INSM - NASDAQ

Thank you for standing-by. My name is Amy, and I will be your conference operator for today. At this time, I would like to welcome everyone to the Insmed First Quarter 2025 Financial Results Call. [Operator Instructions] It is now my pleasure to turn the call over to Bryan Dunn. You may begin.

Thank you, Amy. Good day, everyone, and welcome to today's conference call, in which we will discuss Insmed's first quarter 2025 financial results and provide an update on our business. Before we start, please note that today's call will 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 concerning the risk factors that could affect the company. 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. I'm joined today by Will Lewis, Chair and Chief Executive Officer; and Sara Bonstein, Chief Financial Officer, who will each provide prepared remarks, after which they will be joined by Martina Flammer, Chief Medical Officer, for a Q&A session. I will now turn the call over to Will.

Thank you, Bryan, and welcome, everyone. 2025 is off to an exceptionally strong start for Insmed with our research and development, regulatory and commercial teams executing on their ambitious goals for the year. ARIKAYCE delivered another quarter of double-digit year-over-year revenue growth in Q1 and each of our mid to late-stage clinical programs are on or ahead of schedule. Perhaps most importantly, we have continued to facilitate the FDA's ongoing review of our NDA filing for brensocatib in bronchiectasis, which has been steadily progressing without disruption despite the changes occurring at the agency. We continue to expect the FDA's decision on their review by the August 12 PDUFA date. Before I walk-through our recent progress in more detail, I'd like to reflect briefly on where Insmed currently stands on its development journey and importantly, what still lies ahead. Insmed is advancing three mid to late-stage programs with brensocatib, TPIP and ARIKAYCE. We have achieved an uninterrupted string of positive clinical data for at least one indication from each program, which is a rare accomplishment. These results have offered patients new hope and have given us the confidence to pursue additional indications. In the next 12 months, we look forward to reading out data from TPIP for PAH, brensocatib for CRS without nasal polyps and the ARIKAYCE ENCORE trial for all MAC lung disease. If we are successful, these potential additional indications would represent a meaningful advancement for patients and a substantial growth opportunity for the company. Now let's dive deeper into each of these programs, starting with brensocatib. Last month, the full results of the Phase 3 ASPEN trial of brensocatib in bronchiectasis were published in the New England Journal of Medicine, emphasizing the importance of this dataset to the medical, scientific and patient communities. The publication puts brensocatib among a rare category of drugs that have had both their Phase 2 and Phase 3 results for the same indication highlighted by the New England Journal of Medicine. At the FDA, the review team continues to be engaged and responsive and we are not aware of any turnover or other disruptions to the FDA's review activities. In fact, all components of the review process have occurred on-schedule, including the mid-cycle review meeting and all applicable inspections to date. We look forward to the FDA's decision in the coming months and are hopeful that it will result in this important medicine finally becoming available to bronchiectasis patients waiting for a therapy like brensocatib. As the regulatory process in the U.S. progresses, we are also making meaningful strides on our launch readiness. I am pleased to report that as of the end of April, our disease state awareness website has had over a million unique visits and over 53,000 self-identified patients who have taken action such as downloading support tools or signing up to be kept informed about the latest updates in bronchiectasis. In addition, we continue to engage with both national and regional payers, which is critical as we prepare for our goal of a frictionless launch. So far, we have found a constructive audience in response to the proposals we presented within our initial discussions. As you know, additional U.S. sales reps were hired and deployed in October of 2024 with the aim of educating healthcare professionals about bronchiectasis while also detailing ARIKAYCE. In fact, that team has already successfully engaged with more than 27,000 healthcare professionals in the U.S. We've also recently-completed the expansion of our patient support function, building on the strong foundation that we provided ARIKAYCE patients for many years. This function will be critical to fulfilling our mission to transform the lives of patients living with serious diseases by supporting them through their journey. Another indication of the promise of brensocatib is the encouraging regulatory reception it's receiving internationally. Like at the FDA, both the European and U.K. regulatory authorities have accepted our filings of brensocatib and are conducting their respective regulatory reviews. We also continue to advance our filing for Japanese regulators, and we look-forward to submitting that application soon. Importantly, this progress keeps us squarely on-track for potential approvals and launches in each region in 2026. Our second indication for brensocatib, CRS without nasal polyps, is also advancing at an impressive pace. After sustained strong recruitment, the Phase 2 BiRCh trial completed enrollment last month with 288 randomized patients exceeding our original 270 patient target. We continue to expect top-line results by the end of this year. We remain encouraged by the blinded data we have seen from the study so far and look forward to what those data could mean for patients. If successful, we believe that the BiRCh Phase 2 clinical study could unlock a significant additional commercial opportunity for brensocatib that could match or even exceed that of bronchiectasis given the larger number of patients suffering from this condition. I'm also pleased to mention that while still early, enrollment in our Phase 2 SEDAR trial, which examines the potential role of brensocatib in hidradenitis suppurativa is proceeding well. Based on our current enrollment rate, we anticipate the interim futility evaluation of the first 100 patients to occur in the first half of next year. I also want to briefly touch upon DPP-1 inhibition and the meaningful progress we are making to develop our next generation of DPP-1 inhibitors. The potential of this novel pathway for treating neutrophils-mediated diseases is still in its infancy and represents one of the most exciting and important areas of research we are exploring for patients. As a leader in DPP-1 inhibition, our research team is working tirelessly on next generation molecules with the potential to address other diseases where neutrophilic inflammation is relevant such as COPD, rheumatoid arthritis and many others. We anticipate the first of our next generation molecules could enter the clinic as soon as next year. Turning now to our TPIP program. Our Phase 2 trial of TPIP in patients with pulmonary arterial hypertension continues to progress toward a topline readout. The last patient's Week 16 visit occurred in late March, and we are now in the process of cleaning and locking the database before unblinding the results. Based on this progress, we are narrowing the expected timing for the topline readout to June or the earlier end of our previously communicated timing of midyear. As we approach that readout, our excitement continues to grow for what it could mean for patients. Given its proximity and in keeping with our usual practice, I want to be clear about what we would see as success for this trial before we turn over those results. If the treatment shows a placebo-adjusted reduction in pulmonary vascular resistance from baseline of 20%, we would view that as a clear win. If it shows a 25% reduction on that measure, we believe it would be a homerun, representing a best-in-class PVR reduction for a prostanoid in this setting. When you also consider that participants in this trial are heavily pretreated and that we are measuring this endpoint 24 hours after the most recent dose of TPIP, in other words, at trough or the most conservative time point, such a result would be all the more impressive. Separately, although this study is not powered to show a definitive effect on six-minute walk distance, our hope is that we will see a 15-meter to 20-meter directional benefit favoring TPIP. Regardless of the efficacy results that are achieved in this Phase 2, it is important to remember that this could be the starting point for TPIP's efficacy profile, given that the study's MAX tolerated initial dose was set at 640 micrograms. While this max dose represents about 60% more treprostinil than the combination of four daily doses of TYVASO DPI, we have been encouraged by our study's investigators to allow for even higher dosing. In our Phase 3 program, we intend to allow patients to titrate their dose up to a maximum of 1,280 micrograms or double the highest dose that was allowed in this Phase 2 study. Given that higher doses of treprostinil have been shown both in clinical trials and in real-world practice to yield greater efficacy in a dose-dependent fashion, the potential for safely increasing the dose of TPIP is extremely exciting. Taken together, the prospect of greater efficacy combined with once-a-day dosing emphasizes how potentially powerful this therapy could be for improving patient outcomes in PAH and PH-ILD. One final update that we believe underscores the excitement of our investigators and study participants. Of the patients who completed the full 16 weeks of treatment in our Phase 2 PAH trial, about 95% of them have chosen to enroll in the open-label extension, which allows patients to titrate up to a max of 1,280 micrograms and some have already reached that high dose. Data from this open-label extension will be made available at a future medical conference after the topline readout. Collectively, we will use the information from our Phase 2 trials of TPIP to finalize our clinical plans for Phase 3 trials in both PH-ILD and PAH with PH-ILD expected to start in the second half of 2025 and PAH to follow shortly thereafter. Finally, let me touch on our ARIKAYCE development program, which aims to satisfy the post-marketing requirement for full approval of its current refractory MAC lung disease indication, while also supporting the expansion of the label to include all patients with MAC lung disease. The Phase 3 ENCORE trial continues to progress on-schedule toward its anticipated readout. As you know, this trial has a primary endpoint that is based on a patient-reported outcome measure applicable for the U.S. regulators, which will be measured at month 13. It also has a separate durable culture conversion primary endpoint that is applicable for the Japanese regulators and that is measured at month 15. It is our intention to wait to unblind all the data until the month 15 culture conversion results are available. As a result, we expect the topline results will be available in the first half of 2026 and we will provide more detail as this time approaches. Encouragingly, we have been monitoring the data from ENCORE on a blinded basis, which continues to look very similar to what we saw in the successful ARISE study. Before I hand the call over to Sara, let me simply say that Insmed is ready for the exciting future ahead. Each of our development programs is showing meaningful progress. Our regulatory filings and launch preparations for brensocatib are all advancing on or ahead of schedule and our commercial performance continues to deliver strong year-over-year revenue growth in each of our regions. Let me now turn the call over to Sara.

Thank you, Will, and good morning, everyone. I'm thrilled to be addressing you during one of the most inspiring periods that we have ever seen at Insmed. In the midst of all the excitement going on inside the company, I want to take a moment to address concerns that I often hear about what is happening outside the company, particularly as it relates to tariffs. We have done extensive work to understand the potential impacts of various tariff policies on Insmed. And based on that work, we are comfortable that Insmed is well positioned to thrive even in an environment of relative geopolitical uncertainties. Importantly, Insmed's U.S. intellectual property resides in the U.S. This means we would expect tariffs to be applied only to the actual cost base of the product without any additional exposures due to markups or transfer price strategies, which are commonly used by others in our industry. In addition, Insmed intends to expand its current U.S. manufacturing footprint. We've had projects underway for some time to establish a second source of manufacturing for brensocatib in the United States. Importantly, all manufacturing for our gene therapy programs is already based in the U.S. Based on the tariffs currently in place, we estimate the impact on our business to be in the single-digit millions annually over the next few years. We will continue to monitor and assess any impacts as the macro-environment evolves. Let's move on to our first quarter results, beginning with the strong commercial performance of ARIKAYCE, which is illustrated on this slide. We were pleased to deliver double-digit year-over-year growth in each of our geographic regions in the first quarter, representing the sixth quarter in a row for this achievement. Particularly striking was the percentage growth rates we saw in Japan and Europe, both hovering around 50%. These impressive results were driven by strong volume trends due to an increase in new patient starts. In addition, our U.S. commercial team delivered strong 14% growth for ARIKAYCE this quarter, a remarkable result for our product in its 7th year post launch. Due to the strength of this performance across each of our commercial regions, we remain on track to achieve our 2025 full year ARIKAYCE net revenue guidance of $405 million to $425 million. As a reminder, this guidance range is specific to ARIKAYCE and does not include any future contributions from brensocatib if approved. On Slide 18, you can see our cash balance as of the end of the quarter. At approximately $1.2 billion in cash, cash equivalents and marketable securities, we are well capitalized as we approach our upcoming clinical and commercial catalysts later this year. As is typically the case in the first quarter, our cash burn was higher than our usual quarterly cadence as a result of the timing of our annual employee incentive compensation payout. If you remove the impact of that payment as well as the cash we received due to stock option exercises in the quarter, our underlying burn in the quarter was comparable to prior quarters. Although we don't guide to cash burn levels, in general, we continue to expect our burn to increase as we build out the necessary personnel and infrastructure in anticipation of the brensocatib launch. On the other side of that launch, we anticipate that increases in spending will more than offset - will be more than offset by revenue growth, leading to progressively smaller quarterly operating cash outflows. As I've said many times, we are not currently funded through profitability, but importantly, that is by our own choice because we believe the investments we are making now will lead to outsized returns in the future. We continue to have line-of-sight to becoming a cash-flow positive company and believe our purposeful investments along with future potential revenue growth have put us on that path. Additionally, we expect to have many options for accessing the capital we need when the appropriate time comes. Last month, we announced that we were calling the remaining $570 million of convertible debt on our balance sheet, which would have matured in 2028 with a redemption date of June 6, 2025. If all the debt is converted prior to redemption, it will result in the issuance of approximately 17.8 million additional shares of common stock. This conversion would not only lower our ongoing interest expense but would also meaningfully reduce our outstanding debt. We look forward to providing you with an update after the redemption date. Moving to the next slide, you could see our operating expenses for the quarter. Cost of product revenues for first-quarter 2025 was $21.3 million or 22.9% of revenues, which is consistent with our historical performance. As expected, both our research and development and SG&A expenses were higher this quarter than they were in the previous year's first quarter due to the significant growth of our company during the past year to support our commercial readiness initiatives in anticipation of the U.S. launch of brensocatib as well as our increasing investments in our early and mid to late-stage pipelines. However, I will point out that our operating expenses this quarter were down from the levels we saw in the first quarter of 2024 - in the fourth quarter of 2024. This was driven largely by lower research and development costs across brensocatib for bronchiectasis and TPIP. We anticipate that research and development expenses will increase going forward, as we kick-off the Phase 3 programs for TPIP, continued investments to advance brensocatib in both CRS and HS and advance multiple gene therapy product candidates into the clinic. In closing, we believe Insmed is in a unique position of strength, both financially and operationally. We continue to deliver strong ARIKAYCE revenue growth in all of our regions. The expected launch of brensocatib later this year has the potential to significantly accelerate our revenue growth. In parallel, our team continues to execute with meaningful clinical and data catalysts in the near term. All of this is supported by our strong cash position. I couldn't be more pleased with where Insmed stands. With that, we would now like to open the call to your questions. Operator, may we take the first question, please.

[Operator Instructions] Your first question comes from the line of Andrea Newkirk with Goldman Sachs. Your line is now open.

Good morning. Thanks for taking the question and congratulations on the progress. Will, as you think about brensocatib launching globally and given what you've mentioned is what you think peak sales could be, how much does potential MFN legislation factor into your thinking on how to price both in the U.S. and abroad? And then I have a follow-up.

So, I think, you know, it's hard to speculate on what really will end up being the outcome. It is the pattern of behavior that we've observed that sometimes things are said that are quite dramatic and then there's a period of time for reflection and consideration and then the ultimate outcome is some compromise that orbits around what was originally said, but it's pretty distant from it. Regardless of what the actual outcome is, I think we're in a uniquely strong position because, of course, we don't have to look at brensocatib through the lens of what has already happened. We're setting the price in the U.S. first and then we're going to be setting prices in Europe and U.K. and Japan second, third and fourth respectively. And the consequence of that is it gives us tremendous flexibility to respond to whatever the new environment will be. Importantly, for everyone's recollection, ARIKAYCE was priced at parity between the U.S., Europe and Japan when it was launched.

Right. Okay. And then just one more here, just given the increased engagement with your bronchiectasis disease awareness website that you mentioned, can you speak to what trends, if any, that you're picking up on? And when you think about this patient group, how motivated are they to actively seek out with pulmonologists for treatment? And should we expect there to be a bolus of patients coming onto therapy upon approval? Thanks so much.

Sure. So, one thing we know about commercial launches is that there's always something that's unexpected that occurs within them, at least, oftentimes more than one thing. What I can tell you is that the backdrop that we're approaching here is favorable across the board. The number of patients that are active, the interest and enthusiasm level from them parallel to that that we're receiving from the physicians. The response we got to the New England Journal of Medicine publication was overwhelming and I would just say I feel very good about the landscape we're stepping into, and I think we're ready for it. What that will look like, whether it will be a bolus upfront or whether it will be more gradual, it's hard to say. As we mentioned in the opening remarks, we've now reached all the pulmonologists basically in the United States and that's almost 30,000 physicians. So, we have a very good understanding of the landscape. We're ready to launch this drug, assuming approval and I'm expecting that will go well. I think it's hard to say what the pattern will look like, but we certainly are targeting a frictionless launch and by that we mean easy and rapid uptake for patients that are appropriate to go on therapy and the physicians that are identifying them have an easy process to get them on medicine.

Thank you. Your next question comes from the line of Jason

Great. Good morning. Congrats on the progress and thank you for taking our questions. I had a follow-up on your comments just now. But again, the patient numbers seem pretty compelling in terms of kind of driving that frictionless launch. But what do you see as sort of the big levers there in terms of transitioning a patient who might be interested onto therapy. I appreciate that you're in the field here, but curious as to what you're hearing about potential headwinds here and how you intend to make the process kind of seamless and moving that interest into an actual revenue-generating patient?

Yes. So again, I think it's going to be hard to know until we're actually in the middle of it. What I can say is that when we talked about the numbers we were targeting out of the gate here, we are - it was very important that people understand we're talking about patients that are already diagnosed and have two or more exacerbations. So, this is the label we anticipate receiving. Obviously, that will drive what is an appropriate patient for use and the physicians are prepared knowing that they have patients that have two or more exacerbations within the last 12 months and that this medicine is coming. So, I think making sure we connect those dots and just execute on that is going to be the first order of business. There is a second order that will be occurring in parallel, which is looking at those patients who are very likely bronchiectatic and probably have had two or more exacerbations, but perhaps they have not had their CT scan or have not seen a pulmonologist recently. We've been encouraging through disease state awareness, both for patients and physicians to explore those conditions and patients and try to line them up so they, if appropriate, can be diagnosed as bronchiectatic with two or more exacerbations and would therefore be on label for treatment. Once again, I think we have a healthy number of patients that we've identified. We think we know where they are, and we have built those relationships over the last many months. I think it's not unfair to say that we have a strong reputation in the pulmonology community as a result of the way we've handled ourselves with ARIKAYCE and that will pay dividends in this setting. I just met with the leadership of the U.S. Commercial Team and I can tell you to a person, they are exceptional, and we are going to do an extremely good job at this launch. But the specifics of what that will look like, we're just not going to know it until we're in the middle of it.

And I would just add one additional comment. I'll remind you all that the COPD Foundation, they had an initiative to create 150-ish sites over the next three years that specialize in NTM and bronchiectasis. And my understanding is sort of the first cohort of those have been established in excess of 30 new sites that would specialize in treating NTM and bronchiectasis. So that is obviously encouraging to see for patients as well.

And you asked about levers. So, Sara, it's an excellent point. The COPD foundation efforts. Similarly, there are guidelines out there to treat bronchiectasis. I don't know, Martina, if you want to just comment on those.

Yes. So, I think the guidelines are expecting, of course, been waiting for the publication. We know that tests and as well as ERS are expecting and working on updating their guidelines. We hope, of course, that they take this into consideration. Also remember, right now, patients have nothing to really treat their disease. We are talking about patients who do respiratory therapy and if they have an infection, they are getting an antibiotic. It is nothing that currently truly impacts the progression of their disease or goes to the causation of their disease. And maybe one more comment that shows us also the interest just driven by patients themselves because we've measured who is actually looking at the publications at the New England Journal, and we've seen an exorbitant high amount of over 60% that is coming from the public. So, this is largely representing by patients, inquisite family members and caregivers. We expect always the scientific community to be part of it, but patients who are strongly engaged and their representatives are looking at this publication and this data.

Just to clarify quickly, do you expect the CT scan to be necessary for a prescription and diagnosis there?

Yes. So just to be crystal-clear, the definitive diagnosis of bronchiectasis is achieved with a high-resolution CT scan and symptom evaluation by a pulmonologist. And so, when we identify patients with two or more exacerbations who have a definitive diagnosis of bronchiectasis, all of those criteria are met in the numbers we've outlined. What we've raised for awareness is that there are many, many more behind them who perhaps have COPD or asthma or some other comorbidity and also are experiencing exacerbations despite being on best available treatments for those conditions. And that suggests that they may also be suffering from bronchiectasis. To Martina's point, in the absence of anything to treat these patients, there really hasn't been a strong motivation to get them a CT scan to definitively define and identify the diagnosis of bronchiectasis because there's nothing they can do about it. So, with that potential arrival of this new medicine, that will change that equation dramatically. And it's not uncommon to find when a disease that has a first-ever treatment arrives that many more patients than were originally thought are part of the diagnosed group that eventually emerges.

Thank you. Your next question comes from the line of Jessica Fye with JPMorgan. Your line is now open.

Hi, this is Nick on for Jess. Thanks for taking our questions. First, for the upcoming TPIP update, can you talk about how you're thinking about the relative importance of PVR versus 6-minute walk? And then I know it doesn't sound like it, but can you just remind us if you're powered for 6-minute walk in the Phase 2 trial?

Yes. So, the way we think about it is that the most definitive examination of this is the PVR measure, right. That's a direct measure of pulmonary vascular resistance. These patients typically expire as a result of right heart failure, so the ability to alleviate that pressure is very, very material. It's also an incredibly invasive measure. And so that's why it's not conducted commonly or widely. In the setting of the clinical trial in Phase 2 in particular, you're often seeing it as the definitive measure for whether or not the drug is having an impact. And then people look to the correlate of 6-minute walk test and other biomarkers like NT-proBNP to capture the impact as a result of the treatment. So, we think PVR is the most important measure. I think the agency and physicians would agree with that. And then we look at 6-minute walk as a less specific measure but still capturing the ultimate exercise capacity of patients as an ancillary benefit of the pulmonary vascular resistance improvement. So, when we look at it in this context of this Phase 2 study, we are not powered for statistical significance on 6-minute walk test. However, we are hoping to see a trend somewhere in the 15-meter to 20-meter range, just as we expressed that we're hoping to see a placebo-adjusted PVR reduction of 20% as the threshold for success for this trial. We are - it's our practice to put out these expectations before data is unblinded. We get them by stepping back and saying what would be a definitive way to prove that this medicine is impactful in a Phase 2 setting that would impress physicians and regulators and market access participants. And having done that work, these are the measures that we come back with, and we'll see where the trial comes out. It's been widely reported that the fact that this is a once a day is in and of itself a huge advance for these patients. Clearly, we're not setting ourselves up to top tick the results because we're measuring across, but nonetheless, we think that's the right way to think about it through the lens of the patient, the physician and the regulatory and market access communities. What will this drug really do for patients after they take it? And if we can capture that by an improvement of 20% or so placebo adjusted on PVR, that's a clear win.

Thank you. Your next question comes from the line of Joe Schwartz with Leerink Partners. Your line is now open.

Great. Thanks for taking my question and for the update. On brensocatib, it was great to see the New England Journal of Medicine article recently. The accompanying editorial seemed to raise some questions about the magnitude of the benefit. And I'm just wondering how common is that opinion in the marketplace and what does the company typically - or what kind of company say when - in order to educate folks on the importance of the benefit and how come we don't hear more about the severity of exacerbations as opposed to just the number of exacerbations?

Yes. So, a number of points in there, Joe. The first is to understand that when the New England Journal has published the results from Phase 2 and Phase 3 for the same drug and the same condition, that's an extremely rare occurrence. I think in the last 25 years, it's happened maybe five times in the respiratory field, and it's been for drugs like Dupixent and other extremely impactful medicines. So, we're excited about that. Coupled with that to have two editorials associated with the publication is also equally rare and it highlights the importance that the medical community puts on the arrival of this medicine, which is something that the editorial clearly called out. This is the new kid on the block as they said. It's important to go for a more nuanced look at what those editorials were saying and where they are coming from. And so let me just take a moment to dwell on that. The reference to a macrolide as a potential use of therapy is not uncommon in the most restricted and rationed healthcare systems in the world. That was the lens through which they were examining this. It is not something we have encountered in any of our settings where we are planning on commercializing the drug and it is not something that is common discussion. Clearly, macrolides and other medicines are used for the treatment of bronchiectasis when patients develop infections, but macrolide use as a monotherapy is a really big no-no. And one of the challenges that emerges from that is the potential for resistance development to a macrolide. And once that happens, that patient is in very serious trouble. So you will hear mention of this in rational - healthcare ration communities. I think it was offered as something almost ancillary. We have not encountered it in any of our market access discussions, nor do we expect to, nor would you find it commonly suggested in the medical community, but it is an interesting additional perspective and I think the New England Journal prides itself in ensuring objectivity and third-party points of view are heard and that's why we received the two editorials, which on balance, I would say, were quite positive in terms of their endorsement of the arrival of this new and important medicine.

Thank you. Your next question comes from the line of Vamil Divan with Guggenheim Securities. Your line is now open.

Hi, thank you. This is Daniel on for Vamil. I have a couple of questions on the next generation DPP1s. So, you mentioned that COPD and rheumatoid arthritis, there are potential indications to pursue. So maybe if you could describe in a little more detail the choice of highlighting these two indications in particular? And if there is any sort of hierarchy between those two for which you think would be a higher priority whether due to commercial or scientific reasons? And connected to that, maybe if you could dive into what properties you're looking for in the next generation DPP1 as compared to what you have with the brensocatib profile? Thank you.

Sure. So, I think the first thing that is important to convey is that our North Star is always the patient and the impact of the medicine on the patient. And while that may sound try to ring a little hollow to people in this industry, it is truly something to which we align ourselves. And with that in mind, we look at these areas, COPD, rheumatoid arthritis and many others because we see an unmet medical need and we see this medicine as having a particularly impactful potential in those settings. We've done some early animal work in some of these. And so, we know that DPP1 in that setting is effective. That raises our expectation and excitement and enthusiasm for what we may be able to do. Shortly after the WILLOW study was published, we began work on expanding the library of DPP1 candidates, both from the point-of-view of protecting what we already have, but also to expand potential clinical use into new indications. And so, some of these molecules differ from brensocatib in ways that we hope will ultimately result in clinical benefit to patients in these different disease settings. And that is the primary driver of how we're going about their assessment. As they develop and as we learn more entering the clinic perhaps as early as next year, we certainly are going to be very excited about that because these are substantial indications, and our goal is to have the biggest influence on the largest number of patients and that's why we targeted them.

Thank you. Your next question comes from the line of Ritu Baral with TD Cowen. Your line is now open.

Hi guys. Thanks for taking the question. Apologies for any background noise. Will, can you address if there's any outstanding inspections on the brenso review to be done, whether it's domestic or international? And then I have a follow-up question on TPIP.

So, the short answer to your question, Ritu, is that the FDA can reserve the right to inspect all the way up basically till the end of the approval. So, we can't say definitively whether or not there's any more to come. I can only say definitively, as we mentioned in the comments that we've had some inspections. We've had the mid-cycle review. Everything is going according to plan. We couldn't be happier about the progress we're making and that's being echoed in what we're seeing internationally in terms of the engagement, both in the approval of the initial filing, but also the engagement we're receiving from the regulators almost on a daily basis, as we sit here today. So nothing but thumbs-up from our side at this point to report.

Were there any surprises in the mid-cycle review meeting? And then on the TPIP side, what are your thoughts on either the Phase 3 design or the path forward in the event of divergent 6-minute walk and PVR data? You clearly expressed the 15 to 20 on 6-minute walk and then the 20 plus on PVR. But what if you have sort of extreme, what does that tell you about what you need to do with the Phase 3?

Yes. So, on the midcycle review, no surprises. On the TPIP study, you do see divergence on occasion in these measures, and that's always something that is what gives us caution to otherwise interpreting the blinded data that has been positive as we've shared to date. But I'm not as concerned about that for a number of reasons. The primary one being that this is a known moiety. The underlying drug, the prostanoid class, the vasodilatation it accomplishes is well established to be beneficial in both of these measures. And consequently, we would expect that to be evident. If we see aberrations, we'll obviously look very closely at the data. Many of you have heard the great story from the Phase 2 of last year, where we had a patient who had great PVR reduction and then had a terrible 6-minute walk results and then it turned out that between the beginning and the end of their six-minute walk measure, they had broken their leg. So sometimes it is just something as simple as that that can throw off results. If it's a more a broader trend that - where there's divergence, that would be very unexpected. So I would just say, I think we feel good about where we are. We're going to know in about a month and once we've got that data in hand, we'll obviously share it and be very transparent with it because we think it's important for people to understand if we have enthusiasm where that's coming from.

Thank you. Your next question comes from the line of Jennifer Kim with Cantor Fitzgerald. Your line is now open.

Hi, thanks for taking my question. Congrats on the progress. Maybe to start, during your prepared remarks, you commented on expanding your U.S. manufacturing footprint, specifically for brenso and U.S., can you just talk about timing?

So, part of that is driven by how we managed to pull this through. And as you know, these things are not just as simple as flipping a switch and starting something up. There's qualification, there's other elements of that. But the important point for people to understand is that this is a plan that has been underway for some time. And so, as we begin to implement it, we'll provide further updates. But as a point of departure, as Sara mentioned, our tariff exposure is de-minimis by virtue of domiciling our U.S. intellectual property in the U.S., coupled with the fact that our manufacturing base is already in some cases exclusively in the U.S. in some of - for some of our programs. And for others that are important, we are already underway in establishing duplicative manufacturing capability in the U.S.

Okay. That's helpful. And maybe a question on blinded, blended data. Maybe both for BiRCh for brenso and ARIKAYCE for ENCORE. I think, ARIKAYCE you said blinded blended data looks very similar to ARISE. Is that in terms of the individual components of the PRO? And then on BiRCh, any update on what you've been seeing?

So, on BiRCh and the ENCORE study, I'm going to turn it over to Martina for her comments.

Yes. So, for the ENCORE study, we continue to look at blinded what is the trend that we see in the PRO. It's the PRO, as you know, as we've aligned with the agency will be based on the QLB with eight questions. It's not looking at the individual components. It seems we are blinded at this point, but what we see is consistency of what we have seen in ARISE. With regards to BiRCh, the same is true when you look at the primary endpoint in the BiRCh study is the sino total symptom score. So, this is also a questionnaire that patients fill out every day. And over the treatment period, you'll look of where - what is the difference that you see towards the end or towards between baseline and the end of treatment. So, we're looking and see, is there anything that is unexpected or do we see a trend in the right direction, which is what we currently do. There is a second PRO that is - that you're looking at and that is called the SNOT-22. This is often very - a very good correlator also to the total symptom score and we're seeing that both of those continue to trend in the right direction and most importantly in the same direction.

Thank you. Your next question comes from the line of Liisa Bayko with Evercore. Your line is now open.

Hi, thanks for taking the question. I'm wondering if you could just walk us through this, so we have it kind of all straight. Number of patients with bronchiectasis, this is in the U.S., those with a CT scan, how many are under care and then how many have at least two exacerbations? And when we think about that just to - just ask a little question on that. Is that - would that be like in the last year or is that kind of on average in the prior years, like how do we think about that? But I'm just trying to kind of break-down from sort of top-to-bottom when you launch, how many are actually in care with at least two exacerbations? Thanks.

Sure. So just to be really clear, the numbers that we have put out into the ether as it were about patient numbers in the U.S. are derived from ICD10 coding for bronchiectasis patients with two or more exacerbations in the last 12 months. So, the entry criteria for our Phase 3 study, which we anticipate will be the criteria for use at the market access level. We don't actually anticipate that, that will necessarily be the label, but it doesn't really matter because the market access is what's going to control obviously access to the medicine. From that point-of-view, the roughly 500,000 patients in the U.S. represents those that are diagnosed today with bronchiectasis, including a definitive CT scan, of those roughly half we estimate have had two or more exacerbations documented in the last 12 months, so entirely consistent with that market access criteria and those are the patients that we'll be targeting out of the gate.

Okay, great. Thanks.

Thank you. Your next question comes from the line of Graig Suvannavejh with Mizuho Securities. Your line is now open.

Okay. Thank you. Thanks for taking my question. Congrats on the quarter and the progress. I wanted to get back to the brensocatib launch and the idea that you're going to try to affect a frictionless launch, you've given us great color on what's happening with patients. Just remind us on the payer front, you provided some color on how that's going, but could you provide a little bit more on perhaps based maybe on latest market research like where pricing, where your head is on pricing and also just for our modeling purposes and what we might be able to think about in terms of gross-to-net? Thanks.

Sure. So, I'll turn pricing and gross-to-net over to Sara in a minute. But the frictionless launch ambition we have is just really the - a way to express best possible practice for a commercial launch for any medicine. And what we're trying to do is ensure not only that the access to the medicine once the appropriate patient has been identified is smooth and easy that insurance will support that as quickly as possible and that we can fulfill that to ensure that patient has the best possible experience on the medicine. That obviously includes for a chronic medicine like this one, reauthorization as well as upfront ease of access. And so we are entering into select negotiations and contracting to gain that access and to ensure that the prior authorization is one that is consistent and doesn't introduce any unnecessary onerous aspects to it, like going back and pulling from the records, the scan and the documentation of the exacerbations, what we're looking for is a physician to simply attest to the existence of those, which is the appropriate way to address something like this. So, with all that said, our discussions with the market access world have been very positive. I think, I think we continue to feel very good about the ranges we've expressed to the Street in terms of price and no new information that would direct that any other way. I think this launch is going to go well based on those pre-approval discussions with market access, which can now include detail from the actual Phase 3 study. So, in other words, we're having much more specific dialog with the market access world. Here is what the medicine is going to provide, here is what we propose, and we get to hear their reaction to that and ultimately, we'll come to agreement with them as we get closer to launch. And we won't launch the actual - announce the actual price until the - till just at the time of launch. But Sara, over to you for comments on price and gross-to-net.

Yes, sure. Thanks, Graig, for the question. I'll just remind the listeners that we have put out a price range $40,000 to $96,000 based on other products in this space. We've commented that we believe our price will be in the upper half of that range. I do not expect that we will provide any more narrow guidance on that until we launch. On gross-to-net, we have again not provided formal guidance, but we have studied other specialty launches and what their gross-to-net has looked like as well as the impact of IRA. I'll remind folks that we are not subject to the small manufacturer sort of exception for brenso like we are ARIKAYCE because brenso isn't launched yet. So, we will need to pay for the 20% catastrophic coverage for the Medicare patients. We've commented we believe the breakdown will be pretty similar, so about 60% of patients we will believe will be on Medicare. So, off the bat, that's 12% on gross-to-net. And so, if you study all that and take that into account somewhere between 25% and 35% seems reasonable based on precedent analogs, but again, not formal guidance. Hope that helps.

Thank you. Your next question comes from the line of Leonid Timashev with RBC. Your line is now open.

Hi guys, thanks for taking my question. I just wanted to ask on the HS trial. And can you guys talk a little bit more about what the bar for the futility analysis is going to be? Is that just going to be any positive trend? Is there like a 20% difference that you'd like to see? And then ultimately, just curious what you'd expect or would like to show relative to the jacks and the biologics in that indication? Thanks.

Martina, do you want to take that one?

Yes, sure. So, remember, on the futility analysis of 100 patients, we're not looking for a p-value. We're looking for a signal of efficacy and we're still determining with the - from a statistical perspective exactly how that will look like. For this Phase 2 study, what we are looking at is the difference of the total abscess and nodule count from baseline to the end of treatment. I think the study will tell us what we have in terms of the efficacy and that will allow us to then exit plan for what is it that we can show and that we will plan for in Phase 3.

And just so you're clear, that 100 patient analysis, that will be an unblinded analysis by an outside group of experts. We will not see that data. So, there'll be no data shared with the market or with us for that matter. What we're simply going to hear is a thumbs up or a thumbs down, this trial should continue because we see something going on there that could be positive, or we don't see anything that's futile and shut it down. And that goes to the heart of our belief that we don't want patients on a medicine they're not going to receive benefit from. And this has few animal models that are gold standard in terms of predictability. So, our hope is that this medicine will show something and that first 100 patients will permit us to say so. And if that's the case, then we want to continue with all speed on the completion of that Phase 2 trial from which we'll learn and derive how we're going to structure the Phase 3 trial. In the end, we're anxious to see whether or not this medicine could be a complement to the other medicines that have been developed for the treatment of this condition.

Yes. Maybe just one thing to add. So, what we are looking for from a powering perspective really for this trial is that we are showing a 40% reduction. That's what we're aiming for versus placebo in the AN count. And I just want to remind everybody, the AN count is not exactly the same as the high score, but it has two-thirds of the components of the high score and that will inform how we're powering for Phase 3.

Thank you. Your next question comes from the line of Nicole Germino with Truist Securities. Your line is now open.

Hi, good morning. Congrats on the progress and thanks for taking the question. So just quickly, for CRS without nasal polyps, are you enriching for patients with higher neutrophil level or patients were a lot worse? And is there a minimum threshold to cut-off for NSP in blood or is that something that you're looking for in the pre-subgroups that you'll be examining? And I have a quick follow-up.

So, I'll ask Martina to take that question.

Yes. So, in the BiRCh study, we're allowing patients to enroll up to 750 eosinophilic counts. The reason we're cutting it off at this point is because if you go into very high eosinophil counts, the disease is most likely purely eosinophilic driven and that's not the population that we're looking at. However, patients below 300 as well as above 300 cap - but below 750, both are enrolled into trial. What we've seen in the ASPEN study because we looked at these patients as well as there was not really a difference between either of those patient populations. And in a blinded way, that is what we are currently seeing also in the BiRCh trial. That is the reason why we have made the decision to look at the analysis of the intent-to-treat analysis. And there is no indication right now that we see that both of these patients would be differently. So, with capping patients at 750, you are really capturing the vast majority of patients with CRS without nasal polyps. And maybe just a short comment on how this endotyping, so the mix between neutrophilic and eosinophilic disease works. While in the majority of cases, it's neutrophils that drive the disease, there is a mixed endotype where both neutrophil and eosinophils are part of the disease. And right now, we will look of what BiRCh shows us in CRS without nasal polyps and we can then decide is there an opportunity to go potentially even in-patients with nasal polyps. Maybe just as a reminder, if you look for an example that is similar, in patients with severe asthma have a similar type where they have a mix between neutrophils and eosinophils and that could be also a situation that we see in CRS overall.

And just to highlight this, we originally thought you would see a distinction between higher or lower eosinophil counts. And so, we stratified the trial across the numbers that Martina just mentioned. So, patients below 750, but above 300 and those patients below 300 in terms of eosinophil counts. Because of the ASPEN analysis, which revealed that there was no difference in terms of impact on patients with those different eosinophil profiles, we've now removed that stratification from our statistical analysis plan that's been proposed and that essentially increases the statistical power of the study on that endpoint.

Okay, great. Thanks so much for that. And then one quick clarification. So, the two classifications in the CT scan, is that going to be on the label or is this more for a care requirement?

So, we don't anticipate it will be on the label. It'll obviously - we won't know until we see the label. But in our discussion, that is not our - the direction we're traveling. However, we have always said that market access is going to align their approval pathway with - where the entry criteria of the Phase 3 study and so, we're structuring all of our commercial efforts around that reality.

Yes, maybe just to add - just to clarify, I think I heard you say two HRCT scans, it is the HRCT scan is just to diagnose the disease. The two pulmonary exacerbations is what we've studied.

Right. And those are examined - I mean, pardon me, those are documented separately from the CT scan.

Thank you. Your next question comes from the line of Maxwell Skor with Morgan Stanley. Your line is now open.

Great. Thank you. Just a quick question on the TPIP readout in PAH. Could you remind me the rationale for measuring PVR versus baseline and how we should think about the potential placebo rate? And also, for the potential Phase 3 trial, what do you consider to be a relevant primary endpoint? Will you potentially go with mortality or - morbidity and mortality-based endpoints? Thank you.

I'll ask Martina to address that.

Yes. Maybe let me start with Phase 3. So, the registrational endpoint recognized is a 6-minute walk distance, that would we anticipate we will have as primary endpoint also in Phase 3. Yes, there is clinical worsening, and clinical worsening would be one of the things we consider as an endpoint. We right now look at the primary endpoint being the 6-minute walk distance. With regards to PVR, so you're measuring PVR at baseline and at the end-of-the study to basically see what is the reduction that you can achieve over the treatment period. In our trial, we are titrating up to a maximum of 640 micrograms. That titration goes over a three-week period. Majority of the - many patients have already reached the 640 micrograms, which is why in the open-label study, we are allowing a higher titration up to 1,280 micrograms. We anticipate and plan for a higher up to 1,280 in our Phase 3 study and the exact design we will then determine based on the Phase 2 readout.

Thank you. And your next question comes from the line of Trung Huynh with UBS. Your line is now open.

Thanks for the question. I have one and then just a clarification on TPIP. So, you announced your CCO departed the company late last month. Do you anticipate naming a permanent replacement ahead of brenso's potential launch? And then the clarification on TPIP. Just in your prepared remarks, you said you're locking and cleaning at the moment. Is there anything particularly unusual or complex about that database cleaning or analysis process? Your last patient week 16 visit was late March, and you expect readout in June. That's three months. And should we expect anything with this data release? Thank you.

Yes. So, in regard to the Chief Commercial Officer, that's a transition in a search that is underway. We're not in any rush. We have the benefit of continued access to Drayton during this timeframe. And also, I'll remind everybody that we also have the benefit of our Chief Operating Officer, who is the former Chief Commercial Officer of the company, who is still working with us and so I feel like we are belt and suspenders in terms of the capabilities we have on-board right now. And I'll also just emphasize, our preparation for this commercial launch began two years ago, so we are unusual in that regard. Many of you had many questions about that during the two years before we saw the data and I understand those questions. But now that the data has come out as strong as it has, everyone celebrates that early effort and early investment in the preparation for a successful launch. And I think we're all going to be the beneficiaries of that, most importantly, the patients. The second question was with regard to TPIP and the data cleaning. All right. So, the note I wrote here was registration. So, one of the things we're doing with this TPIP dataset, as we do with all of our datasets now is we want them to be registrational quality. What that means is you can produce topline results pretty quickly after you lock and clean a database, but we want to go back in and make sure that every single detail there is accounted for in every way so that it is prepared and ready for submission to the FDA. And that requires an extra layer of scrutiny and quality control. There is nothing about this database that we have seen that is aberrant or in any way problematic and you should not interpret the time we're taking as being related to that. On the contrary, I'll just remind everybody, the original timeline for this was the second half of this year. The trial was then accelerated once the blended blinded to the treating physician community and they began to come to us with patients that they wanted to put on the trial. And now we're in a place where we're able to narrow down the release of the topline results to June of this year, which is at the front-end of our original guidance of the middle of the year. So overall, I would say this is moving very efficiently. The team is doing a fantastic job of getting the database ready, not only for the release in terms of topline results to the Street, but also equally importantly, if not more so preparation for a registrational submission when that day comes.

Thank you. Your final question comes from the line of Andy Chen with Wolfe Research. Your line is now open.

Hi, this is Emma on for Andy. Thanks for taking our question and congrats on the quarter. Just a question from our side on your gene therapy program. With the patient death reported with Sarepta's DMD gene therapy, has this influenced your development strategy at all? Thank you.

So, I appreciate the question. I think one of the things that we want to emphasize about these programs are that they sit in what we refer to as our fourth pillar. The entire scope of research that's underway at Insmed is while controlled from a capital investment point-of-view at less than 20% of our overall spend, it is nonetheless, I would describe it as extensive. We have advanced a number of different preclinical programs. We haven't commented on them publicly just because we think the right time for a company of our profile to bring those to your attention is as they are entering the clinic. The strategy, in particular with regard to gene therapy and as it relates to DMD is that we are using an intrathecal delivery approach that has several benefits, one of which is that it reduces the amount of drug that you actually have to deliver. That is a clear safety benefit to patients. The other is that by virtue of it being an intrathecal delivery, you're bypassing the first pass effect on the liver, which is typically where the strongest immune reactions occur, and a lot of the viral delivery is frankly lost. So you have to overdose the patient to get past the liver's efficiency at removing a lot of that viral vector. What we've seen in the preclinical models is that this has resulted in a very good transduction throughout the musculoskeletal system as well as the cardiac tissue, quite remarkable given that it's intrathecally delivered. And I think that's going to - we think that's going to provide benefits from a safety point of view as well as an efficacy point of view. We'll see that as we begin to dose these patients. Just to remind everybody, it's going to take a while for us to get patients on drug and then we are going to be for purposes of safety, titrating up slowly to ensure that we have - get these patients get the appropriate dose and that we're putting safety first. We have not seen anything that gives us any concern of the kind that you've seen at other places, and we certainly hope that we don't see any more of that for anyone. But I think one of the reasons we try to take the extra time on our gene therapy program is because of those safety concerns that have appeared. CMC and our control over that is I think a standard setting for the industry. I think as we look at the other gene therapies we're developing for things like ALS and Stargardt, those two are on-track for getting into the clinic between now and sort of 18 months from now. And as those develop and they get in and we begin to see data, safety and efficacy, we'll be sure to share that with everybody.