Q1 2025 Insmed Inc Earnings Call

Speaker Change: Thank you so much for this opportunity to see you, we truly thank you.

Amy: Thank you for standing by. My name is Amy and I will be your conference operator for today.

Speaker Change: At this time, I would like to welcome everyone to the Insmed First Quarter 2025 Financial Results Call.

Speaker Change: All participants have been placed in a listen only mode. After the speaker's remarks, we will conduct a question and answer session. If you would like to join the queue to ask a question, simply press star followed by the number one on your telephone keypad. It is now my pleasure to turn the call over to Bryan Dunn. You may begin.

Bryan Dunn: 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.

Bryan Dunn: 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 a today and inherently involve risks and uncertainties that may cause actual results to differ materially from the results discussed.

Bryan Dunn: Please refer to our filings with the Securities and Exchange Commission for more information concerning the risk factors that could affect the company.

Bryan Dunn: 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 purpose-cribing decisions [inaudible]

Bryan Dunn: 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

Will Lewis: 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.

Will Lewis: Eric Kase 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.

Will Lewis: Perhaps most importantly, we have continued to facilitate the FDA's ongoing review of our NDA filing for Brenso Cateb and Bronky Ectasis, 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 12th Padoofidae.

Will Lewis: 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.

Will Lewis: Insmed is advancing three mid-to-late stage programs with Brinso-Catab, T-P-I-P, and Errakase. We have achieved an uninterrupted string of positive clinical data for at least one indication from each program, which is a rare accomplishment.

Will Lewis: These results have offered patients new hope and have given us the confidence to pursue additional indications .

Will Lewis: In the next 12 months, we look forward to reading out data from T-P-I-P for P-A-H, Brinso Cattib for CRS without nasal polyps, and the Ericace Encore trial for all Mac lung disease.

Will Lewis: If we are successful, these potential additional indications would represent a meaningful advancement for patients and a substantial growth opportunity for the company

Will Lewis: Now, let's dive deeper into each of these programs, starting with Brent Sokata.

Will Lewis: Last month, the four results of the Phase III Aspen Trial, the Brensocadeb and Bronky Actuses, were published in the New England Journal of Medicine, emphasizing the importance of this data set to the medical, scientific, and patient communities.

Will Lewis: The publication puts Brunswick Adam among a rare category of drugs that have had both their phase two and phase three results for the same indication highlighted by the New England Journal of Medicine

Will Lewis: At the FDA, the review team continues to be engaged in 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. This is the end of the review, and we are not aware of any turnover or other disruptions to the FDA's review.

Will Lewis: 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 bronchi-actasis patients waiting for a therapy like Brinsocata

Will Lewis: As the regulatory process in the U.S. progresses, we are also making meaningful strides on our launch readiness.

Will Lewis: I'm 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 bronchiactasis the end of July , the end of July , the end of July , the end of July ,

Will Lewis: In addition, we continue to engage with both national and regional pairs 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.

Will Lewis: As you know, additional US sales reps were hired and deployed in October of 2024 with the aim of educating health care professionals about bronchi-actasis while also detailing error case

Will Lewis: In fact, that team has already successfully engaged with more than 27,000 healthcare professionals in the U.S.

Will Lewis: We've also recently completed the expansion of our patient support function, building on the strong foundation that we provided error case 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.

Will Lewis: Another indication of the promise of Brunswick Cattab is the encouraging regulatory reception it's receiving internationally. [inaudible]

Will Lewis: Like at the FDA, both the European and UK regulatory authorities have accepted our filings of Brinsocadab and are conducting their respective regulatory reviews.

Will Lewis: 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 We continue to advance our filing for Japanese regulators and we look forward to submitting that application soon

Thank you.

Will Lewis: Our second indication for Brenso Cattab, 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.

Will Lewis: We continue to expect top-line results by the end of this year. We remain encouraged by the blind to data we have seen from the studies so far and look forward to what those data could mean for patients.

Will Lewis: If successful, we believe that the Birch Phase II clinical study could unlock a significant additional commercial opportunity for Brinso Cattab that could match or even exceed that of bronchiectasis given the larger number of patients suffering from this condition.

Will Lewis: I'm also pleased to mention that, while still early, enrollment in our phase two cedar trial, which examines the potential role of Brentso Caddab and Hydrata Knight is super-tiva, is proceeding well.

Will Lewis: 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 [inaudible]

Will Lewis: 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 neutrophil-mediated diseases is still in its infancy and represents one of the most exciting and important areas of research we are exploring for patients

Will Lewis: 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 nutrophilic inflammation is relevant, such as COPD, rheumatoid arthritis, and many others. [inaudible]

Will Lewis: We anticipate the first of our next generation molecules could enter the clinic as soon as next year.

Turning now to our TPI P program.

Will Lewis: Our Phase 2 trial of TPIP in patients with pulmonary arterial hypertension continues to progress toward a top line readout [inaudible]

Will Lewis: The last patient's week sixteen visit occurred in late March and we are now in the process of cleaning and locking the database before unblinding the results [inaudible]

Will Lewis: Based on this progress, we are narrowing the expected timing for the top line read out to June , or the earlier end of our previously communicated timing of mid-year [inaudible]

Will Lewis: 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 [inaudible]

Will Lewis: If the treatment shows a placebo-adjusted reduction in pulmonary vascular resistance from baseline of 20%, we would view that as a clear win

Will Lewis: If it shows a 25% reduction on that measure, we believe it would be a home run representing a best in class PVR reduction for a prostinoid in this setting.

Will Lewis: 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.

Will Lewis: 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 to 20 meter directional benefit favoring TPIP.

Will Lewis: Regardless of the efficacy results that are achieved in this phase two, 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.

Will Lewis: While this max dose represents about 60% more traprosnel than the combination of four daily doses of Tavezo DPI, we have been encouraged by our studies investigators to allow for even higher dosing.

Will Lewis: 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 high dose that was allowed in this Phase 2 study.

Will Lewis: Given that higher doses of Croprosanol 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.

Will Lewis: 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 P.H. I.L.D.

Will Lewis: One final update that we believe underscores the excitement of our investigators and study participants.

Will Lewis: 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.

Will Lewis: Data from this open label extension will be made available at a future medical conference after the top line readout.

Will Lewis: Collectively, we will use the information from our Phase 2 trials of TPIP to finalize our clinical plans for Phase 3 trials in both PHLD and PH with PHLD expected to start in the second half of 2025 and PH to follow shortly thereafter.

Will Lewis: Finally, let me touch on our error case 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.

Will Lewis: The Phase III 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 US regulators, which will be measured at month 13. [inaudible]

Will Lewis: It also has a separate durable culture conversion primary end point that is applicable for the Japanese regulators, and that is measured at month 15

Will Lewis: 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 that top line results will be available in the first half of 2026 and we will provide more detail as this time approaches [inaudible]

Will Lewis: 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.

Will Lewis: Before I hand the call over to Sara, let me simply say that Insmed is ready for the exciting future ahead.

Will Lewis: Each of our development programs is showing meaningful progress, our regulatory filings and launch preparations for Brentsoe Cateb 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 Sarah.

Sarah Bonstein: 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 in Insmed.

Thank you for joining us. We appreciate it.

Sarah Bonstein: 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.

Sarah Bonstein: We have done extensive work to understand the potential impacts of various types of policies on Insmed and based on that work, we are comfortable that Insmed is well positioned to survive, even in an environment of relative geopolitical uncertainties.

Importantly, Insmed U.S. intellectual property resides in the U.S.

Sarah Bonstein: 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.

Sarah Bonstein: In addition, INSMED intends to expand its current U.S. manufacturing footprint. We have had projects underway for some time to establish a second source of manufacturing for bread soak acid in the United States.

Sarah Bonstein: Importantly, all manufacturing for gene therapy programs is already based in the U.S in the U.S.

Sarah Bonstein: 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.

Speaker Change: Let's move on to our first quarter results, beginning with the strong commercial performance of Aircase, which is illustrated on this slide.

Speaker Change: 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.

Speaker Change: 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.

Speaker Change: In addition, our US commercial team delivered strong 14% growth for error case this quarter, a remarkable result for a product in its 7th year of post-launch.

Speaker Change: Due to the strength of this performance across each of our commercial regions, we remain on track to achieve our 2025 full-year error case net revenue guidance of $405 to $425 million.

Speaker Change: As a reminder, this guidance range is specific to error case and does not include any future contributions for Brentsocathib, if approved.

Speaker Change: On slide 18, you can see our cash balance as of the end of the quarter. At approximately $1.2 billion in cash cash equivalent to marketable securities, we are well capitalized as we approach our upcoming clinical and commercial catalyst later this year.

Speaker Change: 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

Speaker Change: 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.

Speaker Change: Although we don't guide to cash burn levels, in general, we continue to expect our burns to increase as we build out the necessary personnel and infrastructure in anticipation of the Brensocathed launch.

Speaker Change: On the other side of that launch, we anticipate that increases in spending will be more than offset by revenue growth, leading to progressively smaller, quarterly operating cash outflows.

Speaker Change: 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 outsize returns in the future.

Speaker Change: We continue to have line of sight to becoming a casual 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.

Speaker Change: 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.

Speaker Change: If all the debt is converted prior to redemption, it would result in the issuance of approximately 17.8 million additional shares of common stock

Speaker Change: 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 our redemption date.

Speaker Change: 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. [inaudible]

Speaker Change: As expected, both our research and development and SGA 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 initiative in anticipation of the U.S. launch of Red Socathib. [inaudible]

Speaker Change: As well as our increasing investments in our early and mid-to-late-stage pipelines

Speaker Change: However, I will point out that our operating expenses this quarter were down from the levels we saw on the first quarter of 2024 were down from the levels we saw on the first quarter of 2024.

Speaker Change: in the fourth quarter of 2024. This was driven largely by lower research and development costs across Brents of CACIP for bronchiactasis and CPIP.

Speaker Change: 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 Brentso

Speaker Change: Inclosing, we believe Insmed is in a unique position of strength, both financially and operationally.

Speaker Change: We continue to deliver strong error case revenue growth in all of our regions.

Speaker Change: The expected launch of Brunsocats of 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. [inaudible]

Speaker Change: With that, we would now like to open the call to your question. Operator Mamie, take the first question please

Speaker Change: Thank you. The floor is now open for questions. To enter the queue, please press star followed by the number one on your telephone keypad, and if you wish to withdraw your question, again simply press star in the number one.

Speaker Change: If you are called upon to ask your question, please ensure that your phone is not on mute when asking your question.

Speaker Change: We do request it for today's session that you please limit yourself to one question and one follow up and if you would like to ask additional questions, we invite you to return to the queue by pressing star and the number one. Again, thank you. Your first.

Speaker Change: Excuse me. Your first question comes from the line of Andrea Newkirk with Goldman Sachs. Your line is now open.

Andrea Newkirk: Good morning. Thanks for taking the question and congratulations on the progress. Will, is you think about Brent's account of 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 US and abroad? And then I have a follow-up And then I have a follow-up. And then I have a follow-up.

Thank you. Thank you.

Speaker Change: So, I think, you know, it's hard to speculate on what really will, will end up...

Speaker Change: 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 Brent Soca, through the lens of what has already

Speaker Change: We're setting the price in the US first and then we're going to be setting prices in Europe and UK 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. [inaudible]

Speaker Change: Importantly for everyone's recollection, Erikaase was priced at parity between the US, Europe , and Japan when it was launched.

Thank you for watching.

Speaker Change: Right. Okay. And then just one more here, just give him the increased engagement with your bronchi-actasis disease awareness website that you mentioned. Can you see to what trends of any that you're picking up on? And when you think about this patient group, how motivated are they to actively seek out pulmonologists for treatment? And should we expect there to be a bowl of patients coming onto therapy upon approval? Thanks so much.

Speaker Change: 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. [inaudible]

Speaker Change: Parallels 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 bowl is up front 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. [inaudible]

Speaker Change: 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. [inaudible]

Speaker Change: and I'm expecting that 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...

Speaker Change: Appropriate to go on therapy and the physicians that are identifying them have an easy process to get them on medicine.

Speaker Change: Thank you. Your next question comes from the line of Jason Zemansky of Bank of America. Your line is now open.

Jason Zemanski: Nick, you know, the process kind of seamless in moving that interest into, you know, actual revenue generating patient.

Speaker Change: Yeah, 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, you know, when we talked about the numbers, we were targeting out of the gate here. We're weird.

Speaker Change: It was very important that people understand we're talking about patients that are already diagnosed and have two or more exacerbations [inaudible]

Speaker Change: 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.

Speaker Change: There is a second order that will be occurring in parallel, which is looking at those patients who are very likely bronchiactatic and probably have had two or more exacerbations, but perhaps they have not had their CT scan or have not seen a pulmonologist recently [inaudible]

Speaker Change: We've been encouraging through disease state awareness both for patients and physicians. [inaudible]

Speaker Change: to explore those conditions and patients and try to line them up so that they, if appropriate, can be diagnosed as bronchi-actatic with two or more exacerbations and would therefore be on label for treatment. Thank you very much.

Speaker Change: 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.

Speaker Change: 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 the air case and that will pay dividends in this setting. I've just met with the leadership of the US commercial team and I can tell you to a person they are exceptional. [inaudible]

Speaker Change: and we are going to do an extremely good job at this launch, but the specifics of what that will look like, you know, we're just not going to know until we're in the middle of it. [inaudible]

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

Speaker Change: And you asked about levers. So, Sara, it's an excellent point, the COP Foundation efforts. Similarly, there are guidelines out there to treat bronch exercises. I don't know, Martina, if you want to just comment on those.

Martina Flammer: Yeah, so I think the guidelines are expecting, of course, and has been waiting for the publication. We know that tests 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.

Martina Flammer: 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 impact 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.

Martina Flammer: 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 patient interested family members and caregivers. We expect always the scientific community to be part of it, but patients who are strongly engaged and are representative. [inaudible]

are looking at these publications and this data. [inaudible]

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

Yes

Speaker Change: So, just to be crystal clear, the definitive diagnosis of bronchectasis is achieved with a high-resolution CT scan and symptom evaluation by pulmonologist. And so when we identify patients with two or more exacerbations who have a definitive diagnosis of bronchectasis, all of those criteria are met in the numbers we've outlined. Thank you very much.

Speaker Change: 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 bronchiactasis. 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 Bronk Ectasis, because there's nothing they can do about it. [inaudible]

Speaker Change: 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.

Speaker Change: Thank you. Your next question comes from the line of Jessica Fye with JP Morgan. Your line is now open.

Yeah, so um...

Speaker Change: The way we think about it is that the most definitive examination of this is the PBR 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 and phase two in particular, you're often seeing it as the definitive measure for whether

are the greatests.

Speaker Change: as a less specific measure, but still capturing the ultimate exercise capacity of patients as an ancillary benefit of the pulmonary vascular resistance improvement.

Speaker Change: So when we look at it in this context of this phase two study, we are not powered for statistical significance on six-minute walk test [inaudible]

Speaker Change: However, we are hoping to see a trend somewhere in the 15-20 meter range, just as we express that we're hoping to see a placebo-adjusted PBR reduction of 20% as the threshold for success for this trial. 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 two setting that would impress physicians and regulators and market access participants.

Speaker Change: Bonstein, Eugene Sullivan, William Lewis Bonstein, Eugene Sullivan, William Lewis Bonstein, Eugene

Speaker Change: 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 PBR, that's a clear win. [inaudible]

Speaker Change: Thank you. Your next question comes from the line of Joe Schwartz with Learing Partners. Your line is now open.

Great. Thanks for taking my question and for the update.

Speaker Change: On Brinds and Cate, it was great to see the New England Journal of Medicine article recently, the accompanying editorial theme to raise some questions about the...

Speaker Change: Megatude of the Benefit. I'm just wondering how common is that?

Opinion in the marketplace, and...

Speaker Change: What's the company typically or what kind of company to say when you know 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? [inaudible]

Speaker Change: Yeah, 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

Speaker Change: for the same drug in 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 depictions and other extremely impactful medicines. So we're excited about that.

Speaker Change: Coupled with that, to have two editorials associated with a 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.

Speaker Change: It is 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 [inaudible]

Speaker Change: Take a moment to dwell on that. The reference to a macro light 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.

Speaker Change: and it is not something that is common discussion. Clearly, macrolides and other medicines are used for the treatment of bronchiactasis 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 healthcare ration communities.

Speaker Change: 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 receive the two editorials. [inaudible]

Speaker Change: which on balance, I would say, were quite positive in terms of their endorsement of the arrival of this new and important medicine.

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

Speaker Change: Hi, thank you, Joseph Daniel, on the survival. I have a couple of questions on the next generation DPP ones.

Speaker Change: So, you mentioned that COPD and rheumatoid arthritis, you know, their potential indications to pursue. Maybe if you could describe 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, um,

Speaker Change: You think would be a higher priority, whether due to commercial or scientific reasons, and connected to that, maybe you could dive into what properties you were looking for in the next generation DPP1.

Speaker Change: 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 tried or 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...

Speaker Change: Work in some of these, and so we know the DPP-1 in that setting is effective.

Speaker Change: 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...

Speaker Change: Library of DPP-1 candidates, both from the point of view of protecting what we already have, but also to expand potential clinical use into new indications.

Speaker Change: and so some of these molecules differ from Brenso-Cataban 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. And that's what we're going to do today.

Speaker Change: You know 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.

Joseph Schwartz, David

Speaker Change: Thank you. Your next question comes from the line of Ritu Baral with TD Coen. Your line is now open.

Thank you for watching!

Richie Burrell: Hi guys, thanks for taking this question. Apologies for any background noise.

Speaker Change: Will, can you address if there's any outstanding inspections on the Bremzo Review to be done whether it's domestic or international, and then I have a follow-up question on TPEB.

Speaker Change: So, the short answer to your question, Ritu, is that the FDA can reserve the right to inspect all the way up, basically until 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

Speaker Change: of 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. Thank you very much for your time.

Speaker Change: Were there any surprises in the mid-cycle review meeting and then on the tip of the side?

Speaker Change: What are your thoughts on either the face redesign or the past forward? [inaudible]

Speaker Change: In the event of divergent six minute walk and PBR data, you know, you clearly express the 15 to 20 on six minute walk and then the 20 plus on PBR. But you know, what if what if you have sort of extreme? What does that tell you about what you need to do with the phase three?

Yes, so on the mid cycle review no surprises.

Speaker Change: On the TPP 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 blended blinded data that has been positive as we've shared today.

Speaker Change: But I'm not as concerned about that for a number of reasons. [inaudible]

Speaker Change: The primary one being that this is a known moiety, the underlying drug, the prostanoid class, the vasodilitation it accomplishes, is well established to be beneficial in both of these measures. And consequently we would expect that to be evidence.

Speaker Change: If we see aberrations, we'll obviously look very closely at the data. Many of you have heard the great story from the...

Speaker Change: The phase two of last year where we had a patient who had great PVR reduction and then had a terrible six minute walk result and it turned out that between the beginning and the end of their six minute walk measure they had broken their leg [inaudible]

Speaker Change: So sometimes it is just something as simple as that that can throw off results if it's a more a broader

Trent, where there's divergence, that would be very unexpected.

Speaker Change: 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 [inaudible]

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

Jennifer Kim: Thanks for taking my question, congrats on the progress. Maybe to start during your prepare remarks, you commented on expanding your US manufacturing footprint specifically for Brentio and US. Can you just talk about timing?

Jennifer Kim: 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 will provide further updates [inaudible]

Speaker Change: But as a point of departure, as Sara mentioned, our tariff exposure is diminimous by virtue of domiciling our US intellectual property in the US.

Speaker Change: Coupled with the fact that our manufacturing base is already in some cases exclusively in the US, in some of our programs, and for others that are important, we are already underway in establishing duplicative manufacturing capability in the US.

Speaker Change: Okay, that's helpful. And maybe a question on blinded blended data, maybe both for Birch, for Brent, so an error case for encore. I think error case, you said blinded blended data looks very similar to a rise. Is that in terms of the individual components of the PRO and then on Birch any update on what you've seen? Nothing.

Martina Flammer: So on Birch and the Encore study, I'm going to turn it over to Martina for her comments.

Martina Flammer: Yeah, 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, we'll be based on the QLB with eight questions. It's not looking at the individual components. It's essentially a blinded at this point, but what we see is consistency of what we have seen in a rise. [inaudible]

with regards to BIRCWH.

Speaker Change: The primary end point in the birch study is the final 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 is the difference that you see towards him. Okay, for what's...

Patricia Baseline, and in the end of treatment.

Speaker Change: 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 peer road that is...

Speaker Change: Thank you. Your next question comes from the line of Lisa Bayko with Evercore. Your line is now open.

Lisa Bacow: Hi, thanks for taking the question. I wonder if you could just walk us through this so we have it kind of all straight. Number of patients with bronchiactasis, this is in the US, 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. [inaudible]

Lisa Bacow: I'm just asking a little question on 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 top to bottom, you know, when you launch how many are actually in care with at least two exacerbations. Thanks.

Lisa Bacow: 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.

Lisa Bacow: 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. [inaudible]

Lisa Bacow: From that point of view, the roughly 500,000 patients in the US represent those that are diagnosed today with bronchiectasis, including a definitive CT scan.

Lisa Bacow: 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 will be targeting out of the gate. [inaudible]

Thank you for watching.

Okay, great, thanks [inaudible]

Thank you.

Speaker Change: Thank you. Your next question comes from the line of Craig Sivannavejh with Mizzouho insecurities. Your line is now open.

The idea that you're going to try to...

Speaker Change: Effect of frictionless launch. You've given us great color and what's happening with patience. Just to remind us on the pair of fronts, you've provided some color and how that's going, but could you provide a little bit more on perhaps.

Speaker Change: Based maybe on latest market research, like we're pricing, we're headed on pricing, and also just for our modeling purposes, what we might be able to think about in terms of gross to net thanks.

Sarah Bonstein: Sure, so I'll turn pricing and gross tenets over to Sara in a minute.

Sarah Bonstein: But the frictionless launch ambition we have is just really the way to express a best possible practice.

Sarah Bonstein: for a commercial launch in Freddie 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,

Sarah Bonstein: to gain that access and to ensure that the prioritization is one that is consistent. [inaudible]

and doesn't introduce any unnecessary onerous aspects to it, like...

Sarah Bonstein: Going back and pulling from the records, the scan and the documentation of the exacerbations. What we're looking for is a position 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...

Sarah Bonstein: I think we continue to feel very good about the ranges we've expressed. [inaudible]

Sarah Bonstein: to the street in terms of price and no new information that would direct that in any other way.

Sarah Bonstein: 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 III study.

Sarah Bonstein: So, in other words, we're having much more specific dialogue 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...

Sarah Bonstein: Till just at the time of launch, but Sara, over to you for comments on price and gross to net. Yeah, sure. Thanks Greg for the question. I'll just remind the listeners that we have put out, you know, a price range 40 to 96,000 based on, you know, other products.

Sarah Bonstein: In the 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 until we launched on gross to net we have again not provided formal guidance but we have studied

Sarah Bonstein: All their specialty launches and what their growth 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 Brent. So like we are air case because Brent was at launch 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 growth to net. Thank you.

Sarah Bonstein: So if you study all that and take that into account somewhere between 25% and 35% seems reasonable based on pressing and analogs but again not formal guidance. Hope that helps.

Speaker Change: Thank you. Your next question comes from the line of Leonid Temmichev with RBC. Your line is now open.

Speaker Change: 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 biologists and the indications? Thanks.

Martina, do you want to take that one? [inaudible]

Speaker Change: Yes, sure. So remember on the fertility analysis of a hundred patients, we're not looking for a p-value, we're looking for signals efficacy, we're still determining from a statistical perspective exactly how that will look like. For this phase two 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 this study will tell us [inaudible]

Speaker Change: What we have in terms of the efficacy and that will allow us to then plan for what is it that we can show and that we will plan for in phase three. [inaudible]

Speaker Change: And just so you're clear, that hundred 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.

Speaker Change: Or, we don't see anything, it'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.

Speaker Change: So our hope is that this medicine will show something and that first hundred 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 two trial from which we'll learn and derive how we're going to structure the phase three trial. In the end we're anxious to see whether or not this medicine could be a compliment to the other medicines that have been developed for the treatment of this condition. [inaudible]

Please see the complete disclaimer at https://sites.google.com or at https://sites.google.com

Speaker Change: Yeah, maybe just one thing to answer. What we're 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 three. [inaudible]

Thank you for watching!

Speaker Change: Thank you. Your next question comes from the line of Nicole Germino with truest securities. Your line is now open.

and others. Thank you. Thank you.

Speaker Change: Hi, good morning, congrats on the progress and thanks for taking the question.

Speaker Change: So, just quickly, for CRS, without nasal polyps, are you enriching for patients with higher needles at the level, or patients who are a lot worse, and is there a minimum threshold to cut off for NISP and blood, or is that something that you're looking for in the pre-stubbed subgroups that you'll be examining? No, it has a quick follow-up.

So I'll ask Martina to take this question [inaudible]

Martina Flammer: Yeah, so in the birch study, we're allowing patients to enroll up to 250 years in a field count. The reason we're cutting it off at this point is because if you're going to very high use in a field count, the disease is most likely

Martina Flammer: Purely Eucinophilic-driven, and that's not the population that we're looking at. However,

Martina Flammer: Patients below 300, as well as above 300, but below 750, both are enrolled in the 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.

Martina Flammer: 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.

Martina Flammer: and there is no indication right now that we see that both the dispassions would be differently. So, with capping patients at 750 Euro,

Martina Flammer: You are really capturing the vast majority of patients with CRS without nasal polyps, and maybe just a short comment on how it is endotyping so the mix between neutrophilic and eucinic disease works

Martina Flammer: While in the majority of cases, it's neutrophils that drive the disease. There is a mixed endotype where both neutrophil and eocenophils are part of the disease and

Speaker Change: Right now, we will look at what Bert shows us in CRS without NATO-pollips and then we can then decide is there an opportunity to go potentially even in patients with NATO-pollips?

Speaker Change: Maybe just as a reminder, if you look for an example that is similar, and patients with severe asthma have a similar type where they have a mix between neutrophils and eucinophils, and that could be also a situation that we see in CRS overall. [inaudible]

Speaker Change: And just to highlight this, we originally thought you would see a distinction between higher or lower eosinerville 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 eosinerville counts.

Speaker Change: because of the aspirin 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. [inaudible]

Speaker Change: Okay, great. Thanks so much for that. And then a one quick clarification. So the two exacerbations in the CT scan is that going to be on the label or is this more for a peer

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

Speaker Change: Yeah, maybe just to add, just to clarify, I think I heard you say two HRCT scans, the HRCT scan is just to diagnose the disease.

Speaker Change: Fulmonary exacerbations is what we've studied. Right and those are those are examined I mean pardon me those are documented separately from the CT scan

Speaker Change: Thank you. Your next question comes from the line of Maxwell's score with Morgan Stanley . Your line is now open.

Maxwell Score: Great, thank you. Just a quick question on the TPIP, Readout in PAH.

Maxwell Score: Can you remind me the rationale for measuring PBR versus baseline and how we should think about the potential placebo rates? And also for the potential phase three trial, what do you consider to be a relevant primary endpoints? Will you potentially go with mortality or morbidity and mortality based endpoints? Thank you

Alex Martina, David Russell

Martina Flammer: Yeah, maybe let me start with phase three. So the registrational endpoint recognized is a six minute walk distance. That would re-anticipate. We will have a primary effort also in phase three.

Martina Flammer: 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 six-minute walk distance.

with regards to PDR, so you're measuring PDR.

Martina Flammer: at baseline and at the end of the study to basically see what is the reduction that you can achieve over the treatment period.

Martina Flammer: In our trial, we are titrating up to a maximum of 640 micrograms that titration goes over a three week period [inaudible]

Martina Flammer: majority of the many patients have already reached a 640 micrograms which is why in the open label study we are allowing a higher titration up to 1280 micrograms.

Martina Flammer: We're anticipating plan for a higher up to 1280 in our Phase 3 study. In the exact design, we will then determine based on the Phase 2 readout. In the final phase, we will then determine based on the Phase 2 readout.

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

Speaker Change: Thanks for the question. I have one and then just a clarification on T-Pit. So, um...

Speaker Change: You announced your CCO departed the company late last month to anticipate naming a permanent replacement ahead of Branzo's potential launch, and then the clarification on T-PIP just

Speaker Change: 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?

Speaker Change: Your last patient, week 16, visit with late March and you expect to read out in June , that's three months, and should we expect anything with this data release? Thank you Thank you.

Speaker Change: I'll also just emphasize our preparation for this commercial launch began two years ago.

So we are...

Speaker Change: 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.

Thank you.

Speaker Change: The data cleaning, all right, so the note I wrote here was registration. So, one of the things we're doing with this TPI-P data set, as we do with all of our data sets now, is we want them to be registration quality. [inaudible]

Speaker Change: What that means is you can produce top-line 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 time

Speaker Change: only for the release in terms of top line results to the street, but also equally importantly, if not more so preparation for a registration submission when that day comes.

Speaker Change: Thank you. Your final question comes from the line of Andy Chen with Wolf Research. Your line is now open.

Speaker Change: 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 Sirepto's DMD gene therapy. Has this influenced your development strategy at all? Thank you.

Speaker Change: 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.

Speaker Change: 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. [inaudible]

Speaker Change: 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.

Speaker Change: 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 being a interethical 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. The other is that it reduces the amount of drug that you actually have to deliver. That is a clear safety benefit to patients.

Speaker Change: What we've seen in the preclinical models is that this is resulted in a very good

Speaker Change: System, as well as the cardiac tissue, quite remarkable, given that it's interethically delivered.

Speaker Change: 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...

Speaker Change: 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.

Speaker Change: But I think one of the reasons we've tried 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

Speaker Change: Standard setting for the industry. I think as we look at the other gene therapies we're developing for things like ALS and StarGuard, 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.

Speaker Change: Thank you. That is all the time that we have for question and answer today. On behalf of Insmed I do thank you for your time. That does conclude today's call. You may now disconnect. Thank you very much.

Joseph Schwartz, Joseph