Insmed Incorporated Stock

Thank you for standing by, and welcome to the Insmed Third Quarter 2026 Financial Results Conference Call. [Operator Instructions] Please note that today's call will include forward-looking statements. These statements represent the company's judgment as of today and in and uncertainties that may cause actual results to differ materially from the projections discussed.

Please refer to Insmed's most recent filings with the Securities and Exchange Commission for a full description of these risk factors. The information discussed on today's call is meant for the benefit of the investment community. It is not intended for promotional purposes and it is not sufficient for prescribing decisions.

Today's call will feature prepared remarks about Insmed's quarterly performance and financial position by Will Lewis, Chair and Chief Executive Officer; and Sara Bonstein, Chief Financial Officer, respectively. After their remarks, they will be joined by Martina Flammer, Chief Medical Officer, for the Q&A session. I would now like to turn the call over to Will Lewis.

Good morning. Today's updates are intended to illustrate three overarching ideas. The first is that Insmed has evolved into a diversified biotechnology company that we believe can generate significant revenue and earnings with substantial growth over the next 10 years and beyond.

In addition to exceeding $1 billion in total company revenue year-to-date, I am pleased to announce that BRINSUPRI has already achieved blockbuster status, having generated more than $1 billion in revenue in its first 4 full quarters of launch. We believe we have only scratched the surface of the potential addressable patients who may benefit from this first ever approved foundational medicine in bronchiectasis.

While we have treated tens of thousands of patients in the first year, there remain hundreds of thousands of patients already diagnosed and waiting with potentially millions more who may benefit. We have literally only just begun to see the benefit BRINSUPRI will bring to patients, and this has been achieved while continuing to deliver for patients with NTM with ARIKAYCE. As a result of this performance, we are raising our full year 2026 guidance for both products.

I'm very proud of the work we have done but there's always more we can improve upon. I continue to believe the growth road ahead for our medicines is very substantial.

Looking ahead, we have forecasted our 3 lead respiratory assets to collectively grow at a compound annual growth rate of more than 20% over the next 10-plus years. In doing so, we expect our three lead respiratory assets to collectively exceed $14 billion in estimated peak sales with room for potential upside.

BRINSUPRI's peak sales estimate of more than $7 billion does not include the COPD and asthma comorbid patient populations, which we estimate number in the low single-digit millions of additional patients. We believe the future impact of BRINSUPRI on these additional patients who are on max dose treatments for their conditions, but are still suffering damage from exacerbations could be significant.

The consequent revenue generation from success in treating these patients could represent potentially as much as or even more than the current $7 billion peak sales estimate, and in a moment, I will speak to the initiatives we are deploying to tackle this important opportunity.

TPIP is also expected to be a massive product, potentially hitting the market by the end of this decade with a peak sales estimate of more than $6 billion from four separate indications. Thus far, TPIP has distinguished itself within the [ prostanoid ] class with superior improvement in 6-minute walk distance and PVR reduction among other efficacy measures as well as better safety and convenience with its clearly differentiated profile.

We believe TPIP, a once-daily inhaled Treprostinil prodrug has the potential to unlock previously unknown clinical safety and convenience benefits through a validated mechanism of action. I want to be very clear that we remain fully prepared for any and all challenges brought by companies who try to stand in the way of patients potentially gaining access to this innovative therapy.

Finally, we believe ARIKAYCE with an expanded label possible next year has the potential to achieve more than $1 billion in peak sales with launch preparation in the U.S. and Japan well underway, assuming approvals in both territories. We believe that having a diversified portfolio of respiratory assets, each of which we believe have the potential to be a blockbuster will enable us to deliver among the best revenue growth and ultimately, earnings growth and place Insmed at or near the forefront of commercial stage biopharma companies for the foreseeable future.

The second idea is that Insmed continues to demonstrate operational excellence. We measure operational excellence by our ability to deliver strong revenue performance while scaling commercial, clinical and technical capabilities designed to meet our future. Today, operational excellence is seen in the continued advancement of our four Phase III TPIP trials in PH-ILD, PAH, PPF and IPF. It will continue to be demonstrated through the anticipated initiation of multiple Phase II programs over the next several years, pending positive data from the Phase I healthy volunteer study of INS1033, we expect to initiate a Phase II study in rheumatoid arthritis in 2027, followed by ulcerative colitis and COPD. Also, in 2027, we plan to begin a Phase II study of INS1148 and IP with plans to evaluate it in PPF and other inflammatory and fibrotic diseases thereafter.

And the third idea is that our research engine continues to advance therapies that we believe have the potential to be first or best in class. In 2027, we expect to share data from our Phase I gene therapy programs in DMD and ALS. We are also reiterating our guidance to submit one to two INDs per year through the end of the decade.

While there are many more programs under evaluation, we currently have line of sight to nine research programs from across our four research centers, all of which we believe could be first or best-in-class medicines. These programs have the potential to enter the clinic between now and 2029, and we believe several could qualify for accelerated approval.

Beyond our internal pipeline, we continue to have an active business development effort in search of medicines like BRINSUPRI. They are very hard to find, but we believe they are out there.

The takeaway should be that our combination of sustained commercial growth operational excellence and differentiated scientific innovation has the potential to set Insmed apart from its peers and position it at the forefront of high-performing biotechnology companies.

Now let's take a closer look at BRINSUPRI. BRINSUPRI produced $400.1 million in revenue in the third quarter of 2026. This represents 29% sequential growth versus the prior quarter. On Slide 7, you can see that BRINSUPRI revenues continue to far exceed those of other strong respiratory launches, including blockbusters like DUPIXENT, TEZSPIRE, VISENRA and WINREVAIR on a launch-aligned quarterly revenue basis.

On August 12, we celebrated BRINSUPRI's 1-year anniversary of FDA approval and U.S. launch. With more than 1 year of commercial launch behind us, I am pleased to report that we remain excited by our performance relative to key internal launch benchmarks and we continue to be comfortable with the historic direction we have provided on metrics like new patient starts, which we believe has the potential to expand as we move through 2027.

As previously communicated, now that we are past the first full year of launch, we no longer plan to provide specific updates to each individual launch metric. We are extremely happy with our performance, and we are seeing particular strength in payer approval rates, reauthorization rates, persistency and dispenses and continued positive feedback from patients that say they feel better on BRINSUPRI. Across the board, we are happy with where we are and where we are going.

We remain focused on continuously refining our commercial strategy and optimizing resource allocation to maximize the launches potential. For example, we continue to sharpen our physician engagement strategy prioritizing top tier prescribers where we see the greatest potential for increased depth.

We also look forward to launching our first branded TV campaign, which will contemplate our existing collection of unbranded campaigns and hopefully help patients with bronchiectasis understand that an approved once-daily oral treatment option may be right for them.

We have determined that this type of commercial outreach usually has a very high return on investment, and we are excited for its launch next month.

Given BRINSUPRI's consistent outperformance to date, we are raising our full year 2026 revenue guidance range to $1.35 billion to $1.4 billion, which represents an increase to the low end of our previous guidance range by $100 million.

Turning now to Japan. Last week, we officially launched BRINSUPRI 25-milligram tablets in Japan. Principe is the first and only approved medicine for patients with bronchiectasis in Japan. Recall, Japan is home to approximately 150,000 patients currently diagnosed with bronchiectasis.

In our Phase III ASPEN study, Japanese patients demonstrated a substantially greater reduction in exacerbations with a 68% reduction in annualized exacerbation rate compared to approximately 20% in the global study.

In addition, Japanese patients demonstrated more than twice the improvement in lung function observed in the global study as measured by a change in FEV1 and FDC. While the biological reasons for this differentiation are not known, the difference is dramatic and underscores the potential of BRINSUPRI to make a profound difference in the lives of Japanese patients with bronchiectasis.

As a result of this positive clinical impact on Japanese patients, we are also pleased to have secured very favorable pricing for BRINSUPRI in Japan. We expect Japan to be the main driver of any ex U.S. bins sales.

As a reminder, precedent from other specialty medicines launched in the U.S., Europe and Japan suggests that collectively ex U.S. markets typically represent approximately 10% to 15% of global peak sales.

We are energized by the opportunity to serve Japanese patients, and we celebrate the hard work of our Japanese colleagues for reaching this important milestone while continuing to deliver strong ARIKAYCE performance over the last several years.

Turning now to our efforts to generate real-world evidence for BRINSUPRI. Our medical and clinical teams have been hard at work building a robust body of long-term evidence to support BRINSUPRI. In August, the bronchiectasis and NTM Association announced our collaboration on the first in disease observational study evaluating the real-world effectiveness of 10 and 25 milligrams of brensocatib.

The brensocatib effectiveness, safety and tolerability in bronchiectasis or BEST BE study is designed to measure the incidence and frequency of pulmonary exacerbations in patients with non-cystic fibrosis bronchiectasis over a 2-year period. The study will also track changes in patients' quality of life and the incidence and frequency of adverse events. The study plans to enroll 1,000 adults across 13 U.S. sites with key secondary measures, including changes in lung function time to next exacerbation rate of severe exacerbations and the presence of respiratory pathogens and NTM culture conversion.

We believe the BEST BE study will strengthen the long-term evidence base for BRINSUPRI in the U.S. and corroborate insights from our strategic collaboration with Embark in Europe.

As a reminder, Embark is conducting a 3-year open-label study of 25 milligrams of brensocatib in up to 3,000 patients across six European countries. The study will evaluate whether long-term treatment with brensocatib can modify the course of bronchiectasis and whether earlier use of brensocatib can further slow disease progression.

We look forward to working with the bronchiectasis and NTM Association and Embark to translate real-world evidence into actionable strategies that improve the diagnosis and treatment of patients with bronchiectasis while further strengthening Insmed's leadership position in the space.

In parallel with our BRINSUPRI real-world evidence generation efforts, a dedicated task force has been hard at work advancing initiatives that raise awareness of comorbid bronchiectasis among patients with COPD and asthma and help physicians make more appropriate treatment decisions. We believe this comorbid bronchiectasis opportunity from within the COPD and asthma populations represents one of Insmed's most significant potential value drivers, an underdiagnosed bronchiectasis population that could be several times larger than the approximately 500,000 patients diagnosed in the U.S. today.

If even a single-digit percentage of the approximately 32 million patients with COPD or asthma in the U.S. are found to have undiagnosed bronchiectasis, the addressable population for BRINSUPRI could expand to several million patients. Importantly, this comorbid opportunity is not included in BRINSUPRI's current peak sales opportunity of more than $7 billion, which is why I previously mentioned that this peak sales estimate may have room for significant upside.

You've previously heard us discuss the work at the American Thoracic Society is doing on the diagnosis front as well as our launch of the suspect BE celebrity awareness campaign. As a reminder, ATS is evaluating how physicians identify bronchiectasis in clinical practice to help alter default diagnostic practices to specifically contemplate bronchiectasis and the suspect BE campaign aims to encourage patients with copier asthma still experiencing symptoms to explore further diagnosis with a pulmonologist. Today, I'm pleased to provide more details from our broader diagnosis strategy.

Our initiatives are arranged into three strategic priorities. The first is the generation of evidence to establish the prevalence and scale of undiagnosed bronchiectasis in patients with COPD or asthma.

The second is building strategic partnerships to explore opportunities to transform how bronchiectasis is detected and diagnosed in the care setting.

And the third is educating health care providers to improve their understanding and identification of bronchiectasis in their patients.

Our evidence generation initiatives began earlier this year with three leading COPD and asthma centers in the U.S. using retrospective imaging analysis to identify previously undiagnosed bronchiectasis and evaluate approaches to improve detection. Our goal is to change how bronchiectasis is identified in clinical practice by raising pulmonologists and radiologists suspicion of the disease, encouraging the systematic evaluation of high-res CT scans for the presence of the disease and strengthening hospital protocols to reinforce this process on behalf of patients. We believe these efforts can facilitate earlier diagnosis, improve disease management and help patients make more informed decisions about their care.

In addition to our evidence generation efforts, I'm excited to share that we are in the early stages of developing AI-powered diagnostic tools with strategic partners. These tools are intended to integrate into existing health care provider software to help identify bronchiectasis in patients' medical records and use predictive analytics to flag potential cases of bronchiectasis alongside other common pulmonary conditions like lung cancer, COPD and asthma.

To help physicians better detect bronchiectatic patients in their practices, we recently launched a disease educator program, deploying an initial team of 16 trained nurses across the U.S. These educators engage directly with pulmonologists where our data indicate there is a high concentration of patients with COPD and asthma. Their role is to help physicians recognize signs of underlying bronchiectasis in patients who may have the disease in addition to or instead of their current COPD or asthma diagnosis. As we evaluate the program's impact, we see an opportunity to expand this approach to additional U.S. sites.

These are just a few of the initiatives we have invested in thus far. We remain incredibly excited about the insights these efforts will generate and the strategies we expect to implement as a result.

Given that many of these insights are a derivative of lagging indicators, we anticipate sharing our initial findings in the middle of next year.

Let me now turn to ARIKAYCE. Commercially, ARIKAYCE continues to deliver, generating $124.4 million in revenue in the third quarter of 2026, which represents 9% annual growth versus the prior year period. Following 3 quarters of strong performance, we are raising our full year 2026 ARIKAYCE revenue guidance range to $460 million to $470 million, which represents an increase to the low end of our previous guidance range by $10 million.

On the regulatory front, I'm delighted to report that in September, the FDA granted ARIKAYCE priority review for its supplemental new drug application for the treatment of MAC lung disease. The PDUFA target action date is set for January 28, 2027. Importantly, the FDA indicated that it does not currently plan to convene an advisory committee meeting to discuss this application.

This application's acceptance marks a pivotal moment in our ambition to change the treatment paradigm for MAC lung disease patients. If full approval is granted, ARIKAYCE could reach patients earlier in their disease progression, including those newly diagnosed or facing recurrent infections.

In addition, Insmed plans to submit the ENCORE data to Japan's Pharmaceuticals and Medical Devices Agency in the fourth quarter of 2026 to support a potential label expansion in Japan. If both submissions are successful, we would expect to launch ARIKAYCE under an expanded label in the U.S. and Japan in the first half of 2027. Label expansions that include all patients with MAC lung disease in the U.S. and Japan could increase ARIKAYCE's addressable market in each region from approximately 15,000 patients today to more than 100,000 patients in the future. This represents a potential total addressable market of more than 200,000 patients across the U.S. and Japan. We look forward to engaging with the FDA and the PMDA throughout these review processes.

Let me now turn to TPIP, which I believe will supercharge our growth as we close out this decade. Earlier this month, Insmed featured the global Phase III PALM clinical development program at the CHEST 2026 Annual Meeting. The PALM program, which is comprised of 4 Phase III studies in PH-ILD, PAH, PPF and IPF represents one of the broadest active clinical programs in the pulmonary space. If successful, TPIP, a once-daily inhaled Treprostinil prodrug could emerge as the prostanoid of choice for clinicians and patients. Let me provide an update on each study.

The PALM ILD study of TPIP and PH-ILD continues to enroll ahead of expectations. After enrolling its first patient in December of last year, the study is now more than 35% enrolled, reflecting the medical community's enthusiasm for the strength of TPIP's clinical profile. Based on these enrollment trends, we expect to complete enrollment no later than the first half of 2028, less than 2.5 years after initiation.

In the PALM PAH study, we are pleased to announce that we have enrolled our first patient and believe continued enrollment will benefit from the strength of our 12-month open-label extension data of TPIP in PAH patients presented in July.

In the third quarter, the PALM PPF study initiated its first site. The study remains on track to begin enrollment before the end of the year. And lastly, the PALM IPF study remains on track to be initiated in the first half of 2027. Turning now to the progress we're making in the rest of our pipeline.

As we prepare for the long-term success of Insmed, we continue to invest in our earlier-stage programs. In September, our second TPP1 candidate, INS1033 began actively recruiting patients in a Phase I healthy volunteer study. We expect data on pharmacokinetic exposure and blood NSP levels will be available next year. If these data are positive, we would progress into Phase II development in rheumatoid arthritis in 2027, followed by ulcerative colitis and COPD.

Also in 2027, we plan to initiate a Phase II development program for INS1148 in IPF. With plans to evaluate PPF and other diseases where inhibition of the pro-inflammatory and pro-fibrotic responses mediated by stem cell factor 248 may be beneficial.

Within our gene therapy portfolio, both our DMD and ALS programs continue to progress on track. Our Phase I ASCEND study of INS1201 in DMD is now fully enrolled, with 12 pediatric patients across four cohorts. We are encouraged by the data we have seen to date.

As a reminder, this study is evaluating two dose levels across two pediatric age groups with three patients in each cohort. INS1201 is designed for intrathecal delivery with the goal of minimizing liver exposure and delivering therapy directly to skeletal muscle and cardiac tissue. We look forward to sharing initial data from multiple cohorts within this program in 2027.

Our Phase I ARMOR study of INS1202 and ALS has progressed into Cohort 2 and is actively enrolling patients with both sporadic and SOD1 ALS. The study is expected to enroll up to 23 patients, three of which were already enrolled in Cohort 1, all with sporadic ALS and treated at the lowest dose. Cohort 2 is evaluating a middle dose in patients with both sporadic and SOD1 ALS with five patients planned in each group. If it is determined that patients can be safely dosed higher, we have the option to advance to Cohort 3, which would also enroll sporadic in SOD1 patients and evaluate them at the highest dose. We expect to share initial data from this program in 2027.

Before I turn the call over to Sara, let me take a moment to publicly thank her for being a critical part of the team that brought us to this position of strength. As today's results demonstrate, Insmed sits in as strong a position today as it ever has and Sara has played an important role in getting us here through the securing of capital, the creation and management of our internal financial architecture and the fielding and supporting of the collective inputs of the investment community. Sara remains as well regarded within Insmed as she does outside of it, and we wish her the best in her future endeavors.

With that, let me turn the call over to Sara, who will walk you through our financial results.

Thank you, Will. I'm pleased to share our third quarter 2026 financial results and updated guidance. BRINSUPRI produced $400.1 million in revenue in the third quarter up 29% sequentially from an exceptionally strong second quarter. ARIKAYCE produced $124.4 million in revenue this quarter, representing 9% annual growth compared to the third quarter of 2025.

Based on our strong performance to date, we are raising the low end of our revenue guidance for both our commercial products. For BRINSUPRI, full year revenue guidance of $1.35 billion to $1.4 billion represents a $50 million raise to the midpoint of our previous guidance range and reflects the strong execution and performance we have delivered to date. For ARIKAYCE, full year revenue guidance of $460 million to $470 million reflects the continued strength and durability of the franchise, which is now in its ninth year since launch.

We continue to view potential U.S. and Japan label expansions in 2027 as an important upside catalyst for ARIKAYCE.

On gross to nets, we are reiterating our 2026 guidance ranges for BRINSUPRI of mid- to high 20s and for ARIKAYCE of low to mid-20s. Both products have performed within these ranges to date.

As a reminder, the IRA small manufacturer provision has allowed us to delay the impact of covering catastrophic coverage calls for Medicare patients on ARIKAYCE over the last 2 years. increasing only 1% each year in 2025 and 2026.

According to the small manufacturer phase-in protocol, manufacturer coverage cost for Insmed will increase to 5% in 2027, which will expand ARIKAYCE's gross to net. These phase-in increases will continue annually until the maximum 20% of catastrophic coverage costs are covered by Insmed in 2031.

Moving now to the other relevant financial metrics for the third quarter. Positive product revenues was $78.2 million or 14.9% of revenues which is lower on a percentage basis than the 20.6% we saw in the third quarter of the prior year, reflecting the positive contribution of BRINSUPRI to the company's gross margin profile.

As expected, combined research and development and SG&A expenses increased 40% compared to the prior year period due to the necessary investments made to support the launch of BRINSUPRI and to continue to fund our pipeline. We continue to manage our investments thoughtfully as BRINSUPRI scales, balancing the opportunity in front of us with disciplined resource allocation.

Let me now spend a moment on our cash position and burn rate. As of the end of the third quarter, we had approximately $1.1 billion in cash, cash equivalents and marketable securities. Combined with the continued strong performance of BRINSUPRI, this gives us a clear line of sight towards achieving cash flow positivity in 2027, even as we continue to be a growth story.

Before we open the call to your questions, I want to take a moment to share my deep appreciation for my time at Insmed. When I joined Insmed nearly 7 years ago, we were a single product company with enormous ambition. Today, we have transformed into a multiproduct company on track for cash flow positivity next year. I leave with immense pride in what we have built together and more importantly, in what this organization has accomplished for patients.

I want to close with two thank yous to the Insmed team, every milestone every patient reached every obstacle we navigated together, that is the work that matters and you are extraordinary. And to the financial community, your conviction, your capital and your willingness to believe in our mission made it possible to unlock this potential. Our financial foundation has never been stronger, thanks to your partnership.

With that, we would now like to open the call to your questions. Operator, may we please take the first question.

[Operator Instructions] Your first question comes from the line of Gavin Clark-Gartner with Evercore ISI. Please go ahead.

This is Yash on for Gavin. We understand you're not providing specific metrics, but directionally, we were wondering if you could speak to how discontinue patient trends are evolving as specialists earlier cohorts mature? Are you seeing them stabilize with the longer-term treatment and are newer cohorts tracking similarly?

Yes. Thanks for the question. I would tell you, all of the metrics are positive from my point of view. And I would say in specific response to your question about that. That is doing better than expected. And as we look out, and I know -- I'm sure the questions will come in about new patient starts, everything else, while we gave guidance that after a year, we were going to stop providing the specific metrics I just want to be very clear that, that is positive and where we are going next year. I think that's going to continue to grow.

So across the board, I feel very good about where we are, and I would just say, the things to look at are [ TRxs ] off the Symphony data, while October is not out yet, it's trending in the right way relative to what we see. And then as you look at revenue, those are the two things that I think matter for a product that's now already a blockbuster in its first year of launch.

Your next question comes from the line of Jessica Fye with JPMorgan.

Congrats on the quarter. Can we expect you to guide for BRINSUPRI in January, similar to what you've historically done for ARIKAYCE? And then on TPIP, congrats on the enrollment traction in the ILD trial. What time frame are you circling for top line data for that one in the PAH trial?

Yes. I'm just taking notes. So it's our usual practice to provide guidance if we're going to do it around your conference, frankly, and my expectation is that we would do that again looking at next year for BRINSUPRI as you asked.

On TPIP, we indicate that the enrollment will be completed by the first half of '28, no later than that. And so the data would come with whatever time it takes to sort of make sure the database is in submission ready form and all that kind of stuff.

It usually doesn't take that long. Our team is pretty good at flipping results. But once the full enrollment is taking place, then obviously, they have to go through the length of the trial and then we lock the database and do the primary endpoint. We'll get that done just as quickly as we can.

PAH just got started. It's hard to give guidance on when we think that's going to happen. The thing I'm going to be watching there as much as we have in ILD is how is the market of physicians responding to the data that we just put out.

We're hopeful that PAH because of the open-label data, we'll see acceleration in the enrollment time line as ILD did. Now obviously, PAH is more competitive in terms of the number of trials going on. But our data is really quite strong, and so we're pretty bullish on that. The ILD study, just to put it in a frame of reference relative to expectations is about 6 months ahead of schedule.

Your next question comes from the line of Faisal Khurshid with Jefferies.

Please go ahead. I understand you guys are not giving metrics. I just want to ask if you can speak at least qualitatively to what you're seeing and what investors should expect with respect to seasonal dynamics for this product? Like do you see anything meaningful that you can comment on so far with regards to how the summer shaped up compared to what you're seeing in the fall, for example? And also how that's kind of informing how you're thinking about the fourth quarter?

Yes. There's a lot of in around August and what was seen in Symphony data. I think the Symphony data is pretty accurate, but not always. And I would just say I think it's too early for us to make commentary about seasonality.

I don't think it's a big force to be honest. We didn't really see it in the clinical trial setting to any great degree. But we're going to know a lot more once we see this cold and flu season kick in and what that results in.

Do I think there's a theoretical possibility that, that could raise awareness about exacerbations and get people into their pulmonologists, I do. I think that's not an unreasonable thing to consider might happen. I don't know how that's going to play out in Q4 or into the early part of next year. But I would not model it a lot on seasonality until we can make something more definitive by way of a statement. And I think that won't be until probably the spring of next year, and we can look back at the totality of this time frame and comment on what we've seen.

The trends within the launch are incredibly strong. I just want to be crystal clear about that. And the metrics that we provided, as I've said, new patient starts, I think you will see that grow through next year. I think you're going to see the other metrics that we've talked about in the past, things like persistency, they are way ahead of benchmarks. And so we feel fantastic about the way this launch is looking.

If I could give one piece of insight, I think probably the most powerful force operating behind this launch is persistency. The patients who go on this drug, many of them feel better and they are staying on the drug. And that is -- you see that in a lot of the public commentary by patients. It's just it's -- things are going very, very well.

That's awesome. Thank you, Will. And yes, nice to have a little upside surprise with regard to Symphony. So I appreciate the progress you guys are making.

Your next question comes from the line of Andrea Newkirk with Goldman Sachs.

Please go ahead. And first, maybe, Sara, I'll just say thank you for your partnership and best of luck in your next leadership role.

Will, just as you think about forward growth for BRINSUPRI, what are you seeing on the evolution prescriber breadth versus depth? And what percentage would you estimate right now currently originate outside of those specialists and into the broader community pulmonology setting.

And then if I could squeeze one quick one in for Sara. Just on the path to cash flow positivity. If you could help us think about modeling expenses over the next year as the TPIP studies get underway and what quarterly product revenue threshold across BRINSUPRI and ARIKAYCE are you anticipating would be required to cross into operating cash flow breakeven?

So on the doctor's breadth and depth, what I would say there is, obviously, we're pushing for both, but there's a particular emphasis on depth among the physicians who are already writing, and I would make a further distinction between some of the centers of excellence and some of those doctors who are in robust places but are not necessarily considered, like National Jewish in terms of the prominence of their practice.

At places like National Jewish, almost every patient coming in who has bronchiectasis is being offered for super the rate limiter there is scheduling patients. So the volume that we can get out of there has been great as an example. There are others that are like that as well. But our breadth and depth opportunity, depth goes to the sort of groups behind those centers of excellence who have many patients and have now been -- are now in a place where we can say literally tens of thousands of patients have been put on this medicine the AE profile is incredibly benign, the reports of patients feeling better, although we can't detail on that are now ubiquitous. And the consequence of that is this medicine has a very favorable profile among the treating community.

And I think one of the contributions of [ Samuel Butera ], who has joined as our therapeutic area head for respiratory has been to really direct much more focused calling effort on certain pulmonology practices and generally to be more direct in the discussion about the benefit of this drug to patients in an appropriate and compliant way. What I mean by that is we now have ample evidence that going on this drug is going to provide benefit to patients beyond the clinical trial setting. The real-world evidence data is very strong behind this drug, and that's the message we need to be taking directly to physicians.

So depth first on many of the bigger practices, that lie below the centers of excellence, which are already almost maxed out and then opportunity for breadth as well. And now over to Sara to talk about the cash flow story.

Great. Thanks for the question, and thanks for the kind words, Andrea, I always been a pleasure. A couple of things on cost, while I obviously won't be providing specific quarterly revenue numbers. What I will say is your sort of percentage of revenue to SG&A that we continue to see has the ability to continue to improve and see better and increase margins there.

The strong trajectory of the BRINSUPRI Super revenue, as you heard Will say in the prepared remarks and myself say that continues at being blockbuster status already, and we continue to that growth continue in subsequent years.

Specifically on expenses on TPIP. What you saw in our financials this year, is you actually saw some significant expenses in TPIP, and if you sort of go through sort of the MD&A section in the [ QLC ], you'll see we had to invest in manufacturing to get ready for those 4 Phase IIIs. And so while that investment, we won't we have now had that will then flip to the clinical trial investments.

So we feel really confident on our cash flow positivity next year given the trajectory of our revenue and we will invest appropriately as the science tells us to invest.

Your next question comes from the line of Ritu Baral with Cowen. Please go ahead.

Congratulations on the performance this quarter for BRINSUPRI. I wanted to ask about the comorbid population, Will, you mentioned that campaigns will be underway and some big numbers, I think 200 -- sorry, so just some big numbers on comorbid. And it doesn't seem to align with at least our KOL opinions of the undiagnosed, misdiagnosed comorbid population. Can you go into the specifics on awareness? And also, is that -- do you continue to believe that, that will start being a tailwind for BRINSUPRI in 2027?

Yes. So just so I can clarify, when you say it doesn't comport with what you've heard from KOLs, what is the frame of reference? Just -- I mean, is there anything I can react to specifically?

They just don't think there's that many of them that are comorbid or undiagnosed at least with bronchiectasis worth treating. So wondering what plan to sort of raise awareness on those numbers?

Yes. So I mean, where I would start is with what the medical community has already produced. It is a wide range so we can focus on the low end of the range to be conservative, but the literature right now suggests that between 4% and 64% of COPD patients, this is in published literature, are comorbid with bronchiectasis. And at the low end of that range, that would be 800,000 patients. So more than the existing diagnosed population.

We think it's actually higher than that. Most of the KOLs we've spoken to and it must be different from the folks you're speaking to. And these include people who are at centers of excellence for COPD and asthma estimated it's in the 20% range, which is why we think it's single-digit millions.

We're going to know with much more accuracy in the next, call it, year as we do a lot of refined work going into centers of excellence, retroactively looking at past CT scans, finding evidence of bronchiectasis, et cetera. We hear a loud volume that there is a lot of comorbidity. So I'm interested in where you're -- where that perspective is coming from. I'm sure it's somebody who has a point of view. But I just -- I think it's pretty overwhelming that these patients are out there. We had a get together in Germany, and I'll ask Martina to talk in a moment about the experience. But we brought in some experts from the COPD and asthma world at the World Bronchiectasis Conference and they flew in specifically to talk on this point and probably the best evidence we have that it's a real issue, and there's a lot of it is that they have already modified the gold guidelines for COPD that say if your patient is on max dose treatments and is still exacerbating that these guidelines now recommend they get a high-res CT scan to look for bronchiectasis. And if it's there to put them on BRINSUPRI. Martina, do you want to add anything?

Yes. Maybe, Ritu, this is speaking also about the importance of both physician and expert communities now to work together and look at their patient population. On what might be driving the disease. And if patients continue to exacerbate, is it the underlying PD? Or is it truly bronchiectasis and that importance of looking at what drives it and even asking that question is we're now COPD and experts join forces.

This is not only in Germany. This was the World Bronchiectasis Conference where the first of those meetings took place. It also has taken place in the second meeting now at test. And I think there is where we see the international community of those experts coming together.

Remember, when bronchiectasis -- when there was no treatment for bronchiectasis, it was not on top of mind of the pulmonary community. Now there is, and we've seen this with other areas of diseases, it solicits a different thinking about what is it that drives my patient. You have to ask the question of, if my patient is optimally treated for COPD, but they still exacerbate, what is it that's driving it?

And then you, as a second question, have to look, is there a diagnosis that I might not have seen or I might have actually seen it, but I have not done something about it. And that's what the COPD and CE community is right now discussing. And we can expect that they will, in due time, also take a position on that. But we are still at the early beginnings of it, but it's well recognized by the expert community, and it soon will be by the broader pulmonary community.

Yes. And I would just add one other thought, which is when we talk about COPD and asthma comorbidity with bronchiectasis, we're literally looking for bronchiectasis in those populations. And that means there's no additional clinical trial work we have to do to treat these patients. Once diagnosed with bronchiectasis, they are then eligible and on label for BRINSUPRI.

This is to be distinguished from the COPD patients we are targeting with 1033, assuming that the Phase I study next year goes as we expect it will, we will launch a Phase II study in COPD patients. Martina, do you want to talk a little bit about the profile of those patients and how they differ from patients who are comorbid with bronchiectasis.

Yes. If we think about the COPD population, most of COPD is driven by neutrophils as the inflammatory factor. They take here a leading role in COPD. So what we are looking for with 1033 is a new TPP1 is to address the drivers of disease in the inflammation of patients with UPD. It is not the bronchiectasis component, it is COPD as a disease, that is driven by neutrophils. This will be the focus in the indication that we pursue with 1033.

The reason we are feeling that there is a strong component of that is because there is an overlap of those type of disease pathophysiologies. So 1033 having already been from a mechanistic perspective, well characterized and with a good understanding about what BRINSUPRI does, we've known what the profiles are. It gives us already, I think, a better insight into how the development program goes. And this will be the focus as Will mentioned, on COPD as a stand-alone disease.

Your next question comes from the line of Jason Zemansky with Bank of America.

Congrats on the great progress Well, maybe to connect a few dots here. We wanted to get a sense of how patient mix is evolving now that you're essentially a year into the launch. Are you seeing new starts from the diagnosed high exacerbators who are waiting? Or has there been a shift to those lower severe patients and earlier line use. And then what does this tell us about how much demand is still waiting to be treated, especially as you go deeper with existing prescribers?

Yes. I think we're going to encounter another leg of growth for this drug in this indication, as physicians adjust their mindset from treating their most severe patients, which is how they typically start with a new medicine and particularly a new mechanism, and the experience of that being so positive, and they shift to those who are perhaps less severe, more moderate.

That is a huge part of this market opportunity and getting that urgency to treat and not waiting for the exacerbation to do the permanent damage it will do is an important part of the therapeutic specialist discussions with physicians to make sure, hey, look, "this is a medicine that is working. Patients feel better on it in many occasions." And the consequence of that is you really should be thinking about this for your broader populations.

And as that begins to tip, I think we're going to see this become a default medicine for this condition as opposed to a patient comes in, they present with a certain profile and then the physician takes a proactive move to prescribe it. I think you're going to see this become a very cornerstone element of any bronchiectasis patients, as one physician said to me, and it's a quote I repeat over and over again, when I was at one of these conferences, he slapped me on the shoulder and said, how does it feel to have the statin for the lungs. And I think that's where this is going to go.

Your next question comes from the line of Joe Schwartz with Leerink Partners. Please go ahead.

Will and team, congrats on the strong performance. Sara. Thank you for the excellent financial leadership with branded marketing for BRINSUPRI, what are you assuming for the lift in new patient starts and the time it takes to see that response? And what return would you need to see before materially scaling that spend? And how are you measuring success of that initiative?

Yes. So direct-to-consumer advertising works typically. And so I think it particularly is effective when there is already a groundwork that has been done and laid for a perception of the medicine is very positive in the minds of the physician community, and there's good track record of success already in place. So I think this will give us a better chance to get an even greater return.

Typically, what you see if you were to do an AI search is somewhere in the 2 to 3x range return on capital, I think it could be higher than that in this case. But we'll see. We'll certainly be watching it very carefully. Do I expect it to lift demand? I do. And I think that will begin to show up in probably the first half of next year. We'll be tracking it very closely.

And we are, to be clear, not pulling from one area of advertising and going into DTC, this is additive. It is also going to be something that isn't just singularly, TV ads, we also have digital campaigns going on and other ways to vector in on both patients and physicians in an appropriate way. And so I think what you're going to see is a bigger push across the board, and I think that's going to an air benefit to the brand for sure.

Your next question comes from the line of Maxwell Skor with Morgan Stanley.

Just following up on the comorbid COPD and asthma opportunity. identifying these patients seem to be 1 piece of the puzzle. Maybe you can elaborate a bit more on how AI is contributing to that effort. But on the other side, what has to change or do you see any challenges regarding reimbursement. And then finally, could you narrow potentially when we can expect greater visibility into this opportunity?

Sure. So the comorbid opportunity, I'm glad it's the subject of a lot of attention. I think this is really without a question of a doubt, the biggest opportunity sitting within Insmed today followed closely by TPIP when it is assuming the Phase III work as we have seen in Phase II what that opportunity represents. These two elements are going to drive growth at this company for the next decade.

When we look at identifying these patients, yes, we are working with AI tools to try to accomplish that -- there's -- it's a multilayer effort. We're going directly to some of the manufacturers of some of the machinery to try to see if it can get embedded within the software. We are talking to hospitals who set their rules for what happens when a patient comes in and gets a high-res CT scan. So hopefully increase the possibility that they could be included as a default examination.

Right now, if a radiologist is not asked to look for bronchiectasis, they may not identify it if it's there. So changing that, in light of the fact that there's now a medicine to treat it makes total sense for a hospital that will improve their outcome performance scores in all likelihood. There's a lot of benefit and a lot of momentum behind this, but this is an oil tanker. It's going to take a little while to turn. Your question is how will that ultimately result in patients coming into the top of the funnel as it were, that will begin to see, I think, in '27 and certainly in '28 and beyond. But this is a massive potential opportunity and one we intend to heavily resource.

Do I think it's going to change reimbursement. We haven't seen that yet. We don't expect that, that will be the case. The reality is that these patients are all on labeled. There's nothing that is a non-bronchiectatic patient in terms of a definitive diagnosis. And importantly, those patients as they come through right now, even for the insurance companies that do not have a deal with us as it were, and we're going through on medical exception, our approval rates continue to be exceptionally high.

So whether it's medical exception process or through what's required under their agreement, with the agreements we've reached the patients are getting approved, and this is out there as an understanding among physicians. So I don't anticipate that to be a friction point. If it gets to be so big that it becomes a friction point, that would be a welcome circumstance, I think, for everybody, most importantly, the patients.

And the visibility on when we're going to start to see it, as I said, sort of middle of next year, I think we're going to start to be able to quantify this with greater refinements, which I think will be helpful because it is quite a wide range right now. By any measure, we think it's a very substantial population that warrants the complete attention of a separate task force within the company and that's how it's staffed. So hopefully...

Your next question comes from the line of Leonid Timashev with RBC Capital Markets go ahead.

I wanted to ask on the long-term studies that you're running some of these strategic collaborations. I guess, in particular for the BEST study, I guess, what is your expectation there? Are you broadly expecting the exacerbation rate to mirror what you saw in the clinical trials? Or is because the patient population may be different, you might see a different rate.

I guess what I'm getting at, is there any risk if patients don't perform as well to how physicians may view the drug? And then ultimately, is this something that you can get on label or into a publication that you can detail around?

Certainly, we expect that all the data that gets out from these studies will be circulated and in publications and that always helps a brand or a medicine. I think that long-term evidence is going to be particularly important as we move into a competitive field where the arrival of another company's TPP1 we presume, gets approved. We want to make sure that we have the ability to articulate the long-term benefit, including potentially modifying the disease, which is part of the intent behind the study in Europe. .

So there's a lot that's going to be learned from this. I don't anticipate different performance unless we have an overenrolled section that happens to be Asian patients, where we would expect it to be more than 3x more effective. But that's just sort of a quirky outcome from this medicine in those different populations, which we've now well documented and as have others. So that's an important distinction, particularly as you look at the mix of competitive TPP1 clinical trials that are run, we have a 68% reduction in exacerbations in Japanese patients.

So whatever else anyone brings forward, I would index to that reduction in exacerbations against their Asian population and then do a separate analysis for other patients because it affects people very, very differently.

But these long-term studies are intended to tease out some of those kinds of elements and look at the benefit over many years. to a large group of patients, and I think that's going to be nothing but a positive story.

Your next question comes from the line of Olivia Brayer with Cantor Fitzgerald. Please go ahead.

I also wanted to give a quick thanks to Sara for all her help and contributions over the year. On BRINSUPRI, given how strong the launch has been, has anything changed and how you guys are thinking about the addressable patient population? Is 250,000 still the right number for us to be thinking about? Or are you guys maybe starting to see that opportunity expand maybe even from BRINSUPRI driving awareness and diagnosis is being on the market.

And then I also wanted to follow up on TPIP. Will, you mentioned earlier that enrollment in the ILD study is tracking ahead of expectations. Can you give us a sense of how the monthly enrollment pace has evolved now that you have a lot more sites activated?

Sure. On BRINSUPRI, the addressable market is definitely growing. The last time we provided guidance, it was roughly $500,000 or 550,000 overall diagnosed non-CF bronchiectatic patients in the U.S. that was based on claims data, so it was very specific.

We certainly believe -- and that was 3 years ago. So we certainly believe it's grown since then. What are the drivers of growth? One driver is just population growth. The second driver is clearly the arrival of the medicine always brings patients out of the woodwork because up until now, they've had nothing to treat them, we saw this with ARIKAYCE as well, and that launch was very strong as a consequence of that patient finding exercise and the awareness of the medicine was finally available for these patients.

And then the third growth driver here is clearly patients who are less severe historically, but are now more aware of the exacerbations they're experiencing. They're doing a better job of reporting those exacerbations People are more aware of exacerbations and looking for them. Physicians and offices are asking patients about them. That's going to shift some patients from the mild to moderate less than 2 exacerbations in a given year to a greater number. And so that will increase the population of patients that are two or more, which is where we focused most of our efforts.

Remember that the label allows for any non-CF bronchiectatic patients to use the medicine. We focused on the moderate to severe based on our interaction with key opinion leaders we think that's -- those are the patients that are going to benefit the most out of the gate. But I do think this ultimately expands into broader populations. And I would expect that if all that takes place, you're going to see this population continue to grow at a healthy rate, and that is independent of the COPD and asthma comorbid patients we've talked about earlier.

Your question on TPIP, I think, was the monthly enrollment pattern. We don't -- that level of granularity, we're not going to get into, but I would just tell you that as time has gone on, and we saw this with our Phase II work the arrival of new data on TPIP definitely catalyzes an increased enrollment pattern in response. And so this summer, when we put out the open-label data in PAH that generates a noteworthy increase in interest and desire to enroll patients in both ILD and PAH.

So we're excited about that. I think the ability to for this medicine to be used once a day with essentially a single inhalation and to be able to provide higher levels of the medicine to titrate up to the patient's max tolerated dose. All the way up to 1,280, which is a very significant increase over what's available today. It's convenient. It's more medicine, it's better side effects. To date, what we've seen with this is nothing short of stunning. And I think that's going to continue. And as evidence of that gets circulated and physicians become more aware, it certainly accelerates their desire to get patients on the trial.

There are no further questions at this time. This concludes today's call. Thank you for attending. You may now disconnect.

Hello, everyone. I'm Max Skor, a biotech analyst with Morgan Stanley. And before we get started, for important disclosures, please see the Morgan Stanley research disclosure website, www.morganstanley.com/researchdisclosures.

And with that, I'd like to welcome Will Lewis, the CEO of Insmed. Thank you very much for joining us today.

Thanks for having me here.

All right. Great. Maybe if we could start off, we're almost a year out from -- a little over a year from the approval of BRINSUPRI. I was hoping you can just kind of step back and give us some key takeaways, learnings, anything that you would glean as important from the launch so far?

Yes. Well, I'll just start out by saying this launch has blown away all our expectations. We started out, I remember vividly describing that we were going to use a basket of other specialty respiratory launches to help benchmark whether or not we thought the launch was going well. And we took from that basket of best performers a first year revenue production of about $500 million to $700 million. And at the time, I got a lot of heat for that because people thought, well, why would you set yourself against the best launches out there? You might not be able to achieve that and you'd set yourself on your back heel.

Today, as you know, we sit with an estimate for the first full year of $1.25 billion to $1.4 billion, which is just staggering. And it is now places us on track to be one of the top 20 launches -- commercial launches of all time in any therapeutic category. So by all measures, this launch has outperformed. The team has just done an exceptional job, and I think that bodes well for the future. What we've learned from that, a number of things, actually. I think we know that this is now a highly promotion-sensitive drug. That doesn't surprise us. That's what we expected.

But to see that now play out with a year under our belt, we have really good understanding of how we can activate patient and physician interest, what channels through a media perspective are most effective and most efficient. And we can pull those levers to the extent that we need to, to help reenergize certain parts of the country as we move forward. But we've just upped our guidance. We think peak sales for this drug will be north of USD 7 billion, and that does not include any contribution from the COPD or asthma comorbid populations. So this is going to be a very, very big drug, and we're super excited about the success that the team has produced to date.

Great. So what were you seeing in the launch that supported the raise in guidance? Any key elements or things that really kind of supported getting to the point and going above $1 billion at the end of the year?

Yes. Well, we gathered more confidence in our own commercial effectiveness estimates. We obviously have an extensive dashboard that we track every little metric within the launch very, very carefully. And a shout out to the commercial effectiveness team, we've now tracked along those metrics. We're either at or ahead of pretty much every one of them across the board since launch. And that gives us not only confidence that, that team is doing an exceptional job, but it allows us to lean into the forward forecast where they think we're going to go.

And that's why we had this guidance raise in terms of both the target for the year and the overall peak sales estimate. And the peak sales estimate, just a comment about that because I've gotten a number of questions about it. We upped that guidance in August because every year in August, we not only have a Board meeting and an earnings call, but we take about 1.5 days for a strategic offsite with the Board, where we do a 10-year forward view: what do we think is going on with the company, where are we going, big picture stuff.

And to inform that discussion, we go back and we redo all of our market access, all of our forecasting with the latest data. And since we had shared that with the Board, and it was very, very clear that our TPIP estimates were out of date, BRINSUPRI was stronger than expected, it was time to update, and we thought that was appropriate.

So should we anchor to August next year when you meet with the Board for potential updates?

No, I knew that, that was going to come back to haunt, to provide that level of clarity. But no, August is always a good time to ask us how we're feeling about things as is the beginning of the year. Those are natural breakpoints for us. But as and when we get information and get a real sense of clarity and conviction, that's when you can expect us to update.

Okay. That's fair. Now drilling down a bit on the prescriber base. What percentage of current physician base is still trialing BRINSUPRI, maybe prescribing less than 5 patients? What does the time line look, do you think, to convert these to higher prescribers?

So I think what's exciting about this is that we have gotten such strong performance, as I just was reviewing in terms of revenue generation. The breadth and depth have been very, very good. We still see opportunity, though, both for breadth and depth of prescribing behavior. There are literally more than 25,000 physicians we call on for BRINSUPRI prescription writing. And of those, it's a small fraction that have actually written one or more prescriptions. So there are some that have written none. There are some that have written a handful and are, as you say, trialists -- and then there are some who are higher prescribers.

What's the breakdown? We're not giving the exact percentages, but what I would say is if you were involved in the clinical trial and you know the drug, you're much more inclined to write and write in large volume. That's not surprising. What we're trying to do is spread that knowledge and that experience base across the balance of physicians that we have reached. Those who are trialing are now hearing back from patients and as a result of that positive feedback loop are writing more. Those who have never written before are hearing through speaker bureaus or events that they attend at American Thoracic Society meeting or the upcoming CHEST meeting about the progress with the drug.

The bottom line here is the message across the board is very, very positive. We have tens of thousands of patients who have now taken the drug. We have many, many physicians, thousands of them that have written the drug. So if you want to think about this as a log-normal distribution, there's a huge bolus of physicians that are now able to be aware that everyone around them is writing this prescription. And the revenue just blows away every other launch that's been out there. So all of this inures benefit to the perception of the launch as being strong, no new yellow flags in terms of side effect profiles. I think things only continue to be strong from here. I feel very, very good about where we are and where we're going.

And from a payer perspective, everything on track, if not exceeding?

Yes. I would say, once again, another point of strength in this launch has been the market access picture. I give a strong shout out to the market access team at Insmed. We identified this very early and resourced it accordingly. And consequently, the success rate at one time, we were reporting north of 90% approval. We haven't updated that number, but I can just tell you that it continues to outstrip all benchmarks that are out there. We feel very good about market access. I don't anticipate that changing between now and the end of the year, such that our gross to net update, which was 25% to low 20s, low, high 20s, will remain that way, we think, for the rest of the year.

That just speaks to the fact that this is now a steady cadence. And I think that is a message I would leave you with. When you think about BRINSUPRI, we are now past the first year of launch. We know the trajectory of the launch. We know it's strong, and we expect it to continue to be strong. And we'll just have to see how things go. I would just emphasize, variability quarter-to-quarter a little bit is not the driving factor in whether or not this is going well. The main force that will influence this company's next trajectory is whether or not we're able to secure the COPD or asthma comorbid patient populations into the top of the funnel for this medicine.

When we talk about our estimate of the total addressable market for BRINSUPRI, patients with bronchiectasis in the U.S. That estimate 3 years ago was around 500,000 patients. That grows every year. It grows because of patient population growth, 4%, whatever number you want to use. It grows because these patients do not succumb from this disease. They're around longer. So the incidence population every year gets added to the prevalence population. It doesn't replace those that die off. And that means that the pie keeps getting bigger. And in addition, there are patients who have one or fewer exacerbations who now have 2 or more because people are more sensitive to them. We're tracking them more accurately.

So all these things in air benefit to growing that initial TAM. Having said that, when we talk about COPD or asthma comorbid population patients, let me try and put some numbers that will ground this. It's 500,000 patients we estimate is the original TAM. There are 32 million asthma and COPD patients in the U.S. alone. Of that group, some population also are comorbid with bronchiectasis. We would guess that, that may be in the 10% to 20% range if you include asthma and COPD. So that is literally millions of additional potential patients. Now, how many of those are going to come into the top of the funnel? We think it's the moderate to severe patients, and we think it's those with 2 or more exacerbations.

We know those patients are out there. We need to identify them and get them channeled into the top of the funnel because they will benefit from this medicine and they will be on label, and there are no additional clinical studies we need to pursue that. That presents an enormous opportunity to us because, as I said before, that $7 billion peak sales number does not include any of those patients. So the future -- we'll be focused on that almost like a second launch within the company and bringing them into reach for treating physicians where these patients can benefit is going to be a major driving force in our future.

I think we ran a survey earlier in the year with pulmonologists. They said, I think, around 16% to 20% of their COPD or asthma patients could be comorbid bronchiectasis patients. And I believe 38% of their bronchiectasis patients were previously diagnosed with COPD or asthma. What are -- I guess, what are you focused on to change the prescribing dynamic, educating physicians? And when should we start to see this play out in the revenue numbers?

Yes. I don't think we're going to -- this is turning an oil tanker, right? This is a big group of patients, and we need to get the right ones into the right channel. So I would expect that we will have data because this is all looking back in hindsight until probably the middle of next year, where we'll be able to have at least 6 months looking back our COPD patients being diagnosed with bronchiectasis at an increasing level. What's the degree of use of high-resolution CT scans in COPD patients? The work we're doing right now with the COPD Foundation across nearly a dozen centers in the United States to find out how many of the patients who have COPD and have CT scans actually also already had bronchiectasis, but it just wasn't diagnosed.

We think that number could be in the 20% range. That data will be available in the middle of next year, and it will do 2 things. It will quantify how many patients are out there with actual bronchiectasis that also have COPD. That will allow us to extrapolate. It will also change the rules of hospitals so that when they're doing high-res CT scans of COPD patients, they will automatically look for bronchiectasis, and that should also help channel into the right places whether or not these patients should be considered for treatment.

Separately, from the bronchiectasis patients, the COPD patients who are comorbid, we are also bringing forward another DPP1 inhibitor that's entering Phase I as we speak, looking at COPD patients who have more of an emphysema-type phenotype that may benefit from DPP1 inhibition who are not bronchiectatic patients. So there are slices of the COPD population that we intend to reach and hopefully provide benefit to from a couple of different angles.

Okay. I'll ask a couple of questions in a bit on that. But yes, overall, in regards to potential seasonality, what you're seeing in the launch currently because this is pretty much the first full year we're going through. Any comments you have there?

Well, there's been a lot of questions about whether we're seeing seasonality. And of course, we won't know until we're through the season. We'll look back and we'll say, okay, what happened in the summer, what happened in the fall? And did we see a changeover so that there's more evidence of patient need because of exacerbation increases or what have you. I mean it may be as simple as people were on vacation in the summer, doctors, patients, therapeutic specialists at Insmed. It could be any one or number of these combinations that might have some influence on it.

But I want to be really clear. I continue to feel like this launch is going extremely well. We don't see the weakness that sometimes people associate with the concept of seasonality. It's not that. It's -- is there additional upside either now or in the fall or next year during this time that we can think differently about accessing for the benefit of patients.

And so I imagine everyone is tracking scripts as we are. Do you still -- are you still confident in the capture rate? I think we've noticed an acceleration over the last several weeks in regards to scripts. Any commentary around that?

Yes. I think we've said repeatedly that the Symphony data that is out there, TRx data continues to be proportionately accurate as an estimate of what we are seeing. So that should help reduce the volatility of what the quarter will look like. I would also say that the inherent variability of a launch, which can come from a dozen different sources, shouldn't end up driving an interpretation of how strong this launch is going. We've had quarter after quarter of incredibly strong performance. I'm not $5 million smart one direction or the other, and I wouldn't read it as a positive if it's above or a negative if it's below. We are on a trajectory to produce a mega blockbuster performance here, and that's where our eyes are focused.

Okay. And just going back briefly, next year, we'll all be interested in commentary around the COPD, asthma, comorbid bronchiectasis patient population. How should we expect the team to communicate that? Are we expecting an inflection? I don't think you're going to break out these patients who are comorbid.

No. What we will be looking at is some of these metrics like high-res CT scan rates, diagnosis rates among COPD subpopulations. We have a whole dashboard, as you might imagine, that we're trying to track. A lot of that is backward looking. So we need to see what are the ICD-10 codes, how those evolved. What are we seeing from the data where we're doing this dozen center study across the U.S., what is the percentage of patients who have COPD today that also have bronchiectasis that wasn't previously captured. I think that's going to be quite high.

So all of those things will inform whether or not those patients are there and to what degree are we able to access them and bring them into the top of the funnel as it were. I think we have a pretty good shot at that. We've already made some good inroads. If you think about what we did at the World Bronchiectasis Conference this year in Germany, we had -- we hosted 20 COPD key opinion leaders who came in not for the bronchiectasis conference, but just to talk about COPD, bronchiectasis comorbidity and how they see that as an issue and what they might endeavor to do about it.

We look at that as one point of success. The study that I mentioned before, I think there were the guidelines that were updated this summer. That's quite important, the GOLD guidelines that include highlighting for patients who have COPD, for example, that are on max dose treatments and are still experiencing exacerbations. Those patients should have a high-res CT scan and determine whether they have bronchiectasis.

And in the guidelines, it says, if they do, you should consider BRINSUPRI, our drug. So I think we're making early inroads, but they're important, and they will hopefully continue to support the strength of the launch as we go forward. As we get to next year, I call out the middle of the year as an approximate time frame. We don't really know when we're going to see clear signs, but my guess is by then, we should be seeing some breadcrumbs, if not actual numerical impact.

Okay. And with all successful launches, especially when there is no real standard of care, you attract competition or copycats. Could you comment on that? How should we think about that longer term? Or are there any risks to copycats?

Well, we fully expect our estimate of $7 billion plus in peak sales assumes that the next closest DPP1 competitor is not only successful and approved, but that they will take meaningful market share from us. Moreover, it assumes that in 2035, we will face price renegotiation from IRA. And despite all of that over pressure, we still think we'll do north of $7 billion comfortably. That opens up a whole window of opportunity when we think if either of those is different and/or if we are able to capture the COPD or asthma comorbid populations.

Okay. And then before moving on to the second-generation DPP1s, could you just talk about briefly the Japanese opportunity and thoughts on Europe?

Yes. So international generally for a launch like this is never usually more than about 10% or 15% of overall global revenue. Within that, we think the bulk of that is going to come from Japan. We don't yet have our final price from Japan. But certainly, our interactions with the country so far have been very productive and positive. My expectation is that, that will go well enough that we'll be able to launch aggressively over there. I think the team is certainly ready to run through walls. I was just over there for the launch meeting, and it's a launch meeting not just for BRINSUPRI, but for the expanded label for ARIKAYCE.

So we're sitting over there now with roughly 75 sales reps. We're going to add another 50 in the next year because the opportunity is significant enough. And I'm super excited about what that will yield for that part of the world and its contribution to our overall performance. Japan has been a point of real strength in this company for a long time, and there's just some excellent leadership and capability out there that we've been fortunate enough to be able to work with.

And we're ruling out EU at the moment based on MFN or any comments there?

Yes. I think EU, we continue to have on in a kind of a hold pattern. We're looking for clarity around reimbursability of the drug, and that is really the main driver. People often talk about other issues like MFN and the impact of that from that initial point. But the real issue is whether or not Europe is in a place where it can reimburse this drug at a level that would allow us to support an infrastructure over there. And that's the question that needs to be asked and answered.

And the price in Japan, we should get that by the end of the year?

Yes.

Okay. Any comments around expectations there, but fairly close to the U.S. price?

Well, I wouldn't want to comment on that way. I guess what I would say through the lens of MFN and the risk that people sometimes see there, we're hopeful that a GDP-adjusted price coming out of Japan would be adequate to insulate us from any MFN risk. But of course, MFN is a moving target, and we don't really know what that's going to finally look like. For right now, I would say the vast majority of the revenue is going to come from the U.S. market. That is going extremely well. Japan is set to do a very solid performance. And having just come from there, I can tell you the enthusiasm is extremely high as is the quality of the team.

Okay. Great. So maybe let's move on to the future, DPP1, second generation. You recently announced that INS1033 cleared IND in RA with UC and COPD to follow. Can you just walk us through your rationale, why you chose these indications and when potentially you can learn more about this opportunity?

Sure. Well, our standard for any drug moving forward in Insmed is that it will be first or best-in-class in its respective disease state. And for all 3 of those, DPP1 is a novel mechanism of action and approach for contribution to those diseases. Some of them already have approved medicines. We would see this as a complement, not a replacement for most. So this would be positioned as a combination therapy in those settings. As we think about the probability of success, historically, people are aware that we looked at DPP1 and specifically BRINSUPRI in CRS without nasal polyps and hidradenitis suppurativa.

In Phase II, both of those failed to have statistical significance on their primary endpoints. You have to remember, though, that in both cases, those were biologically plausible opportunities. They were not backed by preclinical animal models. What we've done for these 3 indications is that we have animal models for all 3. We've tested not only this new next-generation drug, but also BRINSUPRI to index off of one another and their relative performance and capability.

So we're very excited about these 3. Glad to be in the clinic now and heading toward producing data next year for the profile that will emerge from Phase I with this drug. Alongside that, we have other stuff coming out of research, but each of these is obviously a very substantial market. And so if we can make an inroad there, I think that's going to be very meaningful.

Yes, very much so. Maybe pivoting now to TPIP. You also raised peak sales estimates there. Can you walk us through the rationale, which indications, I guess, you're not going to break out the share for each indication, but any color would be great.

Sure. Well, remember that TPIP, when we had said the guidance for peak sales was $2 billion or greater, that was based on 2 indications, not 4, and it was done before we had produced Phase II data. So our Phase II data was extremely strong. And very recently, we just put out open-label data that went out a year that was even stronger. What this does is it lays the groundwork for this drug to play a pivotal role in this disease state, all 4 of these disease states, I should say, IPF, PPF, PAH and PH-ILD.

When we think about each of those, know that we have data for treprostinil in 3 of 4 of them. And so we are highly confident that this will be effective. When we think about the degree of impact our drug has had, it blows away any other prostanoid that has produced data for these indications. Materially better on all fronts, convenience for patient, clinical efficacy, safety, we think it's second to none. And we think that the KOL community in PAH and PH-ILD specifically have been extremely vocal in telling us about that.

So from that point of view, we took that new data, went out and did market research and reached the conclusion that the greater than $2 billion estimate for peak sales for 2 indications with the new data was way outdated. So we're now north of $6 billion for the 4 indications. And I would say proportionately, PH-ILD is a bigger indication than PAH and PPF is a bigger indication than IPF. Each is a blockbuster. I wouldn't go in any more refined estimate than that. But certainly, this is the beginning of what we think is going to be the next chapter of growth for Insmed. And it's what makes us really distinct as a mid-cap company.

Today, we sit approaching with our current estimates by the end of the year, what would be almost $2 billion in revenue. From here, while we can't give a perfect estimate of the future, we're talking about very substantial year-over-year compound annual growth, both on the top and bottom line for the next 5 to 10 years, supported by ARIKAYCE and its label expansion, BRINSUPRI in the success of its launch, TPIP in 4 different indications, and that's without even tapping into what we've described by way of the COPD and asthma comorbid populations or anything from our pipeline. If those things start to manifest in years 5 through 10, as we would expect, we're going to a whole other level.

Okay. And can you just outline for us where the TPIP trials stand, how enrollment is going, when we could potentially expect data?

So we haven't given any guidance on timing for data. PH-ILD started first, and I would tell you that, that is doing very well. PAH is now also underway. We expect PPF to kick off its Phase III program by the end of this year and IPF at the beginning of next year. For each of these trials, one of the distinctions of this compound and its formulation is that we can go much, much higher in dosage than any other prostanoid. So we can go all the way to 1,280 micrograms. And indeed, that is set as the upper bound limit for patients to take or be guided to by their treating physician, which is materially more than any other prostanoid out there.

So we should be able to gain greater efficacy and sustain that greater efficacy over time as patients often experience a waning effect from prostanoids as the receptor sensitivity changes, we can continue to titrate up and maintain that effect without needing to go to parenteral treatment, which is a big advantage for patients and physicians.

And without having to comment specifically on the competitive landscape, are there readouts that you're watching closely or launches that really feed into your expectations for TPIP?

So I have no problem calling out a success when it hits. There was a recent drug out of Roivant that just put up a very impressive Phase II data. It's a different mechanism of action in the PH-ILD space. Congratulations to Matt and the team. That's a great drug, it looks like. We have to see Phase III. I think our drug is every bit as good. Remember that we measured ours at 24 hours after administration of the drug. So it's at trough levels. Everybody in this industry, and particularly in this disease state measures at peak levels. We're going to be adding that to our Phase III data set.

So it will be interesting to see where our best data comes out at the end of the Phase III trials. But look, the opportunity here for the arrival of these new technologies is profound. These are fatal diseases for patients with a high mortality rate within 5 years. Our open-label data from Phase II showed that we could improve mortality using various measures in these patients with PAH. That's a game changer. We moved a huge percentage of patients down to Class I, which means that they are asymptomatic for this fatal disease. So the improvements we can bring, we've documented if these other drugs and their metrics suggest that they are going to be impactful as well, then we're going to start having a discussion about combination therapy because we will be the prostanoid of choice.

We're once a day with great efficacy and safety. If they are once a day also with an inhaled formulation and they can bring great efficacy and safety as well, we may be able to change the paradigm and the expectations for this disease for patients. And that's what this is really all about. That would have the benefit, the added benefit of keeping these patients alive for much longer, and therefore, they would be taking the drug much longer to accomplish that. And that's the goal of the medicine. So I see a very bright day forming on the horizon for PAH and PH-ILD patients in particular, and I'm hopeful that will carry through to IPF and PPF as well.

Okay. In the last 8 minutes or so, maybe briefly touching on your gene therapy efforts, DMD, ALS, when can we expect an update there? How are things going in the trials?

Yes. So we are -- we have several platforms that we sort of went out and acquired about 4 years ago. And I'll just review so people understand, expanded the efforts that are underway in New Jersey for DPP1 and related therapies, acquired what's called synthetic rescue capability in Cambridge, England, de-immunized therapeutic proteins using artificial intelligence for design of B and T cell epitope deletion in New Hampshire and gene therapy using viral vectors targeting monogenic diseases out of San Diego. Each of these has been running quietly in parallel and making great progress over the last 4 years.

Next year heralds the arrival of the first data from these different component parts. Understandably, this has not been the focus of Wall Street because we've had so much going on and at such scale with our other respiratory portfolio, but it's important to understand that the answer to the question of what's next in our portfolio is already well in hand at Insmed. We don't need to go out and do some dramatic BD deal to sort of add a new leg of excitement to the company. I'm not ruling out that we wouldn't consider BD, but I want to just be clear, we're in an enviable position of not needing to force that decision kind of matrix.

When we look at what we have in hand, we have DMD and ALS that are well underway in terms of clinical trial work and data collection. Our intention when we put out this data next year is to identify whether or not they clear the threshold of first or best-in-class therapies for these diseases. If indeed they do, you can expect a robust data presentation, which will include a mosaic of measures to ensure that people know that it is not cherry-picking one point or another from the backdrop of how you improve a DMD patient. It will be dystrophin expression, transduction efficiency, safety and NSAA impact on patient actual physical performance.

That mosaic will tell a strong picture, we hope, for the impact of our approach in Duchenne muscular dystrophy gene therapy. In addition, ALS, we're going to have some very good data we hope by the middle of next year that will document whether this is effective not just in SOD1 mutation patients, which is a small portion of the population, but also sporadic patients, which is

[Audio Gap]

we are looking at other indications. Out of New Hampshire, we have Uricase and IgG protease, both of which are being developed as deimmunized therapeutic proteins so that we can treat patients that are unable to take those medicines currently because of the immune system response.

In the U.S. and New Jersey, we have a program for a pathway I'm not going to identify right now, but we are very excited about, which we think represents the answer to the patent cliff already formed by the success of BRINSUPRI. We go to 2039 on our patent protection with BRINSUPRI. We have identified, we think, a novel mechanism that could result in a medicine we could combine with BRINSUPRI so that we continue to own better efficacy for this population well past the 2039 mark, hopefully, for a full patent extension into the 2050s. We're a long way from that. But in the next 3 to 5 years, we'll have the answer to that question, and it is the kind of thing that I think could really represent an inflection point in our value.

Okay. Great. Maybe if we move on to a couple of macro questions in the last couple of minutes we have. How is the rise of China innovation changing your competitive positioning and your R&D or maybe BD playbook?

Yes. I think China's arrival is here. Anybody who is still doubting or thinking that China is not a major player has been asleep at the switch. What they represent is best-in-class earliest-stage development. So right now, from concept through to commercialization is the spectrum of development. They're really good at getting through to proof of concept. There are a variety of reasons for that, but it's something that we can look at and study, a, hopefully, to improve our own capabilities here in this country, but b, as a company, for the fastest way to validate that what we are developing is really going to make a difference.

So I think that's the first and best use of our time in terms of interacting with China right now. We are examining novel molecules that are coming out of there that could represent interesting opportunities for us as are many other companies. You do see a lot of copycats still coming out of there. There are DPP1s that are being developed in China. They are way back in the line relative to where we are and where the next most powerful competitor is. That doesn't bother us at all. We welcome the competition. We think we've got the best-in-class molecule. We don't think that's going to change. But China's arrival presents both opportunities and additional competitive pressure.

Okay. Two last questions from me. We got to touch on AI. Insmed, are they leading the way in AI? How are you embracing it?

So we are very much leaning into the use of AI in every corner of our company. Last night, I was having a conversation with myself, my new AI personality generated inside Insmed, which is supposed to mirror the way I think so that in a bizarre setting, I'm actually asking myself about different ideas, speeches, business development, what have you, and it's supposed to give me my own thinking back in a more refined capacity. It's a little unsettling. But I will tell you, it works pretty well. Just to make a finer point on it, the group that did this for me actually asked me to take a picture of my bookshelf, and they included all of those texts into my AI personality so that it would hopefully reflect the diverse set of interests I have, I guess.

Anyway, watching that unfold is really interesting in terms of decision-making and strategic reflection. But the practical way we see AI being used at the earliest stages on research, the deimmunization of these therapeutic proteins in New Hampshire is driven by AI, and we've been doing that for several years from a professor we stole out of Dartmouth and his colleague. We also use it in commercial settings and in clinical settings for patient finding, for optimizing call efforts. We use -- we've developed our own actual AI engine, which has access to all of Insmed's documents. So it's based off of Claude, but it's hermetically sealed inside our company.

So I can go in and ask it, how do we improve sales in years 3 through 5? And it will have access to all of our forecasting and cross-examine it and come back with ideas. So it's -- we're pretty heavy on the AI front. I'm very proud of that. Mark Pellegrino, who leads -- who's our CIO, has been a champion of that for many years. And I think there's a lot more to come and a lot more benefit to be found there. But as we all know, that's assuming that AI doesn't wipe us all out in the next 3 years, which we were hearing about over the weekend. So who knows?

Yes. Sorry, last question. We've talked about increasing peak revenue. BRINSUPRI launch is going very well. What are investors missing? Or what's your message here at the end?

My message is that we are slow and steady up and to the right. We have just found our rhythm as a company, and we are executing commercially. We're executing clinically, and we're executing on the research front. I'm super excited about where we are. Honestly, you get up here with different degrees of enthusiasm and caution for where you -- where a company you work at is in its life cycle. We are at the beginning of the strongest point of our growth cycle that we have ever been in or frankly, ever could have imagined. This is a series of successful products that are going to be first or best-in-class that I think is just going to inure benefit for at least the next 10 years.

Great. Thank you very much, Will. Really appreciate it.

Pleasure.

Okay. Hi. Good morning, everyone. Welcome to day 1 of our Cantor Healthcare Conference. My name is Olivia Brayer. I'm one of the senior biotech analysts here at Cantor. And really excited to kick off today's conference with Sara Bonstein, who is CFO of Insmed. Sara, thank you so much for being here with us.

Yes. Thanks so much for hosting us. Really appreciate it.

So a lot is going on at Insmed this year, and you guys just came out with a really big update in terms of peak sales guidance. So maybe just talk us through the decision to come out with that update. Why now? And how did you ultimately get to some of those numbers, right, the $7 billion and the $6 billion and the $1 billion?

Yes. Yes. Well, thanks for the question. And again, thanks for hosting us and having us here. And a little old Insmed put up $14 billion in peak sales is our estimate between our 3 either commercial or late-stage products. So really tremendous and our level of conviction is very, very high in those numbers, obviously. So specifically, why did we do the update now? As we go through our own internal processes, we do an annual -- we call it our strategic plan every year.

We do our annual strategic plan in the July, August time frame, share that then with the Board in August during our strategic offsite with the Board. And so we had all of this new information to share. We had almost a year of launch now under our belt with BRINSUPRI. And while we had a ton of conviction in the $5 billion number that we were able to put out, which was obviously a monster number, we learned more about some of the underlying assumptions. And we had shared previously throughout the journey of the launch up to that phase that we were either meeting or exceeding or doing better than our own internal sort of assumptions and benchmarks.

And you see us pull that through in our revenue model and in the guide that we shared with all of you by increasing from [ 5 ] to [ 7 ]. So that's a 40% increase in our conviction in BRINSUPRI. And I'll just put a pin in, that is the base launch. That does not account for this sort of secondary launch that I'm sure we'll touch on in potentially underdiagnosed patients that have COPD and/or asthma today. As we think about TPIP, previously, we had a $2 billion number out there for TPIP for 2 indications. It was for PH-ILD and PAH. And we had put that number out before we even had our Phase II data in hand because it was a proven -- a known mechanism of action.

Now with the strength of the Phase IIb PAH data, the while small but very encouraging Phase IIa PH-ILD data and then most recently, the OLE data for PAH, we now had, again, more new information as well as made the decision internally and shared with all of you to progress into 2 additional large indications, PPF and IPF. So that update from $2 billion to $6 billion for TPIP reflects all 4 indications, each of which we believe could be a blockbuster in and of itself.

ARIKAYCE, we had always assumed for the success of the label expansion, and that was already embedded in the $1 billion. And so yes, tremendous amount of revenue potential, and that obviously doesn't take into account some of our earlier-stage pipeline.

Yes. And maybe we'll start with BRINSUPRI, just given how much focus there is on it. A question that I get asked, and I'm sure you get asked a lot is why the decision to actually increase from -- or what gave you the confidence, right, to increase from $5 billion to $7 billion rather than we'll just get to that $5 billion number maybe faster? Or maybe the answer is both.

Yes. So maybe we'll actually rewind and think through before we launched BRINSUPRI, we were putting out analogs for the best specialty respiratory launches that existed. So we looked at Ofev and Tezspire and Dupi and Fasenra. And in their first year of launch, they put up about $500 million to $700 million in revenue. And that's what really, really successful respiratory launches that I think we would all sit here and agree have been game changers in their space.

And as we have now launched BRINSUPRI and put up the very impressive revenue numbers that we have from an actual basis and have been able to previously had the $1 billion-plus guide for this year and then most recently updated our revenue guide to the $1.25 billion to $1.4 billion this year. That is double plus what really successful specialty respiratory launches look like, right? So our execution, the operational excellence that our commercial team has been able to show in the early days of the launch is absolutely tremendous, and you see that being pulled through in the actuals and the revenue guide for this year. And we needed to continue pulling that through in our peak sales estimate now that we have this level of conviction in the launch.

Yes. And you mentioned your launch. Obviously, you guys are having an incredibly successful launch. What are some of the metrics that maybe are tracking ahead of your own internal expectations that are maybe some of the biggest tailwinds that you guys are experiencing?

Yes. So a lot of sort of unsung heroes in this launch. The team has just been kicking it out of the park. I'll remind you, we started disease state awareness for this launch. Thank you to everyone that supported us financially to be able to do that 3 years before the launch. And that has really shown to be successful, right? This is a first-in mechanism, first-in-disease launch. There was a needed education to set the foundation going into the launch, and you're seeing sort of the fruits of those labors in the actuals.

The team that's on the ground executing, educating compliantly on if it's a therapeutic specialist, it's the field access managers, if it's the case managers, if it's the field-facing medical team, they are all hitting it out of the park with their execution. A lot of, like I said, on unsung heroes, the pricing reimbursement and access side of this is going wonderful. We've commented about 90% payer approval. Patients are getting their drug within about a week.

Those are very high marks to be meeting. Patients are feeling better. They're starting to get that feedback loop in the physicians' offices, and the medical offices. So a lot of really strong opportunity there. We're seeing depth and breadth -- we're seeing sort of increases in the amount of writers. You saw that continue to increase in our Q2, where we went from about 5,000 prescribers cumulatively to about 6,300 cumulative prescribers from Q1 to Q2, and you saw us grow in how many scripts folks had written. Previously, it was about 20% of the physicians had written 5 or more, and we were able to, while adding new writers, increase that to about 30% have written 5 or more.

So really, really impressive. We still have a lot to go. We now have -- if you sort of add up all the new patient start numbers, a little over 26,000 as of Q2, new patients on drug. I'll remind you, there's 500,000 diagnosed patients today with bronchiectasis. That's data that's a couple of years sort of rear in the facing and about half of those are 2 or more. So we've just started to scratch the surface. on patients that could be impacted positively with this medication, and there's over 20,000 prescribers, about 28,000 prescribers. So again, have a ways to go. So we've done really well on all of those metrics, but still more opportunity.

You mentioned that, that 500,000 number is maybe a couple of years old, right, in terms of when you all provided it. So I'm going to ask a little bit of a forward question, but could that number maybe be bigger than we expected? Or could that number maybe be growing over time as awareness and as a new product comes to market?

Yes. I think the number is growing. I think just naturally TAMs grow. And so we'll kind of walk through U.S. patient population, obviously, that's sort of the straightforward one, everyone is aware of that. If you look sort of broadly speaking, any time there is a new product available for a first in disease, you will naturally see TAMs grow. So that's something a dynamic that you will have here. And then the interesting piece with bronchiectasis, while it is a condition that is life altering for those that suffer from it, it is typically not in the sole indication, it is typically not life ending.

And so you have the unique perspective here where you have incidents and prevalence stacking on top of each other. And so that will naturally grow our TAM. And then the other, I think, important piece to highlight is while our label is broad for bronchiectasis indication, the conversations that we've had with payers is that 2 or more exacerbating patients, and we had commented on the diagnosed patients of 500,000, about half of them were 2 or more exacerbating per the claims data that we had at the time. Naturally, over time, if you have an exacerbation, you are going to have future exacerbations.

That's just how this condition works. It is a progressive condition. So you will naturally have over time, your TAM increasing and you will naturally have over time, the patients that are fewer exacerbating patients moving into the more frequent patients. So that sort of organic growth is happening and will continue to happen before we even touch on adding to the top of the funnel for this sort of secondary launch for the underdiagnosed potential for COPD and or asthma patients.

And you also brought up just a number of prescribers that you guys do have writing scripts. So as you think about the launch unfolding from here, I mean, what is the priority between depth versus breadth and kind of balancing the 2? I mean, how many more prescribers do you think you can get to start writing? And then how do you start to convert some of those initial prescribers into writing that 5 or more script number that is your top I guess, 30%.

Yes. So we triangulate the data in all the possible ways we can and ensure that our folks' time is being spent as appropriately, compliantly and efficiently as possible. And so as you look at sort of that top decile of prescribers and sort of decile 1 and 2, they may have up to 100-plus patients in their treatment office. So there is a lot of opportunity in depth in sort of decile 1 and 2. And then as you look at sort of your mid-tier, that's where you have the breadth. And so because we are -- we all live in sort of a data-rich world, we're able to appropriately target time allocation for where we believe we can have the biggest impact on patients.

Okay. Very helpful. And then the other thing that comes up quite often with this launch, and I know last quarter was a big topic of conversation is just persistence and continuations on drug. Maybe just talk about the dynamics there, how you see those unfolding? It sounds like most people have kind of come to the same conclusion in terms of what they should be modeling. But maybe just kind of help us solve for how to think about persistence going forward on BRINSUPRI.

Yes. So persistence compliance continuation, that whole sort of bucket continues to track what we commented on most recently continues to track really well. We're -- we continue to be encouraged by what we're seeing there. We commented on the access side of the world. I know this was a discussion earlier in the year. There is a difference between clinical trial continuation and real-world continuation across the industry. And it is something that we, again, were celebrating on how well the team has been able to execute on this. So sort of nothing to see here, and you could see in our conviction of being able to go from $5 billion to $7 billion that this is a drug that we believe is needed for patients and will be one that will be long-standing.

And then as you think about the launch unfolding, you guys have talked about Symphony TRx being a good proxy. I think all of us in this room track that pretty consistently on a Friday morning basis. So is that something that we should still be looking at in terms of launch proxy on a TRx basis?

Yes. Yes. I really appreciate the question, and we love these types of opportunities to be able to update the market on Symphony. So our most recent public statement had been through the sort of weeks reported through July that Symphony continued to track on a proportionate basis. I'm happy to say here, we don't have -- I think there's a couple of days left in August that haven't been reported. But through all of the reported that has been presented through the month of August, it continues to track on a proportionate basis and it continues to be up and to the right. And so that obviously should give folks encouragement on the strength of the launch.

And we have seen a pretty linear launch curve. And I think that kind of continues to track over the last few weeks as well. So maybe I'll ask like from an expectation perspective, do you continue to expect your launch to stay linear? I mean at what point in the launch do you start to see that curve maybe not plateau, but maybe see the slope start to change?

Yes. So obviously, I won't comment anything intra-quarter forward-looking other than sort of the revenue guide of the $1.25 billion to the $1.4 billion that we continue to have conviction on. We're still learning in the launch. It's still early days. We're still going through certain seasons and all that -- those good things. But the underlying fundamentals of the launch are so strong, and the team is executing on all cylinders and BRINSUPRI is on track to be a top 20 launch of all time.

Congratulations. to you and the team. Gross to net is another thing that I think surprised people to the kind of upside on your second quarter earnings call. Maybe just talk about gross to net. Where is it today? How has it evolved over the launch? And as you think about gross to net going forward, I mean, maybe I'll ask like how have you been able to keep gross to net so low? And do you still have conviction that you can kind of continue to track very favorably from a gross to net perspective.

Yes. So we said right from the beginning on we -- access is really important and appropriate and frictionless access for patient and targeted contract and where appropriate. And so we've been able to execute on that. As I mentioned, around 90% payer approval. And so we've been able to have line of sight into what our contracting sort of needs will be for the year. Our original gross to net guide was mid-20s to low 30s.

We were able to -- now that we have that line of sight, be able to narrow that to mid- to high 20s while still maintaining that positive payer approval perspective. So again, kudos to the team internally on being able to ensure patient access and we continue on that front. I won't comment on forward-looking gross to net, obviously, at this point in the year, but our focus will continue to be on frictionless access for patients.

Are there additional payer contracts that could start to come online going forward? Or at this point, have you all hit the sweet spot?

For 2026, we feel like we have a clear line of sight into what 2026 will look like. We will continue to have appropriate conversations in the future with payers if and when appropriate.

Okay. Great. And you mentioned to start, going back to your comment around that $7 billion kind of peak sales number, not including that potential comorbid patient population that you all are hoping to unlock. I mean what does that opportunity set look like as you think about the COPD asthmatic comorbid patient population? And what are you seeing in terms of real-world setting? Are you starting to see some of those patients enter the funnel? Do you have good line of sight into when those patients start to enter the funnel? Or maybe when do you expect some of those patients to start to come online?

Yes. So this, we believe, is -- could be a very significant opportunity, and we are resourcing it as such internally with a dedicated team to ensure that the base launch of the $7 billion plus and the $1.25 billion to $1.4 billion for the year, all that good stuff that, that base launch is continuing forward without any distraction. This secondary launch of potential underdiagnosed patients, there's 20 million patients in the U.S. with COPD between both COPD and asthma, it's over 30 million patients in the U.S. Literature is all over the map on how many of them may or may not be underdiagnosed or comorbid with bronchiectasis.

And so the literature is not very helpful because it's single digits to north of 60%. But even at the smallest percentage, it is significant potential for more patients being added to the top of the funnel. So as I said, we have a dedicated team focused on that. A lot of these are lagging indicators. So we don't believe we'll have good line of sight until probably middle of next year. But you've started to see some of sort of the fruits of our labor. You started to see our Suspect BE campaign, which is our celebrity campaign with Ty Pennington.

He's a celebrity on HGTV. He's actually also the caregiver for his mom who has bronchiectasis. So it's look behind the walls because he repairs homes, a look behind the walls and see if you should Suspect BE. That's the nature of the campaign. Things like the ATS. We are a sponsor of their initiative, but they're going back through, I believe it's 7 or 8 of their institutions to look at electronic medical records of CT scans that are already in their universe to say, could there be tree in bud patterns?

Could there be patients in their universe that already have bronchiectasis that are just underdiagnosed. So those are some of -- there's a slew of other initiatives that we have ongoing internally. It's -- they are lagging indicators. They will take some time. And so look for an update on that next year. And it could be even at a small percentage basis, it could be meaningful numbers. I would just emphasize that once a patient is diagnosed with bronchiectasis, they are on label for BRINSUPRI. There's no additional clinical work that needs to be done and anything like that. Once they are diagnosed with bronchiectasis, they are on label.

And it sounds like you're approaching this campaign from both the patient perspective, but also the physician perspective, right? So maybe going at it from both angles. So I mean, in a clinical practice setting, right, like let's say, a patient has COPD or has asthma, what are kind of the next steps in terms of actually getting that bronchiectasis diagnosis so that they can get on BRINSUPRI?

Yes. And I think the point you made on sort of hitting it from both is so critically important. And part of the learnings that we got from the disease state awareness work that we did well before we launched BRINSUPRI and how successful that has been as we look at the true operational excellence from the team on the launch thus far. And so continuing those efforts by ensuring that there's appropriate compliance education on both the patient perspective as well as the physician perspective.

Bronchiectasis is a pretty straightforward disease to get diagnosed. It's a high-res CT scan. The radiologist has to just know to look for bronchiectasis and provide a diagnosis of bronchiectasis. -- unless it is sort of checked off on the script to say, look for bronchiectasis, it will not get diagnosed as such. So there is that education element that is underway as well.

Okay. And then for a formal bronchiectasis diagnosis, it's essentially a CT scan, right? Okay. Very helpful. And then as you think about geographies outside of Europe -- I'm sorry, outside of the U.S. Obviously, the Japan approval just came through. Maybe talk about what the opportunity set looks like ex U.S. And then I'd love to hear if any updates on plans in Europe to potentially launch?

Yes. Yes. So to level set to help with models, if you look at precedent launches, if you look at precedent for sort of our geographic territories, you should assume about a 10% to 15% ex U.S. contribution for a product like BRINSUPRI, that's what precedent would tell you. So that should be helpful. Japan is an opportunity that we're very excited about for a host of reasons. I do think that the Japanese government has been open to the supporting of -- from a reimbursement perspective. I do -- you look at the Asian data population.

We don't know why DPP1 works sort of outsized for Asian patients. That is something that, as an industry, we will all figure out. But the data shows us that it does have a higher efficacy impact on Asian patients. And so that's very encouraging as we think about the 150,000-plus diagnosed patients in Japan with bronchiectasis and what that can mean for that patient population. So that is a pathway. Obviously, we are -- we have approval now. We are going through sort of the final steps before we would launch from a pricing perspective and all those good things, but that's something we're highly encouraged about.

I would also just remind you that in Japan, any time a new product is launched, there's -- for the first year, there's a 2-week prescription limit. That's all new products, not BRINSUPRI specific, but also just something to take into account as you're modeling. Europe, again, we have approval in Europe. I think there are separate and different budget constraints in Europe. And so we will do -- we want to ensure access for patients. And so things like the EMBARC study that just kicked off are obviously encouraging just from an access perspective with those 3,000 patients under that program, and we will look for ways to provide access for patients as best as possible.

And speaking of DPP1, you do have a next-generation program. So I mean, what are you hoping that, that next-gen molecule will do differently than BRINSUPRI or maybe even better? I know you're also looking at other indications.

Yes. So BRINSUPRI is a pretty great DPP1 as I think we all have been able to recognize. We have studied many DPP1s in our research lab. We have progressed the first of those, 1033 into IND. That IND is now cleared. The healthy volunteer study is now underway. We will look to progress that in indications starting with RA and then UC COPD. There will be additional follow-on DPP1s that you'll hear about next year. We believe we know a lot about the mechanism because of all the great work that the team has done with BRINSUPRI and our research team had started doing work on additional DPP1s on the heels of the WILLOW data, which I'll remind you was over 6 years ago. So we are encouraged by what that could look like. I'm not going to go into some of the special sauces on the future DPP1s, but it's something in our pipeline to watch out for, for next year and beyond because they are very meaningful indications that could be sort of the next leg of value creation for the story.

Okay. Great. And then your other meaningful pipeline driver, obviously, TPIP, a little more late stage than your next-gen DPP1. You mentioned earlier going from $2 billion to $6 billion in terms of your peak sales trajectory for that drug. Obviously, a big jump. I know a lot has changed since when you initially put out that $2 billion number. But maybe just walk us through the opportunity set. You're looking at 4 different indications currently that are either currently in Phase III or about to move into Phase III. So how do you think about PAH, PH-ILD, IPF and PPF? I don't know if there's a rank order or if you can put some numbers around them.

Yes, yes. So we have 2 of our Phase IIIs ongoing. So PH-ILD sort of end of last year, PAH started this year. PPF will look to kick off that Phase III before the end of this year, and then IPF will start next year. As you're thinking about sort of revenue contribution, I'm not going to break down each one. What I have commented on each one, we believe, has the ability to be a blockbuster status. We do believe PH-ILD will be larger than PAH, and we believe PPF will be larger than IPF as you're sort of like thinking about sort of scale, but all very meaningful opportunities and the data that we have in hand continues to give us a lot of conviction into what that program could mean for patients that are suffering from these very severe...

And is that the kind of PPF above IPF and PH-ILD greater opportunity than PAH. Is that because of the population size? Or is it because of maybe where you guys think that you could fit in from a differentiation perspective?

Yes. I think depending on which one, it's a little of both.

Okay. Fair enough. Anything that you can tell us about the trial designs for PPF and IPF at this point?

Yes. So PPF, it actually just came up on clinicaltrials.gov. So feel free to go out there and check out through the trial design. PPF, it's about an 800-patient study, a pretty traditional study design. So that will be up and running before the end of the year.

Okay. Great. Any thoughts on enrollment at this point? Maybe I'll ask for PAH and PH-ILD specifically, just given that you are maybe starting to track how enrollment is progressing. I hate to ask a time line question. But just kind of thoughts on next steps, time lines. I think enrollment progress will be something that investors are really interested in.

Yes. Yes. So I know it's probably not the most fulfilling answer. We do tend to be conservative. So we have not given specific enrollment time lines. We typically like to have a couple of quarters under our belt of the trials up and running. What I will comment on is both continue to enroll well, continue to exceed our internal expectations and things like the OLE data are really helpful in sort of medical conversations on sort of the strength of that data and what this program could potentially mean for the patient population.

And something you guys have talked about is just the ability to increase your dose and have a little bit more flexibility there. I know you are allowing for increased dose levels in -- or maybe I shouldn't say levels, but kind of a titration scheme in your Phase III programs. So is the hope that you could maybe push the efficacy beyond what you've already seen in your Phase II program? Or is it really more of a tool for flexibility for physicians and patients?

Yes. So each patient has a different sort of need for how high do they need to go in dose. I'll remind you the 640 dose, which was the base -- which was the max dose in the base studies for Phase II is 60% more raw drug than available based on the multiple times a day and all that kind of stuff. So they're already getting a lot more drug being able to have the ability to go up to 1,280 now gives the physician even more of an opportunity. And so you will -- there is a longer titration window in the Phase III is the way it is designed.

But I think most importantly, in the real-world setting, physicians could have the potential to have the ability to have a drug that they can continue to titrate knowing that these are progressive conditions and patients are living longer and need an option to be able to continue to titrate up in their dose over time.

Okay. Great. And maybe just one last question. $14 billion, that's a lot of cash over time. So what do you plan to do with it?

Yes. We have a very exciting pipeline, and we will be profitable next year. So that is a new day here at Insmed that we will be a profitable company next year, which is pretty exciting.

Great. Thank you so much, Sara.

Thank you.

Thank you for standing by, and welcome to the Insmed Second Quarter 2026 Financial Results Conference Call. [Operator Instructions]

I'd now like to turn the call over to Bryan Dunn, Head of Investor Relations. You may begin.

Thank you, Rob, and good day, everyone. Welcome to Insmed's Second Quarter 2026 Earnings Conference Call. Before we get started, please note that today's call will include forward-looking statements. These statements represent our judgment as of today and inherently involve risks and uncertainties that may cause actual results to differ materially from the projections discussed.

Please refer to our most recent filings with the Securities and Exchange Commission for a full description of these risk factors. The information we will discuss on today's call is meant for the benefit of the investment community. It is not intended for promotional purposes and it is not sufficient for prescribing decisions.

Today's call will feature prepared comments from Insmed's quarterly performance and financial position by Will Lewis, Chair and Chief Executive Officer; and Sara Bonstein, Chief Financial Officer, respectively. After their remarks, we will welcome Martina Flammer, Chief Medical Officer, for the Q&A session.

I will now turn the call over to Will.

Good morning. I want to start off today's call by framing what I believe are our 2 key accomplishments this quarter, operational excellence and positioning for our future. Across our commercial, clinical and research efforts, we have demonstrated exceptional operating performance. This has laid the groundwork for Insmed's potential evolution into a reliably consistent revenue and earnings growth story over the next decade and beyond.

Let me briefly summarize what I mean. BRINSUPRI's launch continues at a truly historic pace, delivering another quarter of performance that more than doubled the results of the best specialty respiratory launches our industry has ever seen at this stage. With the potential to expand its reach with improved diagnosis of appropriate patients and a projected approval in Japan later this year, we believe the BRINSUPRI story is just getting started. ARIKAYCE continues to perform well in its eighth year of launch, growing globally by high single digits this quarter compared to the second quarter of last year.

Beyond the current opportunity, there is also potential to expand the label to include all patients with MAC lung disease in the U.S. and Japan next year. From a commercial readiness perspective, we are on track to serve a broader base of appropriate patients while providing education for physicians as we enable them to use ARIKAYCE earlier in the treatment paradigm for MAC lung disease. TPIP is emerging as a potentially differentiated asset across 4 large indications: PH-ILD, PAH, PPF and IPF.

We believe the data from our ongoing open-label extension study of TPIP in patients with PAH shared last month are further evidence of the strength of TPIP's profile, which we believe has the potential to be the prostanoid of choice. In addition to the progress our top 3 assets are making, we are also positioning the company for continued success in the future. We are steadily progressing a broad and diversified early-stage pipeline consisting of multiple potential blockbuster treatments for a wide range of serious diseases. The FDA recently cleared the IND for INS1033, the first of several next-generation DPP1 inhibitors advancing within our pipeline to proceed into the clinic.

The first planned indication for INS-1033 will be in patients with rheumatoid arthritis for which we have promising preclinical data. We anticipate following that with additional clinical programs in ulcerative colitis and COPD for which there is also supportive preclinical data. These indications highlight the potential relevance of DPP1 inhibition beyond bronchiectasis in other large neutrophil-mediated inflammatory diseases.

We also added new talent to our leadership team with the hiring of Samuele Butera as our Senior Vice President and General Manager of our Global Respiratory Therapeutic area. Samuele brings with him a wealth of commercial experience in U.S. and international markets, having led multiple global launches at Johnson & Johnson and Novartis throughout his career. We view his hiring as a huge win for Insmed and an equally large endorsement of Insmed's future. Finally, it is important to mention that we are making all these strides while maintaining our financial strength.

We continue to believe we are sufficiently resourced to fund our business through cash flow positivity next year without raising additional capital. With BRINSUPRI's remarkable performance through nearly 1 full year of launch and the latest results from our ongoing open-label study of TPIP in PAH, our confidence in the future potential of these assets has grown. As a result, we are raising our peak sales estimates for both assets.

For BRINSUPRI, we now estimate global peak sales of greater than $7 billion, up from our previous projection of greater than $5 billion. This updated estimate reflects expected growth of the current addressable market driven by earlier and more consistent diagnosis due to increased awareness among physicians and patients. Importantly, this peak sales projection does not include contributions from the potentially meaningful opportunity to identify additional bronchiectasis patients from the comorbid COPD and asthma populations, which would represent upside to this outlook.

For TPIP, we believe the peak sales opportunity is greater than $6 billion, up from our previous peak sales projection of greater than $2 billion, which was provided prior to seeing the strength of our Phase II readouts in PH-ILD and PAH and before we chose to pursue PPF and IPF. This assumes clinical and regulatory success in all 4 indications and the TPIP's profile continues to distinguish itself as meaningfully differentiated versus other prostanoids with comparable efficacy to sotatercept while maintaining a favorable tolerability profile, which allows for higher dosing.

Along with the reiterated peak sales estimate of greater than $1 billion for ARIKAYCE, the combined peak sales estimates for our 3 lead assets now exceeds USD 14 billion, up 75% from the greater than $8 billion peak sales estimate we previously provided for these 3 products. Let's now move to a deeper discussion of BRINSUPRI's ongoing launch. In its third full quarter of launch, BRINSUPRI produced $309.2 million in revenue.

We believe BRINSUPRI is on its way to becoming the most successful launch in the history of specialty respiratory medicine and has the potential to become one of the top 20 medicine launches of all time in any category. This outstanding performance gives us confidence to increase our full year 2026 BRINSUPRI revenue guidance to between $1.25 billion and $1.4 billion from our previous guidance of greater than $1 billion. This quarter's impressive results demonstrate the remarkable momentum of BRINSUPRI's launch and reinforce our confidence in its future. All detailed metrics we monitor, including payer access, patient compliance and continuation rates continue to track ahead of our expectations.

BRINSUPRI added approximately 7,000 new patients in the second quarter, exceeding our previous expectation of approximately 6,300 new patient starts. This result demonstrates the robust ongoing demand for the treatment. We now expect approximately 7,000 new patient starts per quarter for the remaining quarters in 2026, which is reflected in our updated revenue guidance. Strong new patient demand was driven by an acceleration in new prescribers and a deepening of prescribing.

As of the end of June, we had more than 6,300 cumulative prescribers, which was an increase of approximately 1,300 writers compared to the end of March. We are also making good progress on depth of prescribing. Approximately 30% of BRINSUPRI's writers have prescribed it for at least 5 of their patients, up from around 20% at the end of March. However, there is still significant opportunity here. Many doctors, including some who treat large numbers of patients with bronchiectasis are still trialing the medicine and have considerable capacity to write for more patients if their experience is positive.

This quarter, the European Multicenter Bronchiectasis Audit and Research Collaboration or EMBARC, announced its intention to collaborate with us to evaluate brensocatib's 25-milligram dose in a 3-year open-label study of up to 3,000 patients with bronchiectasis in 6 European countries. EMBARC's intention with this study is to shed light on 2 important questions.

First, whether long-term use of brensocatib has the potential to modify the course of the disease; and second, whether earlier upstream use of brensocatib is effective in further slowing disease progression. We look forward to collaborating with EMBARC to address these important questions. We also have ongoing plans to support additional long-term data generation through Phase IV and real-world evidence trials in the U.S. to further solidify our position as the leader in bronchiectasis and DPP1 inhibition and to show the long-term benefits of BRINSUPRI.

Beyond what we have just discussed, we see a significant opportunity to expand the diagnosed bronchiectasis population by improving diagnosis among patients with comorbid COPD or asthma. This effort to identify patients with comorbid bronchiectasis is being resourced like its own separate launch and is expected to yield increased diagnosis over the next several years.

Some of our initial efforts around improving diagnosis, including our support behind an ATS-led initiative to analyze electronic health records across 7 large academic medical systems, the Suspect BE celebrity campaign with Ty Pennington and hosting the inaugural Bronchiectasis and COPD Stakeholder Summit at the World Bronchiectasis Conference, just to name a few. And we are just getting started with other initiatives currently being piloted, which could advance our efforts to support earlier and more accurate diagnosis of appropriate patients.

We will track a variety of indicators to look for signals of progress, including monitoring claims data for increased diagnosis rates and high-resolution CT scans. Given the time it takes for this information to become available and the fact that they are trailing indicators, we will have insights from these data in approximately the middle of next year. We look forward to sharing updates as these initiatives progress. We are convinced that the best of this story is yet to come as more patients receive a proper diagnosis and gain access to appropriate treatment. Now let me provide an update on ARIKAYCE.

In addition to continued sales growth, we are making progress toward a potential expansion from refractory MAC into all MAC lung disease. Backed by robust clinical evidence and an experienced commercial organization, we believe ARIKAYCE is well positioned to make the transition to this larger opportunity in the U.S. and Japan. We recently submitted the supplemental new drug application to the FDA for ARIKAYCE in newly diagnosed patients with MAC lung disease, and we intend to submit an application to Japanese regulators in the second half of this year in support of potential launches in 2027.

This sets the stage for a particularly dynamic time for our Japan team who could be simultaneously launching both the expanded ARIKAYCE indication and BRINSUPRI in bronchiectasis. These products have clear synergies in terms of their call points, which we expect to benefit both launches. Given the impressive results we have seen from that team as they have executed on ARIKAYCE's current indication, we are excited to see the positive impact they can have on patients once presented with this expanded opportunity.

We look forward to sharing additional updates on ARIKAYCE's progress as the regulatory process continues. Let's turn to TPIP. Last month, we announced positive 12-month data from our ongoing open-label extension study of TPIP in patients with PAH. To contextualize how unique and impressive those results were, let's begin with a recap of the randomized Phase IIb trial that preceded it.

On a placebo-adjusted basis, TPIP demonstrated a 35% reduction in PVR, a 35.5-meter improvement in 6-minute walk distance and a 60% reduction in NT-proBNP at the end of 16 weeks of treatment. Recall, each of these efficacy metrics was measured at trough or approximately 20 hours after the previous dose was administered. The magnitude of these benefits support our belief that TPIP has the potential to become the clear prostanoid of choice.

This study also showed good tolerability with a low 10% dropout rate and 95% of completers choosing to continue in the OLE study. Let's move now to the results of the OLE study. At 12 months, patients who remained on TPIP maintained or improved across all efficacy measures. Moreover, patients who had been on placebo in the lead-in study and switched to taking TPIP in the OLE not only improved but fully caught up to the continued TPIP group.

This trend is something rarely observed in other open-label extension studies in PAH patients. At month 12, compared to the baseline of the lead-in study, patients in the OLE experienced an approximately 55-meter improvement in 6-minute walk distance and an approximately 60% reduction in NT-proBNP. Like the Phase IIb study, these endpoints were measured at trough.

Additionally, about 80% of patients achieved functional Class 1 or 2 with over 25% of all patients achieving functional Class I, meaning these patients no longer have symptoms of PAH. We also looked at REVEAL Light 2.0 scores, which are a validated measure of the risk of morbidity and mortality in patients with PAH. Impressively, the average REVEAL risk status for all OLE patients improved by 2 categories from intermediate risk to refined low-risk status. This improvement in score is associated with moving from a 5% to 10% risk of mortality in the next year to less than 5% risk of mortality in the next 3 years, along with meaningful improvements in the risk of clinical worsening.

Remarkably, 65% of all patients achieved refined low-risk status by month 12. Together, these efficacy benefits far exceeded anything we have seen from other inhaled prostanoids in PAH and were comparable to sotatercept.

On safety, we identified no new safety signals despite longer duration of use and higher doses in the OLE. Notably, we also saw a low 15% rate of treatment-emergent cough, which was predominantly mild and only one discontinuation due to cough over the first 12 months of the study. In addition, we saw a high continuation rate with 91% of patients remaining on treatment at the 12-month point. Overall, these results add to our confidence in TPIP's potential to be the next major advancement in the treatment of PAH.

Our comprehensive Phase III development program is progressing well with both our PH-ILD and PAH studies actively enrolling patients. In the past, we have seen a boost in enrollment after sharing positive data updates from the program. We hope that the strength of the OLE data will once again bolster interest in our trials. We are also pleased to report the first data monitoring committee meeting for the Palm ILD study recently occurred, resulting in a positive recommendation for the study to continue unmodified.

Additional Phase III studies in PPF and IPF, 2 additional large indications remain on track to initiate in the second half of 2026 and the first half of 2027, respectively. In the Phase III studies, patients begin with an initial titration phase to a target dose of 640 micrograms once daily. Upon completing titration, investigators may further escalate the dose to a maximum of 1,280 micrograms once daily when clinically appropriate. The decision to escalate is based on individualized clinical judgment, taking into account the patient's treatment tolerability and clinical status, including evidence of disease progression or the potential for additional therapeutic benefit.

We believe TPIP's broad dosing range could provide physicians with the flexibility to optimize the balance between efficacy and tolerability while also allowing treatment strength to be adjusted as the patient's clinical needs change. The flexibility to quickly and safely dose to much higher levels than other inhaled treprostinil products could represent a meaningful differentiator within the class and resembles the individualized dosing approach physicians already use with parenteral therapy since patients respond differently across treprostinil dose levels and their dose requirements may increase over time.

The ability to continue to dose higher could also expand the duration of time patients spend on inhaled therapy, delaying the need for patients to switch to parenteral options. As I look across our portfolio at BRINSUPRI's historic launch trajectory, ARIKAYCE's steady contributions and TPIP's potential to be the prostanoid of choice in our earlier-stage programs, which are steadily producing encouraging data, I am energized by what the future can hold for Insmed. I believe we are only just scratching the surface of the positive impact this company can have on patients in need.

With that, I'll turn the call over to Sara, who will walk you through the financial details of the quarter.

Thank you, Will, and good morning, everyone. I'm pleased to share our second quarter 2026 financial results and updated guidance and to provide some commentary to help with your modeling. BRINSUPRI produced $309.2 million in revenue in the second quarter, up 49% sequentially from an already strong first quarter in which we saw sequential growth of 44%.

This growth was primarily driven by strength in new and existing patient demand. This quarter also benefited from better-than-expected gross to net dynamics, which brought GTN towards the lower end of our previous guidance range of mid-20s to low 30s. ARIKAYCE produced $116.3 million in revenue this quarter, representing 8% growth compared to the second quarter of 2025. GTN for ARIKAYCE this quarter fell within the guidance range for the year of low to mid-20s. On this slide, you can see our current guidance ranges for BRINSUPRI and ARIKAYCE revenue for full year 2026 as well as our gross to net expectations for each product.

As Will mentioned, based on the strong results we have produced in the first half of the year, we are raising our full year 2026 BRINSUPRI revenue from greater than $1 billion to a range of $1.25 billion to $1.4 billion. While we continue to expect a regulatory decision in Japan for BRINSUPRI in the second half of the year, we do not expect a meaningful revenue contribution from Japan in 2026. ARIKAYCE continues to perform as the steady, reliable contributor it has been for nearly 8 years.

We are reiterating our full year revenue guidance for ARIKAYCE of $450 million to $470 million. We continue to see potential for expanded label in the U.S. and Japan next year as an upside catalyst for this program. On gross to net, we are updating our 2026 gross to net guidance for BRINSUPRI to mid- to high 20s, which represents an improvement from our previous guidance range of mid-20s to low 30s.

Given we are at the midpoint of 2026, we have confidence in this improvement as we do not foresee any large changes in our contracting strategy for the remainder of the year. Therefore, we expect gross to net for BRINSUPRI to remain within this updated guidance range for each of the remaining quarters in 2026. In addition, we are reiterating our GTN guidance for ARIKAYCE of low to mid-20s.

Moving now to the other relevant financial metrics for the second quarter, which are displayed on this slide. Cost of product revenues was $67.2 million or 16% of revenues, which is lower on a percentage basis than the 26% we saw in the second quarter of the prior year, reflecting the positive contributions of BRINSUPRI to the company's gross margin profile. As expected, combined research and development and SG&A expenses increased this quarter, up 38% compared to the prior year period due to the necessary investments made to support the U.S. launch of BRINSUPRI and to continue to fund our pipeline.

Let me now spend a moment on our cash position and burn rate. As of the end of the second quarter of 2026, we had approximately $1.2 billion in cash, cash equivalents and marketable securities, which represents a meaningfully lower burn rate than we have seen in recent quarters. This is attributed to higher revenue generation as well as appropriate financial discipline.

While we continue to expect to increase revenue generation in the second half of the year, we simultaneously expect to invest more in important initiatives to drive future growth, including the Phase III programs for TPIP across 4 indications, the launch and branded direct-to-consumer advertising for BRINSUPRI and incremental investments in Japan to build out an appropriate sales force and other commercial infrastructure to support future launches of both BRINSUPRI and first-line ARIKAYCE.

We also anticipate incurring payments totaling $50 million to AstraZeneca related to regulatory and sales-based milestones for BRINSUPRI in the second half of 2026. We believe we are sufficiently funded to support these initiatives and the current operations of the company until we reach cash flow positivity, which we continue to expect to occur in 2027.

As a reminder, we do not currently intend to raise additional capital before reaching that milestone. Finally, I want to share our perspective on the long-term financial profile of this company because I believe it is not fully appreciated. Based on the value drivers Will described, we expect our revenue trajectory to continue to grow well into the 2030s. But what makes this growth profile even more compelling is that it is driven by a largely synergistic portfolio of respiratory assets with similar infrastructure and overlapping call points. These synergies set us up to leverage our strong expected revenue CAGR into attractive and persistent EPS growth.

Insmed is not simply a revenue growth story. We are building towards a financial profile that we believe will be highly compelling from both a top and bottom line perspective and one that we expect to translate into a period of lasting value creation.

With that, we would now like to open the call to questions. Operator, may we take the first question, please?

[Operator Instructions] Your first question comes from the line of Jessica Fye from JPMorgan.

Congrats on the strong quarter. For the increase to BRINSUPRI's peak potential, can you expand a bit on what underpins that? Anything you can add around the earlier and more consistent diagnosis that you're seeing?

So what I would say about the increase in peak sales and our guidance for the year, they're obviously informed by what's now basically our first year under our belt. We launched last year in August. And the data, I would say, I would describe as remarkably consistent, not only in terms of performance because first quarter was strong, this quarter is strong, maybe even stronger. And I would say that, that matches our internal modeling or it exceeds it. And that is what is really the core of our confidence that this is going to continue for some time.

Every year at this time, we do not only our Board meeting, but we do an off-site, a strategic review of everything at the company. We take a whole day to do that with our Board. And the completion of that has resulted in our -- obviously assessing everything going on in the company and taking a longer-term view on all of those trends and directions. And as a result of that, we have the latest and greatest thinking surrounding peak sales estimates and year estimates. And that's why we've chosen this time to update everybody.

Your next question comes from the line of Joe Schwartz from Leerink Partners.

Congratulations on the strong performance and outlook. You now have a larger cohort of patients with sufficient time on therapy to begin evaluating refill behavior. What can you share about persistence, refill timing, discontinuations and adherence? And how are those things tracking relative to the assumptions you shared with us previously?

Yes. And what I would say is that this is possibly one of the great strengths of this launch. Across all the metrics you just mentioned, we are at or ahead of our internal benchmarks. Not only that, but those elements are both strong and I would say, stable. So again, giving us confidence as we look forward that this is going to continue in this favorable way.

One thing I will just say about some of these forward and new numbers, things like the peak sales number, that assumes a very strong DPP1 competitor introduces -- gets introduced into the market. And it also assumes the IRA Health and Human Services price negotiation takes effect in 2035. So this is a real-world assessment of where we're going to go.

Your next question comes from the line of Vamil Divan from Guggenheim Securities.

Congrats on the impressive results here. So I just have a question on the new patient starts. You mentioned the 7,000 new patient starts this quarter and then sort of the guidance. So I expect around that number remaining quarters of the year. So that's obviously quite a bit higher than the 6,300 that you were expecting just a little bit ago.

So I'm curious the confidence you have on that number staying flat and not continuing to rise since we're still relatively early in the launch. If you can just comment, was all of the 7,000 for the so-called organic patients? Or was there still some of that ready and waiting group that you talked about previously?

Yes. No, thanks for the question. That is all organic. The 7,000 number is just -- it's an impressive expansion from the 6,300 we thought we were going to get, and it speaks to the strength of the commercial team and the performance they've delivered. I fully expect that, that 7,000 will remain. Is there room for it to increase? Of course. We'll see how that goes, but our current guidance for the year assumes it will be 7,000 every quarter for the remainder of the year.

Your next question comes from the line of Jason Zemansky from Bank of America.

Congrats on the stellar quarter. I wanted to dig into prescribing depth for BRINSUPRI a little bit more. I think you said about 30% of prescribers are now writing for at least 5 patients. But what typically gives physicians enough confidence to reach that level? And once they do, do you see prescribing accelerate as they gain experience with the drug? I guess, is there a point at which BRINSUPRI shifts from being evaluated patient by patient to becoming the default treatment within a practice?

Thanks for the question. I think your final line conclusion is exactly what we anticipate will ultimately happen, that there will be a point at which this switches from the trialist sort of going patient by patient to this becoming the default for the treatment of bronchiectasis. And I think that is something we see taking place in the future. Right now, we're pleased to see the improvement.

Remember that last quarter, we had 20% of physicians who had written more than 5. That's now moved to 30%. And the impressive results this quarter reflect that. However, what I'm particularly excited about is that there's so much more room to run here with only 30% having written more than 5 and remembering that our Tier 1 physicians have over 100 patients each, there is a lot of room for even our Tier 1 physicians who are writing more than 5 to really pick up the pace. And that's something we're focused on very much in terms of our commercial calling effort.

Some of the very metrics that we're putting out today actually go into the hands of our therapeutic specialists to inform physicians, hey, look, 26,350 new patient starts since this drug was launched. There are 28,000 physicians of whom we have managed to convince 6,300 to write a prescription. So there is a lot of room to run here, and that's why we see this guidance for the year and the ultimate peak sales number increasing the way we have just reflected.

Your next question comes from the line of Olivia Saunders from Cantor Fitzgerald.

You guys noted that the gross to net obviously came in at the lower end of the range this quarter. And I know you've tightened full year guidance to the mid- to high 20s. So as we think about 2027 and beyond, is that steady-state GTN profile, is that how we should assume it will be going forward in that kind of mid- to high 20s? Just trying to think through where that number could eventually settle and whether we're already at that point in the launch.

Sara, you want to take that? Thanks for that. Sara, do you want to take that question?

Sure. Thanks, Olivia, for the question. Yes, now that we're obviously at the midpoint of the year, we have a clear line of sight. We don't expect any changes for the remainder of this year and expect that the coming quarters this year will be within that range. Payer access has been really favorable, about 90% approval rate, approval in less than a week for a majority of patients. So access sort of top-notch piece of this launch.

As you think about '27 and beyond, we're obviously not providing forward-looking guidance, but you should -- naturally, what you expect to see with gross to net is gross to net does naturally go up a little bit each year. Again, not going to provide forward-looking guidance. But for this year, we have confidence in the mid- to high 20s.

Your next question comes from the line of Ritu Baral from TD Cowen.

And I want to add my congrats on these metrics, too. One of the things that we have been watching on Symphony TRx is seemingly an improved compliance rate or at least fill rate. Can you go over sort of what initiatives you may be conducting to promote compliance? Is it patient focused? Is it insurance focused? Is it doctor focused? And if you could just comment on continuing Symphony TRxs and how accurate they'll be through the end of the year?

Yes. So the first and most important point to understand as it relates to persistence, which, again, is both strong and stable, is that the medicine itself, I think, is the greatest form of advertising. Patients, many of them feel better taking this medicine, and so they want to stay on the medicine. The physicians are hearing that. That becomes something that they reflect to future potential patients and that they themselves trial and experiment with. That then dovetails and extends out into our education of the insurance and physician and patient efforts that we undertake in compliant ways.

This medicine is -- simply put, it's a good medicine. It has a low dropout rate. It is something that makes many patients feel better and the avoidance of what we refer to as the heart attack for the lung and exacerbation or a flare is a very meaningful thing for these patients. Interestingly, those where there are patients who stop taking the medicine, they are inevitably going to have one of those flares or experiences, and that's going to drive them right back into the physician's office with a question of what can I do about it? And the answer being, you can take BRINSUPRI.

So I think we really have a very sort of unique ecosystem around this medicine in terms of its profile and how it's perceived and taken up. And just to address your other question on Symphony TRxs, yes, that continues to track very tightly with what we see internally through its most recent report.

Your next question comes from the line of Gavin Clark-Gartner from Evercore ISI.

Could you just help us understand the 2026 BRINSUPRI guidance a little more? I mean we're sitting here in August, and it's still a fairly wide range for the course of this year. So you noted 7,000 patient adds moving forward. Beyond that, what takes you to the high end or the low end of this BRINSUPRI guidance?

Well, I think it's important to remember that at the beginning of the year, we had gone from what was a referenceable indication of what success looked like that was $500 million to $700 million in revenue in the first full year. That was based on other specialty respiratory launches. We then increased guidance to over $1 billion at the beginning of the year. And here we sit with only 3 full quarters under our belt, and we have just raised that guidance by 25% to 40%. So that is a way to capture the journey that we have gone on.

We're now more than double what we initially thought we might do in the first full year. We will see what the next quarter holds. But I think the guidance is trying to be responsible in saying there's a lot of opportunity here. We can't assume it's going to fall into our lap. I have tremendous confidence in the commercial team. And I'm convinced that whatever can be accomplished with this medicine, they're going to bring it over the finish line.

But I think right now, we feel comfortable raising to this new level of 1.25 to 1.4. And as we move through the rest of the year, we'll certainly provide guidance on how that might -- where we might end up within that and how that might change. That's as much as we can really say at this point.

Your next question comes from the line of Leonid Timashev from RBC Capital Markets.

Just wanted to ask on the TPIP guide actually and the $6 billion. I guess, how are you thinking about the components there? And then specifically on IPF, are you assuming that you succeed in breaking orphan designation there? Is it sort of probability adjusted weighted? I'm just trying to understand sort of how you get to that $6 billion across all the components.

Yes. So I think it's very important for people to understand, we assume that we will be approved in all 4 of the indications, PAH, PH-ILD, IPF and PPF. We assume we do overcome the orphan status for IPF. And we assume that we have a profile that is not only clearly superior to other prostanoids but is comparable to sotatercept.

One of the interesting comments made when we were reviewing our Phase II open-label extension data was the description by the key opinion leader we had invited to join the call that from his point of view, not only does the profile we produced represent the holy grail, to use his words, of data, but it represents something that causes him to rethink the positioning of this prostanoid relative to something like sotatercept. So I'm very excited about where these results, should they continue, where they will take us in each of those 4 indications.

We're not breaking down what part of the 6 comes from where. I will just observe that I've seen some published estimates that sotatercept alone in PAH will achieve somewhere in the neighborhood of $7 billion in revenue from that perspective and assuming comparability and hearing the instinct of the KOL that Insmed may be with TPIP in a place to compete there, I think the $6 billion feels pretty comfortable.

Your next question comes from the line of Faisal Khurshid from Jefferies.

I wanted to ask you, you made some comments in the past about the BRINSUPRI ex U.S. launch sort of pending clarity on MFN. Can we just get an update on your latest views on that and also how the Japan launch plays into that potentially?

Sure. So MFN is but one component part of the assessment of how to bring the medicine to Europe. It's relevant, but it is not controlling. I would say the bigger issue going on in Europe right now is the lack of apparent willingness or interest on the part of most of the European countries because of budget constraints to really lean in and pay for the innovation that all these years and billions of dollars require.

That lack of willingness makes it less attractive to go there with a traditional commercial approach to Europe. But nonetheless, we have tested this drug in the European market. We want to find ways to make sure that the drug can get to patients who are appropriate, and we have some ideas about how we're going to accomplish that. But there's no doubt that the European opportunity is less today than it was in the distant past. And that's true not just for us, but for everybody.

In contrast, Japan, where we have just come from the launch meeting for BRINSUPRI in terms of getting ready, the senior team was over there visiting with our team, getting the review of where they are and how they're positioned for both the BRINSUPRI launch when it gets approved and the ARIKAYCE label expansion. And I can reflect my own enthusiasm for the capabilities of that team and what they're going to be able to produce.

Overall, international sales and revenue for this kind of a product tend to be in the sort of 10% to 15% range. I would expect the majority of that will come from Japan, and I couldn't be more excited about what that team is able to deliver. And based on their history and the expanded efforts they've made, including increasing the sales force, I think there is a very good reason to believe that Japan is going to deliver starting next year.

Got it. And that implies Japan pricing is comparable to the U.S.?

So the assumption is that we get a price from Japan that is acceptable. That is a process that is still underway. And when it's resolved, that's when we'll give full throated support to the launch in Japan and its expected success.

Your next question comes from the line of Matt Phipps from William Blair.

Congrats great execution here. Last quarter, there was a lot of talk about ready and wait patients versus organic demand. So just wondering if the 7,000 patients you feel really fits into that organic demand category you described previously and if that should be the assumption for the rest of the year?

Yes. It is 100% organic demand. Ready and waiting patients are gone. There are no more. And that was a comment we made last quarter, and we stick to it from now and going forward. So all the 7,000 new patient starts that we saw this quarter and expect to see in future quarters will be organic demand.

Your next question comes from the line of Ben Burnett from Wells Fargo.

I want to ask one on TPIP. And just back to one of your prior comments that the sales potential that you outlined could include IPF among other things. But with regards to IPF, I guess, what gives you the confidence that you would be able to navigate around a potential TYVASO ODE?

Yes. And I'll ask Martina to chime in here in a second. I think there are many ways you can -- I guess, the way to say it is to break the orphan status of a particular product. And we feel we have a number of different levers and approaches we can use there. Certainly, the Phase II data, the once-a-day dosing, many different features of this product and what it can do for patients, I think, presents an almost self-evident case for why we're superior. But Martina, do you want to add any comments?

Yes. I think one thing I would add here is that you've seen that the agency, the FDA here has also recognized the potential and possible hypothesis that TPIP is clinically superior. We don't know, but we assume and we can -- we've seen some of those that there may also be better safety and tolerability that we can show. And the third element is how you might impact patient care.

Now a once-daily drug with a better PK profile certainly would be one of them. That's the reason we have received also the PAH orphan drug designation because the agency already recognized the potential for TPIP. Again, I want to emphasize that we are a molecular different design as a prodrug has that potential opportunity for superiority.

Your next question comes from the line of Maxwell Skor from Morgan Stanley.

So you reiterated cash flow positivity in 2027, even with increased second half spend on DTC and launching in Japan. Can you just give us a sense of what's the BRINSUPRI level that underpins that? And how much flexibility do you have if you pursue BD?

Sara, do you want to take that one?

Sure. Happy to. Thanks for the question, Max. Yes, we reiterated cash flow positivity in 2027. I obviously will not comment specifically on what revenue guide that is implying for BRINSUPRI for 2027, but we feel like the trajectory of this launch is going extremely well, as you could see in our revenue guide increase for this year and our peak sales revenue guide overall and that we have confidence in cash flow positivity through 2027 to fund our current business as well as the items that we have in our pipeline without raising additional capital.

Your next question comes from the line of Andy Chen from Wolfe Research.

This is Brandon on for Andy. So curious to know what was the reason for the lower GTN? Was it Medicare patients fewer than previously anticipated, rebates less stringent than previously anticipated? Curious to know on that front.

Sara, over to you.

Yes, sure. So we obviously provided a GTN earlier in the launch. Now that we're in the midpoint of the year, and we have a clear line of sight into contracting for the year, we have confidence in being able to narrow that range, tighten that range to the mid- to high 20s. Importantly, access for patients is going great. I commented earlier around 90% payer approval, less than a week for the majority of patients, and that is the most important. So we're able to have this sort of narrow tighten GTN and patient access is exactly where we want it to be.

Your next question comes from the line of Stephen Willey from Stifel.

Congrats on the execution. So just given what we know about treprostinil dose dependency, can you comment on how you're powering the Phase I TPIP trials might contemplate the percentage of patients that you're expecting to be titrated up to the highest 1280 dose. And are you expecting those percentages to be meaningfully different across the different disease states?

Yes. So I'll turn this one over to Martina to talk about it. It's really important that people understand that the objective of the trial is not per se to push people up to the highest possible dose. It's for the physician to know that they have the flexibility that they can increase dose to achieve the ultimate best outcome for that particular patient. Patients respond to these drugs differently.

And it's a very unique and unusual disease state where the FDA permits that kind of a dosing regimen. But what we can do with 1,280 micrograms as the upper end is give them that room, that head space to continue to increase the dose should they not be able to achieve the best possible outcome at a lower dose. And if we look at just some of the recent data that we put out for TPIP, 25% of these patients in PAH in the OLE study get to Class I, which means they have no symptoms of the disease.

That is a remarkable increase in outcome for what is a fatal condition, and it is facilitated by this medicine and that extra room you have to increase dose. And that is something we want physicians to understand can happen with a modest side effect profile here. And that, too, was one of the remarkable things in the open-label extension study. But let me flip it over to Martina, who can perhaps dive a little deeper.

Yes. So when you think about how we designed the trial, you designed the trial from a regulatory perspective, what do we need to show functional improvement, and that is the 6-minute walk test. And that's what we are also powering for. We're powering the trial with a very high confidence of 96% to get a treatment difference of 30 meters, and that is at a p-value of 0.05.

So what we are looking for is that patients in the trial have the opportunity to reach the dose that they need to be in a better clinical state and to reach a better functional class as well as a risk score because in the real world, that is how physicians decide whether they will change or increase a treatment for patients when it comes to prostanoid treatment. So if you think about what we've looked at in the open-label extension, which is over 12 months, 77% of these patients have not only reached doses of at least 640, but they also maintain that dose.

So what's important for us and for these patients are to have a runway that they can increase dose if they need to. That enables patients and physicians to potentially keep patients on a drug like TPIP for longer. They may not have to go on a pump and that of IV or parenteral treprostinil. That is a huge burden. That is what we're really looking for to put patients in a better clinical state, but we're powering for an approvable endpoint that is functional improvement.

Your next question comes from the line of Qize Ding from Rothschild & Co Redburn.

Congrats on the results. I have one on the capital allocation. So given your balance sheet and active internal programs, going forward, how do you balance the development of your internal pipeline assets versus looking now for external opportunities?

Yes. I appreciate the question. I think this is always the challenge that every biotech company faces, especially as it progresses. We are in the enviable position that we have 3 very substantial franchises that are in the same therapeutic area in the respiratory field. And we also have, for the last 4 years, a very developed research program across 4 different platforms that are now beginning to yield clinical drug candidates.

The criteria for internal development and advancement is that the medicine in question is either first or best-in-class. And next year, we will be able to share with you the clinical trial results of our first programs emerging from this research area, which include a gene therapy for ALS, a gene therapy for Duchenne muscular dystrophy, and as we mentioned today, entering the clinic just now INS1033, a new next-generation DPP1 for the treatment initially of rheumatoid arthritis and then ulcerative colitis and COPD. So there is more to come from this internal research pipeline.

However, at the same time, we are constantly evaluating what is out there because we want to make sure that capital gets deployed against the best opportunities available. And so that, too, is a high bar. It must be first or best-in-class that we're bringing aboard, but we will continue to look and evaluate for those opportunities as well. But this is going to be something we're going to return to again and again as we update you on the progress of the programs coming out of our research department and their progress through the clinic set against what we see in the landscape of business development.

Your final question comes from the line of Danielle Brill from Truist.

Congrats on the execution. I did have a follow-up on the peak sales assumption. So you noted the high-level rationale, but I'm curious if you could kind of break down what specific assumptions changed to move the needle from $5 billion to $7 billion at peak? Was it expansion of the diagnosed population, penetration, persistence, duration on therapy or anything else? If you could just comment on what assumptions changed the most meaningfully, that would be helpful.

Thanks for the question. I think when it comes to BRINSUPRI, yes, we assume that the addressable market will continue to grow over time. And that's going to be driven by not only population growth, but increased diagnosis. We anticipate patients who are in the 1 or fewer exacerbation category to shift to a certain degree into the 2 or more exacerbation category, and that's because of improved awareness and reporting of exacerbations.

We also think that over time, as this medicine's reputation continues to expand, that the default will be to turn to bronchiectasis patients and think of BRINSUPRI in their treatment. I would also say that as we look internally at our modeling efforts, what we have seen is remarkable alignment with what our commercial effectiveness team has forecast. And I have to call them out for the exceptional work that they have done associated with this launch. It allows us to be confident in our presentation of today's new and improved numbers, and it is driven by both strong and stable performance across all the main metrics that we track.

And this concludes today's conference call. Thank you for your participation. You may now disconnect.

Thank you for standing by, and welcome to the Insmed 12-month results from ongoing open-label extension study of TPIP in PAH patients Conference Call. [Operator Instructions]

I'd now like to turn the call over to Bryan Dunn, Head of Investor Relations. You may begin.

Thank you, Rob. Good day, everyone, and welcome to today's conference call to discuss the 12-month results from our ongoing open-label extension study of TPIP in patients with PAH.

Before we start, please note that today's call may include forward-looking statements based on our current expectations. These statements represent our judgment as of today and inherently involve risks and uncertainties that may cause actual results to differ materially from the results discussed. Please refer to our SEC filings for more information.

I'm joined today by Will Lewis, Chair and Chief Executive Officer; and Gene Sullivan, Chief Product Strategy Officer.

The call will begin with some opening remarks from Will before turning it over to Gene to walk us through the study results in detail.

After Gene's remarks, we will welcome Dr. Raymond Benza, who is the George M. and Linda H. Kaufman Academic Chair of Cardiology at Cardiology at Sentara Health. Dr. Benza will share some of his thoughts on these data. After Dr. Benza, we'll turn it back over to Will to share some closing remarks. When we open it at the end for the Q&A session, Martina Flammer, Chief Medical Officer; and Sara Bonstein, Chief Financial Officer, will also join us.

The slides we will review today were furnished with the 8-K we filed with the SEC this morning and can also be found on the Events and Presentations section of our website.

Now let me turn the call over to Will Lewis.

Thank you, Bryan, and welcome, everyone. I am thrilled to announce the exceptional results from the first 12 months of our open-label extension study of TPIP in patients with PAH, which continue to validate our conviction in its transformative potential for patients with PAH.

Let me step back and remind everyone why TPIP could represent such a meaningful advancement in the PAH treatment landscape. TPIP is a prodrug of treprostinil that our research team specifically engineered to unlock the full therapeutic potential of prostacyclin therapy. We designed TPIP to address 3 critical treatment challenges: efficacy, safety and convenience.

On efficacy, TPIP's inhaled delivery targets the lung tissue directly, which has demonstrated efficacy advantages over other delivery methods. But TPIP is unique even amongst other inhaled options due to its ability to release the active drug slowly once it reaches the lung. This creates higher drug availability exactly where patients need it most with consistent 24-hour coverage, including overnight protection.

On safety, we also believe that the slow conversion of TPIP to active drug within the lung may reduce systemic side effects from high peak exposure. In addition, because patients aren't inhaling the active drug itself, TPIP may also improve cough. Our preclinical cough models show that TPIP only induced a cough response when the dose was increased to approximately 7x the dose which induced a cough response with active treprostinil.

And on convenience, TPIP requires just once daily dosing versus the typical 4 times per day dosing with other inhaled options. A single breath delivers up to 640 micrograms of TPIP, which contains nearly 60% more active drug than the highest label dose of TYVASO DPI and doses up to 1,280 micrograms would require only 2 breaths once per day. Additionally, this less frequent dosing may have the advantage of improving patient adherence.

Before we move into the OLE results, it is important to ground the discussion in the randomized Phase IIb study in PAH that preceded it. Those results showed a highly statistically significant 35% placebo-adjusted reduction in pulmonary vascular resistance, which far exceeds the numerical reductions shown for any other prostacyclin treatment of which we are aware.

Treatment effects across other efficacy measures were similarly impressive with a placebo-adjusted 35.5 meter improvement on 6-minute walk distance and a 60% placebo-adjusted reduction in NT-proBNP at week 16. What makes these results even more compelling is that they were measured roughly 24 hours after the most recent administration of TPIP, demonstrating TPIP's sustained therapeutic effect.

Safety was equally encouraging with 90% of patients completing the study and no unexpected safety signals observed. Importantly, all incidences of cough in the trial were mild or moderate with more than 85% classified as mild.

As you will see, all of these efficacy results for TPIP are numerically superior to the published results for other forms of inhaled treprostinil, both nebulized and dry powder. They are also comparable to the results that have been published for sotatercept.

Given the strength of the data produced in the randomized lead-in trial, our desire was to see those efficacy measures sustained over the longer OLE period. I am pleased to report that patients in the continued TPIP group were able to sustain those demonstrated improvements on 6-minute walk distance and NT-proBNP through the first 12 months of the extension study.

Additionally, those patients saw further improvement in functional class from the end of the randomized trial and saw clinically meaningful reductions in their risk of morbidity and mortality as assessed by the REVEAL Lite 2.0 score. Patients who were randomized to placebo in the lead-in trial saw a clinically meaningful response once switched to TPIP with overall improvements in 6-minute walk distance, NT-proBNP, functional class, and REVEAL Lite 2.0 risk scores catching up with those in the continued TPIP group by month 12.

Equally important, over 90% of patients completed the first 12 months of the OLE with no new safety signals being identified at doses up to 1,280 micrograms or double the highest dose in past trials. This is a remarkable result for patients and one that we believe will drive additional interest from investigators and patients for our Phase III trials.

Now I will turn it over to Gene to walk us through the data.

Thank you, Will, and good morning, everyone. I'm very pleased to be with you today to share the 12-month results from our ongoing open-label extension trial of TPIP in patients with pulmonary arterial hypertension.

First, I will provide a review of the study's design. The PAH open-label extension study is a 24-month study, allowing patients to continue on treatment with TPIP and to move patients receiving placebo in the lead-in study on to treatment with TPIP. The study was designed to allow up titration to doses as high as 1,280 micrograms, which is double the maximum dose that was allowed in the lead-in Phase II study.

Using a blinded double-dummy approach during the first 3 weeks of the trial, patients who had received TPIP in the lead-in study were able to remain on the dose that they had achieved in that study and patients who had received placebo in the lead-in study underwent up titration to their individual maximum tolerated dose of active drug.

During the open-label period, investigators were permitted to titrate patients to the level required to optimize clinical benefit up to as high as 1,280 micrograms. This means that patients who were doing well could remain on a stable dose, while patients who may not have achieved optimal clinical status or who showed signs of disease progression could be further up titrated during the course of the study.

The ability to increase the dose of TPIP over the long term is one of the more important differentiating features of TPIP. There is wide variability between patients in terms of their sensitivity to prostanoids, meaning that the initial safe and effective dose will differ across patients. We saw this in the lead-in study, where the safety and efficacy of TPIP were demonstrated as the drug was titrated to each patient's individual maximum tolerated dose rather than to a specified dose.

But another important aspect of prostanoid dosing is that patients will typically require increasing doses over time as the disease progresses. With parenteral prostanoid treatment, for example, the patient's dose is typically gradually increased over time. However, with the currently available inhaled prostanoids, there is a limit to the ability to titrate the dose up over time. And therefore, patients often have to come off of inhaled therapy in favor of parenteral therapy. As a result of its pharmacokinetic profile, the dose of TPIP can be increased over time in a manner similar to the approach taken with oral or parenteral prostanoid formulations.

With this in mind, in this study, physicians were not encouraged to increase the dose, rather they were given the opportunity to do so if they felt that a patient's condition warranted it over time. In that sense, they were able to utilize TPIP in the same manner that they are accustomed to utilizing oral or parenteral prostanoids.

The primary endpoint of this study focused on the safety and tolerability of TPIP during long-term use. Secondary efficacy endpoints include change from baseline in 6-minute walk distance NT-proBNP, WHO functional class and the REVEAL Lite 2.0 score, which is a validated measure of the risk of morbidity and mortality in PAH patients.

Finally, it is important to remember as we review these data that all efficacy measures in this open-label extension study were taken at trough exposure or roughly 24 hours after the most recent dose of TPIP, consistent with the timing of the efficacy assessments in the randomized trial.

On this slide, you can see the baseline characteristics of the patients who participated in this open-label study. It is important to note that all baseline characteristics reflect the measurements taken at the start of the lead-in trials, not at the start of the OLE. We chose that approach so that we could assess the performance of the patients who had initially been randomized to placebo in comparison to those who were randomized to TPIP.

The baseline characteristics were comparable between these 2 groups with only minor imbalances, most notably in the number of background medications. Note that these baseline data described the open-label study population of 91 patients, not the entire Phase IIb lead-in study population, which was 102 patients. This open-label extension study was fed by 2 prior Phase II studies: The first was a randomized placebo-controlled trial that enrolled 102 patients randomized 2:1. A total of 95 patients, 62 treated with TPIP and 33 treated with placebo completed that study. And it is that study that was a major source of patients who rolled into this OLE.

Some of you may remember the second lead-in study shown here, which was a single-dose 24-hour PVR monitoring study that we initiated around the time of the COVID epidemic. We enrolled only 1 patient in that PVR study and chose to give that patient the opportunity to receive TPIP in the OLE once it was initiated. We were very pleased that 95% of patients who completed those Phase II studies chose to enroll in this open-label extension.

Of the 91 patients who entered the OLE, 83 patients or 91% completed at least 12 months of treatment in the OLE. Of the 8 patients who discontinued, 4 were due to death, none of which were considered study drug related, 3 were due to an adverse event, and 1 was lost to follow-up. For reference, a typical mortality rate for patients resembling this population is around 8% versus the 4% incidence of death described here. Only 1 patient or about 1% of the total discontinued TPIP due to cough in the first 12 months.

TPIP was generally safe and well tolerated with no new safety signals identified. 89% of patients experienced a treatment-emergent adverse event, the vast majority of which were mild and moderate. 19% of patients had a serious AE, which we believe is in line with what one might expect in patients with serious diseases like PAH over a 12-month period.

Only 1 serious AE was considered related to the study drug by the investigator. That one was a case of orthostatic hypotension, which did not lead to discontinuation or dose reduction of TPIP. The patient was hospitalized and subsequently discharged after a precautionary workup was completed.

The most common events observed in the OLE were headache, cough, nasopharyngitis and diarrhea. Importantly, all TEAEs of cough were mild or moderate with over 85% being mild. Given that this study is the first to report the clinical experience of patients who received TPIP at doses higher than 640 micrograms, we've included some safety information specifically for those patients.

Among patients who titrated up to doses greater than 640 micrograms, there were no deaths or TEAEs leading to discontinuation. Only 10.5% of these patients experienced an SAE compared to 18.7% overall and only 1 patient experienced a TEAE of cough, which was categorized as mild. There were no new safety signals observed among these patients.

Before I walk through this slide, I want to remind you again that the placebo-adjusted 6-minute walk distance benefit reported in our Phase IIb trial was 35.5 meters, which is by far the largest improvement we have seen from a prostanoid in a randomized trial. This figure shows that over the following 12 months, patients in the continued TPIP arm maintained and even slightly improved their 6-minute walk distance.

PAH is a progressive disease, meaning that you might expect this measure to gradually decline over time, which makes this outcome even more impressive. Patients who had crossed over to TPIP from placebo had a similarly positive outcome on 6-minute walk distance. In fact, these patients essentially caught up with the continued TPIP group by month 12, with both groups showing around a 55-meter improvement in 6-minute walk distance from baseline.

This figure illustrates the changes from baseline in NT-proBNP, an important biomarker of cardiac stress. We were very pleased to see that the continued TPIP group maintained its improvement in NT-proBNP during the OLE period after an already impressive result during the randomized trial. Perhaps even more striking, the placebo crossed group had completely caught up to the continued TPIP group's result by month 6 and maintain that benefit through month 12. Both groups showed approximately 60% reductions from baseline at month 6 and month 12.

Now let's discuss the impact of TPIP that we saw on WHO functional class. The WHO functional classification system categorizes patients according to the magnitude of the limitation that the disease places on their physical activity. Patients in functional Class III experienced marked limitation in their physical activity. While they are comfortable at rest, even less than ordinary activity triggers symptoms, and this can have a significant impact on a patient's quality of life.

At baseline, all patients were in Functional Class II or III. By month 12 in the open-label extension, more than 25% of patients in both groups had achieved Functional Class I status, meaning that they no longer had any limitation on their physical activity and 80% of patients in both groups reached either functional Class I or functional Class II. Also encouraging is that 50% of patients in the continued TPIP group and 42% of those in the placebo crossed group saw at least a one category improvement in functional class by month 12.

Now let's move to the topic of risk stratification. REVEAL Lite 2.0 is a validated instrument that has been shown to predict the risk of mortality and morbidity in patients with PAH. This type of risk stratification is commonly used in clinical practice with many large centers requiring an assessment at every visit. The score is often used in treatment decisions with the aim of achieving low-risk status for the patient.

The REVEAL Lite 2.0 score incorporates BNP or NT-proBNP, functional class, 6-minute walk distance, systolic blood pressure, resting heart rate and renal insufficiency. High intermediate and low scores are associated with mortality risk of greater than 10%, between 5% and 10% and between 1% and 5%, respectively, at 1 year.

A refined low-risk score of less than or equal to 4 points is associated with mortality risk of less than 5% at both 1 year and 3 years. And beyond mortality, low and refined low-risk scores have been shown to predict improved morbidity as compared with higher scores.

Based on the excellent work by Dr. Benza, who we will hear from in a moment, we know that a 1-point reduction in REVEAL score corresponds to a 23% reduction in the risk of mortality and a 21% reduction in the risk of clinical worsening. This is important context for the study results on the next slide.

On this slide, you'll see the results of REVEAL Lite 2.0 scores. I'd like to note that risk stratification was not one of the prespecified efficacy endpoints in the Phase IIb lead-in study. However, it is a prespecified endpoint in this OLE. And because we collected all of the necessary elements to calculate the score at baseline time point in the lead-in study, we can now show those data here alongside the OLE data.

On average, both the continued TPIP and the placebo crossed groups began the randomized trial with intermediate risk scores. While the average score for patients taking placebo remained roughly flat during the 16-week trial, patients on TPIP saw a meaningful drop in score, bringing their average into the low-risk category. Within just 6 months in the OLE, the mean score in both the continued TPIP and the placebo crossed groups had dropped below 4 into the refined low-risk category.

As discussed in the previous slide, this means that at the start of the trial, the average mortality risk for these patients was 5% to 10% at 1 year. And by the end of 12 months in the OLE, their average mortality risk declined to less than 5% at 3 years. In fact, patients in the continued TPIP group saw about a 2-point average improvement and patients in the placebo cross group saw a 1.4 point average improvement in their REVEAL scores. This is very encouraging, particularly in light of the data that I mentioned previously, which showed that a 1-point improvement in REVEAL Lite 2.0 score has been shown to result in a 23% reduction in the risk of mortality and a 21% reduction in the risk of clinical worsening.

It is also notable that 65% of patients in both groups were able to reach a refined low-risk category by month 12 of the OLE.

Looking at the current PAH treatment landscape, we see established inhaled treprostinil like Tyvaso, which have offered meaningful advances but remain constrained by tolerability concerns, dose limitations and 4 times daily dosing.

More recently, WINREVAIR has provided another step forward with its potentially complementary mechanism of action, yet clear need remains for improved prostanoid therapies. We believe TPIP could represent the next major advance in the treatment of PAH.

While cross-trial comparisons require caution due to differences in patient populations, trial designs and how and when endpoints are measured, among other things, we are excited by what we have seen from TPIP so far and its potential impact. This slide provides some examples of what we mean.

Let me just walk through the first 2 of them. TPIP's 35% PVR reduction matches the best result we've shown for WINREVAIR's clinical program. On 6-minute walk distance, TPIP's placebo-adjusted 35.5 meter improvement in the randomized trial and 55-meter improvement in the OLE compares favorably to Tyvaso's 20-meter improvement in the 12-week trial and 25 to 38 meters in the OLE at 12 months.

WINREVAIR showed a 41-meter improvement in a randomized trial and 47 meters at the top improvement in its OLE, both of which are relatively comparable to TPIP's results. Similar patterns are shown across other endpoints shown on this slide as well.

Once again, I want to emphasize that each of these individual comparisons across trials should be noted with caution. However, it's not the individual data points, but rather the totality of this data that we find so encouraging.

Today's results suggest that TPIP has the potential to become the prostanoid of choice and they deliver benefits that could be seen as comparable to those of WINREVAIR. Combined with favorable safety, tolerability and once-daily dosing, we believe that TPIP would be well positioned for an expanded role in the modern PAH treatment, assuming future clinical and regulatory success.

With that, I'm now pleased to hand the call over to Dr. Ray Benza to share his thoughts on these data. Dr. Benza?

Thank you so much, Gene, and it's a real pleasure to be here this morning and to speak with all of you about this open-label extension trial and it's fairly impressive results. And I have to remind everyone on this phone call that pulmonary arterial hypertension, the disease that we treat as clinicians is probably one of the most devastating diseases that I've treated in my clinical practice. And the results of this open-label study really give us a genuine reason for optimism.

The results, just to put in perspective to the various people on the phone call were probably the most impressive results I have seen not only with an inhaled product, but really across the entire landscape of medicines that we use to treat this devastating disease. The impressive efficacy improvements that we're seeing with an inhaled treatment are really quite remarkable.

And going back to what we saw in the Phase IIb study, both the reductions in PVR and the improvement in 6-minute walk test are both well within what we consider the minimally important treatment difference to push our patients in the right direction. And what I mean by that is that patients who have achieved an improvement in walk distance greater than 30 meters not only have improved functionality, but improved quality of life. And this is really the measure that we hold all our drugs against because we want people to function better and feel better at the same time.

In addition, that reduction in PVR that you noticed is at the accepted range that we need in order to ensure appropriate right ventricular remodeling. And remember, right ventricular remodeling is really the essence of predictability of patient outcome with this disease and having a reduction that significant ensures that we will have right ventricular remodeling and improved outcome. And this is seen very impressively through the very robust changes in the REVEAL risk score.

In fact, a 2-point reduction is probably the largest reduction in REVEAL risk score that I have seen throughout many of the clinical trials that I participated in. And achieving ultra-low risk, which we define as a REVEAL score less than 4, not only ensures that our patients are going to survive more, but they're going to survive better because they're not going to have morbidity events, which is really the major thing that we fight now given the improved overall survival rate with the current landscape of current medications. And it does all this with a really great safety profile. The most important thing being the lack of systemic side effects, particularly a systemic hypotension, which we always want to avoid in patients with high pulmonary vascular resistance.

I think one of the other points to really stress is that more than 1/4 of patients by month 12 received functional Class I status. This means that people do not even recognize that they have the disease anymore. That is really impressive. In fact, most of our patients always get stalled in functional Class II, which means they're still symptomatic. But having a large proportion -- they're virtually asymptomatic is a really unique finding to this study.

The results to me are impressive enough where it will probably change my clinical practice once this drug becomes approved as I have always considered inhaled products, particularly inhaled prostacyclin as an edge drug. If I needed to push a person a little bit more in a favorable direction, that was the drug I've used. This changes the entire landscape with TPIP, which is now going to be a major contender for additional therapy when we want to move people from intermediate risk to low risk.

With, I feel, efficacy signals similar to what we're seeing with remodeling therapy like sotatercept, but without the significant side effects that we see with that injectable drug. So I just can't tell you how enthused I am with the results of this particular study and very much looking forward to see if we can reproduce these results in our upcoming studies. And I'd be happy to answer any questions that the audience might have.

Thank you, Dr. Benza, for joining us today and for sharing your valuable insights with our audience. Today's compelling results strengthen our conviction that TPIP has the potential to become the prostanoid of choice.

Let me summarize the key takeaways that reinforce this belief. First, patients who were initially randomized to TPIP in the prior lead-in trial were able to sustain those best-in-class improvements over 12 additional months of treatment and patients who switched from placebo achieved comparable benefits. In addition, patients experienced meaningful reductions from baseline in their average REVEAL Lite 2.0 scores, a validated measure of morbidity and mortality risk. Importantly, TPIP demonstrated a favorable safety and tolerability profile even at higher doses with low rates of cough, which was predominantly mild.

Given the strength of the results we have shared, we are incredibly excited for what is to come for TPIP. This slide illustrates our TPIP clinical program that is currently underway in 4 large indications: Our Phase III PH-ILD study initiated in December last year, and it is currently progressing well. Our Phase III PAH study opened its first trial site in April of this year and sites are now screening patients. Our Phase III trial in PPF is on track to initiate later this year, and our Phase III trial in IPF is expected to begin in the first half of next year.

Finally, keep in mind that this current OLE study is still ongoing. We expect the 24-month data readout from this trial to be available around this time next year. We are energized by TPIP's potential to transform treatment across all 4 conditions. Our team remains committed to advancing this program with urgency, knowing that each milestone brings us closer to potentially changing lives for patients who need better options.

Before we turn to your questions, I want to personally thank the patients and investigators whose continued participation makes this progress possible.

We will now be pleased to take your questions. Operator, may we take our first question, please?

[Operator Instructions]

Your first question today comes from the line of Joe Schwartz from Leerink Partners.

Congrats on the exciting data. I was wondering if you could talk some more about how TPIP's efficacy compares for the PAH patients who were titrated to higher doses versus those who weren't. And is there as much rationale to believe that higher doses of TPIP could be more beneficial in the other indications you're pursuing?

Gene, do you want to start off on that question?

Yes. I'm glad you brought it up because this is a topic that comes up fairly often. It brings up the whole topic of how prostanoids are dosed in the clinic and how the difference -- how that differs from how most other drugs are dosed.

I'm going to -- I tried to address a little bit of this in the introductory comments, and I'll make a few comments here. And then I'm probably going to ask Dr. Benza to give you his perspective. But it's important to remember how prostanoids are dosed, particularly the oral and parenteral prostanoids.

As I mentioned in the opening comments, the inhaled prostanoids have a limitation that they can't be continued titrated -- continue to be titrated. But parenteral and oral prostanoids are dosed to the individual sensitivity to prostanoid, meaning trying to achieve the best therapeutic effect while maintaining optimal tolerability. And there's a wide variability between patients in terms of how sensitive they are to prostanoids. So you may get an equal therapeutic benefit at one dose, but you need a higher dose for another patient to achieve the same therapeutic benefit. There's just some intrinsic differences in the sensitivity.

So with oral and parenteral prostanoids, doctors tend to titrate the dose up limited by tolerability to try to achieve best efficacy and land wherever they land for that patient. And we saw that in the randomized trial, where we allowed patients to go up to 640, but some patients stopped before getting to 640. They were getting good effect, and we saw the outstanding hemodynamic effects and 6-minute walk distance effects that were shown in that trial.

But another point about prostanoids is that over time, patients tend to require more. And so as we talk to the doctors and among them, Ray, the doctors would like the opportunity in an individual patient to be able to keep titrating up the way they titrate up the, say, Remodulin.

And so that's why we opened up in the longer-term study, we saw it might be necessary, doctors might want that opportunity. They wouldn't necessarily need it, but they might want that opportunity in an individual patient to -- in order to maximize that benefit. But as you saw, the outcomes of these patients were dramatic.

And so if you can achieve a patient in functional Class I or even II in a low REVEAL score at a certain dose, there's no need -- the physician wouldn't necessarily increase the dose. So I just want to emphasize that the increase in the ceiling to 1,280 was just to give doctors the ability to respond to any individual patient.

And it really wouldn't make sense to look at the effect of a patient who the doctor decided to go to greater than 640 and compare that to a patient who was doing well and the doctor decided to stop at the dose at 640 or lower. So that's the general background on prostanoid dosing and how to think about dose escalation. Again, one -- in my mind, one -- and Ray, I'll stop in a minute and ask you to comment on this. But in my mind, one of the problems with the existing inhaled prostanoids is that you get to this maximum dose and you can't respond to that need by increasing the dose.

With TPIP, you can dose it the way you might increase the dose of Remodulin. If a patient came in on parenteral prostanoid and you thought they could achieve a better efficacy and they were tolerating it fine, you might increase the dose. And so we wanted to be able -- doctors to be able to use TPIP in that same manner. Ray, maybe I'll ask you to comment on that approach to prostanoids in clinical practice. You've been dosing prostanoids for a long time.

Yes. It's almost 40 years. Having a titratable prostacyclin is really the holy grail of prostacyclin therapy, not only for all the reasons that Gene mentioned because some patients do have tachyphylaxis to those and require dose adjustments every now and then. But having the first really titratable inhaled product that improves significantly hemodynamics opens the window for countless additional opportunities to really push right ventricular remodeling and normalize hemodynamics to achieve complete remission.

So I am totally excited about the ability to really titrate this drug given the known baseline significant improvements in hemodynamics so that I can challenge patients when they get at low risk and try even to push for remission using a titratable product like this.

Your next question comes from the line of Jessica Fye from JPMorgan.

I wanted to ask about some potential differences between the Phase II and Phase III in PAH for the clinician and just the potential implications for the Phase III results. So the 3 things that I'm thinking about are, I think in Phase III, how to see 6-minute walk is being assessed like 1 to 3 hours after dosing compared to trough that was used in Phase II. I think the primary endpoint is being assessed at 24 weeks instead of, was it 16 in Phase II?

And then lastly, I know sotatercept is allowed in Phase III. I was curious what proportion of the patients might be expected to be on sotatercept at the time they initiate prostacyclin therapy with TPIP and what implications that could have?

Thanks, Jess. Well, Gene, do you want to run through the response on that?

Yes, sure, sure. Thanks for the question. And those differences you've identified are right on target. In the Phase II study, I think we held TPIP to the highest standard. We knew that we were introducing a drug that would be dosed once daily and wanted to make sure we had evidence that it was maintaining its activity throughout the dosing interval.

If we had measured, for instance, the hemodynamics at what might be peak exposure, I think there would have been questions and legitimate questions in everyone's mind, is there still an effect at the end of the 24-hour dosing interval. So we chose to kind of actually handicap TPIP in the Phase IIb.

Some people at the time asked us, why -- you could probably get better numbers if you measured hemodynamics in 6-minute walk at the peak exposure. And we decided that wasn't what we needed. What we needed was real evidence to feel confident going into Phase III that we're doing the right thing for patients and that a once-daily administration was, in fact, ideal. So that's why we did it at the trough during the Phase II study.

Now we recognize that there's cross-study comparisons and effect sizes and so forth. And -- we also recognize that FDA has allowed the primary endpoint to be at the peak exposure. And so we've chosen to kind of now put the best face now that we know for sure that this is a once-daily drug, let's explore what the maximum benefit is shortly after dosing. So that's the intention behind that change.

In terms of the duration of the study, right, the Phase IIb was 16 weeks. The Phase III will be 24 weeks. I think that we are really impressed by the ability to maintain patients in the study. So for instance, in this 12-month study, 91% of patients stayed in the study for that time. Often, you worry and at least I did in the old days of PAH trials that if you make them super long, you're going to end up with more missing data and missing data is hard to handle statistically. And so maybe we should use a modest treatment duration.

We felt some confidence that we would have -- we wouldn't have that degree of missing data. And we also see that patients continue to get better with continued exposure beyond 16 weeks. We've shown some of that data here now where there's continued accrual of benefit in some of these endpoints. And so with the Phase III, we'll give a longer period for patients who have been on drug. And hopefully, that might translate into even more dramatic findings at least for certain endpoints than we had already seen in Phase II.

And I think your third question was about sotatercept. Obviously, sotatercept wasn't approved at the time of Phase II study. So we don't have patients that were -- began the trial on sotatercept. But we recognize that that's a new player in the field and physicians are going to want to know how do these interact, does it work on top of sotatercept? What's the -- how should we think about them? Dr. Benza may comment after me, I might bring him in to talk about that.

But one of the questions will be, when should you move to a prostanoid versus sotatercept? Or if a patient is on one of these 2, what's the benefit of the other one? And so we think it's important to inform clinical practice to include patients on sotatercept in the Phase III trial, we plan to do so, knowing that we don't really know what the added benefit will be. We just don't have that data yet.

And we're making some cautious assumptions about the effect size that we might see in patients who are already on sotatercept to inform the powering of the trial. We're going to limit the number of patients who are on sotatercept who are allowed to be on sotatercept in this background. So we'll get some information, but we don't think we're jeopardizing the end result of showing efficacy because we have plenty of patients who are much like the patients we've seen in the Phase II study. And we hope and expect that there will be added benefit on top of sotatercept, although we're not counting on it.

Let's see. So that's it -- and maybe, Ray, you had some comments about -- I mean we spoke about this data about sotatercept and its role and how you might use a drug like TPIP if we continue to show the type of effects that we've seen so far.

Yes. I think it's going to be a really interesting decision tree point. As we use sotatercept more and more, we're continuing to see additional issues with this product that we hadn't seen in the randomized clinical trials, including the increasing number of patients we're seeing with exercise-induced hypoxia due to the development of AV malformations in the lung and intrapulmonary shunting, not to mention the pericardial effusions and other potential side effects that we see with sotatercept.

So in my mind, having an inhaled product with a safety background that we have demonstrated to make it a very close competitor with sotatercept in the decision tree when you're on someone with dual upfront combination therapy and you're looking for a third medication to push them to low risk. So I think TPIP, if it continues to show these type of favorable effects will be a competitor to sotatercept in that area.

And Jess, just to clarify on 6-minute walk, we are measuring primarily at the 1 to 3 hour after administration, but we are also taking measurements 24 hours after administration. So we will have that data to compare to what we saw in Phase II. And it's worth noting that the 24 weeks versus the 16 weeks also will permit a longer period of titration -- up titration should the physician conclude that for that individual patient, they want to go to a higher dose to try to achieve some of these in what has been characterized a remarkable reduction to refine low-risk categories in the REVEAL Lite 2.0 score or functional class reductions, which is certainly the goal of therapy.

It also gives us an opportunity to really look for true right ventricular remodeling because you know that doesn't happen overnight. So I actually like the longer observation period to determine if that's something we can actually achieve.

Your next question comes from the line of Ritu Baral from TD Cowen.

I think some of the client focus I've been getting this morning, guys around the higher doses is sort of less Eugene comparison across patients, understanding that they can get to different levels, required levels of treatment and more about how these patients fared sort of intrapatient as they dose escalated? I believe at one point, you had mentioned that 7 patients were able to get up to the 1,280. As you followed these patients, did they have sort of continued improvement in 6-minute walk or proBNP as they dose escalated? And as they tolerated sort of that dose escalation, were there any patients that had to then sort of dose reduce because of the cough that was triggered after a certain dose?

Gene, go ahead.

Yes. Thanks for that. And these become very complicated to try to assess over the course of time, whether the increase in dose that a doctor decides to go to has resulted in a benefit. And we haven't done those kind of analysis. I think that's very fraught. I think that the main point here is that we're giving the doctors the ability if they so choose to maximize the benefit in those individual patients.

And the end result is an assessment of what that strategy achieves. And that strategy of allowing patients to go wherever they need to go, achieves the results that we've shown here, the number of patients that achieved functional Class I and the reduction in REVEAL scores and so forth. It's that strategy rather than looking at the individual patients.

I think we have in the deck that -- I think there was -- in terms of the safety, as we continue, of course, to me, that's the main question. It's not should you compare the efficacy how they were doing before and after because presumably, the doctor made the decision to increase the dose for a reason. And ultimately, we see the results that we've seen. But we -- so my focus really was on are we going to start to see the emergence of any new safety signals as we got higher.

And that really wasn't the case. I think in the slide deck, we show that in those patients who went above because a lot of attention is paid to cough, we feel like cough has not been extremely problematic. We don't have a lot of dropouts due to cough. And if you look at the -- which we did look at the patients who received greater than 640, there was only 1 TEAE of cough didn't lead to discontinuation or anything. So we felt like there was nothing that emerged in terms of safety. It was the typical -- the same pattern that you might see at lower doses in patients who are more sensitive to prostanoids.

Your next question comes from the line of Vamil Divan from Guggenheim Securities.

Congrats on the data. And I do -- again, I have a titration question. A couple of follow-ups, if I could. So one, it sounds like there were 19 patients that got over 640 and then they got to the 1,280. Can you just -- what was the reason or a limiting factor in terms of why patients are not able to get all the way to the 1,280? Maybe you can just share that.

And what is the plan in Phase III in terms of how dose titration is being managed? Is there specific criteria? Or is it more left to the investigator's discretion? Any details there would be helpful.

Yes. So just to clarify, in all of our Phase III studies, we are permitting patients to go as high as 1,280 micrograms, which is a remarkable opportunity for physicians to get to those higher doses. And it is important to understand that many of these patients, as demonstrated by the fact that we're able to get 65% of patients in both groups to the refined low-risk category by month 12. So in some of these cases, the physicians made a decision they don't need to go any higher because they're getting the patient to the asymptomatic goal, which is a remarkable accomplishment and outcome.

But Gene, do you want to comment on this question?

Yes. I mean I think you put it just right. And so for that reason, there isn't like a CRF in the case report, there isn't an entry of, hey, this patient isn't at 1,280, why aren't they? Because that's not really a clinically relevant question. We're not intending or expecting every patient to get to that dose nor are we wanting to apply to physicians that they should.

Physicians dose these medications and in certain circumstances, add another medication in clinical practice in order to achieve what the clinical outcome they desire in that patient, hopefully, to move that patient to as low risk as can be. So if a patient is at a low-risk status, the patient is doing well, there would be no reason to keep dose escalating. And so we wouldn't really query the doctor, hey, why haven't you -- if you have a patient with a REVEAL score of 2 and a functional Class I, there's no reason to ask them why haven't you increased the dose any further.

Ray, maybe this is really to be kind of challenging and it reflects the prostanoids themselves, how they're dosed in the clinic and because they're dosed differently than other drugs, and this sort of goal-oriented treatment, which has emerged over the last decades where the goal is to improve patients into a low-risk category and be happy when you're there.

But I can see from these questions that it does -- it's a little bit confusing. And so I think it's best maybe to hear from Dr. Benza his perspective on these issues. In other words, why wouldn't you, if you have a patient on parenteral treprostinil, just turn the knob all the way to the right rather than that being guided by their clinical circumstance. So Ray, can you help with this kind of complex topic?

Yes. I mean the decision to titrate parenteral prostacyclins or any prostacyclin really revolves around several central issues, and they're all related to achievement of various goals. Obviously, we want to achieve low risk. And so in most patients, we will continue to titrate parenteral prostacyclins until we achieve low-risk status. So that is probably our primary goal and the primary reason for titrating actively prostacyclins when they're first initiated on patients.

The second thing is really to achieve secondary goals. So once we've achieved low risk, we look to determine whether, one, we can achieve hemodynamic remission, meaning normalization of PVR, cardiac output and right atrial pressure.

And secondly, we determine whether there is a further need to restore right ventricular function to normal. So those are 2 of the reasons once low-risk status is achieved to continue to titrate prostacyclins in any form. The ability to do that with an inhaled product is now opened with TPIP. We've never been able to do this with our other inhaled prostacyclins and the fact that we can almost double the dose and achieve levels similar to what we see with parenteral prostacyclins is very impressive with a once-day inhaled product. So this really opens the door for not only our standard titration schemes, but also these alternative titration schemes that are ultimately very important.

The last thing to note is that, as we've mentioned several times before, many patients who are on stable dose of prostacyclin need a little tweaking now and then, not only because they can tachyphylax to prostacyclin at certain doses, and that doesn't happen with everyone, but in a small minority of patients with tachyphylaxis is a real phenomenon and you have to increase doses to make sure that you continue to keep someone at low risk.

Your next question comes from the line of Olivia Brayer from Cantor Fitzgerald.

Another follow-up from me on higher dose levels. Have you seen anything from the OLE that maybe changes how you're thinking about the potential to see a dose effect in your Phase III programs? And how do you plan to actually look at dose response in the Phase III as you try to measure the different titration schemes?

And then if I could ask a question on cough. Maybe just what do you make of that 15% cough rate? It looks like you're maybe just looking at new onset of cough. So is that reported number lower just because it's a bigger denominator of patients? Or is there maybe something else that you're seeing around a better cough profile? Just trying to get a better understanding of where that number comes from and whether patients who previously reported cough were excluded even if they did have a lingering cough.

Sure. And let me just make it very clear. There is nothing in this study that does anything other than encourage us to believe that our Phase III data will be nothing short of impressive. These results, giving patients to a -- many of the patients to an asymptomatic status is, to the best of our knowledge, without precedent in this quantity. And to do so with the mild safety profile that's presented here, I think, is what we find to be most compelling.

Now we will apply that to broader groups of patients with different conditions and giving the physician the ability to go all the way up to such a high dose level affords many benefits, one of which is that you can continue to increase the dose to achieve the best possible outcome for the patient. And then as Gene and Dr. Benza mentioned, over time, should the need to increase the dose present itself, that opportunity will remain for the patients that aren't already at 1,280. So this opens the door to a usage of this drug in a way that is without precedent at the moment. So that's one of the things we're very encouraged by.

But Gene, do you want to go through perhaps some -- her points directly?

Yes, sure. And again, this gets to how prostanoids are different than other drugs. For other drugs that are being developed, you need to do a dose -- Phase II dose ranging. You randomly assign patients to 2, 3, 4 different doses and you see the dose response. Prostanoids are not dosed that way.

If you look at the oral prostanoids, the parenteral prostanoids, there wasn't a selection of a particular dose. It was an accepted dosing strategy, and it's obviously accepted by the FDA and accepted in terms of our Phase III trial design that we're not doing a dose response. We're testing that if you administer prostanoids in this way with an individually maximum tolerated dose approach, what's the safety and what's the efficacy.

So there's no comparison of how people that got to one dose compared to people that got to another dose because those aren't randomly assigned. Those are defined by individual patient biology. So I think that's -- it's in keeping with a lot of the discussion today, and I'm really glad we're having these conversations because it is complex.

But so we shouldn't look at Phase III nor Phase II. We didn't do a dose response trial because that's not what's done with prostanoid therapy. We're testing the strategy of if you take this drug and you administer it in an individually maximum tolerated dose, what's the ultimate safety and efficacy of that approach. So I think I just want to make that point in terms of dose ranging and such to keep in mind that this is different.

We obviously agreed with the agency on this. We came out of Phase II and they said, fine go to Phase III. And the designs of the other parenteral studies -- parenteral and oral studies reflect the same idea that it's an high MTD dosing approach rather than a specified dose.

I think your second question was about cough and noting that the incidence of cough overall was 15%. I think it was higher in the Phase II in the active, maybe 40%. I think these AEs are -- AEs that are new after entering the study. So there may be doctors who didn't continue to report cough in patients who came into the study on the cough. Probably the best way to do kind of apples-to-pears is to look at the data in the open label, what's the incidence of cough among patients who crossed over from placebo.

And I don't believe that's on the chart, but I can say that, that's about 26%. So if patients came in on placebo and then were obviously not randomized, they began on active drug, cough was about 26%. And so that's roughly -- it's a little bit lower than what we saw in the Phase II trial, but I think within the realm of noise.

And importantly, of those 25%, I think it was 8 patients, all of them but one were mild, and I think there was one that was moderate. And none of those costs, I think ultimately, the test is the cough problematic such that you come out of the trial, none of them led to discontinuation. So that may help to put into context why you're seeing on the slide that we showed a percentage that's 15% when in the randomized trial, it was higher in the active group. I think all those factors come into play.

Your next question comes from the line of Leonid Timashev from RBC Capital Markets.

I just want to stay with the safety topic for 1 minute. There were a couple of AEs of anemia and then some of nose bleed. I don't necessarily recall these earlier. So I was wondering if that's a new signal, if that's somehow related to the underlying disease or if that was in any way correlated to the higher dose?

Gene, do you want to take that?

Yes. So I'm pulling up the chart in front of me to see. I think these are kind of background adverse events that one might see in any population and maybe in the PAH population. So we have not looked at this and said, this is any new signal at all. I'm very clear about that, that these kind of background low rates over the course of the year. So there are going to be some differences in terms of the frequency that you might see any random adverse event in a study that's 16 weeks compared to one that's gone over a year, over a year, almost all patients are going to have some AE, and that's what we've shown in the high 80s, almost 90% had any AE.

So over time, you're going to start to see things. There's nothing that we're concerned about in terms of -- I think you mentioned anemia. There's no suggestion that prostanoids could cause anemia or that it's a drug-related phenomenon. I think I'll leave it at that.

Your next question comes from the line of Matt Phipps from William Blair.

Good to see durability here with longer follow-up. Just wanted to clarify the -- on the dose again, the 19 patients who achieved greater than 640 microgram dose, was that at month 12 or at any point throughout the OLE? And I guess, were there other patients that got above but then went back down?

Gene?

Yes. And this is the output that comes from statistics. And I'm not 100%. I'm pretty sure this is anyone who got to that level. And I don't have the data on anyone who got to a particular dose. In fact, frankly, that could have happened anywhere along the line. I'm not that interested in finding it out because if the doctor decides, you know what, I'd like to go up a little higher, you're having something that you don't like, let's drop back down. That is like typically the way things happen with prostanoids.

And so it's not something that I pay a lot of attention to. So I can't say for sure whether anyone in the 12-month period reached 1,280 and then dropped down a little bit. Again, I don't find it all that clinically important, but I don't have that information at the tip of my tongue, I'm sorry.

Matt, we can find that out for you and get it to you.

Your next question comes from the line of Faisal Khurshid from Jefferies.

I wanted to ask how is the Phase III enrollment going? And to what extent is the availability of 2 commercial therapies a gating factor to enrollment?

The enrollment is, I would say, ahead of schedule. And I suspect that with these data in circulation, we may find additional attention and excitement for bringing patients in. I don't know if, Gene, you want to comment or anyone else, frankly, from the Insmed team on the other question with regard to the other therapy and the availability and that impact. I don't -- we have not had that as a discussion as a point of concern, but I don't know if there's any more specific commentary anyone wants to provide.

Yes. Go ahead, Martina. I think you're...

Well, what we can say is we received a lot of interest from sites to be part of that study. And that is actually what we've seen across from the U.S. as well as on a global level. So it is -- the progression of sites initiation is going well. And I think with additional data such as this becoming available, will further fuel the interest on the patient as well as on the physician side and the investigators to enroll in the study.

And maybe just going back to the question that was asked before because we had -- as you know, in the 12-month data, we had 3 participants who reached the 1,280 microgram before month 12 and none of those patients required a dose reduction. So just to follow up on that one.

Your next question comes from the line of Maxwell Skor from Morgan Stanley.

Great. So is there anything in the OLE data or given the high dose tolerability that's changed your enrollment or dropout assumptions for the Phase III study? And just one more question on dosing. Do you just think -- or could you give us some guidance on whether the lion's share of patients in the Phase III you think will be dosed above 640? Any color around that would be helpful.

Yes. So with nothing that we've learned from this study has changed any of our assumptions driving our approach to Phase III other than our obvious enthusiasm for the outcomes we've seen here today. And I can't recall the other question, maybe Gene, you can take it.

Yes, this is our expectation of what kind of dose -- spectrum of doses that we'll see in the Phase III. As was mentioned before, it's 24 weeks. So there will be more opportunity for doctors to increase the dose. So I would predict maybe that compared to Phase II, which was a little bit shorter, there will be more patients that reach 640 and want to go higher.

It's a little hard to look at the 12-month study and say they'll reach the same dose that patients that have 12 months to keep increasing the dose. So -- and there is -- in the Phase III, patients will be able to dose range throughout the bulk of the study. But towards the end, there will be a period where we sort of locked in out the dose and want people to be at a stable dose for the last certain period of the trial. That's kind of what we did in the Phase II trial as well.

So I think that the bottom line is we have this ceiling of 1,280 now. And there may be some who get that high. I would expect not the majority by any means. Again, if patients are doing well in a low-risk status at 640 or even below 640, I would expect they would stay there. The point is that we just want to give the doctors the opportunity to manage the TPIP in the way that they manage parenteral.

Yes. And I think the one thing I would just emphasize is that this was a safety study. Its primary goal was to establish safety. And I do think that this study clears the path and provides some comfort for physicians in the study that all the Phase III studies that should they wish for whatever reason to go to a higher dose, they can expect these data to inform what the side effect profile would be.

And I think that's probably the most compelling part of this is that you can go higher and the side effect profile doesn't really change. And that is a remarkable opportunity as physicians think about the trade-offs for trying to achieve that lowest risk score for these patients returning them to an asymptomatic status for patients with this condition.

And that range of opportunity now presents itself and gives them a lot more incentive, I think, to explore pushing patients to get to that more favorable outcome. That's really what the goal of the introduction of this therapy is all about. Can we get these patients to the asymptomatic profile? And these data suggest that, indeed, for many of them, we can.

Your next question comes from the line of Jason Zemansky from Bank of America.

Congrats on the data. Gene, to follow up on an earlier point you brought up, have you observed any difference in the degree or timing of the tachyphylaxis between TPIP and native treprostinil? Appreciating it may be somewhat early, but beyond improved efficacy, are there any signals the prodrug could support a more stable or durable treatment effect?

And then Real quickly for Dr. Benza, I was hoping you could provide some quick qualitative feedback on the patient experience and the side effect profile looks improved over the native molecule, but just wanted to get a better sense of how that was translating into terms of treatment burden?

Over to you first, Gene, and then Dr. Benza.

Yes, sure. So the first part of it had to do with tachyphylaxis. And as Ray mentioned, that's one of the elements that can come into play in terms of why doses are slowly increased over time in certain patients, but not others. And also, there is the possibility of disease progression that would require higher doses. It's kind of a complex thing as to why and when a dose would be increased to push for maximum benefit to drive down the REVEAL score, for instance, to deal with any tachyphylaxis that's happening at the molecular level to deal with progression of the disease and so forth.

So all those things are interplay. I don't -- I can't think of a reason why the prodrug formulation would kind of alter that overall dynamic. In other words, like a molecular or tachyphylaxis because the prodrug itself is inert and it's really just a slow release of the active drug. So biologically, it's the active treprostinil that would have its biological effect. So -- I'm going to think about your question. But at the moment, I don't think of a reason why the TPIP formulation would particularly impact molecular mechanisms of tachyphylaxis, which are a number. This is a G-protein coupled receptor, which can be subject to that. So I'll say that about your first portion of the question and maybe turn it over to Ray for the second portion.

Pardon me, this is the operator. Dr. Benza has disconnected. He had to see a patient.

Sorry.

Jason, we'll track down your -- Dr. Benza for the answer to your question.

Your next question comes from the line of Ellie Merle from Barclays.

This is Jasmine on for Ellie. So it seems like the time to benefit from TPIP is very rapid. So when looking at this data, do you think there's room for continued improvement beyond 12 months or at 12 months or even 6 months, patients are kind of reaching near their maximal treatment benefit?

Gene, over to you.

Yes. I mean it's always interesting to hypothesize about what would happen. We don't have obviously data to inform it. When we look at the patterns of achieving, for instance, 6-minute walk distance benefit and seeing that maintained, you probably are seeing you can't keep -- we have 55 meters of improvement compared to the baseline.

I wouldn't expect necessarily that to go to 60, 70, 80, 90, 100 over time. I think more important in this disease is showing that benefit and then showing stability. Now you point out there are some other endpoints like the BNP happens pretty quickly. If you look at the curves, it looks like that sort of predates a little bit of a 6-minute walk distance benefit, and that makes sense to us, showing initially a decrease in right heart strain and then that turns into -- temporarily, that turns into a benefit in 6-minute walk.

Overall, the more comprehensive assessments like WHO functional class or REVEAL, you're right, there does seem to be some continued improvement. It's hard to know after like I'm looking at the WHO functional class and the large number of patients who are Functional Class I, 25%. I don't know whether to expect after a month, after month 12, like into month 24, whether we'll see even more.

I mean that would be wonderful, but I think I'm just tempering my expectations because this is a bad disease. This is a progressive disease. And it's just hard to know how much we can prevent ultimately things getting worse over years. But seeing the stability, seeing -- that was what we really -- what -- I mean, I'm really excited about this data because we showed that the 12-week -- the 16-week data, that was fantastic.

And then the question is, how will people be after a more prolonged use, and we're showing this, in some cases, continued improvement and stabilization in a progressive disease. I just think it's great. And although of all open-label studies in a disease like this, looking at year-long data really makes you think you can see the effect of the drug, like you would not have patients becoming asymptomatic without an intervention.

So I don't know what to expect. I would hope my ultimate would be that you'd see this level of benefit continue beyond month 12? And I suppose it would be possible there to continue accrual of more patients in Class I and so forth.

Your next question comes from the line of Andy Chen from Wolfe Research.

This is Jason speaking in for Andy. And congrats on the results. I just wanted to ask in terms of titration. I know that you guys are doing titration for both this trial and for Phase III. I just wanted to see what you guys expect for real-life dosing? And how that would play into pricing? And also in terms of what are your plans for PH-ILD and if this trial kind of guides this PH-ILD trial towards a different direction?

So we haven't made a decision as it relates to pricing. As we get closer, we'll have more to say about that, obviously, once we see the data from Phase III. The other question, I'll flip over to Gene, if he has any commentary, anyone else?

Yes. In terms of real-world dosing, I would expect the physicians who are participating as investigators in this trial are generally well experienced PAH physicians and they're using it the way they will likely use it if and when it gets approved. So I would think it would be a similar pattern where doctors would be informed by the label as to what we did in this trial.

It would be this initial kind of more rapid up titration to a level that they feel like the patient tolerates and is achieving something in terms of clinical benefit. And then over time, as Dr. Benza mentioned, this ability to continue to titrate a prostanoid that's inhaled, I think will be very welcome. And so I think I would expect the real-world dosing to be reflective of what we've seen here and what we'll continue to see in the remainder of this open-label study, which goes for another 12 months.

Your next question...

Just to add on the PH-ILD. Sorry, this was -- I think you asked about PH-ILD in the other trials. So we allow and encourage in the protocol dosing as high as patients tolerate so they can in all of the trials go up to 1,280 micrograms.

And your final question comes from the line of Sam Lee from Mizuho.

This is Sam on for Graig. Maybe just for the patients that -- maybe for the patients that didn't achieve the low-risk category, are there any theories or trends to help -- could explain why those patients didn't reach that low-risk profile?

And then on -- another question on potential commercial side. Assuming approval, what would you say is the strongest argument for patients that are on WINREVAIR that would compel physicians to switch or add on TPIP?

Go ahead, Gene, on the low-risk profile.

Yes. Yes. And that's a good question. I mean I understand that where it's coming from and as much as doctors are trying to adjust medications to achieve the lowest risk possible in any individual patients. Some of these patients were very severe to start with and had late-stage disease. And so that would be the doctor's judgment of what do I do? Like I have a patient on a certain dose of TPIP. Do I want to increase it?

They also had the opportunity if they thought there was room that they needed to, to add other drugs. And they generally did not do that. I think there was one patient where a drug was added. But for the most part, they were -- for the constellation of clinical reasons, and Ray is no longer here to talk about the complexity of the decision-making. They were comfortable sitting on the patients, for instance, in Functional Class II, maybe they dropped from Functional Class III and they felt that, that was a good outcome and they've done what they can, and they didn't want to be more aggressive in terms of either increasing the dose of TPIP or adding another drug and so forth.

So it's a little hard to put yourself in the mind of each individual doctor about why they made the decision they made for a particular patient who is not in sort of the -- for instance, the REVEAL refined low category, why aren't they being more aggressive? It's a really complex clinical decision.

In regards to your question about WINREVAIR and why might they choose to add -- as on or WINREVAIR and how is that calculus decided? I mean, building off Eugene's comments, it's obviously going to be specific to each patient. But it is worth noting that I think what today's data presents is the opportunity to achieve lowest risk status in a large number of patients, which I think is very exciting.

I would also observe that the side effect profile that was mentioned by Dr. Benza is part of his calculus as he thinks about WINREVAIR versus TPIP. In the perfect world, our ambition is that all the patients get to that lowest risk asymptomatic category and some of the calculus that will go into which drugs to choose, it's going to be different for every physician.

I was struck by Dr. Benza's comment that he would be, in fact, thinking of this versus WINREVAIR as he's making his own treatment decisions. One could theorize that they might be used together to achieve that outcome or the third drug that's added in the usual repertoire might, in fact, be TPIP. What we've heard is that physicians do think that these data, if they are sustained in Phase III, really change the way that they will use this prostanoid in the treatment paradigm. And that's probably the most disruptive and exciting dimension or conclusion from the data that are presented today.

And this concludes today's conference call. We thank you for your participation, and you may now disconnect.

All right. Perfect. Thank you, guys, all for joining us today. I'm Lyla Bibi, I run our Healthcare Equity Capital Markets, and I'm obviously thrilled to have Will Lewis here, CEO of Insmed.

I've got a ton of Q&A in the 35 minutes we've got. But, Will, maybe before I kick off, anything upfront you want to say?

Well, for those that haven't noticed, there's been a bit of a disconnect in the market. And I would say just as a general point for everyone to take away, while the narrative that is out there is sort of exploratory about whether there's something going on with the launch or this is happening or that metric is right or wrong, I would just draw your attention to what our statements have been and what I will reiterate today, which is that the launch continues to perform exceptionally well. We are steady as she goes. Everything is on track or ahead of our internal benchmarks.

And that gives us great conviction in the guidance we've provided, both for the year and for peak sales for BRINSUPRI and more broadly, for ARIKAYCE, for TPIP, everything continues to progress on track or ahead of schedule. So we feel very good about where we are. We're aware that there is some confusion in the market about messaging, but I want to just clear all that up and let everyone know things are going extremely well.

That's a great segue. And I think maybe we'll start just with a million-dollar question, right, as we think about the BRINSUPRI launch. And obviously, you've had a tremendous start as you think about the commercial sales, first quarter sales, $208 million, over 5,000 cumulative prescribers, 7,800 new patient starts. Like, amazing. But despite that, obviously, the shares have underperformed. And so as you think about what's being misunderstood or underappreciated, what are you most focused on?

Yes. I think if you just think about the arc of the launch itself from the beginning to today, we are on track for having just an absolutely stellar launch in the sense that this is going to be top 25 of all time in the industry and that we're going to end up doing $1 billion plus in sales in the first year of launch. So those are just remarkable and impressive statistics.

Now within every launch, there are always things that you can do a little bit better or improve upon. And certainly, we remain focused on that across all of our metrics. But market access is good. The narrative around the medicine is good. We note right now that about 1/3 of the patients that go on this drug experience symptomatic benefit in the first 2 to 4 weeks. So that plays really well into the broader adoption of the medicine as that message gets distilled and understood. And ATS, which just took place, was a big success for us with a lot of positive feedback from physicians about those experiences and the appetite for physicians to write for patients.

That's really helpful, Will. Maybe just one -- maybe just drilling down on one of the thematics that we've seen, obviously, a lot of noise around, which is discontinuations. And as you think about the narrative in the market, as you think about what you're actually seeing in terms of commercial impact, how do you distill the main drivers of discontinuations? When are you seeing it happen? Is it early in the treatment course or a few months in? Anything contextualizing discontinuation rates?

Yes. So what we often refer to as either the discontinuation rate or its shadow, which is the continuation rate by all benchmarks, we are doing exceptionally well. We are ahead of the metrics we had internally when we set our guidance both for revenue for the year and peak sales, and that continues to be the case.

When we look at where discontinuations do occur, it is usually early in the use of the drug. And we know from their self-reporting to the specialty pharmacy why they are dropping out. For example, about 1/3 of them drop out because of adverse events, which is exactly consistent with what we expected would be the case based on our Phase III clinical trial experience.

When we look at the balance of why they discontinue, it's often due to loss of patient follow-up or a patient just discontinues and does not report why. Now both of those are interesting because while they represent roughly 50% to 60% of discontinuations that take place, those are things we can address. We can reengage with these patients. From Q4 to Q1, you always lose patients due to insurance coverage changes or resets.

So there's opportunity there that we have focused on where we've already seen progress in improving getting those patients back on medicine and understand that when patients drop off this medicine, they are going to have another exacerbation. That's the nature of this disease. And when that happens, they're going to return to the hospital or to the pulmonologist. And at that moment, the physician is going to say there's only one medicine you can take that will prevent these exacerbations and you were taking it before and you dropped off, go take it again and stay on it for longer to see that benefit. And I think that narrative is going to support a return to use of the medicine because the patient is going to be forced to face that choice every time they have an exacerbation.

So maybe building on that, as you think about the work that your field force is doing to promote treatment persistence, what's the feedback you're getting from the physician community? How are you thinking about the activation of the field force in terms of educating both the prescribers and then obviously, patients?

So we have, actually, 6 different items and steps that we take to educate physicians, to motivate patients to stay on drug. It includes welcome packs. It includes when they opt into our patient support group, there are nurse practitioners that can reach out to them to talk to them about what their experience is going to be like. There are lots of different tactical moves we've made to look for ways to improve upon what is already a very good continuation rate. And I think that's going to continue to be the case.

When you talk to physicians in surveys, you'll often hear numbers that are far, far lower than that. And I think for many physicians, that is the case. The experience is a very positive one. If we're going to be self-critical, we would probably say that we talked about the continuation rate a little too early in the launch. It was at the end of the first quarter after only 2 quarters of experience. And that's a little early to be giving a continuation picture that is accurate. So I think after a full year, we'd be in a better place to perhaps make more detailed commentary about that. But I want to be really clear, we are at or ahead of all the benchmarks we are looking for, for continuation. And that relative to benchmarks continues to set a standard for excellence in our launch.

You've noted, I think, previously, about 80% of patients on BRINSUPRI opt into the inLighten program. And so what support does that provide? What kind of interactions does it enable with patients that could drive this point further adoption, penetration, continuation?

Yes. So there is an opportunity for there to be some nurse practitioner appropriately compliant informed education to the patient about adverse events, what they can expect. We have the ability to engage with those patients, regular check-ins, are they having any issues with their medicine? How can we be helpful? The support is really white glove from start to finish. And the ambition here is to make sure the patient has the most success with the drug that they can. That is going extremely well.

The opt-in percentage of north of 80% is extraordinarily high in our industry. Normally, you might hope for 50% if you were in a good place. So we're way above that benchmark as well. That means we have a very good connection to a lot of these patients, and it gives us that opportunity for interaction. Notwithstanding that, the continuation rates that you've heard of, I think, as I mentioned before, are probably the subject of a little too much attention at this stage of the launch because things are going extremely well. We expect them to improve from here. And the evidence that we have for that is that some of these tactical adjustments we've made, we've already seen that.

That's great. On the earnings call, you shared Insmed has already penetrated about 25% of prescribing physicians, over 5,000 prescribers. And of that, 20% of the prescribers have written scripts for at least 5 patients. For the remaining 80% of your active writers that are currently operating at lower volume, what is the typical feedback that you're getting from the clinicians that really require them to move to broader volume?

Yes. And this is the biggest opportunity we have with this launch. Notwithstanding the performance we've shown in terms of revenue production, patients reached, physicians reached, we have good depth and breadth of prescribing already. But the opportunity here is to continue to amp that up, and there are a lot of physicians and a lot of patients left for us to go after. Those physicians who had experience during the Phase III trial are the most active writers that are in our physician group. Those that are trying it for the first time are following what we call sort of the trialist playbook, which means that they'll put between 1 and 5 patients on the drug, see how they do. And when those patients come back into their office for the next checkup, which could be in 2 quarters, it could be in 3 quarters, one quarter, it varies by patient and severity. But when they come back in, that feedback loop back to the physician is what motivates the physician to write the prescription again.

And that's why events like ATS and CHEST where their academic gatherings of these physicians are really powerful because they give them an opportunity to trade stories about what it's like to use the medicine. And having just come from ATS at the end of May, I can tell you that those stories are almost universally positive. We hear very good things about the drug from physicians and patients, and I think that just bodes well for the launch to continue.

You mentioned the 80% of physicians who have written fewer than 5 prescriptions. To give you a sense of where we are, our Tier 1 physicians have more than 100 patients in their practice. So if we have some of those physicians who have written 5 or even 10 prescriptions, we have a huge amount of additional depth that we can go after. In the mid-tier, Tiers 3 through 7, it's largely -- you get into the community level physician. And what is important about the launch so far there is that we have already reached more than 5,000 physicians. That means if there are that many that are writing prescriptions that the mid-cycle of the launch is going to be strong because those are the physicians you need to be writing 1, 2, 3 years into the launch.

And it's important that everyone understand, we're talking about an addressable market of 500,000 patients as we identified 3 years ago. This market continues to grow. It is not static. So the 500,000 patients are growing every year because of population growth, increased diagnosis, increased number of exacerbations, shifting them into the 2 or more exacerbating patients. And importantly, these patients do not have a high mortality rate. That means that they are on drug, they stay on drug longer, and you do not lose the prevalence population to a high mortality rate like you do in PAH or IPF. The incidence population gets added to the prevalence population every year, and it continues to expand.

And this is all before we go after what we refer to as the second launch, which is targeting the comorbid COPD and asthma patients and getting the physicians to do CT scans, diagnose the bronchiectasis and put them on label for our drug. That is a second wave of patients that we think is going to be very significant in '27, '28 and beyond.

I'm going to touch on that. I'm going to come back to that topic in a moment. Maybe just one question. Just even as you were just walking through sales force framework prioritization, as you think about second half of '26, how are you prioritizing or shifting resourcing between existing prescriber depth and penetration versus new prescriber reach?

Yes. So the clear statement to our sales force is for Tier 1 or Tier 2, it's about depth. And for Tier 3 through 7, it's about breadth. And that's how they're focusing and deploying their time. And all of our calling efforts are centered around those 2 themes. And that so far is doing very well. I will say that I think what I'm going to be watching very closely in the second half of the year is to what degree does this begin to self-actualize without input from us.

What do I mean by that? When a physician decides that this is the drug for a symptomatic bronchiectatic patients without a therapeutic specialist pushing that agenda, that's when this medicine will begin to really take off because it means that the physicians are just looking for the patients where this drug can be used and it's not responding to the encouragement of a therapeutic specialist. And you see that sometimes happen earlier, sometimes a little bit later. But when it does, that's when the launch really starts to take off. And I'm excited about what we're hearing because that positive feedback loop suggests to me that we may be able to see that in the course of '26 or '27.

And I'll just drop a quote that I heard from a physician at ATS that I've been sort of hesitant to mention, but I'll share it here. He said -- he goes, 'Congratulations, you have the statin for the lungs.' And I think the reason they said that was because the ability to impact the inflammatory cascade of -- in the pulmonary setting, using DPP1 inhibition, is relevant for COPD, asthma, bronchiectasis, bronchitis, any form of lung ailment that is -- includes inflammation. This may be able to have a role to play.

Now for them to be on label, they have to be diagnosed with bronchiectasis, and 2 or more exacerbations is the market access standard. But from all of those different types of disease, I think there's a perception that this drug could really become a cornerstone of treatment for ailments. And as long as they have bronchiectasis, that's a compliant and appropriate way for us to target patients.

And what are you guys doing to that point as you think about just the significant commercial opportunity that asthma and COPD patient populations represent in terms of educating, in terms of broadening engagement and understanding -- having the physicians really understand the need really to drive increased diagnosis of comorbid bronchiectasis in that patient population because it is an enormous opportunity.

Yes. So let's talk about the scale of the opportunity and then talk about how we're approaching it. When we talk about the addressable market, we identified it 3 years ago at 500,000 patients. As I said a moment ago, that's dynamic. It is growing every year. We talk about the asthma and COPD population, let's just take COPD. There are 20 million patients in the U.S. with COPD. They're out there are sort of all over the place right now. But my best guess is somewhere around 20% of COPD patients are also comorbid with bronchiectasis.

Now we're doing work right now as our other groups to validate that number. There are some that put it much, much higher, some that put it a little bit lower. But let's just say it's 20%. That's 4 million patients or 8x the size of the addressable market we are targeting out of the gate. That's why we are approaching this comorbid population as a second launch. And in that sense, we are aware this is going to take time to get those patients into the top of the funnel. It's going to require a CT scan and a diagnosis by a pulmonologist. But once those are completed, if the patient is symptomatic, they are absolutely appropriate for treatment, and that we think will [indiscernible] benefit to years '27 and beyond as we think about where this drug could go.

By the way, the $5 billion in peak sales does not include the contribution from those 2 comorbid populations. So this is substantial potential upside that we're going to be tracking very carefully and resourcing very deliberately to go after.

It's an amazing undertaking for these patients. Maybe the last question before we shift gears to talk about ARIKAYCE. You've noted in the scripts for April, I think this was part of the earnings call, it's tracking with what Symphony is reporting, which is a metric you don't typically provide. How are you thinking strategically about the extent of information to share on the progress of the launch versus, I think, candidly, what could be misinterpreted broadly speaking, by the Street. And so how do you expect to really continue to point investors to the direction of Symphony West in line with your own projections? How do you think about that balance?

Yes. So today, because we're at a public forum, I can update you. We are continuing to track the Symphony TRx number. It is proportionately right on top of where we are internally. So if you want a good proxy for how we're doing, look at the Symphony TRx number on a proportionate basis, and that will give you a guidance about where we're headed. And what you'll see there is that things continue to be positive and up to the right. So we're very encouraged by that.

As we think about what data provide, I think we've learned a lot in terms of communication and what works and what doesn't. And what is clear is that when we try to provide additional anchor points or references of additional data, that tends to confuse more than clarify. Consequently, we are going to stick to new patient adds, which we have told everybody for guidance purposes, they should model as organic demand at 6,300 patients every quarter throughout the rest of this year, and that will get you above our guidance of $1 billion in revenue.

Beyond that, we'll be providing revenue. We'll provide qualitative description of what's happening relative to our internal benchmarks and our dashboards, but we're not going to go into detail beyond that. It tends to be confusing and it ends up raising more questions than answers. Despite our best intentions to be transparent and give more insight, that's kind of backfired and everyone's seen that in the marketplace.

But the unfortunate part about that is every data point we've been putting out and every message we've been trying to convey is that the launch is going extremely well. And so the market correction to us is at odds with the performance of what's happening internally. And even as we pursue that messaging, we continue to improve upon our launch. So it's not just that we're in a static good launch mode. We're working every single day to try and make it even better, and I think making some real progress there.

No, that's very helpful, Will. So maybe with that, we'll turn to ARIKAYCE. You've had obviously impressive ENCORE data earlier this year, which positions ARIKAYCE for a significant commercial expansion. Maybe spend a few minutes on the regulatory front. Alongside the sNDA filing in the second half of this year, you've noted plans to request conversion of ARIKAYCE's current conditional label in the U.S. to traditional approval. Can you speak to the progress made with the regulators? Any refinements around timing assumptions for first-line launch?

Yes. So you should model next year for first-line launch, both in the U.S. and in Japan. And we feel very good about both of those, the progress we're making with regard to that. By the way, the same is true for BRINSUPRI. BRINSUPRI will be launched in Japan starting next year. And so your model should include Japanese revenue for BRINSUPRI and for ARIKAYCE in frontline.

Why is that important? In the case of Japan, we're talking about 150,000 patients with diagnosed with bronchiectasis. And remember that the Asian population are hyperresponders to DPP1 inhibition. So whereas in the U.S., it's a 20% reduction in pulmonary exacerbations that BRINSUPRI is documented in Phase III. For Japanese patients, it's 65% more than threefold better reduction in exacerbations. So the uptake, we expect to be very good in Japan. And in addition, there are more diagnosed NTM patients in Japan than there are in the U.S.

So being able to expand the market over there for both of these and launch both at the same time with a proven commercial sales force, we think is very encouraging and will [ accrue ] benefit to, obviously, our numbers next year. I think ARIKAYCE in the U.S. is going to do very well. We're still trying to figure out what the shape of that launch curve is going to look like. The target product profile, which we now have, makes a very strong case for early adoption, but we'll have to see what the picture looks like and whether it will be a slow adoption or a more rapid adoption. We'll have some more guidance about that as we get closer to the launch.

But clearly, if you can get an 80% of the patients to culture convert in 6 months versus once they become refractory, it's 30%, it makes a strong case for intervening earlier. And our expectation is that, that's what we will see.

Fantastic. Maybe we'll move to TPIP. And so you have 4 Phase III TPIP trials, 2 of which are underway already in PH-ILD and PAH. You plan to share the open-label data for the Phase IIb trial in PAH in the third quarter, where 7 patients have uptitrated. And can you level set maybe for the group expectations into the data? What is the average duration patients have been on treatment? What are you expecting to see more patients reach the max dose at this time point?

Yes. So I'm very excited about Q3 for the TPIP data update. I think that's going to be significant. Why am I excited? Because this is 1 year in the open label on drug. So for patients who've been on drug for the initial time of the trial, this looks at their performance 1 year later. Have they stayed with good performance and has the adverse event profile remained benign. For those patients who have titrated higher, do we see continued improvement in performance? For those patients who were on placebo and went on drug, how did they perform? The data we're going to provide are things like NT-proBNP, 6-minute walk, a functional class change and improvements. Those things will all be available for the population of just under 100 patients.

Let's dig a little deeper into those patient profiles and what we're going to expect to see. While we did not encourage up titration in the open-label study, it was available to physicians at their discretion. And we were pleased to see that 25% of the patients actually increased the dose above 640 micrograms, which was the max tolerated target dose in the original Phase IIb study. In addition, 7 of the 91 patients went all the way up to the 1,280 max dose of the drug. So we will have data that looks at a group of patients that have gone all the way to the top.

What is the safety profile? What's the efficacy profile? For those patients that increase their dose, do we see continued improvement because that will lay the groundwork for a very strong case that this is going to be a drug that's going to dominate in each of these 4 indications.

And I'll remind everybody that for all Phase III 4 -- all 4 of the Phase III trials, 1,280 is the target dose, and we have expanded the time for patients to be able to get higher end dose. We believe that going higher will always provide better efficacy for these patients. And so we want to make sure that, that window is available. And so far, so good. This is a 1-year look. We'll have another 1-year look a year after. So we're going to continue to get data from this trial. We obviously won't have PVR data, pulmonary vascular resistance data because we don't do -- we're not doing the direct measurement. It's so invasive.

But it's important to ground ourselves in an understanding of the baseline profile of this drug. This drug had a 35% reduction in pulmonary vascular resistance compared to sotatercept, which was just under that, 33%, 34%. So the best available drug right now, we beat on this most important measure. Relative to other prostanoids, we're 15% to 20% better. And I don't mean relative, I'm talking absolute better. They are in the teens. We were at 35%. There really is not a close competitor in the prostanoid class based on the available data today. I welcome the introduction of other medicines and their clinical data to make the case as to what is going to be the drug that's going to dominate in this area.

Right now, we look at sotatercept with peak target sales of $8 billion and a very strong launch targeting only PAH. We are targeting PAH, PH-ILD, IPF and PPF. If we have a best-in-class drug in those 4 indications, you can expect TPIP to be a very important commercial driver of this company's future. And so that's what gets us so excited about today. We sit here with ARIKAYCE, BRINSUPRI and TPIP. The next 5 to 10 years of this company's existence are going to be revenue growth up and to the right from all 3 of these franchises. Two of them are first in disease, the other is best-in-class, and all 3 of them are the same call point.

So the leverage we're going to get at the EPS line is going to be significant starting next year when we go cash flow positive. And we have said publicly, we do not intend to raise capital between now and then. So it is a very bright picture for us from here. And that's why it's so frustrating for all of us, including our shareholders who've watched the volatility in the stock recently because from our point of view, performance is steady as she goes, is very, very good, nothing new to take us off that track. And we see the future of the addition of ARIKAYCE. We see the future of the addition of Japan with BRINSUPRI and the future of the addition of 4 Phase III trials for TPIP, creating another blockbuster drug in our franchise. And that's just what we're sitting on today.

Maybe on that point, you just think about how the competitive landscape has obviously evolved, right, as you think about IPF, recent approval of Jascayd. How do you think about that? Could that potentially impact enrollment in the trial? How do you think about that in terms of background therapy to your trial? Anything that you're seeing sort of evolve in the treatment paradigm?

Yes. I think what's interesting about IPF as an example, a fatal disease, the available drugs are impactful, but there's a lot of opportunities and a lot of unmet medical need that still remains. This is a disease that's been targeted for a long time by a lot of different companies. The TETON data that came out from UTHR was very exciting because it showed that prostanoids, the higher you go in dose, the more effective you are at treating the IPF condition. We can get more drug into these patients' lungs than anybody. And that we have established with clinical data already.

As we go into IPF, which we have not tested our drug in, we know that if we can get higher doses, we should see better performance. And that's why we're excited about the Phase III trial that allows us to go up to 1,280 micrograms, which is multiples of what the competition is able to do.

In the end, the enemy here is the disease, not the other companies. So we welcome the other drugs and their clinical data, and we look forward to the comparison of what we are able to do versus others because we have a lot of conviction that this drug is going to really deliver. And one of the important things to remember for this profile of patient is that the safety is just as important. So it's not just about pushing the dose and getting a lot of drug in there. It's how do they respond? Do they have serious issues with cough? Are they adherent to the use of the medicine?

There's a competitive drug out there just to in the TETON study. That drug, you have to take it in 7 to 10 breaths each time, each of those 4x during the day. That means 28 to 40x every day you're breathing in their drug. We do it once, and it covers the patient for 24 hours. And because the drug is inert when it is inhaled, the AE profile so far has been better. And the reason we say that is because what really triggers that cough reflex is the active drug in the upper airway. And because our drug is inert, they don't have that experience.

So we're excited to continue to look at safety in the open-label extension. We're excited to look at the Phase III trial. I can tell you the enrollment, which was a question we get, are you going to have concerns about enrolling? We don't think so. What we're hearing right now is that physicians are very excited about using this drug and putting patients on it in clinical trials. And what we note from the PAH and PH-ILD studies is that physicians even in the U.S. are putting patients on drug.

Why is that relevant? Because there's already an approved medicine that is a prostanoid in the U.S. available for those patients. and physicians for this fatal disease are still willing to put them on our drug where they may be on placebo for 6 months before they get our active drug. That should tell you the level of enthusiasm they have for what that drug will ultimately do to that patient when they finally get it.

It's amazing just to think about how much you guys are executing against commercially as you think about your late clinical stage trials. And then on top of it, we should spend a few minutes on your early-stage pipeline, which is pretty remarkable as you think about yet another pillar of growth. We know you're running 2 Phase I trials evaluating gene therapy in DMD and ALS, where you've indicated updates in '26 and '27. Share a little bit of what gets you excited about these programs, particularly as it relates to intrathecal delivery. And really, to the extent you can share perspectives around what data we might see in those updates.

Yes. And I would take a strategic step back at this moment and remind everybody that about 5 years ago, we did half a dozen acquisitions. These are different platform companies. They were not very expensive at the time we acquired them. And the thinking has always dominated our business development efforts that you want to do business development when you don't need it. And so we had good ASPEN data. We had good ARIKAYCE data and performance. And at that time, we went out and did a number of acquisitions. They have been percolating inside the company for the last 4 to 5 years. And next year, you're really going to see the benefit of those efforts.

So there are 4 different geographies that have independent platforms that are being pursued. One is synthetic rescue, and that's in Cambridge, England. That one is probably the furthest away from entering the clinic, but has some of the most profound science, cutting-edge technology that we are bringing to bear for diseases like ataxia telangiectasia, another neurologic condition that is devastating. And we're very excited about what that could be.

In New Jersey, where we have our original scientists, we have successor DPP1s. So one of the things that's going to enter the clinic this year is a next-generation DPP1, what we call INS1035 -- 33 -- sorry, 1033. We have over 1,000 of them. So give me a break. INS1033, which is going to target rheumatoid arthritis and irritable bowel disease. So we're going into the clinic this year with that drug. That's our intention, and that will be the next generation of DPP1s targeting those significant opportunities.

The third area is deimmunized therapeutic proteins where we're using, yes, here comes the buzzword, artificial intelligence to do B and T cell epitope deletion to make functional proteins not trigger the immune system and still have efficacy. The first area we're targeting there is uricase. So that's going to be for gout. Right now, there is a very effective drug out there, uricase for the treatment of gout, but it only works in about 20% of the population. So this would be a way to bring that medicine to all patients who suffer from that condition.

No one has really been able to deimmunize a therapeutic protein successfully to the best of our knowledge. We believe we've done it. We believe we've cleared the hardest hurdle there. And so we look forward to that entering the clinic in the next year or 2. And then finally, the gene therapy operation, which is out in San Diego, that has 2 medicines that are currently in the clinic, one for DMD and one for ALS, as you mentioned, we will have data from those. We know the internal data that we're looking at between now and the end of the year, but really, we will feature that next year.

What we are looking for there is clearly best-in-class performance. Matching the existing performance is not enough. So if we're bringing a medicine forward there, it is because it is materially better than everything else that we've seen out on the market. It should be better safety, better efficacy. And so far, having dosed all but the last patients in the final cohort, I would say so far, so good with those ambitions.

ALS, we are starting in sporadic patients. This is important because the ALS market, as you know, for SOD1 patients, it's about 2% to 3% of the overall ALS market. But because we saw in our early neuronal cell assays, performance in sporadic patient samples, the FDA agreed that we should be launching this in a clinical setting first in sporadic patients then in SOD1 patients. So if we see performance in sporadic patients, we're going to have another blockbuster on our hands, and that data will be available next year. So we're very excited about those. There are a number of other programs behind it.

I would just say that I think we have found our rhythm in terms of the research operations in the company, and you can expect 1 to 2 INDs a year, every year from here going forward...

That's pretty...

Without any additional business development externally.

It's amazing. And so maybe just in closing, there's obviously so much that you guys are prosecuting, both in the context of BRINSUPRI, ARIKAYCE expansion, a number of early-stage TPIP and early-stage pipeline. What are you most excited about?

I would say just the regular way performance of the BRINSUPRI launch. I mean that just continues to impress me relative to our own ambitions, which were pretty lofty when we started. And the team has just done a fantastic job. That excites me the most because it lays the groundwork for the expansion of ARIKAYCE, the arrival of TPIP. These physicians we call on and the medicines we provide are having a material impact on their patients for the better. And every time we do that successfully, we make a positive impression. And because all 3 of our late-stage franchises have the same call point, we have the ability to have a really positive influence there and continue to build on our reputation.

It's amazing. You've obviously done transformational work in the context of your clinical development and obviously delivering transformational medicine for patients. So thank you for all that you do. We're super excited for the future for Insmed.

It's our pleasure. And I would just say I hope everyone understands how enthusiastic we are about where we are as a company. I think there's a major dislocation right now in value versus operational performance, and we hope to continue to educate about that.

Yes. Well, execution through value. So, yes, thank you.

Thank you very much.

Thanks, everyone.

Thanks, everyone, for being here. We're really happy to have Insmed for our next fireside chat, represented by their CFO, Sara. Thanks for being here.

Thanks so much for having us. Really appreciate it.

So I think we'll jump right into the commercial questions. I'll start maybe just high level. You guys had what I think objectively, at least in my opinion, was a pretty strong quarter. I guess coming out of that, big picture, how do you feel about the guidance you've given, the trajectory for the rest of the year and maybe the key drivers there, and then we can sort of dive into each one.

Yes, sure, sure. So maybe just to start off, we had a tremendous quarter, 44% growth. If you look at really any and all of the analogs out there, we've exceeded that from Q4 to Q1. And I really kind of hang my hat on how did we do that and it's really all around operational excellence.

And that started years and years and years ago from the way we designed the trial to the execution of the trial, to the interactions with the FDA, to the disease state awareness that we did compliantly with both our medical and commercial teams on educating both physicians and potentially patients on what bronchiectasis is, what to look for, to speak up, be heard when you have an exacerbation. That then translates to the great work from our commercial effectiveness team on how do you forecast this product.

If you talk to most sort of CEOs, CFOs and if they -- if you give them truth serum and you say, how did you do with your initial forecasting, they probably were vastly off one way or the other. It's astonishing how great our team has been doing on that front. And then pricing, reimbursement and access. So we all know in this industry, you can develop the most impactful product. And if you don't have a pathway to pricing reimbursement and access, patients are not going to get the products. And we are continuously hitting it out of the park on all of those dynamics, which I'm sure we'll go through.

So this launch could not be going better. It has now positioned us with the revenue guide that we've given of at least $1 billion this year to be a top 25 launch of all time in our sector. So biotech can do it. Biotechs, mid-cap companies can launch very meaningful blockbuster, multi-blockbuster, mega blockbuster, whatever language you want to use, products, and we couldn't be more proud of the impact we're having on this patient population.

Got it. Maybe we can start with the payers. I guess heading into the quarter, there was some concern that there could be some seasonality. I guess, ultimately, was there less of that than expected? And how much of that was due to the work you've done with the payers? And I guess what do we expect for the year going forward?

Yes. So we're obviously early days in launch. So we've just gone through really 2.5 quarters. We had our stub period in Q3, first full quarter in Q4 and first Q1 most recently. So still learning around seasonality, vacations, Q1 dynamics, all of those good things. But specifically on the payers, so a couple of things to kind of peel on that onion.

So first, you have -- are patients able to get it approved, right? And what we're able to see is over 90% of payers are approving this if they're going through -- if the patients are going through specialty pharmacies. So absolutely remarkable. Then refill rates. Industry average for a monthly prescription is about every 37 days would be industry average for refills. We're hitting that out of the park and exceeding that.

If you look at our inLighten program, so that's our patient support program, and that's an ability to provide additional sort of white glove service to patients. Industry average is sub-50% enrollment. We're north of 80% enrollment for inLighten. So all of these are just the foundational elements on why this uptick from a revenue perspective has been able to show such tremendous growth and why we are getting such great support by the payer community.

Got it. That's helpful. You mentioned the refill rate, and I think this ties also into the compliance question that we've been hearing a lot. So maybe we can address that head on. And I guess, as you think about benchmarks for compliance, you've talked about statins. I guess why is statin the right comparison? And then you talked in broad strokes about doing better than that. I mean can you maybe put a finer point on what that means?

Yes. So big lesson learned. This is an area where I think we kind of stubbed our toe with education, and we own that absolutely. So when we were talking about discontinuation rates and really kind of opening up our playbook of launch excellence, we were providing all of those additional metrics and guide to say things are either at or exceeding our internal expectations and things are going really, really well.

So with discontinuations, we were pointing to statins because we thought that was a really high bar. And so we were trying to give ourselves a really high bar, and we were saying we're doing even better than what we perceived as a very, very high bar. I think the disconnect was the education around clinical trial setting versus real-world setting. And I'll give you some other sort of benchmarks that we can kind of hang our hat on.

If you look at things like asthma or COPD, their clinical trial discontinuation is around low -- high single to mid-teens. In real world after a year, they're about a 40%, mid-40s. If you look at IPF/PPF, those are fatal conditions. In the clinical trial setting, sort of mid-teens is the discontinuation.

In real-world setting, it's in the mid-30 percentile. So you can see the fact that we were pointing to statins and we were doing even better was to say we're doing the best-in-class here. There is no issue. Let me be 1,000% clear. There is absolutely no issue with discontinuation. The issue was we didn't appropriately educate ahead of time. This product is being well received by payers. This product is being well received by physicians.

This product is being well received by patients. And the other thing I would just comment on specifically on this topic is if the patient had discontinued for one reason or the other, obviously, that is standard in our industry. If they then have another exacerbation and they go back to their pulmonologists, what is the pulmonologist going to say? There is one approved product for this condition that has a very favorable safety profile. You may want to try BRINSUPRI again and give it an adequate amount of time to see if you're starting to feel better. So we couldn't be -- we think that team is kicking it out of the park, doing a great job and no issue at all on that topic.

I'm going to ask a few more on this topic just try to get at. But I guess as you think about -- as you talk to your physicians and you maybe talk to some patients, I guess, out of those that do stop taking the drug, is it because they feel that there's some adverse event? Is it because maybe they're not feeling the improvement? I guess what's happening on the patient side there?

Yes. Yes. So importantly, we do survey work on both the physician and the payer side -- I mean on the physician and the patient side every month. And we sort of switch up who we're getting that feedback from to make sure it's a very broad and diverse group. And universally, the feedback has been very consistent on no issue on the payer side and very positive patient experience.

And you'll even see that. I know a lot of folks in this room and probably listening on the phone read all the social media posts and all that kind of stuff. So you see that very consistent theme on positive patient experience, especially, again, reading some of the social posts, those patients that are on the 25 milligram, which is very aligned with what you saw in the clinical trial on some of the sort of secondary endpoints on feeling better on the PRO, preservation of lung function, all those good things.

I would remind you that this drug just mechanistically takes a little bit of time to reach full effect. So you have 2 to 4 weeks to reach full pharmacodynamic effects. If you look at the KM curves, it's usually -- there is that time point. So physicians where we can continue to lean in is that education around if it's a KOL physician that was either in the trial or at the medical conferences and know this mechanism inside and out or if it's more of a trialist, more of a community level.

We're obviously targeting both and more of the education on giving your patients adequate time on therapy. We are not seeing -- and again, early days in all of this, but we are not seeing any sort of underlying concern or anything. We are continuing to execute really well. Patients are staying on therapy and the potential for the continued growth on both the chronic use of this therapy and the increased patient population here is going to bode us really well for -- we've said $5 billion peak in revenue. We feel really confident in that number, and there's a couple more sort of layers of that onion to continue to grow that.

Last one on this, I promise.

No, I know it's a hot topic, and it's important that we address it.

You've laid out that you're clearly doing at least as well as some important benchmarks. But I guess you never want to just do good. I guess how do you do even better? I mean are there things that you can do to just not just be better than the industry benchmarks, but to really knock it out of the park like you've been doing in some of the other areas?

Yes. So I will say we're also knocking out of the park in this area as well. We are best-in-class. We believe we are best-in-class in sort of continuation rate. And I hang my hat on why are we able to do that? It's because of the great field teams that we have to support patients. We have our inLighten program. We have our field access managers. Those are folks that can provide white glove service on both the patient and the back office side.

I think companies do sometimes stub their toe and invest in the more traditional sort of sales direct commercial role, but then forget about the patient experience role. And we learned specifically with ARIKAYCE, the importance of that and we've carried that through with BRINSUPRI and provided this inLighten program with over 80% enrolled in inLighten. That sort of patient buzz and that -- those social media discussions has continued to help with the excitement of that program.

Industry average is sub-50%. So patients are seeing the value in enrolling in those inLighten programs, the field access managers helping the back office staff on sort of the paperwork. We know the medical exception process. We've had ARIKAYCE in the market for 8-plus years here and had very favorable payer dynamics with ARIKAYCE, and we're continuing that with BRINSUPRI. And I believe we're hitting out of the park on all of those metrics.

I want to touch on the new patient start dynamic as well. I guess the company presented some data on sort of organic versus patients that had been maybe part of a bolus. I guess how do you think about how that's going to change over the course of the year? I mean you've talked about seeing patient growth. I guess how confident are you in sort of that breakdown that you gave between patients and any leading metrics that suggest that you actually are seeing more patients coming in?

Yes. No, it's a great question. And this is a little bit of an art versus a science because how can you really discern we call them ready and waiting patients, right? But how do you know? And so we feel confident in the numbers that we've been able to put out based on our internal models, based on sort of the list that physicians had created and as you just sort of look at the dynamics.

And so with any new launch, especially a first-in disease, first-in-class, you're going to have a condition that people were diagnosed maybe 6 months ago or maybe 6 years ago or maybe 20 years ago, and they have never been able to really have an approved product until now for this. So you're going to have those ready and waiting patients. And it took a little bit of time to see them. You didn't see them all in the stub period of Q3 because the large institutions needed to get all of their sort of ducks in a row.

So you saw sort of that spike in Q4 and to a lesser extent in Q1. And so we tried to articulate what those numbers were. What we're now able to discern is that true organic growth in Q1 was around 6,300 patients. And if you look at really successful launches, we'll take WINREVAIR as an example. They were able to sustain steady new patient adds at this point in the launch.

And that's what we're aspiring to do. So sort of the -- I'm not giving quarterly guidance, of course, we obviously have our annual of $1 billion plus for 2026. But what we're saying is having steady organic growth at that 6,300 would be what would drive us towards the $1 billion plus. We will obviously always continue to look to see how we can do better for patients that we serve, but you should assume the 6,300 number.

Yes. Another key aspect of, I guess, the bronchiectasis market is how many patients may be misdiagnosed or maybe not have had the full workup. So I guess, how do you think about the point at which in the launch that some of these patients with COPD or asthma might be returning, getting more proper diagnosis and anything you can do to pull that forward?

Yes. So the TAM, this is a really, really important piece as you're just thinking about sort of the overall health and opportunity for this brand. So we had the benefit of, although there was nothing approved in this disease setting before BRINSUPRI got approval last year that there was a reimbursement code.

So there were patients that were diagnosed. There was claims data we were able to analyze. And so what that told us is 500,000 diagnosed patients with non-cystic fibrosis bronchiectasis and about half of them had 2-or-more exacerbations, which while the label is broad, our inclusion/exclusion criteria for the trial was 2 or more, and that's what we anticipate would be where the payers would sit.

That's 2, 3 years old, I think it's about 3-year-old data. TAMs naturally grow for a lot of reasons. They naturally grow because our population increases. And I think sort of everyone has that check the box, but there's a lot more layers to that onion.

As you're thinking about a first-in-disease mechanism and all the disease state awareness and education that we did years in advance, that helps to continue to grow awareness and grow patients coming into the physician's office to ask for a high-res CT scan, which is the definitive diagnosis here and/or physicians getting their patients scanned and/or when they get them scanned, asking to check for bronchiectasis.

Additional sort of layers of this onion are while this is a very impactful condition for patients from a quality of life perspective and lung function perspective, it is not a fatal condition. So you have new incidents adding on top of prevalence. So you have sort of that compounding factor, which you don't have in some other disease states. And then I think -- so that's sort of base TAM. And so a lot of ways for that 500,000 to grow, and we know we need to update you on that.

But then sort of the secondary launch that we talk about are all these potentially undiagnosed patients as you look at the COPD and/or asthma market. In COPD and/or asthma, it's north of, I don't know, 30 million patients in the U.S. You could take a whole bunch of subsets of that and how many of those are actively exacerbating patients, how many of those are actively within the pulmonologist community, but we believe that there could be -- literature is all over the place, 40% to 60%. So it's not really helpful.

But we believe that there could be a cohort of additional patients that are diagnosed today with COPD and/or asthma that may be underdiagnosed and also have bronchiectasis. And you could see folks like the ATS group that we provided a sponsorship, but they are doing a retrospective, real-world analysis with 7 institutions to say, let me go back and look at the scans and see are these patients actually in our sort of -- in our community already and are just underdiagnosed and now we have a potential ability to help these patients.

Another example is the Ty Pennington campaign that we kicked off about 1.5 weeks, 2 weeks ago. His mom suffers from bronchiectasis, and he's been the primary caregiver. So just that education, as you think about who this patient is, they're typically female, they're typically elderly and they're typically the ones that are used to taking care of everybody else.

So the education here and bringing out those patients, while we started early and while we're continuing this, it's not going to be a light switch. It's not going to be overnight. We believe we can potentially start seeing add-ins of the top of the funnel for these underdiagnosed patients probably next year. But most importantly is they would be on label. We don't need to go run another long, expensive Phase III program. They would be on label once they have their definitive diagnosis of non-cystic fibrosis bronchiectasis.

It doesn't take a lot of imagination at this point to see how you can reach your '26 guide or sort of the peak guide and you painted a pretty positive picture. And as much as I'd love you guys to announce a change in guidance at the healthcare conference, it's not going to happen. But I guess, what would you need to see? Or what are the key things that you're tracking just given how well everything is going that may inform any changes to that in the future?

Yes. So I'll remind everyone that we provided revenue guidance very early. So the typical sort of cadence for biotech would be they would launch in the second half of the year, that whole next year, they would not provide any guidance. And then in the beginning of the following year, they would provide guidance.

We had such bullishness in our stub period in our first full calendar -- first full quarter and the confidence in our commercial effectiveness team to forecast this product to be able to provide a guide this year. Because it's so early in the launch, we provided a floor. We said at least $1 billion, and that gets us to top 25 launch of all times. That is something we should all be very much celebrating, and I know we're celebrating that internally, the fact that we can have that much impact on patient lives this early in the launch.

We are a conservative company in nature. So the fact that we even provided guidance was already sort of going out on the limb. We need more than 1 quarter of actuals before we would think about updating guidance. I'll remind you, we just finished calendar Q1 from a revenue perspective. So we'll continue to track the progress here. The launch is going very, very well. I just would like to comment just briefly on the peak sales, both the $1 billion and the $5 billion, we can comfortably get there with U.S.-only diagnosed patients today.

So as you think about sort of that TAM and the additional sort of layers of the onion that we just talked through and what that could mean for '27, '28 and beyond, it could be really impactful as we think about what this product could mean from a peak sales perspective.

Internationally, on the strategy, you've been pretty clear about how you're thinking about Europe. But I wanted to touch on Japan specifically, given that there's a fair amount of patients there as well, and you've had commercial success with ARIKAYCE. I guess how are you thinking about BRINSUPRI in Japan?

Yes, yes. So it's a great call out. Japan has shown tremendous contribution from ARIKAYCE, and we've been able to continue to have great impact on patient lives in Japan for ARIKAYCE. We believe we have the potential to do the same with BRINSUPRI. We're obviously going through that process now from a regulatory perspective. We'll have the appropriate pricing conversations, but we do believe we have a path to be impactful for patients in Japan. The one piece I would comment on is you should not expect any revenue contribution from Japan in 2026. That would be a 2027.

Got it. We've got just about 3 minutes left. You've got a lot of other things going on at the company.

I'm passionate about BRINSUPRI, a lot to talk about.

So am I. Yes, so -- maybe just sticking with ARIKAYCE, I just mentioned it, you recently had some Phase III trial success. How are you thinking about the ability of that trial to grow the opportunity?

Yes. So the ENCORE data, a huge success. We were able to put that out earlier this year, and now we have the work to do with the regulatory authorities for both here in the U.S. and in Japan for that label expansion. I'll remind you that diagnosed patients today in the U.S., about 12,000 to 17,000. Full NTM is about 100,000. Similar in Japan, a little bit bigger, 1,500 to 1,800 refractory, about 125,000 in Japan for all NTM.

What ENCORE showed us is that at the 6-month mark, and the reason I'm saying 6-month mark is that is we can then bring the -- compare that to the refractory trial that we ran. At the 6-month mark, 80% of patients culture converted. For the refractory, it was 30%. So we were able to show that treating early appears to show significant benefit for these patients to be able to clear their sputum.

And the other thing we saw in ENCORE is a lower discontinuation rate. So again, just treating early, lower burden of disease allow patients to be able to tolerate ARIKAYCE. So work is now underway, obviously, with the regulatory authorities in parallel with the payers, being included in the international treatment guidelines would obviously be something that will be important here.

So we can't control that, but looking forward to that potentially being updated. We've said $1 billion plus peak sales here. It's just we need to think through sort of the duration of use for the earlier line setting and all of those good things, but we believe we have another blockbuster on our hands.

I heard you guys that you're a conservative company, but I think the TAM is potentially expanding by at least sixfold here with the frontline label if you get it. And you guys already have a sales force in place. I guess why can't it be more? Or maybe is the shape of the ramp going to be more pulled forward? I guess how do we think about what that actually looks like when you can launch?

Yes. So more work to do now that we have the ENCORE data in hand. I think understanding if we are including in the treatment guidelines, what they say on duration of use and what sort of that initial uptake will do. But we have tremendous confidence in it, just some more work. And once we've done that work, we'll come back to you all and I think we do.

Got 1 minute left. So I mean we just touch on TPIP. You guys are potentially exploring 4 studies, unique molecule. I guess, how is the operationalization of those 4 studies progressing?

Yes. So TPIP, probably the most underlooked program in our company as you're thinking about 4 very meaningful indications, all either in Phase III or progressing to Phase III very soon. We believe that we have the potential to be the best-in-class prostanoid therapy available for patients if we can reproduce what we saw in Phase II.

So a huge opportunity there. Operationally, the team is kicking it out of the park. We have 2 Phase IIIs underway right now in PH-ILD and PAH and then PPF and IPF will initiate either latter part of this year or early next year. Other thing just to kind of draw circle around is you will get open-label extension, 1-year look on the PAH program third quarter of this year and again, looking to show sustained best-in-class proBNP functional class, safety, all those fun things. So more to come on that program.

Unfortunately, we're out of time. We certainly could have gone another 25 minutes. But thank you so much for being here.

Thank you so much.

I'm Jason Zemansky. I'm one of the SMID-cap analysts here at BofA, and thank you for joining us on this -- our first day, second half of our Healthcare Conference in [ Veeva ], Las Vegas. I hope it's hot enough for everyone. Very pleased to have join us right now, Will Lewis, Chair and CEO of Insmed. Will, thanks so much for joining us.

It's a pleasure.

Perfect. Let's dive right in. So last week, despite reporting remarkably strong BRINSUPRI numbers, sales of $208 million, up 44% sequentially, there were some concerns raised over the discontinuation rates. So thus far, can you comment on the discontinuation rates and how that tracks to your expectations? And I guess, relative to similar oral small molecules?

Yes. So maybe I can just take a moment to set the stage. When we put out the additional information, our intention, which obviously did not go as planned, was to provide the anchor points for what is currently one of the strongest launches in recent years. We are on track to be a top 25 launch of all time in our industry, and we are very proud of that. The team continues to deliver, and we're super excited about it. So we're trying to provide the anchor points that give us the ability to speak with confidence about the future based on the success we've had in Q4 and Q1.

There are two elements I want you to take away from today. The first is that the execution on the operational side is going extremely well. And every metric we have within our models, we are at or above. And the original model was designed prior to launch, and it has been remarkably accurate and kudos to our commercial effectiveness team for that kind of capability. But what it's allowed us to do is understand that all the things that are unfolding before us that we've talked about on this call were exactly what we expected them to be. And that operational excellence, I fully expect will continue.

The other component of this that I want you to realize is that we mentioned discontinuation rate. It was but one metric among many. And unfortunately, the Street, I would say, was not prepared to hear that a metric. And so on us for not doing a better job of educating the Street about it. But the important thing to realize is it's not isolated as a variable. If you adjust the discontinuation rate consistent with precedent, which is what we set ours at. In fact, we set it at that of statins, which are one of the best performing continuation medicines, the small molecule out there, and we are exceeding that at the moment, which is very exciting. And that process of establishing that caused some people to plug only that number into their model and the cascade was the peak sales number came crashing down.

And that was unfortunate because the other dimension that we should have talked about is the growth of this market. And one of the exciting things that we see within this market is that the total addressable market is growing. The last update we gave you, which was the total bronchiectasis market defined as of 3 years ago. And as a consequence, it does need to be updated. It is growing every year. It grows because of population. It grows because of increased diagnosis. It grows because patients are living. Even though they decline in health, it's not like IPF or PAH where they fall off because of fatality. So the incidence rate is feeding the prevalence rate and stacking on top of it, and that increases the size of the market over time.

So a different way to think about this is if the discontinuation rate that we discussed was incongruent with what was in your model, you could have easily understood if you hadn't adjusted it, that the growing market would more than compensate for that. And that is again, one of the reason why we're so bullish. So those are the 2 components. great operational excellence and a growing market that gives us such confidence that the performance you've seen will continue.

Excellent. Maybe we can just delve a little bit deeper into persistence. What are the factors right now that you are seeing -- drive and how are these metrics going to evolve over time?

Well, I think the thing to understand about persistence is that right now, we are essentially best-in-class in terms of our performance in regards to this metric. So because it caught some people on Wall Street off guard, the assumption was that we need to do a lot of work on persistence. And in point of fact, we are performing exceptionally well on persistence. So it isn't that there's a problem that needs to be fixed there. There's an opportunity, of course, to gain more patients. And I think the Q4 to Q1 dynamics is an illustration of one driver that we can address as we go forward that may, in fact, help us to continue to improve on that, but time will tell.

Excellent. I guess if you think about it, you talked a lot about the readying and waiting patients in your earnings call last week. Are these patients more or less willing to stay on treatment? Do you have a sense of how that's going to track with a patient kind of coming on later this year?

We don't see any trends yet evolving in that regard. And I can understand how people think that, well, if a patient is ready and waiting, perhaps they're more motivated, they would be more likely to stay on drug. But the counterpoint to that is, as we described, we had a lot of ready and waiting patients who are part or a byproduct of a physician's list at a large institution.

In a way to describe it, one week, we had no prescriptions in the next week, we had 100. And that was because the electronic medical record had been updated and then they were able to suddenly write prescriptions. It's not that 100 people came into the hospital that day. So that's the basis for why we feel good about that particular metric. I would say that I think we can continue to work on improving it, and we have means of doing that because 80% of these patients opt into the inLighten program, which is fantastic. It means we have an interaction with them that's way above industry benchmarks. Just to toot our horn one more time and a shout out to the team that accomplishes that at inLighten. The industry benchmark is comfortably below 50%, and we have north of 80%. So it's really a remarkable engagement with the patient and our ability to support them as they go on their use journey.

Let's dive a little bit deeper into that. I mean you mentioned patient feedback, but do you have a sense of what the -- for an average patient on therapy, what are they experiencing good and bad? And similarly, what about physicians as they prescribe this medication?

So a really important point to get across is that this medicine is perceived as a fantastic good medicine. It does not have adverse events that are unusual and distinct so far that we have seen from any of the clinical trial work we've done. It's very predictable. To remind everybody, we had a discontinuation rate in the clinical trial that was comparable to placebo. Actually, it was a point better, 12% versus 13%. So that profile of drug means it's pretty easy to take. The physicians are enthusiastic in many cases, particularly those who have worked with the drug before. And that sets us up for expanding both breadth and depth among those physicians that have written and targeting those who we think can be trialists.

Got it. Maybe to connect some of the dots from your previous comments, you've long guided to a population that's about 250,000 out of 500,000 that have 2 or more exacerbations. You mentioned that, that market might be growing. What are some of the puts and takes there? Do you see near term the potential of moving that 250,000 to a larger number?

Well, as we learn more about the market, we will certainly update the Street on what we believe is going on. I think we want to be cautious and learn the lesson from last week that changes that are unexpected or new metrics that are not familiar can be disruptive to the market interpretation of our results. But I certainly think that, that market has been growing for the last 3 years. We expect it to continue to grow, possibly accelerate in its growth because the diagnosis rate is something that we think is going to continue to increase. So collectively, this creates a lot of wind in our sales as we continue throughout the launch.

Got it. And then another one of the metrics you brought up on last week's call is the number of prescribing physicians sitting about 25%. How do you see that number growing? And how much of a lever is that in the overall sort of trajectory near term?

So this is another point of accomplishment for the team, getting 25% of all pulmonologists who have written a script by the end of the second quarter is fantastic. It means we have breadth of prescribing behavior that goes down into the community level physician. This is not just high-volume prescribers at big institutions. This is also the community level physician, and that is particularly important as you think about the middle launch of this drug because that's where a lot of the demand is going to come from over time. So again, great performance. I think we can continue to do that. We will be working on breadth and depth. It's something we called out on the call last week. But I think the team has done an excellent job.

Hope you could dive a little bit deeper. I mean, what do you think are some of the main barriers here? Is it institutional P&T processes, conservatism, something else?

We know it's not reimbursement. That is a very, very, very small component of why patients are choosing not to continue on drug. If we talk about physicians and why they're putting patients on drug, those that have familiarity with the drug are very comfortable writing scripts generally. When we think about those physicians who have never seen the mechanism or don't know the drug, that takes a little bit more effort and they become what we call trialists.

Just to put a finer point on that, in the fourth quarter, we had 1,800 physicians who wrote one prescription out of a total of 4,100. By the first quarter -- at the end of the first quarter, 900 of those 1,800 physicians had written at least one other prescription. So that means we have a lot of opportunity given the performance of Q4 and Q1, if we just get those physicians to write more prescriptions. So to give you another metric that sort of frames this out, about 20% of the physicians that we have reached have written 5 or more prescriptions. That leaves 80% who have written less than 5.

And if you think about our tiering, our top tiers are very significant numbers of patients at the very top, it's well over 100. So that gives us a huge opportunity to dive deeper in those that are writing and to invite those who have not to experiment and collectively, that should continue to grow as we go. I want to be clear that what we talked about at the end of the last quarter and what we spent a lot of time at the conference talking about is the number that we see that is organic demand, right?

This distinction between organic and ready and waiting we were talking about earlier, the organic demand, and this is art, not science, admittedly, but this matches our internal model, and we feel very good about those numbers. The organic demand continues to look good. What we have tried to guide people to is that the first quarter organic demand number of 6,300 patient adds is something that you can straight line out through the rest of the year, and we would still get comfortably over $1 billion.

So I think the opportunity for us is to try to build on that. We're not representing we're going to be able to accomplish that. Most launches start to plateau by quarter 2 or 3 or so. And I think we'll see what ours does. I can tell you, maybe this is the moment to do it, just to share with you because we mentioned to everybody that the total prescriptions produced by Symphony, we don't know how they get their data, but they do. And we mentioned on last week that the TRx number, total prescriptions is -- almost sits proportionally right on top of our numbers inside the company.

And I'm pleased to report that for the month of April, that has continued. And if you look at the Symphony TRx number, you will see it going up into the right for each of the weeks of April. So that continues to be an encouraging sign, and we'll see what the future holds, but we feel good about that.

Great. Maybe just again, sort of thinking about levers of growth moving forward. I mean, what gets you into the asthma and COPD populations? I know those are sizable, but I mean, what are the barriers there and kind of what breaks you through them?

Yes. So that's obviously a massive opportunity. We consider it a second launch within the company. And if we think about how we forecast and how we think about the future, the majority of what we are talking about is driven by regular way execution of the launch. And that has gone, as I've said, very well. To that, we can add this concept of a little bit of a potential flywheel within the physician community if and when we can see that, where physicians start to write multiple prescriptions because they become familiar with the medicine instead of the 1 or 2 that we've seen sort of interspersed in the first 2 full quarters. If that were to happen, that would be a very encouraging sign for both the near and medium term of the launch.

Finally, we think about the COPD and asthma comorbid populations, and those are patients who have both COPD and/or asthma and bronchiectasis. And they are CT scan away from being officially diagnosed by a pulmonologist and therefore, on label for the drug. How big is that population? We've said we'll reach peak sales of north of $5 billion from the 500,000 patients with a concentration on 250,000 of them who've had 2 or more exacerbations.

Estimates vary on the COPD market alone, but we would put it at several million patients. And so if we can get some portion of those into the top of the funnel, that would be a dramatic improvement. Now this is very hard to do, but we are putting our best minds and efforts on this and hope to be able to pull that through in the coming years. This is not something that's going to show up one quarter or the next. We hope we might see the first hints of it by the end of the year. But certainly, we'll be looking for it in earnest in '27 and '28, and that could really improve where we go from a peak sales number.

Got it. Will, one of the, I guess, pushbacks that we got during the last earnings call was why not increase guidance if everything looks up and to the right, and there's a lot of conviction in where things are going, why not bump that number up?

Yes. This is one of those judgment calls where we feel like and we maybe tend to be a little bit more of a conservative company in this regard. But we want to see more than 1 quarter in the calendar year before we're going to start to think about those things. I think it is possible to discern positivity within the quarter as we tried to express last week without updating your peak sales number or your yearly target number and still understand that we are trending in a very positive direction. And in the future, we'll certainly look to think about doing so.

Okay. Well, great segue there. I got to ask. And in terms of the pace of these updates, any chance we'll get something mid-cycle?

Well, the number I gave you -- or the information I gave you just a moment ago is the first such example of that where we have indicated that the month of April tracks to the TRx number of Symphony. We don't typically provide that. We're going to -- we think that's a helpful way for people to understand the direction that we're traveling because what it does is it helps people not have to guess what the whisper number is because that has been out of control.

And I think if people track to the TRx number, and we can continue to emphasize that, that's what we're seeing, it really narrows the focus on what that number will be, and that should really help reduce the volatility in terms of the reaction to whatever comes out on the next quarter. And I think doing that at some cadence of broadcast banking conferences, starting with BofA will be the way we manage that. And that would hopefully be helpful to people as they try to understand the direction of the launch.

Got it. Maybe one more on the launch itself. I guess, near term, where is the biggest friction point? And when will we have a better sense of how that's going?

Well, I think the breadth and depth is our top focus. Breadth in the middle tier of our calling effort and depth in the top tier of our calling effort because with those scores of patients in the top tier, there's really opportunity to move into a broader penetration and really see some lift. The breadth, which is already good, has the opportunity to be better, especially in the middle tier. And so that's another area of focus.

I wouldn't call them friction points. I would just say these are efforts we're making. When we think about friction points, you often think about things like market access. And our market access for our specialty pharmacies is 90%. It is absolutely stellar. And the team has done a fantastic job of moving that forward in that way and making it possible for patients to get their medicine made available. And I think, as I mentioned before, as that has gone through, Q4 to Q1 dynamics are in operation. We're still learning what those look like.

But as we think about patients dropping off or stopping medicine, there is the opportunity to go back to them and explore whether they want to go back on medicine. And what that can look like is a patient takes it for a couple of months, stops taking it and then they have an exacerbation. They're going to go to their pulmonologist, and I would guess that the pulmonologist would immediately say, you should consider going back on BRINSUPRI. And this time, try and stay on it for 6 or 12 months to see the benefit you might incur. I also want to emphasize that we are already seeing in the patient population in a very significant number patients feeling better. And that is an incredibly important part of the narrative that is developing around this medicine among physicians and patients, these communities. We have a very good understanding of what's going on. We survey patients and physicians every month in large quantities, and we choose different groups each month. And then collectively, that gives us insight into what's going on, and it helps inform why we're so bullish about where we are.

Will, you bring up an interesting point, and that is sort of managing the patient journey, whether it's going to take x amount of months to start to feel better, side effects, whatnot. As you think about these parameters moving forward, what are your expectations towards that -- the ability of the physicians as they become more familiar, as they become more educated of keeping a patient on therapy?

Well, you see this a lot as medicines become more understood in the treating community, as our speaker programs begin to educate other physicians about how to use the medicine most effectively and their stories get carried forward about the impact it's had on patients, it tends to motivate physicians to follow those guidelines. We see this very dramatically with ARIKAYCE. So we would expect to see it once again with BRINSUPRI. And in that case, that should enure benefit to those patients perhaps having a more successful experience with the drug, and it's just another driver that may address the continuation rate.

Got it. Well, we have about 10 minutes left, and I do want to get to TPIP because that's a significant driver. So Jackie from the team.

Yes. So what is the potential of improving the efficacy overall or over the standard of care -- sorry, especially if the majority of patients can move into the 1,280 dose.

Yes. So what we're really excited about with this program is that it has gone from impressive data for the treatment of PAH to data for PH-ILD and now supported by work done by a competitor, trials for IPF and PPF. And that means we are running 4 Phase III trials for TPIP. IPF and PPF will start later this year. IPF may slip into early next year. But the point of that is we are in a good place with regard to TPIP. The data we've shown to date is absolutely best-in-class in prostanoids. There is nothing that comes close.

Our 34% reduction in pulmonary vascular resistance edges out sotatercept. So it is an extremely impressive use of a well-known moiety. What does that mean for us? That was when we were running Phase II and going up to 640 micrograms. What the treating community and the FDA have agreed to is to permit us to go up to double that dose. So if the response curve continues to go up and to the right, that would bode really well for these patients. We talk about efficacy measures. We're going to be looking in this open-label data release, which will come out in the third quarter, at whether or not they stay on their current dose. And if so, do they continue to see the same benefit? If they up titrate, and we have updates on that.

25% of the patients up titrated from 640 when they were in the open-label study and 7 of the 90-some patients made it all the way to 1,280. Now it's important to understand that we did not promote or push for these physicians to increase the dosing of these patients that was done by them. And so these are really exciting data. When we unblind -- show them to the world, we're going to be particularly excited to see, do we see continued efficacy above what we've already established as best-in-class as we go up in higher doses. What happens to the placebo patients that went on to active drug? What about those 7 patients at 1,280 because the Phase III trials, all 4 of them target 1280 as the max tolerated dose in contrast to the 640 we used in Phase II. So stellar results from Phase II. We're now doubling the potential dose patients can take, and that should result in our ability to demonstrate the superior efficacy even above materially, we hope, what we showed in Phase II.

If you think about the results of previous studies, exposure to treprostinil, the more exposure, the better the outcome. So I'm curious, how much do you think you could push something like 6-minute walk distance, PVO2 as a patient reaches these doses that they really haven't been able to sustain or tolerate in the past?

Well, that's what's most exciting about this because the 6-minute walk test, the NT-proBNP measure, the pulmonary vascular resistance during the course of the trial were all fantastic. And I might add that the adverse event profile was very encouraging and dramatically different from what the competitive products are showing. That gives us a lot of encouragement that we'll be able to push up the dose and time will tell third quarter, in particular, what those results look like. But I think this is probably the single most overlooked item at the company. TPIP, we believe, can be a monster drug if it continues to perform as it has and especially if we show any improvements in the third quarter. That really positions this in a very interesting place, and I think becomes the next leg of growth for the company.

So similarly, your competitors are trying to move new formulations forward, including softness inhalers or next-gen vasodilators. What's the risk here?

From the competitors, we don't perceive a risk. And that's not a statement about their performance or our performance. We see the enemy here as a disease, and we think everybody who can bring forward novel impactful medicines should do so. We happen to believe that ours is the best. And I think the margin for being better is going to be quite significant. The data comparisons will tell. It's not perfect because they won't be in the same trial, but we know the treprostinil mechanism.

Essentially, what we're doing with this formulation is capturing the original intent of prostanoid therapy. The original model -- animal model for this disease was a sheep model. And what was conducted by a competitive company was an inhalation study where the sheep were breathing it in constantly, and they essentially returned to normal as a result of that. Now we can't put masks over people and have them breathe in treprostinil all the time. What we have effectively done with this formulation is create that outcome.

This molecule is treprostinil with a 16 carbon chain appended to it in dry powder form. It's breathed into the lungs as an inert drug. So the upper airway irritation that is associated with treprostinil, we don't see in the same way that others do, and that's incredibly encouraging. Moreover, we're getting to much higher doses as we talked about earlier, and that dose is sustained in the lung over an extended period of time, resulting in us being able to target a once-a-day treatment that covers nighttime as well. And there is not an example of that out there right now. There is a lot of talk about some other stuff coming. I hope it's successful, but I look forward to seeing where we stand relative to them when we each produce our data.

One more on TPIP. What are the implications and opportunities for TPIP as we start to move to a world that's dominated by sotatercept?

Well, I think we're looking at what is already a combination market. So these patients come, they get diagnosed. This is a fatal condition. Patients decline fairly rapidly. The 5-year mortality rate is remarkably high, and it's incredibly unfortunate. But what we are looking at now is a new era where the arrival of sotatercept, the arrival of what we believe will be a very successful TPIP drug.

I could see those 2 being used in combination and really getting these patients where they need to go. We haven't done any of the work on that, but that is certainly my expectation that you will see physicians wanting to try that because, as I said before, we saw a 34% reduction in pulmonary vascular resistance. And I think in sotatercept's best data, they were at 32 or 33. I can't recall.

Got it. So we have a microphone in the back if anyone from the audience wants to ask a question, as we just raise your hand. As we're polling here, one more for you, Will. As you think about the so-called fourth pillar, obviously, some very interesting and intriguing candidates. Can you just give us sort of a rundown of one that you think is especially intriguing and then sort of balance that out with being disciplined and sort of investing in these higher risk, higher reward opportunities?

Yes. So the success of ARIKAYCE and BRINSUPRI, and even TPIP have really enabled us to continue to develop our research capabilities and target the addition and introduction of 1 to 2 INDs every year. That's our goal. This year, we have a gene therapy for Duchenne muscular dystrophy delivered by intrathecal delivery. We have an ALS gene therapy, and we have INS1033, which is a DPP1 inhibitor distinct from BRINSUPRI, which is targeting rheumatoid arthritis and IBD. That -- the INS1033 will enter the clinic this year. The other 2 are currently enrolling patients in trial.

Beyond that, we have deimmunized therapeutic proteins using AI up in New Hampshire. We have synthetic rescue going on for a variety of conditions in our Cambridge, England office. and we have the DPP1s that I just referenced coming out of New Jersey. So each one has a fairly distinct approach to what they're trying to contribute. They all look exciting, and I'm super interested to see what that data looks like next year.

On top of that, I'll just mention business development. We brought in INS1148 for the treatment of fibrotic disease, and that is moving forward into a Phase II trial. We're super excited to see what that can do. That may be just the beginning of where that may be applied. So inside of Insmed, beneath the 3 programs that are multiplexing right now and delivering on every front, we have a robust pipeline, which really puts us in a strong position. And as we move into next year and become cash flow positive, which we expect to do without having to raise any additional money, that puts us in a powerful position to really accelerate into the earnings per share transition that this company will undergo.

And that's where the discipline on research will get increased because we need to make sure that EPS is on a healthy trajectory. And I think we're going to be able to do that. If the standard for any medicine we are developing at Insmed has always been the same. If it is not first or best-in-class, we discontinue it. And that is a discipline we're going to continue to hold.

Got it. Any questions from the audience? I have one. When you think about exacerbations, at least in ASPEN, they're very well defined, very easily adjudicated. But when we get to the real world, a lot of the docs we've talked to have commented that it's not as cut and dry as maybe ASPEN is sort of portray. What are you seeing in the real world? Is it challenging? Is it easy to diagnose an exacerbation? And again, what do you think it's going to have on overall diagnosis rates?

Well, heterogeneity is certainly the watch word associated with pulmonologists who are evaluating exacerbations, and I would expect that to continue. It is certainly the case that we expect exacerbation rates, diagnosis rates to increase, both because we're raising awareness with patients to look for these exacerbations and to document them and tell their physicians about them, but also raising awareness with physicians on the importance of looking for those, diagnosing those and thinking about the implications of those.

This is a progressive disease. And so you lose lung function every year. There is an undercurrent of urgency to treat these patients so that, that lung function can be preserved if they're taking the 25-milligram dose because that was seen statistically significantly in the Phase III trial. So that's a powerful message to the treating community and one of the reasons why I think we're going to continue to see a strong launch.

Got it. Well, Will, thank you so much for joining us.

My pleasure. Thank you.

Thank you for standing by. My name is Danica, and I will be your conference operator today. At this time I would like to welcome everyone to the Insmed First Quarter 2026 Financial Results and Conference Call. [Operator Instructions]

I would now like to turn the call over to Bryan Dunn, Head of Investor Relations. Please go ahead.

Thank you, Danica. Good day, everyone, everyone, and welcome to today's conference call to discuss Insmed's First Quarter 2026 Financial Results and provide an update on our business.

Before we begin, please note that today's call will include forward-looking statements. These statements represent our judgment as of today and inherently involve risks and uncertainties that may cause actual results to differ materially from the projections discussed. Please refer to our filings with the Securities and Exchange Commission for more information.

The information we will discuss on today's call is meant for the benefit of the investment community. It is not intended for promotional purposes, and it is not sufficient for prescribing decisions.

Today's call will feature prepared comments by Will Lewis, Chair and Chief Executive Officer; and Sara Bonstein, Chief Financial Officer. After their comments, they will be joined by Martina Flammer, Chief Medical Officer, for the Q&A session.

I will now turn the call over to Will.

Thank you, Bryan. Good morning, everyone, and thank you for joining for joining us. Insmed's business is off to a strong start in 2026. Commercially, BRINSUPRI delivered strong sequential growth and continues to outpace all past specialty respiratory launch analogs while establishing a new playbook for excellence for a commercial launch. And once again, ARIKAYCE grew year-over-year, which is especially impressive given it is in its eighth year since launch. Both products remain firmly on track to achieve their respective revenue guidance for the year.

Clinically, we made meaningful progress, highlighted by clearly positive and potentially practice-changing results for ARIKAYCE in our Phase IIIb ENCORE study. Additionally, we continue to make steady progress on TPIP's Phase III development with PH-ILD and PAH trials now underway and trial designs for our PPF and IPF studies nearing finalization.

As we look ahead, we will continue to focus on maximizing the impact of BRINSUPRI in patients with a current bronchiectasis diagnosis while also working to increase awareness and proper diagnosis of patients with COPD and asthma who may also be bronchiectatic. In parallel, we are moving quickly to submit the ENCORE data to regulatory authorities in the U.S. and Japan, which we believe have the potential to support an expanded label for ARIKAYCE in the first half of 2027 and a $1 billion-plus peak sales opportunity for that brand. TPIP will remain a central priority for us as well as we execute on our 4 Phase III trials while also generating long-term data from our Phase II open-label extension studies.

Supplementing all these initiatives is our early-stage pipeline, which we expect will continue to produce an average of 1 to 2 INDs per year. We also intend to supplement our pipeline with select business development efforts. Financially, we are well resourced to execute on all of these initiatives as we advance toward cash flow positivity next year.

Let's turn now to discuss BRINSUPRI's progress in more detail. BRINSUPRI's launch continues to exceed our expectations, delivering 44% sequential growth off of an already strong prior quarter baseline. We were particularly pleased by the strength of this growth because it occurred in the calendar first quarter, which tends to demonstrate slower growth for medicines given plan changes, out-of-pocket cost resets and reauthorization dynamics.

In fact, when you look at the basket of strong respiratory launches that we have cited in the past, sequential growth for those products slowed significantly during their first calendar Q1, delivering only around 9% sequential growth on average. Of course, those past analog launches were impacted by the Medicare coverage gap, which was eliminated beginning in 2025 under the Inflation Reduction Act. But if you expand this analog analysis to include comparably strong launches since the coverage gap was removed, you've noticed that BRINSUPRI's sequential growth rate is actually higher than those of WINREVAIR and Rezdiffra, which in the first calendar Q1 of their respective launches generated between 30% and 40% sequential growth versus Q4. Notably, we did not raise the price of BRINSUPRI at the start of 2026, and the impact from inventory stocking this quarter was negligible.

We are extremely pleased with how BRINSUPRI has performed to date and remain confident in our 2026 revenue guidance of at least $1 billion. If we achieve this level of revenue generation, it would place BRINSUPRI among the most impressive launches in our industry's history. We believe that we are setting a new standard for drug launches with BRINSUPRI, which is why we intend to open our playbook and share a lot of detail with you today regarding the metrics we are tracking to gauge this launch's success. Sharing these details is meant to simultaneously help you better understand the components driving BRINSUPRI's performance so far and also why we are so enthusiastic about the future of this launch.

As we walk through our dashboard with you, we will highlight the following key observations. BRINSUPRI has healthy organic demand, and we believe we have treated nearly all patients who are ready and waiting for treatment at the time of approval. Payer access is excellent. We have supported a very high percentage of patients through our inLighten patient support program, reflecting strong patient engagement with their treatment. Time to prescription refill rates are ahead of industry benchmarks. Treatment continuation rates remain high.

We are broadening and deepening our prescriber base with a lot more opportunity to continue to drive that forward. And our education and outreach efforts, which have already yielded positive results have really just begun to accelerate.

Let's dig deeper on each of these items and start with a closer look at patient demand. We believe BRINSUPRI's organic demand is steadily growing. To understand what we mean by organic demand, some context is helpful. We expanded our sales force 10 months before approval so they could promote ARIKAYCE and build disease awareness for bronchiectasis. This effort drove significant interest and helped to build a base of patients who are ready and waiting for a new treatment option at the time of BRINSUPRI's launch. This included nearly 70,000 self-identified patients who registered on our website before approval. The vast majority of whom were being managed at larger institutions, which were involved in our clinical trials and very familiar with BRINSUPRI.

Some of those physicians even shared with us that they were maintaining lists of patients for whom they wanted to prescribe BRINSUPRI when it was approved. By proactively doing this early work, we were able to successfully accelerate new patient demand into the early part of the launch.

As we noted at the time we launched, larger institutions typically take a few weeks to a couple of months to add new drugs to their electronic medical record systems before prescriptions can be written. As a result, most of these ready and waiting patients receive prescriptions in Q4 and to a lesser extent, in Q1. We estimate approximately 3,500 such patients were embedded in the 9,000 new patient starts we saw in Q4, which is supported by comparing the elevated Q4 prescribing volumes at these institutions to the steady pace we have seen in recent months.

Similarly, in Q1, we estimate that about 1,500 of the roughly 7,800 new patients who started treatment in the quarter were part of this ready and waiting patient group. As we enter the second quarter, we believe this surge from ready and waiting patients is now complete. What remains is organic demand, and that demand is growing. In fact, we believe we have seen a steady increase in organic demand in each quarter since we launched as illustrated by the dark blue boxes on this slide.

While total new patient additions in Q1 came in lower than Q4, this was due to a significant influx of ready and waiting patients in Q4. Further, the growth that we have seen in the latter part of Q1 gives us confidence that BRINSUPRI's organic growth is really just getting started. The second quarter will be the first period that we believe will not benefit from a component of ready and waiting demand, but we expect organic new patient demand to continue to grow sequentially from Q2 through the rest of the year.

Now before we move on to discuss other launch metrics, I want to add a word about Symphony script data. We have noticed that Symphony TRx data has historically been valuable as a directional predictor for total dispenses for BRINSUPRI. Having said that, Symphony NRx data has not been as helpful in predicting new patient starts, and we don't know if either measure will be helpful in the future, but it's worth calling out that Symphony TRx has been proportionately well aligned with reality in past periods.

Another crucial component of any healthy launch is a favorable payer access environment. Initially, in a world without established policies, payer approval rates tend to be higher. Our strategy at launch was to focus physician prescribing and payer access on patients with 2 or more exacerbations where payer approval would be most favorable. As a result of this strategy, I'm pleased to say that the initial expected high rate of payer approval has continued. In fact, the approval rate for patients processed through our specialty pharmacies has been impressive at nearly 90% since launch. Also encouragingly, the time required for payer approval, while inherently variable has been less than a week for the majority of patients so far, which is well ahead of our internal benchmarks.

Overall, we are extremely pleased by what we have seen in terms of patient access to date. These strong approval rates are aligned with our ambition to make access to BRINSUPRI as frictionless as possible for patients.

Now just as important as getting patients access to treatment is supporting their successful use of the medicine. We are pleased that more than 80% of patients on BRINSUPRI have signed up for our inLighten patient support program, which is designed to help patients navigate the practical aspects of initiating and managing treatment with a specialty therapy. Separately, we continue to hear feedback from patients that they are feeling better on BRINSUPRI. This positive patient experience, coupled with BRINSUPRI's favorable safety profile are together driving the very high compliance rates and relatively low discontinuation rates that we have observed thus far.

To be more specific on each of these measures, a reasonable industry benchmark for compliance is that a patient would refill a 30-day prescription around every 37 days. This accounts for practical logistics like remembering to take each dose on schedule and order the next prescription as well as the time it takes for the medicine to be delivered. So far, we have seen BRINSUPRI prescriptions refilled at a much faster pace, nearly every 30 days, which we believe speaks to patients' positive experience with the treatment, motivating them to continue therapy with minimal interruption.

Turning to continuation rates. As with any treatment, there will always be patients who choose to stop taking their medicine. Daily oral tablets generally have higher continuation rates in the real world than many other classes of medicine. Well-tolerated oral medicines like generic statins, see around 70% of patients remaining on therapy at 6 months. So far, BRINSUPRI's continuation rate is tracking slightly above these analogs. Overall, we believe this high continuation rate adds evidence that patient experience with BRINSUPRI is largely positive.

Our area of greatest focus is continuing to deepen and broaden BRINSUPRI prescribing. In terms of broadening the number of physicians who have written a prescription for BRINSUPRI, we feel we are on a very strong trajectory. As of the end of the first quarter, our cumulative total writers topped 5,000, which accounts for more than 1/4 of all pulmonologists in the U.S. There remain large institutions who still have not written their first prescription for BRINSUPRI, so there is plenty of opportunity to expand that prescriber base.

We also see significant opportunity to increase prescribing depth. At the end of December, approximately 1,800 physicians had prescribed BRINSUPRI to only one patient. By the first quarter of 2026, roughly half of those physicians have prescribed it to at least one additional patient. We believe this trend represents our greatest growth opportunity, which will be reinforced by the consistently positive feedback we hear from patients and physicians about their experience with the medicine.

As awareness continues to build and patients share their experiences during office visits, we expect physicians will grow more comfortable prescribing BRINSUPRI, naturally accelerating its use.

In addition, we are encouraged by the fact that more than 20% of BRINSUPRI's prescribers have written it for at least 5 patients. And importantly, this group goes well beyond just physicians in large academic centers. This represents both the progress we have made on deepening prescribing and also the opportunity that is still in front of us to potentially expand prescribing among the remaining 80%. We anticipate the dialogue within the treating community facilitated by gatherings like the American Thoracic Society Meeting, which kicks off later this month, could further encourage physicians to trial or expand their prescribing behaviors as news of positive patient experiences spreads.

Collectively, we see expanded prescribing from existing trialing physicians and broadened physician adoption as 2 positive trends, which, if extended, could enable even greater growth than is suggested by the current $1 billion-plus guidance we have reiterated today.

We are also accelerating our work to increase awareness and proper diagnosis of bronchiectasis through appropriate education. Just yesterday, we announced the launch of a new diagnosis-focused disease education campaign called Suspect BE. This campaign features Emmy Award-winning TV host, Ty Pennington, and draws on his personal experience of caring for his mother who has lived with bronchiectasis for more than 40 years, including an extended period of time before she received the appropriate diagnosis.

We also have plans for direct health care provider education and medical congress presence later this year to further support these efforts.

From our point of view, we believe now is the time to elevate disease awareness to enable earlier and more accurate diagnosis of bronchiectasis.

I'd also like to highlight the recently announced initiative from the American Thoracic Society aimed at addressing the underdiagnosis of bronchiectasis in the U.S. This ATS initiative will analyze electronic health records across 7 large academic medical systems to identify potential patterns of misdiagnosis. Based on these insights, the ATS initiative intends to pilot scalable solutions such as electronic health record-based prompts that automatically flag potential signs of bronchiectasis and continuing medical education modules for physicians to help improve the detection of bronchiectasis. Importantly, it also intends to determine how many patients within these medical systems are currently diagnosed with COPD or asthma and may also have undiagnosed bronchiectasis.

We commend ATS for leading this effort to identify a potentially large and underserved population of COPD and asthma patients who may also have bronchiectasis, but have not been diagnosed. By improving recognition, these insights could drive better outcomes for current and future bronchiectasis patients by increasing the likelihood they will be appropriately diagnosed and gain access to care sooner.

In summary, we see strong and growing organic demand. Payer access and patient compliance and continuation rates are exceeding expectations. We see further opportunity in broadening and deepening physician prescribing, while other groups like ATS are taking the initiative with new and significant efforts to raise awareness and improve diagnosis of bronchiectasis.

Let me now shift to ARIKAYCE. Remarkably, ARIKAYCE continues to show year-over-year growth even now in its eighth year of launch, targeting only refractory NTM MAC patients. In March, we announced the clinical success of the Phase IIIb ENCORE trial in newly diagnosed NTM MAC patients, a far larger population than refractory. ARIKAYCE, in combination with a multidrug treatment regimen, delivered a statistically significant outcome on the patient-reported respiratory symptom score primary endpoint compared to the multidrug active control arm. This end point is the most important factor for U.S. regulators.

The ARIKAYCE arm also demonstrated earlier, greater and more durable culture conversion throughout the study with statistically significant benefits at every prespecified time point, including at month 15 or 3 months off therapy, which is the most important factor for Japanese regulators.

Importantly, the ENCORE data make a very compelling case for using ARIKAYCE earlier in the treatment paradigm for patients with an NTM MAC lung infection. As a reminder, in our Phase III CONVERT study in refractory NTM MAC, we observed the treatment with ARIKAYCE resulted in about 30% of patients clearing the bacteria from their sputum after 6 months on treatment. ENCORE showed us that if you treat earlier, you can convert well over 80% of patients to negative sputum cultures in that same period of time. And this conversion is likely to be durable.

ARIKAYCE was also better tolerated in the earlier NTM MAC lung infection setting with much lower rates of discontinuation compared to the CONVERT study. Now that we have these data and a well-defined target product profile, we will be conducting market research to understand how the product might be perceived and used by the prescribing community, which will give us a clearer view of the opportunity.

We are working to submit the ENCORE data to regulators in the U.S. and Japan in the second half of this year. If successful, these label updates could increase the addressable market for ARIKAYCE from around 30,000 patients today to more than 200,000 patients next year, potentially turning ARIKAYCE into a blockbuster brand with no new competition on the horizon of which we are aware.

Let me now turn to TPIP. TPIP represents a very substantial late-stage opportunity where we are pursuing 4 Phase III trials with very meaningful addressable patient populations for each. We are very excited to announce that last month, we opened our first site in the Phase III PALM PAH study of TPIP. Based on the FDA's feedback, this study, if successful, will be the only registrational trial required for potential regulatory approval for the treatment of PAH. Additionally, data from our Phase IIb 24-month open-label extension study in PAH is now expected in the third quarter of this year and will include safety and certain efficacy measures through the first 12 months of the open-label period.

As a reminder, this OLE gave investigators the option to continue to increase the dose of TPIP beyond the 640-microgram maximum dose allowed in the initial Phase IIb trial. During the OLE, we have not required or encouraged uptitration. That said, we are pleased to report that about 1/4 of the participants in the OLE have achieved doses that are higher than the 640 micrograms, and that 7 out of the 91 patients who entered the OLE have gone on to reach the new maximum dose of 1,280 micrograms.

Given the absence of a placebo group in this open-label portion to which we can compare TPIP's effects, a good outcome for this update in our view would be to see that patients are able to sustain the best-in-class improvements in 6-minute walk, NT-proBNP and functional class measures that were demonstrated in the 16-week randomization portion of the trial over this much longer treatment period. For those who have increased their dosage since starting the OLE, we would want to potentially see some discernible improvement in those efficacy measures compared to what was shown in the randomized trial, along with a consistent safety profile with what we've seen in the Phase II trials.

We will also be interested to see the impact of treatment with TPIP for the patients who are initially randomized to the placebo arm of the trial. We look forward to sharing these data once available.

Moving now to our other 3 TPIP studies. In the ongoing Phase III PALM-ILD study, we are encouraged by the trial's progress with patients having been randomized in 7 different countries so far. We are also pleased to see that we are recruiting patients even in the U.S. despite competition from other marketed treprostinil products that could discourage physicians from enrolling patients into a placebo-controlled trial. We believe this willingness to enroll patients reflects excitement for the clinical trial results shown for TPIP to date, given that doctors know their patients will gain access to TPIP either at the start of the trial for those randomized to the TPIP arm or after the 24-week study period completes for those who are initially randomized to the placebo arm.

We believe this represents a very positive early sign for future adoption should the medicine continue to show positive results and gain regulatory approval.

We also continue to anticipate initiating a Phase III study in PPF in the second half of this year to be followed shortly thereafter by a study in IPF. Recent positive clinical data in IPF from another treprostinil product has added to our enthusiasm about the potential opportunity for TPIP in both PPF and IPF. The mechanism by which benefit may be seen in these patient populations is not fully understood yet, but it is believed that treprostinil demonstrates its antifibrotic effects via multiple pathways, including inhibitory impacts on fibroblasts and that those effects may be dose dependent.

As a result, we believe TPIP may be more beneficial by virtue of being able to deliver a greater dose of treprostinil. In this way, we think TPIP could represent the optimization of treprostinil therapy, enabling continuous delivery of much higher doses of treprostinil directly to the lung using once-daily administration.

As a result, since treprostinil has now been shown in other studies to deliver positive results for patients with IPF, we believe TPIP has the potential to provide even greater benefits for those patients.

So let's recap. In a year that will be defined by execution, we remain focused on delivering across our commercial and late-stage clinical programs. BRINSUPRI is setting the bar for commercial success with exceptional progress across each of its key launch metrics, keeping us on track to achieve our ambitious full year revenue guidance of at least $1 billion in global net revenues. ARIKAYCE continues to grow in its current indication. Looking ahead, we see the potential for substantial growth next year if the FDA and PMDA approve a broader label for all MAC lung infection patients in each of these regions. And for TPIP, we have recently initiated our Phase III study in patients with PAH while continuing to enroll patients in our ongoing PALM-ILD study and finalize our trial designs for PPF and IPF. We anticipate announcing data from our open-label extension programs in PAH in the third quarter of this year.

I have not spent any time today on our pipeline beyond our 3 most advanced programs, but these continue to progress as well. INS1148, INS1033 and gene therapies for DMD and ALS are all advancing to or in the clinic, and we look forward to future updates about these programs as clinical data becomes available. We believe in continuing to build out our pipeline through research and select business development and efforts in both areas continue at a robust pace.

With that, I'd like to now turn the call over to Sara.

Thank you, Will, and good morning, everyone. Based on the strength of our performance so far in 2026, I am pleased to reiterate our guidance for this year, which can be seen on this slide, including full year revenue and gross to net guidance for BRINSUPRI and ARIKAYCE. I would add that the actual gross to nets we saw for both products this quarter also fell within these respective ranges.

Let me now spend a moment on our cash position. As of the end of the first quarter of 2026, we had approximately $1.2 billion in cash, cash equivalents and marketable securities. Excluding cash received related to stock option exercises in the period, our underlying cash burn for the quarter was within the range of quarterly burn that we have seen over the past year. We believe this burn will continue to decline as company revenues ramp at a quicker pace than spending in the future.

Importantly, we continue to believe we can achieve cash flow positivity without needing to access additional capital to support our existing business. Presuming we do not add to our expense base through business development, we would expect to achieve sustainable cash flow positivity in 2027.

Now moving to other relevant financial metrics for the first quarter, which are displayed on this slide. Cost of product revenues in the first quarter of 2026 was $47.4 million or 15.5% of revenues, which is lower on a percentage basis than our historical performance, reflecting the positive contributions of BRINSUPRI to the company's gross margin profile. Additionally, as expected, research and development and SG&A expenses increased this quarter compared to the prior year period due to the necessary investment made to support the U.S. launch of BRINSUPRI and to continue to fund our pipeline.

In closing, Insmed continues to execute, both clinically and commercially and remains in a strong financial position, providing us with the capacity to pursue our ambitious goals on behalf of patients and to maximize the opportunities for value creation we have ahead.

We would now like to open the call to questions. Operator, may we take the first question, please?

[Operator Instructions] Your first question comes from the line of Vamil Divan with Guggenheim.

Thanks for details on the launch. It seems to be going well. So the question we're getting, I think, just because of the additional detail you provided is how to think about sort of the sequential growth from here. I know you don't give quarterly guidance, but I know you reiterated your views for the full year. But just given some of these dynamics with maybe this initial bolus of patient and now the more sort of organic demand, if you can provide any visibility on how we should think about sort of 2Q, 3Q, 4Q, especially given some of the unknowns around 1Q? And all the issues that we sometimes see in this quarter, that would be very helpful.

So I know I'm going to disappoint by not providing a forecast on a quarterly basis other than what we said in our comments, which is that we expect organic demand to grow from Q2 throughout the rest of the year. What I would tell you about the inbounds that we've had, are you going to raise guidance? Are you going to adjust peak sales, all those sorts of things. We have 2 quarters under our belt, and we are a cautious company, as you all have learned by now. So while we are extremely enthusiastic about the performance we see here, and importantly, a lot of the metrics we're covering today are designed to convey the notion that the fundamentals are being put in place for what will be a sustained growth of this product launch. I think it's the breadth, it's the opportunity for additional depth and all of the metrics being above our respective targets that gives us that enthusiasm.

So there may be a time when we want to come back and explore what those peak numbers are. I just think after 1 quarter in the year, the calendar year, it's a little premature. And we only have 2 quarters under our belt. But I do want to just remind you that in the first 2 full quarters, we've done $350 million of revenue, which, by any measure, is an impressive result.

Our next question comes from Ritu Baral with TD Cowen.

Another one on BRINSUPRI dynamics. Will, any thoughts on right now, whether breadth of prescribers or depth of prescribing within prescribers is more important to increasing demand? And as you think about that depth, what are you finding that drives that depth? Is it just sheer patient experience, the number of months that the Sentinel patient is on the drug? Is it detailing? Is it just patient flow thoughts?

Yes, sure. So look, I think both are important. When we look at breadth, we know that we've already reached 25% of all pulmonologists that have written -- they've already written at least one prescription. So I think it's important to highlight that, that includes not just large academic centers, but we are already successfully in the community physician pool and convincing them to -- this is a prescription they want to write. That, to me, is a very positive sign because the sustained growth will come on the back of those physicians being participants here.

We know that our Tier 1 call points have at least 100 patients and in some cases, more each. So when we talk about 1,800 physicians who have written one prescription in the fourth quarter, and half of those have written at least one additional prescription in the first quarter set against what that Tier 1 profile looks like, it gives you some sense of the enormous opportunity that is available to us in terms of depth. I think depth will come our way. It may take a little longer than we would like in the sense that we love for everybody to be writing this for 10 or 50 of their patients. But pulmonology community we're learning, particularly for this disease, where there's been nothing approved for more than 200 years since it was identified, are slow to adopt the new novel mechanism of action, and they're a little bit cautious. The good news is that the medicines profile has resulted in feedback that is very positive. Patients feel better on the medicine, and it is certainly doing a job consistent with what was seen in the Phase III data.

That, to me, is the critical element. If you look at strong blockbuster launches, almost all of them share the common feature that the medicine's perception in the early days was very positive, and we're fortunate to be able to enjoy that kind of a status. So as physicians have more experience with the medicine, I think they will naturally turn to write the prescription more frequently. They certainly have the patients. The need is clearly there. We intend to draw attention to this dynamic through our communications efforts, and I am very bullish that whether it's in the next months or quarters, we are going to see organic demand kick up as physicians shift from a mindset that this is a novel medicine that they are going to consider using to this is the default medicine for the treatment of bronchiectasis. And I think that dynamic is going to be very powerful.

The next question comes from the line of Joe Schwartz with Leerink Partners.

Thanks for all the great color on the BRINSUPRI launch. Where do you see the organic demand coming from most now and going forward? Community or academic practices, the KOLs that many of us speak with at the experienced bronchiectasis centers seem to have prescribed BRINSUPRI to many of their highest need patients and note that community palms are still often referring patients to them. And as you think about the durability of the launch, what evidence are you seeing that this isn't likely to be a bottleneck and community physicians are moving beyond first prescriptions towards repeat independent prescribing?

Yes. So this is really important. When we talk about the academic centers, and we talk about ready and waiting demand, what we tried to articulate in the commentary was this notion that it was very clear in the fourth quarter that the physicians at the academic centers were waiting for the electronic medical records systems to update at their institutions before they could write prescriptions. How do we know this? Because 1 week, there were no prescriptions coming from the institution and the next week or 2 weeks thereafter, we saw literally hundreds. So it is the arrival of that ability to prescribe using the electronic medical system that enables that turning to the list of patients that they had in many cases and addressing that demand. And that is what we refer to as the ready and waiting components of the 70,000 folks who have registered on our website.

We look at the first quarter in comparison to the fourth quarter, and we see a steady state and cadence at those larger institutions that may have exhausted their initial lists, but that steady state continues. And importantly, there are many institutions who have yet to write a single prescription. And as we tried to highlight, even though we've already reached 1/4 of all pulmonologists, the vast majority of those have not written multiple or scores of prescriptions, and many of them have that kind of patient count, in fact, almost all of them.

So there's a lot of breadth and depth opportunity here, but I would say depth is the one that I'm more focused on. And I would just refer to sort of 3 dynamics in the launch itself and its durability. The first is the basic blocking and tackling that we've gone into in detail today. How do you execute a launch well? And I think continuation rates, refill rates, all the sort of stuff that we've gone over in detail today, payer access, inLighten support, all that is extremely positive. So the basic blocking and tackling is going well. The commercial team and the customer-facing part of our organization has done an exceptional job in executing on those basics.

The second dynamic is the one we were talking about a moment ago, which is that physicians will ultimately adopt this as the standard of care for bronchiectasis. As that process takes hold, it's less about the promotion and communication interaction and it becomes more the default practice of the pulmonologist to write the prescription. When that starts to take hold, then it will be the volume and traffic through the office that will generate prescriptions and less of the promotional side.

And then the third and final substantial contributor to this launch over the middle to longer term is the comorbid populations that have yet to be appropriately diagnosed. Those are COPD or asthmatic patients who may also be bronchiectatic and would fill the top of the funnel in very large numbers. And so there's some efforts underway to raise awareness about that, not just our own, but those made by ATS.

The combination of all 3 of these things, I think, paints a very robust picture for the potential of this drug in the next quarters, but also the coming years.

Our next question comes from the line of Jessica Fye with JPMorgan.

I was just wondering how you're estimating which patients were ready and waiting versus which fall into that organic demand bucket? And yes, I appreciate all the detail on the patient adds this quarter. Should we continue to expect to get patient metrics?

So on the ready and waiting versus organic, this is always a little bit of a tricky business because it's not as if someone shows up and it self-identifies as one or the other. But what we try to do, as we described, is triangulate through a couple of different measures. The expected yield from the 70,000 registered patients on the website, the behavior of patients at the large institutions and the lumps that came through clearly once the electronic medical record system was cleared and then the steady state that we've seen over the course of the fourth into the first quarter. And I think we also had an anticipation that this would be the case, and it was contained within our own modeling. So we've triangulated through all of this to arrive at the numbers that we shared today, roughly 3,500 in the fourth quarter and roughly 1,500 in the first quarter as ready and waiting patients.

We continue to see organic demand improve throughout the first quarter. And I think as we go through from Q2 through the rest of the year, we certainly expect that will continue. So I think those dynamics are all positive. What was the other part of your question? I can't remember what it was?

If we're going to continue to provide patient numbers.

Well, patient numbers, yes, that's why I forgot it. No. So I would say what we are trying to do is provide the best approach to transparency so that you can model and understand the fundamental dynamics of the launch. That may or may not include patient numbers, it really just depends on the dynamics that are unfolding, but hopefully, today, you've understood that we are quite genuine in our ambition to make sure you understand what is driving the launch and why we have the enthusiasm we do for where we are.

Our next question comes from the line of Jason Zemansky with Bank of America.

Congrats on the solid progress. Will, you've spoken about potential in the COPD and asthma patients. But I was hoping you can provide a little more color on what gets you there? In terms of the potential friction points, is it just awareness? Do you see any pushback from payers? Do you see any, I guess, unwillingness from prescribers to expand the polypharmacy in these patients? I mean what drives you to that population?

So we know from our own clinical trial work that roughly 15% to 20% of patients in the ASPEN trial and the WILLOW study were comorbid with asthma and COPD. And those patients responded just as well as those that did not have those comorbid indications. So the presence of these patients, their existence is understood. It's not documented to a refined degree. And as a consequence, the literature is sort of all over the place as to what percentage of COPD patients, for example, are also comorbid with bronchiectasis, and what percentage of those patients have had 2 or more exacerbations and are continuing to be symptomatic because those are the low-hanging fruit that should definitely be on the top of our funnel. How do we get there?

We get the pulmonologists or the primary care physicians, whoever they are, to refer them for a CT scan to look for the diagnosis of bronchiectasis. Once that has happened and a pulmonologist has done a workup on the patient, they're eligible for treatment, and they are on label. And so that process, we think, is going to take some time, but I think we're going to get there. And I'm very excited about the potential for these patients.

In the U.S. alone, there are roughly 20 million COPD patients. And when we speak to KOLs, they estimate somewhere in the 20% to 40% range are comorbid with bronchiectasis. Now some smaller population of that are experiencing exacerbations despite on max treatment, and it may be that they're misdiagnosed. It may be that they are comorbid. We don't know, and honestly, we don't really care. What we want is for them to get the appropriate treatment and if BRINSUPRI can play a role in helping them, we certainly want to facilitate that. But I think that serves as a top of the funnel feeder that is quite substantial, and it may take time to bring it about, but we are investing in it almost like a second launch within the company with dedicated people focused on that area, and we think that's going to yield benefit over time. So we're pretty excited about that.

Our next question comes from Gavin Clark-Gartner with ISI.

So I wanted to ask on the discontinuation rate in a very specific way. For the 11,500 patients who started on therapy by the end of 2025, for that same cohort of patients, how many were still on paid therapy at the end of the first quarter? Because in order to square the revenue versus the strong new patient starts you reported, I'm seeing there's probably 2,500 or more discontinuations from that cohort, which is in the 22% to 25% realm for a 6-month discontinuation rate. So I'm wondering if that's roughly on track with what you're seeing? And if we should be expecting that same rate of discontinuations moving forward? Like should we expect 40% discontinuations in a year? Any clarity there would be really helpful.

Yes. It's hard to walk through the particular math that you're framing out here because I want to make sure that we're conveying accurate information. What I can tell you is that -- and I'll invite anyone else in the room to comment on this. What I can tell you is that we are tracking above trends for small molecule product use in terms of discontinuation rates. Statins are around, I don't know, 2%, 3% per month that tend to drop off. And the dropout rate is heavier in the first 6 months than the second 6 months, typically. So I think we feel like we're well ahead of industry benchmarks there. I don't know if we can give greater clarity. Would you...

Yes. The only other thing I would comment on is, in the prepared remarks, Gavin, we shared that statins had continuation in the first 6 months of around 70-ish percent. If you look at that over 12 months, it's about 60%. So as Will said, if you're going to have discontinuations, it tends to be earlier, but you do continue to see a level of discontinuations with statins.

So hopefully, those numbers are helpful. I can't go through the particular calculations you're running over the phone, but we'd be happy to do that at sidebar. But in the meantime, I would just draw attention to that discontinuation rate that we've cited for statins and indicated that we're slightly ahead of that, which is about as good as you can hope to do.

Our next question comes from the line of Olivia Brayer with Cantor Fitzgerald.

Yes, I appreciate the color around new starts and underlying demand. Sorry to ask another follow-up here. But the fact that you guys are pointing to sequential growth, I actually think is a really positive sign for 2026 numbers. So maybe a couple of questions there, is where is that confidence coming from? I'm assuming you're seeing some good growth in April trends? And then how long do you actually expect that sequential growth to continue until you start to see some of those new starts level off?

And then I hate to ask a competitor question, but on TPIP, how quickly do you actually think you can enroll some of those studies like PAH in particular? I only asked given some disclosures yesterday around trying to expedite a once-daily DPI program from United.

Yes, sure. So on the sequential growth point, what I would describe for everybody is that there is a massive opportunity that we still have before us with physicians, large practices, community docs and many, many patients, even within practices that have already written prescriptions that are available to us to access. So the opportunity for growth remains and will be there for some time. It's typical that in launches, you see companies get to a steady state after a certain period of time. You can look at the analogs to sort of define where you think the average is. But we would expect certainly to follow that sort of a profile, maybe a little bit better because of the opportunity that we think is before us. All of the metrics we've defined speak to the execution excellence of the team, and I think portend very positive things for when we're able to get those patients into the funnel in terms of our ability to execute and bring them through.

I do think that our efforts in terms of communication and advertising and those sorts of things are going to amp up materially from here. And it takes time to get that stuff through the FDA and cleared and set up once we understand the launch dynamics. We are in that place now. And the Ty Pennington campaign as an example, is the first of what will be additional efforts made to raise awareness. And I think that will activate what is already a very vocal population of patients and probably drive additional demand. So lots of different vectors that give us this confidence. It starts with the capabilities of the team to execute, but it is complemented by the enormous availability of additional patients and physicians and all of the different efforts we've made to raise awareness and bring people into the funnel.

On TPIP, the enrollment timing, we're going to go as fast as we possibly can. We have a good track record of accelerating our enrollment in trials better than standards, certainly in the industry. And I would expect that to be the case here. We tried to highlight today that we're already hearing some positive feedback from physicians even in the U.S. where there are available approved treatments for their patients. They're choosing not to put them on that treatment and instead putting them in our trial where their patient may be on a placebo for 6 months. So I think that speaks to the enthusiasm that is in existence already for our medicine and what it may be able to do for these patients.

A comment on the other programs that are out there. I'm sure we're going to see a lot of talk about different programs and what they may be able to do. We are all about the data. And the data will lead the way, certainly for the physicians and the treatment of their patients, and the data we have so far is second to none in this category. So I think as long as that continues, we're going to be in a very strong position. The sooner we can get it out there, the better for everybody. The fact that we have to run through Phase I, II, III programs is because this is a novel differentiated compound. It is not a copycat, it is not a rewarmed version of an already existing drug. This is a very different drug that is breathed in inertly and then becomes active once in the lung. It has longer residence time, has a lower peak, a longer trough, once-daily coverage for patients, including nighttime with really excellent results.

So I think its profile is very distinct from everything else that is in the prostanoid class, and we hope that, that will continue.

Our next question comes from the line of Ellie Merle with Barclays.

Can you elaborate a bit more on sort of the half of the single patient prescribers in 2025 that have not written an additional script in Q1? I guess why do you think that was the case? And are there any indicators that, that's changing? And I guess, from the organic growth that you've seen in 1Q, I guess, what is the mix that's coming from some of these higher volume prescribers versus some of these sort of like lower volume writers?

Yes. So the half that have not written, there's an interesting dynamic in this therapeutic area and with these particular physicians. There's a conservatism, I think, that is now in evidence with the new mechanism of action and a new treatment for a disease that they've known about forever, but for which they've never had a treatment. And so I think what we've seen is great physician engagement. We have 1/4 of all pulmonologists who've already written a prescription. So they've crossed the hurdle or the rubicon of being willing to put their patient on the medicine. We now have to have the cycle of time take place where they go and they are on the medicine for perhaps 3, maybe as long as 6 months before they come back through the office and tell the physician of their experience.

We are hearing a flood of positive feedback, and we read it in the social media as well. And it's not universal, but it's pretty overwhelming. And I would tell you that, that, I think, is the most powerful motivator for these physicians to write again. When they hear that 1 or 2 of the patients they put on medicine have had a good experience, they want to write again and more broadly, and that becomes a narrative and a dialogue that they share with their peers at places like the American Thoracic Society. So I think we're going to see this pick up throughout the year as physicians who have trialed the medicine have success and get good feedback from their patients and decide to continue to write prescriptions for others. Once they're over a hurdle, I don't know what the breakpoint is, a couple, 2, 3, 5 patients perhaps, we think that the rest of their practice is going to pick up. And so that just provides a really interesting opportunity for us.

We haven't really broken out the organic versus -- between the high writers and the lower writers, that's even harder to discern, but what I would say is it's across the board. The vast majority of the ready-and-waiting patients came through the large centers where physicians had lists of patients and those are the ones that are easily identifiable as, if you will, ready and waiting versus those who are steady state. So hopefully, that's helpful.

Our next question comes from the line of Graig Suvannavejh with Mizuho.

We've got ATS coming around the corner. I know that the ATS put out a statement just on new efforts to improve diagnosing of patients. I was wondering if you could comment just on how much of a potential springboard ATS might be, particularly from a prescribing perspective. And if you could also remind us of past comments that you've made around how maybe AI can help with increasing diagnosing of patients?

Yes. So there's going to be a lot -- we're going to be quite loud at ATS, as you might expect, and also ERS and other academic meetings. And I think you will see both positive feedback stories that are shared by physicians from their experiences just in the hallways, but also a very deliberate effort to talk about the disease, raise awareness. We certainly will have a big presence in that regard. I think what ATS usually represents, you asked if it's a springboard, you take physicians and patients -- or pardon me, physicians and our commercial-facing group out of the market for a week, you tend to see a little bit of a drop during that week because of that, but then it tends to accelerate in the aftermath. How much? We don't know. But again, we pointed to the Symphony data, TRx has been fairly accurate for what we've seen proportionately in our own tracking. So hopefully, that may be something that can give some insight.

With regard to AI, we are looking at a number of different ways to bring that to bear, most prominently in the area of examining historic CT scans and also doing sort of audits of patients -- patient records to try to understand what the diagnosis rate and identification of these patients might be able to be in a world where we bring that to bear in a more broad basis.

I think you could expect us to be talking about a lot of different programs running in parallel to try to raise awareness and identify the appropriate patient and help with the diagnosis. And AI certainly is going to play an important part in that, not just for bronchiectasis, but generally. Hospitals are looking to bring that into the radiography field to help them get to more accurate and timely diagnosis.

Our next question comes from the line of Matt Phipps with William Blair.

I appreciate all the additional color today. At the beginning of this year, you all cited a couple of potential risks to the launch as hypotheticals, including particularly more stringent payer contracting, more prior auths, things like that, that could come into account some point in 2026. First quarter, it doesn't look like that was an issue, still getting good payer coverage and time lines to dispensing. But just curious as you're now 5 months -- getting into 5 months into the year, if you still see that as a risk at some point this year? Or if you think you're at a good point with payer contracting that, that's not a concern?

Yes. So through the specialty pharmacies, we've seen an approval rate of 90%, which is extraordinary. Now we don't expect that, that will sustain for the entirety of the launch. In fact, typically launches, you see that tend to trend down over time. We'll have to see where it goes. But I'm still very excited to be in possession of that kind of an approval rate. I think that speaks volumes about the perceived value of the medicine as well as the physician desire to push to ensure that it gets approved.

Collectively, that lays a very positive forward view for where we may be able to go. I don't think there's as much risk for us in the payer approval collapsing, if you will, because of contracts and policies that are finally put in place. Many of them already have been put in place, more will come, but the point of that is because at the outset, we were focused on the moderate to severe patient for approval, there is not a big shift in what those policies will result in, in terms of holdback of patients. In fact, it may accelerate in some cases, the approval process. So one of the things we're trying to highlight today is that while whenever you start a medicine, it's always medical exception in every way, and you get higher approval as a result without a lot of scrutiny. Because of the way we channeled physicians and focus people on 2 or more exacerbations, we haven't seen a material decline with the implementation of these new policies. So that's a very positive thing.

Our next question comes from the line of Leonid Timashev with RBC Capital Markets.

I wanted to ask on the international side and MFN. I know historically, you guys have been very conservative on how to approach an international launch. Just curious sort of what your latest thoughts there are? How much you expect some of these other governments to work with you around pricing? And then just given the discussion we've had around sort of the ready and waiting patients, how much of that dynamic you might be seeing in other geographies?

Sure. So the interesting thing about MFN is, it does -- it has caused us to pause our launch efforts in Europe and the U.K. We are approved -- BRINSUPRI is approved for use in Europe and the U.K., but we need to be very cautious because the normal logic for selling in those regions is that if you can sell above the marginal cost of production of your medicine, it makes financial sense to do so. It is not intended to be a way for us to ensure that Europe pays the same that the U.S. does. We do not hold that bargaining power. We have 2 medicines that are approved. If I go to Germany and insist that they pay more for the medicine, they're simply going to say no. So we're not in a position to extract a higher price abroad than what we get currently from them.

I think the pressure that's being brought to bear is causing Europe to reconsider some of those positions. But there's not a lot we can do about it, to be blunt. And so that puts us in a place where, if there's a risk that someone is going to import a price control into the U.S. at a fraction of what we're currently able to command based on the impact that is positive for patients, then that's something we simply cannot permit to happen. So we have 2 choices. We can either try to get a much higher price, which we do in Europe, or we sell -- we don't sell the medicine abroad. And in the latter case, I don't think that really serves anyone's interest because the intent behind MFN was to lower prices in the U.S. And at least for the mid-cap biotech companies, that's not going to be the result. The result is we simply won't sell the medicine abroad. And then the copycat medicines that are made in China are going to take our place. And then the result of MFN will be to bankroll the Chinese biotech market, which I don't think is really in anyone's interest.

I appreciate and align with the notion that it is frustrating for Europe to pay far less than what the U.S. pays for the medicine, but we are not in a position to force them to pay more. And as a consequence, we have to be very cautious.

Practically speaking, we will wait for clarity on where MFN is going to go in the coming months, and that will inform whether or not we're able to move forward as we would like to. Because the goal of the company is to make its medicine available to those patients who can benefit from it. And we need to work within the financial constraints that exist in these other countries, but we can't dictate them. Certainly, we think of Japan as a very exciting market opportunity. Europe has a role to play as well, but we need to sort of get to the heart of what MFN is going to be and how it's going to operate first.

Our next question comes from the line of Danielle Brill with Truist Securities.

I wanted to ask on -- a follow-up on discontinuations. Of the discontinuations that you are seeing, can you comment on what's driving them? Like what's the relative contribution of Medicare out-of-pocket resets and payer dynamics versus other variables? And then given the recently unveiled competitor programs, how important is it for TPIP to now demonstrate enhanced efficacy to support the thesis?

We don't really have a breakdown of the reasons for the discontinuation that we can share today. We can step back and take a look at that and see if there's commentary we can provide, so we'll do so. But there isn't something I can tell you right now about the profile of discontinuations and where they're coming from. I think that given that they're at -- sorry, that they are above the best benchmark rates out there, certainly, it is not driven by the medicine. I think it's fair to conclude, this is driven largely by patients having other motivations.

When we talk about the competitor programs, I don't -- we're not particularly focused or worried about them at the moment. The Phase II data we saw from the BI program was not particularly compelling in our mind, and we'll have to see what Phase III looks like. It's going to be several years before they're on the market. So we have a lot of room to run here and really to establish ourselves. We'll have to see what BI's data looks like. I want to remind everybody, BI has targeted 30% enrollment of Asian patients in its Phase III program. That is very deliberate. That is -- it is 8% of the population in the U.S. They are over-indexing to that group because as we saw in our trial, the Asian patient population is a hyperresponding group in terms of reduction of exacerbations.

We had a 20% reduction in pulmonary exacerbations in our Phase III results. If we look at the subpopulation of Asian patients, it was north of 60%. So you can expect the headline number coming from BI to be better than ours. Certainly, that's what we would expect given the over-indexing to the Asian patient population. But when we tease through the data and see what is really there, we'll know what kind of profile that product represents.

Our next question comes from the line of Max Skor with Morgan Stanley.

I was just wondering, have you seen any change in the severity mix or overall profile of the bronchiectasis patients on treatment through the early stages of the launch? And as the commercial base builds, how are you prioritizing business development?

So on the mix of profile of patients, as I was commenting earlier, we really focused on those patients with 2 or more exacerbations, and so that continues to be the phenotype that we really want to advance for attention. We think they're going to benefit the most. Certainly, we saw that in our Phase III study very definitively. I don't expect that to change very much. You are right to highlight that our label is much broader than that. It actually is available for any patient with bronchiectasis, regardless of the number of exacerbations they've had in the last 12 months. This is just trying to work with the insurance companies and their policies, which will be focused primarily on those with 2 or more exacerbations.

Prioritizing BD.

Prioritizing BD. So BD, let me just comment on this. I'm a big believer, and we are collectively as a company that the right time to do BD is when you don't need it. This is a particularly interesting time for us because we have 3 programs that are in excellent position to really be blockbusters or in at least 2 cases, potentially mega blockbusters. That gives us a very strong runway for revenue generation over the next 5 to 10 years. We could sit still and do nothing and perform, I think, exceptionally well. The opportunity is to augment our pipeline and to look for ways in which we can leapfrog from our current position into one of greater strength.

We have done that with INS1148 at the end of last year for a very modest investment. That is a novel mechanism of action that we think has potential applicability in multiple disease states. We will look for similar programs like that. We will be certainly developing our China strategy, and we will be looking for other potentially even more substantial acquisitions if they fit all of our criteria, which is, number one, can it provide an asymmetric return opportunity for our shareholders. And that's the #1 criteria we have for BD that we're pursuing. Simply adding a program that targets a single disease is not interesting to me, unless it has the ability to go into broader disease states.

So we may end up doing nothing. We may end up doing a lot. We don't know. What I can tell you is we are very active in looking, and this is a time when there are a lot of really interesting companies and technologies out there that I think are ripe for potential acquisition.

Our next question comes from the line of Faisal Khurshid with Jefferies.

I just wanted to ask you, you cited that the, I think, persistency rate on oral meds like statins at 6 months are around 70%, and that you're sitting a little bit above that. Just wanted to clarify that comment and also ask if you're seeing any meaningful differences that you can tease out between the kind of ready and wait patient population and your organic new demand patient population to the extent you're able to tell?

Yes. So that is, in fact, the benchmark that we're using. The statin discontinuation rate of 70% is at the 6-month mark. After a year, it's about 60%, as you heard Sara referred to earlier, and we are above that benchmark. So we feel very good about what that portends for our -- for keeping patients on drug and of course, the benefit of that that inures to our shareholders.

I think as we think about where we can go from here, we'll certainly continue to emphasize trying to keep patients on drug. I think the storylines that come back from the use of the medicine are going to help support that more than anything. And patients that come into their physicians' offices and report having their life back or feeling better again, I mean we have very dramatic stories. These are not necessarily indicative of how everybody responds to the medicine. I want to be really clear about that. But we do have quite dramatic stories of patients coming in and breaking down in tears and telling their physician how they couldn't take a short walk and now they're out doing a 4-mile hike. So I think there's a lot to like there.

Yes. The only other thing I would comment on is, I'll just remind you of the benign safety profile for this product, and Will mentioned it earlier, but the best launches in our industry start off with really these positive launch dynamics and experiences, and that is what we're hearing and seeing consistently through. And you guys are all seeing it too on the social media posts and just the feedback loop from the patients themselves, and that is sort of the building blocks of really successful launches. And so very pleased with the continuation rate that we've seen. As Will said, we're a little bit better than statins. So we're encouraged by that.

Our next question comes from the line of Adam Walsh with ROTH Capital Partners.

Going into the quarter, your guidance was $1 billion plus for BRINSUPRI, and consensus was at $1.2 billion. What will you need to see to be able to give more granular guidance going forward as we progress through the 2026 quarters?

Yes. I think we always tend to take a conservative approach to guidance. If things -- dynamics are expected to continue to be positive, and certainly, the -- all signs are pointing in that direction, we'll come back and revisit this every quarter. I'm less focused on giving a higher estimate or putting out new guidance and much more focused on the execution. The execution is there, the numbers will come. And I'm just here to tell you that the execution is there.

Our team is doing an excellent job. And my enthusiasm for where this product is in its launch, if it's not apparent by this point in the call, let me be explicit. I could not be happier about where we are. We are in a fantastic spot, not just for the performance in the first 2 quarters, but what it portends for the future because the building blocks for a long-term sustainable growth of this drug in this disease indication, they're all there. And that's probably the thing that's the most exciting about what we've seen and why we shared so much detail today.

Your next question comes from the line of Ben Burnett with Wells Fargo.

Just a question on TPIP. Great to hear that higher doses were tolerated in the Phase II OLE. But I guess, is this -- is it fair to assume that this will be reflective of sort of the Phase III doses? I guess really the question is, will patients have enough time to titrate up to those doses as high as what you're seeing in the Phase II OLE?

Yes. So I think they are going to have enough time. We thought about that issue very particularly because the top dose is 1,280 micrograms in the Phase III studies. And our experience and our dialogue with physicians has made it very clear that they do have the ability to titrate up all the way to that max dose should they wish to. It is important to emphasize that in the OLE, we did not push physicians to increase the dose. That was a decision they made completely independently of us. And it was an option that was given, but it was not one that was encouraged or pursued. So what you're looking at is true organic decision-making that has driven these patients up in dose. And as we said, I think a total of 7 of them actually went all the way up to 1,280, which I find remarkable given that 640 was the original max dose of the Phase II study.

So in all of the Phase III studies, we're going up to 1,280 as an option, and there's plenty of time to titrate up to that level. And of course, more drug to date has certainly shown better performance. So that's a very exciting dynamic.

Our next question comes from the line of Andy Chen with Wolfe Research.

Just a follow-up regarding the diagnosis rate and expanding the pie. I know you're very excited about your diagnosis initiative and raising awareness, but that's still very qualitative, and we may not see results until sometime in the future. So can you please provide some timing expectation around this diagnosis expansion? Or maybe, in other words, can you maybe speak more regarding the appropriate industry analogs for this diagnosis expansion?

Yes. It's a difficult question to answer accurately at this stage. I think what we believe is that through these efforts, we should begin to see, in the case of the COPD and asthmatic, comorbid patient populations. And we can look at things like CT scan rates or diagnosis rates of bronchiectasis, like there are lots of little markers out there that we can track to see if they're having impact. I would expect that by the end of this year and certainly more robustly in 2027 that these efforts will begin to result in some positive results. And we would expect to be able to look at that and hopefully share that with you at some point.

I'm not concerned with whether it's the fourth quarter of this year or the second quarter of next year, because the size of this opportunity is so significant, potentially that I think it warrants patience for those patients to come around. And the process here is very straightforward. It's a CT scan and a diagnostic workup by a pulmonologist and the patient is at the top of the funnel. So it isn't that far to go. And I think as we think about low-hanging fruit, many of these patients already have CT scans from their interaction with pulmonologists over the years.

In many cases, they were simply not asked at the -- the radiologist was not asked to look for bronchiectasis. So unless they identified it and sua sponte decided to report it, with no treatment available. There's not a lot of reason to do that. So what does that mean? It means that there's a slew of CT scans out there we can go back and look at retroactively to see if there's evidence of bronchiectasis already, and that is really at the heart of the ATS initiative. They see this opportunity as well. They see the risk of under diagnosis. And so they're running this effort at 7 different centers, and that should yield some very interesting information.

And 1 of their 4 priority goals of this was to be sort of loud in terms of the discovery that they have. So I would look to them as a third party for information as well on diagnosis of bronchiectasis and the potential for underdiagnosis and what that will all look like. So I'm sure they'll have some time lines around their publications and the expectation of that. But end of this year, certainly in '27, I would want to see some evidence.

Our final question for today comes from the line of Ash Verma with UBS.

Can you confirm the 1Q BRINSUPRI gross to net that you mentioned? Is it at the top end of the range, the mid-20s to low 30s? And then just trying to get a sense if there's any other extraneous factor like free goods or if the delta from the sales that you printed and new patient adds is just primarily the discontinuation that you talked about?

So I'll ask Sara to address that.

Yes. So on GTN, what I can reiterate is the guidance that we provided for BRINSUPRI mid-20s to low 30s and the actual for Q1 was within that range. We're not providing additional clarity than that, but we were within that range. Same goes for ARIKAYCE, low to mid-20s, and we were within that range for Q1 actuals.

Thank you, everyone. That concludes today's call. Thank you for joining. You may now disconnect.

Thank you for standing by, and welcome to the Insmed's Phase IIIb ENCORE study of ARIKAYCE in patients with newly diagnosed MAC lung infection not yet treated with antibiotics conference call. [Operator Instructions] I'd now like to turn the call over to Bryan Dunn, Head of Investor Relations. You may begin.

Thank you, Rob. Good day, everyone, and welcome to today's conference call to discuss the top line results of the Phase III ENCORE study of ARIKAYCE in patients with newly diagnosed or recurrent MAC lung disease who have not started antibiotics. I am joined today by Will Lewis, Chair and Chief Executive Officer; and Martina Flammer, Chief Medical Officer. The call will begin with opening remarks from Will before turning it over to Martina to walk us through the results.

After the prepared remarks, the presenters will be joined by Kevin Mange, Chief Development Officer; and Sara Bonstein, Chief Financial Officer, for the Q&A session.

Before we start, please note that today's call may include forward-looking statements based on our current expectations. These statements represent our judgment as of today and inherently involve risks and uncertainties that may cause actual results to differ materially from the results discussed. Please refer to our filings with the Securities and Exchange Commission for more information. As a reminder, the information on today's call is for the benefit of the investment community. It is not intended for promotional purposes nor is it sufficient for prescribing decisions. And now let me turn the call over to Will.

Thank you, Bryan, and good morning, everyone. We are extremely excited to share with you that the ENCORE trial was a clear success. On the primary endpoint of change in respiratory symptom score from baseline to month-13, we saw a statistically significant improvement in patients treated with ARIKAYCE on top of multidrug therapy versus the active comparator arm consisting of placebo plus multidrug therapy.

On the equally important culture conversion endpoints, we were very pleased to see earlier, greater and more durable impacts on culture conversion throughout the study, demonstrating highly statistically significant benefits for the ARIKAYCE arm. This result is particularly impressive as it was being compared to an active comparator arm similar to what a patient might receive as first-line treatment in current practice and demonstrates the potential benefit of using ARIKAYCE earlier in the treatment paradigm.

As we celebrate this moment with our investigators and the patient community, it is worth remembering the road that brought us here. As part of our development program, consisting of the ARISE and ENCORE trials, we validated a patient-reported outcome tool for this disease state, a first of its kind, which can be used for future development work in this space.

While other promising treatment candidates have fallen short, ARIKAYCE has consistently shown in each study ever conducted that it is demonstrably effective at clearing MAC bacteria from patients' lungs. Now based on today's result, we can also say that it may help patients find relief from respiratory symptoms after treatment. We are particularly excited to see a lower discontinuation rate in this trial than we have seen in any past study of ARIKAYCE and no new or unexpected safety signals in the trial.

With this successful readout, we will look to move quickly to pursue regulatory submissions with the FDA and PMDA in the second half of this year, which we anticipate will lead to an expanded label to include all patients with the MAC lung infection. If granted, this would bring our addressable patient population from around 30,000 today to more than 200,000.

We also expect these results to support the conversion of ARIKAYCE's current conditional approval in the U.S. to a traditional approval, consistent with Europe and Japan, given that we have now completed the study intended to fulfill the FDA's post-marketing requirement. We are ecstatic about what today's news could mean for patients with MAC lung disease. Now let me turn the call over to Martina to walk you through the results in more detail.

Thank you, Will, and good morning, everyone. I'm pleased to be with you today to share the top line results from our ENCORE study. I'll begin with a brief review of the trial design. ENCORE enrolled 425 adult patients with non-cavitary lung disease with a newly diagnosed or recurrent MAC lung infection that had not yet been treated with an antibiotic regimen for their present infection.

These participants were randomized on a one-to-one basis to receive either ARIKAYCE plus azithromycin and ethambutol or an empty liposome placebo plus azithromycin and ethambutol. Treatment was administered once daily over a 12-month period followed by 3 months of treatment. The primary endpoint in ENCORE was the change from baseline to month-13 in the 8-question Respiratory Symptom Score, or RSS, which was derived from the 9-question QoL-B respiratory domain questionnaire.

This patient-reported outcome tool was previously validated and agreed upon with the FDA. Multiplicity controlled secondary endpoints in the study included the percentage of patients achieving culture conversion by month-13, durable culture conversion at month-15 and culture conversion by month-12 and month-6 in that order of hierarchy as well as the change from baseline in the PROMIS Fatigue T-score at month 13. Safety and tolerability data were also collected throughout the study.

On Slide 9, we provide the baseline characteristics of the trial by treatment arm. Randomization was stratified based on geographic region and whether a patient had a history of previous MAC infection. As you can see, those characteristics used for stratification as well as age, gender and race were all relatively well balanced between the ARIKAYCE and active comparator arms. While there was a modestly higher mean baseline RSS in the ARIKAYCE arm, it is important to note that the primary analysis was designed to adjust for any baseline imbalances in RSS, geographic region and history of MAC infection.

Now let's take a look at our primary endpoint of change in RSS at month 13. I'm pleased to report that patients in the ARIKAYCE arm showed a least square mean improvement in score of 17.77 points compared to a mean improvement of 14.66 points in the control arm. This separation of 3.11 points was statistically significant with a p-value of 0.0299. Interestingly, this symptom benefit continued to expand after month-13, with the difference between arms increasing to 4.8 points at month-15 or 3 months off treatment with a nominal p-value of 0.0015. This further highlights the durability of the symptom improvement that can be achieved with treatment with ARIKAYCE.

In addition to the comparison I just described, we also conducted a responder analysis using covariate-adjusted cumulative distribution function or CDF curve, which are shown in this slide. On the horizontal axis, the CDF graph plots a continuous view of respiratory symptom score changes, both positive and negative, with improvement on the left of the 0 and deterioration on the right of the 0.

The vertical axis plots the cumulative proportion of patients in each study arm that experienced at least that level of respiratory symptom score change. The purple curve represents patients in the ARIKAYCE arm and the blue curve represents patients in the comparator arm. A positive change in respiratory symptom score represents an improvement of symptoms from baseline to month-13 and the negative change represents a worsening of symptoms.

Based on our prior work with this PRO tool, we established a range of thresholds that could be considered a meaningful with inpatient change in RSS score, which is the preferred approach recommended by the PRO experts at the FDA. At the low end of that range is a threshold of 16.67 points and at the high end is 20.83 points. Importantly, this graph demonstrates that the ARIKAYCE arm outperforms the control across the range represented by both thresholds.

The consistent separation you see on this curve means that regardless of what exact values are selected as the range of meaningful within patient change by the FDA, ARIKAYCE used in combination with multidrug regimen would result in more patients achieving a clinically meaningful improvement in respiratory symptoms.

Turning now to culture conversion, which is often cited by physicians as the most meaningful measure of the efficacy of any drug for the treatment of MAC lung disease. To provide some context for our discussion, culture conversion in the ENCORE study is defined as having 2 consecutive months of cultures that remain negative for MAC. The definition of durable culture conversion at month-15 requires all cultures to be negative at month 11, 12, 13 and 15.

Consistent with the results shown in our past trials of ARIKAYCE in both the refractory and frontline setting, ENCORE demonstrated that a significantly greater proportion of patients in the ARIKAYCE arm achieved culture conversion compared to patients in the active control arm, and this was demonstrated across multiple time points in the study.

Beginning with month-13 or the same time period at which we measure the respiratory symptom score for the primary endpoint, we saw that 82.4% of patients in the ARIKAYCE arm achieved conversion compared to 55.6% in the active control arm, a highly statistically significant difference of approximately 27 percentage points with a p-value of less than 0.0001. Perhaps even more striking is that this high rate of culture conversion in the ARIKAYCE arm was maintained over time.

On Slide 13, you will find results from the key secondary endpoint of durable culture conversion at month-15 or 3 months off treatment. 76.2% of ARIKAYCE patients remained converted, while only 47.6% of patients in the active comparator arm maintained negative cultures. This result reflects a separation of approximately 29 percentage points and a p-value that was less than 0.0001.

This is a particular notable outcome because durable culture conversion is the most important data point for the Japanese regulatory authority and for many prescribers, both in the U.S. and Japan. The greater durability of treatment we see in ENCORE is consistent with what we saw in both the CONVERT study in refractory patients and the ARISE study in newly diagnosed patients, where dose in ARIKAYCE saw a much higher level of maintained culture conversion measured at 3 months and 1 month off treatment, respectively.

It is important to note that at any measured time point from the start of treatment through month-15, more patients receiving ARIKAYCE achieved culture conversion compared to those on the active control arm. In fact, the secondary endpoints of culture conversion at month-12 and month-6 were also highly statistically significant with each achieving p-values of less than 0.0001.

The ARIKAYCE arm also showed a significant benefit on median time to culture conversion, which was achieved at month-2 or the first possible time point, meaning that cultures were negative at months 1 and 2. The median time to culture conversion in the active comparator arm was achieved at month-3, meaning that cultures were negative at months 2 and 3. The associated hazard ratio for this measure was 2.03, suggesting that patients treated with ARIKAYCE were roughly twice as likely to achieve earlier culture conversion. The nominal p-value for this comparison was less than 0.0001.

It is also notable that the separation you see on this slide was driven by very strong conversion rate in the ARIKAYCE arm rather than any underperformance in the control arm, which demonstrated similar conversion rates as we saw for the control arm in the ARISE study and which might be expected for a macrolide-based treatment regimen in the real world.

Finally, I want to briefly discuss the safety results from the ENCORE trial. The tolerability profile for ARIKAYCE in combination with multidrug therapy in ENCORE was consistent with the known profiles of this antibiotic treatment. No new safety events were observed in the ARIKAYCE treatment group and safety in general was as expected in both the ARIKAYCE arm and the control arm.

The ARIKAYCE treatment discontinuation rate observed in this trial was 18.3%, which compares very favorably to the 34.8% rate that we saw in the CONVERT study in refractory MAC patients and to the 22.9% rate we saw in the ARISE study. The improvement compared to ARISE is particularly notable because the treatment period in ENCORE was twice as long. The empty liposome control discontinuation rate in the control arm in ENCORE was 11.8%. Importantly, the percentage of patients who completed the study was over 90% for both arms in the trial.

Drilling down a bit further, treatment-emergent adverse events were reported by 98.1% of patients in the ARIKAYCE arm and 97.2% of patients in the control arm. Adverse events that occurred at least 10% of patients in the treatment arm and more frequently in the ARIKAYCE arm were dysphonia, cough, fatigue, dyspnea, nausea and headache, all of which are consistent with the known safety profile of ARIKAYCE. The rate of serious treatment-emergent adverse events was 14.1% for the ARIKAYCE arm and 11.3% for the control arm.

In summary, the combination of all the data we have presented today a statistically significant benefit on patient symptom scores, greater, more rapid and more persistent culture conversion and a consistent safety profile provide clear evidence that treatment with ARIKAYCE and in particular, early treatment with ARIKAYCE can lead to improved results for patients with MAC lung disease. I'll now turn it back to Will.

Thank you, Martina. Today's results are incredibly exciting for all of us at Insmed, but more importantly, for all those who struggle with MAC lung infections and for those who provide treatment to and care for those patients. ENCORE has provided new hope that with the early addition of ARIKAYCE to the treatment paradigm, patients can experience improvement in their respiratory symptoms and have a greater chance to convert sooner and stay converted for longer.

We will now work with urgency toward making this important treatment available as an approved treatment option for use in all patients with a MAC lung infection. We want to thank our patients and investigators for their courage and support on this journey, which we hope will result in many more patients benefiting from treatment with ARIKAYCE. And with that, operator, I'd like to now open the call to questions. Can we take the first question, please?

[Operator Instructions] Your first question today comes from the line of Graig Suvannavejh from Mizuho.

Congratulations on this data. Just for context, bigger picture with respect to how to put this data in the context of the current standard of care, so to speak, which is like triple antibiotic regimen given the study while nicely positive. Can you give a sense of maybe how physicians might look at this data and put it into practice in the real world?

Sure. Well, one of the most exciting things about this study was when we were originally designing it, we worked closely with the KOL community as to what would be the right way to look at this in the frontline setting. And what you see today is very clear evidence that ARIKAYCE in addition to a 2-drug regimen provides a real benefit both in symptoms and in culture conversion. That 2-drug regimen plus ARIKAYCE sets a new standard of care for how to treat initial patients who are diagnosed with MAC lung infection. And that was really the intention behind the study to create a path toward a new standard of care.

The drug that is sometimes included later on is rifampin. It's always been very controversial as to whether or not there's real benefit from its addition, and there are known safety effects there that really dissuade a lot of physicians from using it. So it was left out in this case, and we're happy to be able to present these positive results that show it is not only highly beneficial to add ARIKAYCE, but that really when you look at the baseline or the comparator positive control arm, you don't see any absence of effect or benefit from the removal of rifampin. So positive on all fronts.

Your next question comes from the line of Jason Zemansky from Bank of America.

Let me echo my congratulations on the data. Maybe just a follow-up here, but Will and Martina, especially given the culture conversion data, what sort of long-term benefit is this likely to mean for patients? I mean is there a potential for a survival benefit? Or are we just sort of talking about the benefits associated with the discontinuation of rifampin?

Thanks for the question. I think I'll just make a comment and then turn it over to Martina. The study is obviously unequivocally positive on all fronts, and we're super excited about that. What it may mean for the longer term, I think, can begin to be imagined just by virtue of the experience we've had to date, where the drug has been on the market for 8 years now in the United States. And in that context, lots of patients and lots of physicians have seen the benefits from its administration. We haven't done a specific study to look at things like survival benefit, but those are the kinds of questions that we are certainly going to be curious to engage in and answer. And we're now going to be able to do it from a much larger pool of patients as we move to the all MAC diagnosed population. I don't know, Martina, anything you want to add?

Yes. What I would add is it just shows you what the durable culture conversion benefit is. So these patients at month-13 has been 1 month off drug and at month-15 has been 3 months off drug. And the hypothesis here is that sometimes for the control regimen -- for 2 regimens, you may get a negative culture, but you may not get a full clearing of bacteria. And ARIKAYCE appears highly effective in eradicating bacteria because of its mechanism of being right there in the lung, and that is something that might not be achievable with a systemic oral antibiotic.

So if you think about the achievement and the opportunity a patient can get from treating with ARIKAYCE in that regimen, it is something to consider also to prevent that patients potentially become refractory. So treating early here is based on this data evidence that would be helpful for patients.

Your next question comes from the line of Ritu Baral from TD Cowen.

Let me add my congratulations on this data, especially this culture conversion rate. I did want to focus on safety and tolerability, especially as it relates to if there's a type of first-line patient you're going to target and what it might mean for pricing. Martina, if you could talk about the dysphonia rate and the transient of the dysphonia if patients recovered or if there is any permanent dysphonia and how that may relate to the risk benefit that first-line patients -- basically, which first-line patients might be appropriate for it and then the impact on gross to net?

Go ahead, Martina.

Yes. So dysphonia, along with cough and are very well described potential side effects for ARIKAYCE. And we've seen in the study that the dysphonia rates were slightly higher, and they're at 58.7%, while we see them at 8.5% in the control arm. But what we also know after 8 years on the market and the experience with ARIKAYCE on both the investigator, but also with physicians in general side has now, of course, been increased.

We also have educated sites of how do you prepare patients for what potential side effects or respiratory side effects they may experience. And we've also learned that if you put in certain measures, for example, gargling with warm water or taking ARIKAYCE before that time is a benefit and can ameliorate the symptoms. So overall, the benefit risk is actually very strong. This is a 12-month treatment and patients have -- as you see, the discontinuation rates are lower than what we've seen in ARIKAYCE for ARISE and certainly for CONVERT. So I think everybody has learned how can I work best with this drug. And it is, I would think, even a strengthening of the benefit risk.

Thanks, Martina. And Ritu, on the pricing and GPN question, we had priced originally ARIKAYCE for the broader label, so no change in WACC on gross to net. For this year, as you know, we guided low to mid-20s. You will see a natural uptick in gross to net as the small manufacturer sort of bleed-in happens for ARIKAYCE more broadly, but we have always done and we'll continue to do appropriate and targeted contracting. This will be -- ARIKAYCE is the only controlled product that is approved and now pending FDA approval, will also be that in the broader label.

Your next question comes from the line of Joe Schwartz from Leerink Partners.

Congratulations on the super outcome. Can you help us understand how representative the ENCORE trial population is relative to real-world treatment practices for frontline MAC and how that should inform our expectations for these results to translate into market penetration assuming approval?

Thanks for the question. Sorry, I couldn't be there today, Joe. Over to you, Kevin.

Yes. So thanks for the question. So it is representative of real world. The comparator here is a clinically relevant comparator out of the gate and it's the same control group that we used in the ARISE study. And so as Will had said earlier, often a third antibiotic that's used either right away or subsequently is rifampin, what -- in talking with external experts when we started this program for the United States is more times than not rifampin gets stopped and patients are on azithromycin and ethambutol.

So we do think the study is representative of real-world experience. The control group had activity as would be expected for the conversion rates at month-12. And so I think definitively, this study being the largest study ever done in the disease is a double-blind, randomized controlled superiority study, I think, shows very clearly the benefit of adding ARIKAYCE on top of the background regimen for symptomatic improvement and microbiological improvement as well, too.

Your next question comes from the line of Vamil Divan from Guggenheim Partners.

Congrats as well on the data. And maybe building on some of the other questions people have been asking just about sort of putting this in context. How do you think about the duration of therapy? Or what are you sort of modeling as the average duration given the positive results we're seeing with the culture conversion? Do you think they will stay on a year plus? Or is this a shorter duration? Just any insights there would be helpful as we think about how to model this out.

Martina, do you want to take that one?

Yes. So what we've seen in this study is the 12-month treatment gives patients not only a higher and an early and a greater achievement of culture conversion, but it also gives the durable culture conversion and being 3 months off treatment and still seeing how good the effect was on the ARIKAYCE arm versus as soon as you see that the treatment stops in the control arm, it goes in the other direction.

And that goes with the hypothesis that you may have enough control of the bacteria in the control arm to have a negative culture, but not necessarily enough to sustain that and come to an eradication of the bacteria. And you see that also reflected that patients feel better while they are on treatment also in the control arm. But as soon as that is stopped, you see a decline in the respiratory symptom score, which is also aligned with what we see in the culture conversion at both month-13 and 15.

It's clear that 12 months produces these kinds of results. It will obviously be up to the physician's discretion what they want to do. But I don't think there's any doubt that the 12-month treatment here is seen as beneficial and sustained over time. And that's the most important point, particularly from the market access world where they want to see that kind of impact. And uniquely, because we also did the ARISE study, we have a sort of snapshot of what a shorter duration of treatment might look like. And the simple answer is both the efficacy and the safety are at least arguably better in ENCORE than they are in ARISE. So that also paints a very positive picture for the 12 months of duration.

Your next question comes from the line of Ellie Merle from Barclays.

Congrats on the data. What do you think drove the lower discontinuation rate that you saw in the ENCORE data versus in the ARISE study? And I guess, how are you thinking about what the discontinuation rate would be in the real world?

So discontinuation rate, I think, as Martina commented earlier, is in large part due to people becoming more familiar with how this drug needs to be used, how you prepare the patient for what they can expect. And I think importantly, increasingly, the ability to express to the patient the benefit they will receive if they remain on therapy. I think it's just a collection of all those things and the experience over time that is slowly, but surely improving the adverse event rate that we see reported in this study as compared to ARISE and certainly compared to CONVERT.

I think that is the most important point of this study is that all of the data here and from ARISE and from CONVERT clearly show that you want to treat earlier in order to avoid the patient becoming refractory. Once they're refractory, the dropout rate from the drug gets much higher, the difficulty of taking it, the duration, all of those things, you still see clear benefit, and that's why the drug was approved for that population initially. But here, we see some unexpected and positive findings that the dropout rate is lower.

Remember that we thought it actually could be higher because these patients were less sick, perhaps less willing to tolerate the treatment, and yet that is not the case. It's dramatically lower, almost 15% to 20% lower than CONVERT. And that implies to us that at least at some level, the severity of the disease and its engagement -- our engagement with the antibiotic are causing some of the side effect profile.

In other words, as you overcome that -- the presence of the much more established refractory infection, you may produce more side effects as you achieve ultimate culture conversion. Acting earlier lowers the severity of that experience because the infection, at least theoretically is not as well established. So for all those reasons, I think the discontinuation we see in ENCORE is indicative of what we can expect in the real world, and that's a very positive thing as we move up in the treatment cycle to an earlier-stage patient.

Your next question comes from the line of Maxwell Skor from Morgan Stanley.

Congrats on the update. So as you move to convert ARIKAYCE's conditional label to traditional approval and, of course, expand into a broader population, how should we think about any shifts in payer behavior or reimbursement? And could you just talk about the, let's say, cadence of uptake that you expect over the next 12 to 24 months in both the U.S. and Japan?

Sure. So I think as Sara mentioned earlier, we originally priced this drug for the assumption that we'd be treating all MAC patients. So we don't anticipate a different approach in our discussion with the market access world. And what's important here is that all of the data points in a very positive direction for this earlier use of the drug. I think the symptomatic benefit, the culture conversion benefit, all of these things being aligned makes it a really easy discussion from my perspective when it comes to market access.

As for the uptake in the next 12 to 24 months, what I would say about that is we are seeing an expansion in the total addressable market from 30,000 patients to more than 200,000, but we need to develop the target product profile now based on these data from the study and take that out into the market and do some research, which we will now do in earnest to get a better sense of what we think that will result in, in terms of uptake and what the ultimate benefit will be. And when you begin to see revenue in 2027, assuming that we get approvals in the U.S. and Japan, as we fully expect to, we'll have more to comment about the direction that those revenue growth curves might take.

Your next question comes from the line of Matt Phipps from William Blair.

Let me extend my congrats as well. Maybe can you tell us what percentage of ARIKAYCE patients today use your inLighten patient assistance program? And again, kind of thinking about moving to front line, how do you expand that program to try to capture those patients and any benefits from any changes in the out-of-pocket that has happened with Medicare?

Sure. So while we haven't given out the specific percentage, what I can tell you is that if you were to take a high benchmark for what would constitute an attractive rate of getting patients into such a program, we are well above that threshold, and we always have been with this. This is a very all-encompassing outreach to patients to help them on their journey through the use of this drug and the hopes that it will be the most effective.

We fully anticipate being able to extend that to all MAC lung infection patients. And remember that this is the same backbone architecture that we use not only for ARIKAYCE in the refractory population, but also for BRINSUPRI in the bronchiectasis population. And so the resources we need to be able to address this much broader population with ARIKAYCE are already in place and experienced. So we expect this to be a smooth transition and a full expansion with hopefully the same kind of conversion into the program that we've seen to date.

And just to comment on the out-of-pocket, I'll just also remind you that we estimate about 60% of the current ARIKAYCE label, about 60% of the Medicare patients. So their out-of-pocket under IRA is for all their medicines, capped to $2,000. And then for the commercial payer patients, we have a co-pay assist.

Your next question comes from the line of Ash Verma from UBS Financial.

Congrats on the progress here. So yes, maybe if you can talk about the time line for getting the frontline data on the label? And would the uptake be contingent on getting this added to some of the guidelines? Or is it more that the FDA approval opens up the label for the uptake for physicians?

Sure. So obviously, the data once processed by both the U.S. and Japanese regulatory authorities would result in label expansion. And we expect that, that will be the case. We've indicated that we'll be filing that by the second half of this year. And we would anticipate that those approvals and our ability to launch would take place in 2027, just so we're clear. And I think that, that will be a relatively smooth process. I don't know if anyone wants to add any other comments.

I think maybe just on the guidelines, just to be clear, guidelines are usually completed independently by professional organizations and experts. Obviously, we are independent of that. But what you often see is if there is new, especially important data becoming available, there is a consideration of that.

And let me just make a comment, this is a particularly difficult disease to treat. Every other company that has come along trying to bring forward a medicine has failed to be able to produce clinical trial results in a double-blind study that are adequate for approval. And I think that just highlights the desperate need for this patient population. So a clear and strong win like we have today, I would anticipate would be something that is noticed pretty rapidly by the key opinion leader community that is authoring these guidelines.

Your next question comes from the line of Leonid Timashev from RBC Capital Markets.

Congrats on the data, and thanks for taking my question. I wanted to ask also on the opportunity. I guess there's been significant ex U.S. use of ARIKAYCE, so I guess with the label expansion, I'm trying to understand how you're thinking about the balance between ex U.S. and U.S. revenues, especially given that you guys have been somewhat cautious of MFN impact? And then related to that, is there anything you can say on epidemiology and just the trends you're seeing with diagnosis rates or prevalence of infection over time?

So thanks for the question. Yes, we do get a meaningful percentage of revenue from Japan, in particular, for MAC lung infection in the refractory setting. And that's -- it's important to remember that while it's not fully understood what causes the MAC lung infection to develop in particular patients, factors that certainly lean in favor of that are an elderly population, prior history of smoking or lung issues, proximity to water. And when we talk about the island nation of Japan, that's pretty much a perfect description of its population.

So with that in mind, it's not surprising to understand that there are more -- today, there are more diagnosed MAC patients in Japan than there are in the United States. So the opportunity there is quite significant. There is a price differential there that has evolved over time, but it is important for people to understand, we priced at parity between the U.S. and Japan when we launched on a list basis.

So I think Japan will continue to be an interesting opportunity. There are more MAC patients there than there are in the U.S. Another feature of their annual checkup is that they include an x-ray as a matter of basic practice. So there's a higher propensity to be able to identify this infection that may be contributing to the higher diagnosis rate. So all of those things collectively suggest that we would expect to continue to see material revenue generator from Japan as the label expansion occurs. I don't know if anyone else has any other comments.

Your next question comes from the line of Faisal Khurshid from Jefferies.

Just one quick one. You kind of commented or characterized the overall TAM expansion of being sort of like greater than 6x the refractory TAM in terms of number of patients. Could you characterize like what you -- how you think about the peak potential uptake into this opportunity? Like where do you see this potentially maxing out from a revenue opportunity perspective, given like the other standards of care?

Yes. Thanks. I appreciate the question. We're still working on the answer to that question, to be candid. And we needed the target product profile specifically generated from this study in order to be able to go out and have the dialogue with physicians to see how they interpret the risk reward, how they see it for their patient populations and what the application might be in the practical setting. I think what is important to note here is that the data from this study is unequivocally positive from the perspective of physicians who are seeking to eradicate evidence of the infection in their patient populations.

Moreover, if you just reflect on where CONVERT took us, we saw about 1/3 of patients convert after the CONVERT trial to a point where they had no evidence of bacterial infection. In the case of ENCORE and ARISE, we're seeing north of 80% of the patients converted by month-6. That is a striking improvement compared to what happens if you let a patient become refractory.

So there is a powerful motivation in the data to move to treat these patients earlier and the dropout rate going down suggests that actually the treatment burden for the patient is reduced. So that collectively paints a very positive picture for expansion into this broader population. How big, how fast and what that ultimately means for peak sales, we need to come back to you with specifics on that. But certainly, we anticipate moving in a very positive direction.

Your next question comes from the line of Danielle Brill from Truist Securities.

This is Alex on for Danielle. Congrats on the data. Just a detailed check box question on the discontinuation rate. Given there was a slight imbalance in the rate of discontinuations between the arm, did you perform any sensitivity analysis to query the potential impact of the imbalance? And if so, were the findings consistent with the top line analysis?

I'll turn that one over to Kevin.

Yes. So bottom line is those patients that may have discontinued their treatment and had missing values, they were considered in a prespecified way in the analysis. So what you're seeing here in the RSS as well as culture results does consider all that. And so it's a really strong reflection of how robust the study was and insensitive to things like that.

And there are no further questions. This concludes today's conference call. Thank you for your participation. You may now disconnect.

Good morning. Welcome to this fireside chat with Insmed. I'm Joe Schwartz from the biopharma equity research team at Leerink Partners, and it's my great pleasure to be joined by Sara Bonstein, CFO.

Maybe, Sara, you could start us off with a quick lay of the land and give us a brief overview of the company's recent accomplishments and priorities for '26.

Sure. Happy to. Thank you, Joe and the Leerink team for having us here. Always a privilege and an honor to be here with you today.

Insmed is, I believe, a remarkable story. So we are a company that is focused on serious life-threatening conditions and how can we create first or best-in-class options for patients. We have commercial products now. We have ARIKAYCE, which has been commercialized for about 8 years for nontuberculosis mycobacteria in the refractory setting, and we will have a readout in the March-April time frame for a potential label expansion in that indication that our second commercial product is called BRINSUPRI. That product was launched in August of last year, and that is for bronchiectasis.

Both of those programs, along with some additional programs that we'll go through today, make up our respiratory franchise. Our respiratory therapeutic area. We recently went into these 3 therapeutic areas, respiratory, I&I and neuro and other. And we did this because it's a -- it's just a symbol of how much we have grown as an organization in the company in the past -- yes, 2 years, but really in the past 10 years. You're now seeing that culmination of all the growth that we have done.

So we have a very, very robust pipeline of late stage, mid-stage and early-stage across each of those therapeutic areas. We sit on about 1,500-plus employees across our geographic territories, which include New Jersey, New Hampshire, California as well as Europe and Japan and really just have a great organization where we're able to have great impact on patients. So happy to dig into the commercial programs, the clinical programs, we're excited about all of it.

Great. Okay. Thanks for that excellent overview. So maybe we'll start with ARIKAYCE and the ENCORE study since we've been getting a lot of questions about that event coming up soon. Can you lay out for us your goals with that study and how you designed it on the basis of what you saw in ARISE and maybe what the potential scenarios are coming out of ENCORE?

Sure, happy to. And maybe we'll even take a step back and just remind us all on sort of the design and why we even did ARISE.

So the FDA, as you all know, look for an endpoint for field function survive. So the endpoint here for this nontuberculosis mycobacterium in the sort of frontline or initial stage setting is a patient-reported outcome tool. And there is not a patient-reported outcome tool that exists for this condition.

So we ran essentially 2 parallel studies, ARISE and ENCORE. They were very similar in their design. The difference was one was a little bit shorter in duration, and one was smaller, so we could get the readout first to help determine what a PRO could look like in this disease setting.

So I'll remind you on ARISE. ARISE was about 100-patient studies. It was 99 patients. When we had patients, we randomized 2 of them to ARISE, one of them to ENCORE. So same exact patient population. We did that, as I said, to make sure that ARISE would enroll soon.

ARISE was 6 months on therapy and 1 month off therapy. And we studied -- we looked at 2 things. The U.S. FDA is looking for, as I said, that patient-reported outcome. The PMDA in Japan would be looking for culture conversion. So we studied both.

What did ARISE tell us? What did we learn from ARISE? What ARISE told us is, obviously, it was much, much smaller than ENCORE, so not powered for statistical significance, but it showed that we were trending in the right direction to show a change in the respiratory symptom score between the treatment arm and the nontreatment arm. So it was trending towards seeing a change, and we saw about a 4.5 point change.

And then on the culture conversion, even more interestingly, we saw nominally stat sig results on culture conversion. And at the 6-month endpoint, we saw about an 80% conversion on the drug arm and about a 65-ish percent on the control arm. But even more interestingly, 1 month off of therapy, you saw a point or 2 go down on the control -- on the drug arm. So the 80% went down to like 78% and change, but you saw the control arm went down to 47 sort of high 40s. So it wasn't durable.

And so now as we fast forward to ENCORE, what are we looking for ENCORE? ENCORE is a longer and duration study. It is a 12-month study, and we are looking at the primary endpoint for the U.S. is that PRO. So the change in the respiratory symptom score. So again, we're looking for the change between treatment arm and control arm. We're 90% powered to show a 4-point change, and that's assuming 400 patients. We enrolled 425. So we're a little over enrolled there, which is great, and that is where ARISE was showing us. So we have a high degree of conviction.

The next step is we want to see the responder analysis. We want to see a point -- across any point of the measurement, do you see separation? And FDA will obviously determine what that right separation needs to be. It will potentially be in the 16.5-ish, maybe 16.7 range, but that will be FDA's decision. The important piece is in ARISE; we saw separation across any point change. So that again gives us tremendous confidence.

And then as we spoke about the PMDA as well as the U.S. HCPs, payers, patients, they're very interested in culture conversion. So obviously look for stats to get culture conversion.

On the endpoints for the PRO, we're measuring at month 13. That's important because they get to be off drug for 1 month, which is important because ARIKAYCE has some side effects, but it has been able to show 8 years in real-world data as well as the other studies that we're able to show a difference and clear these bugs. So having that 1 month off therapy is really important.

And then for culture conversion, it's at month 15, which again is really helpful because we can be able to hopefully demonstrate the durability of what ARIKAYCE can do for these patients to be able to not only clear the bug, but to have that durable culture conversion.

So a lot there. It's not as sort of black and white as some other trials. So I kind of just wanted to go into some detail. But March, April will be the timing for that data readout, so be on the lookout. What that means is patient-wise, there's about 12,000 to 17,000 patients in the U.S. diagnosed under the current label, about a little higher than that in Japan, about 15,000 to 18,000 in Japan.

Those numbers increase pretty substantially for total NTM in the U.S., it's about 100,000. In Japan, it's about 125,000. So significant patient populations. Obviously, there will be some education on what that means on how quickly do people get it? How long do they stay on therapy, all that good stuff. We need to see the data, and then we'll educate you on all that as well.

Super helpful.

Yes.

So then what are the potential scenarios coming out of ENCORE? That's been a question we've been getting a lot from folks because it's on the one hand, a confirmatory study for ARIKAYCE, which has accelerated approval. And then it could also open up Japan and expand the market in the U.S. How about the scenarios where it succeeds on everything, maybe it's a mixed result, positive culture conversion-wise and then maybe less so on QLB? And then what if it's just -- probably not, but an all-out failure.

Yes. No, all very, very fair questions. So I think the clear win scenario is pretty straightforward, right? We would look to file before the end of the year and be on market next year. That would be the goal, and that's what we're planning for in a sort of mixed scenario, this would be a conversation with FDA. This is a product that's obviously been on the market, has been able to show big impact for patients. So that would be conversation and discussion. We've never lost on culture conversion. We have a high, high degree of conviction on culture conversion. Obviously, PRO, there's just noise in a PRO instrument. But again, we feel like we've learned a lot from ARISE, and we've been able to apply that into the ENCORE 8 question respiratory sinus symptom score.

In the instance where we don't see what we want to see, I'll remind you that this program is not in the same indication for the approval -- the conditional approval that we have now. So again, it will be a discussion with FDA. I'll also remind you, obviously, can't speak for FDA, but I'll remind you, there's nothing else available for this patient population. It's been on the market for 8 years. Patients have had success with this medicine. They've come -- they've had successful sort of completion of clearing their bug, getting reinfected, going back on medicine. So real-world example, real-world experience here has been very, very positive. I think this would be a tough one for FDA to do anything other than keep this medicine available for patients.

Okay. Very helpful. So maybe we can switch gears and talk about BRINSUPRI now that we've talked about the little diesel engine that just keeps chugging along. Might just be getting broken in if frontline works. And we'll switch gears to the jet engine, if we could.

Yes, I like that. I love cars and engines, all that stuff. So that sounds great.

Great. So BRINSUPRI has really knocked it out of the park with not even a year on the market now. We're detecting a lot of solid demand for the product. And I was wondering if you can just lay out for us your vision of the different waves of the launch for us.

Yes, yes, happy to. So BRINSUPRI is, as I mentioned in the opening, is the first and only available treatment for folks with bronchiectasis. So previously, when a patient would go into their doctor and they would be given this diagnosis and then the patient would say, what do you -- what do I do? And they would say, well, continue doing a lot of the same airway clearance, the shaking vest, there's no approved therapy. So really amazing to have this option for patients.

Although there was nothing approved, there was actually already a diagnosis code, which was actually very helpful to be able to understand the patient population. So here in the U.S., there are 500,000 diagnosed patients with bronchiectasis. If you kind of dig into that information, you can see how many exacerbations do those patients have over the prior 12 months.

And the reason we looked at that is in our ASPEN study, which was our pivotal Phase III, the inclusion/exclusion criteria were 2 or more exacerbations in the prior 12 months. The label does not have that in it. The label is very open, but our understanding and expectation would be 2 or more is where the prescribers and the payers will be.

So if you look into the claims database, about half of the patients that are diagnosed today have had 2 or more exacerbations in the prior 12 months. That is really where we ground as sort of the initial sort of focus of the launch, that 250,000 patients. There's another 250,000 patients that are 0 or 1 exacerbating patient that when you think about an exacerbation, every time you have an exacerbation, you're more likely to have another exacerbation. They're not linear. Every time you have an exacerbation, it causes permanent lung damage.

And I think even most interestingly, a lot of exacerbations may have gone under documented because either a patient didn't realize that it was an exacerbation or they said, why am I going to call my doc, I don't want to get put on an antibiotic. I don't want to get hospitalized. I'm just going to kind of live through this myself. And so now that there's available medicine, you may see more exacerbations be documented.

And how do I have confidence to even say that? There was a real-world claim study done with about 15,000 patients. So decent size, not obviously all the patients, but decent size is a 2-year look. And at that point in time, about 47% of patients had 2 or more exacerbations in the prior 12 months.

Fast forward, that went up by 9% and the 47% went to 56%. So you're already starting to see that migration. So I view that as sort of like the initial low-hanging fruit as you're thinking about available patients for this medicine. You have the initial 250 that the payers will be happy to support. You have the next potential 250 that may now have potentially more exacerbations.

The piece that we're now putting energies towards is what we're calling almost a secondary launch, a second launch, a second focus. And this is the potential underdiagnosed patients that have COPD or asthma. In the U.S., there's over 30 million. I think it's 32 million patients with either COPD or asthma.

If you take just the COPD piece of that, it's about 20 million patients in the U.S. Literature is all over the map on how many of those could also have comorbidities with bronchiectasis, 4% to 60%. It's all over the map. I know that's not super helpful. But if you look at even the most recent literature, it actually says 30% to 50% of moderate to severe COPD patients also have a high likelihood of bronchiectasis.

And so if you kind of do all that math and you put whatever probability on penetration in that, that could be hundreds of thousands, if not millions of more potential patients that could be available to be on drug, available to be on label with a CT scan that shows a tree bud pattern on it that then gets them the bronchiectasis diagnosis.

So we will have a dedicated team focused purely on that underdiagnosed patient population to help with the education on both the commercial and the medical side compliantly to help with that investigation on identifying those appropriate patients that are potentially exacerbating patients that could potentially benefit from the drug. Our existing field force organization, they're going to stay focused on that 250,000 patients and driving the at least $1 billion of revenue that we have committed to this year.

Our survey work has also found that a significant proportion of patients have overlapping symptoms with COPD and bronch.

So I think as strong as the launch has been, still only half of physicians have written 1 script so far, but patients should be entering the zone when they'd be revisiting their doctor. The checks we and others have done have turned up some very positive feedback so far on the response to treatment in the real world. How do you foresee the launch going now as we enter this phase of deeper -- potentially deeper penetration in patient practices?

Yes, yes. So obviously, our first -- yes. No, I understood. Our first full quarter, we put up almost $145 billion in revenue. We were really proud of obviously, the revenue number and I think even more importantly, the ability to have over 11,000 new patient starts cumulatively in 2025 and have that much impact on patient lives. And as Joe said, we had about 4,000 unique prescribers, cumulative number of prescribers through the end of 2025 and about half of them through the end of 2025 had written 1 script.

And so we've spoken a lot about the depth and breadth. In the United States, there's about 20,000 pulmonologists. We have the ability to call on every one of them as well as we call on some infectious disease docs and some other specialties in the totality of about 27,000 health care professionals, and that covers both BRINSUPRI and ARIKAYCE is a shared sales force.

4,000 folks have written -- 4,000 HCPs have written at least 1 script and that is very encouraging. That's a pretty broad net, probably broader than we thought would be out of the gate. So we see the KOLs, we see community people writing scripts. What we now are very focused on is the depth. And this is very traditional that you see in not only a new first-in-disease medicine, but this is a first-in-class medicine.

So you expect to see this. You're going to have probably more depth in KOLs or physicians that maybe were part of the trial and sort of less depth in some of the KOLs that are onesies, twosies, but this feedback loop of having the patient experience, so a positive patient experience. And you see this even if you just look at social media posts and patients are very loud now themselves to hear that feedback on I've had a positive experience, that helps to build momentum. They come back into their physician's office. The physician asks them about their experience.

I'll remind you that the dropout rate in the ASPEN study was actually a little bit higher in the placebo arm than it was in the drug arm. It was about 13% in the placebo arm, around 12% in the drug arm. This is a relatively benign safety profile from a drug perspective. And the fact that we were able to show nominally statistical significance in the 25-milligram arm on quality of life, that is really helpful for folks, right? They're feeling better, and so you're starting to get that feedback loop.

I think another important event will be as the physicians get together at major medical meetings like an ATS and they're being able to share these stories with one another, having that continuous feedback loop, I think, will be the next -- one of the next inflection points for the company. So probably Q2-ish is when we'll probably mostly starting to see the impact there. So really excited about what the year has to come.

And then the other, I think, very important piece is if you think about the -- sort of overall health of the brand, we've said $5 billion peak sales. That is just on the diagnosed patients today. That does not include all this additional sort of low-hanging fruit that we talked about, that could be multiples of that and $1 billion, at least $1 billion this year.

If you think through how the math would need to work to be able to achieve at least $1 billion this year and where the jumping off point will be at the end of this year and what that implies for '27. This is a monster, monster opportunity. There's maybe 20 products in our industry of all times that in quarters 2 through 5 have been able to put up over $1 billion in revenue. Insmed is looking to add their name to that list.

Okay. Great. So I'd like to switch gears again to TPIP because this also, I think, has a very sizable opportunity. It's a bit under the radar because of the -- all the shine that's on BRINSUPRI.

But I guess, I want to ask a big picture first, and that is, where do you see TPIP fitting into the overall treatment paradigm since it seems to be on the cusp of potentially achieving like one of the ultimate goals that I can remember being out there for PAH therapy for a long time, which was just to deliver a lot of prostacyclin once a day. That's a very tall order. And yet we have a lot of excitement around another class of drugs spearheaded by WINREVAIR. So how do you see the overall share for prostacyclin and TPIP driving prostacyclin growth in the future?

Yes. No, it's a great question. And so we have a lot going on. So we have to keep pivoting to different programs, which I love.

So a couple of thoughts here. There's been tremendous development in this space, which is absolutely wonderful for patients. This is both a life altering as well as -- these are life-altering as well as life-ending conditions. So we need to do better for patients. So it's great to see additional innovation here.

I do expect, and this isn't my -- what I expect, this is what the medical community is educating me on that this will is and will continue to be a combination market. And the goal here is to extend life for patients. And while there are additional sort of MOAs that are coming out, the need for prostanoid therapy is seemingly to be a mainstay. And what the medical community is telling us is if we can continue to show what we showed in our Phase II that TPIP has the potential to be the prostanoid of choice.

And why do I believe that? Well, we were able to show in our Phase II study, Phase IIb study in PAH is a 35% improvement on 6-minute walk and 35% -- 35-meter improvement -- 35-meter improvement on 6-minute walk and 35% improvement on PVR. Those are results that no drug in this class has come even close to. And we obviously need to reproduce that in Phase III.

But I still remember when my Chief Medical Officer called to tell me the results, I didn't even believe what my ears were hearing. I thought she said 25 instead of 35. I made it repeat about 3 times. So it is absolutely amazing what that -- what the drug has been able to show.

And it actually makes sense. If you go back to one of your -- the earliest thing that you said, Joe, around the goal here is to get as much drug into the patient's lungs and have it be sustained. And that's what we believe we've created with our TPIP prodrug. We're able to deliver a lot more drug, but it be inert, so it's not active. So you sort of don't have that side effect of the cough, which is a big issue for current patients. And you're able to get a lot of drug into the patient and have it sustained over time.

I'll remind you that our Phase II, we measured 24 hours after the initial. So we were able to show those types of PVR and 6-minute walk results 24 hours, which sort of magnifies the ability that this is overnight coverage, which doesn't exist for these patients today and all that, those good things.

So this year, we've committed to having 4 global Phase III programs underway. PH-ILD kicked off last year. PAH will kick off Q2 and then PPF and IPF on track to kick off second half of this year. So a lot of development going on. More to come here.

We've put out early days, peak sales of $2 billion. That's when we were only going after the first 2 indications before we had Phase II data. We know we need to update that for you guys, but this could be another very, very significant opportunity from a revenue generation perspective as well as a patient impact perspective.

Right. We didn't believe the math when we backed into what the blinded data implied you would show and lo and behold, that's what you delivered. So...

Yes.

Super exciting. Let's switch gears yet again to another approximate readout from the SEDER trial for brensocatib in HS. Can you help us understand where the 20% to 40% bar for success for AN count reduction came from and how this would position BRINSUPRI in the HS treatment paradigm meets that?

Yes. So HS, neutrophil-driven condition, inflammatory in nature. This is why we sort of targeted it. We have said right from the beginning that while all of those hold, this is a very tough disease indication. So we've put sort of a 10% to 20% probability on this indication. Obviously, it would be great if we could show something here the bars. So based on feedback from the medical community as well as what other studies have shown, we believe a 20% improvement on AN count would be meaningful for us to progress into Phase III.

When we talked about the 40%, with the 40%, we call that our "home run scenario" because that's what we would need to show to be able to show stat sig because we -- when we designed the study, we designed it at alpha 0.1, whilst still a very meaningful size study. It's 204 patients. We powered it that way so we can get answers.

I'll also remind you; this is a 16-week endpoint. Our drug usually takes about 2 to 4 weeks to reach full effect. And so we're studying AN count as the primary at 16 weeks. We will have continued data through week 52, with some more sort of traditional high score 50 and 75 at that point, some more information available then.

Okay. Great. And -- on the earlier stage front, can you tell us some more -- give us more color on INS1033, your next-gen DPP1 and maybe how much screening you did to arrive at this agent, how it differs from BRINSUPRI and how you settled on IBD and RA?

Yes. So unlike both HS as well as CRS, which there's no animal models available, RA and IBD do have animal models. And we've run animal models with BRINSUPRI that, that information is published as well as 1033. So 1033 is one of our new DPP1s.

On the heels of the WILLOW data, you may recall, we continued to do a ton of work in our research labs on the mechanism because we believed in this mechanism with a high degree of conviction. And so we developed, I don't know, over 800 different DPP1 follow-ons, we are looking to progress the first of those 1033 through IND by the end of this year. The thought is the indications will be RA and IBD. The benefit of a follow-on DPP1, obviously, we can think about pricing very differently. We can think about IP very differently. We can think about reach differently, all of those good things. We 100% own all the follow-on DPP1s ourselves. So that's also very helpful. So we're excited to move that forward through IND by the end of the year.

Okay. Great. And then maybe lastly, what's the next step for INS1148, the monoclonal antibody that you recently acquired for ILD and asthma. Can you give us a little bit of the back story there?

Yes, yes, sure. So this is a program that we in-licensed end of last year. It's very brenso-like in sort of deal terms, $40 million upfront Phase II-ready asset. It was an asset that was developed by a small company that they licensed it to AbbVie. AbbVie ran a Phase II study, about 150 patients in atopic derm. While that was not published, we obviously saw the data under diligence. It did reach stat sig, atopic derm.

They had a lot of development there. It did not sort of, I guess, meet their bar. They returned it back to the small company. We knew of it. And we came in and we said, we think this can do -- we're not obviously interested in atopic derm, but we think this is a molecule that has shown success, shown promise, shown clear efficacy, good safety profile, we think we can move this forward in things that fit into our therapeutic areas, such as ILD to have it be complementary to TPIP, potentially asthma and others.

So we're really excited about this program. We haven't fully committed to when we'll get it into the clinic. But as soon as possible, the team is just kicking it out of the park and making great progress.

Awesome. Well, thank you so much for the great updates, Sara.

Thank you so much, Joe.

Thanks.

Here we go. All right. Welcome, everyone, to the Insmed fireside chat at the TD Cowen Healthcare Conference. I am covering analyst, Ritu Baral. And with me from Insmed is CEO, Will Lewis.

Thank you, Will, for being here. A big couple of years for you guys ever since the BRINSUPRI Phase III data 18 months ago? 2 years ago. We'll start there. That is the major topic of conversation. It is the major topic of conversation yesterday when I hosted you guys for dinner and a number of you guys. You posted very impressive Q4 numbers of 144. I think even buy-side consensus was less than half that. Sell-side consensus was much lower than that even.

What are right now, the key drivers behind -- what were the key drivers in Q4? And how is that evolving into Q1? Given the caution that you communicated in January at another investor conference, how is that evolving?

So if I could take one thing out of the last 6 months, it would be the degree of caution we introduced at that other conference because I think that was over-interpreted to mean that in some way, the launch was slowing. I want to be really clear, the launch is not slowing.

So it wasn't a bolus? 4Q was not a bolus?

Well, so bolus is a word that means different things to different people. What I would say is the composition of patients coming into the use of this drug fits a variety of different phenotypes. Let's talk about what those look like.

We go all the way back to prior to the -- just after the data. We really kicked off the disease state awareness campaign in earnest. As everyone knows, we brought on our therapeutic specialist force fully 9 months before we even had the drug approved. So with data in hand and awareness increased about the disease state we were out and having very productive discussions with physicians.

That put us in a very strong place for the launch, which is what ended up taking place. We'd like to point out that in the fourth quarter of last year, which is our first full quarter, we did more revenue than DUPIXENT did in its fourth quarter after launch.

So we have a very strong launch out of the gate here. The patients that came into that, there were 9,000 patients in the fourth quarter that were brought on the drug from more than 4,000 physicians. So we have a very broad group of physicians writing prescriptions, and that's very encouraging. It lays the groundwork for continued success.

What's that going to look like? Well, fully half of those physicians have only written one prescription. And so they're testing the drug. They're trying it out in their patient population.

The patients will go away, they'll take the drug. And roughly 2 to 3 months after that is when they tend to come back for a checkup, sometimes as long as 6 months, but it's not typically longer than that when you're taking a new medicine. Physicians want to know how things are going. And the stories we're hearing are that the patients on this drug are having a very positive experience in the way they feel, in the degree to which they're still expectorating or coughing.

Not every patient is going to have this response, but what we have heard has been extremely positive. So the way we think that's going to play out is each of those physicians who've written only one prescription are going to get that feedback from their patients and their peer physicians, and it's going to make them inclined to write again.

So the breadth of prescribing behavior can be something that we can pursue and look to add additional patient volume from as that experience is a positive one. So that's a major driver. Were there any patients that would form some part of a bolus? Almost certainly out of the gate.

When a new medicine arrives, there are going to be patients that are, if you will, stockpiled in some of the centers of excellence that are immediately put on drug. There are a lot of physicians, though, as I've just described, there are still trials...

Those were warehouse -- that's warehousing patients. I guess the question is, was there a bolus of appointments in Q4 where the clinicians -- this is how the investors are defining bolus, right? Like the practices cleared room in Q4 for more bronchiectasis patients to come in, have appointments and start drug.

No. There was nothing that was -- that we could discern that would have established that. I do think that there were some warehouse patients...

Which is different.

Which is different. That's why I say the bolus definition is so important.

Okay. So not a bolus as defined by patient starts, more warehousing of patients for sort of the near term '26.

The single most important driver of this medicine in '26 is going to be the experience that patients have on the medicine and the perception that physicians have with regard to it.

Now we are a company that has been selling ARIKAYCE for 8 years in the United States. That is a difficult medicine to sell. You have a 30% dropout rate. It's a drug device combination. It takes 15 minutes to administer. And yet despite that, we've had very good success with supporting the sale of that medicine to patients that are appropriate.

BRINSUPRI is a once-a-day pill where the placebo rate of adverse events match the treatment rate. So there is a very benign safety profile here. You have a very easy to administer medicine.

So why are you so concerned about this initial treatment experience then? Because you mentioned you want to manage the initial treatment experience, both from a patient and clinician perspective, but it is so tolerable. What's to manage, I guess?

Well, we want to hear that patients are experiencing positive results from the use of the medicine because that increases dramatically the likelihood that they're going to stay on the medicine, that physicians who have noisy patients, by which I mean patients who come in and say, "I'm coughing all the time, I'm expecting all the time. I can't go out in public. I have these flares that keep me home from work, et cetera."

If those patients, and we've heard these stories, come in and say, "I'm no longer coughing. I'm no longer expectorating. My energy is back." Now not every patient is going to have that same experience, but we have seen a lot of public social media discussion by patients a very positive circumstances most dramatically.

I read at a different conference, one of the comments from one of the patients who had gone into their physician's office, and it was the physician who relayed this to us, and have broken down in tears because they had described their life as being back in their control, that this was a miracle drug, et cetera.

Now I want to be cautious for everyone who's listening, we are not advocating for this to be the experience that everyone is going to have on the medicine, but we have heard these anecdotes, and we consider those to be encouraging and powerful forces among the network of physicians that will make them inclined to write again and again and again.

So in the unknown unknowns that we talked, that you mentioned in January, one of the -- a few of the points were co-pay smoothing, payer contracts, inventory dynamics. Last contracting or at least major plans put in place, how have those evolved and your confidence through full year '26?

So the way I would simply describe this as looking at our dashboard, everything is green. We couldn't be happier about the persistence rate, the uptake, the approval, everything is going the way we want it to go.

Where that's going to lead us is the great unknown that I think is probably the subject of attention from everyone on the street because we said initially the 250,000 patients who are diagnosed today with 2 or more exacerbations that we know are out there because they are on the roles as having been diagnosed with this condition with 2 or more exacerbations, that 250,000 patients, that gets us to peak sales in excess of $5 billion.

Now as we think about other populations and the top of the funnel getting filled, we start to think about the other 250,000 diagnosed patients who have between 0 and 1 exacerbations a year.

Now those patients right now are on label. We're not targeting them as intensely because we're trying to work with the insurance companies and the physicians who say that the bulk of the patients they think are appropriate for the medicine at this time are those who are in the moderate to severe category, those with 2 or more exacerbations.

So by working with the insurance companies and agreeing to that restriction to only going after those patients that were studied in the ASPEN trial, we are never going to be friends with the insurance industry, I don't think. But we certainly are trying to meet them halfway.

And I think that is why as market access dynamics continue to look good, we don't anticipate a slowdown from the implementation of new insurance policies. That's the single most important distinction about market access. You start out, everything is a medical exception. We have the infrastructure and the experience to do that because we've been doing it for 8 years for ARIKAYCE.

As the policies get established, they can be more or less restrictive than what you have been bringing online. In our case, it parallels what we've been doing to date. So that this targeting of 2 or more exacerbations in the last 12-month patient profile is, in fact, the sweet spot we're going after. It's where the insurance companies are setting their policies, and it puts us in a very good place to continue to see the kind of uptake as we like to say, up and to the right since the launch of this drug.

So with that access getting expanded in Q1, are you -- and this green across the board that you mentioned, are we taking the possibility for flat to down Q1 off the table?

So I'm not permitted to give any prediction about the quarter. Well, that's the entire front row from Insmed is now saying, "Don't answer that question, Will." The -- I will just say that I think we feel good about where we are. And the way we tried to address this because I know there was concern, we did express some caution at the beginning of January.

But I want to reemphasize that caution we expressed was not because we were in possession of some information that gave us pause. It's because we knew some people were going to run away with the prediction of what this revenue could become. We had originally stated analogs for great performance in quarters Q2 through Q5 would be somewhere in the $500 million to $700 million range.

Everybody thought that was outrageously high that we would never hit it. And now most of the estimates that are out there are north of $1 billion for that same time frame. So everybody has run away and believe that this has now greater potential. And that's a very exciting place to be.

I just want to remind everybody, to the best of our knowledge, there are 15 products in the history of our industry that have ever cleared $1 billion in quarters 2 through 5. J&J has never done it, Merck has never done it. The drugs that have done it are things like COVID vaccines, GLP-1s, Harvoni, Skyrizi; there are not that many that have gotten there. And every company that has ever accomplished that, not one of them has been worth less than $70 billion. So from our perspective, we think we've got the right product. We think it's going to do very well, and we think that's extremely well for the company's future.

So you mentioned that $1 billion of new guidance at floor. And as I mentioned last night, consensus is already at 1.2 right now...

And you're wondering why we introduced caution at the beginning of January. I wonder.

You made me talk my original $800 million down, and then I had to take it back up. So that's an extra note. But if we look at how you're going to meet or exceed the 1.2, certainly beat the 1, what are those levers? Is it expanding lives covered? Is it more guidance? I mean you already haves in [ upper ] included in some guidance, rest of world, depth of prescribing, breadth of prescribing?

Yes. So it's a great question. I think the single most important thing that will drive it, as I mentioned before, the storytelling, the peer-to-peer dialogue among physicians, what is the experience with this medicine? How are your patients doing on the medicine? And what we hear repeatedly is positive feedback there. So that's good.

That should enable us to take advantage of the more than 4,000 physicians who've written at least 1 script to encourage them to write a second or a third. And you can imagine if that is accomplished just with the physicians we've already reached and convinced that the medicine should be written that those are easier to activate to write 2, 3 or 4 prescriptions.

And that's going to be the first area of focus. So that becomes depth from the breadth that has already been established, right? We want to see the breadth continue to grow, right? 4,000 physicians is still just scratching the surface of the 27,000 pulmonologists in the United States.

But with those 4,000 physicians writing and getting as many patients as we have on drug already, it's 11,000 change as of the end of the fourth quarter. We're targeting 250,000 patients who are diagnosed with documented 2 or more exacerbations.

In the U.S.?

In the U.S. alone. So we are just scratching the surface out of the gate. And it's very dramatic, I understand, to come out and say we'll do north of $1 billion in revenue with only 1 full quarter under our belt. But that gives you some idea of where our confidence level is as we look out at this year and beyond.

And so ex U.S. is not part of this $1 billion. It's not -- I mean, when does ex U.S. start factoring in and current thoughts on how to balance the existential MFN threat?

Yes. So right now, we are approved in Europe, and we're approved in the U.K. We have not launched in either of those locations because we're waiting for clarity around MFN. It was not going to be a material part of our revenue this year.

Europe continues to perform very well with ARIKAYCE. Japan, even more so, both in terms of what ARIKAYCE has done over there. They were a huge contributor to last year, and they're hitting this year with stride.

BRINSUPRI is continuing to be pursued over there. We'll see what their pricing decision is and what that would imply for us. But we have to be mindful of MFN and the policy since it has not been finalized yet is one we just have to hold off and respect until it's been clarified what that's going to look like.

To put a finer point on that, in a world where the MFN policy applies only to Medicaid, that's not a big deal. We can manage that. What do I mean by that? If the policy says that your price abroad and very specifically, the second lowest price that you sell the drug outside of the U.S. becomes the price that is applied for Medicaid patients, that's about 3% to 5% of revenue; that's manageable.

If they try to apply it to Medicare Part D patients for almost every biotech company and pharma company out there, it would bankrupt the industry. So I don't think it's going to happen, but they are using that as kind of a stick to motivate people to come to some kind of negotiated agreement. And until those proposed agreements are out there, it's just impossible for us to move forward in Europe.

So we're watching it carefully. I think we're going to come to a rational outcome here. My concern is that if this -- because it's an election year, you're going to hear a lot of drama and see a lot of fireworks. But I think at the end of the day, reducing prices for certain pockets of patient populations in the U.S. is a probable outcome. It's just not going to be as dramatic as I think people would imagine.

And I would just footnote by saying all of those deals that have been done with big pharma, not one of them have been disclosed as an SEC publication, which means not one of them is considered material.

So whatever the agreement is, whatever the hype is, nothing has been disclosed. If it were material, if it was going to have a profound impact on revenue, they would have had to disclose it. So that tells you that whatever the hype is, the substance behind these agreements is not that big.

Drilling down a little on insurance coverage, early indicators of payer access and reimbursement hurdles, what percentage of payers have been implementing, like hard implementing the 2-plus exacerbation prior auth requirement? And what is -- can you talk to sort of the discount you're offering to have this removed?

Yes. So what we did was to go to the insurance companies and say, "Look, this is the only approved medicine for this condition. So technically, you have to cover it." We don't need to negotiate with them. We can just insist that they provide the coverage.

And there are other companies who have taken this approach historically. We didn't feel that was the right one. So what we've gone and done is offered a modest discount, and I'll talk about what that quantity looks like in a moment, in exchange for helping to shape the policy that they develop, which is patients who have 2 or more exacerbations, attestation by the physician that those have occurred as opposed to summing up the documentation and submitting a...

[ They ] are not paying for removal of the 2 plus, you're just making attestation of the 2 plus?

That's correct. The attestation and then it's the reauthorization of the prescription because one of the techniques that's being employed by insurance companies now is they don't want to be on the record for having denied someone access to the medicine. But 6 months after the medicine is used, they may put additional restrictions on its reauthorization.

We are not experiencing that. We have been able to negotiate to avoid that. And frankly, because of the nature of the medicine, it isn't something that insurance companies are going after in our case. But these are the kinds of things you want to think about. And the ability to those policies a little bit in exchange for a modest discount makes sense to us. So that's what we've tried to do.

To be clear, we have not done that with every insurance company. There are some that refused the discount that we offered. They wanted much more, and we said, "No, we're not going to do that." So they're going to be following a policy of documenting the exacerbations and documenting the CT scan and submitting that.

By the way, that's what we've been doing since the launch of the drug because everything has been through medical exception. Now as the policies are established, some of them will require that going forward, some of them will not.

It makes it less difficult if you don't have to provide all that, but it is something we're absolutely prepared to support in terms of companies, doctors' back offices. And many of them have experience with specialty medications like Fasenra. So in that case, they're used to this process. So I don't see it as a break or an impediment in any way.

So part of that -- likely part of the exception process is this idea of CT scans. Now for the plans that took your discount, they're not going to require a submission of a CT read or whatever. But if we think about the plans that are requiring CTs, what percentage are those? Do they need to be recent scans? And how hard is it -- if a patient doesn't have a scan, how fast can they get a scan?

So the temporal component of when the CT scan was taken is less relevant than that there is a definitive diagnosis of bronchiectasis. That's accomplished by a CT scan and a pulmonologist workup. And if that's been documented, then you know the patient has bronchiectasis, that's not in question.

It's a very easy thing to read, by the way, from a radiography point of view. It's a tree and bud pattern. And if it's there, it's a definitive diagnosis of bronchiectasis.

What's interesting is that for many of these ancillary populations, the COPD and asthmatics, many of them have had a CT scan. But if the request has not gone in to look for bronchiectasis, the radiologist may not call it out. So many of these patients may be sitting out there with a CT scan that shows bronchiectasis, but it just hasn't been diagnosed yet.

So there is the ability to retrospectively go back and look at those CT scans and look for bronchiectasis. And we're in the process of doing that in a variety of different ways, trying to support that effort, the use of AI to go back and quickly scan and look for evidence of bronchiectasis is something that some hospitals are making use of.

So I think there's going to be an opportunity to look at that and understand it. And I do want to come back to your earlier question because I didn't answer it on the discount that is associated with these planned negotiations.

What we've guided to is gross to nets of around 25% to low 30s. Knowing that we are responsible for 20% of the catastrophic coverage in the Medicare population means that right out of the gate, our gross to net is going to be at least 12%, 60% of the population, 20% we have to cover, 12%. So if we're guiding 25% to low 30s, you can get a sense that including the other components of the gross to net discount, we're not giving away that much. Otherwise, the gross to net would be much higher.

Going back to what you mentioned about the COPD and asthma population as we think about that undiagnosed pool that you originally talked about, is that CT reread effort the tip of the spear when you think about 3 years from now, 4 years ago now from when you really start focusing on expanding the diagnosed bronchiectasis market?

Yes. So we think of this as almost two different launches. So the first launch is targeting the 250,000 patients diagnosed today with 2 or more exacerbations. That's a massive market. It's a very easy to go after market. There is nothing else approved. There's not expected to be any competition for at least 5 years. That gives us free rein on that initial TAM.

What we're talking about with these comorbid patients is a bigger effort of getting the physicians to increase their index of suspicion, look for bronchiectasis in any COPD or asthmatic patient who is being treated and still has exacerbations because it may be that the source of some of those exacerbations or all of them is actually bronchiectasis, not asthma or COPD.

And so we hesitate to use the phrase misdiagnosis or mistaken diagnosis, but there is probably some portion of patients out there are probably some portion of patients out there that have been misdiagnosed because to diagnose COPD is a spirometry test in the office. To diagnose bronchiectasis requires a CT scan.

Historically, there's no reason to send somebody for a CT scan if you're going to diagnose bronchiectasis and there's nothing available to treat it. Now there is something available to treat it. So you can look for it.

I think the increased diagnosis rates will reflect that over time. And as we shift our attention to that broader population, bringing some of them into the funnel could open up a massive, massive opportunity because the literature right now says somewhere between 40% and 60% of asthma COPD patients are comorbid with bronchiectasis.

Just to put that in perspective, we have a $5 billion peak sales estimate based on 250,000 patients that we're targeting right now. If we take 4% of just the COPD market, the low end of that estimate, that's 800,000 patients. That's more than 3x the market we're going after right now.

So the upside here for this drug in patients on label and which insurance companies will support is multiples of what we're starting after in the first year. So this is a huge opportunity in front of us, and we're going to resource it accordingly.

So we've got 7 minutes left. We need to touch on TPIP because that landscape has been evolving just in the last 24 hours. And your ENCORE readout, which is for ARIKAYCE, which is your next catalyst.

Let me start with TPIP. Thoughts on the competitive landscape in PAH, given the data from [ Tyvaso ] oral treprostinil this morning [ former ] and the conversations around soft mist and potential once-daily Tyvaso, how are you seeing the competitive landscape potentially evolve to time of approval?

So it's still early, and we're getting into the data, but I would just tell you that nothing I saw from this morning's Ralinepag data nor the soft mist inhaler, I think, has any impact whatsoever on the strength of the TPIP target product profile proposition.

We're talking about the only medicine that we have that is available or will be available that is once a day that is inhaled, which is the preferred route of administration and which allows you to get to much, much higher levels of the underlying drug, which is the goal of treatment for this fatal condition.

We saw absolute best-in-class and best-in-disease PVR reduction data in Phase II last year, better than sotatercept. So this drug is more convenient, appears to be more safe and more effective than any other prostanoid bar none.

What is coming out now from [ uther ], I think, is interesting, this soft mist inhaler, for example. That's an attempt to reduce the very difficult problem of cough, but it's one component of the challenge of that medicine. The other components that are challenging are the fact that it's 4 times a day. So you want to use the soft mist inhaler to try and make it easier to take. But what you're doing is you're changing the composition only modestly.

I see this as a product that is going to counter detail YUTREPIA, but I don't see it as a threat to TPIP. Why? The underlying drug that you're breathing in is still active treprostinil and your body reacts to the prostanoid, not to the form. So the more severe cough reaction comes from the fact you're breathing in an active drug. It doesn't come from the fact that it's dry or wet in terms of its inhalation composition.

So yes, you do see some very transient impact from breathing in dry powder, but it is not sustained. And as we saw in our Phase II data last year, it wasn't even hardly in evidence, at least in our case.

The main reason why we don't see a lot of cough with our drug is because it has the 16 carbon chain appended to it. So when you breathe in the drug, it's inert. When you breathe in the soft mist inhaler, the drug is going to be active. You're going to have the same upper airway bronchospasm kind of reaction when that prostanoid is first inhaled, at least that's our prediction. And I will be surprised to see if that is not the case.

Regardless, it's still 4 times a day versus once a day, and we're able to get much, much more drug into these patients. And we've already seen the PVR data from last year's study. We'll have more information by the end of this year as we do the open-label extension in the first year. So that will be interesting. We'll have 6-minute walk data. We'll have NT-proBNP...

With the higher dose.

With higher doses in some cases.

What should we expect? Because I think we're watching -- many investors are watching that [ 12 80 ] higher dose come out of that come out of that open label, what percentage of patients were able to get to that highest dose? And what data could we expect that emerges from that?

So I want to set expectations clearly. We did not set up the open-label extension to push patients to higher doses. It is simply that through the open-label extension, physicians at their discretion, should they wish to, can go above the doses that have been...

We heard they wish to. So that's why I think there's a number of patients.

In some cases, they have raised, but we don't have many patients that are at [ 12 80 ]. Oftentimes, physicians will get patients to a level where they're performing extremely well, and they'll just hold them there. And then as the patient declines later on, that's when they'll increase the dose again.

And that's why you see the opportunity for our drug to be more impactful because with administration once a day, it's very unlikely that patients are going to miss their dose. If you're taking it 4 times a day, that's a bigger burden. And oftentimes, what happens is they'll skip a dose or 2, and that makes it very difficult for them.

But I think the proposition of TPIP and where we are, the open-label extension data, being able to give some additional ideas of what happens as you go up in dose will be very encouraging.

I think certainly, everything that has ever been done with prostanoids shows that the more you give, the more patients benefit. The trick is, can you overcome the adverse event profile? And it certainly seems from our Phase II data that we've been able to do that.

Indeed, our Phase III study targets [ 12 80 ] is the upper end of the dosing range as opposed to 640, which is what we did in Phase II. And the reason we're moving to those higher doses is because the KOLs and the FDA encouraged us to. So this is not just us trying to push the dose as high as we can go. This is us being pulled into that world.

And the best evidence for the perception of this drug as being a real game changer in this industry, Tyvaso right now is approved for PH-ILD. And yet, even though that drug is approved and on the market, we are still able to recruit patients into the PH-ILD study out of the U.S. It's a very encouraging sign. It's early days, but we weren't expecting that.

And last question, I'll ask few minutes. The ENCORE data for frontline, it's only Phase III, could only double your TAM for ARIKAYCE? But what more than -- what do we see?

So it was 30,000 patients is the TAM right now. It goes to north of 200,000 if these data go the way we think they're going to. So it substantially increases the addressable market for ARIKAYCE.

What is good data from ENCORE, especially on that PRO?

Statistical significance on both the PRO in terms of its performance relative to the control arm. And then within group change levels, what percentage of patients show that minimal clinical improvement.

So like a responder analysis within the PRO as well?

Those two, I think, are the most important points. For Japan, it's culture conversion. And certainly for patients and physicians, it's culture conversion.

Even in the U.S.?

Even in the U.S. We've never done a study where we have not won on culture conversion. These patients were recruited at the same time as the ARISE study. The only distinction between these two is that one runs longer.

And what we saw in the ARISE study, which was so compelling, is that we were able to culture convert 80% of patients in 6 months. To put that in perspective, it was considered a breakthrough discovery to convert 30% of patients who are refractory after 12 months of treatment. So this is a major advance. If this continues to hold in the ENCORE study, it also sets up the motivation for physicians to treat these patients earlier.

So control is a double dose of -- I'm sorry, not a double dose. It's a 2-drug combination in ENCORE versus the standard of care, which is 3 drug, right? So you're comparing ARIKAYCE plus a 2-drug with the triple combination.

What is the delta in culture conversion that you think you need to show versus the double combination for this frontline population, right, which does have the option of triple -- cheap triple therapy? What delta do you need to show for doctors to say, yes, we're going to start reaching for this in frontline?

And I wouldn't draw a hard line, but I would say somewhere in the 15% to 20% range in terms of a delta would be clinically meaningful. I think equally important to culture conversion is durability. And you see the Japanese asking for that specifically as a part of their endpoint analysis. So not only do culture convert, but when you go off drug, do you remain culture converted.

And importantly, when you look at ARISE, every patient who had culture converted on the control arm was positive again when next measured. So we are able to provide historically durable culture conversion, which we think is what gives rise to the ultimate benefit to these patients in terms of symptoms, patient-reported outcomes, et cetera.

So all of that aligns very well. We're very confident in these data. We think they're going to go well. And we also know that the FDA is encouraged by the success of this drug and considers it a success story and is anxious to see this get expanded into frontline patients.

With that, we are at time. Thank you very much, Will.

Thank you.

Thank you for standing by, and welcome to the Insmed Fourth Quarter and Full Year 2025 Financial Results Conference Call. [Operator Instructions] I'd now like to turn the call over to Brian Dunn, Head of Investor Relations. You may begin.

Thank you, Rob. Good day, everyone, and welcome to today's conference call to discuss Insmed's Fourth quarter and full year 2025 financial results and provide an update on our business. Before we start, please note that today's call will include forward-looking statements.

These statements represent our judgment as of today and inherently involve risks and uncertainties that may cause actual results to differ materially from the projections discussed. Please refer to our filings with the Securities and Exchange Commission for more information. The information we will discuss on today's call is meant for the benefit of the investment community.

It is not intended for promotional purposes and it is not sufficient for prescribing decisions. Today's call will feature prepared comments by Will Lewis, Chair and Chief Executive Officer; and Sara Bonstein, Chief Financial Officer. After their comments, they will be joined by Martina Flammer, Chief Medical Officer, for the Q&A session. I will now turn the call over to Will.

Thank you, Brian. Good morning, everyone, and thank you for joining us. 2025 was an exceptional year for Insmed, defined by extraordinary execution and transformative impact. Commercially, we witnessed the approval of Brinsupri and its stunning early months of launch performance as well as the continued global performance of ARIKAYCE, which showed significant acceleration from commercial efforts in Europe and especially Japan. .

Clinically, we saw best-in-class performance from TPIP, entered 2 new gene therapies into the clinic for DMD and ALS and completed the acquisition of INS 114. These accomplishments represent a significant expansion of our clinical pipeline despite the discontinuation of CRS without nasal polyps program last quarter. We entered 2026 with the momentum that positions Insmed for sustained leadership in both bronchiectasis and NTM.

In the year ahead, we intend to accelerate and expand the U.S. launch of Brinsupri, while continuing to grow ARIKAYCE. Rarely does the company have the opportunity to own an entire disease category by virtue of having the first approved medicine in a disease with no competition on the immediate horizon.

Insmed enjoys 2 such opportunities in bronchiectasis and NTM, both of which also share a similar call point among pulmonologists to the strong foundation we intend to pursue other first or best-in-class therapies within our 3 target therapeutic areas, which include respiratory, inflammation and immunology and neurology and other rare diseases.

Today, we are pleased to announce revenue guidance for Brinsupri of at least $1 billion in 2026. We are confident providing this guidance earlier than expected due to the additional visibility we have gained into the market access environment and the early performance we have seen from Brinsupri so far this year. To our knowledge, only 15 drug launches in history have been able to surpass the $1 billion mark in their second through fifth full quarters of launch and every company that has achieved that milestone has gone on to reach a market valuation of $70 billion or more.

Coupled with another expected strong year of performance from ARIKAYCE, we anticipate total company revenue in 2026 to be more than double the revenue we produced in 2025. This guidance gives us confidence that we can achieve cash flow positivity without needing to raise additional capital.

However, we may choose to source capital as necessary to support new business development, internal programs or other potentially value-creating initiatives. We are currently evaluating several such opportunities and we'll continue to do so as we prudently seek to expand our pipeline.

Let us now dive deeper into Brinsupri. In 2025, the U.S. launch of Brinsupri surpassed even our most ambitious expectations. Prelaunch, we set a very high bar for what we believe could achieve using a basket of historically strong respiratory launches as our guide with $144.6 million in net revenue in its first full quarter, I'm proud to say that Brinsupri is exceeding that far.

And let me be clear, the launch continues to go well, and the team continues to execute at a very high level. As with many successful medicines, the shape of the launch from one month to another can be inherently variable but the overall trajectory for this launch is strongly up and to the right, and we believe Brinsupri has the potential to be among the best, if not the best specialty respiratory launch ever.

Let me now take a moment to illustrate where we expect the Brinsupri opportunity to evolve over time. In these early months of the launch, we see Brine establishing itself at the forefront of treating bronchiectasis with no competition for several years.

We have previously framed out a peak sales estimate above $5 billion for this indication and everything we have seen so far from this launch has only added to our conviction that the opportunity is at least that large. But I want to emphasize this point. We believe there may be much more.

Let's get specific. We previously defined the total addressable market in the U.S. based on Brinsupri's label as 500,000 currently diagnosed patients with non-CF bronchiectasis. Within that diagnosed population, we estimate that approximately half or 250,000 patients have had 2 or more exacerbations in the last 12 months, matching the profile of the patients who participated in our clinical trials.

Based on those figures, the roughly 11,550 new patients who have started treatment with Brinsupri in 2025 represent less than 5% of that patient population. So there remains an enormous amount of runway within that initial total addressable market. And as a reminder, the greater than $5 billion peak sales estimate was based on us successfully addressing these 250,000 patients only.

In addition, we believe that over time, more of the remaining 250,000 currently diagnosed patients with less than 2 exacerbations will start to move into the category of those who have had 2 or more exacerbations in a 12-month period. This is due to the progressive nature of the disease and better patient reporting and documentation of exacerbation events now that there is an available treatment.

This belief is supported by real-world data in the 2-year study of claims data for nearly 15,000 patients with bronchiectasis, about 47% had 2 or more exacerbations in the first year of follow-up. Then in the second year, another 9% joined that group, meaning that 56% of study patients and 2 or more exacerbations in either the first or second year.

Based on that study, it is our expectation that patients will continue to move into the 2-plus category over time, and this would represent upside to our peak sales estimates. Now if I can leave you with one item to focus on, it is this. There are 32 million diagnosed patients with COPD or asthma in the U.S.

We believe that many of those patients could have undiagnosed bronchiectasis and as a result, may continue to exacerbate despite treatment with standard of care for those diagnoses. I would encourage you to consider and assess this potential for yourself. Recognizing the size of that opportunity, we are turning our attention to outreach and education to physicians in the hopes that they can assess these patients for the presence of bronchiectasis.

The potential additional patients from these populations, which would be on label for Brinsupri, if they are confirmed to have bronchiectasis, towards the initial total addressable market we have just been discussing. We are currently working on a number of different programs to advance the exploration and quantification of these patients.

This effort will be supported by evidence generation in several large respiratory centers who intend to use retrospective data to identify bronchiectasis in patients diagnosed with COPD and asthma who are still exacerbating. We are also creating dedicated teams within our medical and commercial operations to identify these potential patients given the substantial populations they represent.

As many of you know, historical medical literature on this topic provides a wide range of estimates, but a more recent publication that looks specifically at the overlap between COPD, asthma and bronchiectasis suggest that bronchiectasis could be involved in 30% to over 50% of patients with moderate to severe COPD and in 25% to 40% of patients with severe asthma.

These patients may not have received attention or been identified in the past because until Brinsupri came along, there have been no medicine that physicians could turn to upon diagnosis. As we're able to identify patients that may benefit from Brinsupri from within this broader population, we have a chance to help physicians deliver what we believe could be a game-changing medicine for the benefit of their patients.

It is an enormous opportunity to serve patients, and it will take several years to more fully manifest, but it has the potential to expand Brinsupri's impact by orders of magnitude. This is something we are actively working on and we'll continue to monitor, but it is our belief that we could begin to see these patients as early as the end of this year within the pulmonary practices we already call on and more evidently in 2027 and beyond.

Let me now take a step back and describe what we are seeing within the launch to date. Today, we are still in what I would call the exploration stage of the launch. This is a new medicine and as is customary, physicians often want to try it out on a patient or 2 to see how it works, assess safety and then determine how much more broadly they intend to prescribe.

For example, of the 4,000 physicians who have written a prescription through the end of 2025, nearly half have prescribed Brinsupri to just a single patient. As those first patients return to their pulmonologists and share their experience with the treatment early this year, this should play an outsized role in their physicians' interest and willingness to write again.

To date, we have heard very positive feedback through our interactions with physicians and directly from patients through our support services as well as through the patient experiences that have been shared in public forums or on social media.

It can often take several months for patients to return to their physicians' offices to be able to convey these experiences but this positive early feedback suggests that the knock-on effect of these experiences should start to result in additional prescribing behavior by the second quarter, given the large number of new patients that were added in the fourth quarter of 2025.

We believe these positive experiences with the current diagnosed bronchiectasis population, should also increase the likelihood that physicians will be receptive to proactively tracking exacerbations in screening their COPD and asthma patients for bronchiectasis. Turning now to the mechanics of how patients gain access to Brinsupri. A critical element of successful launches is favorable payer access dynamics, and I am pleased to say that this is progressing very well.

In fact, over 90% of targeted patient lives have access to GetranSupery reimbursed either through a documented payer policy or medical exception. We chose to engage payers in an effort to encourage them to make access for appropriate patients as frictionless as possible. For those who have been willing to engage with us and settle on simple attestation based prior authorization and reauthorization criteria, we have offered modest rebates.

Others have chosen to require documentation within their medical policies, which typically means requesting documentation of the CT scan and proof of 2 or more exacerbations. Importantly, we have seen a very high payer approval rate so far, even for payers requiring documentation, which is very promising.

Given our long history with ARIKAYCE, which even now is primarily reimbursed through medical exception, we've become skilled at providing education to health care providers and their offices about documentation and process requirements. We expect these high approval rates to continue in the months ahead as physicians and their staff become more accustomed to the payer reimbursement requirements.

While we expect contracts to continue to officially go into effect over the course of the first half of this year, we've concluded enough of these negotiations to feel confident in the general direction of the market access landscape for Brinsupri. I am pleased to say this landscape is aligned with our prelaunch expectations, with broad access to the treatment for appropriate patients and either physician out of station or manageable documentation required for reimbursement in most cases.

In summary, the Brinsupri launch continues to be very strong. The rate of patient adds, new physicians and manageable market access dynamics gives us comfort that from the initial patients we are targeting, we see a clear path to reaching our stated peak sales goal of more than $5 billion with potentially significant upside from the adjacent populations outlined a few moments ago that could take that peak sales number much higher.

We'll have much more to say in the quarters to come as we gain a clear picture of how big and when those additional patients may be diagnosed and become on label for Brinsupri. The opportunity itself is one that any biotech company would be fortunate to have, and we intend to aggressively resource the launch to maximize its potential. Now let me spend a moment on ARIKAYCE.

Our commercial teams continue to do an excellent job of driving growth of the product. Japan had a particularly impressive 2025, delivering 40% growth compared to 2024 and contributing more than 1/4 of ARIKAYCE's global revenues. In Europe, ARIKAYCE grew even faster, albeit from a more modest revenue base. This strong commercial execution sets the stage for ARIKAYCE's next clinical readout, the Phase II ENCORE trial, which we expect to announce in March or April of this year.

Success in ENCORE could open an opportunity to increase the addressable market for ARIKAYCE from around 30,000 patients today to more than 200,000 patients. Let me now switch gears and spend a moment on TPIP, which was significantly derisked by strong clinical data in 2025, opening up the opportunity for us to pursue 4 Phase III clinical programs in parallel.

We are very excited to announce that last month, we were informed by the FDA's Office of Orphan Drug Products Development of their decision to grant orphan drug designation to treprostinil PALM-ILD for the treatment of pulmonary arterial hypertension. So you can understand the basis for this designation in their own words, I read here from the actual letter we received from the FDA.

"Our decision to grant designation is based on the plausible hypothesis that your drug may be clinically superior to the same drugs already approved the same indication because your drug may be more effective due to greater placebo-corrected improvement in the 6-minute walk distance compared to other approved oral or inhaled formulations of treprostinil and by means of a major contribution to patient care compared to the approved subcutaneous and intravenous formulation of proposal".

This decision, which was based on the FDA's assessment of our Phase II data released last year is a striking validation that our belief that TPIP has the plausible chance to be a meaningfully differentiated treatment compared to other treprostinil options. In our view, this supports our long-held conviction that TPIP could become the prostanoid of choice for physicians and patients.

Last month, we presented the trial design for our PALM PAH Phase III trial of TPIP in patients with PAH at the PVRI conference in Dublin. Recall that the FDA agreed based on the strength of the Phase II results that we would need just 1 Phase III trial powered at the standard 0.05 alpha for a registrational submission.

On this slide, you can see a depiction of the trial design for PALM PAH while much of the design is similar to our Phase II trial, there are some key differences. First, the trial has a longer treatment period of 24 weeks versus 16 weeks in Phase II. This longer treatment period is intended to provide patients with a practical titration window given that this trial will allow patients to dose up to 1,280 micrograms or double the highest dose used in Phase II. To put that high dose into perspective, 1,280 micrograms of TPIP after subtracting the weight of the 16 carbon chain contains about 813 micrograms of treprostinil.

That is more than 3x the highest labeled daily dose of Tyvaso DPI for patients that fully comply with the 4 doses required per day with that treatment. Another difference is that the Phase III study will allow patients to be on background [ sotatercept. ]

Enrollment of those patients will be capped at 20% of the overall population and stratified to ensure balance between treatment arms. Finally, the primary endpoint of 6-minute walk distance will be measured 1 to 3 hours post dose to approximate TPIP's peak effect similar to trials of other treprostinil products. Trough measurements will also be captured as secondary endpoints.

We are incredibly excited to get this trial started in the first half of this year. To recap, I am very pleased with where we are as a company. The Brinsupri launch continues to go well, allowing us to announce revenue guidance for 2026 of at least $1 billion for that therapy. When combined with the strong performance that we expect for ARIKAYCE in 2026 and we expect to produce revenue on a company-wide basis that more than doubles from last year.

And even that could be just the beginning as we await a near-term pivotal readout for ARIKAYCE that could expand its label and we work to identify new patients who could benefit from Brinsupri. For TPIP, we have received an orphan drug designation for treprostinil PALM-ID to the treatment of PAH and have released the Phase III trial design for that indication.

If successful, the FDA has indicated that this single Phase III would be sufficient to support a filing for TPIP in patients with PAH. Finally, we have a strong and growing pipeline of potentially first or best-in-class investigational programs behind the ones we've spoken about today, many of which should also begin to contribute catalysts over the next year and beyond.

With that, let me turn the call over to Sarah.

Thank you, Will, and good morning, everyone. Given that Will has already walked you through our 2026 revenue guidance for ARIKAYCE and Brinsupri, let me provide you with a few additional comments on our expected gross to nets in 2026. In the past, we have highlighted a range of 25% to 35% as a reasonable analog for Brinsupri gross to net at launch. This range was based on precedent launches and the impact of new catastrophic coverage requirements under IRA legislation. .

Today, we believe we have good visibility into where payer contracting is headed and are now positioned to provide a gross to net guidance range of mid-20s to low 30s for Brinsupri in 2026. Importantly, our 2025 actual gross to net for Brent Super was also in that range, which implies that the rebating expected to go into effect into 2026 and will be modest and is therefore not anticipated to have a significant effect on the overall GTN of the product.

For ARIKAYCE, GTN for 2026 is expected to range from the low to mid-20s, a slight increase from 2025 due primarily to the impact of the small manufacturer phase-in and other provisions under IRA. Let me spend a moment on our cash position.

As of the end of 2025, we had approximately $1.4 billion in cash, cash equivalents and marketable securities. Cash burn in Q4 included approximately $70 million of onetime items, largely attributed to the asset acquisition of INS-1148 and the milestone payment to AstraZeneca related to Brinsupri's U.S. approval. Excluding those onetime items and the cash receipts related to stock option exercises in the period, our underlying cash burn for the quarter was similar to the underlying burn levels that we saw in the prior quarter.

Keep in mind that only a portion of the Brinsupri revenue we recognized this quarter had been received in cash as of December 31, so our cash burn does not reflect that full benefit. As we have said before, we expect both revenue and spending to continue to increase as we fully resource and support Brinsupri launch as well as other programs from across our portfolio that are expected to continue to ramp in the near and medium term.

Finally, I would like to reemphasize the statement will made earlier as it relates to our pathway to profitability. Based on our existing development plan and the strength of our commercial engine and its revenue capabilities, I am confident we can achieve cash flow positivity without needing to access additional capital.

That said, I will remind you that we have and will continue to invest in appropriate business development opportunities as well as internal programs and therefore, may choose to source additional capital to advance and expand our pipeline in support of additional future value creation.

Moving now to other relevant financial metrics for the fourth quarter, which are displayed on this slide. Cost of product revenues in the fourth quarter of 2025 was $44.2 million or 16.8% of revenues which is lower on a percentage basis based on our historical performance, reflecting the positive contributions of Brinsupri to the company's gross margin profile. Additionally, as expected, research and development and SG&A expenses increased this quarter compared to prior year period due to the necessary investments made to support the U.S. launch of Brinsupri and to continue to fund our growing pipeline.

In closing, I am pleased to report that Insmed remains in a strong financial position, providing us with the capacity to pursue our ambitious goal to expand our reach and our impact on patients. We look forward to continuing to utilize our resources to pursue the potentially value-creating opportunities we have in front of us.

We would now like to open the call to your questions. Operator, may we take the first question, please?

[Operator Instructions] Your first question today comes from the line of Joe Schwartz from Leerink Partners.

Congrats on the very strong performance. It certainly seems like the TAM for Brinsupri has a lot of room to expand with a very well-designed strategy to identify patients with COPD or asthma who are exacerbating with bronchiectasis, but might not yet be identified as such I look forward to hearing about that progress on that front as you embark on this initiative.

But I was wondering if you have any plans to develop other DPP1 inhibitors within respiratory disease in order to expand your franchise further? And if so, how do these other agents differ from Brinsupri.

Yes, I appreciate the question. Absolutely, we intend to bring other DPP1 forward, not just in the respiratory indications, but in others, as an example, 1033 will enter the clinic this year for rheumatoid arthritis and irritable bowel disease, a couple of indications within that. And that will be in the second half of this year.

In parallel, we're also advancing other DPP 1s into conditions in respiratory like COPD and asthma that is absolutely on the horizon for us. Martina perhaps can comment a little bit here on the distinction between the patients we're targeting who may be responsive to Brinsupri because they are bronchiectatic versus those who are asthmatic and/or COPD of a particular profile distinct from the bronchiectasis patient that these other DPP1 would target. Martina, do you want to address that?

Yes, sure. So we're looking at a phenotype of patients who continue to exacerbate even though they're optimally treated for COPD or for asthma already. And most of those patients not only have a higher increase in pulmonary exacerbations, but also an increased acceleration in lung function decline as well as an increase in mortality. So that is a specific phenotype of patient population that we're looking for.

Your next question comes from the line of Jason Zemansky from Bank of America.

Congrats on the progress, Will, I was hoping you could provide some additional color regarding the guidance for Brinsupri. Can you speak to some of the specific elements of patient behavior that gives you confidence at this point, specifically with regards to dynamics like compliance, discontinuations, prescription abandonment.

I mean I know it's early, but do you have a sense of what that looks like? And how did that influence your projections?

Sure. So we have -- as you might imagine, a number of different data sources we examined, but there is generally a very detailed dashboard. And what I would convey to you is that across all the metrics, we're seeing at or above our targets, and that's very much behind why we have the conviction that we'll do at least $1 billion in revenue in Brinsupri this year. .

So I'd say across the board, we're very encouraged, whether it's market access metrics, whether it's use, low discontinuation rates, reauthorizations going through I'd say we feel very, very good about where things are.

Your next question comes from the line of Olivia Brayer from Cantor.

And my congrats as well on the quarter. Can you comment at all on the Scripps trends that Symphony is picking up? Are those January and early February trends indicative of what you guys are seeing on your end?

And anything you can tell us at this point, just about how new starts are trending so far this year. And then I did just want to ask around interest in BD activity. It looks like you guys flagged that a couple of times in the slides and potentially raising capital around that.

What kind of deals are you guys interested in pursuing? And what's the rationale for potentially doing a bigger deal at this point?

Yes. Thanks. As it relates to the performance, I mean I think things just are very strong out of the gate is the only way I could describe it. And so we see -- we hear a lot of talk about the Symphony data, obviously. We don't track it. We don't pay attention to it. But what our what we were trying to accomplish today because we are always very detailed and I would say, transparent about the puts and takes that may be in operation in any given week for any given medicine.

This is what could hold it back, this is what could accelerate it. that I think is often interpreted as caution or conservatism on our part. And what I want to make sure we get across today is that we feel great about the way this launch is going.

And we do believe we're going to join that very rarest of groups that can produce $1 billion plus in revenue by adding quarters 2 through 5 together. There aren't many in history that have done it and those that have gone on to be very successful companies. And that's because to get to that level by the end of the fourth quarter, you're going to have to be at a run rate that would imply you're going to continue to do very well as you go into '27 and beyond.

So with all that confidence that comes from doing the examination at a very refined level of script trends, physician behavior, surveys that we do, behavior of patients on medicine, the market access picture. All of these things combined to give us a very good feeling about the direction we're traveling and that's why we're able much earlier than expected to give this direction that we'll do at least $1 billion.

That then feeds into the notion that we're on track to get to cash flow positivity without having to access more capital. And that is absolutely the case. The only potential issue we want to raise is that if we see something that's interesting on the business development side, we would not hesitate to bring it on board.

We think now is the time to press the advantage should we find first or best-in-class compounds that we can bring on board.

An example of that would be INS 148 which we got, in our view, for a very modest amount and which has what we consider to be DPP1 like potential in its application across a range of different potential diseases. So more to come on that asset, but assets like that, that we can add that are sort of Phase II ready. Those are in our sweet spot for sure, where we can step right into the clinic bring to bear our capabilities in clinical developments and trial design and get to a next candidate molecule that could be first or best-in-class.

Your next question comes from the line of Ritu Baral from TD Cowen.

Will, kind of dig into some of this baseline guidance a little further, Entera as well. when will you and when will we get more clarity on refinement of this $1 billion-plus level sites already sits right around that.

And if you stretch the numbers out, it implies 15% to 20% quarter-over-quarter guidance, which strikes me as relatively modest given the past few quarters and all of the patient finding initiatives, does this have -- so can you comment on that?

And also, does this idea of requiring the additional paperwork, I guess, and the 2 or more exacerbations factor into the uptake because it sounds like you guys are expecting a certain number of plans to still require this documentation and that it might be higher than you previously expected? Those were the questions.

Yes. So let me be really clear. The market access picture is fantastic from our point of view. It's ahead of where we thought it was going to be internally. So in no way do I want you to interpret are mentioning of some plans requiring documentation and some not as being indicative of any impact on anything other than enthusiasm for our forecast. .

What I would tell you about that existence of those requirements of documentation, we always expected that some portion of these plans would require that. That's why we fielded so many field access managers who can support the back office effectively in navigating that. And to be clear, to date, that's how everybody has done it. It's been all medical exception.

So now that the policy has come into place, that smooths the uptake because our concentration has always been on patients with 2 or more exacerbations, even though our label is for any and all bronchiectatic patients. So strong position with regard to market access and uptake.

And with regard to the baseline guidance, look, we have one full quarter under our belt. So it's, I think, audacious to put out $1 billion plus forecast for quarters 2 through 5 since only 15 products in history have ever done it to the best of our knowledge, and that includes all the COVID products, the GLP-1s, Harvoni and [indiscernible], SKYRIZI, household name programs.

And to that list, Insmed intends to add its name of Brinsupri. So we are incredibly happy about where we are and where we're going. I would not interpret at this stage, which is very early with one full quarter under our belt thinking that by saying $1 billion, we in any way mean to imply that we're slowing down on the contrary.

This is what's giving us the confidence to go and suggest that there's going to continue to be acceleration throughout the year. We will provide more qualitative guidance at least as we go through the year on how the quarters are progressing but given the dashboard and the direction we're traveling right now, we feel very good about this launch.

Your next question comes from the line of Gavin Clark-Gartner from Evercore ISI.

So you said you haven't seen any change in approval rates from start forms to paid drug -- what is that actual approval rate right now? And just on a similar topic, have you seen any changes in the conversion speed from Star form to pay drug?

Yes. So we aren't disclosing particular elements of it like the approval rate itself. What I would tell you is that our benchmark internally based off of our experience with ARIKAYCE, which is very good, is very high, and we are at or exceeding that level. And then with regard to any other thing that is actually driving the launch, as I said, the dashboard for us is green. So I don't know how else to convey to you that we feel that we're in a very strong position.

Your next question comes from the line of Ellie Merle from Barclays.

This is Jasmine on for Ali. Congratulations on the progress. What is the ex U.S. contribution to your Brinsupri guidance of the $1 billion or more for -- and can you just talk a little bit more about your launch strategy ex U.S. for this year? .

Sure. So I'll ask Sarah to comment on the different components of our revenue in a moment. The strategy is to launch in Europe and in Japan. We want clarity on the MFN policies that are coming forward now. I think we're going to have that in the coming weeks and at the most months. But until that's clear, it seems to us that the prudent thing to do is to sort of put things on hold until we know what that's going to look like. .

To be very clear, that does not reduce our enthusiasm for going to Europe and Japan and our teams there are continuing to advance work in contemplation of when that day comes, but we really need clarity from the administration first on what these policies are going to look like, so we can assess those trade-offs and understand where we need to go to.

Sarah, do you want to take the composition question?

Sure. Happy to. And thanks for the question. What I would comment on is, as we have said previously, any ex U.S. contribution for Brinsupri in 2026 was going to be very, very small given the original time lines we put out, we're obviously going to be monitoring the U.S. policy as well stated. So we feel very confident in the $1 billion plus for Brent Superi regardless of sort of the timing of the pause as we're thinking about contributions. And broadly speaking, the contributions for Brinsupri will be vastly weighted towards the U.S.

Your next question comes from the line of Andy Chen from Wolfe Research.

This is Brandon on for Andy. Regarding additional capital to support business development or other value creation -- to us, it sounds like incremental spend on clinical programs. How are you thinking about this relative to achieving cash flow positivity? And is achieving cash flow positive more of a near-term 2026 goal or in the outer years?

Yes. So we -- I would just say we see a very clear path to cash flow positivity. I view it as an inevitability just based on our assumptions about where revenues will go for both Brinsupri and ARIKAYCE our base business that this cash flow positivity journey contemplates includes Phase III programs for HS, which may or may not happen as we all know. But it contemplates some expenditure in these programs that you're making reference to.

So we would put the cash flow positivity journey separate from BD. BD is the thing that is incremental that would result in us approaching the markets for capital. And look, there's plenty of different ways we can do that. And Sarah, maybe you want to just take it from here and share your thoughts.

Sure. Happy to, and thanks for the question. Yes. As Will said, we have -- the $1.4 billion provides us that ability to fund through cash flow positivity for our base business inclusive of the programs that we have under our umbrella today. BD is obviously separate from that. As we think about different ways to augment balance sheet. There are all levers that are -- that exist are available to us, and we have the ability to be thoughtful on that if and when the appropriate BD opportunity did present itself.