Vicore Pharma Holding — Call Transcript 2025

All right, perfect. I'm Tiago biotech analyst here at Wells Fargo, joined today by Vicore. We have Ahmed for a fireside chat discussion. Appreciate you joining us today. No, thank you for having us together. We're very happy to be here. Got it. Vicore now listed in the U.S. For folks that are less familiar with the story, can you just start with an overview and then we'll go into a very boring and detailed discussion of the specifics? That sounds great. Vicore Pharma is a publicly traded company in Europe. We're listed on the Stockholm Exchange currently, and we are developing therapies in the renin-angiotensin system. In particular, our most advanced program is in idiopathic pulmonary fibrosis, where we're advancing an angiotensin II type 2 receptor agonist, which is, in a simplistic way, an upstream tissue repair and fibrosis resolution system. Essentially, we're hypercharging that system against this tough disease in the pulmonary fibrosis space. Perfect. This is a target that has been successful in some other indications, right? We've been trying it in hypertension, neuro. It's a very broad mechanism of action. Can you kind of just compare and contrast why this might be effective in this specific setting and some of the differences relative to comparing versus other attempts? Absolutely. Essentially, this receptor, this AT2 receptor, is, as I mentioned, activating tissue repair fibrosis resolution system. Its role in the body is to be the response system to the AT1 process. AT1 is, when activated, a process that drives fibrosis, inflammation, hypertension. If you have an infection, an injury, an insult, a drop in blood pressure, this AT1 system kicks in very quickly. It drives that hypertension and that inflammation and fibrosis to protect you. That's great. Your body has built in a system to basically counteract that very fast process slowly over time to resolve it. What's really interesting is that, as an industry, we've been able to create blockers of the AT1, basically to stop hypertension, fibrosis, inflammation on that AT1 side. That's been safe and well tolerated and very effective. What we're talking about here are ACE inhibitors and ARBs, like losartan and losartan class, which are antagonists of AT1. Actually, no one to date has developed and really made any serious effort on the AT2 agonism. Our hypothesis is, great, you can get some therapeutic benefit out of blocking the AT1 system. We think you can actually get a ton out of then activating the other side of it, the AT2 system. We think you can do it safely in a very well-tolerated way. We think, as you mentioned, Tiago, this is an upstream system. It's highly conserved across species. It's a reflection of how nicely built in it is. We think that there's a lot of opportunity taking advantage of it. We think that the lung is a really nice place to start. Got it. You've probably ran all the gamut on the preclinical side of things. What are some of the main findings with your lead candidate in bleomycin models? Several different, trying to recapitulate different parts of the disease, right? Exactly. When we think about the disease state at Vicore, pulmonary fibrosis is injury to the lung that leads to scarring, right? That scarring basically stops you from breathing. If you're breathing in, the oxygen is supposed to come through your air sacs, the alveolus, and it's supposed to go through these cells, the epithelial layer. It then goes into this interstitial space, which is basically a space in between the air sacs and the pulmonary vasculature. In order to breathe, you need the oxygen to go air sacs, interstitium, and then your bloodstream. We believe that all three parts of that are important for the disease. What we've basically shown in a number of different experiments is that by activating this receptor, this receptor exists in the lung by and large on a stem cell in the epithelium, in the air sac, called the alveolar epithelial type II cell. Essentially, the hypothesis is that by activating this receptor, we drive a proliferation and a refunctionalization of these stem cells. When you have pulmonary fibrosis, that injury injures these stem cells. They become apoptotic. They start dying off, become dysfunctional. That essentially is quite tough in this disease because that leads to then killing off the stem cells that are actually replacing the epithelial layer. They kind of differentiate into the gas exchange cells. Even if you have no fibrosis, if you have a dying off of these epithelial cells, you can't have gas exchange. The oxygen goes through these epithelial cells that basically are regenerated by these type II epithelial stem cells. That's the first thing that we're able to do, regenerate that epithelial layer. The second thing that we're able to do is these stem cells are responsible for maintaining alveolar integrity. An air sac has this inflated shape, even though it's a very water-containing compartment. Water tends to have a high surface tension. If you were to leave the water in there without any other forces, it would kind of collapse like a pancake. What the type II epithelial cells do, these stem cells do, is they release surfactant proteins. The surfactant proteins then allow the alveolus to maintain that inflated shape. Basically, what's known to happen in IPF is even before the fibrosis accumulates, you have pre-fibrotic alveolar collapse due to loss of surfactant production, which reduces lung function, again, before you even have that buildup of scarring around the air sacs that stops the oxygen from going through. Our mechanism addresses those two things. What happens next is the fibrosis. It turns out, a number of academic groups have now shown this, that the orchestrator of the fibrosis is this pro-fibrotic cytokine that everyone talks about, TGF-β1. It's these type II epithelial cells, these stem cells, that are the main secretor of TGF-β1. Basically, you injure them, and they are the ones that release the injury signal. Again, by refunctionalizing the cell type and driving their normalization, you are able to reduce or cut off that pathological TGF-β1 signal. You can reduce the pro-fibrotic drive, and you have less buildup of fibrosis in the interstitium. What's really nice about this mechanism is not only does it do that, but it also helps to resolve fibrosis. It upregulates a number of enzymes called collagenase MMPs. We've shown this preclinically, that can then actually digest existing collagen. Finally, if we know anything about the angiotensin II pathway, it is that it has a vascular impact, right? The job of the AT2 is to do the opposite of the AT1. To reverse the hypertension, it drives a local vasodilation and a reversal of endothelial remodeling. We think this is also a very intriguing part of the mechanism of action. You expand the vasculature. You reduce the thickening of the endothelial layer so that the oxygen can come from air sac to the interstitium, straight into the pulmonary vasculature. We think this is the right way to go after IPF. This has resulted in great preclinical data in all of the models, including, of course, the traditional bleomycin models. It certainly looks very potent in those models. We've seen some nice clinical data behind this as well so far. Yeah, there's always that question on translating the preclinical findings into clinical. We're going to get to the clinical data. Up until very recently, we hadn't seen many wins in IPF, right? A couple of programs that seemed really promising mechanistically, and even with early stage data, turned out to have a safety signal, right? From a mechanistic perspective, I know you have some data to support that. Any particular concerns in terms of somewhat addressing TGF-β? Not like an integrin, for example. Just from a mechanistic perspective, how comfortable can we be with this mechanism on the safety side? Yeah, we've actually dosed this drug now in over 300 patients, and it's been safe and well tolerated. It has an excellent profile overall. The second piece of the puzzle is, in principle, what we're doing is the type II epithelial cells start spitting out a ton of extra TGF-β1 when they're injured. We refunctionalize them, and we bring that pathological signal down. We do not block TGF-β, right? The other approaches that have been very tough in this disease are you just do systemic blockade of the activation or signaling in TGF-β. That is not what this mechanism does. You see, even in our preclinical models, we bring the TGF-β levels not to zero, but we bring them back down to kind of the normal levels. You need TGF-β for tissue homeostasis and for maintenance of normal extracellular matrix. We recognize that piece. In addition to this mechanism being, in principle, kind of a different risk-reward profile, what's also nice to see is the AT2 receptor, this receptor that we're activating, actually tends to be very selectively expressed. In most tissues, you actually don't find this receptor until there's fibrosis or inflammation. One of the very few tissues that you'll find this receptor in in a healthy person is the lung. We think that's evolutionarily because you tend to breathe in viral particles, infectious particles, pollution. There's always a little bit of inflammatory and fibrotic response to that in your lung. Having this repair system online in your lung all the time makes evolutionary sense. For whatever reason, this AT2 receptor is pretty limited to the lung in a healthy person. It's further upregulated in disease states like IPF. Receptor kind of expression-wise, we also have a differentiated safety profile. Some of these other targets that companies are going after are targets that are expressed everywhere in the body. That's just not the case for the AT2 receptor. Got it. Perfect. Let's move on to the actual clinical data, right? You had the 36-week AIR study. What did you learn from a safety, tolerability, and again, some of the efficacy signals that you saw? We'll kind of go into some of the key debates around that data set. Yeah, no, that sounds great. I think the first really nice thing that was done in this study is following the patients for 36 weeks from the outset. A number of other therapies have kind of done shorter 12-week studies. The challenge with that is, if you reduce inflammation or swelling, you can have some moderate impact on lung function. It might not be sustained as fibrosis continues to build and overtakes whatever benefits you got over time. It was really nice to see how this drug performed over a 36-week period. I also think it's the right way to study a mechanism like this, which is supposed to be slow repair of the tissues and resolution of fibrosis. We saw in this open-label study a 200 mL improvement in lung function at average over that 36-week period, which is quite a dramatic difference from what you would expect. In a placebo group, you'd expect a decline of 180 mL over that time. Instead, we're having a 200 mL improvement. Got it. Once you see that, and this was not a placebo-controlled trial, which I think is one of the main pushbacks that you might get there, you saw an increase on efficacy relative to baseline for a few of these patients. Is any of that being driven by outliers? How can you actually interpret and get some degree of confidence that that's a real signal? Yeah. I think the first thing to think about in the context of an open-label trial is, how good was the diagnostics in the study? Because actually, we know that IPF patients decline, right? Like the percentage of patients over a 36-week period that would have stable or improved FVC is in the single digit. This is not a disease where you're going to have some material portion of the population that will improve. Are you really sure it's IPF? The diagnostics can be challenging. What's nice is a really good job was done making sure that these were IPF patients. In particular, the hallmark of IPF diagnosis is a high-resolution CT scan. What we did is we used a pulmonary radiologist out of the United Kingdom who actually does these phase III trials for BI and other companies in terms of confirming scan by scan the right interstitial lung pattern that would be consistent with a diagnosis of IPF. I think that we have a high degree of confidence that this data set represents IPF patients. Once you have IPF patients to see them improving, I think that it would be a statistical anomaly if it were to be chance. We actually did a synthetic control arm where we built placebo matched patients. To talk more about that, the data was presented at the ATS, right? Can you walk us through some of the work that went into that? What would you have expected from a synthetic matched placebo? Absolutely. The phase II-A trial was a monotherapy study of the population in a treatment-naive setting. Essentially, we pulled out a database of over 10,000 IPF patients. We selected the patients that would be matching our inclusion criteria. From that database, we built 20,000 synthetic control arm cohorts, basically these control cohorts that would meet the same inclusion criteria. We took those 20,000 and matched them on the baseline characteristics. We took the approximately 400 placebo arms that would be closest matching in terms of FEV1, FVC, the different ratios, the age, the gender, all those characteristics, and basically said, what does the aggregate of these 400-ish placebo arms look like? That was about a 114 mL decline in lung function over 36 weeks, which is exactly what you'd expect. It's 180 in these phase III settings. This was a slightly earlier stage population, so you could expect decline in lung function to be a little bit less. When you compare that against what we saw in the phase II-A trial, again, very, very different. Even when you use that placebo arm to impute your data set, we took that placebo arm and said, what if we pretend that every patient who dropped out of our phase 2a trial had that level of decline of lung function, that 114 mL over a 36-week period decline in lung function? You still see the improvement in lung function, and you still see that signal confirmed. Tiago, one other question you asked me is, how do you have some confidence around this data set? Is it driven by outliers? I would say what's beautiful about this data set is it's not outlier driven. 65% of the patients at 36 weeks had improvement in lung function. The study enrolled heavily out of India, where it was easy to find treatment-naive patients. The patients who we enrolled out of U.K. at mean and median also had improvement in lung function. The patients with the more early stage disease had really high levels of improvement in lung function, which is consistent with our mechanism impacting that epithelial compartment even before fibrosis. Even the later stage patients who had more evidence of fibrotic buildup also had improvement in lung function. I think there's a nice biological plausibility and consistency with this type of mechanism of action. It's a slow resolution of fibrosis. You would imagine with the patients coming in where they have more entrenched fibrosis, you can start to improve over that 36-week period. It's the patients really where you can do some of that regeneration in the epithelial compartment, and there's not a lot of scarring to deal with, where you can have even kind of a super effect over that time period. Got it. Again, thinking about the translation of those early findings to a placebo-controlled larger trial, right? You alluded to a lot of scrutiny on the confirmed diagnosis of disease, the simulations to try to imply what placebo could have done, the statistical analysis that you have to get confidence in that positive signal. What are some other factors when trying to consider the odds of success of translating some of those findings? If you look at the high-vaso increase subgroup analysis, you saw an initial increase in FVC in a pulmonary hypertension IPF patient population. That did translate to a clinical benefit in an IPF trial later down the line. You had a couple of those early wins that folks were initially skeptical. A couple of them got across the finish line, right? What are some considerations there? Trial design, there's background therapy now. Can you walk us through the design and some of the puts and takes? Yeah, absolutely. I think the first thing that we really wanted to do in this, it's really a gold standard trial. The ongoing phase 2b is a 52-week trial. It has the registrational endpoint impact on lung function FVC over that 52-week period. It has the positioning of the drug on top of standard of care nintedanib or not on standard of care. It's similar to the other phase 3s, including the [TETEN] studies that recently read out, and then a broad inclusion criteria. We're really trying to demonstrate in this upcoming trial what we can do in a way that would be very relevant to what you would do in the real world in the clinical setting and what you would do in a phase 3. There's no material difference in setup from what we would do subsequent to this phase 2b in a phase 3, and that's very intentional. The thing that we were thinking about also is being conservative on powering, right? We see this really nice signal of improvement in lung function in the phase 2a. Of course, we know that even stabilization would be a huge benefit and certainly a blockbuster therapy. Even something that can materially reduce the decline of lung function would also be a very exciting opportunity. We've powered our study for a 125 mL difference in lung function between the treatment arm and the placebo arm. I think that reflects both that we're being conservative relative to what we saw in the phase 2a. Also, we're pretty bullish on what we think our drug can accomplish. When you think about, as you mentioned, in the [INCREASE] trial, you see this kind of improvement in lung function. Of course, now there's a reported in the [TETEN] studies 95 mL difference from placebo to the treatment arm. I think that's a reflection that as you go into these bigger trials and these other settings, there might be some reversion to the mean. We do think that it's an exciting signal, and we think we've powered responsibly in our phase 2b in view of that type of a signal. What about the dose selection work that went into that? Yeah, absolutely. We've used our preclinical data set to do a lot of dose modeling because in our phase I, we did not see any MTD or DLT. We did see some hair loss or hair thinning. We're trying to strike the balance there. While IPF is a fatal disease and one that unfortunately has a prognosis of only three to four years survival, we still wanted to be mindful of whether we could control or mitigate that type of side effect. In our phase II-A, we selected a dose of 100 mL twice daily, which we believe drives higher than IC90 efficacy levels in terms of concentration of the drug in the lung. I think that bore out in that signal of significant clinical improvement. We also saw in that study 19% of patients had mild to moderate hair loss or hair thinning. In our phase II-B trial, we will also be advancing that 100 mL twice daily. We certainly think this is a very manageable side effect in the context of the deadly disease of IPF. It's also a disease generally of older men on average. We will also be testing a 50 mL twice daily dose. The hair loss or hair thinning is a dose-dependent effect. We do believe that this will have the ability to mitigate or potentially eliminate the effect. Based on our dose modeling, we do believe that the 50 mL twice daily will be an efficacious dose as well. Got it. No, perfect. What about clinical trial execution? Like there's always some degree of skepticism inside of the company, given that it's a competitive environment. Up until very recently, we had a lot of phase IIs ongoing, less so now. Can you talk about some of that dynamic? How broad are you going to enroll these trials? What are some of the steps you're taking to ensure that you can achieve reasonable timelines relative to comps? Yep. This is, as you mentioned, Tiago, a huge undertaking. It's a 270-patient trial. We are building a network of 100 clinical sites across 14 countries. The study is actually well underway in terms of execution. It is executing quite well. We're really heartened to see that. We've already guided that we expect enrollment to be complete in the first half of 2026. We have most of the sites fully up and running, heavily underway on enrollment. What's nice is we are the only 52-week study that I believe is currently enrolling. We are the most advanced therapy that's currently enrolling a study. I think that's led to a lot of enthusiasm because, of course, as you know, BI has had their readout. United Therapeutics has completed their readout for their first phase III. Their second phase III has completed enrollment. Also, BMS, who are the only other phase III or the only other program that's more advanced than us, have also completed enrollment. I think that leaves a nice amount of room for us to continue effectively enrolling this study. We're certainly spending a lot of time engaging with the clinical community to effectively do this. I personally was out in South Korea, where we have a relatively large number of sites for an investigator meeting last week. We're also a team that's on the ground so that we can execute. We have over a half dozen clinical science liaisons who are distributed across these 14 countries. We try to spend a lot of time with the clinical sites explaining the mechanism, the risk-reward, the trial setup, and really making sure that we can effectively execute the study. Got it. Perfect. Again, assuming positive data, what could be the regulatory path going forward for the drug? Yeah, we believe after hopefully a successful phase II-B, a single phase III will be required in order to gain regulatory approval of the drug for IPF. That's in part because of the nature of our phase II-B, because it has many of the features of a phase II. Quite adequate control. Exactly. Yeah, controlling the setup. Of course, ultimately, what we're looking at is a therapy that would be a front line on top of the standard of care. That's how our phase II is set up as well. We expect 70%-80% of the patients coming into our phase II-B to be on nintedanib standard of care and 20%-30% to be not on standard of care. Got it. I think it seems fairly standard with some of the more recent phase II trials, right? Let's talk a little bit about the commercial positioning, right? If you talk to physicians, there seems to be so huge unmet need. At the same time, sometimes you hear that the field is crowded. You just had a couple of wins that we haven't had for a while. Is there really a need for an additional mechanism of action? How much overlap is there? Can you see some synergistic effects? Just a lot of questions on the unknown commercial outlook. I think a lot of those concerns are overblown if you hear through physicians. I'd love to get your take on that. Yeah, I mean, relative to the size of the market, this area is highly, highly underserved, right? I mean, you're talking about two standard of care therapies that don't materially change that three to four-year survival picture that we just discussed and that most patients don't even initiate therapy because of the tough side effects. Only 25% of patients with IPF ever even initiate therapy in the United States. The time on therapy is only 10 months. When you talk to clinicians on the front lines in this space, many of them know how tough it is for patients to stay on these drugs. They wait until they're progressive. They say, you know, I understand that in theory, I'm supposed to put my patients on standard of care to stop them from having a decline in lung function. If they're kind of trending stable in their lung function, then I wait. The problem with that is that ultimately, these declines in lung function can be very sudden and very precipitous. The idea, at least intellectually, is that you should keep patients on therapies as early as possible in order to prevent the decline. Really, I think that we are looking also to try to drive some paradigm shift. To be honest with you, this is why we're quite excited to see United Therapeutics put out some nice data. First and foremost, it's a scientific validation of what we're doing at Vicore because this impact on the vasculature, we think, together with impact on other compartments, can have a huge effect. Even without having formally diagnosed pulmonary hypertension, the beginnings of this occur early with the vascular dysfunction. We think scientifically, this is a huge support and a huge kind of validation in what we're doing at Vicore. The other piece is really it's great to have a sales force out there who's trying to drive and seeking to drive in the years ahead of a potential launch of buloxibutid for IPF, a mindset shift in clinicians so that this market, which is currently $4 billion annually for 25% of patients initiating and 10 months continuation, you then see that number come up hopefully 50% and even beyond that. Of course, hopefully with better tolerated therapies, also having patients stay on longer. Certainly, if you can have therapies that patients can live with longer that are actually more efficacious, you should also see the extended time on therapy, which is a commercial benefit as well. Got it. Is this the kind of product or the kind of opportunity that if you show 60 mL placebo-adjusted, it's zero, and if you show 100, it's mostly how much elasticity is there depending on the kind of product profile that you can achieve? You mentioned some of your talks. There doesn't seem to be a lot of overlapping talks with current standard of care, right? Is that fair? Yes. Combo, mono, again, kind of depends on how everything plays out. What are some of the potential placements in this driven paradigm? Yeah, look, we're aiming high. We're not aiming for an incremental effect. If our drug is not powered, our study, our phase II-B is not powered to show a 60 mL difference, right? That's not where we're aiming. Any positive read on the ASPIRE study, even with the relatively conservative powering in relation to what we saw in phase II-A, would certainly be a blockbuster opportunity. We saw United Therapeutics add many billions to their market cap with a 95 mL difference in lung function. We're even believing that we can aim even higher than that. That's the type of effect that we've powered for in this study. Again, how we think about that ultimate positioning is we think that this is a drug that's great for patients to take at the outset. It drives that epithelial repair that comes even before the fibrosis. We'd like to position this drug as a front line that you take with the available standard of care. As we see BI's nerandomilast and United Therapeutics's TYVASO kind of launch in the marketplace, we'll consider how we design our phase III study, right? Currently, we are allowing the most popular standard of care nintedanib in our phase II-B. We can continue to evolve that thinking and say we can combine on top of other things depending on how they look in the phase III setting as well to set ourselves up for a good commercial launch. What's nice is we know what the universe is ahead of us. It's that BI's nerandomilast, United Therapeutics TYVASO, and then BMA has their LPA1 antagonist. We can plan for that world effectively. Yeah, fair enough. I guess as we're kind of closing, can you recap IP, stay, lifecycle management thoughts, anything on that end? Yeah, absolutely. First on the IP side, we have IP going out until 2042 before any kind of SPC or PTE protection. Quite a robust IP portfolio that certainly I'm excited to work on as a former IP lawyer as well. In addition to that, it's really nice to have a lot of consideration around both indication extension and lifecycle management. Now, you see United Therapeutics coming at pulmonary fibrosis from the pulmonary hypertension space. We have a lot of conviction in this drug for pulmonary hypertension. We think PHILD is a high unmet need. We have some great preclinical data, including in the Sugen hypoxia model, monocrotaline model. We see our indication expansion broadly into the pulmonary space, going the opposite way from United Therapeutics, where we would go into the pulmonary hypertension space. This is a super upstream and broad mechanism. We even think about indications outside of the lung for follow-on compounds that have been optimized. For example, we're really thinking a lot these days about chronic kidney disease space and renal indications, as well as potentially other. Oh, fantastic. We covered a lot of ground. Is there anything else that you'd like to highlight from the story that's still misunderstood or that you're excited about? We can probably wrap up. No, absolutely. I think that on our phase II-A signal, as we discussed a little bit, there are some pieces of the puzzle that are a little bit different in terms of having a longer study that I think are positive. There are some things that we have to wrap our head around, like the open-label nature of the study. We have a high degree of conviction that it represents a true clinical signal and are excited to move forward. I would say on the company front, while we are currently publicly listed in Sweden, we're really excited to engage more and more with the U.S. audience and certainly actively exploring U.S. listing opportunities in the future, hopefully potentially even ahead of the phase II-B readout. Fantastic. Thank you so much for your time. Appreciate you joining us. Thank you, Tiago. Appreciate it.

Speaker 1: All right, perfect. I'm Tiago biotech analyst here at Wells Fargo, joined today by Vicore. We have Ahmed for a fireside chat discussion. Appreciate you joining us today. All right, perfect. all right perfect I'm Tiago biotech analyst here at Wells Fargo, joined today by Vicore . i'm tiago biotech analyst here at wells fargo joined today by vicore We have Ahmed for a fireside chat discussion. we have ahmed for a fireside chat discussion Appreciate you joining us today. appreciate you joining us today

Speaker 3: No, thank you for having us together. We're very happy to be here. No, thank you for having us together. no thank you for having us together We're very happy to be here. we're very happy to be here

Speaker 1: Got it. Vicore now listed in the U.S. For folks that are less familiar with the story, can you just start with an overview and then we'll go into a very boring and detailed discussion of the specifics? Got it. got it Vicore now listed in the U.S. vicore now listed in the u.s For folks that are less familiar with the story, can you just start with an overview and then we'll go into a very boring and detailed discussion of the specifics? for folks that are less familiar with the story can you just start with an overview and then we'll go into a very boring and detailed discussion of the specifics

Speaker 3: That sounds great. Vicore Pharma is a publicly traded company in Europe. We're listed on the Stockholm Exchange currently, and we are developing therapies in the renin-angiotensin system. In particular, our most advanced program is in idiopathic pulmonary fibrosis, where we're advancing an angiotensin II type 2 receptor agonist, which is, in a simplistic way, an upstream tissue repair and fibrosis resolution system. Essentially, we're hypercharging that system against this tough disease in the pulmonary fibrosis space. That sounds great. that sounds great Vicore Pharma is a publicly traded company in Europe. vicore pharma is a publicly traded company in europe We're listed on the Stockholm Exchange currently, and we are developing therapies in the renin-angiotensin system. we're listed on the stockholm exchange currently and we are developing therapies in the renin-angiotensin system In particular, our most advanced program is in idiopathic pulmonary fibrosis, where we're advancing an angiotensin II type 2 receptor agonist, which is, in a simplistic way, an upstream tissue repair and fibrosis resolution system. in particular our most advanced program is in idiopathic pulmonary fibrosis where we're advancing an angiotensin ii type 2 receptor agonist which is in a simplistic way an upstream tissue repair and fibrosis resolution system Essentially, we're hypercharging that system against this tough disease in the pulmonary fibrosis space. essentially we're hypercharging that system against this tough disease in the pulmonary fibrosis space

Speaker 1: Perfect. This is a target that has been successful in some other indications, right? We've been trying it in hypertension, neuro. It's a very broad mechanism of action. Can you kind of just compare and contrast why this might be effective in this specific setting and some of the differences relative to comparing versus other attempts? Perfect. perfect This is a target that has been successful in some other indications, right? this is a target that has been successful in some other indications right We've been trying it in hypertension, neuro. we've been trying it in hypertension neuro It's a very broad mechanism of action. it's a very broad mechanism of action Can you kind of just compare and contrast why this might be effective in this specific setting and some of the differences relative to comparing versus other attempts? can you kind of just compare and contrast why this might be effective in this specific setting and some of the differences relative to comparing versus other attempts

Speaker 3: Absolutely. Essentially, this receptor, this AT2 receptor, is, as I mentioned, activating tissue repair fibrosis resolution system. Its role in the body is to be the response system to the AT1 process. AT1 is, when activated, a process that drives fibrosis, inflammation, hypertension. If you have an infection, an injury, an insult, a drop in blood pressure, this AT1 system kicks in very quickly. It drives that hypertension and that inflammation and fibrosis to protect you. That's great. Your body has built in a system to basically counteract that very fast process slowly over time to resolve it. What's really interesting is that, as an industry, we've been able to create blockers of the AT1, basically to stop hypertension, fibrosis, inflammation on that AT1 side. That's been safe and well tolerated and very effective. Absolutely. absolutely Essentially, this receptor, this AT2 receptor, is, as I mentioned, activating tissue repair fibrosis resolution system. essentially this receptor this at2 receptor is as i mentioned activating tissue repair fibrosis resolution system Its role in the body is to be the response system to the AT1 process. its role in the body is to be the response system to the at1 process AT1 is, when activated, a process that drives fibrosis, inflammation, hypertension. at1 is when activated a process that drives fibrosis inflammation hypertension If you have an infection, an injury, an insult, a drop in blood pressure, this AT1 system kicks in very quickly. if you have an infection an injury an insult a drop in blood pressure this at1 system kicks in very quickly It drives that hypertension and that inflammation and fibrosis to protect you. it drives that hypertension and that inflammation and fibrosis to protect you That's great. that's great Your body has built in a system to basically counteract that very fast process slowly over time to resolve it. your body has built in a system to basically counteract that very fast process slowly over time to resolve it What's really interesting is that, as an industry, we've been able to create blockers of the AT1, basically to stop hypertension, fibrosis, inflammation on that AT1 side. what's really interesting is that as an industry we've been able to create blockers of the at1 basically to stop hypertension fibrosis inflammation on that at1 side That's been safe and well tolerated and very effective. that's been safe and well tolerated and very effective What we're talking about here are ACE inhibitors and ARBs, like losartan and losartan class, which are antagonists of AT1. Actually, no one to date has developed and really made any serious effort on the AT2 agonism. Our hypothesis is, great, you can get some therapeutic benefit out of blocking the AT1 system. We think you can actually get a ton out of then activating the other side of it, the AT2 system. We think you can do it safely in a very well-tolerated way. We think, as you mentioned, Tiago, this is an upstream system. It's highly conserved across species. It's a reflection of how nicely built in it is. We think that there's a lot of opportunity taking advantage of it. We think that the lung is a really nice place to start. What we're talking about here are ACE inhibitors and ARBs, like losartan and losartan class, which are antagonists of AT1. what we're talking about here are ace inhibitors and arbs like losartan and losartan class which are antagonists of at1 Actually, no one to date has developed and really made any serious effort on the AT2 agonism. actually no one to date has developed and really made any serious effort on the at2 agonism Our hypothesis is, great, you can get some therapeutic benefit out of blocking the AT1 system. our hypothesis is great you can get some therapeutic benefit out of blocking the at1 system We think you can actually get a ton out of then activating the other side of it, the AT2 system. we think you can actually get a ton out of then activating the other side of it the at2 system We think you can do it safely in a very well-tolerated way. we think you can do it safely in a very well-tolerated way We think, as you mentioned, Tiago, this is an upstream system. we think as you mentioned tiago this is an upstream system It's highly conserved across species. it's highly conserved across species It's a reflection of how nicely built in it is. it's a reflection of how nicely built in it is We think that there's a lot of opportunity taking advantage of it. we think that there's a lot of opportunity taking advantage of it We think that the lung is a really nice place to start. we think that the lung is a really nice place to start

Speaker 1: Got it. You've probably ran all the gamut on the preclinical side of things. What are some of the main findings with your lead candidate in bleomycin models? Several different, trying to recapitulate different parts of the disease, right? Got it. got it You've probably ran all the gamut on the preclinical side of things. you've probably ran all the gamut on the preclinical side of things What are some of the main findings with your lead candidate in bleomycin models? what are some of the main findings with your lead candidate in bleomycin models Several different, trying to recapitulate different parts of the disease, right? several different trying to recapitulate different parts of the disease right

Speaker 3: Exactly. When we think about the disease state at Vicore, pulmonary fibrosis is injury to the lung that leads to scarring, right? That scarring basically stops you from breathing. If you're breathing in, the oxygen is supposed to come through your air sacs, the alveolus, and it's supposed to go through these cells, the epithelial layer. It then goes into this interstitial space, which is basically a space in between the air sacs and the pulmonary vasculature. In order to breathe, you need the oxygen to go air sacs, interstitium, and then your bloodstream. We believe that all three parts of that are important for the disease. What we've basically shown in a number of different experiments is that by activating this receptor, this receptor exists in the lung by and large on a stem cell in the epithelium, in the air sac, called the alveolar epithelial type II cell. Exactly. exactly When we think about the disease state at Vicore, pulmonary fibrosis is injury to the lung that leads to scarring, right? when we think about the disease state at vicore pulmonary fibrosis is injury to the lung that leads to scarring right That scarring basically stops you from breathing. that scarring basically stops you from breathing If you're breathing in, the oxygen is supposed to come through your air sacs, the alveolus, and it's supposed to go through these cells, the epithelial layer. if you're breathing in the oxygen is supposed to come through your air sacs the alveolus and it's supposed to go through these cells the epithelial layer It then goes into this interstitial space, which is basically a space in between the air sacs and the pulmonary vasculature. it then goes into this interstitial space which is basically a space in between the air sacs and the pulmonary vasculature In order to breathe, you need the oxygen to go air sacs, interstitium, and then your bloodstream. in order to breathe you need the oxygen to go air sacs interstitium and then your bloodstream We believe that all three parts of that are important for the disease. we believe that all three parts of that are important for the disease What we've basically shown in a number of different experiments is that by activating this receptor, this receptor exists in the lung by and large on a stem cell in the epithelium, in the air sac, called the alveolar epithelial type II cell. what we've basically shown in a number of different experiments is that by activating this receptor this receptor exists in the lung by and large on a stem cell in the epithelium in the air sac called the alveolar epithelial type ii cell Essentially, the hypothesis is that by activating this receptor, we drive a proliferation and a refunctionalization of these stem cells. When you have pulmonary fibrosis, that injury injures these stem cells. They become apoptotic. They start dying off, become dysfunctional. That essentially is quite tough in this disease because that leads to then killing off the stem cells that are actually replacing the epithelial layer. They kind of differentiate into the gas exchange cells. Even if you have no fibrosis, if you have a dying off of these epithelial cells, you can't have gas exchange. The oxygen goes through these epithelial cells that basically are regenerated by these type II epithelial stem cells. That's the first thing that we're able to do, regenerate that epithelial layer. The second thing that we're able to do is these stem cells are responsible for maintaining alveolar integrity. Essentially, the hypothesis is that by activating this receptor, we drive a proliferation and a refunctionalization of these stem cells. essentially the hypothesis is that by activating this receptor we drive a proliferation and a refunctionalization of these stem cells When you have pulmonary fibrosis, that injury injures these stem cells. when you have pulmonary fibrosis that injury injures these stem cells They become apoptotic. they become apoptotic They start dying off, become dysfunctional. they start dying off become dysfunctional That essentially is quite tough in this disease because that leads to then killing off the stem cells that are actually replacing the epithelial layer. that essentially is quite tough in this disease because that leads to then killing off the stem cells that are actually replacing the epithelial layer They kind of differentiate into the gas exchange cells. they kind of differentiate into the gas exchange cells Even if you have no fibrosis, if you have a dying off of these epithelial cells, you can't have gas exchange. even if you have no fibrosis if you have a dying off of these epithelial cells you can't have gas exchange The oxygen goes through these epithelial cells that basically are regenerated by these type II epithelial stem cells. the oxygen goes through these epithelial cells that basically are regenerated by these type ii epithelial stem cells That's the first thing that we're able to do, regenerate that epithelial layer. that's the first thing that we're able to do regenerate that epithelial layer The second thing that we're able to do is these stem cells are responsible for maintaining alveolar integrity. the second thing that we're able to do is these stem cells are responsible for maintaining alveolar integrity An air sac has this inflated shape, even though it's a very water-containing compartment. Water tends to have a high surface tension. If you were to leave the water in there without any other forces, it would kind of collapse like a pancake. What the type II epithelial cells do, these stem cells do, is they release surfactant proteins. The surfactant proteins then allow the alveolus to maintain that inflated shape. Basically, what's known to happen in IPF is even before the fibrosis accumulates, you have pre-fibrotic alveolar collapse due to loss of surfactant production, which reduces lung function, again, before you even have that buildup of scarring around the air sacs that stops the oxygen from going through. Our mechanism addresses those two things. What happens next is the fibrosis. An air sac has this inflated shape, even though it's a very water-containing compartment. an air sac has this inflated shape even though it's a very water-containing compartment Water tends to have a high surface tension. water tends to have a high surface tension If you were to leave the water in there without any other forces, it would kind of collapse like a pancake. if you were to leave the water in there without any other forces it would kind of collapse like a pancake What the type II epithelial cells do, these stem cells do, is they release surfactant proteins. what the type ii epithelial cells do these stem cells do is they release surfactant proteins The surfactant proteins then allow the alveolus to maintain that inflated shape. the surfactant proteins then allow the alveolus to maintain that inflated shape Basically, what's known to happen in IPF is even before the fibrosis accumulates, you have pre-fibrotic alveolar collapse due to loss of surfactant production, which reduces lung function, again, before you even have that buildup of scarring around the air sacs that stops the oxygen from going through. basically what's known to happen in ipf is even before the fibrosis accumulates you have pre-fibrotic alveolar collapse due to loss of surfactant production which reduces lung function again before you even have that buildup of scarring around the air sacs that stops the oxygen from going through Our mechanism addresses those two things. our mechanism addresses those two things What happens next is the fibrosis. what happens next is the fibrosis It turns out, a number of academic groups have now shown this, that the orchestrator of the fibrosis is this pro-fibrotic cytokine that everyone talks about, TGF-β1. It's these type II epithelial cells, these stem cells, that are the main secretor of TGF-β1. Basically, you injure them, and they are the ones that release the injury signal. Again, by refunctionalizing the cell type and driving their normalization, you are able to reduce or cut off that pathological TGF-β1 signal. You can reduce the pro-fibrotic drive, and you have less buildup of fibrosis in the interstitium. What's really nice about this mechanism is not only does it do that, but it also helps to resolve fibrosis. It upregulates a number of enzymes called collagenase MMPs. We've shown this preclinically, that can then actually digest existing collagen. It turns out, a number of academic groups have now shown this, that the orchestrator of the fibrosis is this pro-fibrotic cytokine that everyone talks about, TGF-β1 . it turns out a number of academic groups have now shown this that the orchestrator of the fibrosis is this pro-fibrotic cytokine that everyone talks about tgf-β1 It's these type II epithelial cells, these stem cells, that are the main secretor of TGF-β1 . it's these type ii epithelial cells these stem cells that are the main secretor of tgf-β1 Basically, you injure them, and they are the ones that release the injury signal. basically you injure them and they are the ones that release the injury signal Again, by refunctionalizing the cell type and driving their normalization, you are able to reduce or cut off that pathological TGF-β1 signal. again by refunctionalizing the cell type and driving their normalization you are able to reduce or cut off that pathological tgf-β1 signal You can reduce the pro-fibrotic drive, and you have less buildup of fibrosis in the interstitium. you can reduce the pro-fibrotic drive and you have less buildup of fibrosis in the interstitium What's really nice about this mechanism is not only does it do that, but it also helps to resolve fibrosis. what's really nice about this mechanism is not only does it do that but it also helps to resolve fibrosis It upregulates a number of enzymes called collagenase MMPs. it upregulates a number of enzymes called collagenase mmps We've shown this preclinically, that can then actually digest existing collagen. we've shown this preclinically that can then actually digest existing collagen Finally, if we know anything about the angiotensin II pathway, it is that it has a vascular impact, right? The job of the AT2 is to do the opposite of the AT1. To reverse the hypertension, it drives a local vasodilation and a reversal of endothelial remodeling. We think this is also a very intriguing part of the mechanism of action. You expand the vasculature. You reduce the thickening of the endothelial layer so that the oxygen can come from air sac to the interstitium, straight into the pulmonary vasculature. We think this is the right way to go after IPF. This has resulted in great preclinical data in all of the models, including, of course, the traditional bleomycin models. It certainly looks very potent in those models. We've seen some nice clinical data behind this as well so far. Finally, if we know anything about the angiotensin II pathway, it is that it has a vascular impact, right? finally if we know anything about the angiotensin ii pathway, it is that it has a vascular impact right The job of the AT2 is to do the opposite of the AT1. the job of the at2 is to do the opposite of the at1 To reverse the hypertension, it drives a local vasodilation and a reversal of endothelial remodeling. to reverse the hypertension it drives a local vasodilation and a reversal of endothelial remodeling We think this is also a very intriguing part of the mechanism of action. we think this is also a very intriguing part of the mechanism of action You expand the vasculature. you expand the vasculature You reduce the thickening of the endothelial layer so that the oxygen can come from air sac to the interstitium, straight into the pulmonary vasculature. you reduce the thickening of the endothelial layer so that the oxygen can come from air sac to the interstitium straight into the pulmonary vasculature We think this is the right way to go after IPF. we think this is the right way to go after ipf This has resulted in great preclinical data in all of the models, including, of course, the traditional bleomycin models. this has resulted in great preclinical data in all of the models including of course the traditional bleomycin models It certainly looks very potent in those models. it certainly looks very potent in those models We've seen some nice clinical data behind this as well so far. we've seen some nice clinical data behind this as well so far

Speaker 1: Yeah, there's always that question on translating the preclinical findings into clinical. We're going to get to the clinical data. Up until very recently, we hadn't seen many wins in IPF, right? A couple of programs that seemed really promising mechanistically, and even with early stage data, turned out to have a safety signal, right? From a mechanistic perspective, I know you have some data to support that. Any particular concerns in terms of somewhat addressing TGF-β? Not like an integrin, for example. Just from a mechanistic perspective, how comfortable can we be with this mechanism on the safety side? Yeah, there's always that question on translating the preclinical findings into clinical. yeah there's always that question on translating the preclinical findings into clinical We're going to get to the clinical data. we're going to get to the clinical data Up until very recently, we hadn't seen many wins in IPF, right? up until very recently we hadn't seen many wins in ipf right A couple of programs that seemed really promising mechanistically, and even with early stage data, turned out to have a safety signal, right? a couple of programs that seemed really promising mechanistically and even with early stage data turned out to have a safety signal right From a mechanistic perspective, I know you have some data to support that. from a mechanistic perspective i know you have some data to support that Any particular concerns in terms of somewhat addressing TGF-β ? any particular concerns in terms of somewhat addressing Not like an integrin, for example. not like an integrin for example Just from a mechanistic perspective, how comfortable can we be with this mechanism on the safety side? just from a mechanistic perspective how comfortable can we be with this mechanism on the safety side

Speaker 3: Yeah, we've actually dosed this drug now in over 300 patients, and it's been safe and well tolerated. It has an excellent profile overall. The second piece of the puzzle is, in principle, what we're doing is the type II epithelial cells start spitting out a ton of extra TGF-β1 when they're injured. We refunctionalize them, and we bring that pathological signal down. We do not block TGF-β, right? The other approaches that have been very tough in this disease are you just do systemic blockade of the activation or signaling in TGF-β. That is not what this mechanism does. You see, even in our preclinical models, we bring the TGF-β levels not to zero, but we bring them back down to kind of the normal levels. You need TGF-β for tissue homeostasis and for maintenance of normal extracellular matrix. We recognize that piece. Yeah, we've actually dosed this drug now in over 300 patients, and it's been safe and well tolerated. yeah we've actually dosed this drug now in over 300 patients and it's been safe and well tolerated It has an excellent profile overall. it has an excellent profile overall The second piece of the puzzle is, in principle, what we're doing is the type II epithelial cells start spitting out a ton of extra TGF-β1 when they're injured. the second piece of the puzzle is in principle what we're doing is the type ii epithelial cells start spitting out a ton of extra when they're injured We refunctionalize them, and we bring that pathological signal down. we refunctionalize them and we bring that pathological signal down We do not block TGF-β , right? we do not block right The other approaches that have been very tough in this disease are you just do systemic blockade of the activation or signaling in TGF-β . the other approaches that have been very tough in this disease are you just do systemic blockade of the activation or signaling in That is not what this mechanism does. that is not what this mechanism does You see, even in our preclinical models, we bring the TGF-β levels not to zero, but we bring them back down to kind of the normal levels. you see even in our preclinical models we bring the levels not to zero but we bring them back down to kind of the normal levels You need TGF-β for tissue homeostasis and for maintenance of normal extracellular matrix. you need for tissue homeostasis and for maintenance of normal extracellular matrix We recognize that piece. we recognize that piece In addition to this mechanism being, in principle, kind of a different risk-reward profile, what's also nice to see is the AT2 receptor, this receptor that we're activating, actually tends to be very selectively expressed. In most tissues, you actually don't find this receptor until there's fibrosis or inflammation. One of the very few tissues that you'll find this receptor in in a healthy person is the lung. We think that's evolutionarily because you tend to breathe in viral particles, infectious particles, pollution. There's always a little bit of inflammatory and fibrotic response to that in your lung. Having this repair system online in your lung all the time makes evolutionary sense. For whatever reason, this AT2 receptor is pretty limited to the lung in a healthy person. It's further upregulated in disease states like IPF. Receptor kind of expression-wise, we also have a differentiated safety profile. In addition to this mechanism being, in principle, kind of a different risk-reward profile, what's also nice to see is the AT2 receptor, this receptor that we're activating, actually tends to be very selectively expressed. in addition to this mechanism being in principle kind of a different risk-reward profile what's also nice to see is the at2 receptor this receptor that we're activating actually tends to be very selectively expressed In most tissues, you actually don't find this receptor until there's fibrosis or inflammation. in most tissues you actually don't find this receptor until there's fibrosis or inflammation One of the very few tissues that you'll find this receptor in in a healthy person is the lung. one of the very few tissues that you'll find this receptor in in a healthy person is the lung We think that's evolutionarily because you tend to breathe in viral particles, infectious particles, pollution. we think that's evolutionarily because you tend to breathe in viral particles infectious particles pollution There's always a little bit of inflammatory and fibrotic response to that in your lung. there's always a little bit of inflammatory and fibrotic response to that in your lung Having this repair system online in your lung all the time makes evolutionary sense. having this repair system online in your lung all the time makes evolutionary sense For whatever reason, this AT2 receptor is pretty limited to the lung in a healthy person. for whatever reason this at2 receptor is pretty limited to the lung in a healthy person It's further upregulated in disease states like IPF. it's further upregulated in disease states like ipf Receptor kind of expression-wise, we also have a differentiated safety profile. receptor kind of expression-wise we also have a differentiated safety profile Some of these other targets that companies are going after are targets that are expressed everywhere in the body. That's just not the case for the AT2 receptor. Some of these other targets that companies are going after are targets that are expressed everywhere in the body. some of these other targets that companies are going after are targets that are expressed everywhere in the body That's just not the case for the AT2 receptor. that's just not the case for the at2 receptor

Speaker 1: Got it. Perfect. Let's move on to the actual clinical data, right? You had the 36-week AIR study. What did you learn from a safety, tolerability, and again, some of the efficacy signals that you saw? We'll kind of go into some of the key debates around that data set. Got it. got it Perfect. perfect Let's move on to the actual clinical data, right? let's move on to the actual clinical data right You had the 36-week AIR study. you had the 36-week air study What did you learn from a safety, tolerability, and again, some of the efficacy signals that you saw? what did you learn from a safety tolerability and again some of the efficacy signals that you saw We'll kind of go into some of the key debates around that data set. we'll kind of go into some of the key debates around that data set

Speaker 3: Yeah, no, that sounds great. I think the first really nice thing that was done in this study is following the patients for 36 weeks from the outset. A number of other therapies have kind of done shorter 12-week studies. The challenge with that is, if you reduce inflammation or swelling, you can have some moderate impact on lung function. It might not be sustained as fibrosis continues to build and overtakes whatever benefits you got over time. It was really nice to see how this drug performed over a 36-week period. I also think it's the right way to study a mechanism like this, which is supposed to be slow repair of the tissues and resolution of fibrosis. We saw in this open-label study a 200 mL improvement in lung function at average over that 36-week period, which is quite a dramatic difference from what you would expect. Yeah, no, that sounds great. yeah no that sounds great I think the first really nice thing that was done in this study is following the patients for 36 weeks from the outset. i think the first really nice thing that was done in this study is following the patients for 36 weeks from the outset A number of other therapies have kind of done shorter 12-week studies. a number of other therapies have kind of done shorter 12-week studies The challenge with that is, if you reduce inflammation or swelling, you can have some moderate impact on lung function. the challenge with that is if you reduce inflammation or swelling you can have some moderate impact on lung function It might not be sustained as fibrosis continues to build and overtakes whatever benefits you got over time. it might not be sustained as fibrosis continues to build and overtakes whatever benefits you got over time It was really nice to see how this drug performed over a 36-week period. it was really nice to see how this drug performed over a 36-week period I also think it's the right way to study a mechanism like this, which is supposed to be slow repair of the tissues and resolution of fibrosis. i also think it's the right way to study a mechanism like this which is supposed to be slow repair of the tissues and resolution of fibrosis We saw in this open-label study a 200 mL improvement in lung function at average over that 36-week period, which is quite a dramatic difference from what you would expect. we saw in this open-label study a 200 ml improvement in lung function at average over that 36-week period which is quite a dramatic difference from what you would expect In a placebo group, you'd expect a decline of 180 mL over that time. Instead, we're having a 200 mL improvement. In a placebo group, you'd expect a decline of 180 mL over that time. in a placebo group you'd expect a decline of 180 ml over that time Instead, we're having a 200 mL improvement. instead we're having a 200 ml improvement

Speaker 1: Got it. Once you see that, and this was not a placebo-controlled trial, which I think is one of the main pushbacks that you might get there, you saw an increase on efficacy relative to baseline for a few of these patients. Is any of that being driven by outliers? How can you actually interpret and get some degree of confidence that that's a real signal? Got it. got it Once you see that, and this was not a placebo-controlled trial, which I think is one of the main pushbacks that you might get there, you saw an increase on efficacy relative to baseline for a few of these patients. Is any of that being driven by outliers? once you see that and this was not a placebo-controlled trial which i think is one of the main pushbacks that you might get there you saw an increase on efficacy relative to baseline for a few of these patients. is any of that being driven by outliers How can you actually interpret and get some degree of confidence that that's a real signal? how can you actually interpret and get some degree of confidence that that's a real signal

Speaker 3: Yeah. I think the first thing to think about in the context of an open-label trial is, how good was the diagnostics in the study? Because actually, we know that IPF patients decline, right? Like the percentage of patients over a 36-week period that would have stable or improved FVC is in the single digit. This is not a disease where you're going to have some material portion of the population that will improve. Are you really sure it's IPF? The diagnostics can be challenging. What's nice is a really good job was done making sure that these were IPF patients. In particular, the hallmark of IPF diagnosis is a high-resolution CT scan. Yeah. yeah I think the first thing to think about in the context of an open-label trial is, how good was the diagnostics in the study? i think the first thing to think about in the context of an open-label trial is how good was the diagnostics in the study Because actually, we know that IPF patients decline, right? because actually we know that ipf patients decline right Like the percentage of patients over a 36-week period that would have stable or improved FVC is in the single digit. like the percentage of patients over a 36-week period that would have stable or improved fvc is in the single digit This is not a disease where you're going to have some material portion of the population that will improve. this is not a disease where you're going to have some material portion of the population that will improve Are you really sure it's IPF? are you really sure it's ipf The diagnostics can be challenging. the diagnostics can be challenging What's nice is a really good job was done making sure that these were IPF patients. what's nice is a really good job was done making sure that these were ipf patients In particular, the hallmark of IPF diagnosis is a high-resolution CT scan. in particular the hallmark of ipf diagnosis is a high-resolution ct scan What we did is we used a pulmonary radiologist out of the United Kingdom who actually does these phase III trials for BI and other companies in terms of confirming scan by scan the right interstitial lung pattern that would be consistent with a diagnosis of IPF. I think that we have a high degree of confidence that this data set represents IPF patients. Once you have IPF patients to see them improving, I think that it would be a statistical anomaly if it were to be chance. We actually did a synthetic control arm where we built placebo matched patients. What we did is we used a pulmonary radiologist out of the United Kingdom who actually does these phase III trials for BI and other companies in terms of confirming scan by scan the right interstitial lung pattern that would be consistent with a diagnosis of IPF. what we did is we used a pulmonary radiologist out of the united kingdom who actually does these phase iii trials for bi and other companies in terms of confirming scan by scan the right interstitial lung pattern that would be consistent with a diagnosis of ipf I think that we have a high degree of confidence that this data set represents IPF patients. i think that we have a high degree of confidence that this data set represents ipf patients Once you have IPF patients to see them improving, I think that it would be a statistical anomaly if it were to be chance. once you have ipf patients to see them improving i think that it would be a statistical anomaly if it were to be chance We actually did a synthetic control arm where we built placebo matched patients. we actually did a synthetic control arm where we built placebo matched patients

Speaker 1: To talk more about that, the data was presented at the ATS, right? Can you walk us through some of the work that went into that? What would you have expected from a synthetic matched placebo? To talk more about that, the data was presented at the AT S, right? to talk more about that the data was presented at the at s right Can you walk us through some of the work that went into that? can you walk us through some of the work that went into that What would you have expected from a synthetic matched placebo? what would you have expected from a synthetic matched placebo

Speaker 3: Absolutely. The phase II-A trial was a monotherapy study of the population in a treatment-naive setting. Essentially, we pulled out a database of over 10,000 IPF patients. We selected the patients that would be matching our inclusion criteria. From that database, we built 20,000 synthetic control arm cohorts, basically these control cohorts that would meet the same inclusion criteria. We took those 20,000 and matched them on the baseline characteristics. We took the approximately 400 placebo arms that would be closest matching in terms of FEV1, FVC, the different ratios, the age, the gender, all those characteristics, and basically said, what does the aggregate of these 400-ish placebo arms look like? That was about a 114 mL decline in lung function over 36 weeks, which is exactly what you'd expect. It's 180 in these phase III settings. Absolutely. absolutely The phase II-A trial was a monotherapy study of the population in a treatment-naive setting. the phase ii-a trial was a monotherapy study of the population in a treatment-naive setting Essentially, we pulled out a database of over 10,000 IPF patients. essentially we pulled out a database of over 10,000 ipf patients We selected the patients that would be matching our inclusion criteria. we selected the patients that would be matching our inclusion criteria From that database, we built 20,000 synthetic control arm cohorts, basically these control cohorts that would meet the same inclusion criteria. from that database we built 20,000 synthetic control arm cohorts basically these control cohorts that would meet the same inclusion criteria We took those 20,000 and matched them on the baseline characteristics. we took those 20,000 and matched them on the baseline characteristics We took the approximately 400 placebo arms that would be closest matching in terms of FEV1, FVC, the different ratios, the age, the gender, all those characteristics, and basically said, what does the aggregate of these 400-ish placebo arms look like? we took the approximately 400 placebo arms that would be closest matching in terms of fev1 fvc the different ratios the age the gender all those characteristics and basically said what does the aggregate of these 400-ish placebo arms look like That was about a 114 mL decline in lung function over 36 weeks, which is exactly what you'd expect. that was about a 114 ml decline in lung function over 36 weeks which is exactly what you'd expect It's 180 in these phase III settings. it's 180 in these phase iii settings This was a slightly earlier stage population, so you could expect decline in lung function to be a little bit less. When you compare that against what we saw in the phase II-A trial, again, very, very different. Even when you use that placebo arm to impute your data set, we took that placebo arm and said, what if we pretend that every patient who dropped out of our phase 2a trial had that level of decline of lung function, that 114 mL over a 36-week period decline in lung function? You still see the improvement in lung function, and you still see that signal confirmed. Tiago, one other question you asked me is, how do you have some confidence around this data set? Is it driven by outliers? I would say what's beautiful about this data set is it's not outlier driven. This was a slightly earlier stage population, so you could expect decline in lung function to be a little bit less. this was a slightly earlier stage population so you could expect decline in lung function to be a little bit less When you compare that against what we saw in the phase II-A trial, again, very, very different. when you compare that against what we saw in the phase trial again very very different Even when you use that placebo arm to impute your data set, we took that placebo arm and said, what if we pretend that every patient who dropped out of our phase 2a trial had that level of decline of lung function, that 114 mL over a 36-week period decline in lung function? even when you use that placebo arm to impute your data set we took that placebo arm and said what if we pretend that every patient who dropped out of our phase 2a trial had that level of decline of lung function that 114 ml over a 36-week period decline in lung function You still see the improvement in lung function, and you still see that signal confirmed. you still see the improvement in lung function and you still see that signal confirmed Tiago, one other question you asked me is, how do you have some confidence around this data set? tiago one other question you asked me is how do you have some confidence around this data set Is it driven by outliers? is it driven by outliers I would say what's beautiful about this data set is it's not outlier driven. i would say what's beautiful about this data set is it's not outlier driven 65% of the patients at 36 weeks had improvement in lung function. The study enrolled heavily out of India, where it was easy to find treatment-naive patients. The patients who we enrolled out of U.K. at mean and median also had improvement in lung function. The patients with the more early stage disease had really high levels of improvement in lung function, which is consistent with our mechanism impacting that epithelial compartment even before fibrosis. Even the later stage patients who had more evidence of fibrotic buildup also had improvement in lung function. I think there's a nice biological plausibility and consistency with this type of mechanism of action. It's a slow resolution of fibrosis. You would imagine with the patients coming in where they have more entrenched fibrosis, you can start to improve over that 36-week period. 65% of the patients at 36 weeks had improvement in lung function. 65% of the patients at 36 weeks had improvement in lung function The study enrolled heavily out of India, where it was easy to find treatment-naive patients. the study enrolled heavily out of india where it was easy to find treatment-naive patients The patients who we enrolled out of U.K. at mean and median also had improvement in lung function. the patients who we enrolled out of u.k at mean and median also had improvement in lung function The patients with the more early stage disease had really high levels of improvement in lung function, which is consistent with our mechanism impacting that epithelial compartment even before fibrosis. the patients with the more early stage disease had really high levels of improvement in lung function which is consistent with our mechanism impacting that epithelial compartment even before fibrosis Even the later stage patients who had more evidence of fibrotic buildup also had improvement in lung function. even the later stage patients who had more evidence of fibrotic buildup also had improvement in lung function I think there's a nice biological plausibility and consistency with this type of mechanism of action. i think there's a nice biological plausibility and consistency with this type of mechanism of action It's a slow resolution of fibrosis. it's a slow resolution of fibrosis You would imagine with the patients coming in where they have more entrenched fibrosis, you can start to improve over that 36-week period. you would imagine with the patients coming in where they have more entrenched fibrosis you can start to improve over that 36-week period It's the patients really where you can do some of that regeneration in the epithelial compartment, and there's not a lot of scarring to deal with, where you can have even kind of a super effect over that time period. It's the patients really where you can do some of that regeneration in the epithelial compartment, and there's not a lot of scarring to deal with, where you can have even kind of a super effect over that time period. it's the patients really where you can do some of that regeneration in the epithelial compartment and there's not a lot of scarring to deal with where you can have even kind of a super effect over that time period

Speaker 1: Got it. Again, thinking about the translation of those early findings to a placebo-controlled larger trial, right? You alluded to a lot of scrutiny on the confirmed diagnosis of disease, the simulations to try to imply what placebo could have done, the statistical analysis that you have to get confidence in that positive signal. What are some other factors when trying to consider the odds of success of translating some of those findings? If you look at the high-vaso increase subgroup analysis, you saw an initial increase in FVC in a pulmonary hypertension IPF patient population. That did translate to a clinical benefit in an IPF trial later down the line. You had a couple of those early wins that folks were initially skeptical. A couple of them got across the finish line, right? What are some considerations there? Trial design, there's background therapy now. Got it. got it Again, thinking about the translation of those early findings to a placebo-controlled larger trial, right? again thinking about the translation of those early findings to a placebo-controlled larger trial right You alluded to a lot of scrutiny on the confirmed diagnosis of disease, the simulations to try to imply what placebo could have done, the statistical analysis that you have to get confidence in that positive signal. you alluded to a lot of scrutiny on the confirmed diagnosis of disease the simulations to try to imply what placebo could have done the statistical analysis that you have to get confidence in that positive signal What are some other factors when trying to consider the odds of success of translating some of those findings? what are some other factors when trying to consider the odds of success of translating some of those findings If you look at the high-vaso increase subgroup analysis, you saw an initial increase in FVC in a pulmonary hypertension IPF patient population. if you look at the high-vaso increase subgroup analysis you saw an initial increase in fvc in a pulmonary hypertension ipf patient population That did translate to a clinical benefit in an IPF trial later down the line. that did translate to a clinical benefit in an ipf trial later down the line You had a couple of those early wins that folks were initially skeptical. you had a couple of those early wins that folks were initially skeptical A couple of them got across the finish line, right? a couple of them got across the finish line right What are some considerations there? what are some considerations there Trial design, there's background therapy now. trial design there's background therapy now Can you walk us through the design and some of the puts and takes? Can you walk us through the design and some of the puts and takes? can you walk us through the design and some of the puts and takes

Speaker 3: Yeah, absolutely. I think the first thing that we really wanted to do in this, it's really a gold standard trial. The ongoing phase 2b is a 52-week trial. It has the registrational endpoint impact on lung function FVC over that 52-week period. It has the positioning of the drug on top of standard of care nintedanib or not on standard of care. It's similar to the other phase 3s, including the [TETEN] studies that recently read out, and then a broad inclusion criteria. We're really trying to demonstrate in this upcoming trial what we can do in a way that would be very relevant to what you would do in the real world in the clinical setting and what you would do in a phase 3. Yeah, absolutely. yeah absolutely I think the first thing that we really wanted to do in this, it's really a gold standard trial. i think the first thing that we really wanted to do in this it's really a gold standard trial The ongoing phase 2b is a 52-week trial. the ongoing phase 2b is a 52-week trial It has the registrational endpoint impact on lung function FVC over that 52-week period. it has the registrational endpoint impact on lung function fvc over that 52-week period It has the positioning of the drug on top of standard of care nintedanib or not on standard of care. it has the positioning of the drug on top of standard of care nintedanib or not on standard of care It's similar to the other phase 3s, including the [TETEN] studies that recently read out, and then a broad inclusion criteria. it's similar to the other phase 3s including the [teten] studies that recently read out and then a broad inclusion criteria We're really trying to demonstrate in this upcoming trial what we can do in a way that would be very relevant to what you would do in the real world in the clinical setting and what you would do in a phase 3. we're really trying to demonstrate in this upcoming trial what we can do in a way that would be very relevant to what you would do in the real world in the clinical setting and what you would do in a phase 3 There's no material difference in setup from what we would do subsequent to this phase 2b in a phase 3, and that's very intentional. The thing that we were thinking about also is being conservative on powering, right? We see this really nice signal of improvement in lung function in the phase 2a. Of course, we know that even stabilization would be a huge benefit and certainly a blockbuster therapy. Even something that can materially reduce the decline of lung function would also be a very exciting opportunity. We've powered our study for a 125 mL difference in lung function between the treatment arm and the placebo arm. I think that reflects both that we're being conservative relative to what we saw in the phase 2a. Also, we're pretty bullish on what we think our drug can accomplish. There's no material difference in setup from what we would do subsequent to this phase 2b in a phase 3, and that's very intentional. there's no material difference in setup from what we would do subsequent to this phase 2b in a phase 3 and that's very intentional The thing that we were thinking about also is being conservative on powering, right? the thing that we were thinking about also is being conservative on powering right We see this really nice signal of improvement in lung function in the phase 2a. we see this really nice signal of improvement in lung function in the phase 2a Of course, we know that even stabilization would be a huge benefit and certainly a blockbuster therapy. of course we know that even stabilization would be a huge benefit and certainly a blockbuster therapy Even something that can materially reduce the decline of lung function would also be a very exciting opportunity. even something that can materially reduce the decline of lung function would also be a very exciting opportunity We've powered our study for a 125 mL difference in lung function between the treatment arm and the placebo arm. we've powered our study for a 125 ml difference in lung function between the treatment arm and the placebo arm I think that reflects both that we're being conservative relative to what we saw in the phase 2a. i think that reflects both that we're being conservative relative to what we saw in the phase 2a Also, we're pretty bullish on what we think our drug can accomplish. also we're pretty bullish on what we think our drug can accomplish When you think about, as you mentioned, in the [INCREASE] trial, you see this kind of improvement in lung function. Of course, now there's a reported in the [TETEN] studies 95 mL difference from placebo to the treatment arm. I think that's a reflection that as you go into these bigger trials and these other settings, there might be some reversion to the mean. We do think that it's an exciting signal, and we think we've powered responsibly in our phase 2b in view of that type of a signal. When you think about, as you mentioned, in the [INCREASE] trial, you see this kind of improvement in lung function. when you think about as you mentioned in the [increase] trial you see this kind of improvement in lung function Of course, now there's a reported in the [TETEN] studies 95 mL difference from placebo to the treatment arm. of course now there's a reported in the [teten] studies 95 ml difference from placebo to the treatment arm I think that's a reflection that as you go into these bigger trials and these other settings, there might be some reversion to the mean. i think that's a reflection that as you go into these bigger trials and these other settings there might be some reversion to the mean We do think that it's an exciting signal, and we think we've powered responsibly in our phase 2b in view of that type of a signal. we do think that it's an exciting signal and we think we've powered responsibly in our phase 2b in view of that type of a signal

Speaker 1: What about the dose selection work that went into that? What about the dose selection work that went into that? what about the dose selection work that went into that

Speaker 3: Yeah, absolutely. We've used our preclinical data set to do a lot of dose modeling because in our phase I, we did not see any MTD or DLT. We did see some hair loss or hair thinning. We're trying to strike the balance there. While IPF is a fatal disease and one that unfortunately has a prognosis of only three to four years survival, we still wanted to be mindful of whether we could control or mitigate that type of side effect. In our phase II-A, we selected a dose of 100 mL twice daily, which we believe drives higher than IC90 efficacy levels in terms of concentration of the drug in the lung. I think that bore out in that signal of significant clinical improvement. We also saw in that study 19% of patients had mild to moderate hair loss or hair thinning. Yeah, absolutely. yeah absolutely We've used our preclinical data set to do a lot of dose modeling because in our phase I, we did not see any MTD or DLT. we've used our preclinical data set to do a lot of dose modeling because in our phase i we did not see any mtd or dlt We did see some hair loss or hair thinning. we did see some hair loss or hair thinning We're trying to strike the balance there. we're trying to strike the balance there While IPF is a fatal disease and one that unfortunately has a prognosis of only three to four years survival, we still wanted to be mindful of whether we could control or mitigate that type of side effect. while ipf is a fatal disease and one that unfortunately has a prognosis of only three to four years survival we still wanted to be mindful of whether we could control or mitigate that type of side effect In our phase II-A, we selected a dose of 100 mL twice daily, which we believe drives higher than IC90 efficacy levels in terms of concentration of the drug in the lung. in our phase ii-a we selected a dose of 100 ml twice daily which we believe drives higher than ic90 efficacy levels in terms of concentration of the drug in the lung I think that bore out in that signal of significant clinical improvement. i think that bore out in that signal of significant clinical improvement We also saw in that study 19% of patients had mild to moderate hair loss or hair thinning. we also saw in that study 19% of patients had mild to moderate hair loss or hair thinning In our phase II-B trial, we will also be advancing that 100 mL twice daily. We certainly think this is a very manageable side effect in the context of the deadly disease of IPF. It's also a disease generally of older men on average. We will also be testing a 50 mL twice daily dose. The hair loss or hair thinning is a dose-dependent effect. We do believe that this will have the ability to mitigate or potentially eliminate the effect. Based on our dose modeling, we do believe that the 50 mL twice daily will be an efficacious dose as well. In our phase II-B trial, we will also be advancing that 100 mL twice daily. in our phase ii-b trial we will also be advancing that 100 ml twice daily We certainly think this is a very manageable side effect in the context of the deadly disease of IPF. we certainly think this is a very manageable side effect in the context of the deadly disease of ipf It's also a disease generally of older men on average. it's also a disease generally of older men on average We will also be testing a 50 mL twice daily dose. we will also be testing a 50 ml twice daily dose The hair loss or hair thinning is a dose-dependent effect. the hair loss or hair thinning is a dose-dependent effect We do believe that this will have the ability to mitigate or potentially eliminate the effect. we do believe that this will have the ability to mitigate or potentially eliminate the effect Based on our dose modeling, we do believe that the 50 mL twice daily will be an efficacious dose as well. based on our dose modeling we do believe that the 50 ml twice daily will be an efficacious dose as well

Speaker 1: Got it. No, perfect. What about clinical trial execution? Like there's always some degree of skepticism inside of the company, given that it's a competitive environment. Up until very recently, we had a lot of phase IIs ongoing, less so now. Can you talk about some of that dynamic? How broad are you going to enroll these trials? What are some of the steps you're taking to ensure that you can achieve reasonable timelines relative to comps? Got it. got it No, perfect. no perfect What about clinical trial execution? what about clinical trial execution Like there's always some degree of skepticism inside of the company, given that it's a competitive environment. like there's always some degree of skepticism inside of the company given that it's a competitive environment Up until very recently, we had a lot of phase IIs ongoing, less so now. up until very recently we had a lot of phase iis ongoing less so now Can you talk about some of that dynamic? can you talk about some of that dynamic How broad are you going to enroll these trials? how broad are you going to enroll these trials What are some of the steps you're taking to ensure that you can achieve reasonable timelines relative to comps? what are some of the steps you're taking to ensure that you can achieve reasonable timelines relative to comps

Speaker 3: Yep. This is, as you mentioned, Tiago, a huge undertaking. It's a 270-patient trial. We are building a network of 100 clinical sites across 14 countries. The study is actually well underway in terms of execution. It is executing quite well. We're really heartened to see that. We've already guided that we expect enrollment to be complete in the first half of 2026. We have most of the sites fully up and running, heavily underway on enrollment. What's nice is we are the only 52-week study that I believe is currently enrolling. We are the most advanced therapy that's currently enrolling a study. I think that's led to a lot of enthusiasm because, of course, as you know, BI has had their readout. United Therapeutics has completed their readout for their first phase III. Their second phase III has completed enrollment. Yep. yep This is, as you mentioned, Tiago, a huge undertaking. this is as you mentioned tiago a huge undertaking It's a 270-patient trial. it's a 270-patient trial We are building a network of 100 clinical sites across 14 countries. we are building a network of 100 clinical sites across 14 countries The study is actually well underway in terms of execution. the study is actually well underway in terms of execution It is executing quite well. it is executing quite well We're really heartened to see that. we're really heartened to see that We've already guided that we expect enrollment to be complete in the first half of 2026. we've already guided that we expect enrollment to be complete in the first half of 2026 We have most of the sites fully up and running, heavily underway on enrollment. we have most of the sites fully up and running heavily underway on enrollment What's nice is we are the only 52-week study that I believe is currently enrolling. what's nice is we are the only 52-week study that i believe is currently enrolling We are the most advanced therapy that's currently enrolling a study. we are the most advanced therapy that's currently enrolling a study I think that's led to a lot of enthusiasm because, of course, as you know, BI has had their readout. i think that's led to a lot of enthusiasm because of course as you know, bi has had their readout United Therapeutics has completed their readout for their first phase III. united therapeutics has completed their readout for their first phase iii Their second phase III has completed enrollment. their second phase iii has completed enrollment Also, BMS, who are the only other phase III or the only other program that's more advanced than us, have also completed enrollment. I think that leaves a nice amount of room for us to continue effectively enrolling this study. We're certainly spending a lot of time engaging with the clinical community to effectively do this. I personally was out in South Korea, where we have a relatively large number of sites for an investigator meeting last week. We're also a team that's on the ground so that we can execute. We have over a half dozen clinical science liaisons who are distributed across these 14 countries. We try to spend a lot of time with the clinical sites explaining the mechanism, the risk-reward, the trial setup, and really making sure that we can effectively execute the study. Also, BMS, who are the only other phase III or the only other program that's more advanced than us, have also completed enrollment. also bms who are the only other phase iii or the only other program that's more advanced than us have also completed enrollment I think that leaves a nice amount of room for us to continue effectively enrolling this study. i think that leaves a nice amount of room for us to continue effectively enrolling this study We're certainly spending a lot of time engaging with the clinical community to effectively do this. we're certainly spending a lot of time engaging with the clinical community to effectively do this I personally was out in South Korea, where we have a relatively large number of sites for an investigator meeting last week. i personally was out in south korea where we have a relatively large number of sites for an investigator meeting last week We're also a team that's on the ground so that we can execute. we're also a team that's on the ground so that we can execute We have over a half dozen clinical science liaisons who are distributed across these 14 countries. we have over a half dozen clinical science liaisons who are distributed across these 14 countries We try to spend a lot of time with the clinical sites explaining the mechanism, the risk-reward, the trial setup, and really making sure that we can effectively execute the study. we try to spend a lot of time with the clinical sites explaining the mechanism the risk-reward the trial setup and really making sure that we can effectively execute the study

Speaker 1: Got it. Perfect. Again, assuming positive data, what could be the regulatory path going forward for the drug? Got it. got it Perfect. perfect Again, assuming positive data, what could be the regulatory path going forward for the drug? again assuming positive data what could be the regulatory path going forward for the drug

Speaker 3: Yeah, we believe after hopefully a successful phase II-B, a single phase III will be required in order to gain regulatory approval of the drug for IPF. That's in part because of the nature of our phase II-B, because it has many of the features of a phase II. Yeah, we believe after hopefully a successful phase II-B, a single phase III will be required in order to gain regulatory approval of the drug for IPF. yeah we believe after hopefully a successful phase ii-b a single phase iii will be required in order to gain regulatory approval of the drug for ipf That's in part because of the nature of our phase II-B, because it has many of the features of a phase II. that's in part because of the nature of our phase ii-b because it has many of the features of a phase ii

Speaker 1: Quite adequate control. Quite adequate control. quite adequate control

Speaker 3: Exactly. Yeah, controlling the setup. Of course, ultimately, what we're looking at is a therapy that would be a front line on top of the standard of care. That's how our phase II is set up as well. We expect 70%-80% of the patients coming into our phase II-B to be on nintedanib standard of care and 20%-30% to be not on standard of care. Exactly. exactly Yeah, controlling the setup. yeah controlling the setup Of course, ultimately, what we're looking at is a therapy that would be a front line on top of the standard of care. of course ultimately what we're looking at is a therapy that would be a front line on top of the standard of care That's how our phase II is set up as well. that's how our phase ii is set up as well We expect 70%- 80% of the patients coming into our phase II-B to be on nintedanib standard of care and 20%- 30% to be not on standard of care. we expect 70%- 80% of the patients coming into our phase ii-b to be on nintedanib standard of care and 20%- 30% to be not on standard of care

Speaker 1: Got it. I think it seems fairly standard with some of the more recent phase II trials, right? Let's talk a little bit about the commercial positioning, right? If you talk to physicians, there seems to be so huge unmet need. At the same time, sometimes you hear that the field is crowded. You just had a couple of wins that we haven't had for a while. Is there really a need for an additional mechanism of action? How much overlap is there? Can you see some synergistic effects? Just a lot of questions on the unknown commercial outlook. I think a lot of those concerns are overblown if you hear through physicians. I'd love to get your take on that. Got it. got it I think it seems fairly standard with some of the more recent phase II trials, right? i think it seems fairly standard with some of the more recent phase ii trials right Let's talk a little bit about the commercial positioning, right? let's talk a little bit about the commercial positioning right If you talk to physicians, there seems to be so huge unmet need. if you talk to physicians there seems to be so huge unmet need At the same time, sometimes you hear that the field is crowded. at the same time sometimes you hear that the field is crowded You just had a couple of wins that we haven't had for a while. you just had a couple of wins that we haven't had for a while Is there really a need for an additional mechanism of action? is there really a need for an additional mechanism of action How much overlap is there? how much overlap is there Can you see some synergistic effects? can you see some synergistic effects Just a lot of questions on the unknown commercial outlook. just a lot of questions on the unknown commercial outlook I think a lot of those concerns are overblown if you hear through physicians. i think a lot of those concerns are overblown if you hear through physicians I'd love to get your take on that. i'd love to get your take on that

Speaker 3: Yeah, I mean, relative to the size of the market, this area is highly, highly underserved, right? I mean, you're talking about two standard of care therapies that don't materially change that three to four-year survival picture that we just discussed and that most patients don't even initiate therapy because of the tough side effects. Only 25% of patients with IPF ever even initiate therapy in the United States. The time on therapy is only 10 months. When you talk to clinicians on the front lines in this space, many of them know how tough it is for patients to stay on these drugs. They wait until they're progressive. They say, you know, I understand that in theory, I'm supposed to put my patients on standard of care to stop them from having a decline in lung function. Yeah, I mean, relative to the size of the market, this area is highly, highly underserved, right? yeah i mean relative to the size of the market this area is highly highly underserved right I mean, you're talking about two standard of care therapies that don't materially change that three to four-year survival picture that we just discussed and that most patients don't even initiate therapy because of the tough side effects. i mean you're talking about two standard of care therapies that don't materially change that three to four-year survival picture that we just discussed and that most patients don't even initiate therapy because of the tough side effects Only 25% of patients with IPF ever even initiate therapy in the United States. only 25% of patients with ipf ever even initiate therapy in the united states The time on therapy is only 10 months. the time on therapy is only 10 months When you talk to clinicians on the front lines in this space, many of them know how tough it is for patients to stay on these drugs. when you talk to clinicians on the front lines in this space many of them know how tough it is for patients to stay on these drugs They wait until they're progressive. they wait until they're progressive They say, you know, I understand that in theory, I'm supposed to put my patients on standard of care to stop them from having a decline in lung function. they say you know i understand that in theory i'm supposed to put my patients on standard of care to stop them from having a decline in lung function If they're kind of trending stable in their lung function, then I wait. The problem with that is that ultimately, these declines in lung function can be very sudden and very precipitous. The idea, at least intellectually, is that you should keep patients on therapies as early as possible in order to prevent the decline. Really, I think that we are looking also to try to drive some paradigm shift. To be honest with you, this is why we're quite excited to see United Therapeutics put out some nice data. First and foremost, it's a scientific validation of what we're doing at Vicore because this impact on the vasculature, we think, together with impact on other compartments, can have a huge effect. Even without having formally diagnosed pulmonary hypertension, the beginnings of this occur early with the vascular dysfunction. If they're kind of trending stable in their lung function, then I wait. if they're kind of trending stable in their lung function then i wait The problem with that is that ultimately, these declines in lung function can be very sudden and very precipitous. the problem with that is that ultimately these declines in lung function can be very sudden and very precipitous The idea, at least intellectually, is that you should keep patients on therapies as early as possible in order to prevent the decline. the idea at least intellectually is that you should keep patients on therapies as early as possible in order to prevent the decline Really, I think that we are looking also to try to drive some paradigm shift. really i think that we are looking also to try to drive some paradigm shift To be honest with you, this is why we're quite excited to see United Therapeutics put out some nice data. to be honest with you this is why we're quite excited to see united therapeutics put out some nice data First and foremost, it's a scientific validation of what we're doing at Vicore because this impact on the vasculature, we think, together with impact on other compartments, can have a huge effect. first and foremost it's a scientific validation of what we're doing at vicore because this impact on the vasculature we think together with impact on other compartments can have a huge effect Even without having formally diagnosed pulmonary hypertension, the beginnings of this occur early with the vascular dysfunction. even without having formally diagnosed pulmonary hypertension the beginnings of this occur early with the vascular dysfunction We think scientifically, this is a huge support and a huge kind of validation in what we're doing at Vicore. The other piece is really it's great to have a sales force out there who's trying to drive and seeking to drive in the years ahead of a potential launch of buloxibutid for IPF, a mindset shift in clinicians so that this market, which is currently $4 billion annually for 25% of patients initiating and 10 months continuation, you then see that number come up hopefully 50% and even beyond that. Of course, hopefully with better tolerated therapies, also having patients stay on longer. Certainly, if you can have therapies that patients can live with longer that are actually more efficacious, you should also see the extended time on therapy, which is a commercial benefit as well. We think scientifically, this is a huge support and a huge kind of validation in what we're doing at Vicore . we think scientifically this is a huge support and a huge kind of validation in what we're doing at vicore The other piece is really it's great to have a sales force out there who's trying to drive and seeking to drive in the years ahead of a potential launch of buloxibutid for IPF, a mindset shift in clinicians so that this market, which is currently $4 billion annually for 25% of patients initiating and 10 months continuation, you then see that number come up hopefully 50% and even beyond that. the other piece is really it's great to have a sales force out there who's trying to drive and seeking to drive in the years ahead of a potential launch of buloxibutid for ipf a mindset shift in clinicians so that this market which is currently $4 billion annually for 25% of patients initiating and 10 months continuation you then see that number come up hopefully 50% and even beyond that Of course, hopefully with better tolerated therapies, also having patients stay on longer. of course hopefully with better tolerated therapies also having patients stay on longer Certainly, if you can have therapies that patients can live with longer that are actually more efficacious, you should also see the extended time on therapy, which is a commercial benefit as well. certainly if you can have therapies that patients can live with longer that are actually more efficacious you should also see the extended time on therapy which is a commercial benefit as well

Speaker 1: Got it. Is this the kind of product or the kind of opportunity that if you show 60 mL placebo-adjusted, it's zero, and if you show 100, it's mostly how much elasticity is there depending on the kind of product profile that you can achieve? You mentioned some of your talks. There doesn't seem to be a lot of overlapping talks with current standard of care, right? Is that fair? Got it. got it Is this the kind of product or the kind of opportunity that if you show 60 mL placebo-adjusted, it's zero, and if you show 100, it's mostly how much elasticity is there depending on the kind of product profile that you can achieve? is this the kind of product or the kind of opportunity that if you show 60 ml placebo-adjusted it's zero and if you show 100 it's mostly how much elasticity is there depending on the kind of product profile that you can achieve You mentioned some of your talks. you mentioned some of your talks There doesn't seem to be a lot of overlapping talks with current standard of care, right? there doesn't seem to be a lot of overlapping talks with current standard of care right Is that fair? is that fair

Speaker 3: Yes. Yes. yes

Speaker 1: Combo, mono, again, kind of depends on how everything plays out. What are some of the potential placements in this driven paradigm? Combo, mono, again, kind of depends on how everything plays out. combo mono again kind of depends on how everything plays out What are some of the potential placements in this driven paradigm? what are some of the potential placements in this driven paradigm

Speaker 3: Yeah, look, we're aiming high. We're not aiming for an incremental effect. If our drug is not powered, our study, our phase II-B is not powered to show a 60 mL difference, right? That's not where we're aiming. Any positive read on the ASPIRE study, even with the relatively conservative powering in relation to what we saw in phase II-A, would certainly be a blockbuster opportunity. We saw United Therapeutics add many billions to their market cap with a 95 mL difference in lung function. We're even believing that we can aim even higher than that. That's the type of effect that we've powered for in this study. Again, how we think about that ultimate positioning is we think that this is a drug that's great for patients to take at the outset. It drives that epithelial repair that comes even before the fibrosis. Yeah, look, we're aiming high. yeah look we're aiming high We're not aiming for an incremental effect. we're not aiming for an incremental effect If our drug is not powered, our study, our phase II-B is not powered to show a 60 mL difference, right? if our drug is not powered our study our phase ii-b is not powered to show a 60 ml difference right That's not where we're aiming. that's not where we're aiming Any positive read on the ASPIRE study, even with the relatively conservative powering in relation to what we saw in phase II-A, would certainly be a blockbuster opportunity. any positive read on the aspire study even with the relatively conservative powering in relation to what we saw in phase ii-a would certainly be a blockbuster opportunity We saw United Therapeutics add many billions to their market cap with a 95 mL difference in lung function. we saw united therapeutics add many billions to their market cap with a 95 ml difference in lung function We're even believing that we can aim even higher than that. we're even believing that we can aim even higher than that That's the type of effect that we've powered for in this study. that's the type of effect that we've powered for in this study Again, how we think about that ultimate positioning is we think that this is a drug that's great for patients to take at the outset. again how we think about that ultimate positioning is we think that this is a drug that's great for patients to take at the outset It drives that epithelial repair that comes even before the fibrosis. it drives that epithelial repair that comes even before the fibrosis We'd like to position this drug as a front line that you take with the available standard of care. As we see BI's nerandomilast and United Therapeutics's TYVASO kind of launch in the marketplace, we'll consider how we design our phase III study, right? Currently, we are allowing the most popular standard of care nintedanib in our phase II-B. We can continue to evolve that thinking and say we can combine on top of other things depending on how they look in the phase III setting as well to set ourselves up for a good commercial launch. What's nice is we know what the universe is ahead of us. It's that BI's nerandomilast, United Therapeutics TYVASO, and then BMA has their LPA1 antagonist. We can plan for that world effectively. We'd like to position this drug as a front line that you take with the available standard of care. we'd like to position this drug as a front line that you take with the available standard of care As we see BI 's nerandomilast and United Therapeutics's TYVASO kind of launch in the marketplace, we'll consider how we design our phase III study, right? as we see bi 's nerandomilast and united therapeutics's tyvaso kind of launch in the marketplace we'll consider how we design our phase iii study right Currently, we are allowing the most popular standard of care nintedanib in our phase II-B. currently we are allowing the most popular standard of care nintedanib in our phase ii-b We can continue to evolve that thinking and say we can combine on top of other things depending on how they look in the phase III setting as well to set ourselves up for a good commercial launch. we can continue to evolve that thinking and say we can combine on top of other things depending on how they look in the phase iii setting as well to set ourselves up for a good commercial launch What's nice is we know what the universe is ahead of us. what's nice is we know what the universe is ahead of us It's that BI 's nerandomilast, United Therapeutics TYVASO, and then BMA has their LPA1 antagonist. it's that bi 's nerandomilast united therapeutics tyvaso and then bma has their lpa1 antagonist We can plan for that world effectively. we can plan for that world effectively

Speaker 1: Yeah, fair enough. I guess as we're kind of closing, can you recap IP, stay, lifecycle management thoughts, anything on that end? Yeah, fair enough. yeah fair enough I guess as we're kind of closing, can you recap IP, stay, lifecycle management thoughts, anything on that end? i guess as we're kind of closing can you recap ip stay lifecycle management thoughts anything on that end

Speaker 3: Yeah, absolutely. First on the IP side, we have IP going out until 2042 before any kind of SPC or PTE protection. Quite a robust IP portfolio that certainly I'm excited to work on as a former IP lawyer as well. In addition to that, it's really nice to have a lot of consideration around both indication extension and lifecycle management. Now, you see United Therapeutics coming at pulmonary fibrosis from the pulmonary hypertension space. We have a lot of conviction in this drug for pulmonary hypertension. We think PHILD is a high unmet need. We have some great preclinical data, including in the Sugen hypoxia model, monocrotaline model. We see our indication expansion broadly into the pulmonary space, going the opposite way from United Therapeutics, where we would go into the pulmonary hypertension space. This is a super upstream and broad mechanism. Yeah, absolutely. yeah absolutely First on the IP side, we have IP going out until 2042 before any kind of SPC or PTE protection. first on the ip side we have ip going out until 2042 before any kind of spc or pte protection Quite a robust IP portfolio that certainly I'm excited to work on as a former IP lawyer as well. quite a robust ip portfolio that certainly i'm excited to work on as a former ip lawyer as well In addition to that, it's really nice to have a lot of consideration around both indication extension and lifecycle management. in addition to that it's really nice to have a lot of consideration around both indication extension and lifecycle management Now, you see United Therapeutics coming at pulmonary fibrosis from the pulmonary hypertension space. now you see united therapeutics coming at pulmonary fibrosis from the pulmonary hypertension space We have a lot of conviction in this drug for pulmonary hypertension. we have a lot of conviction in this drug for pulmonary hypertension We think PHILD is a high unmet need. we think phild is a high unmet need We have some great preclinical data, including in the Sugen hypoxia model, monocrotaline model. we have some great preclinical data including in the sugen hypoxia model monocrotaline model We see our indication expansion broadly into the pulmonary space, going the opposite way from United Therapeutics, where we would go into the pulmonary hypertension space. we see our indication expansion broadly into the pulmonary space going the opposite way from united therapeutics where we would go into the pulmonary hypertension space This is a super upstream and broad mechanism. this is a super upstream and broad mechanism We even think about indications outside of the lung for follow-on compounds that have been optimized. For example, we're really thinking a lot these days about chronic kidney disease space and renal indications, as well as potentially other. We even think about indications outside of the lung for follow-on compounds that have been optimized. we even think about indications outside of the lung for follow-on compounds that have been optimized For example, we're really thinking a lot these days about chronic kidney disease space and renal indications, as well as potentially other. for example we're really thinking a lot these days about chronic kidney disease space and renal indications as well as potentially other

Speaker 1: Oh, fantastic. We covered a lot of ground. Is there anything else that you'd like to highlight from the story that's still misunderstood or that you're excited about? We can probably wrap up. Oh, fantastic. oh fantastic We covered a lot of ground. Is there anything else that you'd like to highlight from the story that's still misunderstood or that you're excited about? we covered a lot of ground. is there anything else that you'd like to highlight from the story that's still misunderstood or that you're excited about We can probably wrap up. we can probably wrap up

Speaker 3: No, absolutely. I think that on our phase II-A signal, as we discussed a little bit, there are some pieces of the puzzle that are a little bit different in terms of having a longer study that I think are positive. There are some things that we have to wrap our head around, like the open-label nature of the study. We have a high degree of conviction that it represents a true clinical signal and are excited to move forward. I would say on the company front, while we are currently publicly listed in Sweden, we're really excited to engage more and more with the U.S. audience and certainly actively exploring U.S. listing opportunities in the future, hopefully potentially even ahead of the phase II-B readout. No, absolutely. no absolutely I think that on our phase II-A signal, as we discussed a little bit, there are some pieces of the puzzle that are a little bit different in terms of having a longer study that I think are positive. i think that on our phase ii-a signal as we discussed a little bit, there are some pieces of the puzzle that are a little bit different in terms of having a longer study that i think are positive There are some things that we have to wrap our head around, like the open-label nature of the study. there are some things that we have to wrap our head around like the open-label nature of the study We have a high degree of conviction that it represents a true clinical signal and are excited to move forward. we have a high degree of conviction that it represents a true clinical signal and are excited to move forward I would say on the company front, while we are currently publicly listed in Sweden, we're really excited to engage more and more with the U.S. audience and certainly actively exploring U.S. listing opportunities in the future, hopefully potentially even ahead of the phase II-B readout. i would say on the company front while we are currently publicly listed in sweden we're really excited to engage more and more with the u.s audience and certainly actively exploring u.s listing opportunities in the future hopefully potentially even ahead of the phase ii-b readout

Speaker 1: Fantastic. Thank you so much for your time. Appreciate you joining us. Fantastic. fantastic Thank you so much for your time. thank you so much for your time Appreciate you joining us. appreciate you joining us

Speaker 3: Thank you, Tiago. Appreciate it. Thank you, Tiago. thank you tiago Appreciate it. appreciate it