Good morning, and welcome to the Vicore Pharma program update. At this time, all attendees are in a listen-only mode. A question and answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. As a reminder, this call is being recorded and a replay will be made available on the Vicore website following the conclusion of the event. I'd now like to turn the call over to Carl-Johan Dalsgaard, Chief Executive Officer of Vicore Pharma. Please go ahead, Carl-Johan. Thank you very much, Tara, and welcome to this webinar, where we're going to present the interim analysis number two of the AIR-IPF trial. We're pleased to share this strong data with you. It's really an exciting data set showing that we have a stabilization of lung function already at week number six, following treatment. This is followed by an increase from week 18, and onwards in lung function. This is really unprecedented data. I think since we last did the interim in February, it's been also a challenge to perform an IPF trial, and that's basically to go on as normal with recruitment and retention. There's basically three reasons for that. One is COVID, the second one is fear of COVID, and the third one is the war in Ukraine. Ukraine and Russia is normally very good recruiting sites in studies like this. COVID we thought was over with, but we actually had, during spring, two cases of COVID that of course caused dropouts in the trial. Despite this, I think we have a very successful trial that give us really the confidence to take the next step to develop C21 for IPF. I'll be happy to start this call. If I can have the next slide, please. To go through a little bit about the receptor, about the uniqueness of the approach that we're taking based on preclinical and clinical data, and the mode of action that is so specific for this approach that also resonates well with the data that we see here. Then I will be joined with. by Rohit Batta, our CMO, who will guide you through the study and the outline of the study, and then by Professor Toby Maher, who will review the data, and then we will have the Q&A session. Can I have the next slide, please? The target that we have, the receptor, is the angiotensin type two receptor. If I can have the next slide. First of all, the renin-angiotensin system, why do we really have this? It's a system that is there to protect us. It's conserved in evolution, and it's dating more than 400 million years back, and it's really essential for survival. Not only does it monitor fluid and tissue homeostasis, but in acute situations and emergencies, it prevents blood pressure drop, when you have a big bleeding. Not only that, it also kicks in to help the body to regenerate and repair. That's really where our agonist is functioning. That's also why we believe that this is an important mechanism in IPF. Can I have the next slide, please? Now, the two types of receptors that we deal with when it comes to the angiotensin system. Angiotensin II is the mother molecule that activate the Type 1 receptor. That's the rescue part, that's the blood pressure part. The Type 2 receptor is activated both by angiotensin but also by down or degraded products from angiotensin itself. That then later on kicks in the resolution. It's an inducible receptor. C21, the little molecule you see there, is acting as an activator of this system. To the right, we have the difference between the two. Again, the AT1 is increasing the blood pressure. The AT2 then is there for repair, but also to dilate small vessels, making sure that the blood reach the area where needed for regeneration and repair. Here we have the new class of drugs, the ATRAGs, that are agonists to this receptor, that is activating the system in the body. I think the beauty with ATRAGs and the system is that it is really precision pharmacology. Precision pharmacology by nature is not something that we have done. We're working with agonists, which means that we're stimulating something that we want to be done. We're not blocking mediators, receptors or enzymes throughout the body. The receptor is upregulated, so it's only really present when needed. It's not constitutive, so it doesn't bring us non-selective effects or pharmacological effects that we do not want. Also thirdly, it's a hit and run. I know this may not be a good word in English, but it's a well-known word when it comes to receptor pharmacology. We have a short exposure, so it's the Cmax that is important. We activate a system. We have a short exposure over time, which means that we have a reduced risk for drug-drug interactions and adverse events. It's really an ideal concept for pharmacological treatment. Can I have the next slide, please? The next one, I will go through a little bit of the preclinical data. I will not go into too many details. The next slide, please. We have data for C21 in the relevant gold standard models, the bleomycin model in rat, the monocrotaline model, which is a model of both IPF and pulmonary arterial hypertension. They're very much alike in many ways. Finally, the Sugen hypoxia model, which is a pulmonary arterial hypertension model, which is maybe the most disease-like model of these three because you have a destruction of the endothelium and you expose the animals for hypoxia, which induces the changes that you look for. We can, in summary, in all these models, see that we have a reduction of the lung fibrosis that's been looked at with histology. We have a remodeling of pulmonary vessels, which I think is a little bit more unique among the IPF drugs. We know that IPF patients, they do have hypertension in their lung system as well, and also in small vessels. I think that could be an important and contributing factor to the effects that we are seeing and certainly important for IPF. We do see a reduction of the cardiac remodeling that comes as a consequence of the increased pulmonary pressure. We see then also, of course, a reduced pulmonary hypertension and an increased cardiac output. Everything that we would like to see with a treatment like for IPF, we see with C21. Models that I think may be a little bit more relevant in a way is the human ex vivo model. We have used the human precision-cut lung slices, which means that patients that are undergoing lung transplant will have their one of their lungs taken out and pathologists will cut out a piece of the lung that is representative for the disease, and then that is cut into smaller pieces and kept in tissue culture or in cell culture as an explant, and you can then test your own drug in the system. We can look at biomarkers of fibrosis processes. We have in those models a very dose-dependent and significant reduction of TGF-β and also collagen I that we look at regularly. We know by testing the other molecules that we are developing for the type II receptor that this is a pharmacological effect. We see this for all of them. I think also, which is important when you're dealing with models, is that we see it in clinically relevant concentrations. We've also co-cultured the primary airway epithelial cells together with fibroblasts and can see then also significant reductions of TGF and collagen and in vitro markers of ongoing fibrosis and even fibrolytic enzymes. These results are consistent with both the animal models, but also I think important for understanding the effects that we see in the clinic. If I can have the next slide, please. The PK profile. You can see that we have a fast uptake and a fast Cmax concentration maximum, and then also a fast elimination. This is now again the hit-and-run effect. We have a linear pharmacokinetics which means that if we double the dose, we double the exposure. We're activating the receptor, and we have a low exposure over time. As you can see, after four hours, there's basically nothing left from the 100 mg dose and that means that the rest of the day you're not exposed to this drug. You don't need that because the effect is already taken care of in the first half hour. We have also done extensive cardiovascular examination of healthy individuals, including 24-hour ECG that has been monitored and looked at by a certified cardiologist, and there's really no findings on the cardiovascular scene. All in all, it's been well-tolerated, safe, in now three Phase 1 studies and also then in 1 P hase 2 and 1 Phase 3 COVID-19 trial. The safety profile I think has it's very good for a pharmaceutical drug. Can I have the next, please? In summary, we have strong data in multiple preclinical models, all of them. We're targeting, we're going for, of course inhibiting the fibrosis and also we're targeting the vasculopathy. What we're not really showing here today is that we have demonstrated very nice effects on human vessels with nitric oxide re-release and vasodilation, which is of course important in the endothelial dysfunction situation. These patients do have endothelial dysfunction as well. We have an oral administration and we have a very good safety profile so far. If I can move on and have the next slide, please. Coming now to the more critical part in terms of why the C21 and the ATRAGs play an important role here and the mechanism of action and what's behind our successful results in the clinic, because I think it really sticks together in a good way. If I can have the next slide. Coming back to what IPF really is. It is a disease where there is a insufficient repair of the alveoli, which then leads to a scarring process. I think that's now been very well established in many different models and laboratories, and it's been now covered by a number of reviews. To the left you have a normal alveoli, the little bubble where the gas exchange occurs. You have two types of cells. Funnily enough, they're called type one and type two, or alveolar epithelial cell one or two. The type one cell is the cell where the gas exchanges occur through the cell. That's where the oxygen goes to the bloodstream and the carbon dioxide comes off. The type two cell is a progenitor cell that proliferates and differentiate into type one cells, because there is a constant exchange of type one cells. I think that's very much because of things that we inhale, vapors, and there is a constant repair of the alveoli. To the right then, when this type two cell is dysfunctional, apoptotic or senescent, the healing doesn't really occur and there is a disturbance or a destruction of the integrity, which then triggers a scarring process. Buildup of extracellular matrix, fibroblasts turn into myofibroblasts. You have all these growth factors and factors released and driving the fibrotic process. This is really now the trigger and the senescence of the type two cells has really been pointed out as a very important piece in this disease. Now, if I can have the next slide, please. When you look at RNA in single cells from the lung, you will find that you have a high expression in these very type two cells that are responsible for healing and repair of the alveoli. It's even more expressed in the IPF situation, but as you can see, even in the control situation, there is a continuous repair ongoing, and we will have that expression. It's one of the only places in the body where we actually have expression of this. The other place, under normal circumstances, is the endometrium. We know in other disease it increases, when you get into, for instance, fibrotic kidney disease and IPF and so forth. Now if I can have, the next slide, please. This may be a little bit of a busy slide, but, we wanted to show here that in the lung, and if you look at the upper left, you have six pieces of tissue, where we have exposed them to, radioactive angiotensin II. So the parent molecule that binds the type one and type two receptor. With the radioactivity we can label, receptors and receptor binding. When we give a, type one receptor blocker, a blood pressure, drug like Valsartan in excess to this, exposure to the, radioactive angiotensin, nothing happens. It means that the type one receptor is not really present here. The binding of the angiotensin II is actually to the type two receptors. When we then give C21 that binds to the type two receptor, we completely block the angiotensin labeling here. Which means that interestingly enough, in the lung there is primarily type two receptor. And we can demonstrate that with radiolabeled angiotensin. What we then also have shown is below there that we can radioactively label C21, and we will have a very nice binding to the tissue in clinically relevant doses. And this binding then could be displaced with cold or unlabeled C21 showing specificity. We have played around with cold and radioactive C21 angiotensin and different other binders. We know that we have a true target engagement in the very right tissue in humans, the human lungs. Then we can do displacement curves, and we can look at concentrations that are completely activating the receptor. It's clear that the concentration is really hitting the clinical Cmax where you have this starting point for this displacement curve, which is really encouraging. Now we're also comparing all the new molecules with C21 so we can get a full picture of how these compounds work. As I mentioned before, the human precision-cut lung slices, those experiments we look for a few days, both we can look at both protein and we can also look at the mRNA expression levels. We have robust effects on reducing the mediator then the TGF-β and also collagen, and we do that repeatedly and also for all the new compounds and even now in other tissues, other human tissues. This kind of ties the story together for us. If we can go to the next slide, then I can just will summarize the situation. That is that the type two cell is important for repairing the injury that otherwise would lead to scarring in IPF tissue. It is actually that very cell that carries our receptor that is a regeneration repair receptor. By doing so, it can stimulate the alveolar to maintain the alveolar integrity, which we think is a very important mechanism for dealing with the disease IPF. That's why we believe we can stop the disease. But it's also why we believe we can cause even maybe not tissue regeneration, but a functional regeneration of the capacity that the lung has that has not completely been destroyed by fibrosis, which can then translate into an increased FVC over time. I will stop there and hand over to Rohit Batta to go through the details of the IPF trial. That's great. Thank you, Carl-Johan. If we go to the next slide. IPF patients have a poor prognosis, and the disease naturally progresses, which is a scary proposition. I've heard Toby describe IPF as the lung equivalent of Alzheimer's disease, where the lung is aging much faster than the rest of the body. This 240 mL much faster decline in FVC. This has been demonstrated in numerous studies such as the INPULSIS trial. We designed the AIR study based on that by carefully applying a historic arm, and you can see that in the graph. The green is the lung function decline of an untreated group. The yellow is the likes of pirfenidone or nintedanib, which half that decline. However, that sort of juxtaposition to the quality of life as one of the largest challenges with these approved antifibrotics is the GI intolerance, because up to 70% of patients suffer from it, and about a third discontinue or take suboptimal doses. Now, the orange space there is our C21 target, demonstrating better efficacy and demonstrating better safety, and that's how the trial was sort of designed to assess these outcomes. Now, just to highlight, this only works if you've actually confirmed that you have IPF patients in the trial. At screening, the historic scans were sent to the U.K. to be read by a professor of radiology specializing in ILD, and that's critical, really. The second aspect is that you have a tight control over the spirometry. Patients came frequently over the nine months to the clinic, and actually in the first three months it was every fortnight, which was, you know, quite burdensome at times. We also contracted the market leader, Clario, to centrally overread the data to ensure that we have this high quality data. Thus we were able to conduct this trial as an open label trial and remove that placebo lottery, which actually helped aid recruitment and we're very pleased with the progress that we've made. The AIR study is an ongoing multi-center trial. The target is 60 subjects and the primary endpoint is safety. We have an independent data monitoring committee in place. According to the charter, they've had three meetings now, and reassuringly, there's not been any safety signals identified by them. The primary efficacy endpoint is the FDA preferred change in FVC, and the eligible population was treatment naive. The reason being is that, you know, in this early proof of concept study, we wanted to firstly fully characterize what C21 does in monotherapy so that we get a clear go, no go signal. We go to the next slide. On that note, we're thrilled to present the latest interim data set for the 45 subjects that have been enrolled. Here is the baseline overview and the demographics and clinical characteristics are very similar to other IPF interventional studies that have enrolled based on that HRCT central reading. The mean age is 67 years, which is not surprising. It's predominantly male, and the mean time since diagnosis was 0.6 years, which is reflective of a untreated population. Now, the HRCT usual interstitial pneumonia, UIP pattern, helps radiologists determine the certainty of diagnosis. A typical pattern has honeycombing, and that's the result of a progressive fibrosis. The probable, you have honeycombing is absent, but you have other distinguishing features such as traction bronchiectasis. It is thought that the remodeling process appears to be a continuum from traction bronchiectasis to honeycombing. The split in this study is fairly similar to other published studies. These patients had impaired lung function, as you'd expect. The mean percent predicted FVC was 76.8%, very close to the pooled INPULSIS, which was 79.5%. They didn't have an overly obstructive picture. The FEV1 FVC mean was 0.8, which is good because a large amount of coexisting emphysema can actually impact the serial FVC endpoint. If anything, you know, the most recent recruitment has put sort of the patient base very close to sort of what we've seen in trials like the INPULSIS studies. If you go to the next slide. Here is the patient disposition. We enrolled 45 subjects. 18 are ongoing, 18 discontinued, and nine completed. Let me drill down into the 18 that discontinued. I think firstly and foremost, as Carl-Johan Dalsgaard mentioned, moving forward for the next study, we will certainly try to avoid a global pandemic and also screen patients' relocation plans. Because collectively, COVID and the fear of getting COVID and logistical reasons of moving homes, you know, that contributed to 50% of all discontinuations. That's totally understandable. I mean, we enrolled our first subject in November 2020 at the height of the pandemic, and actually in January 2021, you had the highest number of daily deaths due to COVID, you know. We were asking patients to come in frequently. Let's look at the adverse event withdrawals, and there were six. Five of those were actually not related to IMP. Again, three of those out of the 6, 50%, was associated with COVID-19. In terms of the subjects that met the withdrawal criteria, just to first highlight that, you know, IPF patients when they suffer, you know, the cough, it's incredibly distressing, disabling, and has a major impact on quality of life and the spirometry. Two of those subjects really struggled to perform the spirometry due to the cough, and then the other one actually got bronchiectasis. Overall, we didn't see anything discerning here. Can you go to the next slide? A question you might ask is, "Well, where was each of these patients in terms of their IPF progression and change from baseline in FVC?" Here you have a nice visual of the last data point for each subject. Yes, there, you can see there's one subject there who's a rapid decliner, which again is not uncommon in IPF. Overall, you have this positive upward trend. You know, recently, I heard a patient advocacy member describe IPF as a one-way street, and a very short street, but perhaps no longer now. Before I hand over to Toby, I just wanna say a heartfelt thank you to the amazing study team because it takes a small village to actually do a study like this, and also a big thank you to all the patients that participated. Over to you, Toby. Thanks, Rohit. Hi, everyone. Thanks to the Vicore team for inviting me. I will apologize, I've lost my voice, so, hopefully you'll still be able to hear me. It's also a little bit early in the morning here in California, so I've not had a chance to warm it up either. Anyway, Rohit has done a nice job of introducing the study. I think he made some key important points there that the patients were adjudicated by central screening of the CT scan, and that's important because we know that these patients are comparable to those that we've seen in other IPF clinical trials. I think the other important point has been the central overreading of spirometry, which again has tended to be the gold standard in the last decade for late phase IPF clinical trials, and again, adds some confidence that the readings we're seeing are comparable to other late phase clinical trials in this space. This here is the analyzed data at the interim performed after 45 patients. You can see for yourselves the shape of the data. This is, I believe the observed FVC at each time point, and you can see the N numbers at each time point available for analysis. I think you can appreciate that over the first 16 weeks, when the majority of patients have provided readings, there does appear to be a genuine stabilization in FVC. Beyond that point, obviously the numbers become smaller, but there is this tantalizing improvement in FVC seen in patients who've completed visits beyond the 16-week time point. Additionally, on the graph, you've got the trajectory that we would expect for FVC for patients with IPF, based on historic data from Phase 3 studies. Again, if you look at the IPF literature, you will find that the placebo group in Phase 3 studies have tended to behave fairly consistently, losing somewhere between 200-260 mL of FVC over 12 months. Albeit this is an open label study, the stabilization over 16 weeks is quite striking, and the improvement, as I say, beyond 16 weeks is fascinating. I hesitate to read too much into it at this stage, but it is certainly thought-provoking. I can have the next slide, please. You’ve sort of been shown some of this data already, but this is providing additional context. The background slide, the black lines on here, come from a study that I ran with colleagues at the Brompton and Imperial College a few years ago where we had patients perform daily handheld spirometry. We had them measure their FVC every day for 18 months. The black lines represent the disease trajectories for each individual patient based on their daily FVC. From that data, we see that small proportion of patients with IPF do show FVC stability over a year, and that number is probably about 8%. Furthermore, we see that a larger proportion, about three times as many patients, have rapidly progressive disease and lose 50% or more of their FVC over that first 12 months. We see that the median FVC loss, and none of these patients were on antifibrotics because the study was conducted prior to the availability of antifibrotic therapy. The median FVC loss was about 11%. Superimposed on that in orange are the data for the patients who completed 36 weeks of treatment in the AIR study. You can see that the distribution of disease trajectory is quite different from our historic cohort from the Brompton. In theory, these patients are very similar. They're all untreated with antifibrotic therapy. They all have a centrally defined diagnosis of IPF. If we were watching the natural history of the disease, you would expect the orange group to better match the black group. Again, providing some confidence that what we're seeing in this open label study represents a genuine treatment response. If we can have the next slide, please. I think Rohit alluded to this in his introduction. This is looking now at the individual disease trajectories on treatment in the AIR study over 24 weeks. This is a slightly larger number of patients, 22 of them. On the left-hand side, you've got all of the patients in the study with data out to 24 weeks. On the right-hand side, you've got separation of that data into patients who've got what is considered by the current American Thoracic Society, European Respiratory Society guidelines as either typical or definite UIP, which is to say they've got honeycomb destruction of the lung. These are patients with more advanced architectural destruction of the lung with loss of abnormal functioning alveolar units. On the top panel on the right-hand side, you've got the patients with probable UIP. That is to say that on their CT scan they have clear evidence of fibrosis in the pattern that we expect to see for patients with IPF, but they lack the honeycomb change. In some ways these are patients with better preserved lung architecture in whom the fibrosis has not necessarily entered that sort of terminal phase of the disease. You can see that the treatment responders, the patients who show the striking improvement in FVC over the 24 weeks of the study, predominantly tend to lie in that group of patients with probable UIP, which raises the hypothesis that maybe treatment is most effective when you've got more preserved lung tissue for the drug to work on. If we can have the next slide, please. This is just moving on from the efficacy is the summary of adverse events. Again, this table just tries to contextualize what has been seen in the AIR study. Here you have the first two columns on the left are lifted from the INPULSIS trial, the pivotal trial of nintedanib in patients with IPF that led to the regulatory approval of the drug. This just shows the proportion of adverse events by category for patients who were on nintedanib, but also importantly on placebo. This just provides a bit of background context, given that AIR is open label and we therefore don't have a comparative placebo group. It's worth remembering, of course, that INPULSIS was over 52 weeks, so there was a little more time for adverse events to accumulate. We are looking at proportions, so these should be comparable to a certain extent. You can see that unlike nintedanib, where we see a lot of gastrointestinal side effects, in the AIR study with C21, we don't really see any gastrointestinal signal, which I think is important when you think about the future role for C21. If approved, it will enter an environment where many patients will be on background nintedanib or pirfenidone, both of which are drugs that cause GI upset, and therefore having a drug with a clean GI profile is going to be important. Obviously COVID has cropped up in the AIR study, unfortunately just due to timing. Alopecia has been the side effect that has been reported most frequently. In most cases, I'm told that alopecia in this context doesn't represent total hair loss. It simply represents excess hair loss. This was a recognized side effect from the early phase studies with this compound. If you look at the proportion of fatal and severe adverse events, these compare favorably to that was seen in INPULSIS. If we can have the next slide, please. Again, this just recapitulates essentially what Rohit showed in his introduction. These are the explanations for some of the dropouts and withdrawals that have been seen in the study. Many of them relate either directly or indirectly to COVID. I think the frequency with which we're seeing these COVID related dropouts is comparable to other studies that have been running in the last two years. If we look at the remainder of the dropouts, then there are no concerning signals that appear to arise. If I can have the next slide. These are stories that have been collected by the site PIs relating to how patients in the study have been feeling. You can see here, of course, there's. One is prone to collect comments that are positive, but you can see here that there are a number of important comments, particularly around improvements of cough, and sorry, it's always a danger of talking about cough. It causes one to cough oneself. But you can see the range of positive comments made by patients. The next slide, please. This is the final slide of the presentation. This here is just providing a summary of what you've been shown. You've seen the rationale for why C21 ought to be effective in IPF, and we've now looked through this further interim analysis of the data performed on 45 patients. We've seen that disease appears to stabilize early on, and in the patients who've continued longer term, there even appears to be some signal of improvement. The drug has been safe and well tolerated, and importantly, with no GI side effects. The patients who've been on the drug, in general, have provided enthusiastic testimonies about the benefits of treatment. For an open label study, I think the results are as positive as one could possibly have hoped they might be at this stage. Thank you very much, and I'll hand over to Tara now for the question and answers. Great. Thank you, Toby. At this time, we'll be conducting a question and answer session with our speakers. As a reminder, if you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. Please hold for a brief moment while we pull for questions. Our first question comes from Viktor Sundberg from Nordea. Please go ahead, Viktor. Yeah. I hope you can hear me. Yes, we can. Yeah. Viktor Sundberg from Nordea. I have a few questions. I guess I'll start with the first one. Yeah, you mentioned alopecia as a side effect here in the study, and most of them were mild to moderate. I'm just wondering how you could treat that, say, in a larger Phase 3 study in terms of blinding for placebo, et cetera. Is that something you have thought about going forward here? Thanks. I can take that question, if you'd like. Thank you first for that question. The magnitude of the hair loss that we saw in the phase 1 study is not what we'd seen here in the AIR trial. Therefore, that gives us the confidence to move forward in a blinded phase 2b RCT. The other point to make is, I mean, it is possible that one or two subjects, you know, in the AIR trial are reaching the exposure levels that we saw in the Phase 1 study when we doubled the dose. That is possible. As you saw from the slides, no one dropped out of the study specifically due to hair loss. That is also reassuring. We've also got to remember that hair loss is incredibly subjective. I mean, the moment you put it into an informed consent form in an open label study, the IPF male patient, you know, has a heightened awareness and is intensively, obviously, monitoring for that change of those few hairs, which may or may not be true. Overall, we think we're in a good place with respect to a blinded Phase 2b study. I hope that answers your question. I would also say that, you know, of the existing treatments, we had similar problems of sort of unblinding by adverse events. With nintedanib, the diarrhea is very different to the diarrhea that placebo patients experienced. With pirfenidone, there's a photosensitive rash that in the Phase 3 trials occurred in 20% of patients. The risk of unblinding by adverse event is really comparable to prior Phase 3 studies in the disease area. Okay. Thank you. Maybe if I go back to that slide that you showed with the natural FVC decline from the Russell study. Can you give a bit of color on the baseline characteristics of those patients in the natural history study versus the AIR study? I know that the, you know, FVC predicted in the AIR study seems to be a notch higher compared to the pivotal trials for nintedanib and pirfenidone. I just wanted to get your view on that. Thanks. From memory, it was a little while ago that we did the study, but the average patient was approximately 69 with an average FVC at entry of about, I think 74%-75% predicted, and a DLCO of about 40%-45% predicted. I think when it comes to trying to compare the sort of patients with different levels of disease severity, it's worth saying that when we've done analyses of the pivotal studies for nintedanib and pirfenidone, we find that the rate of FVC decline is actually the same irrespective of level of disease severity. If you have a patient who has IPF as defined by central adjudication of a CT scan, then you can predict that their FVC decline as a population will behave consistently across all levels of disease severity. That's really one of the reasons why FVC is such an appealing endpoint in pivotal trials because it has a linear rate of decline, irrespective of sort of baseline physiological characteristics. Okay, thanks. I just had a final question before I jump back in the queue. In terms of fatal events, I guess one was COVID, but could you perhaps elaborate on the second fatal event here in the study? Thanks. We actually only had one fatal event due to COVID. Again, we've not had any related serious adverse events. We've not had any SUSARs, which is a term that we use from a pharmacovigilance safety perspective. No related serious adverse events. It was only one, but it constitutes 2% for the comparisons. Maybe that's the confusion. Yeah. Okay. Yeah. Yes. Yeah. Okay. Got it. Thank you. I'll jump back in the queue. Thanks. Thanks for the questions, Viktor. Our next question comes from Adam Karlsson from ABG. Please go ahead, Adam. Hello. Thanks for taking my questions. Just a couple from me. First one then, just back solving from the two data cuts, we can see that the new patients reaching each time point since the last data cut have or appears to have less of an FVC gain compared to the patients that made up that first data cut. They're still clearly benefiting, stabilizing and improving, but numerically, looks to be less, sort of half as much on average, it seems. Small numbers, of course, but do you have a theory as to why these new incremental patients seem to be gaining less, gaining back less lung function than the first patients from the first data cut? Did they have more end-stage destruction of the lung, for instance? Your thoughts there would be helpful. A second one, I'll rattle it off right away. On the distribution of benefit across the study participants, you helpfully broke that out by IPF severity, now probable versus typical. My question is whether even in that more severe category, the typical, where FVC gain is lower, do these patients in their studies still appear to have a benefit relative to what their natural course might expect? Well, would have been had they not been on C21. Thank you. Maybe I can start, Rohit and Toby will, of course, jump in. I think for the first question, one very reasonable explanation is that the latter additional patients haven't reached as far as 39 and 36 weeks. So we have lesser that have gotten into that phase, where we see this increase. As you point out, the group is also constituting of more probable than typical that we have from the previous time. So that is certainly one explanation. When it comes to the distribution between the typical, I think it's fair to say that we have, I think 4 or 5 above the X-axis and the others below. I think this is more than what we would expect in a severely affected lung patient population. You may comment on that, Toby and Rohit. Toby, do you wanna go ahead? I was gonna let you go first, Rohit, but. Please do. Yeah. No, I think, you know, the trajectory even in the patients with the typical UIP looks to be more shallow than we would expect. I, you know, don't have a huge amount extra to add to what Carl-Johan just said, really. I would agree with what he said. Yeah. Yeah, same here. Great. No, that's helpful. I might squeeze in another question then, unrelated to this interim data that we just got. A mechanistic question. You said as part of that presentation that AT2R is only expressed when it's needed in the lungs of IPF patients, for instance. Given this, how is it that you see vasodilation in that forearm study, which was run in healthy volunteers, given that they don't have diseased tissue, so to say? Something that we've been wondering about. Yeah, it's a good question. We haven't looked specifically, for instance, with receptor autoradiography in the small vessels. The resolution of the autoradiography is not that great, or you do very specific things and you need fresh tissue. We are continuing to use autoradiography for identification of receptors in disease and also in healthy. It's clear that you have a response. In healthy volunteers, vasculature. I mean, just to speculate, I think the reason for being there is to direct the blood flow to an area where you basically need it. I think maybe it's there just in case when it happens, so to speak, that you need this direction and you probably have a different sensitivity of this receptor, when you really need them. I've seen other situations of compromised blood flow where you have a much better effect on your vasodilator. I don't think that's unreasonable. Second, I think it's even though we had this effect on the small vessels in the forearm, maybe out in the hand. We don't see a fall in systemic blood pressure. It's not so that it's regulating blood pressure and causing a blood fall. It is regulating kind of tissue blood rather than the whole body, so to speak. It may be there in small amounts, enough to elicit a nitric oxide release and give us this response. But again, the response is there, and it is clear, and it's useful. It was also meaningful in the systemic sclerosis study that we did. It's not there so much so that you get for instance out in all muscles where you regulate blood pressure and blood volumes. We don't get a systemic blood pressure for it. Okay. More speculations than real answers, but it is an intriguing question. It's also something that we're looking into more and more and trying to complete the story. Okay, understood. No, that's helpful. Thank you. Thanks for the questions, Adam. Our next question comes from Fredrik Thor from Redeye. Please go ahead, Fredrik. Hello and thank you. My first question was about the recruitability for the next trial. You mentioned that the trial is very recruitable, but then, of course, you have these external events. Would you say that there are any learnings from this trial that you can apply for the next one, or is it, yeah, mainly due to external factors that, yeah, can explain the discontinuation rate? Should I take that? I think that's a question for Rohit Batta, yeah. I mean, I suppose it might be worth bringing in the dialogue we've had with the FDA first. I mean, the dialogue we've had has been very positive. We presented the AIR study to them at the meeting, and the agency views C21 as an important drug for IPF patients. The reason why that's important and relevant for your question is obviously they've guided us on the design in terms of dose separation. There'll be two doses. There'll be a lower dose in the next study. It also presents and they also presented an opportunity, really, that if we repeat this data in a Phase 2 B study, then it could account for substantial evidence for effectiveness, meaning that we will only need to do one single Phase 3 confirmatory study. Obviously, you know, going back to your question now, you know, that sort of guided us with respect to the design of the next study. Obviously, as you say, you know, we've taken a lot of learnings from our Phase 2 A. We've just done a study through the pandemic. I think the next study, we are gonna be incredibly conscious about the patient burden as well, try and cover different eventualities. We've also got a digital therapy study ongoing, separate program, a decentralized. We'll take those learnings as well. Our overall clinical operations team and so forth is maturing and we will take all those learnings for the next study. Perfect. Yeah, maybe this is early, but, I mean, if you were to look at a low and high dose, at what time would you be able to separate between which is the most effective, given that you see especially strong effect in the later weeks? I can take that again. Yeah. I mean, if you look at the AIR study, I mean, you can see that, the stabilization and then obviously the improvement. You know, that's critical for us in terms of designing the study. You know, we are evaluating all options in terms of the duration. The AIR interim data is gonna play a key part into that, the dialogue and the insights we've had from the FDA. We've also just formed an advisory committee, and Toby is part of that. The insights, the decades worth of experience that we can gain from that will also help us with the design of that study as well. Perfect. Maybe a short final question about the readout in week 24. If I remember correctly, it was not statistically significant. Is that just due to the lower number of patients and that the curve doesn't or FVC doesn't decrease enough? Or, can you give some more context to that week? Carl-Johan Dalsgaard, do you wanna take that one? Could you repeat the question? I didn't get it. Yes. At week 24, the results was not significant, but it was before and after, if I remember correctly. Is there any specific reason for that in- No, I got it. No, it's variability. And that's very close, but it's because of the variability in the results and still low numbers, so to speak, to get the significance. I think it's more impressive that we have significance before and after, and up to 36 it's a strong significance. It's pretty close to being significant to the x-axis, so to stabilization. We compare it then at the 24-week data with the unfitted trajectory as a cohort. Yeah. Okay. Yeah, that's all for me. Thank you. If I could just add to your question, what about the learnings? I mean, we had a study that was very unfavorably designed for a COVID pandemic because we had a frequency of visits every fortnight in the beginning, and that was really something that patients didn't like. I think what we have learned, as Rohit pointed out is to really make these studies patient-friendly and look at the patient's need and the patient's perspective of things, because that will be important. Also to this advisory group we have the patient organizations invited, so we will definitely pick that up for the future. Thank you. Thanks for the questions, Fredrik. Our next question comes from Eric Yu from Bryan, Garnier & Co. Please go ahead, Eric. Hello. Congrats on the positive review. It's you know, it's very impressive to see this level of FVC improvement. I have two questions revolving around one of the data points that you guys presented today that I may have misunderstood. On the slide where you compare INPULSIS one and the AIR interim analysis, it says adverse event leading to discontinuation is N 20. If you go to the other slide where you broke down the causes of discontinuation, it says N 18, and among them 6 were due to adverse events. I would love to hear more detail around that. Beside that, also it says severe AE and serious AE. Beside that there is an N number. It seems like it's, for example, like serious AEs is seven, but then there's only n three. What are the other causes of the four cases? That would be very helpful for us to know. Yeah, so those are two questions. Thank you. You can take the question, but the numbers to compare is percentages, which means that when we, for instance, have a number in the column 7%, it means three individuals. Just so we make sure that we talk about the same things. Please, Rohit, go ahead. Yeah. No, I was just about to make the same point, and apologies for the confusion. Obviously, the N is the subject numbers and in the column you can see the percentage number. To fatal adverse events, you know, again, there was one subject which accounts for 2% so far in the 45 enrolled. We've had two serious, sorry, three serious adverse events. We had one which was the COVID death that I mentioned previously, again, not related to C21. We had actually an IPF exacerbation which was actually associated again with COVID-19, and these types of events can be intertwined and I know acute exacerbations are tough to define and actually even tougher to manage. Again, that was not related. Then the third one, it says squamous cell carcinoma, and of the mouth and actually the patient had a pre-existing lesion before they actually went into the study there. Again, not related. Three events and hence 7%. Yeah. If I may, one more question. I remember in the RS data there were three cases hyperglycemia, but did that disappear? 'Cause I don't see that on the breakdown. Is there any detail around that? Maybe I can take that one. That was the COVID trial where we're treating patients, so it's the ICU setting and they all had a little bit of higher glucose, which is very normal, for that circumstance and nothing alarming at all. At one point, suddenly the placebo group was a bit lower, and that turned into the relative hyperglycemia in that very situation. The next time it went back to the same level as well. It is not an issue with the drug. It was a reflection of the ICU situation. That goes through for all patients. They had a bit higher glucose levels. Thank you very much. That's very helpful. Last question. I forgot to ask this. For this data, would you mind sharing maybe a breakdown of the Indian sites and the UK sites? I can take that. The actual sites and locations and actually names of the PIs are actually on ClinicalTrials.gov. I mean, I suppose just to sort of reading into your question, I mean, first of all, there's no scientific or medical reasons to suggest that IPF is different in different countries. I mean, you know, and yes, the majority of patients in this study have come from India. I suppose, and I think Toby would agree with me, is that the most important aspect here is really to confirm that diagnosis and confirm it centrally, which we did in terms of the UIP pattern, and also have that tight control of that spirometry, that overread. Here, Clario, we use Clario's machines, and the data was uploaded and overread and so forth. Then the third point, I suppose, to mention is that these countries such as India, you know, they've been part of the global registration IPF programs for many other studies as well. Hope that answers your question. For sure. Thank you very much. Very helpful. Thanks for the questions, Eric. Our next question comes from Dan Akschuti from Pareto Securities. Please go ahead, Dan. Thank you, and hello, everyone, and congratulations to this unprecedented data update. With that, I've a question to Toby Maher. I'm trying. I'm following the space and trying to understand what is causing this kind of completely different profile. Obviously it is somehow related to the mechanism of action since, as you argue that the patient characteristics are quite similar across the trials. If you look at other drugs, I only see treprostinil to have kind of a, maybe due to its vasodilative effect, kind of a halfway similar effect, while all the others are really very weak and prone to side effects. What's your view, and how would you classify all the kind of the space of drugs that we see in IPF? Certainly pirfenidone and nintedanib sort of, on average, slow disease decline rather than prevent it, or reverse it. However, if you dig into the data from the registration studies, you will see that maybe 20%-25% of the population treated with both drugs show an improvement in FVC over 52 weeks. That compares to about 5% in the placebo group who show some improvement over that time period. It's not unprecedented to see some improvements in FVC with treatment. It's just that the existing drugs do it fairly inconsistently and only in a small proportion of patients. When you look at other drugs that we've seen reported, BI's PDE4 drug appeared to stabilize FVC over 12 weeks. Obviously the study was only 12 weeks in duration, so we don't see what happens beyond that. Pliant presented something similar. With the newer generation of more targeted IPF therapies, we are perhaps seeing better treatment effect. You know, I think we've talked this through before in previous settings, but you know, when we're treating IPF patients, a lot of the lung is destroyed, and we're not hoping to improve it. When you look at a patient's lung histologically, we see regions of early fibrosis with well-preserved lung tissue. We see areas of advanced fibrosis with sort of honeycomb change and complete destruction of the lung. My sense is that if you have an effective drug that has true anti-fibrotic properties and is capable of reversing some of that fibrosis, then even in patients with the most advanced disease, one can hope to reverse some of those areas of early fibrosis. Albeit, you know, once you have advanced disease, the scope for improving things is probably diminished. I think there is a biological rationale for why one might see improvement. I think there is precedent already for seeing improvement with existing drugs. It may just be that this mechanism is more appropriately targeting the early fibrotic tissue rather than the late advanced fibrosis and that may be why we're seeing this. Of course, you know, we're still discussing early phase data and one would want to see this repeated at Phase 2b and Phase 3. You know, I think as I said in my talk, it's tantalizing. Okay, thank you. As a follow-up, have you seen data where you really see these kind of hundreds of milliliters in FVC gains over this period of time, or is that something that is a bit outside of what we would see with the others? It's been seen, it's just the proportion is very small. I think what's more unusual about the data that you've seen now is that the proportion of patients showing a response is bigger, hence. Why you're seeing the sort of deflection in average FVC being upwards rather than downwards. Okay. Thank you. Considering the cough data, so you listed some of the comments from patients, and then in the adverse events, we can see much fewer adverse events related to cough. Is there any rationale or understanding from your end that cough would be kind of attenuated? Well, I can start and someone else can chip in. I think the IPF cough is very different from any other cough. You know, there are programs for IPF cough and we have one with thalidomide as an inhaled drug. It seems to be one of the few that could change IPF cough. Normal opioids and normal antitussives do not do anything. The question comes, where is this cough elicited from? Is it from the upper airways, or is it from the areas where you have alveoli or fibrosis? If the latter case is true, then it may well be that healing of the alveolar integrity will reduce the stimulation of cough in the lung. Again, I mean, it's a hypothesis. It's certainly true that the IPF cough is different from idiopathic chronic cough or any other cough. Simple explanation, if we can restore the alveolar integrity, we may also affect the cough. It remains to be followed up. Okay. Thank you. The last question is for the next trial. I think everyone agrees that this data warrants at least further development. Can we expect a kind of a trial that would allow to enroll patients faster, that you can include a standard of care or maybe all comers or something like that, and obviously more sites? If the effect is demonstrated as in this trial, in a larger randomized trial, could it then be potentially pivotal? I'll hand that over to Rohit. Yeah. I mean, first of all, we're pleased that C-21 is phase IIb ready. We are also pleased that the FDA agrees with us. Actually that's great. You know, we're looking and exploring all different options at this stage. You know, right up at the top there obviously is to make sure that we get to a point that C-21 becomes phase III ready, and we confirm, you know, we're able to repeat what we've seen in the 2A and obviously confirm the dose. That's really important. Also do that in a way that we can reduce the patient burden as well. We're looking at, you know, in-clinic and home type of assessments and things like that as well. Obviously including cough-type assessments, as we've just been discussing as well. All these types of things, and we've got this advisory committee now, which is great, which we have got patient representation, as Carl-Johan said as well. You know, the gears have started to move, and so you know, at this time we're really exploring options, and I suppose that's probably as much as I can say at this point. Thanks. Thank you very much. Our next question comes from Patrik Ling from DNB Markets. Please go ahead, Patrik. Yes. Thank you. I actually also have some question about next trial. Maybe you can elaborate a little bit on it, both size-wise, if you're gonna include the two different doses, price-wise, how much you think you will have to spend on it. Also if I understood you correct, I mean, it's not necessarily so that you're gonna have to use some sort of standard of care to compare with. Or could you do it more like a carbon copy of this trial and then move to a comparator trial in Phase 3 instead? I mean, yeah, we're designing the study. You know, obviously it would be a randomized, double-blind, placebo-controlled study. There will be obviously, you know, the placebo. But you know, in terms of the standard of care and obviously the population, the eligible population, all comers and so forth, you know, those things right now we're actually discussing with the advisory committee. There'll be more to come soon. Would it be ethical to actually have another trial that is placebo-controlled when there are two approved drugs for this indication? I mean, don't you run a risk that no one would actually like to join the trial because, I mean, the risk of ending up in the placebo group? Yeah. I think, I mean, first of all, I'll let Toby comment. I suppose it's questionable whether the antifibrotics are standard of care, and how they're viewed. Obviously, that's what patients have today and you have this GI intolerance, and they come off and so forth and suboptimal. So there's that aspect. And I think, you know, ideally, you know, you would wanna run a study on top of standard of care. So this again is something that we're evaluating on top of standard of care, the rescue type of treatment as well, the duration, the eligible population. These are all things that we're discussing with the advisory committee. Yeah. I don't know, Toby, if you want to say anything else about the previous and the current studies that are ongoing? Yeah. There are studies ongoing without standard of care. The FibroGen CTGF inhibitor studies have been run without standard of care. Essentially that involves recruiting patients who are either intolerant to drug, have made a decision not to go on one of the antifibrotics or, as is the case in many countries, the UK included, are unable to access reimbursed antifibrotic therapy. There remain a large proportion of patients not on antifibrotic drugs, and it's just a case of accessing those. You know, it obviously creates challenges of its own, but it also has advantages. Okay, then lastly, when do you think that you will have concluded the discussions with the regulatory agencies so you can come to a more firm conclusion on how the next step will look like? I mean, the good news is we've concluded our initial discussions with the FDA. We have a good idea of what they want to see. That's great. And types of endpoints and so forth and so that's good from that perspective. I think maybe you know, obviously they're seeking advice about the design of the study, and that's what we've done. Then there's obviously you know, starting the whole engine of the study and clinical trial applications and so forth. That will then come you know, next year at some point as well. Okay. Great. Thank you. I'll say to what. Oh, sorry. What Rohit said, that we've had very positive discussions with the FDA, and as we understand now, I don't think we need more advice. It has also been said, there's pros and cons, and you can do a naive or treatment-naive or all-comers or on top of standard of care, and they have advantages and disadvantages. That's what we're dealing with. We are, from a regulatory point of view, pretty clear on what we need to do, irrespective of what we decide, which type of study we decide to do. That part is clear. Okay, great. Thank you, guys. Thank you. Thanks. Yes. We have some questions, inbound questions that have been submitted. I think I'll start with the one for Toby, since I know that you have to leave. If this data holds true in, how do you foresee paradigm changing? I think you're on mute, Toby Maher. Yeah. There we go. Sorry. Yeah, I think if the data were replicated in a Phase 3 study, that is to say we see an improvement in FVC over 52 weeks in a pivotal study, then you know, I think that would lead to a paradigm shift in treatment. At the moment, our goal is to slow disease progression. I think if we had a drug that genuinely improved outcomes in patients, then there would be an incredibly strong rationale to be switching patients to a new therapy. You know, the thinking in the area continues to be that we you know that the next generation of treatment will further slow things. I think that's what makes this so exciting, albeit an open label study, is that it could potentially lead to a paradigm shift in how we treat patients clinically. Thanks for that, Toby. If you have to drop then, thanks a lot. Thank you. Yeah, apologies. I have another meeting to go to. Bye, guys. Thanks, Toby. Hans, we just have one follow-up question from Viktor Sundberg from Nordea. Viktor, please go ahead. Yes. Hi. I think my question might have been for Toby, but maybe I can ask it anyway here and see if you could answer that question as well. So just coming back to the UIP patterns, I just wondered if the patients that have improved on the pivotal trials with pirfenidone and nintedanib also have shown a milder UIP pattern. Related to that, I just also wondered if you could stratify patients based on UIP pattern to include milder patients in the next study, or if you think that they will force you to include all patients in the next study. Yeah, maybe I can start. I mean, theoretically, you can, yes, stratify. I think one should look upon it and do a subgroup analysis at least. I think that's probably the right thing to do. I think the IPF community is more still on the total IPF patient group for studies and not for splitting up at this stage. But it is an interesting hypothesis, and I think we should definitely make sure that we capture that in the next trial. Maybe not by stratifying because there is normally about 40% of these probable UIP patients in trials. So I think we will get our share. But we should definitely make sure that we do subgroup analysis here. Thank you. Yeah, we have some more inbound questions here. Maybe the next one for Carl-Johan Dalsgaard. It's generally perceived that FVC improvements of more than 200-300 ml are unlikely unless C21 drives lung regeneration. How would you scientifically explain the FVC improvements? Well, I guess it is the mechanism of action, the target cell that is the regenerative repair cell in the alveoli that it's there to replace the type one cells when needed. That IPF is a disease where that process is not functioning properly which then leads to a scarring process. In turn then drives the fibrosis in the lung. The lung seems to be very susceptible to that. Since there's many ways by which patients get fibrosis, not only IPF. I think by doing the repair job that is then insufficient in the IPF patient and support that with C21, I think it is possible to regain function and regenerate. Maybe not regenerate lung tissue like whole lungs, but to regenerate the tissue in the vicinity of functional lung, so that you can improve the FVC or the lung capacity. Also importantly to stop the further development of the fibrosis in other parts of the lung and other alveoli, so to speak. I think it's possible. Okay. Thanks, Carl-Johan. Maybe next one for Rohit. Can you provide more granularity on the hair loss observed in the study? Did any of the cases of hair loss lead to discontinuation from the study? Yeah. I think actually, we've covered some aspects of that in the previous questions. Again, yeah, the magnitude of the hair loss we saw in phase 1 is not what we're seeing here. We don't expect it to be a problem, and therefore we're moving forward and have that confidence with respect to the Phase 2b. To your question, sorry, Hans, no one dropped out specifically due to the hair loss. So none of the withdrawals were specifically due to the hair loss. Yeah. Again, you know, it's an incredibly subjective thing, particularly in an open-label study. It's something that we'll certainly monitor in the Phase 2b trial as well. Yeah. You know, I've spoken to many patient advocacy groups and we've discussed this quite openly in terms of the benefit risk as well. Obviously if you you know factor in this as a you know a progressive you know devastating condition and on top of that you know you have this GI intolerance then obviously in weighing everything up you know this C-21 certainly has a positive benefit risk profile. Thanks, Rohit. Maybe last question and also for you. How many acute exacerbations have you had in the study and can comment upon them? Acute exacerbation is where you get a sudden acceleration of the disease. It's, you know, the one-year incidence I think is around 15%. In our study we've had one event and it was associated with COVID-19. It was actually challenging to decipher whether it was actually due to, you know, COVID-19. I think that's the nature of the beast of acute exacerbations. As I mentioned, they're tough to define and they're actually even tougher to manage. They have a mortality of about 50%. I know the AIR study is ongoing, but it is a nine-month trial, and by now we would have expected to have seen more acute exacerbation events and acute exacerbation related deaths. The latter we have not seen. You know, we will build this into the Phase 2b trial, and ideally, and then obviously confirm it in a Phase 3. If we do confirm this, that we can in some ways reduce the acute exacerbations, then this will clearly show that C-21 is getting ahead of the disease and will then obviously differentiate us among the other medicines out there. Thanks, Rohit. I think that's it from a Q&A perspective on the inbound questions. Maybe come back to Carl-Johan Dalsgaard for some concluding remarks. I always like some pantomimes, but I'll try to actually start that one. In summary then, I think we have an unprecedented data set, and we're very confident that we would continue and proceed with this drug into the next step of development. I think we have shown that by the genuine stabilization and the increase and also by having a mechanistic and medical scientific explanation for it. All in all, I think we're very enthusiastic about what we're seeing, and I would like to thank the speakers here, the Vicore team behind the study, and of course, our patients who have been participating in the study to all make this happen. I really look forward to the future. Thank you.