Insmed Incorporated ($INSM)

Good morning. Welcome to this fireside chat with Insmed. I'm Joe Schwartz from the biopharma equity research team at Leerink Partners, and it's my great pleasure to be joined by Sara Bonstein, CFO. Maybe, Sara, you could start us off with a quick lay of the land and give us a brief overview of the company's recent accomplishments and priorities for '26.

Sure. Happy to. Thank you, Joe and the Leerink team for having us here. Always a privilege and an honor to be here with you today. Insmed is, I believe, a remarkable story. So we are a company that is focused on serious life-threatening conditions and how can we create first or best-in-class options for patients. We have commercial products now. We have ARIKAYCE, which has been commercialized for about 8 years for nontuberculosis mycobacteria in the refractory setting, and we will have a readout in the March-April time frame for a potential label expansion in that indication that our second commercial product is called BRINSUPRI. That product was launched in August of last year, and that is for bronchiectasis. Both of those programs, along with some additional programs that we'll go through today, make up our respiratory franchise. Our respiratory therapeutic area. We recently went into these 3 therapeutic areas, respiratory, I&I and neuro and other. And we did this because it's a -- it's just a symbol of how much we have grown as an organization in the company in the past -- yes, 2 years, but really in the past 10 years. You're now seeing that culmination of all the growth that we have done. So we have a very, very robust pipeline of late stage, mid-stage and early-stage across each of those therapeutic areas. We sit on about 1,500-plus employees across our geographic territories, which include New Jersey, New Hampshire, California as well as Europe and Japan and really just have a great organization where we're able to have great impact on patients. So happy to dig into the commercial programs, the clinical programs, we're excited about all of it.

Great. Okay. Thanks for that excellent overview. So maybe we'll start with ARIKAYCE and the ENCORE study since we've been getting a lot of questions about that event coming up soon. Can you lay out for us your goals with that study and how you designed it on the basis of what you saw in ARISE and maybe what the potential scenarios are coming out of ENCORE?

Sure, happy to. And maybe we'll even take a step back and just remind us all on sort of the design and why we even did ARISE. So the FDA, as you all know, look for an endpoint for field function survive. So the endpoint here for this nontuberculosis mycobacterium in the sort of frontline or initial stage setting is a patient-reported outcome tool. And there is not a patient-reported outcome tool that exists for this condition. So we ran essentially 2 parallel studies, ARISE and ENCORE. They were very similar in their design. The difference was one was a little bit shorter in duration, and one was smaller, so we could get the readout first to help determine what a PRO could look like in this disease setting. So I'll remind you on ARISE. ARISE was about 100-patient studies. It was 99 patients. When we had patients, we randomized 2 of them to ARISE, one of them to ENCORE. So same exact patient population. We did that, as I said, to make sure that ARISE would enroll soon. ARISE was 6 months on therapy and 1 month off therapy. And we studied -- we looked at 2 things. The U.S. FDA is looking for, as I said, that patient-reported outcome. The PMDA in Japan would be looking for culture conversion. So we studied both. What did ARISE tell us? What did we learn from ARISE? What ARISE told us is, obviously, it was much, much smaller than ENCORE, so not powered for statistical significance, but it showed that we were trending in the right direction to show a change in the respiratory symptom score between the treatment arm and the nontreatment arm. So it was trending towards seeing a change, and we saw about a 4.5 point change. And then on the culture conversion, even more interestingly, we saw nominally stat sig results on culture conversion. And at the 6-month endpoint, we saw about an 80% conversion on the drug arm and about a 65-ish percent on the control arm. But even more interestingly, 1 month off of therapy, you saw a point or 2 go down on the control -- on the drug arm. So the 80% went down to like 78% and change, but you saw the control arm went down to 47 sort of high 40s. So it wasn't durable. And so now as we fast forward to ENCORE, what are we looking for ENCORE? ENCORE is a longer and duration study. It is a 12-month study, and we are looking at the primary endpoint for the U.S. is that PRO. So the change in the respiratory symptom score. So again, we're looking for the change between treatment arm and control arm. We're 90% powered to show a 4-point change, and that's assuming 400 patients. We enrolled 425. So we're a little over enrolled there, which is great, and that is where ARISE was showing us. So we have a high degree of conviction. The next step is we want to see the responder analysis. We want to see a point -- across any point of the measurement, do you see separation? And FDA will obviously determine what that right separation needs to be. It will potentially be in the 16.5-ish, maybe 16.7 range, but that will be FDA's decision. The important piece is in ARISE; we saw separation across any point change. So that again gives us tremendous confidence. And then as we spoke about the PMDA as well as the U.S. HCPs, payers, patients, they're very interested in culture conversion. So obviously look for stats to get culture conversion. On the endpoints for the PRO, we're measuring at month 13. That's important because they get to be off drug for 1 month, which is important because ARIKAYCE has some side effects, but it has been able to show 8 years in real-world data as well as the other studies that we're able to show a difference and clear these bugs. So having that 1 month off therapy is really important. And then for culture conversion, it's at month 15, which again is really helpful because we can be able to hopefully demonstrate the durability of what ARIKAYCE can do for these patients to be able to not only clear the bug, but to have that durable culture conversion. So a lot there. It's not as sort of black and white as some other trials. So I kind of just wanted to go into some detail. But March, April will be the timing for that data readout, so be on the lookout. What that means is patient-wise, there's about 12,000 to 17,000 patients in the U.S. diagnosed under the current label, about a little higher than that in Japan, about 15,000 to 18,000 in Japan. Those numbers increase pretty substantially for total NTM in the U.S., it's about 100,000. In Japan, it's about 125,000. So significant patient populations. Obviously, there will be some education on what that means on how quickly do people get it? How long do they stay on therapy, all that good stuff. We need to see the data, and then we'll educate you on all that as well.

Super helpful.

Yes.

So then what are the potential scenarios coming out of ENCORE? That's been a question we've been getting a lot from folks because it's on the one hand, a confirmatory study for ARIKAYCE, which has accelerated approval. And then it could also open up Japan and expand the market in the U.S. How about the scenarios where it succeeds on everything, maybe it's a mixed result, positive culture conversion-wise and then maybe less so on QLB? And then what if it's just -- probably not, but an all-out failure.

Yes. No, all very, very fair questions. So I think the clear win scenario is pretty straightforward, right? We would look to file before the end of the year and be on market next year. That would be the goal, and that's what we're planning for in a sort of mixed scenario, this would be a conversation with FDA. This is a product that's obviously been on the market, has been able to show big impact for patients. So that would be conversation and discussion. We've never lost on culture conversion. We have a high, high degree of conviction on culture conversion. Obviously, PRO, there's just noise in a PRO instrument. But again, we feel like we've learned a lot from ARISE, and we've been able to apply that into the ENCORE 8 question respiratory sinus symptom score. In the instance where we don't see what we want to see, I'll remind you that this program is not in the same indication for the approval -- the conditional approval that we have now. So again, it will be a discussion with FDA. I'll also remind you, obviously, can't speak for FDA, but I'll remind you, there's nothing else available for this patient population. It's been on the market for 8 years. Patients have had success with this medicine. They've come -- they've had successful sort of completion of clearing their bug, getting reinfected, going back on medicine. So real-world example, real-world experience here has been very, very positive. I think this would be a tough one for FDA to do anything other than keep this medicine available for patients.

Okay. Very helpful. So maybe we can switch gears and talk about BRINSUPRI now that we've talked about the little diesel engine that just keeps chugging along. Might just be getting broken in if frontline works. And we'll switch gears to the jet engine, if we could.

Yes, I like that. I love cars and engines, all that stuff. So that sounds great.

Great. So BRINSUPRI has really knocked it out of the park with not even a year on the market now. We're detecting a lot of solid demand for the product. And I was wondering if you can just lay out for us your vision of the different waves of the launch for us.

Yes, yes, happy to. So BRINSUPRI is, as I mentioned in the opening, is the first and only available treatment for folks with bronchiectasis. So previously, when a patient would go into their doctor and they would be given this diagnosis and then the patient would say, what do you -- what do I do? And they would say, well, continue doing a lot of the same airway clearance, the shaking vest, there's no approved therapy. So really amazing to have this option for patients. Although there was nothing approved, there was actually already a diagnosis code, which was actually very helpful to be able to understand the patient population. So here in the U.S., there are 500,000 diagnosed patients with bronchiectasis. If you kind of dig into that information, you can see how many exacerbations do those patients have over the prior 12 months. And the reason we looked at that is in our ASPEN study, which was our pivotal Phase III, the inclusion/exclusion criteria were 2 or more exacerbations in the prior 12 months. The label does not have that in it. The label is very open, but our understanding and expectation would be 2 or more is where the prescribers and the payers will be. So if you look into the claims database, about half of the patients that are diagnosed today have had 2 or more exacerbations in the prior 12 months. That is really where we ground as sort of the initial sort of focus of the launch, that 250,000 patients. There's another 250,000 patients that are 0 or 1 exacerbating patient that when you think about an exacerbation, every time you have an exacerbation, you're more likely to have another exacerbation. They're not linear. Every time you have an exacerbation, it causes permanent lung damage. And I think even most interestingly, a lot of exacerbations may have gone under documented because either a patient didn't realize that it was an exacerbation or they said, why am I going to call my doc, I don't want to get put on an antibiotic. I don't want to get hospitalized. I'm just going to kind of live through this myself. And so now that there's available medicine, you may see more exacerbations be documented. And how do I have confidence to even say that? There was a real-world claim study done with about 15,000 patients. So decent size, not obviously all the patients, but decent size is a 2-year look. And at that point in time, about 47% of patients had 2 or more exacerbations in the prior 12 months. Fast forward, that went up by 9% and the 47% went to 56%. So you're already starting to see that migration. So I view that as sort of like the initial low-hanging fruit as you're thinking about available patients for this medicine. You have the initial 250 that the payers will be happy to support. You have the next potential 250 that may now have potentially more exacerbations. The piece that we're now putting energies towards is what we're calling almost a secondary launch, a second launch, a second focus. And this is the potential underdiagnosed patients that have COPD or asthma. In the U.S., there's over 30 million. I think it's 32 million patients with either COPD or asthma. If you take just the COPD piece of that, it's about 20 million patients in the U.S. Literature is all over the map on how many of those could also have comorbidities with bronchiectasis, 4% to 60%. It's all over the map. I know that's not super helpful. But if you look at even the most recent literature, it actually says 30% to 50% of moderate to severe COPD patients also have a high likelihood of bronchiectasis. And so if you kind of do all that math and you put whatever probability on penetration in that, that could be hundreds of thousands, if not millions of more potential patients that could be available to be on drug, available to be on label with a CT scan that shows a tree bud pattern on it that then gets them the bronchiectasis diagnosis. So we will have a dedicated team focused purely on that underdiagnosed patient population to help with the education on both the commercial and the medical side compliantly to help with that investigation on identifying those appropriate patients that are potentially exacerbating patients that could potentially benefit from the drug. Our existing field force organization, they're going to stay focused on that 250,000 patients and driving the at least $1 billion of revenue that we have committed to this year.

Our survey work has also found that a significant proportion of patients have overlapping symptoms with COPD and bronch. So I think as strong as the launch has been, still only half of physicians have written 1 script so far, but patients should be entering the zone when they'd be revisiting their doctor. The checks we and others have done have turned up some very positive feedback so far on the response to treatment in the real world. How do you foresee the launch going now as we enter this phase of deeper -- potentially deeper penetration in patient practices?

Yes, yes. So obviously, our first -- yes. No, I understood. Our first full quarter, we put up almost $145 billion in revenue. We were really proud of obviously, the revenue number and I think even more importantly, the ability to have over 11,000 new patient starts cumulatively in 2025 and have that much impact on patient lives. And as Joe said, we had about 4,000 unique prescribers, cumulative number of prescribers through the end of 2025 and about half of them through the end of 2025 had written 1 script. And so we've spoken a lot about the depth and breadth. In the United States, there's about 20,000 pulmonologists. We have the ability to call on every one of them as well as we call on some infectious disease docs and some other specialties in the totality of about 27,000 health care professionals, and that covers both BRINSUPRI and ARIKAYCE is a shared sales force. 4,000 folks have written -- 4,000 HCPs have written at least 1 script and that is very encouraging. That's a pretty broad net, probably broader than we thought would be out of the gate. So we see the KOLs, we see community people writing scripts. What we now are very focused on is the depth. And this is very traditional that you see in not only a new first-in-disease medicine, but this is a first-in-class medicine. So you expect to see this. You're going to have probably more depth in KOLs or physicians that maybe were part of the trial and sort of less depth in some of the KOLs that are onesies, twosies, but this feedback loop of having the patient experience, so a positive patient experience. And you see this even if you just look at social media posts and patients are very loud now themselves to hear that feedback on I've had a positive experience, that helps to build momentum. They come back into their physician's office. The physician asks them about their experience. I'll remind you that the dropout rate in the ASPEN study was actually a little bit higher in the placebo arm than it was in the drug arm. It was about 13% in the placebo arm, around 12% in the drug arm. This is a relatively benign safety profile from a drug perspective. And the fact that we were able to show nominally statistical significance in the 25-milligram arm on quality of life, that is really helpful for folks, right? They're feeling better, and so you're starting to get that feedback loop. I think another important event will be as the physicians get together at major medical meetings like an ATS and they're being able to share these stories with one another, having that continuous feedback loop, I think, will be the next -- one of the next inflection points for the company. So probably Q2-ish is when we'll probably mostly starting to see the impact there. So really excited about what the year has to come. And then the other, I think, very important piece is if you think about the -- sort of overall health of the brand, we've said $5 billion peak sales. That is just on the diagnosed patients today. That does not include all this additional sort of low-hanging fruit that we talked about, that could be multiples of that and $1 billion, at least $1 billion this year. If you think through how the math would need to work to be able to achieve at least $1 billion this year and where the jumping off point will be at the end of this year and what that implies for '27. This is a monster, monster opportunity. There's maybe 20 products in our industry of all times that in quarters 2 through 5 have been able to put up over $1 billion in revenue. Insmed is looking to add their name to that list.

Okay. Great. So I'd like to switch gears again to TPIP because this also, I think, has a very sizable opportunity. It's a bit under the radar because of the -- all the shine that's on BRINSUPRI. But I guess, I want to ask a big picture first, and that is, where do you see TPIP fitting into the overall treatment paradigm since it seems to be on the cusp of potentially achieving like one of the ultimate goals that I can remember being out there for PAH therapy for a long time, which was just to deliver a lot of prostacyclin once a day. That's a very tall order. And yet we have a lot of excitement around another class of drugs spearheaded by WINREVAIR. So how do you see the overall share for prostacyclin and TPIP driving prostacyclin growth in the future?

Yes. No, it's a great question. And so we have a lot going on. So we have to keep pivoting to different programs, which I love. So a couple of thoughts here. There's been tremendous development in this space, which is absolutely wonderful for patients. This is both a life altering as well as -- these are life-altering as well as life-ending conditions. So we need to do better for patients. So it's great to see additional innovation here. I do expect, and this isn't my -- what I expect, this is what the medical community is educating me on that this will is and will continue to be a combination market. And the goal here is to extend life for patients. And while there are additional sort of MOAs that are coming out, the need for prostanoid therapy is seemingly to be a mainstay. And what the medical community is telling us is if we can continue to show what we showed in our Phase II that TPIP has the potential to be the prostanoid of choice. And why do I believe that? Well, we were able to show in our Phase II study, Phase IIb study in PAH is a 35% improvement on 6-minute walk and 35% -- 35-meter improvement -- 35-meter improvement on 6-minute walk and 35% improvement on PVR. Those are results that no drug in this class has come even close to. And we obviously need to reproduce that in Phase III. But I still remember when my Chief Medical Officer called to tell me the results, I didn't even believe what my ears were hearing. I thought she said 25 instead of 35. I made it repeat about 3 times. So it is absolutely amazing what that -- what the drug has been able to show. And it actually makes sense. If you go back to one of your -- the earliest thing that you said, Joe, around the goal here is to get as much drug into the patient's lungs and have it be sustained. And that's what we believe we've created with our TPIP prodrug. We're able to deliver a lot more drug, but it be inert, so it's not active. So you sort of don't have that side effect of the cough, which is a big issue for current patients. And you're able to get a lot of drug into the patient and have it sustained over time. I'll remind you that our Phase II, we measured 24 hours after the initial. So we were able to show those types of PVR and 6-minute walk results 24 hours, which sort of magnifies the ability that this is overnight coverage, which doesn't exist for these patients today and all that, those good things. So this year, we've committed to having 4 global Phase III programs underway. PH-ILD kicked off last year. PAH will kick off Q2 and then PPF and IPF on track to kick off second half of this year. So a lot of development going on. More to come here. We've put out early days, peak sales of $2 billion. That's when we were only going after the first 2 indications before we had Phase II data. We know we need to update that for you guys, but this could be another very, very significant opportunity from a revenue generation perspective as well as a patient impact perspective.

Right. We didn't believe the math when we backed into what the blinded data implied you would show and lo and behold, that's what you delivered. So...

Yes.

Super exciting. Let's switch gears yet again to another approximate readout from the SEDER trial for brensocatib in HS. Can you help us understand where the 20% to 40% bar for success for AN count reduction came from and how this would position BRINSUPRI in the HS treatment paradigm meets that?

Yes. So HS, neutrophil-driven condition, inflammatory in nature. This is why we sort of targeted it. We have said right from the beginning that while all of those hold, this is a very tough disease indication. So we've put sort of a 10% to 20% probability on this indication. Obviously, it would be great if we could show something here the bars. So based on feedback from the medical community as well as what other studies have shown, we believe a 20% improvement on AN count would be meaningful for us to progress into Phase III. When we talked about the 40%, with the 40%, we call that our "home run scenario" because that's what we would need to show to be able to show stat sig because we -- when we designed the study, we designed it at alpha 0.1, whilst still a very meaningful size study. It's 204 patients. We powered it that way so we can get answers. I'll also remind you; this is a 16-week endpoint. Our drug usually takes about 2 to 4 weeks to reach full effect. And so we're studying AN count as the primary at 16 weeks. We will have continued data through week 52, with some more sort of traditional high score 50 and 75 at that point, some more information available then.

Okay. Great. And -- on the earlier stage front, can you tell us some more -- give us more color on INS1033, your next-gen DPP1 and maybe how much screening you did to arrive at this agent, how it differs from BRINSUPRI and how you settled on IBD and RA?

Yes. So unlike both HS as well as CRS, which there's no animal models available, RA and IBD do have animal models. And we've run animal models with BRINSUPRI that, that information is published as well as 1033. So 1033 is one of our new DPP1s. On the heels of the WILLOW data, you may recall, we continued to do a ton of work in our research labs on the mechanism because we believed in this mechanism with a high degree of conviction. And so we developed, I don't know, over 800 different DPP1 follow-ons, we are looking to progress the first of those 1033 through IND by the end of this year. The thought is the indications will be RA and IBD. The benefit of a follow-on DPP1, obviously, we can think about pricing very differently. We can think about IP very differently. We can think about reach differently, all of those good things. We 100% own all the follow-on DPP1s ourselves. So that's also very helpful. So we're excited to move that forward through IND by the end of the year.

Okay. Great. And then maybe lastly, what's the next step for INS1148, the monoclonal antibody that you recently acquired for ILD and asthma. Can you give us a little bit of the back story there?

Yes, yes, sure. So this is a program that we in-licensed end of last year. It's very brenso-like in sort of deal terms, $40 million upfront Phase II-ready asset. It was an asset that was developed by a small company that they licensed it to AbbVie. AbbVie ran a Phase II study, about 150 patients in atopic derm. While that was not published, we obviously saw the data under diligence. It did reach stat sig, atopic derm. They had a lot of development there. It did not sort of, I guess, meet their bar. They returned it back to the small company. We knew of it. And we came in and we said, we think this can do -- we're not obviously interested in atopic derm, but we think this is a molecule that has shown success, shown promise, shown clear efficacy, good safety profile, we think we can move this forward in things that fit into our therapeutic areas, such as ILD to have it be complementary to TPIP, potentially asthma and others. So we're really excited about this program. We haven't fully committed to when we'll get it into the clinic. But as soon as possible, the team is just kicking it out of the park and making great progress.

Awesome. Well, thank you so much for the great updates, Sara.

Thank you so much, Joe.

Thanks.