyone, and thank you for joining us today. to discuss Moderna's First Quarter 2026 Financial Results and Business Update. You can access the press release issued this morning as well as the slides that we'll be reviewing by going to the Investors section of our website.

On today's call are Stephane Bancel, our Chief Executive Officer; Stephen Hoge, our President; and Jamie Mock, our Chief Financial Officer.

Please note that this conference call will include forward-looking statements made pursuant to the safe harbor provisions Securities Litigation Reform Act of 1995. Please see Slide 2 of the accompanying presentation and our SEC filings for important risk factors that could cause our performance and results to differ materially from those expressed or implied in these forward-looking statements.

With that, I will turn the call over to Stephane.

Thank you, Lavina. Good morning or good afternoon, everyone. Thank you for joining us today. I will start with a review of our first quarter, jimmy will then cover our financial results and outlook, followed by Stephen on commercial and clinical progress. I will close by discussing our value drivers before we take your questions.

The Moderna team delivered a great quarter all around. In the first quarter, we grew year-over-year revenues significantly to $0.4 billion, driven primarily by execution of our long-term strategic partnership in -- with the U.K. government. With a strong Q1, we are reiterating up to 10% growth in 2026.

We reported a net loss of $0.5 billion, excluding the previously announced Arbutus litigation settlement or $1.3 billion on a GAAP basis. We ended the quarter with $7.5 billion in cash and investments, maintaining a strong balance sheet as a result of continued financial discipline.

Our cost reduction efforts continued in the first quarter, building on actions taken in 2025 and resulting in a 26% year-over-year reduction in adjusted cash cost in the first quarter, excluding the litigation settlement. This performance keeps us on track with our full year objective of approximately $4.2 billion in adjusted cash costs.

We also advanced our commercial portfolio and our pipeline. In our respiratory portfolio, we achieved an important milestone with the approval of [indiscernible] in the European Union. [indiscernible] was known before as amounted 1083 of flu plus COVID combo vaccine. This is the first flu plus COVID combo vaccine approved in the world, and this marks Moderna a fourth approved product. I am very proud of the team for bringing this innovation to patients. This is exactly what Moderna stands for. We also secured approval for [indiscernible] in the European Union. These 2 new approved products in Europe will be important growth drivers in the EU in 2027, and when we anticipate COVID market reopening for Moderna.

In the U.S., our seasonal flu vaccine mRNA-1010, was assigned a pot of August 5. In oncology, for Intismeran, we initiated a new Phase III clinical trial in non-small cell lung cancer for patients with Stage 1 disease. It's our first Phase III clinical trial evaluating Intismeran in a monotherapy arm in patients with early-stage disease. I am very excited about this new clinical development because Stage 1 lung cancer is mainly treated with surgery alone today.

Additionally, we look ahead to our upcoming ASCO oral presentation, where we'll report a 5-year update of our Intismeran in adjuvant melanoma.

We were also pleased to recently present at AACR the new clinical data for mRNA-4359, which is currently in Phase II for patients in Stage IV disease, metastatic disease in melanoma and lung cancer.

Lastly, with support from [indiscernible], our Pandemic flu program, mRNA-1018 has now initiated its Phase III study. I'm very pleased with the company's strong performance in Q1 and very thankful for our team that executive across the board.

With that, I'll turn it over to Jamie.

Thanks, Stephane, and hello, everyone. Today, I'll cover our first quarter financial results and then review our 2026 financial framework. Let me start with our commercial performance on Slide 7.

For the first quarter, total revenue was $400 million, coming in above our guidance and represents a $300 million increase versus the prior year. Our geographic mix was approximately 80% from international markets and 20% from the United States. This strong international revenue performance was primarily driven from deliveries under our long-term strategic partnerships.

For the second quarter, we are expecting revenue of between $50 million and $100 million, evenly split between U.S. and international markets, which would bring our first half revenue to approximately $440 million to $490 million.

Our strong revenue performance year-to-date puts us on a solid path to achieve our full year revenue growth target of up to 10%, which we are reiterating today.

Now I'll round out our full first quarter financial performance on Slide 8. As I just mentioned, revenue was $400 million in the quarter. Cost of sales for the quarter was $955 million. This includes $878 million related to our previously disclosed litigation settlement. Excluding this item, cost of sales was $77 million, a 14% year-over-year decline on a non-GAAP basis, driven by reduced unutilized capacity costs, losses on purchase commitments and inventory write-downs, partially offset by higher sales volume.

Regarding the litigation settlement in March, we announced that we entered into a settlement agreement with [indiscernible], resolving all litigation with them worldwide. Under the deal terms, we will make a lump sum payment of $950 million in the third quarter of 2026, of which $878 million was recognized in cost of sales during the first quarter of 2026, and the remaining $72 million is being amortized over the next 3 years. Under the agreement, Moderna will appeal to the Federal Circuit to argue its government contractor immunity defense, which limits its liability under federal statute 1498. If Moderna ultimately prevails on that issue, no further payments will be due. If, however, the Federal Circuit of firms liability under Section 1498, Moderna has agreed to make an additional payment of up to $1.3 billion. We have concluded that a loss related to this pending Section 1498 proceeding is not probable.

And accordingly, no charge has been recorded. R&D expenses for the quarter were $649 million, a 24% decrease compared to last year, driven by lower clinical development and manufacturing costs as we wind down large Phase III respiratory programs, and our CMV Phase III study, partially offset by higher post-marketing commitments from our COVID products.

SG&A expenses for the quarter were $173 million, an 18% decrease compared to last year, driven by lower spend across all functions, reflecting continued cost discipline while supporting the business.

Our income tax provision was immaterial in both periods as we continue to maintain a global valuation allowance, which limits our ability to recognize tax benefits from losses.

Net loss for the quarter was $1.3 billion or $3.40 per share compared to a net loss of $1 billion or $2.52 per share last year, primarily driven by the litigation settlement. Excluding this item, the net loss would have been $0.5 billion or $1.18 per share, down over 50% versus the prior year.

We ended the first quarter with cash and investments of $7.5 billion compared to $8.1 billion at the end of 2025. The decrease was primarily driven by operating losses as we continue to invest in R&D and advance our pipeline. The litigation settlement did not impact cash in the first quarter as the $950 million payment is due in the third quarter of 2026.

Now let's turn to our financial framework for 2026. As mentioned earlier, we expect total revenue to grow up to 10% in 2026, with a geographic mix of roughly 50% from the U.S. market, and 50% from international markets. Our 2026 revenue guidance factors in potential future declines in COVID vaccination rates, offset by increased penetration of mNEXSPIKE and revenue from our long-term strategic partnerships. As a reminder, this guidance assumes no revenue from our flu vaccine or [indiscernible].

Our cost of sales projection has increased from $0.9 billion to $1.8 billion, and now includes the $0.9 billion litigation settlement charge. Without the litigation charge, our cost of sales projection would have been unchanged versus our previous guidance and reflects our expectation of gross margin improvement from manufacturing efficiency gains and volume leverage. R&D expenses are still anticipated to be approximately $3 billion as we continue to invest in our pipeline while maintaining financial discipline. We now expect the timing of our R&D spend to be slightly weighted more to the second half of the year.

SG&A expenses are still expected to be approximately $1 billion, flat versus the prior year. Similar to 2025, our commercial spend will be more heavily weighted to the second half of the year due to the seasonality of our commercial business.

In aggregate, excluding the $0.9 billion litigation charge, we are expecting total GAAP operating expenses of $4.9 billion and cash costs of $4.2 billion, which excludes stock-based compensation, depreciation and amortization.

Additionally, we do not see any material impacts from the ongoing conflict in the Middle East to our 2026 financial outlook, but we'll continue to monitor geopolitical developments.

We expect taxes to be negligible in 2026. Capital expenditures are still projected to be between $0.2 billion and $0.3 billion, and we expect to end 2026 with between $4.5 billion to $5 billion of cash and investments. Our cash guidance does not assume any additional drawdown from our remaining $0.9 billion undrawn credit facility.

Overall, we are encouraged by the strong start to the year and remain focused on executing in Q2 and beyond.

With that, I will now turn the call over to Stephen, who will walk through the commercial outlook in more detail.

Thank you, Jamie, and good morning or good afternoon, everyone. Today, I'll review our commercial outlook as well as progress across our pipeline. Slide 11 outlines our multiyear revenue growth strategy, anchored in both geographic expansion and continued advancement of our product pipeline. In 2026, as Jamie mentioned, we expect a 10% revenue growth driven by our long-term strategic partnerships in the United Kingdom, Canada and Australia, and supported by the continued growth of mNEXSPIKE.

Looking across the 3-year horizon, we are building a diversified portfolio, adding a flu vaccine, a combination vaccine and a norovirus vaccine as well as late-stage assets in oncology and rare diseases, and all while expanding our global footprint into new markets. We made good progress against this strategy in the quarter. We delivered our first shipment under a strategic partnership in the United Kingdom. We secured key regulatory approvals in the European Union, including mNEXSPIKE for individuals 12 and older, and [indiscernible] for adults 50 and above. positioning us well in the large $1.8 billion annual European respiratory vaccines market. We expect both products to contribute to revenue growth starting in 2027 and in the U.S., our flu program continues to advance with a PDUFA date for set for August 5, 2026. Stepping back, our execution in the quarter gives us confidence in our ability to deliver in the near term and to grow over the long term.

Slide 12 highlights our approved products within the infectious disease portfolio. With the recent EU approval of mComvriax, we now have 4 approved products, a remarkable milestone for our commercial portfolio. Starting with our COVID vaccines. We plan to submit annual strain updates across all approved geographies shortly. More than 30 countries for Spike Fax and in the United States, Canada and Australia and now the European Union for mNEXSPIKE. mNEXSPIKE also remains under review in Taiwan, Japan and Switzerland, with additional filings planned for the second half of 2026 to further expand global access to this important vaccine.

Turning to RSV. mRESVIA is approved in the United States, European Union and Canada. Most recently, the European Commission also extended that approval to expanded indications to include adult age 18 and older, broadening the eligible population. For our flu plus COVID combination vaccine, mCOMBRIAX, we recently received approval in the European Union for adults 50 and older. The product is also under review in Canada and Australia, and we are awaiting further guidance from the FDA on the next steps for resuming filing in the United States.

Finally, at ESCMID, we presented new data supporting heterologous vaccination with mRESVIA as well as results from a Japanese cohort from our Phase III mCOMBRIAX studies. Links to both presentations are included on this slide.

Our late-stage infectious disease pipeline also continues to progress. Following with -- starting with flu, mRNA-1010 is under review in the United States, Europe, Canada and Australia, and the U.S. FDA PDUFA date is set for August 5. We recently presented revaccination data for mRNA-1010 at SMED, with a link to the presentation included on this slide. And for our norovirus vaccine, our ongoing Phase III study is now fully enrolled in its second Northern Hemisphere season. Based on case accrual to date, we continue to expect data from this study in 2026.

Turning to oncology, starting with Intismeran, our individualized cancer therapy developed in partnership with Merck. This trial program continues to expand with 9 ongoing Phase II and Phase III studies. As Stephane previously mentioned, we have initiated another Phase III study in non-small cell lung cancer, our third Phase III in lung cancer. This one is in high-risk Stage 1 disease, expanding us to the earliest stage of the disease. The trial includes an evaluation of Intismeran as a monotherapy. This is our second monotherapy study following our non-muscle invasive bladder cancer study announced previously and highlighting Intismeran's safety and tolerability profile as we move into earlier stage disease.

Across the portfolio, we now have multiple late-stage studies fully enrolled, including Phase III adjuvant melanoma as well as Phase II studies in renal cell carcinoma and muscle invasive bladder cancer, all of which are accruing events towards their interim readouts.

We continue to make progress towards completing enrollment in our other Phase III and Phase II trials, including in non-small cell lung cancer, bladder cancer and metastatic melanoma. This broad late-stage portfolio is supported by the strong clinical data including robust 5-year results from our Phase II adjuvant melanoma study, which will be presented at ASCO.

Beyond late-stage programs, our Phase I studies in pancreatic and gastric cancers are also fully enrolled, and we look forward to providing updates on those trials later this year.

Now outside of Intismeran, we continue to advance additional oncology programs. For mRNA-4359, our cancer antigen therapy, Phase II cohorts are enrolling across first-line metastatic melanoma and first-line metastatic non-small cell lung cancer. We recently presented new data in first-line metastatic melanoma setting at AACR with a link to the presentation included on this slide.

And finally, our early stage pipeline includes -- continues to progress, including our T cell engager, mRNA-2808 in a Phase I/II study, a cancer antigen therapy mRNA-4106 and cell therapy enhancer mRNA-4203 in Phase I studies in patients actively dosing. Now in rare diseases, our propionic acidemia or PA program is fully enrolled in its potentially registrational study. We continue to expect pivotal data from this study later in 2026. For our methylmalonic acidemia or MMA program, we have decided to defer the start of a registrational trial for that program until after we receive the pivotal readout from the PA or propionic acidemia program later this year.

With that review, I will hand over the rest of the call over to Stephane.

Thank you, Stephen and Jamie. Looking ahead to 2026, we see multiple value drivers across our company in commercial, in new product approvals and in [indiscernible] pipeline. On the commercial side, we continue to expect up to 10% revenue growth and remain focused on delivering our adjusted cash cost target of approximately $4.2 billion. We'll continue to invest in AI with a number of cross enterprise projects to reinvent work with AI. We will, of course, continue to drive increased personnel productivity across the company.

We also expect potential approvals across the respiratory portfolio in additional geographies. We could, later this year, see our fifth product approved with mRNA-1010 for flu. From a pipeline perspective, oncology remains a key focus with upcoming data for Intismeran and mRNA-4359. We're also waiting for a Phase III data for norovirus, subject to case approvals, and of our PA programs, which should read out this year.

The team remains focused on disciplined execution across these priorities. Over the coming months, we also look forward to engaging with the investment in medical communities at several upcoming events. This includes our investor event on June 1 at ASCO. But also, we would like to invite you in person to Cambridge or via webcast for our Science Day on June 25, where we'll provide a deeper look into our early stage pipeline, also how we're using AI and robotics to accelerate our ability to discover new technology to expand the use of mRNA to new drug modalities.

On November 12, we also hosted our Annual Analyst Day, where we plan to focus on commercial priorities, product launches and expanding late-stage pipeline.

In closing, I want to thank our teams around the world for the progress we've delivered this quarter. We have been executing consistently over the past 1.5 years, and I'm very excited of what is to come in 2016 and beyond. We are advancing our science, expanding our portfolio and continuing to translate mRNA into innovative medicines for patients. Each milestone achieved as important momentum and reconfirms our commitment to deliver [indiscernible] impact to people for mRNA medicine. With this, operator, we'll be happy to take questions.

[Operator Instructions] Our first question comes from Salveen Richter with Goldman Sachs.

So you newly disclosed initiation of a Phase III study for Intismeran as monotherapy and in combination with KEYTRUDA subcu for the treatment of high-risk Stage 1 small cell lung. Can you just -- and you spoke to it a little bit, but could you discuss your strategy to pursue this line and where it fits into the treatment landscape and why pursue a monotherapy here in addition to the combination?

Yes. Thank you for the question, Salveen. We and our partner, Merck, have been really excited by the clinical data that we've seen with Intismeran to date, including the Phase II. And it's important to highlight that the 2 pieces of that, one is obviously the efficacy signal we see, but the second is the remarkable safety profile associated with that efficacy, really no significant increase in serious or Grade 3 events when you get combination IO-IO like benefit. So the real question for us has been could we get that benefit risk profile in a monotherapy context? Could Intismeran provide IO-like protection against a relapse or recurrence of disease with a profile that really looks like a vaccine? And the best opportunity for us to do that, we and Merck have decided is it's across a couple of studies. Now the first I previously discussed was in bladder cancer, but we ultimately decided that in lung cancer, given the incredibly high burden of disease, the right approach there was to go into a Phase III potentially pivotal study.

In that context, as Stephane mentioned, as you referenced, standard of care, more often than not a surgery and then watchful waiting. And so essentially, there is no other intervention. And we're looking at, therefore, INT as monotherapy as opposed to just surgery and watchful waiting for high-risk Stage 1 disease.

Now we're also going to look at whether or not there's an incremental benefit of combining INT with KEYTRUDA in that setting because obviously, the best way to address cancer is to have it never occur after Stage 1. Unfortunately, what happened in the treatment landscape is many of those Stage I patients will recur, sometimes even recur as Stage IV or metastatic disease, and that is when we're fighting very late to try and control a quite progressed cancer. And so our goal, simply put, is to intervene early, prevent the relapse or recurrence from ever happening and in so doing, try and achieve cures in the earliest stages of disease.

Benefit risk there needs to have a very good safety profile, and we really do think that the monotherapy safety profile of INT will be really strongly supportive if we can see in that Phase III study a strong efficacy signal.

So we and Merck have been talking about this one for a while. Our strategy has been to focus on the adjuvant settings, but we have -- and we have started, as you know, some metastatic studies, but we have always wanted to move earlier, signaled that from the beginning because of that benefit/risk profile of INT and we are really excited to see the potential now in Stage 1 disease in a Phase III lung cancer trial.

Our next question comes from Jessica Fye with JPMorgan.

With a significant amount of international sales this quarter, I remember the -- I think the U.K. order from last year got pushed into early '26. I'm just trying to think about those contracts and the right way to think about what more could come from the U.K. for the remainder of '26? Like is it possible this is a double order year? And maybe you could just elaborate on how that works?

Yes, sure, I'll take that. And so the delivery that happened in the first quarter is for their spring campaign. And so for -- in the United Kingdom, there's a recommendation for both spring and fall booster for the targeted population does over the age of 75 or with significant risk factors. And so a second campaign is planned for the fall, and so the third and fourth quarter of this year, and that would be an additional delivery later this year.

Our next question comes from Terence Flynn with Morgan Stanley.

Great. Just wondering if you can be any more specific about the timing of the interim Phase III of the INT and adjuvant melanoma. I know you said 2026, but can you refine that at all at this point? And then maybe talk to the range of potential outcomes there? Are there only 2 outcomes, either the trial hits at the interim and continues as planned? Or is futility also a potential outcome on this interim?

Yes. Thank you for both questions. So I will disappoint in the sense that we won't refine that guidance. We have said we are confident based on the event accrual that we will see interim analysis conducted in 2026. I shouldn't say more, except that, that confidence should indicate where we think we are. On the question of the outcomes, there is not a built-in futility assessment. The interim analysis is either to declare early success or to continue to accrue events in the trial towards a subsequent interim analysis or final analysis both of which could happen in the years ahead. The study is very well powered and has been balanced in terms of its accrual. And so we have continued to accrue events in a way that we would expect, and therefore, we're optimistic about that interim analysis. But obviously, if we have not yet hit the critical hazard ratio to declare early success, we will have the benefit of continuing to look at more events afterwards, but futility is not a part of the current plan.

Our next question comes from Luca Issi with RBC.

Great. Maybe, Jamie, on IP, can you just walk us through why the legal team deemed the additional $1.3 billion charge on 1498 is not probable. I guess the question is what gives you confidence that you will ultimately prevail there? And then maybe just kind of bigger picture, remind us that time line of when the final ruling could come? And then maybe quickly, Stephen, what's the latest thinking on flu in the U.S. ahead of PDUFA? We obviously now have a new acting director [indiscernible]. So I wonder if you have had any interactions with her, and whether you think that having her need is incrementally positive or incrementally negative for you? So any color there, much appreciated.

Yes. Thanks for the question, Luca, I think I may disappoint as well because we're not really going to comment too much on the merits of the trial. So all I can say is our legal team and ourselves, we are confident, and therefore, we believe it improbable that we would lose and therefore, have not recorded anything. From a time line perspective, it's always difficult to exactly read, but we think that it could be perhaps late 2027 maybe into 2028 is where we think that this might be resolved. But again, that's a moving target.

And for the question on the FDA and the -- particularly the flu 1010 program, we continue to progress well in that review in the normal back and forth with the review team and the folks in the office of vaccines towards our PDUFA date, obviously, at this point through a mid-cycle. And we would describe that as a pretty normal course, the kinds of exchanges we're having. And so we're encouraged by that and look forward to that August 5 PDUFA date. Obviously, we'll work hard to answer any questions, any remaining questions that the FDA has as they complete that review.

As to the senior leadership, whether it's [indiscernible] or otherwise, we don't usually interact with them in these reviews at all. Really, this is the review staff, the folks in the office of vaccines, and that is the only place that we've been going back and forth. And we don't expect any impact, certainly didn't before, today or after as a result of the new Acting Director. We do look forward to working with the leadership of [indiscernible] broadly across our portfolio. So the 1010 flu vaccine review continues somewhat independently, but we have a large portfolio of other products from in Intismeran, INT to norovirus to our first rare disease program, the propionic acidemia program, all of which we hope have pivotal readouts this year, and we look forward to bringing those forward. So it's an exciting time for us, hopefully, for the field, and we are very grateful for the partnership across FDA and CBER as we try to bring these medicines forward to patients.

Our next question comes from Tyler Van Buren with TD Securities.

Congrats on the quarter. For the Phase III Intismeran adjuvant melanoma top line data, can you remind us what it is powered for? And perhaps more importantly, can you give us your latest thoughts on what constitutes success from a clinical standpoint? And what you need to show in RFS on an absolute basis or as we think about relative benefit there?

Thank you, Tom, for the question. So we haven't disclosed the powering assumptions for the IA. Suffice it to say, we -- the Phase II data had a really strong hazard ratio, very narrowly missed and a substantially smaller powering 150, 160 participants as opposed to 1,100. And so we're -- we think we are well powered -- very well powered if we see a similar hazard ratio. That would obviously be a huge success. But to your second part of your question on sort of the range of things that we would be pleased with, obviously, anything looks like the Phase II would be spectacular. But candidly, we think the opportunity for benefit could be anywhere between that 1.5% that we saw in a number like 0.8, where there's a significant benefit still in terms of survival and treatment of melanoma -- adjuvant melanoma, Stage II melanoma. Now across that range is a wide range of outcomes that we want to understand the raw data in what's happening. If you see really strong RFS and really strong eventually overall survival, as we've seen so far in the Phase II study, that's encouraging. If you saw maybe the overall survival or just a [indiscernible] data was better even if the RFS was not, that would probably equally be encouraging. And so there's a range of outcomes for how we would declare success that will depend upon the different clinical benefits that we see in the study.

But for now, we feel like we are well powered going into that interim analysis. If not, we look forward to the subsequent analysis. And we think there are a range of outcomes here ranging from the Phase II results to a whole bunch of events that are much more modest, that could still be really meaningful patients and move forward successfully commercially as a treatment for Stage 3 mono.

Our next question comes from Ellie Merle from Barclays.

Curious what your expectations are for timing for data from RCC and muscle invasive bladder cancer. And can you elaborate on what good data would look like in these indications? And then what the next steps would be in those indications if the data are positive?

Yes. Thank you for the question. As we've previously said, both of those randomized Phase II studies are fully enrolled, about 300 participants in each. And so we're really excited to to fill in the picture on the strength of performance for INT across a range of different tumors. I would point particularly to the RCC as 1 that we're we're interested to see whether or not we can provide a really meaningful clinical benefit because we still think there is an opportunity, headroom for improvement there that's quite significant.

Now those are event-driven trials, and we did want to protect the registrational possibility for those trials. So we're blinded, and we're accruing events towards that first interim analysis in both. For obvious reasons, we -- if possible, we would want those studies to be registrational. And so we want to make sure we accrue a good number of events and that we treat those analyses the right way. And because that it's hard to guide right now.

We don't exactly know when potentially this year or even early next year that those results could come in because they are event-driven analysis. But when we have accrued sufficient cases to conduct that blind analysis, we will definitely be doing so. And all of us are eager to see the results because it will help not only guide whether or not those products or those indications are reasonable to move forward more quickly, again, potentially to a registrational study or towards a Phase III pivotal study, which we would look to start quickly. But also, they feel in that picture of how broadly INT is going to play. And in some ways, if you think of RCC as an example of a place where it's relatively far from melanoma in terms of mutational burden, and therefore, an opportunity for us to demonstrate a potential benefit that would then widen the aperture of where we think INT might have a role.

So we're keen to see that data, but we are blinded at this point. We're following those events, and we are eager to provide updates once we have more. But for now, we can't guide on when that timing would be.

Our next question comes from Michael Yee with UBS.

We have 2 questions on INT. The first was on the melanoma study. Would we expect that, that's a similarly designed protocol as it relates to the interim? I recall that the Phase II strongly hit at the interim. And so just trying to understand if a similar type of standard interim was built in here such that if it doesn't stop at the interim, it would imply some sort of different hazard ratio for the first term versus the second room?

Similarly, on the renal study, we understand that this is a much slower progressing tumor if you look at the KEYTRUDA adjuvant studies, just trying to understand how it would be possible that a potential interim would come this year, or that's a much differently designed study in terms of an interim?

Yes. Thank you, Michael, for both questions. So first, we obviously haven't given any statistical guidance on the Phase III interim analysis. But suffice it to say, I just did a moment ago. We wouldn't be conducting the interim unless we thought there was a chance of success. And in that sense, we are not defining that as the hazard ratio that existed in the Phase II. There were some differences in the population, but certainly, that would be a situation we would want to have a relatively early look at. And so it's somewhere between there and obviously, not significant that we're looking for.

We are -- we have -- we are really excited, but we also just need to wait and let the data mature and see those results. And so we're optimistic about that first interim. But it's fair to say that if it isn't successful, there's still opportunity in the second and the final. And we definitely have reserved alpha for both of those for what we think would still be commercially important products. So that's Point 1.

Now on the renal, the renal is -- RCC is, as you said, the events can happen more slowly. There is a benefit, obviously, from KEYTRUDA, but there's a substantial headroom still. Even if you look to the combination products, KEYTRUDA plus Bezu, Merck has just had a great success there, with a hazard ratio of 0.72, there's still headroom even above that for improvement in terms of disease free survival. And so we're keen to look at that result. There are about 300 participants enrolled in that study. And I'll remind you as a reference, that's about twice as large as the Phase IIb adjuvant melanoma study that we've all been speaking so much about.

We're not intending to power that as a registrational study, but it has registrational potential. And what that means is we could have a lower statistical threshold for declaring that there's a strong result there, a strong signal, I think, again, like what we saw in the Phase IIb with melanoma. The key there though, would be we would not want to unblind that study if at a lower threshold, call it 0.1 -- alpha 0.1, we wouldn't want to unblind the study if it was trending towards statistical significance and registration potential. And so that's the key unknown in that RCC study in terms of timing is we will hit a trigger for conducting human analysis based on events. The DSMB will look at that result and then advise us whether it's appropriate to declare early success or whether to remain blinded or alternative outcomes that are more like futility, but that would cause us to want to look at that data and quickly determine whether or not we want to run a Phase II.

And so it's a high degree of uncertainty of what that looks like, but it's all about trying to make sure that if we have a drug here, a strong signal in RCC with registrational potential, we did not disrupt that. Or if it's strong, it needs a Phase III more powered analysis that we get that going quickly. And I think that's the decision that lies ahead of us in partnership with the DSMB.

Our next question comes from Courtney Breen with Bernstein.

Just a couple more on INT. What I wanted to understand as we're getting closer and closer to the kind of it's becoming a meaningful lot of model [indiscernible], but there's obviously still a big [indiscernible], but also on revenue recognition between you and your partner. Number one, can you help us kind of understand the parameter here, and I think through what this might look like to moda kind of realized contribution in the P&L recognizing that it is [indiscernible]?

And then second, in the Stage 1 monotherapy and combination study, can you just again help us understand a little bit about that Stage 1 prevalence of diagnosis relative to later stages? Cancer lung cancer is obviously relatively, compared to other cancers, age quite late. So it would be helpful to understand how you think about this market and potential building if we can see kind of some opportunities for those patients? And speaking of that opportunity, any comments on kind of what the bar looks like particularly compared to a watching and waiting scenario?

Yes. Thanks, Courtney. I think we're breaking up a little bit, but I think the first question was around rev rec as it pertains to INT. So let me take that one. And I'll put a caveat out there that we don't even have the product approved. We're working with our auditors. It's not a traditional joint venture. So -- but this is -- I'll give you to the best of our knowledge, how we think it will work. So it will end up being that we deliver the product to Merck because they're obviously the market authorization holder, and they were sell it on to the customer. So that will be the first part of our transaction. And so you can imagine some amount of our COGS plus some markup. Thereafter, whatever the profit split is, then we will take that share -- Our share of that of 50%. So it ends up being naturally somewhat greater than 50% of the profit share because it's predicated upon first shipping the product and having some markup on that and then taking the margin on top of that. So that will change over time because we -- as we've laid out before, we're working on our cost of goods sold and with that will continue to come down over time as we continue to drive automation. So it will start a little higher as our cost of goods sold. Well, obviously, like any product starts higher and then get more productive over time. But that's the general framework, and I hope that helps. But again, we hope to be in that position next year to be able to start recognizing that revenue.

.

[indiscernible] cancer Stage 1. So lung cancer really represents a pretty unique opportunity because screening through X-rays has actually been an important intervention for identifying early-stage disease, Stage 1 disease. Now the majority of diagnoses still show up later at Stage 3, Stage 4, in particular, but you're seeing an increase almost 1/3, north of 30% of diagnoses are now earlier stage, Stage 1, Stage 2. And that has grown over the last decade and hopefully continues to grow through better screening, including a relatively easy intervention, a chest x-ray that your primary care doctor can provide.

So we do hope and expect that there's a big push on earlier -- catching lung cancer earlier. And that is a natural place, therefore, to try and intercept and intervene if you have a great benefit risk profile, again, to be proven, but we know we have the safety profile. And if we can do that, then we'll be able to dramatically impact the number of Stage 4 or Stage 3 and 4 diagnoses that start to show up.

You've already seen evidence of that, right? I mean if you look in the United States, over the last decade or 2, there has been an increase in the number of diagnoses that have -- the percentage of diagnoses that are happening in earlier stage and a commensurate decrease that are happening in the later stages. And so we do think it's a unique tumor opportunity for us to go demonstrate Stage 1 intervention because of that screening regime around chest x-rays and the overall trajectory in the field.

Our next question comes from Jeff Meacham with Citigroup.

I have 2 quick ones. The first 1 on Intismeran, as you grow the experience and data here, I know most of the trials are in combo with KEYTRUDA are there other I-O combo mechanisms that could also bear fruit, or is that better addressed with the rest of your oncology pipeline? And the second 1 on norovirus. As we get closer to data, do you have any updated view of what success looks like here, just given the standard of care? My sense is a significant benefit is all you need, but want to get you guys' perspective?

Yes. Thanks for both questions. So first, on the alternative IO-IO combinations, we are looking in the adjuvant setting and earlier in many of these Phase III studies. We do have a metastatic melanoma study, as you know. But we -- in that context, generally IO-IO combinations and the toxicity associate has not been seen as advantageous. And so for now, most of our focus is on the combination with the PD-1 and KEYTRUDA because of our partner, Merck.

We would be interested in subsequent studies in exploring alternative I/O combinations. But as you kind of alluded to, that's already something we're starting to do in the rest of our pipeline. And in particular, I'd point to 4359, where we are looking in metastatic melanoma and alternative regimens, CTLA-4 plus PD-1 combinations, EPI, Nivo as an example, have been important intervention showing benefits in those populations. And that's a place where, if we want to add a third I-O agent for hopefully some benefit, we are doing some early Phase I/II exploratory work right now.

So you might see, just as a function of the huge amount of work we're already doing in INT, you might see us first explore those other combinations for our cancer vaccines platform in the other off-the-shelf context first. But that doesn't rule out that in the future, we might explore the use of INT on top of other regimens. Certainly, both ourselves and our partner, Merck are interested in that.

Now on the norovirus side, I think you hit the nail on the head. We we think given that there is not currently an approved vaccine for norovirus, and given that particularly for those at highest risk, those over the age of 75, those that have other medical comorbidities, there really is a high societal and medical costs associated with the profound dehydration that can happen with even just what might feel like a 2-day norovirus infection, not just hospitalization, but the significant exacerbations of underlying medical diseases as well and some death.

And so that population, anything that can be done to reduce that burden would be ultimately value creating for the health care system, put aside the benefits for the individual patient. And so we're -- we think statistical significance is the bar. Obviously, we want to see a vaccine efficacy that's also meaningful and so north of 50%. But on -- but given that there currently is no standard of care or treatment, we would take anything above there as a success.

Our next question comes from Cory Kasimov with Evercore ISI.

I also have 1 on Intismeran. So wondering how critical is it to demonstrate an overall survival benefit in Interpath-001. Given the challenges of showing OS and adjuvant melanoma, do you believe physicians would interpret the data set any differently absent a clear OS signal?

Yes. So I'd make a couple of observations. So first, RFS is a pretty good predictor. I mean this is a relapse-free survival. So again, it's not progression-free survival, it is survival, and tends to correlate. And if you look at our Phase II study, we have released previously the RFS, DMFS and even OS trend data. We look forward to the ASCO presentation to provide the 5-year update and the view on RFS, DMFS and OS. And I would point to that presentation and the data, and we hope that, that will provide confidence for physicians, for health care systems, for patients on that relationship in this case and in the case of Intismeran in combination with KEYTRUDA in the adjuvant melanoma setting, and that, that would provide sufficient confidence to move forward if the Phase III is positive.

Now the Phase III data, we will follow OS. And we're through 5 years in the Phase II. So it will take us some time to get to that same level of data in the Phase III, but it will be a part of the trials going forward and can provide a significant degree of confidence going forward, but again, RFS really is survival in this case.

Our next question comes from Simon Bick with Rothschild & Co Redburn.

Just looking at the Q2 revenues, a couple of quick questions. Firstly, should we -- or could you give us any color on the split? Or should we assume that the entirety is SPIKE vax? And also, Jamie, I wonder if you could give us any comments on phasing. It was a very strong number against our expectations, but I just wanted to know if there was any pull-through of expected revenues from Q2, particularly with some of those governmental orders outside the U.S.?

Yes. Thanks, Simon. So let me address the first question. as it pertains to product split. This was largely, the majority is COVID still. So we have not been -- as we've always said, we don't anticipate RSV being a significant growth driver in the year 2026. We believe that will take a little bit of time for us. So this is still primarily COVID-related.

As for the timing, we laid out the second quarter. So -- and then I think maybe your question is more on the second half. But for the second quarter, we laid out $50 million to $100 million in the second quarter. So that should bring our first half to almost $0.5 billion of revenue. And that, if you look at that as probably $400 million outside the United States and $100 million in the United States.

So let me talk to the timing of the year and give big picture and kind of compare it to last year. Last year, we had $700 million of sales outside the United States, and it was $100 million in the first half and $600 million in the second half. So with $400 million is in the first half of this year, if we repeat last year, that's $1 billion. And we've been talking about saying that our mix between the U.S. and international is going to be about a 50-50 split. So if we just repeat last year, that should get us $1 billion. And then in the U.S. last year was $1.2 billion. I said in my prepared remarks that we're expecting some amount of decline and we've modeled for that.

So hopefully, that gives you a little bit of the phasing and timing here. And the last point I'll say is back to the question that was asked earlier, is in the second half of last year, we didn't have any U.K. revenue. So to Stephane's point that if there is a fall season, in last year, $600 million outside of the United States. We did not have in the U.K. There are other puts and takes that's why we've guided up to 10%. I'm not giving explicit guidance here, but I'm trying to give you the picture and contextualize what the year might look like from a U.S. versus OUS split.

Next question comes from Andrew Tsai with Jefferies.

It's a bigger picture question. I'm just curious what your guys' latest thoughts are on BD and even considering technology or assets beyond mRNA. Does it make sense to add more assets to your pipeline? Or do you think you're right sized for now?

Thanks for the question. So if you think about the company, as you know, we've always focused on building the most impactful mRNA platform to enable modalities, families of medicines to enable them a lot of medicines happening using the same technology components. We've done it with infectious vaccines. We don't it with Intismeran. I look at a number of studies now. We are doing it in rare disease. And as we share more at our Science Day on June 25, we have been investing heavily to keep increasing in new modalities. You see it with a T cell engager that Stephen talked about [indiscernible]. You see it with 1439. And there's many more assets, we're going to walk you through what the science has enabled. So we're very focused on expanding to new modalities to enable new families of medicine.

As you've seen in the past, we acquired a company in Japan a couple of years ago because it was expanding the mRNA operating growth of Moderna. We are continuing to look at science across the board, whether it's from academic labs or from companies, public or private. If we find the right opportunity to increase what we can do, we will, of course, execute on those priorities. But we don't have a pipeline problem like most companies in the industry. We have an abundance of products. As you know, we have been very disciplined on cost right now to get back to breakeven. But we have a lot of exciting science that is waiting to go into the clinic soon, and we'll share more of that on June 25.

Our last question comes from Alex Alexandria Hammond with Wolf Research.

So with the recent approval of the COVID flu vaccine in the EU, can you just walk us through your commercialization strategy? And I guess what is the successful launch of like a year from now and 5 years from now?

Yes. Thank you for the question. So first, I want to start by saying, as is our pattern, our path, we do not expect revenues in the year of approval for these vaccines. And so 1083 [indiscernible] or flu in the United States, none of those are in our guidance that Jamie was speaking about. Now your question is more kind of looking forward in '27 and '28, what does success look like? The first step, the one we're engaging in right now across the major markets in Europe is securing market access and so that is pricing and reimbursement. That is a national process, and one that is underway, even publicly underway, for instance, in France, where they have initiated that, frankly, quite quickly after approval, which we think is an encouraging sign.

It's important to note that across Europe, there's about a $2 billion respiratory vaccine market. We previously sort of summarized that. Flu is a big part of that, and COVID is the second large part of that and it's much more portion reserve for RSV. So we see it as a very large opportunity for our combination COVID vaccine.

Lots of benefits to payers, to health care systems, to patients. Patients appreciate the -- it's only 1 shot and there's a strong preference on that. But payers and health care systems really appreciate the lower burden of work. It's a single product. It's only 1 injection. You don't have to procure both. And the amount of time you get back from a health care provider, be that a physician, a nurse, a pharmacist that they can get back to do other things that are value creating for the health care system is actually a huge part of the value proposition of the product.

And so what we've been doing with those governments, and we will do throughout the back half of this year, is help build that economic value story. We've got real-world effectiveness coming -- data coming out from our products, and we hope to be able to show their benefit for the individual, but we also want to help the health care systems understand and value the savings that they will get from a respiratory combination vaccine. And so that's the big push really over the next 12 months. We do hope for a successful launch in '27 in the first markets where we can get pricing and access. And in some cases, in Europe, that takes a couple of years as a process, and it would really be 2028 when you'd start to see that more significant uplift.

Our hope is that we end up with a very large share of that $1.8 billion to $2 billion respiratory vaccines market because we really do think we have a unique product that can save the health care system money and deliver better value for patients and providers. And so we're -- we'll have more guidance as we move forward. But rest assured that we are spending the next year securing that market access pricing and reimbursement and helping people understand the value of that combination. Patients get it quickly, health care systems are also getting it quickly, and we've got the work ahead of connecting those dots so that we can have a successful launch in '27 and really drive growth of the business in '28.

Thank you, ladies and gentlemen, this concludes the question-and-answer portion of today's program. I'd like to turn the call back to Stephane for any further remarks.

Well, thank you very much for joining us today. As you can see, we're excited about 2026, returning to sales growth and critical Phase III readouts norovirus, Intismeran and propylene acidemia. We look forward to talking to many of you over the next few days and a few weeks. We're excited to host you more from them Monday, June 1 at ASCO. And on June 25, Han Cambridge for a Science Day. Have a nice day, and have a great weekend.

Thank you. Ladies and gentlemen, this does conclude today's presentation. We thank you for your participation. You may now disconnect, and have a wonderful day.

Hi, guys. Good morning. Welcome to sunny Miami. I'm Ellie Merle, one of the biotech analysts here at Barclays. Very happy to have Lavina Talukdar here with us today, Head of Investor Relations at Moderna. It's been a very eventful year for you. So maybe if you could start with an overview of some of the key highlights from Moderna over '25 and into the first quarter of '26.

Sure. Thank you so much for having me, Ellie. This is great to be here. So for 2025, I'd characterize 2025 as a year of execution, and we really executed on all fronts. On the revenue side, we came in at $1.9 billion, which is towards the high end of the revenue range we gave on the third quarter call. And that was really driven by execution from the commercial teams. We were very happy to get mNEXSPIKE, our second COVID vaccine approved in June, and they really executed and made sure that, that was available on the market for the fall season.

We also brought down costs. We set out in 2025 to take $1 billion of cost out, and we ended up achieving in excess of $1 billion. So in total, $2 billion of cost that came out in 2025. And that's really a testament to the finance team setting targets and the broader Moderna teams taking cost out of the system. So it really positions us nicely for 2026. It led to a cash balance of $8.1 billion, which also includes $600 million that we took down from a credit facility with Ares that we executed in 2025 as well.

And that brings me to the pipeline, which was also a lot of progress that we saw. We had mNEXSPIKE approved. We had 2 other programs approved. RSV 18- to 59-year-old high-risk individuals saw a broadening of the indication there. And we also were able to get our COVID vaccine approved in the pediatric setting. We're the only ones that has an approval in 6 months old to 5 years of age.

Aside from the approvals, we had positive data from our Phase III study in flu, which then led to the filing of the flu application in the U.S. and other territories around the world. So we're looking forward to that approval. And we also advanced our cancer pipeline, intismeran, which is already in a Phase III for adjuvant melanoma continues to accrue events there. But we -- in that program, we also fully enrolled the renal cell carcinoma study in 2025. PA in rare diseases was also fully enrolled. So it really sets us up nicely for 2026 as we look forward to pipeline readouts.

Yes. Certainly, a lot of exciting pipeline readouts, which I'm sure we'll get into. But maybe first, just starting with the respiratory vaccine franchise. So you're guiding for up to 10% revenue growth in 2026. I think that number may be surprised some investors given some of the trends that have been seen in the COVID landscape. I guess, what's underpinning your confidence in the potential for a return to growth this year?

Yes. So we have 2 contributors to growth that we see in 2026 that gets us to get up to 10% revenue growth that we've guided to. And the 2 major growth drivers is continuation of mNEXSPIKE penetration in the U.S. We have 24% market share as of the end of the fall season in 2025. So we expect that to continue to penetrate into the U.S. and also some approvals outside of the U.S. as well. And then the other major driver for that up to 10% growth is going to be from our strategic partnerships with the U.K., Canada and Australia. And in those partnerships, we've built facilities to make vaccines and other products. And so those facilities all came online in 2025 throughout the year, towards the end of the year. And they will go into full effect this year, those agreements. They are multiyear agreements that provide us visibility. We expect to see a major step-up in revenue from those 3 countries because of these strategic partnerships.

Interesting. And yes, I mean, the ex-U.S. revenue, I think that's particularly interesting considering a lot of that is essentially locked in through contracts.

That's right. And we'll have visibility for multiple years. The step-up in revenue from our guidance last year, we did $700 million in ex-U.S. revenue. The bulk of that $700 million was made up of Canada, Australia and the U.K., both the 3 strategic partnerships. This year, we're expecting international revenue to be $1 billion. So the key step-up in our up to 10% growth is predominantly coming from ex-U.S. revenues. In fact, in the U.S., last year, we ended the year with $1.2 billion in sales. And this year, we are planning for another decline in U.S. sales down to about $1 billion, which is a 20% decline to be prudent. Obviously, we're not aiming for a decline. But to be prudent, we don't actually need the U.S. to grow in order for us to meet the up to 10% growth.

That's interesting. And congratulations on the positive CHMP opinion with the flu, COVID combination. I think that's a very interesting program. It certainly differentiated from Pfizer-BioNTech, where you have the combination. I guess maybe starting first with in Europe, how we should think about the opportunity for this combo vaccine and when we could potentially start seeing revenues from these programs?

So we are very excited about the combination flu plus COVID product. In Europe, you're right, we just received the CHMP positive opinion. So we do expect an approval later this year. However, it will be contributing to revenue in the 2027 time frame. I'll remind you that, Europe, is right now a territory that we're not selling in because it has been locked up by a competitor contract in COVID. And that contract will lapse later this year, opening the territory up to us in 2027. So we'll be ready with the approval in flu plus COVID with that product, but it won't contribute to revenue until 2027.

Okay. Makes sense. And the U.S., a little bit more of a complicated situation. Sort of -- and I'll leave it to you in terms of what you can or can't say here. But how should we think about the latest in terms of the 1010 filing for flu, got the RTF, now the filing is accepted. How are you thinking about the outlook for this in the U.S.?

So you're right. We did have the RTF reversed and it's now accepted to have a PDUFA date of August 5 later this year. So we look forward to continuing the engagement we have with the FDA review staff. They've been phenomenal with all of our applications in the past. And so we look forward to continuing that collaborative work on the flu application. For the combination flu plus COVID, we still are seeking guidance from the FDA in terms of when we will refile that program. So as we have more information, we will update you.

How should we think about the uptake of the COVID flu vaccine? I mean I think just there's more investor skepticism on sort of the vaccine landscape. But then again, you'd be the only ones with this combination. How can we think about how this could impact, say, market share from a pricing dynamic, how this might play out?

So I'll answer that question ex-U.S. and in U.S. as well. So ex-U.S., we've received a lot of feedback from health ministers about the combination of flu plus COVID. They're pretty excited about that program. It's mainly because in countries outside of the U.S., you have single-payer systems, and it's those single-payer systems that are very incented to make sure that their populations are protected against pathogens that could lead to bad outcomes or hospitalizations, because it ends up costing the system more -- it's more expensive for the system, for the medical system. Preventing those hospitalizations is something that health ministers are very keen on. And when you can do it through one vaccine and you're protecting the individual against 2 different pathogens, it actually is -- leads to better compliance, lower administration costs. It's something that health ministers are looking forward to. So internationally, we think it's going to be a great product.

In the U.S., we also think there's a place for a combination flu plus COVID vaccine that could be competitively advantaged. And that's because, again, you have compliance, you have lower health care costs and potentially a better economic backdrop for the customers as well. In terms of the pricing, we're still strategically thinking through what that might look like. It's a little bit premature. But obviously, there's lots of ways to think about that. We can just price it some of the parts or we can price it at a premium to some of the parts and possibly even at a discount. It's still yet to be determined.

I think an interesting contributor potentially to keep an eye on in the coming years. So in terms of the pipeline, an incredible amount of focus on the upcoming melanoma data. Maybe can you frame for us first sort of just how we should think about from a timing perspective? You said 2026. I think a lot of investors are curious as to the confidence that it will come in 2026 or if you have any granularity on when in 2026, we might see this data?

So it's really difficult to pinpoint when we think the data is going to read out because it is an event-driven trial. The confidence around 2026 really just comes from using the Phase II data set as a proxy. And the Phase II data read out 18 months, you started to see the separation in the curves around the 18-month time frame after the last patient was enrolled. And so since the Phase III study was enrolled in September of 2024, we hit the target enrollment. If you add 18 months to that time frame, you get to about the first quarter of -- early second quarter of this year. However, there are differences in the study. First and foremost, it's a Phase III study, so much larger, you'll need more events to actually get to the point where you can look at the data. It also has patients that are Stage II patients, which may lead to longer time frame before we start seeing recurrences. And so when you put all of that together, you're still solidly in that 2026 time frame, but it is event-driven. So it's impossible for us to know exactly when in '26 or possibly even in early '27, it may read out.

Makes sense. I had to try. Can you frame for us maybe what the relevant benchmarks are here from a data perspective and what you would consider, I guess, good data from this Phase III?

So I'll remind everyone about the Phase II data set. We had a hazard ratio at the 3-year follow-up of 0.51, which is remarkable and on the recurrence-free survival endpoint. That continued and sustained itself at the 5-year mark, which we just reported earlier this year. And that data is really remarkable. In terms of benchmarks, we would be thrilled to see data like that, but I don't think it's necessary.

If you were to look through the oncology landscape, you would quickly realize that there are products on the market that have had hazard ratios in the 0.75, 0.8, that are now successful products on the market. So that hopefully gives you a sense of what may be necessary to have a meaningful benefit. And the other thing I'd say is this is intismeran plus KEYTRUDA, which is above and beyond a very active drug in KEYTRUDA monotherapy. And so even seeing a 0.8 hazard ratio, I think, would be a clinically meaningful result.

And how should we think about the market opportunity in adjuvant melanoma?

So in adjuvant melanoma, the way we characterize the market opportunity there is worldwide, it's a multibillion-dollar opportunity. We are 50-50 with our partners, Merck. And in that scenario, we would still consider our share as a multibillion-dollar opportunity at peak worldwide.

And I guess if this data are positive, how should we think about the read-through to other indications?

It's a great question. We believe that there is a synergism between intismeran and KEYTRUDA. And we've seen that in a number of tumor types during our Phase I study, the basket study, where we saw data in adjuvant melanoma, in non-small cell lung cancer. But again, it's a Phase I study. So the synergism we think, is there. However, we do have to run these studies to see what the magnitude of benefit there may be in all the different tumor types and the different histologies. So we're running a pretty extensive development program with our partners, Merck.

We have 8 late-stage studies and the different cancer types, obviously, are adjuvant melanoma as we just talked about, renal cell carcinoma in a Phase II study. Muscle invasive bladder cancer also in a randomized Phase II study. All 3 of those studies are fully enrolled. We continue to enroll 2 studies in Phase III for non-small cell lung cancer. And we just initiated Phase II studies in first-line melanoma and first-line non-small cell squamous lung cancer. So we're active in the program for sure and really eagerly looking for additional histologies that may read out in the future.

And I know you mentioned some of these studies are fully enrolled like RCC. How should we think about the cadence of readouts after we get the melanoma data?

So the Phase II studies, RCC as well as muscle invasive bladder cancer, our Phase II studies. So the number of events you need there are lower than a Phase III study. They also have different rates of when recurrences happen. So I would say that after the adjuvant melanoma data, you should think a cadence of several months for each of these potential programs to read out. And then when we update you on full enrollment for non-small cell lung cancer, then that's when the clock starts ticking for when that particular histology reads out as well.

And how long from when non-small cell finishes enrolling, should we think about when we would get data?

It's really hard to speculate on that. But I think the key thing to hear -- to listen for is when that study -- when those 2 studies are fully enrolled.

Great. Well, certainly an exciting program. I know a lot of eyes are on it this year. Turning to some of your other pipeline programs. So, norovirus, we could potentially see Phase III data this year. I guess, can you help frame what you're looking for in the data and what benchmarks would be for good data here?

Sure. So norovirus, we just announced that it was fully enrolled in that second Northern Hemisphere season. And we're accruing cases. So this is another event-driven or case accrual dependent readout. We do anticipate that, that will happen in 2026. In terms of what we expect on the vaccine efficacy side there, because there aren't any products or any vaccines approved for norovirus, we do think that a minimum of a 50% vaccine efficacy rate would be needed to get this product through and on to the market. And that's because you've had other vaccines come to market with a 50% vaccine efficacy rate. Obviously, we're shooting for better than that, but a minimum of 50% is what we think you would need to come to market.

And obviously, a huge opportunity, but it's been challenging from a vaccine development perspective. What are some of the reasons why Moderna could be successful, whereas our focus in the past have faced challenges?

Great question. So we are targeting the adult population with a predominance in our clinical study of the older adult population. I think other programs that have failed in the past we were looking at children or infants. And in that population, I do think you need to vaccinate people multiple times in order to get them primed against the pathogen. And so having the benefit of going into seropositives in that adult population, I think, gives us a benefit. The other thing is that it is an mRNA therapy that we're using versus some of the others that have failed, our recombinant protein. So there is something to be said about that as well.

Great. Turning to operating expenses and your assumptions for breakeven. This is another area where we get a lot of investor questions given sort of the degree of investment in R&D. Maybe can you walk us through what your current assumptions are in terms of time to breakeven and what some of the levers are in terms of the ability to ramp down spend if, say, some of these Phase III trials are not successful?

Yes, great question. So obviously, we're planning for many of the Phase IIIs to be successful. But there are Phase IIIs that will be rolling off, particularly in the seasonal vaccine space. So norovirus is the last of the Phase IIIs in the seasonal vaccine portfolio that we're still running and that will run through 2026, and it will start winding down after that. So we do anticipate the anniversarying of the data sets in Phase III to be a big contributor of why our R&D spend comes down. We're going to continue to spend in oncology and invest in the clinical programs there, both with our partner, Merck, on the intismeran programs, but also our emerging oncology programs.

The cost of oncology Phase III development or Phase II development is much, much lower than the cost of developing vaccines because of the sheer number of participants in vaccine studies versus the patients that we treat in the studies for oncology. And so all of that being said, we do anticipate that costs overall, cash cost for the company will be coming down to the tune of $3.5 billion to $3.7 billion in 2027, which would mean that we would need to be in that range for revenue in 2028 to breakeven. And we've got multiple growth drivers, 2 of which we talked about for 2026. Next year, we have Europe opening up, and that's a $1.8 billion respiratory vaccine market where currently, our sales are less than $100 million. So that's a big opportunity for us in 2027.

Flu is a big opportunity as well in 2027 around the world, should we get the approvals as they come through later this year as well as partnerships now internationally in Lat Am, Latin America as well as Asia Pacific. So we just announced a deal with Mexico and Taiwan. Brazil was one that we announced last year. Those are also multiyear contracts that start to go into effect in 2027. And in 2028, on top of all of that growth, we anticipate the combination flu plus COVID coming to market as well as norovirus, both of which could be multibillion-dollar products at peak.

How should we think about the time frame for when the strain selection might vary for your flu products, I guess, thinking ex U.S. now because we'll have to wait to see what happens in the U.S. But I mean, there's so much data that shows that better strain selection and strain selection closer to the season leads to better efficacy. So I mean, now that you have the approval in Europe, how should we think about when we could potentially see you targeting different strains?

Yes, I think that's an excellent question. So one of the advantages of mRNA vaccines is that we can make a vaccine very close to the flu season. In fact, we've already demonstrated that in COVID, where we typically just need 2 months of heads up on the strain selection for COVID before having enough product to supply to the market. And indeed, for COVID, selections for the strain are happening in the May, June time frame, and we're able to have product on the market by late August.

Similarly, with flu, we'll be able to do that as well. The difference between mRNA technology and traditional flu vaccine technology is that traditional vaccine makers require 6, maybe 9 months of lead time to make the product for the fall season, at which point you may have the flu virus mutate away from what's in those traditional vaccines, which leads to this mismatch that you're talking about. If you can minimize that mismatch because you're closer to the flu vaccine season, then that should, in theory, lead to better vaccine efficacy. And mRNA vaccines are the only ones that can actually achieve that at the current time. And so we look forward to that opportunity. There are many years. Last year was a big year where there was a mismatch in terms of what was in the flu vaccines versus what was circulating that, another opportunity like that could really help mRNA technology shine in that respect.

Yes, it's really interesting. On the rare disease side, you mentioned the PA study being fully enrolled. Can you talk about sort of how we should think about the opportunity here and the landscape for treatment?