Vertex Pharmaceuticals Stock

Good day, and welcome to the Vertex Pharmaceuticals Third Quarter 2026 Earnings Call.

[Operator Instructions]

Please note this event is being recorded. I would now like to turn the conference over to Ms. Susie Lisa. Please go ahead.

Good evening, all. My name is Susie Lisa, and as the Senior Vice President of Investor Relations, it is my pleasure to welcome you to our third quarter 2026 financial results conference call. On tonight's call, making prepared remarks, we have Dr. Reshma Kewalramani, Vertex's CEO and President; Charlie Wagner, Chief Operating Officer and Chief Financial Officer; and Duncan McKechnie, Chief Commercial Officer. Given the January 1 transition by Charlie to the COO role solely, note that this is his last quarterly earnings call and as successor, Jonathan Poole, our current SVP of Finance, will join us for our Q4 2026 call in February. We recommend that you access the webcast slides as you listen to this call. The call is being recorded, and a replay will be available on our website. We will make forward-looking statements on this call that are subject to the risks and uncertainties discussed in detail in today's press release and in our filings with the Securities and Exchange Commission.

These statements, including, without limitation, those regarding are marketed medicines for cystic fibrosis, sickle cell disease, beta thalassemia, moderate to severe acute pain and acromegaly, our pipeline the recently completed acquisition of Crinetics Pharmaceuticals and the expected benefits of that transaction and Vertex's future financial performance are based on management's current assumptions. Actual outcomes and events could differ materially.

I would also note that select financial results and guidance that we will review on the call this evening are presented on a non-GAAP basis. I'll now turn the call over to Reshma.

Thanks, Susie. Good evening all, and thank you for joining us on the call today. I'm pleased to note that Vertex achieved another quarter of excellent commercial results and pipeline advancement. Third quarter total revenue grew 12% year-on-year. Revenue growth was nicely balanced coming from both the U.S. and international from CF and from our 2 more recently launched medicines, CASGEVY and JOURNAVX as well as a contribution from PALSONIFY for the month of September post close of the Crinetics acquisition.

Rare endocrine is now our fourth commercial pillar. And with the PDUFA date later this month for povetasecept in immunoglobulin A nephropathy, or IgAN, we plan to soon establish our fifth in renal. Before turning to the R&D update, I want to acknowledge Charlie's final and 31st earnings call as CFO. Charlie's leadership, integrity, judgment and intellectual rigor are unparalleled. He has definitely helped lead our transition from a CF-only company with $4 billion in revenue in 2019 to a company soon to be commercialized in 5 disease areas with more than triple the revenue with our guidance for over $13 billion in 2026.

I look forward to continuing to work with Charlie in his role as COO, driving forward the Crinetics integration and our key priorities as we grow and scale the company. I can think of no better success to Charlie then Jonathan Poole, our SVP and Current Head of Finance, who will take over as CFO January 1, 2027.

Moving now to the R&D update for the quarter. I'll cover 4 disease areas: CF, endocrinology, both rare endocrine disorders in type 1 diabetes and renal in detail. But first, let me start with quick highlights from 4 other programs. In severe sickle cell disease and transfusion-dependent beta-thalassemia, we were pleased to have recently received approval for CASGEVY in patients ages 2 to 11 in the U.S. UAE, Bahrain as well as in patients ages 5 to 11 in the U.K. In pain, along with the strong growth in prescriptions, we're also seeing fast growth in the body of compelling JOURNAVX's real-world data emerge, such as a recent paper detailing 80% or greater freedom from opioid use total knee replacement when the pain management regimen included JOURNAVX. In chronic pain, both Phase III studies in painful diabetic peripheral neuropathy remain on track to complete enrollment by the end of this year and for us to be able to share results by mid-2027. In myotonic dystrophy type 1, or DM1, we remain on track to share interim results from the Galileo global Phase I/II clinical trial of VX-670 before the end of the year. And in generalized myasthenia gravis, we have completed enrollment of the Aetna Phase II dose-ranging study of povetasercept and expect to share proof-of-concept data in the first half of 2027.

Moving on to the more detailed R&D review, starting with cystic fibrosis. We see ALYFTREK as the most effective medicine approved for CF. With once-daily dosing, ALYFTREK truck can treat up to 95% of people with CF and in our trials, more than 75% of all treated patients ages 12 and older achieved sweat chloride levels in the range of CF carriers. That is to say ALYFTREK treated patients are achieving sweat chloride levels associated with no manifestation of CF disease nor reduced life expectancy. On the regulatory front, we continue our work to expand to treating younger patients and have initiated global submissions for ALYFTREK approval in children ages 2 to 5.

Lastly in CF, an update on our next-generation 3.0 correctors. We studied VX-828 as part of a triple combination in a cohort of 8 people with CF and as a dual therapy in another cohort of 8. All 16 patients had FMF mutations, which is a more challenging population to treat than patients with FF mutations. In this FMF population, the VX-828 dual combination did not alter sweat chloride relative to the TRIKAFTA baseline. In the triple combination versus a baseline on TRIKAFTA, VX-828 delivered a 6.6 millimole per liter reduction in sweat chloride at day 28 and a 9.4 milimole reduction through day 28. The VX-828 regimen is oral once daily with a good safety, tolerability and DDI profile.

In short, these are excellent results. However, given the very high bar set by ALYFTREK, we intend to wait for all the data from the next gen 3.0 family of molecules before determining next steps, namely advancement into pivotal development, VX-581 and VX-272, the other next gen 3.0 correctors are currently in first-in-human studies and the next gen 4.0 molecules are in late preclinical development.

Moving to our newest pillar, rare endocrinology. With the Crinetics acquisition now closed, PALSONIFY in acromegaly is our eighth commercialized medicine, and Duncan will provide details on the ongoing U.S. launch. On the R&D side, the most advanced molecule after PALSONIFY is atremelmant in congenital adrenal hyperplasia, or CAH, which has orphan drug designation in the U.S. EU and Japan and where the Phase III pivotal trial is well underway. The primary efficacy endpoint for this Phase III study is the proportion of patients achieving the combination of normalization of androgens and physiologic gleucocorticoid dose levels. This is the true goal in CAH therapy, and it is what was demonstrated in the Phase II trial. It is also what no other CAH medicine to date has attempted to achieve.

In adult CAH, we are targeting completion of enrollment in the Phase III study in Q1 2027. The study then calls for 32 weeks of dosing. In pediatric CAH, [indiscernible] is in a Phase II dose-ranging study. Our goal is to rapidly advance the pediatric program into pivotal development following planned regulatory interactions. In addition, the adaptive Phase II/III global study of atumelnat in ACTH-dependent Cushing's syndrome is already underway outside the U.S. and was recently granted orphan drug designation in the U.S. We have planned engagements with the FDA to confirm their expectations for this program and look forward to updating you in the coming months.

Let me now turn to T1 Day. After careful analysis, we have chosen to prioritize acceleration of VX-017 as our lead program, recall VX-017 is an allogeneic off-the-shelf glucose responsive insulin producing fully differentiated iLet cell therapy. It has a similar target product profile to zemilocell, but is designed for people with all blood types. This doubles the eligible patient population to about 120,000 people. The potential to bring transformative benefit to even more patients is the key reason to focus on VX-017 given the resource intensity, complexity and manufacturing demands of cell therapy programs. We have already begun dosing patients with VX-017 in a Phase I/II study. Our near-term goals are to demonstrate proof of concept and to scale up manufacturing with the goal of moving to pivotal development next year.

Finally, we continue to progress our serial innovation work in T1D, focused on improved immunosuppression and on generating hypoimmune islets with the goal of making this potentially curative therapy available to even more people. Turning now to renal, where we have 4 programs in mid- and late-stage development. Starting with Pove in IgAN, we are both excited and ready for our PDUFA date on November 30, just weeks away. Duncan will address our launch readiness. We just wrapped up a sparkling ASN Annual Meeting with the Rainier Phase III interim analysis presentation and publication in the New England Journal of Medicine supporting what we believe is a differentiated potentially best-in-class profile for Pove in IgAN. Simply put, Pove will offer a trifecta of excellence in efficacy, tolerability and patient-centric administration features. I'll focus tonight just on the patient-centric features. The commercial presentation of Pove is clearly differentiated with a small volume 0.46 mills once every 4 weeks subcutaneously dosed via auto-injector at home. On this point, this advantage is reflected in the poster presented by if at all, at the recent ASN of a qualitative survey study of about 25 adults with IgAN in the U.S. that revealed 96% of patients preferred an auto-injector relative to injection via prefilled syringe and 80% preferred dosing every 4 weeks versus weekly.

Our ambition is to launch Pove globally. To that end, we have already completed our filing for potential accelerated approval in the Kingdom of Saudi Arabia, where it has been granted breakthrough status we estimate KSA represents an incremental 7,000 patient opportunity. And we are planning forward for our regulatory submissions in other regions, including Europe and Asia. When the study completes and the 2-year eGFR data are available, on Pove in membranous nephropathy, our OLYMPUS Phase II/III pivotal trial is ongoing with Phase III enrollment and dosing well underway at the selected dose of 80 milligrams subcutaneously every 4 weeks.

Recall, this study has a 104-week endpoint. On [indiscernible] and AMKD, we have 2 pieces of news since our last earnings call: First, to recap the exciting results from the AMPLIFIED study in cohort 1 of patients with AMKD and modest proteinuria treatment with anaxiplin on top of optimized standard of care led to a 42.7% reduction in urine albumin to creatinine ratio, or UACR, at week 13 compared to baseline with the UPCR down 44.7%. This is remarkably consistent with the treatment effect previously shared in the Phase II data at AMKD published in the New England Journal of Medicine. In Cohort 2 of people with AMKD in type 2 diabetes treatment with anaxiplint led to a 17.3% reduction in UACR and a 25.4% reduction in UPCR at week 13.

Of note, the majority of patients in both cohorts did not have a diagnosis of FSGS, [indiscernible] was generally safe and well tolerated with no serious adverse events related to [indiscernible]. All adverse events were mild or moderate in severity. We look forward to discussing these results with regulators in the context of the AMPLITUDE study next year.

The second key milestone was that we completed full enrollment in the pivotal amplitude Phase II/III trial, and we are fully on track to share the results from the interim analysis of AMPLITUDE early next year. If positive, this interim analysis will support potential accelerated approval in the U.S., rounding out on renal enrollment in the VX-407 [indiscernible] Phase II study in ADPKD completed enrollment, and we are now on track study readout next year. With that, I'll turn the call over to Duncan for a commercial update.

Thanks very much, Reshma. Our commercial story continues to be one of excellence in launch execution across CF, heme, pain and most recently, rare endocrinology. Through the first 9 months of the year, our ongoing launches of ALYFTREK, CASGEVY and JOURNAVX have generated over $2 billion in revenue, led by over $1.7 billion in ALYFTREK sales and more than $350 million in combined CASGEVY and JOURNAVX sales.

To give you a brief overview and put quarter 3 revenue patient and prescription growth in context. In CF, we delivered $3.3 billion in revenue with strong switching to ALYFTREK and over 18,000 patients benefiting from ALYFTREK around the world. In heme, CASGEVY achieved $99 million in quarterly revenue with approximately 200 infusions completed since launch and a fourth consecutive quarter with more than 100 patient initiations.

In moderate to severe acute pain, JOURNAVX reported over 750,000 prescriptions and $58 million in revenue. More than 1.6 million patients have now been treated with JOURNAVX in the U.S., and JOURNAVX is now the #1 prescribed branded oral analgesic in the U.S. And in rare endocrinology, PALSONIFY contributed $10 million in revenue for the month of September following the close of the acquisition.

For the full third quarter, PALSONIFY revenue was approximately $24 million. I'll now cover these disease areas in more detail, starting with CF. The Q3, $3.3 billion in global CF revenue represents 8% year-over-year growth. Global growth overall was led by ALYFTREK, which delivered $706 million in worldwide sales in Q3. In the U.S., ALYFTREK sales year-to-date have now surpassed $1 billion in both the U.S. and outside the U.S., ALYFTREK sales continue to build primarily from patients switching from TRIKAFTA and new patients with rare mutations. Outside the U.S., we now have a life reimbursement in 31 countries.

Looking ahead, our CF growth drivers remain consistent and clear. label expansions in rare mutations, penetration into younger age groups, additional geographies and by the underlying survival benefit of patients on CFTR modulators.

Turning to CASGEVY in severe sickle cell disease and transfusion-dependent beta-thalassemia, where $99 million in Q3 revenue reflects 30% sequential growth. We have infused twice as many patients in the first 9 months of 2026 as all of 2025. Since launch, we have initiated over 750 patients worldwide on CASGEVY and with 4 consecutive quarters of initiation numbers exceeding 100 patients, we now have patients at all stages of the treatment journey. We've also continued to enhance the patient journey, shortening the overall time from referral to infusion and decrease the number of mobilizations. We have excellent visibility into the number of infusions, which is when we recognize revenue for the rest of this year as well as into 2027. That said, infusion timing reflects patient choice with some expected seasonality in quarter 4.

So I'd encourage you to focus on the strong annual performance rather than any single quarter. CASGEVY will contribute meaningfully to our greater than $500 million non-CF revenue goal this year and is on its way to achieving its own blockbuster potential.

With JOURNAVX in moderate to severe acute pain, we are building a franchise for the long term and are focused on the following critical markers of success. Broad payer coverage, prescription growth, breadth and depth of prescribing the addition of generics to hospital pathways and revenue. These are the building blocks of a sustainable, long-term, multibillion-dollar pain business.

Let me start with prescriptions because that's the best indicator of underlying physician and patient demand. In the third quarter, JOURNAVX prescriptions totaled over 750,000, up more than 40% sequentially from quarter 2 2026. At the end of quarter 3 2026, we are well on our way to achieving our guidance of more than 3x the number of prescriptions in 2026 versus 2025. Prescriptions continue to split roughly 50-50 between hospital and retail channels. Third quarter JOURNAVX revenue of $58 million, up 18% quarter-over-quarter reflects continued high gross to net with the patient support savings program remaining on.

Let me walk you through the revenue growth dynamics. A significant driver of gross to net is continued utilization of our patient support program. We have chosen to leave the PSP in place and extend it into 2027 so that people who are prescribed JOURNAVX, but whose plans do not yet cover it can receive the therapy. Accordingly, when we sunset the PSP mid next year, we continue to expect gross to net to stabilize at a level close to other mass market brands in the range of 50% to 60%. In addition, in quarter 3, gross to net and revenue were both affected by the onetime impact of securing broad Medicare Part D access in July. As that access came online, previously uncontracted prescriptions shifted to contracted rebated pricing, resulting in a onetime reset in net revenue. This is in line with our overall strategy to secure broad sustained access across commercial and government plans so we can successfully convert physician practices to JOURNAVX for all their patients.

This quarter marks our first opportunity to speak about PALSONIFY as part of Vertex following the deal closed at the beginning of September, and we are pleased with the launch trajectory to date. Let me briefly describe the disease, the unmet need and frame the key metrics at this stage in the launch. Acromegaly is a symptomatic disease that affects approximately 20,000 patients in the U.S. and a similar number in the 5 largest European markets plus Japan. Although surgery is the first line of treatment, only 40% to 50% of people achieve durable remission. So the majority of patients need lifelong treatment. In the U.S., they're treated by approximately 3,000 endocrinologists until the launch of PALSONIFY, the main option has been monthly injections with somatostatin receptor ligands, or SRLs, delivered using large gauge needles.

These treatments have 3 limitations: Firstly, they can cause painful injection site reactions at the beginning of the month; secondly, efficacy tends to taper off in the latter part of the month, leading to breakthrough symptoms such as joint pain, swelling and fatigue; and thirdly, the recurring logistical challenges and burden of chronic depot therapy. The unmet need is therefore significant. The ideal treatment for patients will be a highly effective easy-to-take, well-tolerated oral medicine that provides sustained control of the disease and one that has a broad indication for both naive and switch patients. This is the exact profile of PALSONIFY as the first and only once-daily oral SST2 selective agonist.

As we integrate the Crinetics business, there are 3 areas of focus for the success of PALSONIFY, building on the excellent base of 80% reimbursed coverage: Firstly, build a broad base of repeat HCP [indiscernible] for PALSONIFY; secondly, drive growth in both the new and switch settings; and thirdly, deliver on our revenue goals. We are very pleased with the progress that the Crinetics team and now the integrated Vertex team are making against these goals. Approximately 500 endocrinologists are writing PALSONIFY prescriptions, and there was a significant increase in the number of repeat writers in quarter 3 compared to the first half of 2026. PALSONY now has the leading brand share at over 40% among patients initiating or switching therapy. And lastly, we see continued strong growth in patient enrollments, leading to $10 million in revenue in September, $24 million in quarter 3 and approximately $60 million for the first 3 quarters of 2026. Our focus is on excellence in execution to further accelerate the U.S. performance and prepare for international launches.

Let me conclude with an update on our commercial readiness for Pove in IgAN. Reshma has already highlighted the trifecta of efficacy, safety and patient-centric dosing of povetatercept. Put simply, with the PDUFA date just days away now, we are 100% ready, and we are incredibly excited to bring Pove to patients with IgAN. Our field team is fully hired, trained and ready to go. Over 90% of the team have deep nephrology experience and many of them have been engaging with nephrologists in IgAN disease educational activities since early this year. We also know that the patient experience is of supreme importance in biologics and IgAN is no different. Based on years of providing comprehensive patient support to our CF patients, we have built a people-based and tech-enabled patient support program to facilitate patients to get their prove as fast and as easily as possible.

In addition, our payer conversations continue to proceed very well. Payers understand the significant unmet need are very familiar with Pove's clinical profile and have responded positively to its differentiation and overall value proposition. We've had many engagements with nephrologists over the last few months, including the excellent ASN Kidney Week meeting last month. They're looking for treatments that meaningfully and rapidly reduce proteinuria, have a favorable tolerability profile and offer convenient dosing alongside a seamless treatment experience built on access and patient support. Our discussions with physicians over the last quarter have increasingly revealed the importance of dosing frequency, dose volume and viscosity and method of administration. We continue to believe that in addition to an excellent efficacy and safety profile, the low dose easy-to-use at-home auto injector will be an important differentiator for Pove. I'll now turn the call over to Charlie.

Thanks, Duncan. Vertex delivered strong third quarter results with total revenue growth of 12% year-over-year, reflecting revenue growth of 10% in the U.S. and 16% internationally. Results include an approximate 1 percentage point favorable impact from foreign exchange and $10 million of revenue from Crinetics following the close of the transaction. Globally, CF revenue grew 8% year-over-year with 5% growth in the U.S. and 12% outside the U.S. or 10% on a constant currency basis. On a non-GAAP basis, third quarter gross margin was 85.6%. On a GAAP basis, gross margin of 84.7% includes intangible asset and inventory step-up amortization resulting from the purchase accounting for the Crinetics acquisition.

Turning to Q3 operating expenses, which include approximately $60 million of Crinetics operating and integration-related expenses in September. Third quarter non-GAAP R&D expense was $936 million, an increase of $74 million or 9% year-over-year. Approximately $30 million of the increase was attributable to Crinetics. Non-GAAP SG&A expense was $556 million, an increase of $187 million or 51% year-over-year. Nearly 80% of the incremental spend was to enhance our commercial capabilities. Within the increase in commercial spend, the biggest drivers were Pove in renal, and JOURNAVX and then PALSONIFY. Approximately $30 million of the incremental SG&A spend is related to Crinetics. We also recorded $41 million in acquired IP R&D expense in the quarter, including a $28 million upfront payment for new business development agreement with [indiscernible]. During Q3, we incurred approximately $50 million in nonoperating costs associated with the Crinetics transaction financing, including higher interest expense due to the new bank loans and other related costs. In addition, interest income was $15 million lower than it otherwise would have been as a result of lower cash balances after the acquisition.

Our third quarter non-GAAP effective tax rate was 18%, up approximately 40 basis points compared to Q3 2025. Third quarter 2026 non-GAAP net income was $1.21 billion and third quarter 2026 non-GAAP earnings per share were $4.76.

Turning to the balance sheet. We ended the quarter with approximately $9.8 billion in cash and investments following the close of the Crinetics acquisition. Note that we raised $4.5 billion of term loans to fund a portion of the acquisition currently bearing interest at approximately 4.8%. Even with a busy period for BD, we also deployed approximately $120 million during the quarter to repurchase roughly 250,000 shares. Year-to-date, we have repurchased approximately 2 million shares for $921 million. Our strategy for capital deployment remains unchanged with the priority on investing in innovation, including external innovation and an additional allocation for share repurchases.

Now turning to guidance. For total revenue guidance, we are raising our prior range of $13.1 billion to $13.2 billion to a revised range of $13.15 billion to $13.25 billion. The increase reflects the addition of Crinetics, which we expect to contribute $40 million to $50 million to full year 2026 revenue. The underlying drivers of our revenue outlook are unchanged. Continued CF performance, including the ongoing ALYFTREK launch together with growing contributions from heme, pain and now rare endocrinology. We continue to expect more than $500 million in revenue from CASGEVY and JOURNAVX with additional contribution from 4 months of PALSONIFY. Consistent with prior guidance, our outlook continues to include an expected full year benefit from foreign exchange of roughly 150 basis points. Given our visibility into the drivers of our business and with just 2 months of the year remaining, we have a high degree of certainty in our revenue guidance range.

We continue to expect full year gross margin slightly below 86%. On operating expenses, we are revising our prior combined non-GAAP operating expense guidance of $5.65 billion to $5.75 billion to a revised estimate of approximately $6 billion. The stand-alone Vertex business remains at the high end of our prior range and the increase in guidance is attributable to the inclusion of approximately $250 million of Crinetics operating expenses and integration-related costs. This updated operating expense guidance reflects continued investment in our late-stage clinical pipeline and the commercial infrastructure supporting our launches and revenue diversification.

For the full year of 2026, we expect total nonoperating costs of approximately $105 million related to the financing of Crinetics, including higher interest expense and other related costs. In addition, interest income is projected to be approximately $60 million lower than it otherwise would have been as a result of lower cash balances after the acquisition.

Please see Slide 23 of the earnings presentation for full details on the impact of Crinetics upon Q3 results and full year 2026 guidance. We continue to expect our full year non-GAAP effective tax rate to be between 19.5% and 20.5%. In summary, Vertex delivered strong third quarter results with 12% revenue growth and increasing revenue diversification beyond our leading CF business. The integration of Crinetics is well underway. And with the strong commitment of the Crinetics team, we are accelerating commercial, clinical and valuable preclinical programs. Our continued leadership in CF, the increasing contribution of CASGEVY and JOURNAVX, momentum in rare endocrinology and with Pove on the doorstep of launch, we are well positioned for continued attractive growth and profitability for years to come. We look forward to updating you on our continued progress across multiple disease areas with key upcoming milestones detailed on Slide 24. I'll now ask Susie to begin the Q&A period.

Thanks, Charlie. Chuck, can you please open it up to questions?

[Operator Instructions]

Today's first question will come from Cory Kasimov with Evercore.

Charlie, congrats on the new role. It's very well deserved. So on Pove, I wanted to ask about the recent citizen petition that raises the question of whether Ranir's IgG monitoring and dose hold rules need to be carried into clinical practice. So I guess, how frequently do patients actually fall below the IgG threshold or require treatment interruptions. And what do those data support or potentially indicate in terms of monitoring requirements in the commercial label.

Cory, it's Reshma. Let me take that one. With regard to the citizens petition, there are about 200 or so of these that happen every year. About 80% or so of them are from named individuals or companies and about 20% of them are anonymous. This one, as you know, was anonymous. If the question behind your question is, how do we feel about the label, where our conversations with the agency, everything that you would expect to be happening with the FDA is happening, and we're really looking forward to our PDUFA date.

On the specific of how can we think about what values IgG levels can achieve. The bottom line is before this wave of B cell modulating therapies the way a lot of folks thought about IgG levels were from congenital diseases of immunologic basis. And that's where a lot of these values came from. So in this day and age, what numbers could IgG levels come to.

I think the best example is to look at are the clinical trials. In our example, we studied over 500 people. We measured every 4 weeks if the IgG was going to go down, we certainly would have found it because we looked and we considered a single excursion to be worth noting. I would say the most important point to think about is infections. And on that note, there are no opportunistic infections, as you know, in the Pove program.

The SAEs of infection are balanced. It's exactly 0.5% in Pove and 0.5% in the placebo group and the rest of the infections are mild to moderate. You put this together and you can see why we're so excited about the PDUFA date.

Next question will come from Jessica Fye with JPMorgan.

Can you help set expectations for what would represent a win coming out of the amplitude [indiscernible] on both proteinuria and eGFR.

Yes. Just on the AMPLITUDE study, that's the one that is completed full enrollment and it completed the interim analysis cohort enrollment last year, setting us up for the interim analysis early in 2027, but when would be a statistically significant result on the GFR slope. And I say that because, of course, we're going to measure proteinuria and GFR. But our agreement with the FDA on what would be acceptable for accelerated approval is GFR. That's where they are on the disease AMKD. I expect the Phase III to look a whole hell of a lot like the Phase II in terms of proteinuria, but the key element here is GFR, and it's a statistically significant difference between the anaxaplin-treated group and the placebo on top of standard of care. Now I won't share with you the power analysis and such, but that's what we're looking for because GFR is what the accelerated approval agreement with the FDA is based on.

Your next question will come from Salveen Richter with Goldman Sachs.

Just a follow-up on Cory and Jess' questions. With regard to POB, can you speak to your comfort and history with the manufacturer. And then with regard to enaxiplan, can you just walk through further for the reasons for confidence into the 48-week interim data early next year, specifically how we get comfortable thinking about the separation between drug and placebo at that time point? And just to read through from some of the data sets that you've generated to date.

You bet. So Salveen, let's do Pove first, and then let's get to an [indiscernible]. On Pove, the specific question you had is, how is it going with manufacturing. We've been with the same manufacturer all through Phase III and through to the lead up for our PDUFA date. We feel really good about where we are. And as you know, in addition to the review of safety and efficacy, clinpharm, there's also a review of the CMC manufacturing package and all of the interactions that you would expect us to be having with the FDA are occurring. So overall, I feel very good about where we are.

Moving then to inaxapline, but staying within renal. One way to think about the inaxiplin program and GFR because to date, in both the original Phase IIa study that we published in the New England, that was the 1 that had the 47.6% reduction in proteinuria and the more recent amplified results, which were from the more cohort 1, the more modest proteinuria. That one was a 44.7% reduction in UPCR I think the best way to think about that in terms of GFR, which is the endpoint we've agreed upon with FDA in these 2 ways: one, substantial reductions in proteinuria in homogeneous proteinuric kidney disease have timing again been linked to improvements in GFR. That's one general statement.

Maybe a second way to look at this is talking about IgA nephropathy. We used to talk about IgA nephropathy as a fairly indolent disease. But as you can see from the placebo arm of IGAN trials, those patients are losing about 5 ccs per ml per year, right? AMKD is a rapidly progressive disease. So more than that, 6, 7 ccs per ml per year.

And the FDA themselves have set in IgAN that they are going to be comfortable accepting 1-year GFR differences. So when I put that all together, it adds to my confidence level of what we're going to see with AMPLITUDE. But I'd say those are 2 ways to think about anaxipline in AMKD.

The next question will come from Geoff Meacham with Citibank.

I also want to offer up some congrats to Charlie. I just have a couple of quick ones. On Pove, Reshma, you mentioned data should continue to mature post approval, including the 2-year eGFR data. Just the question is, how much of a factor do you think this will play in your competitive position ultimately. I wasn't sure if you looked at this as maybe a tipping point in terms of what the payer and physician community is going to look at.

And the second one, real quick on pain. I know it looks like the trials are continuing to enroll midyear data next year. Maybe just at a high level, give us some context for kind of what you think at this point, a win would look like kind of [indiscernible] versus [indiscernible]?

Yes. Let's do DPN first, and then I'll split the Pove question with Duncan. On DPN, we are fully on track to complete enrollment in both the 2 Phase III VX-548 or sucetridine trials and on track to complete the enrollment in the VX-993 DPN trial. That would put us for results somewhere mid of next year. And when would be the susetrigene arm beating placebo treatment in the DPN -- in the 2 DPN studies. In one of the studies, we have a gabapentin arm to give us context, but a win would be beating placebo. That's the regulatory enabling end point.

On Pove, I'll just give you a top line comment. We're going to go to the 2-year eGFR full completion of the trial as originally designed because our ambition is to launch Pove around the globe. The FDA has said that they're comfortable with 1-year GFR, but other regulators have different expectations. So that's why we're going to completion. And I do think the results are fully mature at that point, and that's another advantage for all of us to have fully mature 2-year data. Duncan, do you want to talk a little bit about differentiation GFR and the Pove launch in the U.S.?

Indeed. Geoff, so we thought about this question quite a lot, as you can imagine, we've discussed it with nephrologists, and I would encourage you to think about it this way. Nephrologists already had a very strong level of conviction in the connection between proteinuria and eGFR, especially in IgAN. And I would say the data that has come out from the APRIL -- APRIL BAFF d inhibitors over the last couple of months has only served to strengthen that conviction. So we believe on the basis of that, that Pove continues to have best-in-class potential through its excellent efficacy profile, impact on proteinuria, hematuria, Gd-IgA1, in just 36 weeks as well as being well tolerated. And as Reshma alluded to in her prepared remarks, an incredible profile from a patient point of view with low volume, low viscosity at home once a month auto injector. So when we've been engaging with nephrologists on this topic, which we've done a lot over the last couple of months, including, of course, ASN week, they're very excited in the profile of povitacercept and looking forward to trying it post approval. So we're very comfortable with where we're at.

Next question will come from Evan Seigerman with BMO Capital Markets.

So we're seeing some good traction with JOURNAVX, but you're keeping the PSP on through the rest of the year and now pointing to a gross to net normalization around mid-2027. Can you help us think about kind of the bridge between prescription growth and eventually reported revenue as the PSP rolls off. And when do you expect revenue growth to reflect as normalization occurs?

Sure thing. Duncan, maybe you could take that one for us.

Yes. So just to step back a little bit, Evan, just to make a couple of points, and then I'll dive into the PSP program, gross to net and revenue. We are very pleased with the performance of JOURNAVX. This is hard work. We're changing decades of ingrained prescribing behavior and seeking to convert practices over to the use of JOURNAVX. So 750,000 prescriptions in 1 quarter, 1.6 million Americans treated, the #1 oral branded analgesic would all indicate that we're making great progress. As far as the gross to net is concerned, I would make the comment that obviously, negotiated agreements to secure access for the full population with payers are important to the long-term sustainable growth of the product. And so it's important that we're able to get those plans in place, for example, the 2 Medicare Part D plans that came in place in July this year.

At this point, we have about 82% managed lives covered. But that does mean that there are patients who are yet to be covered, and we want to make sure that those patients have a great experience. So we are taking the strategic decision to keep the PSP program switched on. We will sunset it by the middle of 2027 and at that point, you can expect, as we've said before, I think gross to net to stabilize at the sort of normal oral branded level of 50% to 60% and revenue growth to grow commensurately.

The next question will come from Brian Abrahams with RBC Capital Markets.

Congrats to Charlie from us as well. Just on the Pove launch, it sounds like you guys have had great engagement with physicians and payers. I'm just wondering what's the right way to think about how initial uptake might balance both the growing awareness and enthusiasm versus the potential that a lot of nephrotic patients may have already come on to therapy with the drug in the class. And then just secondarily, ALYFTREK conversion looks like it's been picking up steam in the last few quarters. Just wondering the right way to think about the continued trajectory there.

You bet. Brian, I'm going to ask Duncan to comment on both. Let's see your second question first, and then we'll go back to Pove.

Yes, Brian. So ALYFTREK has been driven predominantly by new reimbursement agreements obviously, outside the U.S., we've had another slew of those agreements in quarter 3. And it's also being driven by the new rare mutation indications, which obviously offer a de novo patient population to the CFTR modulator class read large in some cases and certainly ALY specifically. So those are essentially the 2 main drivers of ALY growth over the last couple of months, which we're particularly happy with. In terms of Pove and [indiscernible], a couple of comments there. Firstly, as with, say, CASGEVY and JOURNAVX, we will be providing you with the metrics that we think are most useful to look at in earnings call at the beginning of 2027.

And I would say you make a great point, the physician enthusiasm for the new BAFF -- or BAFF APRIL inhibitors has been incredible, and that is certainly driving success in the market. And the numbers are a little bit unclear at this point. But let's say -- sorry, not Pove, [indiscernible] closed the year with about 3,000 patients on medicine, which is probably roughly where they're going to end up. That leaves us with 163,000 yet to go. So with the level of nephrology, enthusiasm for advanced therapy and treating early in the disease, for the nephrologist enthusiasm for povetasecept specifically, both its clinical profile and the patient experience and that vast number of patients who still need treatment. Remember, 75% of patients with IgAN have a proteinuria above 1 gram. We think there's a huge opportunity here.

Your next question will come from Michael Yee with UBS.

Mike Yee at UBS. Two questions on anoxaplan. Reshma, you made some great comments about some of the previous data we already know in Phase II. I guess One new thing that has come out is obviously some of the IgAN data that shows significant eGFR benefits even at 9 months on just a couple ml per minute deltas and similar premier reduction you're seeing with the [indiscernible] plan. So my question is, given the significant benefits you're seeing and given a 12-month time point, our math suggests that a 2 ml per minute benefit should be static. Just wanted to understand your view about the IgAN data and how that translates here given the deltas you see. And the second question is Parasol. I think the working group has been trying to push proteinuria as an endpoint. Was there any color that you got out of their working group and how that may be an accelerated endpoint?

Yes. Mike, first, let's do Parasol. Parasol is a very important and influential group. You know they've come together multiple times over time and work with the FDA to evolve endpoints and FSGS and their work with the agency, I do think help to move the agency to a protein-based endpoint. We are members of the broader Parasol community. The thing that I'm paying most attention to is the community clearly seem interested in moving to a proteinuria endpoint for AMKD. And at the same time, the FDA and our agreement is indeed with GFR. So given that, we're focused on GFR. On your math for GFR, I won't argue with your math seems reasonable enough. The thing to say, Mike, is I think what we're learning from the example of IgA nephropathy because there are so many different classes now that have been used in IgAN. It matters not only that you get the proteinuria down. It matters how you get the proteinuria down and decreasing proteinuria by way of APRIL BAFF inhibition has more beneficial impact on GFR than perhaps other methods of reducing proteinuria.

And the thing that I take away from it is targeting the underlying cause of disease is always a better move than going upstream or downstream. It's actually another reason I have confidence in amplitude because it's another example of a proteinuric kidney disease where we're targeting the underlying biology. So I think both in the dimension of quantity of protein reduction, but also the how, the quality of protein reduction in IgAN APRIL BAFF upstream in the fat hypothesis has beneficial effect. I think that's what we're going to see with amplitude because inaxiplin is equally targeting that underlying cause.

The next question will come from Tazeen Ahmad with Bank of America.

Let's go back to the CF franchise for a second. Can you just give us your thoughts, Reshma, on how the data for 828 compare to your expectations just based on the preclinical data that you looked at? And then if you think about the other CFT or modulators that you have, where do you think is the biggest undermet need at this point? And where is the most room for improvement over what you have with ALYFTREK?

You have such a good question, Tazeem, what is the unmet need. So let me just take a step back and tell you about 828 and then where we're going. The -- if you look -- and I think we provided it on the slide, if you look at the range of outcomes, the decrease in sweat chloride, certainly the range of outcomes covers our expectations on sweat chloride reduction that is. But it is obviously a small study, it says n equals 8. The reason we are not advancing 828 in and of itself, although the results are excellent. If you were at a different company, you would just be over the moon with results like this, right? At 28 days, we are more than 6 points of sweat chloride improvement and through 28 days. We're touching 10 points of sweat chloride. Those are good numbers, especially when you take into account it's versus TRIKAFTA, this is not versus a placebo baseline. So those are excellent results.

And it's once a day, good DDI is favorable safety. The thing for us is we have 3 medicines in this NG 3.0 family, and we want to pick the best one. We're going to have the results from the other 2 medicines, 571 and 272 next year. When we have all of those results, we'll pick the one that's best suited to move forward. And if you say, what is the residual unmet need I think, Tazeen, that's a very, very hard question to answer because when we look at the data with a lift truck, we are almost superimposable onto the Gaussian distribution of Sweco of normal people. So really, it's a matter of now not almost being super imposable but be fully superimposable. So a little bit more sweat chloride, more patients getting to less than 30. That's what we're looking for.

Next question will come from Akash Tewari with Jefferies.

A bit more -- can you talk a bit more about your decision to file on 2-year eGFR data. I know you were going to make a decision. I was anticipating sometime next year, it sounds like you're making the call now. And just from a statistical perspective, if a patient on placebo starts another April BAF drug during that kind of 1- to 2-year window, how are they actually accounted for statistically? Are they included in the EGFR final analysis?

Yes. I just want to make sure I understood your question about the decision for 2 years. I think you were saying why continue to your GFR, did I understand correctly?

Right. Why make the call now? Because I know you had previously talked about regulators in a global setting 1- and 2-year data, but we already knew that. So what led to the decision to go forward with 2 year today?

Yes. Obviously, we can decide if we wish to cut the data and do a 1-year cut. We could do that at any time. But our decision to indicate that we are going to continue to 2 years is because people have asked us the question, including our clinical trial sites about what our goal is and how we see this. So to allow preparation for everyone, we've let folks know. That our intention is and our ambition is global filings, and that's going to require to your GFR because ex U.S. Not all the regulators have agreed to 1-year GFR. So that's the rationale for that.

With regard to how our patients manage, there are [indiscernible] rules in the statistical analysis plan that not only the FDA but global regulators have set forward for management of drop out missing data and how to handle if patients are no longer in the study. So we're simply going to follow the rules that are very clearly laid out. I won't go through all of them in excruciating detail, but they are in excruciating detail.

The next question will come from Terence Flynn with Morgan Stanley.

Great. I guess one more on anaxiplin. I was just wondering on the AMPLIFY data I know there's been some questions about the breadth of response in the moderate proteinuria cohort. So -- just maybe, Reshma, if you could provide a little bit more detail. I just want to ensure that there wasn't a small subset of FSGS patients that was driving that proteinuria reduction that was broader based. Maybe you could talk about kind of the response rate across the population in that cohort 1.

Yes. So Terence, on AMPLIFIED and Cohort 1 that let's call it, the modest proteinuria group because this was the 0.3 to 0.7 UPCR proteinuria cohort. The majority of patients did not have FSGS. So they didn't have a biopsy and they didn't have FSGS, which you would expect because their proteinuria is modest. And you are correct, the response, therefore, was not driven by an FSGS cohort because they weren't many of them. Most people in the study were non-FSGS patients.

One more question, please, Chuck.

The next question will come from Mohit Bansal with Wells Fargo.

Congrats on all the progress. My question is kind of surging back to poly manufacturing. And 1 concern is around the potential use of continuous manufacturing in this process, which is relatively new for Biologics at this point. So the question is like, should we worry about it at all? Or do you think FDA has been involved enough from the beginning here for us to feel comfortable about this?

On whether the agency has been involved? Yes, the agency has been involved. And we're now coming towards the end of the process, right? So we're at the point where all data has been submitted. There's an entire module on CMC and manufacturing. And you know we filed towards the end of March of this year. So they've had all that data now for a long time. All of the discussions that you expect us to be having we're having. And if you ask me if I was feeling good about the filing, all included, including manufacturing, I'd say, yes, I feel good about the filing.

[indiscernible] please wrap us up.

Will do. And this will conclude our question-and-answer session as well as our conference call for today. A replay will be available shortly after the call concludes by dialing 1 (855) 669-9658 or 1 (412) 317-0088 using replay access code 10208189. Thank you for your attendance today. You may now disconnect.

We're going to get started. Thank you very much to everyone here in the room for finding us despite locked doors and escalators and challenging room locations. We really appreciate it. Obviously, a very, very exciting ASN meeting overall, and I think particularly for Vertex Pharmaceuticals. So very, very happy that you all can be with us tonight for our kidney program updates at the American Society of Nephrology Kidney Week 2026.

I do just want to go through the agenda briefly. Reshma will kick us off with some remarks about our R&D strategy and our programs, give a quick portfolio overview. Then I have the pleasure of introducing to many of you, I think, for the first time, Dr. Akin Lou Ojo from the University of Kansas, who will discuss the recent AMPLIFY data and our AMKD program with expand -- and then we'll hand it over to Dr. Richard Lafayette, whom you all know well, and he will discuss the data release this morning in the New England Journal of Medicine about povetasecept in IgAN. And then we'll have time for your questions. We'll try and keep it really punchy. We do have a hard stop right at 7:00 p.m. and again, thank you for joining us. Please note that we will be making forward-looking statements, and we ask you to consult all of our SEC filings to discuss the risk factors. And with that, Reshma.

Thank you so much. Susie, I appreciate it. It is very surprising for me to see so many of you at ASN. And it is a real pleasure to see all of you here for the Vertex event. Believe it or not, when I was an actual practicing nephrologists and would come to ASN as a doctor, there were no real analyst meetings. There were no investors here. There were hardly any people here. So the field has come a long way.

And interestingly enough, while Vertex started as a CF company, we are quite the renal company now. And this slide talks to you about on the left side, our strategy, which has not changed. It's a disease first strategy. We are not about platforms, we are not about franchises, but it simply turns out to be the case that when you think about unmet need, causal human biology, the ability to have validated targets usually genetic, but pharmacologic is just fine biomarkers that translate and efficient regulatory and development pathways in a way where we can do our work with a low SG&A spend, it turns out that there are few renal diseases that meet every mark. And what you see there are the 4 renal diseases that are in mid- and late-stage development for us.

A1-mediated kV disease. Dr. Ajay will talk about that. Egan, Dr. Lafayette will talk about that one. membranes is another pot indication. You'll remember when we did the Alpine acquisition, we talked about Povias a pipeline and a product. And while we're not going to touch on it today, watch the space for ADPKD, we are excited about a molecule. It's a small molecule that properly folds a misfolded protein. And if that sounds like something you've heard from Vertex before, you have, that's how our CF medicines work. So there are some reasons for us to be optimistic there.

When you think about these diseases, they are actually rare diseases, many of them in the U.S. or in Europe, but they are big rare diseases. So we're talking about 100,000 to 300,000 and when you think about IgAN, it's well over 1 million because it's a particularly prevalent disease in Asia. You'll remember, for Asia, we have partnerships with [indiscernible], they do our -- they will be marketing for us in China and other regions. And we have another partnership with Ono who will be bringing this medicine to Japan and other regions. So it's an interesting area of rare but big rare diseases.

The other interesting point to note is the $13 billion. Let's just round and think about CF as a $10 billion franchise. Many people ask me what I think could be another CF-like franchise? And there are a few, but renal is amongst them. I think when you put these diseases together, the 4 that I've mentioned, and remember, the ADPKD disease that I'm mentioning to you is only 10% of the overall ADPKD. So ADPKD is about 350,000 people worldwide. Our first approach will be appropriate for about 35,000. But just in those 4 diseases, I see it being about a $10 billion franchise.

This is renal in a box. And if you wanted to have a quick reference guide, this is the one to look for. There are some B cell-driven diseases. That's where POV plays for IgAN and membranes, not on the side because it's not in renal, but we also have a trial for pove in myasthenia gravis, because that is another 1 of these very B-cell-mediated diseases. APOL1-mediated kidney disease in the middle. The Phase III program is amplitude but you would never know that because people are so interested in amplified. So Dr. Ojo is going to cover both for you today. And the ADPKD program is in Phase II proof of concept. I want to just do 1 slide before I turn over the stage to the stars of the show, Dr. Ojo and Dr. Lafayette. These are all of the results, the latest available from the various April, April bats. They're not meant to be there for comparison because these were not head-to-head studies. It's meant as a compilation of information, so everything is in 1 place at 1 time.

The thing I want to focus on is Pove in the middle, and you'll hear a lot about it. But we are excited about the fact that the PDUFA date is right around the corner, November 30, all of the things that you would expect to be going on between the company and FDA are going on, and we are really excited about bringing Pove as our first renal medicine. The other thing I want to point out is sort of towards the top of the slide and towards the bottom of the slide, preclinically Pove was specifically engineered to have some characteristics. We wanted those characteristics so that we could get broad tissue penetration really good binding affinity as well as potency and they manifest themselves in the bottom of the slide. This is the ability to have a once-monthly dose with a small volume in an auto-injector. These are not separate that sort of kind of happen to come together by good luck. This is how we engineered this medicine to behave.

With that, I'm going to turn it over to Dr. Ojo, it's A real pleasure to introduce him. He's an MD PhD scientist. He has worked in multiple disease areas, but you will hear from him why he has a passion for AMKD. And we know Dr. Ojo because he sits on the steering committee. The good news on amplitude, the Phase III study is fully enrolled. It did take a long time as we predicted, but it is fully enrolled. The other piece of good news is we are fully on track to be able to share the interim analysis results early next year. Dr. Ojo.

Thank you very much, Reshma. Good evening to all of you. I am practicing nephrologists and I also do research and the focus of my clinical work as well as my research programs have been on kidney disease in black populations for the last 3 decades. What is represented to you on this slide is the summary of the results of the amplified study. The AMPLIFY study is a study of individuals who have AMKD but were not studied in the amplitude trial for a number of very cogent reasons. There are 3 points to note on these summary results. One is that the 2 cohorts there that is cohort 1 individuals who have a very modest amount of excess urinary protein excretion, low level of proteinuria as well as cohort 2 individuals who have moderate amount of proteinuria board also have evidence of diabetic kidney disease or diabetic nephropathy. Those 2 cohorts represents the largest fraction of individuals with chronic kidney disease in the United States and in the rest of the world.

In the United States alone, these 2 cohorts represents individuals that numbers in several hundred thousands. The second thing to note is that the participants in the amplified stories are already on the most contemporary and the most comprehensive background treatment for both chronic kidney disease and diabetic nephropathy were relevant. That is in cohort 2. So these are individuals who before entering the trial are getting the best treatment for their conditions that we have.

The third point to note on this result is the reduction in urinary protein excretion in both cohorts. In both cohorts, the reduction in urinary protein excretion is substantial and clinically meaningful. You will note that in Cohort 2, the reduction in urinary protein excretion is between 17% and 25% and the confidence interval cross is one. Let us not detract from the significance of these findings because if you go back and look at registration trials for RAF inhibition therapy the renal study that led to the approval of Losartan, for example, at 3 months after randomization, your reduction in urinary protein excretion was 25%, exactly what you see in the Cohort 2 here.

At the end of 4 years of follow-up, reduction in proteinuria continues and that translated into a 44% reduction in urinal outcome and a 30% reduction in cardiovascular outcome. So the numbers that you see here, the study population, the sample is small, is demonstrative of significant clinical benefit on the long run when this study is followed for a longer period of time or if ligatures conducted in this population.

Now the Amplitude study. The Amplitude study is a Phase III study of inasapline in individuals with AMKD. This clinical trial is monumental for a number of reasons, including the fact that it is the first Phase III study of treatment disease-modifying treatment in a population that had not had any disease-modifying therapy. [indiscernible] we have known about the excess boarding of kidney disease in people of African answers. As you know, people of African ancestry, they carry a fourfold excess risk of kenophilia compared to any other Retalic group and for the last 50 years, we have not found a treatment that will address the core problem. We have had a variety of ameliorative therapies that are not specific and not targeted to the underlying mechanism of disease. That is why amplitude is different.

As Reshma said [indiscernible] fully enrolled. It included 66 patients who were carried over from Phase IIb study of inasapline along with 456 individuals who are newly enrolled into Phase II for a total of 52. And as Reshma pointed out, the interim analysis is forthcoming beginning of next year.

Now what does amplitude -- what is amplified study means for someone like myself, who is a clinician who disputes and somebody who is interested and have worked in this area for a very long time. In fact, the reason why I went into nephrology was to deal with to sort kidney disease in black. But that's a separate story and I can share that with you. So what this represents for me is that what we are looking at in Amplify is a study that is showing a potential for beneficial clinical outcomes based on urinary protein excretion reduction in a population whose need -- whose therapeutic need has never been met before. And Grishma showed the number of individuals could benefit. We have AMKD in the $250,000 range. And if I agree with that estimate, my own estimate will put that number between 600,000 and 700,000 people in the United States alone.

If you recall, 7 million lack patients in the U.S. have chronic kidney disease, the prevalence of 2 APOL1 13% in black. Individuals who have chronic kidney disease who are blacked equivalence of P1 to risk allele. It's about 20%. And if you carry that forward and you see maybe only 70% of those patients have the kidney disease due to AMD KD, you will end up on a number between $600,000 and $700,000, and that is the conservative estimate in my judge ment and in my experience.

As I pointed out, Amplified represents a significant meaningful reduction in proteinuria. You can leave the statistic society, and it is important to note that in the Phase IIb study, when the study ended at 12 weeks, those individuals continue to have a monotonic reduction in proteinuria. So the proteinuria did not stop. It was still going down. And if you were to carry Amplify forward, that is probably what you will see quite confident that, that is what you will see in this type of situation. The fact that the reduction in proteinuria in Cohort 2 was not as large as cohort 1 because those individuals have 2 diseases. They have diabetic nephropathy and they have AMTD and in [indiscernible] both in street MDD.

The result of AMPLIFY are compelling and whether you call individuals with AMPD, FSGS and hypotensive sclerosis, I think we shouldn't get hung up on that. We should focus on the underlying driver of disease, which is the presence of 2 allelic variants that are pathogenic in causing this particular disease condition. And there is no -- I am very confident that as the resource of Amplitude comes along early next year. What we are going to see is a continuous evidence of improvement in clinical outcome based on what we know today. And that is true, because we know that AMPLIFY demonstrate that even in a population that is not as homogeneous and the Ambit study, which is what Amplified is it is not a homogeneous population. And that is the majority of patients with chronic in disease. They are not a homogenous group. They are reach demonstrable benefit as shown by reduction in proteinuria, which is a strong marker of improvement in renal outcome.

At this point, I will turn it over to Dr. Lafayette.

Thank you, Dr. Or, I'm going to ask you guys to hold your questions, and we'll get through again, and then we're all available to you. Dr. Lafeyette.

It's wonderful to see you again. I think Dean Ojos presentation gives us that full sense of promise where a small proof of concept -- but through blood sweat and tears Phase II program is showing amazing promise. This is where we were last year when we talked about the Phase II results of [indiscernible] and then this year, we're able to sort of fulfill that with the Phase III interim analysis. So I'm going to go ahead and go through the presentation that we're going to give tomorrow and again, I promise it should be under 8 minutes. Otherwise, I'll get pulled off the stage tomorrow. So we'll see how this is going to go. Someone, please feel free.

I got you.

So as you know, Ranir is our ongoing global Phase III randomized double-blind, placebo-controlled trial, which is evaluating OV in adults with biopsy-proven IgAN nephropathy, who in the screening period have proven to be at high risk by having substantial proteinuria, urine protein crackers, greater than 0.75 grams per gram eGFR greater than 30 ml per minute. They're very well-treated patients who are maximum dose RAS inhibitors and allow to have standard of care with SGLT2 inhibitors, MRAs and even endothelin blockers if it was available and stable at baseline, and they get randomized 2:1 to povetacacept every 4 weeks in a small injection and versus placebo in every 4 weeks in a small injection. And then as you well know, the interim analysis was planned at 36 weeks. We're expected to see a robust proteinuria reduction and wanted to look at other biomarkers, including the impact on galactose-deficient IgA 1, an important marker of disease response, looking at hematuria and of course, looking at safety and tolerability.

So this is the population that we have in this interim analysis, it reflects very well with the overall study population and has been consistent with the studies you've been seeing presented here. And over the last 5 years, this global population is representative of high-risk patients. We're going to have progressive kidney failure over the short term. So these are 40-year-old, slightly predominantly men, predominantly Asians, but globally represented who have substantial proteinuria despite their excellent baseline therapy at around 1.5 grams per gram as a mean value. Your GFR is depressed from normal running around 60 to 70 ml per minute. And there's modest prior treatments with immunosuppression, but it's well balanced between the groups.

Here, you can see that hematuria was defined only on dipstick by moderate or large amount, not including small. So we have half the patients who have substantial hematuria at baseline. And again, by protocol, all patients had to be on maximally tolerated RAS inhibition and they are, but there is a sizable number, 2/3 who are on stable SGLT2 inhibitors at baseline and significant numbers of patients on MRA and even a few on endothelin blockers. But again, very well balanced at baseline, and again, here's -- the money shot is the drug works beautifully. And as predicted from the Phase II program right there in the exact same region where at this endpoint at week 36, we see a very robust 52% reduction in proteinuria.

Again, no doubt, statistically significant and highly clinically meaningful with no change. On the right-hand side, you can see that time course that there's rapid separation between placebo and the povitacacept group such that there's already clinically meaningful reduction in the early weeks. Difference here is this is our input into creatinine ratio, which is actually more noisy and can fluctuate, but yet you're seeing this very clear progressive reduction in proteinuria out to about 5 months, which is stable to the 36 week period.

Again, in subgroup analysis, we really can't not define a subgroup that does not respond beautifully to this intervention with that, again, 50% reduction in proteinuria seen regardless of age, race of baseline protein, baseline kidney function, hematuria or use of SGLT2 inhibitors. So again, so far, it looks like every patient group does wonderfully, and this is driven by very, very consistent rapid control of galactose-deficient IgA 1, the putative antibody and antigen that contributes to IgA nephropathy. And you can see this very robust reduction by nearly 80% at the end of this interim analysis period and associated with that is a very early progressive accrual of patients whose cardinal feature of IgA nephropathy is also resolving over time.

And by 20 weeks, again, you see more than 80% of patients having resolution of their hematuria associated with their therapy. Even more so, we have our KDIGO guidelines telling us our target must include not only excellent reduction in proteinuria, but getting to a target of less than 0.5 grams per day. And here at KDIGO line goal of the 24-hour urine PCR less than 0.5 grams per gram, occurred in nearly half of the patients. This is a group again with high-grade proteinuria at baseline and even better coming to completely normal proteinuria in a much larger fraction, nearly 1 in 6 patients normalized their proteinuria on the study within this interim analysis at just 36 weeks.

And again, safety, just like in Phase II and with this class is just beautiful. Please remember, there's -- it's a 2:1 randomization. So look at the percentages, not the numbers, but you can see that overall adverse events are percentage-wise lower. But otherwise, if you look all up and down at any AE infections related events that other than injection site reactions, which are mild, did not cause patients to leave the study overall low in number, only 1 in 7 patients, having meaningful injection site reactions that led to them complaining and it being listed as an AE, of course, no deaths. And so during these times as in Phase II, this is tolerated just the same as placebo.

So here, you have the result that Povetacocept treatment leads to rapid, sustained, clinically meaningful reductions across multiple outcome measures. We have the beautiful triad of reducing proteinuria, our most direct predictor of GFR benefit as well as hematuria, galactose-deficient IgA 1. It's a very remarkable reduction of proteinuria 52% reduction at just 36 weeks. We're going to hope that this is progressive, but that's already something that's going to predict amazing outcomes when we get to the end of the study and look at GFR, again, the benefit is consistent across all of our subgroups, again, importantly, including the North American subgroup and that there's high numbers of patients who are getting even to clinically meaningful targets of proteinuria reduction.

Again, a very fabulous sustained, safe reduction in galactose-deficient IgA1, hematuria resolution in the vast majority of treated patients and a safety marker that looks identical to placebo, thus far, again, remember povetacecept was dosed as Q4-week subcu dosing in a prefilled syringe. It will be available in open-label extension already an auto-injector. So at a very low volume, so also in a very convenient package. And so the take home is this is transformational efficacy, something we hadn't seen in previous classes that has disease-modifying characteristics to it for sure and a beautiful safety patient-centered viewpoint.

So thanks for looking at that. And again, hopefully, you've already dived into the New England Journal of Medicine because I know that's your homework and due diligence that you need to do, and you can come back for the presentation tomorrow, but other than the Q&A, it won't be meaningfully different. So thanks for your attention.

Dr. Lafayette, Thank you. I'll invite you to join on stage. Thank you. And we will make sure that we have some mics in the back. Susie, are we ready to take questions?

And I will start just speaking when we got online. But also I want to mention we also have Duncan McKechnie here, who is our Chief Commercial Officer, if you have commercial questions as well. Reshma, just a quick 1 from Terence Fan at Morgan Stanley. Can you comment on confidence for POV and FDA approval in IgAN and that the label will not have any different monitoring requirements relative to Atsuko Orbera?

I am confident.

This is Anand from Mint. Question for Dr. Rojo. Given the past all recommendation a couple of weeks back on the EGFR, do you see how important is statistic for the 1-year endpoint? And then the next question is made for the company. Like how many patients are we expecting to be reported at the 12-month endpoint for the GFR?

Yes. So the first question is about 12-month end point? .

Yes. Like how important do you think is a static at 1 year EGFR endpoint given that the parasol body kind of alluded to that the near is generally noisy. -- which also most of the cables also agree. So would you like to see a static at the 1-year endpoint for amplitude? Or if there is a direction you will be happy and if there is a considerable protein area reduction along with it?

The 1-year end point is not noisy for a disease condition that has a more rapid progress rate of progression. So individuals with typically have a rate of loss of eGFR of between 5 and 8 ml per minute per year. And if you follow those people for 1 year, there is no noise in the benefit that you see if there is a true benefit. That is one. Secondly, there are -- if you look at all the previous studies that have looked at proteinuria earlier than 12 months. The 12-month result always correlates in terms of eGFR reduction with the migrant degree of reduction in proteinuria. So I have a high degree of confidence in the 12-month eGFR endpoint in this type of population.

In a population with chronic disease that is indolent and progressive aerate of maybe 2 or 3 miles per minute per year. Yes, you have a lot of variability and lab aero alone can give you a variation that may approach that number about not at 5, 6, 8 or 10 ml per minute rate of loss of eGFR.

I guess 1 for the physicians on Poli. Can you talk about how you see the B-cell modulators being used longer term in the real world as it relates to drug holidays? And then maybe for Duncan, how long should we expect it to take to establish reimbursement?

Okay. Why don't we go to Dr. Lafayette first and then we'll come back to Duncan. .

I think data is very, very incomplete for off-drug activity. We've had very limited release for accept where it shows a signal that GFR could decline relatively rapidly off the drug. And then others have only shown stability. We know that the immune situation tends to return to baseline within about 4 to 6 weeks after discontinuation of multiple B-cell modifiers. So I think we have to have some balance. We are planning right now, of course, to look at long-term extensions, see continuous dosing for up to 5 years. But I think that there's a lot of backroom discussions about if patients want to get pregnant, if patients just are doing very, very well, and want to come off the medication and see what happens, that's almost certainly going to be reasonable to try.

But right now, I think we have to go with the biology and say that we're planning to see these drugs as very long-term commitments and that attempts to really figure out drug-free periods of time. We're moving to other more conservative therapies, are going to have to be very carefully monitored and figured out over the near term. But we will see longer and longer extension. And I do hope we will learn more about off-drug exposure.

Duncan, do you want to make a comment on what you're thinking about for access and reimbursement?

Yes, sure. Well, that was loud. Yes. So a quick bit of framing. Firstly, about 70% of the IGAM patients are commercial patients. So our focus really is the commercial business, the 3 PBMs there. We have been working with them and engaging with them since July 2025. So we've been talking to them about IgAN and Povotacercept for a significant period of time. We have a high sense of urgency in order to secure coverage. I would say that probably first half 2027 is when you could expect to hear some very specific announcements about coverage.

In the meantime, it's likely that there'll be many patients covered on a case-by-case basis and like the other organizations in this space, we are putting in place a bridge program, so patients can have access to povetacecept ahead of formal coverage.

Thank you so much. Other questions?

Andy Chan, Wolf Research. Maybe a question for the 2 doctors. Now that we have complement inhibitors approved, -- and we don't have a lot of data on complement inhibitors, and we have far more in bath April. But absent more data, how are you going to use complement inhibitors versus BAFApril?

Richard, do you want to take that one?

Yes. So I think SP-9 Complement is really an important feature of IgA nephropathy and a lot of complement mediated kidney diseases, which ultimately may include AP1 diseases as well. But I really think that there's lots of ways to control complement. And again, the only mature program is iptacopan, where we've seen GFR data that's stunning and wonderful, but only half as good as what we've seen across B-cell modulators. So given that, it may be that the best way to control complement activation is to control immune complexes first, you get rapid control as you see of hematuria of proteinuria of those immune complexes. And so if we want to have a complement reducing therapy, it may be a B cell modulator as our top choice.

Now again, I think we have to offer patients options and complement agents can be offered in multiple different ways as pills, whereas intermittent confusion so far for the approved drugs. So it can be an option. But again, if we want the highest efficacy and still want to control complement, we can achieve that with B cell modulators.

One for the Vertex team. If there's anything you can share about the powering for the interim for an explant in early next year. And then for the KOLs, just kind of speak to the importance of the small volume auto-injector and how that could impact uptake? And if you think patients who aren't an agent given via PFS would want to switch over?

Sounds good. On Inaxipline and the amplitude Phase III interim analysis for early next year, we haven't shared the powering or number. But maybe what I could say -- I won't give you the number or the powering, but maybe a roundabout way to say it is you could expect a couple of hundred people in the interim analysis set. And you heard today the overall number is a little north of $500. So maybe that's 1 way you can think about it. Dr. Lafayette. And Dr. Ojo, do you have any comments to make about the biologic and its format and what that means?

Do you have a comment?

So at least in terms of PV, -- we've discussed this together quite a bit and we've been public about it, that the sense when you talk to patients, and again, this is something I often defer back to you who asked the question is what do you think to which you'd like a large volume injection frequently under your skin? Or would you like a small volume injection on your skin and would you like to have to pull the plunger put the needle in yourself? Or would you like a device that just does it for you without you even really having to look. And so I say it in that way because I always think you're going to answer yes, less frequent, smaller without doing a lot of work is going to be preferable. And I know you've got access to Vertex's patient survey which supports other instruments that we've seen that really suggests that most patients feel the same, if offered a choice between frequent versus infrequent they'll like it infrequently, and small volume auto-injector will be quite preferred.

On that point, I'll just make 1 note. I don't know if it's already happened or coming, but there is a poster presentation of patient preference at this ASN meeting. It already happened. Okay, if you want, I'm sure Susie can get you that. And I'll make another plug. There's another study that just went online like 2 days ago on a non-peer-reviewed online publication -- and what that 1 evaluates is the volume and viscosity of various ones of these Aprils and maps and you can produce through that and look at the viscosity and volume and what that might mean. Susie, back to you. .

Question from Brian Abrams at RBC on naxiplin. One for you, Reshma, what is the go-forward plan for NXP in diabetics and for Dr. Ojo. I think you touched on this, but this question is -- how do you think the more modest Protea benefits will translate to meaningful reduction in the kidney function decline in that Cohort 2 population?

Okay. Why don't I go first and then I'll go to Dr. Ojo. So, the plan for the diabetic cohort, remember that's the Phase Ib cohort is to go talk to the FDA about what they want to see and what they need to see for inclusion in the label when we go to them with the amplitude Phase III study. So I'll have more to say about that next year. When -- as you know, when you are trying to figure out what next, you need to go to the agency at a particular time point in the clinical development program. And the best next time point for us to go to them is when we have Amplitude Phase III results, and we can ask them all of our questions about what they want to see and how they want to see this included in the label at that time.

So more on it next year, after amplitude and the point of the matter is we'll talk about type 2 diabetes once we get to that Phase III population. Dr. Ojo, I think the question for you is -- how do you view the more modest proteinuria and amplify and how that translates to GFR versus the amplitude population?

So I'll start by saying that any amount of excess urinary protein excretion is bad for enafunction. And proteinuria is a -- that vicious cycle that when you are excreting proceeding the urine, it causes reduction in renafunction and further reduction in renal functional cost, so it's a visual cycle. And if you have a 20%, 25% reduction in proteinuria, that is sustained over time, it is not conceivable and there is no embrace evidence that does not lead to improvement in rate of loss of renal function. And that is why some of these other studies in IgAN, you see approval based on proteinuria alone. And as I mentioned, in the renal trial, eaithelusatin registration trial for type 2 diabetic nephropathy at 3 months in 1,500 patients reduction in proteinuria was 25%. When it go to 2 years, the reduction in proteinuria was 30% and at 4 years, it was that you are seeing in Cohort 1 here at 12 weeks in the amplified.

That 25% reduction at 3 months in the renal study translated when those participants were followed to a 44% reduction in adverse renal outcome. You have to remember that proteinuria is not just a problem for the kidney loan. But CKD a small problem for the kidney is a bigger problem for the had. Anytime you have proteinuria or CKD, it is a precursor of aggressive cardiovascular disease. So when we are treating people with clints to reduce proteinuria, we're not only aiming to preserve enough function, we are trying to prevent cardiovascular disease because majority of individuals who have chronic kidney disease will never leave long to get to the lysis they would die from cardiovascular disease. And that is why you see 100,000 out of 37 million Americans who have CKD gets to dialysis every year. A lot more people than 100,000 with CKD, die from the cardiovascular disease that has been, if you will, driven aggressively by the presence of CKD.

Sorry, we'll let someone else do apologize. And this is our last question in the back. Sorry.

One for the company. Maybe, Duncan, if you can talk about the peer discussions you had so far. Should we expect Povito receive like a pretaxes at launch? Or is there a meaningful risk of a kind of a step therapy through an established kind of April pathway product? And maybe 1 for the doctors here. Based on looking across all the ball inhibitors? And do you see a clinically meaningful difference today in terms of like the data you have seen so far? Or do you need to see more data like EGFR to kind of conclude this drug is better?

Maybe we go to Rich first, then we go to you, Duncan? .

Yes. So I'll reply that. As you said, across this class, it's really remarkable, the wonderful proteinuria reduction that we've seen the rapidity of that, the association with galactose-deficient IgA reduction and improvement in hematuria, numerically, this looks a tiny bit better. So I can say, yes, congratulations. But I certainly am going to watch for what I'm sure will be meaningful GFR protection, but we're going to look to see how that compares. Again, predictably, it will probably be near 100% protection of kidney function and depending on how this high-risk group does progress, we'll see how the separation looks. So it looks really promising. It's a great agent comparing it to the others. It's a little premature, but all the signals look wonderful.

Talking a little bit on what you're expecting on payer.

Yes. So maybe I just -- the first part of that, I think, was what we're hearing from nephrologist. I would say, a little bit like Dr. Lafayette said incredibly positive reaction to vets, I would say, specifically, this is all about the product that's the easiest to use. So this idea that it is a 1-monthly auto-injector, roughly 2 seconds to inject low volume, low viscosity that is incredibly important in this market. And in terms of the payers, the answer to the question is no, we're not expecting step-edits through the April Bafor other type products.

I know Susie said 1 last question, but there are 2, we'll just get them done. Let's do it.

This is Manos from Jefferies. Just 1 on -- so do you expect any meaningful switch when we get on to the market, do you expect any meaningful switch from the existing approved drugs? And also like how easy like a patient already own EDA to switch from wonder and then kind of get on to , just to understand.

Yes. So the question is do we expect switches? I think it can occur. I think it's a matter of mass volume. Let's say, there's 150,000 people with IgA nephropathy, let's say there's 1,000 people on 1 of the existing drugs, take 2,000 people. There's 148,000 who are not on anything. So it seems like the more likely sources of patients are patients who are coming into the system and want to try therapy, but there's nothing that obstructs a person who says, "Look, the only thing available was a once-weekly medicine? Or look, there was only a prefilled syringe, I want an auto-injector or my doctor prefers this." There's nothing that obstructs that. But I think if you just look at the number of patients, there's maybe 1,000 on a April, April BAF and there's 149,000 not on anything. So it seems more likely they would come from there.

Back to Lafayette. I don't know if you have anything you'd add?

I'll just agree. It will be technically, I think, easy to switch unless there's some massive price differential or a technical company insurer problem. But I think it will be possible. And our patients are more and more proactive. I'm thinking of a patient of mine who's on CIB doing extremely well and still every visit saying like, "Oh, I wonder if I should go to an auto-injector instead. And we haven't made that jump, but just the fact that that's being thought of and patients know they have options and if they do think it's more convenient, less painful, there will be switches.

Now Susie, if you want the last question? All right.

Okay. Just a follow-up on Brian's question and anyone can answer. Given the moderate proteinuria patient population for the amplified Cohort 1, what was the biggest takeaway from the Parasol data with respect to eGFR? And what does that tell you?

Dr. Ojo, do you want to take that one?

Yes. So you can SP1760998335 As you know, Ares is a combination of multiple data sets. And there are because of the variability among the type of patients in the parasol data I don't think we can draw a conclusion from that data set at this point when we have the opportunity to see the interim results of the AMPLE study, and we have the corrobotin result of the Amplified. I think what the Parasol PL-1 data analysis is could do is to supplement the type of information that we will see from the amplitude interim analysis. It is a clinical trial, lifeclinical trial large clinical trial. And a lot of factors come into meta-analysis of multiple data assets from various sources. The best value of Parasol AP1 data is collaborating evidence in joints.

And I just want to clarify before we call it a wrap the Parasol group is doing amazing work. There's a lot of work going on in the field and you saw it happen with IgAN, where the work done by the field by doctors, by FDA, by patients led to a movement away from GFR to proteinuria and IgAN. That has not happened in AMKD. And I want to be abundantly clear that our agreement with the FDA for potential accelerated approval is based on 1-year GFR. That's where they are. If Parasol can move them, so be it, but our agreement is based on 1 year.

Terrific. Thanks, everyone. Really appreciate it. Dr. Oz, Dr. Lafayette, Dr. Kewalramani, thank you for your time, and that's it.

Thank you all very much.

Thank you.

Welcome, everyone, to day 2 of the Bank of America London Healthcare Conference. I'm Dan Lundquist. I'm the health care specialist over in New York. I'm very pleased to have Susie Lisa, Senior Vice President of Investor Relations with me from Vertex. A lot to talk about, Susie, not to mention saying yesterday, you had me change up all my questions. But maybe we'll start with just an intro. Can you give us an overview, anything that you want to flag today with the commercial franchise, key upcoming milestones for the maturing kidney and endocrinology franchises, and then we'll launch into some questions on the products.

Sure. Thanks for having me, Dan. Thanks for being here. And I think it is a really exciting time at Vertex with a lot of commercial progress and momentum. We call this a year of execution for us, and then an exciting lineup of upcoming catalysts in terms of data.

So maybe first up, I'd talk about is that we see continued expansion of our leadership in CF, and it's been an exciting year there and continue to see good progress with our switch to ALYFTREK and development of our NextGen 3.0 family. On CASGEVY, really good commercial progress and seeing nice 3 quarters straight now of 100 or more patient initiations and good progress in the ultimate number of infusions and recent label expansion down to ages 2 and up.

And then for JOURNAVX, I think on acute pain, we remain very excited and on track for tripling our prescriptions this year versus -- in 2026 versus 2025. And in terms of upcoming catalysts there on the chronic pain side of things, in peripheral neuropathic pain, we remain on track for our 2 Phase III diabetic peripheral neuropathy studies to complete enrollment by the end of this year. They are 12-week studies. We haven't given definitive time lines, but I think that would put you at least roughly midyear, mid-'27 for data from diabetic peripheral neuropathy, the 2 Phase IIIs there.

Then moving to our next commercial area now, which is Crinetics and the rare endocrine space. I think very pleased with the uptake of PALSONIFY thus far. And we called that a blockbuster opportunity. And then we see multibillion in sales opportunities from Atumelnant, where we haven't given updates on timing in terms of completing the Phase III enrollment in congenital adult adrenal hyperplasia in adult or pediatric, but look for us to do that likely on our third quarter call, November 2, we'll update time lines there.

And then in terms of one of the biggest upcoming catalysts is in the renal area, we have the November 30 PDUFA date for Pove in immunoglobulin A nephropathy, or IgAN, that remains on track and pleased with the progress there for November 30. And then with inaxaplin, we just had our AMPLIFIED Phase II proof of concept, if you will, patient expansion population study that -- the results were yesterday and then remain on track for Q1 of '27 for you to see the Phase III interim analysis results.

We also were excited to announce yesterday that we completed enrollment of that Phase III AMPLITUDE study. And then in terms of other catalysts before year-end, in the myotonic dystrophy type 1 space, you'll see proof-of-concept data from VX-670 from us. And we've talked about seeing initial data from sort of the first in the NextGen 3.0 CF family, 828.

Great. So maybe just digging back into inaxaplin. What were the key takeaways from the Phase II data you reported yesterday from the AMPLIFIED study?

Yes. I think really excited about the results and to see the consistency and the magnitude and the reduction of proteinuria. So we reported UACR, which is albumin, which is the endpoint for this type of trial, but I'll do the conversion to UPCR because I think particularly with IgAN, that's how everyone is used to talking. So in Cohort 1, which just to remind folks was you have 2 APOL1 alleles and then a more modest level of proteinuria than in the AMPLITUDE Phase III study.

So in AMPLITUDE, you're 0.7 and above. In AMPLIFIED, you could be in the 0.2 to 0.7 range. And so the proof of concept of the expansion here was, could you get that sort of proteinuria reduction with less dynamic range starting from a lower baseline, right? And we did see that. So the UACR reduction was 42.7%. That converts to 44.7% proteinuria reduction at just 13 weeks. And so that's very consistent with the Phase IIa, we saw from AMPLITUDE, which was in just an FSGS population. So this was less severe proteinuria and minority FSGS population. And so I think very encouraging and exciting results to us there.

Similarly, while not a strong reduction in Cohort 2, so 2 APOL1 alleles as well as type 2 diabetes. The UACR reduction was 17.3%. That converts to UPCR reduction of 25.4%. So I think getting into that mid-20% level, again, at just 13 weeks is exciting, promising as well, not as much reduction because clearly, we know we're inhibiting APOL1, but we are not acting on their type 2 diabetes, which is also impairing kidney function. But I think a really encouraging, exciting result. And now we're looking forward to the interim analysis from AMPLITUDE on the Phase III and then going to FDA with the -- having a discussion in the context of the AMPLITUDE results about AMPLIFIED and seeing where things go from here.

And maybe can you provide any color on the safety profile? I know that there were 5 people who had some AEs of transaminase elevations. Just any thoughts on that, and whether it's a source of concern?

Yes. So I think important to recognize that overall, there were no SAEs. SAEs related to inaxaplin and no liver SAEs. We did see the 5 patients with transaminase elevations, as you said. They were all isolated, asymptomatic and they all resolved, but you did see 2 discontinuations of these patients, 2 in each cohort. And so I think that, again, the important thing is that they all resolved, but you did see 2 in each cohort discontinue. I think not uncommon or surprising necessarily in small molecule drug development.

We certainly have experience and have seen this in CF. And I think, obviously, AMPLITUDE, the much larger study will be sort of the definitive safety outlook. But I think we're pleased with the outlook, a small study and some small numbers. But again, back to the resolution and no SAEs encouraging to us, otherwise, well tolerated.

And how are you thinking about potential next steps in these specific subgroups? You alluded to the AMPLITUDE study will read out next year. It's a much broader population, a much bigger study. Just how are you thinking about these 2 populations?

Yes. So if I might parse words a bit, right, it is a narrower population in some ways, a bigger study, narrow population. So for AMPLITUDE, it is 2 APOL1 alleles and again, that severe proteinuria at 0.7 or above. I think with the results from AMPLIFIED getting from 0.2 to 0.7 and seeing very consistent results, at least on a Phase II basis, that's encouraging to us. And if you think about the patient population, it doesn't line up exactly with AMPLITUDE or AMPLIFIED, but broadly speaking, 2 APOL1 alleles and no comorbidities. We view that as 150,000 patients.

The vast majority of those are in the U.S., probably 80% or so. And a majority of them, we would say, are in the severe, that 0.7 or above. And then if you take people with 2 APOL1 alleles, kidney disease and some sort of comorbidities, whether it's diabetes or HIV, et cetera, that adds another 100,000 patients. So getting to 250,000 total.

Got it. Okay. And how are you thinking about the competitive positioning in AMKD vis-a-vis some of what else is out there from a molecule standpoint?

Yes. I think that we're clearly sort of years ahead with Phase III interim analysis data early next year. And if the data are supportive, we'll move to filing as quickly as possible. And I think you have seen some other data in the field, but very heterogeneous populations unlike very narrowly defined populations that we think you can draw clear conclusions from. And we'll wait and see how the landscape develops. But I think particularly you can add to the excitement we have in renal broadly, right?

Pove in IgAN will be our first commercial launch, but then to follow up quickly potentially with inaxaplin, I think, will be exciting, and it's helping us kind of carve out a leadership space in disease-modifying therapies in renal, which is an area that's had sort of repurposed cardiovascular meds for a long time.

So a lot of excitement and buzz around what we're doing because recall after that, you also have Pove being studied in primary membranous nephropathy. And then we have another compound in -- also in a Phase II study that's completed enrollment called the AGLOW study, and that's for autosomal dominant polycystic kidney disease, which is another 330,000 patients. So large rare diseases, rare disease populations. And I think really trying to carve out a leadership position with novel disease-modifying therapies.

Maybe one last one for me on inaxaplin. Can you just help us think about what would be good data for AMPLITUDE's interim next year? Just help me frame some of the expectations.

We haven't given a bogey and recall the endpoint here, although the PARASOL meeting is happening today, I believe, right? The endpoint here for accelerated approval is the slope of eGFR. So it's a controlled study where you have inaxaplin on top of standard of care and then placebo on top of standard of care.

And I should have mentioned that on AMPLIFIED, very high levels of background therapy, sort of well-treated patients with ACEs, ARBs, SGLT2s and GLP-1s for the diabetics. And so it is a 48-week endpoint of eGFR slope and essentially separation of the curve. So we haven't given a bogey there. But I think with the 47.6% reduction you saw in the Phase IIa at 13 weeks, now with what you've seen in the more modest proteinuria arm, I think we feel confident that, that type of proteinuria reduction at 13 weeks will translate to a change in the slope or starting to approach stabilization, particularly compared to placebo because these patients progress at twice the rate in terms of the deterioration of their eGFR versus sort of traditional kidney diseases. We'll also report out UPCR for AMPLITUDE, but the FDA endpoint for accelerated approval is the eGFR slope.

Great. So maybe sticking with renal, we'll shift to Pove. So you mentioned the PDUFA on November 30, very exciting opportunity would be your first renal launch. Can you just frame the competitive dynamics? You have 2 therapies that are already approved, both of which have been off to a good start. Just trying to help kind of think about the initial launch opportunity again.

Yes. I think that they have been off to a good start. We're excited to see that. I think it speaks to the unmet need, right? IgAN patients are biopsy diagnosed. They're typically pretty young in their 40s and otherwise healthy and sort of in these ticking time bombs, waiting to see how fast they progress.

So I think that speaks to the early launch. But even with that, it still leaves, I don't know, 159,000 patients in the U.S. to go after. Again, it's a rare disease, but a pretty relatively large rare disease population. And we're excited to come to market with what we think is sort of the perfect trifecta of differentiation. So more to come in terms of data, but believe we have potential for best-in-class in terms of efficacy. Recall, we had just 36 weeks in our interim analysis compared to peers that were at 40 weeks and really, I think, looked best or near best in terms of proteinuria reduction, hematuria resolution as well as Gd-IgA1 reduction and the percentage of patients getting to KDIGO guidelines. I think a good safety profile.

And then the third pillar of our trifecta is, we believe, clear differentiation in terms of patient administration characteristics. So we are monthly or every 4-week dosing with very small volume, 0.46 ml, and it's an auto-injector, and that compares to one peer who is a weekly injection and one peer who is monthly, but it is closer to 2 mls, which gets more painful, and it's prefilled syringe, which requires more dexterity. So I think in this type of chronic disease, as we've seen in other areas, right, patient convenience, adherence, compliance, all of that does matter.

So obviously, a big focus on the patients who are yet on drug, a large opportunity, but we'll go after switchers as well and certainly aim to have a really commanding market share over time.

And in terms of what's driving physician choice, what do you think that the key aspects they're going to account -- take into account when deciding to prescribe Pove?

Yes. I think certainly, patient adherence and compliance, that will be part of it. But I do think that if this is a chronic therapy, you hear some people say stable is stable in terms of eGFR. Our view is that if you can get more proteinuria reduction, no one wants protein in the urine or physicians don't want their patients to have it, no one wants blood in their urine. And if you're taking this every year and you're getting a percentage point or 2 more in proteinuria reduction, that's compounding over time. And so our belief is that you will see efficacy as a key driver as well as the patient convenience aspect in terms of driving physician and patient choice.

And maybe shifting a little bit to the pre-commercial activities and commercial activities, how is your sales force planning to detail the product in IgAN? Do you expect that this sales force build-out will allow you to support multiple launches in nephrology?

Yes, yes. So the investment in the renal sales force is -- we have made the vast majority of that this year. We sort of had headquarter corporate types a year ago and then have fully built out our sales force. Very pleased to see the vast majority of them have prior nephrology experience, I think because they're excited about the profile of Pove as well as the pipeline behind that. And sort of, again, this space in renal, the halo effect that we'll be able to carve out. They are launch ready.

We've been having payer discussions for over a year now as well. And I think ready to go and also excited about Pove's pipeline and the product potential, thinking about physicians who are saying, well, if I get to know the ins and outs of Pove, then potentially I can treat both my IgAN and my PMN patients as well as many of them do know us from our ongoing AMKD work, too. So...

And maybe just kind of thinking about the long-term relevance of eGFR changes for IgAN. So we've been seeing a stabilization across the board. Any thoughts about how important that metric is as it relates to the field?

Certainly, it is critical, but I also think that there is well understood now continued base of evidence, right, that UPCR reduction highly correlates to eGFR stabilization. And in addition, I think it's important to think that eGFR stabilization is in itself a proxy for time to end-stage renal disease and delaying the onset of need for death dialysis or not need but delaying the onset to dialysis or need for transplant or potentially death. So I think well understood of the correlation there.

I think having the ultimate 1- or 2-year eGFR data is important, but I think that it won't hinder us in our launch that we won't have that eGFR data because of the magnitude of our proteinuria reduction as well as the other parameters I mentioned like hematuria, Gd-IgA1 and getting people to guidelines.

And do you think -- are you planning to report the full 2-year eGFR data? Or do you think you could take an earlier look perhaps to secure the traditional approval?

I'd say that's still a TBD. We are looking at the Pove opportunity as in the entire global opportunity. And although it is significant in the U.S. with 150,000, 160,000 patients and similar size in Europe, there are even more patients in Asia. And we think the total global population is north of 1.5 million, maybe 1.6 million patients. And we are not focused just domestically, but looking at the global opportunity and regulators outside the U.S., whereas the FDA has made it clear they'll take a 1-year eGFR endpoint, regulators in other regions will not at this point. So we are looking at the entire global opportunity, and I'd say more to come in terms of where our strategy ultimately lands.

And you mentioned PMN in the broader conversation about the Pove opportunity. How does IgAN derisk PMN in your view? And how do you think about the size of that opportunity over time?

Yes. I think that with the dual BAFF + APRIL inhibition, our mechanism of action, right? The autoantibody that you look at there is Gd-IgA1 in IgAN. It's PLA2R in PMN. And I think that's where you could see potentially even more compelling data from our RUBY-3 Phase II, the basket study that we did. So I think, again, this gets back to sort of how Vertex likes to operate in terms of understanding the causal biology and having validated biomarkers and sort of what you measure in Phase II is what you measure in Phase III, and you can derisk your going from proof of concept to a Phase III study.

So we're excited about PMN. There's no pathway to accelerated approval there. It's a 104-week study. We moved from -- it's a combo Phase II/III, and we moved into Phase III, chose the dose from Phase II and moved into Phase III earlier this year, continue to enroll and dose patients. And it's a significant opportunity as well. But I think the ultimate patient size is -- I'd have to go back and check, but I think it's probably something closer to maybe 150,000 patients between U.S. and Europe, so maybe half the size of IgAN and a little smaller, but also a significant global opportunity as well.

And what gives you confidence in potential for Pove in gMG? What type of profile do you think Pove would need to show to be competitive in that space?

Yes. We're really excited about the opportunity in myasthenia gravis. It stems largely from a trial in China looking at a wild-type TACI that had excellent results in a myasthenia gravis population. It was a China-only study, but I think very encouraged by the results. And then we view myasthenia gravis as kind of this -- the poster child, the B-cell-mediated diseases, if you will, and also know that we have an engineered TACI, right, that's engineered specifically for higher potency and better tissue distribution. So we're excited about the potential in myasthenia gravis.

We have a small Phase II proof-of-concept study that we -- I think it's about 30 patients. We're looking to enroll that as quickly as possible and then it's 12-week follow-up, and we'll see the results and move from there. Clearly, a lot of agents in this space, but I think still unmet need in terms of many of them need to be cycled on and off whereas the autoantibodies don't. And so if you could have a chronic therapy that didn't require that cycling, I think that could be, again, with monthly dosing, small auto-injector, et cetera. I think that's the opportunity there that we're excited about.

Great. So maybe moving away from renal and touching on Crinetics. So can you remind us some of the rationale and why now is the right time for the Crinetics acquisition? And how do you think endocrinology fits within the broader Vertex portfolio?

Yes. Thanks for the question. So we have a very strict R&D strategy criteria that need to be met in order for us to pursue a disease area internally or externally. A few of the criteria include understanding the human causal biology, are there validated biomarkers? Are there relatively -- can we see a pathway to a transformative effect that could help engender pretty efficient clinical development and regulatory pathways? Is it a specialty commercial infrastructure that can deliver it?

And the specialty endocrine, the rare endocrine space that Crinetics has carved out fits all of those criteria really, really well. And I think that we have confidence in our due diligence process that when we identify an asset that does meet all those criteria, and there aren't many, right, and it can take some time to find them. When we identify an asset, we have confidence that we don't need to wait for Phase III for it to be derisked that we can do due diligence and have confidence, right?

If you recall, Pove was Phase II ready, right? And we surveyed the landscape and identified that and do feel confident that we have potential best-in-class data there. So we identified Crinetics as fitting all of these criteria and didn't want to wait for it to be further derisked from Atumelnant Phase III data or potentially see another bidder in the space get interested in it. So we decided to act and are really excited to have them on board.

And I think over time, in addition to the ongoing potential for PALSONIFY to only be a blockbuster in acromegaly, I think we see lots of potential in Atumelnant across a couple of different disease areas and then some upside from the pipeline as well. Existing commercial sales force, some really great medicinal chemists at targeting tough targets, if you will, and fits in over time with our type 1 diabetes work in the endocrine space.

And how would you say you're thinking about the opportunity in CAH, how that could be differentiated vis-a-vis chronicity for Atumelnant?

I think the important thing to -- where we would seek to differentiate is not only can you see your androgen levels come down, but that you can do that simultaneously with being at physiologic doses of glucocorticoids. And I think the opportunity lies in the fact that you can see if the androgen levels are coming down with some other therapies, glucocorticoids are still staying quite high, above at supraphysiologic doses. So our belief is the Atumelnant profile can be differentiated in going to physiologic doses of glucocorticoids and still being able to maintain your androgen levels at lower levels where you want them to be.

Got it. So maybe shifting to the pipeline more broadly. How the initial data for VX-670 and DM1 expected later this year inform the development plan and competitive positioning?

Yes. So VX-670 in myotonic dystrophy type 1, obviously, huge unmet need, obviously, a tricky space, right? But I think that we feel that there's definitely differentiation in our approach. When we signed a deal with Entrada a few years ago, right, we had surveyed the landscape and felt that our approach to have an oligo was desirable over, say, messenger RNA because we felt it's important to be acting in the nucleus of the cell as opposed to the cytoplasm where messenger RNA is working.

We also felt that delivery of that cargo is important and wanted to go with a cyclic peptide, circular peptide approach as opposed to a transferrin receptor. That said, I think clearly, this disease state is challenging. Is splicing the right indicator? Are the endpoints of QMT or vHOT the right ones? There's a lot to learn, I think, from both competitors and our data. But we are -- it's primarily safety as an endpoint, but we are measuring splicing QMT and vHOT, and we'll see later this year.

And would you say that there's -- you've had any learnings from the recent failure of del-desiran in DM1?

I think that initially, we had seen that the splicing index was relatively low. I think it was just at 11%. Is that the right indicator or not, but really, it came down to mechanism of both the cargo and the delivery, as I mentioned. So wanting to be with an oligo versus siRNA and then wanting to use a cyclic peptide as opposed to a transferrin receptor. We think that's the differentiation. But clearly, a lot to learn in this disease space. So that's why we run the trials, and we'll see how it looks.

And at times, it feels like with Vertex, people narrow in on certain products or businesses such as CF. Is there anything that you believe within the pipeline, which is fairly broad that's not getting enough attention?

I think that we've -- in type 1 diabetes, we've had some stops and starts, most recently a manufacturing pause that's been resolved. But I think that, that could be a really exciting, essentially a functional cure type of therapy. I think the Street fields type 1 diabetics are really well controlled. There's not much need there when, in fact, only 25% of them are at recommended HbA1c levels. And this is -- you go from 35, 40 units of exogenous insulin a day to not needing any, right? So I think that's exciting, but more to come. And we need to update on time lines later this year or early next year. So stay tuned. I think that...

Sorry, what was that in development?

Type 1 diabetes, it's our first-gen zimislecel is currently in a Phase I/II/III study. And then we've recently announced -- and that's for Type A and AB blood types. And then VX-017 is a universal donor, a type O stem cell bank, and that is -- that's approaching the clinic, but more to come in terms of time lines there. So I think T1D and then I think sort of sleeper upside, we mentioned DM1 potentially, and we continue to be really pleased with the commercial progress of CASGEVY.

And then I think the outlook for continued growth in CF, I guess, less controversy there to talk about as a development space now, but we continue to be excited by the progress ALY is making in terms of conversions and then the next-gen work that we're doing, too.

So we made 30 minutes without actually touching on CF.

And I brought it up.

Yes, you did. We stick to inaxaplin. So can you maybe talk us through the evolution of ALYFTREK from here? What are going to be the key driving factors? I think there's been more enthusiasm of late in terms of that launch starting to really continue its momentum. So just trying to think about it.

Sure. So TRIKAFTA is a terrific drug, and many patients are getting down to carrier or normal type levels of sweat chloride. But what ALYFTREK offers is even more patients getting to those levels as well as once daily. And you have to take CFTR modulators with a fatty meal. So once daily is more than just a simple convenience, right? It can help impact healthy diet, et cetera. So -- and I think the strength of the launch has been accelerated a bit by the launches in U.K. and the EU, where you do not see the need for 6 months of incremental liver monitoring like you do in the U.S.

I think even in the U.S., whereas for some patients, it might not be the right time for -- to add on that incremental liver monitoring, they perhaps they can wait until the summer months when it is more appropriate. So I think that's why you're seeing the strength of the launch. It's the focus on sweat chloride as well as the once daily and then not having the incremental liver monitoring outside the U.S. and continued progress in the U.S.

And you will see -- we've talked about in younger patients, we're getting 2/3 of them to the carrier levels of sweat chloride, and you'll see data NACFC even in older patients and adult patients, that's where we still have a little bit more room to go in terms of unmet need that if you overlay sort of the distribution of normal or carrier patients of sweat chloride that the overlay of ALYFTREK is looking very strong, and you're getting north of 50% of adult patients there, too.

And are there any learnings from the recent updates in the space, you've got some competitive data that was a little bit lackluster that you're taking as you think about development of your own programs?

I think that it does point to what we have said that we feel, particularly with our recent label expansion into virtually all rare mutations that specific binding site is not what matters. And we don't name our binding sites, but I think as evidenced by our -- the multitude of commercial products we have that we have chosen very good binding sites, a range of them. I think that drug-drug interactions and safety, et cetera, are all perhaps harder than they appear from the outside in CF and also the importance of -- and this is another one of our R&D criteria, right, is having ideally human-based assays, not solving things in rodents, but solving things in human cells from a preclinical basis.

And so our human bronchial epithelial cell assays, I think, continue to be a real key advantage for us in terms of predicting future success of any future product. But the unmet need is shrinking given how good TRI and ALY are. And so potentially, over time, you could see us look to report more on things like reduction in pancreatic enzyme replacement therapy or potentially even more improved dosing, et cetera, as well as continuing to make progress if we can on sweat chloride.

So it's actually a good transition question to sort of what we should start to expect from the next-generation CFTR modulators in the near term, what will it take to move those forward in the clinic? And to your point that you bring up, given what we've seen with TRIKAFTA with ALYFTREK, where is the ball going in terms of what you're trying to accomplish?

Yes. So I think as Reshma said on our Q2 call in August, right, if this NextGen 3.0 family isn't a clear step above ALY, given how good ALY is, right, then it's not something that will move forward. So you need to see clear differentiation if it's -- there's still limited need, but even more in terms of sweat chloride reduction or potentially ancillary therapy reduction or dosing improvement, et cetera. So in this NextGen 3.0 and then there's the NextGen 4.0 behind that, if there is room to improve upon ALY, we aim to be the firm that will do that. And so that's the work that's ongoing. But it needs to be clearly differentiated from ALY in order to move it on to a Phase III.

And maybe thinking sort of more broadly and strategically, are there -- you've moved into endocrinology. Are there other therapeutic areas that you thought that could be of interest to Vertex?

Yes. So I think it's a really exciting time because now we are commercial in 4 disease areas: CF, heme, acute pain and endocrinology with a fifth soon to come with potential Pove in IgAN launch before the end of this year. And we see all of them as having significant unmet need and large patient populations and making really exciting progress there. But you could see a neurology call point, right, with myasthenia gravis, potentially other areas there.

I would say that BD continues to be an area of focus for us, remain ever vigilant. A lot of time and attention on integrating Crinetics as well as possible. But we'll still look to do potentially earlier-stage tuck-ins for a little while here. We focus on the Crinetics acquisition. It was about 2 years between Alpine and Crinetics. Crinetics is a little bit bigger, but we'll continue to look in other areas, but then some earlier-stage pipeline work in -- yes, I think you could see us continue to add new verticals over time, but lots of room to run on the existing ones that we have.

Great. So maybe in the closing minutes, we can just touch on pain. So you mentioned there's a number of trials that are upcoming. Can you just remind us sort of what the glide path there is on the pipeline side? And then also any recent momentum and sort of metrics that you can share on success for JOURNAVX?

Yes. So maybe I'll start on the acute pain side with JOURNAVX, and we remain well on track in 2026 to triple the number of prescriptions from 2025, so something north of 1.6 million. Really pleased with the breadth of prescribers, with the breadth in terms of settings of care, right? It's a very broad moderate to severe acute pain label. And we're seeing uptake from emergency rooms, anesthesiologists, plastic surgeons, OB/GYNs, dentists, et cetera. So really building a strong base for the long-term sustained growth of JOURNAVX.

Continuing to make progress on revenue conversion and bringing down gross to net, remain on track to get to something more normalized by middle of 2027 and working through remaining reimbursement contracts, et cetera. So -- and lots more marketing initiatives. We just did another round. Jayson Tatum came into the office. Lindsey Vonn, we've signed now and lots of other marketing initiatives. And I think exciting to see now investigator studies, single center series of total knees that are done with 80%, 90% opioid-free, and those are getting published by physicians, not sponsored by Vertex and getting presented at medical conferences. And as we get on more formularies and discharge order sets, continue to see the momentum build.

And then in terms of chronic pain or peripheral neuropathic pain, I mentioned the 2 DPN Phase IIIs are on track to complete enrollment by the end of this year. They're 12-week studies, so you could see data mid-2027 potentially. And then we also remain in late preclinical development on a 1.7 inhibitor. Recall JOURNAVX inhibits the sodium ion channel 1.8, which propagates the pain signal, 1.7 initiates it. So we think that having a combo 1.7, 1.8 inhibitor could have synergistic effect in terms of the efficacy, and we're getting closer and excited about the potential there.

Great. I think that's all the time we have.

Sorry, the combo is in preclinical?

So we have JOURNAVX is a 1.8 inhibitor, which is commercialized and then a 1.7 is still -- is in -- we have chemical matter, but we are not yet in the clinic. And then we need to do -- our intent would be combination work over time.

So first, mono and then combo...

I don't think we develop it as mono. We go right to combination therapy.

Injectable instead of rather than oral.

No, oral.

Great. Thanks, Susie. Appreciate it.

Thanks, everyone.

Great. Good morning, everybody. I'm Terence Flynn, Morgan Stanley's U.S. biopharma analyst. Pleased to be kicking off our 24th Annual Healthcare Conference here in New York City. 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. I'm very pleased to be kicking off the conference this morning with Vertex Pharmaceuticals. Joining me is Reshma Kewalramani, who is the company's CEO and President. Thank you so much, Reshma. It's great to see you this morning, bright and early.

Good morning, Terence.

So maybe I'll turn it over to you to just give us an update on the company's diversification journey. I know that's been a big focus of yours as the CEO here. There's been a lot of movement on the company's pipeline and also the Crinetics acquisition recently. And so maybe just give us a mark-to-market on kind of where you stand on that journey.

You bet. Well, good morning all and for you, brave souls, who've made it here at 7:00 a.m. It's very nice to see you. We have been on a journey, it's more than 10 years now, to diversify our company and continue to grow. I do want to make sure that we talk about CF for 1 minute. CF has been and remains important to us, and we see more growth in CF as we now launch ALYFTREK around the world and get down to lower age groups. We also have our last 5% of patients for which we don't yet have a therapy. And so that foundational pillar of CF continues to go strong.

Outside of CF, over the last 3 years, we've been bringing CASGEVY to more people around the globe. And you know CASGEVY has a very significant patient journey. And now we're at a point where we can see patients who are initiating, who have first cell collections and have infusions. And so we can see the -- we have line of sight into the growth, and it looks very good. And I continue to believe CASGEVY is going to grow into a multibillion-dollar asset.

Over the last year or so, we've been launching JOURNAVX in acute pain. This is the first non-opioid in more than 2 decades, and I really like what I see in the growth there. And then we were talking about the fourth pillar, which was going to be renal medicine. And it is, but I think it's actually going to just switch places with where endocrine and Crinetics, which is our fourth pillar now with PALSONIFY, which is an approved medicine in the U.S. It's approved in Europe, launched in the U.S. This is a medicine for acromegaly.

And then, of course, there is the renal pillar. The PDUFA date for our first renal medicine, pove in IgAN is November 30, and I'm sure we'll get into a little bit more there. And there's much more beyond that. In total, there's something like 6 programs in Phase III, more than that in Phase II, and I like what's coming out of the bench into the clinic as well. So lots going on inside and outside of CF.

Great. Well, no, that's a perfect framing. So I guess the area I want to dig into first is just your kidney franchise. Obviously, that's been a big focus of investors. You mentioned the pove PDUFA date coming up here. Maybe just level set us on differentiation. I think that's a question we get a lot from investors is there's 2 competitors that have launched into the market already. So as you come from a third-to-market position, how do you think about differentiation of pove?

Yes. So when you think about IgA nephropathy, just to level set, you're looking at something like 300,000 patients between the U.S. and Europe, let's say, 150,000 inside the U.S. and then add another 1 million or so in Asia, where we're going with Zai in China and associated countries and with Ono in Japan and a few other countries. So it's one of these rare diseases that is a common rare disease.

In terms of coming to market, it turns out that this is an interesting area where there are 3 medicines that are all launching, let's call it, within a year or so of each other in the category of APRIL or APRIL/BAFF. In my mind, as I think about IgA nephropathy, and I happen to be a nephrologist, this is a disease that is very well understood in terms of its etiology. It is a B-cell-mediated disease. It is a disease that results from autoantibody production. And when you think about it that way, it makes most sense to have a medicine that works on both APRIL and BAFF because those are the 2 cytokines that are most responsible for B-cell development maturation, and it wouldn't make sense to me to work on only APRIL or only BAFF, unless you saw some concern in the safety profile.

We now have the profile. We have -- we put out a fairly extensive press release. The safety profile looks really good. And the efficacy, and this is numerical and it's cross-trial comparisons, you got to take this with a grain of salt. But when I look at the numerical response, pove has the best numerical response in terms of proteinuria, hematuria, Gd-IgA1 levels, and that's important.

But maybe the most important thing, which could be surprising to you, is the fact that it's also the most patient-friendly dosing. This is a biologic. A patient will be taking this for the rest of their life and their ability to take a small volume, pove is 0.46 mLs in an auto-injector once monthly, is a very favorable presentation. And I think that's actually going to be one of the greatest differentiators.

I also think our ability to support patients through their journey is going to be important. We've learned a ton doing the same in cystic fibrosis. I think that's going to be important. And the last thing I'll call out is we have built the largest sales force, and that is to serve patients where they are. There are certainly centers of excellence and large clinics, but there's also a smaller number of patients in the community setting, and we want to be able to serve all patients.

Great. Maybe just 1 follow-up there is that GFR kidney function is the other endpoint that you guys are studying. The trial is going on for 2 years to look at that. So as you think about positioning the kidney function data, how do you think about the importance of that in either a label or at some point down the road, given one of your competitors who already have some of that data?

Yes. So this one has been a rapidly evolving field. 10 years ago, 15 years ago, the FDA wasn't yet comfortable with proteinuria as an accelerated endpoint. And the community, the renal community has been working with the FDA, with academic centers, with industry to get proteinuria to be it. We are now at a point where proteinuria is routinely accepted in IgAN as an accelerated approval endpoint.

And your point, Terence, is around, all right, where are we with GFR? On GFR, the agency has been hinting and in the spring renal meetings, they all said they're going to get comfortable with 1-year GFR as the endpoint as opposed to 2-year GFR, which is where it was at prior to those meetings with the FDA.

Where we are is that we want to launch pove around the globe. That is our ambition. That is what we are going to do. For that to happen, we have to meet the global regulators where they are and global regulators, so think MHRA for the U.K., the EMA for EU and the Asian regulators, not to mention Australia, are not yet at the point where proteinuria is acceptable. They are at the point where 2-year GFR is okay. And so we're methodically making our way around to understand where they are with 1-year GFR, but we won't cut our data set early because our ambition and our goal is to have pove go around the globe. It is true that the FDA has become increasingly comfortable and they've all but said 1-year GFR would be acceptable to them.

Great. So it seems like you're unlikely going to get that 1-year GFR on because you want to keep -- preserve the integrity of the data set for that.

That's exactly right. That's exactly right. If you cut the data early, as you remember, the FDA had instructed all 3 companies in the APRIL, APRIL/BAFF space to not share the GFR because it was ongoing. And so once you cut the GFR and share it, that would be the concern for -- if the U.S. is okay with it, that would be the concern for the global regulators.

Okay. Maybe just 1 on the commercial side. You mentioned you're going to have one of the largest renal sales forces out there. What have been some of your early conversations with payers? Obviously, we've seen a couple of quarters from Otsuka now in terms of the uptake of their IgAN drug, but how are your preliminary conversations with kind of payers going and anything to update us on there?

Yes. On the payer side, they are familiar with the disease. They are familiar with proteinuria, the accelerated approval, the correlation to GFR and such. And they're very familiar with the outcomes of patients with IgA nephropathy. Unfortunately, that is progression to dialysis, transplantation or death. And the value of slowing that progression is well understood to them.

So we've been in conversations, the ones that we are allowed to have legally and appropriately since about last summer. We've targeted and discussed pove with more than 70% of payers and the conversations have been productive and positive. I expect that we will be able to secure reimbursement. I expect that it will be the kind of reimbursement that would be appropriate and commensurate with what you've already seen in the field. But this one seems like the payers are familiar and they are understanding of the value of medicines that prevent death, dialysis or transplantation.

Okay. Great. I think the other thing as we think through differentiation is breadth of program or breadth of indication set on a label. I think back to some of the historical examples here where that is oftentimes pretty important as you think about formulary position. So maybe just give us an update on kind of where we stand with the pove program in terms of breadth of opportunity and the next set of data that we should focus on here.

Yes. I think the Alpine team did a really nice job in studying pove in multiple potential indications by way of these Phase II basket studies that they conducted for us. After pove in IgAN, that's the November 30 PDUFA date, I expect the next Phase III readout to be in membranous nephropathy. I think that has an advantage to our first discussion point around differentiation. I think nephrologists are going to find it helpful and easier for their clinical practice to pick a single B-cell modulating drug across the various glomerular diseases that they're dealing with. And so having pove in IgAN and pove in membranous, I think, will be valuable.

I do think membranous will be next, and I think the one after that is going to be in myasthenia gravis. The myasthenia program is in Phase II. The membranous nephropathy program is in Phase III. And to close out on membranous, the DSMB has met and they have picked 80 milligrams, which is the same dose that we had studied in Phase II in the RUBY-3 trial in the event you want to look at those data as the Phase III dose.

Great. And then as we think about read-through, I guess, from IgAN to these 2 other indications, either one of those that you put a higher probability than the other? Are they both about the same given B-cell biology? How do you think about read-through from IgAN to those 2?

Yes. I think it's reasonable to look at the Phase II RUBY-3 trial for membranous to get a sense of where that's going. It's the same dose. It's 80 milligrams. So you know the safety because we just announced the results of the interim analysis accelerated approval cohort for IgAN. And there are lots of similarities between IgAN and membranous. As Gd-IgA1 is to IgAN, PLA2R is to membranous, and you can see what that reduction was. So I think that's a very -- it's a reasonably easy analogy to make.

I am very excited about the myasthenia opportunity because there is a wild-type TACI that already completed a study, a Phase II study in a China-only population. So you got to think about that. But when you look at the timeline and if you plot, for example, time on the X-axis and the ADL, the activities of daily living on the Y-axis, the wild-type TACI in that China-only cohort had really nice results. Of course, pove is an engineered TACI. It has better binding affinity, higher potency, better tissue distribution.

So I am very excited about this. This is a patient population that has a disease that is one of the most B-cell-mediated diseases, if I can call it that way. And while there are medicines that are available that have been real game changers, unfortunately, they have to be cycled on and cycled off, but the disease doesn't cycle. And pove would be a medicine that could be taken consistently over the period of the patient's life, and I think that could bring a real benefit.

Okay. Great. Maybe we'll move over to inaxaplin, which is another one of your pipeline assets. This is for APOL1-mediated kidney disease. And so first, maybe just, again, give us a little bit of background on the disease and the need there. And then as we think about the upcoming data from AMPLIFY, I'd like to dig into that a little bit because I think that's expected in the fall here, and this is from a Phase II study.

Absolutely. So staying with the renal franchise, this is about inaxaplin in a disease called AMKD, APOL1-mediated kidney disease. The disease itself is fairly new. It was just described in about 2010 or so. And basically, it's a disease that occurs only in people of recent sub-Saharan African descent. It is a very rapidly progressive disease. And fundamentally, what you see is if you have 2 APOL1 alleles versus if you don't, your risk of progression is something like 5x, 6x. It's extremely high compared to those who do not have APOL1.

There are about 150,000, let's say, 100,000 to 150,000 people with AMKD in the United States. It's largely a disease in the Western world that is in the U.S. And these patients have no medicines that have been specifically approved for their condition. We have a program that is going to read out. It's called AMPLITUDE early next year. It's in Phase III development. We have an agreement with the FDA for potential approval, and the accelerated approval is based on 1-year GFR. The FDA is not yet comfortable in AMKD, unlike in IgAN, for proteinuria to be the accelerated approval endpoint. That study finished its enrollment in the IA cohort last year. We are on track to finish the full cohort enrollment in 2H of this year, and we're fully on track for the Phase III interim analysis readout early next.

That's AMPLITUDE. But as Terence said, there is another study, AMPLIFY, and we do have to talk to the teams about not naming them so similarly. AMPLIFY is a IIb study. That one will read out this year and in the fall is about right. We are on track for that readout this fall. That one, I would think of as an expanded population as an indication expansion from AMPLITUDE. So AMPLIFY has 2 cohorts in that Phase II study. Cohort 1 is modest proteinuria. So up to 0.3 to 0.7 grams of proteinuria whereas AMPLITUDE is more than 0.7 grams. And Cohort 2 in AMPLIFY is patients who have AMKD. So they have 2 APOL1 alleles, but they have a second disease. And that second kidney disease is type 2 diabetes.

The reason I consider them expansion cohorts is obviously, when you have lower proteinuria, this modest proteinuria cohort, the dynamic range is smaller. And when you have 2 kidney diseases, it's not clear what kidney disease is causing your proteinuria. Is it 50-50 type 2 diabetes and AMKD? Is it disproportionately AMKD, disproportionately type 2 diabetes? And of course, our medicine, inaxaplin, only takes care of the AMKD portion. And so that's why that's an indication expansion, a potential indication expansion. Those results could expand the 150,000 people in the U.S. that maybe add another 100,000 or so. So that's what the AMPLIFY study looks like.

Great. Maybe we'll just focus on the modest proteinuria cohort. What would you view as kind of a good result there? And what are the implications then for the AMPLITUDE study as we think about that Phase III if we see the data from Cohort 1, recognizing Cohort 2 is type 2 diabetics. So again, a bit more of a wildcard, but in Cohort 1, how do you think about what the bar is for success there?

I hesitate to offer a bar. I think what I said when we were doing the Phase II for AMPLITUDE is double-digit proteinuria improvements would be beneficial. Some took that to mean 10.1%, others took it to mean 99.9% improvement. I would say anything in the 20%, 30% range would be a positive. Again, remember, in modest proteinuria, your dynamic range is just smaller. But I think if you have double-digit improvement in that line, I think that would be a positive. If I'm remembering correctly, the lowest level of proteinuria that later turned out to have value when the sponsor did the time to ESRD, dialysis or death trial was something like 14%, 15%. So I think numbers like that tell you that those are values of proteinuria improvement where when you go on to do the hard outcomes trials, you show benefit.

Great. And just remind us what would be needed for an indication expansion here? Would you need a separate Phase III program for both of these? Or could you somehow use this Phase II data in support, assuming AMPLITUDE was positive and supported the primary approval? Like how does the regulatory path work, I guess, for these indications?

It's really an excellent question, Terence. And the real answer is I don't know as we sit here today. We haven't had our end-of-Phase II meeting with the FDA because we're not at the point of having the Phase II data. What I would say is we -- the way to think about this is secure the results from the AMPLIFY study, if positive, have discussions with regulators around what the next steps are. And I strongly suspect that what you say is about right that they'd want to see what AMPLITUDE says because AMPLITUDE would be the study that has a proteinuria improvement and the GFR endpoint. And then what additional work the agency might want to see in the lower proteinuria group or the diabetic cohort group would come after that. But I wouldn't expect this to be the kind of a situation. And you know Vertex moves very fast where after we have the AMPLIFY data, we'd be moving on to more clinical trials. It's the kind of situation where we need to have conversations with the regulators.

Okay. Great. Before we move to 1 commercial question I had is just on the AMPLITUDE Phase III trial, you mentioned 1-year GFR. I know in IgAN, there was a lot of debate about kind of slope of decline. And fortunately, with the data we've seen so far from some of the drugs is stability of GFR. In this disease, you mentioned very rapid progression, unfortunately. So how do we think about what kind of delta, what we want to see on a GFR endpoint from AMPLITUDE?

Yes. So you'll remember that the AMKD patient population, even in comparison to how we used to think about IgAN, although I think our own views are evolving, IgAN, it turns out is not a slowly smoldering disease. As you can see from the results that have been revealed, 1-year GFR declines quite rapidly. AMKD is known to be a rapidly declining renal condition, which is why the agency was comfortable with 1-year GFR and why we were able to power the study to that end. I won't share with you what our power calculations are, but based on the rapidity of decline in AMKD, we have confidence that we powered the study correctly and that we'll be able to show a difference at the 1-year point.

Okay.

It's actually interesting that you can show that difference now with IgAN at the 1-year point.

For sure. All right. So we'll stay tuned for that data next year. The commercial opportunity, kind of similar question to pove. Walk us through kind of how you're thinking about the build-out here, the rollout, less competition here, so you guys are in a first-to-market position. But I know there's some work on the diagnosis front that you and the team have been doing.

Yes. So this one is exceptionally high unmet need. There is no targeted therapy in this area. And as we already discussed, the progression of kidney disease is unfortunately very fast. So here, the thing to think about is diagnosis. AMKD is a disease that was just described in 2010, and genetic testing is not commonplace. So when we started the Phase III trial, we started to do genetic testing as part of the trial infrastructure so that patients who are diagnosed with AMKD, if they qualify, could go into the clinical trial.

Separately, we also started up testing, genetic testing in the real world, offering free testing as appropriate with groups like Natera. So they have genetic testing for genetic kidney disease. If you're a nephrologist and you have a patient that you suspect could have AMKD, you could avail yourself of free testing. Through those programs, which have been going on for quite a few years now, 3, 4 years now, we've already identified a number of patients. And so if and when a drug is approved, we would have a bit of a head start in patient identification.

But that's going to be the primary focus of our sales team if and when the drug is approved, to make sure that physicians are aware and the education has already started that genetic testing is happening. I will tell you as an aside, as we talk to nephrologists, which we're doing now largely for IgAN, it's interesting enough that AMKD has really captured the hearts and minds of nephrologists because they see it as the first precision medicine opportunity in nephrology. And so we have the advantage of being able to do education on both these dimensions, IgAN and AMKD.

Okay. Great. Maybe just 2 follow-ups. The first, I know you're not going to guide on pricing because it's too early. But just obviously, maybe talk to us about some of the puts and takes high level, this disease versus IgAN. It sounds like there are similar prevalence numbers, again, similar rapidity of kidney decline, but anything else that we should think about potential price points? And the second is leveraging your existing infrastructure. You mentioned you're building out already with one of the largest renal sales force. Can you use that for inaxaplin? Or is there an incremental build that you need to...

So the overlap between the physicians treating inaxaplin or who could use inaxaplin for AMKD and who might use pove for IgAN is about 70%. So there's a hefty overlap, but it's not 100% overlapping circles. The reason we decided to build the largest team for IgA nephropathy versus the other APRIL or APRIL/BAFF is this desire to get to all patients, whether they're in centers of excellence, large practices or the smaller ones. And then we have the advantage of being able to then bring out inaxaplin. But we also have programs after that. We talked about membranous and there's an ADPKD, that's autosomal dominant polycystic kidney disease after that one. So we have an expectation to be in renal medicine for a long time across a number of diseases. But first things first, and it is indeed pove in IgAN that we think we're going to be there first.

On pricing for inaxaplin, I think that the right way to think about it is these medicines, if they're approved, whether it's pove or inaxaplin, they will come with data on GFR and proteinuria that speak to its potential in time to death, dialysis and transplantation. That's all the same. So I think the price points that you're seeing now are fair enough. I think when you do the health economics, whether you do it formally or for something like a NICE or an NHS or you do it in a less formal way for other payers, the health economics are very supportive. So I think it's a reasonable proxy with what you're seeing in the current wave of medicines.

Okay. Great. You mentioned in the beginning how important the cystic fibrosis franchise has been, but also will be on the forward. You're, again, rolling out the Gen -- I forget 3.0, 4.0 at this point with ALYFTREK. It's been so many years now. And obviously, it's been great to see all the progress. Maybe just high level, talk about some of the puts and takes as we think about that franchise in 2027. Obviously, you mentioned you're still going to some of the lowest age groups now. You have the ALYFTREK conversion going on. I'm not sure if there's any other geographies left, but anything we should think about for '27?

Yes. So maybe 3 things as you think about the near term, so let's call it, the next few years. For the here and now, it is about getting ALYFTREK around the globe. It is regulatorily approved in almost all regions. In some regions, we're working on pricing and access. Where we have regulatory approval and access, it is about getting people who would prefer to be on ALYFTREK. It's the best medicine we think we've made to date. So people who are on TRIKAFTA, they want to be on a once-daily medicine or they just want to be on the best medicine that we think we've made. That is the switch that's happening.

There are also naive patients. So for example, in certain countries like Italy, there's a lot of these ultra-rare mutations for which ALYFTREK has an approval. And so there are some of these very rare mutations that are coming on to ALY. So think about the ALY launch around the globe. Then think about ALY in the original ALY application, it was 6 years and above. We're working on 2 to 5, and then we're going down the age groups. So that's the next thing that you can anticipate. The last thing is emerging countries, think Brazil, think Turkey. There are some countries that we're still getting to in terms of reimbursement, smaller countries, but important nonetheless. And that would be what we are thinking about in the near term with the commercialized medicines in CF.

Those medicines, ALY is part of what we call NG 2.0, NextGen 2.0. The next one after that is NextGen 3.0. There are 3 medicines in that one, I should call them potential medicines, VX-828, which is the lead, VX-581 and VX-272. And then after that, there's a NextGen 4.0, and you can believe that there will be a 5.0 and beyond. Until we can demonstrate to ourselves that we have reached the peak of the best sweat chloride that we can achieve, we're going to keep going.

We've talked about the fact that we believe we've already achieved that asymptote for ppFEV1, the lung measurement. And we're getting awful close to sweat chloride. We have submitted some abstracts to the fall North American CF meeting. And fundamentally, when you diagram out the Gaussian distribution of sweat chloride in carriers or normals, you'll see that it's the center point, the median is about 30 millimole and then there's a normal distribution around that. And when you look at people treated with ALYFTREK, for example, it closely approximates that Gaussian distribution, telling us that we're getting close. But as long as we haven't proven that to ourselves, we're going to keep going, and that's what NG 3.0 and 4.0 is about.

Great. One follow-up, just you mentioned the global rollout of ALYFTREK. I know historically, every year, there's pricing declines in a lot of these geographies. Given the profile of ALYFTREK, does that allow you to at least keep price more stable than maybe otherwise you would if you just had TRIKAFTA? Or should we expect kind of the same progression as you typically see, which is pricing declines year-over-year?

ALYFTREK and actually TRIKAFTA before it in the ex-U.S. regions, you know that you have to go for a rebid every 3 years, 4 years as the contracts call for. What they look at is real-world data and the real-world data that they're looking at is the decline of lung function. And TRIKAFTA and now ALY are one of the few medicines that I've ever worked on that actually look better in the real world than they even did in the clinical trial because you see this flattening of the decline of lung function, everybody's lung function, just like kidney function declines, it's about maintaining it at the most stable levels that you can.

And we have been able to hold price steady in some countries based on that kind of real-life data. But I wouldn't want to leave you with the impression that that's doable in all countries across the globe. There are some countries by just simply the way the country operates, there are expectations of price declines. But where there is an opportunity to present data and decisions are made on that data, we have been able to hold price stable because the data are even better in the real world.

Great. Maybe just in the last couple of minutes, anything else on the pipeline that you want to highlight for us? I know you guys have also a deep early-stage pipeline. You mentioned some of the Gen 3.0 cystic fibrosis assets with ADPKD, but anything else that should be on our radar in the next 6 months?

All right. I will -- I'll call out a few, but don't tell anyone that I called those out and left some of the others behind. Maybe in the Phase III pipeline, the thing to call out is the type 1 diabetes program. There are -- there is Zimislecel program that's a cell therapy that could be a one-and-done curative therapy. And I am super excited about that one. But I'm even more jazzed about the type O program that I think I mentioned on the earnings call because that opens up the opportunity to even more patients than the type A program. The IND is cleared, and I'm excited about dosing patients in that Phase I/II study.

Also in Phase III is atumelnant. That is an asset that we -- that came to us by way of the Crinetics acquisition. Atumelnant is a medicine that I see having multibillion-dollar potential and the opportunity to serve 20,000 patients, some number between 15,000 and 20,000 in the U.S., add another 15,000 ex-U.S. for CAH, congenital adrenal hyperplasia as well as a second disease called Cushing's disease. And atumelnant is in Phase III development for CAH, Phase I/II development for Cushing's.

And if I pick something from the very earlier stage pipeline, and this is not in the next 6 months, but I really like the progress that we're making in the NaV1.7 space. As you know, I have a lot of enthusiasm for this opportunity of making a combination NaV1.7/1.8. That one is in late preclinical development. So we have chemical matter, and now it's a matter of going through the standard procedures to bring that potential medicine into the clinic.

Great. Well, I think we're up against time. But thank you so much, Reshma. Really great to see you.

Very nice to see you, Terence, and thank you all.

Okay. Good afternoon, and welcome to the second day of the Cantor Global Healthcare Conference. My name is Carter Gould. I cover large-cap biopharma here at Cantor. I am pleased to welcome Vertex to the stage. Joining us from the company, Susie Lisa and Manisha Pai from the IR squad. Plenty of momentum in the past 12 to 16 months cystic fibrosis leadership has been sort of reaffirmed most recently and tangible progress on the povetacicept front.

From our perspective, the CF and Pove story has been pretty easy to tell, but there's lots going on -- if I like to say, there's lots going on with Pove beyond IgAN. There's lots going on in renal beyond Pove, and there's lots going on in CF beyond renal.

So looking forward to a discussion. I hope we can touch on a whole number of those topics. And I guess maybe to just kick things off, Susie, maybe you had a very high-profile acquisition announced most recently. I think the timing of that raised a lot of questions and would love to kind of just hear why is the right time for you guys to make such a notable high-profile acquisition and really add some diversification efforts.

Great. Thanks, Carter. I appreciate you having us and a great question to start with. And I think as many people know, the Vertex story from an investor standpoint, is more difficult to tell because there isn't a clear therapeutic category, right, or a platform.

Instead, we adhere strictly, very strictly to our R&D strategy, which has the set criteria. And a few of those criteria include things like understanding the human causal biology. Are there validated biomarkers? Is it a specialty market? Are there streamlined pathways in terms of regulatory and clinical development? And we apply those criteria so strictly to any disease area we pursue internally as well as any acquisition we consider externally.

Now something fits in what we call the sandbox disease areas, and it can help accelerate one of our existing programs. We go after it like Entrada and DM1 is a good recent example or if we don't have a presence in a disease area that we've identified and we see an asset that can launch our presence into that space with a differentiated product like an Alpine or like a Crinetics, then we move forward aggressively on it. And I think that we do -- we executed this deal from a position of strength, right? We're expanding our leadership in CF. You're seeing good commercial uptake on CASGEVY and Dravics. We're on target for $500 million plus in revenue from both of those products this year. The renal pipeline, as you mentioned, is really exciting. But this rare specialty endocrinology space where what you measure in Phase II is what you measure in Phase III, right? It feels very derisked to us. And we love the call point. I think a lot of our learnings from our CF commercial expertise can be deployed for Crinetics and that like we did with Alpine, we can hopefully accelerate some of the launch timings or expand the global footprint, et cetera, and bring our expertise.

So when we see something that we identify, we move aggressively to get it before we don't feel like with Aside, if you recall, there were a lot of assets. We were confident in our due diligence and move forward the one that we thought was best-in-class, potentially best-in-class. And with Crinetics, it's the same sort of story.

Okay. So without such a sort of multipolar kind of narrative for Vertex, how do you sort of frame the strategic priorities for the company into the end of the year and into next year?

Yes. So we are excited to be now with the closing Crinetics last week, right? We talk about these disease area pillars. So commercialized in, obviously, CF as well as hematology with CASGEVY and acute pain. Now with Talsonifi's launch underway in acromegaly in rare endocrine diseases. And then we look very much forward to a PDUFA date of November 30 for povetacicept in IgAN. So that will be the first launch in our fifth pillar, if you will, in renal. And with 3 programs behind that, we're excited for that.

So the Pove PDUFA date is a key milestone, November 30. Before that, though, I would say you're likely to get the Phase II proof-of-concept data in essentially a patient population expansion study for Anexapin. And that's the AMPLIFIED Phase II study, which is looking at -- it's a Phase II study of about 50 patients. All patients have 2 APO1 alleles. About half of them have more modest proteinuria than you see in the pivotal study, AMPLITUDE and about half of them have a heavier proteinuria, but type 2 diabetes. And so we see this as separate and above from the AMPITUDE pivotal study. That catalyst technically flies into 2027, but you'll get that interim analysis of the Phase III study in early 2027. And that's about 150,000 patients. This study, separate and above would be an incremental 100,000 patients if you were to see positive results from AMPLIFY.

So we're excited for that. And that is probably the nearest-term catalyst in the Pove IgAN that I mentioned. And Also, we have promised Phase II proof-of-concept data in our myotonic dystrophy type 1 program before the end of the year as well as a look at the first of our NextGen 3.0 CF portfolio of products that's VX-828. So I think those are the key milestones before the end of the year. And then also, we'll complete enrollment in our 2 Phase III studies in diabetic peripheral neuropathy in our chronic pain franchise. Those studies are both 12-week studies, and so you could look at data, say, maybe by mid-2027. And happy then to go into the outlook in type 1 diabetes and some of the other areas that we have, too. But those are the key near-term catalysts as well as continued commercial execution.

I think that teed up most of the rest of the conversation here. But maybe before we jump down any of those sort of -- one thing that we get asked all the time is -- or oftentimes we kind of go down this is really understanding how much the company has really matured over the past sort of 2 to 3 years. And I think for folks sometimes the development on the commercial side has been maybe lost in the mix a bit. So maybe just lay out kind of how that commercial infrastructure has kind of evolved since you guys were solely a CF study story not too many years ago.

Yes. I think that's a really good insight. And I think sometimes investors think -- sometimes we even joke CF sells itself. That's not the case, right? But it is a very efficient model, but I think there are a lot of learnings from CF particularly on the patient support side of things that we can leverage into other areas, like I mentioned. But I think the company has evolved, right, initially with the hiring of the sales force and support structure around CASGEVY, right, with a very long patient journey and a lot of support that's required both at the authorized treatment center level as well as for patients and their families for a functional cure, like truly transformative therapies.

These people are in the hospital 2 or more times a year and now they're not. So hiring the sales force for that completely separate and distinct from CF. And then the learnings going into a mass market like acute pain with 80 million prescriptions, right, initially starting with about 100 sales force reps there, 150, while we were building up the reimbursement and access there. We doubled that sales force earlier this year in the March, April time frame as more reimbursed access came online and have been adding things like marketing initiatives, directed TV content on streaming services. If you search for total knee replacement, have you thought about your pain therapy as well, right? Celebrity spokes people like Jason Tatum and Lindsey Vaughan, right, and educating about the total cost of the opioid crisis, the pain crisis because people are undertreated, et cetera.

So I think a lot of maturation and growth. And what we're excited for is Crinetics comes with its own sales force for the specialty endocrine space. And then in renal, we are ready to go. And this is really the first time where you will see synergies in the sales force, if you will. It's not why we did it, but with 4 programs in renal, IgAN to be the first, we see sort of a great halo effect.

So we were able to, I think, very excited. We were able to hire the vast majority of the reps have prior nephrology experience because I think they're excited about Plovine IgAN as well as the pipeline behind that and their relationships with nephrologists. And so I think this one will be really exciting. We aim to have the largest sales force and greatest share of voice of the novel disease-modifying therapies in that space.

Okay. So since you teed it up, let's talk a little bit about Pove. At this point, we're 2-plus months out from the PDUFA date. How would you sort of frame updates on the FDA interactions and confidence into the PDUFA? You clearly sound pretty confident, but I'll let you refine it.

I think that nothing -- nothing really to disclose, but the Renal division has a good -- has been a really good partner to us, and I think everything remains firmly on track with good visibility for November 30.

Okay. As far as some of the emerging competitor data and I guess, more clarity on sort of the longer-term eGFR trends. How that impacts positively or negatively your view of differentiation for Pove versus some of the earlier movers?

Yes. I think that all things equal, it would be nice to have all your data all the time, but we feel strongly that there is such a good understanding and acceptance of the correlation of UPCR reduction to eGFR stabilization, right?

And then those competitors who have released the data, you have seen that, right? And so we feel that we are truly differentiated in our UPCR reduction with that 52% at 36 weeks, whereas some competitors had an extra month of data, right? So we truly think it's best-in-class in terms of UPCR reduction, best-in-class hematuria resolution of Gd-IgA1 reductions and in getting more patients to KDIGO guidelines to 0.5 grams, right? So we think we have a good story to tell there as well as not just the greatest reduction but the shape of those curves, the speed of the reduction, I think, really matters. And so I think UPCR reduction is a proxy for eGFR stabilization, which in and of itself is a proxy for progression to ESRD, right, and death dialysis and transplant.

So I think we feel very good about that clinical story as well as the safety profile. And then we know that we have a clear advantage in terms of the patient administration characteristics with the only folks with the lowest dose 0.46ml, so it's not painful. It's through an auto-injector, and it's monthly compared to weekly or much higher dose with a prefilled syringe from the competitor.

So with those points in mind, how much should we read through from the competitor launch data, right, you guys are going to launch later this year. Obviously, there's going to be a period as the product's ramping. In the meanwhile, we're going to have sort of incremental updates from the companies, other earlier movers on how their launches are going. Why should we not read through from those launches to the overall market size in the interim?

I think that we have been quite gratified. I'm pleased to see the strong uptake so far. It points to the fact that IgAN patients are -- they're 130-plus thousand of them in the U.S. that are biopsy confirmed with their diagnosis. They're typically younger patients, otherwise healthy in their 40s and have been kind of these ticking time bombs, right, waiting for a therapy.

So I think that certainly the first mover with Otsuka and [indiscernible] will benefit from those -- from being first mover. But even with the strong uptake, we're still talking really small numbers out of that total pie here in the U.S. And so I think that there's still plenty of patients to go after. We'll also be going after switchers in this type of market. I think you will potentially see that and not giving any color on sort of shape of the curve, but we do aim to have winning share over the long term.

Have you guys thought about how you're going to communicate launch metrics in the early kind of quarters and months of the launch? I don't know what you guys have said around communicating or being allowing scripts to be visible or beyond that, how you guys are planning on communicating?

Yes. I think stay tuned and still working through that.

As far as povetacicept beyond IgAN, you're moving into a number of other programs, but there's -- there's been sort of illusions to potentially expanding beyond the initial 4 indications. How should we think about that? And to the extent that, that might be sort of teased out with greater clarity over the course of the balance of the year or into next year?

Yes. So we are currently in the Phase III portion or Phase II/III for primary membrane nephropathy and that there's no accelerated approval pathway there. So that is a 104-week study. But we were -- we chose the -- there was a dose-ranging study. We chose the 80 mg dose to move forward with. So that's ongoing. And then we're also currently not in renal, but in a Phase II in Myasthenia Gravis, that's ongoing as well in Pove and still evaluating the RUBY-4 data in WAHA. And so we do still are very excited about the Pove pipeline and a product potential here and are executing on that as quickly as we can and more to come.

Okay. As far as the MG effort, how should we sort of Think about that trial design, I guess, the rationale for that trial design. Obviously, there's some compelling data out of China. You guys have talked about trying to recapitulate that in a Western population. But this really short-term trial is maybe kind of walk through that and exactly what you guys are trying to show?

Sure. So I think a couple of things. One is that we do view Myasthenia Gravis as kind of the poster child for B-cell-mediated diseases. So that's sort of the cause of biology there. Secondly, we found the China-only data very, very compelling, and that's with a wild-type TACI versus we have this designed engineered TACI for better tissue distribution, et cetera. So we'd hope to be able to perform as well or better. And I think in terms of the duration or the size of the trial, about 30 patients, 12 weeks, we are looking for a meaningful treatment effect, right? And it is a dose-ranging study. And that's really what we're looking to get out of it. And I think that the opportunity here, again, you could say like IgAN a crowded space, but with the FcRns, for example, the need for cycling, et cetera. We don't see that with Pove and so we think it could be a much better option for patients.

Okay. We touched in your opening comments on an axon, and maybe we should pivot there. We're going to get amplified data, as you mentioned before the end of the year. Should we have lower expectations here relative to what you showed with AMPLITUDE? Clearly, your competitor in the space had, let's just say, noisy data. I think sort of validating your decision to kind of approach these populations separately. That certainly looks like the right decision in retrospect. But should we go into this with maybe a different set of expectations than maybe the people went into the original study.

The Phase II.

Yes.

So I thank you for saying it that way. I think we would concur that we do feel sort of validated in our decision of a very homogeneous population for the Phase III pivotal study and focus on those patients with a high [indiscernible]. For the AMPLIFY study, the population expansion study, I think that it is proof of concept, right? There is no control arm as well. But I think that there -- maybe you could characterize it as a clearer through line, if you will, in the more modest proteinuria patients to the AMPLITUDE study just less dynamic range, if you will, in which to operate. And on the type 2 diabetes arm, right, arguably, that's a bit more exploratory, certain good reasons in the literature to believe in the risk factors here in terms of why we think it should succeed. But we know definitively, we are inhibiting APOL1. What we don't know is how much of the impaired kidney function is from the type 2 diabetes and the hyperglycemia versus how much is from the APOL1. So that's what we'll learn in this study. But from very clear distinct populations. And the overriding key factor is that you have two APOL1 variants.

Okay. And as far as in AMPLITUDE. To what extent do you have good clarity on exactly these sort of -- where FDA is going to draw the line, what's the regulatory hurdle for that interim analysis. Clearly in IgAN, we had -- there were a bunch of earlier movers. We kind of had a better sense of what would look like for a lack of a better term. We don't really have that same sort of precedent here. So how should we think about that?

Yes. I think to be clear, right, this study has been ongoing for quite some time, these patients are not diagnosed and waiting, right? So we've been enrolling this study for several years and are really pleased with the market development work we've done and the increase in pace there and are on track to complete full enrollment by the end of this year now. But as a result, it is not a UPCR endpoint, right? And in fact, it's actually UACR. But the primary endpoint -- sorry, for naxiplan and the Phase III interim analysis, it is eGFR slope, right? And so how does it separate from placebo. And I think the closest outcome to really answering your question is that these patients progress in terms of their eGFR decline at almost twice the rate of traditional kidney disease patients.

So I think the combination of -- we saw just 13-week data in the Phase II of 47.6% reduction in UPCR. As well as this faster rate of decline, being able to show that differential in terms of the eGFR slope even at just 48 weeks is where our confidence stems from.

Okay. Maybe let's switch gears to the pain franchise. It's one of the things we commented we remarked upon really sort of all somewhere long has been the strength of ZRavax -- we want to monitor plenty of launches, some of which hit plateaus, some which have down -- up weeks, down weeks, et cetera. But -- the steady growth of ZRavax has been one of the more kind of remarkable dynamics we've seen over the past couple of months.

At this point, what do you think are really sort of the key drivers to really continue to see that growth and really to drive another inflection here, not just this year but into the next couple of years.

Yes. I'll try and give a short answer, but it really is many, many different factors, all of which we are trying to execute as best we can. So I think, first and foremost, is the drug works really well, right? And the physician and patient feedback has been very, very positive.

Secondly is the fact that we have worked very hard on reimbursed access, right, with 260 million covered lives as of early August. As well as working through some of the machinations if you will, of going from sort of signing a contract at the parent plan level to getting things to work at the Street at the patient level. We expanded the field force, as I mentioned, some more feet on the street. We have very purposely gone very broad in terms of the prescriber base because we want to build this for the long term.

So everything from ER and trauma anesthesiologists to OB/GYNs and plastics, dentists, et cetera, orthopods are a big focus as well. And that's another area where you started to see orthopedic surgeons publishing single center series, for instance, a total knee series, showing 80%, 90% opioid-free. So those sorts of studies are being published and presented now. That helps continue the momentum, too.

A lot of marketing initiatives. I mentioned celebrity spokespeople and things like being on the boards at the Stanley Cup, and I understand you may see us in a professional pickleball tour, et cetera. So those types of things continue. But really focus on continuing to execute in terms of reimbursed access, the field force and then focus on prescribers, getting additive formularies, treatment protocols, discharge protocols.

Is this going to be the most complicated launch that we see in Vortex.

I think it is best. So we are very pleased with the script progress. As you mentioned, we're on track to 3x our scripts in '26 versus '25. Even at 1.6 million, though, that compares to 80 million scripts are written, 80 million Americans get a script each year. So I think it is very complex, and it's very different from the other things we do, which is one reason for some of the recent management changes that we recently brought on a new member of our executive committee to focus on.

Sure. So we're very pleased to have a new EVP in Jasper Van Grunson, who'll be focused on the pain franchise in its entirety. As well as on some of our newer products and working closely with Duncan McCagney who's our Chief Commercial Officer.

How should we think about the chronic pain studies at this point. We -- I think there's been sort of ups and downs in terms of where the -- how the Street is viewed or how much value they've kind of ascribed to Vertex I would argue for the past year, there's been very little credit ascribed to chronic pain, maybe rightfully so, maybe not. But you're going to have some readouts soon. So how should we think about that? How should we think about where the bar is for not only approvability but for -- really to derisk the products commercially.

Yes. I think you're right that there is a high degree of street skepticism around pain or maybe it's just caution is maybe a better word. And I think that going back about a year ago, as you said, when we said that our hope for moving into peripheral neuropathic or chronic pain with one diabetic [indiscernible] and one lumbosacral radiculopathy study would hopefully enable a broad peripheral neuropathic pain level an agency and the agency declined.

So we pivoted quickly and began our second DPN study because there is real clarity from a regulatory standpoint to studies in any peripheral neuropathic pain category, and you'll get that indication. And I think DPN is a much better understood type of pain, if you will. There are more centers that have run these types of trials before and well understand how to manage the placebo effect, which really has been the drug works, it's really been managing the placebo effect. So going to a more limited number of sites with significant experience in DPN and in running DPN studies and managing DPN placebo effect is how we decided to execute that. It's 2 studies, one is about 1,100 patients with split 1:1:1 between suzetrogene, placebo and pregabalin arm. And the second one is about 700 patients just versus placebo.

Okay. And how should we think about those -- obviously, you have your combination efforts behind those two, which I think given some of the M&A in the space has certainly stimulated a lot of attention. Should we think about those efforts in any way being stage gated by the outcomes of these chronic pain opportunities. Just trying to get a sense on kind of urgency with the combination of...

We remain very excited about the opportunity and think that combining a 17 and 18 because 17, the sodium ion channel that triggers, right, and then 18 propagates it. Challenging targets to inhibit, which is why we did 18 first. But if you could do both, we think it could be synergistic in terms of the efficacy benefit and so rather than I would say waiting on the DPN results, I would say it's more of potentially waiting for the combo and to see where it might be able to go both in terms of acute and chronic.

Okay. In the past, you talked about potentially needing a partner. If you were going to go into these larger potentially more primary care kind of oriented settings, but a lot of that commentary was a couple of years ago now. And as we kind of talked about already, it's a drastically different company than it was 2 to 3 years ago. Are you still viewing it the same way? Has maybe some of that calculus shifted? Or would it kind of stimulate a broader rethink in the event of positive data?

I think in the event that we decided to pursue musculoskeletal pain over time, that's clearly a primary care market and would be a candidate for partnership. I think we do feel that we have made some pivots and learned some lessons, but still feel like it can be a specialty commercial model in peripheral neuropathic as well as in acute, but I'd say we're always learning and evaluating.

Okay. Maybe we touched on it right at the start, the Crinetics deal added a commercial asset right now in Pulsonify. And of course, the CAH asset, which I still can't pronounce a little bit still to come. Maybe on Pulsonify maybe help us just think about the market opportunity and how Vertex is best positioned to maximize this commercial opportunity?

Sure. And as Susie mentioned at the outset, 1 of the reasons we really like this deal was because of the perfect strategic fit. It is with the Vertex portfolio and with our expertise. So Acromegaly is a rare genetic disease. It's a specialty market, so there are about 3,000 endocrinologists in the U.S. who are treating acromegaly, so a very tractable footprint and we bring all of our expertise in rare disease commercialization and also expanding it to OUS countries as well, where we have a track record of commercialization, securing reimbursement, et cetera.

So we think that we can bring all of that to accelerate the launch and expand it globally.

Okay. And when you think about acumelenant. Its been a lot of practice. You guys -- when you announced the deal, you talked about a multibillion kind of commercial opportunity. I guess the question is what do we need to see on efficacy as well as on safety to really kind of deliver on that. There's been a lot of talk around the liver elevations that we're seeing in an earlier study. You guys sort of made your case and why you maybe it was a little bit overblown or why it's noise or it's surmountable. But would love to hear kind of like an update on how you view that aspect of the profile.

Sure. So what we had said is with the Crinetics acquisition, we see potential for $5 billion in peak sales with Palsonify as a potential blockbuster and Acumelan as a multibillion-dollar asset. So obviously, we see a lot of value on that side of it. It's in Phase III study right now in congenital adrenal hyperplasia. And I know it's a hot topic time lines for enrollment completion data, et cetera. We just closed the transaction. So we're getting our hands around all of that, and we'll have updates later, including updated accounting and financial information on our Q3 call.

But in terms of what we're looking for, so CAH is a disease of impaired cortisol synthesis, which leads to elevated androgens. And so the goal in treating it is you want to normalize the androgen levels sustainably or durably over time, while allowing these patients to taper down their doses of glucocorticoids to physiologic levels, basically. And we think that's a unique proposition that acumelenant can offer. And I'll have to see that borne out by the Phase III data, of course.

On the safety front, yes, there have been questions about that 1 incident of liver enzyme elevation. And I say 1 because I think there were a few, but there was only 1 that could not be ruled out as possibly related to acumelenant and what we saw there was some elevations of ASTs, ALTs that was reversible. There was no elevation in bilirubin, so no cases of Hy's law there. And so once the patient rolled off a study drug because it happened toward the end of the study, they were fine, no clinical consequences, everything went back to normal. And those data were shared with the FDA and other regulatory agencies, and they didn't ask for any changes to monitoring protocols or anything like that.

So based on the Phase II data, we're confident in the safety profile and look forward to seeing the Phase III.

So I have a little bit of a comment, a little bit of a question. Are we going to continue to have everything XCF broken out in some basket of non-CF because next year, you're going to deliver more growth on an absolute basis XCF than NCF. So final question.

Yes, I would say that as we grow and diversify as your initial question started, right, we continue to seek ways to make sure that people can understand the story and the key growth drivers. So even going back last year, right, I think it was still footnotes with the different revenue lines, right? And so we have progressed there and given that basket of guidance, I think -- some of it will be just when they kind of hit critical mass, et cetera.

So stay tuned. I don't have a more definitive answer for you, but we'll try and make it easy to understand.

Perfect. Vertex. Thank you very much for joining us.

Awesome. Last session of the day. Thank you very much for all for joining us today. My name is Mohit Bansal. I'm one of the biotech and pharma analyst here at Wells Fargo. And I have the Vertex IR team with us, Susie Lisa, Head of IR; and Manisha Pai. She's part of the IR team as well. So thank you very much, both of you to join us.

Thanks for having us, Mohit.

I don't have ED, Investor Relations, sorry, I do not have the title -- thank you. So exciting times at Vertex. There's a lot more to talk about, not just CF at this point. So talk a little bit about what you are -- where investors are asking most of the questions and where you're spending most time in terms of talking about the Vertex story at this point?

Sure. So I think it is an exciting time, and we have sort of a catalyst-rich period coming up. So I'd say most of the conversations relate around that. I will say recent news last month, we have been getting a lot of CF questions heading into competitor data that I think ended up being not as much of a concern as many have thought. And so CF questions have gone back more towards commercial aspects, the ALYFTREK, which continues to go very well and then our Next-Gen 3.0 family of therapies that are in the pipeline. But the majority of questions, I think, focus on upcoming catalysts, and that's primarily within our new disease area pillar of renal therapies, namely disease-modifying therapies that are addressing unmet need in the renal area where historically, they've had basically repurposed cardiovascular medicine. So really, we're calling it a renal renaissance in a very exciting time.

The most near-term catalyst will be on our inaxaplin therapy, which is for APOL1-mediated kidney disease. And that's where we said that you should expect in the next couple of months, our Phase II proof-of-concept study for a patient population expansion study called AMPLIFIED, which is looking at patients with 2 APOL1 alleles and then 2 cohorts, one that has more modest level of proteinuria and the other cohort has the 2 APOL1 alleles and type 2 diabetes. So you'll get that proof-of-concept data sometime in the coming months.

The next catalyst that's super exciting will be our November 30 PDUFA date for povetacicept in IgAN. So this will be our first launch -- commercial launch in the renal area. We're very excited for that. We are launch ready. Our sales force is hired. We have very high degrees of nephrology experience in that sales force given the depth of the pipeline, the clinical differentiation of pove, the safety profile and the patient administration benefit. So we're very excited for that. And then the next -- we've got a couple of other data sets before the end of the year, likely one in myotonic dystrophy type 1, which is certainly timely right now. We can go into more detail there.

In our CF therapies, VX-828 is the first of the NextGen 3.0, you could see data before the end of the year. And then we'll complete enrollment in our 2 Phase III diabetic peripheral neuropathy studies, and that's in the chronic pain space. We'll complete enrollment before the end of the year. Those are 12-week studies that would put us on pace for data sometime in the first half of 2027, likely. And then very importantly is you will get the Phase III interim analysis in the first quarter of 2027 on inaxaplin in the sort of primary or pivotal study there of primary AMKD, which is patients with 2 APOL1 alleles and heavy proteinuric burden. And so we're very excited for that. It's been a long time coming and likely would be our second launch in -- commercially in the renal space.

And sorry, I would just add that Crinetics just closed last week, right? And so more to come there in terms of updating guidance, but continue to be encouraged by the PALSONIFY launch in the U.S. and hoping to be able to accelerate launches outside the U.S. and then look forward to atumelnant in CAH and getting -- completing enrollment in that Phase III study. I think those are most of the key catalysts, but it is a lot going on between now and the first half of next year.

Clearly a lot going on basically, and we barely mentioned CF here. Awesome. So let's just talk -- why don't we start with the time like in the chronological order, the catalyst here, right? So inaxaplin in AMKD, but let's just talk about the Phase II portion of the trial. So there is a population expansion study for diabetic patients. And you have characterized this being a little bit more risky than the broader patient population. So talk about that. And then also, I want to touch upon the moderate proteinuria patients because so far, with this molecule, we have only seen data in FSGS patients. So how much does the moderate proteinuria patient data set derisk the eventual trial, at least for the proteinuria endpoint?

Sure. So maybe to start with that group and then go back to diabetes. I think that the data that you have seen was the Phase II portion of the Phase II/III for the pivotal, right? And yes, that was an FSGS population. But what we think, and we have long held this belief is that what is crucial is not the FSGS diagnosis, but the confirmation that you have 2 APOL1 variants, right? You need the genetic test. And FSGS is just a histological confirmation. It's a scarring pattern. But you don't see patients referred for biopsy to confirm that unless they have a very heavy proteinuric burden. So in the Phase III study, it's likely you will see a high percentage of FSGS patients. But if you had FSGS, you were welcome. If you didn't, you were welcome as long as you had 2 APOL1 alleles and a high proteinuric burden.

So I think in the modest proteinuria group here, we think the important thing is inhibition of APOL1. And we have 98% plus inhibition of that, and that's why we have confidence. We still need to see the data. But in this proof of concept in that more moderate proteinuria group, it's not FSGS that we're treating. It's the APOL1 inhibition and hence, our view or our optimism for the data. The one difference, obviously, will be you have less dynamic range because you're starting at a lower point, there's less reduction, if you could, on an absolute basis because you aren't starting at 0.7 or 0.8, right? You're starting at something like 0.3 or lower.

Now to your diabetes question, I think there, too, we're excited for that data. But the question here is we know we're inhibiting APOL1 what we don't know is how much of their kidney function is impaired by their type 2 diabetes as opposed to the APOL1, and we're not treating the type 2 diabetes, right? So that's what we look forward to learning. I think that we are quite pleased with how rigorous we were. It was a real challenge to enroll the interim analysis in the more homogeneous population of the Phase III study, AMPLITUDE. And now we're looking forward to having decent 20-plus patient size cohorts in each of those 2 arms for the AMPLIFIED data in the coming months.

Got it. So you're more -- like do you think the probability is higher for a good data set in the moderate patient followed by the diabetes patients.

I think you could say there's a clearer through line, if you will, and there's more of a question mark on the type 2 diabetes impact upon kidney function. Yes.

Got it. And these trials are -- these cohorts are a gating factor for you to expand the program into those indications.

That's right. We talk about in the AMPLITUDE study, the pivotal study with interim analysis next year that we view that as about 150,000 patients in the U.S. and Europe. And that if you expand the separate cohort here from AMPLIFIED, it's likely adding about 100,000 additional patients to the target population.

Got it. So one question we get, so moving to the AMPLITUDE Phase III trial. So these are so similar that I had to say Phase II and Phase III. So I think the agreement with the FDA was that at 1-year mark based on proteinuria reduction and what -- where do you stand on eGFR, it could be a potential file label data set at that point. So the question we get a lot is that is 1-year time point enough to see good enough improvement on eGFR or like the ranges of outcome could be like you continue the trial or not.

So it is a 48-week endpoint for the interim analysis of the Amplitude Phase III study. And the endpoints there, the accelerated approval endpoint, to be clear, is the change in eGFR from baseline. And then in addition, right, it is the reduction in proteinuria. And I would say that our confidence in this study stems from 2 things. One is that in the Phase II portion of this Phase II/III study, we saw at just 13 weeks, a 47.6% reduction in proteinuria. And that's pretty dramatic, and it continues to decline from there. And so that sort of proteinuria reduction, I think it's reasonable to assume would be associated with stabilization of eGFR, right? And it's -- you have to look at how it's doing versus placebo on top of current standard of care.

The second thing is that we know that AMKD patients, the rate of decline of their eGFR is about 50% faster than typical CKD patients. And so they're losing about 6 or 7 per year versus something more like losing or 4 or so, 3 or 4 for typical CKD patients. So that's why we think that at 48 weeks, we are hopeful that we can show this -- demonstrate this type of result in addition to strong reduction in UPCR.

Got it. And then how should we think about the disclosure there? So FDA wants to see eGFR not in this indication, but I mean, typically in IgAN, they do want to see eGFR data, but you do not necessarily want to disclose it. So like should we expect data on both endpoints or just proteinuria when you...

I think that for the Amplitude inaxaplin study in the interim analysis, that's the endpoint. So we will disclose that 48-week eGFR. And if it's successful, right, then we will continue to enroll the study -- sorry, we hope we're on target to complete enrollment by the end of this year, right? But we will continue to follow patients for the full 2-year endpoint. in IgAN. And I would say that the field may be changing in AMKD, but it's not there yet, and there's still clearly this eGFR endpoint.

In IgAN, in contrast, as you know, the agency has moved to UPCR as an endpoint. And I think there is still debate ongoing about disclosures of 1- or 2-year eGFR. The U.S. FDA clearly will accept 1-year eGFR data. Other global regulators will not, right? There isn't a path to accelerated approval in Europe. And there are more patients in Asia with IgAN than there are in U.S. and Europe combined. So that's some of the work that we're going back to consider in terms of disclosures and timing on pove in IgAN.

Got it. So for pove, FDA is allowing 1 year eGFR at this point. Got it. That's probably the reason some of your competitors are looking at the early data and then just trying to...

I think some who are more focused solely on the domestic opportunity versus we are thinking about the entire global opportunity. Got it. So stay tuned.

Got it. Very helpful. So moving to pove. So ahead of the launch later this year, so I mean, you have -- you are preparing for a broad launch in the -- with a large field force here. Talk a little bit about like you are probably going to -- you are the third one to the market, but you have the best offering in terms of overall profile of the product. Talk a little bit about, is there a low-hanging fruit or KDIGO guidelines updating to like less is better kind of situation. So like -- how should we think about the early adopters and ultimately before your profile kind of broadens the scope for you?

Yes. I think that we've been very happy to see the early launches from competitors and the reactions in the marketplace, right? IgAN patients are typically otherwise very healthy and on the younger side, right, they're -- in their 40s typically and sort of have been these ticking time bombs. But there are 160,000 patients in the U.S. that are biopsy confirmed in terms of their diagnosis. And even with the strong launches that you've seen, we're still talking very small penetration into those 160,000 or so patients.

I think that we are really looking forward to our PDUFA date and launch later this year. Our sales force is in place and ready. I think we're quite pleased to see how many of them have prior nephrology experience given their optimism around the broader renal pipeline that we have. I think the messaging clearly will be on the trifecta, as you mentioned, of better clinical data, clean safety profile and then the patient administration characteristics, which we think are clearly differentiating in terms of once weekly low-volume 0.46 ml -- sorry, once monthly low-volume auto-injector at home. And I think that -- this will be a market where we will -- I think you will see switching and we'll go after switchers and we'll go after de novo patients as well.

I think initially, as the field is moving so fast and you see fairly recent changes to KDIGO guidelines, right, in terms of trying to get patients to that threshold of 0.5 in terms of their proteinuria. I think initially, you probably will see physicians targeting higher proteinuric burden patients, but we would expect to see that coming down over time and a goal to get more and more patients to those guidelines. And KDIGO also, right, recall, instead of previously it was treated serially ACEs, ARBs, SGLT2s, then disease-modifying therapies.

Now I think it is more of a move to do things concurrently and recognizing sort of saving nephrons sooner is better. And so looking to get patients on these disease-modifying therapies. And so between share of voice, the clinical profile, clean safety, the patient administration benefits and then also, we think our expertise in CF with patient programs around getting them on drug, supporting them on drug, helping them with reimbursed access, et cetera, that's important in the chronic therapy as well, and our expertise in CF will serve us well there, too, and that's how we're looking to have winning share.

Very helpful. And we have seen eGFR data for like eGFR for wild-type, then some eGFR data for Vera as well. So how do you internally think about those eGFR data sets? Like they look more robust than anything that we have seen in IgAN so far. So let's say, using [indiscernible] as a benchmark, I mean, do you -- like -- so do you have to be in that ballpark? Like I mean, like is there a number where it looks inferior or superior to existing therapies? Or like how do you think about that?

Yes. I think that there are a couple of ways to look at it. On the one hand, right, stabilization, you could say, is stabilization, right? But we do think that there's potential that, again, sort of back to time is nephron, if you will, you'd rather save more of them sooner. And if you're on a chronic therapy, could a 42% reduction versus something in the 30% reduction in UPCR, does that compound over 10 years. And we think that it potentially will. We also know that we had best-in-class results from our interim analysis in terms of reductions in Gd-IgA1 and resolution of hematuria as well as in getting the percentage of patients to both KDIGO guidelines. So I think all of that is what will help differentiate us understanding that those are strong.

eGFR itself is a proxy for progression to end-stage renal disease and death, dialysis and transplant, right? So I think understanding these other endpoints like proteinuria, hematuria and Gd-IgA1 are proxies for eGFR. There's strong understanding by physicians and even payers there. So I don't think we'll necessarily -- I think we are well positioned to advocate our case, if you will.

Got it. Completely makes sense. The other indication, which doesn't get talked a lot about is myasthenia gravis here. I mean, Vor has shown seen or RemeGen has seen some interesting data in China there. So mechanistically, how BAFF and APRIL could differentiate versus what is out there, FcRns are the front line and then you have complement inhibitors out there. What is the value proposition for BAFF/APRIL inhibitor in myasthenia gravis based on your thoughts?

Yes. I think we view myasthenia gravis as, if you will, sort of the poster child for a B-cell-mediated disease. So being able to inhibit at really 2 points on the maturation cycle, we think, is very compelling. And the data out of China with a wild type, we felt were -- did support that view of myasthenia gravis as being sort of a prime candidate for a B-cell inhibitor. And we think with the design, the engineering that's gone in to TACI in terms of its tissue distribution and penetration, et cetera, that we would be hopeful that we could show even better results in myasthenia gravis.

So we're currently enrolling a Phase II study. It's a 12-week study. We haven't given time lines on that, but that's another catalyst to look forward to probably over the next 12 months or so. And sorry, on FcRns and others, right, I think the key advantage of BAFF/APRIL inhibition is that you -- other therapies, right, you need to cycle on and cycle off, but the autoantibodies continue to develop, right? So with the BAFF/APRIL inhibitor, you wouldn't -- you could have chronic therapy and you wouldn't need to cycle on and cycle off and you could have sustained benefit.

Makes sense. So the Phase II study is actually not that big a study, like 30 patients across placebo, and I think there are 2 treatment arms there. So given the small size here, what exactly are you looking for? Because I think you'll make a go/no-go decision for Phase III based on this. So what exactly are you looking for to make that decision here?

Yes. We haven't given a bogey for that. But we do think...

I have to ask.

Yes, you had to ask, but we do think that the 12-week data on those 30 patients or so will be sufficient given what we hope -- I guess we could hint at the magnitude of the treatment effect, right, that we hope to see that that's enough time and enough patients in order to be able to make a decision.

Fair to assume you'll be looking at biomarkers as well more than not just the MG-ADL and all that.

I think, yes, that's right.

Got it. Very helpful. Moving to the pain franchise, JOURNAVX . I mean, so initially, it was off to a little bit slower launch, and now it seems like you're gaining traction in the last couple of quarters and with the formal placement at hospitals and all that. Talk a little bit about what you are seeing in terms of how P&T committees are actually implementing JOURNAVX and like what are the gating factors at this point for JOURNAVX uptake here?

Yes. I think we've been pleased with the progress in terms of adoption, whether it's by formulary or treatment protocols or care pathways. And there's all different aspects, whether it's inpatient, outpatient ambulatory surgery center, et cetera. And you see different levels of adoption at different facilities ranging from let's have a more measured adoption -- inclusion on our formulary to we've done the work and we're comfortable here, let's open it up broadly. But I think that it's one of the key drivers to the strong prescription growth that we've seen this year, where we remain on track to hit our goal of tripling prescriptions in 2026 versus 2025. But it is one of many factors.

So formulary care pathway treatment protocol adoption, along with improvement in reimbursed access covered lives as well as the doubling of the sales force, our marketing initiatives and celebrity spokespeople like Jayson Tatum. We're also, I think, very encouraged to see of late more and more physician-sponsored studies being published. For instance, orthopedic surgeons, in particular, are publishing their single center series of, say, total knee, and you're seeing really compelling results of 90%-plus type opioid-free results from some of the most painful surgeries out there. So I think that and then presenting it, we are doing more and more in terms of our patient outreach and micro targeting of it direct to -- directed TV advertisements and radio, et cetera. So I think it's the combination of this really sort of all-out approach that is leading to the strong growth in scripts and continued improvement in terms of gross to net. I'm happy to talk about that more, if you'd like as well.

Let's just talk about that because like -- I mean, there was also a portion there part where hospital versus retail split is also slightly more tilted towards hospital versus what you would want to see in long term. That's why the script length is also shorter. So talk a little bit about that as well because we are just using the script and multiplying with whatever number is there, but that's probably not true.

Sure. So we very purposely are thinking about this for the long term and therefore, went after a broad -- and it's a very broad label, right, moderate to severe acute pain. So we went after trying to be as broad as possible in terms of types of prescribers as well as settings of care. And so the market itself for acute pain is about 1/3 in-hospital use and 2/3 at home or retail. Our mix continues to be a bit more 50-50 because we are focused on those in-hospital prescribers who will then take it to their ancillary clinics, et cetera. So trying to build for the long term and focus there.

And I should have mentioned one of the other key drivers of script growth is this breadth of prescribers, where I think we're north of 36,000 prescribers, and it ranges from ER and trauma docs to orthopods to dentists, obviously, plastics, OB/GYN, anesthesiologists, et cetera. So pleased with that. But I think that the average hospital script is something more in kind of the 2- to 5-day range versus a retail script is something in the 14-day range. But I think the real sort of lag, if you will, between the revenue recognition that we had initially hoped to see versus what we now expect is related more towards reimbursed access and some of the delays there and where our patient support program essentially is still being triggered, if you will, at the point of care in retail prescriptions.

So it's like a safety net that kicks in sort of blinded to both the patients and the pharmacist if there isn't reimbursed access, we don't want that patient to walk away or call their physician and say, I couldn't get my drug, right? We're trying to convert entire practices. So the PSP kicks in if you don't have reimbursed access. And what we're finding is sometimes you may have coverage at the parent plan level and it takes time to implement at the child plan level or there may be some minutia or technical aspects of how the script is written for a 14-day quantity limit or a prior auth that is getting in the way sometimes and the PSP is being triggered when it technically shouldn't be. And we're working through those issues and why we expect we'll keep the PSP in place as we work through them and continue to expect to see more revenue recognition.

Got it. So that is more of a '27 story? Or is it...

We talked about a more normalized gross to net in sort of mid-2027, probably something plus/minus 50% range.

Got it. Makes sense. Talk about the DPN trial as well a little bit here. I mean, you had robust data in Phase II. So the drug is active. The question here is placebo responses because a lot of pain trials have been killed because of the placebo response here. So to that extent, how are you managing that part of the control arm of the trial and I mean site training and all those aspects of things.

Yes. So thanks for remembering in the Phase II, right, we had greater than a 2-point improvement in NPRS. And so we know there's activity here. And I think sort of the good news of having to narrow our focus, if you will, in peripheral neuropathic pain is by going to DPN is there's a lot more clinical trial experience, both in terms of CROs and sites and our own and as well as with regulators. So a controlled number of sites significant training in terms of how to manage placebo effect and I think a better understanding of how to characterize the pain, how to work with patients, et cetera. So I think we are optimistic and excited to complete enrollment of those 2 studies by the end of the year, as I mentioned, and then see the data from there. But it is a lot about training and management of placebo effect. And with more experienced sites in this type of pain and a limited number of sites, we hope to be able to address that.

Got it. Very helpful. So last one, last set of questions about the Crinetics deal, right? So the one question we get a lot is that, I mean, you talked about $5 billion peak opportunity there versus at that point, consensus was somewhere around $3 billion for the company there. So in your internal projections, like where do you see the disconnect between like what you projected versus what analysts are projecting for Crinetics at that point?

Yes. So I can talk to you about how we get to that approximate $5 billion number in peak sales, and there are multiple ways to get there. So first, with PALSONIFY, which is approved for acromegaly, we see that as a blockbuster opportunity. The launch is off to a great start, and our goal is to accelerate it to expand outside of the U.S. And then atumelnant in congenital adrenal hyperplasia, we see that as the larger opportunity as a multibillion dollar opportunity. So between those 2, you could get to $5 billion. And atumelnant is also being studied in Cushing's disease, which could provide additional upside on top of that. So that's how we think about it.

And $5 billion doesn't include the early-stage assets at all at this point?

That's right.

Right. Okay. Got it. That's all upside. Awesome. So -- and then you will disclose the financial impact once you close -- like now you have closed the deal. So next quarter, we should expect the updated...

That's right.

Very helpful. So last question for both of you. Wells Fargo Healthcare Conference 2027. I hope you are here. I hope I'm here. So we are sitting here next year same time. By the way, dates are same 8 to 10 September next calendar.

Calendar.

So what would make you look back at the year and say it was a great year for us?

I think that it will be -- we look forward to saying we have a diversified commercial revenue picture with established disease area pillars across 5 areas, right? CF, hematology, acute pain or pain, broadly speaking, the specialty rare endocrinology with the Crinetics acquisition and then in renal. And potentially September '27, getting close to a second launch potentially in renal at that point in time and hopefully sitting on top of good DPN data in pain, a strong pove launch at that point in time, continued strength in the CF outlook, continued progress in CASGEVY in terms of number of patients and their essentially functional cure and the amazing outcomes there and then continue to push their earlier pipeline, right, whether that's in DM1 or in ADPKD or in other areas.

But I think it's those 5 established pillars, 3 of which are commercialized today. And with the Crinetics closing, we've got the fourth, but expanding that and then bringing along -- we didn't even mention type 1 diabetes, right? But then also, I think, hopefully getting close to a second -- a successful first launch in renal and getting close to a second potentially.

Anything to add?

That was pretty comprehensive. I'm not sure I have anything of value to add on top.

Thank you very much. On that high note, I really appreciate you coming here and all the best.

Good day, and welcome to the Vertex Pharmaceuticals Second Quarter 2026 Earnings Call. [Operator Instructions] Please note this event is being recorded.

I would now like to turn the conference over to Ms. Susie Lisa. Please go ahead.

Good evening, all. My name is Susie Lisa, and as the Senior Vice President of Investor Relations, it is my pleasure to welcome you to our Second Quarter 2026 Financial Results Conference Call. On tonight's call, making prepared remarks, we have Dr. Reshma Kewalramani, Vertex's CEO and President; Charlie Wagner, Chief Operating Officer and Chief Financial Officer; and Duncan McKechnie, Chief Commercial Officer. We recommend that you access the webcast slides as you listen to this call. The call is being recorded, and a replay will be available on our website.

We will make forward-looking statements on this call that are subject to the risks and uncertainties discussed in detail in today's press release and in our filings with the Securities and Exchange Commission. These statements, including, without limitation, those regarding Vertex's marketed medicines for cystic fibrosis, sickle cell disease, beta-thalassemia and moderate-to-severe acute pain, our pipeline, proposed acquisition of Crinetics Pharmaceuticals and the expected benefits of that transaction and Vertex's future financial performance, are based on management's current assumptions. Actual outcomes and events could differ materially. I would also note that select financial results and guidance that we will review on the call this evening are presented on a non-GAAP basis.

I'll now turn the call over to Reshma.

Thanks, Susie. Good evening all, and thank you for joining us on the call today. Vertex's second quarter performance was excellent, with strong momentum in the commercial portfolio, rapid progress across our R&D pipeline, and the announcement of the definitive agreement to acquire Crinetics Pharmaceuticals, which brings rare endocrine diseases as a fifth pillar to Vertex. Second quarter total revenue grew 12% year-on-year, driven by the strength of our cystic fibrosis portfolio and the growing contributions from our newer products, Casey and dynamics.

As I've previously highlighted, this is a year of execution for Vertex across commercial, clinical and regulatory. And on each of those fronts, we advanced significantly in the second quarter. Commercially, we delivered strong revenue growth across all diseases, made meaningful progress in reimbursed access and continue to execute on near-term launch planning to drive the next phase of growth.

Clinically, we continue to make significant progress in advancing our pipeline, including completing enrollment in the GLO Phase II study of VX-407 in ADPKD, tracking to complete enrollment in the AMPLITUDE Phase III study in AMKD by the end of this year and reporting results from the interim analysis cohort of amplitude in the beginning of 2027. We also remain on track to release results later this year from a proof-of-concept study in DM1 and an expanded population for AMKD in the AMPLIFY trial as well as the initial patient data from VX-828 in CF.

On the regulatory front, the BLA for Pove and IgAN was accepted in the U.S. with a November 30 PDUFA date. We achieved expanded labeling in record time for CASGEVY in patients ages 2 to 11 in the U.S. And I'm very pleased to share that as we continue to dose the Phase I/II/III study of zomilacell in type 1 diabetes, the IND was cleared for the blood type O islet cells in our T1D program, VX-017. We expect initiation of the VX-017 Phase I/II study in the near term.

Finally, with the announced acquisition of Crinetics Pharmaceuticals, we look forward to multiple benefits of the deal, establishing a fifth pillar in rare endocrine diseases adding to our innovative R&D pipeline, accelerating revenue growth and enhancing long-term earnings. Tonight, I'll limit my R&D comments to new news in CF, renal and type 1 diabetes and close with some additional remarks regarding the Crinetics acquisition.

Let me start with CF, where we continue to extend our market leadership. Data we presented at ECFS reinforced that a lift trek best restores CFTR function amongst the available CFTR modulators. In particular, among children with CF under 12 years of age, the majority across all eligible genotypes achieve a sweat chloride less than 30 millimoles, which is the median among CF carriers. This is remarkable because at these sweat chloride levels, CF carriers do not exhibit manifestations of disease. In addition, we have initiated global regulatory submissions for ALYFTREK in children, ages 2 to 5. Global regulatory submissions for TRIKAFTA in patients ages 1 to 2 are also in progress.

Turning to our next wave in CF and VX-828, our next-generation 3.0 CFTR modulator recently completed dosing in the patient cohort and data are expected in the second half of this year. Behind VX-828, we continue to advance additional correctors in the NextGen 3.0 family and both VX-581 and VX-272 are in healthy volunteer studies. Let me close on CF with this. Our ultimate goal has been consistent for 2-plus decades to bring patients to carrier levels of sweat chloride.

Frankly, ALYFTREK's remarkable results, where nearly 2/3 of younger patients achieved sweat chloride levels less than 30 millimole per liter and for patients ages 12 plus more than 75% achieved sweat chloride levels within the carrier range of CFTR function means we are very close to that goal. Given the improvements in sweat chloride, PPFEV1 pulmonary exacerbations, hospitalizations, lung transplant and survival that we have seen in patients in clinical trials and/or the real world, we recognize that the unmet need is far lower today and the bar for any medicine to beat a lift truck is very, very high.

Thus, as we develop our next Gen 3.0 and BEYOND programs, we will evaluate multiple regimens in Phase I and cohorts of patients with CF. However, we will only advance assets into Phase II and beyond that show promise to beat ALYFTREK. In other words, to bring even more patients to sweat chloride levels less than 30 across all genotypes with once-daily dosing and excellent drug-like properties, including drug-drug interactions, anything less would not be competitive.

Moving now to our renal franchise, where we have 4 programs in mid- and late-stage development, povetacicept in IgAN in primary membranous nephropathy and axiplin in APOL1-mediated kidney disease NVX-407 in ADPKD, or autosomal dominant polycystic kidney disease. Let me start with the most advanced program and significant milestone. In late May, the FDA accepted our BLA for Pove and IgAN and assigned a PDUFA date of November 30 of this year. As a reminder, the RAINIER Phase III interim analysis was a home run, delivering statistically significant and clinically meaningful results across the primary and all secondary end wines with a favorable safety profile and consistency in the primary endpoint of change from baseline in proteinuria across all groups.

We are in the final stages of launch readiness. Duncan will provide more details regarding our approach and excitement to go to market with Pove's differentiated profile of potentially best-in-class efficacy, a well-tolerated safety profile and patient-centric administration through small volume once-monthly dosing VN autoinjector at home. We are also advancing Pove internationally. We have completed the regulatory submission for accelerated approval of Pove in IgAN in Saudi Arabia, where Pove has received breakthrough designation and -- turning to POV in membranous nephropathy, our OLYMPUS Phase II/III pivotal trial is well underway.

The Phase II portion is complete and the Phase III portion initiated next quarter. I'm pleased to share that the IDMC has completed its review and selected the Phase III dose, 80 milligrams subcutaneously every 4 weeks. We hold fast track, orphan drug designation and EMA PRIME designations for Pove in Membrana. Stepping briefly outside of renal, on Pove in myasthenia gravis. I'm also pleased to share that the 30 patient Phase II proof-of-concept study is on track to complete enrollment by the end of this year.

Recall this study evaluates 80 milligrams and 240-milligram doses of Pove versus placebo for 12 weeks.

Turning now to inaxaplin in AMKD. On AMPLITUDE, our pivotal Phase II/III study in AMKD, we completed enrollment of the interim analysis cohort in September of last year. and are on track to complete full enrollment by the end of this year. The interim analysis will be conducted following 48 weeks of treatment, and we remain on track to share these IA results in early 2027. If positive, we would be positioned to file for potential accelerated approval in the U.S. thereafter. Amplified is our Phase Ib basket study of inaxaplin in AMKD patients with either lower proteinuria or AMKD patients with diabetes, expanded patient populations not studied in amplitude. The AMPLIFIED study has completed enrollment and dosing and we expect to share results this fall.

Lastly, in the renal portfolio is VX-407 in ADPKD, or autosomal dominant polycystic kidney disease. Our GLOW Phase II study has completed enrollment. This is a proof-of-concept study with up to 52 weeks of treatment. We are excited about the potential for VX-407 in ADPKD and look forward to sharing more information as dosing continues and the data matures. Let me now touch on type 1 diabetes. We had very constructive meetings with the FDA following our voluntary pause in order to conduct a manufacturing analysis of absumylacell. As we shared on our Q1 call, we have resumed dosing patients in the Zimi Phase I/II/III study.

The new news today is that the FDA has cleared the IND for VX-017, our typo or universal donor cell product. VX-017 has a similar target product profile to zimislecel, but is designed for people of all blood types and we expect the VX-017 Phase I/II study to initiate in the near term. by designing and bringing to market VX-017, another allogeneic off-the-shelf, glucose responsive insulin producing fully differentiated islet cell therapy, in this case, for any blood type, we anticipate doubling our market opportunity from about 60,000 to about 120,000 patients.

A silver lining to the pause we took in the zimislecel Type A program is that the type 0 program time differential versus the mile cell has shortened. Type O is making rapid progress. And thus, we are considering options to further streamline our regulatory strategy and commercialization approach. We expect to provide updated T1D plans, including time lines later this year. We also continue to progress our serial innovation work focused on improved immunosuppression and hyperimmune programs to make our potentially one-and-done curative therapy available to even more patients with type 1 diabetes.

Let me close with a few words on our announced acquisition of Crinetics Pharmaceuticals, which we detailed in a separate call last month. Crinetics is an excellent strategic fit for Vertex with its focus on serious endocrine diseases, high unmet need, validated targets and well-understood causal biology as well as a strong people and culture fit we believe the 2 lead assets, Palonify and Acumelnent together represent a peak sales opportunity of about $5 billion. Both are small molecules that address serious diseases for patients treated by a concentrated group of specialized endocrinologists, this fits directly within Vertex's proven efficient specialty commercial model.

We enter this transaction from a position of strength. We view CF as a long-duration franchise with sustained growth. We continue to expect both CASGEVY and JOURNAVX to be multibillion-dollar assets. and we anticipate our emerging renal franchise could one day rival CF in revenue. In addition, we have a broad and deep pipeline in earlier stages of development, the Crinetics acquisition will add to this innovation pipeline and enhance our revenue growth and long-term earnings profile by adding a fifth commercial pillar in rare endocrine diseases. The transaction is expected to close in the third quarter, and we really look forward to welcoming the talent Crinectics team to Vertex.

With that, I'll turn the call over to Duncan for a commercial update.

Thanks very much, Reshma. Our commercial story this quarter is one of building momentum across each of our franchises, supported by the appropriate investments to drive growth. We are very excited for the close of the Crinetics acquisition and for Vertex to establish a new pillar in specialty endocrine diseases like acromegaly, CAH and Cushing's syndrome. Crinetics Q2 results were excellent, with strong growth in Palsonify revenue and patients treated, but I will hold any further comments until after the deal closes.

So tonight, let me start with CF. CF continues to perform very well. Global CF revenue grew 11% year-over-year in the second quarter with balanced growth across the U.S. and internationally and continued strength from both ALYFTREK and TRIKAFTA. ALYFTREK performance has been excellent and crossed another significant milestone, exceeding $1 billion in revenue in the first half of 2026. In the U.S., we continue to see patients initiating ALYFTREK who are new to therapy, returning to therapy and patients switching from TRIKAFTA.

The majority of ALYFTREK revenue continues to come from these TRIKAFTA switch patients, which reflects the benefits of ALYFTREK and our success establishing ALYFTREK as the new standard of care. We're pleased with the pace at which physicians and patients are embracing ALYFTREK given its improved sweat chloride profile and once daily dosing. We've seen accelerated uptake of ALYFTREK from the recent approvals in rare mutations as well as patients rolling off our open-label extension studies.

Outside the U.S., the ALYFTREK European launches remain very strong with no requirement for augmented liver monitoring in the EU, we are seeing rapid uptake by patients in Europe, transitioning from TRIKAFTA or one of our other CFTR modulators. In fact, in Germany and the U.K., more than 1 in 3 eligible CF patients are now benefiting from ALYFTREK. Globally, the CF growth drivers for the remainder of 2026 are clear: continued a ALYFTREK uptake, the label expansion into rare mutations, younger patients and additional geographies.

Shifting to heme and CASGEVY, where the momentum continues to build. During the second quarter, we delivered $76 million in CASGEVY revenue, reflecting approximately 75% sequential growth versus quarter 1, 2026 and over 150% year-over-year growth. This was in line with our expectations based on our visibility into patient scheduling patterns. The strength of the CASGEVY franchise continues to build new data on CASGEVY at EHA with simultaneous publication in the New England Journal of Medicine demonstrated its transformative potential in pediatric patients as well as durable benefits, reinforcing the importance of early intervention to prevent the complications of sickle cell disease and beta thalassemia in children.

Stemming from this compelling data last month, save became CASGEVY and only gene therapy FDA approved to treat children as young as 2 years old in both sickle cell disease and beta thalassemia. CASGEVY received supplemental approval in the U.S. in a record 53 days post filing, and our first pediatric patient has already initiated therapy and conducted cell collection. Outside the U.S., CASGEVY regulatory submissions in the 5 to 11 age group are now complete in Saudi Arabia and the United Kingdom.

On the reimbursement front, we are seeing strong trends in initiations in Germany after reaching a historic reimbursement agreement there as well as continued strong uptake in the U.K., Italy and the Middle East the negotiations of sustainable access agreements. The CASGEVY story continues to be one of an increasingly robust pipeline of patients initiating the treatment journey. There were more CASGEVY infusions in the first half of 2026 than in all of 2025. Second quarter 2026 was also the third sequential quarter with more than 100 patient initiations, which enhances our visibility to continued growth for the rest of this year and early 2027 as patients continue to move through cell collection, editing and infusion.

Quarter-to-quarter variability in CASGEVY revenue will continue and reflects the timing of patient infusions as people choose to receive their infusions when it best suits them. As we look forward, we expect continued CASGEVY momentum with the pipeline of patients at every stage continuing to build. CASGEVY is well positioned to contribute meaningfully to our $500 million non-CF revenue goal this year and to achieve its stand-alone multibillion dollar potential.

Turning to genetics in moderate-to-severe acute pain, where our launch continues to gain traction. In the second quarter, JOURNAVX generated $50 million in revenue, reflecting sequential revenue growth of approximately 70% and sequential prescription growth of approximately 45% versus quarter 1, 2026. Unpacking Q2 performance, revenue was positively impacted by channel build after we've seen a drawdown in quarter 1. At this stage in an acute product launch, we continue to expect some quarterly volatility in inventory build and drawdown as full line wholesalers and retail channel buying patterns normalize to reflect formulary adoption, physician awareness and seasonality in elective surgeries.

We are building a pain franchise for the long term and are focused on the following 4 critical markets of success: prescription growth, breadth and depth of prescribers, the addition of JOURNAVX to hospital and IDN pathways and broad payer coverage. These are the building blocks of a sustainable, long-term, multibillion-dollar business. We are extremely pleased with the prescription growth we continue to build, which is ahead of our forecast for 2026. The breadth and depth of prescriptions across a wide range of settings of care as well as the clinical impact of JOURNAVX continue to be very strong and all go well for the long-term growth of JOURNAVX in acute pain.

The consequence of this rapid prescription growth is that we are seeing greater use of the PSP program than we forecast as securing unrestricted payer access and physician education catches up with prescription growth. Let me break down what I mean by that. At this point, we have a total of 260 million lives covered out of a total possible of approximately 320 million. Of the 260 million covered lives, 180 million of them have unrestricted coverage. This means that there are 60 million lives yet to be covered and about 80 million lives who have coverage, but with some form of restriction, making some of them eligible for the PSP program.

These restrictions are usually very minor in nature, such as a 14-day quantity limit or a prior authorization to indication. As we continue to educate physicians and their office staff about the quantity limits and prior authorizations, we expect the PSP to be triggered less frequently and therefore, more revenue to be recognized. Let me now provide you with some more details on prescriptions, prescribers and access before concluding our thinking on the PSP program and gross to net.

In terms of prescriptions, quarter 2, 2026 JOURNAVX prescriptions totaled approximately 535,000 and just over 900,000 for the first half of 2026.The prescriptions continue to be split roughly 50-50 between the hospital and retail channels. In both channels, monthly prescriptions were approximately 50,000 in January and doubled to approximately 100,000 in each channel in June. In terms of prescribers, we added approximately 18,000 new HCP prescribers to JOURNAVX in Q2 26 and are pleased that JOURNAVX is now on 1,400 hospital and 130 IDN pathways in terms of formulary, protocol or order sets.

These are important metrics as we seek to convert practices and continue to embed the use of JOURNAVX among our target physicians. We've also made further progress with respect to AX. We recently signed agreements to expand reimbursed access to JOURNAVX with 2 additional Medicare Part D plans, effective from July 1. With these additions, 3 of the big 4 Medicare Part D plans now provide covered access alongside the 3 large commercial PBMs.

As mentioned, this brings the total covered lives for JOURNAVX to approximately 260 million out of a total possible of 320 million and within that, approximately 180 million lives with unrestricted access. Our goal continues to be to ensure the prescribing experience for physicians and patients is as seamless as possible in a market where the delivery of the medicine is highly time-sensitive.

We will continue to work to educate physicians to navigate the minimal quantity limits and prior authorizations that exist and secure ever broader coverage. In the meantime, we will maintain the PSP program so that patients who are prescribed JOURNAVX can get it. We continue to see this as a strategic choice as we seek to convert physician practices away from decades of reliance on opioids and to ongoing and sustained use of JOURNAVX for many years to come.

As a result, we continue to expect gross to net to normalize in line with other branded oral medicines, but now in the first half of 2027. To conclude on pain, we also continue to be on track to exceed our goal of more than tripling the 550,000 prescriptions and more than tripling revenue from 2025 into 2026 as well as delivering more than $500 million in revenue from CASGEVY and JOURNAVX combined in 2026.

Let me conclude with an update on our commercial readiness in renal and specifically Pove and IgAN. WIth the FDA's acceptance of our BLA and the November 30 PDUFA date, we are in the final stages of commercial launch preparation. We're investing in our renal franchise and the nephrology community for the long term, given our innovative pipeline of multiple potentially transformative kidney disease medications that address the underlying causes of serious renal conditions.

Our goal is for Pove to be physicians first choice among disease-modifying therapies for IgAN and we know from our market research and from nephrologist feedback that physicians are looking for treatments that meaningfully and rapidly reduce proteinuria have a favorable tolerability profile and offer a seamless treatment experience from access through patient support to convenient dosing. We believe Pove has the winning trifecta of efficacy, tolerability and ease of use for patients and physicians alike. With dual BAF April inhibition, Pove has clear best-in-class potential and delivers effectively on all the needs we've heard from the community in research and advisory boards making it the ideal first choice after baseline therapy with ACE arbs and SGLT2s.

We have completed the hiring of our renal field force of whom about 90% have nephrology experience and was built with the breadth of our renal pipeline in mind. We anticipate that we will have the largest field force among the novel April or April Bath therapies for IgAN our payer conversations are also proceeding well. In the U.S., approximately 70% of patients with IgAN have commercial coverage from our engagements with payers, their awareness of IgAN and the new BA April inhibitors is high. pay us understand the unmet need, have a good understanding of the KDIGO guidelines and how the new therapies fit into treatment pathways.

Payers are also very aware of the strength of the Pove Phase III interim analysis data and November 30 PDUFA date. Our market access teams continue to actively engage with payers to prepare for the upcoming launch of Pove. Additionally, we will provide robust patient support programs drawing on our decades of experience in CF. Pove and IgAN is the first component of our emerging renal franchise, and we're excited to bring it to nephrologists and to their patients. we believe Pove's trifecta of efficacy, tolerability and ease of use delivers exactly what nephrologists are seeking.

And just as we've done for over a decade in CF, though the success will be driven by a field force delivering a high science cell fueled by a potentially best-in-class product, broad reimbursement and robust high-quality patient programs. We are very excited to commercialize Pove and IgAN and begin building a multibillion-dollar renal franchise at Vertex.

I'll now turn the call over to Charlie to review the financials.

Thanks, Duncan. As Reshma noted, Vertex's second quarter results demonstrate our consistent strong performance and attractive growth profile. Second quarter 2026 total revenue of $3.3 billion increased 12% year-over-year with growth balanced between the U.S. and international markets. As expected, Q2 2026 revenue growth reflects an approximate 170 basis point benefit from foreign exchange rates. Q2 '26 Global CF revenue grew 11% year-over-year, and new disease areas also contributed with CASGEVY delivering $76 million compared to $30 million in Q2 of 2025 and JOURNAVX revenue of $50 million compared to $12 million in Q2 of 2025.

As a reminder, Q2 25 results also included $21 million of collaboration revenue. Q2 '26 U.S. CF revenue grew 9% year-over-year, led by strong volume growth from ALYFTREK uptake, continued performance from TRIKAFTA and higher realized net price. Outside the U.S., CF revenue grew 12% year-over-year, driven by strong ALYFTREK launches timing of orders in certain geographies as well as the benefit from FX.

Note that global CF revenue growth for the first half of 2026 was 8%, including the benefit of prior year U.S. price increases and foreign exchange. We expect both of these factors to contribute less to growth in the second half of the year. Our second quarter 2026 gross margin was 85.6%, and expected sequential step down from Q1 of '26. This step down reflects the impact of product mix as well as manufacturing network investments in various products. As our new products, particularly CASGEVY, increase in revenue contribution with higher cost of goods sold than our small molecule CF products, we continue to expect full year gross margin of just under 86%, roughly in line with this quarter's result. The impact from product mix and manufacturing network investment costs will be more pronounced in the second half than they were in the first half of 2026.

Turning to operating expenses. We continue to invest appropriately given the attractive opportunity presented by our ongoing and near-term launches as well as our attractive mid- and late-stage pipeline. Second quarter non-GAAP R&D expense of $889 million increased 1% year-over-year with steady progress across multiple Phase III studies and the earlier stage pipeline. Non-GAAP SG&A expense of $520 million increased 45% year-over-year, driven primarily by commercial investment split roughly evenly between pain and renal.

We also recorded $21 million in acquired IP R&D expense in the quarter. Note that while R&D continues to account for nearly 2/3 of our operating expenses, the modest growth rate reflects that we are in a period where we can redeploy dollars from programs that wind down to fund programs that are new or scaling up. In contrast, much of our commercial spending is to build new businesses and thus is incremental, as reflected in the higher year-over-year growth rates when compared to R&D spending.

Our second quarter 2026 non-GAAP effective tax rate was 21.1%, including some onetime expenses. Year-to-date, our non-GAAP effective tax rate was 20.4%, within our guidance range of 19.5% to 20.5%. Our second quarter 2026 non-GAAP earnings per share of $4.73 represents 5% growth versus prior year, reflecting strong revenue growth as well as investments in our pipeline and commercial capabilities.

Turning to the balance sheet. We ended the quarter with approximately $13.6 billion in cash and investments. During the second quarter, we deployed approximately $455 million to repurchase roughly 1 million shares. This activity reflects our ongoing commitment to returning value to shareholders while maintaining the flexibility to act on strategic growth opportunities. Of course, a top priority for capital deployment remains investing in innovation as evidenced by our recent announcement to acquire Crinectics for approximately $8.8 billion net of cash acquired.

Now turning to guidance. Given our strong first half performance and the momentum across the business, we are raising our full year 2026 total revenue guidance to a range of $13.1 billion to $13.2 billion, 2026 revenue guidance reflects continued strong performance from the CF franchise, including ALYFTREK and TRIKAFTA as well as growing year-over-year contributions from CASGEVY and JOURNAVX. We continue to expect revenue of $500 million or greater from our non-CF products, and our outlook also continues to include an expected 150 basis point benefit from foreign exchange net our hedging program.

As I previously mentioned, we continue to expect full year gross margin of just under 86%. On operating expenses, we are reiterating our combined non-GAAP operating expense guidance of $5.65 billion to $5.75 billion, though we now expect to be at the high end of that range. This reflects continued investment in our late-stage clinical pipeline and the commercial infrastructure and activities that support our new launches and revenue diversification. We continue to expect our non-GAAP effective tax rate to be in the range of 19.5% to 20.5% for the full year 2026.

I would note that today's guidance does not yet reflect the pending Crinetics acquisition, which is expected to close in the third quarter. Given the anticipated timing, we expect the packed 2026 revenue and non-GAAP operating expenses to be relatively modest, and we will provide updated guidance for 2026 around the time of closing. As a reminder, we like to fund the transaction through a combination of cash on hand and proceeds from a $4.5 billion term loan, and we expect the transaction to become accretive to non-GAAP operating income in 2029.

In summary, Vertex delivered strong second quarter results. Our commercial launches and diversification are gaining momentum, and we continue to invest with discipline in innovation and commercialization. Over our financial performance and outlook remain compelling, with expanding CF leadership, human pain scaling, renal on the doorstep of launch and the addition of a fifth pillar in specialty endocrine through the pending Crinetics acquisition, Vertex is exceptionally well positioned for continued growth. our high success rate in R&D and our disciplined specialty commercial model allow us to maintain industry-leading margins even as we step up investments to support our launches and pipeline.

With this unique profile, we are well positioned to continue expanding our impact for patients, investors and all stakeholders. We look forward to updating you on our continued progress across multiple disease areas with key upcoming milestones detailed on Slide 19.

I'll now ask Susie to begin the Q&A period.

[Operator Instructions] And our first question for today will come from Salveen Richter with Goldman Sachs.

Two for me. One is you announced that the Phase II/III OLYMPUS study for Pove in PM is going to move to Phase II with an 80-milligram dose every 4 weeks. Can you frame what signal this was based on and whether you're the DSMB or what you are the DSMB saw on the Phase IIb portion to move forward? And then on the pain front, it was really nice to see the progress here. Maybe help us understand where the bottlenecks lie now or what needs to be worked on with regard to formulary as well as the payer dynamics as you look at co-pay, et cetera.

Sure thing, Alvin. Let me kick us off with the first question, which is about Polvinmembranas. The Phase II is complete, the Phase III was already initiated, you might recall, a couple of months ago as we designed it as a seamless Phase II/III. The DSMB was asked to base their decision and it was their decision because we do not have access to the unblinded data to look at on efficacy PLA2R, which is the biomarker equivalent in membranous as GDI A1 is to IgAN.

Of course, they had full access to the safety results as they made their decision. I suppose in many ways, it's not surprising that they pick the 80-milligram dose given the Ruby III results. where you could see that the 80 milligrams had a very nice reduction in PLA2R, but that's how the decision was made, studies well on its Phase III portion, and we look forward to getting that study enrolled and completed. Duncan, I'm going to turn it over to you for a little commentary on JOURNAVX scripts and what more we're working on.

So as you know, our goal with JOURNAVX is to fundamentally transform how pain is treated and to move physician practices away from decades of reliance on opioids. In terms of our progress, we're very pleased with the prescription numbers that we're seeing, also very pleased with the increased number of hospitals that have adopted genetics, now 1,400 or so with 130 IDNs, having it on formularies and we have also now secured 2 additional Medicare Part D plans to cover genetics starting from July 1.

So overall, our progress is very well and going very well. And I would add that those prescriptions are coming from a broad range of physician types and being used in a broad range of pain types consistent with our label. In terms of the payer side and access, we're very pleased with the coverage that we've secured to date, 200 -- 260 million lives, and that's ahead of those 2 Medicare Part D plans coming in.

And I would say we have obviously more work to do to secure the final elements of access for generics. And we also have to make sure that those patients whose physicians might have, say, a quantity limit are able to navigate that in order to ensure the patient can secure access. In the meantime, we have the PSP program in place and anticipate that we'll continue to see prescriptions transition to increasing growth in revenue in the second half of 2026.

And indeed, as we've communicated before that our gross to net will ultimately normalize at the same level as our oral branded medicines in the pharmaceutical arena. So we're very happy with the progress. We have a little bit more work to do, but we are very happy with where we're at right now in terms of physician adoption, payer coverage and hospital usage.

The next question will come from Jeff Meacham with Citibank.

Have 2 quick ones. The first one is CF on A2A or the other assets in Phase I, what are some of the clinical attributes you're looking for? I wasn't sure if you're looking for perhaps a not only better treatment effect or if there is a potential to not need liver monitoring, for example, in future combos.

Second question on JOURNAVX. You guys have had substantial discussions with payers, hospital systems, physicians on acute pain. But in these conversations, have you gotten any perspectives or context on DNA like what the clinical profile needs to show as we look to the data end of the year, beginning of next year, what the access and reimbursement could look like is setting?

Sure thing, Jeff. Let me take the second question first. On your Namics, we have been hyper-focused on dynamics and acute pain to make sure that we get all of those reimbursement contracts done and get access. So I think it would be just very fair to say, we've spent all of our time to be focused on acute pain. We'll have more to say on where we are with DPN, the data, what payers are looking for, what doctors are looking for, et cetera, in the coming months. But for here and now, it's acute pain.

On VX-828 and the next-gen molecule, so just to give you all of the numbers, VX-828 is the first of the next Next-gen. The second and third are 581, VX-581 and VX-272. We are looking for potential improvement in efficacy, i.e., more people who can get down to less than 30 millimoles. And of course, we're looking for safety as well. So the monitoring will depend on what the results in the clinical trial are. So sure, there's opportunity for monitoring to be different with this 828 program.

It just depends on what the actual results are through the clinical trial program. Last thing to say, once daily dosing, really good-looking DDIs as well as other drug-like properties remain really important as I mentioned in my prepared remarks.

SP1 The next question will come from Jessica Fye with JPMorgan.

Maybe for Reshma. I'm curious if you expect to see material differentiation on eGFR across the new IgAN products like Posy and its competitors? And if so, over what time horizon do you think any differentiation on that endpoint would become apparent?

Sure thing, Jess. As we've discussed before, in IgAN in particular, but you could say this for homogeneous pregeneric kidney diseases in general. Good reductions in proteinuria should, based on everything we know result in stabilization of GFR. I expect that to be the case with April BAF inhibitors as well. I think so that your question is asking a very important second point. And to me, the most important point. What is the differentiation we can expect between various molecules if you have more reduction in proteinuria or hematuria or in the case of IgA nephropathy, GDIGA on, these insighting antibodies.

And I think for that, the answer is it's really about time to ESRD. That's to say time to dialysis, transplantation or death. And I do expect that the medicine that has the stronger reductions in proteinuria the medicine that gets more patients to less than 0.5 or 0.3 better improvements in hematuria and GDIgA1 are more likely to have an improved profile when it comes to that ultimate endpoint.

Proteinuria, 1-year GFR, 2-year GFR, these are all endpoints on the way to the ultimate endpoint. And I think that's where you'll see the real differentiation.

Your next question will come from Cory Kasimov with Evercore ISI.

Wanted to ask about inaxaplin in the AMPLITUDE study? And what kind of data would be necessary in that interim analysis to file for accelerated approval? Basically, like what constitutes the win with this first data look .

Sure thing. Cory, I think you're asking about AMPLITUDE. So the core study that's now in Phase III in patients with 2 APOL1 alleles, moderate-to-heavy proteinuria and depressed GFR. We were really pleased and remain very pleased that the agency has provided and we have an agreement with the agency for a potential accelerated approval based on the primary endpoint at the time of the IA, which is 1 year GFR. So that's what our agreement is based on. Obviously, we're also going to look at the proteinuria, but the agreement with the agency for the potential to file for accelerated approval based on the interim analysis is 1-year GFR. .

Next question will come from Brian Abrahams with RBC Capital Markets.

Congrats on the quarter. On pain, we've seen some data published recently from another NAV 18. And I'm just curious how you see the acute pain dynamics playing out with additional entrants into the market potentially? And then secondarily, just on Zimi. Just wondering if you could talk about the potential impact to launch timing if you do end up sinking the filing with 017 .

Yes. Thanks for the kind words, Brian. Maybe I'll do the pain one first and then come on to type 1 diabetes. I did see the publication. And maybe, Brian, what I'd say is that Ever since Vertex published VX-150, which you'll remember was the molecule circa 2017 or so. We saw a spike in others following our footsteps and pursuing NAV 18 as a target. And what I'll say is that we decided not to advance 150, VX-150 because we didn't think it had, as I described at the time, the perfect drug-like molecule properties that we were looking for and we bypassed 150 in favor of what is now susetrigene or VX-548.

So we know the space very well. We know the molecule well, and we know that every time we publish a patent, there is a slew of followers. Maybe if you say, well, what's the takeaway from that, I think that there is a high appetite in the biopharma industry to make nonopioids. There is high unmet need for non-opioid effective pain medicines that have not only the right efficacy, but the right safety tolerability, drug-like properties profile. And I really like where we are well on the market with Gernavics, and I'm very much looking forward to the possibility of NAV1718 combination. And I've never felt better in Vertex history for the fact that may come to pass for us to be able to bring that to the clinic.

Switching then to the type 1 diabetes program. So let me just say what I said in my prepared remarks. I may have gotten a little quick there. The zimislecel program is in Phase I, II, III, back up in dosing. And because it's a type A program, it serves about 60,000 people in the U.S. and Europe. The 017 program because type O has the potential to serve 120,000 people because it's the universal donor type out.

And now what we're trying to do is see if we can't get the type O program to go even faster and bring that program out either first or very close behind. That's what we're working on in terms of both the regulatory approach and the commercial approach. I don't have a time line for you today, but we should be able to tell you our exact plans with time lines in the back half of this year. But I am very excited about the opportunity to perhaps bring type O out first or very, very close behind.

Your next question will come from Evan Seigerman with BMO .

From the progress, so you've maintained the expectation for at least $500 million of non-CF revenue this year, while CASGEVY and JOURNAVX delivered roughly $125 million this quarter. So as you think about the path to this target, should we expect that the majority of the upside comes from accelerating patient starts with CASGEVY, continued growth with JOURNAVX or kind of a relatively balanced contribution from both franchises.

Evan, I'll ask Charlie, if he wants to make any additional comments on our guidance on the $500 million.

Yes, Evan, thanks. As you pointed out, so far in the first half of the year, CASGEVY and JOURNAVX combined delivered about $200 million in revenue. So we're well on our way to achieving our target of $500 million plus in that first half. CASGEVY has been a bigger contributor than JOURNAVX, but I'm not willing to give further color on the balance of the year other than to say we're very confident in getting to that $500 million less. .

The next question will come from Michael Yee with UBS.

For the question. I guess the IgAN competitor data to your EGFR data is hot off the press, and it's out there on the tape, and you can see that the approved product has essentially a stabilization of EGFR, if not baseline. So to what extent Reshma that you have an approval coming up June should we think about comparing the 2, either from a launch perspective or perhaps given the strong numbers that they're putting up, it speaks to the significant market opportunity and you look can get equivalent share. Maybe just talk a little bit about the data that the competitor is putting up and how you think about your launch?

Sure thing. Mike, the -- I did just see the eGFR data, but I've just seen the top line number. And as you say, it shows a stabilization right around 0. That is what we should expect given the proteinuria reduction. So that seems very much in line. With regard to what it means for the povetacicept IgAN program, I would say all the more reason if anybody needed a little bit more conviction, you can certainly look at these data that were presented today, look at the proteinuria reduction, look at the GFR and we confirm for yourself that significant reductions in proteinuria should and have resulted in GFR stabilization.

So it makes a lot of sense to me. For what I see for PO I see us putting up very strong numbers on proteinuria, numerically, the best out there, 52% change from baseline in terms of proteinuria reduction, 70-plus percent reductions in hematuria and 70-plus percent reductions in GDIG1. That bodes very well for Pove. And then I'll emphasize, Mike, the patient centric attributes of delivery once monthly small volume, 0.46 via an auto-injector. And I think when you put all of that together, real excitement for me for what Pove bring to patients once the PDUFA date comes and goes, and we have the opportunity to launch.

The next question will come from Tazeen Ahmad with Bank of America.

Are you still planning on presenting additional data from the Rainier study this year? And if so, what level of data? And where could that be? And then secondly, for Pove and GMG, it's becoming an increasingly competitive space. So how are you thinking about what additional benefit your drug could provide into this space either with efficacy, safety or dosing frequency?

Yes, on RAINIER. We are planning to present data. The conferences don't like it when we suggest the name when submissions have been made, but acceptances haven't come through yet. So maybe I'll just leave it at, yes, we plan to present the full RAINIER A data set. We're looking forward to do so. I'll say at a fall conference, and I'll leave it to your imagination for which one.

On GMG and Pove, this one is really exciting. And you gave me 3 options for why we're excited about Pove and GMG efficacy, safety or patient benefits administration all 3. This is another one of those trifectas that Duncan has talked about on efficacy. There is another molecule, a wild-type take, so not engineered for optimal potency, binding affinity or tissue distribution. That has already shown substantial efficacy benefit.

And remember, that's a wild-type tacky compared to Pub, which is an engineered take. So that's on efficacy. On safety, Pove does not need to have a cycle on and a cycle off. That gives real benefit on safety, but that also has the secondary benefit on efficacy because you don't have that off period where the autoantibodies are allowed to return. And the third is same thing, auto-injector. We have to figure out whether it's the 80 or 240, but in either case, it will be auto-injector, once-monthly at-home low-volume dosing. So of your options, I expect Pove to be better across the board on all 3 dimensions.

The next question will come from Phil Nadu with TD Cowen.

There's a lot of focus on the upcoming data from one of your competitors where we're going to get incremental sweat chloride reductions above TRIKAFTA we're curious to hear Vertex's depending on how you're going to interpret that data? Is there a level of sweat chloride reduction that would get your attention or Reshma as you've suggested in the prepared remarks, is it more about simply the proportion of patients who get to less than 30 millimoles per liter and the exact reduction maybe isn't as meaningful because it can be influenced by things like baseline characteristics?

Yes. Phil, I think you have it right on our perspective. Where we sit today with Ally, a lift track. We already know we can get 2/3 of patients to less than 30. That's that normal or carrier threshold. And furthermore, if you think about as all physiologic parameters do, there is a calcium distribution around that median sweat chloride 30. If you superimpose across all age groups, the lift data on the carrier data, more than 75% of people across age groups overlap that distribution.

So with those kind of data, I think that the bar is exceptionally high. and rests on getting more patients to less than 30%. That is the mark and that's the mark that we or anyone else has to hit in order to have a competitive medicine. And of course, it goes out saying it has to be safe, it has to be well tolerated. That has to have good DDIs, it has to be once daily. But on pure efficacy, it has to be a molecule that gets more patients to less than 30 in terms of sweat chloride.

The next question will come from Terence Flynn with Morgan Stanley.

Another ONE on inaxaplin. I was just wondering if you can help set expectations for the upcoming AMPLIFY Phase II trial? And then how to think about any read-through to AMPLITUDE?

Yes. So AMPLIFY is the study that's Phase II. It's the expanded AM KD population -- by that, I mean, it's the population with 2 APOL1 alleles. And in one arm of the basket study, it's 2APL,-1 alleles diabetes and in the other arm, it's 2 APOL1 alleles, and let's call it, modest proteinuria, so low-grade proteinuria. The way I would frame it up is the study is completed. We are on track for us to be able to share results this fall.

And what I'd be looking for and looking to understand is and we derive benefit on proteinuria when you have very modest pitineria to start with. So this is 0.2 to point grams of protein as opposed to 0.7 grams and above. And of course, it all comes down to what the mean and try baseline level of protein is. Or in the case of diabetes, can we alter the proteinuria when you have second kidney disease involved.

These are questions worth studying, but there are clearly different populations than amplitude, which is why we specifically did not include them in the Phase II original study of axle and equally why we didn't include them in the Phase III study called Amplitude. So we're super excited to look at these results. We're going to learn a lot and I'm very, very, very happy, and I think you'll see the wisdom of our approach, given what has happened in the field for others to keep these populations, which are expanded populations separate and look at each one individually in this basket amplified study.

The next question will come from Mohit Bansal with Wells Fargo.

Just maybe a question for Duncan, if you want you want to help with the prescription trends here for JOURNAVX, so obviously, prescription growth is very strong. But how should we think about the prescribing behavior in terms of how many days of therapy physicians are writing? Has it changed at all in last few quarters or so because it does seem like you have good access, you have good prescription, but probably this is probably a missing piece, which could improve here.

It's to answer your question specifically, as I think we've communicated before, in hospitals, the prescription duration is around about 5 days or so. in retail, it's around about 12, 14 days. So on average, you net out at around about 10 or 11 days or so for each generic prescription. And candidly, that dynamic has not changed since the launch because it's really driven by the dynamics of the institution that the patients in rather than anything else. So to answer your question simply, those are the numbers, and it has not changed over the last few months.

The last question will come from Eli Merrill with Barclays.

So in terms of the DM1 program, what would be good data at the data update in the second half? And how are you thinking about it in the context of the broader competitive landscape in DM1?

Sure, ElI. Maybe I can take that one. In DM1, as you know, there hasn't been a clear correlation between the various endpoints that others in the field have looked at, albeit with different approaches. What people have tended to do in their Phase II studies to get an early read is look at splicing, a functional endpoint called vHOT and another functional endpoint called QMT. We had to sort of how long does it take to open close your hand and QMT is a measure of muscle function.

And what I would say is that of all of those, splicing is an important one, and we certainly are looking at splicing and these measures of muscle function are also something that we're looking at. The reason I like this approach compared to anything else has more to do with mechanism of action. And that has to do with the fact that it's an oligo, which others are also trying but it's an oligo linked to a circular peptide to a nuclear localizing domain peptide which we believe will allow it to get into the cell and get into the nucleus where it has to do its work.

So that is a plus. And I would also say some of the other programs in order to get into the cell have used mechanisms that have some safety tolerability concerns, and that has not been occurred through the circular peptide program that we use. So therefore, the efficacy endpoints in Phase II splicing, and we will also look at these QMT and vHOT endpoints, albeit in small numbers of patients.

And that will conclude our question-and-answer session as well as our conference call for today. Thank you for your participation. A replay will be available shortly after the call concludes by dialing 1 (855) 669-9658 or 1 (412) 317-0088 using replay access code 10208186 and thank you for attending today's presentation. You may now disconnect.

Good day, and welcome to the Vertex Pharmaceuticals Conference Call to announce the acquisition of Crinetics Pharmaceuticals. [Operator Instructions] Please note this event is being recorded.

I would now like to turn the conference over to Ms. Susie Lisa. Please go ahead.

Thanks, Chuck. Good afternoon, everyone, and thank you for joining us on short notice for this exciting announcement. I'm Susie Lisa, and as Senior Vice President of Investor Relations, it's my pleasure to welcome you to this conference call to discuss Vertex's acquisition of Crinetics Pharmaceuticals. Making prepared remarks on today's call, we have Dr. Reshma Kewalramani, Vertex's CEO and President; Duncan McKechnie, Chief Commercial Officer; and Charlie Wagner, Chief Operating and Financial Officer. We recommend that you access the webcast slides as you listen to this call. The call is being recorded, and a replay will be available on our website.

We will make forward-looking statements on this call that are subject to the risks and uncertainties discussed in detail in today's press release and in our filings with the Securities and Exchange Commission. These statements, including, without limitation, those regarding Vertex's marketed medicines for cystic fibrosis, sickle cell disease, beta thalassemia and acute pain, the proposed acquisition of Crinetics and the expected benefits of the transaction. The commercial potential of PALSONIFY and the clinical potential of Atumelnant and Crinetics other pipeline assets, the expected timing of closing and associated financing and Vertex's future financial performance are based on management's current assumptions. Actual outcomes and events could differ materially.

I would also note that select financial guidance we discussed this evening is presented on a non-GAAP basis. Please consult our forward-looking statement on Slide 2 and see our filings for more information.

I'll now turn the call over to Reshma.

Thank you, Susie, and good afternoon, everyone. We are excited to announce that we've entered into a definitive agreement to acquire Crinetics Pharmaceuticals for $85 per share in cash in a transaction with a total equity value of about $10 billion or $8.8 billion net of estimated cash acquired. Crinetics is an excellent strategic fit for Vertex with its focus on serious diseases in specialty markets with significant unmet need, well-understood causal human biology and potentially best-in-class medicines that could deliver transformative benefit to patients.

Crinetics has 2 compelling derisked potential best-in-class specialty endocrine assets, PALSONIFY in the early days of its U.S. commercial launch and Atumelnant in pivotal development for congenital adrenal hyperplasia, or CAH, and in Phase II for Cushing's syndrome. There are additional preclinical and clinical programs in the Crinetics pipeline that we won't highlight today, but we will discuss post closing. We believe that these assets have a combined peak sales potential of more than $5 billion.

PALSONIFY is the first and only once-daily oral therapy for adults with acromegaly. PALSONIFY is already FDA approved and generating strong early momentum in the U.S. post an October 2025 launch. More recently, it was approved by the EMA. We see blockbuster potential for Atumelnant. Atumelnant is a once-daily oral ACTH receptor antagonist currently in Phase III development for CAH. Atumelnant has additional potential in ACTH-dependent Cushing's syndrome, another rare endocrinology disease. It is currently in Phase II development for this indication. Across the indications for Atumelnant, we see multibillion-dollar potential. Given the significant unmet medical need in acromegaly, CAH and Cushing's along with the best-in-class potential of both PALSONIFY and Atumelnant for the treatment of these conditions, we see the Crinetics acquisition accelerating Vertex's revenue growth and diversification as well as enhancing our long-term earnings profile.

We are truly excited by what the Crinetics team has built in the endocrinology space over the last 18 years. Their world-class R&D capabilities are focused on their [ G-protein ] coupled receptor drug discovery platform and differentiated small molecules. Crinetics has uniquely and successfully discovered and/or developed multiple small molecule drug candidates for rare endocrine diseases where the natural ligand is a peptide. This is a capital-efficient model, focused in rare endocrine conditions with high unmet need, where achievement of proof of concept benefits from evaluation of disease markers early in development and reaches patients via targeted SG&A footprint, all of which is strongly aligned with Vertex's strategy and our own strengths in development, regulatory and specialty commercialization.

As we've discussed previously, it's not only the assets, but the people and culture that factor heavily into our assessment of companies. It's no different in this instance. The Crinetics team focus is singular. Their science is rigorous. They are committed to world-class commercialization and their culture is dedicated to excellence and patients. We value deeply this alignment on these important dimensions and believe it will ensure our combined success going forward. We are excited to work with the talented Crinetics team to build on the momentum they've created and to bring these specialty endocrine medicines to more people faster.

On strategic fit, we have a high bar when we evaluate acquisition opportunities, applying a consistent set of criteria that you can see detailed here on Slide 5. Serious diseases with high unmet need, well-understood causal human biology, validated biomarkers that enable efficient clinical and regulatory pathways, specialty markets and first-in-class or potentially best-in-class medicines. Both PALSONIFY and Atumelnant meet every one of these criteria and check every one of these boxes. We believe Vertex's global infrastructure and commercial footprint will meaningfully amplify the reach of Crinetics science, and we are confident that we can accelerate the trajectory of both lead assets.

Let me walk you through these programs in more detail, starting with PALSONIFY and Acromegaly. Acromegaly is a rare chronic hormonal disease caused by the overproduction of growth hormone, most commonly due to a benign pituitary tumor, which in turn stimulates excess insulin-like growth factor 1 or IGF-1 from the liver, which is responsible for most of the overgrowth symptoms that define Acromegaly. An estimated 20,000 people in the United States are diagnosed with the disease and more than 35,000 people outside the U.S. It's a serious disease. If left untreated patients with Acromegaly [indiscernible] enlargement of the hands and feet, serious heart and metabolic consequences, reduced quality of life and shortened lifespan.

Surgery is a first line of treatment, but unfortunately, only 40% to 50% of people achieve durable remission and thus, the majority of patients require lifelong medical therapy. The current standard of care injectable somatostatin receptor ligands or SRLs are used to reduce production of growth hormone and IGF-1. However, current standard of care SRLs are viscous, require large gauge injectables that must be administered intramuscularly or via deep subcutaneous injection. They're inconvenient, often need to be administered by a health care professional and carry low patient compliance.

Outside of PALSONIFY, oral options have limited efficacy, challenging dosing logistics or are not indicated for treatment-naive patients. In short, there is significant unmet need to be addressed. This is where PALSONIFY comes in. PALSONIFY is an oral selective somatostatin receptor type 2 or SSTR2 non-peptide agonist. By binding to SSTR2 receptors, PALSONIFY suppresses growth hormone release, which in turn suppresses IGF-1 secretion. PALSONIFY offers multiple important features for patients, first and only once-daily oral therapy, simpler dosing logistics, fast-acting efficacy, a well-tolerated profile with low discontinuation rates and a broad label indicated for both SRL switch and treatment-naive patients.

The Phase III PALSONIFY data are compelling and detailed on Slide 8. PATHFNDR-1 on the left side of this slide enrolled patients switching from injectable SRLs. 83% of these "switch patients" treated with PALSONIFY maintained IGF-1 levels within the normal range compared to just 4% on placebo. Indeed, when you look further into the data, you'll see all but 1 patient in the PALSONIFY treated arm had IGF-1 levels that were lower than 1.1x the upper limit of normal.

On the right-hand side of the slide is PATHFNDER-2, which enrolled treatment-naive patients as well as patients who stopped treatment for 4 months or more or patients who were washed out of treatment for at least 3 months. In this study, 56% of Acromegaly treated naive patients achieved IGF-1 normalization compared to just 5% on placebo. Both results were highly statistically significant with p-values of less than 0.0001. PALSONIFY was well tolerated with no serious adverse events and low discontinuation rates. Given the differentiated mechanism of action, benefit risk profile and significant patient dosing advantages as well as the broad label, we see blockbuster potential for PALSONIFY, which I'll now ask Duncan to highlight.

Thanks, Reshma. The left side of the chart details the unmet need and significant gaps in the current standard of care. At 3 years, less than 20% of patients remain on SRLs given the painful monthly injections with large gauge needles and end-of-dose symptom breakthrough. The right-hand side of the slide highlights the market research that indicates high target physician awareness and very positive perception for PALSONIFY. Physician awareness is building quickly. Market research conducted in quarter 1, 2026 shows approximately 80% unaided awareness amongst endocrinologists and approximately 70% indicated a high intention to prescribe. Physicians perceive PALSONIFYas equivalent to injectable SRLs in IGF-1 reduction, symptom control, safety and best-in-class for speed of onset, duration of response, route of administration and dosing convenience.

This physician awareness, the broad label in both switch and treatment-naive patients and the quality of the product profile are a compelling combination. In the context of the depth of unmet need in Acromegaly, this has led to strong early launch dynamics for PALSONIFY. Based on quarter 1, 2026 data, as previously disclosed on May 7, PALSONIFY generated $10.3 million in net product revenue with strong patient enrollment forms and good breadth of prescribers. Overall, in just its second quarter of launch, PALSONIFY achieved an impressive 40% to 50% share of new-to-brand prescriptions with broad uptake across both pituitary centers and community endocrinologists and across all patient segments, injectable SRL switch, treatment-naive, switch patients from other therapies and patients who have discontinued therapy entirely.

With respect to reimbursement, this market is 60% private pay and the remainder Medicare and Medicaid. The Crinetics team have made excellent progress securing reimbursement. Payer coverage currently stands at 60% through either formal coverage or medical exceptions. Crinetics have emphasized that they are on track to achieve 75% coverage by quarter 3 2026.

And on the next slide, let me double-click and give some more details on PALSONIFY. Overall, given the unique attributes PALSONIFY offers to physicians and patients, we believe it is positioned to become first-line therapy in a growing specialty disease area with a high unmet need. We see multiple target patient populations totaling 10,000 in the U.S., including patients on injectable SRLs or other therapies, those who are post surgery, actively managed by an endocrinologist who may now need treatment, those who have discontinued therapy and those patients who are new to treatment annually.

While switch patients represent the majority of the patient opportunity, PALSONIFY has a uniquely broad label and is the only oral therapy with data and the label in treatment-naive patients. Market research confirms that HCPs would start the majority of treatment-naive patients on PALSONIFY. We believe Vertex's experience in commercializing medicines for rare genetic diseases around the globe, combined with the extremely strong foundation Crinetics has built in endocrinology, positions PALSONIFY to become the standard of care in Acromegaly, and our expectation is that PALSONIFY holds the promise to be a blockbuster medicine.

Back to you, Reshma.

Thanks, Duncan. Let me now turn to Atumelnant and Congenital Adrenal Hyperplasia or CAH. Classic CAH is a rare chronic genetic disorder affecting about 17,000 people in the U.S. with an additional 15,000 or more outside the U.S. In about 95% of cases, it's caused by mutations in the [ CYP21A2 ] gene, resulting in a deficiency of adrenal enzyme 21 hydroxylase. That enzyme deficiency means people can't produce adequate cortisol. Low cortisol levels lead to increases in ACTH production, which in turn causes steroid precursor buildup. Ultimately, this leads to excess production of adrenal androgens.

To manage the disease at minimum, patients must take glucocorticoids for life. Glucocorticoids are administered to these patients to replace the missing cortisol and patients are often given high or super physiologic doses in order to suppress the androgen production. This creates a dual burden for patients. High androgen levels drive abnormal growth, early puberty, infertility and long-term physical and emotional consequences. High-dose glucocorticoids can cause heart disease, obesity, diabetes, bone loss and persistent quality of life issues. There has been limited therapeutic innovation in this field for the last 50-plus years. No currently approved medicine can both normalize androgens and allow people to be maintained on physiologic glucocorticoid doses.

A recent market entrant works upstream in the pituitary gland and has shown it can reduce glucocorticoid doses modestly, but it does not concurrently improve androgens with physiologic glucocorticoid dosing, leaving both the steroid burden and androgen excess incompletely addressed for many people. Atumelnant takes a fundamentally different approach. This is the key point. It's an ACTH receptor antagonist that acts directly at the adrenal cortex. By blocking ACTH signaling at the adrenal level, Atumelnant suppresses excess androgen production while concurrently enabling people to reduce their glucocorticoid doses to physiologic levels, the true goal of CAH management.

In terms of program status, Atumelnant is currently enrolling its Phase III [ CALM ] CAH study of 150 adults. [ CALM ] CAH is a 2:1 randomized placebo-controlled study with a primary endpoint of proportion of participants with A4, that's the androgen level at or below the upper limit of normal, while on physiologic glucocorticoid replacement therapy at week 32. To be clear, no other drug for CAH has ever evaluated this control of androgens and maintenance of physiologic GC replacement, glucocorticoid replacement as the primary endpoint. The study enrolled its first patient in December of last year and is currently enrolling and dosing patients. So is a Phase II/III pediatric study in CAH. Atumelnant has also demonstrated therapeutic potential in ACTH-dependent Cushing's syndrome, where our Phase II trial has initiated.

I'll turn it back over to Duncan to recap the Phase II Atumelnant data in CAH, which is a major value driver and one of the primary reasons we are so excited about this acquisition.

Thanks, Reshma. As Reshma alluded to, the true goal of therapy in CAH is to normalize androgen levels and simultaneously enable patients to be managed with physiologic levels of glucocorticoids to replace their missing cortisol. Currently, this means seeking an almost impossible balance between androgen suppression and glucocorticoid treatment to avoid adrenal crisis while also preventing the metabolic and cardiovascular consequences of excess glucocorticoids. Essentially, physicians and their patients are currently forced to choose between androgen excess or [ supraphysiologic ] doses of glucocorticoids.

As a result, there are 2 important points to share regarding the Phase II data from the [ Atumelnant-2CAN ] study. firstly, the impact of Atumelnant on androgen levels; and secondly, the impact of Atumelnant on glucocorticoid dose. To that end, the Phase II Cohort 4 data demonstrated both rapid reduction in A4 and down titration to physiologic levels of glucocorticoids. Specifically, there was an unprecedented 67% reduction from baseline in mean A4 androgen levels even with tapering of glucocorticoid dosing. 87% of patients achieved physiologic glucocorticoid dosing while A4 reduction was maintained.

In summary, we believe Atumelnant achieves the previously unattainable holy grail of CAH management. It has the transformative potential to concurrently and durably normalize androgen levels while also allowing physiologic doses of glucocorticoids as well as being well tolerated and given through once-daily oral dosing. In addition, market research with target endocrinologists confirms high awareness of these impressive Phase II data and the top reason physicians select Atumelnant's profile in research is efficacy. Specifically, 75% of respondents cite the data on [ angroostamdion ] and glucocorticoid reduction. Physicians see Atumelnant as the future standard of care for people with classic CAH. We believe Atumelnant has multibillion-dollar potential in the CAH market alone and meaningful additional opportunity in Cushing's syndrome.

Before I turn it back over to Reshma to cover Cushing's, let me take one moment to step back and summarize the commercial opportunity. Going back to the strategic fit of the deal, these rare endocrine diseases are all managed by specialty endocrinologists that can be reached with a small commercial footprint. As an example, Crinetics currently serves the Acromegaly market with a roughly 40-person field sales team. In total, there are approximately 8,000 endocrinologists in the U.S., and each of these diseases is managed by a subset of approximately 3,000 to 4,000 specialty endocrinologists, where we also see opportunity for synergy across these rare endocrine diseases.

I'll now turn the call back to Reshma to describe the additional opportunity for Atumelnant in Cushing's syndrome.

There are several additional areas of opportunity within the Crinetics pipeline, both clinically and preclinically. Tonight, I'll highlight just one, ACTH-dependent Cushing's syndrome or ADCS. ADCS is another serious rare endocrine disease with high unmet need affecting about 10,000 patients in the U.S. and about 50,000 patients outside the U.S. Surgery is first-line therapy, but many patients will require chronic medical management. Excess cortisol secretion from a benign pituitary adenoma accounts for 80% to 90% of ADCS, while another 10% to 20% comes from atopic ACTH secretion. This prolonged excess cortisol can lead to high patient morbidity, including heart disease, obesity, diabetes and more.

By directly blocking ACTH signaling, Atumelnant reduces cortisol production and thus holds transformative potential for this disease. The data in Cushing's syndrome are impressive. The Phase I/II study of Atumelnant in patients with ADCS treated at 40 milligrams showed at day 10, a rapid lowering of urine-free cortisol, or UFC, with 3 of 6 patients having UFC within the normal range, while on physiologic doses of glucocorticoids. Data from the 80-milligram cohort also demonstrated rapid lowering of UFC with 5 of 6 patients or 83% achieving normalization of urine free cortisol on physiologic doses of glucocorticoids.

With regard to program status, the Phase II study has been initiated, and we are excited about taking this program into development into pivotal development and further. Post closing, we look forward to sharing more on the other Crinetics pipeline programs. For now, let me reiterate our excitement for the lead assets, PALSONIFY and Atumelnant, our admiration for the Crinetics team's deep scientific expertise in endocrinology, GPCR biology and their drug discovery platform as well as the culture they have built.

I'll now turn over the call to Charlie for highlights of the transaction and our outlook for the combined companies.

Thank you, Reshma. Vertex will acquire all outstanding shares of Crinetics common stock for $85 per share in cash. The total equity value is approximately $10 billion or $8.8 billion net of estimated cash acquired. To finance the transaction, Vertex expects to use a combination of cash on hand and debt, supported by $4.5 billion of fully committed bridge financing. The transaction is subject to customary closing conditions, including approval by Crinetics shareholders and receipt of regulatory approvals. We currently anticipate closing in the third quarter of 2026.

In terms of financial impact, this transaction is consistent with Vertex's capital allocation priorities, which remain focused on internal and external innovation in disease areas where we can deliver transformative benefit to people and sustainable value for shareholders. The financial case is straightforward and compelling. PALSONIFY is already generating revenue and building momentum with the potential to be a blockbuster drug in acromegaly. Atumelnant has the potential to be a multibillion-dollar opportunity in CAH with meaningful additional upside from the market opportunity in Cushing's syndrome.

At peak, these assets have the potential to deliver more than $5 billion in combined annual revenue. That revenue profile furthers Vertex's goal of sustained double-digit revenue growth and is expected to be margin accretive over time. Oral small molecules in specialty endocrinology markets carry attractive commercial profiles and Crinetics' capital-efficient development model is well aligned with Vertex's own approach to operating leverage. The transaction is expected to become accretive to non-GAAP operating income in 2029. On guidance, given the anticipated June 3, 2026 closing, the impact to 2026 revenue and non-GAAP operating expenses is expected to be modest. We will provide updated 2026 guidance at the time of closing.

I'll take a minute now to frame what this acquisition means for Vertex's long-term growth story. Beginning in 2023, we've spoken about our goal of 5 launches in 5 years. With this transaction, not only do we reach that goal more than 2 years ahead of schedule, we're also adding a fifth pillar, endocrinology to our disease area and commercial framework alongside cystic fibrosis, heme, acute pain and our emerging renal area. Across each of those 5 areas, we have a uniquely attractive product portfolio and pipeline. In CF, ALYFTREK and TRIKAFTA continue to generate strong revenue with growth driven by approvals in younger patients, geographic expansion and patients living longer. In heme, CASGEVY is approved for both sickle cell disease and transfusion-dependent beta thalassemia. And importantly, just last week, CASGEVY received supplemental approval in the U.S. for patients ages 2 years and older with either SCD or TDT.

In acute pain, JOURNAVX is in year 2 of its launch and on track to triple prescriptions in 2026 versus 2025. Additional pain programs are in development. In renal, [ povetacicept ] is advancing rapidly in IgAN with a November 30 PDUFA date and is also in a Phase III study in primary membranous nephropathy and a Phase II study in myasthenia gravis. To this mix, we now add endocrinology as a fifth pillar with PALSONIFY already on the market and Atumelnant in pivotal development plus the Vertex internal endo assets of our type 1 diabetes programs. We also see value in Crinetics' additional pipeline assets, and we'll discuss that post close. We believe this combination makes Vertex a stronger, more diversified company with a long runway of growth while staying true to the strategy that's driven our success.

To reiterate the investment thesis behind the acquisition, Crinetics is an excellent strategic fit for Vertex. Both PALSONIFY and Atumelnant mil meet every element of our strategic acquisition criteria, serious diseases with high unmet need, well-understood causal biology, validated biomarkers, specialty markets and best-in-class potential. Together, these assets add more than $5 billion in combined peak sales potential, and they do so in a disease area, specialty endocrinology, where Crinetics has built deep, durable expertise and exactly fits our commercialization framework. We're excited about this combination, and we look forward to sharing more details as we progress toward closing and beyond.

With that, we're happy to take your questions.

And our first question for today will come from Jessica Fye with JPMorgan.

Curious on the $5 billion peak projection for PALSONIFY and Atumelnant. How do you break that out between the assets? And does it factor in carcinoid for PALSONIFY 2? And then related to Atumelnant specifically, how much diligence were you able to conduct on the clinical profile? Did you see any safety data from ongoing trials?

Jess, it's Reshma. Let me take those 2 questions. I'll take the second one first. We were able to do the kind of diligence you would expect from Vertex. And everything we've seen, including efficacy, safety makes us feel really good about what Atumelnant could do for patients, not only in CAH, but in ACTH-mediated Cushing's syndrome as well.

On the $5 billion, one of the reasons we like this deal so much is that there are many paths to the $5 billion in revenue that we outlined. Maybe the most visible and straightforward path is just focusing on the 2 lead assets. We see PALSONIFY in acromegaly as a blockbuster medicine. And then we have multibillion-dollar potential for Atumelnant in CAH and then add on to that really significant opportunity in ACTH-mediated Cushing's syndrome. You add that all up, and that's the $5 billion revenue we outlined. But there are many other pathways. As you mentioned, there's a program in Phase III in carcinoid based on mechanism of action, I have every reason in the world to believe it will be successful. There are very interesting preclinical programs in other rare endocrine diseases that are of interest to us. I'll just call one out, Graves' disease and thyroid eye disease. So many paths to the $5 billion that we outlined. The most straightforward is the focus on 2 lead assets.

The next question will come from Salveen Richter with Goldman Sachs.

With regard to Atumelnant, could you speak to how we think about the ramp of the drug and the sales outlook in the context of what's played out with Neurocrine's drug here? And then secondly, for PALSONIFY, the -- maybe speak to the ex U.S. launch outlook here given the recent EMA approval?

Yes. Sure. Thanks, Salveen. Let me take the first question on how we see the Atumelnant ramp, and then I'll ask Duncan to comment on PALSONIFY and commercialization. Let me just make a top line comment for both. Obviously, we're just announcing the merger agreement today. The deal still has to close. So I'm going to be thoughtful about not going too far forward before the deal closes. That being said, as you heard Duncan say, the awareness for Atumelnant in CAH is very high. And this idea that you can have a drug that can control both physiologic levels of GC, glucocorticoid and concurrently manage the androgens, that is the holy grail of what physicians and patients want. And so we see a lot of opportunity, a lot of awareness, and it's an oral small molecule. So for this opportunity to play out in a nice launch uptake. But I won't go further than that until the deal closes.

Duncan, do you want to say a couple of words about PALSONIFY and where you would take that once the deal closes?

Yes. Salveen, briefly, PALSONIFY has been approved in Europe in April earlier this year. And without sort of prejudging exactly what we would do, our plan would be to conduct a global launch of PALSONIFY beyond, of course, the excellent launch that the Crinetics team are executing here in the U.S. right now.

The next question will come from Cory Kasimov with Evercore ISI.

This is Josh on for Cory. In regards to Atumelnant, what data did you see to make you feel comfortable that there won't be a liver safety signal as was a concern that was brought up by investors previously. And we'll leave it at that.

Yes. We've looked at the totality of available data generated to date with Atumelnant in all of the indications. So that means CAH as well as in the early study in ACTH-dependent Cushing's. What we see is minor elevations. I believe there were a handful of cases, I think 7 actually to be exact, of minor elevations in LFTs. There are no cases of LFTs plus bilirubin. There -- most of the cases, 6 of the 7 resolved without any intervention on continued therapy. So we feel really good about the safety profile, not only in the liver dimension, which you asked about, but as we reviewed the data, we felt really good about the profile overall.

The next question will come from Andy Chen with Wolfe Research.

And I think you mentioned that the deal is going to be accretive by 2029 based on your internal assumptions. Would this largely be driven by PALSONIFY? Or is it possible for Atumelnant to launch before then? If you can provide some metrics on timing of Phase III data, that would be great.

Charlie, do you want to comment on that?

Yes. Thanks for the question. Obviously, the commentary about this becoming accretive to operating margins in 2029 factors in both our view on revenue ramp as well as OpEx trajectory over the next couple of years. We'll be more specific about that at the time of close.

The next question will come from Geoff Meacham with Citibank.

This is Jarwei on for Geoff. Maybe 2 from us. First, on PALSONIFY, what gives you confidence that the Phase II CAH profile would be reproducible in a larger, more heterogeneous Phase III population? And then on Atumelnant, what's the one risk you're most focused on as you move through the Phase III study?

Sure thing. I think you mean Atumelnant in CAH, what gives us confidence that we're going to recapitulate the results in Phase III as seen in Phase II. One of the really -- one of the things we like so much about this platform is the disease biology is extremely well understood. The manifestation of the disease is clear. You can tell if the medicine is working, as I said in my prepared remarks, early on because these are exactly the biomarkers that we study as you're developing proof of concept as is the endpoint in Phase III.

So based on the mechanism of action, the presentation of the disease, it is a rare genetic endocrine disease and the strength of the data, the magnitude of the treatment effect, I have high confidence in the Phase III program. You also asked about what risks are we looking for. There's nothing special that I would call out here. The risks for any program that is transitioning between Phase II and Phase III is simply to ensure that the safety and tolerability profile is the same in Phase III as was in Phase II, and we already talked about the efficacy. But I see no unique risks that concern me here.

The next question will come from Evan Seigerman with BMO Capital Markets.

On the proposed acquisition. So mechanistically, when you think about the kind of competition out there, walk me through why you think the Crinetics asset is potentially better than chronicity. I know you have some data in the slides, but when you did your diligence, what was it that was striking that caused you to decide to acquire the company or propose the proposed acquisition of the company?

Yes. You bet, Evan, and thanks for your kind words. So the key here, Evan, if we just focus on CAH is that the long-standing and very well known to the field. So this is a rare endocrine disease taking care of by a small number of endocrinologists. Endocrinologists in any case, is only 8,000, 9,000 endocrinologists in the U.S., kind of the same number as nephrologists. So it's a small specialty. And of that, only like 4,000 or so take care of this kind of rare endocrine disease.

When you look at the disease itself, it's very clear that it's this dual burden of needing to supplement with glucocorticoids, but the best outcome would be using physiologic doses of glucocorticoids or GCs. But that's not really possible. People end up using super physiologic doses of GCs because without doing so, the androgens, which have a whole host of complexities, as I described in my prepared remarks, growth challenges, [ HERsutism ], virilization, a whole host of excess androgen challenges. So you use more GCs. And when you do that, you're constantly tiering between too much glucocorticoids and the downstream negative consequences of that or too little glucocorticoids and then having excess androgens.

So I think Duncan described it exactly right. The holy grail has been can we have a medicine that allows glucocorticoids at physiologic levels while suppressing androgens. And when you look at the Phase II data, and we shared some of it on the slide, that is exactly what you get. And I would say, Adam, the key thing to look at is look at the end of the trial period where you have GCs at physiologic levels and look at that point at the androgen or A4 level. That's the key data. When we saw that data, we were floored. That is very, very important to this field.

I'm going to ask Duncan to see if he wants to make any additional comments.

My only additional comment to that is, and we believe that's unique that there is no other company that have data that has shown the ability to achieve that holy grail of both managing androgen levels as well as and simultaneously enable patients to be treated with physiologic doses of glucocorticoids. And that is unique and no one else has shown that.

The next question will come from Michael Yee with UBS.

Mike Yee from UBS. Two questions, maybe Reshma. One is just thinking about the premium on the acquisition of approximately 100% and appreciating that nearly every deal, I think, year-to-date nearly has been a much more modest premium speaking to sort of bid-ask spreads and where we are in the market. So talk a little bit about either was this a very competitive situation? Or how do we arrive at such a high premium?

The second question is more scientific and competitive in nature. And in understanding the difference between your drug and chronicity, it looks like your -- Crinetics is using quite a different endpoint in Phase III. And perhaps is it that endpoint that speaks to exactly what you're trying to address in terms of normalizing performance?

Yes. Michael, this is Reshma. Let me take the second question first, and then I'll turn it over to Charlie to tell you more about how we think about value. You are exactly right about the endpoint. And I do think that the Phase III endpoint of the Atumelnant CAH study tells you exactly what you need to know about what we think is most important in this disease. And to reiterate that, it is physiologic doses of glucocorticoids and at physiologic levels of glucocorticoids getting the androgens under control. So you're spot on, on that.

With regard to value, let me top line it by saying we see significant intrinsic value in this acquisition, and I'll ask Charlie to give you some more color.

Yes, Mike, thanks for the question. Listen, there are obviously a lot of ways to think about value, both absolute and relative. To Reshma's point, as we looked at the opportunity to acquire Crinetics, what we saw was the potential for best-in-class products with transformative benefit. We toplined for you the potential for $5 billion in peak sales and as well as a meaningful addition to profitability after a few years. So it's a very attractive fit, both strategic and financial. And on those merits, we see a lot of intrinsic value that justifies the price.

Maybe if you think about other measures, if you think about the value relative to peak sales, so roughly 2x, those measures are right in line with -- if you think about other deals of really high-quality assets, either commercial or near commercial, I think it's right in line. So we feel great about this. The price reflects the value that we see, and we look forward to both growing and accelerating this business once the deal closes.

The next question will come from Brian Abrahams with RBC Capital Markets.

This is [ Nevin ] on for Brian. Just wanted to touch on and expand on what you think the commercial dynamics may look like in the event that Atumelnant is approved. So some of the patient feedback that we've gotten on CAH patients from CAH patients indicate that there might be some hesitancy for those who are currently on chronicity to switch just given the potential need to reequilibrate their glucocorticoids. So how are you thinking about this as a potential barrier to switching off of chronicity in the case Atumelnant is approved? Would you look to pursue a switch study? And what specific profile do you think could potentially demonstrate a compelling enough profile to incentivize switching?

Yes. this is Reshma. Maybe I'll just answer with a top line. I don't want to go further than where we are at the moment that the deal hasn't closed yet. We'll have more to say on this. But what we have heard from patients and physicians and as you heard Duncan outline, is high awareness of the possibility of Atumelnant in CAH, very, very clear goals from physicians and patients that they want to have both their glucocorticoids at physiological doses with control of androgens and there's high awareness that that's not happening. This is not an asymptomatic disease. It's actually a very pronounced and symptomatic disease and troubling to patients because they feel the excess of the glucocorticoids or the excess of androgen. So it doesn't go by quietly or unnoticed and both physicians and patients want these measures under control. The point that you raised about switch studies is a very good idea. I'll just leave it at that, and we'll talk more after the deal closes.

The next question will come from Phil Nadeau with TD Cowen.

I guess our question is on the timing of the deal. Why is this the right time for Vertex to add a fifth pillar? I think you have a lot going on in your early-stage pipeline or early-stage launches with JOURNAVX, CASGEVY in the early stages of their commercial uptake, [ povetacicept and innaxaplin ], not yet making it to market but being pretty close. So a skeptic would say you have plenty going on already. What are you trying to diversify away from? Why is this the right time to add a fifth pillar to Vertex's commercial strategy?

Thanks for the question, Phil. We see ourselves as a company that is looking to bring transformative medicines to patients around the globe. We see ourselves as a growth company. We see ourselves as a company that has the ability, bandwidth resources, judgment, taste, commercial prowess to do this in many areas. And when we saw the data from Crinetics, met the team from Crinetics, looked at the pipeline, looked at the potential, this is absolutely the kind of deal that fits us perfectly. And the timing is now because the company is available now. The data are available now. And we believe that we are the right group to take on PALSONIFY, add to what the Crinetics team has done and take this around the globe, accelerate the launch in the U.S. and start the launch ex U.S.

And we feel really terrific about what they designed in Phase III. And we feel like this is the right time to get to the company with the Phase III program well underway, so we can now help shape how that launch is going to go. So we're doing this now because we are interested in ensuring that we remain the kind of company that when we see wonderful assets in our own pipeline or outside, we take full advantage of it and we drive hard. This is exactly the kind of deal that fits us perfectly.

The next question will come from Tazeen Ahmad with Bank of America.

I wanted to get a sense of the synergy that you think these group of assets will have on your already established commercial infrastructure. And also the particular focus on endocrinology, can you just talk about why that makes sense just given everything else that's already been mentioned that you're developing in the pipeline? And do you think there's opportunities to leverage that in the future beyond the assets that you're acquiring?

Tazeen, I couldn't hear the end of your question, but I think the fundamental point was why endocrine and do we see synergies. I'll ask Duncan to comment, but I'll just top line it by saying, of course, we have our T1D cell therapy-based program in endocrine. And so that's an important thing to consider. And I'll ask Duncan to comment on that as well as the synergies we see between these various assets in the Crinetics portfolio.

And lastly, to talk a little bit about why we like the endocrine space so much and why it reminds us of CF. Duncan?

Yes. So just to cover a couple of points here. So there clearly will be synergies between the different diseases in the Crinetics portfolio. They're essentially all treated by about a total of 8,000 endocrinologists in the U.S. But each of those diseases is probably treated by about 3,000 or 4,000 physicians, and there's going to be significant synergy and significant overlap between those patients -- sorry, between those physician groups. There's certainly plenty of synergy with the endocrinology space.

And as we've talked about before, it's a space where there is an incredible significant patient unmet need in the diseases that we're talking about. They are symptomatic diseases and they are serious diseases for patients, and we have highly differentiated best-in-class molecules in each of those diseases. So we see that candidly very similarly to how we think about our CF portfolio. So certainly, there's plenty of synergy in that area.

I think the first part of your question might have been about synergy on these assets across the rest of our commercial infrastructure. And with regard to that question, I think it's a little bit early to be making any comments in that regard at this point.

The next question will come from Brian Skorney with Baird.

Congrats on the deal. I guess how do you think about the market opportunity for PALSONIFY in Acromegaly versus carcinoid syndrome versus nonsymptomatic [indiscernible]. I think the market for injectable SRL is more heavily weighted towards neuroendocrine tumors. So do you have a perspective on how that market is currently split up for the injectables? And do you think ultimately at peak PALSONIFY has a different market dynamic in terms of the ratio of acromegaly versus neuroendocrine?

Brian, I think you're asking how do we see the market for PALSONIFY for acromegaly versus neuroendocrine tumors, maybe including carcinoid. I think that's what you're asking. It was a little hard to hear.

Yes, that's exactly correct.

Okay. I'll ask Duncan to comment. I don't think we're going to have any specific comments on the split between the market. But what I can tell you is we see real opportunity for PALSONIFY as best-in-class for acromegaly and we'll hold on the neuroendocrine tumors in carcinoid after the deal closes. But I will ask Duncan to comment on PALSONIFY Acromegaly.

Sure. So Brian, as far as Acromegaly is concerned, just to repeat some of the comments we made earlier, this is about 20,000 patients in the U.S., about 35,000 patients around the world. As we've talked about before, there's a very significant unmet need for these patients and PALSONIFY offers a unique oral once-daily dosing with rapid and sustained up to 22 months symptom control, which compares very favorably with the current sort of standard of care after surgery, which is sort of large gauge intramuscular injections that are given once a month. They're fairly viscous injections cause a number of painful injection site reactions and tend to have a tapering of symptom control towards the end of the month.

So you sort of start the month with the injection site reaction and you end the month with limited symptom control. So we think PALSONIFY in Acromegaly for sure, has the opportunity to become best-in-class, as I say, as an oral once-daily treatment. And as you know, it's priced at around about $290,000 here in the U.S. So we're very excited about the opportunity for acromegaly and very excited about the work that the Crinetics team have already done in order to drive physician awareness, uptake, patient enrollment forms and really nice broad market access this early in launch.

Your next question will come from Ellie Merle with Barclays.

This is Jasmine on for Ellie. Congratulations. So a couple on PALSONIFY. First, how would you segment the addressable acromegaly market across switch versus naive patients? Where do you expect the strongest initial uptake for PALSONIFY? And how do you expect to work to gain share across both segments? And then secondly, can you talk a little bit about the level of motivation across these rare endocrinologist prescribers to actually switch to new therapies like PALSONIFY.

Yes, you bet. I'm going to ask Duncan to comment on the -- let's just narrow down the buckets and maybe Duncan will expand, but there's the switch population and then there is naive, discontinued as well as the group who have just recently had surgery but are not yet on medicine. And then to talk a little bit about the new prescriptions that we're seeing, which I think speaks directly to your point about comfort of physicians. Duncan?

Yes. Thank you for the question, Ellie. I'm not going to go into too much detail in providing sort of guidance on where we expect the business to come from. But safe to say, as I mentioned in our prepared remarks, we do expect, at least initially, the vast majority of PALSONIFY business to continue to come from switch patients. As I alluded to in my answer to the last question, these are patients that are on very unpalatable injectable SRLs. And so we see a significant opportunity for the switch patients but there are also, as Reshma alluded to, patients who are treatment naive. It's about 500,000 new patients a year. There's also patients who 500,000, sorry.

[indiscernible] equals [ 500 ].

And there are also about a number of patients that have treatment discontinued. As I showed in the presentation, there's a lot of patients that start on these therapies, but because of either the challenges in taking them or lack of symptom control, they tend to come off those therapies. So there's plenty of patients who have discontinued existing treatments for existing available treatments who we think would be great candidates for PALSONIFY.

I would say in terms of the level of motivation from HCPs, both the engagements that we've had with physicians, the market research we've done and the data that Crinetics have themselves communicated, there is incredibly high awareness of PALSONIFY. There is incredibly high awareness amongst the target endocrinologists of the Crinetics organization and PALSONIFY. And we've seen really nice uptake in terms of new physicians prescribing each month, patient start forms and as I alluded to before, strong payer coverage, all of which I think are good indicators of, a, the significant and visible unmet need in the disease; and b, the clinical impact of PALSONIFY.

The next question will come from Carter Gould with Cantor.

Congrats on the deal. Follow-on to an earlier question around adding a fifth vertical. What are the implications for future BD, both in terms of capacity and areas of focus? Should we expect a downshifting in BD as you rebuild cash balances? And I guess, should we rule out you adding a sixth or seventh pillar in the near term with this recent deal?

This is Reshma. Thanks for the question. First things first, super excited about announcing the merger agreement today. We have a close still to go. As you heard Charlie say, we are very serious about our R&D strategy. We're very serious about our capital allocation approach that it goes to innovation. Nothing changes on that front, and you should not expect any change going forward.

Chuck can you give the replay info, please?

We'll do. That will conclude our question-and-answer session as well as our conference call for today. A replay will be available shortly after the call concludes by dialing 1 (855) 669-9658 or 1 (412) 317-0088 using replay access code 1734853. Thank you for attending today's presentation. You may now disconnect.

Good morning, everyone. Thank you so much for joining us. It's my pleasure to introduce Vertex Pharmaceuticals. And with us, we have Reshma Kewalramani, who's President and CEO of the company. Reshma, thank you for being here.

You bet.

Maybe just start here, a high-level overview on the company. Help us understand where Vertex stands today in terms of your core cystic fibrosis and emerging pain and kidney autoimmune franchises, the key pipeline priorities and the outlook and strategy for the company as we head into the end of the decade?

Sure thing. Sounds good. First of all, it's very nice to be here with you, Salveen. I know we're the last fireside chat, so it's good to see those of you in the room. I've described 2026 and for the next 6, 12, 18 months as a year, a period of time for Vertex. That's an execution-rich period, and that's exactly how the first part of this year has played out, and I expect the back half of this year.

And as we go forward, it's going to be about expanding and extending our leadership in CF. You know that we now have medicines that can get up to 95% of people with cystic fibrosis and we continue to expand geographically as reimbursements come out outside the U.S. and lower in age groups. For our last 5,000 or so patients, we're working on a nucleic acid therapy approach. You know that the approach we had started with is not going to be the one that goes forward.

So in CF, we are looking forward to all of that work and potentially bringing the next-in-class molecules, although it is getting awfully difficult to beat the medicines we have. I know I said that when we were working on the ALYFTREK when TRIKAFTA was available, but it's even more so to try and beat a ALYFTREK with something else. Nonetheless, we have 3 programs in that area, VX-828, VX-271 and VX-582 as those next-gen programs.

Then moving on to pain. JOURNAVX is now about a year into its launch. There were more than 500,000 scripts written last year. We're expecting to more than 3x that this year. And of course, with that comes commensurate increases in revenue.

The hematology franchise with CASGEVY is growing nicely, and I like the momentum there. It's a long patient journey. So we have line of sight to the number of patients who've been initiated, the number of doses that are to be administered. And I like what I see there. And of course, pove. It was at this conference last year that I think Salveen was the first to recognize that the fourth vertical of Vertex was about to be created. And fast forward a year, just last week, we learned from the FDA that the filing for accelerated approval has been accepted. And therefore, the PDUFA date for pove in IgAN is set at November 30.

As we look through the end of the decade then, it's certainly about these programs and driving them to their full potential as we complete the launches or get them launched in the example of pove. And it's a lot about moving forward rapidly the Phase III programs. And I'll just name them, and we can certainly talk about whichever ones are of interest. But the type 1 diabetes program, the cell-based therapy, that's in Phase III. There are -- there's a DPN diabetic peripheral neuropathy study in Phase III. Inaxaplin is in Phase III for something called APOL1-mediated kidney disease and pove in both IgAN and membranous are also in Phase III. And of course, there's a whole pipeline behind that.

And then as we look at the balance sheet, it continues to grow. We really like the way we're allocating capital largely to innovation. But as the company grows and the balance sheet grows, we're also doing more stock buybacks, and you should expect more of the same from us on that front. That probably takes us through at least 2030.

Yes. Perfect. Maybe on the balance sheet side here. So how does BD play a role here in terms of decent-sized BD like you did with Alpine? And also, how are you thinking about dividends on the forward?

Yes. Maybe 3 things to say on that front. The first is, if you look at our pipeline, about 60% of our clinical stage pipeline comes from internal innovation and a full 40% comes from external innovation. So we've been active in both for quite some time.

Maybe the second thing to point out is the Alpine acquisition looked really good to us as we were going through the process. And boy, I excited the more we peel the onion, the better and better it looks. The Seattle site is extremely productive, some really great people who came to us from Alpine. And I think you're going to see some medicines that come into the clinic in the near future that are from our site in Seattle. The last thing to say is I really do think the strategy around investing in innovation is the right one for us. And as I look into my crystal ball, I don't see dividends in my crystal ball from where I sit today.

Perfect. Starting with the cystic fibrosis franchise here. How do you view the long-term trajectory and speak to the extent of market share remaining or any additional growth levers?

Yes. So in cystic fibrosis, I'm going to round a little bit, but there are around about 100,000, 107,000 people around the globe. The vast, vast majority of patients who can be on medicine are on medicine. So as I think about the medium-term growth and near and medium-term growth, it's going to be about getting to additional countries. So there are countries, think Turkey, think Brazil that aren't yet at the place or just getting to the place where reimbursement has come through. And so that's going to get us more patients to be on medicine and more growth.

We're still working on the lower age groups. So KALYDECO is in 6-months-olds. The TRIKAFTA medicine, we're soon going to file for the 1- to 2-year olds. And for ALYFTREK, we're filing -- just getting ready to file for 2- to 5-year olds. That brings more patients into the fold and that brings more growth. And then lastly, in the more medium to long term, it's the last 5,000 patients, for that we are going to need nucleic acid therapies. So we're working through both the delivery, which frankly has been the greater obstacle than the payload. So that's where we are with CF.

And of your existing franchise here, maybe talk to what proportion of patients you think will transfer to ALYFTREK and over what time frame and what factors are moderating conversions given I think it has about 15% share of the franchise currently?

Yes. That's about right. So ALYFTREK now cumulatively has hit over $1 billion in revenue, and it was launched around about January of '25. So that's a program that's picking up momentum. The key attributes for ALYFTREK are: one, it's once-a-day dosing. You'll remember TRIKAFTA is twice-a-day dosing. It actually is interesting. It's turned out to be more important than perhaps I've even given it credit for, especially in our younger patients where once daily dosing is a real benefit.

The second is that it's approved for even more mutations than TRIKAFTA. So there are more patients with the ultra-rare mutations that can access a drug that treats the underlying cause of their disease. And then lastly, a benefit for all is that in head-to-head studies versus TRIKAFTA, the ALYFTREK molecule had even greater reductions in sweat chloride. So those are the attributes.

And if you think about the conversion, in the U.S., the label is such that there is additional monitoring a patient needs to go through if they start a new medicine, whatever the new medicine is, if it's ALYFTREK or TRIKAFTA. And so for the conversions that counts as a new medicine, there's additional monitoring. In Europe, the label is just playing different, and it does not have this additional monitoring. And so if you look in Europe, if you look at certain Nordic countries, for example, it's more than 70% of the CF patients have converted to ALYFTREK from TRIKAFTA.

So I think as the years go by, I continue to expect that the majority of patients are going to choose to be on the medicine that has the best profile and that is ALYFTREK, and I do think the majority are going to switch to ALYFTREK. We've never forced switching in the past, and we don't intend to do so here, but I think patients and physicians will choose ALY over the next period of time.

And how are you positioning your next-gen correctors, your 3.0 versus your existing franchise as you think about the future and any time lines you can give us here?

Yes, yes. So the next, next wave are the 3 that I named 828, 271 and 582. The first of that next wave, we should be able to see some patient results in the back half of this year. That's 828. And for 271 and 582, they're a little bit behind [Technical Difficulty] to what we're looking for. Our long-term goal has been to bring the vast majority of patients to below carrier [Technical Difficulty]. That number is 30 millimoles. Where we are today with ALYFTREK, we have 2/3 of patients who start medicine early in life already getting to that goal.

More than 90% of patients are at a sweat chloride of less than 60. That's the diagnostic threshold and more than 2/3 are less than 30. So one of the interesting things in CF today is to think about, is there more room to get even better? And when you look at the sweat chloride values and you think about the median, when we talk about median of less than 60 or median of less than 30, there's a normal distribution around that as you would expect.

And when we plot this lower age groups who are on ALE and you look at their median less than 30 and you look at the distribution and then you plot carriers. So those who are the parents of the children with disease who are essentially free of disease, they are now overlapping. So our young kids who are taking ALE on their distribution of sweat chloride and you look at normals, we are near overlapping. That's a wonderful milestone to achieve. So we're there with 2/3 of our patients. So what are we looking for? We're looking to get even more patients to under 30. That's the North Star that we're following.

In that carrier population, is there any benefit to going even lower?

Now that is an absolutely excellent question. It does not appear to be the case that even lower is better. But to be fair, we don't have a lot of data in the even lower. We're just getting patients now. It's really the wave of ALYFTREK that's gotten large numbers of patients to less than 30. TRIKAFTA got patients to less than 60. So we're exploring this. And I do think you're going to need exceptionally long-term data.

You're going to need data over 5, 10, 15, 20 years because if you look at model data from ALE or TRI as an example, this is model data, patients are living to more than 70 years of age. And so we're getting to these points of very good survival. And the key question is, but can we get your protein function, your CFTR protein function to essentially carrier levels, and that's what we're trying for. But I don't know that there's any additional benefit beyond getting you to less than 30.

If you look at the less than 60 and the less than 30, now you're sort of maximizing benefit. Maybe there's a little bit more between less than 30 -- less than 60 and less than 30, but I don't think there's even more under 30. I think that's the goal, get our patients to less than 30.

And then finally, on this topic, there is a competitor, Sionna, that's developing assets in cystic fibrosis targeting NBD1 under the belief that it would lead to increased efficacy in FEV1 over Vertex's assets, namely TRIKAFTA in that first data set this summer. Describe the work you've done to understand this target and why you believe your assets have reached a ceiling here in FEV1 or overall the saturation of the protein?

Yes. Because we've been working in CF for so long and have data all the way back to KALYDECO and have data that looks at sweat chloride levels and ppFEV1 lung function, we have an enormously large data set for this rare disease population. And what I can tell you is that there is a good correlation between sweat chloride and ppFEV1 up to a point. After that, you don't get more PPFEV1 benefit.

And it is for that reason, I don't think it has anything to do with which drug you use, a potentiator, a corrector or something that binds to a different location like an NBD1 that drives additional ppFEV1. It does appear to be an asymptote of lung function improvement. And maybe the easy way to think about it is these medicines don't reverse the damage already done. What they do is prevent further damage, and we have reached an asymptote of that with where we are today.

So if you ask me, do I think that there's going to be improvement in ppFEV1 regardless of mechanism after you are at the levels of ALYFTREK, TRIKAFTA, I don't think so. And you can see that in the ALYFTREK to TRIKAFTA comparison.

Okay. Turning to pove. So this drug is going to enter market with 2 currently approved drugs. One area pove is differentiated versus the other drugs in IgAN is by its presentation as a low-volume subcutaneous auto-injector delivered once every 4 weeks at home. So you've got that delivery profile benefit, but there are also clinical profile benefits that you pointed to. Maybe help us understand how you go in and take that dominant position?

Yes, absolutely. I actually think, Salveen, what you pointed out with regard to presentation or what others might call administration, I actually think that's going to be the key feature of these medicines. I'll tell you a little bit about the safety and efficacy. But one thing that's clear is the patient is not going to get the benefit if they don't take the medicine. And this medicine is chronic lifelong therapy. It is a biologic. So it's an injectable. And the ability -- the Vertex medicine is once monthly. It's subcutaneous small volume, 0.46 mL in an auto-injector. And none of the emerging medicines have that profile. And I think that, that feature is going to be amongst the most important once these medicines come out.

On safety and efficacy, the big thing to say is, in my view, as I've looked at the data, I believe pove is best-in-class based on the following features. When you look at the proteinuria reduction, so that's protein in your urine, hematuria reduction and improvements in Gd-IgA1. Gd-IgA1 is the PD or pharmacodynamic marker that is -- all those measures look best-in-class. And then when you look at the safety profile, quite favorable and you put that together with the dosing and administration elements we were talking about, I believe pove is best-in-class and is poised to be the medicine that most doctors and patients will want to take. And boy, am I excited to get this out into the hands of patients and doctors because it happens to be Vertex's first biologic, and it happens to be our first medicine in renal disease, and that's a wonderful place for a nephrologist like myself.

And do you think that Otsuka and Vera having eGFR data out that versus you will impact that uptake curve?

So the eGFR data has an interesting context point to make, and that is the FDA, so the U.S. regulatory agency has asked all companies who are going through the accelerated approval pathway to not share GFR because the study -- the Phase III study is ongoing because all of these are accelerated approvals. Once your Phase III study is complete, of course, you can share the GFR.

So one important thing is that the Phase III study has to be complete. One of the programs has completed their study, which is why they've shared data. The other 2 programs have not completed their Phase III study, which is why the Vertex program, for example, won't be sharing GFR data. I think that it's well known in the kidney community, and it is the reason for the agency, the FDA accepting proteinuria as the accelerated approval endpoint that proteinuria is very related to stabilization of GFR and that, that ultimately leads to delay of dialysis, transplantation or death, which is the real goal.

So I think that's very, very familiar. And it is indeed the renal community that worked for many years, I'd say, decades with the FDA for proteinuria to be an accelerated endpoint. So I think that's well understood. I don't think it's a big surprise that when you have, like you do with the pove medicine, good reductions in proteinuria, you're going to get stabilization in GFR when that GFR is known. I'll also say the agency has asked all of the companies to share GFR data with them, and they will make a decision about whether they're comfortable with what they're seeing before they provide the accelerated approval. So I see that as very helpful to know. And I don't see it as a big surprise. I think it's an expected outcome when you have good reductions in proteinuria that you get stabilizations in GFR.

And speak to your confidence here about this drug moving forward and translating into the follow-on indications. And for myasthenia gravis in particular, where would this be positioned in that landscape?

Sure. So in renal medicine, in IgA nephropathy, it's a 52% improvement in proteinuria change from baseline. It's some 83% on hematuria and it's some 77% on Gd-IgA1. Those are really good numbers. On the next program and therefore, the next approval, just given where it is in its cycle, I believe, will be in membranous nephropathy, another kidney disease. There, the study is a Phase II/III adaptively designed study. The Phase II portion of it has completed its enrollment, and we're now in the Phase III portion of it. That one is a traditional approval, 104-week, what's called remission. It's a combination of proteinuria and GFR. I do think that will be the second pove indication.

Third, we are prosecuting an indication called WAHA. It was in one of the basket studies that the company we acquired, Alpine had initiated. It's warm autoimmune hemolytic anemia. I think we'll have some updates for you this summer, early fall. The next one after that, which is in Phase II study is myasthenia. To your question of where do we position it in myasthenia, there's been some real advancements in this disease where when you look at the endpoints, there have been substantial improvements.

One of the difficulties, though, is that some of these medicines have to be cycled on and cycled off. In the cycled off period -- that's for safety reasons, in the cycle-off period, you can imagine autoantibodies returning and damage continuing until you can get back to the on-period. So what I expect with a drug like pove and there is another example of an APRIL BAFF inhibitor that has done a study in China that has shown remarkable benefits. These are -- you have to look and do comparisons, which have all of the challenges and have all the [Technical Difficulty] same and the benefit was remarkable.

And one of the reasons I think it has that kind of benefit is because it's a medicine you can take continuously. You don't have this cycle-on, cycle-off matter to work through. And then I think about pove compared to that APRIL BAFF, that's a wild-type medicine. Pove was specifically engineered to have better binding affinity, better potency, better tissue distribution, and that's what gives me a lot of enthusiasm and confidence for the pove program in myasthenia. That one is in Phase II. It's about 40 people. We're studying 2 doses. And I do think we will have something important to look at in the coming months.

Great. Inaxaplin. So you'll have data -- Phase II data in APOL1-mediated kidney disease with modest proteinuria and diabetes in the second half. Help us understand or frame for us how to think about this data set, recognizing we saw some data from MACE as well?

Yes. Yes, sure thing. So on inaxaplin and this disease, APOL1-mediated kidney disease, AMKD, there's 2 things to think about when you think about the Vertex program. The first is AMPLITUDE. That's the Phase III study. We completed the enrollment of the accelerated approval cohort late last year. And I expect that we'll be able to see and share results early next year. So that's AMPLITUDE.

The key thing to know and remember about AMPLITUDE is that it's a study of 2 APOL1 mutations, reduced kidney function and proteinuria. Let's call it primary AMKD. We specifically did not include people who had modest proteinuria, and we specifically did not include people with a second kidney disease, think diabetes, because those are different populations based on all of the available evidence we have.

I think those second and third populations that we discussed, modest proteinuria or diabetes are worthy of study, but they are different. So we've studied them in AMPLIFY, a Phase IIb study. There -- it's a basket study. There's about 15 to 20 patients in each arm. The arm that has a modest proteinuria is separate from the arm that is the diabetic cohort. And what we're going to be able to assess is whether or not inaxaplin works in those conditions.

The modest proteinuria cohort is important but distinct from AMPLITUDE because it has lower levels of proteinuria. That means there's a certain dynamic range and there's lower headroom to move. That's why we're studying it separately. The cohort that has diabetes, it is not clear based on all of the available literature, if when you have 2 APOL1 alleles and you have diabetes, is the kidney disease driven by the diabetes? Is it driven by the APOL1 mutations or both? It's worthy of study, as I said, and therefore, we're studying it in the separate cohort. We are fully on track to see and share those data in the back half of this year. So we'll know the answer to those questions shortly.

And for AMPLITUDE, maybe speak to the confidence and speak to the risks, but also when you look at the Phase II data that was published in the New England Journal of Medicine and kind of translate to the Phase III, the Phase II included only FSGS confirmed disease, whether that's on inclusion criteria now. So help us kind of understand that.

Yes. So now switching to AMPLITUDE, which is 2 APOL1 alleles reduced GFR or renal function and proteinuria. Remember, this is the primary cohort. We studied in Phase II the same thing, primary AMKD. That's the New England Journal publication that Salveen refers to, we saw a very impressive 47.6% reduction in proteinuria. That's really good.

In that study, we chose to evaluate patients with something called FSGS. FSGS or focal and segmental glomerulosclerosis is a histological diagnosis. You have to do a biopsy in order to know whether or not you have that. FSGS is so-called because that's what you see on biopsy. It's not to say that you don't have APOL1-mediated kidney disease if you don't have this diagnosis associated with you that says FSGS, it simply means we did not biopsy you.

We chose to do the biopsy proven FSGS because it was our first study in patients, and we wanted to make sure we knew exactly what disease you had, and we wanted to make sure we had a biopsy. But the disease you have comes from having 2 APOL1 alleles. And therefore, when we went into Phase III, we have 2 APOL1 alleles, reduced renal function and proteinuria, same as the Phase II study. And we have patients in that cohort, in that Phase III study who actually have FSGS because their doctor decided they wanted to biopsy them. And we also have patients who have all of those other characteristics, but their doctor did not decide to biopsy them.

We see that as a homogeneous patient population. That's the population we've discussed with the FDA. That's the study that's in Phase III where the accelerated -- the potential accelerated approval cohort or the interim analysis cohort will be available early next year.

Great. Switching over to JOURNAVX and your pain franchise here. You have guided that JOURNAVX prescriptions would triple in 2026. Help us understand what's driving the momentum and how to think of that growth outlook for 2027 and beyond?

Yes. So now switching to acute pain and JOURNAVX. JOURNAVX was launched about March of last year. We had the approval in January and drug in channel in March of last year. We had about 500,000-plus prescriptions in calendar year 2025, and we have guided to more than 3x that this year.

What I see in its use and as we go out and talk to physicians is broad use in accord with the label postsurgical. And in the surgical domain, it's a lot of orthopedic surgery and a lot of general surgeries. And in the nonsurgical domain, it's things like fractures or use in wisdom teeth extraction, that kind of use. And it's broad. It's 50% in hospital. It's 50% in retail with a fairly broad prescriber base.

And I like the way people who are using it consistently, particularly in the postoperative, for example, post total knee surgery or shoulder or hips, how those who have used it and were early adopters are converting practices over to this. I think that's really important to see because this is acute pain. It's not a medicine where it builds on itself with the same patients. Hopefully, a patient who has acute pain has their pain episode, takes their medicine and then they are fine.

What we then have to do here is make sure that practices convert and people reach for JOURNAVX instead of reaching for an opioid. And I like some of the early anecdotal reports around practices making that decision. I think it's really, really important to understand the need to have great reimbursement because if you're doing that, but you have to think about is my patient a Medicare patient or a private pay patient? Is it a patient that does have their insurance reimbursed or not? That adds friction to the process. And so I'm really happy now to being at the place where the 3 large PBMs are covering. The last one just started the coverage as of January of this year. 2 of the 4 large Medicare payers we have signed our contracts with them, and I'm confident we'll get to the other 2.

So as these contractual arrangements come into place and people have access, that gives us the ability to sunset the PSP or patient support programs that normalizes gross to net [Technical Difficulty] 3x the prescriptions, but more than 3x the revenue as we sunset these patient support programs.

As we look beyond that, it will get more and more to be the case as we look at '27 and beyond, where practices are making their decision to use JOURNAVX, keep opioids not as the first thing they reach for. And as these -- as patients get more access, and I think word of mouth ends up being important, social and digital ends up being more important, we are looking for even greater momentum.

Great. On your broader programs here. So in DM1 muscular disorder, Vertex is developing an internal small molecule program, but you also have in-licensed an oligo plus circular peptide approach from Entrada with Phase I/II data in the second half. Discuss your view on these assets and what you're looking for in the upcoming data?

Yes. You're exactly right. In DM1 muscular, it's a kind of muscular dystrophy that is even more common than Duchenne's muscular dystrophy. It's actually the most common muscular dystrophy out there. We have 2 approaches. The small molecule approach, which is our internal approach is still in preclinical development. So it's on the bench. But I like the progress we're making, and I think a small molecule approach has the obvious benefit of ease of use.

The lead program is an asset we in-licensed from Entrada. Here's our scientific bet. It's an oligo linked to a circular peptide. And our scientific bet is that the circular peptide will be important in localizing the oligo to where it needs to be, which is not only in the cell, but in the nucleus where it can do its work.

There are other programs that use other approaches to targeting the oligo to its appropriate location, but ours is the circular peptide approach that we think has the greatest likelihood of success. We're in Phase II development. I believe that we will have results in the back half of this year. And what we're looking for is splicing as well as early signals of muscle strength. So you [Technical Difficulty] difficult to relax and contract. So [Technical Difficulty] it's hard to let go. So there's some particular measurements we do on that. So we're going to be looking for early reads on that as well as muscle splicing.

Great. As a last question here, you do have more pipeline assets behind this. So is there anything else that you want to highlight with regard to either a pipeline asset that you think is super interesting or just your strategy or outlook for the company as we look ahead?

Okay. Let's pick 2 things. I'll pick one in Phase III, and then I'll pick something that's on the bench to whet your appetite. In Phase III, I really like the type 1 diabetes program. It's an allogeneic, so read off-the-shelf cell therapy that is in Phase III development. And I like this program a lot because the data that we shared last year in the New England shows that 10 of 12 patients treated with this cell therapy were free of insulin with excellent glucose control. That is remarkable. It's never happened with an allogeneic cell therapy.

That one is the program that you have to take immunosuppressives with, and we're working on follow-on programs with either gentler immunosuppressives or no immunosuppressives through hypoimmune cell editing.

And I'll pick one on the bench. I'll pick the NaV1.7 program. That one is very interesting because it makes so much sense scientifically and it's so elegant to imagine that we can combine a NaV1.7 with something like JOURNAVX, a NaV1.8 inhibitor, and prevent the initiation of the action potential, that's NaV1.7, and propagation of the action potential. That's still on the bench, but I like the progress that we're making, and I look forward to bringing those 2 as a combination to the pain area.

Great. Well, with that, thank you so much, Reshma.

Yes. You bet. Thank you, Salveen.

Welcome, and thank you for joining us. My name is Will Pickering. I cover U.S. biotech at Bernstein. I'm privileged to be sharing the stage with Dr. Reshma Kewalramani, CEO of Vertex. The company looks very different today from just a few years ago, building on the base in CF with launches in pain, sickle cell and soon to be in IgAN. We'll dig into all of those topics and more over the next 50 minutes. I would encourage everyone in the audience to use the Pigeonhole app to submit your own questions so that we can make this as relevant for you as possible.

And with that, this being the Strategic Decisions Conference, Reshma, I'd like to start with a broad framing question. What would you say are the top strategic priorities for Vertex? And how does that align with how you're spending your own time?

Great. Well, good morning, Will, thank you for the invitation. Good morning to all of you. It's really nice to be here. Maybe 4 or 5 things to highlight in terms of strategic priorities. In terms of our products, as Will alluded to, just compared to 3 years ago, we now are in 3 distinct franchises, whereas we were in just one through the early 2020s. So for us, it's about extending our leadership in cystic fibrosis. The second is to build the next 2 franchises into blockbuster products. The one after cystic fibrosis is in hematology for sickle cell disease in beta-thalassemia with something called CASGEVY, it's a CRISPR-Cas9-based medicine that's a one and done potentially curative therapy.

The one after that is in pain, first in acute pain with something called JOURNAVX. It's a non-opioid peripherally acting nonaddictive medicine. After we get through those 3, the next big thing in our minds is our renal franchise. That franchise looks to have 4 potential medicines starting with something called povetacicept in a disease called IgA nephropathy. It's a rare disease, but it's a common rare disease with about 150,000 people in the Western world. Beyond launching these medicines, setting up that fourth vertical, which I'm sure we'll get back to. I think that's the vertical that is substantial enough to rival cystic fibrosis in terms of its overall potential.

We're also focused my time and the Executive Committee's time on building out our company for all of this innovation and this wave of products that are making their way through late-stage development and into the clinic. That means a focus on a tech-enabled workforce, how do we responsibly incorporate AI and I would say well compared to 2 years ago when I thought there was far more hype than reality. Today, I think there's a lot more reality in companies, including at Vertex and we're also gearing up and building out for things like type 1 diabetes, which is an entirely different approach using a cell-based therapy to potentially cure that disease. That takes a lot of effort, not only in the commercial build-out, but also in manufacturing.

And then to just round all that up, compared to cystic fibrosis, which is not only a genetic disease, it's also a disease with a founder effect. What that means is it's really only prevalent in Northern and Western European people and people of that descent. So that's where our business was. That's very different than something like sickle cell disease or type 1 diabetes or pain. And so we're also building out geographically. And the best example would be the flag that we planted in the Middle East in Riyadh in 2023 to bring CASGEVY to the Middle East.

On the policy front, at the industry level, when you were here last year, it was just a few months since Liberation Day. There are a lot of unknowns about tariffs, FDA, you name it. Fast forward to today, are there any sources of policy risk or uncertainty you'd call out as being especially relevant to Vertex.

Vertex is in a somewhat different position than many other companies simply by virtue of our size and what we do in maybe the thumbnail is that we're reasonably insulated from what has been going on with regard to MFN and some of the work with the larger companies. We did not receive a letter from the administration, and therefore, we haven't been inside the room in terms of the deal-making that has been reported. We have a small but mighty team in D.C. We're very aware of the conversations. We monitor them very closely, but we have not been involved in it directly because we simply haven't received a letter to be involved.

Cystic fibrosis is a rare disease. There are certain rare disease carve-outs and that's part of it. The medicine CASGEVY is a Part A medicine. So it's neither B nor D so that has a certain distance from what's going on. At the moment, we simply do not have any Part B as in boy medicine. So what is being called GLOBE doesn't apply because it applies to Part B. JOURNAVX is only a medicine that we sell in the U.S. So it doesn't have MFN because it's only for the U.S. There are, of course, some considerations for tariffs. The 282 reviews just occurred, we are making our way through it. What I would say is we have a very diverse supply chain. A large portion of our manufacturing happens right here in the U.S. And as you may have heard on our Q1 earnings we shared that we expect no impact from tariffs in '26.

And on the FDA, how is your interaction with the FDA.

Yes. Good question. Obviously, there's a lot going on, and it's uncommon to have so much discussion about the FDA. The U.S. FDA is genuinely the bright shining light on the hill in terms of policy, evolution, innovation, and there has just been a lot of disruption, and we see that with the news that's coming out with a lot of personnel changes. What I'll say for the Vertex portfolio, and we do have filings in front of the agency, we have a BLA in front of them right now. We have several INDs. We have ongoing interactions on programs in flight. We have not seen any interruption in our ability to secure meetings, to get feedback for the filings to process within the PDUFA time lines. So we haven't seen impact on our business. But clearly, there's a lot going on there.

Moving to CF. How has the Alyftrek launch performed versus your expectations? And what have been the biggest learnings or surprises?

Yes. So for those who haven't been following the CF story very closely, Alyftrek is our fifth medicine in the CF franchise. And the biggest move was when we had Trikafta approved in October of 2019. And I say that because we went from about 50%, 60% of patients being eligible up to Trikafta to 90% being eligible with Trikafta. So that was the big move to get to all of our patients. If you think about CF patients as a full 100% pie, about 5,000 cannot benefit from these CFTR modulator medicines, these pills. And the reason for that is that they don't make any CFTR protein.

So you need a different approach, we can get back to that. For the vast, vast majority, 95% of people who could benefit from these medicines with Alyftrek we're now at 95% of the patients who can benefit. So Alyftrek is a once daily medicine, Trikafta was 2 times a day. Alyftrek has more mutations than even Trikafta. And Alyftrek gets you to even lower sweat chloride levels, which is the marker of what we call the pharmacodynamic marker of this disease. So the launch has gone really well in the U.S. The launch has gone even better outside the U.S. And the reason for that difference is there are a lot more patients outside the U.S. with these ultra-rare mutations, it's just part of the genetics of the disease. And it's also the case that the labels are different in terms of monitoring in the U.S. versus outside the U.S.

There's a little bit more monitoring in the first year in the U.S. that more monitoring is not in the labels outside the U.S. So the transitions can happen a lot faster because you don't have to do this additional monitoring. But I'm really happy with how the Alyftrek launch is going. Almost all new patients in the U.S. who start on medicine same thing in the ex U.S. regions where we have approval and reimbursement, all the new patients are starting on Alyftrek. And so the bottom line on that I would say, Alyftrek is the emerging standard of care for CF. And so as we start to think about the next generation of medicines in our portfolio and what do we want to bring out next, now we're trying to beat Alyftrek. We used to try to beat Trikafta.

Thinking about the growth algorithm for CF going forward, even as the market has matured, the company has still been able to grow revenues substantially faster than population growth. What are the drivers of that? And what's your most relevant looking forward?

Yes. There are 3 or 4 drivers. The most important is patients with CF are living longer. This is a chronic medicine, patients start at the lowest age group where we have an approval. So for our oldest medicine, KALYDECO, which was approved circa 2012, 2013, we're down now to 1 month old. So they start at that age and they continue lifelong. So the biggest driver is patients are simply living longer. A second driver is this march down in age group. When we start doing our clinical trials and get approvals, we start with the adults and then we go to 5 to 11-year olds, for example, then 2- to 5-year-olds and so on and so forth. And as we bring these medicines out for the lower age groups, more people come on medicine. The next one is growth through geographic expansion. The vast majority of patients because of this founder effect that I mentioned are in Northern and Western Europe and the Americas, that's where we get regulatory approval first and reimbursement first, and then we make our way to the other countries, think Turkey, think Brazil, and there's growth in those areas.

And lastly, as we discussed when we went from SYMDEKO to Trikafta, we went from 60% eligible patients to 90%. With Alyftrek, we're up to 95% so these ultra rare mutations, and those patients now can also be treated with these medicines. You add them all up, and that's where we get the growth. I think it was about 7% growth in CF in 2025. In Q1 '26, we reported 6% growth in CF.

Turning to competition. Stock has been under a little bit of pressure heading into the competitor readout that's coming up this summer. Obviously, no one knows what the data is going to look like. But maybe speak to your confidence in the durability over the long term of the Vertex CF business, including in scenarios where the competitor meets the bar that they have set.

Yes. For those of you less familiar, there is a company that is supposed to report results from a late Phase I so let's call it a Ib study in patients with a medicine from their portfolio added to our medicine, Trikafta. So that's what we're talking about here. I think the important -- to the direct question about my confidence in the durability of our franchise, the overwhelming majority of patients who are eligible for medicine. And when I say overwhelming majority, I mean 90% plus patients who are eligible for our medicines are on medicine. They start their medicine in the case of KALYDECO at 1 month of age.

And in the case of Trikafta at 2 years of age, and they continue this for life. People take their picture and they send it to us, and they post it on social media with their Trikafta box or their Alyftrek box, there's an emotional attachment to their medicine because it's the first thing that has made them feel not like a patient anymore. And so when I see that kind of the data are spectacular with the medicine, it's the one area that I've worked in where the data actually gets better in the real world as we collect registry data and such than what you even saw in the clinical trial, I expect that our franchise will be durable for a long time to come because of safety, efficacy in the clinical trials added to safety and efficacy in the real world, added to going all the way down to the youngest age group.

It's very difficult to imagine that a child who starts on medicine that's helping them at age 2 does that -- continue with that medicine later on? Last thing I'll say is if you think about KALYDECO, which was our first medicine, the first approval was, let's say, 2012, 2013, it was in 2024 that we got down to 1 month olds. So that's a 12-year journey, and we work exceptionally fast. So that's a long time for one to be in an area and to keep that drug development effort up. We can talk very specifically about details, but I think the top line is I have very high confidence in the Vertex portfolio. At the end of the day, if somebody wants to add a medicine to Trikafta, I find that interesting. Trikafta is still a Vertex medicine.

Serial innovation has been a big part of the Vertex R&D strategy as it becomes increasingly difficult to demonstrate incremental benefit on FEV1 relative to your new products, like what's your interest in running -- collecting either longer-term outcomes data or extra pulmonary disease manifestations, just other ways of measuring the incremental value of your new products.

Yes. So Will, this is an incredibly important question because we're coming upon a time for CF that one might liken to the journey that, for example, multiple myeloma went through or disease like HIV, we're at the point where the measurements we used to use, we have reached an asymptote and so the question is an excellent one. Well, what next? I think it's actually a really, really difficult question to answer. When we look at carriers, carriers are those people who have one CF allele, they are the parents of kids with CF, for example, they have no disease that you can identify. They're fairly normal. You can think about their sweat chloride levels and the variability around that.

When we look at the Alyftrek sweat chloride levels and the variability around that, they're virtually superimposable. So we're at that -- our goal for the last 25 years was get our patients to carrier levels of sweat chloride and we seem to be approaching that asymptote so we are looking at these very long-term outcomes, like you mentioned, what happens to exocrine and endocrine pancreas function, what happens to liver function, what happens to longevity, what happens to hospitalization, lung transplant, things that take years and we do that work in registries because we're very fortunate. CF has almost 100% capture in the U.S. registry and there's an equivalent registry outside the U.S.

I don't know that it's humanly possible to do an RCT. We've done some detailed evaluations. It would be thousands of patients in a rare disease and very, very long periods of time. And I don't even know if that's really required because of the registry being as robust as it is. I'll tell you one anecdote in the country of Switzerland there are virtually no lung transplants. I think there was one done in 2024 compared to many being done for cystic fibrosis for this reason. So I think that the registry collection of these kind of long-term data are going to be very telling, which is why I go back to the durability of the franchise. It takes 5 years, 10 years, 15 years to look at longevity pulmonary transplants, hospitalizations and such, and we are fortunate to have that data.

Excellent. Moving to pove, I wanted to ask about the upcoming launch. So this is your fourth franchise, but it's also the first one in which you're competing directly with other branded therapies. How are you approaching the launch differently?

Yes. So pove is the asset that we acquired through the Alpine acquisition in 2024, it is what is called a dual APRIL/BAFF inhibitor. It's a way of modulating B cells, and it is B cells that are the bad actors for this disease, IgA nephropathy. There are other medicines that are trying to do the same thing. And what I would say is clinically, scientifically, medically, the difference for pove is that it's highly potent, has very high binding affinity, has really excellent tissue distribution and therefore, has qualities that lead to the kind of profile you've seen. We've put out a press release that hasn't been presented at a conference, it will be. But the press release was frankly a Novella. It's very detailed and you can get most of what you want to see.

The efficacy is, it looks best-in-class. The safety, it looks very favorable. And very importantly, and I want to emphasize this, this is not an add-on or a nice to have or look at that how sweet. It's very, very important. This is another chronic biological therapy. It's an injectable. You have to take it over the course of your lifetime. Our medicine is once-monthly low-volume 0.46 mLs auto-injector at home. And that suite of clinical efficacy, favorable safety profile and these characteristics, it's not the Trikafta, which is our medicine in CF, but it is the trifecta of what we are looking for in this disease. So I'm thrilled with the results. We are planning our launch as we speak.

We've hired our field force. We've deployed the first wave. We are looking to bring our high science sell approach that we have in CF to nephrology. We're looking to cover 80-plus percent of the nephrologists who serve the patients who have this disease, we're looking to bring the best-in-class patient services programs like we did in CF. And the other advantage we have is we're already well underway with additional renal diseases that could be tackled by this medicine.

So physicians -- as nephrologists as we learn how to use these medicines and as you know, we've had a dry spell in nephrology for 20 years. So this is a very new period for us with medicines that can actually tackle the underlying cause of disease. This is a medicine that we can use in multiple renal diseases, which I see as a great advantage. I happen to be a nephrologist by background and training. And so I can say that this is one of the most exciting periods that we've been through not just for Vertex in general in our field.

On the payer front, how aggressive do you expect them to be in trying to extract concessions for favorable access, particularly within the APRIL and/or APRIL/BAFF class?

Two comments on that. One is the consequence of having something like IgA nephropathy or any of these aggressively declining renal function diseases is death dialysis or transplantation. It's very obvious what's going to happen. And in that regard, those consequences are very well understood by payers, the expense of transplantation or dialysis is known and very high. And I think for that reason, payers are very educated on this field and are willing to pay for medicines that bring value. So that's a good foundation. And you can see that with the most recent launches that have happened in this area. With regard to rebates, discounts and all of that, that's part of how the U.S. system works. And it's important, therefore, to have a really high-class payer access team, and we have that.

PMN is your second indication for pove and I believe you recently completed the Phase II enrollment. Could you frame the opportunity here and compare and contrast it with IgAN?

Yes. So IgA nephropathy and PMN, primary membranous nephropathy are both what we call glomerular diseases. These are rare, but common rare diseases. If we say there's about 350,000 or so people with IgA nephropathy in the Western world and another 1 million-plus in Asia, there's about 100,000, 130,000 people with membranous nephropathy in the Western world and then add a few hundred thousand more in Asia. This membranous disease is another B-cell-mediated disease. In this one, your B cells are making antibodies to something called PLA2R. In IgAN, the B cells are making these antibodies against something called GD-IgA1. So they're similar in that there, these glomerular diseases. They're well understood. The way you know you have one of these diseases is you have a decrease in kidney function, you're spilling protein or blood in your urine, your doctor does a biopsy, and we know the diagnosis. So those are commonalities.

In membranous, we're trying to curb the amount of PLA2R in your body and we're trying to get your proteinuria down and we're trying to get your hematuria down and we get into -- we want to stabilize your renal function or you don't move on to death dialysis and transplantation, very similar goals to IgA nephropathy. There, we're trying to get your GVIGA1 down, proteinuria down, hematuria down so that you don't go on to these bad outcomes. That one, exactly, as Will said, we have our data in membranous and it's very good-looking data in something called the RUBY-3 study. It was a basket study that our Alpine colleague started. So we know that the data look really nice.

The Phase II portion of the Phase II/III study is done in terms of enrollment. The Phase III portion of the study is up and running. And this one is a traditional approval. Remember, the IgA nephropathy is an accelerated approval. This one is a traditional approval. We need to treat patients for 104 weeks, and remission is the endpoint for membranous. Same drug, though, pove. The thing that we are doing in the Phase II portion is dose-ranging pove. The dose for IgAN is 80 milligrams, and we're testing 80 and 240 for the membranous study.

Moving to AMKD, you're seeing investors begin to -- yes, yes. You're seeing investors begin to dig into that a little bit more. What are the aspects of the drug and the trial design that give you confidence for that Phase III trial that you've got? And maybe you could touch on the implications from the MAZE data that came out.

Yes, yes, definitely. So continuing with the alphabet soup of kidney diseases, AMKD is APOL1-mediated kidney disease. As I said, I was a trained nephrologist, I finished all my training in the early 2000s, this disease was not even named when I finished being a nephrologist so this disease was just described in about 2010 or so. So it's very new. It's a disease that comes about by having 2 of these APOL1 alleles. It's a disease of people from sub-Saharan Africa only. And it's a disease where you have exceptionally aggressive decline in kidney function.

So if you have 2 APOL1 alleles, you have a decline in renal function -- GFR and you're spilling protein. Those are the people we studied in our Phase III program. The Phase III program has an interim analysis built in, and we have an agreement with the FDA that if the interim analysis is positive, we have a path to accelerated approval. That interim analysis cohort completed enrollment last year. We expect results from the interim analysis in early '27. The full enrollment for the study will complete this year, and we're on track to do that. And what you're really looking for here is GFR stabilization. That's the endpoint that we and the agency have agreed to at 1 year.

That's a real move for the agency because usually unlike in certain diseases like IgAN, where they've gotten to a point of comfort for proteinuria to be the accelerated endpoint, you have to do 2 years. So that -- the study that I'm describing in AMKD is a 2-year study, if we meet the accelerated approval endpoint that we will know next year early. Will mentioned MAZE data. It's another company. And while I don't like talking about other companies, I understand that you'd like our perspective on this. So here's what I'll say. The Vertex belief is that when you are studying something like AMKD, but you add some heterogeneity into that, it is unclear what you're going to get at the other end. And so we don't do that.

So our amplitude trial, that's the Phase III study I just described is 2 APOL1 alleles, heavy proteinuria, no other kidney disease. That's who we studied. It is worthy of study to think about people who may have 2 APOL1 alleles, modest proteinuria and a low renal function. It's a perfectly good question. And we're asking that question in a separate trial called AMPLIFY, that's in Phase II. It's also worthy question to ask what about 2 APOL1 alleles and a second disease that can impact the kidney, think diabetes. It's a good question to ask. But these are different than the Phase III program because in the modest proteinuria group, you have to have some amount of headroom to show a reduction in protein. There has to be some amount of dynamic range. So we did not want to mix the modest protein group with the heavy protein group.

And if you throw in a second disease like diabetes, you don't know an epidemiology that you can study tells you it's a bit unknown how much of the contribution of renal disease is the APOL1 part of it and how much of the disease is the diabetes part of it. Our drug does not take care of diabetes. Our drug only takes care of the APOL1 part of it. So we've studied those 2 patients, modest proteinuria and what happens with a second kidney disease in a separate trial called AMPLIFY. That's in Phase II. I expect the results in the second half of this year. If the results are positive, that would mean we have the opportunity to add another 100,000 or so patients to the epi of amplitude. So we believe there's about 150,000 people or so that would be eligible based on amplitude. If this is positive, I would add another 100,000. If it is not positive, it means nothing for amplitude.

And the relationship to the other companies that they studied diabetics and nondiabetics in their Phase II trial and they made some divisions of people who have a particular kind of kidney disease, another alphabet soup term called FSGS. But by the time you do FSGS, non-FSGS diabetes, non-diabetes, there's 2 people in each cell and it's very, very difficult to tell what the answer to the question is. And so I think in retrospect, you'd say the wisdom of our decision-making was sound to do this separately. Our data from Phase II is 46.7% reduction in protein, that's a very strong number. And so I'm looking forward to the amplitude results.

Thinking a bit more Blue Sky, do you think this drug perhaps at a lower dose could help prevent AMKD in the first place?

I think it's a really interesting question. And I think it's honestly not so much about the drug as it is about the pathophysiology of disease for AMKD. The best that we understand AMKD, we understand a lot of it. It's a genetic disease. It takes 2 alleles. If you have 1 allele, it does not look like it has a risk associated with progression of kidney disease. If you have 1 allele, it prevents -- it is protective against a particular kind of disease in Africa. So it's kind of like if you think back to the malaria story. So it has all of these relationships. What the protein does is it punches pores, holes in the glomerular basement membrane, which leaks potassium, which then leads to damage in that leaks protein. But it does look like you need a second hit.

That second hit is it might be an infection. It might be an inflammatory reaction. It might be something that we can't figure out. But it does look like you need a second hit and so the prevention question is interesting because how will we know if we actually prevented the disease or you just didn't get a second hit on the disease. I also think preventative medicines are more difficult from a payer access perspective because it is hard to know whether you were or were not going to get the disease and did you prevent it. So I think the best way to do drug development in this area is look at patients with 2 APOL1 alleles with proteinuria and reduced renal function and treat them and treat them early so that they never go on to this horrible outcome of death dialysis or transplantation.

Moving to pain. Maybe you could talk about where you are in the launch today, and there's a lot of questions about when we'll start to see realized price improve?

Yes, yes, yes. So pain for us, most people divide pain into 2 categories: acute and chronic. We are Vertex, we do everything differently. So we do pain into 3 categories: acute and then we have neuropathic and then we have everything else. Neuropathic and the everything else are forms of chronic pain. But the reason we divide it that way is because we are most interested and believe that we can commercialize with our specialty sales force approach in acute and neuropathic. I believe that our medicines will work on the other think musculoskeletal pain, low back pain, I believe our medicine will work in that chronic condition, but we won't commercialize in a primary care area so we'll get to that later. So I'll put that in a box.

Right now, what we're talking about and Will's question pertains to acute pain. We've launched this medicine called JOURNAVX. It's a NaV1.8 inhibitor. It's a peripherally acting drug that is a non-opioid, does not have addictive potential. And I can say that confidently because there are no receptors to NaV1.8 centrally. This is a peripherally acting drug. We launched it in March of last year. We talked about the fact that we've had over 500,000 scripts by the end of last year. And our guidance, and I feel very confident about it is that we will 3x the number of scripts this year, and we will more than 3x the revenue this year. The use is broad, commensurate with the label, surgical and nonsurgical uses. In surgical, the bread and butter uses post hip surgery, post knee surgery orthopedic surgeons, general surgeons doing belly surgery, anesthesiologists using this medicine.

And in the community, it's fractures, sprains, acute flare up of whatever pain that ails you very broad base of prescribers. I like the depth that we're seeing and about 50% of the use is in hospital and about 50% of the use is in the community. The important point is that we see this as a franchise that we are going to build and hopefully lead in over the next not only years but decades. Acute neuropathic and we will also get to chronic, although, as I said, we won't commercialize there by ourselves because I do see that as a primary care sell. So as you think about this franchise that we're looking to build and lead over many, many years, if not decades, we want to do a couple of things, which is make sure that the pricing is commensurate to the value that this is bringing, make sure that patients and doctors who want to use this medicine have a seamless experience.

And therefore, while we go through the access which takes time that patients get the medicine. And so we have a PSP program, a patient support program. We provide free drug if the patient comes to the CVS counter or wherever they go and the drug is not yet covered by their insurance company, we cover the cost. And what that means is that the gross to net isn't yet normalized. We said that we expect the gross to net to normalize by the second half of this year. I expect that, that will happen. And I expect that the revenue will not only be commensurate with the script growth, but it will exceed the script growth as we guided to earlier in the year.

Great. One question from the audience. You've invested more in sales and marketing for JOURNAVX than originally envisioned. Is pain still a Vertexian category and is Vertex still the best owner for this drug.

Yes. I love the word Vertexian. That's how we describe ourselves. Yes, Vertex is the right group to commercialize this medicine. We secured all 3 major PBMs in terms of reimbursement at value that recognizes this innovation in less than 1 year. That is not an easy task and it is indeed Vertex who did that. On the sales force size, we are a specialty sales force company, right? That doesn't mean we are going to have a sales force that is the CF size. CF is 14. That's not specialty. That's very specially CF. We had always planned to bring more sales reps on at the right time. When the reimbursement got to be at a particular point, we thought that would be the right time to pull the trigger for a bigger sales force, and that's what we did. Because obviously, early in the launch, it was not a reimbursed medicine. There was a lot of the PSP program in play. So I know that we've been thinking about this diligently as we think about everything. The first wave was the first wave by design. The second wave was the second wave by design. And I'm looking forward to doing even more in this area.

Great. One more here on the diabetic pain study. Could you speak to how important it is to beat Lyrica versus just a placebo?

Yes. The regulators have been abundantly clear. We have to beat placebo that is what they want to see. That is the bar for regulatory approval. We decided to include a gabapentin arm in one of the 2 studies so that we had a reference group so that we can have some kind of context for the magnitude of the treatment effect, but it's extremely clear what we need to do.

Okay. You've talked about acute pain alone being a multibillion-dollar opportunity. Could you talk about the role that evidence going forward needs to play to unlock that?

Yes. So in acute pain and often is the case for medicines that are used inside the hospital setting or within a hospital network, hospitals want to do their own studies, networks want to do their own studies. And pain is very interesting, right? They have a very broad label by design. It is -- JOURNAVX is indicated for the treatment of moderate-to-severe pain, whatever the etiology and we did the data package for what the regulators wanted to see. So we're doing a lot more Phase IIIb, Phase IV studies and providing a lot more data post the approval because it's such a broad label. So for example, we published some data in abstract form that has to do with the use in a variety of other surgical types, knees, shoulders, belly procedures, aesthetic procedures.

And what we're doing in this is looking to see how it's used in multimodal therapy. Of course, the regulatory -- the studies we did for regulatory approval are monotherapy because we wanted to study the pure effect safety and efficacy of a single therapy. But that's not how medicines are used in the real world. Pain medicines are using multimodal approaches so these studies that we completed are multimodal use, and we evaluated, for example, the -- what happens to opioid use and opioid use goes down compared to historical controls. And we intend to do more of this as people tell us they're interested in the use in spinal procedures or they're interested in the use. There's actually an interesting use going on in the community, especially with oral surgeons who do wisdom teeth extractions in young adults and they're particularly sensitive to not wanting to prescribe opioids. So there's a lot more study going on because there's a lot more interest.

Great. And when do you see the first NaV1.7...

So this is a really important program, a very hard nut to crack. NaV1.7 has even -- this is sodium voltage-gated channels 1.7 as opposed to 1.8, which is JOURNAVX. It has even more genetic validation than NaV1.8. The NaV1.7 is the -- you'll remember the Kindred, the family in Pakistan, who are fire walkers, they feel pressure, they're normal in every other way, except they don't feel pain. That's where the big idea came from many years ago to study 1.7s. Everyone has tried to do this, including ourselves, and we've been at it for more than 20 years. It's just a really hard nut to crack. I'm very happy with the progress that's been made. I will call it in late preclinical development.

What you can take away from that is that we have chemical matter. And the real big idea here is, I would like to leapfrog where we are, take the NaV1.7s, which I believe would work as a monotherapy, but combine them with NaV1.8s and make that combination the next wave of drug development that we do. For the uninitiated, that's scientifically very elegant to me because NaV1.7s are what's responsible for the initiation of the action potential and NaV1.8 carries that action potential. So it makes so much sense to me to combine the 2. Preclinically, what we see is NaV1.7 plus NaV1.8 has a synergistic, not additive but synergistic effect. So super exciting. I'll just leave it at late preclinical development.

Okay. Okay. On capital allocation, are you considering any change to your historical approach, for example, ramping the buyback or a larger appetite for BD?

No. I think our approach to capital allocation has worked really well. We are very interested in using our capital to support innovation, be that internal or external. You know our sandbox, you know our approach that applies equally to anything internal, anything external. Commensurate with our increasing size and our balance sheet, we are doing more stock buybacks, and I think that's a really fruitful way to return value to shareholders. So you should expect more of the same.

Okay. Okay. In the past, you've described Vertex as TA agnostic. But now that you're starting to build more of a critical mass in renal. Is there a case to be made that, that should make this more of a deliberate focus going forward?

I know it's going to sound unbelievable, but it is true. The reason we have a renal franchise is not because I'm a nephrologist. It really isn't. And we didn't go about trying to create a renal franchise. Our sandbox of diseases, and you know we are a disease first company. We're not a therapeutic area company. We're not a platform company. We are at our core and part of our strategic underpinning of our R&D strategy is to be a disease area company. AMKD, the whole alphabet soup, APOL1-mediated kidney disease, it's in our sandbox. ADPKD, which we didn't talk about, but that's another renal program in Phase II development. That's a really neat program. This is autosomal dominant polycystic kidney disease because it's also a protein-folding defect, which harkens back to CF, which is also a protein-folding defect, that's in our sandbox.

IgA nephropathy was in our sandbox. Membranous was Sandbox adjacent because it's a smaller disease and we would have gone after IgAN, which is in our sandbox, but membranous just comes along because of all of those similarities. It just happens that these all are in renal. We are not anti-synergy. Please don't get me wrong. We love the fact that we have 4 diseases in a given vertical. It's fantastic. But I also don't want to leave you with the wrong impression. Our core belief is that we are really good at understanding causal mechanisms of disease and then going after those and we're not afraid if one of the diseases we understand and have deep insights in and we think we can crack that one, if it happens to be CF, which is a pulmonary disease.

And if the next one, we believe we can go after is in the kidney. We're not afraid of that. Sales and marketing is not the hardest thing in our industry. Translating basic science from the lab with higher success rates than has been industry average -- that's the big problem in our industry, and that's why we've oriented ourselves around this strategy, which we believe will lead to greater success. It's not going to be 100% success, but we believe it's going to lead to greater success.

We're nearing the end of our time today, and we hope to have you back next year. So in that vein, how do you think that Vertex could look differently as a company a year from now? And what would you highlight as especially notable for investors?

I think the biggest thing to look for is the emerging fourth franchise from the company. And it will happen to be in renal.

All right. Very good. Thank you so much.

Thank you, Will.

All right. Well, thanks, everybody, for being here. Again, I'm Brian Abrahams, senior biotech analyst here at RBC Capital Markets. Really pleased to have our next featured company, Vertex Pharmaceuticals, represented by their CFO and COO, Charlie Wagner. Charlie, thanks so much for being here.

Yes. Thanks for having us.

So a lot I would love to cover, but why don't we start -- why don't we start with CF. It's obviously been a core driver for many years for you guys. Can we talk about the growth opportunities in CF? And maybe in the near term, can you elaborate a little bit more on the additional 800 patients you've talked about with the Trikafta and Alyftrek label expansions this year. I guess, just what we should expect the cadence of those patients coming on therapy to look like? How quickly you're seeing that happen? How much of that -- how many of those patients were already being treated off-label?

And then as we kind of look beyond that bolus, 2027 and beyond, what do you -- and some of the additional age and geographic expansions, what do you foresee as the key additional growth drivers for the CF franchise over the long term? Because it's continued to grow so nicely and you reach more and more patients. Talk to us about what the cadence looks like from here on end?

Sure thing. Yes. Listen, we are -- continue to be really excited about CF, very proud of the leadership position that we've built over the last 20 years. We have an outstanding portfolio of medicines and hundreds of thousands of patient years of experience at this point, and yet the business continues to grow. Generally speaking, the playbook in CF has been a few drivers. It's serial innovation. It is moving to younger patients. It is picking up patients with rare mutations who maybe couldn't benefit from previous generations of medicines. It is geographic -- expanding access and reimbursement through geographic expansion. And then lastly, there is a benefit from price increases as well.

You see all of those playing out in the guidance that we gave for 2026. And maybe if you don't mind me backing up, the company's guidance for the year is revenue of $12.95 billion to $13.1 billion. We said that, that includes $500 million or more from Casgevy and Journavx. So implied the resulting revenue from CF, and that implies healthy growth over 2025. And it's all of those drivers. Obviously, we see the Alyftrek uptake, both in some naive patients, particularly those with rare mutations, some from patients who've discontinued from previous medicines and then significant switching for Alyftrek as well.

And we will talk about that as well.

Yes, and that's the serial innovation piece. We continue to see younger patients coming on medicine. And then we haven't talked as much about geographic expansion this year. But for example, Alyftrek, we got Alyftrek reimbursement agreements done in 11 countries in the first quarter. And then Alyftrek aside for a second, in recent years, we've expanded to markets like Brazil, Mexico, Turkey, not some of the core European markets where that drove the growth 3, 4, 5 years ago. But those markets have a significant number of patients, and we continue to try to reach CF patients wherever they are around the world.

So if you look at 2026, I would say healthy growth drivers. The themes will be the same in 2027. We are filing for approval for Alyftrek 2 to 5 late this year, Trikafta 1 to 2. And so hopefully, we would expect approvals in those younger age groups next year. You'll continue to see some geographic expansion. So very much the same themes. Year-to-year, the mix is a little bit different, but we continue to see growth in CF.

Excellent. And then maybe speaking of Alyftrek, conversion seems to be progressing steadily, I think, particularly outside of the U.S. How has this aligned with your initial vision? And are there ways to accelerate this further in the U.S.? How have -- have some of those initiatives started to take hold? And what is the level of importance on conversion? Or is this something you just will kind of step back and let play out organically over time?

Yes. Listen, it's crystal clear to us that Alyftrek [Technical Difficulty] outstanding efficacy in ppFEV1, great results on sweat chloride, great safety profile, convenience of once-a-day dosing. So it is the best CFTR modulator we have. That said, we've learned that people are super loyal to their Trikafta. And so that's not a terrible thing either.

They're doing well on it.

Yes. They're doing incredibly well. So if you look -- we have said we've described the rate of switching from Trikafta to Alyftrek in the U.S. as steady, and that continues. And to your point, certainly, the results in the first quarter were very good.

Outside the U.S., you see even, let's say, a steeper ramp Alyftrek for a couple of reasons. One, I'd say European physicians are very, very attuned to sweat chloride and the advantages of Alyftrek on-sweat chloride are very clear to them. The label is a little bit different in Europe and therefore, doesn't require liver monitoring to switch. And so there's less of an impediment there. And then lastly, there were a series of rare mutations that were picked up in the Alyftrek label, and there are more of those rare mutations in Europe than there are in the U.S. So you do see a little bit of a steeper ramp in Europe in markets where it's reimbursed.

So important, I mentioned we had 11 reimbursements in the fourth quarter. We are -- Alyftrek is reimbursed in several large markets like the U.K., Ireland, Germany, Italy, but not throughout Europe. So there are additional reimbursements to gain over the course of this year that will also fuel the Alyftrek ramp. So I would say, overall, it's been very much in line with our expectations. I think we reported in the first quarter earnings call that cumulatively now Alyftrek has surpassed the $1 billion mark since launch. And if you look at the kind of sequential ramp in the first quarter, I think things look really good for a very strong year for Alyftrek.

Excellent. Great. Let's shift gears to acute pain and Journavx. I know you guys have talked about a lot of really good progress you've made on Medicare deals, securing reimbursement access overall. What's left to do? And when should we expect that we're going to start to see the strong prescription density you're seeing pull through to revenue -- more robust revenue growth? I know there are some first quarter dynamics like inventory that may have obscured things. But maybe talk us through what's kind of the expectation on that?

Sure thing. No, listen, I personally am very excited about the Journavx launch and the progress that we're making. Again, if I could bring it back to the guidance, we said that Journavx and Casgevy combined would represent $500 million or more of revenue this year. Additionally, with regard to Journavx, we said that prescription volume would triple compared to 2025. We are off to a great start on that in the first quarter. And prescriptions will triple and revenue will more than triple because there will be a higher revenue conversion as gross to net normalized. So you can sort of take all that into account.

First quarter, you asked about progress. The progress on access has been fantastic. So we previously reported we got the third of the large PBMs signed at the very end of 2025. Those -- as you contract with those, sometimes it takes a little while for the economics to trickle down into some of the subordinate plans throughout the first quarter, but we've made very good progress there with commercial payers and are largely done. We secured a large Medicare provider in May and are in conversations with a couple of more. We would hope to have an update on that sometime this summer. We'll see. Negotiations take as long as they take basically.

But at this point, we have 240 million covered lives. And so we're really far along in terms of our expectations for coverage and certainly would hope that by the end of this year that we're not talking about access and coverage anymore. I think that would be the goal. So with that, as we gain coverage, we are able to roll back some of the free drug that's being offered through the patient support program. That, of course, in turn, helps normalize gross to net. And as that gross to net normalizes, you get better revenue conversion on the prescriptions.

So you mentioned the first quarter, we had 350,000 prescriptions, $29 million in revenue. There was -- I appreciate that outside the company, you can see revenue and you can see prescriptions. What you can't see is shipments. And so there is a little bit of a timing difference between shipments and prescriptions. And so we had a small channel inventory build in the fourth quarter that drew down in the first quarter. I'm not expecting to talk about that any further in the second quarter. And we have said publicly, we expect to see a meaningful sequential ramp in Journavx revenues in Q2.

And so we shouldn't expect that access would come with any more barriers than the free drug program? In other words, should -- will removing the free drug program change the cadence of utilization?

Yes. In our view, it should not. So we have worked very hard in these contracts to avoid things like step edits and other impediments to accessing the drug. In some cases, that's why it's taken longer to negotiate contracts. But that's -- in our view, that's well worth it. We don't want there to be impediments to accessing a drug like Journavx, and we're willing to wait and secure the right type of access at the right value. So again, now 5 quarters, if you will, into the launch, I think we're -- I think access and coverage is becoming less and less of a story, and now it's about revenue conversion.

Great. Let's talk about some of the pipeline. So on povetacicept. Our KOL feedback has indicated a huge appetite for APRIL/BAFF agents in IgAN, but maybe a little bit less certainty around how the late-stage agents differentiate from one another. What are the key learnings that you can take from the [indiscernible] launch about the market and your commercial strategy that can potentially benefit you as a fast follower there? And what do you think you need to do to convince docs around pove's differentiation, especially once -- one, if not more, of the other competitor drugs potentially do have a once-monthly subcu label?

Yes. No, I appreciate the question, and it's good that your KOL checks match ours, which is that for those docs that distinguish between APRIL and APRIL/BAFF, there's a very strong preference for APRIL/BAFF. I would say we've said with pove, it's an engineered fusion protein that engineering leads to greater binding affinity and potency and PK distribution. So pove really is designed to be optimal for impacting APRIL/BAFF.

We've talked about the profile. You saw the results from the trial that we published recently, 52% reduction in UPCR, 77% reduction in Gd-IgA autoantibodies, resolution of hematuria. So across -- and that was true -- the numbers aren't -- that the efficacy impact was true across all cohorts. So gender, age, race, geography. Importantly, the impact is deep and sustained across all types of patients, which we think is very powerful.

Additionally, the safety profile was excellent. No SAEs attributed to pove. No serious -- very low incidences of serious infection, similar to what we saw with placebo. Nobody discontinued the trial because of SAEs or serious infections. So a great profile there. And then lastly, we do think the presentation of the drug, the patient factors are important as well. It's a low dose, 0.46 mL monthly dosing auto-injector. So the convenience -- not just convenience, these drugs only work if you take them. And if you're worried about a self-injection, a format like pove is outstanding.

So we think it's the Trikafta, if you will. It's the combination of those factors that really differentiate pove, and we are certainly in our pre-approval conversations out there emphasizing those benefits. You asked specifically about the Otsuka launch. It seems like the launch is off to a good start, right? And that's great. I think our view is that this is a huge market with a lot of unmet need: 160,000 patients in the U.S., more than enough room for multiple transformative therapies. I have no doubt our view is that pove is a best-in-class offering, and we intend to be delivering that message consistently.

But the early signs on that launch are promising because there are patients there that are eager for access to transformative medicines. Timing-wise, obviously, we have submitted for accelerated approval. We're waiting for acceptance of the filing, hopefully very soon. And if that is the case, then we would at least be on track for the possibility of accelerated approval at the end of the year.

Okay. We're coming up on eGFR data from Otsuka in the very near term. So I guess what do you guys think constitutes good data versus not good data? And what's good for Vertex and pove?

In our data or in their data?

In their data. Because this has the potential to validate the connection of proteinuria -- further validate the connection of proteinuria, validate I think is eGFR, further validate time if there's room for improvement, that could also benefit you guys. I'm curious what you guys are expecting, looking for or hoping to see.

I think the literature and the KOL view and our view is that proteinuria reduction and eGFR stabilization are very, very highly correlated. You see that in the data from the RUBY trial and from other companies' trials that there is a high correlation there. So I suppose with the Otsuka eGFR data, we're not expecting any surprises. I think the correlation is well understood. But we'll see.

With pove, again, part of the filing for the accelerated approval, we're submitting, of course, UPCR and eGFR data. We're not able, because of agency restrictions, can't communicate the eGFR data at this point. But given the high correlation between the 2 markers, we're not expecting any surprises there.

Okay. And then beyond IgAN, you have a program in gMG, generalized myasthenia gravis as well. How important is that market? And how quickly can you move into a pivotal study there?

Yes. So as we talk about gMG, we should just talk a little bit about PMN as well. I think between IgAN, PMN and gMG, you can already see validation of the thesis that we had about pove being a pipeline and a product. And I am personally really happy to see that playing out so quickly. So we do have a trial ongoing in PMN as well, Phase II/III there.

Specifically, you asked about gMG. We think that pove is really well suited for gMG. GMG is sort of a prototypical B-cell-mediated disease. The majority of patients with gMG have elevated BAFF/APRIL levels. Pove targets BAFF/APRIL. So we really feel confident that it's a good fit. There is -- as you well know, there is data from another company in China that shows that these mechanisms can have a serious -- a significant impact on gMG. And so for those reasons, we had confidence in moving forward into a Phase II trial.

I can't really give you an expectation on timing. That trial is enrolling and it will take as long as it takes. But we do think pove is well suited, not only because of the mechanism and the impact on BAFF/APRIL, but also because some of the existing medicines for gMG have limitations because patients have to cycle on and off because of concerns about adverse events, whereas we believe pove is going to be able to be dosed chronically given the safety profile and that consistency of action on the disease, we think is valuable. So we think there's a great opportunity. We think pove is very well suited to it, but we'll let the data speak for itself.

Okay. Good. Going back to CF for a second and on the -- maybe some of the next-generation agents. I know you have several in development, 828, 581, 272. You guys have been serial innovators in the space. I guess when would you make a go -- what will you be looking for to guide a go/no-go decision there? And if you see some early biomarker data that looks strong, are there ways to potentially craft a pivotal program to potentially enable a next-gen to reach the market even if you may already be at a ceiling in FEV1 with Trikafta and Alyftrek? Like I guess, how can you do -- what are you looking to try to show so these next-generation drugs can actually do better than what's out there, sort of high bar you've set?

Yes. And if you don't mind, I'll just kind of reaching back to what I said earlier, Alyftrek is the best CFTR modulator on the market. We think the benefits even over Trikafta are meaningful. And so it sets a really high bar for subsequent development by us or anybody else for that matter. That said, given our decades of leadership and our commitment to the CF community, we're going to keep trying to do better than Alyftrek.

One of your questions was about when -- what are we looking for and when will we advance. And I think the answer is that we want to keep that to ourselves right now. So we will have data on 828 later this year. Of course, we'll be looking at things like safety and tolerability and sweat chloride, looking at some other dimensions as well. Behind 828, we have 2 other molecules as well, and they're not so far behind 828. So there's a scenario where we wait to see which is sort of the strongest horse in the stable there or it's possible that the data is so compelling that we move right ahead. So we're going to reserve the right to make that choice. In terms of trial design...

How do you move ahead?

And going faster. I mean, listen, the agency is pretty clear on endpoints for CF trials and they're crystal clear on the existing standard of care. So while we like to think of ourselves as always innovating, including in our approaches to regulatory, I think the reality is that we or anybody else is going to have to run a full large trial against the standard of care. And so I'm not sure there is a way to make that go faster, again, for us or anybody else.

Okay. Maybe just in the last few minutes, you guys are in a pretty favorable capital position. In fact, we did an analysis, and this was sort of back of the envelope. But from what we can tell, you're one of only 2 large biopharma companies that are net cash positive that don't have net debt. You've had some time now to absorb Alpine. I guess where do you stand with regards to that overall integration? And just because you're in a favorable capital position doesn't mean you need to necessarily deploy your capital and you can be opportunistic. You have -- but how do you think about that overall? What's your appetite for looking externally at BD opportunities? Do you like what's out there? Where might you go? What are the ways you might deploy this capital?

Yes. It's a great question. And it's -- in my 7 years with the company, it's been very interesting, which 7 years in the scheme of things isn't that long, and the company had only become cash flow positive slightly before that, right? So we don't have a long history with capital deployment. But that said, in the 7 years, I think we've been pretty responsible.

So top priority does continue to be investment in innovation, both internally and externally. So we have an appetite for BD. I am really proud that we got the Alpine deal done in 2024. And again, like I said, it was the right deal, the right disease, the right size, the right stage of development. And I think the whole -- not only pove and IgAN, but the pipeline and the product really is validated by what we're seeing. So that's encouraging.

It's fully integrated at this point. And so the organization has capacity. I mean it was a significant effort to integrate it and accelerate it, but that -- I think it's in a steady state right now. So BD continues to be a top priority. Maybe the only challenge, and I think it's a good one, is that we have incredibly high standards for science and medicine. So there just aren't a lot of assets or companies that kind of clear the hurdle for us. But when we find one that does, we move decisively, and that's what we did with Alpine.

So we are active in BD. We'll continue to be active and do what we need to grow the portfolio. As a secondary use of capital, we've also scaled our share buyback program over the last several years. Again, at the beginning of my tenure, we had a $500 million authorization. We currently have a $4 billion authorization. And we lean into that authorization in periods when we think the stock is not priced correctly. And so there have been periods where we've been very light in terms of share repurchase, periods where we've been very heavy in terms of share repurchase. And so I like the flexibility of that program, the combination of innovation and share buybacks. That's likely -- that's certainly the right order of priority, and that's the program for the next little while.

Any particular profile of what you might be looking for externally? Are you looking for the next Alpine, like pipeline in a product, derisked late-stage specialty indication? Or might the next BD transaction be larger, smaller, different in profile?

Obviously, hesitant to try to characterize that. Again, Alpine was a wonderful deal. And of course, if we could find something similar, given the great experience we had with that, it would be wonderful. But we're -- much like we're modality agnostic, we're a bit agnostic on BD too, which is there are certain programs where what we need is early-stage technology or access to capabilities. We'll go get that. But yes, if we can find something that is further along in development where we can still add value, either clinically or regulatory or commercial, that's a great fit for us. And I think we have the confidence and the positive experience from Alpine to stay active.

Great. Out of time. Charlie, thank you so much. Really great to speak with you.

Yes. Brian, thanks for having us.

Appreciate it.

Appreciate it.

Good day, and welcome to the Vertex Pharmaceuticals First Quarter 2026 Earnings Call. [Operator Instructions] Please note this event is being recorded. I would now like to turn the conference over to Ms. Susie Lisa.

Good evening, all. My name is Susie Lisa, and as the Senior Vice President of Investor Relations, it is my pleasure to welcome you to our first quarter 2026 financial results conference Call. On tonight's call, making prepared remarks, we have Dr. Reshma Kewalramani, Vertex's CEO and President; Charlie Wagner, Chief Operating Officer and Chief Financial Officer; and Duncan McKechnie, Chief Commercial Officer. We recommend that you access the webcast slides as you listen to this call. The call is being recorded, and a replay will be available on our website.

We will make forward-looking statements on this call that are subject to the risks and uncertainties discussed in detail in today's press release and in our filings with the Securities and Exchange Commission. These statements, including, without limitation, those regarding Vertex's marketed medicines for cystic fibrosis, sickle cell disease, beta thalassemia and moderate to severe acute pain, our pipeline and Vertex's future financial performance are based on management's current assumptions. Actual outcomes and events could differ materially. I would also note that select financial results and guidance that we will review on the call this evening are presented on a non-GAAP basis.

I'll now turn the call over to Reshma.

Thanks, Susie. Good evening all, and thank you for joining us on the call today. Vertex is off to a terrific start in 2026. which we see as a year defined by execution. Q1 revenue growth was strong across the portfolio as we reach more patients with more products and delivered total product revenue of $2.99 billion, reflecting 8% growth year-on-year. Importantly, we achieved key commercial milestones for each of the newer products since launch through end of Q1. A lift Trek exceeded $1 billion in cumulative revenue. More than 500 people have initiated their Kasei treatment journey. and over 1 million prescriptions have been written for dynamics.

Another highlight in Q1 was that products from the new disease areas, namely Cassebi and Gernavics, drove approximately 25% of total product revenue growth. Execution in R&D was equally strong with multiple regulatory submissions recently completed and more anticipated combined with rapid progress across clinical trials and important advancement in research. Let me spotlight a few accomplishments.

First, on Pove, the interim analysis results from the Phase III RAINIER study in IgAN on efficacy and safety from top to bottom, were sparkling and further fueled our enthusiasm for POV as a potentially best-in-class bath April inhibitor. I was exceptionally pleased with the rapidity and quality of the recently submitted BLA filing for pove in IgAN, indeed, at 27 days from database lock to regulatory submission. This was the fastest submission in Vertex history. Equally notable is the urgency with which the pove primary membranous nephropathy and the povymyasthenia gravis programs are advancing. In membranes, the Phase II study has been fully enrolled and the Phase III program has already initiated.

In addition, the Phase II proof-of-concept myasthenia gravis trial is underway. Second, on Casey, I'm also very pleased with the rapidity and quality of this SBLA submission forecast Jebi in 5 to 11-year-olds with sickle cell disease or beta-thalassemia. The Cascevi filing has been granted a Commissioner's National Priority Voucher reflecting the importance of treating this younger age group before some of the most serious complications of the disease can begin.

Overall, Vertex continues to extend its leadership in CF, drive growth with new product launches while building out our next disease area franchise in nephrology, accelerate programs in mid- and late-stage development and advance the earlier stage R&D pipeline. Tonight, I'll limit my R&D comments to CF as well as the pipeline programs with the most significant new information to share certain renal programs, ovine myasthenia gravis and zumilacell in type 1 diabetes.

Starting with CF, 4 quick R&D updates for this quarter. We recently reached a significant milestone in the U.S. with label expansions for both liftrec and Trikafta with this expansion, patients with a clinical diagnosis of CF who have at least 1 variant in the CFTR gene that is responsive based on clinical and/or in vitro data are now covered by the Lift Trek and Trikafta labels. reinforcing the impact of these medicines regardless of the location of the variant in the CFTR protein.

This is a significant expansion of eligibility that reflects decades of investment, effort and a relentless pursuit of the science. It is also a great example of innovation using results from clinical trials complemented by in vitro data to expand the benefit of Vertex CFTR modulators to about 95% of people with CF including those with rare and even NF-1 genotypes. As we expand the liftrec and Trikafta labels to additional mutations, we're also expanding the label to younger patients.

We will soon submit for approval for lift trek in patients 2 to 5 years of age, where you may recall our pivotal trial demonstrated a remarkable 65% of children reaching normal levels of CFTR function and we also plan to submit for Trikafta in children 1 to 2 years of age in the near term. In addition, we continue to advance our next-generation 3.0 CFTR modulators, including VX 828, which is currently in a study of patients with CF. We are on track to complete the study and share results in the second half of this year.

Following closely behind VX 828 in the family of NextGen 3.0RVX581 and VX-272, both of which are currently in the clinic in Phase I healthy volunteer studies, as we have consistently said if it is possible to do better in CF, we're committed to being the ones who do so.

And finally, on VX 522, the mRNA therapy we've been developing for people who produce no CFTR protein and therefore, cannot benefit from our modulators, we previously disclosed tolerability issues in this program despite actions we have taken in the trial to overcome these issues, we have not been able to do so. And as such, we have chosen to discontinue the program. Given this early termination, we will not be able to assess the efficacy or full safety of VX 522.

We will be working with sites to close out the study in the coming weeks. Moving on to our renal franchise, which continues to make quick progress and is rapidly establishing itself as Vertex's fourth franchise along CF, heme and pain. In total, we have 4 programs in mid- and late-stage development in renal. PoviandiGaN, Pova primary membranous nephropathy, enaxiplinin AMKD and VX-407 AV PKD. Tonight, I'll cover the first 3 programs, starting with Pope and IgAN. Recall Poby's differentiated potential best-in-class profile stems from its specific design as an engineered tachyfusion protein with binding affinity, potency and PK properties that deliver optimal dual BAF APRIL inhibition.

The dual inhibition and engineering advantage is evident in both the interim analysis data of the RAINIER study where we saw rapid deep and sustained improvement in proteinuria, a favorable safety profile and consistency across all subgroups as well as in 3 key patient dosing benefits, once monthly dosing, small volume and subcutaneous administration via an auto-injector.

Overall, the Phase III interim analysis data represent a home run in terms of study design, execution and the results with Pulvy achieving statistically significant and clinically meaningful results across all primary and secondary end points. Patients in this trial received excellent standard of care with high rates of background medicines, including the highest rates of SGLT2s seen in any EGAN study. Baseline characteristics were well matched to real-world IGAM patients in terms of age, renal function and degree of proteinuria.

In addition, as a measure of study quality, it's important to look at discontinuations. In this study, treatment discontinuations were low and trial discontinuations were even lower at a rate of 1.5% on the placebo group and 0.8% in the POV Group. To replay the top line primary and secondary efficacy results, for the primary endpoint, Pulvy achieved a 52% reduction from baseline in proteinuria as measured by 24-hour UPCR. That's a 49.8% reduction versus placebo.

For the first secondary endpoint, Hobi treatment led to a 77.4% reduction from baseline in serum GDIgA1 levels. That's a 79.3% reduction versus placebo. For the second secondary endpoint of those patients with hematuria baseline, 85.1% poly treated patients achieved hematuria resolution, which is a 61.7% reduction versus placebo. In addition, 42.2% of patients reached the exploratory endpoint of 24 UPCR of less than 0.5 grams per gram, an important clinical threshold.

These are remarkable results and particularly noteworthy, considering that at the time of the interim analysis, patients had received just 36 weeks of cobi treatment. On safety, Popi was generally safe and well tolerated. The majority of adverse events were mild to moderate, and there were no serious adverse events related to Povi. Importantly, in terms of infections, most were mild to moderate. The rate of SAEs of infection was low at 0.5%, observed in both the placebo and pub groups. There were no opportunistic infections and no discontinuations related to POV overall, including no discontinuations due to infections.

Lastly, on antidrug antibodies, or ADAs, ADAs were observed as expected with biologics, but had no impact on Poby's efficacy or risk profile. We look forward to sharing more details of the interim analysis results and anticipate doing so at upcoming medical meetings this fall. Shifting to Pova primary membranous nephropathy, I am pleased to share we have completed enrollment of the Phase II portion of the Olympus Phase II/III study and have already initiated the Phase III portion ahead of our previously announced mid 2026 goal.

And finally, on Pobi, as part of its pipeline and a product potential for B-cell mediated diseases beyond renal, I'm also pleased to share that the Phase II proof-of-concept study of POV in generalized myasthenia is underway. This is a 30-patient study of people with GMG evaluating both the 80 and 240-milligram dose for 12 weeks with the primary endpoints of safety and the percent change from baseline in IgG at week 12. The rationale for studying pop in myasthenia is compelling. It's a serious B-cell mediated disease with high morbidity affecting approximately 175,000 people in the U.S. and Europe. There is high unmet need as current therapies have meaningful limitations, which means there is room for improved efficacy, a better benefit risk profile and more patient-friendly dosing and administration, which we have discussed in the context of IgAN as being critically important when considering a chronic biologics market.

We believe Povy's mechanism of action striking at the heart of autoantibody production with an engineered protein format provides best-in-class promise in myasthenia and we are excited to develop this opportunity. Shifting back to Renal to finish up with the maxaplin in APOL1-mediated kidney disease or AMKD. First, on amplitude, the pivotal Phase III study of primary AMKD, that is to say patients with 2 APOL1 variants perneuric kidney disease and no other renal-related comorbidities. We are on track to conduct the interim analysis, which occurs after 48 weeks of treatment and to share data from this cohort in early 2027.

If positive, we will be poised to file for potential accelerated approval in the U.S. thereafter. Second, on AMPLIFY, our Phase IIb study of enaxiplin in separate populations. Patients with 2 APOL1 variants, modest proteinuria and no other kidney disease and patients with 2 APOL1 variants moderate to severe proteinuria and a second disease, type 2 diabetes that could impact the kidney. These 2 populations are not being studied in amplitude. We recently completed enrollment in the AMPLIFY study, which is a study of 13 weeks in duration.

Given the clear differences in these populations, we made the decision early on to study them in separate trials. Emerging data in the field confirm the wisdom of this decision. We are excited to learn from the amplified study and look forward to sharing results in the second half of this year.

Finally, on type 1 diabetes, a reminder that zomilacel has very strong clinical results to date as detailed in last year's New England Journal of Medicine among patients who received a full dose and had at least 1 year of follow-up 10 out of 12 patients were insulin free. These results are unprecedented and are particularly noteworthy, given that these patients are those with 20-plus years of type 1 diabetes, undetectable endogenous insulin production at baseline, taking 40-plus units of exogenous insulin per day and with 2 or more severe hypoglycemic events per year despite best available care.

You may recall that in the second half of last year, we paused dosing of the Phase I/II/III study in order to conduct a manufacturing analysis, which we have now completed. I am pleased to report that dosing in the study has resumed and multiple patients have been dosed. With dosing now restarted, we will update you in the coming months on the revised time lines for study completion and regulatory filings.

With that, I'll turn the call over to Duncan for a commercial update.

Thanks very much, Reshma. I'll start with CF, which continues to perform very well. Year-over-year revenue growth was 6% globally balanced nicely between U.S. growth of 5% and international growth of 8% in quarter 1. Global growth reflects continued lift track uptake as its once-daily dosing and improved sweat chloride profile continue to resonate with the clinical and patient communities. As mentioned, Aliftreck has now surpassed $1 billion in cumulative global revenue since its approval in the U.S. in late December 2024 and Europe in July 2025.

Outside the U.S., we have signed reimbursement agreements in 11 countries for Aliftreck in quarter 1 alone, building on the access generated in the second half of last year. The tremendous scientific and regulatory achievements represented by the label expansions for Eliftrec and Trikafta also represent a meaningful incremental commercial opportunity of approximately 800 people in CF who are newly eligible in the U.S. This broad labeling is 1 of several key CF growth drivers for the remainder of 2026, along with the global rollout of a lift track, treating younger patients and expanding into additional geographies.

We have worked closely with the CF population for 2 decades and remain focused on continuing to serve the CF community and expand our leadership across all genotypes, age groups and geographies. Shifting to heme, the rollout of Cash Jebi continues to gather momentum across all 3 regions, and I'm pleased to highlight another significant commercial milestone since launch. Over 500 patients have now initiated the Caster treatment journey. Hundreds have had their first cell collection and many patients have had their cells edited and are ready for infusion.

During the first quarter, we delivered $43 million in cash Jebi revenue. Importantly, we worked on securing a pricing agreement for Cash Jebi in Germany in quarter 1 and are currently working through the implementation steps. This is a historic moment and we're excited that German patients with sickle cell disease and TDT may soon be benefiting from long-term access to Cascevy at a sustainable price.

Overall, we are very encouraged by the robust flow of patients in the U.S., in Europe and the Middle East moving from referral to cell collection and infusion. First quarter revenue reflects expected variability quarter-to-quarter as patients choose the timing for their infusion that suits them best. For the full year 2026, the Casey outlook is very promising as we have built our ATC network, secured reimbursements and now have many patients at all stages of the treatment journey.

We, therefore, have very strong visibility to revenue for the rest of 2026 for Cash Jebi to contribute meaningfully to our $500 million plus revenue goal for non-CF products this year and towards CashJevy's ultimate multibillion-dollar potential for genetics in moderate to severe acute pain, prescriptions, prescribers and awareness all continue to build. More than 350,000 prescriptions were filled in the quarter compared to approximately 550,000 in all of 2025, which was in line with our expectations.

We also surpassed the milestone of over 1 million genomics prescriptions written since launch. Prescriptions this quarter were once again split roughly 50-50 between the hospital and retail channels and generated $29 million in revenue, also in line with our expectations. Overall, prescription growth remained strong, although quarter 1 revenue reflects some normal inventory destocking. We remain on track to more than triple the 550,000 prescriptions from 2025 and for revenue growth to significantly exceed prescription growth.

I'll now outline some of the key drivers of our continued growth and expected success for genetics in 2026. Firstly, physician and patient clinical experiences on generics continue to be excellent, which provides a great foundation for continued growth. We also continue to see outstanding breadth of physician uptake as well as generics additions to hospital and IDN formularies, protocols and order sets. Secondly, we continue to make good progress in the payer space with 240 million lives now covered. In addition to the big 3 commercial PBMs, I'm delighted to announce that we've reached an agreement with the first of the Big 4 Medicare Part D plans to start covering genetics effective as of May 1, given the multiple and well-documented challenges that opioids present seniors, this is welcome news, and we are in discussions with the remaining Medicare Part D plans as well as the smaller regional plans.

Thirdly, we have completed doubling the size of our field force to 300 representatives slightly ahead of plan. As we've communicated before, Genavics is highly promotionally responsive, and we're excited about the impact of this new field team on Genavics growth. Lastly, we also continue to execute multiple initiatives to drive awareness, growth and provide new mechanisms for patient access, including the launch of Vertex's first direct-to-patient telehealth platform informed pain care.

This platform is accessible from genavics.com and provides appropriate and independent telehealth evaluations for nonsurgical acute pain patients, if eligible. We're also pleased that Genavics was recently added to the list of non-opioid medicines eligible for separate payments under the no pain Act effective retroactively to January 23.

In summary, with the increased size of our field organization, our continued progress in securing payer and hospital coverage as well as strong gains in formulary status, we remain confident we will triple prescriptions for genomics in 2026. In addition, our strong reimbursement progress continues to position us to taper our patient support program over the course of 2026 and enter 2027 with a normalized gross to net. We continue to expect Genavics to contribute meaningfully to the $500 million plus we expect in revenue outside CF this year.

I'll conclude with an update on the commercial initiatives for our emerging renal business. We're investing in the nephrology community for the long term and povetasercept is the first in a series of potentially transformative medicines that tackle the underlying cause of 4 serious renal diseases, namely IGAN, PMN, AMKD, and ADPKD. We were thrilled with the interim analysis results of the Rainier Phase III study with excellent results across the board in efficacy, safety across all subgroups and in the areas of greatest interest in nephrologists and patients. The results create a superb foundation for the commercial launch of a potentially best-in-class medicine.

Our goal for povetatercept is to be physicians first choice for their IgAN patients given Povi's compelling trifecta of differentiated efficacy results, well-tolerated profile and patient-centric administration characteristics due to its low-volume monthly dosing via subcu auto-injector. Based on our market research and discussions with nephrologists plus feedback from our field team engagements, we know nephrologists are looking for treatments in IgAN that meaningfully and rapidly reduce proteinuria in the patients they treat. As they see proteinuria as the key indicator of where the patient is headed clinically. nephrologists also seek a favorable tolerability profile and both physicians and patients communicate to us the need for a seamless treatment experience, which includes everything from access to patient support, to monthly dosing size of dose and administration in an auto-injector.

We believe that uniquely POV has the clinical profile and that Vertex has the capabilities to meet all of these needs. Our renal field force will be specialty-sized and large enough to cover nephrologists who see approximately 80% of U.S. IgAN patients. We will target key facilities that represent a combination of renal centers of excellence, glomerular disease clinics and key high-volume private practices. Our payer conversations are proceeding well in a U.S. market where approximately 70% of patients have commercial coverage.

We have a proven track record in securing broad and rapid access for our medicines and plan to establish the same for POV and IgAN. And lastly, we know that the quality of the patient support provided is critical in the biologics space. With that in mind, Vertex programs to support POV patients will enable speed to therapy and personalized support through the treatment journey, delivering a seamless experience of onboarding for patients and physicians alike. Hovi and GaN is the first component of our emerging renal franchise. We're excited to bring it to nephrologists and their patients.

Based upon our work with them, we know they're excited to try it as well. we believe POV delivers exactly what nephrologists are looking for in IgAN and just as we've done for over a decade in CF, HOV success will be driven by a field force delivering a high science cell fueled by a potentially best-in-class product, broad reimbursement and robust and high-quality patient programs. We are very excited to begin building our fourth commercial pillar and creating another multibillion-dollar franchise in Vertex.I'll now turn the call over to Charlie to review the financials.

Thanks, Duncan. As Reshma noted, Vertex's Q1 2026 results demonstrate our consistent strong performance and attractive growth profile. First quarter 2026 total revenue increased 8% year-over-year to $2.99 billion. CF Global revenue increased 6% year-over-year, and new disease areas also contributed with Casjevy delivering $43 million and Gernavics $29 million in Q1 sales. representing about 25% of total year-over-year growth for the quarter.

By region, U.S. revenue growth of 7% year-over-year was driven by continued steady performance in CF and growing contributions from Casey and genetics. International revenue grew 9% year-over-year, driven by continued CF expansion and increasing contribution from Cascevi and as anticipated, a benefit from year-over-year changes in foreign exchange. First quarter 2026 combined non-GAAP R&D acquired IP R&D and SG&A expenses were $1.29 billion, an increase of 5% compared to $1.23 billion in the first quarter of 2025.

Within total OpEx, non-GAAP R&D expenses were down 2% year-over-year partly driven by the timing and mix of certain clinical trial expenses. In addition, certain Pogey manufacturing expenses were included in R&D in 2025 and are now recorded in cost of sales following the positive interim analysis data. Non-GAAP SG&A expenses increased 30% year-over-year, driven primarily by commercial investments, with roughly 40% attributable to Genavics in pain and approximately 1/3 to renal launch programs.

We also recorded $1 million in IP R&D expense in the quarter versus $20 million in the first quarter of 2025. First quarter 2026 non-GAAP operating income was $1.31 billion compared to $1.18 billion in non-GAAP operating income in the first quarter of 2025. First quarter 2026 non-GAAP effective tax rate was 19.6%. First quarter 2026 non-GAAP net income was $1.1 billion, an increase of $93 million compared to the first quarter of 2025, primarily due to increased product revenue, partially offset by increased operating and income tax expenses in the first quarter of 2026.

First quarter 2026 non-GAAP earnings per share were $4.47 compared to $4.06 in the first quarter of 2025, reflecting our strong revenue growth and disciplined expense management. We ended the quarter with $13 billion in cash and investments after deploying approximately $344 million to repurchase more than 741,000 shares in the first quarter. This activity reflects our ongoing commitment to returning value to shareholders while maintaining the flexibility to act on strategic growth opportunities.

Overall, our priorities for cash deployment remain unchanged with a primary focus on investing in innovation. Now switching to guidance. We are reiterating our 2026 total revenue guidance of $12.95 billion to $13.1 billion, representing growth of 8% to 9%. This outlook reflects continued solid performance from the CF franchise, driven by the Elliptic launch expansion into younger patient groups, incremental patients from the label expansion and geographic expansion. We continue to have high confidence in our outlook for revenue of $500 million or more from non-CF products driven by growing cash JV infusions, where we have good line of sight given the length of the patient journey and the meaningful ramp in Gernavic's prescriptions and revenue as gross to net normalizes through the second half of the year.

Lastly, our revenue outlook continues to include an expected impact from foreign exchange, net of our hedging program. Our outlook for full year gross margin remains at just under 86%, reflecting the growing non-CF product mix impact and ongoing investments in manufacturing network and process development for various products. We are also reiterating our combined non-GAAP operating expense guidance of $5.65 billion to $5.75 billion reflecting continued investment in our late-stage clinical pipeline and commercial infrastructure and activities for new launches and revenue diversification.

We also continue to expect our non-GAAP effective tax rate to be in the range of 19.5% to 20.5% for the full year 2026. On the subject of tariffs, we do not expect any material impact to the income statement in 2026. We continue to evaluate the details of recent announcements and the potential applicability to Vertex.

In summary, Q1 2026 was a very strong start to the year. Financial results are on track, commercial launches and diversification are gaining momentum, and we continue with targeted investment, both in innovation and commercialization as the pipeline is advancing across our multiple disease areas. Our increasingly diversified commercial portfolio now spanning 3 disease areas and soon to before with the establishment of the renal franchise is driving new revenue streams and adding to our near- and long-term growth profile. Vertex is well positioned to continue expanding its impact for patients, investors and all stakeholders.

These and other anticipated milestones of continued progress in multiple disease areas are detailed on Slide 17. We look forward to updating you on our progress on future calls.

I'll now ask Susie to begin the Q&A period.

We will now begin the question-and-answer session. [Operator Instructions] And our first question for today will come from Jessica Fye with JPMorgan.

So you've talked about renal 1 day rivaling the cystic fibrosis business in size. Can you speak to what needs to play out from here to realize that vision? And among your renal assets, which you see having the greatest long-term revenue potential?

Jess, this is Reshma. I guess as a nephrologist at the company, maybe I can take this and Duncan, please feel free to add. So just what we're talking about in our emerging renal franchises for assets, Kobi 4 diseases for the assets, Kobi for Povormembraness, a axipline for AMKB and what we call the VX407 in ADPKD. The reason I think that this has the potential to be as big, if not larger, than CF is that -- the diseases that these medicines treat are rare diseases, but they are common rare diseases. And when you add them all up together, they're well into the hundreds of thousands of patients. For example, we talk about 150,000 or so patients with IgAN in North America and Europe, 100,000 patients with membranes in the same geography, for AMKD, that's another 150,000 or so patients with the aplite population, not including the Amplify population, which adds about 100,000 and ADPKD is about 300,000 patients. Of course, the first medicine that we're studying the EXPLORER 7 can treat about 10% of that 300,000.

So one, while each 1 is a rare disease there common rare diseases and when you add it together, we're hundreds of thousands of patients in just the Western world. The second is that in renal medicine, unfortunately, the outcome of these diseases is a relentless decline in renal function and a movement then to death, dialysis and transplantation, Obviously, those are enormous burn for society. I don't need to say much more about death, but dialysis in particular, is exceptionally expensive. And while it allows you to live, it is a very, very difficult life and life expectancy is like a very serious cancers, like pancreatic cancer.

And then last of that block, when we look at the emerging results for pove, for example, in IgAN in membrane, you can look at the Phase II and for Ian, you can certainly look at the Phase III interim announce these results. As I said on the call, they are sparkling from top to bottom, safety, efficacy, this is a kind of medicine that can bring transformative value. When I think about AMKD, same thing you look at the Phase II results that we published in the New England Journal, 47.6% reduction in proteinuria is a very big deal.

And when we think about ADPKD, no human results yet. But when you look at the mechanism of action, this is to say, to properly fold the misfolded PC1 and what we see preclinically another 1 where we think transformative effect. That's why we believe this is another vertical that can rival if not Crest CF. Best renal assets. That's a tough one, Jeff. I'm going to focus my attention for the here now on Tobi. It just looks sparkling. You can call it near-term bias because we just looked at the Phase III results.

Your next question will come from Salveen Richter with Goldman Sachs.

Could you discuss the read-through from NASA's recent data to the enaxipline program? And also, could you just speak for that program, whether there were enrollment considerations to rip for patients with larger APOL1 contribution to CKD, especially in the non-FSGS patients?

Salveen. On the MA data, you know we don't like commenting on other company's assets and results, but I'll simply say the top line, the Vertex results were 47.6% reduction in proteinuria as published in the New England, and my recollection of the mad data is 35.6% at the top line. Going below that is difficult because we're talking about groups of 2 and 3 patients with or without diabetes and such. And I just don't think you can make very much when you're down to 2 or 3 patients. What I will say is I'm very happy about the decision we made early on to not mix a heterogeneous group and to focus our program on those with heavy partenariat 2 APOL1 alleles and reduced kidney function and mat study those who have a comorbid condition like diabetes, Instead, what we did is studying those people in a separate trial called AMPLIFY along with a group of patients with lower proteinuria. That trial is done enrollment, and I do expect to have results in the second half of this year.

The next question will come from Brian Abrahams with RBC Capital Markets.

With the Poly launch not too far off, what do you think you'll need to convey to KOLs and community physicians to convince them of hovitasecept's differentiation and overcome first-mover advantage by competitors?

In that, Brian, let me ask Duncan to take that. He's been spending a lot of time with nephrologists, both in academic institutions and centers of excellence as well as in the community. Duncan?

Brian, So 1 comment before we dive into your answer. I just made the point that obviously, this is a huge market opportunity of about 160,000 patients -- in the U.S., it's 5x bigger than CF, for example. And the vast majority, about 75% of those patients are nowhere near the Codiga guideline goal in terms of proteinuria. So the opportunity is significant. We've been engaging through market research and other mechanisms with many nephrologists. And essentially, they tell us they're looking for a product that significantly impacts proteinuria. We'll come back to that, is well tolerated and is easy for patients to use. And we believe that povitasteset uniquely meets those needs.

We think it has a sort of winning trifecta of incredible clinical effects, as you heard in the prepared remarks, things like the rapid deep and sustained reduction in proteinuria as well as GDI G1 and hematuria. It has a supremely favorable tolerability profile and very attractive dosing and administration. So as you know, it's once a month. It's a small volume dose and it's delivered by an auto injector. So we think we have an incredible product as we saw on the clinical data. We also know from our market research that those nephrologists that distinguish between last April and April alone, the vast majority of them prefer dual inhibition with Bath in April.

And in our patient market research, that the vast majority of patients prefer monthly dosing over weekly dose. In fact, 8x more patients prefer monthly dosing to weekly dosing. So in terms of the profile of the product matched against the needs of the physicians and patients, we think we have a best-in-class asset on our hands. And I would also add on the commercial capability side, we know how to execute a high science cell. We know how to secure bracket deep and broad reimbursement, and we know how to build patient support programs, which are incredibly important in the biologics space as we have done for the last 12, 13 years or so in cystic fibrosis.

So -- we're feeling really good about the profile of provitacercept. We are getting ready for launch, and we're going to be ready to go, the day the FDA give us regulatory approval.

The next question will come from Jeff Mechem with Citi.

I have 2 quick ones. So on pain and on 993 in particular, as you guys have got commercial experience with Dynavax, are there settings where an IV modality is perhaps a better fit in the clinical practice. I imagine that's maybe the hospital setting in the Cuba wanted to obviously get your perspective. And then on POB, congrats on the quick filing in IgAN, but looking beyond PMN and GMG, -- is it worth it to do a basket setting? Are there other autoimmune indications that make sort of that you could have the most differentiation for Poviand then maybe you have the highest probability of success.

Jeff, this is Reshma. On the pain portfolio and whether or not an IV medicine would be helpful, I think it would be helpful to have an IV medicine and what we're really looking to do here and the reason we have not only susetrigene or dynamics, but 993 and additional not one, but very importantly, MAG-17 is to make sure that we have the best medicine, whether it's PO or IV and that formulatability into IV is 1 of the features that we're looking at and are interested in.

Switching then to poly and where we see things go, IGAM is already done in terms of the interim analysis and filing. membranes Phase III is already underway. Myasthenia Phase II is underway -- there are some additional B-cell mediated diseases that we are thinking about. And I do think a basket study is a very efficient way of evaluating those conditions through Phase II development. I won't say much more about exactly which conditions. But suffice it to say, there are some B-cell mediated conditions. autoantibodies are important, where we think pulling would fit nicely and I do think that going about this by way of basket studies and efficient Phase II/III are the right way to go.

You'll be hearing us talk more about pub and our immunology portfolio in the coming months and in the coming time. But I like your idea.

The next question will come from Cory Kasimov with Evercore ISI.

I wanted to follow up on Salveen's question on aniline. And when you think about the pending data from AMPLIFY, looking at AMKD patients with moderate proteinuria or diabetes, what's needed in this population for a clinically meaningful benefit to justify advancement in this patient segment?

Or I would say that generally speaking, in renal medicine, we've been thinking about double-digit improvements as being valuable -- by that, I don't mean 10% or 11%. I would say if we can show a 30% improvement -- some number between 20% and 40%, 25% and 50%, some substantial double-digit improvement in proteinuria on top of standard of care, of course. So on top of ACS or ERPs, et cetera. that would be meaningful. And we'll be able to see how we fare shortly. The enrollment is done. It's a 12-week study. So we'll be able to tell you the results in the near term.

Your next question will come from Mike Yee with UBS.

This is Mike from UBS. On Toby, do you believe that your -- on the efficacy standpoint that your differentiation on eGFR will be able to come through over 9, 12 or 24 months versus, say, Asuka which I think is presenting the EGFR 9-month data, I think, next month and then there are 2-year data coming up. And so I just wanted to think about where you would start to see differentiation for yours and a read-through to their data that they're going to present.

And then on the safety component for POV. Reshma, can you talk a little bit about the hypogammaglobulineremia? And I think there are some questions around whether 150 or 300 matters and the noise within the assay and the timing of the measurement and why you don't think that will be any issue here for Pony?

Start with safety and the question on hypogammaglobulinemia and then we'll go to efficacy. On safety, the results are really terrific because Poly and any medicine that works on April or back April, in essence is modulating B cells, you do need to think about the safety profile and in the safety profile, the domain to think about is infection. So specifically, what we focused on and what I was very pleased to see is we can get this level of efficacy on proteinuria, on hematuria, on GDI on getting down to these very low levels, less than 0.5 grams per gram, which is the important clinical threshold, we can get down to those levels with a very favorable safety profile.

So the infection, most of the infections are mild to moderate, think upper respiratory infection. There's no opportunistic infections, no uncommon infections, the SAEs of infection are low and balanced. It's exactly 0.5% in the placebo group and the same exact number in the pull we treated group. So that looks really nice. With regard to the actual immunoglobulin levels, and let's focus on IgG. The IgG levels of less than 300 or 150 or 200. Some people use 400. These thresholds are important because that's how people set up their trials, and that's how the trials may have certain actions taken, you are correct each trial defines a different threshold. You measure it in different number of times. Some people measure monthly like us. other people measure quarterly. Some people require multiple measurements to call it less than that threshold, others require a simple 1 level.

So it's not very easy at all to cross-compare. The important thing, though, Michael, if you're asking me, hey, is there anything there that gives you concern not at all -- the important thing to look at is the infections and the infections look very balanced between these groups. On efficacy, you asked about GFR, which is the regulatory enabling end point, right? So the regulators have said Purtinuria is acceptable at 9 months for accelerated approval, but they are looking for 2-year GFR for full approval.

Note, however, GFR is actually not the hard endpoint in renal medicine. The hard endpoint is death dialysis or transplantation. That's what we're really trying to avoid. It's just that, that endpoint takes a long time. And so the acceptable regulatory enabling endpoint for full approval is GFR. The reason I think that the proteinuria is so important is when you think about that hard endpoint of death dialysis and transplantation, which takes years to develop, the thing is most proximately reflects that is proteinuria. And what I would do is think about pretinari, okay, if I got 1 point of protenuria, improvement more than any other medicine, 2 points, 5 points, 10 points outbound that over years, and you start to see why protenuria is so very important.

The agency has said very clearly that we're not allowed to share GFR, but they equally said that they need to see GFR to provide accelerated approval. So what I would say is any medicine in IgAN that gets accelerated approval has the proteinuria that we've already shared and has GFR that the agency finds comforting.

Your next question will come from Tazeen Ahmad with Bank of America.

I wanted to ask what your thoughts are Reshma, on the read-through from this positive IGAM study that you provided the top line for recently onto the PMN study that you're currently running for pop? And then secondly, on the CF pipeline, I just wanted to get a sense of what data you plan on showing in the second half of the year for -- and what would be considered good data there?

Okay. Let's do IgAN first. because we might see the -- some data that are from the IgAN as very important and positive for membranes because now we study hundreds of patients over a 9-month period, which is an additive information to the Phase II results. So things like PK, PD, the reduction in protuneria, I see all of that in terms of efficacy is important. Clearly, the autoantibody of interest is different. One is PLA2R, -- that's what we're looking for membranes versus GDIA1. So that has to play itself out. But in terms of those other parameters, I see that as really positive.

The other variable that I see is very positive is on safety. The fact that there is such a favorable safety profile, I see as a positive. Of course, the IGAM study was at 80 milligrams. And in the membrane study, we're studying both AN and 240 to Prickne. Lastly, I feel very good about the way the study is being conducted -- that is to say low discontinuations in terms of study discontinuations and treatment discontinuations and I also feel really good about the background therapy. It's very important to look at as you think about doing these studies in contemporary practice.

On switching now to CF. The 828 results are a CF cohort after we completed the healthy volunteer study. And so what you should see is data from the single dose that's gone into the patient cohort, and you should expect to see sweat chloride results. and safety results as well. It's a small cohort, so you shouldn't expect anything on PPFEV1, but the readout, the efficacy readout that we're looking for is sweat chloride. So you should expect us to share that.

Next question will come from Evan Seigerman with BMO.

I want to expand a little bit on the discontinuation of VX-522. Anything else you can share on the tolerability issues. And then looking ahead, do you plan to utilize another technology to help these patients that are not currently untreatable with your current portfolio?

On VX 522, what I can tell you is that the tolerability issue that we have been monitoring and sharing with you now that the study is being discontinued, has to do with lung inflammation, like an inflammatory response probably in response to the LNP that's being used to deliver it. And I say that because this is not unusual in that regard. So with regard to what are we going to do for our patients, I want to be clear about the fact that our commitment to CF is absolute and steadfast. If there is any more that we can do for our patients in the 95% group, we're going to be the ones who do it. And for our last 5,000 or so patients, we're going to work on that as well. I expect that the challenge is going to continue to be delivery. And in terms of modalities, we're going to have to go back to the drawing board on modality. These last 5,000 are going to require some nucleic acid therapy, right, because they simply don't make any protein.

And so the big question is not necessarily what the nucleic acid therapy is we have some big -- there are ideas in their, I think, obvious. But how do you deliver it without having this lung irritation, and that's what we're going to be working on.

Next question will come from David Risinger with Leerink Partners.

Yes. Thanks very much, and thanks for all the updates. So my questions are on Jernavics. Could you maybe help reconcile the $29 million in revenue in the first quarter with the volume of either prescriptions or pills. And then given that your NavEx has PBM coverage for 240 million lives now, which is over 2/3 of the population. Does Gernavixs need to achieve more employer opt-ins and more Tier 2 formulary positions for the gross to net to normalize?

Duncan, do you want to take that one?

Sure. David. So in terms of the first part of your question, I would say, overall, by the way, we are extremely pleased with the progress. On Genomics. We are fully on track in terms of our prescription numbers and our revenue numbers. In terms of reconciling quarter 1 dollars and volume, as I mentioned, in the prepared remarks. We did see a small but relatively normal channel inventory destocking in quarter 1 between quarter 4 '25 and quarter 1, 2026. It's also true that in that quarter, of course, Medicare Part D plans are resetting, which can lead to higher co-pays and more abandonment. And then also, we saw the traditional reduction in the number of elective surgeries in January, which are a little bit harder impacted this year because of the sort of fairly strong flu season.

So overall, I would say that the quarter 1 performance was in line with our expectations. We are absolutely on track to more than triple the number of prescriptions that we delivered in 2025. And to answer the second part of your question, we have just achieved our 240 million lives covered. As you know, we're very happy with that. And actually, in an update since we finalized the script, you know that we've been working on 4 Medicare Part D plans. And in the script, we communicated that we had secured coverage at 1 of those 4 plans, we've actually secured coverage at 2 of those 4 plants and are very close to securing coverage at 1/3 of those plans or deferred of those plans. And that coverage starts from between May 1 to July 1.

So I don't think we need to be focused on downstream plans and employer plans. As we have said all along, as we secure the final pillars of access, the patient support program will taper down our gross to net will normalize by the end of the year, and you will see revenue significantly accelerate and accelerate faster than prescription growth as we go through the balance of the year.

Your next question will come from Terence Flynn with Morgan Stanley.

Just 2 questions for me. I was just wondering if you can tell us if there's a defined percentage of FSGS patients in the amplitude Phase III trial for anaxaplan,e if there's a cutoff or if you just pretty much all comers and that mix will be dictated by who's enrolled. And then for a lift track, just curious to know if you're seeing anything different in terms of patient mix this quarter versus prior quarters in terms of the 3 different buckets that you guys have focused on?

Terence, I'll take your FSGS question for Phase III and Acolle. -- and I'll turn it over to Duncan. I won't be able to share what the baseline characteristics look like because we haven't looked at those data and we don't know those data. But what I will tell you is that what's common in AMKD is because they tend to be heavily purtneuric, -- so we're talking about people who are coming in with proteinuria of 0.7 grams or more they often tend to have a biopsy because that's a lot of proteinuria and people are trying to figure out whether there is an underlying identified cause. So it wouldn't surprise me at all if many -- maybe even the majority of patients in the AMKD Phase III AMPLI trial, actually were at known FSGS patients because a lot of these patients actually do get a biopsy, not all of them, but it's not an uncommon act.

So that would be my guess, but I don't have a formal answer for you. Fortunately, the IA enrollment is complete. The full study enrollment will complete this year and we fully expect to have results from the IEA in early 2027. So we'll know the answer real soon. Duncan. A lift track characteristics transition -- new.

Yes, Terence, thank you for the question. So yes, I'm assuming the 3 categories you're talking to the naive -- talking about the naive patients that discontinued patients and the transition patients I would say that we see continued strong progress in all of those. Once we have both regulatory approval and reimbursement, we see the naive patients coming on first, then we see the discontinuation patients coming on. And then finally, the transition patients are moving on to a lifting indeed exactly as we desire.

So at this point, essentially, I would tell you that all new patients are going on to a lift track. No 1 is going on to Trikafta. They're all going on to a lift track. We see the discontinued patients largely moving on to aliftrec and the vast majority, of course, of our patients. Now our transitions from tricaptar to Elifrek exactly as we would expect. So the 3 drivers really the lift-truck growth this year, our continued uptake in the U.S. more European countries securing reimbursements and the expanded labels, for example, the additional 800 patients that were recently included in the most recent labeling updates. So hopefully, that answers your question, but we're seeing essentially a similar profile to that which we saw before. I'm super happy that we are well over $1 billion on the lift truck at this point.

And the next question will come from Ellie Merle with Barclays..

An efficacy or safety perspective. And I guess, as you think about the CF landscape broadly, how are you thinking about sort of the bar set by a lift track versus where you see room for incremental improvement?

Ellie, we couldn't catch the first part of your question. Would you restart, please?

Sure. Sorry about that. Let me know if you can't hear me now. Just another question on -- you can hear me okay good. Just on 828, just a follow-up on the earlier question. I guess, what are you seeing as a bar for what you would want to see to bring this forward from an efficacy or safety perspective? And then just as you think about the cystic fibrosis landscape overall, how are you thinking about sort of the bar set by a lift track versus where you see room for improvement?

When we had Trikafta and we're working to see what the unmet need was. Honestly, Elie was a little bit easier to see as amazing as Trikafta is, we could see that a once-daily medicine would be better for patients. And we could see that getting more CFTR protein function, that's the same or we chloride more patients below the diagnostic threshold of 60, and the normal level of 30 would be advantageous. Now fast forward to where we are today with the lift truck, and genuinely, there is very little unmet need. And so it's going to take something special for us to advance. And that's why we're looking at VX828, we're looking at VX 581 and we're looking at VX-272 because we want to really interrogate to see that there's more that we can bring to the table.

And what I'm really saying in the event is unclear is this. Today, 90% of people would you start at a young age, which Elite is now approved down to years old and we're filing for 2 to 5 years old, 90% are less than 60. 2/3 of our patients are at sweat chloride that's below normal. And this is with a once-a-day medicine. And now when you think about it, everyone is Dunkin' describe all our new patients, all our young patients are coming on to Alley, there's very little room for improvement here. So if it's possible, we're going to be the ones who do it, but it's getting really, really tough because we're already down to once a day, good-looking -- DDis, excellent sweat chloride function with 2/3 normal, it's tough. So -- if we see it, we'll certainly let you know, but that's why we're being so particular in bringing these number of medicines forward to see if anything can be better than a lift truck.

Great. I think we'll wrap there. Chuck, can you give the replay information?

We'll do -- this will conclude our question-and-answer session as well as our conference call for today. The conference has now been concluded, and thank you for attending today's presentation. A replay of today's event will be available shortly after the call concludes by dialing 1 (877) 344-7529 or 1412-317-0088 using replay access code 102-08180. Thank you for your participation. You may now disconnect.

Hi, everyone. I'm Ellie Merle, one of the biotech analysts here at Barclays. Very excited to have Vertex here with us to discuss a lot of exciting news this week with the povetacicept Phase III amongst a lot else going on in the pipeline. Joining us is Miroslava and Susie Lisa from the Investor Relations team. Thank you both so much for joining us.

Maybe to kick it off before we jump right into pove after. But we've seen Vertex shift from being a cystic fibrosis biotech to a more diversified story across several verticals. Could you walk us through the strategy behind the efforts you've made so far and what's coming on the horizon?

Sure. Thanks, Ellie, and thanks for having us very much. Yes, it's a really exciting time. We have long been proud of the work we've done in cystic fibrosis, but have also long had the goal to diversify our revenue base as well as the patient groups that we can address. And I think are very pleased with the progress that we have been making, all while maintaining the utmost diligence and care towards that CF patient community and continuing to move the bar forward there in terms of our ongoing ALYFTREK launch now, which is our fifth commercialized medicine as well as having a NextGen 3.0 family of therapies already in the clinic, and we can talk more about that if there's time.

But we're very pleased with the progress that we have made with our ongoing launches in CASGEVY for sickle cell disease and beta thalassemia as well as for JOURNAVX in acute pain to the point where we have built really strong foundations for these products in terms of the patient outreach and support the commercial capabilities as well as the clinical data to support these transformative therapies and have said for 2026, right, that we expect those 2 products combined to do over $500 million in revenue and have established strong basis for their growth.

And then given additional targets for JOURNAVX, I think, excitingly to more than triple the number of prescriptions in 2026 versus 2025 and revenue growth should outpace that on a year-over-year basis. And then I think as we'll get into the pove data, what we are really excited about is we feel that this exciting Phase III data from the interim analysis firmly establishes our vision for renal ultimately to rival the size of our cystic fibrosis franchise.

And there are 3 therapy -- 3 Phase III ongoing programs in the renal franchise as well as an exciting Phase II for autosomal dominant polycystic kidney disease. And I think this is an exciting time in renal medicine overall, and we look to be a thought leader there and expanding that. And then beyond that, all the while, we've remained very, very true and disciplined to our R&D strategy with our identified sandbox diseases where we under -- they're serious diseases, we understand the causal human biology. There are validated markers.

There are efficient pathways for both clinical and regulatory progress as well as specialty commercial infrastructure. And so I think sticking true to that discipline and then just the focus on R&D, the outsized investment that we maintain, that's what enables us to continue to diversify away from CF, all while maintaining a strong outlook for growth there.

Great. Yes, certainly, a lot going on beyond cystic fibrosis. Turning to the pove data. Outside of just the top line proteinuria result, which I think a lot of investors were focused on, what are the other important data points that you think people should be focused on coming out of that release?

Yes. So I think there's a lot, bear with me. I'll try and keep it quick. But I think we were very excited by the overall, what feels to us like a best-in-class profile from an efficacy standpoint. Keep in mind, too, that we feel we definitively have an advantage from a patient administration and dosing standpoint, where we have the lowest dose of 0.46 mls in an at-home auto-injector, and it's once monthly versus peers are either higher dose and/or weekly injections that are required.

And we also feel that we will have best-in-class from a commercial capability standpoint as well and there are actually a lot of similarities between the CF and renal markets and nephrology community. And so we're excited for that. But in terms of the key data highlights, UPCR certainly does grab everyone's attention, and that's where we saw a 52% reduction at 36 weeks. I think that's important because some of the peers have had primary endpoint measurements at 40 weeks and you continue to see improvement over time. So seeing that type of reduction at 36 weeks is important.

From Gd-I -- on the secondary objectives, 2 endpoints there, one on Gd-IgA1 with a 77% reduction as well as an 85% resolution for patients' hematuria, an 85% rate of resolution. And those 2 were at 36 weeks. Again, some of the peers are measuring secondary endpoints at 48 weeks, so even more potential for differentiation. I think another key highlight, particularly in physicians' minds is the fact that 42% of our patients got to the KDIGO recommended guidelines of a UPCR less than 0.5 grams per gram that also compares quite favorably.

And this is very much a real-world population, right? With the most recent of the IgAN studies, we enrolled the fastest. We also had the highest rates of background therapy. Nearly everyone was on ACEs and ARBs and more than 65% of patients were on SGLT2 inhibitors. We also saw that the average duration from time of diagnosis, biopsy diagnosis to enrolling in the study was 3.8 years, right?

So it very much is a real-world population that high background therapy and still seeing that level of improvement on there, I think, is really significant. The other big piece of news is that they -- we announced that we'll submit our -- complete our rolling submission by the end of this month. I think that's beating expectations by about a full quarter for most. And we have used a priority review voucher. So after the FDA has 2 months, to accept the filing, consider and hopefully accept the filing, then it will be a 6-month review from there. And I think those are the key highlights. Yes. If others come up, we can bring them up later.

Yes. And I think that's particularly compelling, particularly the proportion of patients that got below 0.5 grams given that is in the guidelines now in terms of where patients should be going.

Exactly.

So I think that's an interesting from an efficacy perspective. And considering the patient baseline, which I think you appropriately called out, seems to be a more real-world patient population. A question that we're getting a lot of is on safety. Maybe if we could talk about that. I mean you have the potential to be more potent, but with the immune system that also comes at the potential risk of some more like infection risk. Can you talk through what was actually seen in the study and how you're thinking about the safety here?

Yes. We were quite pleased with the overall safety results, and it's a very, very clean profile. I think perhaps to start that the vast majority of adverse events were mild or moderate and that there were no severe serious -- no SAEs that were deemed related to pove and no SAEs that were inherent in that, right, is none due to infection. We can also confirm that there were no discontinuations related to infection. and there were no opportunistic or unusual infections either.

Most of the -- we included in our release that the greater than 10% rate were upper respiratory tract infections, nasopharyngitis and injection site reactions, right? So all very common. And I think a very favorable profile, and we're excited to move forward.

And a question that we got has been on hypogamma. I guess what can you say on what was seen here and when we can expect to learn more about that?

Yes. Thanks for the question. And I think there has been a lot of discussion around this. And it's very -- I think in general, everyone cautions from cross-trial comparisons, right? And particularly when it comes to issues like infection, I think it's even more fraught with peril. And there are very different definitions across the industry in terms of definitions of what the thresholds were for hypo IgG as well as what counted as a case of it.

For us, in the RAINIER study, any patient who went below a level of 300 milligrams per deciliter that, that was then deemed to be monitored. And if the patient went below 150, then treatment was discontinued or would be discontinued. We have told you there are no discontinuations through the interim analysis group. And so due to -- in order to maintain study integrity, we're not disclosing the number of that below 300 number or numbers.

But we have told you all the information on infections because the so what of hypo-IgG is infection. And you're just not seeing it as we went through previously. I would say a similar question, we did disclose that there was evidence of ADAs, but the so what there is on efficacy. And as we mentioned and discussed, right, I think very, very good efficacy even with all of the background therapy.

And in addition, we provided a fourth plot in the press release that shows you excellent results across every subgroup, including by race as well as by region. So you don't see any of the outliers perhaps you've seen in other studies. So I think both on hypo-IgG as well as ADAs, I know investors always want more disclosures, but we feel that we've given the consequences, the answers to the potential consequences of those, and there's nothing there.

That makes sense. In terms of pove, what I think is interesting is that this could be a pipeline and a product and has applications in a number of other conditions. Can we talk through that and sort of the rationale you see in PMN, myasthenia gravis and the time lines for those?

Yes. So in primary membranous nephropathy, I think very much akin to thinking about IgAN and in terms of that patient population. But IgAN is a little bit larger, right, 330,000 patients in U.S. and Europe and PMN is slightly smaller. There's no -- we're in an ongoing Phase II, Phase III study. There is no interim analysis or accelerated approval pathway here. It's a 104-week study, but we're underway and excited to keep progressing.

And I do think as physicians are considering their choices, the thought of having to learn and be fully immersed in one therapy to treat a broader array of their patients is a potential advantage we could have. And then for myasthenia gravis, we said that we'll initiate a Phase II study in the first half of this year. And I think if you're looking for a [ poster ] trial for B-cell-mediated disease, that's probably myasthenia gravis. And you have seen data out of China that looks quite compelling. And I think the rationale just makes all the sense in the world, and that's why we're moving forward and excited for that. And there could be additional indications beyond those 3 that we have discussed.

Makes sense. And how should we think about kind of the commercial opportunity for each of these considering unmet need, patient population, but also the competitive landscape?

Yes. So I think in -- let's maybe just start with IgAN that there is a clear unmet need, right? There's 330,000 of these patients who are diagnosed today, really with no good options. You've heard physicians describe them as kind of just waiting to see how and when and how fast they'll progress. And to have a disease-modifying therapy that can stave off the need for dialysis or transplant and ideally death, right, that, that is, I think, obviously compelling to patients, physicians and to payers as well because all of those options are expensive ones.

There are -- I think about 4,000 nephrologists treat 80% of these diagnosed patients in the U.S. We've had ongoing conversations with them from an access -- with payers about access since the middle of last year and continue to have those conversations. We have built out sort of the initial phase of our sales force. And now with this data, we'll look to complete that. Vast majority of the ones we have hired have nephrology experience in the community. And again, we've been in nephrology for a long time with our inaxaplin study.

And I think definitely, as we saw at ASN last November, a real excitement and buzz about the innovation that Vertex is bringing to the renal community, not the least of which is helped by the fact that our CEO is a trained transplant nephrologist. So that certainly helps. PMN, similarly, I think no real disease-modifying therapies. And in myasthenia gravis, we view the opportunity as some of the existing therapies, the drawback there is that they need to be cycled on and off, whereas we don't see that need given the mechanism with pove, but we need to do the trials and move forward from there.

Okay. Makes sense. And then I guess, in terms of inaxaplin, you have some exciting data either late this year or early next year. Let's talk about that opportunity and what you're looking to see in the Phase III program.

Yes, sure. So this is a disease that has no existing therapies, nothing that addresses the underlying cause of disease. And we think that the cause is the APOL1 mutations that people inherit that ultimately, there is a second trigger, but they drive poor formation in the kidney that ultimately results with the progression of kidney disease and rapid progression to kidney failure. So what we're developing there is our molecule is inaxaplin.

It's in Phase II/III pivotal development, and we expect to read out the interim results from this trial late this year or early next year. The goal is reduction in proteinuria, and we will also look at eGFR slope versus placebo. So those are the endpoints. It is clear we need to show stabilization of eGFR versus placebo as a pathway to file for accelerated approval.

And what gives you confidence that you'll be able to see the stabilization in eGFR slope?

Yes. So it's a great question. AMKD, this is really the first trial for this population. So obviously, we are the first to study this disease. But what gives us confidence is these patients, based on all the literature and everything we know about them, they progress twice as fast to renal failure and to dialysis than their peers who don't have the APOL1 alleles. So based on all of the -- everything we know about the patients and the progression of disease, there is reason to be optimistic that the curves can separate even at 1 year.

I'd also mention in our Phase II study, which we published in New England Journal that even just at 13 weeks, right, you saw a 47.6% reduction in UPCR. So we're hopeful with that sort of speed and depth of reduction that, that can lead to the endpoint in eGFR. I think admittedly, 48 weeks typically would be a short time frame for eGFR, but we're optimistic.

Great. Turning to the cystic fibrosis business, maybe just the latest that you're seeing in terms of a ALYFTREK uptake. We saw some decent growth in the fourth quarter. How should we think about the trajectory over 2026?

Yes. We would expect a continuation of the same solid trends in terms of ALYFTREK and conversions from TRIKAFTA to ALYFTREK. I would say that virtually all new patients are initiating on ALYFTREK given the lower sweat chloride that you can see with it as well as the once-daily dosing convenience as well as the fact that, that means only 1 fatty meal a day and patients have appeal there. We're also excited by the ongoing launches and reimbursed access in Europe.

And for instance, just given the derivation of the disease, you actually see more of the rare mutations in Europe than you do in the U.S. And we gave an example on the fourth quarter call that there are now 1,500 patients with access for the first time in Italy given the rare mutations that are -- that can be addressed by ALYFTREK. There's also no incremental liver monitoring anywhere outside the U.S. So that's helpful for uptake outside the U.S., too.

But I think continued good progress and a focus on the messaging around lower sweat chloride is better and ALYFTREK gets you there, right? And we also just published or released top line data from our study in ALYFTREK, where you see in the 12-plus population, right, about 30% of patients are getting to diagnostic levels. In the 6 to 11, I think it's about 53%. And by the time you get to 2 to 5, which is the one we just released, you're getting to north of 60% of patients getting below the diagnostic threshold.

So these are kids who essentially be asymptomatic of their CF. And we've begun a study in 1- to 2-year olds with ALYFTREK. So that will continue the momentum. So we've talked about growth overall in CF from younger patients, additional geographies, additional patients with the rare mutations and then the underlying population growth, which has averaged 3% over the past 5 years due in large part to the survival benefit that you're seeing from our meds.

Makes sense. And as we think about long term and life cycle management, any thoughts on NBD1?

Sure. So NBD1, we know the CFTR protein intimately well. I've been studying it for 20 years. NBD1 is a known binding site on the protein for many years. It's been in the literature, I think, over a decade. And we have -- we are looking at NBD1, we've disclosed, but that the binding sites that we have used for our 5 commercialized medicines have been different ones. And as I mentioned, as we're getting close to now almost 2/3 of 2- to 5-year-olds getting to carrier levels of sweat chloride.

I think we are happy with the binding sites that we have chosen. But we'll continue to look to try and improve until we can get virtually all patients to those carrier levels. I don't know that there's anything particularly unique, particularly given the breadth that we're seeing in terms of over 300 rare mutations, et cetera, about NBD1. But we are continuing to look to move forward. We have a NextGen 3.0 family of therapies one of which is in patients, one of which is in healthy volunteers, and we'll look to continue to raise the bar, and we'll see what others can do in terms of data middle of this year, I believe, which is on top of TRIKAFTA, which is our therapy.

But as I said, we'll see, and we continue to move the bar forward. And it's a long pathway from proof of concept, if that's what you see to finding a molecule -- a combination therapy is inherently difficult and then the head-to-head studies and then just getting it down into the younger patients. It took us a decade to get into the 1-month old from initial approval.

Yes, makes sense. That's helpful context. Turning to JOURNAVX. You said you expect scripts to triple this year, which is certainly impressive growth. This is a program that I think investors should be paying more attention to. Maybe talk through some of the investments in the sales force that you've made and what's driving some of the script growth.

Yes. On JOURNAVX, we are very pleased with the momentum, frankly, entering 2026. We came into 2026 having secured the last remaining commercial PBM for access to -- for coverage to JOURNAVX. So we are at over 200 million covered lives. That's 67% of all covered lives in the U.S. We -- as you remember, Ellie, we had 550,000 scripts written for JOURNAVX in 2025 in year 1, which was pretty broad across the hospital and the retail segment and different specialties, 35,000 physicians writing prescriptions.

So we were very pleased with the momentum going into 2026. And we feel strongly that now is the right time to double down and invest further behind the launch. So we are doubling the sales force from 150 to 300 reps. These reps will be active in the field in the second quarter. And the goal for them will be to go broader and deeper with accessing physicians and driving adoption of JOURNAVX. And in addition to that, we are also increasing our marketing investment.

So things like direct-to-consumer, where we are launching advertising across Connected TV, Hulu, Paramount+ and the like. We have a campaign with Basketball Star, Hall of Famer, Jayson Tatum. So we're out there. We're promoting heavily, and we expect that to increase over the course of 2026. And as coverage broadens, the gross to net we are realizing on JOURNAVX will improve over 2026. So that will result in more revenue and higher revenue growth, as Susie mentioned, relative to the script growth.

One other thing I'd add is, and maybe touch on it is 2 Phase IV studies that we're excited about. One we just published -- was presented last week in aesthetic and reconstructive procedures. We'll have one next month in arthroscopic and laparoscopic orthopedic procedures, but showing really tremendous patient satisfaction as well as high, high rates of patients being opioid-free in the 14 days post treatment.

I think in the aesthetic one, it was 90% of patients were opioid-free. And typically in that patient group, you see only 10% of patients are opioid-free according to the literature, and we look forward to similar results in the orthopedic one. So I think that will also help continue to fuel the momentum.

Yes. We've certainly heard very positive feedback from physicians in the aesthetic setting as well. So exciting data. As we head into 2027 and potential Phase III data for DPN, sort of remind us of the time lines and the trial design there? And what gives you confidence in potential success? Because this certainly would dramatically, in my view, expand the market opportunity given the duration of the script would be much longer than a chronic type of pain.

Yes. We are well underway with our 2 Phase III trials in diabetic peripheral neuropathy. We expect to complete enrollment in both trials by year-end. and that would set us up for results in 2027. So we feel very good about the progress of this program. There's 2.5 million patients with diabetic peripheral neuropathy in the U.S. who have a significant unmet need. The current available treatments are either not well tolerated, I would say, or just don't provide sufficient relief. And so we think we have a lot to offer here with JOURNAVX, but we'll have to read out the results and see how it plays out.

There are 12-week studies with 2 weeks of follow-up. Is that right?

Yes, yes.

Great. Well, a lot to look forward to. I think we're out of time, but thank you both so much for joining us, and I appreciate the time today.

Thanks very much for having us.

Welcome, everyone, to our session with Vertex. It's very much my pleasure to welcome members of the leadership team on the screen, if you're in the room, Duncan has been retitled as CSO. I guess that's in the wake of the positive pove data, trying to take credit for that.

Yes, hopefully.

So he's out of a title. But to my immediate left is Charlie Wagner, company's COO and CFO; and Duncan McKechnie is to his left, Chief Commercial Officer; and Susie Lisa, Senior Vice President of Investor Relations to Duncan's left.

So thank you very much for being here. Great timing. Thanks for issuing the press release last night I had a conference...

It's for you, it's for you, yes.

So why don't we start with pove? It would be great to hear -- how you view the data, and then we'll go from there.

If you don't mind, I'd like to make just a couple of general remarks, too...

Please.

And then we will, of course, dive into that. Anyways, thank you for hosting us this year. We came into 2026 with four primary goals for the company: one, to extend our leadership in CF; two, to accelerate our commercial diversification, particularly with JOURNAVX and CASGEVY; three, to advance our broad and deep pipeline, which has 5 Phase IIIs ongoing right now; and four, to deliver consistent and attractive financial results while we scale the company for the future.

We are, I think, off to a very good start relative to that. We gave guidance for the year -- revenue guidance of $12.95 billion to $13.1 billion, which implies 8% to 9% growth. We said that, that would include at least $500 million of revenue from non-CF products, so JOURNAVX and CASGEVY, which would be a significant acceleration in 2026 over 2025, and we can talk about some of those metrics.

But of course, one of the key things that we're doing this year is advancing the pipeline. As I mentioned, we have 5 Phase IIIs ongoing in AMKD, type 1 diabetes, DPN, and two with pove, one in pMN and one in IgAN. Of course, I mentioned that last because last night, we issued a press release on the results of pove in IgAN.

There was a 36-week interim analysis. I would say the data are remarkable, and it was a clean sweep across the endpoints for efficacy as well as the safety profile for pove. And if I could just headline it, we showed statistically significant and very clinically meaningful efficacy results -- on all primary and secondary endpoints for efficacy and the safety profile was very attractive.

Drilling down into the efficacy data. The primary endpoint was UPCR reading at 36 weeks. We showed a 52% reduction in UPCR relative to baseline, a 50% reduction relative to placebo, very consistent with what we saw at 36 weeks in the Phase II results, very strong data overall. On the secondary endpoints, we saw a 77% reduction in Gd-IgA1 antibodies. And we -- for patients with hematuria, we saw an 85% resolution rate in hematuria. So fantastic results overall.

The profile was very rapid, very deep and very durable response across all subgroups. We provided data so that you could see the efficacy results in the patient population by age, by gender, by race, by geography and across all of those dimensions, the clinical data, the efficacy data was statistically significant and very clinically meaningful.

On safety, there were no SAEs related to pove. There were no deaths in the trial. There were no unusual or opportunistic infections. There were no discontinuations in the trial due to infection. So overall, a really attractive safety profile as well and one that gives us confidence to move forward.

On that point, we had previously said we would expect to submit the filing in the first half of 2026. We've now pulled that in. We've accelerated it, and we expect to submit by the end of this month, which should put us on track, hopefully, for a commercial launch in the not-too-distant future. So as far as the year goes, I think we're confident we're off to a great start. And certainly, the pove data last night punctuates certainly what we are hoping to see in the pipeline.

Excellent. Congrats on that. So could you just go into a little bit more on safety and what you've -- I mean, you highlighted it, but any additional details you can provide and also discuss when we will expect to -- or when we should expect to see additional disclosures?

Yes. Listen, like I said, the safety data was excellent. I think importantly, with no discontinuations in the trial due to infection tells you a lot. The rate of infection -- rate of serious infection in the trial was very low, and it was very similar between the placebo arm and the pove arm at 0.5% for serious infections. So overall, quite low and again, no discontinuations. So overall, we feel great there.

In terms of additional data, we will provide additional data through publication and congresses in the future. Though some of that data we can't release until the trial itself is completed. And so that will be -- we'll release additional data at the appropriate time in the future.

And with respect to benchmarking data versus competitors, so your data was at week 36. I believe the Otsuka data that's in the label is at a slightly later time point. Could you just discuss that as well?

Yes. Our data is week 36. Their data is week 40. So ours was 9 doses, theirs was 10. I think you could see in our Phase II data that there was improvement -- further reduction in UPCR beyond 36 weeks. We don't have that measurement here in the Phase III. But again, with the 52% reduction at 36 weeks for pove tells you that there was a very rapid and strong response. You would expect that, that would continue over time. But again, we won't have the data on that to publish at this time.

Dave, if I could just add that on the Otsuka data, their secondary endpoints were actually at 48 weeks, so an even longer duration than all of ours, we're at 36 weeks. And I think to contextualize the strong efficacy data that we had, you should also note that it had the highest rates of patients on background therapy in terms of almost 100%, I think 98% on ACEs and ARBs, and 67%, 66% on SLGT2 inhibitors (sic) [ SGLT2 inhibitors ] ...

For our trial...

Yes, for our trial, yes. As well as we think it's very much a real-world population, given it was almost 4 years, right, from diagnosis to enrollment in the study, it was 3.8.

Excellent. Great. Well, I know we have a lot of ground to cover. So why don't we pivot to -- I guess, just a little bit at the higher level, and then we'll go into some of the franchises. So with respect to the growth prospects for the company, could you just talk about the top line outlook as you see it going forward and then the margin outlook as you reinvest?

Yes. We don't give long-term guidance, but I think I can provide some context. Obviously, two of the four goals that I mentioned to start 2026 have to do with the growth, and it's extending our leadership in CF and accelerating our commercial diversification. CF continues to grow. We continue to reach more patients. The ALYFTREK launch is ongoing in the U.S. We now have several launches ongoing outside the U.S. We continue to reach patients in younger age groups. We continue to reach patients in new geographies. And so I expect in 2026 to see healthy growth in CF, and I expect that to continue beyond 2026 as well -- I would say '26 and more meaningfully beyond.

With CASGEVY, you saw we had a very strong fourth quarter. In 2026, we expect continued growth in patient initiations for cell collections infusions. In JOURNAVX, we had a very strong year in 2025 with 500,000 prescriptions. We said in our guidance that we expect that number to triple in 2026. And the revenue conversion on those prescriptions will be greater because we've done so well with our coverage goals, and we now have roughly 200 million lives covered for JOURNAVX. So CASGEVY and JOURNAVX, both are on -- at a nice inflection point. And we believe that both of them are going to be multibillion-dollar businesses over time.

And you think about that in addition to the growth in CF. We just announced the pove data in IgAN. I think that clearly is a multibillion-dollar opportunity just in IgAN alone. We've got the Phase III ongoing in pMN. So if you look out 2, 3, 5 years, pick your time frame, I would fully expect that we've continued our leadership in CF with growth there. And then we have multiple multibillion-dollar franchises on top of that, allowing for commercial diversification.

The second probability of success in generating revenue in the near term. So we're investing in the 5 Phase IIIs that we have ongoing. We're investing in building the commercial organization for CASGEVY, for JOURNAVX and for pove. Those investments are appropriate and will deliver growth in the next couple of years. And so even with the investment, though, we've been able to maintain operating margins in the low to mid-40s, which is super attractive, and we'll continue to manage both the investment and the operating margin in a way that's going to deliver value over the long term. So particularly as these non-CF businesses scale and become multibillion-dollar businesses, that's going to be very attractive and accretive to our profitability.

Excellent. And when you said multibillion for JOURNAVX, what is your assumption that you're including for DPN?

In the statement I just made, I'm honestly just talking about acute. And so obviously, DPN is a separate multibillion-dollar opportunity, but we'll wait to talk about that until we see the Phase III results in late this year, early next year, early next year.

Okay. Great. And so -- maybe we could just touch on ALYFTREK first, and then we'll come back to JOURNAVX. So Duncan, could you comment on the conversion and the prospects for conversion going forward?

Yes, I can. If you don't mind, Dave, before that, I'll just make a couple of other comments on pove...

Please.

And IgAN as the commercial guy. Just to reinforce the point, this is genuinely remarkable data that we saw on pove this week. We are incredibly excited about the profile of the product because we really do believe it has best-in-class potential when you combine 3 things. Firstly, the superb efficacy and safety data that we saw in the data set this week. Secondly, when you add to that, the dosing administration advantages that we believe povetacicept has. So as you know, it's dosed once a month. It's a low-volume dose. It's with an easy-to-use at-home auto-injector, which we think has a very differentiated profile in the market.