Vicore Pharma Holding — Call Transcript 2025

Awesome. Happy to be joined next here by Ahmed Mousa, CEO of Vicore Pharma for fireside. So Ahmed, maybe over to you for a quick introduction to the company, and then we'll get into it. Yeah, absolutely. Thanks for having us again, Alex. Yeah, so Vicore Pharma is a Nordic biotech company. We're developing drugs in the angiotensin II pathway. In particular, we've zeroed in on a target called the angiotensin II type 2 receptor. This is a target that activating it drives endogenous tissue repair, fibrosis resolution, and vasodilatory effects. It's a relatively upstream target. It drives a number of different activities. It sits in the body as the opposing force to a receptor that we know very well called the AT1 receptor. This is the target that drives hypertension, inflammation, and fibrosis. There's been incredible success in the industry in developing ACE inhibitors and ARBs, which are AT1 receptor antagonists, to kind of block that side of the pathway. We think that activating the other side of the pathway, that counterforce, can be very fruitful across a large number of diseases. We're starting out in pulmonary fibrosis. It is great to be here and talk more about our lead program as well. Yeah, so maybe to start, the IPF space has seen a lot of ups and downs. It seems like we're on a little bit of an upswing more recently. Maybe could you sort of lay out where we're at right now in the IPF space? What does the clinical development landscape look like? What the early launch feedback might be from that recent launch from BI? Absolutely. There are, right up until a few weeks ago, two approved drugs for IPF, pirfenidone and nintedanib, which incrementally slowed the decline of lung function. Unfortunately, IPF is a disease with a three to four-year survival, and that was not significantly impacted by these therapies. Nonetheless, certainly they were used for that purpose. They also had significant tolerability challenges, which limited their uptake, including GI side effects as well as other side effects. As you mentioned, Alex, there is now a third entrant to the market, which is BI has a drug called nerandomilast, marketing it as JASCAYD, which also incrementally slows the decline of lung function. I would say that the clinician consensus we've been hearing is this is not groundbreaking relative to the other therapies from that perspective. It does appear to be better tolerated. There is in the U.S. some clinician enthusiasm based on what's been seen in clinical development in this program to maybe use this therapy. As IPF is a disease also of older individuals, they tend to have other issues. A drug that's easier for them to take is certainly not something to underestimate. That would be very interesting to see then how that launch ultimately plays out. There has also been another program. United Therapeutics has inhaled treprostinil, which has shown in the first of their two phase III studies, again, an incremental effect on lung function in terms of slowing the decline, but also kind of a better numerical effect. It appears to be kind of better from the efficacy side. It's a tougher to take drug based on the clinical feedback we've heard from folks who treat patients with pulmonary hypertension already with the drug. It'll be interesting to see how that then second phase III reads out next year and how it might be deployed in the landscape. The final drug that's in development ahead of Vicore's buloxibutid is an LPA1 antagonist that BMS is developing. That data will come out next year. I would say overall, the landscape remains one where IPF is a fatal disease, three to four-year survival, drugs that are incremental in slowing the decline of lung function. We really have a need for more effective drugs as well as better tolerated drugs in general. Certainly, this is also a landscape where clinicians are excited to try combination therapies where that's possible. Yeah, in general, though, I think the unmet need is clear. Clinical development has been challenging. I mean, what do you think are the main issues with these challenges? Is it the endpoints? Is it the underlying disease pathology? Is it just we haven't found the right targets at this point? How would you rate what's been happening over the last five years? Absolutely. I think with the benefit of hindsight and a lot of learning from the different successes and failures in the landscape, when you step back and think about what is IPF or what is pulmonary fibrosis, it's injury to the epithelial layer of the alveolus. It's injury to the air sacs. That injury causes the scarring or the kind of runaway fibrosis around that epithelial layer, which then ultimately also drives vascular dysfunction as you put pressure in that interstitial space on the capillaries and the other vessels of the pulmonary compartment. I think that what we've basically learned over time is that trying to block the fibrosis in the interstitium, like blocking activity of fibroblasts in terms of depositing collagen, is not an invalid way to go after this disease. It may only give you these incremental results. It's interesting to see that a vasoactive drug like the inhaled treprostinil provides for a better numerical response. We think that's consistent with the mechanism of action where you should think about IPF as a disease that's impacting three compartments: the epithelium and the alveolus, the interstitium, and the vasculature. We think that going then beyond interstitial targeting or fibrosis targeting compounds can have a huge benefit in this space as well. Yeah, I think that's a perfect segue into talking about the AT2 receptor target, the design of buloxibutid, the underlying mechanism of action here in IPF. Yeah, absolutely. As I'd mentioned, Alex, what happens in IPF is the kind of focal point in our view of this disease is that injury to the alveolar compartment, the injury to these air sacs, and that epithelial layer. In particular, actually, there's a stem cell called the alveolar epithelial type 2 cell. We believe it's the injury to that cell that is the core of the disease driver and what kind of starts this process out. There's a lot of good scientific evidence for that too. As these stem cells become injured, they're the ones that are supposed to differentiate into the gas exchange cells. Of course, when you have the injury in this disease, the gas exchange cells die off. Now the stem cells that are supposed to replenish them are also dying off. You have impaired lung function even before you have any fibrosis buildup. The second thing that happens is these stem cells, these type 2 epithelial cells, are supposed to be producing surfactant protein to break up the natural surface tension of water to keep the air sacs inflated. Actually, when you start to kill off or cause these type 2 epithelial cells to dysfunction, you have a phenomenon in IPF that's known as prefibrotic alveolar collapse due to loss of surfactant. Basically, what that means is these alveoli, these air sacs, flatten like a pancake because of the surface tension of water. Again, this comes before the fibrosis. What's so rough about this disease is it's the injury to these type 2 epithelial cells, these stem cells. When they become dysfunctional, they're the ones that start spitting out the profibrotic factors, the TGFβ, the wound healing signal. They become the key orchestrator then of the fibrotic buildup around them. What we're doing at Vicore with this AT2 receptor, by activating it, they actually sit on these type 2 epithelial cells, on these stem cells. You refunctionalize and drive proliferation of the cell type. It means you can replenish the gas exchange capability. It means you can reverse that prefibrotic alveolar collapse. It also means you cut off the pathological profibrotic signal, that TGFβ1 signal at its kind of source. We think that's a very potent way to go after this disease. You actually have clinical data. Before we get into that, can you talk a little about the preclinical models that you've developed to sort of understand this specific mechanism as well? Absolutely. We've looked at this molecule in a large number of preclinical models. I would say we look at it in models as simple as you take these type II epithelial cells, these stem cells, and you injure them using a toxin like bleomycin, which is commonly used to simulate IPF in animal models. It starts to cause these cells to die off. When you add buloxibutid in a concentration-dependent way, you're able to protect these cells from apoptosis. It shows that you can actually do exactly what you're doing in a very simple model. If you take this to a more complicated model, like let's call it human IPF precision cut lung slices. When IPF patients become very progressed, they actually get a lung transplant. You can then take tissue from the IPF lung, add your drug to it, and see what happens. What we see is we increase significantly surfactant protein expression. As I mentioned, Alex, these surfactant proteins are coming from these type II epithelial cells. It is evidence that we are addressing the prefibrotic alveolar collapse and that we are protecting the type II epithelial cells. What you also see in the human IPF lung slices is you see the decrease in TGFβ1 and the decrease in collagen production. It is really nice evidence that we are driving exactly the mechanism we are looking for. The other thing that we are doing with this mechanism is actually upregulating enzymes called collagenase matrix metalloproteinases. These are enzymes that digest existing collagen. We believe that not only are we stopping new fibrosis, but actually being able to resolve existing fibrosis. That is what this mechanism of action is supposed to do. Yep. OK, so let's get into the phase II-A. Can you talk about the design and I guess really at a high level what the goal was for this study? Yeah, so the goal was initial clinical signal. So phase II-A study where we looked at buloxibutid in monotherapy. So we want to understand how is this drug working by itself before we combine it in a treatment naive population of IPF patients. And we wanted to look at it over nine months. Many companies look at IPF studies, look at doing initial IPF studies over 12 weeks. And certainly, there's a practical reason why you do it shorter. It's cheaper and it's quicker to do. But ultimately, we don't think you can see fibrosis signals that quickly. And because we believe that our mechanism of action is more dominated by this epithelial repair and fibrosis resolution rather than a quick anti-inflammatory effect, we thought it was important to study it over that longer period of time. So that was the setup. Actually, what we ultimately saw in this open label study was not just a stabilization of lung function, but an improvement in lung function by over 200 ml out to 36 weeks. This is certainly something that's not been seen before in the IPF space. How confident, I mean, part of the clinical development trials and tribulations in the IPF space has been early proof of concept data turning out to be more than what we thought or running into safety issues, et cetera. How confident are you in the realness of that signal? Yeah, I would say that we have a strong conviction that this is a real clinical signal. And there are a few reasons for that. I think first is the time out to which we've went, right? Because one of the issues you mentioned, Alex, is people study the drug in a phase II-A, 12 weeks, they see some improvement in lung function. And if you're reducing swelling, you see that improvement because you've opened up space in the lung for more milliliters of lung capacity. But then over a longer period of time, the fibrosis continues to march forward and constricts the lung capacity, which is why we believe some companies will show an improvement in lung function or a good effect. And then it starts to wane over a longer period of time. So we're not plagued by that issue in our nine-month study setup. That gives us a lot of conviction in what we're doing. We also have a great deal of conviction in what we're seeing because it matches the mechanism of action. You kind of have this slow improvement in lung function. That we think is associated then with slowly resolving the fibrosis and repairing the epithelial compartment. It's not kind of a quick shot effect, which would be kind of surprising relative to this biology. I think the third piece of the puzzle is we measured different biomarkers. We're seeing a trend in decreasing TGFβ1 in the plasma of these patients. It is known that there's elevated systemic TGFβ1 in IPF patients. We're also seeing an increase in these collagenase matrix metalloproteinases in the plasma of the IPF patients, in particular MMP-13. It's nice evidence that we're driving the biology that we're going after. I think one of the other potential critiques of the study is geography, the signal you're seeing in different geographies. Can you tease that out a little bit and why, again, this is not something to be worried about? Yeah, absolutely. The study enrolled about 75% of the patients out of India. One of the reasons for this was in order to get treatment naive patients in monotherapy, right? For market access reasons, unfortunately, in that geography, they have less access. Essentially, there are a few things I would say about this. First of all, when you look at the IPF patients that came into the trial, they were confirmed in their diagnosis by a central reader or a central pulmonary radiologist out of the U.K. who does this for the large pharma in phase II and phase III settings. We have a strong conviction that these are really IPF patients who are coming in. When you talk about IPF patients, then certainly the data out of India show you that they have the same trajectory. They fit in that global trend, unfortunately, of a rough disease with a short mortality. The other piece of the puzzle is the U.K. patients who came into the study, who comprised most of the balance, also had improvement in lung function at mean and median in 36 weeks. It is not like the Indian data is telling you anything different than what the U.K. data is telling you in terms of an overall clinical signal. The last thing that we did is we did a synthetic placebo arm where we did kind of very strong baseline characteristic matching for the patients. Then we pulled real-world patients and saw how their progress would be. They had that decline in lung function. It allows you to interpret these phase II-A results in that we're pulling in patients that if you look at what their characteristics look like, you would expect them to decline absent treatment. What about discontinuations and looking at data as observed versus imputed? Absolutely. The study was conducted during COVID in 2020 and 2021. As a result of that, there was a higher discontinuation rate than you typically expect in an IPF trial. I think first of all, just looking at the reasons for discontinuation, it was folks who were afraid of getting COVID, some folks who got COVID. It tended to be very early in the study as the pandemic was unfortunately progressing in a number of these geographies. First, there's an explanation for what's going on. The second thing is you look at the FVC trajectory or the lung trajectory of the patients who are discontinuing. They're consistent with the rest of the patients who stay in until they discontinue, i.e., you don't have people who are declining and then they're coming off the study and then the rest of your data is coming up. I think when you look at then the observed data, you see this improvement in lung function. We actually asked ourselves the question, what if we're wrong? What if actually these patients who left the study, who discontinued early, would have actually been progressors? We did this analysis using our synthetic placebo on our arm where we had this 115 ml decline in lung function over 36 weeks for the synthetic placebo. We said, let's pretend that every patient who left the study had that trajectory of decline. In that analysis, you then result in a more modest improvement in lung function at 20 ml over 36 weeks, but statistically significant compared to that 115 ml decline. The signal remains even if you're very conservative about what you're looking at. Yep. I think the other component of IPF drugs, both sort of today and in the future, is tolerability and safety. That's one of the issues with the drugs that are on the market today. What does the profile look like for your drug in the combinability as well? In clinical development to date, this has been a safe and well-tolerated drug. We have been really pleased to see that. Buloxibutid has now been tested in over 350 patients for up to nine months. It has a good building safety database. The one observation we have in the phase II-A that is notable is 19% of the patients experienced mild to moderate hair loss or hair thinning. That is an effect that we think is ultimately manageable in the context of IPF, given that it is a disease of older men largely. At the same time, in our ongoing phase II-B, we are exploring also a lower dose of buloxibutid, which we believe can be effective and may allow us to have less or mitigate that kind of hair loss or hair thinning effect. The other thing to note is that that effect is reversible. As patients came off of the study in the phase II-A, the hair regrew as well. Yep. Moving on, you're running a phase II-B study right now. Uniquely, it's a 52-week study versus 24 or less. What was the decision around actually going for a full 52-week study? Yeah, absolutely. I mean, we really wanted to run a robust study and really run a gold standard study. This study is comparable to the phase III studies you would do in this setting. We're enrolling broadly. We're enrolling the therapy on top of the available standard of care nintedanib or for patients who are not on standard of care. We're looking at the phase III or the regulatory endpoint, which is the change in lung function over one year. As we saw in our phase II-A study, we believe this drug builds its efficacy over time as it resolves fibrosis and rebuilds the epithelium. We were certainly interested in looking over a longer period of time than 12 weeks. We also believe that this data package, hopefully successful, will be part of that substantial evidence of efficacy package and help us design with the FDA's collaboration a streamlined phase III program. Yep. I think one of the other questions here, as we've seen an evolving landscape in IPF, is what do placebo arms look like today? How confident are you in the powering of the study to see an effect? Should we be concerned about that? Yeah, I think as we see more and more placebo arms, it's been useful. There is variability in IPF. At the same time, in particular, thinking about the FIBRONEER study where we have a little bit more information versus the TETON-2 who haven't yet published, it's nice to see what's going on in the placebo arm in view of kind of our expectations. I would say there's a lot of consistency. Certainly, as you design IPF trials, you want to be conservative in thinking about there's always expected variability in your placebo arms. That's certainly something that's been on our minds and is on our minds as we've designed this kind of phase II-B study as well. I would say that that's why, even though we see this signal of improvement in lung function, we've certainly powered the phase II-B study to capture a broader range of efficacy than that. Are you worried about functional unblinding with hair loss? No. I mean, it is something to think about. At the same time, when we're talking about a side effect that's coming in in the phase II-A at 19% and actually in the phase II-B to date, we're seeing it at even a little bit of a lower level. Plus, when you tell patients at the outset, you're coming into a clinical trial, you might experience some hair loss. I'm sure it'll be interesting to see kind of what that placebo arm looks like in terms of the amount of reported hair loss. I'm sure it'll be higher. If you contrast that, for example, with nintedanib, where the majority of patients experience diarrhea and unfortunately more than mild diarrhea, we think that this is a side effect of the nature that is something that's common to clinical studies in this disease space as well as in others. What can you say about enrollment progress and timelines at this point? Yeah, so we're enrolling very well. We're the most advanced IPF study that we know of that's currently enrolling because the three phase IIIs that we've touched on have completed their enrollment. I think that's getting us very good attention from our approximately 100 clinical sites across 14 different countries. We've guided that we anticipate completing enrollment in the first half of next year. We're on track to achieve that. Great. And then what does a good outcome look like? Is statistical significance sufficient? Or is there some level of comparability or superiority to nerandomilast, et cetera? Yeah, so relative to our powering, statistical significance is certainly sufficient to have a very attractive therapy, right? As we'd mentioned, nerandomilast showed kind of a positive outcome on the primary endpoint, that 69 ml difference in lung function, which would be considered to be a relatively modest effect. Nonetheless, they've gotten the approval from FDA. That certainly underscores how high the unmet need is. Certainly, with a successful readout, we believe that this would be a very, very attractive therapy as part of the broader landscape. You mentioned, obviously, combinability, just given how terrible this disease is, is a core component probably of the future landscape. How can you enable that in your phase II-B or potentially in phase III and moving forward? Yeah, so we're allowing patients, as I mentioned, on nintedanib, standard of care and not on standard of care as kind of the core of the study. We're not allowing patients on the second therapy, pirfenidone, which tends to be a bit of a dirtier molecule due to a drug-drug interaction risk. We'll continue to watch that. There is a way to kind of do a dose adjustment and allow it in future clinical development if that's something that appears warranted. Of course, with these emerging therapies, that's where our eye is looking to now. For example, as nerandomilast is now approved in the U.S. and based on the review of the literature, we don't believe that there's a drug-drug interaction issue. We'll actually be allowing patients on the background nerandomilast to join our clinical study in the phase II-B. We don't believe this will be a very large number of patients who ultimately come into the study on background nerandomilast just because of the timing. We think we're going to be well underway or close to complete as kind of more patients take that drug. At the same time, it'll still be good to get some early experience because particularly if that drug launches well as it might, then certainly thinking about how you combine with that drug in phase III makes sense. Then moving forward, you have a partnership right now with Nippon Shinyaku. Can you talk a little bit about what the context is there and just broadly how you're thinking about moving forward as a company? Yeah, absolutely. Nippon Shinyaku have Japanese rights to the program. We have a great partnership structure in place where, of course, there are the financials associated with it, including royalties up to the low 20s % on sales of the drug in Japan. They also are contributing to the non-clinical development costs even from now. Of course, there is a lot of phase III and commercial CMC work that is ongoing that we are both working with them on collaboratively, but also they are contributing to financially. In addition to that, they will contribute to the kind of phase III program in terms of providing kind of Japanese patients financial support as well as operational support to help us execute that larger clinical study subsequently. We are really happy to have the partnership with them. They have actually developed and commercialized a number of the pulmonary hypertension drugs. They're really experts in this space, know the clinicians well in Japan, and a good partner for us there. Is IPF a market that a biotech can launch competitively into? Yes, we believe it is. Because the amount of sales force, given the nature of the disease, it's a larger, rare disease, but it is a rare disease. The nature of where the patient population goes in terms of clinical centers makes us confident that this is the type of project that a biotech could launch in the U.S. on its own. I think we've talked separately too about your pipeline of AT2 receptor agonists that are out there. Where is that going? What other types of indications might you be exploring or thinking about exploring? Absolutely. As I'd mentioned, this is a relatively upstream pathway. If you think about where ACE inhibitors and ARBs play, they certainly don't just play in hypertension. They're used across a number of diseases. We have a similar view here. When you think about other fibrotic and inflammatory conditions, we get very excited about those, both in the lung and outside of the lung. Certainly, when you think about in the lung, the natural places to expand are progressive pulmonary fibrosis and other interstitial lung diseases, but also thinking about pulmonary hypertension, both pulmonary arterial hypertension as well as group 3 pulmonary hypertension or PH-ILD. Those are all certainly on our list. Also, looking at diseases outside of the lung, we have a great interest, for example, in renal indications and chronic kidney disease. We're developing a pipeline of follow-on programs to interrogate those. We look forward to sharing more about that over time as well. I guess the expansion, is that with buloxibutid or is this with the pipeline? I guess what's the path forward for other indications? Absolutely. I mean, I think that that's still something that we're looking at. Certainly, we are actively kind of developing newer compounds because we think that certainly there are ways to optimize the particular therapy for the particular organ or indication in a favorable way. That is also on our mind. Great. Maybe last question, can you talk about your cash runway and what assumptions go along with that? Yeah, absolutely. We reported about $90 million in cash as of the end of last quarter. That's sufficient for us to be able to complete the phase II-B study that we've discussed in its current sizing as well as have additional cash runway for about a year thereafter. We're well positioned from that perspective. Great. Any additional questions? If not, Ahmed, thank you. Thank you, Alex.

Speaker 2: Awesome. Happy to be joined next here by Ahmed Mousa, CEO of Vicore Pharma for fireside. So Ahmed, maybe over to you for a quick introduction to the company, and then we'll get into it. Awesome. awesome Happy to be joined next here by Ahmed Mousa, CEO of Vicore Pharma for fireside. happy to be joined next here by ahmed mousa ceo of vicore pharma for fireside So Ahmed, maybe over to you for a quick introduction to the company, and then we'll get into it. so ahmed maybe over to you for a quick introduction to the company and then we'll get into it

Speaker 1: Yeah, absolutely. Thanks for having us again, Alex. Yeah, so Vicore Pharma is a Nordic biotech company. We're developing drugs in the angiotensin II pathway. In particular, we've zeroed in on a target called the angiotensin II type 2 receptor. This is a target that activating it drives endogenous tissue repair, fibrosis resolution, and vasodilatory effects. It's a relatively upstream target. It drives a number of different activities. It sits in the body as the opposing force to a receptor that we know very well called the AT1 receptor. This is the target that drives hypertension, inflammation, and fibrosis. There's been incredible success in the industry in developing ACE inhibitors and ARBs, which are AT1 receptor antagonists, to kind of block that side of the pathway. Yeah, absolutely. yeah absolutely Thanks for having us again, Alex. thanks for having us again alex Yeah, so Vicore Pharma is a Nordic biotech company. yeah so vicore pharma is a nordic biotech company We're developing drugs in the angiotensin II pathway. we're developing drugs in the angiotensin ii pathway In particular, we've zeroed in on a target called the angiotensin II type 2 receptor. in particular we've zeroed in on a target called the angiotensin ii type 2 receptor This is a target that activating it drives endogenous tissue repair, fibrosis resolution, and vasodilatory effects. this is a target that activating it drives endogenous tissue repair fibrosis resolution and vasodilatory effects It's a relatively upstream target. it's a relatively upstream target It drives a number of different activities. it drives a number of different activities It sits in the body as the opposing force to a receptor that we know very well called the AT1 receptor. it sits in the body as the opposing force to a receptor that we know very well called the at1 receptor This is the target that drives hypertension, inflammation, and fibrosis. this is the target that drives hypertension inflammation and fibrosis There's been incredible success in the industry in developing ACE inhibitors and ARBs, which are AT1 receptor antagonists, to kind of block that side of the pathway. there's been incredible success in the industry in developing ace inhibitors and arbs which are at1 receptor antagonists to kind of block that side of the pathway We think that activating the other side of the pathway, that counterforce, can be very fruitful across a large number of diseases. We're starting out in pulmonary fibrosis. It is great to be here and talk more about our lead program as well. We think that activating the other side of the pathway, that counterforce, can be very fruitful across a large number of diseases. we think that activating the other side of the pathway that counterforce can be very fruitful across a large number of diseases We're starting out in pulmonary fibrosis. we're starting out in pulmonary fibrosis It is great to be here and talk more about our lead program as well. it is great to be here and talk more about our lead program as well

Speaker 2: Yeah, so maybe to start, the IPF space has seen a lot of ups and downs. It seems like we're on a little bit of an upswing more recently. Maybe could you sort of lay out where we're at right now in the IPF space? What does the clinical development landscape look like? What the early launch feedback might be from that recent launch from BI? Yeah, so maybe to start, the IPF space has seen a lot of ups and downs. yeah so maybe to start the ipf space has seen a lot of ups and downs It seems like we're on a little bit of an upswing more recently. it seems like we're on a little bit of an upswing more recently Maybe could you sort of lay out where we're at right now in the IPF space? maybe could you sort of lay out where we're at right now in the ipf space What does the clinical development landscape look like? what does the clinical development landscape look like What the early launch feedback might be from that recent launch from BI ? what the early launch feedback might be from that recent launch from bi

Speaker 1: Absolutely. There are, right up until a few weeks ago, two approved drugs for IPF, pirfenidone and nintedanib, which incrementally slowed the decline of lung function. Unfortunately, IPF is a disease with a three to four-year survival, and that was not significantly impacted by these therapies. Nonetheless, certainly they were used for that purpose. They also had significant tolerability challenges, which limited their uptake, including GI side effects as well as other side effects. As you mentioned, Alex, there is now a third entrant to the market, which is BI has a drug called nerandomilast, marketing it as JASCAYD, which also incrementally slows the decline of lung function. I would say that the clinician consensus we've been hearing is this is not groundbreaking relative to the other therapies from that perspective. It does appear to be better tolerated. Absolutely. absolutely There are, right up until a few weeks ago, two approved drugs for IPF, pirfenidone and nintedanib, which incrementally slowed the decline of lung function. there are right up until a few weeks ago two approved drugs for ipf pirfenidone and nintedanib which incrementally slowed the decline of lung function Unfortunately, IPF is a disease with a three to four-year survival, and that was not significantly impacted by these therapies. unfortunately ipf is a disease with a three to four-year survival and that was not significantly impacted by these therapies Nonetheless, certainly they were used for that purpose. nonetheless certainly they were used for that purpose They also had significant tolerability challenges, which limited their uptake, including GI side effects as well as other side effects. they also had significant tolerability challenges which limited their uptake including gi side effects as well as other side effects As you mentioned, Alex, there is now a third entrant to the market, which is BI has a drug called nerandomilast, marketing it as JASCAYD, which also incrementally slows the decline of lung function. as you mentioned alex there is now a third entrant to the market which is bi has a drug called nerandomilast marketing it as jascayd which also incrementally slows the decline of lung function I would say that the clinician consensus we've been hearing is this is not groundbreaking relative to the other therapies from that perspective. i would say that the clinician consensus we've been hearing is this is not groundbreaking relative to the other therapies from that perspective It does appear to be better tolerated. it does appear to be better tolerated There is in the U.S. some clinician enthusiasm based on what's been seen in clinical development in this program to maybe use this therapy. As IPF is a disease also of older individuals, they tend to have other issues. A drug that's easier for them to take is certainly not something to underestimate. That would be very interesting to see then how that launch ultimately plays out. There has also been another program. United Therapeutics has inhaled treprostinil, which has shown in the first of their two phase III studies, again, an incremental effect on lung function in terms of slowing the decline, but also kind of a better numerical effect. It appears to be kind of better from the efficacy side. There is in the U.S. some clinician enthusiasm based on what's been seen in clinical development in this program to maybe use this therapy. there is in the u.s some clinician enthusiasm based on what's been seen in clinical development in this program to maybe use this therapy As IPF is a disease also of older individuals, they tend to have other issues. as ipf is a disease also of older individuals they tend to have other issues A drug that's easier for them to take is certainly not something to underestimate. a drug that's easier for them to take is certainly not something to underestimate That would be very interesting to see then how that launch ultimately plays out. There has also been another program. that would be very interesting to see then how that launch ultimately plays out. there has also been another program United Therapeutics has inhaled treprostinil, which has shown in the first of their two phase III studies, again, an incremental effect on lung function in terms of slowing the decline, but also kind of a better numerical effect. united therapeutics has inhaled treprostinil which has shown in the first of their two phase iii studies again an incremental effect on lung function in terms of slowing the decline but also kind of a better numerical effect It appears to be kind of better from the efficacy side. it appears to be kind of better from the efficacy side It's a tougher to take drug based on the clinical feedback we've heard from folks who treat patients with pulmonary hypertension already with the drug. It'll be interesting to see how that then second phase III reads out next year and how it might be deployed in the landscape. The final drug that's in development ahead of Vicore's buloxibutid is an LPA1 antagonist that BMS is developing. That data will come out next year. I would say overall, the landscape remains one where IPF is a fatal disease, three to four-year survival, drugs that are incremental in slowing the decline of lung function. We really have a need for more effective drugs as well as better tolerated drugs in general. Certainly, this is also a landscape where clinicians are excited to try combination therapies where that's possible. It's a tougher to take drug based on the clinical feedback we've heard from folks who treat patients with pulmonary hypertension already with the drug. it's a tougher to take drug based on the clinical feedback we've heard from folks who treat patients with pulmonary hypertension already with the drug It'll be interesting to see how that then second phase III reads out next year and how it might be deployed in the landscape. it'll be interesting to see how that then second phase iii reads out next year and how it might be deployed in the landscape The final drug that's in development ahead of Vicore's buloxibutid is an LPA1 antagonist that BMS is developing. the final drug that's in development ahead of vicore's buloxibutid is an lpa1 antagonist that bms is developing That data will come out next year. that data will come out next year I would say overall, the landscape remains one where IPF is a fatal disease, three to four-year survival, drugs that are incremental in slowing the decline of lung function. i would say overall the landscape remains one where ipf is a fatal disease three to four-year survival drugs that are incremental in slowing the decline of lung function We really have a need for more effective drugs as well as better tolerated drugs in general. we really have a need for more effective drugs as well as better tolerated drugs in general Certainly, this is also a landscape where clinicians are excited to try combination therapies where that's possible. certainly this is also a landscape where clinicians are excited to try combination therapies where that's possible

Speaker 2: Yeah, in general, though, I think the unmet need is clear. Clinical development has been challenging. I mean, what do you think are the main issues with these challenges? Is it the endpoints? Is it the underlying disease pathology? Is it just we haven't found the right targets at this point? How would you rate what's been happening over the last five years? Yeah, in general, though, I think the unmet need is clear. yeah in general though i think the unmet need is clear Clinical development has been challenging. clinical development has been challenging I mean, what do you think are the main issues with these challenges? i mean what do you think are the main issues with these challenges Is it the endpoints? is it the endpoints Is it the underlying disease pathology? is it the underlying disease pathology Is it just we haven't found the right targets at this point? is it just we haven't found the right targets at this point How would you rate what's been happening over the last five years? how would you rate what's been happening over the last five years

Speaker 1: Absolutely. I think with the benefit of hindsight and a lot of learning from the different successes and failures in the landscape, when you step back and think about what is IPF or what is pulmonary fibrosis, it's injury to the epithelial layer of the alveolus. It's injury to the air sacs. That injury causes the scarring or the kind of runaway fibrosis around that epithelial layer, which then ultimately also drives vascular dysfunction as you put pressure in that interstitial space on the capillaries and the other vessels of the pulmonary compartment. I think that what we've basically learned over time is that trying to block the fibrosis in the interstitium, like blocking activity of fibroblasts in terms of depositing collagen, is not an invalid way to go after this disease. It may only give you these incremental results. Absolutely. absolutely I think with the benefit of hindsight and a lot of learning from the different successes and failures in the landscape, when you step back and think about what is IPF or what is pulmonary fibrosis, it's injury to the epithelial layer of the alveolus. i think with the benefit of hindsight and a lot of learning from the different successes and failures in the landscape when you step back and think about what is ipf or what is pulmonary fibrosis it's injury to the epithelial layer of the alveolus It's injury to the air sacs. it's injury to the air sacs That injury causes the scarring or the kind of runaway fibrosis around that epithelial layer, which then ultimately also drives vascular dysfunction as you put pressure in that interstitial space on the capillaries and the other vessels of the pulmonary compartment. that injury causes the scarring or the kind of runaway fibrosis around that epithelial layer which then ultimately also drives vascular dysfunction as you put pressure in that interstitial space on the capillaries and the other vessels of the pulmonary compartment I think that what we've basically learned over time is that trying to block the fibrosis in the interstitium, like blocking activity of fibroblasts in terms of depositing collagen, is not an invalid way to go after this disease. i think that what we've basically learned over time is that trying to block the fibrosis in the interstitium like blocking activity of fibroblasts in terms of depositing collagen is not an invalid way to go after this disease It may only give you these incremental results. it may only give you these incremental results It's interesting to see that a vasoactive drug like the inhaled treprostinil provides for a better numerical response. We think that's consistent with the mechanism of action where you should think about IPF as a disease that's impacting three compartments: the epithelium and the alveolus, the interstitium, and the vasculature. We think that going then beyond interstitial targeting or fibrosis targeting compounds can have a huge benefit in this space as well. It's interesting to see that a vasoactive drug like the inhaled treprostinil provides for a better numerical response. it's interesting to see that a vasoactive drug like the inhaled treprostinil provides for a better numerical response We think that's consistent with the mechanism of action where you should think about IPF as a disease that's impacting three compartments: the epithelium and the alveolus, the interstitium, and the vasculature. we think that's consistent with the mechanism of action where you should think about ipf as a disease that's impacting three compartments the epithelium and the alveolus the interstitium and the vasculature We think that going then beyond interstitial targeting or fibrosis targeting compounds can have a huge benefit in this space as well. we think that going then beyond interstitial targeting or fibrosis targeting compounds can have a huge benefit in this space as well

Speaker 2: Yeah, I think that's a perfect segue into talking about the AT2 receptor target, the design of buloxibutid, the underlying mechanism of action here in IPF. Yeah, I think that's a perfect segue into talking about the AT2 receptor target, the design of buloxibutid, the underlying mechanism of action here in IPF. yeah i think that's a perfect segue into talking about the at2 receptor target the design of buloxibutid the underlying mechanism of action here in ipf

Speaker 1: Yeah, absolutely. As I'd mentioned, Alex, what happens in IPF is the kind of focal point in our view of this disease is that injury to the alveolar compartment, the injury to these air sacs, and that epithelial layer. In particular, actually, there's a stem cell called the alveolar epithelial type 2 cell. We believe it's the injury to that cell that is the core of the disease driver and what kind of starts this process out. There's a lot of good scientific evidence for that too. As these stem cells become injured, they're the ones that are supposed to differentiate into the gas exchange cells. Of course, when you have the injury in this disease, the gas exchange cells die off. Now the stem cells that are supposed to replenish them are also dying off. Yeah, absolutely. yeah absolutely As I'd mentioned, Alex, what happens in IPF is the kind of focal point in our view of this disease is that injury to the alveolar compartment, the injury to these air sacs, and that epithelial layer. as i'd mentioned alex what happens in ipf is the kind of focal point in our view of this disease is that injury to the alveolar compartment the injury to these air sacs and that epithelial layer In particular, actually, there's a stem cell called the alveolar epithelial type 2 cell. in particular actually there's a stem cell called the alveolar epithelial type 2 cell We believe it's the injury to that cell that is the core of the disease driver and what kind of starts this process out. we believe it's the injury to that cell that is the core of the disease driver and what kind of starts this process out There's a lot of good scientific evidence for that too. there's a lot of good scientific evidence for that too As these stem cells become injured, they're the ones that are supposed to differentiate into the gas exchange cells. as these stem cells become injured they're the ones that are supposed to differentiate into the gas exchange cells Of course, when you have the injury in this disease, the gas exchange cells die off. of course when you have the injury in this disease the gas exchange cells die off Now the stem cells that are supposed to replenish them are also dying off. now the stem cells that are supposed to replenish them are also dying off You have impaired lung function even before you have any fibrosis buildup. The second thing that happens is these stem cells, these type 2 epithelial cells, are supposed to be producing surfactant protein to break up the natural surface tension of water to keep the air sacs inflated. Actually, when you start to kill off or cause these type 2 epithelial cells to dysfunction, you have a phenomenon in IPF that's known as prefibrotic alveolar collapse due to loss of surfactant. Basically, what that means is these alveoli, these air sacs, flatten like a pancake because of the surface tension of water. Again, this comes before the fibrosis. What's so rough about this disease is it's the injury to these type 2 epithelial cells, these stem cells. You have impaired lung function even before you have any fibrosis buildup. you have impaired lung function even before you have any fibrosis buildup The second thing that happens is these stem cells, these type 2 epithelial cells, are supposed to be producing surfactant protein to break up the natural surface tension of water to keep the air sacs inflated. the second thing that happens is these stem cells these type 2 epithelial cells are supposed to be producing surfactant protein to break up the natural surface tension of water to keep the air sacs inflated Actually, when you start to kill off or cause these type 2 epithelial cells to dysfunction, you have a phenomenon in IPF that's known as prefibrotic alveolar collapse due to loss of surfactant. actually when you start to kill off or cause these type 2 epithelial cells to dysfunction you have a phenomenon in ipf that's known as prefibrotic alveolar collapse due to loss of surfactant Basically, what that means is these alveoli, these air sacs, flatten like a pancake because of the surface tension of water. basically what that means is these alveoli these air sacs flatten like a pancake because of the surface tension of water Again, this comes before the fibrosis. again this comes before the fibrosis What's so rough about this disease is it's the injury to these type 2 epithelial cells, these stem cells. what's so rough about this disease is it's the injury to these type 2 epithelial cells these stem cells When they become dysfunctional, they're the ones that start spitting out the profibrotic factors, the TGFβ, the wound healing signal. They become the key orchestrator then of the fibrotic buildup around them. What we're doing at Vicore with this AT2 receptor, by activating it, they actually sit on these type 2 epithelial cells, on these stem cells. You refunctionalize and drive proliferation of the cell type. It means you can replenish the gas exchange capability. It means you can reverse that prefibrotic alveolar collapse. It also means you cut off the pathological profibrotic signal, that TGFβ1 signal at its kind of source. We think that's a very potent way to go after this disease. When they become dysfunctional, they're the ones that start spitting out the profibrotic factors, the TGFβ, the wound healing signal. when they become dysfunctional they're the ones that start spitting out the profibrotic factors the tgfβ the wound healing signal They become the key orchestrator then of the fibrotic buildup around them. they become the key orchestrator then of the fibrotic buildup around them What we're doing at Vicore with this AT2 receptor, by activating it, they actually sit on these type 2 epithelial cells, on these stem cells. what we're doing at vicore with this at2 receptor by activating it they actually sit on these type 2 epithelial cells on these stem cells You refunctionalize and drive proliferation of the cell type. you refunctionalize and drive proliferation of the cell type It means you can replenish the gas exchange capability. it means you can replenish the gas exchange capability It means you can reverse that prefibrotic alveolar collapse. it means you can reverse that prefibrotic alveolar collapse It also means you cut off the pathological profibrotic signal, that TGFβ1 signal at its kind of source. it also means you cut off the pathological profibrotic signal that tgfβ1 signal at its kind of source We think that's a very potent way to go after this disease. we think that's a very potent way to go after this disease

Speaker 2: You actually have clinical data. Before we get into that, can you talk a little about the preclinical models that you've developed to sort of understand this specific mechanism as well? You actually have clinical data. you actually have clinical data Before we get into that, can you talk a little about the preclinical models that you've developed to sort of understand this specific mechanism as well? before we get into that can you talk a little about the preclinical models that you've developed to sort of understand this specific mechanism as well

Speaker 1: Absolutely. We've looked at this molecule in a large number of preclinical models. I would say we look at it in models as simple as you take these type II epithelial cells, these stem cells, and you injure them using a toxin like bleomycin, which is commonly used to simulate IPF in animal models. It starts to cause these cells to die off. When you add buloxibutid in a concentration-dependent way, you're able to protect these cells from apoptosis. It shows that you can actually do exactly what you're doing in a very simple model. If you take this to a more complicated model, like let's call it human IPF precision cut lung slices. Absolutely. absolutely We've looked at this molecule in a large number of preclinical models. we've looked at this molecule in a large number of preclinical models I would say we look at it in models as simple as you take these type II epithelial cells, these stem cells, and you injure them using a toxin like bleomycin, which is commonly used to simulate IPF in animal models. i would say we look at it in models as simple as you take these type ii epithelial cells these stem cells and you injure them using a toxin like bleomycin which is commonly used to simulate ipf in animal models It starts to cause these cells to die off. it starts to cause these cells to die off When you add buloxibutid in a concentration-dependent way, you're able to protect these cells from apoptosis. when you add buloxibutid in a concentration-dependent way you're able to protect these cells from apoptosis It shows that you can actually do exactly what you're doing in a very simple model. it shows that you can actually do exactly what you're doing in a very simple model If you take this to a more complicated model, like let's call it human IPF precision cut lung slices. if you take this to a more complicated model like let's call it human ipf precision cut lung slices When IPF patients become very progressed, they actually get a lung transplant. You can then take tissue from the IPF lung, add your drug to it, and see what happens. What we see is we increase significantly surfactant protein expression. As I mentioned, Alex, these surfactant proteins are coming from these type II epithelial cells. It is evidence that we are addressing the prefibrotic alveolar collapse and that we are protecting the type II epithelial cells. What you also see in the human IPF lung slices is you see the decrease in TGFβ1 and the decrease in collagen production. It is really nice evidence that we are driving exactly the mechanism we are looking for. The other thing that we are doing with this mechanism is actually upregulating enzymes called collagenase matrix metalloproteinases. These are enzymes that digest existing collagen. When IPF patients become very progressed, they actually get a lung transplant. when ipf patients become very progressed they actually get a lung transplant You can then take tissue from the IPF lung, add your drug to it, and see what happens. you can then take tissue from the ipf lung add your drug to it and see what happens What we see is we increase significantly surfactant protein expression. what we see is we increase significantly surfactant protein expression As I mentioned, Alex, these surfactant proteins are coming from these type II epithelial cells. as i mentioned alex these surfactant proteins are coming from these type ii epithelial cells It is evidence that we are addressing the prefibrotic alveolar collapse and that we are protecting the type II epithelial cells. it is evidence that we are addressing the prefibrotic alveolar collapse and that we are protecting the type ii epithelial cells What you also see in the human IPF lung slices is you see the decrease in TGFβ1 and the decrease in collagen production. what you also see in the human ipf lung slices is you see the decrease in tgfβ1 and the decrease in collagen production It is really nice evidence that we are driving exactly the mechanism we are looking for. it is really nice evidence that we are driving exactly the mechanism we are looking for The other thing that we are doing with this mechanism is actually upregulating enzymes called collagenase matrix metalloproteinases. the other thing that we are doing with this mechanism is actually upregulating enzymes called collagenase matrix metalloproteinases These are enzymes that digest existing collagen. these are enzymes that digest existing collagen We believe that not only are we stopping new fibrosis, but actually being able to resolve existing fibrosis. That is what this mechanism of action is supposed to do. We believe that not only are we stopping new fibrosis, but actually being able to resolve existing fibrosis. we believe that not only are we stopping new fibrosis but actually being able to resolve existing fibrosis That is what this mechanism of action is supposed to do. that is what this mechanism of action is supposed to do

Speaker 2: Yep. OK, so let's get into the phase II-A. Can you talk about the design and I guess really at a high level what the goal was for this study? Yep. yep OK, so let's get into the phase II-A. ok so let's get into the phase ii-a Can you talk about the design and I guess really at a high level what the goal was for this study? can you talk about the design and i guess really at a high level what the goal was for this study

Speaker 1: Yeah, so the goal was initial clinical signal. So phase II-A study where we looked at buloxibutid in monotherapy. So we want to understand how is this drug working by itself before we combine it in a treatment naive population of IPF patients. And we wanted to look at it over nine months. Many companies look at IPF studies, look at doing initial IPF studies over 12 weeks. And certainly, there's a practical reason why you do it shorter. It's cheaper and it's quicker to do. But ultimately, we don't think you can see fibrosis signals that quickly. And because we believe that our mechanism of action is more dominated by this epithelial repair and fibrosis resolution rather than a quick anti-inflammatory effect, we thought it was important to study it over that longer period of time. So that was the setup. Yeah, so the goal was initial clinical signal. yeah so the goal was initial clinical signal So phase II-A study where we looked at buloxibutid in monotherapy. so phase ii-a study where we looked at buloxibutid in monotherapy So we want to understand how is this drug working by itself before we combine it in a treatment naive population of IPF patients. so we want to understand how is this drug working by itself before we combine it in a treatment naive population of ipf patients And we wanted to look at it over nine months. and we wanted to look at it over nine months Many companies look at IPF studies, look at doing initial IPF studies over 12 weeks. many companies look at ipf studies look at doing initial ipf studies over 12 weeks And certainly, there's a practical reason why you do it shorter. and certainly there's a practical reason why you do it shorter It's cheaper and it's quicker to do. it's cheaper and it's quicker to do But ultimately, we don't think you can see fibrosis signals that quickly. but ultimately we don't think you can see fibrosis signals that quickly And because we believe that our mechanism of action is more dominated by this epithelial repair and fibrosis resolution rather than a quick anti-inflammatory effect, we thought it was important to study it over that longer period of time. and because we believe that our mechanism of action is more dominated by this epithelial repair and fibrosis resolution rather than a quick anti-inflammatory effect we thought it was important to study it over that longer period of time So that was the setup. so that was the setup Actually, what we ultimately saw in this open label study was not just a stabilization of lung function, but an improvement in lung function by over 200 ml out to 36 weeks. This is certainly something that's not been seen before in the IPF space. Actually, what we ultimately saw in this open label study was not just a stabilization of lung function, but an improvement in lung function by over 200 ml out to 36 weeks. actually what we ultimately saw in this open label study was not just a stabilization of lung function but an improvement in lung function by over 200 ml out to 36 weeks This is certainly something that's not been seen before in the IPF space. this is certainly something that's not been seen before in the ipf space

Speaker 2: How confident, I mean, part of the clinical development trials and tribulations in the IPF space has been early proof of concept data turning out to be more than what we thought or running into safety issues, et cetera. How confident are you in the realness of that signal? How confident, I mean, part of the clinical development trials and tribulations in the IPF space has been early proof of concept data turning out to be more than what we thought or running into safety issues, et cetera. how confident i mean part of the clinical development trials and tribulations in the ipf space has been early proof of concept data turning out to be more than what we thought or running into safety issues et cetera How confident are you in the realness of that signal? how confident are you in the realness of that signal

Speaker 1: Yeah, I would say that we have a strong conviction that this is a real clinical signal. And there are a few reasons for that. I think first is the time out to which we've went, right? Because one of the issues you mentioned, Alex, is people study the drug in a phase II-A, 12 weeks, they see some improvement in lung function. And if you're reducing swelling, you see that improvement because you've opened up space in the lung for more milliliters of lung capacity. But then over a longer period of time, the fibrosis continues to march forward and constricts the lung capacity, which is why we believe some companies will show an improvement in lung function or a good effect. And then it starts to wane over a longer period of time. So we're not plagued by that issue in our nine-month study setup. Yeah, I would say that we have a strong conviction that this is a real clinical signal. yeah i would say that we have a strong conviction that this is a real clinical signal And there are a few reasons for that. and there are a few reasons for that I think first is the time out to which we've went, right? i think first is the time out to which we've went right Because one of the issues you mentioned, Alex, is people study the drug in a phase II-A, 12 weeks, they see some improvement in lung function. because one of the issues you mentioned alex is people study the drug in a phase ii-a 12 weeks they see some improvement in lung function And if you're reducing swelling, you see that improvement because you've opened up space in the lung for more milliliters of lung capacity. and if you're reducing swelling you see that improvement because you've opened up space in the lung for more milliliters of lung capacity But then over a longer period of time, the fibrosis continues to march forward and constricts the lung capacity, which is why we believe some companies will show an improvement in lung function or a good effect. but then over a longer period of time the fibrosis continues to march forward and constricts the lung capacity which is why we believe some companies will show an improvement in lung function or a good effect And then it starts to wane over a longer period of time. and then it starts to wane over a longer period of time So we're not plagued by that issue in our nine-month study setup. so we're not plagued by that issue in our nine-month study setup That gives us a lot of conviction in what we're doing. We also have a great deal of conviction in what we're seeing because it matches the mechanism of action. You kind of have this slow improvement in lung function. That we think is associated then with slowly resolving the fibrosis and repairing the epithelial compartment. It's not kind of a quick shot effect, which would be kind of surprising relative to this biology. I think the third piece of the puzzle is we measured different biomarkers. We're seeing a trend in decreasing TGFβ1 in the plasma of these patients. It is known that there's elevated systemic TGFβ1 in IPF patients. We're also seeing an increase in these collagenase matrix metalloproteinases in the plasma of the IPF patients, in particular MMP-13. That gives us a lot of conviction in what we're doing. that gives us a lot of conviction in what we're doing We also have a great deal of conviction in what we're seeing because it matches the mechanism of action. we also have a great deal of conviction in what we're seeing because it matches the mechanism of action You kind of have this slow improvement in lung function. you kind of have this slow improvement in lung function That we think is associated then with slowly resolving the fibrosis and repairing the epithelial compartment. that we think is associated then with slowly resolving the fibrosis and repairing the epithelial compartment It's not kind of a quick shot effect, which would be kind of surprising relative to this biology. it's not kind of a quick shot effect which would be kind of surprising relative to this biology I think the third piece of the puzzle is we measured different biomarkers. i think the third piece of the puzzle is we measured different biomarkers We're seeing a trend in decreasing TGFβ1 in the plasma of these patients. we're seeing a trend in decreasing tgfβ1 in the plasma of these patients It is known that there's elevated systemic TGFβ1 in IPF patients. it is known that there's elevated systemic tgfβ1 in ipf patients We're also seeing an increase in these collagenase matrix metalloproteinases in the plasma of the IPF patients, in particular MMP-13. we're also seeing an increase in these collagenase matrix metalloproteinases in the plasma of the ipf patients in particular mmp-13 It's nice evidence that we're driving the biology that we're going after. It's nice evidence that we're driving the biology that we're going after. it's nice evidence that we're driving the biology that we're going after

Speaker 2: I think one of the other potential critiques of the study is geography, the signal you're seeing in different geographies. Can you tease that out a little bit and why, again, this is not something to be worried about? I think one of the other potential critiques of the study is geography, the signal you're seeing in different geographies. i think one of the other potential critiques of the study is geography the signal you're seeing in different geographies Can you tease that out a little bit and why, again, this is not something to be worried about? can you tease that out a little bit and why again this is not something to be worried about

Speaker 1: Yeah, absolutely. The study enrolled about 75% of the patients out of India. One of the reasons for this was in order to get treatment naive patients in monotherapy, right? For market access reasons, unfortunately, in that geography, they have less access. Essentially, there are a few things I would say about this. First of all, when you look at the IPF patients that came into the trial, they were confirmed in their diagnosis by a central reader or a central pulmonary radiologist out of the U.K. who does this for the large pharma in phase II and phase III settings. We have a strong conviction that these are really IPF patients who are coming in. When you talk about IPF patients, then certainly the data out of India show you that they have the same trajectory. Yeah, absolutely. yeah absolutely The study enrolled about 75% of the patients out of India. the study enrolled about 75% of the patients out of india One of the reasons for this was in order to get treatment naive patients in monotherapy, right? one of the reasons for this was in order to get treatment naive patients in monotherapy right For market access reasons, unfortunately, in that geography, they have less access. for market access reasons unfortunately in that geography they have less access Essentially, there are a few things I would say about this. essentially there are a few things i would say about this First of all, when you look at the IPF patients that came into the trial, they were confirmed in their diagnosis by a central reader or a central pulmonary radiologist out of the U.K. who does this for the large pharma in phase II and phase III settings. first of all when you look at the ipf patients that came into the trial they were confirmed in their diagnosis by a central reader or a central pulmonary radiologist out of the u.k who does this for the large pharma in phase ii and phase iii settings We have a strong conviction that these are really IPF patients who are coming in. we have a strong conviction that these are really ipf patients who are coming in When you talk about IPF patients, then certainly the data out of India show you that they have the same trajectory. when you talk about ipf patients then certainly the data out of india show you that they have the same trajectory They fit in that global trend, unfortunately, of a rough disease with a short mortality. The other piece of the puzzle is the U.K. patients who came into the study, who comprised most of the balance, also had improvement in lung function at mean and median in 36 weeks. It is not like the Indian data is telling you anything different than what the U.K. data is telling you in terms of an overall clinical signal. The last thing that we did is we did a synthetic placebo arm where we did kind of very strong baseline characteristic matching for the patients. Then we pulled real-world patients and saw how their progress would be. They had that decline in lung function. They fit in that global trend, unfortunately, of a rough disease with a short mortality. they fit in that global trend unfortunately of a rough disease with a short mortality The other piece of the puzzle is the U.K. patients who came into the study, who comprised most of the balance, also had improvement in lung function at mean and median in 36 weeks. the other piece of the puzzle is the u.k patients who came into the study who comprised most of the balance also had improvement in lung function at mean and median in 36 weeks It is not like the Indian data is telling you anything different than what the U.K. data is telling you in terms of an overall clinical signal. it is not like the indian data is telling you anything different than what the u.k data is telling you in terms of an overall clinical signal The last thing that we did is we did a synthetic placebo arm where we did kind of very strong baseline characteristic matching for the patients. the last thing that we did is we did a synthetic placebo arm where we did kind of very strong baseline characteristic matching for the patients Then we pulled real-world patients and saw how their progress would be. then we pulled real-world patients and saw how their progress would be They had that decline in lung function. they had that decline in lung function It allows you to interpret these phase II-A results in that we're pulling in patients that if you look at what their characteristics look like, you would expect them to decline absent treatment. It allows you to interpret these phase II-A results in that we're pulling in patients that if you look at what their characteristics look like, you would expect them to decline absent treatment. it allows you to interpret these phase ii-a results in that we're pulling in patients that if you look at what their characteristics look like you would expect them to decline absent treatment

Speaker 2: What about discontinuations and looking at data as observed versus imputed? What about discontinuations and looking at data as observed versus imputed? what about discontinuations and looking at data as observed versus imputed

Speaker 1: Absolutely. The study was conducted during COVID in 2020 and 2021. As a result of that, there was a higher discontinuation rate than you typically expect in an IPF trial. I think first of all, just looking at the reasons for discontinuation, it was folks who were afraid of getting COVID, some folks who got COVID. It tended to be very early in the study as the pandemic was unfortunately progressing in a number of these geographies. First, there's an explanation for what's going on. The second thing is you look at the FVC trajectory or the lung trajectory of the patients who are discontinuing. They're consistent with the rest of the patients who stay in until they discontinue, i.e., you don't have people who are declining and then they're coming off the study and then the rest of your data is coming up. Absolutely. absolutely The study was conducted during COVID in 2020 and 2021. the study was conducted during covid in 2020 and 2021 As a result of that, there was a higher discontinuation rate than you typically expect in an IPF trial. as a result of that there was a higher discontinuation rate than you typically expect in an ipf trial I think first of all, just looking at the reasons for discontinuation, it was folks who were afraid of getting COVID, some folks who got COVID. i think first of all just looking at the reasons for discontinuation it was folks who were afraid of getting covid some folks who got covid It tended to be very early in the study as the pandemic was unfortunately progressing in a number of these geographies. it tended to be very early in the study as the pandemic was unfortunately progressing in a number of these geographies First, there's an explanation for what's going on. first there's an explanation for what's going on The second thing is you look at the FVC trajectory or the lung trajectory of the patients who are discontinuing. the second thing is you look at the fvc trajectory or the lung trajectory of the patients who are discontinuing They're consistent with the rest of the patients who stay in until they discontinue, i.e., you don't have people who are declining and then they're coming off the study and then the rest of your data is coming up. they're consistent with the rest of the patients who stay in until they discontinue i.e you don't have people who are declining and then they're coming off the study and then the rest of your data is coming up I think when you look at then the observed data, you see this improvement in lung function. We actually asked ourselves the question, what if we're wrong? What if actually these patients who left the study, who discontinued early, would have actually been progressors? We did this analysis using our synthetic placebo on our arm where we had this 115 ml decline in lung function over 36 weeks for the synthetic placebo. We said, let's pretend that every patient who left the study had that trajectory of decline. In that analysis, you then result in a more modest improvement in lung function at 20 ml over 36 weeks, but statistically significant compared to that 115 ml decline. The signal remains even if you're very conservative about what you're looking at. I think when you look at then the observed data, you see this improvement in lung function. i think when you look at then the observed data you see this improvement in lung function We actually asked ourselves the question, what if we're wrong? we actually asked ourselves the question what if we're wrong What if actually these patients who left the study, who discontinued early, would have actually been progressors? what if actually these patients who left the study who discontinued early would have actually been progressors We did this analysis using our synthetic placebo on our arm where we had this 115 ml decline in lung function over 36 weeks for the synthetic placebo. we did this analysis using our synthetic placebo on our arm where we had this 115 ml decline in lung function over 36 weeks for the synthetic placebo We said, let's pretend that every patient who left the study had that trajectory of decline. we said let's pretend that every patient who left the study had that trajectory of decline In that analysis, you then result in a more modest improvement in lung function at 20 ml over 36 weeks, but statistically significant compared to that 115 ml decline. in that analysis you then result in a more modest improvement in lung function at 20 ml over 36 weeks but statistically significant compared to that 115 ml decline The signal remains even if you're very conservative about what you're looking at. the signal remains even if you're very conservative about what you're looking at

Speaker 2: Yep. I think the other component of IPF drugs, both sort of today and in the future, is tolerability and safety. That's one of the issues with the drugs that are on the market today. What does the profile look like for your drug in the combinability as well? Yep. yep I think the other component of IPF drugs, both sort of today and in the future, is tolerability and safety. i think the other component of ipf drugs both sort of today and in the future is tolerability and safety That's one of the issues with the drugs that are on the market today. that's one of the issues with the drugs that are on the market today What does the profile look like for your drug in the combinability as well? what does the profile look like for your drug in the combinability as well

Speaker 1: In clinical development to date, this has been a safe and well-tolerated drug. We have been really pleased to see that. Buloxibutid has now been tested in over 350 patients for up to nine months. It has a good building safety database. The one observation we have in the phase II-A that is notable is 19% of the patients experienced mild to moderate hair loss or hair thinning. That is an effect that we think is ultimately manageable in the context of IPF, given that it is a disease of older men largely. At the same time, in our ongoing phase II-B, we are exploring also a lower dose of buloxibutid, which we believe can be effective and may allow us to have less or mitigate that kind of hair loss or hair thinning effect. The other thing to note is that that effect is reversible. In clinical development to date, this has been a safe and well-tolerated drug. in clinical development to date this has been a safe and well-tolerated drug We have been really pleased to see that. we have been really pleased to see that Buloxibutid has now been tested in over 350 patients for up to nine months. buloxibutid has now been tested in over 350 patients for up to nine months It has a good building safety database. it has a good building safety database The one observation we have in the phase II-A that is notable is 19% of the patients experienced mild to moderate hair loss or hair thinning. the one observation we have in the phase ii-a that is notable is 19% of the patients experienced mild to moderate hair loss or hair thinning That is an effect that we think is ultimately manageable in the context of IPF, given that it is a disease of older men largely. that is an effect that we think is ultimately manageable in the context of ipf given that it is a disease of older men largely At the same time, in our ongoing phase II-B, we are exploring also a lower dose of buloxibutid, which we believe can be effective and may allow us to have less or mitigate that kind of hair loss or hair thinning effect. at the same time in our ongoing phase ii-b, we are exploring also a lower dose of buloxibutid which we believe can be effective and may allow us to have less or mitigate that kind of hair loss or hair thinning effect The other thing to note is that that effect is reversible. the other thing to note is that that effect is reversible As patients came off of the study in the phase II-A, the hair regrew as well. As patients came off of the study in the phase II-A, the hair regrew as well. as patients came off of the study in the phase ii-a the hair regrew as well

Speaker 2: Yep. Moving on, you're running a phase II-B study right now. Uniquely, it's a 52-week study versus 24 or less. What was the decision around actually going for a full 52-week study? Yep. yep Moving on, you're running a phase II-B study right now. moving on you're running a phase ii-b study right now Uniquely, it's a 52-week study versus 24 or less. uniquely it's a 52-week study versus 24 or less What was the decision around actually going for a full 52-week study? what was the decision around actually going for a full 52-week study

Speaker 1: Yeah, absolutely. I mean, we really wanted to run a robust study and really run a gold standard study. This study is comparable to the phase III studies you would do in this setting. We're enrolling broadly. We're enrolling the therapy on top of the available standard of care nintedanib or for patients who are not on standard of care. We're looking at the phase III or the regulatory endpoint, which is the change in lung function over one year. As we saw in our phase II-A study, we believe this drug builds its efficacy over time as it resolves fibrosis and rebuilds the epithelium. We were certainly interested in looking over a longer period of time than 12 weeks. Yeah, absolutely. yeah absolutely I mean, we really wanted to run a robust study and really run a gold standard study. i mean we really wanted to run a robust study and really run a gold standard study This study is comparable to the phase III studies you would do in this setting. this study is comparable to the phase iii studies you would do in this setting We're enrolling broadly. we're enrolling broadly We're enrolling the therapy on top of the available standard of care nintedanib or for patients who are not on standard of care. we're enrolling the therapy on top of the available standard of care nintedanib or for patients who are not on standard of care We're looking at the phase III or the regulatory endpoint, which is the change in lung function over one year. we're looking at the phase iii or the regulatory endpoint which is the change in lung function over one year As we saw in our phase II-A study, we believe this drug builds its efficacy over time as it resolves fibrosis and rebuilds the epithelium. as we saw in our phase ii-a study we believe this drug builds its efficacy over time as it resolves fibrosis and rebuilds the epithelium We were certainly interested in looking over a longer period of time than 12 weeks. we were certainly interested in looking over a longer period of time than 12 weeks We also believe that this data package, hopefully successful, will be part of that substantial evidence of efficacy package and help us design with the FDA's collaboration a streamlined phase III program. We also believe that this data package, hopefully successful, will be part of that substantial evidence of efficacy package and help us design with the FDA's collaboration a streamlined phase III program. we also believe that this data package hopefully successful will be part of that substantial evidence of efficacy package and help us design with the fda's collaboration a streamlined phase iii program

Speaker 2: Yep. I think one of the other questions here, as we've seen an evolving landscape in IPF, is what do placebo arms look like today? How confident are you in the powering of the study to see an effect? Should we be concerned about that? Yep. yep I think one of the other questions here, as we've seen an evolving landscape in IPF, is what do placebo arms look like today? i think one of the other questions here as we've seen an evolving landscape in ipf is what do placebo arms look like today How confident are you in the powering of the study to see an effect? how confident are you in the powering of the study to see an effect Should we be concerned about that? should we be concerned about that

Speaker 1: Yeah, I think as we see more and more placebo arms, it's been useful. There is variability in IPF. At the same time, in particular, thinking about the FIBRONEER study where we have a little bit more information versus the TETON-2 who haven't yet published, it's nice to see what's going on in the placebo arm in view of kind of our expectations. I would say there's a lot of consistency. Certainly, as you design IPF trials, you want to be conservative in thinking about there's always expected variability in your placebo arms. That's certainly something that's been on our minds and is on our minds as we've designed this kind of phase II-B study as well. Yeah, I think as we see more and more placebo arms, it's been useful. yeah i think as we see more and more placebo arms it's been useful There is variability in IPF. there is variability in ipf At the same time, in particular, thinking about the FIBRONEER study where we have a little bit more information versus the TETON-2 who haven't yet published, it's nice to see what's going on in the placebo arm in view of kind of our expectations. at the same time in particular thinking about the fibroneer study where we have a little bit more information versus the teton-2 who haven't yet published it's nice to see what's going on in the placebo arm in view of kind of our expectations I would say there's a lot of consistency. i would say there's a lot of consistency Certainly, as you design IPF trials, you want to be conservative in thinking about there's always expected variability in your placebo arms. certainly as you design ipf trials you want to be conservative in thinking about there's always expected variability in your placebo arms That's certainly something that's been on our minds and is on our minds as we've designed this kind of phase II-B study as well. that's certainly something that's been on our minds and is on our minds as we've designed this kind of phase ii-b study as well I would say that that's why, even though we see this signal of improvement in lung function, we've certainly powered the phase II-B study to capture a broader range of efficacy than that. I would say that that's why, even though we see this signal of improvement in lung function, we've certainly powered the phase II-B study to capture a broader range of efficacy than that. i would say that that's why even though we see this signal of improvement in lung function we've certainly powered the phase ii-b study to capture a broader range of efficacy than that

Speaker 2: Are you worried about functional unblinding with hair loss? Are you worried about functional unblinding with hair loss? are you worried about functional unblinding with hair loss

Speaker 1: No. I mean, it is something to think about. At the same time, when we're talking about a side effect that's coming in in the phase II-A at 19% and actually in the phase II-B to date, we're seeing it at even a little bit of a lower level. Plus, when you tell patients at the outset, you're coming into a clinical trial, you might experience some hair loss. I'm sure it'll be interesting to see kind of what that placebo arm looks like in terms of the amount of reported hair loss. I'm sure it'll be higher. If you contrast that, for example, with nintedanib, where the majority of patients experience diarrhea and unfortunately more than mild diarrhea, we think that this is a side effect of the nature that is something that's common to clinical studies in this disease space as well as in others. No. no I mean, it is something to think about. i mean it is something to think about At the same time, when we're talking about a side effect that's coming in in the phase II-A at 19% and actually in the phase II-B to date, we're seeing it at even a little bit of a lower level. at the same time when we're talking about a side effect that's coming in in the phase ii-a at 19% and actually in the phase ii-b to date we're seeing it at even a little bit of a lower level Plus, when you tell patients at the outset, you're coming into a clinical trial, you might experience some hair loss. plus when you tell patients at the outset you're coming into a clinical trial you might experience some hair loss I'm sure it'll be interesting to see kind of what that placebo arm looks like in terms of the amount of reported hair loss. i'm sure it'll be interesting to see kind of what that placebo arm looks like in terms of the amount of reported hair loss I'm sure it'll be higher. i'm sure it'll be higher If you contrast that, for example, with nintedanib, where the majority of patients experience diarrhea and unfortunately more than mild diarrhea, we think that this is a side effect of the nature that is something that's common to clinical studies in this disease space as well as in others. if you contrast that for example with nintedanib where the majority of patients experience diarrhea and unfortunately more than mild diarrhea we think that this is a side effect of the nature that is something that's common to clinical studies in this disease space as well as in others

Speaker 2: What can you say about enrollment progress and timelines at this point? What can you say about enrollment progress and timelines at this point? what can you say about enrollment progress and timelines at this point

Speaker 1: Yeah, so we're enrolling very well. We're the most advanced IPF study that we know of that's currently enrolling because the three phase IIIs that we've touched on have completed their enrollment. I think that's getting us very good attention from our approximately 100 clinical sites across 14 different countries. We've guided that we anticipate completing enrollment in the first half of next year. We're on track to achieve that. Yeah, so we're enrolling very well. yeah so we're enrolling very well We're the most advanced IPF study that we know of that's currently enrolling because the three phase IIIs that we've touched on have completed their enrollment. we're the most advanced ipf study that we know of that's currently enrolling because the three phase iiis that we've touched on have completed their enrollment I think that's getting us very good attention from our approximately 100 clinical sites across 14 different countries. i think that's getting us very good attention from our approximately 100 clinical sites across 14 different countries We've guided that we anticipate completing enrollment in the first half of next year. we've guided that we anticipate completing enrollment in the first half of next year We're on track to achieve that. we're on track to achieve that

Speaker 2: Great. And then what does a good outcome look like? Is statistical significance sufficient? Or is there some level of comparability or superiority to nerandomilast, et cetera? Great. great And then what does a good outcome look like? and then what does a good outcome look like Is statistical significance sufficient? is statistical significance sufficient Or is there some level of comparability or superiority to nerandomilast, et cetera? or is there some level of comparability or superiority to nerandomilast et cetera

Speaker 1: Yeah, so relative to our powering, statistical significance is certainly sufficient to have a very attractive therapy, right? As we'd mentioned, nerandomilast showed kind of a positive outcome on the primary endpoint, that 69 ml difference in lung function, which would be considered to be a relatively modest effect. Nonetheless, they've gotten the approval from FDA. That certainly underscores how high the unmet need is. Certainly, with a successful readout, we believe that this would be a very, very attractive therapy as part of the broader landscape. Yeah, so relative to our powering, statistical significance is certainly sufficient to have a very attractive therapy, right? yeah so relative to our powering statistical significance is certainly sufficient to have a very attractive therapy right As we'd mentioned, nerandomilast showed kind of a positive outcome on the primary endpoint, that 69 ml difference in lung function, which would be considered to be a relatively modest effect. as we'd mentioned nerandomilast showed kind of a positive outcome on the primary endpoint that 69 ml difference in lung function which would be considered to be a relatively modest effect Nonetheless, they've gotten the approval from FDA. nonetheless they've gotten the approval from fda That certainly underscores how high the unmet need is. that certainly underscores how high the unmet need is Certainly, with a successful readout, we believe that this would be a very, very attractive therapy as part of the broader landscape. certainly with a successful readout we believe that this would be a very very attractive therapy as part of the broader landscape

Speaker 2: You mentioned, obviously, combinability, just given how terrible this disease is, is a core component probably of the future landscape. How can you enable that in your phase II-B or potentially in phase III and moving forward? You mentioned, obviously, combinability, just given how terrible this disease is, is a core component probably of the future landscape. you mentioned obviously combinability just given how terrible this disease is is a core component probably of the future landscape How can you enable that in your phase II-B or potentially in phase III and moving forward? how can you enable that in your phase ii-b or potentially in phase iii and moving forward

Speaker 1: Yeah, so we're allowing patients, as I mentioned, on nintedanib, standard of care and not on standard of care as kind of the core of the study. We're not allowing patients on the second therapy, pirfenidone, which tends to be a bit of a dirtier molecule due to a drug-drug interaction risk. We'll continue to watch that. There is a way to kind of do a dose adjustment and allow it in future clinical development if that's something that appears warranted. Of course, with these emerging therapies, that's where our eye is looking to now. For example, as nerandomilast is now approved in the U.S. and based on the review of the literature, we don't believe that there's a drug-drug interaction issue. We'll actually be allowing patients on the background nerandomilast to join our clinical study in the phase II-B. Yeah, so we're allowing patients, as I mentioned, on nintedanib, standard of care and not on standard of care as kind of the core of the study. yeah so we're allowing patients as i mentioned on nintedanib standard of care and not on standard of care as kind of the core of the study We're not allowing patients on the second therapy, pirfenidone, which tends to be a bit of a dirtier molecule due to a drug-drug interaction risk. we're not allowing patients on the second therapy pirfenidone which tends to be a bit of a dirtier molecule due to a drug-drug interaction risk We'll continue to watch that. we'll continue to watch that There is a way to kind of do a dose adjustment and allow it in future clinical development if that's something that appears warranted. there is a way to kind of do a dose adjustment and allow it in future clinical development if that's something that appears warranted Of course, with these emerging therapies, that's where our eye is looking to now. of course with these emerging therapies that's where our eye is looking to now For example, as nerandomilast is now approved in the U.S. and based on the review of the literature, we don't believe that there's a drug-drug interaction issue. for example as nerandomilast is now approved in the u.s and based on the review of the literature we don't believe that there's a drug-drug interaction issue We'll actually be allowing patients on the background nerandomilast to join our clinical study in the phase II-B. we'll actually be allowing patients on the background nerandomilast to join our clinical study in the phase ii-b We don't believe this will be a very large number of patients who ultimately come into the study on background nerandomilast just because of the timing. We think we're going to be well underway or close to complete as kind of more patients take that drug. At the same time, it'll still be good to get some early experience because particularly if that drug launches well as it might, then certainly thinking about how you combine with that drug in phase III makes sense. We don't believe this will be a very large number of patients who ultimately come into the study on background nerandomilast just because of the timing. we don't believe this will be a very large number of patients who ultimately come into the study on background nerandomilast just because of the timing We think we're going to be well underway or close to complete as kind of more patients take that drug. we think we're going to be well underway or close to complete as kind of more patients take that drug At the same time, it'll still be good to get some early experience because particularly if that drug launches well as it might, then certainly thinking about how you combine with that drug in phase III makes sense. at the same time it'll still be good to get some early experience because particularly if that drug launches well as it might then certainly thinking about how you combine with that drug in phase iii makes sense

Speaker 2: Then moving forward, you have a partnership right now with Nippon Shinyaku. Can you talk a little bit about what the context is there and just broadly how you're thinking about moving forward as a company? Then moving forward, you have a partnership right now with Nippon Shinyaku. then moving forward you have a partnership right now with nippon shinyaku Can you talk a little bit about what the context is there and just broadly how you're thinking about moving forward as a company? can you talk a little bit about what the context is there and just broadly how you're thinking about moving forward as a company

Speaker 1: Yeah, absolutely. Nippon Shinyaku have Japanese rights to the program. We have a great partnership structure in place where, of course, there are the financials associated with it, including royalties up to the low 20s % on sales of the drug in Japan. They also are contributing to the non-clinical development costs even from now. Of course, there is a lot of phase III and commercial CMC work that is ongoing that we are both working with them on collaboratively, but also they are contributing to financially. In addition to that, they will contribute to the kind of phase III program in terms of providing kind of Japanese patients financial support as well as operational support to help us execute that larger clinical study subsequently. We are really happy to have the partnership with them. They have actually developed and commercialized a number of the pulmonary hypertension drugs. Yeah, absolutely. yeah absolutely Nippon Shinyaku have Japanese rights to the program. nippon shinyaku have japanese rights to the program We have a great partnership structure in place where, of course, there are the financials associated with it, including royalties up to the low 20s % on sales of the drug in Japan. we have a great partnership structure in place where of course, there are the financials associated with it including royalties up to the low 20s % on sales of the drug in japan They also are contributing to the non-clinical development costs even from now. they also are contributing to the non-clinical development costs even from now Of course, there is a lot of phase III and commercial CMC work that is ongoing that we are both working with them on collaboratively, but also they are contributing to financially. of course there is a lot of phase iii and commercial cmc work that is ongoing that we are both working with them on collaboratively but also they are contributing to financially In addition to that, they will contribute to the kind of phase III program in terms of providing kind of Japanese patients financial support as well as operational support to help us execute that larger clinical study subsequently. in addition to that they will contribute to the kind of phase iii program in terms of providing kind of japanese patients financial support as well as operational support to help us execute that larger clinical study subsequently We are really happy to have the partnership with them. They have actually developed and commercialized a number of the pulmonary hypertension drugs. we are really happy to have the partnership with them. they have actually developed and commercialized a number of the pulmonary hypertension drugs They're really experts in this space, know the clinicians well in Japan, and a good partner for us there. They're really experts in this space, know the clinicians well in Japan, and a good partner for us there. they're really experts in this space know the clinicians well in japan and a good partner for us there

Speaker 2: Is IPF a market that a biotech can launch competitively into? Is IPF a market that a biotech can launch competitively into? is ipf a market that a biotech can launch competitively into

Speaker 1: Yes, we believe it is. Because the amount of sales force, given the nature of the disease, it's a larger, rare disease, but it is a rare disease. The nature of where the patient population goes in terms of clinical centers makes us confident that this is the type of project that a biotech could launch in the U.S. on its own. Yes, we believe it is. yes we believe it is Because the amount of sales force, given the nature of the disease, it's a larger, rare disease, but it is a rare disease. because the amount of sales force given the nature of the disease it's a larger rare disease but it is a rare disease The nature of where the patient population goes in terms of clinical centers makes us confident that this is the type of project that a biotech could launch in the U.S. on its own. the nature of where the patient population goes in terms of clinical centers makes us confident that this is the type of project that a biotech could launch in the u.s on its own

Speaker 2: I think we've talked separately too about your pipeline of AT2 receptor agonists that are out there. Where is that going? What other types of indications might you be exploring or thinking about exploring? I think we've talked separately too about your pipeline of AT2 receptor agonists that are out there. i think we've talked separately too about your pipeline of at2 receptor agonists that are out there Where is that going? where is that going What other types of indications might you be exploring or thinking about exploring? what other types of indications might you be exploring or thinking about exploring

Speaker 1: Absolutely. As I'd mentioned, this is a relatively upstream pathway. If you think about where ACE inhibitors and ARBs play, they certainly don't just play in hypertension. They're used across a number of diseases. We have a similar view here. When you think about other fibrotic and inflammatory conditions, we get very excited about those, both in the lung and outside of the lung. Certainly, when you think about in the lung, the natural places to expand are progressive pulmonary fibrosis and other interstitial lung diseases, but also thinking about pulmonary hypertension, both pulmonary arterial hypertension as well as group 3 pulmonary hypertension or PH-ILD. Those are all certainly on our list. Also, looking at diseases outside of the lung, we have a great interest, for example, in renal indications and chronic kidney disease. Absolutely. absolutely As I'd mentioned, this is a relatively upstream pathway. as i'd mentioned this is a relatively upstream pathway If you think about where ACE inhibitors and ARBs play, they certainly don't just play in hypertension. if you think about where ace inhibitors and arbs play they certainly don't just play in hypertension They're used across a number of diseases. they're used across a number of diseases We have a similar view here. we have a similar view here When you think about other fibrotic and inflammatory conditions, we get very excited about those, both in the lung and outside of the lung. when you think about other fibrotic and inflammatory conditions we get very excited about those both in the lung and outside of the lung Certainly, when you think about in the lung, the natural places to expand are progressive pulmonary fibrosis and other interstitial lung diseases, but also thinking about pulmonary hypertension, both pulmonary arterial hypertension as well as group 3 pulmonary hypertension or PH-ILD. certainly when you think about in the lung the natural places to expand are progressive pulmonary fibrosis and other interstitial lung diseases but also thinking about pulmonary hypertension both pulmonary arterial hypertension as well as group 3 pulmonary hypertension or ph-ild Those are all certainly on our list. those are all certainly on our list Also, looking at diseases outside of the lung, we have a great interest, for example, in renal indications and chronic kidney disease. also looking at diseases outside of the lung we have a great interest for example in renal indications and chronic kidney disease We're developing a pipeline of follow-on programs to interrogate those. We look forward to sharing more about that over time as well. We're developing a pipeline of follow-on programs to interrogate those. we're developing a pipeline of follow-on programs to interrogate those We look forward to sharing more about that over time as well. we look forward to sharing more about that over time as well

Speaker 2: I guess the expansion, is that with buloxibutid or is this with the pipeline? I guess what's the path forward for other indications? I guess the expansion, is that with buloxibutid or is this with the pipeline? i guess the expansion is that with buloxibutid or is this with the pipeline I guess what's the path forward for other indications? i guess what's the path forward for other indications

Speaker 1: Absolutely. I mean, I think that that's still something that we're looking at. Certainly, we are actively kind of developing newer compounds because we think that certainly there are ways to optimize the particular therapy for the particular organ or indication in a favorable way. That is also on our mind. Absolutely. absolutely I mean, I think that that's still something that we're looking at. i mean i think that that's still something that we're looking at Certainly, we are actively kind of developing newer compounds because we think that certainly there are ways to optimize the particular therapy for the particular organ or indication in a favorable way. certainly we are actively kind of developing newer compounds because we think that certainly there are ways to optimize the particular therapy for the particular organ or indication in a favorable way That is also on our mind. that is also on our mind

Speaker 2: Great. Maybe last question, can you talk about your cash runway and what assumptions go along with that? Great. great Maybe last question, can you talk about your cash runway and what assumptions go along with that? maybe last question can you talk about your cash runway and what assumptions go along with that

Speaker 1: Yeah, absolutely. We reported about $90 million in cash as of the end of last quarter. That's sufficient for us to be able to complete the phase II-B study that we've discussed in its current sizing as well as have additional cash runway for about a year thereafter. We're well positioned from that perspective. Yeah, absolutely. yeah absolutely We reported about $90 million in cash as of the end of last quarter. we reported about $90 million in cash as of the end of last quarter That's sufficient for us to be able to complete the phase II-B study that we've discussed in its current sizing as well as have additional cash runway for about a year thereafter. that's sufficient for us to be able to complete the phase ii-b study that we've discussed in its current sizing as well as have additional cash runway for about a year thereafter We're well positioned from that perspective. we're well positioned from that perspective

Speaker 2: Great. Any additional questions? If not, Ahmed, thank you. Great. great Any additional questions? any additional questions If not, Ahmed, thank you. if not ahmed thank you

Speaker 1: Thank you, Alex. Thank you, Alex. thank you alex