Vicore Pharma Holding AB (publ) ($VICO)

Good day, and thank you for standing by. Welcome to the Vicore webcast Buloxibutid and the Evolving-IPF Landscape. Today, we have with us Ahmed Mousa, Chief Executive Officer; Bernt van den Blink, Chief Medical Officer of Vicore Pharma; and Phil Molyneaux, Professor of Interstitial Lung Disease and Asthma, Imperial College London and Respiratory Physician at Royal Brompton Hospital. [Operator Instructions] Please be advised that today's webcast is being recorded. I would now like to hand the webcast over to your first speaker today, Ahmed Mousa. Please go ahead.

Thank you, Heidi, and thank you to everyone for joining. It's great to spend some time with you all after the recent ATS meeting where there were some new insights in idiopathic pulmonary fibrosis development across the landscape, some new presentations by the Vicore team as well. And of course, this recent ATS meeting comes shortly after Vicore completed enrollment in its ongoing Phase IIb study of buloxibutid and IPF. At the outset, on the first slide, I refer to our forward-looking disclaimers as we'll be making some reference to our ongoing Phase IIb and future plans today. Following that, the agenda for our meeting is, after my introduction. Dr. Phil Molyneaux will give us an overview of the pulmonary fibrosis and IPF landscape, continuing unmet need, including highlighting some recent data sets. Dr. Bernt van den Blink, our Chief Medical Officer, will review our Phase IIb study design, which recently completed enrollment as well as some clinical presentation, highlighting data from our Phase IIa trial that was presented at ATS. And then to conclude the substantive session, I'll do a recap of our mechanism of action as well as highlighting some preclinical data sets that reinforce our conviction in this mechanism of action that we presented at the ATS recently as well. And of course, we'll save some time for Q&A and look forward to that, too. On the next slide, it's just a very quick company overview. Vicore is a transatlantic company. with presence in the United States as well as in the Nordics and Europe. We have about USD 370 million market cap, a strong $110 million financial cash position as of the end of last quarter and really pleased to be supported by a wide range of high-quality institutional and specialist investors. On the next slide, we have our pipeline, which really highlights how focused we are on buloxibutid in idiopathic pulmonary fibrosis. It really is core area of our focus at this time, ongoing Phase IIb, as we mentioned. This is a program that slated to read out in IPF. After the completion of the 52-week dosing period in the middle of next year. We have the asset fully unencumbered aside from Japanese rights, which we licensed to [indiscernible] in an attractive partnership in 2024 as well. And of course, beyond what we're working on the late stage side, we do have a number of programs in early-stage development against this mechanism of action and this pathway which we think can be a broad and useful intervention point for not just pulmonary fibrosis, but a number of other pulmonary and fibrotic conditions. With that, I'll turn things over to Dr. Phil Molyneaux, who's Professor and Chair of Respiratory Research at Imperial College, Respiratory Physician at the Royal Brompton and a PI in the ongoing Phase IIb ASPIRE study.

Thank you very much, Ahmed. So I'm going to spend the next 20 minutes or so running through a few updates from the ATS. And on my first slide, I'll start with a reminder of what is idiopathic pulmonary fibrosis. I won't dwell too much. It's a disease that cause scarring of the lung, causes the lungs to shrink down and it causes the lungs to be less efficient is not only can you not take a big enough breadth in, but when you take a breath, you can't actually extract all the oxygen that you need. So it causes breathlessness, cough and ultimately, death in 3.5 years from the time of diagnosis. It affects well, globally, we're going to go between 20,000 and 100,000. The incidence is definitely rising and none of the current drugs that I'll provide [indiscernible] with have actually impacted on that meaningfully. On the next slide, you see the real burden and what we're dealing with here. You look at the survival here on the right in IPF, it's 3.5 years, and that is worse than most of the common cancers. Yes, it's a disease that's underappreciated probably at public field. It's got a high symptom but on the right of the screen see that. You see shortness of breath. You see fatigue and you see cough. Another features of aches of joints and aches and pain. So it's associated with not only the symptom of breathlessness, but also of cough, fatigue, and is ultimately very debilitating for patients. On the next slide, we look at the treatment options. And up until 12 months ago, we only had 2. We have pirfenidone and we had nintedanib. They have been joined by nerandomilast, with Jascayd, they're all antifibrotic drugs and they all aim to slow down the progression of disease, not only aimed [indiscernible] modification or improvement of symptoms. As [indiscernible] have been approved now for probably over a decade. They're all oral drugs. And at all at this moment in time, have a number of significant side effects. Phase III is coming through, that I'll touch on some of the data for is Tyvaso for inhaled [indiscernible] and [indiscernible] from BMS. On the next slide, you'll see what I referred to by slowing disease progression. So the bottom line on all 3 of these graphs are the placebo, and that shows inevitable decline of untreated patients with pulmonary fibrosis. They lose lung function day by day. The antifibrotic drug, you see pirfenidone, nintedanib, and then nerandomilast on the far right, essentially shift this curve up. So they don't stop everything, they slow it down. Statistical method aside, you can't really compare all of these results. So -- but essentially, we're looking at between about 100 and 150- ml difference between placebo and active drug across these studies. And my intake is that they're all about the same if you ignore the statistics. They will slow it down, but they don't stop it. Now that's good news, but the bad the next slide is the side effect burden. We don't have enough real-world data for nerandomilast last year. But when you look in real-world evidence base for pirfenidone and nintdanib side effects. You see a significant burden for patients. And that means that really translates to the fact that patients don't day on the therapy. Discontinuation rates peak around 10 months and people are on it for less than a year. In the real world, they just don't tolerate the drugs. Pirfenidone's main side effects being fatigue, loss of appetite, weight loss. It has a photosensitivity reaction, rash as well, meaning everybody has to wear sunscreen. Nintedanib main side effects of GI. And you see here on the left of the screen, highlighted diarrhea, which affects a significant number of patients. Now that's important because in the Fibro [indiscernible] study, we see that diarrhea was reported in 40% of the patients that had nerandomilast on their own, but when it's used in combination with nintedanib that went up to 62%. I do have to say that in the clinical trial, the discontinuation diarrhea itself, where were relatively low. But that's probably reflecting the fact that the patients that were selected into the study already antifibrotics, we're already tolerating it and have been on a stable dose. So we do wait real-world data for that. Now moving on to some of the new data from the ATS. On the next slide, you see the subgroup analysis from fibro [indiscernible] study. So we already know it slows down disease progression. We already know that when you combine IPF and PPF and look at the 72-week data, there's a signal for [indiscernible] but what we now see at the ATS is that the benefit in FVC is borne out across disease groups, and we're looking here specifically at FVC group. So how severe is your disease. They split them into less than 50%, of which there weren't very many patients given the entry criteria of FVC had to be above 45 and then 50 to 70, 70 to 90 and then 90 and above. And you see, as you would expect, patients with lower FVC have more severe disease. There's more patients on supplemental oxygen for instance. But there's nothing unsurprising to me about those groups. When you look at the benefits, you obviously see in the forest plot at the higher dose, the benefit is clearly obvious. And it seems albeit not all of the lines across the threshold completely, they do all move towards favoring nerandomilast. So it looks nerandomilast working at all the disease severity subgroups as you probably would expect the data for less than 50 just uninterpretable given the number of patients that are in there. On the next slide, we move to what was probably most anticipated, which was the TETON data, and this is a recap of the TETON II data that we've seen, ERS. Just to remind you, this is an inhaled teprostinol drug transitioned over from pulmonary hypertension studies. They ran 2 parallel programs, TETON-1 and TETON-2. We got the results of TTI, which showed 95 to 100 milligram difference between placebo and active drug. Obviously, very encouraging. We have the headline press release before ATS. But on the next slide, you see the results from TETON I, which presented in full. And TETON I actually showed a much larger improvements with a delta of 150 mills between placebo and inhaled [indiscernible]. Again, what we see is the adverse events. So if you look at the table on the right, you see even the placebo patients who are reporting 30% cough showing us what their inhaled delivery device does. But when you put to [indiscernible] in that device. Over 50% of the patients had cough. Headache was an effect of taprostinol, known effects. So there really was a relatively high symptom burden. So while it did meet its primary endpoints, the discontinuation rates were high and they were 40% in the [indiscernible] arm, 30% in the placebo arm. So again, that's telling me that the drug has an -- the drug has a side effect profile, but also the delivery method and a number of times that the device has to be used each day also has a fatigue ability for our patients. But 130 mills is a positive outcome. And so some of these country outcomes are positive, too. On the next slide, you can see some of the pool data that was briefly presented. And this is obviously the path to regulatory approval, it's 2 independent studies, put them together. And you get -- as you would imagine, with a 95 mill in 1 group and 130 mill in other group, you finish about 112 million difference between the 2. So a positive study when you combine it together. When you combine the SAE data together, Again, it's about the same as the vital ones, cough, 50% of the patients, headache, 25% of the patients on active drug. So you're seeing still a significant burden of side effects. And on the next slide, I like to look at the breakdown of the studies because it really talks to us about what we're going to see in the real world, I think. So in TETON-I, 600 patients, give or take, randomized in each 100 pressure or discontinuations in the treprostinil arm and 73 in the placebo arm. This is a significant dropout rate and something that is and will be a concern for me as a clinician trying to use this clinically because as you know, we do our best to a patient in a clinical trial, but very well supported. And these patients had significant coaching, nebulizer, remote help and everything else. And still, we were losing 30% of patients. So I think that for me is one of the downsides of the data that we saw presented probably not unsuspecting -- unexpected given the PH data and given the TETON-1 data, but now we're seeing it in the second study, and we see what the combined results look like. I mentioned that all of the other -- all of these antifibrotic drugs just slowed things down. And on the next slides, you see the results from the [ CORAL ] study, which doesn't try and slow down disease progression, tries to focus on cough which is a significant problem, 85% of our patients with pulmonary fibrosis have cough. And that ATS we presented a number of abstracts looking at Nalin. So CORAL study was a randomized double-blind controlled dose-ranging study. I'm looking [indiscernible] 3 doses of now [indiscernible] and study was based on a cough recording of 24 hours at baseline, my cough recording at 24 hours at week 6 to see what the impact was on cough counts. And what we see on this -- in the figure on the left is you see placebo. So just giving somebody bit of extra care and enrolling them in study improves the cough by 16%. But on top of that, you don't see a dose effect looking at the 3 doses of [ nalbuphine ] to reduce cough on top of placebo by about 50%. On the right, you see the rate of change that this occurs in. So we did cough counting for and 6 weeks. And actually, for all doses, the cough counts drop right down by week 2 and the benefit of [indiscernible]. So that's pretty good news for the patients to moving forward into Phase III. We also presented data looking at the subgroups. These effects were the same over patients on and off background antifibrotic therapy. Again, reassuring and informative for the Phase III study design. On the next slide, we presented some more exploratory data. Now we do cough counting. So we look at how many times the people cough an hour. But actually, our patients tell us that cough [indiscernible] are important. So when they all say a cough 3 or 4 times in a row, I lose my breath. I can't get my breath back, I panic. Cough [indiscernible] are associated with things like urinary incontinence, blackouts, collapse. So they carry a significant burden to our patients. we look to cough bouts in IPF and also -- and look at the effect of nalbuphine and get bogged down into the various definitions of bouts. But across all of the definitions, essentially, patients had significant cost bouts. Look off you have, the more likely you were to have cough bouts. And actually, nalbufin reduced cough episode as well. So it reduced the number of bouts, and it reduced the duration of them. So even if it didn't let clearly obliterate the bouts events, it did shorten the event time down. So it looks quite promising from that perspective. It can drop cough count, it can drop cough bouts and it was effective across patients on and off background therapy. So [indiscernible] we say given I presented it, people are excited by that data. And however, on the next slide, we haven't solved everything. So while it's good news, I think. Independently, I can say we've got nerandomilast now. We start to see some subgroup data from that. We've got Tyvaso that also looks to work with side effects and with problems. And we've got drugs that are trying to look at symptoms, but we still have a big unmet need. All of the drugs are presented to you have side effects. None of them slow down, none of them stopped disease progression, they only slow it down, not only trying undue areas of early disease. So what we've got is a drug that we need to clear people earlier on, people who have really bad established disease. It's often too late with the current drugs. They're just there to slow things down. So there's a big unmet need to either reverse or improve or stabilize lung function. There's an unmet need because the drugs are broadly tolerated, whether that's GI side effects, whether that's weight loss, whether that's cough or headache that, none of the current drugs are perfect. And combination regimens are not clear. Nerandomilast last is the only 1 that's been studied with in combination in [indiscernible] do on mix well from a side effect profile, nerandomilast obviously, has issues with pirfenidone given the drug-drug interaction. And as you see on top of in does increase the rates of diarrhea to above 60%. So we don't really have ideal combination therapy data and there's probably a lot more room for improvement there, albeit I can't be too negative because we've waited 10 years for a new drug. On the final slide, I have looking forward to what we've got to look forward to. Well, we've seen the data for Tyvaso and we anticipate the submission second half 2026, [indiscernible]. So that is an oral drug and LPA1 antagonist, we've recruited, we expect top line data towards the end of the year. going to be watching that 1 closely. They have issues with blood pressure. And at the moment, they have to do postural blood pressure monitoring. So patients have to have drug on site. They have to have a line in standing blood pressure pre and post drug. And I think how that lands from an indication perspective is going to be important, presuming the readout is positive. We are Insmed, who have got a the [indiscernible], which is a prostacyclin analog. So essentially Tyvaso that's once a day. So they're hoping to capitalize on the positive results of United Therapeutics. But minimize the side effects with a once-a-day delivery device. PureTech reiterated pirfenidone, which is going into 3 study. quite interesting study design because they're going to go head-to-head with pirfenidone to no placebo in that one. Phase 2, obviously, we're going to hear more from Vicore about angiotensin receptor agonist. As Ahmed said, fully recruited ahead of time, so congratulations on that, and now we're all just waiting for the results. [ Avelin ] you've got their inhaled pirfenidone and intetinib drugs across various Studies I'm about to finish. I'm about to start, but all in Phase II endeavor with the hedgehog inhibitor, they finished recruitment, and they're just waiting for their final patient in the 24-week study and probably going to be interested to look at the FVC signal in more than 20 patients and also their side effect profile will be the things to watch out for at the end of the year. Coruna have finished recruitment and again, waiting for their results. I think they're going to be slightly later and we'll get a readout from them next year. Interesting small molecule. And then Lilly with the Whisper readouts, which again will probably be a bit later than Aurora in 2027. So a lot of things to look forward to. And with that, I think on time, I'll hand over to Bernt.

Thanks Dr. Molyneaux, thank you so much. I think really a very nice recapitulation and also very clearly illustrating sort of there's still unmet high need in this area, and need for drugs that are better tolerated and we combined with other standard of care and have improved efficacy. So if we go to the design slide of the Phase IIb ASPIRE trial, it is what we are aiming to develop with a [indiscernible]. And we're currently have an ongoing large Phase IIb randomized db-blind, placebo-controlled study. It's a global study. And as just mentioned, we have full year goods, a little bit ahead of schedule, which we're really delighted with. I think reflecting on -- again, I think unmet needs. Patients are keen to go into trials looking for better treatment options. Also, I think enthusiasm with our investigator and lastly, certainly, I think the really strong execution of the entire team working on development of this drug. So this study, as I mentioned, is a randomized study. We're randomizing patients across a high dose, 100-milligram a day lower dose, 50-milligram and placebo, randomized well into 1 patients can enter on background therapy and nintedanib or nerandomilast, although the latter was only a small proportion of patients as this was only approved in the U.S. relatively late in the recruitment period of the study. And primary endpoint at week 52 is changed from baseline CT the registrational endpoint for Phase III studies as well. Key secondary endpoint is proportion of patients with disease progression similar to the definitions used in the TETON study. This was truly global -- is a truly global study on the next slide. Patients were recruited across the globe and we're really pleased to see that is very well distributed across the globe with about 25% of patients in the U.S., 25% in Europe. And then also APAC, Australia, South Korea and Taiwan and also patients in South America. So what is next for the ASPIRE trial. So next up is a replan futility analysis on the next slide. So as part of our plan, our independent data monitoring committee will conduct a futile analysis once to about 27% or 100 patients have completed the study. Main purpose of the futile analysis is to protect the patients participate in the study. So this is 1 of the -- 2 of the tools our team has to perform their duty in protecting patients and to come to a well-balanced risk-benefit assessment and they will do this futility analysis within the context of a regular DMC meeting. It's not insignificant as we do know that a number of IPF trials have filled during the conduct of the study because there were safety concerns. So we do see this as a meaningful risk mitigation step the manner in which will be conducted is set up in order to fully protect the integrity of the trial. So we, as a sponsor will not know any other readouts than whether the futility has been met or not, and we'll get that signal from the DMC on the next meeting. The method used is using a conditional power approach. The futility will only be met if the power, conditional power lower than 20%. And overall, the threshold has been set in a way that on the 1 hand, we will protect the patient's safety. On the other hand, also not stop too early as we know that you do need a large, robust, radically long study come to a confident assessment of a drug in the IPF field. We expect to share the outcome of this futility analysis in the [indiscernible] of this year. So what's after the you futility analysis on the next slide. So obviously, then we go already -- we're heading to top line data readout. So we expect top line data in middle of next year, and we hope, of course, to share those data as soon as possible afterwards. So then maybe moving towards some news from ATS on the next slide. So as you may be aware, a lot of enthusiasm for oxybated including that what led us to the current Phase IIb is that our Phase IIa AIR study. This was a single arm, open-label study conduucted in to assess blocks but in patients with IPF and these patients were treatment at ease to get a very clear and clean signal both on safety and tolerability but also helped us really to explore the efficacy in this data set. To do so, patients were recruited in regions where treatment read patients were readily sort of available to enter study. So we recruited patients in India, Ukraine, Russia and the U.K. And if we go to the slide, you can see that overall, the patient baseline patient characteristics in this study, where I think very similar to other late-stage IPF studies, but was notable that approximately 70% of patients was from Asian ethnicity, they were from India. And one of the questions we asked ourselves, right, is this are these patients, they're similar to other IPF patients or could this have [indiscernible] our results. So we, together with our partners at [indiscernible], our imaging and data partner in the U.K. We did an additional analysis on both baseline characteristics as well as imaging characteristics to see to these patients match what we would expect from an external cohort of IPF patients. So if you go to the next slide, first, you'll see sort of the data that I think you all agree, are very encouraging in this field. These are the patients that completed the 9-month treatment period. And in these patients, we saw the stabilization and even improvement in FVC, means over more than 20 and even median 60 mL in these patients. And when we looked at patients by subgroups, I think the message here is that there was a consistency in signal, whatever subgroup we looked at the data trended to be positive, notably, as you can see here in India patients, but also looking at when we look at different types of imaging characteristics or gender. So next, we leverage an external data set on the next slide to compare our AIR trial population to a relatively large external data sets. On the left, you see the AIR trial population. We enrolled 52 patients had 48 patients available with FVC data, including follow-up. And then we looked at the entire cohort, but also [indiscernible] so at the patients from India versus those who are not in India, and compared it with a large external data set for a large part, U.K. patients versus also patients from Asia Pacific and North and Southern America. And then on the final slide on the clinical data from ATS, you can see the baseline characteristics of these sets of data on the left. What you may appreciate, you see a different sort of graphs and without going to too much detail, what you may appreciate is overall, the chracteristics are quite similar, particularly when you look at page, and when you look at predicted loan volumes, FVC predicted, [indiscernible] 1% predicted. What was different was the absolute lung volume. So absolut FVC, absolute on total loan volume. And this was most likely due it was actually due to smaller height in the India patients. So when we look at the height of patients in India, there was, on average, 10 centimeters less than the patients not from India, when you look at percent predicted data, then the height is 1 of the larger variables that is sort of taking into account to [indiscernible] predicted and then indeed users, in particular are very much sort of in line. We did see somewhat more fibrosis in the patient from -- coming from India. I think that is somewhat meaningful. In the past, there have been concerns that if you have a lot of fibrosis, you might be sort of beyond the point of no repair and there might be no stabilization or even improvement but obviously, that's not what we're seeing. So we do see this as overall encouraging data. I think most meaningful is actually on the right. Our initial question was, are these patients representative of the larger global IPF patient, and there, we did isone mapping. So we reduced these variables to 2 components. And then you can see within the larger cloud of IPF patients from an external cohorts across the world in blue dots, you can see that AIR patients, both from India and not for India, sort of sit within this distribution. I think really emphasizing that these patients sort of are representative IPF patients. Third, I think supporting our confidence that what we've seen in AIR is representative and that we hope, of course, to conclude that in the current Phase IIb study. And with that, I'm concluding my little section and handing the word to Ahmed.

[indiscernible] And what we have here is an agonist of the [indiscernible], which is shown in orange on the right-hand side of the schematic. This is an intervention, a dilatory effect and anti-inflammatory effect. And while it's a novel intervention point for clinical drug development. It is part of a more familiar system. It is the body's response system to the AT1 receptor, which drives hypertension, fibrosis and inflammation and is blocked by ARBs or which are AT-1 agonists or ACE inhibitors, which deplete the available ligand and angiotensin II for the AT1 receptor. One of the reasons why we're so excited to advance this intervention point pulmonary fibrosis in particular, is the high expression of the AT2 receptor, including constitutive expression of this receptor on a precursor cell called an aviola epithelial type 2 cell. On the next slide, we talk a little bit about what these AEC 2 cells do in the lung. And the kind of key functions are basically differentiation or replenishment of type 1 epithelial cells or AEC 1 cells. These are the workhorse of the lung, they're responsible for gas exchange. So oxygen coming out of the abiola, the airsac diffusing across the interstitial space to the pulmonary vasculature and pulling carbon dioxide out. In addition to that, these precursor cells are the exclusive cells in the lung that produce surfactant protein and surfactant protein is critical for Abiola integrity. So it addresses the surface tension associated with water to enable the aviola's to maintain its confirmation and ability to participate in gas exchange. On the next slide then, we look a little bit at what happens in IPF on the right hand side -- on the left-hand side, apologies side what we believe buloxibutid does and relate to these [indiscernible] processes and the IPF. At the outset, IPF like other pulmonary fibrosis is a disease of epithelial injury, that injury affects the type 2 epithelial cells. They then become senescent or unable to proliferate, unable to function properly, no longer producing that surfactant protein, which causes a phenomenon IPF known as pre-fibrotic Abiola collapse. And in addition to that, you have damage to the type 1 epithelial cells, the gas [indiscernible] cells and an inability to replenish them because the type 2 epithelial cells have also become injured. So even ahead of fibrosis, the key message is there is epithelial injury, that believe is quite relevant to this disease process. In addition to that, you then have the kickoff the fibrotic process as a response to this injury, and that is highly mediated by the type 2 epithelial cells. So they are 1 of the main secretors of TGF beta and other profibrotic cytokines. These pro-fibrotic cytokines then drive a phenomenon known as epithelial to [indiscernible] transition. So more fiber blast building up the fibroblast become activated. They start moving into this interstitial space, which is the space around the aviolis between the pulmonary vasculature. And then they become activated and begin depositing collagen in that interstitial space. And this is what then drives a physical barrier to oxygen diffusion as well as essentially an encroachment on the Abiolis and the overall lung, what ultimately impacts them, the forced vital capacity, which is the regulatory endpoint and IPF trials. In addition to them, this buildup of fibrosis, you also have the fibrotic matrix build putting pressure on the vascular compartment. And this is why a large proportion of patients with IPF ultimately have pulmonary hypertension as well. You have this injury driving a hyperplasia and a metaplasia of the smooth muscle cell and endothelial cell compartments. That causes a reduction in the size of the lumen, leading to that pulmonary hypertension. And that injured pulmonary vasculature also drives TGF-beta 1 release. So there's more profibrotic in the disease that are coming out, not just from the epithelium now, but also from that endothelial compartment. So I would say the main message for Vicore is that IPF's a disease that has kind of an aviola [indiscernible] compartment injury, a fibrotic build in the interstitium anti vascular dysfunction. And all 3 of those compartments are important parts of the disease. On the right-hand side, what buloxibutid fundamentally does is it's an agonist of this A2 receptor, which we believe and based on preclinical data have shown, drives a reproliferation of the type 2 aviola epithelial cells. This can then allow for a differentiation on a replenishment to the type 1 epithelial cell. So you replenish that gas exchange capability. In addition to that, we have the ability to produce surfactant protein again to address that feminomenoof pre-fibrotic aviola collapse. And one of the key pieces in relation to them that second kind of compartment, the interstitial compartment and the fibrotic build is that we then attenuate the pathological TGF-beta signal from one of its key sources, these type 2 epithelial cells, we have the ability to slow or stop that kind of profibrotic drive in the interstitial space, which we think is also a key to the mechanism of action. In addition to that, this mechanism, AT2 agonism is also known to resolve fibrosis, not just to stock current fibrotic build, and it does that by upregulating [indiscernible] expression. And so then you have the ability to resolve fibrosis that built up as well, not just to stop new fibrotic buildup, which we think could be a key to potential disease-modifying effect based on the Phase IIa signal that we observed. Finally, we have the ability with this mechanism of action. And as one in the Antisen 2 pathway, quite easy to understand that it's a vasoactive mechanism. It drives a local vasodilatory effect, but we also have shown the ability of this mechanism of action to resolve that vascular remodeling component which we believe can have a big impact in this disease. And certainly with United Therapeutics, TETON-1 and 2 results of vasoactive drug has shown certainly the ability to have potent impact on FVC. And we do believe that we have a similar potential as well. If we then take this mechanism into some of the recent data sets. On the next slide, we look in particular at MMP-13 and MMP-13 is 1 of these collagenase matrix [indiscernible], these digest [indiscernible] collagen. We, in particular, have observed in a number of preclinical studies run by third parties that if you, for example, knock out MMP in animals, and subject them to bleomycin challenge, basically simulate that pulmonary fibrosis, it does not resolve, and it gets much more significant. So you'll see this in the kind of bottom left-hand corner, where you have wild-type mice in the top row, you subject them to the bleomycin challenge, and you have a certain level of fibrotic buildup after 28 days, which you could expect. And the MMP-13 knockout mice, it's much more significant, and that is a result in ability to have that resolution of fibrosis mechanism built in. And what we observed in our Phase IIa study and the biomarkers of the patients is the significant upregulation of MMP-13 over the 36-week treatment period, which we think is a really nice sign that we're able to drive that fibrolytic effect in the patients in our Phase IIa study. But then on the next slide, we also made some very interesting observations when we ran some RNA scope experiments. These are experiments where you can localize the RNA expression of different proteins. And so what you see on the left-hand side first is in animals that are subjected to bleomycin challenge, you can see the production of surfactant protein C which is a marker of type 2 epithelial cells. As I mentioned, surfact proteins are exclusively produced by that cell type. And then what we observe is that when you also look for MMP-13, you find that there's a significant upregulation of the MMP in particular, out of the type 2 epithelial cells directly. And so what we observed here is really nice evidence that the signal that we're seeing in our peripheral biomarker, that upregulation of MMP-13, a nice evidence that is directly connected to the cellular compartment that where we believe we're most impacting because of the high expression of AT2 receptor on aviola epithelial type 2 cells, but also the cell type that we believe is 1 of the key linchpins to this disease, the 1 that really by becoming injured coming into that senescent state really driving a lot of the fibrotic process. So this is a really nice kind of data reflecting and contextualizing that clinical signal that we observed on the increase in MMP and why that might be so relevant to our particular mechanism of action. On the next slide, a description of a pulmonary hypertension model called the Sugen-Hypoxia model that we tested buloxibutid. This is a model that replicates a pulmonary vascular disease, a compound known as Sugen-5416, is deployed along with [indiscernible]. And this then actually simulate pulmonary hypertension by causing that hyperplasia and metaplasia in the vascular compartment in pulmonary architecture as well as then driving the common follow-on effects of pulmonary hypertension and pulmonary arterial hypertension. So in animals that are subjected to these conditions, the first, the Sugen and then the Hypoxia conditions. They then develop that phenotype. And you can actually after you've established pulmonary hypertension in these animals, then look at different drugs and their ability to have an effect on that disease phenotype. And so what we see here on the next slide, is, first of all, you're able to establish that pulmonary hypertension. That's the left-hand column, you increase the size of the right ventricle. It has to work harder to push blood through the pulmonary vasculature. that also corresponds to an increase in right ventricle pressure, pulmonary arterial pressure, reduced cardiac output and, reduce arterial pressure as well. Now when you look at what buloxibutid is able to do after the offset of disease, you're able to decrease the right ventricle size, reduce the pressure, both in the right ventrical as well as pulmonary arterial and increase the cardiac output, which is really nice to see is a nice signal that this is a drug that is highly relevant for pulmonary hypertension, but again, recognizing that vascular dysfunction is a key part of IPF as well, a really nice sign that we can impact that access of the disease as well. On the next slide, 1 of the really nice outputs of this study as well as looking at the impact of buloxibutid on vessels of different sizes in terms of both wall thickness and luminal opening. And one of the observations here is that, for example, pulmonary arterial hypertension tends to afflict more of the smaller vessel size, PH-ILD or pulmonary [indiscernible] associated with interstitial lung diseases tends to kind of afflict a broader range. And it's really nice to see that we're able to address wall thickness across a range of vessel sizes as well as luminal opening across a range of vessel sizes. And what's really nice to see also is while the impact on Lumino -- on might see modest in terms of a percentage, these have outsized and nonlinear impacts on the ultimate [indiscernible] arterial pressure, so signals that are really nice to see. And as might not be surprising then, on the next slide, what we show is the impact of buloxibutid on pulmonary fibrosis in this pulmonary hypertension model. As you might expect, when you indulminary vasculature, it will start pushing out profibrotic factors, right? And so this is what's causing them, and you can see versus the control in the vehicle, you have an increased staining for collagen, a reflection that you're building in pulmonary fibrosis in this disease. And again, showing that buloxibutid is able to essentially address that endothelial or vascular source pulmonary fibrosis as something that is additional and exciting to the ability to impact epithelial which in fibrosis as we observe in cliomysin models and other models where we show the effect of buloxibutid as well. So 2 really nice preclinical experiments that kind of show what we believe is the effect on the epithelial compartment as well as the vascular compartment. And so we're really excited to do that at ATS and it drives further conviction in this mechanism of action. But yes, thank you, everyone, for joining and really happy to move to Q&A now.

[Operator Instructions] Your first question comes from the line of Steve Seedhouse from Cantor.

I had a few on to hopefully get through here. First, just briefly on the futility analysis later that year in ASPIRE and the potential outcomes of that. I wanted to ask if there's any chance that the study stops for efficacy on that analysis, or is further resized or neither of those possibilities here? And then relatedly, is there any chance of initiating Phase III early based on the outcome of the futility [indiscernible] while we're waiting for the final data in the study?

Yes. Bernt, why don't I have you address that one?

Yes. Thanks, Steve, thanks for asking that. So as I mentioned, we see the first analysis mainly as a safety guard rule, but it is, of course, looking at FVC. FVC is the measure by which futility will be less. That means that if there is truly no effect or I think better set of detrimental effect on FVC. So there's no efficacy in absence of efficacy or harm on FVC, then there will be futility. Futilities will not serve as a sample size reestimation. So the futility analysis will not lead to any resizing in that respect. And similar, it will also not be used as any accelerator, for example, for Phase III. We will need a complete data sets from Phase I to do so. And I think one of the reasons is it is -- I think it's well doable to derisk on harm in a futility analysis. It's very difficult to come to a confident answer on positive effect I think that's one of the learnings in the IPF to do 2 short, 2 small studies. So we are conducting, I think, a very robust relatively long study. And that answer will give us a confident assessment of the buloxibutid treatment effect and will help us to derisk transitioning to Phase III, but also, of course, will inform us how large a study will be and many other of the aspects.

Perfect. And then second, just as you think about the evolving landscape, that you highlighted at the outset of the call for standard of care and what ultimately could be background medication, maybe even during a Phase III study for Vicore. do you expect any combinatorial efficacy? Or conversely, any unwanted combinatorial adverse event signal for buloxibutid with any of the newer or legacy IP therapeutics?

Yes. Shall I comment on that as well. So the current -- so maybe sort of our overall plan, of course, is to develop buloxibutid as a broader treatment for a patient with IPF. And we think that the treatment landscape and maybe if you can comment on that in a bit as well. We'll move for a large part in the end to combination therapy. But the drive to if combination therapy is currently limited by tolerability, right? That is I think the gating item. So we think that buloxibutid will be well combinable with several standard of care. We are currently testing it on top of nintedanib and a little bit on top of nerandomilast. So we'll have data on that. We are still also looking at patients not on standard of care. My -- or our assumption is we'll do the same in Phase III to make sure that this can also be a first-line treatment, depending on different treatment strategies. To what extent will allow different types of standard of care as background in Phase III. I think that's an item of ongoing discussions, but we are actively sort of exploring how to do that as broadly as possible. Again, I think in the buloxibutid is probably very well combinable as we are not seeing, for example, in the AIR study, any signal on gastrointestinal tolerability, which is currently sort of 1 of the biggest obstacles.

Yes, I suppose if I come in on what will standard of care be. I mean the answer is we don't know. I can speculate. I've already shown you data that, the first 2 antifibrotic drugs aren't well tolerated and people aren't staying on them for 12 months. So my anticipation is that nerandomilast will become the de facto single agent that people will use Certainly, that's what patients are asking for. At this moment in time, they perceive it as having a better side effect profile, doesn't have to have blood test monitoring. So it is establishing itself, and I think for new patients, certainly where cost is no issue or reimbursement is not an issue, then nerandomilast will be the first line. I don't anticipate that as patients progress, people will add in other drugs, whether nintedanib or pirfenidone, you can take your choice. But I feel that they will be added in a world with [indiscernible] and that appears to have a relatively good side effect profile apart from the postural blood pressure. So you take that out of the equation and potentially got 2 drugs with specific pathways that may go together. That would be how I would see it. But the one thing to say is that from a trial design, I know I said you can't compare everything. The effect sizes are all about the same. So actually, being on 1 drug, 1 drug or another drug actually probably doesn't affect your power calculations too much. When it's about patients who are on combination therapy, they are often patients who are already declining more rapidly. So again, it probably doesn't affect your trial design that much. I think when you think about third drugs, you're probably getting a step too far and you're going to have to obviously watch out for drugs that have high dropout rates or dose changing. But I don't see the Phase III landscape becoming much more complicated.

That's great. That's great. Last question for me, just going back to AIR and appreciate the work you've done, obviously, to show the demographics there pretty comparable to the external controls. That's pretty helpful. And I'm curious separately though, about the efficacy assessment itself in AIR measuring FVC, so the spirometry measurement. Can you just talk about was the asset payment or the measurement of FVC different in AIR compared to what it will be ultimately or what it is and ASPIRE or compared to other contemporary studies? Or was it pretty standard? Just curious if there's anything to note about the actual protocol in AIR versus ASPIRE?

Yes, not substantially different, right? So AIR was also century overread spirometry. I think we have learned a little bit in driving high-quality spirometry, not just we as a company with [indiscernible]. ATS standards have been updated. They have been taking some time to percolate into actually study execution. So I think we have developed another 2 to drive spirometry quality. That's, I think, also a necessary component when you do such a large global study. but also AIR was sort of a [indiscernible] overhead study. In 1 other component that we learn from Ares that we were ambitious to get a lot of data. So we had spirometry data every 2 to 3 weeks in the beginning. That sort of was I think from a scientific perspective, had a solid rationale, but execution-wise, I think in the end, led also to discontinuations. People were afraid to come into clin many times, particularly because this [indiscernible] during COVID. It's also not in the end, not very patient friendly. And we have adopted, I think, a better balance in clinic and phone visits in [indiscernible] study.

Your next question comes from the line of Vamil Divan from Guggenheim Partners.

SP-11 Great. for hosting us and for taking our questions. So I think I have 2, if I could. Great. So 1 for the company, just in terms of the ASPIRE trial. I think you did resize that a few months back, and I believe the example what you were saying is sort of based on what you saw from TETON-2 to kind of use that as a guidance, what the FVC improvement you'd want to see in ASPIRE, but now TETON-1 come in with a little bit higher results on FVC's, just curious how just in general, sort of how you're thinking the ton results and what are shown there, how that impacts what you need to show in ASPIRE, sort of how we'd be able to interpret the results. And then the other one is the [indiscernible] there. If you could just maybe give you a perspective in terms of what ASPIRE and then the other things that are in development. Obviously, a lot of unmet need in this space. And just trying to get a sense of you had to pick one, what is your sort of top unmet need you're looking to get addressed by these products if something was similar to what we have now with efficacy but actually has a better safety profile. Would you prefer that? Or is it really efficacy driven still that you're looking for greater efficacy even if the side effect profile for some of the [indiscernible] might be at got from the current there?

Ahmed, let me jump in and just [indiscernible]. So I mean, the problem with both of the current drugs is that they don't affect lifespan because people are on them long enough. So I'll take a drug that's better tolerated with the current rate of change of FVC. So if you can be on a drug for 5 years, it's more chance of prolonging your life. I'll also take a drug that does much better with a side effect profile that is worse because the patients are there, the patients want to take these drugs. So I think if you give me a same side effect, if you give me a better side effect profile, same FVC, happy. If you give me better FEC signal and worse side effects, I'm still happy because more patients will take that incremental improvement.

Yes. No, thanks, Dr. Molyneaux for the answer. It's actually a great dovetail to [indiscernible] your first question. Because I think that 1 of the observations that we've made on the overall landscape is how important better tolerated therapies are for patients for exactly the reasons that Dr. Molyneaux mentioned, and from that perspective, looking at powering our studies for a range of efficacy outcomes becomes very important because the feedback we've gotten on the tolerability profile based on what we've observed in the AIR study, which, of course, studied the drug for approximately 9 months but is also a part of a larger database where over 350 either healthy volunteers or patients were subjected to buloxibutid treatment. And so we have a really nice overall picture on the tolerability profile for that development to date, and as well as, of course, an observation of the blinded safety data in the ASPIRE study to date as well as a number of DSMB interactions makes us optimistic that this is going to be a profile from a tolerability perspective that's very attractive across a range of efficacy outcomes. And so certainly, that was has really highlighted to us as we observed before we decided to increase the study size, we saw the [indiscernible] study readout. It was about 70 million difference in lung function between the treatment arm and the placebo arm at 52 weeks, as well as then the TETON-2 study, which showed a 95, 96-milliliter difference in lung function between the placebo arm and the treatment arm at 50 weeks. I think, Vamil, what you're kind of hinting at is a 1 study showed even kind of better numerical difference between placebo and treatment arm. I think the 1 caution that we make, of course, people naturally look at these different results and look at comparing them. But because some of the differences in the studies, including differences in statistical methods, I think that most individuals, and I think Dr. Molyneaux, you mentioned this as well in the field are seeing these relatively similar from an effect perspective. So I think the underlying message and rationale for kind of Vicore's increase of the study size, which is really to power for a range of different effects and FVC holds quite true. And so we're very excited to see how the therapy works in this larger trial.

[Operator Instructions] Our next question comes from Arvid Necander from DNB Carnegie.

So I have a couple of questions for Dr. Molyneaux, if I may. So first off, on the outcome in Asian versus Western patients. The seed progression is -- or the T-score is obviously not well documented in the end population. So I was just wondering whether or not you have picked up any emerging evidence case or clinical experience that could point to a different disease course compared to Western patients? And then secondly, on [indiscernible] in the treatment algorithm, just sort of acknowledging the tolerability challenges here discussed with the standard of care antifibrotics, how would you think about the trade-offs between buloxibutid monotherapy and buloxibutid together with background standard of care. I guess more specifically, what magnitude of the incremental effect is on FVC decline would you need to see from the combination to justify keeping patients on standard of care rather than going with buloxibutid monotherapy. And I understand, of course, that is sort [indiscernible] data, but it would be interesting to hear your thoughts on this. I'll start there.

Okay. The first part is easy. So I think what we're seeing from IPF is that IPF is IPF is around the world, 2 global studies. And it makes it relatively easy from a study delivery perspective, if you have the demographics of a patient, you have a CT scan then it's pretty much IPF and the disease behavior globally is relatively standard. I don't have specific data on Indian subcontinent for specific trends, but we haven't seen any areas where FVC signal is an issue. So that doesn't worry me, and I haven't seen anything from an Indian subcontinent perspective. From where do I see this? That's a difficult question to ask without data in front of me. I would tell you that from we now have an option to add in drugs. And at this moment, people are adding in drugs to patients who are tolerating the drug. And that's the main thing you have to understand is that a lot of our patients aren't tolerating the drug. They've been on it, and we persevered with it because we didn't have an option to switch. So I think in any patient tolerating the drug if there was another 1 available, I would add that drug on top as long as they continue to tolerate them. I don't think we're in a point where we're stopping drugs to move on to another 1 because we don't have any specific evidence that I can pick one over the other. So any change incrementally that is well tolerated as a positive outcome in my mind.

Great. Just a quick follow-up on that one. And I guess you touched on this. But broadly, how manageable do you consider the side effects seen with standard of care to be in clinical practice for an experienced physician? How much do you believe the continuation rates in the real world different from what's seen in clinical trials?

So I presented at the ATS real-world data on discontinuation rates. And once any study gets past 12 months, the discontinuation rates go up above 35% in any study you look at in our clinical -- in my clinical practice, the discontinuation rates are probably not as high as elsewhere, but they're still very high. And I can't give you exact numbers, but even with the best centers in the world, the discontinuation rates are still high. And what we're not seeing is people persisting out past 12, 24 months. And when you think about we want patients to live longer, if you don't take the drug long enough for the FVC impact to have a knock-on effect on survival, that's the issue that we're facing at this moment in time. our clinical trials built on the premise that FVC decline predicts mortality. So the counterargument is that slowing decline improves mortality. But if you're not on a drug long enough to slow decline, you can't improve mortality.

There are no further questions from the phone lines. I would like to hand over for any closing remarks.

Great. Thanks. So we've got the number of written questions that have come through. A few of them have already been answered during the dial-in Q&A. Given the time we're delimited to 2 questions. So let's start with the first one, which comes from Dan Akschuti and [ Pareto ], and maybe Ahmed can respond to it. Considering the vascular mechanism of action of treprostinil, do you see some sort of read across to blockbuty? And if yes, which and to what extent?

Yes. It's a great question, Dan. Generally speaking, there was some level of [indiscernible] that drugs acting primarily on the vascular compartment, could have a strong impact in IPF. And I believe that the TETON studies reflect that drugs acting on this compartment can play a key role. It's our belief, and it is more in the zone of hypothesis is right, the vascular dysfunction driving further pulmonary fibrosis is a key part of that pathology. And so when we look at buloxibutid in the Sugen-Hypoxia model, as an example, in this model, where also treprostinil has been tested. We're really enthusiastic about some of the mechanistic access, the ability for buloxibutid to drive a strong level of effects on this main. And ultimately, wherever the pulmonary fibrosis drive is coming from, whether it's coming from epithelial injury [indiscernible] or endothelial or vascular dysfunction, ultimately, both of those are going to drive that interstitial fibrosis. And so your ability to impact that interstitial fibrosis at either or potentially in the case of buloxibutid based on our mechanistic data, both sources, we think, show that they have a really potent effect, and that makes us quite excited and we do believe that there is some mechanistic read-through there.

Great. Thanks, Ahmed. Maybe Philip could best address the last question. What is the ceiling for IPF efficacy when old patients still lose FVC due to aging?

Yes. So it's a good question. You do lose lung every year as you age. So there is somewhat of a ceiling effect or nowhere near it. I think there's an upcoming piece of work that will be out in the next few months. I think looking at this in aging adults comparing it to IPF. So there's room for maneuver. There's room for improvement. And we're now [indiscernible] healthy aging. What you have to remember is we've got our untreated patients in there. So we see what the difference is to untreated. We see what normal aging is in real life, and it's nothing like we see in IPF. So there's a lot of room to maneuver. I think what we're looking at 15 to 30 mls if you're going to put me on the spot. And that's an average. So yes, lots of room to improve.

Thanks, Phil. That's it from a Q&A perspective on the inbound questions. We appreciate the engagement today. If you have any additional questions, please follow up with our IR team. Thank you for your continued interest.

This concludes today's conference call. Thank you for participating. You may now disconnect.