All right. So wrapping up day two of the Barclays Global Healthcare Conference. I'd like to welcome CFO of Insmed, Sara Bonstein. Sara, great to be here and thank you for joining us. Yeah, thanks so much for having us. Really appreciate it. Yeah. You know let me know if you have any introductions or any opening statements. Otherwise we can kinda jump into quick Q and A. Yeah. Yeah, I guess the only thing I would just comment on is this is probably the most transformational year in Insmed's history. Really excited about the upcoming pending data readouts in Q2 and wishing the calendar returned faster. So happy to address any questions that you have. All right. Perfect. So yeah, just diving right in. I guess more on the news from the recent front. So AZ exercised the licensing agreement to further develop brensocatib and commercialize it, potentially commercialize it in COPD and asthma. Can you give those who might be unfamiliar a quick overview of the agreement? And what's your thoughts on kinda like why now? Sure. Well, I obviously can't comment specifically why, you know, AZ decided to take an action. They notified us on Friday of their desire to exercise what's called the second option in the agreement that triggers the ability for both companies to enter in good faith negotiations for commercially reasonable terms to move that asset forward into either COPD or asthma. We will obviously, you know, enter into those discussions in good faith with AZ. What I can say is from our perspective it changes nothing. We continue to be full steam ahead. We continue to have our, you know, laser focus on the upcoming asthma data readout in Q2 H2 of Q2 of this year. Are excited to hopefully deliver what could be a very meaningful medicine to patients very much in need. Gotcha. And you know there is some overlap between like COPD, bronchiectasis and such. So when you're thinking about this and AZ's potential to you know go into COPD and asthma, can you give us this idea of kind of how much overlap is there? Number one, how much overlap is there in a real world setting? And just how clear cut kinda is the diagnosis between let's say like COPD and bronchiectasis? Yeah. So as you know, to diagnose bronchiectasis it's actually pretty straightforward. High-res CT scan you could see the tree-in- bud patterns in the lungs. And so it's a very it's a pretty clear diagnosis. Today we estimate there to be about 1 million patients as our initial TAM between our three geographies in the U.S., Japan, and Europe that are diagnosed with a diagnosis code all of those good things. I think what you also saw in both the WILLOW study as well as the ASPEN study is you saw patients that have comorbidities. And so patients that are bronchi that have bronchiectasis but they are also comorbid with COPD and/or asthma. And you saw representation of those as I mentioned in both WILLOW and ASPEN. Assuming success on ASPEN I would anticipate those patients would be on label for our drug. As long as you have a primary diagnosis of bronchiectasis, you would be on label for the drug assuming success. And the patients that I believe can benefit from brensocatib would be able to benefit as such. The literature's really all over the place. I almost kinda feel you know silly even quoting some of the literature. But per the literature, anywhere between 4%-54% of COPD patients are also comorbid with bronchiectasis. Like I said earlier, it's a simple diagnosis but patients may not be getting that CT scan because there's no available treatments today. Some of the disease state awareness activities that we picked up last year at ATS continue to you know have ongoing with medical education. And now in the payer conversation I think is bringing bronchiectasis to the forefront. And as may allow for patients to take the action to get that high-res CT scan. Mm-hmm. Great. And so in terms of like you mentioned there's gonna be patients that's you know may not know that they have the actual disease. So when you're thinking about market size and penetration you're using a very objective endpoint on the ASPEN study in terms of rate of exacerbation right? And I understand that you know that's because it's a very hard endpoint and you can derive performance from you know how the drug affects the patient and p-values from this. But I guess a more skeptical person might look at this and say well the KOLs say it's a 15% level reduction in exacerbations but these patients are having you know 2 exacerbations a year coming in. When you look at the actual I guess nominal number of exacerbations one might say it doesn't seem like that's a huge difference. But on the other side, when I'm thinking about bronchiectasis, it's not like one day you're perfectly fine and then the next day you're waking up with exacerbations. Or, you know, or I could be wrong. With that, can you talk about what constitutes as an exacerbation in ASPEN? And kind of what may be the most convincing element in terms of where you can discern between where you can really control the placebo effect? Why don't we start there? Yeah, sure. So we abide by the strictest definition of exacerbation very and very consistent with how we defined it in WILLOW. So the entry criteria for our program is 2 or more exacerbations in the prior 12 months. That needs to be a documented exacerbation, meaning that this is a patient that had an incident. They contacted their physician. The physician then either changed their medication and/or the patient was hospitalized. So it can't be the patient thinks they might have had a flare and so kind of decided that themselves. There needed to be patient interaction and it needed to be documented as such. This is a high bar. We thought that was the best way to define and the most respected way to define what an exacerbation is. And again consistent with WILLOW and really helps us to ensure that we have exacerbating patients that enter the trial. As you may have heard us say before and you know I obviously don't have a medical background in a sort of a non-medical way to describe it an exacerbation is somewhat like a heart attack for the lung. So this is something that causes damage and then it continues to build on one another. So exacerbations are not linear events but every time an exacerbation occurs it causes damage to the patient's lung. And then their disease essentially progresses right? They now have this permanent damage to their lung and so those are things we obviously want to stop. What you hear the medical community say is anywhere between a 15%-20% clinical effect they view will be meaningful. We get similar feedback from some of the payer conversations that have already begun and are underway now. I'll remind everybody that in WILLOW we studied exacerbations. So a lot of the studies that have happened in this space they didn't study exacerbations as a primary endpoint or as an endpoint in their phase II. And then they jumped to phase III and started studying exacerbations for the first time. So we studied exacerbations in phase II. We were stat-sig on both the primary and secondary exacerbation endpoints for a 10 mg 10 mg dose and we were trending towards the 25 mg dose. I would also remind folks that in WILLOW if you look at the rate of exacerbation and what was the clinical effect that we actually saw in WILLOW for the 10 mg dose we saw a 36% clinical effect. For the 25 mg dose we saw a 25% clinical effect. So very meaningful effect. And so we're really excited about the opportunity that ASPEN affords to potential patients here. And you know if we can't make Q2 the H2 of Q2 come fast enough in our in our world. Gotcha. And so let's say we are in Q2 and you have a positive ASPEN readout. What other metrics do you think that investors should focus on? And And any kind of read-through into what we could see in terms of understanding potential penetration rates into this patient population? Yeah. So what we've committed to is we appreciate that there's a lot to digest with the Insmed story. So we will obviously you know have a call share the clinical results from the ASPEN study. We've outlined what a clear win is. A p-value of less than 0.01 with a clinical effect you know anywhere sort of north of 20 that we would view as a very clear win. And we have every reason to believe that is what the you know outcome will be. We obviously need to you know turn over the data card in the event that we have a p-value between 0.01 and 0.05. We still have a viable drug because of the strength of the WILLOW data. What we've promised is within a week, so within short order, a handful of days, within a week, we will then host a commercial event. It will be, you know, a webinar-type event, and we will go through each of our three programs: ARIKAYCE, brensocatib, and TPIP. Over the last 6-9 months, we will have put out what we believe is very important and de-risking data from each of those pillars. We'll be able to walk through some of those assumptions as you're trying to build your commercial models, such as pricing, all of those kind of components. What we've said thus far, we have not provided pricing guidance. What we've said thus far is a Fasenra-like price at around $40,000 is a reasonable floor. Once we have that clinical effect in hand, we'll be able to provide some clear direction as you're building your models. We said earlier this year a $5 billion peak sales opportunity is the way we view brensocatib in just bronchiectasis and CRS, the two indications that are ongoing. Mm-hmm. And to clarify, that $5 billion, is that something that you see at the 20% reduction? Or is that something you see as a 30% reduction? Have you given more guidance on that? Yeah. We're comfortable with that at a 20% reduction. At a 20%. Gotcha. Okay. On the ASPEN study and there's been a lot of questions on powering and this is gonna be another one of them. So you mentioned that the ASPEN study is 90% powered to show 30% risk reduction in bronchiectasis. And to clarify now is that 90% for like each contrast in terms of like you know the 10 mg dose versus the placebo that has 90% power? Or is 25 versus placebo has 90% power? Or is this just an overall 90% powering on the statistical side? We need one dose to win. So any dose at 90% is powered at 90%. Each individual dose is powered at 90%. Gotcha. Okay. And another question that we're getting from investors to kinda just suss out this what the how this trial may actually flip when you guys flip the cards over. So you previously mentioned the exacerbation rate of bronchiectasis was trending at what 1.12-1.15 per year. But have you or can you give any indication on it has changed but can you give any indication on you know has this gone up or has this gone down? Has there been a direction on how this exacerbation rate has evolved? Yeah, sure. So I guess two Januarys ago, January of 2023, we put out the blended blinded exacerbation rate 1.12-1.15. The reason and rationale we put that out was to show confidence that we continue to see in ASPEN what we saw at WILLOW at the time and the consistency of the two programs. It is blended and blinded. There is not a way to kinda back yourself into what does that sort of mean for each of the arms. I know folks have tried and so we have not specifically updated it because I think folks were trying to do a calculation that you cannot do while the trial is blended and blinded. What we want to make sure people understand and see is if you look at all the past trials in this space, one of the issues was they did not have enough events. So by looking at the blended blinded rate, and this is something we continuously look at and we continue to like what we're seeing and continues to track, what I can share is we feel very confident that we're seeing enough events. And that should really be the takeaway that we are seeing events out of this program. Now we don't know where those events are; which arm the trial remains blinded in the fall. But we are seeing events and we feel we will get a definitive answer when we turn over the data card in H2 of Q2 because we will have enough events. We have overpowered this trial. We have designed this study in a way to give us definitive answers. That is what we are very eager to share with all of you in that sort of 45-day window that we've committed to. Great. Great. And another question. So back in January you guys mentioned that the dropout rate was less than what you saw in WILLOW. And WILLOW was overall a six months study. Obviously ASPEN is a lot longer. To clarify you mean that the dropout is I would say relative when you adjust for the time difference right? Is that less than a WILLOW even when you adjust for the fact that ASPEN itself is a longer study? Yeah. What I can say is we continue to track and be very happy that the dropout rate is either at or less than what we've seen in WILLOW and I think that really speaks to the safety profile of this drug. As a reminder we had a higher dropout rate in placebo in WILLOW than we did in the drug arms. This is; this has been shown in WILLOW to be a very safe product. We've gone through five DSMBs now in ASPEN. No safety concerns. To be clear DSMB only looks for safety no futility. We do not wanna give up alpha. But we are really we feel really great about the safety profile of this drug. And as we all know the first thing the data looks at is safety and then obviously efficacy. So we feel you know as much confidence as we can as we enter into this period. Okay. Perfect. And when you're thinking about just and a lot of people have thought about different scenarios of what could happen when you guys flip the ASPEN card over. Now one of the thoughts that I have is, in terms of a possible scenario, let's say you get statistical significance on just the 25 mg arm and the 10 mg did not get stat-sig. Can you just clarify, in this situation, would you go forward with approval using both the WILLOW and the ASPEN data? And And also your level of confidence in this type of readout. And perhaps an unfair question but Yeah. No, I appreciate you asking the question 'cause I know this gets to the heart of, you know, people are trying to understand. To be as clear as I can on this, we need one dose to win regardless of the dose. And we feel obviously we will need to file and FDA will need to, you know, opine on that. But we feel very comfortable that one dose wins. It's a clear win for this drug and a clear win for patients irrespective of which dose that is. There's a high likelihood that if both doses are stat-sig then we may choose to only move one forward. We'll obviously need to see the data. But in a lot of ways simple is better as we're thinking about commercialization. So we need one dose to win here. We moved both doses forward because we thought we saw enough in the WILLOW data that with the longer study there could be benefits to patients at the higher dose. We don't need to see that, and we will get all the questions answered. What I get very confident about in our design and how we approach this is when we turn over that data card and find out you know the p-values of the primary and the secondaries and all of those good things we're gonna feel confident that we designed it in a way to get the questions answered that we need answered. That we're not going to wake up and say well what if we just enrolled another 100 patients? What if we just you know moved both doses forward? We will answer all of these questions and I appreciate the investors' patience and their capital support to get ourselves to this place. Gotcha. Excellent. Why don't we move on to TPIP another pillar of Insmed and one that doesn't get as much screen time as Brenzo but also there is a tremendous opportunity here as well. Can you quickly go over well your thoughts on differentiation TPIP versus what's currently on the market and perhaps what's you know that's going to come on the market? Yeah. Yeah, absolutely. So I think we all appreciate that PAH and PH-ILD is going to be a great innovation space and there's a need for that with patients. These are obviously life-altering life-ending conditions for patients. And it's you know our duty to try and find the best available treatment for these patients. I believe that there will be a need for a prostanoid as part of that treatment paradigm. And we are hopeful that if we continue with what we've been able to show thus far that TPIP has the potential to be the alternative choice if we listen to what the medical community says. So you know why do we believe that? What data will be coming out? I'm sure you would is probably kinda the next place that we'll go. We'll look to put out data before ASPEN. We'll look to put out the top-line results for PH-ILD. As a reminder, that is predominantly a safety study. We've over-enrolled it, so it's 39 patients. We'll be able to share with the investment community the tolerability profile on an unblinded basis. What patients were able to max titrate up to from a dose perspective. It was randomized 3-to-1. So you do have a fair amount of patients that are on drug, which is wonderful. Obviously be able to look at any adverse events. There are some exploratory endpoints, but those will be available. They will not be available at the time of top-line. Those will be available later, and we'll share those as soon as possible. The data just won't be available at the time. So a couple points that I just want to highlight on the dose. We are up titrating max titrated dose from 80 to 640 micrograms. Why is that important? I think we all appreciate that the more treprostinil you can get into the lung the more beneficial to patients. And our pro-drug formulation allows for that sustainable release of the treprostinil including overnight coverage. All max titrated dose if you adjust for the hours is once daily. Other available therapies are multiple times a day or the carbon chain weight all of those things. If you truly put it apples to apples at the max titrated dose we provide 60% more drug. And that is really encouraging as we see the importance of getting more more treprostinil into the body. We will also at that time update the blended blinded PAH data. So why are we excited about that? It's blended and blinded and we appreciate sort of the nuances with that. But PVR pulmonary vascular resistance does not happen spontaneously. So what we were able to show last October was in the first 22 patients in PAH we were able to show a 21.5% overall reduction on a blended blinded basis of PVR. If you look at comparable studies in the drug arms you usually you don't even get to that. And then if you just look at the 64% of patients that actually had a PVR reduction and why is that important? That's important because this doesn't happen spontaneously. So if you look at just those patients you see a 47% PVR reduction. Those are unheard-of type numbers. So we'll update that blended blinded PVR data. We'll have about 40 patients or almost double the amount of data. So there can be some additional kind of efficacy endpoints while blended and blinded but also shared at the same time as ILD. So you'll get the dose information. You'll get the safety, the tolerability, as well as you've got the updated PVR data from PAH. Yeah. And remind me that's for that study it's a one-to-one randomization for patients and drug arm for placebo and drug. For the PAH study it's 2:1 randomized. Two-to-one. Which is ironically pretty close to what we saw 64% of the patients actually having a PVR reduction. It's all blended and blinded you know. You can think you know take whatever inferences you want there but it was definitely of interest. Exactly. Great. And so to move this forward you still need to do registrational much larger studies. And when I'm looking at that probably will get you to and more closer to the H2 near the end of the decade for potential commercialization in I would say PAH, PH-ILD. One of the questions I'm getting and just curious about is in terms of the patent IP protection how what is the patent that you have right now? And how are you thinking about protecting it let's say into the 2030s and beyond? Yeah. So a couple comments. We've committed to initiating phase III for the TPIP program in 2025. So that's something we're looking forward to next year. As we think about TPIP, this is a product that we developed in our own research labs similar to ARIKAYCE. So we developed our own patents through 2034. That That does not include any extensions that we would obviously continue to work through. And we feel very confident in our patent protection. Gotcha. Okay. Great. And we're running up on time but perhaps just one last question. This one's on ARIKAYCE, the other pillar. Can you clarify on PRO the timelines and next steps for filing under Subpart H? And how should investors think about essentially what's the next update that you're gonna get and the timeframe that you could potentially show those updates? Yeah. So ENCORE remains our base case. We have been very consistent in that message. We do feel based on the strength of the ARISE data that it's appropriate to ask the question. So we received some encouraging feedback from the FDA latter part of last year. We'll look to finalize you know the PRO and the statistical plan for ENCORE I would say probably around the Q2 timeframe. And once that's finalized then we'll pivot to the other side of the agency to have the Subpart H conversation. So we feel these are appropriate questions to ask. But ENCORE remains our base case and we're really encouraged by the ARISE data that we saw last year. Okay. Gotcha. With that we'll wrap this up, Sara. Thank you. Thanks again for coming. Thank you so much.