Insmed Incorporated Aktie

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

That's pretty...

Without any additional business development externally.

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

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

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

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

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

Thank you very much.

Thanks, everyone.

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

Thanks so much for having us. Really appreciate it.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Last one on this, I promise.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Thank you so much.

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

It's a pleasure.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Well, I think we're looking at what is already a combination market. So these patients come, they get diagnosed. This is a fatal condition. Patients decline fairly rapidly. The 5-year mortality rate is remarkably high, and it's incredibly unfortunate. But what we are looking at now is a new era where the arrival of sotatercept, the arrival of what we believe will be a very successful TPIP drug.

I could see those 2 being used in combination and really getting these patients where they need to go. We haven't done any of the work on that, but that is certainly my expectation that you will see physicians wanting to try that because, as I said before, we saw a 34% reduction in pulmonary vascular resistance. And I think in sotatercept's best data, they were at 32 or 33. I can't recall.

Got it. So we have a microphone in the back if anyone from the audience wants to ask a question, as we just raise your hand. As we're polling here, one more for you, Will. As you think about the so-called fourth pillar, obviously, some very interesting and intriguing candidates. Can you just give us sort of a rundown of one that you think is especially intriguing and then sort of balance that out with being disciplined and sort of investing in these higher risk, higher reward opportunities?

Yes. So the success of ARIKAYCE and BRINSUPRI, and even TPIP have really enabled us to continue to develop our research capabilities and target the addition and introduction of 1 to 2 INDs every year. That's our goal. This year, we have a gene therapy for Duchenne muscular dystrophy delivered by intrathecal delivery. We have an ALS gene therapy, and we have INS1033, which is a DPP1 inhibitor distinct from BRINSUPRI, which is targeting rheumatoid arthritis and IBD. That -- the INS1033 will enter the clinic this year. The other 2 are currently enrolling patients in trial.

Beyond that, we have deimmunized therapeutic proteins using AI up in New Hampshire. We have synthetic rescue going on for a variety of conditions in our Cambridge, England office. and we have the DPP1s that I just referenced coming out of New Jersey. So each one has a fairly distinct approach to what they're trying to contribute. They all look exciting, and I'm super interested to see what that data looks like next year.

On top of that, I'll just mention business development. We brought in INS1148 for the treatment of fibrotic disease, and that is moving forward into a Phase II trial. We're super excited to see what that can do. That may be just the beginning of where that may be applied. So inside of Insmed, beneath the 3 programs that are multiplexing right now and delivering on every front, we have a robust pipeline, which really puts us in a strong position. And as we move into next year and become cash flow positive, which we expect to do without having to raise any additional money, that puts us in a powerful position to really accelerate into the earnings per share transition that this company will undergo.

And that's where the discipline on research will get increased because we need to make sure that EPS is on a healthy trajectory. And I think we're going to be able to do that. If the standard for any medicine we are developing at Insmed has always been the same. If it is not first or best-in-class, we discontinue it. And that is a discipline we're going to continue to hold.

Got it. Any questions from the audience? I have one. When you think about exacerbations, at least in ASPEN, they're very well defined, very easily adjudicated. But when we get to the real world, a lot of the docs we've talked to have commented that it's not as cut and dry as maybe ASPEN is sort of portray. What are you seeing in the real world? Is it challenging? Is it easy to diagnose an exacerbation? And again, what do you think it's going to have on overall diagnosis rates?

Well, heterogeneity is certainly the watch word associated with pulmonologists who are evaluating exacerbations, and I would expect that to continue. It is certainly the case that we expect exacerbation rates, diagnosis rates to increase, both because we're raising awareness with patients to look for these exacerbations and to document them and tell their physicians about them, but also raising awareness with physicians on the importance of looking for those, diagnosing those and thinking about the implications of those.

This is a progressive disease. And so you lose lung function every year. There is an undercurrent of urgency to treat these patients so that, that lung function can be preserved if they're taking the 25-milligram dose because that was seen statistically significantly in the Phase III trial. So that's a powerful message to the treating community and one of the reasons why I think we're going to continue to see a strong launch.

Got it. Well, Will, thank you so much for joining us.

My pleasure. Thank you.

Thank you for standing by. My name is Danica, and I will be your conference operator today. At this time I would like to welcome everyone to the Insmed First Quarter 2026 Financial Results and Conference Call. [Operator Instructions]

I would now like to turn the call over to Bryan Dunn, Head of Investor Relations. Please go ahead.

Thank you, Danica. Good day, everyone, everyone, and welcome to today's conference call to discuss Insmed's First Quarter 2026 Financial Results and provide an update on our business.

Before we begin, please note that today's call will include forward-looking statements. These statements represent our judgment as of today and inherently involve risks and uncertainties that may cause actual results to differ materially from the projections discussed. Please refer to our filings with the Securities and Exchange Commission for more information.

The information we will discuss on today's call is meant for the benefit of the investment community. It is not intended for promotional purposes, and it is not sufficient for prescribing decisions.

Today's call will feature prepared comments by Will Lewis, Chair and Chief Executive Officer; and Sara Bonstein, Chief Financial Officer. After their comments, they will be joined by Martina Flammer, Chief Medical Officer, for the Q&A session.

I will now turn the call over to Will.

Thank you, Bryan. Good morning, everyone, and thank you for joining for joining us. Insmed's business is off to a strong start in 2026. Commercially, BRINSUPRI delivered strong sequential growth and continues to outpace all past specialty respiratory launch analogs while establishing a new playbook for excellence for a commercial launch. And once again, ARIKAYCE grew year-over-year, which is especially impressive given it is in its eighth year since launch. Both products remain firmly on track to achieve their respective revenue guidance for the year.

Clinically, we made meaningful progress, highlighted by clearly positive and potentially practice-changing results for ARIKAYCE in our Phase IIIb ENCORE study. Additionally, we continue to make steady progress on TPIP's Phase III development with PH-ILD and PAH trials now underway and trial designs for our PPF and IPF studies nearing finalization.

As we look ahead, we will continue to focus on maximizing the impact of BRINSUPRI in patients with a current bronchiectasis diagnosis while also working to increase awareness and proper diagnosis of patients with COPD and asthma who may also be bronchiectatic. In parallel, we are moving quickly to submit the ENCORE data to regulatory authorities in the U.S. and Japan, which we believe have the potential to support an expanded label for ARIKAYCE in the first half of 2027 and a $1 billion-plus peak sales opportunity for that brand. TPIP will remain a central priority for us as well as we execute on our 4 Phase III trials while also generating long-term data from our Phase II open-label extension studies.

Supplementing all these initiatives is our early-stage pipeline, which we expect will continue to produce an average of 1 to 2 INDs per year. We also intend to supplement our pipeline with select business development efforts. Financially, we are well resourced to execute on all of these initiatives as we advance toward cash flow positivity next year.

Let's turn now to discuss BRINSUPRI's progress in more detail. BRINSUPRI's launch continues to exceed our expectations, delivering 44% sequential growth off of an already strong prior quarter baseline. We were particularly pleased by the strength of this growth because it occurred in the calendar first quarter, which tends to demonstrate slower growth for medicines given plan changes, out-of-pocket cost resets and reauthorization dynamics.

In fact, when you look at the basket of strong respiratory launches that we have cited in the past, sequential growth for those products slowed significantly during their first calendar Q1, delivering only around 9% sequential growth on average. Of course, those past analog launches were impacted by the Medicare coverage gap, which was eliminated beginning in 2025 under the Inflation Reduction Act. But if you expand this analog analysis to include comparably strong launches since the coverage gap was removed, you've noticed that BRINSUPRI's sequential growth rate is actually higher than those of WINREVAIR and Rezdiffra, which in the first calendar Q1 of their respective launches generated between 30% and 40% sequential growth versus Q4. Notably, we did not raise the price of BRINSUPRI at the start of 2026, and the impact from inventory stocking this quarter was negligible.

We are extremely pleased with how BRINSUPRI has performed to date and remain confident in our 2026 revenue guidance of at least $1 billion. If we achieve this level of revenue generation, it would place BRINSUPRI among the most impressive launches in our industry's history. We believe that we are setting a new standard for drug launches with BRINSUPRI, which is why we intend to open our playbook and share a lot of detail with you today regarding the metrics we are tracking to gauge this launch's success. Sharing these details is meant to simultaneously help you better understand the components driving BRINSUPRI's performance so far and also why we are so enthusiastic about the future of this launch.

As we walk through our dashboard with you, we will highlight the following key observations. BRINSUPRI has healthy organic demand, and we believe we have treated nearly all patients who are ready and waiting for treatment at the time of approval. Payer access is excellent. We have supported a very high percentage of patients through our inLighten patient support program, reflecting strong patient engagement with their treatment. Time to prescription refill rates are ahead of industry benchmarks. Treatment continuation rates remain high.

We are broadening and deepening our prescriber base with a lot more opportunity to continue to drive that forward. And our education and outreach efforts, which have already yielded positive results have really just begun to accelerate.

Let's dig deeper on each of these items and start with a closer look at patient demand. We believe BRINSUPRI's organic demand is steadily growing. To understand what we mean by organic demand, some context is helpful. We expanded our sales force 10 months before approval so they could promote ARIKAYCE and build disease awareness for bronchiectasis. This effort drove significant interest and helped to build a base of patients who are ready and waiting for a new treatment option at the time of BRINSUPRI's launch. This included nearly 70,000 self-identified patients who registered on our website before approval. The vast majority of whom were being managed at larger institutions, which were involved in our clinical trials and very familiar with BRINSUPRI.

Some of those physicians even shared with us that they were maintaining lists of patients for whom they wanted to prescribe BRINSUPRI when it was approved. By proactively doing this early work, we were able to successfully accelerate new patient demand into the early part of the launch.

As we noted at the time we launched, larger institutions typically take a few weeks to a couple of months to add new drugs to their electronic medical record systems before prescriptions can be written. As a result, most of these ready and waiting patients receive prescriptions in Q4 and to a lesser extent, in Q1. We estimate approximately 3,500 such patients were embedded in the 9,000 new patient starts we saw in Q4, which is supported by comparing the elevated Q4 prescribing volumes at these institutions to the steady pace we have seen in recent months.

Similarly, in Q1, we estimate that about 1,500 of the roughly 7,800 new patients who started treatment in the quarter were part of this ready and waiting patient group. As we enter the second quarter, we believe this surge from ready and waiting patients is now complete. What remains is organic demand, and that demand is growing. In fact, we believe we have seen a steady increase in organic demand in each quarter since we launched as illustrated by the dark blue boxes on this slide.

While total new patient additions in Q1 came in lower than Q4, this was due to a significant influx of ready and waiting patients in Q4. Further, the growth that we have seen in the latter part of Q1 gives us confidence that BRINSUPRI's organic growth is really just getting started. The second quarter will be the first period that we believe will not benefit from a component of ready and waiting demand, but we expect organic new patient demand to continue to grow sequentially from Q2 through the rest of the year.

Now before we move on to discuss other launch metrics, I want to add a word about Symphony script data. We have noticed that Symphony TRx data has historically been valuable as a directional predictor for total dispenses for BRINSUPRI. Having said that, Symphony NRx data has not been as helpful in predicting new patient starts, and we don't know if either measure will be helpful in the future, but it's worth calling out that Symphony TRx has been proportionately well aligned with reality in past periods.

Another crucial component of any healthy launch is a favorable payer access environment. Initially, in a world without established policies, payer approval rates tend to be higher. Our strategy at launch was to focus physician prescribing and payer access on patients with 2 or more exacerbations where payer approval would be most favorable. As a result of this strategy, I'm pleased to say that the initial expected high rate of payer approval has continued. In fact, the approval rate for patients processed through our specialty pharmacies has been impressive at nearly 90% since launch. Also encouragingly, the time required for payer approval, while inherently variable has been less than a week for the majority of patients so far, which is well ahead of our internal benchmarks.

Overall, we are extremely pleased by what we have seen in terms of patient access to date. These strong approval rates are aligned with our ambition to make access to BRINSUPRI as frictionless as possible for patients.

Now just as important as getting patients access to treatment is supporting their successful use of the medicine. We are pleased that more than 80% of patients on BRINSUPRI have signed up for our inLighten patient support program, which is designed to help patients navigate the practical aspects of initiating and managing treatment with a specialty therapy. Separately, we continue to hear feedback from patients that they are feeling better on BRINSUPRI. This positive patient experience, coupled with BRINSUPRI's favorable safety profile are together driving the very high compliance rates and relatively low discontinuation rates that we have observed thus far.

To be more specific on each of these measures, a reasonable industry benchmark for compliance is that a patient would refill a 30-day prescription around every 37 days. This accounts for practical logistics like remembering to take each dose on schedule and order the next prescription as well as the time it takes for the medicine to be delivered. So far, we have seen BRINSUPRI prescriptions refilled at a much faster pace, nearly every 30 days, which we believe speaks to patients' positive experience with the treatment, motivating them to continue therapy with minimal interruption.

Turning to continuation rates. As with any treatment, there will always be patients who choose to stop taking their medicine. Daily oral tablets generally have higher continuation rates in the real world than many other classes of medicine. Well-tolerated oral medicines like generic statins, see around 70% of patients remaining on therapy at 6 months. So far, BRINSUPRI's continuation rate is tracking slightly above these analogs. Overall, we believe this high continuation rate adds evidence that patient experience with BRINSUPRI is largely positive.

Our area of greatest focus is continuing to deepen and broaden BRINSUPRI prescribing. In terms of broadening the number of physicians who have written a prescription for BRINSUPRI, we feel we are on a very strong trajectory. As of the end of the first quarter, our cumulative total writers topped 5,000, which accounts for more than 1/4 of all pulmonologists in the U.S. There remain large institutions who still have not written their first prescription for BRINSUPRI, so there is plenty of opportunity to expand that prescriber base.

We also see significant opportunity to increase prescribing depth. At the end of December, approximately 1,800 physicians had prescribed BRINSUPRI to only one patient. By the first quarter of 2026, roughly half of those physicians have prescribed it to at least one additional patient. We believe this trend represents our greatest growth opportunity, which will be reinforced by the consistently positive feedback we hear from patients and physicians about their experience with the medicine.

As awareness continues to build and patients share their experiences during office visits, we expect physicians will grow more comfortable prescribing BRINSUPRI, naturally accelerating its use.

In addition, we are encouraged by the fact that more than 20% of BRINSUPRI's prescribers have written it for at least 5 patients. And importantly, this group goes well beyond just physicians in large academic centers. This represents both the progress we have made on deepening prescribing and also the opportunity that is still in front of us to potentially expand prescribing among the remaining 80%. We anticipate the dialogue within the treating community facilitated by gatherings like the American Thoracic Society Meeting, which kicks off later this month, could further encourage physicians to trial or expand their prescribing behaviors as news of positive patient experiences spreads.

Collectively, we see expanded prescribing from existing trialing physicians and broadened physician adoption as 2 positive trends, which, if extended, could enable even greater growth than is suggested by the current $1 billion-plus guidance we have reiterated today.

We are also accelerating our work to increase awareness and proper diagnosis of bronchiectasis through appropriate education. Just yesterday, we announced the launch of a new diagnosis-focused disease education campaign called Suspect BE. This campaign features Emmy Award-winning TV host, Ty Pennington, and draws on his personal experience of caring for his mother who has lived with bronchiectasis for more than 40 years, including an extended period of time before she received the appropriate diagnosis.

We also have plans for direct health care provider education and medical congress presence later this year to further support these efforts.

From our point of view, we believe now is the time to elevate disease awareness to enable earlier and more accurate diagnosis of bronchiectasis.

I'd also like to highlight the recently announced initiative from the American Thoracic Society aimed at addressing the underdiagnosis of bronchiectasis in the U.S. This ATS initiative will analyze electronic health records across 7 large academic medical systems to identify potential patterns of misdiagnosis. Based on these insights, the ATS initiative intends to pilot scalable solutions such as electronic health record-based prompts that automatically flag potential signs of bronchiectasis and continuing medical education modules for physicians to help improve the detection of bronchiectasis. Importantly, it also intends to determine how many patients within these medical systems are currently diagnosed with COPD or asthma and may also have undiagnosed bronchiectasis.

We commend ATS for leading this effort to identify a potentially large and underserved population of COPD and asthma patients who may also have bronchiectasis, but have not been diagnosed. By improving recognition, these insights could drive better outcomes for current and future bronchiectasis patients by increasing the likelihood they will be appropriately diagnosed and gain access to care sooner.

In summary, we see strong and growing organic demand. Payer access and patient compliance and continuation rates are exceeding expectations. We see further opportunity in broadening and deepening physician prescribing, while other groups like ATS are taking the initiative with new and significant efforts to raise awareness and improve diagnosis of bronchiectasis.

Let me now shift to ARIKAYCE. Remarkably, ARIKAYCE continues to show year-over-year growth even now in its eighth year of launch, targeting only refractory NTM MAC patients. In March, we announced the clinical success of the Phase IIIb ENCORE trial in newly diagnosed NTM MAC patients, a far larger population than refractory. ARIKAYCE, in combination with a multidrug treatment regimen, delivered a statistically significant outcome on the patient-reported respiratory symptom score primary endpoint compared to the multidrug active control arm. This end point is the most important factor for U.S. regulators.

The ARIKAYCE arm also demonstrated earlier, greater and more durable culture conversion throughout the study with statistically significant benefits at every prespecified time point, including at month 15 or 3 months off therapy, which is the most important factor for Japanese regulators.

Importantly, the ENCORE data make a very compelling case for using ARIKAYCE earlier in the treatment paradigm for patients with an NTM MAC lung infection. As a reminder, in our Phase III CONVERT study in refractory NTM MAC, we observed the treatment with ARIKAYCE resulted in about 30% of patients clearing the bacteria from their sputum after 6 months on treatment. ENCORE showed us that if you treat earlier, you can convert well over 80% of patients to negative sputum cultures in that same period of time. And this conversion is likely to be durable.

ARIKAYCE was also better tolerated in the earlier NTM MAC lung infection setting with much lower rates of discontinuation compared to the CONVERT study. Now that we have these data and a well-defined target product profile, we will be conducting market research to understand how the product might be perceived and used by the prescribing community, which will give us a clearer view of the opportunity.

We are working to submit the ENCORE data to regulators in the U.S. and Japan in the second half of this year. If successful, these label updates could increase the addressable market for ARIKAYCE from around 30,000 patients today to more than 200,000 patients next year, potentially turning ARIKAYCE into a blockbuster brand with no new competition on the horizon of which we are aware.

Let me now turn to TPIP. TPIP represents a very substantial late-stage opportunity where we are pursuing 4 Phase III trials with very meaningful addressable patient populations for each. We are very excited to announce that last month, we opened our first site in the Phase III PALM PAH study of TPIP. Based on the FDA's feedback, this study, if successful, will be the only registrational trial required for potential regulatory approval for the treatment of PAH. Additionally, data from our Phase IIb 24-month open-label extension study in PAH is now expected in the third quarter of this year and will include safety and certain efficacy measures through the first 12 months of the open-label period.

As a reminder, this OLE gave investigators the option to continue to increase the dose of TPIP beyond the 640-microgram maximum dose allowed in the initial Phase IIb trial. During the OLE, we have not required or encouraged uptitration. That said, we are pleased to report that about 1/4 of the participants in the OLE have achieved doses that are higher than the 640 micrograms, and that 7 out of the 91 patients who entered the OLE have gone on to reach the new maximum dose of 1,280 micrograms.

Given the absence of a placebo group in this open-label portion to which we can compare TPIP's effects, a good outcome for this update in our view would be to see that patients are able to sustain the best-in-class improvements in 6-minute walk, NT-proBNP and functional class measures that were demonstrated in the 16-week randomization portion of the trial over this much longer treatment period. For those who have increased their dosage since starting the OLE, we would want to potentially see some discernible improvement in those efficacy measures compared to what was shown in the randomized trial, along with a consistent safety profile with what we've seen in the Phase II trials.

We will also be interested to see the impact of treatment with TPIP for the patients who are initially randomized to the placebo arm of the trial. We look forward to sharing these data once available.

Moving now to our other 3 TPIP studies. In the ongoing Phase III PALM-ILD study, we are encouraged by the trial's progress with patients having been randomized in 7 different countries so far. We are also pleased to see that we are recruiting patients even in the U.S. despite competition from other marketed treprostinil products that could discourage physicians from enrolling patients into a placebo-controlled trial. We believe this willingness to enroll patients reflects excitement for the clinical trial results shown for TPIP to date, given that doctors know their patients will gain access to TPIP either at the start of the trial for those randomized to the TPIP arm or after the 24-week study period completes for those who are initially randomized to the placebo arm.

We believe this represents a very positive early sign for future adoption should the medicine continue to show positive results and gain regulatory approval.

We also continue to anticipate initiating a Phase III study in PPF in the second half of this year to be followed shortly thereafter by a study in IPF. Recent positive clinical data in IPF from another treprostinil product has added to our enthusiasm about the potential opportunity for TPIP in both PPF and IPF. The mechanism by which benefit may be seen in these patient populations is not fully understood yet, but it is believed that treprostinil demonstrates its antifibrotic effects via multiple pathways, including inhibitory impacts on fibroblasts and that those effects may be dose dependent.

As a result, we believe TPIP may be more beneficial by virtue of being able to deliver a greater dose of treprostinil. In this way, we think TPIP could represent the optimization of treprostinil therapy, enabling continuous delivery of much higher doses of treprostinil directly to the lung using once-daily administration.

As a result, since treprostinil has now been shown in other studies to deliver positive results for patients with IPF, we believe TPIP has the potential to provide even greater benefits for those patients.

So let's recap. In a year that will be defined by execution, we remain focused on delivering across our commercial and late-stage clinical programs. BRINSUPRI is setting the bar for commercial success with exceptional progress across each of its key launch metrics, keeping us on track to achieve our ambitious full year revenue guidance of at least $1 billion in global net revenues. ARIKAYCE continues to grow in its current indication. Looking ahead, we see the potential for substantial growth next year if the FDA and PMDA approve a broader label for all MAC lung infection patients in each of these regions. And for TPIP, we have recently initiated our Phase III study in patients with PAH while continuing to enroll patients in our ongoing PALM-ILD study and finalize our trial designs for PPF and IPF. We anticipate announcing data from our open-label extension programs in PAH in the third quarter of this year.

I have not spent any time today on our pipeline beyond our 3 most advanced programs, but these continue to progress as well. INS1148, INS1033 and gene therapies for DMD and ALS are all advancing to or in the clinic, and we look forward to future updates about these programs as clinical data becomes available. We believe in continuing to build out our pipeline through research and select business development and efforts in both areas continue at a robust pace.

With that, I'd like to now turn the call over to Sara.

Thank you, Will, and good morning, everyone. Based on the strength of our performance so far in 2026, I am pleased to reiterate our guidance for this year, which can be seen on this slide, including full year revenue and gross to net guidance for BRINSUPRI and ARIKAYCE. I would add that the actual gross to nets we saw for both products this quarter also fell within these respective ranges.

Let me now spend a moment on our cash position. As of the end of the first quarter of 2026, we had approximately $1.2 billion in cash, cash equivalents and marketable securities. Excluding cash received related to stock option exercises in the period, our underlying cash burn for the quarter was within the range of quarterly burn that we have seen over the past year. We believe this burn will continue to decline as company revenues ramp at a quicker pace than spending in the future.

Importantly, we continue to believe we can achieve cash flow positivity without needing to access additional capital to support our existing business. Presuming we do not add to our expense base through business development, we would expect to achieve sustainable cash flow positivity in 2027.

Now moving to other relevant financial metrics for the first quarter, which are displayed on this slide. Cost of product revenues in the first quarter of 2026 was $47.4 million or 15.5% of revenues, which is lower on a percentage basis than our historical performance, reflecting the positive contributions of BRINSUPRI to the company's gross margin profile. Additionally, as expected, research and development and SG&A expenses increased this quarter compared to the prior year period due to the necessary investment made to support the U.S. launch of BRINSUPRI and to continue to fund our pipeline.

In closing, Insmed continues to execute, both clinically and commercially and remains in a strong financial position, providing us with the capacity to pursue our ambitious goals on behalf of patients and to maximize the opportunities for value creation we have ahead.

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

[Operator Instructions] Your first question comes from the line of Vamil Divan with Guggenheim.

Thanks for details on the launch. It seems to be going well. So the question we're getting, I think, just because of the additional detail you provided is how to think about sort of the sequential growth from here. I know you don't give quarterly guidance, but I know you reiterated your views for the full year. But just given some of these dynamics with maybe this initial bolus of patient and now the more sort of organic demand, if you can provide any visibility on how we should think about sort of 2Q, 3Q, 4Q, especially given some of the unknowns around 1Q? And all the issues that we sometimes see in this quarter, that would be very helpful.

So I know I'm going to disappoint by not providing a forecast on a quarterly basis other than what we said in our comments, which is that we expect organic demand to grow from Q2 throughout the rest of the year. What I would tell you about the inbounds that we've had, are you going to raise guidance? Are you going to adjust peak sales, all those sorts of things. We have 2 quarters under our belt, and we are a cautious company, as you all have learned by now. So while we are extremely enthusiastic about the performance we see here, and importantly, a lot of the metrics we're covering today are designed to convey the notion that the fundamentals are being put in place for what will be a sustained growth of this product launch. I think it's the breadth, it's the opportunity for additional depth and all of the metrics being above our respective targets that gives us that enthusiasm.

So there may be a time when we want to come back and explore what those peak numbers are. I just think after 1 quarter in the year, the calendar year, it's a little premature. And we only have 2 quarters under our belt. But I do want to just remind you that in the first 2 full quarters, we've done $350 million of revenue, which, by any measure, is an impressive result.

Our next question comes from Ritu Baral with TD Cowen.

Another one on BRINSUPRI dynamics. Will, any thoughts on right now, whether breadth of prescribers or depth of prescribing within prescribers is more important to increasing demand? And as you think about that depth, what are you finding that drives that depth? Is it just sheer patient experience, the number of months that the Sentinel patient is on the drug? Is it detailing? Is it just patient flow thoughts?

Yes, sure. So look, I think both are important. When we look at breadth, we know that we've already reached 25% of all pulmonologists that have written -- they've already written at least one prescription. So I think it's important to highlight that, that includes not just large academic centers, but we are already successfully in the community physician pool and convincing them to -- this is a prescription they want to write. That, to me, is a very positive sign because the sustained growth will come on the back of those physicians being participants here.

We know that our Tier 1 call points have at least 100 patients and in some cases, more each. So when we talk about 1,800 physicians who have written one prescription in the fourth quarter, and half of those have written at least one additional prescription in the first quarter set against what that Tier 1 profile looks like, it gives you some sense of the enormous opportunity that is available to us in terms of depth. I think depth will come our way. It may take a little longer than we would like in the sense that we love for everybody to be writing this for 10 or 50 of their patients. But pulmonology community we're learning, particularly for this disease, where there's been nothing approved for more than 200 years since it was identified, are slow to adopt the new novel mechanism of action, and they're a little bit cautious. The good news is that the medicines profile has resulted in feedback that is very positive. Patients feel better on the medicine, and it is certainly doing a job consistent with what was seen in the Phase III data.

That, to me, is the critical element. If you look at strong blockbuster launches, almost all of them share the common feature that the medicine's perception in the early days was very positive, and we're fortunate to be able to enjoy that kind of a status. So as physicians have more experience with the medicine, I think they will naturally turn to write the prescription more frequently. They certainly have the patients. The need is clearly there. We intend to draw attention to this dynamic through our communications efforts, and I am very bullish that whether it's in the next months or quarters, we are going to see organic demand kick up as physicians shift from a mindset that this is a novel medicine that they are going to consider using to this is the default medicine for the treatment of bronchiectasis. And I think that dynamic is going to be very powerful.

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

Thanks for all the great color on the BRINSUPRI launch. Where do you see the organic demand coming from most now and going forward? Community or academic practices, the KOLs that many of us speak with at the experienced bronchiectasis centers seem to have prescribed BRINSUPRI to many of their highest need patients and note that community palms are still often referring patients to them. And as you think about the durability of the launch, what evidence are you seeing that this isn't likely to be a bottleneck and community physicians are moving beyond first prescriptions towards repeat independent prescribing?

Yes. So this is really important. When we talk about the academic centers, and we talk about ready and waiting demand, what we tried to articulate in the commentary was this notion that it was very clear in the fourth quarter that the physicians at the academic centers were waiting for the electronic medical records systems to update at their institutions before they could write prescriptions. How do we know this? Because 1 week, there were no prescriptions coming from the institution and the next week or 2 weeks thereafter, we saw literally hundreds. So it is the arrival of that ability to prescribe using the electronic medical system that enables that turning to the list of patients that they had in many cases and addressing that demand. And that is what we refer to as the ready and waiting components of the 70,000 folks who have registered on our website.

We look at the first quarter in comparison to the fourth quarter, and we see a steady state and cadence at those larger institutions that may have exhausted their initial lists, but that steady state continues. And importantly, there are many institutions who have yet to write a single prescription. And as we tried to highlight, even though we've already reached 1/4 of all pulmonologists, the vast majority of those have not written multiple or scores of prescriptions, and many of them have that kind of patient count, in fact, almost all of them.

So there's a lot of breadth and depth opportunity here, but I would say depth is the one that I'm more focused on. And I would just refer to sort of 3 dynamics in the launch itself and its durability. The first is the basic blocking and tackling that we've gone into in detail today. How do you execute a launch well? And I think continuation rates, refill rates, all the sort of stuff that we've gone over in detail today, payer access, inLighten support, all that is extremely positive. So the basic blocking and tackling is going well. The commercial team and the customer-facing part of our organization has done an exceptional job in executing on those basics.

The second dynamic is the one we were talking about a moment ago, which is that physicians will ultimately adopt this as the standard of care for bronchiectasis. As that process takes hold, it's less about the promotion and communication interaction and it becomes more the default practice of the pulmonologist to write the prescription. When that starts to take hold, then it will be the volume and traffic through the office that will generate prescriptions and less of the promotional side.

And then the third and final substantial contributor to this launch over the middle to longer term is the comorbid populations that have yet to be appropriately diagnosed. Those are COPD or asthmatic patients who may also be bronchiectatic and would fill the top of the funnel in very large numbers. And so there's some efforts underway to raise awareness about that, not just our own, but those made by ATS.

The combination of all 3 of these things, I think, paints a very robust picture for the potential of this drug in the next quarters, but also the coming years.

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

I was just wondering how you're estimating which patients were ready and waiting versus which fall into that organic demand bucket? And yes, I appreciate all the detail on the patient adds this quarter. Should we continue to expect to get patient metrics?

So on the ready and waiting versus organic, this is always a little bit of a tricky business because it's not as if someone shows up and it self-identifies as one or the other. But what we try to do, as we described, is triangulate through a couple of different measures. The expected yield from the 70,000 registered patients on the website, the behavior of patients at the large institutions and the lumps that came through clearly once the electronic medical record system was cleared and then the steady state that we've seen over the course of the fourth into the first quarter. And I think we also had an anticipation that this would be the case, and it was contained within our own modeling. So we've triangulated through all of this to arrive at the numbers that we shared today, roughly 3,500 in the fourth quarter and roughly 1,500 in the first quarter as ready and waiting patients.

We continue to see organic demand improve throughout the first quarter. And I think as we go through from Q2 through the rest of the year, we certainly expect that will continue. So I think those dynamics are all positive. What was the other part of your question? I can't remember what it was?

If we're going to continue to provide patient numbers.

Well, patient numbers, yes, that's why I forgot it. No. So I would say what we are trying to do is provide the best approach to transparency so that you can model and understand the fundamental dynamics of the launch. That may or may not include patient numbers, it really just depends on the dynamics that are unfolding, but hopefully, today, you've understood that we are quite genuine in our ambition to make sure you understand what is driving the launch and why we have the enthusiasm we do for where we are.

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

Congrats on the solid progress. Will, you've spoken about potential in the COPD and asthma patients. But I was hoping you can provide a little more color on what gets you there? In terms of the potential friction points, is it just awareness? Do you see any pushback from payers? Do you see any, I guess, unwillingness from prescribers to expand the polypharmacy in these patients? I mean what drives you to that population?

So we know from our own clinical trial work that roughly 15% to 20% of patients in the ASPEN trial and the WILLOW study were comorbid with asthma and COPD. And those patients responded just as well as those that did not have those comorbid indications. So the presence of these patients, their existence is understood. It's not documented to a refined degree. And as a consequence, the literature is sort of all over the place as to what percentage of COPD patients, for example, are also comorbid with bronchiectasis, and what percentage of those patients have had 2 or more exacerbations and are continuing to be symptomatic because those are the low-hanging fruit that should definitely be on the top of our funnel. How do we get there?

We get the pulmonologists or the primary care physicians, whoever they are, to refer them for a CT scan to look for the diagnosis of bronchiectasis. Once that has happened and a pulmonologist has done a workup on the patient, they're eligible for treatment, and they are on label. And so that process, we think, is going to take some time, but I think we're going to get there. And I'm very excited about the potential for these patients.

In the U.S. alone, there are roughly 20 million COPD patients. And when we speak to KOLs, they estimate somewhere in the 20% to 40% range are comorbid with bronchiectasis. Now some smaller population of that are experiencing exacerbations despite on max treatment, and it may be that they're misdiagnosed. It may be that they are comorbid. We don't know, and honestly, we don't really care. What we want is for them to get the appropriate treatment and if BRINSUPRI can play a role in helping them, we certainly want to facilitate that. But I think that serves as a top of the funnel feeder that is quite substantial, and it may take time to bring it about, but we are investing in it almost like a second launch within the company with dedicated people focused on that area, and we think that's going to yield benefit over time. So we're pretty excited about that.

Our next question comes from Gavin Clark-Gartner with ISI.

So I wanted to ask on the discontinuation rate in a very specific way. For the 11,500 patients who started on therapy by the end of 2025, for that same cohort of patients, how many were still on paid therapy at the end of the first quarter? Because in order to square the revenue versus the strong new patient starts you reported, I'm seeing there's probably 2,500 or more discontinuations from that cohort, which is in the 22% to 25% realm for a 6-month discontinuation rate. So I'm wondering if that's roughly on track with what you're seeing? And if we should be expecting that same rate of discontinuations moving forward? Like should we expect 40% discontinuations in a year? Any clarity there would be really helpful.

Yes. It's hard to walk through the particular math that you're framing out here because I want to make sure that we're conveying accurate information. What I can tell you is that -- and I'll invite anyone else in the room to comment on this. What I can tell you is that we are tracking above trends for small molecule product use in terms of discontinuation rates. Statins are around, I don't know, 2%, 3% per month that tend to drop off. And the dropout rate is heavier in the first 6 months than the second 6 months, typically. So I think we feel like we're well ahead of industry benchmarks there. I don't know if we can give greater clarity. Would you...

Yes. The only other thing I would comment on is, in the prepared remarks, Gavin, we shared that statins had continuation in the first 6 months of around 70-ish percent. If you look at that over 12 months, it's about 60%. So as Will said, if you're going to have discontinuations, it tends to be earlier, but you do continue to see a level of discontinuations with statins.

So hopefully, those numbers are helpful. I can't go through the particular calculations you're running over the phone, but we'd be happy to do that at sidebar. But in the meantime, I would just draw attention to that discontinuation rate that we've cited for statins and indicated that we're slightly ahead of that, which is about as good as you can hope to do.

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

Yes, I appreciate the color around new starts and underlying demand. Sorry to ask another follow-up here. But the fact that you guys are pointing to sequential growth, I actually think is a really positive sign for 2026 numbers. So maybe a couple of questions there, is where is that confidence coming from? I'm assuming you're seeing some good growth in April trends? And then how long do you actually expect that sequential growth to continue until you start to see some of those new starts level off?

And then I hate to ask a competitor question, but on TPIP, how quickly do you actually think you can enroll some of those studies like PAH in particular? I only asked given some disclosures yesterday around trying to expedite a once-daily DPI program from United.

Yes, sure. So on the sequential growth point, what I would describe for everybody is that there is a massive opportunity that we still have before us with physicians, large practices, community docs and many, many patients, even within practices that have already written prescriptions that are available to us to access. So the opportunity for growth remains and will be there for some time. It's typical that in launches, you see companies get to a steady state after a certain period of time. You can look at the analogs to sort of define where you think the average is. But we would expect certainly to follow that sort of a profile, maybe a little bit better because of the opportunity that we think is before us. All of the metrics we've defined speak to the execution excellence of the team, and I think portend very positive things for when we're able to get those patients into the funnel in terms of our ability to execute and bring them through.

I do think that our efforts in terms of communication and advertising and those sorts of things are going to amp up materially from here. And it takes time to get that stuff through the FDA and cleared and set up once we understand the launch dynamics. We are in that place now. And the Ty Pennington campaign as an example, is the first of what will be additional efforts made to raise awareness. And I think that will activate what is already a very vocal population of patients and probably drive additional demand. So lots of different vectors that give us this confidence. It starts with the capabilities of the team to execute, but it is complemented by the enormous availability of additional patients and physicians and all of the different efforts we've made to raise awareness and bring people into the funnel.

On TPIP, the enrollment timing, we're going to go as fast as we possibly can. We have a good track record of accelerating our enrollment in trials better than standards, certainly in the industry. And I would expect that to be the case here. We tried to highlight today that we're already hearing some positive feedback from physicians even in the U.S. where there are available approved treatments for their patients. They're choosing not to put them on that treatment and instead putting them in our trial where their patient may be on a placebo for 6 months. So I think that speaks to the enthusiasm that is in existence already for our medicine and what it may be able to do for these patients.

A comment on the other programs that are out there. I'm sure we're going to see a lot of talk about different programs and what they may be able to do. We are all about the data. And the data will lead the way, certainly for the physicians and the treatment of their patients, and the data we have so far is second to none in this category. So I think as long as that continues, we're going to be in a very strong position. The sooner we can get it out there, the better for everybody. The fact that we have to run through Phase I, II, III programs is because this is a novel differentiated compound. It is not a copycat, it is not a rewarmed version of an already existing drug. This is a very different drug that is breathed in inertly and then becomes active once in the lung. It has longer residence time, has a lower peak, a longer trough, once-daily coverage for patients, including nighttime with really excellent results.

So I think its profile is very distinct from everything else that is in the prostanoid class, and we hope that, that will continue.

Our next question comes from the line of Ellie Merle with Barclays.

Can you elaborate a bit more on sort of the half of the single patient prescribers in 2025 that have not written an additional script in Q1? I guess why do you think that was the case? And are there any indicators that, that's changing? And I guess, from the organic growth that you've seen in 1Q, I guess, what is the mix that's coming from some of these higher volume prescribers versus some of these sort of like lower volume writers?

Yes. So the half that have not written, there's an interesting dynamic in this therapeutic area and with these particular physicians. There's a conservatism, I think, that is now in evidence with the new mechanism of action and a new treatment for a disease that they've known about forever, but for which they've never had a treatment. And so I think what we've seen is great physician engagement. We have 1/4 of all pulmonologists who've already written a prescription. So they've crossed the hurdle or the rubicon of being willing to put their patient on the medicine. We now have to have the cycle of time take place where they go and they are on the medicine for perhaps 3, maybe as long as 6 months before they come back through the office and tell the physician of their experience.

We are hearing a flood of positive feedback, and we read it in the social media as well. And it's not universal, but it's pretty overwhelming. And I would tell you that, that, I think, is the most powerful motivator for these physicians to write again. When they hear that 1 or 2 of the patients they put on medicine have had a good experience, they want to write again and more broadly, and that becomes a narrative and a dialogue that they share with their peers at places like the American Thoracic Society. So I think we're going to see this pick up throughout the year as physicians who have trialed the medicine have success and get good feedback from their patients and decide to continue to write prescriptions for others. Once they're over a hurdle, I don't know what the breakpoint is, a couple, 2, 3, 5 patients perhaps, we think that the rest of their practice is going to pick up. And so that just provides a really interesting opportunity for us.

We haven't really broken out the organic versus -- between the high writers and the lower writers, that's even harder to discern, but what I would say is it's across the board. The vast majority of the ready-and-waiting patients came through the large centers where physicians had lists of patients and those are the ones that are easily identifiable as, if you will, ready and waiting versus those who are steady state. So hopefully, that's helpful.

Our next question comes from the line of Graig Suvannavejh with Mizuho.

We've got ATS coming around the corner. I know that the ATS put out a statement just on new efforts to improve diagnosing of patients. I was wondering if you could comment just on how much of a potential springboard ATS might be, particularly from a prescribing perspective. And if you could also remind us of past comments that you've made around how maybe AI can help with increasing diagnosing of patients?

Yes. So there's going to be a lot -- we're going to be quite loud at ATS, as you might expect, and also ERS and other academic meetings. And I think you will see both positive feedback stories that are shared by physicians from their experiences just in the hallways, but also a very deliberate effort to talk about the disease, raise awareness. We certainly will have a big presence in that regard. I think what ATS usually represents, you asked if it's a springboard, you take physicians and patients -- or pardon me, physicians and our commercial-facing group out of the market for a week, you tend to see a little bit of a drop during that week because of that, but then it tends to accelerate in the aftermath. How much? We don't know. But again, we pointed to the Symphony data, TRx has been fairly accurate for what we've seen proportionately in our own tracking. So hopefully, that may be something that can give some insight.

With regard to AI, we are looking at a number of different ways to bring that to bear, most prominently in the area of examining historic CT scans and also doing sort of audits of patients -- patient records to try to understand what the diagnosis rate and identification of these patients might be able to be in a world where we bring that to bear in a more broad basis.

I think you could expect us to be talking about a lot of different programs running in parallel to try to raise awareness and identify the appropriate patient and help with the diagnosis. And AI certainly is going to play an important part in that, not just for bronchiectasis, but generally. Hospitals are looking to bring that into the radiography field to help them get to more accurate and timely diagnosis.

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

I appreciate all the additional color today. At the beginning of this year, you all cited a couple of potential risks to the launch as hypotheticals, including particularly more stringent payer contracting, more prior auths, things like that, that could come into account some point in 2026. First quarter, it doesn't look like that was an issue, still getting good payer coverage and time lines to dispensing. But just curious as you're now 5 months -- getting into 5 months into the year, if you still see that as a risk at some point this year? Or if you think you're at a good point with payer contracting that, that's not a concern?

Yes. So through the specialty pharmacies, we've seen an approval rate of 90%, which is extraordinary. Now we don't expect that, that will sustain for the entirety of the launch. In fact, typically launches, you see that tend to trend down over time. We'll have to see where it goes. But I'm still very excited to be in possession of that kind of an approval rate. I think that speaks volumes about the perceived value of the medicine as well as the physician desire to push to ensure that it gets approved.

Collectively, that lays a very positive forward view for where we may be able to go. I don't think there's as much risk for us in the payer approval collapsing, if you will, because of contracts and policies that are finally put in place. Many of them already have been put in place, more will come, but the point of that is because at the outset, we were focused on the moderate to severe patient for approval, there is not a big shift in what those policies will result in, in terms of holdback of patients. In fact, it may accelerate in some cases, the approval process. So one of the things we're trying to highlight today is that while whenever you start a medicine, it's always medical exception in every way, and you get higher approval as a result without a lot of scrutiny. Because of the way we channeled physicians and focus people on 2 or more exacerbations, we haven't seen a material decline with the implementation of these new policies. So that's a very positive thing.

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

I wanted to ask on the international side and MFN. I know historically, you guys have been very conservative on how to approach an international launch. Just curious sort of what your latest thoughts there are? How much you expect some of these other governments to work with you around pricing? And then just given the discussion we've had around sort of the ready and waiting patients, how much of that dynamic you might be seeing in other geographies?

Sure. So the interesting thing about MFN is, it does -- it has caused us to pause our launch efforts in Europe and the U.K. We are approved -- BRINSUPRI is approved for use in Europe and the U.K., but we need to be very cautious because the normal logic for selling in those regions is that if you can sell above the marginal cost of production of your medicine, it makes financial sense to do so. It is not intended to be a way for us to ensure that Europe pays the same that the U.S. does. We do not hold that bargaining power. We have 2 medicines that are approved. If I go to Germany and insist that they pay more for the medicine, they're simply going to say no. So we're not in a position to extract a higher price abroad than what we get currently from them.

I think the pressure that's being brought to bear is causing Europe to reconsider some of those positions. But there's not a lot we can do about it, to be blunt. And so that puts us in a place where, if there's a risk that someone is going to import a price control into the U.S. at a fraction of what we're currently able to command based on the impact that is positive for patients, then that's something we simply cannot permit to happen. So we have 2 choices. We can either try to get a much higher price, which we do in Europe, or we sell -- we don't sell the medicine abroad. And in the latter case, I don't think that really serves anyone's interest because the intent behind MFN was to lower prices in the U.S. And at least for the mid-cap biotech companies, that's not going to be the result. The result is we simply won't sell the medicine abroad. And then the copycat medicines that are made in China are going to take our place. And then the result of MFN will be to bankroll the Chinese biotech market, which I don't think is really in anyone's interest.

I appreciate and align with the notion that it is frustrating for Europe to pay far less than what the U.S. pays for the medicine, but we are not in a position to force them to pay more. And as a consequence, we have to be very cautious.

Practically speaking, we will wait for clarity on where MFN is going to go in the coming months, and that will inform whether or not we're able to move forward as we would like to. Because the goal of the company is to make its medicine available to those patients who can benefit from it. And we need to work within the financial constraints that exist in these other countries, but we can't dictate them. Certainly, we think of Japan as a very exciting market opportunity. Europe has a role to play as well, but we need to sort of get to the heart of what MFN is going to be and how it's going to operate first.

Our next question comes from the line of Danielle Brill with Truist Securities.

I wanted to ask on -- a follow-up on discontinuations. Of the discontinuations that you are seeing, can you comment on what's driving them? Like what's the relative contribution of Medicare out-of-pocket resets and payer dynamics versus other variables? And then given the recently unveiled competitor programs, how important is it for TPIP to now demonstrate enhanced efficacy to support the thesis?

We don't really have a breakdown of the reasons for the discontinuation that we can share today. We can step back and take a look at that and see if there's commentary we can provide, so we'll do so. But there isn't something I can tell you right now about the profile of discontinuations and where they're coming from. I think that given that they're at -- sorry, that they are above the best benchmark rates out there, certainly, it is not driven by the medicine. I think it's fair to conclude, this is driven largely by patients having other motivations.

When we talk about the competitor programs, I don't -- we're not particularly focused or worried about them at the moment. The Phase II data we saw from the BI program was not particularly compelling in our mind, and we'll have to see what Phase III looks like. It's going to be several years before they're on the market. So we have a lot of room to run here and really to establish ourselves. We'll have to see what BI's data looks like. I want to remind everybody, BI has targeted 30% enrollment of Asian patients in its Phase III program. That is very deliberate. That is -- it is 8% of the population in the U.S. They are over-indexing to that group because as we saw in our trial, the Asian patient population is a hyperresponding group in terms of reduction of exacerbations.

We had a 20% reduction in pulmonary exacerbations in our Phase III results. If we look at the subpopulation of Asian patients, it was north of 60%. So you can expect the headline number coming from BI to be better than ours. Certainly, that's what we would expect given the over-indexing to the Asian patient population. But when we tease through the data and see what is really there, we'll know what kind of profile that product represents.

Our next question comes from the line of Max Skor with Morgan Stanley.

I was just wondering, have you seen any change in the severity mix or overall profile of the bronchiectasis patients on treatment through the early stages of the launch? And as the commercial base builds, how are you prioritizing business development?

So on the mix of profile of patients, as I was commenting earlier, we really focused on those patients with 2 or more exacerbations, and so that continues to be the phenotype that we really want to advance for attention. We think they're going to benefit the most. Certainly, we saw that in our Phase III study very definitively. I don't expect that to change very much. You are right to highlight that our label is much broader than that. It actually is available for any patient with bronchiectasis, regardless of the number of exacerbations they've had in the last 12 months. This is just trying to work with the insurance companies and their policies, which will be focused primarily on those with 2 or more exacerbations.

Prioritizing BD.

Prioritizing BD. So BD, let me just comment on this. I'm a big believer, and we are collectively as a company that the right time to do BD is when you don't need it. This is a particularly interesting time for us because we have 3 programs that are in excellent position to really be blockbusters or in at least 2 cases, potentially mega blockbusters. That gives us a very strong runway for revenue generation over the next 5 to 10 years. We could sit still and do nothing and perform, I think, exceptionally well. The opportunity is to augment our pipeline and to look for ways in which we can leapfrog from our current position into one of greater strength.

We have done that with INS1148 at the end of last year for a very modest investment. That is a novel mechanism of action that we think has potential applicability in multiple disease states. We will look for similar programs like that. We will be certainly developing our China strategy, and we will be looking for other potentially even more substantial acquisitions if they fit all of our criteria, which is, number one, can it provide an asymmetric return opportunity for our shareholders. And that's the #1 criteria we have for BD that we're pursuing. Simply adding a program that targets a single disease is not interesting to me, unless it has the ability to go into broader disease states.

So we may end up doing nothing. We may end up doing a lot. We don't know. What I can tell you is we are very active in looking, and this is a time when there are a lot of really interesting companies and technologies out there that I think are ripe for potential acquisition.

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

I just wanted to ask you, you cited that the, I think, persistency rate on oral meds like statins at 6 months are around 70%, and that you're sitting a little bit above that. Just wanted to clarify that comment and also ask if you're seeing any meaningful differences that you can tease out between the kind of ready and wait patient population and your organic new demand patient population to the extent you're able to tell?

Yes. So that is, in fact, the benchmark that we're using. The statin discontinuation rate of 70% is at the 6-month mark. After a year, it's about 60%, as you heard Sara referred to earlier, and we are above that benchmark. So we feel very good about what that portends for our -- for keeping patients on drug and of course, the benefit of that that inures to our shareholders.

I think as we think about where we can go from here, we'll certainly continue to emphasize trying to keep patients on drug. I think the storylines that come back from the use of the medicine are going to help support that more than anything. And patients that come into their physicians' offices and report having their life back or feeling better again, I mean we have very dramatic stories. These are not necessarily indicative of how everybody responds to the medicine. I want to be really clear about that. But we do have quite dramatic stories of patients coming in and breaking down in tears and telling their physician how they couldn't take a short walk and now they're out doing a 4-mile hike. So I think there's a lot to like there.

Yes. The only other thing I would comment on is, I'll just remind you of the benign safety profile for this product, and Will mentioned it earlier, but the best launches in our industry start off with really these positive launch dynamics and experiences, and that is what we're hearing and seeing consistently through. And you guys are all seeing it too on the social media posts and just the feedback loop from the patients themselves, and that is sort of the building blocks of really successful launches. And so very pleased with the continuation rate that we've seen. As Will said, we're a little bit better than statins. So we're encouraged by that.

Our next question comes from the line of Adam Walsh with ROTH Capital Partners.

Going into the quarter, your guidance was $1 billion plus for BRINSUPRI, and consensus was at $1.2 billion. What will you need to see to be able to give more granular guidance going forward as we progress through the 2026 quarters?

Yes. I think we always tend to take a conservative approach to guidance. If things -- dynamics are expected to continue to be positive, and certainly, the -- all signs are pointing in that direction, we'll come back and revisit this every quarter. I'm less focused on giving a higher estimate or putting out new guidance and much more focused on the execution. The execution is there, the numbers will come. And I'm just here to tell you that the execution is there.

Our team is doing an excellent job. And my enthusiasm for where this product is in its launch, if it's not apparent by this point in the call, let me be explicit. I could not be happier about where we are. We are in a fantastic spot, not just for the performance in the first 2 quarters, but what it portends for the future because the building blocks for a long-term sustainable growth of this drug in this disease indication, they're all there. And that's probably the thing that's the most exciting about what we've seen and why we shared so much detail today.

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

Just a question on TPIP. Great to hear that higher doses were tolerated in the Phase II OLE. But I guess, is this -- is it fair to assume that this will be reflective of sort of the Phase III doses? I guess really the question is, will patients have enough time to titrate up to those doses as high as what you're seeing in the Phase II OLE?

Yes. So I think they are going to have enough time. We thought about that issue very particularly because the top dose is 1,280 micrograms in the Phase III studies. And our experience and our dialogue with physicians has made it very clear that they do have the ability to titrate up all the way to that max dose should they wish to. It is important to emphasize that in the OLE, we did not push physicians to increase the dose. That was a decision they made completely independently of us. And it was an option that was given, but it was not one that was encouraged or pursued. So what you're looking at is true organic decision-making that has driven these patients up in dose. And as we said, I think a total of 7 of them actually went all the way up to 1,280, which I find remarkable given that 640 was the original max dose of the Phase II study.

So in all of the Phase III studies, we're going up to 1,280 as an option, and there's plenty of time to titrate up to that level. And of course, more drug to date has certainly shown better performance. So that's a very exciting dynamic.

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

Just a follow-up regarding the diagnosis rate and expanding the pie. I know you're very excited about your diagnosis initiative and raising awareness, but that's still very qualitative, and we may not see results until sometime in the future. So can you please provide some timing expectation around this diagnosis expansion? Or maybe, in other words, can you maybe speak more regarding the appropriate industry analogs for this diagnosis expansion?

Yes. It's a difficult question to answer accurately at this stage. I think what we believe is that through these efforts, we should begin to see, in the case of the COPD and asthmatic, comorbid patient populations. And we can look at things like CT scan rates or diagnosis rates of bronchiectasis, like there are lots of little markers out there that we can track to see if they're having impact. I would expect that by the end of this year and certainly more robustly in 2027 that these efforts will begin to result in some positive results. And we would expect to be able to look at that and hopefully share that with you at some point.

I'm not concerned with whether it's the fourth quarter of this year or the second quarter of next year, because the size of this opportunity is so significant, potentially that I think it warrants patience for those patients to come around. And the process here is very straightforward. It's a CT scan and a diagnostic workup by a pulmonologist and the patient is at the top of the funnel. So it isn't that far to go. And I think as we think about low-hanging fruit, many of these patients already have CT scans from their interaction with pulmonologists over the years.

In many cases, they were simply not asked at the -- the radiologist was not asked to look for bronchiectasis. So unless they identified it and sua sponte decided to report it, with no treatment available. There's not a lot of reason to do that. So what does that mean? It means that there's a slew of CT scans out there we can go back and look at retroactively to see if there's evidence of bronchiectasis already, and that is really at the heart of the ATS initiative. They see this opportunity as well. They see the risk of under diagnosis. And so they're running this effort at 7 different centers, and that should yield some very interesting information.

And 1 of their 4 priority goals of this was to be sort of loud in terms of the discovery that they have. So I would look to them as a third party for information as well on diagnosis of bronchiectasis and the potential for underdiagnosis and what that will all look like. So I'm sure they'll have some time lines around their publications and the expectation of that. But end of this year, certainly in '27, I would want to see some evidence.

Our final question for today comes from the line of Ash Verma with UBS.

Can you confirm the 1Q BRINSUPRI gross to net that you mentioned? Is it at the top end of the range, the mid-20s to low 30s? And then just trying to get a sense if there's any other extraneous factor like free goods or if the delta from the sales that you printed and new patient adds is just primarily the discontinuation that you talked about?

So I'll ask Sara to address that.

Yes. So on GTN, what I can reiterate is the guidance that we provided for BRINSUPRI mid-20s to low 30s and the actual for Q1 was within that range. We're not providing additional clarity than that, but we were within that range. Same goes for ARIKAYCE, low to mid-20s, and we were within that range for Q1 actuals.

Thank you, everyone. That concludes today's call. Thank you for joining. You may now disconnect.

Thank you for standing by, and welcome to the Insmed's Phase IIIb ENCORE study of ARIKAYCE in patients with newly diagnosed MAC lung infection not yet treated with antibiotics conference call. [Operator Instructions] I'd now like to turn the call over to Bryan Dunn, Head of Investor Relations. You may begin.

Thank you, Rob. Good day, everyone, and welcome to today's conference call to discuss the top line results of the Phase III ENCORE study of ARIKAYCE in patients with newly diagnosed or recurrent MAC lung disease who have not started antibiotics. I am joined today by Will Lewis, Chair and Chief Executive Officer; and Martina Flammer, Chief Medical Officer. The call will begin with opening remarks from Will before turning it over to Martina to walk us through the results.

After the prepared remarks, the presenters will be joined by Kevin Mange, Chief Development Officer; and Sara Bonstein, Chief Financial Officer, for the Q&A session.

Before we start, please note that today's call may include forward-looking statements based on our current expectations. These statements represent our judgment as of today and inherently involve risks and uncertainties that may cause actual results to differ materially from the results discussed. Please refer to our filings with the Securities and Exchange Commission for more information. As a reminder, the information on today's call is for the benefit of the investment community. It is not intended for promotional purposes nor is it sufficient for prescribing decisions. And now let me turn the call over to Will.

Thank you, Bryan, and good morning, everyone. We are extremely excited to share with you that the ENCORE trial was a clear success. On the primary endpoint of change in respiratory symptom score from baseline to month-13, we saw a statistically significant improvement in patients treated with ARIKAYCE on top of multidrug therapy versus the active comparator arm consisting of placebo plus multidrug therapy.

On the equally important culture conversion endpoints, we were very pleased to see earlier, greater and more durable impacts on culture conversion throughout the study, demonstrating highly statistically significant benefits for the ARIKAYCE arm. This result is particularly impressive as it was being compared to an active comparator arm similar to what a patient might receive as first-line treatment in current practice and demonstrates the potential benefit of using ARIKAYCE earlier in the treatment paradigm.

As we celebrate this moment with our investigators and the patient community, it is worth remembering the road that brought us here. As part of our development program, consisting of the ARISE and ENCORE trials, we validated a patient-reported outcome tool for this disease state, a first of its kind, which can be used for future development work in this space.

While other promising treatment candidates have fallen short, ARIKAYCE has consistently shown in each study ever conducted that it is demonstrably effective at clearing MAC bacteria from patients' lungs. Now based on today's result, we can also say that it may help patients find relief from respiratory symptoms after treatment. We are particularly excited to see a lower discontinuation rate in this trial than we have seen in any past study of ARIKAYCE and no new or unexpected safety signals in the trial.

With this successful readout, we will look to move quickly to pursue regulatory submissions with the FDA and PMDA in the second half of this year, which we anticipate will lead to an expanded label to include all patients with the MAC lung infection. If granted, this would bring our addressable patient population from around 30,000 today to more than 200,000.

We also expect these results to support the conversion of ARIKAYCE's current conditional approval in the U.S. to a traditional approval, consistent with Europe and Japan, given that we have now completed the study intended to fulfill the FDA's post-marketing requirement. We are ecstatic about what today's news could mean for patients with MAC lung disease. Now let me turn the call over to Martina to walk you through the results in more detail.

Thank you, Will, and good morning, everyone. I'm pleased to be with you today to share the top line results from our ENCORE study. I'll begin with a brief review of the trial design. ENCORE enrolled 425 adult patients with non-cavitary lung disease with a newly diagnosed or recurrent MAC lung infection that had not yet been treated with an antibiotic regimen for their present infection.

These participants were randomized on a one-to-one basis to receive either ARIKAYCE plus azithromycin and ethambutol or an empty liposome placebo plus azithromycin and ethambutol. Treatment was administered once daily over a 12-month period followed by 3 months of treatment. The primary endpoint in ENCORE was the change from baseline to month-13 in the 8-question Respiratory Symptom Score, or RSS, which was derived from the 9-question QoL-B respiratory domain questionnaire.

This patient-reported outcome tool was previously validated and agreed upon with the FDA. Multiplicity controlled secondary endpoints in the study included the percentage of patients achieving culture conversion by month-13, durable culture conversion at month-15 and culture conversion by month-12 and month-6 in that order of hierarchy as well as the change from baseline in the PROMIS Fatigue T-score at month 13. Safety and tolerability data were also collected throughout the study.

On Slide 9, we provide the baseline characteristics of the trial by treatment arm. Randomization was stratified based on geographic region and whether a patient had a history of previous MAC infection. As you can see, those characteristics used for stratification as well as age, gender and race were all relatively well balanced between the ARIKAYCE and active comparator arms. While there was a modestly higher mean baseline RSS in the ARIKAYCE arm, it is important to note that the primary analysis was designed to adjust for any baseline imbalances in RSS, geographic region and history of MAC infection.

Now let's take a look at our primary endpoint of change in RSS at month 13. I'm pleased to report that patients in the ARIKAYCE arm showed a least square mean improvement in score of 17.77 points compared to a mean improvement of 14.66 points in the control arm. This separation of 3.11 points was statistically significant with a p-value of 0.0299. Interestingly, this symptom benefit continued to expand after month-13, with the difference between arms increasing to 4.8 points at month-15 or 3 months off treatment with a nominal p-value of 0.0015. This further highlights the durability of the symptom improvement that can be achieved with treatment with ARIKAYCE.

In addition to the comparison I just described, we also conducted a responder analysis using covariate-adjusted cumulative distribution function or CDF curve, which are shown in this slide. On the horizontal axis, the CDF graph plots a continuous view of respiratory symptom score changes, both positive and negative, with improvement on the left of the 0 and deterioration on the right of the 0.

The vertical axis plots the cumulative proportion of patients in each study arm that experienced at least that level of respiratory symptom score change. The purple curve represents patients in the ARIKAYCE arm and the blue curve represents patients in the comparator arm. A positive change in respiratory symptom score represents an improvement of symptoms from baseline to month-13 and the negative change represents a worsening of symptoms.

Based on our prior work with this PRO tool, we established a range of thresholds that could be considered a meaningful with inpatient change in RSS score, which is the preferred approach recommended by the PRO experts at the FDA. At the low end of that range is a threshold of 16.67 points and at the high end is 20.83 points. Importantly, this graph demonstrates that the ARIKAYCE arm outperforms the control across the range represented by both thresholds.

The consistent separation you see on this curve means that regardless of what exact values are selected as the range of meaningful within patient change by the FDA, ARIKAYCE used in combination with multidrug regimen would result in more patients achieving a clinically meaningful improvement in respiratory symptoms.

Turning now to culture conversion, which is often cited by physicians as the most meaningful measure of the efficacy of any drug for the treatment of MAC lung disease. To provide some context for our discussion, culture conversion in the ENCORE study is defined as having 2 consecutive months of cultures that remain negative for MAC. The definition of durable culture conversion at month-15 requires all cultures to be negative at month 11, 12, 13 and 15.

Consistent with the results shown in our past trials of ARIKAYCE in both the refractory and frontline setting, ENCORE demonstrated that a significantly greater proportion of patients in the ARIKAYCE arm achieved culture conversion compared to patients in the active control arm, and this was demonstrated across multiple time points in the study.

Beginning with month-13 or the same time period at which we measure the respiratory symptom score for the primary endpoint, we saw that 82.4% of patients in the ARIKAYCE arm achieved conversion compared to 55.6% in the active control arm, a highly statistically significant difference of approximately 27 percentage points with a p-value of less than 0.0001. Perhaps even more striking is that this high rate of culture conversion in the ARIKAYCE arm was maintained over time.

On Slide 13, you will find results from the key secondary endpoint of durable culture conversion at month-15 or 3 months off treatment. 76.2% of ARIKAYCE patients remained converted, while only 47.6% of patients in the active comparator arm maintained negative cultures. This result reflects a separation of approximately 29 percentage points and a p-value that was less than 0.0001.

This is a particular notable outcome because durable culture conversion is the most important data point for the Japanese regulatory authority and for many prescribers, both in the U.S. and Japan. The greater durability of treatment we see in ENCORE is consistent with what we saw in both the CONVERT study in refractory patients and the ARISE study in newly diagnosed patients, where dose in ARIKAYCE saw a much higher level of maintained culture conversion measured at 3 months and 1 month off treatment, respectively.

It is important to note that at any measured time point from the start of treatment through month-15, more patients receiving ARIKAYCE achieved culture conversion compared to those on the active control arm. In fact, the secondary endpoints of culture conversion at month-12 and month-6 were also highly statistically significant with each achieving p-values of less than 0.0001.

The ARIKAYCE arm also showed a significant benefit on median time to culture conversion, which was achieved at month-2 or the first possible time point, meaning that cultures were negative at months 1 and 2. The median time to culture conversion in the active comparator arm was achieved at month-3, meaning that cultures were negative at months 2 and 3. The associated hazard ratio for this measure was 2.03, suggesting that patients treated with ARIKAYCE were roughly twice as likely to achieve earlier culture conversion. The nominal p-value for this comparison was less than 0.0001.

It is also notable that the separation you see on this slide was driven by very strong conversion rate in the ARIKAYCE arm rather than any underperformance in the control arm, which demonstrated similar conversion rates as we saw for the control arm in the ARISE study and which might be expected for a macrolide-based treatment regimen in the real world.

Finally, I want to briefly discuss the safety results from the ENCORE trial. The tolerability profile for ARIKAYCE in combination with multidrug therapy in ENCORE was consistent with the known profiles of this antibiotic treatment. No new safety events were observed in the ARIKAYCE treatment group and safety in general was as expected in both the ARIKAYCE arm and the control arm.

The ARIKAYCE treatment discontinuation rate observed in this trial was 18.3%, which compares very favorably to the 34.8% rate that we saw in the CONVERT study in refractory MAC patients and to the 22.9% rate we saw in the ARISE study. The improvement compared to ARISE is particularly notable because the treatment period in ENCORE was twice as long. The empty liposome control discontinuation rate in the control arm in ENCORE was 11.8%. Importantly, the percentage of patients who completed the study was over 90% for both arms in the trial.

Drilling down a bit further, treatment-emergent adverse events were reported by 98.1% of patients in the ARIKAYCE arm and 97.2% of patients in the control arm. Adverse events that occurred at least 10% of patients in the treatment arm and more frequently in the ARIKAYCE arm were dysphonia, cough, fatigue, dyspnea, nausea and headache, all of which are consistent with the known safety profile of ARIKAYCE. The rate of serious treatment-emergent adverse events was 14.1% for the ARIKAYCE arm and 11.3% for the control arm.

In summary, the combination of all the data we have presented today a statistically significant benefit on patient symptom scores, greater, more rapid and more persistent culture conversion and a consistent safety profile provide clear evidence that treatment with ARIKAYCE and in particular, early treatment with ARIKAYCE can lead to improved results for patients with MAC lung disease. I'll now turn it back to Will.

Thank you, Martina. Today's results are incredibly exciting for all of us at Insmed, but more importantly, for all those who struggle with MAC lung infections and for those who provide treatment to and care for those patients. ENCORE has provided new hope that with the early addition of ARIKAYCE to the treatment paradigm, patients can experience improvement in their respiratory symptoms and have a greater chance to convert sooner and stay converted for longer.

We will now work with urgency toward making this important treatment available as an approved treatment option for use in all patients with a MAC lung infection. We want to thank our patients and investigators for their courage and support on this journey, which we hope will result in many more patients benefiting from treatment with ARIKAYCE. And with that, operator, I'd like to now open the call to questions. Can we take the first question, please?

[Operator Instructions] Your first question today comes from the line of Graig Suvannavejh from Mizuho.

Congratulations on this data. Just for context, bigger picture with respect to how to put this data in the context of the current standard of care, so to speak, which is like triple antibiotic regimen given the study while nicely positive. Can you give a sense of maybe how physicians might look at this data and put it into practice in the real world?

Sure. Well, one of the most exciting things about this study was when we were originally designing it, we worked closely with the KOL community as to what would be the right way to look at this in the frontline setting. And what you see today is very clear evidence that ARIKAYCE in addition to a 2-drug regimen provides a real benefit both in symptoms and in culture conversion. That 2-drug regimen plus ARIKAYCE sets a new standard of care for how to treat initial patients who are diagnosed with MAC lung infection. And that was really the intention behind the study to create a path toward a new standard of care.

The drug that is sometimes included later on is rifampin. It's always been very controversial as to whether or not there's real benefit from its addition, and there are known safety effects there that really dissuade a lot of physicians from using it. So it was left out in this case, and we're happy to be able to present these positive results that show it is not only highly beneficial to add ARIKAYCE, but that really when you look at the baseline or the comparator positive control arm, you don't see any absence of effect or benefit from the removal of rifampin. So positive on all fronts.

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

Let me echo my congratulations on the data. Maybe just a follow-up here, but Will and Martina, especially given the culture conversion data, what sort of long-term benefit is this likely to mean for patients? I mean is there a potential for a survival benefit? Or are we just sort of talking about the benefits associated with the discontinuation of rifampin?

Thanks for the question. I think I'll just make a comment and then turn it over to Martina. The study is obviously unequivocally positive on all fronts, and we're super excited about that. What it may mean for the longer term, I think, can begin to be imagined just by virtue of the experience we've had to date, where the drug has been on the market for 8 years now in the United States. And in that context, lots of patients and lots of physicians have seen the benefits from its administration. We haven't done a specific study to look at things like survival benefit, but those are the kinds of questions that we are certainly going to be curious to engage in and answer. And we're now going to be able to do it from a much larger pool of patients as we move to the all MAC diagnosed population. I don't know, Martina, anything you want to add?

Yes. What I would add is it just shows you what the durable culture conversion benefit is. So these patients at month-13 has been 1 month off drug and at month-15 has been 3 months off drug. And the hypothesis here is that sometimes for the control regimen -- for 2 regimens, you may get a negative culture, but you may not get a full clearing of bacteria. And ARIKAYCE appears highly effective in eradicating bacteria because of its mechanism of being right there in the lung, and that is something that might not be achievable with a systemic oral antibiotic.

So if you think about the achievement and the opportunity a patient can get from treating with ARIKAYCE in that regimen, it is something to consider also to prevent that patients potentially become refractory. So treating early here is based on this data evidence that would be helpful for patients.

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

Let me add my congratulations on this data, especially this culture conversion rate. I did want to focus on safety and tolerability, especially as it relates to if there's a type of first-line patient you're going to target and what it might mean for pricing. Martina, if you could talk about the dysphonia rate and the transient of the dysphonia if patients recovered or if there is any permanent dysphonia and how that may relate to the risk benefit that first-line patients -- basically, which first-line patients might be appropriate for it and then the impact on gross to net?

Go ahead, Martina.

Yes. So dysphonia, along with cough and are very well described potential side effects for ARIKAYCE. And we've seen in the study that the dysphonia rates were slightly higher, and they're at 58.7%, while we see them at 8.5% in the control arm. But what we also know after 8 years on the market and the experience with ARIKAYCE on both the investigator, but also with physicians in general side has now, of course, been increased.

We also have educated sites of how do you prepare patients for what potential side effects or respiratory side effects they may experience. And we've also learned that if you put in certain measures, for example, gargling with warm water or taking ARIKAYCE before that time is a benefit and can ameliorate the symptoms. So overall, the benefit risk is actually very strong. This is a 12-month treatment and patients have -- as you see, the discontinuation rates are lower than what we've seen in ARIKAYCE for ARISE and certainly for CONVERT. So I think everybody has learned how can I work best with this drug. And it is, I would think, even a strengthening of the benefit risk.

Thanks, Martina. And Ritu, on the pricing and GPN question, we had priced originally ARIKAYCE for the broader label, so no change in WACC on gross to net. For this year, as you know, we guided low to mid-20s. You will see a natural uptick in gross to net as the small manufacturer sort of bleed-in happens for ARIKAYCE more broadly, but we have always done and we'll continue to do appropriate and targeted contracting. This will be -- ARIKAYCE is the only controlled product that is approved and now pending FDA approval, will also be that in the broader label.

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

Congratulations on the super outcome. Can you help us understand how representative the ENCORE trial population is relative to real-world treatment practices for frontline MAC and how that should inform our expectations for these results to translate into market penetration assuming approval?

Thanks for the question. Sorry, I couldn't be there today, Joe. Over to you, Kevin.

Yes. So thanks for the question. So it is representative of real world. The comparator here is a clinically relevant comparator out of the gate and it's the same control group that we used in the ARISE study. And so as Will had said earlier, often a third antibiotic that's used either right away or subsequently is rifampin, what -- in talking with external experts when we started this program for the United States is more times than not rifampin gets stopped and patients are on azithromycin and ethambutol.

So we do think the study is representative of real-world experience. The control group had activity as would be expected for the conversion rates at month-12. And so I think definitively, this study being the largest study ever done in the disease is a double-blind, randomized controlled superiority study, I think, shows very clearly the benefit of adding ARIKAYCE on top of the background regimen for symptomatic improvement and microbiological improvement as well, too.

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

Congrats as well on the data. And maybe building on some of the other questions people have been asking just about sort of putting this in context. How do you think about the duration of therapy? Or what are you sort of modeling as the average duration given the positive results we're seeing with the culture conversion? Do you think they will stay on a year plus? Or is this a shorter duration? Just any insights there would be helpful as we think about how to model this out.

Martina, do you want to take that one?

Yes. So what we've seen in this study is the 12-month treatment gives patients not only a higher and an early and a greater achievement of culture conversion, but it also gives the durable culture conversion and being 3 months off treatment and still seeing how good the effect was on the ARIKAYCE arm versus as soon as you see that the treatment stops in the control arm, it goes in the other direction.

And that goes with the hypothesis that you may have enough control of the bacteria in the control arm to have a negative culture, but not necessarily enough to sustain that and come to an eradication of the bacteria. And you see that also reflected that patients feel better while they are on treatment also in the control arm. But as soon as that is stopped, you see a decline in the respiratory symptom score, which is also aligned with what we see in the culture conversion at both month-13 and 15.

It's clear that 12 months produces these kinds of results. It will obviously be up to the physician's discretion what they want to do. But I don't think there's any doubt that the 12-month treatment here is seen as beneficial and sustained over time. And that's the most important point, particularly from the market access world where they want to see that kind of impact. And uniquely, because we also did the ARISE study, we have a sort of snapshot of what a shorter duration of treatment might look like. And the simple answer is both the efficacy and the safety are at least arguably better in ENCORE than they are in ARISE. So that also paints a very positive picture for the 12 months of duration.

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

Congrats on the data. What do you think drove the lower discontinuation rate that you saw in the ENCORE data versus in the ARISE study? And I guess, how are you thinking about what the discontinuation rate would be in the real world?

So discontinuation rate, I think, as Martina commented earlier, is in large part due to people becoming more familiar with how this drug needs to be used, how you prepare the patient for what they can expect. And I think importantly, increasingly, the ability to express to the patient the benefit they will receive if they remain on therapy. I think it's just a collection of all those things and the experience over time that is slowly, but surely improving the adverse event rate that we see reported in this study as compared to ARISE and certainly compared to CONVERT.

I think that is the most important point of this study is that all of the data here and from ARISE and from CONVERT clearly show that you want to treat earlier in order to avoid the patient becoming refractory. Once they're refractory, the dropout rate from the drug gets much higher, the difficulty of taking it, the duration, all of those things, you still see clear benefit, and that's why the drug was approved for that population initially. But here, we see some unexpected and positive findings that the dropout rate is lower.

Remember that we thought it actually could be higher because these patients were less sick, perhaps less willing to tolerate the treatment, and yet that is not the case. It's dramatically lower, almost 15% to 20% lower than CONVERT. And that implies to us that at least at some level, the severity of the disease and its engagement -- our engagement with the antibiotic are causing some of the side effect profile.

In other words, as you overcome that -- the presence of the much more established refractory infection, you may produce more side effects as you achieve ultimate culture conversion. Acting earlier lowers the severity of that experience because the infection, at least theoretically is not as well established. So for all those reasons, I think the discontinuation we see in ENCORE is indicative of what we can expect in the real world, and that's a very positive thing as we move up in the treatment cycle to an earlier-stage patient.

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

Congrats on the update. So as you move to convert ARIKAYCE's conditional label to traditional approval and, of course, expand into a broader population, how should we think about any shifts in payer behavior or reimbursement? And could you just talk about the, let's say, cadence of uptake that you expect over the next 12 to 24 months in both the U.S. and Japan?

Sure. So I think as Sara mentioned earlier, we originally priced this drug for the assumption that we'd be treating all MAC patients. So we don't anticipate a different approach in our discussion with the market access world. And what's important here is that all of the data points in a very positive direction for this earlier use of the drug. I think the symptomatic benefit, the culture conversion benefit, all of these things being aligned makes it a really easy discussion from my perspective when it comes to market access.

As for the uptake in the next 12 to 24 months, what I would say about that is we are seeing an expansion in the total addressable market from 30,000 patients to more than 200,000, but we need to develop the target product profile now based on these data from the study and take that out into the market and do some research, which we will now do in earnest to get a better sense of what we think that will result in, in terms of uptake and what the ultimate benefit will be. And when you begin to see revenue in 2027, assuming that we get approvals in the U.S. and Japan, as we fully expect to, we'll have more to comment about the direction that those revenue growth curves might take.

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

Let me extend my congrats as well. Maybe can you tell us what percentage of ARIKAYCE patients today use your inLighten patient assistance program? And again, kind of thinking about moving to front line, how do you expand that program to try to capture those patients and any benefits from any changes in the out-of-pocket that has happened with Medicare?

Sure. So while we haven't given out the specific percentage, what I can tell you is that if you were to take a high benchmark for what would constitute an attractive rate of getting patients into such a program, we are well above that threshold, and we always have been with this. This is a very all-encompassing outreach to patients to help them on their journey through the use of this drug and the hopes that it will be the most effective.

We fully anticipate being able to extend that to all MAC lung infection patients. And remember that this is the same backbone architecture that we use not only for ARIKAYCE in the refractory population, but also for BRINSUPRI in the bronchiectasis population. And so the resources we need to be able to address this much broader population with ARIKAYCE are already in place and experienced. So we expect this to be a smooth transition and a full expansion with hopefully the same kind of conversion into the program that we've seen to date.

And just to comment on the out-of-pocket, I'll just also remind you that we estimate about 60% of the current ARIKAYCE label, about 60% of the Medicare patients. So their out-of-pocket under IRA is for all their medicines, capped to $2,000. And then for the commercial payer patients, we have a co-pay assist.

Your next question comes from the line of Ash Verma from UBS Financial.

Congrats on the progress here. So yes, maybe if you can talk about the time line for getting the frontline data on the label? And would the uptake be contingent on getting this added to some of the guidelines? Or is it more that the FDA approval opens up the label for the uptake for physicians?

Sure. So obviously, the data once processed by both the U.S. and Japanese regulatory authorities would result in label expansion. And we expect that, that will be the case. We've indicated that we'll be filing that by the second half of this year. And we would anticipate that those approvals and our ability to launch would take place in 2027, just so we're clear. And I think that, that will be a relatively smooth process. I don't know if anyone wants to add any other comments.

I think maybe just on the guidelines, just to be clear, guidelines are usually completed independently by professional organizations and experts. Obviously, we are independent of that. But what you often see is if there is new, especially important data becoming available, there is a consideration of that.

And let me just make a comment, this is a particularly difficult disease to treat. Every other company that has come along trying to bring forward a medicine has failed to be able to produce clinical trial results in a double-blind study that are adequate for approval. And I think that just highlights the desperate need for this patient population. So a clear and strong win like we have today, I would anticipate would be something that is noticed pretty rapidly by the key opinion leader community that is authoring these guidelines.

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

Congrats on the data, and thanks for taking my question. I wanted to ask also on the opportunity. I guess there's been significant ex U.S. use of ARIKAYCE, so I guess with the label expansion, I'm trying to understand how you're thinking about the balance between ex U.S. and U.S. revenues, especially given that you guys have been somewhat cautious of MFN impact? And then related to that, is there anything you can say on epidemiology and just the trends you're seeing with diagnosis rates or prevalence of infection over time?

So thanks for the question. Yes, we do get a meaningful percentage of revenue from Japan, in particular, for MAC lung infection in the refractory setting. And that's -- it's important to remember that while it's not fully understood what causes the MAC lung infection to develop in particular patients, factors that certainly lean in favor of that are an elderly population, prior history of smoking or lung issues, proximity to water. And when we talk about the island nation of Japan, that's pretty much a perfect description of its population.

So with that in mind, it's not surprising to understand that there are more -- today, there are more diagnosed MAC patients in Japan than there are in the United States. So the opportunity there is quite significant. There is a price differential there that has evolved over time, but it is important for people to understand, we priced at parity between the U.S. and Japan when we launched on a list basis.

So I think Japan will continue to be an interesting opportunity. There are more MAC patients there than there are in the U.S. Another feature of their annual checkup is that they include an x-ray as a matter of basic practice. So there's a higher propensity to be able to identify this infection that may be contributing to the higher diagnosis rate. So all of those things collectively suggest that we would expect to continue to see material revenue generator from Japan as the label expansion occurs. I don't know if anyone else has any other comments.

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

Just one quick one. You kind of commented or characterized the overall TAM expansion of being sort of like greater than 6x the refractory TAM in terms of number of patients. Could you characterize like what you -- how you think about the peak potential uptake into this opportunity? Like where do you see this potentially maxing out from a revenue opportunity perspective, given like the other standards of care?

Yes. Thanks. I appreciate the question. We're still working on the answer to that question, to be candid. And we needed the target product profile specifically generated from this study in order to be able to go out and have the dialogue with physicians to see how they interpret the risk reward, how they see it for their patient populations and what the application might be in the practical setting. I think what is important to note here is that the data from this study is unequivocally positive from the perspective of physicians who are seeking to eradicate evidence of the infection in their patient populations.

Moreover, if you just reflect on where CONVERT took us, we saw about 1/3 of patients convert after the CONVERT trial to a point where they had no evidence of bacterial infection. In the case of ENCORE and ARISE, we're seeing north of 80% of the patients converted by month-6. That is a striking improvement compared to what happens if you let a patient become refractory.

So there is a powerful motivation in the data to move to treat these patients earlier and the dropout rate going down suggests that actually the treatment burden for the patient is reduced. So that collectively paints a very positive picture for expansion into this broader population. How big, how fast and what that ultimately means for peak sales, we need to come back to you with specifics on that. But certainly, we anticipate moving in a very positive direction.

Your next question comes from the line of Danielle Brill from Truist Securities.

This is Alex on for Danielle. Congrats on the data. Just a detailed check box question on the discontinuation rate. Given there was a slight imbalance in the rate of discontinuations between the arm, did you perform any sensitivity analysis to query the potential impact of the imbalance? And if so, were the findings consistent with the top line analysis?

I'll turn that one over to Kevin.

Yes. So bottom line is those patients that may have discontinued their treatment and had missing values, they were considered in a prespecified way in the analysis. So what you're seeing here in the RSS as well as culture results does consider all that. And so it's a really strong reflection of how robust the study was and insensitive to things like that.

And there are no further questions. This concludes today's conference call. Thank you for your participation. You may now disconnect.

Good morning. Welcome to this fireside chat with Insmed. I'm Joe Schwartz from the biopharma equity research team at Leerink Partners, and it's my great pleasure to be joined by Sara Bonstein, CFO.

Maybe, Sara, you could start us off with a quick lay of the land and give us a brief overview of the company's recent accomplishments and priorities for '26.

Sure. Happy to. Thank you, Joe and the Leerink team for having us here. Always a privilege and an honor to be here with you today.

Insmed is, I believe, a remarkable story. So we are a company that is focused on serious life-threatening conditions and how can we create first or best-in-class options for patients. We have commercial products now. We have ARIKAYCE, which has been commercialized for about 8 years for nontuberculosis mycobacteria in the refractory setting, and we will have a readout in the March-April time frame for a potential label expansion in that indication that our second commercial product is called BRINSUPRI. That product was launched in August of last year, and that is for bronchiectasis.

Both of those programs, along with some additional programs that we'll go through today, make up our respiratory franchise. Our respiratory therapeutic area. We recently went into these 3 therapeutic areas, respiratory, I&I and neuro and other. And we did this because it's a -- it's just a symbol of how much we have grown as an organization in the company in the past -- yes, 2 years, but really in the past 10 years. You're now seeing that culmination of all the growth that we have done.

So we have a very, very robust pipeline of late stage, mid-stage and early-stage across each of those therapeutic areas. We sit on about 1,500-plus employees across our geographic territories, which include New Jersey, New Hampshire, California as well as Europe and Japan and really just have a great organization where we're able to have great impact on patients. So happy to dig into the commercial programs, the clinical programs, we're excited about all of it.

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

Sure, happy to. And maybe we'll even take a step back and just remind us all on sort of the design and why we even did ARISE.

So the FDA, as you all know, look for an endpoint for field function survive. So the endpoint here for this nontuberculosis mycobacterium in the sort of frontline or initial stage setting is a patient-reported outcome tool. And there is not a patient-reported outcome tool that exists for this condition.

So we ran essentially 2 parallel studies, ARISE and ENCORE. They were very similar in their design. The difference was one was a little bit shorter in duration, and one was smaller, so we could get the readout first to help determine what a PRO could look like in this disease setting.

So I'll remind you on ARISE. ARISE was about 100-patient studies. It was 99 patients. When we had patients, we randomized 2 of them to ARISE, one of them to ENCORE. So same exact patient population. We did that, as I said, to make sure that ARISE would enroll soon.

ARISE was 6 months on therapy and 1 month off therapy. And we studied -- we looked at 2 things. The U.S. FDA is looking for, as I said, that patient-reported outcome. The PMDA in Japan would be looking for culture conversion. So we studied both.

What did ARISE tell us? What did we learn from ARISE? What ARISE told us is, obviously, it was much, much smaller than ENCORE, so not powered for statistical significance, but it showed that we were trending in the right direction to show a change in the respiratory symptom score between the treatment arm and the nontreatment arm. So it was trending towards seeing a change, and we saw about a 4.5 point change.

And then on the culture conversion, even more interestingly, we saw nominally stat sig results on culture conversion. And at the 6-month endpoint, we saw about an 80% conversion on the drug arm and about a 65-ish percent on the control arm. But even more interestingly, 1 month off of therapy, you saw a point or 2 go down on the control -- on the drug arm. So the 80% went down to like 78% and change, but you saw the control arm went down to 47 sort of high 40s. So it wasn't durable.

And so now as we fast forward to ENCORE, what are we looking for ENCORE? ENCORE is a longer and duration study. It is a 12-month study, and we are looking at the primary endpoint for the U.S. is that PRO. So the change in the respiratory symptom score. So again, we're looking for the change between treatment arm and control arm. We're 90% powered to show a 4-point change, and that's assuming 400 patients. We enrolled 425. So we're a little over enrolled there, which is great, and that is where ARISE was showing us. So we have a high degree of conviction.

The next step is we want to see the responder analysis. We want to see a point -- across any point of the measurement, do you see separation? And FDA will obviously determine what that right separation needs to be. It will potentially be in the 16.5-ish, maybe 16.7 range, but that will be FDA's decision. The important piece is in ARISE; we saw separation across any point change. So that again gives us tremendous confidence.

And then as we spoke about the PMDA as well as the U.S. HCPs, payers, patients, they're very interested in culture conversion. So obviously look for stats to get culture conversion.

On the endpoints for the PRO, we're measuring at month 13. That's important because they get to be off drug for 1 month, which is important because ARIKAYCE has some side effects, but it has been able to show 8 years in real-world data as well as the other studies that we're able to show a difference and clear these bugs. So having that 1 month off therapy is really important.

And then for culture conversion, it's at month 15, which again is really helpful because we can be able to hopefully demonstrate the durability of what ARIKAYCE can do for these patients to be able to not only clear the bug, but to have that durable culture conversion.

So a lot there. It's not as sort of black and white as some other trials. So I kind of just wanted to go into some detail. But March, April will be the timing for that data readout, so be on the lookout. What that means is patient-wise, there's about 12,000 to 17,000 patients in the U.S. diagnosed under the current label, about a little higher than that in Japan, about 15,000 to 18,000 in Japan.

Those numbers increase pretty substantially for total NTM in the U.S., it's about 100,000. In Japan, it's about 125,000. So significant patient populations. Obviously, there will be some education on what that means on how quickly do people get it? How long do they stay on therapy, all that good stuff. We need to see the data, and then we'll educate you on all that as well.

Super helpful.

Yes.

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

Yes. No, all very, very fair questions. So I think the clear win scenario is pretty straightforward, right? We would look to file before the end of the year and be on market next year. That would be the goal, and that's what we're planning for in a sort of mixed scenario, this would be a conversation with FDA. This is a product that's obviously been on the market, has been able to show big impact for patients. So that would be conversation and discussion. We've never lost on culture conversion. We have a high, high degree of conviction on culture conversion. Obviously, PRO, there's just noise in a PRO instrument. But again, we feel like we've learned a lot from ARISE, and we've been able to apply that into the ENCORE 8 question respiratory sinus symptom score.

In the instance where we don't see what we want to see, I'll remind you that this program is not in the same indication for the approval -- the conditional approval that we have now. So again, it will be a discussion with FDA. I'll also remind you, obviously, can't speak for FDA, but I'll remind you, there's nothing else available for this patient population. It's been on the market for 8 years. Patients have had success with this medicine. They've come -- they've had successful sort of completion of clearing their bug, getting reinfected, going back on medicine. So real-world example, real-world experience here has been very, very positive. I think this would be a tough one for FDA to do anything other than keep this medicine available for patients.

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

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

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

Yes, yes, happy to. So BRINSUPRI is, as I mentioned in the opening, is the first and only available treatment for folks with bronchiectasis. So previously, when a patient would go into their doctor and they would be given this diagnosis and then the patient would say, what do you -- what do I do? And they would say, well, continue doing a lot of the same airway clearance, the shaking vest, there's no approved therapy. So really amazing to have this option for patients.

Although there was nothing approved, there was actually already a diagnosis code, which was actually very helpful to be able to understand the patient population. So here in the U.S., there are 500,000 diagnosed patients with bronchiectasis. If you kind of dig into that information, you can see how many exacerbations do those patients have over the prior 12 months.

And the reason we looked at that is in our ASPEN study, which was our pivotal Phase III, the inclusion/exclusion criteria were 2 or more exacerbations in the prior 12 months. The label does not have that in it. The label is very open, but our understanding and expectation would be 2 or more is where the prescribers and the payers will be.

So if you look into the claims database, about half of the patients that are diagnosed today have had 2 or more exacerbations in the prior 12 months. That is really where we ground as sort of the initial sort of focus of the launch, that 250,000 patients. There's another 250,000 patients that are 0 or 1 exacerbating patient that when you think about an exacerbation, every time you have an exacerbation, you're more likely to have another exacerbation. They're not linear. Every time you have an exacerbation, it causes permanent lung damage.

And I think even most interestingly, a lot of exacerbations may have gone under documented because either a patient didn't realize that it was an exacerbation or they said, why am I going to call my doc, I don't want to get put on an antibiotic. I don't want to get hospitalized. I'm just going to kind of live through this myself. And so now that there's available medicine, you may see more exacerbations be documented.

And how do I have confidence to even say that? There was a real-world claim study done with about 15,000 patients. So decent size, not obviously all the patients, but decent size is a 2-year look. And at that point in time, about 47% of patients had 2 or more exacerbations in the prior 12 months.

Fast forward, that went up by 9% and the 47% went to 56%. So you're already starting to see that migration. So I view that as sort of like the initial low-hanging fruit as you're thinking about available patients for this medicine. You have the initial 250 that the payers will be happy to support. You have the next potential 250 that may now have potentially more exacerbations.

The piece that we're now putting energies towards is what we're calling almost a secondary launch, a second launch, a second focus. And this is the potential underdiagnosed patients that have COPD or asthma. In the U.S., there's over 30 million. I think it's 32 million patients with either COPD or asthma.

If you take just the COPD piece of that, it's about 20 million patients in the U.S. Literature is all over the map on how many of those could also have comorbidities with bronchiectasis, 4% to 60%. It's all over the map. I know that's not super helpful. But if you look at even the most recent literature, it actually says 30% to 50% of moderate to severe COPD patients also have a high likelihood of bronchiectasis.

And so if you kind of do all that math and you put whatever probability on penetration in that, that could be hundreds of thousands, if not millions of more potential patients that could be available to be on drug, available to be on label with a CT scan that shows a tree bud pattern on it that then gets them the bronchiectasis diagnosis.

So we will have a dedicated team focused purely on that underdiagnosed patient population to help with the education on both the commercial and the medical side compliantly to help with that investigation on identifying those appropriate patients that are potentially exacerbating patients that could potentially benefit from the drug. Our existing field force organization, they're going to stay focused on that 250,000 patients and driving the at least $1 billion of revenue that we have committed to this year.

Our survey work has also found that a significant proportion of patients have overlapping symptoms with COPD and bronch.

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

Yes, yes. So obviously, our first -- yes. No, I understood. Our first full quarter, we put up almost $145 billion in revenue. We were really proud of obviously, the revenue number and I think even more importantly, the ability to have over 11,000 new patient starts cumulatively in 2025 and have that much impact on patient lives. And as Joe said, we had about 4,000 unique prescribers, cumulative number of prescribers through the end of 2025 and about half of them through the end of 2025 had written 1 script.

And so we've spoken a lot about the depth and breadth. In the United States, there's about 20,000 pulmonologists. We have the ability to call on every one of them as well as we call on some infectious disease docs and some other specialties in the totality of about 27,000 health care professionals, and that covers both BRINSUPRI and ARIKAYCE is a shared sales force.

4,000 folks have written -- 4,000 HCPs have written at least 1 script and that is very encouraging. That's a pretty broad net, probably broader than we thought would be out of the gate. So we see the KOLs, we see community people writing scripts. What we now are very focused on is the depth. And this is very traditional that you see in not only a new first-in-disease medicine, but this is a first-in-class medicine.

So you expect to see this. You're going to have probably more depth in KOLs or physicians that maybe were part of the trial and sort of less depth in some of the KOLs that are onesies, twosies, but this feedback loop of having the patient experience, so a positive patient experience. And you see this even if you just look at social media posts and patients are very loud now themselves to hear that feedback on I've had a positive experience, that helps to build momentum. They come back into their physician's office. The physician asks them about their experience.

I'll remind you that the dropout rate in the ASPEN study was actually a little bit higher in the placebo arm than it was in the drug arm. It was about 13% in the placebo arm, around 12% in the drug arm. This is a relatively benign safety profile from a drug perspective. And the fact that we were able to show nominally statistical significance in the 25-milligram arm on quality of life, that is really helpful for folks, right? They're feeling better, and so you're starting to get that feedback loop.

I think another important event will be as the physicians get together at major medical meetings like an ATS and they're being able to share these stories with one another, having that continuous feedback loop, I think, will be the next -- one of the next inflection points for the company. So probably Q2-ish is when we'll probably mostly starting to see the impact there. So really excited about what the year has to come.

And then the other, I think, very important piece is if you think about the -- sort of overall health of the brand, we've said $5 billion peak sales. That is just on the diagnosed patients today. That does not include all this additional sort of low-hanging fruit that we talked about, that could be multiples of that and $1 billion, at least $1 billion this year.

If you think through how the math would need to work to be able to achieve at least $1 billion this year and where the jumping off point will be at the end of this year and what that implies for '27. This is a monster, monster opportunity. There's maybe 20 products in our industry of all times that in quarters 2 through 5 have been able to put up over $1 billion in revenue. Insmed is looking to add their name to that list.

Okay. Great. So I'd like to switch gears again to TPIP because this also, I think, has a very sizable opportunity. It's a bit under the radar because of the -- all the shine that's on BRINSUPRI.

But I guess, I want to ask a big picture first, and that is, where do you see TPIP fitting into the overall treatment paradigm since it seems to be on the cusp of potentially achieving like one of the ultimate goals that I can remember being out there for PAH therapy for a long time, which was just to deliver a lot of prostacyclin once a day. That's a very tall order. And yet we have a lot of excitement around another class of drugs spearheaded by WINREVAIR. So how do you see the overall share for prostacyclin and TPIP driving prostacyclin growth in the future?

Yes. No, it's a great question. And so we have a lot going on. So we have to keep pivoting to different programs, which I love.

So a couple of thoughts here. There's been tremendous development in this space, which is absolutely wonderful for patients. This is both a life altering as well as -- these are life-altering as well as life-ending conditions. So we need to do better for patients. So it's great to see additional innovation here.

I do expect, and this isn't my -- what I expect, this is what the medical community is educating me on that this will is and will continue to be a combination market. And the goal here is to extend life for patients. And while there are additional sort of MOAs that are coming out, the need for prostanoid therapy is seemingly to be a mainstay. And what the medical community is telling us is if we can continue to show what we showed in our Phase II that TPIP has the potential to be the prostanoid of choice.

And why do I believe that? Well, we were able to show in our Phase II study, Phase IIb study in PAH is a 35% improvement on 6-minute walk and 35% -- 35-meter improvement -- 35-meter improvement on 6-minute walk and 35% improvement on PVR. Those are results that no drug in this class has come even close to. And we obviously need to reproduce that in Phase III.

But I still remember when my Chief Medical Officer called to tell me the results, I didn't even believe what my ears were hearing. I thought she said 25 instead of 35. I made it repeat about 3 times. So it is absolutely amazing what that -- what the drug has been able to show.

And it actually makes sense. If you go back to one of your -- the earliest thing that you said, Joe, around the goal here is to get as much drug into the patient's lungs and have it be sustained. And that's what we believe we've created with our TPIP prodrug. We're able to deliver a lot more drug, but it be inert, so it's not active. So you sort of don't have that side effect of the cough, which is a big issue for current patients. And you're able to get a lot of drug into the patient and have it sustained over time.

I'll remind you that our Phase II, we measured 24 hours after the initial. So we were able to show those types of PVR and 6-minute walk results 24 hours, which sort of magnifies the ability that this is overnight coverage, which doesn't exist for these patients today and all that, those good things.

So this year, we've committed to having 4 global Phase III programs underway. PH-ILD kicked off last year. PAH will kick off Q2 and then PPF and IPF on track to kick off second half of this year. So a lot of development going on. More to come here.

We've put out early days, peak sales of $2 billion. That's when we were only going after the first 2 indications before we had Phase II data. We know we need to update that for you guys, but this could be another very, very significant opportunity from a revenue generation perspective as well as a patient impact perspective.

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

Yes.

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

Yes. So HS, neutrophil-driven condition, inflammatory in nature. This is why we sort of targeted it. We have said right from the beginning that while all of those hold, this is a very tough disease indication. So we've put sort of a 10% to 20% probability on this indication. Obviously, it would be great if we could show something here the bars. So based on feedback from the medical community as well as what other studies have shown, we believe a 20% improvement on AN count would be meaningful for us to progress into Phase III.

When we talked about the 40%, with the 40%, we call that our "home run scenario" because that's what we would need to show to be able to show stat sig because we -- when we designed the study, we designed it at alpha 0.1, whilst still a very meaningful size study. It's 204 patients. We powered it that way so we can get answers.

I'll also remind you; this is a 16-week endpoint. Our drug usually takes about 2 to 4 weeks to reach full effect. And so we're studying AN count as the primary at 16 weeks. We will have continued data through week 52, with some more sort of traditional high score 50 and 75 at that point, some more information available then.

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

Yes. So unlike both HS as well as CRS, which there's no animal models available, RA and IBD do have animal models. And we've run animal models with BRINSUPRI that, that information is published as well as 1033. So 1033 is one of our new DPP1s.

On the heels of the WILLOW data, you may recall, we continued to do a ton of work in our research labs on the mechanism because we believed in this mechanism with a high degree of conviction. And so we developed, I don't know, over 800 different DPP1 follow-ons, we are looking to progress the first of those 1033 through IND by the end of this year. The thought is the indications will be RA and IBD. The benefit of a follow-on DPP1, obviously, we can think about pricing very differently. We can think about IP very differently. We can think about reach differently, all of those good things. We 100% own all the follow-on DPP1s ourselves. So that's also very helpful. So we're excited to move that forward through IND by the end of the year.

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

Yes, yes, sure. So this is a program that we in-licensed end of last year. It's very brenso-like in sort of deal terms, $40 million upfront Phase II-ready asset. It was an asset that was developed by a small company that they licensed it to AbbVie. AbbVie ran a Phase II study, about 150 patients in atopic derm. While that was not published, we obviously saw the data under diligence. It did reach stat sig, atopic derm.

They had a lot of development there. It did not sort of, I guess, meet their bar. They returned it back to the small company. We knew of it. And we came in and we said, we think this can do -- we're not obviously interested in atopic derm, but we think this is a molecule that has shown success, shown promise, shown clear efficacy, good safety profile, we think we can move this forward in things that fit into our therapeutic areas, such as ILD to have it be complementary to TPIP, potentially asthma and others.

So we're really excited about this program. We haven't fully committed to when we'll get it into the clinic. But as soon as possible, the team is just kicking it out of the park and making great progress.

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

Thank you so much, Joe.

Thanks.

Here we go. All right. Welcome, everyone, to the Insmed fireside chat at the TD Cowen Healthcare Conference. I am covering analyst, Ritu Baral. And with me from Insmed is CEO, Will Lewis.

Thank you, Will, for being here. A big couple of years for you guys ever since the BRINSUPRI Phase III data 18 months ago? 2 years ago. We'll start there. That is the major topic of conversation. It is the major topic of conversation yesterday when I hosted you guys for dinner and a number of you guys. You posted very impressive Q4 numbers of 144. I think even buy-side consensus was less than half that. Sell-side consensus was much lower than that even.

What are right now, the key drivers behind -- what were the key drivers in Q4? And how is that evolving into Q1? Given the caution that you communicated in January at another investor conference, how is that evolving?

So if I could take one thing out of the last 6 months, it would be the degree of caution we introduced at that other conference because I think that was over-interpreted to mean that in some way, the launch was slowing. I want to be really clear, the launch is not slowing.

So it wasn't a bolus? 4Q was not a bolus?

Well, so bolus is a word that means different things to different people. What I would say is the composition of patients coming into the use of this drug fits a variety of different phenotypes. Let's talk about what those look like.

We go all the way back to prior to the -- just after the data. We really kicked off the disease state awareness campaign in earnest. As everyone knows, we brought on our therapeutic specialist force fully 9 months before we even had the drug approved. So with data in hand and awareness increased about the disease state we were out and having very productive discussions with physicians.

That put us in a very strong place for the launch, which is what ended up taking place. We'd like to point out that in the fourth quarter of last year, which is our first full quarter, we did more revenue than DUPIXENT did in its fourth quarter after launch.

So we have a very strong launch out of the gate here. The patients that came into that, there were 9,000 patients in the fourth quarter that were brought on the drug from more than 4,000 physicians. So we have a very broad group of physicians writing prescriptions, and that's very encouraging. It lays the groundwork for continued success.

What's that going to look like? Well, fully half of those physicians have only written one prescription. And so they're testing the drug. They're trying it out in their patient population.

The patients will go away, they'll take the drug. And roughly 2 to 3 months after that is when they tend to come back for a checkup, sometimes as long as 6 months, but it's not typically longer than that when you're taking a new medicine. Physicians want to know how things are going. And the stories we're hearing are that the patients on this drug are having a very positive experience in the way they feel, in the degree to which they're still expectorating or coughing.

Not every patient is going to have this response, but what we have heard has been extremely positive. So the way we think that's going to play out is each of those physicians who've written only one prescription are going to get that feedback from their patients and their peer physicians, and it's going to make them inclined to write again.

So the breadth of prescribing behavior can be something that we can pursue and look to add additional patient volume from as that experience is a positive one. So that's a major driver. Were there any patients that would form some part of a bolus? Almost certainly out of the gate.

When a new medicine arrives, there are going to be patients that are, if you will, stockpiled in some of the centers of excellence that are immediately put on drug. There are a lot of physicians, though, as I've just described, there are still trials...

Those were warehouse -- that's warehousing patients. I guess the question is, was there a bolus of appointments in Q4 where the clinicians -- this is how the investors are defining bolus, right? Like the practices cleared room in Q4 for more bronchiectasis patients to come in, have appointments and start drug.

No. There was nothing that was -- that we could discern that would have established that. I do think that there were some warehouse patients...

Which is different.

Which is different. That's why I say the bolus definition is so important.

Okay. So not a bolus as defined by patient starts, more warehousing of patients for sort of the near term '26.

The single most important driver of this medicine in '26 is going to be the experience that patients have on the medicine and the perception that physicians have with regard to it.

Now we are a company that has been selling ARIKAYCE for 8 years in the United States. That is a difficult medicine to sell. You have a 30% dropout rate. It's a drug device combination. It takes 15 minutes to administer. And yet despite that, we've had very good success with supporting the sale of that medicine to patients that are appropriate.

BRINSUPRI is a once-a-day pill where the placebo rate of adverse events match the treatment rate. So there is a very benign safety profile here. You have a very easy to administer medicine.

So why are you so concerned about this initial treatment experience then? Because you mentioned you want to manage the initial treatment experience, both from a patient and clinician perspective, but it is so tolerable. What's to manage, I guess?

Well, we want to hear that patients are experiencing positive results from the use of the medicine because that increases dramatically the likelihood that they're going to stay on the medicine, that physicians who have noisy patients, by which I mean patients who come in and say, "I'm coughing all the time, I'm expecting all the time. I can't go out in public. I have these flares that keep me home from work, et cetera."

If those patients, and we've heard these stories, come in and say, "I'm no longer coughing. I'm no longer expectorating. My energy is back." Now not every patient is going to have that same experience, but we have seen a lot of public social media discussion by patients a very positive circumstances most dramatically.

I read at a different conference, one of the comments from one of the patients who had gone into their physician's office, and it was the physician who relayed this to us, and have broken down in tears because they had described their life as being back in their control, that this was a miracle drug, et cetera.

Now I want to be cautious for everyone who's listening, we are not advocating for this to be the experience that everyone is going to have on the medicine, but we have heard these anecdotes, and we consider those to be encouraging and powerful forces among the network of physicians that will make them inclined to write again and again and again.

So in the unknown unknowns that we talked, that you mentioned in January, one of the -- a few of the points were co-pay smoothing, payer contracts, inventory dynamics. Last contracting or at least major plans put in place, how have those evolved and your confidence through full year '26?

So the way I would simply describe this as looking at our dashboard, everything is green. We couldn't be happier about the persistence rate, the uptake, the approval, everything is going the way we want it to go.

Where that's going to lead us is the great unknown that I think is probably the subject of attention from everyone on the street because we said initially the 250,000 patients who are diagnosed today with 2 or more exacerbations that we know are out there because they are on the roles as having been diagnosed with this condition with 2 or more exacerbations, that 250,000 patients, that gets us to peak sales in excess of $5 billion.

Now as we think about other populations and the top of the funnel getting filled, we start to think about the other 250,000 diagnosed patients who have between 0 and 1 exacerbations a year.

Now those patients right now are on label. We're not targeting them as intensely because we're trying to work with the insurance companies and the physicians who say that the bulk of the patients they think are appropriate for the medicine at this time are those who are in the moderate to severe category, those with 2 or more exacerbations.

So by working with the insurance companies and agreeing to that restriction to only going after those patients that were studied in the ASPEN trial, we are never going to be friends with the insurance industry, I don't think. But we certainly are trying to meet them halfway.

And I think that is why as market access dynamics continue to look good, we don't anticipate a slowdown from the implementation of new insurance policies. That's the single most important distinction about market access. You start out, everything is a medical exception. We have the infrastructure and the experience to do that because we've been doing it for 8 years for ARIKAYCE.

As the policies get established, they can be more or less restrictive than what you have been bringing online. In our case, it parallels what we've been doing to date. So that this targeting of 2 or more exacerbations in the last 12-month patient profile is, in fact, the sweet spot we're going after. It's where the insurance companies are setting their policies, and it puts us in a very good place to continue to see the kind of uptake as we like to say, up and to the right since the launch of this drug.

So with that access getting expanded in Q1, are you -- and this green across the board that you mentioned, are we taking the possibility for flat to down Q1 off the table?

So I'm not permitted to give any prediction about the quarter. Well, that's the entire front row from Insmed is now saying, "Don't answer that question, Will." The -- I will just say that I think we feel good about where we are. And the way we tried to address this because I know there was concern, we did express some caution at the beginning of January.

But I want to reemphasize that caution we expressed was not because we were in possession of some information that gave us pause. It's because we knew some people were going to run away with the prediction of what this revenue could become. We had originally stated analogs for great performance in quarters Q2 through Q5 would be somewhere in the $500 million to $700 million range.

Everybody thought that was outrageously high that we would never hit it. And now most of the estimates that are out there are north of $1 billion for that same time frame. So everybody has run away and believe that this has now greater potential. And that's a very exciting place to be.

I just want to remind everybody, to the best of our knowledge, there are 15 products in the history of our industry that have ever cleared $1 billion in quarters 2 through 5. J&J has never done it, Merck has never done it. The drugs that have done it are things like COVID vaccines, GLP-1s, Harvoni, Skyrizi; there are not that many that have gotten there. And every company that has ever accomplished that, not one of them has been worth less than $70 billion. So from our perspective, we think we've got the right product. We think it's going to do very well, and we think that's extremely well for the company's future.

So you mentioned that $1 billion of new guidance at floor. And as I mentioned last night, consensus is already at 1.2 right now...

And you're wondering why we introduced caution at the beginning of January. I wonder.

You made me talk my original $800 million down, and then I had to take it back up. So that's an extra note. But if we look at how you're going to meet or exceed the 1.2, certainly beat the 1, what are those levers? Is it expanding lives covered? Is it more guidance? I mean you already haves in [ upper ] included in some guidance, rest of world, depth of prescribing, breadth of prescribing?

Yes. So it's a great question. I think the single most important thing that will drive it, as I mentioned before, the storytelling, the peer-to-peer dialogue among physicians, what is the experience with this medicine? How are your patients doing on the medicine? And what we hear repeatedly is positive feedback there. So that's good.

That should enable us to take advantage of the more than 4,000 physicians who've written at least 1 script to encourage them to write a second or a third. And you can imagine if that is accomplished just with the physicians we've already reached and convinced that the medicine should be written that those are easier to activate to write 2, 3 or 4 prescriptions.

And that's going to be the first area of focus. So that becomes depth from the breadth that has already been established, right? We want to see the breadth continue to grow, right? 4,000 physicians is still just scratching the surface of the 27,000 pulmonologists in the United States.

But with those 4,000 physicians writing and getting as many patients as we have on drug already, it's 11,000 change as of the end of the fourth quarter. We're targeting 250,000 patients who are diagnosed with documented 2 or more exacerbations.

In the U.S.?

In the U.S. alone. So we are just scratching the surface out of the gate. And it's very dramatic, I understand, to come out and say we'll do north of $1 billion in revenue with only 1 full quarter under our belt. But that gives you some idea of where our confidence level is as we look out at this year and beyond.

And so ex U.S. is not part of this $1 billion. It's not -- I mean, when does ex U.S. start factoring in and current thoughts on how to balance the existential MFN threat?

Yes. So right now, we are approved in Europe, and we're approved in the U.K. We have not launched in either of those locations because we're waiting for clarity around MFN. It was not going to be a material part of our revenue this year.

Europe continues to perform very well with ARIKAYCE. Japan, even more so, both in terms of what ARIKAYCE has done over there. They were a huge contributor to last year, and they're hitting this year with stride.

BRINSUPRI is continuing to be pursued over there. We'll see what their pricing decision is and what that would imply for us. But we have to be mindful of MFN and the policy since it has not been finalized yet is one we just have to hold off and respect until it's been clarified what that's going to look like.

To put a finer point on that, in a world where the MFN policy applies only to Medicaid, that's not a big deal. We can manage that. What do I mean by that? If the policy says that your price abroad and very specifically, the second lowest price that you sell the drug outside of the U.S. becomes the price that is applied for Medicaid patients, that's about 3% to 5% of revenue; that's manageable.

If they try to apply it to Medicare Part D patients for almost every biotech company and pharma company out there, it would bankrupt the industry. So I don't think it's going to happen, but they are using that as kind of a stick to motivate people to come to some kind of negotiated agreement. And until those proposed agreements are out there, it's just impossible for us to move forward in Europe.

So we're watching it carefully. I think we're going to come to a rational outcome here. My concern is that if this -- because it's an election year, you're going to hear a lot of drama and see a lot of fireworks. But I think at the end of the day, reducing prices for certain pockets of patient populations in the U.S. is a probable outcome. It's just not going to be as dramatic as I think people would imagine.

And I would just footnote by saying all of those deals that have been done with big pharma, not one of them have been disclosed as an SEC publication, which means not one of them is considered material.

So whatever the agreement is, whatever the hype is, nothing has been disclosed. If it were material, if it was going to have a profound impact on revenue, they would have had to disclose it. So that tells you that whatever the hype is, the substance behind these agreements is not that big.

Drilling down a little on insurance coverage, early indicators of payer access and reimbursement hurdles, what percentage of payers have been implementing, like hard implementing the 2-plus exacerbation prior auth requirement? And what is -- can you talk to sort of the discount you're offering to have this removed?

Yes. So what we did was to go to the insurance companies and say, "Look, this is the only approved medicine for this condition. So technically, you have to cover it." We don't need to negotiate with them. We can just insist that they provide the coverage.

And there are other companies who have taken this approach historically. We didn't feel that was the right one. So what we've gone and done is offered a modest discount, and I'll talk about what that quantity looks like in a moment, in exchange for helping to shape the policy that they develop, which is patients who have 2 or more exacerbations, attestation by the physician that those have occurred as opposed to summing up the documentation and submitting a...

[ They ] are not paying for removal of the 2 plus, you're just making attestation of the 2 plus?

That's correct. The attestation and then it's the reauthorization of the prescription because one of the techniques that's being employed by insurance companies now is they don't want to be on the record for having denied someone access to the medicine. But 6 months after the medicine is used, they may put additional restrictions on its reauthorization.

We are not experiencing that. We have been able to negotiate to avoid that. And frankly, because of the nature of the medicine, it isn't something that insurance companies are going after in our case. But these are the kinds of things you want to think about. And the ability to those policies a little bit in exchange for a modest discount makes sense to us. So that's what we've tried to do.

To be clear, we have not done that with every insurance company. There are some that refused the discount that we offered. They wanted much more, and we said, "No, we're not going to do that." So they're going to be following a policy of documenting the exacerbations and documenting the CT scan and submitting that.

By the way, that's what we've been doing since the launch of the drug because everything has been through medical exception. Now as the policies are established, some of them will require that going forward, some of them will not.

It makes it less difficult if you don't have to provide all that, but it is something we're absolutely prepared to support in terms of companies, doctors' back offices. And many of them have experience with specialty medications like Fasenra. So in that case, they're used to this process. So I don't see it as a break or an impediment in any way.

So part of that -- likely part of the exception process is this idea of CT scans. Now for the plans that took your discount, they're not going to require a submission of a CT read or whatever. But if we think about the plans that are requiring CTs, what percentage are those? Do they need to be recent scans? And how hard is it -- if a patient doesn't have a scan, how fast can they get a scan?

So the temporal component of when the CT scan was taken is less relevant than that there is a definitive diagnosis of bronchiectasis. That's accomplished by a CT scan and a pulmonologist workup. And if that's been documented, then you know the patient has bronchiectasis, that's not in question.

It's a very easy thing to read, by the way, from a radiography point of view. It's a tree and bud pattern. And if it's there, it's a definitive diagnosis of bronchiectasis.

What's interesting is that for many of these ancillary populations, the COPD and asthmatics, many of them have had a CT scan. But if the request has not gone in to look for bronchiectasis, the radiologist may not call it out. So many of these patients may be sitting out there with a CT scan that shows bronchiectasis, but it just hasn't been diagnosed yet.

So there is the ability to retrospectively go back and look at those CT scans and look for bronchiectasis. And we're in the process of doing that in a variety of different ways, trying to support that effort, the use of AI to go back and quickly scan and look for evidence of bronchiectasis is something that some hospitals are making use of.

So I think there's going to be an opportunity to look at that and understand it. And I do want to come back to your earlier question because I didn't answer it on the discount that is associated with these planned negotiations.

What we've guided to is gross to nets of around 25% to low 30s. Knowing that we are responsible for 20% of the catastrophic coverage in the Medicare population means that right out of the gate, our gross to net is going to be at least 12%, 60% of the population, 20% we have to cover, 12%. So if we're guiding 25% to low 30s, you can get a sense that including the other components of the gross to net discount, we're not giving away that much. Otherwise, the gross to net would be much higher.

Going back to what you mentioned about the COPD and asthma population as we think about that undiagnosed pool that you originally talked about, is that CT reread effort the tip of the spear when you think about 3 years from now, 4 years ago now from when you really start focusing on expanding the diagnosed bronchiectasis market?

Yes. So we think of this as almost two different launches. So the first launch is targeting the 250,000 patients diagnosed today with 2 or more exacerbations. That's a massive market. It's a very easy to go after market. There is nothing else approved. There's not expected to be any competition for at least 5 years. That gives us free rein on that initial TAM.

What we're talking about with these comorbid patients is a bigger effort of getting the physicians to increase their index of suspicion, look for bronchiectasis in any COPD or asthmatic patient who is being treated and still has exacerbations because it may be that the source of some of those exacerbations or all of them is actually bronchiectasis, not asthma or COPD.

And so we hesitate to use the phrase misdiagnosis or mistaken diagnosis, but there is probably some portion of patients out there are probably some portion of patients out there that have been misdiagnosed because to diagnose COPD is a spirometry test in the office. To diagnose bronchiectasis requires a CT scan.

Historically, there's no reason to send somebody for a CT scan if you're going to diagnose bronchiectasis and there's nothing available to treat it. Now there is something available to treat it. So you can look for it.

I think the increased diagnosis rates will reflect that over time. And as we shift our attention to that broader population, bringing some of them into the funnel could open up a massive, massive opportunity because the literature right now says somewhere between 40% and 60% of asthma COPD patients are comorbid with bronchiectasis.

Just to put that in perspective, we have a $5 billion peak sales estimate based on 250,000 patients that we're targeting right now. If we take 4% of just the COPD market, the low end of that estimate, that's 800,000 patients. That's more than 3x the market we're going after right now.

So the upside here for this drug in patients on label and which insurance companies will support is multiples of what we're starting after in the first year. So this is a huge opportunity in front of us, and we're going to resource it accordingly.

So we've got 7 minutes left. We need to touch on TPIP because that landscape has been evolving just in the last 24 hours. And your ENCORE readout, which is for ARIKAYCE, which is your next catalyst.

Let me start with TPIP. Thoughts on the competitive landscape in PAH, given the data from [ Tyvaso ] oral treprostinil this morning [ former ] and the conversations around soft mist and potential once-daily Tyvaso, how are you seeing the competitive landscape potentially evolve to time of approval?

So it's still early, and we're getting into the data, but I would just tell you that nothing I saw from this morning's Ralinepag data nor the soft mist inhaler, I think, has any impact whatsoever on the strength of the TPIP target product profile proposition.

We're talking about the only medicine that we have that is available or will be available that is once a day that is inhaled, which is the preferred route of administration and which allows you to get to much, much higher levels of the underlying drug, which is the goal of treatment for this fatal condition.

We saw absolute best-in-class and best-in-disease PVR reduction data in Phase II last year, better than sotatercept. So this drug is more convenient, appears to be more safe and more effective than any other prostanoid bar none.

What is coming out now from [ uther ], I think, is interesting, this soft mist inhaler, for example. That's an attempt to reduce the very difficult problem of cough, but it's one component of the challenge of that medicine. The other components that are challenging are the fact that it's 4 times a day. So you want to use the soft mist inhaler to try and make it easier to take. But what you're doing is you're changing the composition only modestly.

I see this as a product that is going to counter detail YUTREPIA, but I don't see it as a threat to TPIP. Why? The underlying drug that you're breathing in is still active treprostinil and your body reacts to the prostanoid, not to the form. So the more severe cough reaction comes from the fact you're breathing in an active drug. It doesn't come from the fact that it's dry or wet in terms of its inhalation composition.

So yes, you do see some very transient impact from breathing in dry powder, but it is not sustained. And as we saw in our Phase II data last year, it wasn't even hardly in evidence, at least in our case.

The main reason why we don't see a lot of cough with our drug is because it has the 16 carbon chain appended to it. So when you breathe in the drug, it's inert. When you breathe in the soft mist inhaler, the drug is going to be active. You're going to have the same upper airway bronchospasm kind of reaction when that prostanoid is first inhaled, at least that's our prediction. And I will be surprised to see if that is not the case.

Regardless, it's still 4 times a day versus once a day, and we're able to get much, much more drug into these patients. And we've already seen the PVR data from last year's study. We'll have more information by the end of this year as we do the open-label extension in the first year. So that will be interesting. We'll have 6-minute walk data. We'll have NT-proBNP...

With the higher dose.

With higher doses in some cases.

What should we expect? Because I think we're watching -- many investors are watching that [ 12 80 ] higher dose come out of that come out of that open label, what percentage of patients were able to get to that highest dose? And what data could we expect that emerges from that?

So I want to set expectations clearly. We did not set up the open-label extension to push patients to higher doses. It is simply that through the open-label extension, physicians at their discretion, should they wish to, can go above the doses that have been...

We heard they wish to. So that's why I think there's a number of patients.

In some cases, they have raised, but we don't have many patients that are at [ 12 80 ]. Oftentimes, physicians will get patients to a level where they're performing extremely well, and they'll just hold them there. And then as the patient declines later on, that's when they'll increase the dose again.

And that's why you see the opportunity for our drug to be more impactful because with administration once a day, it's very unlikely that patients are going to miss their dose. If you're taking it 4 times a day, that's a bigger burden. And oftentimes, what happens is they'll skip a dose or 2, and that makes it very difficult for them.

But I think the proposition of TPIP and where we are, the open-label extension data, being able to give some additional ideas of what happens as you go up in dose will be very encouraging.

I think certainly, everything that has ever been done with prostanoids shows that the more you give, the more patients benefit. The trick is, can you overcome the adverse event profile? And it certainly seems from our Phase II data that we've been able to do that.

Indeed, our Phase III study targets [ 12 80 ] is the upper end of the dosing range as opposed to 640, which is what we did in Phase II. And the reason we're moving to those higher doses is because the KOLs and the FDA encouraged us to. So this is not just us trying to push the dose as high as we can go. This is us being pulled into that world.

And the best evidence for the perception of this drug as being a real game changer in this industry, Tyvaso right now is approved for PH-ILD. And yet, even though that drug is approved and on the market, we are still able to recruit patients into the PH-ILD study out of the U.S. It's a very encouraging sign. It's early days, but we weren't expecting that.

And last question, I'll ask few minutes. The ENCORE data for frontline, it's only Phase III, could only double your TAM for ARIKAYCE? But what more than -- what do we see?

So it was 30,000 patients is the TAM right now. It goes to north of 200,000 if these data go the way we think they're going to. So it substantially increases the addressable market for ARIKAYCE.

What is good data from ENCORE, especially on that PRO?

Statistical significance on both the PRO in terms of its performance relative to the control arm. And then within group change levels, what percentage of patients show that minimal clinical improvement.

So like a responder analysis within the PRO as well?

Those two, I think, are the most important points. For Japan, it's culture conversion. And certainly for patients and physicians, it's culture conversion.

Even in the U.S.?

Even in the U.S. We've never done a study where we have not won on culture conversion. These patients were recruited at the same time as the ARISE study. The only distinction between these two is that one runs longer.

And what we saw in the ARISE study, which was so compelling, is that we were able to culture convert 80% of patients in 6 months. To put that in perspective, it was considered a breakthrough discovery to convert 30% of patients who are refractory after 12 months of treatment. So this is a major advance. If this continues to hold in the ENCORE study, it also sets up the motivation for physicians to treat these patients earlier.

So control is a double dose of -- I'm sorry, not a double dose. It's a 2-drug combination in ENCORE versus the standard of care, which is 3 drug, right? So you're comparing ARIKAYCE plus a 2-drug with the triple combination.

What is the delta in culture conversion that you think you need to show versus the double combination for this frontline population, right, which does have the option of triple -- cheap triple therapy? What delta do you need to show for doctors to say, yes, we're going to start reaching for this in frontline?

And I wouldn't draw a hard line, but I would say somewhere in the 15% to 20% range in terms of a delta would be clinically meaningful. I think equally important to culture conversion is durability. And you see the Japanese asking for that specifically as a part of their endpoint analysis. So not only do culture convert, but when you go off drug, do you remain culture converted.

And importantly, when you look at ARISE, every patient who had culture converted on the control arm was positive again when next measured. So we are able to provide historically durable culture conversion, which we think is what gives rise to the ultimate benefit to these patients in terms of symptoms, patient-reported outcomes, et cetera.

So all of that aligns very well. We're very confident in these data. We think they're going to go well. And we also know that the FDA is encouraged by the success of this drug and considers it a success story and is anxious to see this get expanded into frontline patients.

With that, we are at time. Thank you very much, Will.

Thank you.

Thank you for standing by, and welcome to the Insmed Fourth Quarter and Full Year 2025 Financial Results Conference Call. [Operator Instructions] I'd now like to turn the call over to Brian Dunn, Head of Investor Relations. You may begin.

Thank you, Rob. Good day, everyone, and welcome to today's conference call to discuss Insmed's Fourth quarter and full year 2025 financial results and provide an update on our business. Before we start, please note that today's call will include forward-looking statements.

These statements represent our judgment as of today and inherently involve risks and uncertainties that may cause actual results to differ materially from the projections discussed. Please refer to our filings with the Securities and Exchange Commission for more information. The information we will discuss on today's call is meant for the benefit of the investment community.

It is not intended for promotional purposes and it is not sufficient for prescribing decisions. Today's call will feature prepared comments by Will Lewis, Chair and Chief Executive Officer; and Sara Bonstein, Chief Financial Officer. After their comments, they will be joined by Martina Flammer, Chief Medical Officer, for the Q&A session. I will now turn the call over to Will.

Thank you, Brian. Good morning, everyone, and thank you for joining us. 2025 was an exceptional year for Insmed, defined by extraordinary execution and transformative impact. Commercially, we witnessed the approval of Brinsupri and its stunning early months of launch performance as well as the continued global performance of ARIKAYCE, which showed significant acceleration from commercial efforts in Europe and especially Japan. .

Clinically, we saw best-in-class performance from TPIP, entered 2 new gene therapies into the clinic for DMD and ALS and completed the acquisition of INS 114. These accomplishments represent a significant expansion of our clinical pipeline despite the discontinuation of CRS without nasal polyps program last quarter. We entered 2026 with the momentum that positions Insmed for sustained leadership in both bronchiectasis and NTM.

In the year ahead, we intend to accelerate and expand the U.S. launch of Brinsupri, while continuing to grow ARIKAYCE. Rarely does the company have the opportunity to own an entire disease category by virtue of having the first approved medicine in a disease with no competition on the immediate horizon.

Insmed enjoys 2 such opportunities in bronchiectasis and NTM, both of which also share a similar call point among pulmonologists to the strong foundation we intend to pursue other first or best-in-class therapies within our 3 target therapeutic areas, which include respiratory, inflammation and immunology and neurology and other rare diseases.

Today, we are pleased to announce revenue guidance for Brinsupri of at least $1 billion in 2026. We are confident providing this guidance earlier than expected due to the additional visibility we have gained into the market access environment and the early performance we have seen from Brinsupri so far this year. To our knowledge, only 15 drug launches in history have been able to surpass the $1 billion mark in their second through fifth full quarters of launch and every company that has achieved that milestone has gone on to reach a market valuation of $70 billion or more.

Coupled with another expected strong year of performance from ARIKAYCE, we anticipate total company revenue in 2026 to be more than double the revenue we produced in 2025. This guidance gives us confidence that we can achieve cash flow positivity without needing to raise additional capital.

However, we may choose to source capital as necessary to support new business development, internal programs or other potentially value-creating initiatives. We are currently evaluating several such opportunities and we'll continue to do so as we prudently seek to expand our pipeline.

Let us now dive deeper into Brinsupri. In 2025, the U.S. launch of Brinsupri surpassed even our most ambitious expectations. Prelaunch, we set a very high bar for what we believe could achieve using a basket of historically strong respiratory launches as our guide with $144.6 million in net revenue in its first full quarter, I'm proud to say that Brinsupri is exceeding that far.

And let me be clear, the launch continues to go well, and the team continues to execute at a very high level. As with many successful medicines, the shape of the launch from one month to another can be inherently variable but the overall trajectory for this launch is strongly up and to the right, and we believe Brinsupri has the potential to be among the best, if not the best specialty respiratory launch ever.

Let me now take a moment to illustrate where we expect the Brinsupri opportunity to evolve over time. In these early months of the launch, we see Brine establishing itself at the forefront of treating bronchiectasis with no competition for several years.

We have previously framed out a peak sales estimate above $5 billion for this indication and everything we have seen so far from this launch has only added to our conviction that the opportunity is at least that large. But I want to emphasize this point. We believe there may be much more.

Let's get specific. We previously defined the total addressable market in the U.S. based on Brinsupri's label as 500,000 currently diagnosed patients with non-CF bronchiectasis. Within that diagnosed population, we estimate that approximately half or 250,000 patients have had 2 or more exacerbations in the last 12 months, matching the profile of the patients who participated in our clinical trials.

Based on those figures, the roughly 11,550 new patients who have started treatment with Brinsupri in 2025 represent less than 5% of that patient population. So there remains an enormous amount of runway within that initial total addressable market. And as a reminder, the greater than $5 billion peak sales estimate was based on us successfully addressing these 250,000 patients only.

In addition, we believe that over time, more of the remaining 250,000 currently diagnosed patients with less than 2 exacerbations will start to move into the category of those who have had 2 or more exacerbations in a 12-month period. This is due to the progressive nature of the disease and better patient reporting and documentation of exacerbation events now that there is an available treatment.

This belief is supported by real-world data in the 2-year study of claims data for nearly 15,000 patients with bronchiectasis, about 47% had 2 or more exacerbations in the first year of follow-up. Then in the second year, another 9% joined that group, meaning that 56% of study patients and 2 or more exacerbations in either the first or second year.

Based on that study, it is our expectation that patients will continue to move into the 2-plus category over time, and this would represent upside to our peak sales estimates. Now if I can leave you with one item to focus on, it is this. There are 32 million diagnosed patients with COPD or asthma in the U.S.

We believe that many of those patients could have undiagnosed bronchiectasis and as a result, may continue to exacerbate despite treatment with standard of care for those diagnoses. I would encourage you to consider and assess this potential for yourself. Recognizing the size of that opportunity, we are turning our attention to outreach and education to physicians in the hopes that they can assess these patients for the presence of bronchiectasis.

The potential additional patients from these populations, which would be on label for Brinsupri, if they are confirmed to have bronchiectasis, towards the initial total addressable market we have just been discussing. We are currently working on a number of different programs to advance the exploration and quantification of these patients.

This effort will be supported by evidence generation in several large respiratory centers who intend to use retrospective data to identify bronchiectasis in patients diagnosed with COPD and asthma who are still exacerbating. We are also creating dedicated teams within our medical and commercial operations to identify these potential patients given the substantial populations they represent.

As many of you know, historical medical literature on this topic provides a wide range of estimates, but a more recent publication that looks specifically at the overlap between COPD, asthma and bronchiectasis suggest that bronchiectasis could be involved in 30% to over 50% of patients with moderate to severe COPD and in 25% to 40% of patients with severe asthma.

These patients may not have received attention or been identified in the past because until Brinsupri came along, there have been no medicine that physicians could turn to upon diagnosis. As we're able to identify patients that may benefit from Brinsupri from within this broader population, we have a chance to help physicians deliver what we believe could be a game-changing medicine for the benefit of their patients.

It is an enormous opportunity to serve patients, and it will take several years to more fully manifest, but it has the potential to expand Brinsupri's impact by orders of magnitude. This is something we are actively working on and we'll continue to monitor, but it is our belief that we could begin to see these patients as early as the end of this year within the pulmonary practices we already call on and more evidently in 2027 and beyond.

Let me now take a step back and describe what we are seeing within the launch to date. Today, we are still in what I would call the exploration stage of the launch. This is a new medicine and as is customary, physicians often want to try it out on a patient or 2 to see how it works, assess safety and then determine how much more broadly they intend to prescribe.

For example, of the 4,000 physicians who have written a prescription through the end of 2025, nearly half have prescribed Brinsupri to just a single patient. As those first patients return to their pulmonologists and share their experience with the treatment early this year, this should play an outsized role in their physicians' interest and willingness to write again.

To date, we have heard very positive feedback through our interactions with physicians and directly from patients through our support services as well as through the patient experiences that have been shared in public forums or on social media.

It can often take several months for patients to return to their physicians' offices to be able to convey these experiences but this positive early feedback suggests that the knock-on effect of these experiences should start to result in additional prescribing behavior by the second quarter, given the large number of new patients that were added in the fourth quarter of 2025.

We believe these positive experiences with the current diagnosed bronchiectasis population, should also increase the likelihood that physicians will be receptive to proactively tracking exacerbations in screening their COPD and asthma patients for bronchiectasis. Turning now to the mechanics of how patients gain access to Brinsupri. A critical element of successful launches is favorable payer access dynamics, and I am pleased to say that this is progressing very well.

In fact, over 90% of targeted patient lives have access to GetranSupery reimbursed either through a documented payer policy or medical exception. We chose to engage payers in an effort to encourage them to make access for appropriate patients as frictionless as possible. For those who have been willing to engage with us and settle on simple attestation based prior authorization and reauthorization criteria, we have offered modest rebates.

Others have chosen to require documentation within their medical policies, which typically means requesting documentation of the CT scan and proof of 2 or more exacerbations. Importantly, we have seen a very high payer approval rate so far, even for payers requiring documentation, which is very promising.

Given our long history with ARIKAYCE, which even now is primarily reimbursed through medical exception, we've become skilled at providing education to health care providers and their offices about documentation and process requirements. We expect these high approval rates to continue in the months ahead as physicians and their staff become more accustomed to the payer reimbursement requirements.

While we expect contracts to continue to officially go into effect over the course of the first half of this year, we've concluded enough of these negotiations to feel confident in the general direction of the market access landscape for Brinsupri. I am pleased to say this landscape is aligned with our prelaunch expectations, with broad access to the treatment for appropriate patients and either physician out of station or manageable documentation required for reimbursement in most cases.

In summary, the Brinsupri launch continues to be very strong. The rate of patient adds, new physicians and manageable market access dynamics gives us comfort that from the initial patients we are targeting, we see a clear path to reaching our stated peak sales goal of more than $5 billion with potentially significant upside from the adjacent populations outlined a few moments ago that could take that peak sales number much higher.

We'll have much more to say in the quarters to come as we gain a clear picture of how big and when those additional patients may be diagnosed and become on label for Brinsupri. The opportunity itself is one that any biotech company would be fortunate to have, and we intend to aggressively resource the launch to maximize its potential. Now let me spend a moment on ARIKAYCE.

Our commercial teams continue to do an excellent job of driving growth of the product. Japan had a particularly impressive 2025, delivering 40% growth compared to 2024 and contributing more than 1/4 of ARIKAYCE's global revenues. In Europe, ARIKAYCE grew even faster, albeit from a more modest revenue base. This strong commercial execution sets the stage for ARIKAYCE's next clinical readout, the Phase II ENCORE trial, which we expect to announce in March or April of this year.

Success in ENCORE could open an opportunity to increase the addressable market for ARIKAYCE from around 30,000 patients today to more than 200,000 patients. Let me now switch gears and spend a moment on TPIP, which was significantly derisked by strong clinical data in 2025, opening up the opportunity for us to pursue 4 Phase III clinical programs in parallel.

We are very excited to announce that last month, we were informed by the FDA's Office of Orphan Drug Products Development of their decision to grant orphan drug designation to treprostinil PALM-ILD for the treatment of pulmonary arterial hypertension. So you can understand the basis for this designation in their own words, I read here from the actual letter we received from the FDA.

"Our decision to grant designation is based on the plausible hypothesis that your drug may be clinically superior to the same drugs already approved the same indication because your drug may be more effective due to greater placebo-corrected improvement in the 6-minute walk distance compared to other approved oral or inhaled formulations of treprostinil and by means of a major contribution to patient care compared to the approved subcutaneous and intravenous formulation of proposal".

This decision, which was based on the FDA's assessment of our Phase II data released last year is a striking validation that our belief that TPIP has the plausible chance to be a meaningfully differentiated treatment compared to other treprostinil options. In our view, this supports our long-held conviction that TPIP could become the prostanoid of choice for physicians and patients.

Last month, we presented the trial design for our PALM PAH Phase III trial of TPIP in patients with PAH at the PVRI conference in Dublin. Recall that the FDA agreed based on the strength of the Phase II results that we would need just 1 Phase III trial powered at the standard 0.05 alpha for a registrational submission.

On this slide, you can see a depiction of the trial design for PALM PAH while much of the design is similar to our Phase II trial, there are some key differences. First, the trial has a longer treatment period of 24 weeks versus 16 weeks in Phase II. This longer treatment period is intended to provide patients with a practical titration window given that this trial will allow patients to dose up to 1,280 micrograms or double the highest dose used in Phase II. To put that high dose into perspective, 1,280 micrograms of TPIP after subtracting the weight of the 16 carbon chain contains about 813 micrograms of treprostinil.

That is more than 3x the highest labeled daily dose of Tyvaso DPI for patients that fully comply with the 4 doses required per day with that treatment. Another difference is that the Phase III study will allow patients to be on background [ sotatercept. ]

Enrollment of those patients will be capped at 20% of the overall population and stratified to ensure balance between treatment arms. Finally, the primary endpoint of 6-minute walk distance will be measured 1 to 3 hours post dose to approximate TPIP's peak effect similar to trials of other treprostinil products. Trough measurements will also be captured as secondary endpoints.

We are incredibly excited to get this trial started in the first half of this year. To recap, I am very pleased with where we are as a company. The Brinsupri launch continues to go well, allowing us to announce revenue guidance for 2026 of at least $1 billion for that therapy. When combined with the strong performance that we expect for ARIKAYCE in 2026 and we expect to produce revenue on a company-wide basis that more than doubles from last year.

And even that could be just the beginning as we await a near-term pivotal readout for ARIKAYCE that could expand its label and we work to identify new patients who could benefit from Brinsupri. For TPIP, we have received an orphan drug designation for treprostinil PALM-ID to the treatment of PAH and have released the Phase III trial design for that indication.

If successful, the FDA has indicated that this single Phase III would be sufficient to support a filing for TPIP in patients with PAH. Finally, we have a strong and growing pipeline of potentially first or best-in-class investigational programs behind the ones we've spoken about today, many of which should also begin to contribute catalysts over the next year and beyond.

With that, let me turn the call over to Sarah.

Thank you, Will, and good morning, everyone. Given that Will has already walked you through our 2026 revenue guidance for ARIKAYCE and Brinsupri, let me provide you with a few additional comments on our expected gross to nets in 2026. In the past, we have highlighted a range of 25% to 35% as a reasonable analog for Brinsupri gross to net at launch. This range was based on precedent launches and the impact of new catastrophic coverage requirements under IRA legislation. .

Today, we believe we have good visibility into where payer contracting is headed and are now positioned to provide a gross to net guidance range of mid-20s to low 30s for Brinsupri in 2026. Importantly, our 2025 actual gross to net for Brent Super was also in that range, which implies that the rebating expected to go into effect into 2026 and will be modest and is therefore not anticipated to have a significant effect on the overall GTN of the product.

For ARIKAYCE, GTN for 2026 is expected to range from the low to mid-20s, a slight increase from 2025 due primarily to the impact of the small manufacturer phase-in and other provisions under IRA. Let me spend a moment on our cash position.

As of the end of 2025, we had approximately $1.4 billion in cash, cash equivalents and marketable securities. Cash burn in Q4 included approximately $70 million of onetime items, largely attributed to the asset acquisition of INS-1148 and the milestone payment to AstraZeneca related to Brinsupri's U.S. approval. Excluding those onetime items and the cash receipts related to stock option exercises in the period, our underlying cash burn for the quarter was similar to the underlying burn levels that we saw in the prior quarter.

Keep in mind that only a portion of the Brinsupri revenue we recognized this quarter had been received in cash as of December 31, so our cash burn does not reflect that full benefit. As we have said before, we expect both revenue and spending to continue to increase as we fully resource and support Brinsupri launch as well as other programs from across our portfolio that are expected to continue to ramp in the near and medium term.

Finally, I would like to reemphasize the statement will made earlier as it relates to our pathway to profitability. Based on our existing development plan and the strength of our commercial engine and its revenue capabilities, I am confident we can achieve cash flow positivity without needing to access additional capital.

That said, I will remind you that we have and will continue to invest in appropriate business development opportunities as well as internal programs and therefore, may choose to source additional capital to advance and expand our pipeline in support of additional future value creation.

Moving now to other relevant financial metrics for the fourth quarter, which are displayed on this slide. Cost of product revenues in the fourth quarter of 2025 was $44.2 million or 16.8% of revenues which is lower on a percentage basis based on our historical performance, reflecting the positive contributions of Brinsupri to the company's gross margin profile. Additionally, as expected, research and development and SG&A expenses increased this quarter compared to prior year period due to the necessary investments made to support the U.S. launch of Brinsupri and to continue to fund our growing pipeline.

In closing, I am pleased to report that Insmed remains in a strong financial position, providing us with the capacity to pursue our ambitious goal to expand our reach and our impact on patients. We look forward to continuing to utilize our resources to pursue the potentially value-creating opportunities we have in front of us.

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

[Operator Instructions] Your first question today comes from the line of Joe Schwartz from Leerink Partners.

Congrats on the very strong performance. It certainly seems like the TAM for Brinsupri has a lot of room to expand with a very well-designed strategy to identify patients with COPD or asthma who are exacerbating with bronchiectasis, but might not yet be identified as such I look forward to hearing about that progress on that front as you embark on this initiative.

But I was wondering if you have any plans to develop other DPP1 inhibitors within respiratory disease in order to expand your franchise further? And if so, how do these other agents differ from Brinsupri.

Yes, I appreciate the question. Absolutely, we intend to bring other DPP1 forward, not just in the respiratory indications, but in others, as an example, 1033 will enter the clinic this year for rheumatoid arthritis and irritable bowel disease, a couple of indications within that. And that will be in the second half of this year.

In parallel, we're also advancing other DPP 1s into conditions in respiratory like COPD and asthma that is absolutely on the horizon for us. Martina perhaps can comment a little bit here on the distinction between the patients we're targeting who may be responsive to Brinsupri because they are bronchiectatic versus those who are asthmatic and/or COPD of a particular profile distinct from the bronchiectasis patient that these other DPP1 would target. Martina, do you want to address that?

Yes, sure. So we're looking at a phenotype of patients who continue to exacerbate even though they're optimally treated for COPD or for asthma already. And most of those patients not only have a higher increase in pulmonary exacerbations, but also an increased acceleration in lung function decline as well as an increase in mortality. So that is a specific phenotype of patient population that we're looking for.

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

Congrats on the progress, Will, I was hoping you could provide some additional color regarding the guidance for Brinsupri. Can you speak to some of the specific elements of patient behavior that gives you confidence at this point, specifically with regards to dynamics like compliance, discontinuations, prescription abandonment.

I mean I know it's early, but do you have a sense of what that looks like? And how did that influence your projections?

Sure. So we have -- as you might imagine, a number of different data sources we examined, but there is generally a very detailed dashboard. And what I would convey to you is that across all the metrics, we're seeing at or above our targets, and that's very much behind why we have the conviction that we'll do at least $1 billion in revenue in Brinsupri this year. .

So I'd say across the board, we're very encouraged, whether it's market access metrics, whether it's use, low discontinuation rates, reauthorizations going through I'd say we feel very, very good about where things are.

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

And my congrats as well on the quarter. Can you comment at all on the Scripps trends that Symphony is picking up? Are those January and early February trends indicative of what you guys are seeing on your end?

And anything you can tell us at this point, just about how new starts are trending so far this year. And then I did just want to ask around interest in BD activity. It looks like you guys flagged that a couple of times in the slides and potentially raising capital around that.

What kind of deals are you guys interested in pursuing? And what's the rationale for potentially doing a bigger deal at this point?

Yes. Thanks. As it relates to the performance, I mean I think things just are very strong out of the gate is the only way I could describe it. And so we see -- we hear a lot of talk about the Symphony data, obviously. We don't track it. We don't pay attention to it. But what our what we were trying to accomplish today because we are always very detailed and I would say, transparent about the puts and takes that may be in operation in any given week for any given medicine.

This is what could hold it back, this is what could accelerate it. that I think is often interpreted as caution or conservatism on our part. And what I want to make sure we get across today is that we feel great about the way this launch is going.

And we do believe we're going to join that very rarest of groups that can produce $1 billion plus in revenue by adding quarters 2 through 5 together. There aren't many in history that have done it and those that have gone on to be very successful companies. And that's because to get to that level by the end of the fourth quarter, you're going to have to be at a run rate that would imply you're going to continue to do very well as you go into '27 and beyond.

So with all that confidence that comes from doing the examination at a very refined level of script trends, physician behavior, surveys that we do, behavior of patients on medicine, the market access picture. All of these things combined to give us a very good feeling about the direction we're traveling and that's why we're able much earlier than expected to give this direction that we'll do at least $1 billion.

That then feeds into the notion that we're on track to get to cash flow positivity without having to access more capital. And that is absolutely the case. The only potential issue we want to raise is that if we see something that's interesting on the business development side, we would not hesitate to bring it on board.

We think now is the time to press the advantage should we find first or best-in-class compounds that we can bring on board.

An example of that would be INS 148 which we got, in our view, for a very modest amount and which has what we consider to be DPP1 like potential in its application across a range of different potential diseases. So more to come on that asset, but assets like that, that we can add that are sort of Phase II ready. Those are in our sweet spot for sure, where we can step right into the clinic bring to bear our capabilities in clinical developments and trial design and get to a next candidate molecule that could be first or best-in-class.

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

Will, kind of dig into some of this baseline guidance a little further, Entera as well. when will you and when will we get more clarity on refinement of this $1 billion-plus level sites already sits right around that.

And if you stretch the numbers out, it implies 15% to 20% quarter-over-quarter guidance, which strikes me as relatively modest given the past few quarters and all of the patient finding initiatives, does this have -- so can you comment on that?

And also, does this idea of requiring the additional paperwork, I guess, and the 2 or more exacerbations factor into the uptake because it sounds like you guys are expecting a certain number of plans to still require this documentation and that it might be higher than you previously expected? Those were the questions.

Yes. So let me be really clear. The market access picture is fantastic from our point of view. It's ahead of where we thought it was going to be internally. So in no way do I want you to interpret are mentioning of some plans requiring documentation and some not as being indicative of any impact on anything other than enthusiasm for our forecast. .

What I would tell you about that existence of those requirements of documentation, we always expected that some portion of these plans would require that. That's why we fielded so many field access managers who can support the back office effectively in navigating that. And to be clear, to date, that's how everybody has done it. It's been all medical exception.

So now that the policy has come into place, that smooths the uptake because our concentration has always been on patients with 2 or more exacerbations, even though our label is for any and all bronchiectatic patients. So strong position with regard to market access and uptake.

And with regard to the baseline guidance, look, we have one full quarter under our belt. So it's, I think, audacious to put out $1 billion plus forecast for quarters 2 through 5 since only 15 products in history have ever done it to the best of our knowledge, and that includes all the COVID products, the GLP-1s, Harvoni and [indiscernible], SKYRIZI, household name programs.

And to that list, Insmed intends to add its name of Brinsupri. So we are incredibly happy about where we are and where we're going. I would not interpret at this stage, which is very early with one full quarter under our belt thinking that by saying $1 billion, we in any way mean to imply that we're slowing down on the contrary.

This is what's giving us the confidence to go and suggest that there's going to continue to be acceleration throughout the year. We will provide more qualitative guidance at least as we go through the year on how the quarters are progressing but given the dashboard and the direction we're traveling right now, we feel very good about this launch.

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

So you said you haven't seen any change in approval rates from start forms to paid drug -- what is that actual approval rate right now? And just on a similar topic, have you seen any changes in the conversion speed from Star form to pay drug?

Yes. So we aren't disclosing particular elements of it like the approval rate itself. What I would tell you is that our benchmark internally based off of our experience with ARIKAYCE, which is very good, is very high, and we are at or exceeding that level. And then with regard to any other thing that is actually driving the launch, as I said, the dashboard for us is green. So I don't know how else to convey to you that we feel that we're in a very strong position.

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

This is Jasmine on for Ali. Congratulations on the progress. What is the ex U.S. contribution to your Brinsupri guidance of the $1 billion or more for -- and can you just talk a little bit more about your launch strategy ex U.S. for this year? .

Sure. So I'll ask Sarah to comment on the different components of our revenue in a moment. The strategy is to launch in Europe and in Japan. We want clarity on the MFN policies that are coming forward now. I think we're going to have that in the coming weeks and at the most months. But until that's clear, it seems to us that the prudent thing to do is to sort of put things on hold until we know what that's going to look like. .

To be very clear, that does not reduce our enthusiasm for going to Europe and Japan and our teams there are continuing to advance work in contemplation of when that day comes, but we really need clarity from the administration first on what these policies are going to look like, so we can assess those trade-offs and understand where we need to go to.

Sarah, do you want to take the composition question?

Sure. Happy to. And thanks for the question. What I would comment on is, as we have said previously, any ex U.S. contribution for Brinsupri in 2026 was going to be very, very small given the original time lines we put out, we're obviously going to be monitoring the U.S. policy as well stated. So we feel very confident in the $1 billion plus for Brent Superi regardless of sort of the timing of the pause as we're thinking about contributions. And broadly speaking, the contributions for Brinsupri will be vastly weighted towards the U.S.

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

This is Brandon on for Andy. Regarding additional capital to support business development or other value creation -- to us, it sounds like incremental spend on clinical programs. How are you thinking about this relative to achieving cash flow positivity? And is achieving cash flow positive more of a near-term 2026 goal or in the outer years?

Yes. So we -- I would just say we see a very clear path to cash flow positivity. I view it as an inevitability just based on our assumptions about where revenues will go for both Brinsupri and ARIKAYCE our base business that this cash flow positivity journey contemplates includes Phase III programs for HS, which may or may not happen as we all know. But it contemplates some expenditure in these programs that you're making reference to.

So we would put the cash flow positivity journey separate from BD. BD is the thing that is incremental that would result in us approaching the markets for capital. And look, there's plenty of different ways we can do that. And Sarah, maybe you want to just take it from here and share your thoughts.

Sure. Happy to, and thanks for the question. Yes. As Will said, we have -- the $1.4 billion provides us that ability to fund through cash flow positivity for our base business inclusive of the programs that we have under our umbrella today. BD is obviously separate from that. As we think about different ways to augment balance sheet. There are all levers that are -- that exist are available to us, and we have the ability to be thoughtful on that if and when the appropriate BD opportunity did present itself.

Your next question comes from the line of Leonid Timashev from RBC Capital Markets. I wanted to ask a little bit about the depth of prescribing. I think you mentioned that a lot of scripts are currently coming from physicians writing just on script. I guess, is there something that they're waiting for in that initial experience with patients that's giving them pause from increasing their prescribing right now?

Is there any additional education that you guys are doing to sort of try to drive that depth? And I know really at one point, you had mentioned that in some of the centers of academic centers of excellence, the drug is still working its way through P&T committees. I guess, are you seeing that work its way through? And can we expect an increase in depth of prescribing across physicians and centers.

Yes. So this is really important with almost half having written only one prescription and obviously, the vast majority of patients added in the fourth quarter what we're trying to frame out is that what we've seen is physicians will try with 1 or 2 patients.

And as I just mentioned, fully half of them have only done one so as those patients experience the use of the drug with what has been to date, a benign safety profile and a pretty good experience that's reported back, we know that, that will fuel the use of the medicine in other patients within those practices.

And all of these practices we think of as having multiple patient candidates for the drug. Now if we take a deeper dive on these physicians and their behaviors, it's typical that they would wait a few months for the patient to return to the office to express what their experience has been.

That dovetails nicely with what we saw as the onset of symptom benefit during the Phase III and Phase II programs, that gives us some confidence that as we enter the first and second quarter of the year, those patients come back in. They report positive experiences. Obviously, that won't be universal, but it has been our experience that it has been very positive.

And the consequence of that is those physicians are going to be inclined to write again. Of note, we have a very broad prescribing base already. So the ability to gain depth that positive experience and reinforcement is just one office visit away. And that, to us, is incredibly encouraging as we come into 2026. And yes, we are absolutely drawing attention to that.

We now have up and running an extensive speakers bureau. So this is a compliant way of educating people on the experience of the medicine peer to peer. And I think that's going to be very beneficial. We have a number of other programs that we activate to make sure that we get, if you will, vocal about what people are seeing, and that allows everyone to understand what the benefits could be and make their own assessment.

But I would say universally, their experience to date, we have had a very good feedback loop beginning, and I think that's going to earn benefit throughout '26 and beyond.

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

You talked about the launch being up strong and to the right. Well, I think also in the prepared remarks, you noted that quarters can sometimes vary along that strong trend line. Back at JPMorgan, you've kind of flagged some unknowns just related to being so early on in the Brinsupri launch. So I'm curious, have any of those unknowns that you alluded to at the start of the year just become more known now that we're at least halfway through the first quarter?

And then just a quick kind of second part to my single question. With revenue guidance now in the picture, should we expect Insmed to continue providing things like patient starts and prescriber metrics going forward?

So with regard to the unknowns becoming known, yes, we've seen some things that we weren't aware of and how they would to shake out things that are very important like market access, policies, the actual experience and timing of getting a prescription filled.

Are patients staying on drug or dropping off. Are they getting reauthorizations even as they change plans, are those going through? What's the approval rate, whether you have a policy or it's just medical exception. All of those things, I would say, are trending positive from our internal benchmarks in a way that gives us confidence to be able to provide the guidance we have.

And I think as we think about that revenue guidance going forward, we'll obviously provide additional clarity but I think in general, the most important thing we recognize, which is why we put it out today based on our confidence, is that people want to know what this drug's potential could be from a revenue-generating point of view.

We see behind each one of those dollars, obviously, a patient that is benefiting from the medicine. And so the revenue is derivative of that patient benefit. And it's very important to keep that North Star in mind because ultimately, that's what we're in the business of doing.

It's helping these patients and the positive stories that are coming back from the use and experience with this medicine, we believe will yield additional revenue benefit, and that's where this revenue guidance is coming from. And as those unknowns that -- some of which I reviewed become clear, it absolutely gives us greater confidence that we're going to be, as we say up into the right.

It's a little bit hard after only 1 quarter full quarter in a partial first quarter to give upside direction in terms of what the cap could be -- but I would say we see this as a year of incredible potential sitting there with at least $1 billion just for Brinsupri and 450 to 470 for ARIKAYCE that's a very interesting profile where both drugs are first in disease have no competition for the foreseeable future and are called on by the same commercial infrastructure.

So there's synergy, there's leverage, there's upside and growth. And when Encore comes out, assuming those results are positive, we have the expansion of that market opportunity. So this is just the beginning of this kind of direction and guidance.

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

Great. So I was just wondering, how do you expect pulmonologists to navigate payer requirements around ruling out COPD or asthma as the primary driver of symptoms I'm just trying to think about what needs to change in these practices to potentially recognize bronchiectasis as the main driver in maybe a comorbid patient?

Sure. So in our Phase II and Phase III trial, we had about 15% to 20% of patients who are comorbid with asthma and COPD. And importantly, particularly if we did something like asthma, it's a spirometry test in the office that enables the diagnosis of COPD.

In order to get a definitive diagnosis of bronchiectasis, you need a CT scan and a pulmonologist evaluation but you're that proximate to that diagnosis. In many cases, CT scans don't get ordered because, let's say, you were able to diagnose it as broad kiectasis. What good does that do if there's no medicine to treat it.

Now there's something that can treat it that can lower -- is demonstrated to lower exacerbations and all the other benefits that we've discussed in the past of note at the 25-milligram arm preservation of lung function, which is particularly relevant for a COPD patient.

So these are exciting opportunities for those patients who have bronchiectasis to gain potential benefit from this treatment. -- and they are literally one CT scan away. So it's not a difficult distinction to make if you do the CT scan, and that's really the funnel change that will have to take place and why we're encouraging physicians to give consideration when they have asthma or COPD patients who are on MAX treatments and still experiencing exacerbations, hey, maybe there's an undiagnosed bronchiectatic patients in front of me.

And the numbers that are suggested by the literature are quite substantial here. So while this may take a little time to turn and activate in terms of a patient population, literally internally, we think of it as another launch, it will eventually yield, we think, a significant number of patients on label for Brinsupri treatment.

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

Continued execution commercially. And the work that you guys have mentioned that looks at the COPD and bronchitis overlap. Is there any correlation with asinophil levels? And just given you've had 2 biologics targeting type 2 inflammation approved for COP recently.

I wonder if that just becomes another step for physicians before they order a CT scan as we're thinking about additional pathophysiology for their patients.

Sure. And Martina, do you want to field that question? .

Yes, sure. So I think if you think about the COPD or the asthma patients, physicians will go with what are their standard of care. And then a medication as patients need many COPD patients or after patients have multiple treatments.

So for COPD, clearly, those are bronchodilators inhalers, but also lab [ Alana ] combinations and of course, corticosteroids. So it depends very much of what is the status of your COPD patients? Are they benefiting it or not. And then you have the opportunity to accelerate into a different treatment paradigm and potentially consider what are biologic treatments and made these patients benefit from them.

So there is always a treatment paradigm that you look at from -- depending on what the clinical status is of your patients. you have to have a physician also the clinical suspicion that it may not only be the underlying disease that you're treating. So the COPD and or the asphalt that you're trading.

But if your patient is becoming optimally treated, even if this is a biologic and continues to exacerbate, then the question has to be raised off? Is that what's driving an exacerbation, not really COPD or asthma.

They may still have that, and you're treating that optimally, but then you're asking now I have to see if there is something else. And that is where the question comes in, have a runout scale. And I think often patients, if you add additional medications along that treatment paradigm, physicians will ask themselves the question, what else do I have to look for before I continue escalating a treatment paradigm.

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

This is Alex on for Danielle. I was curious if you could give a little bit of a breakdown of the payers that are requiring documentation versus at a station versus the plants that require medical exception? And what percentage of covered lives does that represent? And then lastly, just if you could share your confidence in getting policies in place that are currently using medical exemption going forward?

Yes. So Alex, I'm going to disappoint you. I'm not going to break out the covered lives and what is documentation, what is not. I would just tell you this, which is the benchmarks we set for what percentage would be required documentation.

They're right in line were probably a little better than what we were thinking. And I think what's important is that all of the guidance that's coming out that we've seen so far is aligned with the guidance that came out at Chest which is that the patients you want to be thinking of first for this are 2 or more exacerbations and that's the way that the market access world is interpreting it.

It's the way we've driven physicians to think about the use of this drug in terms of first patients to try it on. And so I think all of that aligns nicely. And so what you've seen in the partial third quarter and first full quarter in the fourth quarter, is this market access picture that is not expected to change dramatically in terms of our ability to add patients without a lot of friction.

And that's because not only are we very experienced with the market, medical exception pathway, but we are getting many plans to agree to doing at a station which should, if anything, help the process. The more predictable it becomes, the easier it is for the back office to know what to do, and our teams are there in a compliant way to support that. education and execution.

So I feel very good about the market access picture. I think within the launch, when we look back at this and talk about what has gone very well. Market access is going to be one component that we got right.

Your next question comes from the line of Adam Walsh from ROTH Capital. Adam, your line is open.

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

Just curious if you're expecting the majority of patient reauthorizations to occur 6 months after starting therapy. And I know your comments seem to suggest that some payers have already required reauthorization at earlier time points. So just curious if there's anything that you can say about the seamlessness of the reauthorization experience you've seen last .

Yes. The point of greatest friction, I think in this world is when you get into the first quarter and you have some patients who change medical plans, does that get bridged effectively? Is the reset of the co-pay, what kind of a break does that put on things and I would say that in our first quarter, we feel very good about the way things have gone so much so that we can give the guidance that we provided.

I don't know that we can give a lot more detail beyond that, except to say that if we were seeing difficulty or breaks of some kind, we would be calling that out, and we're just -- we're not .

Your next question comes from the line of Graig Suvannavejh from Mizuho.

I really want to tap into the additional Brinsupri opportunity in the 32 million or so patients who have COPD and asthma as a potential revenue opportunity. Just to clarify, to be able to tap into that patient population. Is there anything that you need to do, i.e., do you need to run a clinical study? Or how would that mechanically work to be able for a doctor to prescribe that medicine, would that be off-label or just any color there, please?

Yes. So we're speaking very specifically on label exclusively, and that's all we would ever focus on. And the way that flow occurs is for a physician who has, as Martin described, either asthma or COPD perhaps is fully treated for that condition and yet continues to exacerbate and perhaps have sputum expectoration.

That patient becomes potentially a candidate for a CT scan to evaluate if the additional difficulties they're experiencing are a byproduct of bronchiectasis. The moment that CT scan and pulmonologists have a definitive diagnosis of bronchiectasis, they are on label for our drug, if they have had 2 or more exacerbations, their path to reimbursement for the use of the medicine should be very smooth.

And so that's really what we're describing is that all of the COPD and asthma patients million we estimated as the number. What percentage of those may still be experiencing exacerbations despite best treatment? And then of those, how many have either already had a CT scan. And so we can go back and review those CT scans to see if there's evidence of bronchiectasis because remember, if you do a CT scan, and it's not that uncommon for many of these patients to have one it doesn't mean that they would have identified bronchiectasis.

They have to go looking for it or perhaps the radiologist called it out, but it doesn't get coded because back then, there was nothing approved to treat it. So there is advantage in going back and looking at existing CT scans and doing a definitive assessment of whether there's bronchiectasis and evidence and there's also the patients that are having the experiences on describing getting an additional CT scan for the first time and having it evaluated it at that moment.

So our education efforts are both medical and through commercial channels. compliantly raising the index of suspicion about this, and hopefully, identifying those patients who would benefit with a definitive diagnosis of bronchiectasis and getting them on Brinsupri.

Your next question comes from the line of Ash Verma from UBS.

This is par Josh on for Ash. A question on the GBI-IBF study design. How critical do you think it is for you to show survival benefit to claim a major contribution to patient care versus Tyvaso? And does your potential study design change based on what division shows on the survival endpoint in the TDM-1 study that's about readout.

Yes. So what I would say is that, that study design is not yet finalized. I don't know, Martin, you want to comment on anything further with regard to where we're going with that TPIP program and particularly the survival endpoint he was raising.

Yes. So we haven't really looked at exactly what that -- what the design will be. I think looking at [indiscernible] and what endpoints to use and also the design is a good guidance. Certainly, that will be one considerations for us, but we have not, at that point, really communicated on the design, but we'll discuss that also with the FDA, and then we'll share it with you once we have a better picture of what we will move forward with.

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

This is Jane on for Ben. So 2 quick ones. First one, I just want to make sure I understand correctly. So the $1 billion guidance is all 2 pulmonary exacerbation in patients and any 1 PE patient is going to be upside. And second one on ARIKAYCE. Data is around the corner. Any commentary that you can provide on blinded data, whether it's PRO or put conversion rate? And what is kind of internally, how do you think about a bar for approval and most importantly, commercial success? Thanks for your time.

Sure. So on the $1 billion dollar question, are they all -- is that revenue guidance is that based on patients who have 2 or more exacerbations, yes, is the answer to that. we think there is upside from the additional 250,000 patients.

This is a progressive disease, and we do anticipate as the most recent paper I mentioned in the remarks, identifies that some of those patients with less than 2 or more exacerbations will fall into 2 or more exacerbations as time goes on because of the progressive nature of the disease and the heightened awareness of diagnosis and all the rest.

In response to your second question, you'll be pleased to know we've decided we're not going to be getting into the game of blended data anymore. We certainly monitor that. I think the challenge of it is always knowing that there is an alternate explanation for whatever promising direction it may be suggesting where I feel confident in the ARIKAYCE ENCORE readout is that we've already run multiple studies using this drug in this disease and have seen the primary endpoint and secondary endpoints measured with success on more than one occasion.

The exception of that, obviously, is the newly developed PRO, but that PRO was developed in conjunction with the FDA using the ARISE data as the benchmark for understanding what we think is likely to be the way to interpret clinical relevance. And what does that mean?

It means that we feel very good going into the discussion with FDA that the results will be compelling enough to enable a full approval for all MAC NTM. In Japan, all they want is culture conversion. Obviously, it has to be safe and effective, but they measure effectiveness by culture conversion, and that's the primary endpoint.

And we've never had a trial where we have not definitively won on that front. To remind you, the ARISE trial was basically a 6-month trial with one month of and the ENCORE trial is simply a longer version of that same trial design. We recruited the patients at the same time.

We simply randomized more of them to the shorter-term ARISE trial, and so for all of these reasons, we feel very good about ENCORE being -- producing data that will enable approval in the U.S. and Japan. We obviously have to see the data to make final conclusions, but that's right around the corner, and it will unlock a very substantial additional population for ARIKAYCE going from roughly 30,000 addressable patients to over 200,000. So this is a very substantial future contributors starting in 2017, assuming that these data are what we expect them to be, and then we're able to launch in the U.S. and in Japan.

Your final question comes from the line of Adam Walsh from ROTH Capital.

My question is on Brinsupri persistence. We recently talked to a pulmonologist who like in brine blood pressure pill, and that it prevents long-term damage, but doesn't deliver necessarily immediate symptomatic relief and a flag the 1-year mark as the key discontinuation risk based on his biologic experience.

With your earliest patients now approaching 6 months on therapy, can you share any aggregate persistence or refill data and talk to your strategy about ensuring persistence with the medicine.

Yes. So the first thing I would say is that refills so far are going very well. So I think that, that's a very positive sign early on. We know that what is great about this medicine as was once described by someone at one of the faculty I described it as the holy grail of pulmonary medicine because it was the last unaddressed patient population and the treatment burden of a once-a-day pill is unbelievably low relative to what these people typically take for other indications in the respiratory arena or otherwise.

It's often inhaled medicines, as you know, and those kinds of treatments. As we think about where we go from here, I would tell you that profile, that dynamic should an air benefit to the uptake of the medicine. We know from the secondary endpoints in the Phase III study, especially at the 25-milligram dose, these patients had a highly nominally statistically significant finding in favor of feeling better on the medicine. So it's our expectation that, that story line will come back and empower physicians to write additional prescriptions.

And through that process, we would expect things to grow and expand as our depth increases. I don't worry so much about the continuation of the use of the drug given some of the early stories we've heard about patients feeling better on the drug.

But even without that, knowing the avoidance of losing lung function which many of these patients are focused on the 25-milligram dose, we were statistically significant in preserving lung function. So even if you don't feel it to be told that by your physician, I think, is a very compelling driver for use and certainly, the refill rate would suggest that.

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

Great. Welcome, everyone. My name is Jess Fye. I'm a biotech analyst at JPMorgan, and we're delighted to be continuing the 44th Annual Healthcare Conference today with Insmed. First, you're going to hear a presentation from the management team, and then we're going to go into some Q&A. [Operator Instructions] So with that, let me pass it over to the company CEO, Will Lewis.

Thank you. Thanks, Jess, and thanks, everyone, for joining us today. I want to start out the presentation with the call out to our forward-looking statements. The forward-looking statements mentioned here in our public filings should be something that everyone reviews carefully. Before I begin the presentation, I'd like to take a moment to talk about what drives us at Insmed, and that is our impact on patients and to highlight that I'm going to read a quote from a physician that we recently got in regards to the BRINSUPRI product that is now on the market for non-cystic fibrosis bronchiectasis, goes like this, "I see a patient who is a mother of 2 teenagers with a history of bronchiectasis since her 20s. Her chronic cough has kept or from attending sporting events, plays, movies, et cetera. She doesn't sleep most nights because of the cough. She has broken ribs due to it. She even has to work from home because her cough causes incontinence. After 4 weeks on BRINSUPRI, her CAT score went from a 32, which is a terrible score to a 6. She doesn't cough anymore. Her FEV1 increased 15%, she broke down in tears in my office. No more antibiotics, no more IVs, no more chest physiotherapy."

Now I want to emphasize that we see these stories like this is inspirational and not necessarily representative of a typical patient or our clinical data, but it's extremely gratifying to hear that kind of an impact of the medicine that you see identified here in the upper left-hand corner. Insmed is a company organized around 3 therapeutic areas, respiratory, immunology & inflammation, and neuro & other rare. And in the upper left-hand corner, you see BRINSUPRI, which is the recently approved product for the treatment of non-cystic fibrosis bronchiectasis, the first ever approved for the same.

ARIKAYCE, which is approved for the treatment of refractory MAC lung disease, the first ever approved for that disease. And beneath that, highlighting TPIP in its 4 indications we intend to pursue, the first of which PH-ILD is already in Phase III. PAH is going to follow shortly, followed by PPF and IPF in the second half of this year. Beneath that, we identify INS1148, which is a monoclonal antibody we recently acquired. And then we have DPP1 other generation molecules that will be targeting other diseases.

In immunology & inflammation, we highlighted a number of things we're targeting. Brensocatib we'll be looking at HS in this space. We'll have more to say about that. We can look at our other DPP1 that's going to be entering the clinic this year. In this case, for rheumatoid arthritis and irritable bowel disease. We have next-generation products, which are deimmunized therapeutic proteins, Uricase for the treatment of gout, and that's something that we believe will be able to evade the immune system's response to Uricase as it's currently is a problem that, that program faces. IgG protease will similarly be deimmunized and launched. We have other applications in the I&I space for INS1148, and then we have a novel mechanism of action within the clinic right now -- pardon me, within our internal research right now that we think could be as impactful as DPP1.

Finally, I'm very excited to talk about neuro & other rare. The first 2 identified here are gene therapies to treat Duchenne muscular dystrophy. We're already through our first cohort there and have 2 other cohorts behind it, which have already begun to enroll patients and we are now enrolling patients in our ALS study. Beyond that, we see a gene therapy that will enter hopefully, IND approval for Stargardt and then several other programs that are earlier in development.

But collectively, you see our ambition to develop first or best-in-class therapies with each of these programs supported by further research and business development. Our company has gone from focusing on the 2 products in the upper left hand of respiratory to the entire collection that you see here today, and it is indeed an exciting time for Insmed.

The last 18 months has seen our market cap increase on average $2 billion per month every month for the last 18. As we look forward, we see this collection of different milestones, both commercial and clinical that will be reading out, and this is what gives us encouragement that we will continue to be able to have impact in driving shareholder value. that shareholder value is identified here on the left-hand side of this slide.

On the right-hand side of the slide, we try to highlight the different areas that will hopefully drive future value. We like to think that if we take care of patients, we'll take care of our investors as a consequence. And many of these compounds and trial readouts here represent first or best-in-class therapies that we should be able to either provide proof of concept or full approval for.

Let's take a deeper dive into the first of the 3 therapeutic areas, which is respiratory. The lead program here, BRINSUPRI has just had what can only be described as a stellar full fourth quarter. It's our first fourth -- our first full quarter of performance, and we added 9,000 patients in that quarter, which gives us a cumulative total of more than 11,500 since the launch in August of last year. We have now more than 4,000 prescribers who are writing for this drug. It's very important that everyone understand that when we look at these 2 numbers, the 11,500 patients, that's from a targeted total of 250,000 and the 4,000 prescribers is from a targeted total of 27,000. So as impressive as these numbers are, they are just the beginning of a very long journey.

On the left-hand side, the consequence of this is we put out very impressive revenue numbers for BRINSUPRI in the fourth quarter, $144.6 million. To put that into perspective for you, DUPIXENT's first full year of launch this number is higher than their fourth quarter from that first year. There's a lot of momentum behind this launch but there's still a lot more that we need to understand in order to gain a real confidence of where this is going to go and how high up is up. And those things include out-of-pocket reset dynamics. It always haunt the first quarter of the year for every drug, regardless of what it is. And the possibility of the clarity around insurance programs and how they will authorize or not, the use of this drug. I will tell you right now, we have had very good success in the market access arena. We expect that to continue, but it is something we're going to be watching very carefully.

We called out inventory stocking. It was around 9% of Q4. We are contractually bound with our specialty pharmaceuticals -- pharmacies that they are not able to stock more than 2 weeks of inventory. So this number we don't expect to grow or be material as we move forward. It's important to remember that the other product we have approved ARIKAYCE also performed well this last year. We beat our guidance, which was raised during the year.

And this year, we are targeting $450 million to $470 million for the full year. This represents continued growth in the eighth year that this drug has been on the market. We had particularly strong performance, as you see on the left-hand side, from international, which is Europe and Japan, and we expect that to continue.

The next clinical trial readout will be ENCORE. This is the expansion opportunity for ARIKAYCE to treat frontline MAC patients. There is a current total addressable market that we target of around 30,000 patients. Should this trial be successful, that will increase to in excess of 200,000 patients. If you remember, we're targeting $450 million to $470 million in revenue this year from just the refractory market, one can imagine that the success going into the frontline market will bode very well for the future growth prospects of this program. Importantly, for both refractory and frontline MAC, there is nothing approved to treat this condition. So this meets our threshold of being first or best in class.

We look at our next program in respiratory, which is TPIP. This is treprostinil palmitil inhalation powder, this is a 16 carbon chain appended to treprostinil by an ester bond. And with that dry powder formulation, it enters the body when it's inhaled with a single breadth and the esterases in the lung cleave off that ester bond and release the active drug. This has shown very good data in PH-ILD and PAH in Phase II, best-in-class. Clearly, very efficacious in terms of pulmonary vascular resistance as well as NT-proBNP and 6-minute walk benefit.

And so our Phase III study is centered around those metrics and objectives. For PH-ILD, this program is already underway. It's called the PALM-ILD study. It initiated in December of last year. And for PAH, we expect to initiate that Phase III program imminently.

PPF and IPF will begin later this year once we've had a meeting with the FDA and clarified what that will look like, but we're excited to be announcing that TPIP is going to be pursuing 4 Phase III programs in parallel and the opportunity that this would represent in terms of patient impact, because of the clinical data we produce to date, should it be replicated, is profound. This program, I like to say is every bit as exciting and promising as BRINSUPRI is and bronchiectasis is and where it could go remains to be seen, but certainly, the early data have been very, very encouraging.

Let's talk a minute about INS1148. This is a program we in-licensed recently. It's a first-in-class therapy monoclonal antibody for the treatment of both respiratory and I&I diseases. Essentially, what this does is it targets stem cell factor III and the c-Kit signaling pathway that's associated with inflammatory disease Importantly, it does not impact stem cell factor 220, which is involved in homeostatic and tissue healing.

The consequence of this, we believe will be that this program will be very effective in these diseases we're targeting initially ILD and moderate to severe asthma. And we hope that the data that has been available so far, which is an atopic dermatitis which showed a very benign safety profile and very clear efficacy will be replicated in these disease states.

We'll have more to say about this program once we get, if you will, our arms around it through later in the year, but this is a very exciting addition to our repertoire. This is a snapshot of the swim lane just in respiratory. And here, you can see a broad collection of assets which are first or best-in-class all along the development time line. And on the right-hand side, the catalysts that are associated with each of them. You can see it is going to be a very busy year ahead for the respiratory therapeutic area.

As we turn our attention to immunology and inflammation, the first readout we'll have here is in the second quarter of '26, the so-called CEDAR trial. This is looking at BRINSUPRI in the treatment of hidradenitis suppurativa or HS, which is a dermatologic disease or condition, we're going to be targeting AN count as the primary endpoint and a clear win in this trial that would encourage us to move into Phase III would be a 20% reduction in AN count versus baseline, a home run or, if you will, a World Cup win, as is more timely, is a 40% reduction in AN count versus baseline.

We will be looking at the high score as well. For those of you who are familiar with this disease state, that takes longer to see impact in certain of its measures. And so that will be done at the end of the 52 weeks that this study will run. This is the balance of the pipeline in I&I. It's not as robust as respiratory, but there's some very exciting programs in here, including our next-generation DPP1s going into RA and IBD. Many of you are familiar with the CRS study we executed that did not work, that we reported that in December. That study has been shut down. That was with a DPP1 BRINSUPRI -- rather brensocatib targeting that disease state, but it was a clear miss and from that perspective, we consider the trial of success in answering the question of whether or not it's going to be effective.

It's important to note that for both CRS and HS, there are no animal models available for those diseases. So it makes it very difficult to predict whether or not your particular drug candidate is going to be efficacious. For RA and IBD, it's different. There are available animal models, and we have tested the INS1033, this DPP1 in both of them. We indeed published our RA data from our brensocatib test in that model. It's very encouraging, and that lays a very strong round work for our belief that this is going to be a successful development program. We have another -- other programs in this area, and we certainly expect to keep our eyes out in the BD arena to see if there are ways we can augment here.

As we turn to neuro and other rare, I mentioned at the start, both DMD and ALS. These programs are now up and running. In the DMD space, this is a novel approach. We're using intrathecal delivery for the treatment of this condition, which is counterintuitive because why would administering this gene therapy through the spinal cord result in effective transduction in muscle and cardiac tissue, but in fact, that is what we saw in animal model data.

This is an incredibly exciting program because by virtue of going through the intrathecal delivery route, we avoid the IV challenges of first pass effect going through the liver or the majority of the virus is weeded out and creates oftentimes an immune response that can be very dangerous to the patient in question. Indeed, several young boys have lost their lives to the attempt of using this route. We're pleased to say that we are focused on the intrathecal route, and we think that will allow us to dose lower and be safer while still getting comparable or better efficacy, and that's the objective of this study.

It's very exciting to be into cohort 2 and cohort 3 already. There's a lot of enthusiasm in the community for this program and you're going to be hearing more about it as we go through the year. Importantly, we are not using weight-based dosing, and that is significant distinction from other companies that have programs in this arena.

Similarly -- and that's the ASCEND study for your reference. In ALS, we have the so-called ARMOR study, which initiated in the fourth quarter of last year. We are studying both SOD1 and sporadic patients. In our preclinical work, we took note that in the cell assay, we were using 7 of 10 cells that were taken from sporadic ALS patients were responsive to this treatment. That is an incredibly encouraging sign and is something we took to the FDA, and they agreed that in this study design, we could go after both sporadic and SOD1 patients.

So in Cohort 1, we're actually starting off with sporadic patients. And we're super excited because as everyone is probably well aware, this is an absolutely devastating disease with nothing really available that makes a material impact, there's a lot of work still to be done here, and we want to hopefully be able to contribute to that. But we're very excited about these programs, and they'll continue to enroll this year. We haven't yet decided when we're going to begin to share data. We've obviously seen some of the DMD biopsy data already but there's more to come, and we want to make sure we have a complete data package when we finally bring this forward for everybody to evaluate.

This is a snapshot of the neuro & rare therapeutic area pipeline beyond DMD and ALS. We have Stargardt. We have another gene therapy target we're considering right now. It's advancing. And then we have 2 other programs coming out of our Cambridge England operation for Ataxia-Telangiectasia and AOA1. This is using the synthetic rescue technology that is specific to that research site. Collectively, these 3 therapeutic areas are extremely exciting, and we will look to augment modestly through business development as we move forward. This comes built upon financial strength, as of the end of September, we had $1.7 billion of cash. We've talked about the guidance for this year for ARIKAYCE of $450 million to $470 million. And while we're not providing guidance for BRINSUPRI because it's too early in the launch, to be able to do that accurately, we feel very confident that we're off to a very strong start and that will continue. We're looking to take the capital that we have and look to deploy it against all these commercial and clinical opportunities as well as additional business development opportunities that we see suitable for in-license or acquisition.

Behind all of this is the greatest strength of the company, which is our culture. I am incredibly proud of what we collectively have built at Insmed in this respect, and it has been recognized externally. We're now 5 years in a row, the #1 on the science top biopharma employer list, that's a feat that's matched by only 1 other company called Genentech. Everybody at the company is extremely excited about the work we've been doing. Often, people talk about the dramatic change in the company over the last 18 months. We like to say it's an overnight success, 13 years in the making. But the point is that we have assembled really a first-class collection of employees who are very motivated to help patients and as a consequence, drive value for our shareholders.

So let me just end by summarizing the momentum that we had in '25 was hard to match. We're aware that sets a higher hurdle for us. And honestly, we welcome it. We are very driven to continue to see the success of BRINSUPRI. This is a first in disease approval and a first in mechanism approval. We're very excited to bring that forward. The strong start we've had to date, we hope is indicative of what's to come. with international launches to augment that this year.

We are already approved in Europe. We will launch there in the first half of the year, along with the United Kingdom is our expectation. And then in the second half of the year, Japan, where we both already have commercial infrastructure in both regions. The 3 therapeutic areas I reviewed give structure and direction to where we intend to deploy our resources and our managerial attention and we're super excited to augment those through business development.

The next 18 months will have more events commercial and clinical than the prior 18 months, and we know what that represented in terms of our value creation. So we're hopeful to be able to build on this momentum for the benefit of shareholders by benefiting patients. And with that, I'll stop, and we'll go to questions. Thank you.

Great. [Operator Instructions] Maybe just picking up where you left off, you mentioned the therapeutic area structure and business development, is that a priority across all 3 areas or more of a priority in some than others? And what type of deal structure are you kind of interested in right now?

Well, it's interesting. I think the deal we just did mirrors the one we did for DPP1 which we paid, I think, $30 million upfront for. This one, we paid $40 million upfront. Those are no-brainers. I'll do those all day long where you have a novel mechanism of action that targets multiple potential diseases and where we think scientifically we have seen evidence for why it will be effective and safe.

Oftentimes, a little differently than perhaps the rest of the market does, which is why they're available at these inexpensive levels relatively speaking. I will do those all day long in any of those therapeutic areas. Part of the reason we did the architecture we did was to enable us to not only modularly add on new programs within each therapeutic area, but also to consider more ambitiously additional therapeutic areas we might target. We don't have anything on the agenda right now.

But I would tell you, we would not limit ourselves to just the 3 therapeutic areas if we found something truly compelling Insmed views itself as being on a mission to create a self-sustaining biotech company. We've got a lot of growth within the pipeline already, but you want to do business development when you don't need it, that's something I'm a big believer in, and we've done that throughout our history, sometimes to the chagrin of some of our investors who would like to see us focus only on what's in front of us. But my belief is you've got to get there and you have to have development across the spectrum because inevitably, drugs are not going to work in certain diseases or they'll work, but they'll be meager. And I'm not interested in bringing forward a drug that isn't highly impactful on patients because when you do that, it makes the rest of the process so much easier.

Okay. So I guess related -- the third 1 is rare and not necessarily -- it's not necessarily like 1 therapeutic area, right? So we got a question here on the portal that was about the rationale for entering the retinal space with Stargardt disease. And what Insmed's aspirations are as it relates to becoming a big player in retina?

Yes. So I think right now, we call it neuro & rare and that's sort of a catch-all for the stuff that is coming out of our research labs that might be off of a platform that is related, but not disease related. So Stargardt is a good example. That's another gene therapy construct. There, we're harnessing a different kind of clinical technology, scientific technology, which is really fascinating. It's RNA enjoining. One of the limitations of gene therapy is the size of the gene cassette.

And so what you can put inside a viral vector that gene cassette can't get bigger than that viral vector. That's why in the treatment of Duchenne muscular dystrophy, what's used is microdystrophin. It's not a full-length dystrophin. You can't make the full-length protein because what you can fit in the viral vector is constrained. RNA enjoining allows us to send in 2 viral vectors, 2 transgenes, which are then rejoined intracellularly and then read by the cellular mechanism to produce the protein that is therapeutic -- thought to be therapeutically beneficial. This is really cutting edge science, we've seen very good progress so far. The first place we're going to be applying it is in Stargardt because we'll be able to make the full-length protein. And we think that will be hopefully very impactful and safe, it's hermetically sealed in the eye so that makes it easier not to have to worry about ancillary implications from that approach we're taking.

But we are also doing work in Duchenne muscular dystrophy for mid-length dystrophin. And as excited as we are about our microdystrophin program, our ambition here is to really impact this disease state. And the way we're going to go about doing that next is by using RNA enjoining to create a mid-length dystrophin and produce that in the hopes that they will be even more beneficial for patients with that devastating disease.

When can we start seeing some of that data, clinical data?

I don't know. I would say we're not going to put that data out. We might put a little bit out in '26, but probably '27. And the reason we say that is because, look, we've seen biopsy data. We know where we're going with the preclinical data. I am well aware that from the point of view of the investment community, the vast majority of the energy is focused on BRINSUPRI and ARIKAYCE and TPIP and the expansions that surround those 3 programs, and those are incredibly significant and important value drivers.

But I am here to tell you that it is just the beginning, within Insmed for many years, we did these acquisitions 4, 5 years ago. We have been percolating the next gen of compounds that will be first or best in class. And the next place we're going to go is using gene therapy in DMD, ALS, Stargardt, possibly RET other places. So there's a lot out there for us to still do but each 1 of these programs needs to be first or best-in-class, and we need to convince you of that. And the way we're going to do that is not by putting out the first piece of data we have, but by building a mosaic that makes it very clear how the drug is in terms of its safety and its efficacy. And that includes both biopsy measures plus NSAA measures which are the ability to actually impact the patient's functionality.

And we think that collective data is important for people to make their assessment. ALS is a little bit different. We'll have to look at what kind of data we unearth there as we move forward and how quickly the patients enroll but I am incredibly excited about this. We have several scientists who have devoted their entire lives to the treatment of this disease, and they are over the moon that we are now treating patients with this therapy because the preclinical animal data was just unbelievably exciting. When that data comes out in humans, we will share it. And hopefully, it will be just as compelling as it was in the animal models. That's probably not until '27.

So coming back to TPIP, a multipart question. One, you mentioned ramping manufacturing to support the IPF and PPF trials. What do you need to do to start those trials? Second part would be you've got multiple trials, multiple indications. Should we think of any of those as being kind of faster to recruit and get to data than others? And lastly, within the Phase II PAH, open-label extension data that I think we're getting later this year. What should we be looking out for when that data comes out?

Yes. So on the manufacturing side, we just need to make more drug. We have just added 2 massive Phase III programs to our original ambitions, and that's going to require more manufacturing. It's not a hurdle, we will be challenged to clear, but it is just a logistical reality we have to cross. At the same time, we also want to have dialogue with the regulatory agencies about the design of the IPF and PPF studies so that we're really clear on what those studies need to deliver in order to achieve approval because these are all Phase III studies for TPIP, it's registrational work we're doing.

So we want to make sure that, that's clear, particularly because we haven't done Phase II or Phase I work in these areas prior, PPF or IPF. So once we have that clarity, I think we'll move as quickly as we possibly can to kick off those trials. But we're big believers in going slow to go fast as it relates to registrational study work. The second question related to?

Which of those indications or trials might go faster...

Which 1 can go faster in terms of enrollment. So ILD and PAH, we have data for. And just to refresh everyone's recollection, ILD data showed improvement in time to clinical worsening, improvement in 6-minute walk, it was a very small study, and it was really intended to be more of a safety study than actually an efficacy study. So the fact that we saw that was incredibly encouraging, so encouraging that it was discounted at the time. It also happened to come out right around the time of our ASPEN Phase III results. So to be honest, nobody really cared. But if you look at what happened in PAH, we had a 33.9% reduction in pulmonary vascular resistance, which is hands down to the best of our knowledge, above anything else in the prostanoid class. No one's ever come close to that.

That is, in fact, comparable to sotatercept for PAH. So that result with a once-a-day dry powder formulation that covers patients for 24 hours is incredibly impressive. And it suggests that the ILD study was, in fact, as strong results as it appeared to be. Now these data getting into circulation have certainly raised the interest and appetite of the key opinion leader community in PAH to use this drug for the treatment of their patients. So we expect that our enrollment will be faster than it was in Phase II.

We won't know that until we're into it a little bit. And since we just started the ILD study, and we'll shortly start the PAH study, it's going to take us a little while to get a sense of the tempo but we're very excited about what that could mean IPF and PPF are further down the line second half of the year ideally. And if that's the case, we'll have a better read on that once we get going, final question?

OLE data?

OLE, second half of the year, PAH open-label extension data, we will be looking at patients, some of whom may have titrated up even further in dose and others for all of them will have 6-minute walk data updated NT-proBNP data, which is a great correlate to impact on pulmonary vascular resistance and of course, safety data. It's important to understand that the doses we were looking at in Phase II were up to 640 micrograms, which is well above the highest dose you can get to with any other form of treprostinil. We then were told by our Data Safety Monitoring Board and the FDA that it is okay to go to double that level. So our Phase III studies will be targeting up to 1,280 micrograms of drug. In the open-label extension, we permitted patients to go higher if their physician thought it warranted it.

So we may have some insight into what a higher dose above 640 would look like for these patients in terms of safety and efficacy. But this is incredibly exciting to be able to go that high with this drug for what is a fatal disease and have impact that at the Phase II study showed was a 33.9% PVR reduction that bodes very well for the higher doses, potentially having even more impact. And that would be a profound change for these patients.

So BRINSUPRI, what were your kind of key takeaways from this kind of initial launch experience? And how are you thinking about the growth and market penetration in the coming year?

The reason I started out with that quote from the patient that we got from one of our physicians is that that's not the only one we've received. We've received a number of these, and it's very encouraging. It's very exciting. It's inspirational. Obviously, it's not necessarily indicative of what every patient experience is. But the point of this is when you first launch a drug, particularly 1 that is for a disease like bronchiectasis, this disease has been around since '18, '19 with nothing approved to treat it.

Every company that has tried has failed along comes the unknown Insmed, and we have success with this DPP1 inhibitor. And so the reticence to engage with this drug right out of the gate is a little bit there, right, new drug, new mechanism, and physicians are probably going to try it on 1 or 2 patients and see what happens. The immediate feedback loop that they get after a month or 2 of these patients being on drug, if it contains these kinds of anecdotes, is incredibly powerful to the further prescribing of the drug much more broadly and to the ultimate appetite of the patients to seek out the drug when they go in to talk to their physician.

So we see this as the beginning of a potential virtuous cycle that will support the expanded use of the drug, encourage the physicians to continue to go and write more prescriptions. And we are starting with 4,000 physicians who've already written a prescription, out of 27,000. So we have a lot broader to go, and I'm confident we'll get a lot broader in the coming quarters. Importantly, those physicians will then hopefully write more prescriptions, which is to say, we'll increase our depth of prescribing behavior.

So as those things expand, the opportunity for this drug to really deliver value to patients is going to be self-evident. And I hope those stories circulate because if they do, that's the big learning from this launch, not only do the patients experience the benefits that we're seeing in Phase III, but they are feeling better. And that's what we've heard from some of these anecdotes. It's not surprising. If you look at the secondary data secondary endpoints from the Phase III study, we had a very nominally statistically significant value for quality of life, bronchiectasis questionnaire or patient-reported outcome on how they felt on the drug.

It was in the hierarchy below something that missed. So we can't say it's statistically significant. But if you look at the data, it's very encouraging. And to hear the real-world experience match that is very powerful. That means we think this will pick up momentum as patients and physicians talk to 1 another. And that's probably the biggest takeaway from the early days of the launch.

Okay. Can you talk a little bit more specifically about what you're seeing from a patient access and payer perspective. So do you feel like you've achieved the frictionless launch that you were aiming for?

Well, certainly out of the gate, we have a lot of experience with the medical exception process which is where every drug starts. We did that for 8 years with ARIKAYCE and to great success. I think our ambition here is that as we've engaged with market access players, we've tried to offer modest discounts as a part of our strategy to engage with them and work with them to ensure that their guidelines for use match things like the CHEST guidelines, which encourage the use of our drug and endorsed that when they were released in draft form in the October time frame.

Going forward, we will know much more once we are into '26 about what the new policies are that are finally written by the different market access players and how those read through to patient uptake and the ease with which physicians can get a prescription filled. I want to emphasize that we have built the infrastructure in the field to support these physicians as they try to navigate the back-office authorization in a very compliant way, so the field access managers are there to help navigate through the [ Byzantine ] world of getting a prescription approved, and so far, that has gone extremely well.

We have a very high number of patients who are opting into our patient support program. That is another positive. So really from every angle and every metric, this launch out of the gate is extremely strong. We've called out in our slide and certainly in our press release, some of the things that may be a little bit of a headwind as we go into '26, we don't know that they will be, but we just want to make sure that people are aware, there is a co-pay reset that hits in the first quarter of every year. It affects every drug. It could slow things a touch. But I would say the momentum behind this well outweighs the potential holdbacks.

What's your latest thinking on peak sales potential for BRINSUPRI in bronchiectasis? And what would drive either upside or downside to that?

So if you think about BRINSUPRI and what we've guided to in the past, it was prior to launch north of $5 billion in market -- in revenue. That's a very big number. it was built off of the price that we were charging, the fact that we're targeting 250,000 patients in the U.S. who are diagnosed with bronchiectasis already and have 2 or more exacerbations, if we can access that addressable population, we will get north of $5 billion in revenue in our estimation.

I can tell you that, that 250,000 patients from a number of different angles is probably understated in terms of potential. We know there are 500,000 patients in the U.S. that are diagnosed with bronchiectasis. They don't all have 2 or more exacerbations but as we move through this process of learning more about the disease and as physicians learn how to diagnose these patients and treat them more effectively definition of an exacerbation and how they identify that and their patients will change. We think there's a reasonable chance that, that will increase in number and many of those patients may end up having 2 or more and therefore, be on label and definitely easily pass through the insurance process.

Beyond that, the real big opportunity for this drug is the comorbid patients. Let me take a moment to drill into that because it's kind of important. COPD and asthma patients have bronchiectasis in some cases. It's not clear how widespread bronchiectasis is in that population. We know we had 15% to 20% of our patients in our Phase III study that were comorbid with those indications. But if we just take COPD for a minute, there are some 20 million patients in the U.S. who have COPD. The literature would tell you somewhere between 4% and 60% of those patients also have bronchiectasis.

Now if we just take the lowest end of that range that's 800,000 patients. Remember, out of the gate, we're targeting 250,000 and that's what got us to north of $5 billion in peak sales. So you can quickly see, as you move into those broader populations of comorbid patients who are diagnosed with bronchiectasis or perhaps misdiagnosed with COPD or perhaps have both diseases. Those patients will be on label and they will represent the enormous opportunity for this drug to make a real difference in patients' lives as we get through '26 and definitely into '27 and beyond. This drug is just at the beginning of its journey, and I think physicians are going to be learning how best to apply it to the patients for their benefit, and that's going to start with an effort on their part whether they have asthma or COPD to get CT scans, look at old CT scans, see if these patients are carrying bronchiectasis, at which point they become eligible for treatment.

That's what is really exciting beyond the initial launch of this drug is that there may be a massive opportunity out there for us yet to get.

And then maybe just coming off of the BiRCh results in CRC for brensocatib. Did that impact at all your expectations on the probability of success for [ BRINSU's ] CEDAR trial in HS? And what about -- did it impact your thinking about just your next-gen DPP1 potential for success in other settings like RA and IBD.

So the important thing to remember is that we're taking brensocatib, which is the BRINSUPRI drug, and we're looking at other disease states where DPP1 inhibition may be relevant in a clinical setting.

CRS is 1 such indication because it affects the sinus area, it's closely related to the lung. It turns out DPP1 inhibition did not have any impact there. There was an outsized placebo effect, and we've decided that we're done with that disease state.

We're also looking at HS, that's going to read out, as I mentioned before, in the second quarter. We're anxious to see those data. We think that's a long shot too. And the reason we say that is because neither of those disease states had animal models that allowed us to test and see whether or not DPP1 inhibition would be impactful.

As we move into RA and IBD, those will be entering in the second half of this year with our next-gen DPP1 inhibitor. Both of those have animal models, and we have tested both BRINSUPRI and the next-gen 1033 INS DPP1 in those disease states, and we saw very good results. And in fact, we've even published some of the RA results from the BRINSUPRI work we did. So it's fundamentally different to think about CRS and HS. They're without precedent, if you will, the RA and IBD, which are much more significant market opportunities, have good animal data behind them.

Great. Well, we are out of time. So we're going to stop there. Thank you.

Thanks very much.

All right. Let's go ahead and get started. So thanks for joining us, everyone. Next up, we have Insmed's CFO, Sara Bonstein. Sara, over to you for an overview of the company, where things stand today on the back of a huge 2025 and another exciting '26. After that, we'll get into it.

Great. Great. Thank you so much, Gavin, for having us, and thank you to Evercore for hosting this great conference. It's nice to be in some warm weather coming from an area where there was snow today. And so Insmed, as you said, we've had a tremendous 2025. And what I think is most important for everyone to walk away from is we are not done yet. We believe we have the ability to have a tremendous '26 and beyond, pending additional data readouts. So let's maybe just dig into each one of those just really quickly, and then we'll go into your questions, of course.

ARIKAYCE specifically, this is our program that has been on the market for about 8 years. In first half of next year, we could have the potential to increase our addressable patient population today. We treat about 25,000 patients in our 3 geographic territories. We have the potential to grow that to 250,000 patients in our 3 territories, assuming success in ENCORE. So look out for that data readout first half of next year.

As you move forward into BRINSUPRI, we are now happy to say we're a 2-product company. We launched our second product back in August. And so that launch, we put out, obviously, our first quarter. It was a short quarter with 6 weeks of revenue, but cautiously optimistic about the progress we've been able to make with BRINSUPRI and the lives that we've been able to touch with that very important therapy, and now it is also approved in Europe, which is great.

If you think about the clinical side of that world under brensocatib, we have chronic rhinosinusitis, we refer to it as our BiRCh trial. That data will read out by early January, and that we believe could be just as large, if not larger, than the bronchiectasis opportunity and patient reach. And then HS, also known as our CEDAR trial, we'll look for that Phase II to read out first half of next year. So a lot going on with that program.

Treprostinil palmitil inhalation powder, we'll call TPIP because it's a much better way to say it. That we will look to move forward in 4 different indications in Phase III. PH-ILD, that Phase III now is underway with sites initiating the PAH Phase III, we'll look to start that early next year. And then 2 additional indications, IPF and start those Phase IIIs. Hopefully, next year, we just have to make some more drug now that we're moving forward into those 2 additional indications.

And then what we have historically referred to as our early-stage research, but a ton there and things now progressing into the clinic. So we have our DMD program that completed its first cohort. We'll look to expand into Cohort 2 and 3. Our ALS program that now has a cleared IND, and that's in both sporadic and SOD1. So we'll be able to potentially have an impact on a broad amount of patients there, we'll move that forward into clinic next year.

Our DPP1 follow-ons, we'll move those into IND next year, the great work being done in Cambridge, U.K. on synthetic rescue in New Hampshire on deimmunizing capsids, tremendous amount of opportunity forthcoming. I'll just ground this with about 1,600 employees that I feel so talented to work alongside of around the globe to be able to move this program forward -- all these programs forward in what I believe could be a really tremendous 2026 setup.

So happy to dig into any of it.

Awesome. Way too much to talk about in the 16 minutes here. Let's try. Starting off on the bronchiectasis launch. I guess most frequent question is cadence of new patients starting on drug, especially as you're thinking about the rate kind of exiting Q3 into -- into Q4, and then we should also probably say into 2026.

Yes, yes. So underwhelming, we're not going to talk intra-quarter. So apologies about that right off the start. But we -- again, we're cautiously optimistic about the performance in that first 6 weeks. We were able to show over 2,500 new patient starts. And I think also just as important, if not more important, the 1,700 prescribers. So having that very wide breadth of prescribing. Now what we commented on is we believe most of those prescribers wrote 1 to 2 scripts. So now seeing depth as well as increased breadth will bode really well for the future success of the launch.

So I ask you to watch really closely to the next 2 quarters. So our first full quarter of revenue. That will be an important piece of information for you as you're shaping your curve. And then Q1 revenue will also be important as you're flipping the calendar year and seeing -- but cautiously optimistic, we have the ability, 500,000 diagnosed patients in the U.S. We believe about half of those have 2 or more exacerbations now on the heels of the Europe approval and what that label looks like. Great sales force, great medical team driving this program forward into -- for patients that are very, very needed of a treatment.

Awesome. I guess one of the questions is big population. So as you're adding additional prescribers as well, like why should the cadence not be picking up of patients coming on to drug? You previously have mentioned that some of the prescribers kind of sampled a little bit like 1 or 2 and maybe we'll take a little break before kind of coming back in more detail. Like how do we think about that dynamic?

Yes, yes. So it's typical any new mechanism of action. So I'll remind you, first ever DPP1 that has ever been approved. So a new mechanism of action and first time anything has ever been approved for bronchiectasis patients. So you got 2 first time. So it's standard and typical that doctors will typically write a script or 2, see other patients sort of feel function, how the medicine does before they go sort of broader. So that's why I highlighted the depth and breadth is definitely something we want to track. We have a high level of confidence that we'll be able to continue to see both increases in depth and breadth, but we need to see that. And that's why I point to getting those first 2 full quarters under our belt and being able to use that to appropriately shape what the curve looks like from a slope perspective will be important data points for all of us as we enter 2026.

Yes. I guess this calls for a little bit of speculation, right? But thinking ahead next year after you do have another couple of quarters, where do you think the curve is going to go from there? Is it kind of flat, up, down? Like I guess also like outside of your own data, what do your analog suggest that it will be...

Yes. So a couple of things here. So we've said -- we've given a peak sales number just for bronchiectasis. We've said $5 billion peak sales. And a couple of just important pieces in that. That is based on the diagnosed patients today. So unlike most first-in disease medicines, there was already an ICD-10 code. So we already knew how many patients were diagnosed, the claims data, how many had 2 or more exacerbations. So we had some of that data. And we had said, based on the patients that are diagnosed, we believe our global peak sales number is $5 billion.

What that does not take into account is the broad potential of underdiagnosed or misdiagnosed patients. So as you think more broadly, there could be several million patients pick your number. The literature says 4% to 54%. So it's all over the map. There's 30 million patients that have COPD or asthma, right? So pick whatever number you want on that, but it's a significant number of potentially additional patients that could potentially benefit by just getting a simple CT scan and getting a bronchiectasis diagnosis. This is a noninvasive diagnosis pathway.

And we are continuing to do work compliantly on the medical side, on continuing medical education and appropriate programs on having folks relook at scans to make sure did you even -- have we considered bronchiectasis as a potential indication for that depth and breadth. So the shape of the curve, there's a lot of factors in there. We obviously have a lot of conviction in being able to put the $5 billion out there, but there could be additional opportunity on top of that.

If you think about analogs, we've done a ton of work on analogs, shout out to the amazing Investor Relations team that supports Insmed. They've done a ton of work on analogs and looked at what do really good launches look like. And so we've studied all of those. And if you look at those, their first 2 full quarters are $70 million to $80-ish million, sort of the best is maybe closer to $90-ish million. And then their next 4 full quarters are in the $500 million to $600 million range. So those are just analogs. It's not guidance. We're just saying what does -- what do really, really good launches look like and what would we want to aspire to try and be like.

Awesome. All right. I'm aware you're not giving a ton of quantitative metrics on this point, but I'll ask anyways is just what you're seeing from the prescription start forms kind of the enrollment side, converting to paid drug -- so whatever kind of qualitative comments you can give on that process, like timing, how smoothly it's going, any of those metrics are helpful.

Yes, sure, sure. So we invested early on a couple of items. We had our field force in place in October of last year. So our field force was in trains, ARIKAYCE on brands, bronchiectasis, disease state awareness to build up those relationships. We also invested early in the payer access and the market access, both internally and externally. So we started the conversations with the payers well in advance and with the goal of frictionless launch. So how can we have the most frictionless launch for both the treating physicians as well as the patients. The benefit for all of us is to get patients on drug as fast as possible. That's going to benefit patient, and that's obviously going to help with the shape of the revenue curve.

So we had those conversations early and often on physician attestation on the initial approval and the reauthorization. Yes, I have bronchiectasis. Yes, I've had 2 or more exacerbations. Those were the conversations pre-label. Obviously, we're only -- we're not talking intra-quarter. So there's only 6 weeks of information. Those conversations, as you would expect, are continuing to be happening now or all ordinary course.

The other piece that we also invested in is what's called a field access manager. So these are folks that help with the back office. So we brought in, we expanded this. We had this capability already with ARIKAYCE. We expanded this capability earlier this year to allow some of that service to the back office to help with the processing of paperwork as well as have what we call our case managers, our enlighten program to help if patients compliantly opt into this program, they can compliantly interact with the case manager to help with white glove service on the patient experience side.

All right. Great. I guess on the payer access side, what's your assumption for how the policies are going to read? Specifically, if it's kind of more aligned to the label or the clinical trial criteria. I think the most specific criteria most investors are focusing on is that 2 or more exacerbations. But I guess maybe more importantly, like even if there are criteria around 2-plus exacerbations, what does that really mean? Like is it really restrictive criteria?

Yes. So a couple of comments there. We were very open and transparent with the payers initially, which they appreciate, I believe, is 500,000 diagnosed based on literature, about half of them are 2 or more exacerbating patients. While the label is broad, we have assumed that the payers would look more stringent to the inclusion/exclusion criteria of the clinical trial. And so no sort of new information there. So that's sort of point one. Give me the question again.

So even if the criteria does read with 2-plus exacerbations, like what does that really mean? Is the documentation really is it actually a restrictive requirement?

Yes. The other important piece here is our goal is the frictionless launch. So frictionless launch is not going through medical records, it's that physician attestation of the 2 or more. The other important piece is as there is now an approved product, there was never an approved product, the benefit of documenting an exacerbation, we're not going to treat the patient any different. Now that there's an approved product, just that ongoing conversation of, did I have an exacerbation, was this an exacerbation? Should I document that, that typically across all different therapeutic areas when there's an approved medicine, usually the medical records and the documentation sort of catch up.

So exacerbations, when you have an exacerbation, you're more likely to have a future exacerbation. They're nonlinear. If you had 1 in the last 12 months, in the next 12 months, could you have 1, could you have 3? Could you -- they're nonlinear and each exacerbation causes permanent lung damage. So we think this will continue to evolve over time.

I guess on the documentation of the exacerbations, right, like if it's physician at a station to kind of check off, there's a little more flexibility than if providers -- if payers are going out and requesting a whole boat load of EMR, et cetera, data, right? So there's that dynamic to consider, too.

Correct. Yes.

Okay. All right. Makes sense. Maybe we can talk about the EU side of things actually. Maybe just big picture, in the EU, how should we think about the speed of that launch relative to the U.S.

Yes. Yes. So EU, we were obviously very pleased that much earlier than I think folks even internally anticipated. So that bodes really well for their confidence in the medicine. The label is 25 milligrams in 2 or more exacerbations. We were actually very pleased with that label. I think that helps on the access side and the payer side. Broadly speaking, the vast majority of our revenue, we believe, will be from the United States, but we are very grateful that we now have the ability to impact patients and patient lives in Europe.

Awesome. And how do you think about the, I guess, the sequencing of different ex-U.S. countries coming online, kind of the relative contribution for those companies historically for other products versus U.S. products?

Yes. So throughout sort of first half, we'll look to launch in the various countries as well as U.K. and then second half would be Japan. Again, if you look sort of broadly at companies that are only in those 3 regions, not sort of some of the broader regions, their typical revenue is -- the vast majority is the United States from a revenue perspective. And so you shouldn't think anything different sort of in the model here. ARIKAYCE was a little bit more of an anomaly as you think about the contribution that we had from Japan.

Perfect. All right. Going over to the BiRCh data on the CRS side. I mean there was a lot of discussion on the last earnings call about some of the blinded data, clinical meaningfulness. Maybe we can skip some of that. Maybe just from like a modeling perspective, what's the best way to think about this? Because there's kind of a prevalent patient dynamic. There's also an incident patient going on a surgery each year dynamic, which you could kind of stack? Like what's the best way to think about that?

Yes. So we know we owe all of you more education on sort of the TAM, the funnel, all that good stuff as we have done with bronchiectasis, we had some data before we gave you that education. So we need to see the data ourselves as well. But if you look at the patient population, close to 30 million, around 30 million U.S.-only CRS without nasal polyps patients. So tremendous, tremendous -- about 3 million, I think it's about 3.1 million are steroid nonresponders. So this is a very, very significant patient population. And on an annual basis, in the United States alone, 200,000 patients get surgery. And this is a very onerous surgery for these patients. And so obviously, we need to see the data. What we have said, depending on the data is CRS has the potential ability to be just as large, if not larger, from a revenue contribution perspective as bronchiectasis. We have stated that the 3 indications that we've gone forward with brensocatib, BE, CRS and HS, we believe the WACC of 88 would be supportive across all 3.

Perfect. And they harmonize on a net price basis and payer access basis, too, do you think?

Data will prevail, but that would be the expectation.

All right. That makes sense. Additional, I guess, next-gen DPP1 molecules that I believe we're entering the clinic fairly soon. What's the indication plan there? Like how quickly can you go into a whole host of indications, like not just on the respiratory side, but also beyond respiratory.

Yes. Yes. So we view ourselves as a broad, how can we have biggest impact for patient on either first-in-class or best-in-class. So we have a lot of success in respiratory, but we believe we're much broader than that as well. So the follow-on DPP1s, we started doing work on this 5 years ago. On the heels of the WILLOW data, we had said we believe in this mechanism, and we have developed now over 800 different follow-on DPP1s in our research lab. So kudos to the great scientists that we have as part of the Insmed community. We'll look to move forward. The first of those into IND next year. We plan on the first being most likely in RA and IBD, so very significant patient populations and then obviously have plans thereafter to go into additional indications with additional future DPP1 candidates.

Awesome. TPIP how quickly can you move through recruitment and kind of through everything clinically there?

Yes. So we had a couple of really big wins. The FDA agreed to one Phase III program in PAH powered at 0.05. So that is a huge, huge win for us. These trials, obviously, they will take some time. I think the strength of the data that we saw in the Phase II will provide some excitement -- has provided excitement in the medical community, and you can potentially be able to see through that as you think about recruiting. But we will put the resources behind it, and I know you're all eagerly waiting.

The one shout out I will give all of you is the PAH open-label extension program. That you may be able to start seeing the first of those data potentially as early as second half next year. It would be the 12 month, not the 2-year, but be able to start seeing potentially even at some higher doses, not PVR data because that isn't measured in OLE, but things like 6-minute walk and those kind of things, and that could be an interesting data point for you to kind of circle on your calendar for second half of next year.

Have you said anything about the retention in the OLE for that study?

What we have said is a huge amount rolled from the base study into the OLE. So it was 90% plus from the base study went into OLE. We haven't provided any further comments beyond that.

Got it. I guess on the financial side of things, consensus right now is not modeling that much step-up really at all in SG&A and R&D as you go into next year, kind of exiting fourth quarter and into next year, it's pretty flat. It feels like given everything you just laid out, there should be some step-up. What's the right way to think about that next year, but also bigger picture, like over the next 5 years, how much you're going to kind of reinvest in that?

Yes. While we don't provide formal guidance on OpEx, I think it's important to recognize that we have had Phase IIIs ongoing between ASPEN and ENCORE. The amount of Phase IIIs, assuming clinical success that we have forthcoming can be substantial. We could have CRS, HS, 4 different TPIP programs. There may be 1, maybe 2 Phase III. So a significant amount of Phase IIIs. And that's a good problem to have, right? That means we're having clinical success. All those costs will not happen at once. So they will ramp over time. And so you just need to be thoughtful on sort of the ramp over time. That will then be sort of overlaid by the revenue contributions for both brensocatib in BE as well as ARIKAYCE potential label expansion.

All right. Well, right on time. I think we'll wrap it up there. Thank you very much, Sara.

Thank you so much. Thank you.

Good morning, everyone. Thanks for joining the session -- fireside session was Insmed and my name is Clara Dong, one of the biotech analysts here. Sitting next to me is the Chief Executive Officer of Insmed. Will Lewis, welcome.

Thank you very much. I appreciate you having us here.

Great. And it has really been a landmark year for Insmed. I have to say a first in disease FDA approval and very strong launch and impressive data in PAH and then really more to comment. I'll pass it to you to give an audience of what's going on at Insmed and what have kept you really busy for the past year.

Yes. It's been an interesting last 18 months for sure. But as we like to point out, we're facing an even more eventful next 18 months because we've just had the ASPEN trial readout, which was successful, obviously, and then the approval of brensocatib for the treatment of bronchiectasis. Beyond that, we have the TPIP data that came out and then [ Uther's ] data, which validated TPIP, its potential in IPF and PPF. So we are now looking at 3 programs at the company ARIKAYCE, which is approved for refractory MAC lung disease, conditionally in the U.S. and full approvals in Europe and Japan that is going to enjoy the ENCORE trial readout, which should expand that market opportunity from 30,000 patients to over 250,000. So that's a big expansion should that data read out as we expect it to.

The second program we have is brensocatib, the DPP1 inhibitor that, as you just pointed out, is approved in bronchiectasis. This is a disease that has been around since '18, '19 and never had anything approved to treat it. So we're very proud of the fact that this medicine has cleared that hurdle and is now available for patients. The launch early days, it's just a handful of weeks, but certainly was going well. I think we want to be cautious about where it goes next. We're going to be learning more with this first full quarter but we've said publicly, we think this medicine could clear $5 billion in peak sales just in that indication. So we're very excited about that and are resourcing that effort. It has the potential to be used in other diseases as well.

Anywhere there's a neutrophil component to the disease. We think it may have applicability. So we're studying it in CRS and HS to other diseases. The CRS data will read out by the end of the year. We'll make that public shortly thereafter, probably in early January. And then HS will read out in the first half of next year. And while that's a longer shot as we like to describe it, both are really interesting opportunities and very substantial. We've said CRS could be bigger than bronchiectasis. So another major readout here in the near term. As we look out beyond that, we think of next-generation DPP1s that we have in our library, they're going to be entering the clinic next year for sizable market indications like rheumatoid arthritis, IBD and others, COPD, asthma. So there's a lot more to come with DPP1 assuming that it is working as effectively in these other diseases as it has in bronchiectasis.

And then finally, TPIP, which is going to be kicking off Phase III trials in PAH, PH-ILD, IPF and PPF. So if you take a snapshot of where we're going to be in the next 18 months, all of those things kicking off, all of the data reading out plus the commercial launch update in the U.S., the addition of Europe and Japan. The sales force we use for ARIKAYCE is the same one we're using for bronchiectasis. So this is a territory we know very well. And that gives us an awful lot to talk about over the next 18 months. Next year, for example, we could be kicking off as many as close to a dozen Phase III programs.

So before we talk about BRINSUPRI launch in bronchiectasis, let me also just want to talk about your vision here. So you're kind of moving into a multi-franchise commercial company. You have a lot of R&D going on as well. So how are you thinking about the prioritization between your commercial execution for ARIKAYCE and BRINSUPRI and your R&D efforts?

Well, this is the byproduct of rational design. So we are hitting our stride here just as we intended to and try to create a kind of news flywheel, if you will, where in the next 18 months, these data readouts will give us additional momentum in addition to the performance of the commercial launch of the drug. Beyond that, we have 30 programs in preclinical development right now that span a range of diseases and technologies in therapeutic areas. Several of those are in the clinic right now, gene therapy for DMD, for ALS and Stargardt will all be in the clinic next year.

Beyond that, we have programs using our deimmunized therapeutic technology for proteins, it's driven by AI, which is kind of interesting. It's obviously a buzzword right now, but we've been doing this for several years, and we think we may have successfully de-immunized a version of your case, so that will be entering the clinic probably in '27. That's a pretty exciting program for us and would be a landmark achievement if we were to be able to successfully bring that all the way through. We also have efforts for novel mechanisms of action that are complementary to DPP1, which are being developed in our New Jersey research labs. And then finally, we have a program using a technology called synthetic rescue, which is looking at CNS disorders out of Cambridge England that's a few years away from the clinic, but exciting, nonetheless.

So I mentioned all this stuff because we've always referred to that as our fourth pillar, and there's always been a little bit of discomfort with why are you investing in that. Now it becomes apparent why because with the 3 main commercial programs we were just describing and these 30 programs internally, we really don't need to do anything else in order to continue to build value for the company. In this franchise, we just need to execute on what we have. Now we will be selectively engaging in business development as well, but we'll be looking at very high hurdle to bring those programs in, and we are going to be targeting low upfronts for asymmetric returns in these novel MOAs.

One of the lessons of our industry is that if you get a novel mechanism of action, like DPP1, the upside potential of that is almost unlimited, whether it's CFTR modulation and Vertex, the franchise they built or PD-1 at Merck, that's a $30 billion franchise. We all know GLP-1 and where that could go. So that's what we're focused on. Novel MOAs that are first in disease or best-in-class for these various diseases. And we've got a lot in-house that we're executing on right now and thanks to the excellent work of our Chief Financial Officer. We are well capitalized to be able to pursue all of that. I think your question really goes to how you're going to prioritize.

Right now, the pedal is down, and we are full on development because of all the positive readouts we've had and we're going to continue to do so. I think even in that circumstance, we're very fortunate because the revenue generation potential of BRINSUPRI will outstrip the expenses related to these development programs. So we're on -- what we like to think of as an almost inevitable journey to cash flow positivity. We haven't timed that yet for the market, but it's coming.

Great. And let's maybe dive deeper a little bit to BRINSUPRI launch, and there has been a lot of -- has been a lot of recent focus in the first partial quarter fresh out of the gate, it has been really strong. And how does the initial performance kind of compared to your initial launch expectations? And what has been the key drivers contributed to this early traction?

So it was a partial quarter, and we obviously posted $28 million in revenue, which was very encouraging. I think we want to urge a little bit of caution around that because some of that is inventory build on the part of the pharmacies. And it's still too soon to know what this launch curve is going to look like. We really need a few quarters under our belt. But certainly out of the gate, this is positive. And I think the greatest positive that we see in the launch so far is the breadth of prescribing.

So we're very encouraged that we've seen script writing not just in the centers of excellence. We believe over time, the centers of excellence will get there and write high volume for their patients. What we're really trying to make sure is that we also get the community-level physicians to be writing early and then focus on creating depth of prescribing behavior there. We are just now beginning to turn on some of the additional elements that can drive a launch of success, things like speaker programs, advertising, there's a lot of awareness of this disease among the patient community, and we're seeing a lot of proactive outreach by them to their physicians.

So I think all of these are positives directionally, but it's still very early, and we need to see where things go before we know what the true demand is versus things like inventory build market access is going to be a huge driver. So far, that's gone very well, but we don't know what the final program decisions will be from the different plans, and that will obviously potentially put a break on some of the uptake. So we'll just have to see. We'll know much more with the fourth quarter and the first quarter of next year.

And in terms of the market access criteria, so you mentioned some of them are being finalized. So how should we think about the time line for those criteria to be finalized? And what's your expectation?

So we're going to see some of those plans finalize their decisions between now, really in the first quarter of next year, and that's -- that will give us a clearer picture on what we can expect for uptake. What we're trying to do with a little bit of outreach and some discounting modest is ensure both frictionless uptake and then also a frictionless reauthorization process. which we think is important for this because it is a chronic medication that's going to be used for life. So we want to make that as easy as possible for patients, and we'll see how that goes.

And you also have other regions following on their way. So kind of -- tell us what are the key milestones for ex U.S. launches. And how do you plan to set the pricing? I think you mentioned in Europe, you're going to set the pricing in parallel.

Yes. So Europe has already come out with a recommendation to approve the medicine. So we expect that, that will happen sort of between now and the end of the year. That puts us in a very positive position, obviously, with the European launch next year. We already have all the infrastructure in place to execute that launch, because of ARIKAYCE, which has been on the market for -- in the U.S. almost 8 years now. Europe, similarly, has been on the market for several years. Japan is right behind it.

And I'll remind you that our Japanese colleagues have just done fantastic work in terms of driving volumes for ARIKAYCE's use, and I expect that, that will lay the groundwork for a very successful launch of BRINSUPRI. When we think about pricing in a world of MFN, we obviously want to be sensitive to this but I'll remind everyone that we priced ARIKAYCE at list price parity between the U.S., Europe and Japan. There is discounting that goes on. Some of that is visible. That may change with the MFN pressures that are being brought to bear, particularly in Europe, and it's something we're watching carefully. But our ambition is obviously to bring the medicine wherever patients will benefit.

And if the systems that provide that final pricing structure are constructive, then we'll bring the medicine there. And if they're not, we frankly won't. So we'll have to see how that unfolds. We don't have a lot of leverage over the country of, say, Germany to dictate that they're going to accept a particular price. It's up to them what they'll ultimately offer to pay, and then we'll have to make a difficult decision about whether or not we can support bringing the medicine forward. but list price parity is the way we're going to approach all of these markets.

And how are you thinking about the long-term opportunity, maybe in COPD patients as well?

So if we just talk about bronchiectasis as a target market, we've said that there are in the U.S., 500,000 patients that are diagnosed today with the disease, and about half of those have 2 or more exacerbations. Beyond that, we know there are patients with COPD, some 20 million of them in the United States and some portion of them experienced exacerbations, which are probably indicating that the underlying disease may also include a diagnosis of bronchiectasis if examined. So we're encouraging that examination to take place.

And I think in the medium term, not upfront. But in the medium term, that may fill the top of the funnel with more patients, the literature right now suggests somewhere between 4% and 60% of COPD patients are also bronchiectatic. So you can see behind that 250,000 initial patient target group that we're going after in the U.S. which are 2 or more exacerbations in the last 12 months are all these COPD and asthmatic patients who may be comorbid and that could number in the millions. So there's a lot further for us to go, and that's why we are comfortable with the guidance that we think this could be a $5 billion-plus peak sales drug in this indication.

And I also want to talk about another disease that BRINSUPRI is being studied for and you have the data -- upcoming data in early next year, that CRS without nasal polyps. So for those might be less familiar with the disease. Can you just maybe talk a little bit about what are the unmet needs for this disease? And how do you see BRINSUPRI might potentially address them?

So CRS comes in sort of 2 forms with nasal polyps and without nasal polyps. With nasal polyps, there are surgical options to treat it. There are also a lot of the biologics available approved like DUPIXENT and HUMIRA are available to treat that population. CRS without nasal polyps, which is what we're targeting, has nothing approved treated except for a generic steroid. So there is a clear unmet medical need. There are some more than 30 million patients in the U.S. that have this condition. We're going to be targeting those who are at the severe end of the spectrum.

And indeed, the entry criteria for this study are patients who have a score on a what's called a total symptom score or TSS above 5 on a scale of 1 to 9. So these are highly symptomatic patients. They come in with that score. They then are randomized -- then they are placed on the generic steroid for 30 days, and that's to ensure that the best available treatments are already been -- they've already been exposed to. They still have to have a score of 5 or greater at the end of that 30-day run-in period, then they're randomized in the trial. That should, we hope, mute the placebo effect that is sometimes seen in the treatment of these patients.

We're targeting in this trial, a 0.7 improvement. If we see 0.7 or greater, we will move forward into Phase III, and we set that number based on the fact that, that's what Optinose, the only approved generic steroid in this indication achieved and they secured approval. So on the basis of that, we think that's the right target. If we get above that, obviously, that would be a home run. But 0.7 is the threshold we're looking for. Probably won't be statistically significant just to set everyone's expectations.

Trial is not designed or powered that way. But if we get the directional benefit or indeed, if we see a subpopulation of patients that are responders, we would go forward with them because this market is so substantial.

And are you going to show any secondary endpoints as well? Maybe SNOT 22? And what's the significance of that secondary endpoint?

Yes, it's unfortunate that someone with a sense of humor named the symptom score, the SNOT-22 score, but that is actually the benchmark that is used in clinical practice. The TSS or total symptom score, which is the primary endpoint of our study is what the FDA look at. So we are studying both, and we'll have the data from both of those. And as we've commented publicly, we do see directionally in the blended blinded data improvement on both measures. It's always dangerous to look at blended blinded data, so buyer beware.

But we like to look at that because if the drug is having an effect, you should see something in the blended blinded data. And indeed, we do, we see a 2-point move in the totality of the data. So that could lay the groundwork for a success. We just won't know until we unblind. That will be by the end of the year, and then we'll probably report at the early part of January.

And then maybe just when we are thinking about the bronchiectasis and CRS without nasal polyps, how should we think about when we extrapolate the advocacy we've seen in bronchiectasis to CRS and maybe talk about the overlap of patient populations between these 2 diseases as well.

There's quite a bit of overlap between those populations and also with NTM. Indeed, the COPD Foundation has gone about qualifying centers of excellence in the United States to treat both NTM and bronchiectasis. And so that will lay the groundwork for additional patients coming into the funnel. But what's interesting about CRS without nasal polyps and bronchiectasis is that they are part of this thing called the integrated airway, where it's believed that anything that starts out of the nose essentially ends up in the lungs.

And so it may be that bronchiectasis is a downstream manifestation of people who get CRS with or without nasal polyps, and it results in bronchiectasis down the road. So this could be a really important aspect of the treatment paradigm for these patients. Of note, we talked about subpopulations and CRS without nasal polyps that we may be able to treat. One of the things we looked at was eosinophil count, so patients above and below 750 down to 300 and then below 300 that we stratified the statistical analysis plan initially for CRS without nasal polyps for that particular subpopulation.

Having looked now at the ASPEN data, we can see that we are able to treat patients successfully regardless of eosinophil count, and that puts us in a very strong position. It means we may be able to go after CRS with nasal polyps as well. So there's a lot more room for this to run. If this trial reads out successfully. And I would say the biggest point of intrinsic value creation for this company in the next 6 months is the readout of CRS because if CRS works and we move into Phase III. We probably have unlocked what we like to call a skeleton key of medicine, which means that this should be applicable in multiple diseases.

And so then you start to adjust the probability of success for things like rheumatoid arthritis, irritable bowel disease, COPD, asthma. These are massive market opportunities that we'll be bringing DPP1s into, and that just gives us an awful lot of room to run as a company.

And maybe just talk about how large exactly is this opportunity for CRS, if you have to put a number.

Well, we can say that the bronchiectatic patient population we're targeting with 2 or more exacerbations right now in the U.S. is 250,000. As I mentioned before, there are more than 30 million that have CRS without nasal polyps. So even if we're going after the most severe end of the spectrum, this is in massive prevalence population and a significant incidence population every year exceeding the size of the bronchiectatic population. So if we talk about being $5 billion in peak sales just for bronchiectasis, and we are successful in CRS, you can see where this can go. This could be a very substantial additional opportunity for us, and we'll know that answer in a couple of months.

And I also want to -- for the rest of the time, I want to talk about TPIP as well. And maybe can you talk about your -- the trials you're running and the pivotal opportunities for TPIP in multiple indications?

So TPIP is -- has advantages because it is once a day. It is a dry powder, it is able to show benefit 24 hours after administration. So you're getting benefit in these patients, not only during the daytime, but while they sleep. And so with those data that came out showing the best available pulmonary vascular resistance reduction. We had a 35.5% reduction. That's better than Sotatercept has. So this is a very significant finding, and it opens the door to the use of this drug in PAH, PH-ILD, IPF and PPF. So we are going to be running 4 different Phase III programs with this medicine, and we have advantages, not only the kind I've described, but also because we can titrate up to much higher doses. We went up to 640 micrograms in these studies.

We're going to be able to go up as high as 1,280 in the next set of studies. We're also going to be measuring 3 hours after administration as opposed to 24 hours after administration in the Phase III trial that parallels what's been studied by companies like United Therapeutics, our ambition here is to simply put forward the best-in-class medicine and we have seen such positive results to date that we are really bullish on where this could go for all 4 of these indications.

So if you think about where the company is, we have ARIKAYCE, it's about to get an expanded opportunity. We have bronchiectasis, and we're looking at CRS and HS and then IBD, RA, COPD and asthma. We look at TPIP going into PAH, PH-ILD, IPF and PPF. That's just the first 3 medicines, which have been largely derisked. This company has had a very good run in the last 18 months. But from our point of view, because of all of these programs and their probability of success, we have a lot further to go. And I think what you're looking at is the creation of the company we had in our vision, which is the next biotechnology company on par with the likes of Vertex and others.

So what kind of regulatory feedback have you received on the TPIP clinical development strategy so far?

We've talked to them only about PAH and ILD, and what's encouraging is that we're only going to have to run a single Phase III study. So that lowers the cost and hopefully the time line to accomplish this. We always say that the order is quality first, speed second and budget third in terms of our prioritization, but that served us well to date. And I think just given the promise of the data we've seen we'll be powering these studies conservatively to make sure that we show a treatment effect, but if we see something like 35.5% PVR reduction in the PAH Phase II study, and we can replicate that in Phase III, we will be clearly not only best-in-class but best in disease with that kind of performance.

Right now, there is some that models Sotatercept just in PAH at $7 billion in peak sales. Even if you take a discount to that, we're going after PH-ILD IPF and PPF. So this is a very substantial program.

And for the last 2 minutes, I also want to touch on your first product, ARIKAYCE. I mean you do have clinical readout in the frontline disease coming up. So what's your expectation for that data readout? And what's the opportunity for that?

So right now, we're going to be -- we've got guidance of $425 million to $435 million, $440 million. What is it? $420 million to $430 million. I never remember, but that's because we just raised it. So it's been a very successful year despite the launch of BRINSUPRI, shout out to Sara Bonstein, our Chief Financial Officer for knowing things I should know. But what's really interesting about this is we're about to expand that. If ENCORE works as well as ARISE did in terms of Phase III readout, which will be in the first half of next year, we're going to go from an addressable patient population between the U.S., Europe and Japan of 30,000 to 250,000. It's a very substantial expansion.

Every other company that has come along and tried to create a medicine for NTM has failed. This is a very, very difficult disease to treat and the success we've had to date should be able to put us in a strong position to target the broader market opportunity as well. Japan, just as an example, is now responsible for more than 20% -- almost 30% of our revenue, and it is a very exciting time to think that they could expand as well. because it's going to drive our revenue into '26 and beyond without competition.

And I also want to quickly touch on the gene therapy you mentioned earlier, I think it's pretty under the radar. So maybe talk about what's the next milestone we should expect from your gene therapy?

So this is part of our fourth pillar, gene therapy. We have programs in Duchenne muscular dystrophy. We're using an intrathecal delivery approach, which lowers the amount of virus you have to deliver and should improve the safety profile while also ensuring good transduction in both skeletal muscle tissue and cardiac tissue, which is what we've seen in our work to date. We've already completed the first cohort of treatment without any issue. So we're excited about that and progressing into others. We're going to be bringing forward treatment for ALS. We're looking at both SOD1 patients and sporadic patients. So there is a very substantial opportunity if ALS works.

It's a terrible disease and the ability to have an impact there would be a capstone in a career as far as I'm concerned, and the possibility that we could actually treat sporadic patients makes that a blockbuster drug, if it works. And we're hopeful that it will. Beyond that, we also have a treatment for Stargardt. So there are 3 gene therapy programs in the clinic next year, and we're excited about what those will yield. There's a lot more in our pipeline. We don't tend to talk about it as you say, but that's because we want the data to speak for itself.

Perfect. That brings to the end of our discussion. And thank you all for joining us here, and thank you for all the audience joining us in person and online.

Thank you.

Enjoy the rest of the conference.

Thank you for standing by. My name is Kayla, and I will be your conference operator today. At this time, I'd like to welcome everyone to the Insmed Third Quarter 2025 Financial Results. [Operator Instructions]

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

Thank you, Kayla. Good day, everyone, and welcome to today's conference call to discuss Insmed's Third 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. These statements represent our judgment as of today and inherently involve risks and uncertainties that may cause actual results to differ materially from the projections discussed. Please refer to our filings with the Securities and Exchange Commission for more information. Also note that our call today will include blinded observations from our ongoing Phase II study of brensocatib in CRS without nasal polyps. These observations may not be representative of results once the study is completed and all data is collected and analyzed. As a result, any future interim data readouts and the final data from this study may be materially different than the observations described today.

The information we will discuss on today's call is meant for the benefit of the investment community. It is not intended for promotional purposes and it is not sufficient for prescribing decisions.

Today's call will feature prepared comments by Will Lewis, Chair and Chief Executive Officer; Roger Adsett, Chief Operating Officer; and Sara Bonstein, Chief Financial Officer. After their comments, they will be joined by Martina Flammer, Chief Medical Officer, for the Q&A session.

I will now turn the call over to Will.

Thank you, Bryan. I'm enormously pleased to welcome all of you to Insmed's first earnings call as a company with multiple commercial products. The FDA approval of BRINSUPRI in August marked a new day for patients living with bronchiectasis and a step change in the number of patients Insmed can now serve with its medicines. Financial success is a downstream result of accomplishing the primary goal of developing first and best-in-class medicines that provide real meaningful benefits to patients.

Today's update, in my view, confirms that we have a medicine in BRINSUPRI that achieves that primary goal. While we're still early in the launch and only have a few weeks of data to steer our interpretation, the positive reception we have seen to date supports our expectations of a large commercial opportunity for BRINSUPRI.

So far, we have seen physicians who are motivated to prescribe it, patients who are eager to take it and payers that have been willing to reimburse it. Please bear in mind that today's results represent only 6 weeks of sales and include inventory stocking and other factors that make it difficult to discern the underlying dynamics in the early days of any launch. Given these considerations, it is challenging to glean much insight into the longer-term slope of the launch from this partial period.

Our first full quarter of launch, which we anticipate reporting in early 2026, will provide a clearer look at how the launch is progressing. While we are very pleased with these results, we recognize that a lot can change as the launch progresses, and we will need to continue to execute for this launch to live up to its potential.

For now, we can say that the breadth of prescribing achieved in these first 6 weeks of launch is impressive. We will continue our education efforts to build the depths to match the clear unmet medical need for this important medicine. As we have said many times, our ambition is to place BRINSUPRI in the conversation with some of the strongest respiratory launches the industry has ever seen, including DUPIXENT, Fasenra, Tezpire and Ofev. These products, on average, produced revenues in the high double-digit millions in their first 2 full quarters combined. For BRINSUPRI, that period would correspond to fourth quarter 2025 and first quarter 2026 combined.

As much excitement and attention has been rightfully placed on the U.S. launch of BRINSUPRI, it is important to remember that Insmed has three late-stage or commercial programs, each with the ability to address multiple populations. In addition, beyond these programs is a significant pipeline of earlier-stage programs that have the potential to contribute catalysts over the near and medium term.

Let's take a closer look at the commercial and clinical catalysts we are expecting from across our portfolio. As illustrated on this slide, Insmed's pipeline is poised to deliver far more catalysts over the next 18 months than it achieved in the previous 18-month period. On the commercial side, we have the continued U.S. launch and the expected future launches of brensocatib in the EU, U.K. and Japan, if approved.

In addition, we expect continued commercial execution for ARIKAYCE's current label and the anticipated label expansion to include recently diagnosed patients with NTM MAC lung disease, assuming approval for that much broader indication. Simultaneously, we expect a host of clinical drivers in that same time frame, including data readouts from the Phase II BiRCh study in CRS without nasal polyps, the Phase III ENCORE study in recently diagnosed NTM MAC lung disease, the Phase II CEDAR study in hidradenitis suppurativa and continued progress on our Phase III TPIP program, which will include pivotal Phase III trial starts in PH-ILD, PAH, PPF and IPF. We also expect to see the first of our next generation of DPP1 enter the clinic to potentially address a range of unmet medical needs for diseases with very large populations such as rheumatoid arthritis and inflammatory bowel disease.

Finally, in the next 18 months, we hope to have first looks at human data from our DMD and ALS gene therapy programs. Behind these programs is a growing and increasingly promising pipeline of first or potentially best-in-class therapies, which we expect to enter the clinic at a rate of 1 to 2 INDs per year. It is going to be a busy 2026 and 2027, and we believe we are prepared and well resourced to achieve these important milestones. Let me now take a moment to walk you through our recent regulatory and clinical progress.

Let's start with brensocatib. Earlier this month, Europe's CHMP issued a positive opinion recommending the approval of brensocatib for the treatment of non-cystic fibrosis bronchiectasis in the EU. We now expect a decision from the EMA by the end of this year, setting up a potential launch in the EU in the early part of 2026. We look forward to potentially expanding brensocatib reach to include the approximately 600,000 patients with bronchiectasis in the EU.

As with our prior launch of ARIKAYCE, we intend to launch BRINSUPRI in the EU at the same list price as the U.S. Elsewhere in the world, I'm pleased to report that our regulatory filing for brensocatib in the U.K. continues to progress on schedule, and our filing has now been accepted in Japan. We anticipate each of these filings could open up additional growth opportunities with potential approvals and launches in the U.K. in the first half and Japan in the second half of 2026.

Moving now to our clinical progress. The BiRCh trial of brensocatib in patients with CRS without nasal polyps, continues to progress on schedule for completion by the end of 2025. Depending on the time it takes to thoroughly clean and lock the data, we expect to announce the top line results for the study no later than the early part of January. As you know, our practice is to clearly define what we believe to be the bar for success ahead of any top line readout.

Currently, the only approved treatment option for CRS without nasal polyps is a nasal steroid device that showed a 0.7 placebo-adjusted improvement for the lowest approved dose on the same scale being used as the primary endpoint in BiRCh.

As a reminder, brensocatib is being studied on top of a stable course of nasal steroids, so any treatment effect shown would be additive to the standard of care. As such, we would consider a placebo-adjusted 0.7 treatment benefit, a clear win, matching what was adequate for FDA approval in the past.

BiRCh is 80% powered to show a 0.97 placebo-adjusted treatment effect, which is a larger treatment effect than what we believe would be adequate for approval. If the study were to demonstrate that level of effect for brensocatib, that would represent a home-run scenario.

Please note that BiRCh powering, I just mentioned, is based on an alpha level of 0.1. Given that this is the first study ever conducted for this mechanism in this patient population, the goal is to gather strong directional information as quickly as possible to inform our potential pursuit and design of a future Phase III program in CRS without nasal polyps.

And alpha of 0.1 is a stringent bar for a Phase II that is designed to detect early evidence of efficacy. This level of powering means that a successful outcome could generate a p-value for the primary endpoint that is higher than 0.05, presuming the magnitude of the treatment effect is meaningful, and we see consistency of improvement across multiple efficacy end points.

With nearly 30 million patients diagnosed with CRS without nasal polyps in the U.S., we will be interested in selling any subpopulations in the trial where the treatment appears to have the greatest impact. While we have no reason to believe at this time that only a subpopulation will respond, even a subset of these patients could represent a very large additional patient population for us to serve should a future Phase III program demonstrate adequate safety and efficacy results.

We continue to observe promising blended blinded data from the study with the improvement across all patients who have completed the study exceeding a 2-point change from baseline. We look forward to sharing the top line results with you after the study is completed.

Now let me provide an update on our CEDAR trial in hidradenitis suppurativa. I'm very excited to report that due to strong patient interest, the CEDAR trial is now fully enrolled. This timing is well ahead of our internal projections and exceeded the study's 204 patient enrollment target with 214 total participants randomized.

In fact, the trial completed enrollment so quickly that the final readout is now expected only weeks after our planned interim futility analysis of the first 100 patients. For this reason, we have decided to forgo the interim futility analysis, which was planned for the first quarter of 2026 and instead plan to report CEDAR's top line readout, including data from all 214 patients in the first half of 2026.

The primary endpoint in the study is the percentage reduction in abscess and nodule count, or AN count from baseline. AN count differs slightly from the commonly used high score endpoint because there is no requirement to show a stabilization or decrease in draining tunnels. While we believe that brensocatib is likely to have a positive impact on tunnels, we think that impact may take longer to manifest itself, which is why we chose and count as the primary endpoint for this 16-week study.

Let me also provide you with a clear definition of what we would consider a win for this top line readout. We view an approximately 20% placebo-adjusted reduction in AN count for either dose to be the bar for success in this trial. We believe that this magnitude of effect would be viewed as clinically meaningful and would encourage us to advance the program into Phase III. Our CEDAR trial is 95% powered to show a 40% placebo-adjusted reduction in AN count. We would consider this outcome to be a home run for this data readout.

Like the BiRCh trial, CEDAR is powered at an alpha of 0.1 so they can more quickly inform the design of a Phase III program, if warranted. As we've said before, HS is a challenging disease to treat successfully with recent clinical trial results from other programs underscoring this sentiment. However, we remain hopeful that our novel approach will yield a positive outcome for moderate to severe HS patients that we believe would welcome a safe and effective oral treatment option.

Turning now to TPIP. We continue to receive consistently positive feedback from the treating community for our Phase II data in patients with PAH. Last month, we presented the full results at the European Respiratory Society's meeting in Amsterdam, and we're pleased by the reception it received. We are now focused on conducting an expansive registrational TPIP program, which will include Phase III studies in PH-ILD, PAH, PPF and IPF.

The first of these studies is called PALM-ILD, a 344 patient trial in PH-ILD, which remains on track to open sites before the end of the year. This trial will measure the change in 6-minute walk distance at 24 weeks of treatment as the primary endpoint, and we'll take those measurements 1 to 3 hours post-administration of the most recent dose.

Measuring the primary endpoint 1 to 3 hours post-dose is the change from the approach we took in Phase II, where all efficacy measures were taken approximately 24 hours after the most recent dose. We designed the prior trials that way, so we could definitively answer the question of whether our once-daily formulation provide a benefit throughout the entire dosing interval.

Now that we have clearly established that benefit, we have chosen to design our pivotal trials more consistently with the trials of other approved prostanoid treatments, which took their measurements at peak exposures. Importantly, treatment effect on 6-minute walk distance at crop exposure or approximately 24 hours after the most recent dose will also be captured as a secondary endpoint.

I'm pleased to share that the data monitoring committee for TPIP convened earlier this month and reviewed unblinded data from Phase II programs and the open-label extension studies for PAH and PH-ILD. Not only did they recommend that the OLE studies continue unmodified, but they also strongly encouraged us to move into Phase III based on their review of the data.

Additionally, we recently completed our end of Phase II meeting with the FDA and align with the agency on the data package that will be required to support a regulatory submission for TPIP and PAH. Based on the outcome of that meeting, we plan to conduct a single Phase III study in patients with PAH with the primary endpoint of 6-minute walk measured at an alpha level of 0.05.

If successful and as discussed at the end of Phase II meeting, we will submit an NDA that will include the Phase III data, along with our Phase II trial data as confirmatory evidence. We expect to initiate the single Phase III trial of TPIP in patients with PAH in the early part of 2026.

We have also begun ramping up our manufacturing of TPIP to adequately source the additional supply needs of the Phase III studies in PPF and IPS. Given those supply requirements and the need to align with the FDA on trial design, we anticipate initiating the registrational trials in PPF and IPF as soon as possible, but likely in the second half of 2026.

When you add potential Phase III starts for brensocatib in CRS without nasal polyps and HS pending positive Phase II results we may be kicking off as many as six new Phase III programs requiring up to almost a dozen Phase III clinical trials in just the next 12 months alone.

Now let's touch on ARIKAYCE. Even with an enormous amount of activity happening at the company, ARIKAYCE has continued to perform. Not only did ARIKAYCE posted another strong quarter of year-over-year revenue growth, but the Phase III ENCORE trial continues to progress on schedule towards its readout. If successful, ENCORE could expand the label for ARIKAYCE to include all patients with the MAC lung infection, increasing the addressable patient population in the U.S. from around 15,000 today to more than 100,000.

The number of patients who could be served by this medicine in Japan would be even larger, resulting in more than 25 million patients worldwide. As a result, we believe success in ENCORE could lead to ARIKAYCE becoming a blockbuster product.

Recall that in our first Phase III study in this patient population, ARISE, patients treated with ARIKAYCE showed faster, greater and more durable effects on culture conversion compared to the active control. In fact, about 80% of patients in the ARIKAYCE arm achieved and maintained a negative sputum culture at month 7, which was 1 month off treatment compared to 47% of patients in the control arm.

These results emphasize the benefits of treating earlier with ARIKAYCE, given that in our Phase III refractory trial convert about 1/3 of patients converted by month 6. And on a much more challenging endpoint of durable culture conversion after 3 months off treatment, 16% of patients in the ARIKAYCE arm were able to show durable culture conversion compared to 0 of the patients in the control arm. ARISE also validated a patient-reported outcome tool while showing encouraging directional benefits on that measure.

The ENCORE trial was recruited at the same time and for many of the same sites as the ARISE trial and the patient demographics look very similar between the studies. So we remain cautiously optimistic that the trial results will also be similarly positive. As a reminder, a primary endpoint of culture conversion will be used in Japan, while the PRO will be the primary endpoint in the U.S. We look forward to turning over this data card in the first half of 2026.

Moving on to our early-stage pipeline. The Phase I ASCEND trial of our gene therapy for DMD has completed dosing of its first cohort of three patients. While early, no concerning safety signals have been observed to date, which is encouraging.

We believe this may reflect the benefit of our intrathecal delivery approach, which was designed to avoid passing through the liver prior to getting to the skeletal muscle and cardiac tissues where it is needed. We look forward to expanding the ASCEND trial to include a cohort of younger patients and a cohort testing a higher dose in patients of the same age as the first group.

Our second gene therapy program for the treatment of patients with ALS is also making strong progress. The IND for the treatment recently was cleared to move forward into the clinic, so we are now preparing for the start of a Phase I trial.

Like our DMD therapy, this treatment will be administered intrathecally. We are particularly excited for this program because we will be studying it in both SOD1 and the much larger population of sporadic patients based on strong data generated preclinically for models for both populations.

In addition to our gene therapies, we continue to advance our next-generation DPP1 candidates were the first expected to enter the clinic in 2026. These novel next-gen molecules will be used to pursue indications in very large patient populations where there still exists significant unmet need. We'll begin by introducing INS1033 in simultaneous studies in rheumatoid arthritis and inflammatory bowel disease, followed by other novel DPP1 in COPD and possibly many other indications. We look forward to sharing more details as these programs progress.

Before I pass the call over to my colleagues, I want to reiterate that we are just at the start of this wave of commercial and clinical readouts trial initiations and research translation into the clinic. As gratified as we are by our recent achievements, we are even more enthusiastic about Insmed's future.

Over the next 18 months, we will be focused on executing on the many opportunities we have just reviewed. This is a very exciting time for Insmed as the many years of planning are finally yielding the results for which we had all hoped. This presents us with the opportunity to further realize our mission of bringing these promising first or best-in-class medicines to patients with serious diseases.

Finally, I must mention that for the fifth year in a row, we were awarded the distinction of the #1 ranking on Science Magazine's Top Employers list. The only other organization to achieve this in the 20-year history of the survey was Genentech, which puts us in rare company. We are extremely proud of this accomplishment, which punctuates the preservation and success of our culture despite our rapid growth.

Let me now turn the call over to Roger, who will walk us through the recent launch performance of BRINSUPRI in the U.S. and the third quarter's commercial performance of ARIKAYCE.

Thank you, Will. I'm delighted to provide some detail on BRINSUPRI's performance. In its first partial quarter of launch, BRINSUPRI achieved $28 million in net sales. We are very pleased by the strength of BRINSUPRI launch in these early days and the reception it has received from the treating and patient communities.

As of the end of September, approximately 2,550 new patients had started treatment with BRINSUPRI and about 1,700 physicians had written at least one script including physicians in academic centers as well as many in the community setting. Most of these prescribers through September have written just one or two scripts in total. This pattern is consistent with the common practice of trying out a new medicine by prescribing it to a small number of more severe patients and then waiting to see how those patients do on the treatment before expanding the medicine's usage.

Remember that it can take 4 to 6 weeks for BRINSUPRI to reach its full pharmacodynamic effect and potentially much longer than that for patients and physicians to notice this effects. So those physicians who are testing their medicine in a few patients may need time to determine whether they will expand their prescribing habits.

Overall, I would describe the early days of the launch is seeing very broad prescribing in terms of the number of physicians. If we also see deeper prescribing patterns where physicians move to the adoption phase and begin prescribing BRINSUPRI to larger percentages of the patients both at centers of excellence and in the community, we should see the launch accelerate. But of course, it's too early to know if or when that will happen.

This is why we feel BRINSUPRI's first full quarter Q4 and will provide us far greater insight. The medicine specific inclusion in electronic medical records for selection of prescribing and prior authorization criteria at insurance companies getting more standardized should together enable the wide range of physicians an easier path for prescribing. This is particularly true at the centers of excellence where large numbers of patients are treated and back office logistics can limit the number of new prescriptions processed each week. None of this comes as a surprise to us, and we believe we have extensive compliance support systems to assist where we can.

Additionally, just last week, we saw an update on U.S. guidelines for the treatment of patients with non-CF bronchiectasis at the CHEST conference in Chicago. We are encouraged that BRINSUPRI has been included in the preliminary CHEST guidelines, and we look forward to the forthcoming publication.

We hope that these guidelines, once published, will help physicians to make treatment decisions that are best for their patients while providing supportive guidance of best medical practice to payers in setting their prior authorization criteria.

On the market access side, the early days of the launch have also been encouraging. Due to BRINSUPRI being the only approved therapy for this condition, broad patient access has been achieved from day 1 as we expected. Even without formal contracts in place, the vast majority of prescriptions have been approved for coverage, both on the Medicare and the commercial side of the business. However, there is still plenty of work to be done. We continue to engage with payers in both the national and regional level to establish simple and convenient prior authorization and reauthorization requirements that can allow access to BRINSUPRI that is as frictionless as possible.

These discussions are still ongoing, and we will need more time before we have a good sense as to where contracting and access requirements will shake out. As it is common to see some slowdown, once criteria are firmly established and enforced it is important to interpret this quarter's relative ease of access within that context.

When assessing the revenue and patient figures achieved this quarter, it's important to recognize that these sales numbers benefited from a couple of factors. Firstly, based on our prior experience with ARIKAYCE, we had said it could take up to a month from the time of FDA approval for the first sales to be recorded. In the case of BRINSUPRI, we accomplish this in less than half that time, which is a testament to the readiness of our commercial and technical operations teams. This meant that the third quarter reflected about 6 weeks of revenue and patient starts rather than the 2 or 3 weeks we have previously expected.

Secondly, these results reflect the impact of necessary inventory stock in the channel, which accounted for approximately 40% of BRINSUPRI revenue this quarter. Importantly, our specialty pharmacies can get BRINSUPRI within 24 hours of placing an order and aim to hold only a limited number of weeks of supply on hand at any given time. As a result, we do not anticipate a significant contribution from inventory stocking in the fourth quarter.

In summary, the early days of the launch have left us feeling excited about the future possibilities for this new medicine. There is plenty of work ahead to ensure that in super is successful in the way that we hope and believe it can be. We are wholly committed to working tirelessly toward that goal.

Now let me provide some commentary on ARIKAYCE's performance in the third quarter. We continue to be extremely pleased by the strength of the brand even as we approach the end of its seventh year on the market. This quarter, ARIKAYCE once again posted its largest quarter of revenue ever up 22% compared to the same quarter last year. This result was driven by double-digit growth in each of our geographic regions. In the U.S., despite the significant attention that has been placed on BRINSUPRI's launch, ARIKAYCE grew 11% compared to last year, demonstrating our commercial team's ability to execute with excellence on multiple products at once.

Outside the U.S., we saw a continuation of the impressive growth we've seen for several quarters now. With our international business comprised of Japan and Europe, setting a new all-time high and growing more than 50% compared to the same quarter last year. We are proud of the dedicated work of our commercial teams across the globe to bring this medicine to ever more patients who need it.

So with that, let me turn the call over to Sara.

Thank you, Roger, and good morning, everyone. On the heels of Rogers commercial review of our two approved products. I am pleased to report that we are raising our 2025 full year global ARIKAYCE net revenue guidance to $420 million to $430 million, up from a range of $405 million to $425 million previously. As a reminder, this guidance range is specific to ARIKAYCE only.

The updated guidance range demonstrates the team's ability to execute across multiple products as well as reflects the excellent execution of our commercial teams around the globe. Now representing a 15% to 18% increase over full year 2024 ARIKAYCE revenues.

Now let me spend a moment on our cash position. At approximately $1.7 billion in cash, cash equivalents and marketable securities as of the end of the quarter. I believe Insmed continues to be well capitalized. Excluding cash received related to option exercises, our underlying cash burn for the quarter was relatively consistent with the underlying burn levels that we have seen for the past several quarters.

Keep in mind that only a portion of the BRINSUPRI revenue we recognized this quarter have been received in cash as of September 30. So our cash burn does not yet reflect that full benefit.

As we have said before, we expect both revenue and spending to continue to increase as we fully resource and support BRINSUPRI's launch as well as the other portfolio programs expected to initiate in the near term. We are pleased to be entering this exciting period in a strong cash position.

Moving now to the other relevant financial metrics for the third quarter, which are shown here on the slide. Cost of product revenues in the third quarter of 2025 was $29.4 million or 20.6% of revenues, which is lower on a percentage basis than our historical performance, reflecting the positive contribution of BRINSUPRI to the company's gross margin profile.

Additionally, as expected, research and development and SG&A expenses increased this quarter compared to the prior year period. due to the necessary investment made to support the U.S. launch of BRINSUPRI and to continue to fund our growing pipeline.

In closing, we have so much to look forward to. The remarkable string of clinical and commercial successes we have experienced in the past 18 months have provided us with new opportunities to serve patients in need, whether that be with the launch of a new product to hopefully change the lives of patients or the initiation of new Phase III programs, which can provide hope to patients waiting for new treatment options. Insmed remains in a uniquely strong financial position from which to execute on each of these opportunities.

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

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

Congrats on the launch. I was curious if you could talk a little bit about some of just the early feedback you're hearing from the field about the physician experience with BRINSUPRI? Both in terms of how they feel like their patients are doing kind of speaking to that phenomenon where they might try it in a few first and then go from there, but also their experience with the reimbursement process.

Yes. So I'll just make a quick general comment and then turn it over to Roger.

I think the word from the field net-net is positive. We've attended both European Respiratory Society, but more relevantly, CHEST recently, where we had the opportunity to interact with a lot of physicians. And I would say to a person that I encountered there's nothing but enthusiasm out there for this, and its potential. And I've heard anecdotes that are supportive of the statements that Roger made related to market access.

But Roger, I wonder any other thoughts you might want to add?

Yes. Thanks, Will. No, I think the sentiment is, as we described, quite positive. I think that the broad prescribing base that we've seen so far reflects some enthusiasm for these physicians to at least try with their more severe patients who are in the office and need that attention. And so as we talked about that, they're in that trial phase and hopefully, we'll move into an adoption phase.

And it's still early days, right? So I think as we talked about the pharmacodynamic effect of BRINSUPRI and the way that it works, it could take a little while for that response, and we're hoping that the positive feedback that comes from patients to the physicians, once they feel that impact, hopefully, less coughing, et cetera, will encourage additional prescribing.

On the market access side, I think what we're hearing is actually some positive sentiment there. It's been quite straightforward to get for most patients to get this through from a payer perspective. It's not uncommon for that to happen in the early days of launch as we talked about. The payers haven't yet finalized their criteria. Medicare has to review this within a certain time period. And so we expect that patients are experiencing that a little bit of a honeymoon period from the first approvals.

As payers start to finalize their criteria and as they start to enforce that criteria, while the physicians and their back office staff adjusted that, and we can help them with what that criteria looks like in a compliant manner. It may slow down just a little bit. But we expect that given that profile is the only approved product in the category into the disease state that we can achieve our goal of having frictionless access for patients and physicians going forward. And that's what we continue to work towards.

And let me just say, I want everyone to take away from this call. We feel great about where we are with the launch, but we're just incredibly cautious because we only have 6 weeks of data to work off of. And it's very difficult to extrapolate that because there are lots of puts and takes in these data in this short period of time.

We really feel like we need the fourth quarter to know what the directions are that are being established in both physician treatment across the spectrum of community to centers of excellence. So sort of encouraging, but let's hold off on reading too much into this until we've got a full quarter under our belt.

And your next question comes from the line of Ritu Baral with Cowen.

Roger, well, you guys have been really good at sort of setting thresholds and bars for success across data, et cetera.

What threshold do you see for that payer coverage that we should keep in mind going forward? Are you going to set a bogey for us going forward and they covered lives or time to fill. We've had great feedback on so far, but to your point of early coverage. Also, what criteria are you aiming for, for that final threshold for prior ops and the reauthorizations, Will, that you mentioned?

I'll make the general comment that our objectives with market access are to accomplish what we described as a frictionless launch. What that looks like is in the practical setting, is that the criteria for approval are clear and well established and are not overly burdensome to physicians.

These are patients who have two or more exacerbations and have a confirmed diagnosis of bronchiectasis. And we think it's appropriate for physicians to be able to attest to that without necessarily providing all of the backup documentation for that kind of a diagnosis. If it's required to do all of that, then so be it. But we would prefer that, that not be the case. And we're willing to do some modest discounting out of the gate to try to accomplish that set of criteria and to make it easy for physicians and back office and also for the process of reauthorization. And I think so far, we're making very good progress on that front.

I don't know, Roger, if you want to add anything to that?

I think you captured it well, Will. I think the only thing I would add is that as we look to get this criteria established and that's really our goal, and we've been as you know, pre-approval, we've been engaging with payers representing about 90% of our targeted lives.

And we -- at both the national and the regional level. And what our goal is, as Will described it, to get -- to make this as easy as possible for patients to get the product and easy on the back office of physicians as they're tax with all the usual paperwork that they have to go through across a variety of medicines.

Our goal is not necessarily a formulary addition. So we don't really have targets for that. Our goal is to get that criteria clear and as easy as possible for the physicians, as Will described, and we continue to work towards that.

And your next question comes from the line of Joseph Schwartz with Leerink Partners.

Hats off to such strong execution so far. So I guess how frictionless has the launch been to date in your view based on the amount of documentation physicians have had to provide to payers? Do you have any early reads on how this dynamic has been playing out so far?

Well, I think what we would say is that, so far, so good. There is actually a mix of what has been required in terms of the medical exception process. And in some cases, it has been necessary for physicians to provide both the documentation of CT scan with a positive diagnosis and documentation of the exacerbations.

And in those cases, what we've heard from physicians is it's not that bad or onerous to do that. We're just trying to make it easier for them through some potential modest discounting there's not a ton of room to be able to do that. I mean if we look at benchmarks for what Sara has commented on in terms of -- it's not guidance, but it's what you would see in early launch of a product of this profile fully half of that discount is attributed to our contribution needed under IRA. So it doesn't leave a huge amount to offer in terms of discount, but we're doing what we can to try to make this process easier for the physicians in the back office, as Roger described it. And I think, so far, so good.

But time will tell. And all I would say is that whether we need to provide all of that documentation or none of it that will be something we determine in the coming months. But either way, we're going to be able to ensure that we can support compliantly the efforts to gain access to this medicine for patients.

And I think this is one point that's really in our favor. This is a great medicine. This has a low AE profile from its Phase III data as published in the New England Journal of Medicine. Its efficacy is clear. It's across multiple end points. highly statistically significant. And this is easy to take with a low burden on patients. So it really suggests itself both by its ease of use and by its potential for these patients in terms of them getting better. So for all those reasons, I think market access should continue to be something that we're able to navigate.

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

Congrats on the great progress. Will, I was hoping you could provide some additional color on some of the softer dynamics about the patient journey for BRINSUPRI's launch. How has the DTC impacted awareness? Are you seeing more sort of interest from the patient side of things, more from the prescriber side of things? As they inquire about treatment for their disease.

Thanks for the question. Look, it's always hard to discern the qualitative side of the launch from both the physician and patient side.

What I can tell you is that there is clear enthusiasm from the patient side of the equation. One of the most gratifying things to us when we got a product in the channel and patients were getting their first prescriptions filled is that they were posting images of themselves holding the bottle on social media. That's about as good as it gets in terms of patients' enthusiasm for the arrival of a medicine that can make a difference in their lives, and that is what we're all about at Insmed.

I think the physicians are also similarly well aware of the arrival of the medicine by virtue of all the excellent work that our commercial team has done. But the practical application of the awareness of the medicine to a patient population is where the rubber meets the road, and it's too early in these early weeks to discern what that pattern of behavior is going to look like. And I think that's what Roger was commenting on in his prepared statements in describing trial use of the medicine and then a broader adoption phase and depth of prescribing. And that's what we're really going to be looking for in Q4 and indeed in 2026 to ensure that this launch continues to go the way we hope it does.

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

Just as you look to launch in Europe in early next year, what types of investments are needed to prepare for commercialization, maybe particularly with respect to your sales force infrastructure. And then, Sara, I was just wondering if you might be willing to share what your gross to net adjustment looked like for BRINSUPRI in the quarter?

Sure. I think thematically, our strategy in Europe is to sort of ensure that the reimbursement ends up the way we need it. to end up before we start doing significant additional investments. We've done some in preparation, obviously.

And in Japan, we have expanded our sales force already by virtue of the opportunities for ARIKAYCE, which has proven to be a very wise decision, and I think prepares us for the launch of BRINSUPRI if and when that receives approval, which we expect in the second half of next year. At that time, we would also consider expanding even more in Japan.

But I don't know, Sara, perhaps you want to comment in greater detail on that on the margin question.

Sure. Happy to. Thanks, Andrea, for the question. So on the margin question, we're not providing quarter-to-quarter BRINSUPRI gross to net. What I can say, obviously, most folks are where off the bat of any launch, you see a little bit of flexibility lumpiness in your gross to net, while not formal guidance, as Will mentioned earlier, we did provide sort of those analogs of 25% to 35% at launch, when you take in the half of that is the IRA impact and then sort of normal standard contracting for an at-launch product, and we remain to say those are still reasonable analogs. As you're thinking about investment, as Will said, will be a little bit more cautious in Europe as we're thinking through sort of the reimbursement piece there.

And your next question comes from the line of Vamil Divan with Guggenheim Securities.

Great progress. Obviously with BRINSUPRI, I wanted to actually ask about TPIP, which we're also very excited about. I'm curious -- at it all is on the Phase III design. As you're thinking about it for the IPF and PPF trials. And specifically, we've been getting questions from [indiscernible] your potential -- new potentially need to overcome orphan drug exclusivity in that space, given the progress United Therapeutics is showing. I'm just curious if maybe you can comment on how you would need to design that program to ensure your ability to launch it?

Sure. Well, as you are well aware, there are a number of ways to overcome the orphan designation, which would be over in a second. But I think it's still early for IPF and PPF. We are ramping up our production. We certainly intend to go into Phase III, and it is our strong belief that it will not be a too high a hurdle for us to overcome the orphan designation.

But I wonder, Martina, if you want to just walk in a little bit more detail where we are in our thoughts about that.

Yes. So on IPF and PPF, I mean, as you know, TETON was a clear win for patients. And we will take the TETON study and what we've learned from that in how we -- how it informs our design. What we've taken away is also -- and you've seen that in the TETON study that the dosing, it has a big impact. And I think our ability to dose and titrate the dose up to a need optimally for the patient. So it's an individual dosing exercise gives us certainly an advantage.

And otherwise, I think you look at what TETON has shown that gives you a very good road map of how we think about IPF and PPF. And when you -- especially when you think about orphan, I know that was one of your questions, if you are intending to be better than on currently existing orphan designation, exclusivity, you have the ability to show you superiority in terms of efficacy, safety or an impact on patient care, one or more of them.

We have the opportunity to do that from an efficacy perspective, you've seen our strong results in PAH from a trial impact perspective, but also how we are able to provide maybe a once-daily dosing, this is not only important from a tolerability perspective, but it is also an impact on how patients are able to actually stay on treatment and to increase the dose on the treatment. So both on efficacy, safety and potential impact on patient care are opportunities for us to show how good TPIP can be in this indication.

And your next question comes from the line of Gavin Clark-Gartner with Evercore ISI.

Congrats on a really fantastic quarter. I just wanted to ask a couple of questions on BiRCh really quickly. What's your expectation for the control arm TSS reduction from baseline?

And then just on the baseline characteristics of the trial, what's the baseline TSS score? And how many patients are above or below 300 for the eosinophil fill cutoff?

Martina, do you want to take that?

Yes. So with regards to what our placebo background rate or placebo assumptions are. So we get some indication from other trials that have been done, the reopen trial, which was on with the Optinose exhale device, which is based on a steroid treatment then also we're looking at trials like the ORION trial that was done with DUPIXENT.

But I do want to keep in mind for all of you that we are conducting our BiRCh trial on top of a steroid. So patients are already 4 weeks on a stable steroid therapy, and patients come into the trial with baseline score of the sTSS or the final total symptom score of 5 or above. And we're looking at that at screening as well as baseline sort of randomization.

We look also at the last 7 days of this score. So we are taking the 7-day average of the sTSS and look for above 5. Just so you know, the most severe is 9.

And your second question was about what do we see with eosinophils at baseline. So we enrolled both for the low and above 300 eosinophils, and we're looking what will be -- irregardless of where patients are our ITT analysis will be based on the entire population. So both for patients above and below 300 will be the assessment for the primary endpoint.

And your next question comes from the line of Clara Dong with Jefferies.

Congrats on the great quarter. Really great to see BRINSUPRI your launch of a real good start.

So just for BRINSUPRI, are you anticipating any seasonality effect for the patient flow in fourth quarter and beyond such as weather-related factors or availability of diagnostic procedures like CT scans during the holiday season?

Roger or Martina, do you want to take that?

So maybe I can just comment on generally, seasonality is always something that you see in it could be a trigger of exacerbations. We've not seen really a significant limitation on patients being able to access CT scans. I mean, over the holidays, patients usually don't seek out unless they are in an acute situation, their physicians, but it has not been a limitation as far as we know at this point.

And maybe I can just share some color from -- as we think about it from a commercial perspective, I think obviously, with the holidays, sometimes you see a little slowdown from physicians seeing patients. But I think probably what we're watching more closely is as we go into 2026 and we think about the reset from a Medicare perspective and the co-pays that will be required for the deductibles, we'll keep a close eye on that as well as any kind of reauthorization criteria.

So that's -- again, I don't know what's going to happen there, but we'll continue to monitor that and see what impact we have going forward.

And your next question comes from the line of Ash Verma with UBS.

Congrats on this strong quarter. So just on the BiRCh study, do you have this data in-house already just realizing that the primary completion was also August and I think you mentioned that it will come in early Jan, depending on how much time it takes to clean and process. But as of today, do you have this in-house?

So I know that we're moving as quickly as we can to process the data and lock the database and do all the necessary cleaning in order to accomplish that. I don't know, Martina, if you can give any more color on it than that.

Certainly, our time line is as soon as we can get it, but it may just end up making more sense for this to be coordinated in the early part of January, versus trying to blow up people's holidays and have it put out between something like Christmas and New Year's, which I don't think would serve anyone's interest. But Martina, any commentary?

Yes. So for BiRCh, like many of our studies, we tend to get data in-house almost in real time. The last patients are still just completing the study. So there is still some data that is coming in, but the vast majority is in the cleaning process.

And as you know, we've done this also in ASPEN or also in TPIP. When we look at the database close when we look at how we clean the data, we do this from a perspective so that it meets the highest regulatory standards, and it will always then put us in a position to also demonstrate that these are supporting evidence. And that's why we're taking our time to ensure that we have the highest regulatory standards with database lock as well as with the cleaning of the data.

And your next question comes from the line of Ben Burnett with Wells Fargo.

And congrats on the quarter so far. Just on BRINSUPRI, I appreciate that it sounds like some of the early use of this has been with severe patients. some of the early adopters. But I guess what's been like the feedback among physicians and sort of the appetite among physicians to use this in maybe more moderate patients or even patients with only one recent sort of exacerbation?

Well, I think it's still early days with the medicine. We can start with the parameters that we know, beginning with the label, which is, as you know, quite broad, I think from our point of view, we've heard from physicians, and we try to stay in close dialogue with them that they feel that the most obvious patient that's a candidate for this would map the entry criteria of the ASPEN study.

So two or more exacerbations in the last 12 months. And that's really where their early efforts have been focused and I would call that a moderate to severe patient profile. And I think that's certainly the sweet spot for the medicine out of the gate.

We'll learn more about other populations that may be appropriate. Those could include patients who are a little bit more moderate than what was described. But I think just to work clear, our focus with the market access world has been on two or more exacerbations to match the entry criteria of our Phase III program. We'll see what physicians want and where they want to take it.

I also think that it's interesting for us to consider as time goes on, the opportunity to get to the COPD and asthma comorbid patients who may either have been misdiagnosed and have bronchiectasis or are comorbid with those indications. Remembering that in Phase III in our ASPEN study, there were about 15% to 20% of the patients who are actually comorbid with either asthma or COPD and bronchiectasis and they were all responsive to treatment.

So there's a big opportunity out there for sure. One step at a time. And as physicians learn their way with this medicine and see the patient response to it, I think that will shape this as much as anything.

And your next question comes from the line of Leonid Timashev with RBC Capital Markets.

I wanted to ask on CRS. And you guys mentioned subgroups that you may be looking at. I just wonder if you could speak a little bit more about which subgroups you might be considering diving deeper into beyond maybe just being the eosinophil counts and whether that's driven by your thoughts around the commercial opportunity given that CRS is a much larger population than pharmacy ectasis or whether it's driven by trying to maximize clinical benefit in some of these populations?

Yes, I think the short answer to that question is we don't know yet. There isn't a lot of background in CRS without nasal polyps generally in terms of subsegmenting the population.

The overall population is in excess of 30 million patients in the U.S. And this study is designed to look for signals and directional groups that might benefit from it. It could be that we see benefit as we did with ASPEN across all etiologies that gave rise to the bronchiectasis.

In this case, for CRS without nasal polyps, there may be all patients benefit. It may be just a subpopulation. We don't really have any theories about which group might be responsive in that way. And I want to be really clear, we're not suggesting based on anything we've seen that it will only be subpopulations, we just want to highlight that if it is a subpopulation still could be a very substantial opportunity given the enormity of patients with this condition. So we're going to follow the science. We're going to see what the data shows us, and we'll certainly share that -- those conclusions as we move forward.

Eosinophil count is an interesting one because we theorize that, that could be relevant. But once we looked at the ASPEN data, it became clear that it was not going to be controlling on the performance of the medicine in these patient populations. And so we consolidated that stratification we'll still be examining it in the study, but it's no longer in our judgment required out of the gate to separate patient populations with regard to the primary endpoint.

So it's an example of the kind of learning we're going to do as we go. And as I said, we'll follow the science and see where the medicine is of greatest benefit, and that's where you can expect us to concentrate our efforts should the data be strong enough to take us into Phase III.

And your next question comes from the line of Olivia Brayer with Cantor Fitzgerald.

On brenso's EU list price, can you just comment on the decision to keep that the same in Europe versus the U.S.? What's been the feedback from payers on the price point?

And is there anything that you can tell us at this point just around how gross to net discounts in Europe might look versus those in the U.S.? And then just quickly on the prescriber mix in the U.S., what proportion of those initial 1,700 writers or from an academic versus community settings? And how does that compare to the overall mix in the broader bronchiectasis market?

So thanks for the questions. The prescriber breadth, I think, is a point that we've called out as something of strength because it indicates that we're getting access to -- with that number of prescribers obviously are gaining access to both centers of excellence, which we fully expected, but also much more broadly in the community, which was a deliberate focus of our calling effort.

So we're excited to see that breadth of prescribing. We now need to see those physicians and more like them go deeper with multiple prescriptions written for patients and that will become clear in the coming quarters. Whether or not that's happening in which way. But there's nothing we can discern at this moment other than the engagement from physicians has been very broad.

With regard to the EU list price, it's our practice as we did with ARIKAYCE to match the list price in the U.S. with Europe and Japan. They all are often negotiations that take place in the gross to net discussions with payers that can impact the ultimate net price paid quite substantially in some cases, but we have less control over that.

What we want to make clear is that we think this medicine has value for patients. We think the price we've selected is the appropriate one, and we look forward to the discussions with the different reimbursement authorities to determine what the ultimate net price will be.

And your next question comes from the line of Stephen Willey with Stifel.

Congrats on execution. Just a TPIP question. So should we assume that the single Phase III PAH trial that you reached alignment on with FDA will be looking at a patient population that's similar to the Phase II?

And then also curious if there was any feedback around kind of what a label might be able to claim and how you may be thinking about additional studies to potentially support utilization of TPIP across a broader spectrum of functional class patients?

Appreciate the question. I'll ask Martina to comment in a minute.

What I would just say is that our perspective on this medicine because of our ability to titrate higher, because of our ability to deliver once a day and its formulation is a dry powder we have really the high ground with regard to patient potential impact and convenience, and that is a very important driver in this population.

But what is most remarkable to me was that we were able to see a 35.5% PVR reduction, which, to the best of our knowledge, the very best score ever achieved for any medicine in any clinical study in PAH. We keep looking for something better. We haven't seen it. Sotatercept, I think, came in around 33 or 35, so we edged that out, and it's a different kind of medicine, obviously, and it's not an apples-to-apples comparison, but using that metric as an anchor point, we can see that TPIP really has quite a bit to offer these patients.

Where we go from here will be determined by the strength of the Phase III data for sure in terms of label. But Martina, perhaps over to you for some commentary on our TPIP drug.

Yes. So for PAH, as you know, it is our practice that we try to keep our Phase III studies consistent with what we've seen in our Phase II studies. And that is what we are looking to do also in this particular study.

What we have now seen in between this in the OLE program that we were able to titrate patients up to a higher dose. In the Phase II study, we did not have the dose up to 1,280 micrograms. And in the Phase III study, the plan is to allow titration up to 1,280 the maximum tolerated dose on the individual level. And that is something which will likely be a change, but we're doing this also based on the experience and what we have seen from both the safety side in the open-label extension study already. But otherwise, you can expect some consistency over from the Phase II study.

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

Congrats on all the infection at pipeline and commercially. Do you have any sense yet on what dose is getting preference for prescription of BRINSUPRI? Is the 25 mg potential loan function benefit resonating with physicians to go with that and may help some of the kind of feedback loop you talked about earlier?

Roger, do you want to take that?

Yes, sure. So right now, we're seeing the majority of the prescriptions coming in for the 25 milligrams, but we are seeing that some of the physicians are choosing to start with a 10. So we do think that the lung function is resonating, particularly with the thought leader community. But as it's not atypical with new medicines, some physicians start to choose to start low, and they may be increasing their dose as they go forward and move into that adoption phase as they get more experience with the medicine.

And your next question comes from Maxwell Skor with Morgan Stanley.

Congratulations on a very strong quarter. So I appreciate that we're still early in the launch, but how would you characterize BRINSUPRI's performance to date relative to the launch analogs you provided?

And how is this stacking up to expectations for the next 2 full quarters and then the following 4 quarters, I believe that you've provided some guidance towards?

Yes. So to be clear, we haven't provided formal guidance of any kind. We've only tried to put out benchmarks for what good looks like in our industry with regard to launches that are in or around the respiratory space. And using those analogs, which we've mentioned a number of times, we take note that the first 2 full quarters combined usually end up in the high double-digit millions and those products that have accomplished that represents some of the strongest launches that you can find in the commercial setting.

So those are our ambitions. It's certainly not something we're providing guidance on today, and we're cautious about interpreting the first 6 weeks of data that we have because it really is not a lot, and there's a lot of sorting out going on at this stage as different physicians are taking different approaches to the medicine that the market access is getting sorted out.

And while that, as Roger said, can be easier at the start once the criteria gets established and in force that can change that dynamic. So I would say we're very pleased with the breadth of prescribing. We now want to see the depth of prescribing take hold as we move into the adoption phase. That will take several quarters in my mind. But we'll be looking very carefully at Q4, and we should have enough data in Q4 to really begin to discern some of these issues and be much more specifically responsive to your question.

I just -- at this point, I think we're just cautious about over-interpreting what is a quarter that includes inventory build. It includes first trials. It includes certainly some patients who are waiting for day 1 for the medicine to arrive and some physicians looking to prescribe it right away. But as that dissipates, what is the real landscape look like. And that's something we're going to have to learn over time.

Your next question comes from the line of Graig Suvannavejh with Mizuho.

This is Sam on for Graig. Congrats on the awesome launch. Maybe just a follow-up with Ben's question on the more mild to moderate population for BRINSUPRI. I know it's still early days, but curious have you seen any payers start to restrict use to patients who have less than two more pulmonary exacerbations?

So I want to be clear, the focus is on those with two or more out of the gate. That's really where we think the medicine is going to be quite obviously, the most successful because you'll higher exacerbations, the better the chance to show the reduction in those events. But it's equally important for everyone to appreciate that these other secondary endpoints where we were highly statistically significant in Phase III in the 10 and 25-milligram arms are really quite relevant. That is how long before your next exacerbation, the probability that you may have no exacerbations in the next year.

These kinds of metrics, which were favorable to BRINSUPRI, I think also bear on the consideration of the physicians when they're trying to disc who they're going to prescribe this for. But to be clear, out of the gate, I think it's appropriate, the focus is squarely on those with two or more exacerbations.

I don't know, Roger, if you want to comment or anything you've heard from the field on those with less than two.

No, I think that, that characterizes it will. And we do see the patients who are exacerbating the ones that are in front of the physicians. And I do think that as we go forward and that criteria from pairs gets formalized they're going to be looking to mimic the clinical trial and what we saw with ASPEN with that two or more exacerbations.

So the focus really has not been on sort of the patients who don't have those recorded exacerbations at this point. The enthusiasm from physicians for those patients who have been waiting for this is those patients who are frequent exacerbators. And that's what we primarily believe is going through at this point.

And your next question comes from the line of Andy Chen with Wolfe Research.

Brandon, on for Andy. On HS, will you be sharing HiSCR data at the top line readout? And how do you imagine brenso fitting into the HS landscape?

So I'm sorry, I'm not sure I caught the first part of the question. Will we be sharing what?

HiSCR data.

The HiSCR data. So Martina, you want to describe the different secondary end points we're going to be looking at?

Yes. So the HiSCR, we will look at the secondary endpoint of the HiSCR 50 as well as for a HiSCR 75. And right now, we anticipate that would not necessarily be something that you see right away at the week 16. You will see some 16-week treatment period, but what that really should indicate for us is we will go on to 52 weeks, and it's the HiSCR at 52 weeks both for 50 and 75 that we will be also looking at for Phase III. But you will see it at the top line results, the 16-week treatment period.

And there are no further questions at this time. This does conclude today's conference call, and you may now disconnect.

I'm [indiscernible], biotech analyst with Morgan Stanley, and I am honored to have Will Lewis here, CEO of Insmed. Before we get started though, I have to read some brief disclosures. For important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. So with that, I'd like to just congratulate you and the Insmed team. What's been an exceptional year so far. You secured FDA approval for BRINSUPRI, delivered impressive TPIP data and are building strong momentum going into year-end. With that, I'll open up the floor if you have any opening remarks.

Well, I'll just say, I echo your commentary, I think we have had an extraordinary really last 18 months as we've seen our market value grow from roughly $3 billion to the current $30 billion and that value creation is all centered around 3 main franchises is the way I would refer to them. One is ARIKAYCE, the approved drug for the treatment of refractory MAC lung disease. The second is brensocatib, now known as BRINSUPRI, for the treatment of bronchiectasis and the third is TPIP, which is for the treatment of pulmonary hypertension. Each of these can go after more than one indication and that creates a diversified 3 product or as we like to say, 3 for 3 profile with multibillion-dollar compounds in each place. It's a very enviable position to be in and I couldn't be more proud of what our collective team has been able to accomplish.

Okay. So before we dig into BRINSUPRI and the launch, I'd like to zoom out for a second. Insmed has done an exceptional job identifying unmet need and delivering first-in-class therapies. So setting life cycle management work aside for a moment, is it fair to say the road ahead is a bit more competitive in TPIP and potentially higher risk in, let's say, your gene therapy programs like DMD and ALS?

So it's an interesting way to think about the profile of what we are up against. In our view, we only bring forward drugs that are first or best-in-class. So regardless of what the competitive landscape is, if there is a competitive landscape, then we need to be best in class. And I think TPI is a good example of that. We had data where the PVR reduction, just to highlight on 1 data point in that PAH study was a reduction of 3.5%. And which is better than any other study, the best of our knowledge that's ever been done. And that really sets us up to be that best-in-class prostanoid therapy for the treatment of that condition, and we would expect to keep that profile for any drug we bring forward. You made reference to our so-called fourth pillar.

One aspect of that is gene therapy. We are bringing forward DMD ALS treatments those need to be best-in-class in a competitive landscape, and that's the best way to bring value because we know in that circumstance, we're bringing that value to patients.

Okay. And then in the same breath, how do you frame Insmed's intrinsic value today? And what are the most meaningful drivers of value creation going forward?

So the best way we can talk about intrinsic value creation is to look for novel mechanisms of action that are first or best-in-class. And those tend to spider web into adjacencies, other indications. If we take ARIKAYCE, this is a liposomal formulation of the inhaled antibiotic -- of the antibiotic amikacin, which is inhaled and paired with an ultrasonic nebulizer, specifically targeting the macrophage within the lung, so that we can eradicate hopefully, the nondivertous mycobacteria avium complex infection that is very, very difficult to get rid of. We then expand that to all NTM diagnosed patients and the ENCORE study that will read out the medium next year, which is a complement to the ARISE study that has already read out and was successful should give us a clear pathway, we hope, to full approval of that drug in all MAC NTM patients.

And just to drill down on that, that takes the addressable market from 30,000 addressable patients to roughly 250,000 in the U.S., Europe and Japan. So it's a very substantial expansion. This is an indication where there is nothing else approved. So it puts us in a very strong position for a very long franchise. And we replicate that across all that we're doing. Most of the Street is very focused on BRINSUPRI and its launch in bronchiectasis. And while we aren't commenting today on the specifics of that launch because it's just started. I can tell you that behind bronchiectasis where we are the first ever approved therapy for that condition and a little footnote, that's a condition that's been around since '18, '19 for hundreds of years, companies have tried to develop therapies and every one of them has failed until Brands came along. So this is a major advance in that arena, and that really motivates everybody at Insmed.

But behind that, we're looking also at CRS without nasal polyps and HS, both conditions that the clear unmet medical need exists in CRS, there's only an inhaled generic steroid that's approved for treatment. And in HS, there are many compounds, biologics that are primarily targeting that disease. If we can have impact on those as well, I think we really will have put our finger on DPP1 inhibition as a kind of skeleton key for treating any neutrophil-mediated disease. And [indiscernible], as we talk about TPIP and the other compounds, they all have this profile to them. So the intrinsic value is a byproduct of all of those things running in parallel in 3 different commercial territories, U.S., Europe and Japan.

Okay. That's very helpful. And then let's transition to BRINSUPRI. And in light of your ARIKAYCE success, potentially moving the first line, but being the first mover in that indication, what is the learnings from that experience, how does that translate to your BRINSUPRI launch?

Yes. The 2 are very much in parallel. ARIKAYCE was a first-in-disease indication, as I mentioned, and therefore, one, where there needed to be some education to physicians about the disease state itself. We took an at-risk posture and began that education process prior and we had our therapeutic specialist in the field doing compliant disease state awareness and education. We have replicated that. We've BRINSUPRI we had our entire expanded sales force out in the field fully trained as of October 1 of last year. And so they've had almost an entire calendar year to both detail ARIKAYCE in the refractory MTM setting, but also to talk about disease state awareness for this very substantial patient population of bronchiectatic patients.

Okay. So we have MAC patients, ARIKAYCE identifying that. And then we have bronchiectasis and BRINSUPRI. How -- could you talk to the patient journey, how similar or different that is patient diagnosis, the process overall of how patients go from diagnosis to potential treatment?

Well, the interesting thing about these 2 diseases that they share a common call point in the pulmonologist. And so all of the infrastructure and learnings we've had over the last 8 years that we've launched ARIKAYCE in the U.S. are now brought to bear in that same population of physicians for BRINSUPRI and treatment of bronchiectasis. The patient journey is somewhat parallel in the sense that both are heavily frustrated by finally getting to a point where they have a diagnosis. And until we arrived, there's really nothing the physician can do about it. And the consequence of that is frustrated patients, frustrated physician -- and so along comes a therapy that can really make a material impact in our judgment on what these patients experience.

In the case of BRINSUPRI and bronchiactisis, these are so-called pulmonary exacerbations the field, not us, but the field talks about ambitious vortex where you have inflammation that results in poor mucociliary clearance that can result in an infection that further complicates mucociliary clearance and promotes inflammation. So we use DPP1 inhibition to inactivate the neutrophil serine proteases that are recruited by that are part of neutrophils and recruited 2 sites of inflammation in the body. So this is an I&I play in that sense. And by breaking that inflammatory cascade, we have the ability to reduce the pulmonary exacerbations that are experienced.

Pulmonary exacerbation, I like into sort of a heart attack for the lung. It does permanent damage and again, further complicates the mucociliary clearance and challenges that these patients face. So the drug has a novel biological pathway for impacting that outcome. And in this sense, it's very exciting for the patients who have bronchiactisis but it also implies that wherever there is a neutrophil-mediated disease, we may have a role to play. And that's what really unlocks a whole other enormous universe in our mind of potential because behind brensocatib, we also have some 850 DPP1 compounds that we've formulated in our library after our Phase II data was so successful, and we are now thinking about bringing those forward starting next year in new additional indications where each compound is dedicated to a separate indication.

Okay. And then can you just comment on the BRINSUPRI label? It's fairly broad. I know you've commented that 2 exasperations may be the threshold for payers, but any color around that would be helpful.

So we think the label is -- we refer to it as very clean. That's partially because the data itself was. It was a very clear statistical win on the primary endpoint and multiple secondary end points. We saw a preservation of lung function at the 25-milligram dose as measured by FEV1. We saw trends in patients having improved symptom scores. So couple that with a safety profile that's comparable to placebo in our estimation, and that gives you a once-a-day pill for the last substantial major pulmonary indication that has nothing to treat it where the adverse event rate is comparable to placebo. It's just a very compelling profile for patients who want a treatment for this condition, and it suggests that we have the opportunity to have a really big blockbuster in this space.

Okay. Without asking for specific guidance or numbers, but just more qualitatively, what are the bigger choke points in regards to diagnosis and potential treatment of patients with bronchiectasis. Is it CT scan, prior authorization? Anything you'd call out there?

Yes. I think what we've seen is that to date, there are roughly 500,000 patients in the U.S. who have an ICD-10 coded diagnosis of bronchiectasis. We estimate of those roughly half have 2 or more exacerbations in the last 12 months, which is what we are centering on and targeting in our initial launch. These are what we described as moderate to severe patients. And by targeting those patients we think we're going to have a very significant impact and consequently, some real benefit. We think about choke points bringing those patients in. Behind those patients, there are some 20 million patients in the U.S. that have COPD. And I don't know what the latest estimate is for asthma, but it's another additional sizable population. Those patients are probably also including some who also have bronchiectasis. But because the disease has nothing approved to treat it, there's really very little motivation for the physician to come forward with a definitive diagnosis, which you can do with a CT scan and a single meeting with a pulmonologist.

And if you can diagnose that, now there is a therapy to treat it. So we suspect that you will see patients, as people often say, come out of the woodwork as this medicine arrives and physicians can turn and say, okay, my COPD patients who are max those LABA/LAMAs and are still experiencing exacerbations, I'm going to get them CT scan, and I'm going to have them talk to a pulmonologist to make sure that this isn't bronchiectasis that we're seeing here. In our Phase III study about almost 20% of the patients were comorbid with COPD and bronchiectasis or asthma and bronchiectasis there's quite a substantial population we think out there that is comorbid or misdiagnosed, and that unlocks a whole new raft of patients that we think we can benefit.

And from the 250,000 patients you noted with 2 or more exacerbations, what percentage of these patients have had a CT scan or have all of them?

All of those patients that we just described have a definitive diagnosis of bronchiectasis which requires a CT scan and a pulmonologist visit.

Okay. That's interesting. So what specific levers are you using to potentially compress time to therapy and sustained adherence at scale?

It begins with disease state awareness. We want to make sure that people are asking their patients who have symptoms that are consistent with bronchiectasis, have they had the CT scan, now that there's a therapy out there to treat it will really motivate, we think, both patients and physicians to take a closer look. And as that process unfolds, I think you're going to not only see more patients diagnosed, more documentation of exacerbations but we're really going to be able to unlock and very much like in other therapeutic areas, start to slice up the pulmonology patient populations along the lines of those who have COPD exclusively, COPD with bronchiectasis, just bronchiectasis, asthma and shades of gray around that. That's specialization of identification and treatment of those patient populations is the way that most major disease states ultimately go once there's an ability to really refine and define an understandable way what is the specific challenge that each patient faces.

Okay. That's helpful. And I guess if you can outline potential guardrails or milestones over the next 12 to 16 months. So we can better understand the launch progression. I know you're not going to be providing script data or anything we shouldn't be watching that. But overall, how can we get an understanding of penetration in the bronchiectasis patients. Are you pulling patients from COPD and asthma? What could you comment there?

Yes. So we're going to watch this unfold. We have an absolutely first-rate commercial effectiveness team at Insmed that is very focused on collecting more data than you could possibly imagine to be sure that we understand exactly what is happening with these various patient journeys and where are the friction points, where there are opportunities to intervene to try to help patients even more in a compliant way. I feel very good about the way this launch should go. We're not commenting on the launch itself. But coming into the launch, we had extensive dialogue with market access. We wanted what we refer to as a frictionless launch. That means ensuring that when a patient is given a prescription, they can get it fulfilled and get access to the medicine quickly. Once on the medicine, we want to provide the option to have a patient support capability for them, and that is very much in place.

We saw that work extremely well with ARIKAYCE in that program. So we're doing that again here for bronchiectasis. And as we move forward, on a quarterly basis, we'll certainly report what's going on with the launch. But we've set our bar for where we want to go across a spectrum of other drugs that have performed exceptionally well. Think of Tespire, think of OFEV, think of Fasenra, think of DUPIXENT. When you look at the average of those drugs, that gives you a ballpark of what we think good in this space looks like. And we would be disappointed if we didn't approach those kinds of results. Specifically, what that means in the first 2 full quarters, we would expect those group of drugs to produce roughly high double-digit million revenue combined -- and then for quarters 3 through 6, combined somewhere in the $500 million to $600 million revenue range. That's not guidance. That's what good looks like in this space. So we would like to be within reach of that if we could be.

Okay. And based on your market research, talking to KOLs, where do you think pulmonologists fall on the first batch of patients they'd like to put on therapy initially?

So we think of this broadly as the community pulmonologists and then the sort of KOL specialist at the academic center. They're very different profiles. The KOLs are probably seeing dozens of patients the community pulmonologists may be just a handful or 1 or 2. And so I think their approach is going to be slightly different. Almost to a person, the KOLs we've known over the last 8 years that we've been bringing ARIKAYCE to the market, have been enthusiastic supporters of brensocatib potential role, BRINSUPRI role in the treatment of bronchiectasis. And consequently, now that it's approved, I think you'll hear them vocally supporting and advising its use in the appropriate patient population. I think the community level physician will respond to that and take some of that guidance on board, there will ultimately be consideration of things like guidelines and the COPD Foundation, as an example, is running a program to qualify up to 150 different centers across the United States that are particularly qualified to treat NTM and bronchiectasis.

And as those come online, those centers of excellence will also be folks that will be pretty prominently involved in identifying and treating their patients. We know coming into this, we had north of 90% of physicians saying they were inclined to use this drug to treat the condition in their patients. And we had more than, I don't know, close to 70,000 patients self-identified patients sign up on our website to get more information. So the patient demand is there, the physician appetite is there. We just need to put these folks together and make sure that, that process goes smoothly in a compliant way.

Okay. So you clearly have a first-to-market advantage, but success often defines a category and attracts competition. Can you comment on the competitive landscape here and your thoughts going forward?

Yes, if we start and take a look at who else is out there with the DPP1 inhibitor, this class was originally pursued by Glaxo Smith Kline, AstraZeneca, DI and all 3 of them dropped their programs. And in fact, it was AZ that called us and said, "Look, we're going to drop this program, but you may be able to find a use for it in a rare condition like bronchiectasis." Going back in time to 2016 when we did this transaction, first of all, bronchiectasis was thought to be an orphan disease. And secondly, the definitive paper published by James Chalmers out of Scotland that correlated reduction in neutral elastase with reduction in pulmonary exacerbations has not yet been published. So people sometimes go and pick on AZ for having licensed this drug to us. At the time, they were being pursued by a larger company called Pfizer, so they had some things on their mind and they were getting rid of some things that they weren't developing.

The data was not there to support the drug's use in the way that we have seen it evolve. And so in their defense, that was not clear. It was about 2 or 3 months after we in-licensed it, that the paper was published and the FDA changed bronchiectasis into being a nonorphan condition at which case they came back and knocked on the door. And so any chance we can get that drug back. And of course, we said, no, sorry, but thank you very much, and we look forward to working with you. And we have collaboratively since then. I give them high marks. They took a drug that was going to sit on the shelf and they put it in the hands of somebody that was going to take a chance in developing it. And today, we sit here with the first ever approved therapy for bronchiectasis. And I think that's a victory we share with AstraZeneca.

Okay. And then just briefly on Verona Merck's product and COPD. Do you see any risk to them, let's say, expanding in the bronchiectasis granted you're trying to go from bronchiactisis to COPD. But how do you think about that dynamic?

We're not going to go into COPD with our drug, just to be clear, but there are some COPD you may have bronchiectasis. And that nuance is important just for understanding. The Verona drug is an exciting addition to the armamentarium of the treatment of COPD patients. And as I was describing earlier, if you look at the COPD category, it's 20 million patients in the U.S. there are subtleties of profile of COPD patients that are going to be more suitable for the Verona drug or if they have bronchiectasis for our drug. And that nuance will get teased out. But we don't see them as a competitive threat. You asked earlier, who the other competitive programs, BI reactivated their program after our Phase II data came out, and they are right now kicking off a Phase III study in bronchiectasis.

There's another compound that not surprisingly came out of China and is being developed and the data in that population look interesting. I don't think it's -- either one of those are necessarily competitive with ours because we're now approved, so they're going to have to explain why it's substantially better or additive to what we have. But it is good to see attention turning to the class. And I think there are a lot of places where there are neutrophil-mediated diseases or DPP1 inhibition may be applicable. And that is why we went off and developed another 850 of these compounds so that we can target these diseases systematically one at a time.

Okay. So you have 2 additional readouts, HS, CRS with nasal polyps. Could you level set expectations going into those readouts? How should we think about them and benchmark expectations a bit.

So we looked when we were first developing the drug, at what other indications we might want to target, and that list is very long. There are a number of neutrophil-mediated diseases. We picked CRS without nasal polyps because that's a condition that some people in a simplistic sense, often referred to as sort of bronchiectasis for the nasal passage. So there's some comparability there, neutrophil driven. There is a clear unmet medical need. There's only a generic inhaled steroid that's available for treatment. And that condition numbers 32 million people in the United States. It is massive. We're going to be targeting the severe end of that spectrum. And we're very excited about the possibility of having a dent there. If we can make an impact there. We've just added a disease indication where we would be the first truly novel biology in that indication.

So again, meeting our first or best-in-class definition, and it is one that is larger than the bronchiectasis opportunity. So another very significant milestone will lead out for us between now and the end of the year in that indication. HS follows behind that next year. HS is a more complex disease etiology. And I think from that perspective, while we're excited about the potential, we're a little more cautious about the possibility of DPP1 having impact there, but we are going to look at the first 100 patients and do a kind of futility analysis, have that read by an outside group of experts, and they'll give us the thumbs up, thumbs down, the study should continue or not. And that data will be available in the early part of next year. We don't want to waste time on behalf of patients with the drug that we don't think will work. There aren't great animal models in this. So this is really the only way to find that balance. If that's a thumbs up and that trial continues, that would be a very exciting development.

Okay. So maybe in the last 10 minutes or so, we pivot to TPIP, impressive readout in PAH the TETON trial recently read out. How are you thinking about the opportunities there and the cadence of readouts to come.

Yes, here we go. So TPIP had great data in PAH. It had great data in PH-ILD and now it has the possibility of going after 2 additional indications, IPF and PPF, and those were somewhat validated by the United Therapeutics study that just came out that showed Tyvaso having a benefit in IPF patients. I think collectively, most people felt that it was not obvious that our drug would work in those indications. But given the -- what was seen with Tyvaso, we're now very encouraged by that, and we intend to go after both of those indications. We actually had the protocol written before the data came out just in the off chance that it was going to be good or close enough. We know our drug does better than Tyvaso in PAH and we've already established that with our data, so we think here the same will be true, and that gives us access to 4 indications from this one compound, and that is a very substantial opportunity.

Just to put this in context, People know the drug sotatercept, which was at Acceleron purchased by Merck for about $11.5 billion after their Phase II data. The peak sales estimate when that was done was about $1.5 billion. today approved. It sits at a peak sales estimate of around $8 billion, and that's just for PAH. We're talking about our drug being best-in-class for the treatment of PAH, PH ILD, potentially IPF and FL. So this is a very substantial drug as much as people pay attention to bring [indiscernible] and how exciting that could be, I think TPIP is every bit as exciting.

Okay. And so the first readouts to come will be PH-ILD then PAH, is there any opportunity to potentially compress time lines? How have interactions been going with regulators?

Internally, I think everybody loves when I show up and ask, is there any way we can compress time lines because that is the clearing call of everybody inside biotech. Happily, we have some precedent here when we look at the ASPEN data. That study was 450 centers around the world, 1,700 patients conducted during COVID and our team did a first-class world-class job in getting that enrolled in less than 2 years. So I'm very optimistic that we can bring that same innovative approach to PHL and get those done sooner rather than later and then turn our attention, of course, to IPF and PFF. And if we can get those completed and the data is as consistent as it has been to date, boy, we have another whole series of launches that we can expect to be forthcoming.

Okay. So now moving to, I guess, financials or just the path ahead overall. How do you balance commercial scale-up for BRINSUPRI, late-stage development, TPIP, early research velocity and BB while also protecting your P&L on a path to profitability.

Yes. I think most people who are investors know that we go for it. I've been at this company for 13 years. And when I joined, there were roughly 30 people and our market value at the time of $75 million, and we had $75 million in the bank. So basically, we won't treat thought the drugs were worth 0. It turns out that the 1 drug, ARIKAYCE, did have a role to play in refractory NTM. And with that conditional approval in the U.S., we were off to the races. And on the basis of that, we have laddered in other opportunities and at every turn that we have made a major advance, we've taken that moment to both capitalize ourselves and to go out and look for modest additional business development opportunities. So when ARIKAYCE looked good, we went out and bought Brensocatib. When Brensocatib looked good, we went out and did about half a dozen different platform technology acquisitions, which were all very modest upfront, success-based milestones and those are now getting ready to start to read out. And that has created a company composition which has, I think, in many ways, a very enviable profile with 3 for 3 with our late-stage, very substantial multibillion-dollar opportunities, and we have another 30 compounds that are in preclinical development, now just entering the clinic across those different platforms.

And these technologies are unrelated to one another in many ways, synthetic rescue out of Cambridge England. We have immunized therapeutic proteins out of New Hampshire. We have gene therapy out of San Diego, and we have next-gen DPP1 and novel MOAs to complement DPP1 coming out of New Jersey. And all of that research, we say we'll keep below 20% of overall spend, but it sort of ticks away in the background. Those acquisitions, for example, we did about 4 years ago, and they're just now starting to show around the corner to provide clinical data. Just as ARIKAYCE expands, [indiscernible] goes into bronchiectasis and we read out CRS and HS and TPIP goes after 4 separate indications with promising data, we'll begin to add new clinical compounds at the rate of 1 to 2 INDs a year with clinical data that we think will again meet the criteria first or best-in-class. That gives us a very clear line of sight for the next 3 to 5 years for value creation from where we are today, which has been a substantial growth, but is really just the beginning.

Okay. And then near term or relatively near term, the next 6 to 12 months. I mean, hopefully, we're sitting down again next year. But what 3 outcomes would you want to point to is proof that Insmed is tracking towards a multibillion-dollar portfolio.

While we better start to put up a multibillion-dollar revenue line, I think the honest answer is we need to see the performance of brensocatib in bronchiectasis. We need to see ARIKAYCE now in its eighth year in the U.S. continue to grow at double-digit rates, and we've seen that consistently. We want to see these clinical data readouts from CRS, HS, ALS, DMD, Encore DPP1 next generation. All of that, while we're launching in Europe and Japan for BRINSUPRI in the treatment of bronchiectasis, if all that comes to fruition within the next roughly 12 months, which is what we're on track for, we should see substantial in our opinion, value creation from where we are today. This is almost like a freight train that has gotten going and we're building that momentum around these positive readouts to get us to a place where we can continue to bring benefit for patients. And we're doing it with a balance sheet that's close to $2 billion right now in terms of cash and equivalents on our balance sheet.

Okay. So BRINSUPRI is launching in the third quarter, but the fourth quarter is going to be the full -- first full quarter. So can we expect let's say, a competitor conference in early January being a key catalyst for investors to get a sense of how the launch is going?