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] of Vicore Pharma, 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. At this time, all participants are in a listen-only mode. After the speakers' presentation, there will be a question and answer session. To ask a question during this session, you will need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. If you wish to ask a question via the webcast, please use the Q&A box available on the webcast link anytime during the webcast. 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. 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. 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 statement 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. Scott Mullaney 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. To conclude the substantive sessions, 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. Of course, we'll save some time for Q&A, and look forward to that, too. On the next slide is just a very quick company overview. Vicore's a transatlantic company with presence in the U.S. as well as in the Nordics and Europe. We have about $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 and idiopathic pulmonary fibrosis. It really is a core area of our focus at this time. Ongoing phase IIb, as we mentioned. This is a program that was 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 Nippon Shinyaku in an attractive partnership in 2024 as well. Of course, beyond what we're working on 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. I'm going to spend the next 20 minutes or so running through a few updates from the ATS. On my first slide, I start with a reminder of what is idiopathic pulmonary fibrosis. I won't dwell too much. It's a disease that causes scarring of the lung, causes the lungs to shrink down, and it causes the lungs to be less efficient. Not only can you not take a big enough breath in, but when you take a breath in, you can't actually extract all the oxygen that you need. It causes breathlessness, cough, and ultimately death in three and a half years from the time of diagnosis. It affects, well, globally, we're going to go between 20 and 80 per 100,000. The incidence is definitely rising. None of the current drugs that I'll provide an overview 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 three and a half years, and that is worse than most of the common cancers. Yeah, it's a disease that's underappreciated probably in the public field. It's got a high symptom burden. On the right of the screen, you see that. You see shortness of breath, you see fatigue, and you see cough, and other features of aches and joints, and aches and pains. 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. Up until 12 months ago, we only had two. We had pirfenidone, and we had nintedanib, and they've been joined by nerandomilast, with Jascayd. They're all anti-fibrotic drugs, and they all aim to slow down the progression of disease. None of them are aimed at modification or improvement of symptoms. Esbriet and OFEV have been approved now for over a decade. They're all oral drugs, and they all, at this moment in time, have a number of significant side effects. Phase III is coming through. I'll touch on some of the data for TYVASO for inhaled treprostinil and Admilprint from Bristol Myers Squibb. On the next slide, you'll see what I refer to by slowing disease progression. The bottom line on all three of these graphs are the placebo, and that shows the inevitable decline of untreated patients with pulmonary fibrosis. They lose lung function day by day. The anti-fibrotic drugs, and you see pirfenidone, nintedanib, and then nerandomilast on the far right, essentially shift this curve up. They don't stop everything. They slow it down. Statistical methods aside, you can't really compare all of these results. Essentially, we're looking at between about 100 ml and 150 ml difference between placebo and active drug across these studies. My clinical take is that they're all about the same, if you ignore the statistics. They all slow it down, they don't stop it. That's good news, the bad news on the next slide is the side effect burden. We don't have enough real-world data for nerandomilast yet. When you look in the real-world evidence base for pirfenidone and nintedanib side effects, you see a significant burden for patients. That really translates to the fact that patients don't stay on the therapy. Discontinuation rates peak around 10 months. 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's main side effects are GI, and you see here on the left of the screen highlighted diarrhea, which affects a significant number of patients. That's important because in the FIBRONEER study, we see that diarrhea was reported in 40% of the patients that had nerandomilast on their own. 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 rates due to diarrhea itself were relatively low. That's probably reflecting the fact that the patients that were selected into the study already on anti-fibrotics were already tolerating it, and had been on a stable dose. We do wait real-world data for that. Moving on to some of the new data from the ATS. On the next slide, you see the subgroup analysis from the FIBRONEER study. 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 mortality. 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 groups, 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, FVC had to be above 45, and then 50- 70, 70- 90, and then 90 and above. 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. You look at the benefits, you obviously see in the forest plot that at a higher dose, the benefit is clearly obvious, and it seems to, albeit not all of the lines cross the threshold completely. They do all move towards favoring nerandomilast. It looks like nerandomilast is working at all the disease severity subgroups. As you probably would expect, the data for less than 50 is 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-2 data that we see in ERS. Just to remind you, this is an inhaled treprostinil drug transitioned over from pulmonary hypertension studies. They ran two parallel programs, TETON-1 and TETON-2. We got the results of TETON-2, which showed 95 to 100 mL difference between placebo and active drug. Obviously very encouraging. We had the headline press release before ATS, on the next slide, you see the results from TETON-1, which were presented in full. TETON-1 actually showed a much larger improvement with a delta of 130 ml between placebo and inhaled treprostinil. Again, what we see is the adverse events. If you look in the table on the right, you see even the placebo patients were reporting 30% cough, showing us what their inhaler delivery device does. When you put treprostinil in that device, over 50% of the patients had cough. Headache was an effect of the treprostinil, known effects up at 30%. There really was a relatively high symptom burden. While it did meet its primary endpoint, the discontinuation rates were high, and they were 40% in the treprostinil arm and 30% in the placebo arm. Again, that's telling me that the drug has a side effect profile, but also the delivery method and number of times that the device has to be used each day also has fatigue ability for our patients. 130 ml is a positive outcome. Some of the secondary outcomes were positive, too. On the next slide, you can see some of the pool data that was briefly presented. This is obviously the path to regulatory approval, the two independent studies, put them together and you get, as you would imagine, with a 95 ml in one group and 130 ml in another group, you finish out about 112 ml difference between the two. A positive study when you combine it together. When you combine the SAE data together, again, it's about the same as the individual ones. Cough, 50% of the patients. Headache, 25% of the patients on active drug. You're seeing still a significant burden of side effects. 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. In TETON-1, 600 patients, give or take, randomized. In each arm, you see 100 premature 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 to me as a clinician trying to use this clinically. As you know, we do our best to keep patients in a clinical trial. They're very well-supported. These patients had significant coaching, nebulizer, remote help, and everything else, and still we were losing 30% of patients. I think that, for me, is one of the downsides to the data that we saw presented. Probably not unexpected given the PH data and given the TETON-1 data, but now we've seen it in the second study, and we see what the combined results look like. I mentioned that all of these anti-fibrotic drugs just slowed things down. On the next slide, you see the results from the CORAL study, which doesn't try and slow down disease progression. It tries to focus on cough, which is a significant problem. 85% of our patients with pulmonary fibrosis have cough. At the ATS, we presented a number of abstracts looking at nalbuphine. CORAL study was a randomized, double-blind, placebo-controlled, dose-ranging study, looking at three doses of nalbuphine. The study was based on a cough recording at 24 hours at baseline and a cough recording at 24 hours at week six, to see what the impact was on cough counts. What we see in the figure on the left is you see placebo. Just giving somebody a bit of extra care and enrolling them in the study improves the cough by 16%. On top of that, you then see a dose effect looking at the three doses of nalbuphine, which reduce cough on top of placebo by about 50%. On the right, you see the rate of change that this occurs in. We did cough counting at baseline two, four, and six weeks. Actually, for all three doses, the cough counts drop right down by week two, and the benefit is sustained. That's pretty good news for the patients moving forward into phase III. We also presented data looking at the subgroups. These effects were the same over patients on and off background anti-fibrotic therapy. Again, reassuring and informative for the phase III study design. On the next slide, we presented some more exploratory data. We do cough counting, so we look at how many times do people cough an hour. Actually, our patients tell us that cough bouts are important. They'll say, "I cough three or four times in a row. I lose my breath. I can't get my breath back. I panic." Cough bouts are associated with things like urinary incontinence, blackouts, collapse, so they carry a significant burden to our patients. We looked at cough bouts in IPF and also looked at the effect of nalbuphine. I won't get bogged down into the various definitions of bouts, but across all of the definitions, essentially, patients had significant cough bouts. The more coughs you had, the more likely you were to have cough bouts. Actually, nalbuphine reduced bout episodes as well. It reduced the number of bouts, and it reduced the duration of them. Even if it didn't completely obliterate the bout events, it shortened the event time down. 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. I can unashamedly say, given I presented it, people are excited by that data. On the next slide, we haven't solved everything. While it's good news, I think independently I can say we've got nerandomilast now. We're starting to see some subgroup data from that. We've got TYVASO that also looks to work, with side effects and with problems. We've got drugs that are trying to look at symptoms, but we still have a big unmet need. All of the drugs I've presented to you have side effects. None of them stop disease progression. They only slow it down. None of them try and undo areas of early disease. What we've got is drugs that we need to give 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. There's a big unmet need to either reverse or improve or stabilize lung function. There's an unmet need because the drugs are poorly tolerated, whether that's GI side effects, whether that's weight loss, whether that's cough or headache. None of the current drugs are perfect, and combination regimens are not clear. The nerandomilast is the only one that's been studied in combination. nintedanib and pirfenidone don't mix well from a side effect profile. nerandomilast obviously has issues with pirfenidone given the drug-drug interaction. As you see on top of nintedanib, does increase the rates of diarrhea to above 60%. 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 forwards, what have we got to look forward to? We've seen the data for TYVASO. We anticipate the submission second half 2026. BMS, Adempas. That is an oral drug and LPA1 antagonist. They've fully recruited. We expect top-line data towards the end of the year. Going to be watching that one 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, have to have a lying and standing blood pressure pre and post-drug. I think how that lands from an indication perspective is going to be important, presuming the readout is positive. We have Insmed, who have got their TPIP, which is a prostacyclin analog, essentially TYVASO that's once a day. 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, with deuterated pirfenidone, which is going into a phase III study. Quite an interesting study design because they are going to go head-to-head with pirfenidone, no placebo in that one. Phase II, obviously, we are going to hear more from Vicore about the angiotensin II receptor agonist. As Ahmed said, fully recruited ahead of time, congratulations on that. Avalyn's got their inhaled pirfenidone and nintedanib drugs across various studies. Some about to finish, some about to start, all in phase II. Endeavor, with the hedgehog inhibitor, they have finished their recruitment, they are just waiting for their final patient in the 24-week study. Again, probably going to be interested to look at their FVC signal in more than 20 patients, also their side effect profile will be the things to watch out for in the end of the year. Calluna have finished their recruitment, again, waiting for their results. I think they are going to be slightly later, we will get a readout from them next year. Interesting small molecule. Lilly with the WHISPER readouts, which again, will probably be a bit later than AURORA in 2027. A lot of things to look forward to. With that, I think on time, I will hand over to Bernt. Phil Molyneaux, thank you so much. I think really a very nice recapitulation, very clearly illustrating sort of the still unmet high needs in this area, a need for drugs that are better tolerated, be combined with other standard of care, and have improved efficacy. If we go to the design slide of the Phase IIb ASPIRE trial, that is what we are aiming to develop with buloxibutid. We currently have an ongoing large phase IIb randomized double-blind placebo-controlled study. It is a global study. As just mentioned, we have fully recruited, a little bit ahead of schedule, which we are really delighted with. I think reflecting, one, again, unmet need. Patients are keen to go into trials looking for better treatment options. Also, enthusiasm with our investigator. Lastly, certainly, the really strong execution of the entire team working on development of this drug. This study, as I mentioned, is a randomized study. We are randomizing patients across high dose, 100 milligram twice a day, lower dose, 50 milligram, and placebo, randomized 1: 1: 1. Patients can enter on background therapy, a nintedanib or a nerindone malonate, 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. Primary endpoint at week 52 is change from baseline FVC, 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 is a truly global study on the next slide. Patients were recruited across the globe. We're really pleased to see that it's very well distributed across the globe with about 25% of patients in the U.S., 25 across in Europe. Also APAC, Australia, South Korea, and Taiwan, and also patients in South America. What is next for the ASPIRE trial? Next up is a pre-planned futility analysis on the next slide. As part of our plan, our independent data monitoring committee will conduct a futility analysis once about 27% or 100 patients have completed the study. Main purpose of this futility analysis is to protect the patients participating in the study. This is one of the tools that our DMC has to perform their duty in protecting patients and to come to a well-balanced risk-benefit assessment. 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 failed during the conduct of the study because there were safety concerns. We do see this as a meaningful risk mitigation step. The manner in which it will be conducted is set up in order to fully protect the integrity of the trial. 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 conditional power is lower than 20%. Overall, the threshold has been set in a way that on the one hand, we well-protect the patient's safety, on the other hand, also do not stop too early as we know that you do need a large, robust, relatively long study to come to a confident assessment of a drug in the IPF field. We expect to share the outcome of this futility analysis in Q4 of this year. What's after the futility analysis on the next slide? Obviously, we're heading to top-line data readout. We expect top-line data in middle of next year, and we hope, of course, to share those data as soon as possible afterwards. Maybe moving towards some news from ATS on the next slide. As you may be aware, a lot of the enthusiasm for buloxibutid, including that what led us to the current phase IIb is our phase IIa AIR study. This was a single-arm open-label study conducted to assess buloxibutid in patients with IPF, and these patients were treatment-naive 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-naive patients were readily available to enter studies. We recruited patients in India, Ukraine, Russia, and the U.K. If we go to the next slide, you can see that overall, the baseline patient characteristics in this study were, 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. One of the questions we asked ourselves, are these patients very similar to other IPF patients, or could this have impacted our results? We, together with our partners at Qure.ai, 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, do these patients match what we would expect from an external cohort of IPF patients? If you go to the next slide, first you will see the data that I think we all agree are very encouraging in this field. These are the patients that completed the nine-month treatment period. In these patients, we saw a stabilization and even improvement in FVC means over more than 200 ml and even median more than 60 ml in these patients. When we looked at patients by subgroups, I think the main message here is that there was a consistency in signal. Whatever subgroup we looked at, the data tended to be positive, notably, as you can see here in India patients, but also when we look at different types of imaging characteristics or gender. Next we leverage an external data set on the next slide, to compare our AIR trial population to a relatively large external data set. On the left, you see the AIR trial population. We enrolled 52 patients, had 48 patients available with the FVC data, including follow-up. We looked at the entire cohort, but also at the patients from India versus those who are not in India, and compared that with a large external data set, for a large part U.K. patients, but as you can see, also patients from Asia-Pacific and Northern and Southern America. On this 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 eight different sort of graphs, and without going to too much detail, but what you may appreciate is that overall the characteristics are quite similar, particularly when you look at age. When you look at predicted lung volumes, FVC percent predicted, FEV1% predicted, what was different was the absolute lung volume. Absolute FVC, absolute FEV1, total lung volume and this was most likely due to smaller height in the India patients. When we look at the height of patients in India, that was on average 10 centimeters less than the patients not from India. When you look at percent predicted data, then the height is one of the larger variables that is sort of taken into account to come to percent predicted, and then indeed you see the percent predicted are very much sort of in line. We did see somewhat more fibrosis in the patient 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 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 the most meaningful is actually on the right. Our initial question was, are these patients representative of the larger global IPF patient? There we did Isomap, so we reduced these variables to two components, and there you can see within those larger cloud of IPF patients from an external cohort across the world in blue dots, you can see that the AIR patients, both from India and not from India, sit well within this distribution. I think really emphasizing that these patients are representative IPF patients. Third, I think supporting our confidence that what we see in AIR is representative and that we hope, of course, to confirm that in the current phase IIb study. With that, I'm concluding my little section and handing the work to Ahmed. What we have here is an agonist of the AT2 receptor, which is shown in orange on the right-hand side of the schematic. This is an intervention vasodilatory effect, an 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, which are AT1 antagonists or ACE inhibitors, which deplete the available ligand, angiotensin II for the AT1 receptor. One of the reasons why we're so excited to advance this intervention point for pulmonary fibrosis in particular is the high expression of the AT2 receptor, including constitutive expression of this receptor on a precursor cell called an alveolar epithelial type 2 cell. On the next slide, we talk a little bit about what these AEC2 cells do in the lung and the kind of key functions are basically differentiation or replenishment of type 1 epithelial cells or AEC1 cells. These are the workhorse of the lung. They're responsible for gas exchange, so oxygen coming out of the alveolus or the air sac, diffusing across the interstitial space into 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 alveolar integrity. So it addresses the surface tension associated with water to enable the alveolus to maintain its confirmation and ability to participate in gas exchange. On the next slide, we look a little bit at what happens in IPF on the left-hand side, and on the right-hand side, what we believe buloxibutid does in relation to these pathological processes in 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 in IPF known as pre-fibrotic alveolar collapse. In addition to that, you have damage to the type 1 epithelial cells, the gas exchange cells, and an inability to replenish them because the type 2 epithelial cells have also become injured. Even ahead of fibrosis, the key message is there is epithelial injury that we believe is quite relevant to this disease process. In addition to that, you have the kickoff to the fibrotic process as a response to this injury, and that is highly mediated by the type 2 epithelial cells. They are one of the main secretors of TGF-beta and other pro-fibrotic cytokines. These pro-fibrotic cytokines drive a phenomenon known as epithelial-to-mesenchymal transition, so more fibroblasts building up. The fibroblasts become activated. They start moving into this interstitial space, which is the space around the alveolus between the pulmonary vasculature. They become activated and begin depositing collagen in that interstitial space. This is what drives a physical barrier to oxygen diffusion, as well as essentially an encroachment on the alveolus and the overall lung, what ultimately impacts the forced vital capacity, which is the regulatory endpoint in IPF trials. In addition to this buildup of fibrosis, you also have the fibrotic matrix build putting pressure on the vascular compartment. 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. That injured pulmonary vasculature also drives TGF-beta1 release. There's more pro-fibrotic factors in the disease that are coming out, not just from the epithelium now, but also from that endothelial compartment. I would say the main message from Vicore is that IPF is a disease that has an alveolar compartment injury, a fibrotic build in the interstitium, and a vascular dysfunction, and all three 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 AT2 receptor, which we believe, and based on preclinical data, have shown drives a reproliferation of the type 2 alveolar epithelial cells. This can allow for a differentiation and 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 phenomena of prefibrotic alveolar collapse. One of the key pieces in relation to that second kind of compartment, that interstitial compartment and the fibrotic build, is that we 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 pro-fibrotic 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 stop a current fibrotic build, and it does that by upregulating collagenase matrix metalloproteinase expression. You have the ability to resolve fibrosis that's 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 angiotensin II pathway, quite easy to understand that it's a vasoactive mechanism. It drives a local vasodilatory effect. 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 TETON-2 results, a vasoactive drug has shown certainly the ability to have a potent impact on FVC, and we do believe that we have a similar potential as well. If we take this mechanism to some of the recent data sets, on the next slide, we look in particular at MMP13. MMP13 is one of these collagenase matrix metalloproteinases, these enzymes that digest fibrillar 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. You'll see this in the bottom left-hand quarter, 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. In the MMP13 knockout mice, it's much more significant, and that is a result of the inability to have that resolution of fibrosis mechanism built in. What we observe in our phase IIa study in the blood biomarkers of the patients is the significant upregulation of MMP13 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. On the next slide, we also made some very interesting observations when we ran some RNAscope experiments. These are experiments where you can localize the RNA expression of different proteins. 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, surfactant proteins are exclusively produced by that cell type. What we observe is that when you also look for MMP13, you find that there's a significant upregulation of that MMP, in particular, out of the type 2 epithelial cells directly. What we observe here is really nice evidence that the signal that we're seeing in our peripheral biomarker, that upregulation of MMP13, a nice evidence that 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 alveolar epithelial type 2 cells. Also the cell type that we believe is one of the key linchpins to this disease, the one that really, by becoming injured, coming into that senescent state, really driving a lot of the fibrotic process as well. This was really nice 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 in. This is a model that replicates pulmonary vascular disease, a compound known as Sugen 5416, is deployed along with hypoxic conditions. This then actually simulates pulmonary hypertension by causing that hyperplasia and metaplasia in the vascular compartment in the pulmonary architecture, as well as then driving the common follow-on effects of pulmonary hypertension and pulmonary arterial hypertension. In animals that are subjected to these conditions, first the Sugen and then the hypoxic 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. 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 reduced mean arterial pressure as well. Now, when you look at what buloxibutid is able to do after the onset of disease, you're able to decrease the right ventricle size, reduce the pressure, both in the right ventricle as well as pulmonary arterial, and increase the cardiac output, which is really nice to see and is a nice signal that this is a drug that highly relevant for pulmonary hypertension. Again, recognizing that vascular dysfunction is a key part of IPF as well, a really nice sign that we can impact that axis of the disease as well. On the next slide, one of the really nice outputs of this study as well is looking at the impact of buloxibutid on vessels of different sizes in terms of both wall thickness and luminal opening. 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 hypertension associated with interstitial lung diseases, tends to kind of afflict a broader range. 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. What's really nice to see also is while the impact on luminal opening might seem modest in terms of a percentage, these have outsize and nonlinear impacts on the ultimate pulmonary arterial pressure. Signals that are really nice to see. As might not be surprising, 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 injure the pulmonary vasculature, it will start pushing out pro-fibrotic factors, right? This is what's causing, 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. Again, showing that buloxibutid is able to essentially address that endothelial or vascular sourced pulmonary fibrosis as something that is additional and exciting to the ability to impact epithelial origin fibrosis as we observe in bleomycin models and other models where we show the effect of buloxibutid as well. Two really nice preclinical experiments that kind of show what we believe is the effect on the epithelial compartment as well as the vascular compartment. We're really excited to do that at ATS, and it drives further conviction in this mechanism of action. Yeah, thank you everyone for joining. I'm really happy to move to Q&A now. Thank you. We will now begin the question and answer session. If you wish to ask a question, you will need to press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. If you wish to ask a question via the webcast, please type it into the box and click submit. We will take our first question. Your first question comes from the line of Steve Seedhouse from Cantor. Please go ahead. Your line is open. Yes. Hi. Thanks so much for hosting the call here and for taking the questions. Had a few I want to hopefully get through here. First, just briefly on the futility analysis later this 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 are neither of those possibilities here? Relatedly, is there any chance of initiating phase III early based on the outcome of the futility analysis while we're waiting for the final data in the study? Yeah. Bernt, why don't I have you address that one? Yeah. Thanks, Steven, and thanks for asking that. As I mentioned, we see the futility analysis mainly as a safety guard rail, but it is, of course, looking at FVC. FVC is the measure by which futility will be assessed. That means that if there is truly no effect, or I think better said, a detrimental effect on FVC, so there's no efficacy, an absence of efficacy or harm on FVC, then there will be futility. The futility will not serve as a sample size re-estimation, the futility analysis will not lead to any resizing in that respect. Similar, it will also not be used as an accelerator, for example, for phase III, we will need a complete data set from phase II to do so. I think one of the reasons is, I think it's well doable to de-risk 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 field, to do two short, two small studies. We are conducting, I think, a very robust, relatively large, long study. That answer will give us a confident assessment of the buloxibutid treatment effect and will help us to de-risk transitioning to phase III, but also, of course, will inform us how large the study will be and many other of the aspects. Perfect. Thanks for that. 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 Pharma, do you expect any combinatorial efficacy or conversely, any unwanted combinatorial adverse event signal for buloxibutid with any of the newer or legacy IPF therapeutics? Yeah. Shall I comment on that as well? Our overall plan, of course, is to develop buloxibutid as a broader treatment for a patient with IPF. We think that the treatment landscape, and maybe Phil can comment on that in a bit as well, will move for a large part, in the end, to combination therapy. The drive to give combination therapy is currently limited by tolerability, right? That is, I think, the gating item. We think that buloxibutid will be well combinable with several standard of care. We're 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 we'll allow different types of standard of care as background in phase III, I think that's an item of ongoing discussions. We are actively exploring how to do that as broadly as possible. Again, thinking that 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 one of the biggest obstacles. Yeah, I suppose if I come in on what will standard of care be, the answer is we don't know. I can speculate. I've already shown you data that the first two anti-fibrotic drugs aren't well-tolerated, and people aren't staying on them for 12 months. 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. 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 that nintedanib or pirfenidone, you can take your choice. I feel that they will be added in a world with buloxibutid and that appears to have a relatively good side effect profile apart from the postural blood pressure. Take that out of the equation, then you've potentially got two drugs with specific pathways that may go together. That would be how I would see it. 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. Actually being on one drug, one drug, or another drug actually probably doesn't affect your power calculations too much. When you think about patients who are on combination therapy, they're often patients who are already declining more rapidly. 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. I don't see the phase III landscape becoming much more complicated. That's great. Thank you. Last question from me, just going back to AIR, and appreciate the work you've done, obviously, to show the demographics there are pretty comparable to the external controls. That's pretty helpful. 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 ascertainment or the measurement of FVC different in AIR compared to what it will be ultimately or what it is in 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. Yeah. Not substantially different, right? AIR was also centrally overread spirometry. I think we have learnt a little bit in driving high quality in spirometry, not just we as a company, but we as a field. ATS standards have been updated. They have been taking some time to percolate into actually study execution. I think we sort of developed another tool to drive spirometry quality. That's, I think also a necessary component when you do such a large global study. Also AIR was sort of essentially an overread study. I think one other component that we learned from AIR is that we were ambitious to get a lot of data, so we had spirometry data every two to three weeks in the beginning. That sort of wasn't, 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 clinic so many times, particularly because this study was run during COVID. It's also, in the end, not very patient-friendly and we have adopted, I think, a better balance in clinic and phone visits in our current study. Sure. Thank you so much. You're welcome. Thank you. We will take our next question. Your next question comes from the line of Vamil Divan from Guggenheim Partners. Please go ahead. Your line is open. Great. Thank you so much for hosting this and for taking our questions. I think I have two, if I could. One, for the company, just in terms of the ASPIRE trial, I think you did resize that a few months back, and I believe at that point you were saying it was sort of based on what you saw from TETON-2 and to kind of use that as a guide in terms of what sort of FVC grouping you'd want to see in ASPIRE. Now TETON-1 has come in with a little bit of higher results on FVC. I'm just curious how, just in general, how you're thinking the TETON results and what you know, data shown there, how that impacts what you need to show in ASPIRE and sort of how we'd be able to interpret the results. The other one for the doctor there, if you could just maybe give your perspective in terms of what for both ASPIRE and the other things that are in development. Obviously, a lot of unmet need in this space. Just trying to get a sense of if you had to pick one, what is your sort of top unmet need you're looking to get addressed by these products of 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 a greater efficacy even if the side effect profile for some of these might be similar to what we got from the current therapies? Well, let me jump in. Yeah, of course I mean, the problem with both of the current drugs is that they don't affect lifespan because people aren't on them long enough. I'll take a drug that's better tolerated with the current rates of change of FVC. If you can be on a drug for five 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. I think if you give me a better side effect profile, same FVC, happy. If you give me better FVC signal and worse side effects, I'm still happy because my patients will take that incremental improvement. No, thanks, Dr. Molyneaux for the answer. It was actually a great dovetail to Vamil, your first question, because I think that one 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 mentions. From that perspective, looking at powering our study 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 nine months, but is also part of a larger database where over 350 either healthy volunteers or patients were subjected to buloxibutid treatment. We have a really nice overall picture on the tolerability profile for that development to date, 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. It 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. Certainly that was really highlighted to us as we observed before we decided to increase the study size. We saw the FIBRONEER study readout. It was about 70 milliliter difference in lung function between the treatment arm and the placebo arm at 52 weeks, as well as the TETON-2 study, which showed a 95, 96 milliliter difference in lung function between the placebo arm and the treatment arm at 52 weeks. I think, Vamil, what you're kind of hinting at is the TETON-1 study showed an even kind of better numerical difference between placebo and treatment arm. I think the one caution that we'd make, of course, people naturally look at these different results and look at comparing them. Because of some of the differences in the studies, including differences in statistical methods, I think that most individuals, and I think Dr. Molyneaux mentioned this as well, in the field are seeing these as relatively similar from an efficacy perspective. 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 in FVC holds quite true. We're very excited to see how the therapy works in this larger trial. Okay, thanks again for hosting this. Thank you. Thank you. Thank you. Once again, if you wish to ask a question, please press star 11 on your telephone. We will take our next question, and the question comes from Arvid Necander from DNB Carnegie. Please go ahead. Your line is open. Good afternoon, and thanks for taking my questions. I have a couple of questions for Dr. Molyneaux, if I may. First off, on the outcome in Asian versus Western patients. Disease progression is, or the disease course is obviously not well documented in the Indian population. I was just wondering whether or not you have picked up any emerging evidence, case studies, or clinical experience that could point to a differing disease course, compared to Western patients. Secondly, on buloxibutid in the treatment algorithm, just sort of acknowledging the tolerability challenges here discussed for the standard of care antifibrotics. How would you think about the trade-off between buloxibutid monotherapy and buloxibutid together with background standard of care? I guess more specifically, what magnitude of incremental efficacy 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? Understand, of course, that it's hard to judge ahead of data, it would be interesting to hear your thoughts on this. I'll start there. Thanks. Okay. The first part is easier. I think what we're seeing from IPF is that IPF is IPF around the world. You did see 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 subcontinents for specific trends, but we haven't seen any areas where FVC signal is an issue. That doesn't worry me, and I haven't seen anything from an Indian subcontinent perspective. From a where do I see this? That's a difficult question to ask without data in front of me. I would tell you that 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. 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've persevered with it because we didn't have an option to switch. I think in any patient who was tolerating a drug, if there was another one 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 one because we don't have any specific evidence that I can pick one over the other. Any change incrementally that is well-tolerated is a positive outcome, in my mind. Great. Thanks for that, Dr. Molyneaux. Just a quick follow-up on that one, and I guess you touched on this, but more broadly, how manageable do you consider the side effects seen with standard of care to be in clinical practice for an experienced physician? Yeah. How much do you believe the continuation rates in the real world differ from what's seen in clinical trials? 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 my clinical practice, the discontinuation rates are probably not as high as elsewhere, but they're still very high. I can't give you exact numbers, but even with the best centers in the world, the discontinuation rates are still high. What we're not seeing is people persisting out past 12, 24 months. When you think about we want patients to live longer, if you don't take the drug long enough for the FVC impact to having a knock-on effect on survival, that's the issue that we're facing at this moment in time. Our clinical trial is built on the premise that FVC decline predicts mortality. The counterargument is that slowing FVC decline improves mortality. If you're not on a drug long enough to slow decline, you can't improve mortality. Great. Thank you so much. I'll jump back in the queue. Thank you. There are no further questions from the phone lines. I would like to hand over for any webcast questions. Great, thanks. We got a 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 will be limited to two questions. Let's start with the first one, which comes from Dan Akschuti at 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 buloxibutid? If yes, which and to what extent? Yeah, it's a great question, Dan. Generally speaking, there was some level of skepticism 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, right, the vascular dysfunction driving further pulmonary fibrosis is a key part of that pathology. When we look at buloxibutid in the Sugen-Hypoxia model as an example, and this is a model where also treprostinil has been tested, we are really enthusiastic about from the mechanistic axis, the ability for buloxibutid to drive a strong level of effects on this domain. Ultimately, wherever the pulmonary fibrosis drive is coming from, whether it's coming from epithelial injury and dysfunction or endothelial or vascular dysfunction. Ultimately, both of those are going to drive that interstitial fibrosis, 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 this can have a really potent effect. That makes us quite excited, and we do believe that there is some mechanistic read-through there. Great. Thanks, Ahmed. Maybe Phil could best address the last question. What is the ceiling for IPF efficacy when older patients still lose FVC due to aging? It's a good question. You do lose lung every year as you age, there is somewhat of a ceiling effect. We're nowhere near it. I think there's an upcoming piece of work that will be out in the next few months, looking at this in aging adults, comparing it to IPF. There's room for maneuver, there's room for improvement, and we're nowhere near healthy aging. What you have to remember is we've got our untreated patients in there, we see what the difference is to untreated. We see what normal aging is in real life, and it's nothing like what we see in IPF, there's a lot of room to maneuver. I think, what are we looking at? 15 ml-30 ml, if you're going to put me on the spot. That's an average. Yeah, 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. 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