Thanks, everyone, again for joining us this year for our inaugural Healthcare innovation conference. It's been a good start to the first day coming out of an entertaining, interesting, and entertaining lunch discussion. So for those of you who don't know, I'm Vamil Divan, one of the biopharma analysts here at Guggenheim. Joining from the Guggenheim side, we have Daniel Crozier, one of the members of the team as well. Next up in this room, we have Insmed. We have Martina Flammer, the Chief Medical Officer up here. Also, Brian Dunn from the investor relations side in the audience in case we need to tap into his knowledge at any point. But we're mainly going to focus on the medical and scientific side of things. Obviously, a lot going on in the company. And I think what I'm thinking, just kind of based on where the questions have been coming for us, we'll focus on Brenzo, obviously. A lot of interest in that asset, but not just the bronchiectasis side, but also the other indications. And then we'll spend some time later talking about the other pillars. So maybe just on Brenzo to kind of kick things off, let's start on the bronchiectasis side. And obviously, impressive data you released over the summer and also some subgroup data that came out more recently here in Boston last month. Maybe you can talk through kind of your view of the overall profile that's coming together here, especially on the subgroup data, sort of anything that you're kind of highlighting that's interesting or maybe that investors are not appreciating properly. Yeah, sure. I'm happy to. So first of all, obviously, we were all thrilled with end of May when we had the ASPEN study readout for both doses to hit the primary and then also key secondary endpoints, I think, that are clinically meaningful for patients, but also for the healthcare providers, and you're right, about a month ago here in Boston, at CHEST, we released subgroup data, and it was quite a battery of subgroup data. We had 19 pre-specified analyses looking at patients from different ethnicity based on race. We looked at geography. We looked at age. We looked at patients who were Pseudomonas co-infected. We looked at different comorbidities and shared that data. I think the most exciting for us and also for physicians at the conference was to see the consistency, to see the consistency that we saw with ASPEN on the primary endpoint and to see it across the vast majority of the subgroups for the primary endpoint and also for lung functions. Remember, everybody, studies are powered on the overall study and not on subgroups. Seeing such a consistency, I think, was important. It was contributing to the overall profile from the efficacy side, but also from the safety side, because that, as we know, is a really important element for any chronic treatment. Seeing that was truly important for us. I think it gave an understanding of physicians also of their patient population. When there's a new treatment that comes to the market and is available to use a physician, you think about, "Okay, which of my patients could I actually give or would I give that to?" And so that is where aspects of subgroup analysis also help you to organize yourself of which patients. And so seeing that, I think, strengths of the data and the consistency was very pleasing. So I guess, as you see the data here, I think some of the questions we've gotten is around some of the geographic distribution of the results, people with asthma or COPD, sort of baseline. Is there anything you're seeing where you're seeing sort of more opportunity for Brenzo versus others or other areas where maybe you think the opportunity may be a little less now that you've seen all the data? Yeah, so I think there's two things. And I'm sure that is something lots of people have looked at. And this is why do you see such really amazing additional data in Asian patients? And we have looked at this from three different angles. Those patients who self-identified as Asian, patients from a pure geographic perspective, so everybody who was Asian, and that was Japan for sure as one country, but also Philippines, Taiwan, South Korea, who were part of the study. And to see that across both doses and to also see that on the primary endpoint was important. And we also saw that with regards to lung function. Now, you could ask, why is that? And to be honest, I have to say, we don't know. We don't have an answer to that yet. Why do we see up to, if you look at the data, almost up to 60% in this patient population? There could be several hypotheses, and that is something we will look into. Is the disease a little different in this population? Are there elements you think about? Is exposure something? Because Asian patients tend to be a little slimmer and not something we can really put our hands on at this point. We're glad to see it. And it's interesting to see it, but it's not something we really know the answer why. So I think that is certainly something where we see the benefit. And we hear a lot of questions and interest of that from patients also. Okay, so one more from me, then I'll turn to Daniel. Just around the filing process here. So it sounds like anytime in the next few weeks, you'll be filing this. Maybe you can just talk about sort of what's left, what to get to the point of getting this submitted. Yeah. So we've said we will file in the first quarter, and that is what the plan is. We will file in the first quarter, and we'll ask for a priority review. We think that's what the data warrants. We have breakthrough designation, so that is also the basis for it. In addition to the data, we're now putting the dots on the i and crossing the t's, and maybe just a little bit of context of this is a massive study, and I just looked at this actually myself. So this is a study that has 13 phase one studies. It has all the preclinical data. It has every data that was ever generated with brensocatib. It has case report forms and entire data sets, and the full volume of that is actually more than 25 gigabytes. So when we press that button, it will arrive at the FDA 24-36 hours later, just so you see what type of a volume that really is. And then I think everybody who's worked with submissions knows the modules that go into it and all have to be in there. So we are on track as we communicate it to file in the first quarter. Actually, one more from me, then I'll turn. Just around the competitive dynamics and other DPP1s in development and what you've seen from them. So how do you see, aside from being ahead, what do you see in terms of your ability to differentiate from some of these other players? And then we'll shift to some of the other indications. Yeah, so yes, 2024 was a reveal of data. I think in DPP1 space, BI has a DPP1 compound that has read out the phase II study in the middle of the year in three doses. I think there is still work to be going on really on those findings since there wasn't the statistical significance for any dose, and we don't know enough about the safety profile, but they're planning to move forward into a phase III study, see what they will look for, but we had Haisco data, which was a Chinese company, and it was only limited to really Chinese patients, but what it tells us in the DPP1, it validated the mechanism of action, and I think that is something that is important to see, that is good to see. What do we differentiate on the clinical side apart from being ahead? I think first, and that is something we had also learned, this is not a simple population. This is a heterogeneous population. You need to be very careful and really thoughtful in the design. Who is the patients that you're selecting and what are your criteria that you want to demonstrate at the end? That will be influenced by it. The other point about it is you have to balance, and you should hit a clinical functional efficacy profile that is relevant, and you need to be able to balance it with a safety profile of a chronic medicine. So often you think about, can you inhibit something more and get more efficacy in this particular patient population? We don't know that that is necessarily the case. We've seen it really, we often think about this and have talked about it as a Goldilocks status where you really inhibit that much on the mechanism and have a good safety profile. The subpopulations showing that you apply that actually across a really wide subpopulation, I think, is of clinical importance, and then, of course, there's the timing factor, so remember when we recruited ASPEN, it took us a little bit over two years, two and a quarter years, so once you're going into, you need to recruit against the drug that is on the market. I think that is a consideration, especially when you have maybe two or three others who are in the same stage in a phase II, phase III environment. I think we would expect that we have a good runway for. I can't say exactly, but I think for a good couple of years, several years, and maybe just to recognize also there is ensifentrine, which is a dual inhibitor. It is an inhaled medication, dual inhibitor of PDE3 and PDE4. So from just the mechanism of these drugs, you'd think it has an impact potentially on smooth muscle, so potential bronchodilation and a nonsteroidal kind of effect on inflammation. It's a twice a day inhaled using a jet nebulizer. So that may not sometimes be as easy to handle, but this is, they're just starting off in phase II. So I think there's lots of time to come. Yeah. Okay. Agree. Yeah. So you're also looking at this drug and other indications. You have CRS without nasal polyps, as well as HS. So maybe starting with CRS, can you maybe discuss the logic behind pursuing this drug in this indication, the specific populations you're looking for within this broader CRS population? And then maybe briefly discuss kind of like the current standard of care for these patients. Yeah, so chronic rhinosinusitis without nasal polyps. I'm just going to use it once and then go into CRS because it's such a mouthful, but it is really a chronic inflammatory disease, and what it impacts is basically the air-filled bones around the nose, and those are the paranasal sinuses. Chronic rhinosinusitis as a disease itself is driven by neutrophil inflammation, so it's a strongly neutrophil-associated disease. That gives you the first reason why brensocatib would impact it. The overall disease of chronic rhinosinusitis has basically two large subgroups, one without nasal polyps and the other one with nasal polyps, and it's the one without nasal polyps that is actually the larger group of both of them. In the group with nasal polyps, we know they are biologics and they are more eosinophilic probably driven than neutrophilic. What was the reason or the argumentation behind why we would go with Brenzo? That is based really on the mechanism of action. In this disease, because of its strong neutrophil association, what you have is that there's a chronic inflammation in the sinuses. It's really a disease that is a dysfunction of the cells in the mucosal lining of the sinuses. Neutrophils get attracted and will migrate to these areas. Once they're there, they'll unload their entire cargo of neutrophil serine proteases, which then stay in the tissue, are a cause for chronic inflammation, and eventually lead to tissue damage, which is why these patients often have obstruction of the sinuses, discharge, facial pain, loss of sense of smell, or reduction in sense of smell. Many of those patients, once they're chronic, have repeated surgery. With surgery, you can remove some obstructions, but it doesn't really help you with the disease, an interruption of the disease. What you want to impact is the same thought process that applies with bronchiectasis. How do I interrupt that circle of inflammation? I can't do that once the neutrophil is already on location. I have to do that before it starts activating the proteases. That happens in the bone marrow. With brensocatib, that's where the effect of brensocatib takes place. While that neutrophil cell matures in the bone marrow, it inhibits an enzyme that leads to the activation of this proteases. Once neutrophils migrate out there, even then they don't have these heavy cargoes to unload. In the disease, you can think about it a little bit similar like bronchiectasis, but it's not in the lung. It's in the paranasal sinuses, but you can think about it in the same way. And also, there is no real preclinical data, either for chronic rhinosinusitis nor actually for hidradenitis suppurativa. The mechanistic element of it makes sense. And that's why we've selected to go to both of them. And you see, if you look at tissue samples also in both, you see a high concentration of neutrophils and neutrophil elastase. So we know that there is an importance of interrupting that cycle. And right now, patients right now have nasal sprays, inhaled steroids, nasal irrigation, and then it goes eventually some antibiotics because eventually they will also have infections and painkillers, a lot of over-the-counter painkillers usually. And then often as a last resort, it is surgery, but in many cases, surgery is repeated and it doesn't really bring you a lasting functional relief. Okay. Yeah, that all makes sense. Maybe in the interest of time, I'll move over to HS. So maybe like a similar question there, like what gives you confidence that? Yeah, so the mechanistic element that I tried to build is very similar, but in HS and hidradenitis suppurativa, now you're talking about the lesions or the tissue that is damaged is in the skin. And the way it manifests itself is with abscesses and nodules. Eventually, it creates tunnels under the skin that become scar tissue. And currently, what are these patients doing? Topical antiseptics, topical antibiotics, sometimes injections with antibiotics or drainage to alleviate. Is this a very painful disease? And also you have here, you do have also biologics or treatments available, but as with many treatments, there is a lot of additional benefit to be had. And with an oral antibiotic that can start potentially treating your interruption of inflammation and giving you relief, we have to see, we are at the beginning of the program, so we'll have to see where we go there. But I think an oral is a very attractive opportunity and mechanistically it makes sense for us, but we're at the beginning of HS. Okay, great. And maybe just wrapping up the brensocatib discussion, can you maybe go a little deeper into the broader applicability of brensocatib and DPP1 inhibitors in general for these neutrophil-mediated diseases? And are there any other indications you're looking for both for brensocatib, but also some of these next generation DPP1s you're working on? Yeah, so I think we've been very focused on, I think, the DPP1 pathway scientifically, and that was one of our focus over several years, so we've looked at several thousands, I want to say, of compounds that potentially could become eventually a drug, and we've narrowed it down to a handful of that we would now be at a stage where we say we will pursue something like IND enabling studies. Which indications? There are many indications in neutrophil-mediated diseases, but I think the ones that we looked at closer and are for consideration is certainly the opportunity in rheumatoid arthritis, lupus nephritis, COPD, and asthma. I think those are the larger ones that come to mind that we are right now thinking about. All right, why don't we just shift gears then a little bit? We've got a few minutes left to talk about some of the other programs, so TPIP, we'll go to next, so obviously the two different programs going there, so one question we get, I think especially on the PH data that's coming up here soon, so what is the right bar to think about? A lot of times when we're looking at other companies, we say PVR reduction of 20% is sort of a good threshold. Is that similar to what you're thinking of? Anything different? And then just maybe more generally your level of confidence in this, that is obviously treprostinil that you're working with here. We have some good mechanistic rationale for why this should work. Yeah. Yeah, you're right. So treprostinil, we know it works in PAH as well as in PH-ILD. And when you tell me what is success, so we expect the PAH phase II data to read out in the second half. What does success look like? Yes, we're looking for at least 20% reduction in PVR and 30 meters in six-minute walk. So I think this is what we're aiming for. Obviously, we'd hope it to be more, but that is what we would call is success. And when you think about TPIP versus what is the other advantage or how does it differentiate versus another treprostinil? And I always want to talk about, because it's important to remember that TPIP is a pro-drug. It's not the treprostinil itself that you are actually inhaling. It's a pro-drug. You inhale it with a very simple device. Once it hits the lung tissue, there's esterases in the lung that will now activate the actual drug. So the drug is at the site of where you want it to work. Because of that mechanism, treprostinil doesn't normally, if you give treprostinil, it gets absorbed into the system. It hits your peak within 45 minutes to an hour, and then it gets metabolized and it's lost. This is the reason you need to dose very often if it's pure treprostinil. Later on, that's why patients have to be on IV. At the same time, you have a limitation of how high you can dose because the side effects, if you go up very high and my peak has to be very high up there, my side effects are now rate limiting of how much treprostinil I can actually give a patient. But the goal for these patients isn't. The better treatment is to give them as much as you can. So you want to do that in two things over time. Not only how long does it last. So with TPIP, we know when you measure it after 24 hours, there's still a treprostinil presence that you normally wouldn't see. That would be gone within an hour. And how high can I dose? So we have communicated before. We had in our blinded data we saw that over about 80% of patients could titrate up to the maximum dose that we had offered at 640 micrograms at the time. Because we've seen this with a good safety profile, there wasn't really any limitation to how they would be able to titrate patients up. We're in the open label extension now [and we've] allowed patients to potentially titrate up to twice the dose to 1280 micrograms. So that's not that they don't have to, but it is the opportunity for physician and patients if it's the right thing to go all the way up there. So that is important factors. In this disease, you want to give the patient as much treprostinil that you can, but you want to give it safely over time. And so that with TPIP are both of those ways that are clinically very different from what are currently available treprostinils. At the same time, we want to give a patient also overnight coverage because remember pulmonary arterial hypertension, it continues overnight even so when you don't have coverage. So that I think is very important on top of it. In the phase 2 PAH trial, you've mentioned I think most recently more than 90% enrolled. Yes. Can you comment just at all more than that around kind of geographic distribution there? Or I think the one question we get a lot around when Winrevair entering the U.S. market, how that impacts other products in development. Has that impacted any way enrollment in your trial? Actually, it hasn't. We've seen really enthusiastic enrollment in the PAH study, and it's both, it's in Europe, it's in the US, it's in Europe, and it's in Asian countries, so yes, we're 90% enrolled. You know, it's about 99-100%, 100-patient study, and we are on track for that. It hasn't really impacted it with others on the market. It is different than PH-ILD where we have to say the Tyvaso was on the market already in the US, so there we see, we saw and also in our safety study already a lot much more enrollment has come from Europe. Okay. And then, just switching to PH-ILD, that data will get soon here, I think early next year. Again, maybe just framing expectations, what should we be looking for when you release that data? Yeah, so that was a safety study. Really, the reason we did PH-ILD as a safety study is we wanted to make sure that there isn't a mismatch between the ventilation and between the perfusion. Because of PH-ILD patients, we have to think about them differently than PAH. PAH, it's a vascular disease. PH-ILD, these patients have both. They have a vascular disease and they have a lung disease, and so what you will see in the data, and that's why we also look at that, is you will get additional PK data in this population, and we will also have functional respiratory imaging data, so we've done high resolution CT scans in the PH-ILD population, and what you look for is what type of blood vessels are being recruited when you give the drug. And you're looking for, in many PH patients, the small blood vessels are not really functional. So you're looking for recruitment of those small blood vessels and then see what is the ratio of how much small blood vessels do I see actually activated versus just the large ones. And as part of that, there is also a fibrosis score because of the scarring and the dead tissue that you have in PH-ILD data. So you will see the data coming out in the early parts of next year. Okay, we just have about a minute left. So quickly on Arikayce, it sounds like you're in conversation. I know there's a sort of unlikely scenario the way the company talks about it, but in terms of the frontline opportunity here based on ARISE, when would we get the next? Sounds like soon we should be getting the update there. And then any comments around the ongoing work you're doing? Yeah. So we will meet with the agency. We will have the discussion, but as you know, in a meeting, the agency will not immediately tell you what their perspective is. But we do expect that we will have a little bit more clarity on that in the first quarter of 2025. And then we will absolutely give you an update. So we are continuing to enroll ENCORE very enthusiastically, and we see lots of patients who want to enter into the study. And we've targeted at the end 400 patients, and that was based off when we had after the last discussion with the agency where we had aligned on the respiratory score. And we will do the PRO will be based on the eight questions of the respiratory score. The ENCORE study itself is, I think, very well powered with 90% on the PRO and to show a difference of four points between the two groups and as well as for culture conversion. At the time when we will read out ENCORE, you will get both the PRO at month 13, so that's one month off drug, as well as culture conversion at month 12 and at month 13. There is a longer time point at month 15, and that's really mostly relevant for the Japanese regulatory authority. They are interested in that culture conversion endpoint. Okay. I think we're pretty much out of time. So why don't we leave it there? Thank you so much again for joining us at the conference and hope the rest of the conference goes well. Thank you.