Vicore Pharma Holding AB (publ) (VICO) Earnings Call Transcript & Summary

All right. Good morning, everyone. My name is Brandon Folkes, and I am one of the biopharma and biotech analysts here at H.C. Wainwright. We're going to have a fireside discussion today with Vicore Pharma. Joining me from Vicore is CEO, Ahmed Mousa. And then we've also got an expert in the space, Dr. Toby Maher. Maybe, Ahmed, if you can introduce yourself quickly and then Dr. Maher following that.

Wonderful. Thank you for having us, Brandon. Yes, I'm Ahmed Mousa, I'm the CEO at Vicore Pharma, and it's a pleasure to be with you here today. Looking forward to telling you more about our program for development of a new therapy for idiopathic pulmonary fibrosis.

Yes, thank you. So I'm Toby Maher. I'm an academic pulmonologist. I'm Professor of Clinical Medicine and Director of the Interstitial Lung Disease Unit at the University of Southern California, Los Angeles. And I spent most of the last 20 years running clinical trials in IPF and I think been working with Vicore for 7 or 8 years now as they develop their program.

Great. Thank you to you both for joining us. Ahmed, maybe if you can just give us a bit of an overview of Vicore Pharma as well as buloxibutid.

Absolutely. So Vicore Pharma is a company that has built a strong understanding of the biology and chemistry of the renin-angiotensin system and has really looked at ways of modulating that system in order to drive beneficial therapeutic effect. And we've really zeroed in on a receptor called the AT2 receptor as a potential kind of disease-modifying intervention point for treatment of fibrotic diseases generally and then, of course, particularly in this context, idiopathic pulmonary fibrosis. And why we like this intervention point so much is it's quite upstream of fibrosis. So it is a pathway that we're actually agonizing or activating rather than blocking. And it is a system that is existent in the body to drive tissue repair and fibrosis resolution. So it's actually intended to resolve those pathological or physiological processes in a natural way and quite a highly conserved system. In a simplistic way, this AT2 receptor sits as the opposing force of the AT1 system in the body. And the AT1 system is a system that turns on to drive fibrosis, inflammation and hypertension when you have different types of infections and injuries and insults. So that's kind of the endogenous role or the natural role of this AT2 system is to respond to those types of processes. What's interesting is, as a biopharmaceutical industry, we've done a very good job of building drugs that block the AT1 system. So if you've ever heard of ACE inhibitors, which help control blood pressure, or angiotensin receptor blockers, ARBs like losartan and the rest of the losartan drug class. All of those are actually blocking that AT1 system to block some of those negative inflammatory fibrotic and hypertensive processes. But really, what's underexplored in our view is then activating the other side of that, the kind of repair process. And that's what we've been doing at Vicore, and that's what buloxibutid is designed to do. This is a drug that has shown really nice effects and then the specific disease models preclinically for idiopathic pulmonary fibrosis, showing the ability to do that fibrosis resolution tissue repair. And it starts by activating this receptor, which actually in the lung sits on a precursor cell called the alveolar epithelial type 2 cell. And by basically activating this receptor on the type 2 epithelial cells, we are able to replenish this population of cells that get basically dysfunctional in IPF disease state. And when you're able to do that, you can then regenerate parts of the alveolus. They can differentiate into the gas exchange cells. And you also then attenuate or block the fibrotic process because it turns out that these type 2 epithelial cells that have a receptor that we're activating release that key signal that drives fibrosis, this profibrotic cytokine called TGF-Beta-1. So in addition to the nice preclinical evidence, we've generated some really great early clinical signals showing that we're able to not just stop or even slow the decline of lung function, but actually improve lung function in IPF patients over a 36-week period, which makes us really excited to advance the drug into Phase IIb development, which is now ongoing. And if we're able to replicate these types of effects in 52-week large placebo-controlled study, I think that would be very exciting for the field, and that's what we're working on now.

Great. That's very interesting. Dr. Maher, just turning to you, can you maybe just give us an introduction on your work in IPF -- maybe start with what IPF is? Why is it so difficult to treat? And how do you currently manage or treat patients?

Yes. So as I said, I'm an academic pulmonologist, which means that I spend half my week seeing patients looking after people with idiopathic pulmonary fibrosis, the other half running research, whether that's clinical trials or preclinical basic research. So idiopathic pulmonary fibrosis, I'm sure everyone that's dialed into the call will know, is an inevitably progressive scarring disorder of the lung that untreated has a median survival of about 3 years. I think the challenges of treating IPF are partly the disease is often diagnosed very late in the day. So by the time patients present to us, they're already in respiratory failure and have very little respiratory reserve. I think one of the other challenges that we will probably discuss over the course of this call is there has been a degree of therapeutic nihilism. I think pulmonologists have been very used to treating acute diseases like pneumonia and other infectious diseases and perhaps have had less experience in managing chronic progressive diseases of aging. And so when it has come to using drugs that slow disease progression down, there's been a slight reluctance to treat patients. And then I think that the current treatments that have been available to us have had significant tolerability issues. And in essence, when we start patients on treatment with idiopathic pulmonary fibrosis, we're imagining that they're going to need lifelong therapy to try and control the rate at which their fibrosis progresses. And so drugs that cause side effects tend to be difficult for patients to take in the long term. And then at the moment, in terms of treating my patients, I'm using either nintedanib or pirfenidone as single agents. As patients develop progressive disease, we use oxygen to manage respiratory failure. We also use treprostinil to treat pulmonary hypertension related to the disease. And then a lot of what we're doing is managing end-stage disease and the symptoms and problems that go with that.

Maybe, if we sort of look at those comments, why do you think buloxibutid potentially is the right drug for IPF patients? Can you just talk about some of the attributes that you believe will address some of these challenges?

Absolutely. So I think as Dr. Maher mentioned, tolerability has been a huge challenge for the approved therapies and some of the emerging therapies also have some tolerability issues as well. Now the reason for this from maybe a scientific perspective is many of the approaches that are either approved or in development for treating IPF are blockers of some of these fibrotic receptors or pathways that drive fibrosis. The problem is maintenance of normal tissue hemostasis and extracellular matrix requires these processes as well. So you have kind of normal process and then they get driven up in our pathological. And when you come in and try to block these fibroblast, for example, activation migration and then their ability to deposit collagen, you can have a slowing effect on the kind of the build of fibrosis, but you're also going to lead to these types of liabilities. What makes us so excited about the Vicore approach and agonizing this natural tissue repair system is we come at it in a very different way, a fundamentally different way. And this drug has shown the ability in development to date to be quite well tolerated. So the drug has actually now been dosed in over 350 patients for duration of over 36 weeks, and we haven't seen the same types of issues you see if you're trying to block fibrotic processes systemically. So that makes us quite excited, first and foremost. And then, of course, second of all, as Dr. Maher mentioned, what we've been able to do with the current standard of care therapies is slow the decline of lung function by, again, kind of blocking some of these receptors, but it still is a disease that builds up over time. And actually, it's quite fatal disease, only 3 or 4 years of survival, worse than many types of cancer. And so if you can change the paradigm by also stabilizing the lung function, maybe even improving the lung function, that would be quite a difference. And we think there's the possibility of that with buloxibutid because of its more reparative mechanism of action.

And you touched on the sort of the prognosis and Dr. Maher, you touched on it as well. So if we think about even a 3- to 5-year prognosis, Dr. Maher, why is the average length of therapy only closer to 10 months? Are these patients simply going off therapy altogether? Are they opting for off-label therapy? Given the prognosis, you would think patients would want to stay on some sort of therapy. What's the disconnect between the average length of therapy and this prognosis?

Yes. So I think there's a few things that contribute to that. So early in disease, patients actually have very few symptoms. The initial symptom is exertional breathlessness. But as many of us know, when we become unfit, we avoid the issue of exertional breathlessness by doing less. So generally speaking, patients can find lifestyle modifications that deal with the symptoms of breathlessness and day-to-day, they feel very well. I think at that point, both they and their pulmonologists often underestimate disease severity and they over or put extra weight on the potential negative side effects of the existing drugs, which are primarily gastrointestinal upset with diarrhea. And so I think for someone who's feeling well, who perhaps hasn't appreciated how serious their disease is, the thought of going on a treatment that might cause GI upset is not very appealing. And if the pulmonologist looking after them hasn't reinforced the serious nature of the disease, then often patients will put off treatment until later. It's not uncommon that patients then present with end-stage respiratory failure are on oxygen and only at that point in time, consider treatment. It is worth saying that the drugs do have an appreciable side effect profile. So in our hands at a specialist center where I have nurses able to coach patients to stay on drug, we have a drop-off rate of about 15%, so 1-5 percent over 12 months. But we know that in community practices where there isn't as much support to allow patients to stay on drug to give the necessary lifestyle advice, the drop-off rate is about 50%, 5-0 at 12 months. And so I think a lot of that drop-off rate reflects the challenge of using drugs with appreciable tolerability issues. And I believe that if we have better tolerated, more effective drugs going forward, then the likelihood of patients staying on treatment for the longer term and actually starting them early in disease would be much, much higher.

Great. And if we think about drugs going forward, as you touched on there, I'd love to get both of your opinions on this. But firstly, maybe why do you think we've seen a number of failures in IPF drug development? What do you think we've learned from these prior failures? And maybe, Ahmed, this one is for you, but Maher, you can chime in on this. What do you believe is different about the Vicore approach in getting this development right? Either of you can start.

Shall I go first because then Ahmed can answer the Vicore bit at the end. And I think there have been a number of factors at play. And firstly, I think a key challenge with IPF is the complexity of the disease by the time patients reach end stage, most of the cell types in the lung are abnormally activated. There is dense fibrosis. The patients are prone to infection. They develop complications like pulmonary hypertension. So it is a complex environment in which to both select the right target and then show efficacy. I think, however, there have been a number of fairly basic mistakes made in drug development in the IPF space. For instance, Galapagos went from a 23-patient Phase IIa to a 1,500 Phase III program. They discovered during the Phase III program that there was an unknown bidirectional drug-drug interaction with nintedanib that's had a significant effect on drug exposure throughout the trial. And they didn't fully explore their dosing rationale in earlier phase studies. So I think had they gone down a traditional IIb before doing a Phase III approach, then a lot of what was unknown at Phase III and that caused problems might have been discovered. I think Genentech with their drug, which is escaping my mind at this second. I've been doing too many talks recently. Pentraxin, the original Phase II of that trial, as they admitted with the publication of their Phase III data, the positive result was driven by outliers. It seems to me surprising that a large company doing due diligence on that data wouldn't have picked it up ahead of time, but there were already clues in the Phase II data, for instance, in excess of respiratory adverse events occurring in the active treatment arm to suggest the drug wasn't perhaps as effective as the sort of headline primary endpoint data that was presented suggested. FibroGen, I think, had issues with handling missing data in their Phase II studies that led them to overestimate the effectiveness of their drug. And I think had they powered their study correctly, they probably would have had a drug with about a 25% to 30% effect size. But as it was, their Phase III trial program was underpowered. And then Pliant's recent failure, I know, we wait to see all of the information and data. But I think the reality is that there was a known liability around that compound. We've seen the prior issues that Biogen had. I think it was entirely reasonable for Pliant to do what they did. They followed a very good pathway in terms of drug discovery. And I think it's just unfortunate that they weren't able to dial out the sort of the more harmful effects of alpha(v)beta6 inhibition. So I think the reasons for failure are mixed. Some are a failure following appropriate process in drug design, clinical trial development and following an appropriate pathway through to Phase III. And I think some of it is just a reflection of the challenge that is posed by a chronic progressive disease of aging.

Yes. Certainly, what I would add then about kind of what makes the Vicore approach, what makes us optimistic about the Vicore approach even in view of some of these challenges and failures that Dr. Maher described I think first and foremost, as I mentioned, mechanistically, we think that this approach is a little bit different. So it's less likely to have some of the safety or tolerability issues that we've observed with some of these therapies that ultimately haven't worked out by driving kind of this more reparative mechanism of action rather than blocking targets that can be more associated with extracellular matrix maintenance or tissue hemostasis. So that's certainly one big piece of the puzzle for us. And then certainly, as Dr. Maher mentioned as well, having the right drug development program is critical. And we believe we're exactly in that zone with our ongoing Phase IIb. So we're running it for the 52-week endpoint, so we can really see how this drug behaves for the regulatory endpoint, the approval endpoint for this therapy in the Phase IIb setting. We're running it relatively large in size. So again, that we really think carefully and in a conservative way about the correct powering for the study. We've done the DDI work in advance. So we've confirmed that we work well with nintedanib, which just Dr. Maher mentioned, had been a challenge in the past. We're also excluding pirfenidone in our Phase IIb study to avoid some risk of DDI, even though we might be able to look at ways to combine in the future. Again, we want to get a clear result on the Phase IIb. And we're running it in quite a robust way. So it's being conducted across 14 different countries and 100 clinical centers in order to really build a nice patient population for the study. So I would say that the way to think about it is we've hopefully addressed both kind of the selection of the right mechanism for a really tough disease and having the appropriate drug development program, in particular, the appropriate Phase IIb study to derisk in Phase III development and bringing hopefully a new therapy to the market.

Great. And maybe coming back to Dr. Maher, just sort of focusing a little bit on some of the things coming at ATS this week. From a clinical perspective, how do you interpret the significance of the nerandomilast Phase III data presented at ATS earlier this week, particularly in terms of how it may shift the current treatment paradigm?

So I will just say I presented the data. So clearly, I have a slight conflict of interest. But I think if we look at the results, we saw the trial results both from IPF and from progressive pulmonary fibrosis in both sort of disease states, the drug slowed FVC progression by a magnitude that is comparable to pirfenidone and nintedanib. In the progressive pulmonary fibrosis trial, certainly with the later database lock, there was a mortality signal that came through. But I think for me, the important result is the tolerability or safety tolerability, which does, to my mind, look to be better than both existing drugs. And there was some diarrhea seen, particularly when it was used in combination with nintedanib but the frequency and magnitude of that was a lot less than we saw in the Phase III trials for the other two drugs. So I think we have a drug with similar efficacy to existing treatment, but a much better tolerability profile. And added to that, unlike the existing drugs, which can't be used in combination because they're too intolerable together, nerandomilast can be used in combination with existing treatments. So I think all things being equal, it seems to me like nerandomilast should replace the existing two drugs as first-line treatment, if only because it's much more likely to be tolerated by patients over the longer term. But also, I think we will begin to see patients who have progressive disease despite therapy going on to combination treatment. So we will see something of a paradigm shift in the way we treat our patients in practice.

Great. And just staying with you, Dr. Maher, and staying with ATS. Are there any emerging trends or therapeutic approaches that you believe are the most promise for IPF patients?

So yes, again, I will declare that I'm involved with all the programs I'm going to mention. So again, conflicted. Clearly, the most developed is BMS' admilparant program with LPA receptor 1 antagonist. They presented nice Phase II data a year ago at ATS. They've gone on to develop a Phase III program in IPF and PPF and that's currently in the midst of recruiting. And we saw at the conference a number of strategies for trying to better utilize existing drugs, so pirfenidone and nintedanib. So we saw PureTech's deuterated pirfenidone Phase II readout. We also have seen data from Avalyn and other companies on inhaled approaches to delivering pirfenidone, nintedanib. And then the other bit of data I presented was on the hedgehog inhibitor from Endeavor. So I think BMS is slightly ahead of everyone else because they've already shown their Phase II data. But everyone else at the moment is sort of well positioned at Phase IIb to explore efficacy in more detail. And for me, what's exciting is that all of these things are going after different mechanisms. So if we imagine that the future of IPF treatment will follow what we've seen in the pulmonary hypertension space, we will be looking to use combination therapy and therefore, the more unique drug classes we have that show efficacy in the disease, the more ability we will have to combine treatments to really make a difference for patients.

Great. Ahmed, in light of this evolving potential -- potential evolving treatment landscape, right, we've seen some positive data. We've got some sort of later-stage data coming as well. But how do you envision buloxibutid potentially fitting into the evolving treatment landscape? In your view, what differentiates it from potentially these emerging standards of care?

Yes. Absolutely. So I think the first point is then if we're able to continue to confirm a good safety and tolerability profile in buloxibutid as we've observed to date, I think it will quite nicely be something that's easy to utilize early on. As Dr. Maher mentioned, sometimes even today, pulmonologists can be hesitant to deploy the standard of care therapy because of its side effect profile and because essentially, what you need to do is give these therapies over a very long term to slow the decline of lung function. So we think that a well-tolerated therapy will really help with that hesitation and kind of buy-in to then deploy a therapy that a patient can take as early as possible and then, of course, for as long as possible. I think also, as Dr. Maher mentioned, having then a potential combination paradigm as we do in the field for pulmonary hypertension can make a lot of sense. And I would say, again, there, Vicore is very well positioned because our mechanism is so conceptually different from other approaches, it should play quite nicely with these other kind of more fibroblast targeting or more fibrotic kind of antifibrotic kind of mechanisms of action. And so you could really envision if you do have approved therapies coming from the emerging pipeline that Dr. Maher shared, we would play nicely, we think, with any of those. And certainly, that's part of the reason why in our Phase IIb, we're very excited to see how the drug combines with nintedanib as a therapy.

Great. And just staying with you. Any adverse events coming out of the early buloxibutid trials you are watching and paying attention to?

Yes. So in the earlier development, the notable kind of adverse event is some mild to moderate hair loss or hair thinning. So in the Phase IIa trial, the 36-week trial, 19% of patients experienced some of that shedding. It is a side effect or an issue that is reversible. So certainly, everyone as they came off of therapy had recovery of hair. And then actually a number of patients experienced it during therapy. There was kind of a period of shedding or thinning of hair and some evidence of recovery. So we'll look at that closer in the Phase IIb development. We're also testing multiple doses in the Phase IIb. So we'll be testing the same dose as we did in the Phase IIa, but also a half dose of that, which we do know that this kind of -- this hair loss or hair shedding phenomena is dose dependent. So we should be able to observe if in line with that, a lower level of that effect. And then we'll have to see how it looks on the efficacy side. But then hopefully, we could potentially have an efficacious therapy that even limits or eliminates that type of a side effect. But I do also think that we have to remember, again, that this is IPF that it's such a tough disease in terms of the prognosis, survival is worse than most cancers. And when you look at the therapy in terms of the GI toxicities or side effects that are observed with other therapies, our drug has not seen any of that type of effect nor any other kind of notable effect to date in the side effect profile. So generally, we believe this will be a relatively easy drug to take if that safety profile bears out. And that's really nice for IPF, which is a bit of elderly population. And we also think that because IPF is more skewed towards older men also should be a little bit more manageable with that tolerability issue that I mentioned.

Fantastic. Dr. Maher, I just want to get you to weigh in here a little bit. How do you think about hair thinning in these patients? Obviously, it's a patient population where the prognosis is not very good, right? Now with that, obviously, there's sort of a potential that how do patients and physicians weigh up sort of side effect profile versus a more efficacious drug. So I guess if the drug was to have a hair loss side effect, do you think that drug will need to prolong survival, modify disease? Or do you think if the rest of the adverse event profile is much cleaner than what's available today, but as a clinician, you'd pick the side effect of hair loss and as a patient, where do you think they may fall into that?

Yes. So there's a little bit to unpack there. I think as Ahmed said, it will help as we define slightly better this issue of hair loss. And one of the challenges of interpreting clinical trials is that you just have a label appears in the safety table, and it's always difficult to know what that means in clinical practice. Slight hair thinning in an older population is not such a big issue. Total hair loss would give certainly female patients a lot of pause for thought. But I think as Ahmed has said, IPF is a disease of older men. So if we look at the FIBRONEER trial, the recent nerandomilast trials presented at ATS, the average patient in the IPF study was a 72-year-old man. So 80% of them were men, only 20% were women, and that fits with our knowledge of the epidemiology of IPF. It is a male predominant disease. So I think in IPF, I don't really see hair thinning or even hair loss to be a major barrier to treatment. In the progressive pulmonary fibrosis population, it is a more equal gender balance. So in FIBRONEER, it was 55% men. But again, the average age was 67. But of course, I think the increased incidence of females there, we may encounter some reluctance for patients to experience hair loss as a side effect, but I see it as a relatively small problem. And a lot of it will come down to the profile of the drug once we've taken it through Phase II and Phase III. And if as we hope the drug has some remodeling benefits and we actually see perhaps a step change in efficacy compared to existing treatments, then I think what is a very painless and day-to-day easy to deal with side effect would certainly rank buloxibutid above drugs that cause intrusive side effects that patients live with sort of all day every day. And it's hard to compare things directly, but hair thinning compared to diarrhea that necessitates you taking a spare pair of trousers out of the house every time you go to visit people. I think I would take the hair thinning any day of the week.

Great. Thanks very much for your input. I go, I'll give you a last word on this AE profile before we move to efficacy. So you covered pretty thoroughly what you're doing and the potential to mitigate this as we move forward. Anything else you want to add just before we move on to efficacy?

No, just that we're, again, really, really excited to advance something that we -- as Dr. Maher mentioned, is a little bit kind of different differentiated AE profile. And again, that fits nicely with the mechanism where we're driving more of a reparative mechanism of action rather than kind of potentially interfering with tissue hemostasis extracellular matrix.

Great. So Dr. Maher, coming back to you, just moving to the efficacy side of things. How do you think about a drug showing stable lung function versus perhaps an improvement in FVC in IPF patients?

Yes. So a lot of what we focused on with our clinical trials to date has been slowing the rate of disease progression in patients with IPF. And the expectation is that if we slow progression, we will improve mortality. And we've certainly seen that happen with the advent of pirfenidone and nintedanib. But despite that improvement in survival, my patients are still ultimately dying of respiratory failure. They're still dying of their idiopathic pulmonary fibrosis. So I think the holy grail is really to find a drug that at least genuinely stabilizes disease and if possible, partially reverses disease. I think as we currently diagnose IPF, by the time we see patients, a lot of the lung is destroyed. So it's unrealistic to think we will truly cure the disease and get rid of fibrosis, but there are reasons to believe it's possible to partially remodel the lung and perhaps recover lung function, which in turn would have positive effects on symptoms and everything else. So I would love to see a drug that improves the situation rather than just slowing progress over time.

Fantastic. And just staying with you here. The Phase IIb study is being run on top of nintedanib. Yes, if buloxibutid were to be approved, is that how you would look to use the drug initially in practice? Would you ever use it ahead of the tender? What would you need to see in the clinical trials to kind of make a decision on how to use this drug?

So again, I think if we just look at the FIBRONEER trials that were presented at ATS with nerandomilast, and the way those studies were designed was on top of standard of care. There's an expectation from regulators and IRBs that patients have to be allowed to be on effective therapy. And so the standard trial design really is to allow patients on background treatment. But in some cases, that might be no treatment at all because they've been intolerant of existing drugs or they've made a choice not to go on the existing drugs. And the reason for highlighting FIBRONEER is really just the conversation in this space has very much been about how we might use nerandomilast as first line, given data that was generated on top of standard of care. And I think the same would be true of buloxibutid. I think it's necessary that patients be offered the opportunity to be on background treatment. So there will be patients on nintedanib. There will also be a subgroup of patients who aren't on nintedanib because they've been intolerant of that. And so when it comes to analysis of the data, we will have information on combination therapy, and we will have some information as monotherapy. And I think if efficacy -- if either efficacy was transformational or tolerability was considerably better than existing treatments, there would be no reason to think that people wouldn't consider buloxibutid as potential first line based on the data that could be generated from the Phase IIb and a similarly designed Phase III study going forward.

Great. Ahmed, coming back to you. Can you talk about the current ASPIRE trial? How are you seeing enrollment progress there?

Yes, absolutely. So we're about 80% up in terms of the clinical sites. As I mentioned, we're targeting about 100 clinical sites across 14 different countries to enroll 270 patients. I would say, overall, enrollment is moving quite well. It is a tough disease area for enrollment for a number of reasons both in terms of -- it is -- while it's a larger rare disease, it still is a rare disease. The patients tend to go to specialized clinical centers. So there's a little bit of, let's call it, competition or a number of clinical options typically for IPF patients. I will say that it's unfortunate to see some of the other therapies not having worked out, although that probably has facilitated some additional enrollment. The kind of the -- of the programs that Dr. Maher mentioned, the PureTech program, they've completed enrollment and reported their data and have not yet initiated a Phase III development. Avalyn is working a little bit more in the progressive pulmonary fibrosis space currently in their late-stage activity. And then the BMS program that Dr. Maher mentioned is probably in the later stages of enrollment. And so there isn't really a lot going on in terms of that later-stage zone, that Phase IIb or Phase III zone. So I think that's been quite useful for us. And I also think that the safety and tolerability profile that we've generated to date is also quite useful when a physician and a patient might be discussing the different clinical trial options and the patient wants to understand better what's been observed in this therapy. We think also that's been useful, too. And of course, we still have to confirm it, but what we've observed in the Phase IIa is quite encouraging. And so that might be also a nice facilitator for our enrollment process. But it's against a backdrop of difficult enrollment for all the reasons that I mentioned, plus, of course, ultimately, IPF patients are or older. It's a tough disease. And so many opt not to participate in clinical trials at all. I would say that's probably a big challenge here as well.

Great. And Dr. Maher, as we have seen a few failures in the space, from your perspective, do you feel that makes it easier to enroll IPF clinical trials going forward as there's perhaps fewer trial options? Or do you think it actually makes it a bit more challenging as perhaps the bar has been raised in terms of maybe what you would consider putting a patient into a clinical trial or a patient may ask about sort of the effectiveness of going into clinical trial given we've seen failures?

So I think to answer the second part first, I don't think the failures really have any negative impact on recruiting patients into new trials. Maybe I'm an overoptimist. I have to be dealing with IPF and being involved in IPF trials for the last 20 years. But I think we hope that with the more trials we run, the more experience we get in running trials, the better we will be at delivering effective trials. So the hope is always that the next trial is better than the last ones that we've run. And in that sense, I think Vicore's timing is good. Had we been having this conversation 18 months ago, BI was recruiting FIBRONEER. BMS were just beginning to start with recruitment for their Phase III. And Pliant were also gearing up to recruit for their adaptive Phase IIb/III. So it was a very congested space. Now that BI have completed their program, BMS are a good way along with their program and plant unfortunately, have left the field, there really is an opportunity for companies like Vicore to come in and recruit very quickly to studies. And I think the phase -- we'll chat about it in a second, but I think the Phase IIa data has been of interest to patients. I've certainly had a lot of e-mails from patients who want to participate in the trials because they've seen the Phase II data. And so I think Vicore is certainly at an advantage having the data set that they do when it comes to providing a sort of USP for patients to think about the Vicore study over other studies available.

Great. And I'm going to dive into the Phase IIa trial right now. So Dr. Maher, can you just give us your thoughts on the signal that we did see in that Phase IIa trial?

Yes. So people have probably heard me say all of this before, but I will say it again. And we did present a slightly new analysis at ATS. I was there on the very last afternoon with almost the last talk of the conference presenting Vicore data to a surprisingly large audience for Wednesday afternoon. But -- and essentially, as everyone knows, the Phase IIa study was an open-label study. I think the important things about the study are that patients underwent central reading of CT scans, which is the standard for Phase III studies to make sure the patients really do have IPF before they go into the trial. The other important aspect of the study is that the forced vital capacity that was measured using a standardized biometer with central overreading. So again, applying Phase III standards to a Phase IIa study. I think the challenges with the trial or the major challenge with the trial was the timing. It was run during COVID. So there were some issues with patient retention, primarily due to the pandemic and patients not wanting to come back to study centers on a frequent basis. And of course, we always have difficulty interpreting open-label data because we lack the placebo. But notwithstanding all of those things, first of all, the tolerability profile looked good. As has been said, there was some hair thinning in just under 20% of patients. But otherwise, the drug looks to be very well tolerated. And then I think what's got everyone excited is that when we look at the 36-week data for the patients who were in the study, 40% of them saw an improvement in lung function. Overall, the average trend was actually improvement in FVC over the 36 weeks. And what we presented at ATS was essentially a responder analysis, just looking at the proportion of patients who showed improvement compared to what was reported in the Phase III studies for nintedanib and pirfenidone. And there's a very marked and striking difference in the number of patients showing a 5% or 10% improvement in FVC over time compared to those pivotal studies. And then the other thing that was done, Vicore worked with a company called Qureight, an imaging-based company who have access to a very large data set of real-world patients with IPF. And what Qureight did was essentially matched the patients in the IIa study to real-world patients and looked at the differences in disease trajectory. And they were able to sort of continuously resample their real-world population of patients and make an estimate of how likely it would have been to see the results in the Phase IIa study by chance alone. And essentially, the number they came out with was less than 1 in 400. So to sort of see that level of improvement, if you were trying to take a Bayesian approach and calculate the prior odds of seeing the degree of lung function improvement that we see in the Phase IIa study, it would be about 1 in 400 chances of finding a group of patients whose disease was naturally going to show some improvement over time. So the data is very compelling, and I think that's generating a lot of excitement and momentum for the Phase IIb study because, obviously, we sincerely hope that what we saw in the open-label study will be borne out in the Phase IIb trial.

Great. And Ahmed, can you just talk about the patient populations between the Phase IIa and Phase IIb? Just any difference in inclusion, exclusion criteria?

Yes. So I think first is thinking about the kind of positioning. So the signal that we generated in Phase IIa is a monotherapy signal. So it's really nice to see, right, of course, at Priority, we didn't know how this drug would look from an efficacy perspective with nintedanib. So I think there was an interest in saying, okay, what does this drug by itself do to lung function, and we're able to run a small study to confirm that we really do have a signal of efficacy in monotherapy. So we think that's a nice basis in the larger Phase IIb to then combine with what we know is an active agent in nintedanib. So that's one difference, though. So that will be one aspect. In general, we had maybe slightly higher predicted FVC in terms of the cutoff, slightly higher DLCO. So slightly kind of higher criteria. And that was part of the approach in terms of running this in a monotherapy setting. It was a little bit of the kind of, let's call it, like the upper half of what you'd expect to enroll in a Phase IIb study. Now we've certainly in our Phase IIb then expanded out to basically what would be in line with the Phase III population. But I would say it will have a very nice overlap with the types of characteristics that will -- were observed in the Phase IIa, but we'll go broader now as we advance the development as well.

Great. And this is going to be my last question as we sort of get towards the end of time here. But I just want to bring it back to everything we've spoken about even all the way at the beginning. Can you just recap for us the mechanistic rationale of buloxibutid and the work you've done that gives you confidence in this -- in the potential for a successful trial here in Phase IIb?

Yes. I mean, ultimately, what we're talking about with pulmonary fibrosis is injury to the lung and it's injury to these air sacs, this epithelial layer of the air sacs that drives this runaway wound healing process, the scarring process. And I think ultimately, why we're so excited is that we take these precursor cells that are responsible for differentiating into the gas exchange cells, and we drive a reproliferation and a protection of them. So we're actually able to, again, drive more gas exchange cells for more gas exchange capability and repair that injury, which is upstream of fibrosis. And we think that's a very exciting way to go after this disease. And then at the same time, it's when you injure these cells that they release the profibrotic signals. So by refunctionalizing the cell type, you are naturally downregulating the wound healing signal without taking a sledge hammer and blocking all of these kind of wound healing signals because low levels of them are associated with normal maintenance of tissues. And so we think that's the right way to go after this disease. And then the last piece is how you deal with existing fibrotic material that's built. Dr. Maher is absolutely right that if a tissue is fully fibrosed and there are no cells left, there's nothing you can do there. But we do think that there's a mid-stage in between a healthy lung and fully fibrosed lung where there's a buildup of fibrosis. And we've shown in this mechanism, and it's, again, part of its natural function that it can upregulate the formation of enzymes called matrix metalloproteinases that are collagenases that will actually digest existing collagen. And what's really nice is we've seen a significant upregulation of those enzymes in our Phase IIa study. So alongside the improvement in lung function that Dr. Maher described over 36 weeks, we also see a significant increase in these collagenases that can digest collagen and hopefully help with that resolution and repair.

Fantastic. Well, in the interest of time, I'm going to leave it there. But Ahmed, thanks so much. Dr. Maher, thanks so much for the very insightful discussion today, and I appreciate both of your time. With that, Jed, we can end the recording.

Thank you, Brandon.