Good morning, and welcome to the Vicore Pharma R&D Day. 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 your host, Carl-Johan Dalsgaard, CEO of Vicore Pharma. Please go ahead, Carl-Johan. Thank you very much, Tara, and welcome to Vicore R&D Day. It's actually the first in Vicore's history, and I hope many more will come. I'm really proud today to share with you both an update on where we are in rare lung disorders, that's our primary focus, but also with the new indication, pulmonary artery hypertension added to this portfolio. As well as give you a glimpse on what can be the future with angiotensin type 2 receptor agonist as a new drug class. Who knows, maybe in the coming edition of Goodman & Gilman, you will find a chapter that is AT2R axis in the future. That's at least where we sometimes see the horizon for this effort. We're honored to have a distinguished group of experts with us. Can I have the next slide, please? Then the next slide. That together with myself, our CSO, Johan Raud, and CMO, Rohit Batta, will present today. That is Toby Maher, Gerry Coghlan, Maureen Horton. They will share with you the background and the disease and the status in IPF, in pulmonary arterial hypertension, and in COVID, respectively, and also to put the Vicore data that has been achieved so far a little bit in perspective of the current situation. Can I have the next slide, please? First, I will give you a little bit of an update on the key programs that are ongoing. When we start with COVID-19, I can tell you that about half the study is enrolled. I will also tell you that recruitment in Ukraine and Russia has been stopped for obvious reasons, and this will have an impact on timelines and the population that we are reviewing. We have already announced that top line data will not be first half 2022, but second half 2022. We're closely monitoring the development, both in terms of the opportunity to save data in Ukraine and Russia, and of course, also to find new hotspots in the world for recruitment of new patients. We had a safety update with 150 patients, and there's been no safety concern in the study so far. Coming to the phase II study in IPF, again, about half the study is enrolled. Again, recruitment in Ukraine and Russia is stopped for the same reason. This has not as big impact on the recruitment, but of course, we will do the utmost both to secure data in these countries and also make sure that patients, if possible, can get to their enrolled patients can get to their visits and for the safety of them as well. In the phase II IPF, we recently reported an interim analysis with some unprecedented data in terms of not only stabilizing disease, but increasing lung function. Scientifically in this study, I think we have already shown what we needed to show, and we are now starting the preparations for a pivotal trial. That means that we are advancing this program, and in my mind, we should go directly for a pivotal trial and try to bring this medicine to patients as soon as we can. I think that's our obligation as drug developers. In digital therapy, we are on track for a pilot this month and we will certainly come back with a specific Investor Day on this topic because I'm convinced now that with all the feedback I get from patients and from even KOLs, this is going to be a very important tool and help for these patients. When it comes to the IPF cough program, we've taken one step back and we're evaluating different formulations, and that's still ongoing and the current amorphous silica microspheres that we've worked with for a while have not met our specifications. Finally, the new angiotensin type 2 agonist molecules. We've just announced that the first new molecule's preclinical evaluation is being prepared now for a phase I trial starting the next quarter, so quarter two. In addition to that, we actually have four more compounds, three of which are pre-CDDs and will be evaluated during this year in the final tox studies, and one is already deselected in favor of the C106 that is now being forwarded. All in all, I think we have made great progress and this will be a good starting point for the next step, which is, can I have the next slide, please? That we are looking into this receptor, the angiotensin type 2 receptor as a new drug target. We're certainly first in class and by definition then best in class because no one else is really working with this target, at least not in clinical trials yet. I think this is an important opportunity for us to benefit from all the knowledge and competence and efforts that's been made to characterize this receptor and to work with this receptor and its molecules. Can I have the next slide, please. There is more than 100 scientific publications on C21 and its effects and in various and a variety of animal models. This is really amazing what kind of background there is for this work. Until recently, there were really no clinical data. We didn't really know if we were dealing with another asthma drug for guinea pigs or if this was for real. I think we can say now with the three phase I studies we've done, the three phase II studies we have done and it's ongoing, and also the emerging tissue explant experiments that are also ongoing. That at least in the area of interstitial lung disease, IPF, and the associated diseases, I think we've taken a big step to confirm that the preclinical promises hold true for clinical treatment. This is, I think, also something very important, that if we believe that this represent a new class of drugs, there is certainly a huge unmet need and a huge opportunity in a number of diseases. We will review a little bit of that during today, but this will, of course, be an ongoing work. Our focus will remain on the rare lung disorders. Can I have the next slide, please? What is part of the work that has been done is to figure out via which mechanisms angiotensin type 2 receptor agonists may work. You will hear more about this later in this presentation. One important thing is that we do have this receptor on the progenitor cell in the alveoli type 2 cell. This type 2 cell is really keeping up the integrity of the alveoli, which is important for preventing fibrosis to start, and also the cell produces surfactant, which is another very important feature of the cell. In addition, we certainly have proven vascular remodeling, and I think that comes especially at hand for pulmonary arterial hypertension, but I think this is also inherent in all IPF patients and their pathology. We have shown anti-fibrotic effects, but not only that, we've also shown fibrolytic effects. It means that we can actually resolve some of the fibrosis that's already been generated with these mechanisms. If I can have the next slide. The multitude of effects that we have shown or the mechanisms that we have talked about will also lead to a multitude of opportunities. We're more or less now putting our own internal efforts into different boxes where COVID-19 is COVID-19. We didn't plan for COVID-19. It came to us and we did the phase II trial and the data were very good. That represents one opportunity. Interstitial lung disease where we now are focusing, still focusing. We have not only an IPF study ongoing, but we also have the digital therapy, the cough program, and now also taking on pulmonary artery hypertension. I will give you a little bit of glimpse later on in the end of the presentation of two areas that we are kind of investigating, and that is preeclampsia and diabetic nephropathy. There are several other areas that could be of interest for this class of drugs. With that, I'm very happy to kick off this event and hand over to Johan Raud, CSO of Vicore. Okay. Thank you. 10 minutes of some scientific background on the renin-angiotensin system, and in particular about the angiotensin type 2 receptor and Vicore's drug candidates. Take the next slide. From an evolutionary perspective, this is a very old hormone system, with the main purpose being to prevent too low blood pressure, for example, after injury with major blood loss. It's fundamentally an ancient rescue system in a way. The main pathway to this is the hormone angiotensin II, which binds to the angiotensin I type 1 receptor and activates it, which leads to constriction of blood vessels and reduced fluid losses from the body. Activation of this type 1 receptor also promotes inflammation and thereby helps the immune system to fight infections, which is also common after injuries. The drawback is that the AT1 receptor pathways is a bit so to say, trigger-happy and can overshoot and cause disease, for example, hypertension. As most of you probably know, there are several antihypertensive blood pressure drugs that block either the formation of angiotensin II or block the AT1 receptor. This system also has a parallel pathway that basically does the opposite via the angiotensin type 2 receptor, which is also the target of Vicore's drugs. Activating this type 2 receptor basically triggers resolution and repair, which includes things like vasoconstriction, immunomodulation, and high anti-fibrotic effects. This receptor has been known for quite some time, but at least from a clinical point of view, it's certainly a novel target. C21, like Carl-Johan Dalsgaard said, this is the first AT2R agonist to reach the clinical stage. I would also like to briefly mention the angiotensin peptides, Ang-(1-7) and Ang-(1-9), which are suggested to be endogenous AT2R agonists. There has been some contradictory both views and findings in this area, where involvement of the so-called MAS, M-A-S, receptor is suggested. We can take the next slide. As you can see in this table, we have done some work with these peptides. Most of this is wholly unpublished data. If you start with C21, it's a very potent AT2R ligand. It's highly selective compared to AT1 binding, and it does not seem to activate the MAS receptor. The Ang-(1-7) peptides have a potency profile that's actually very similar to C21. They are potent AT2R ligands and don't seem to bind AT2R, and they didn't activate the MAS receptor in this system. So we can take the next slide. Next slide. Thanks. C21 was first synthesized and described almost 20 years ago, and since then, a very large number of labs around the world have shown quite impressive effects of C21 in a range of different animal models like Carl-Johan Dalsgaard mentioned. This includes models for pulmonary fibrosis, pulmonary hypertension, kidney fibrosis, preeclampsia, just to name a few. To the right is a published example showing that C21 can effectively protect against experimental pulmonary fibrosis. By the way, for those who don't know, preeclampsia is a complication of pregnancy characterized by severe hypertension, but you will hear more about this later on. We can take the next slide. If we switch to the human lung, this slide shows that we can visualize both angiotensin and C21 binding in thin sections of fresh human lung tissue. In the upper left image, you see binding of isotope-labeled angiotensin II alone. One step to the right, you see that the AT1 receptor blocker, valsartan, does not block this angiotensin binding. While the next image shows that adding C21 completely displaces angiotensin II. This altogether suggests quite strongly that the lung expresses the AT2 receptor, but very little AT1 receptor. The curve to the right is also interesting. It just simply shows how increasing concentrations of C21 displace this Ang II binding, and with an IC50 or inhibitory concentration 50 of 4.5 nanomolar, which is almost identical to the receptor binding data that we have done. This is, of course, very encouraging. Also importantly, the red asterisk that you can see on the curve is showing the concentration of free C21 that will reach the patients with the doses that we are using in our clinical trials. If you look at the two images below, the left one shows binding of a very low concentration of a C21 isotope to the lung tissue. To the right, you see a displacement of this C21 binding with cold, non-labeled C21, which then further supports that we have so-called target engagement with C21 in the lung. Take the next slide. If you continue with C21 and the human lung, this slide shows the anti-fibrotic activity in fresh IPF tissue from transplants with dose-dependent inhibition of both the pro-fibrotic factor TGF and the collagen 1 alpha 1, which is the major component of type I collagen, which in turn is the major collagen type in fibrotic tissue. This assay is obviously more specific than animal models, and importantly, the concentrations that we have used are in the clinical range. I can also mention that we see similar effects in human fresh kidney tissue, and also with our new AT2R agonist. We can take the next one. We can take the next one. We can now go. Next slide. Can move? Yeah. Right. Thanks. If we now go outside the lung, the AT2R receptor, the AT2 receptor is also present in other human tissues, which together with all the preclinical studies I mentioned before, makes targeting this receptor interesting in a range of diseases. In our view, in particular, diseases like diabetic nephropathy, preeclampsia, heart failure, and pulmonary hypertension. You will hear more about some of these later. In a few minutes. You can take the next slide. So you've seen this already. Carl-Johan has said a few words about this. If you dig a little bit deeper, the effects of the AT2 receptor appears to be mediated by at least these four mechanisms. If we start with the first box, Johan described briefly, the AT2 receptor is highly expressed on these type 2 epithelial cells. These are then important for repairing alveolar. They also produce surfactant, which helps expand the lungs. Secondly, in box two, the activation of AT2 is known to stimulate vascular endothelial cells to release nitric oxide, which is a vasodilator and important molecule for keeping blood vessels healthy. Thirdly, as I've already shown before, C21 is anti-fibrotic, and at least in part due to inhibition of TGF. Also there is direct inhibition of myofibroblast, which produces fibrotic components. As shown in the fourth box, C21 has some very interesting fibrolytic activities, in that it can increase so-called matrix metalloproteinase enzymes that can break down fibrotic tissue that has already been formed. I also would like to emphasize that all of these mechanisms that I have described have experimental support. I have two more slides describing our new molecules. We can move to the next one. As I mentioned before, C21 was developed quite a while ago. We have worked extensively to develop new improved AT2R agonists where this compound C106 is the most advanced so far. These new candidates all have improved stability and metabolism compared to C21. Their AT2R affinity and selectivity is similar to or often better than C21, and they also suppress TGF in human tissues. Also often better than C21, as you can see below in the graph for C106 IPF tissue. We can take the last slide. These are currently our most advanced drug candidates. C106 expected to enter into the U.S. during Q2 this year. And with C111, C112 and C103 also progressing very well. C21, as Carl-Johan Dalsgaard indicated, is very similar to C106, which has some lower priority right now. These new compounds can all be used in new indications, so interesting. They have slightly different profiles. We will provide more details about this at a later stage. All in all, we made a large number of compounds, 700 within seven classes. And these compounds have pending patents projected through IP protection to 2040 and beyond. I will stop here and pass the word on to Dr. Batta, our CMO. That's great. Thank you very much, Johan. I mean, I'm Rohit Batta, and I'm the Chief Medical Officer for Vicore. Our core focus really is to bring novel therapeutic solutions to patients with severe lung diseases like idiopathic pulmonary fibrosis. I was at an IPF patient conference not too long ago, and the motto there was living well. Unfortunately, that's not really what's happening today with approved antifibrotics. They haven't impacted mortality, but on the flip side, they have negatively impacted quality of life. We've made great progress with our clinical programs, and I'm gonna take you through some of these successes today, and the key milestones for the year ahead. We go to the next slide. Firstly, I'm not going to avoid the use of the word dashboard. It's an overused term and can feel a bit of a disservice to the fantastic work completed by the team that I'm showcasing here today. Instead, here's a visual display of our clinical programs led by C21, our pathfinder medicine. If I start on the left-hand side, idiopathic pulmonary fibrosis, we're looking at the disease in a 360 way. We're really positioning ourselves as a one-stop shop. You know, with C21 or VP01, the project name, we aim to stop the progression of the disease. VP02, which is not shown here, is an inhaled version of thalidomide. The aim is to alleviate the disabling and distressing IPF cough. Then VP04 or the DTx is addressing the mental health burden of IPF. I don't believe there is any company really that's taking this holistic approach like we're doing in IPF. In the middle, you'll see COVID-19. Sadly, we're not at the end of this crisis. I mean, yes, things have improved, you know, in the short term with vaccinations. But the virus is still very much in control. We only have a handful of therapies for patients that are hospitalized and hypoxic. I'll take you through our phase III design there. Then on the right, we have pulmonary hypertension. It's coined the cardiologist's cancer 'cause it's due to the high morbidity and mortality that's seen there. It complicates many ILDs. About up to 80% of IPF patients have been reported to have some type of PH, and it's an independent risk factor for mortality. You know, we'll be sharing some of our preclinical data with the Sugen/ hypoxia model, which shows that C21 has a remodeling effect. It's similar, if not better, than what's been seen in sotatercept studies. We've recently heard about the Merck acquiring Acceleron for sort of eye-watering amounts there. We're moving expeditiously into a phase II proof of concept study, and I'm going to take you through the design. Go to the next slide. You'll hear from Toby about the disease IPF and the unmet need. Instead, I'm gonna give you an industry physician's perspective here about really picking the right disease, getting medicines into the clinic, and then out through the other end and changing and hopefully even creating a new standard of care. Why IPF? Well, it displays homogeneity. We have a consistent decline that's been reported in many studies in terms of decline in lung function, reported in natural history studies, placebo arms of RCTs. We have a reliable endpoint, change in FVC, which regulators seem to favor. We can make an impact here. There's a large gap to fill. Again, we have the two approved therapies, but they have limited efficacy, significant GI side effects. About 40% of U.S. patients are not on these agents, and about 11%, if not higher actually, discontinue these drugs. We've really taken all of these learnings and applied them to our phase II AIR study. If you go to the next slide. 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 in terms of FVC decline 240 ml per year much faster. This has again been described in many studies time and time again. We designed the AIR study based on this carefully applied historical arm, and you'll see that in the graph. In green, you have this natural history lung function decline in an untreated group. In yellow, you have the likes of pirfenidone, nintedanib halving this decline. The white space, or in this case orange space, is our C21 target. Our target product profile was to demonstrate better efficacy and better safety. Go to the next slide. The interim analysis data is hot off the press and Toby will run through it during his presentation. I suppose despite the relatively small numbers and open label design, the results are unexpected and unprecedented. It suggests that we are stabilizing the disease with C21 and that between six and nine months, actually, there's an increase in FVC. C21 appears to be outside the classical mold of simply just reducing this decline, but instead stabilizing or perhaps even reversing it. The second point here is that we have a DMC in place. They've had a couple of data reviews, and there's not been any safety signals, no SUSARs. It's been well-tolerated. Again, there's no GI signals. The third point here is that unlike the majority of the late-stage phase III medicines, C21 comes in a convenient oral capsule. I suppose you don't need a sort of a clunky, expensive IV clinic set up for it, which can be fraught with challenges, particularly during a pandemic. The fourth point here is that the mode of action, you know, it's working, as Johan's mentioned in the epithelial and the endothelial cells, so it has this dual anti-fibrotic and remodeling effect. With these results, there's obviously a heightened sense of urgency from our side, and the next stop is to really talk to the FDA and agree the design of the pivotal phase III trial. And obviously try and see if we can have opportunities to try and expedite or fast track the development of this medicine. Go to the next slide. Another business sort of buzzword is differentiation. What we mean by that is how will C21 be different and add value, you know, if we consider sort of the long game here, you know? At the top here, you have the likes of the, again, the pirfenidone and nintedanib. Yes, they are approved. Yes, they're oral. They don't appear to stabilize the disease. Obviously, then you have the compliance issues. You know, given this profile of C21, and we'll share again the data, you know, obviously with the approved therapies, the lack of the documentation of mortality benefits, you know, there could be compelling evidence here to go head-to-head with the standard of care. Obviously, we would want to discuss this with the FDA, and really try and position ourselves as first line therapy. Next row, you'll see the anti-CTGF from FibroGen, the pamrevlumab. Looking at the eligibility criteria of their phase III study, it seems to suggest that they're really more positioning in third line, actually, where patients either cannot tolerate or failed antifibrotics or have refused it. Which is obviously a smaller piece of the pie. Then also acknowledging that it's an intravenous therapy. Next, you have Roche there. It's human pentraxin- 2. It's on top of standard of care. It's IV, okay? Then you have the inhaled treprostinil, and you know, that's been with recent successes in PH. But however, it's up to about 12 breaths four times a day. That may not be then obviously consistent with living well. You know, if from a C21 perspective, yes, we're in phase II, so I suppose chronologically we're a bit behind there. There's opportunities now to speed up and obviously then deliver improvements, these improvements to patients. Go to the next slide. This is my final slide on IPF. You know, IPF is a complex disease, and it's important not to be single-threaded, you know, i nstead you need to really sew together an effective recipe that sort of creates value for patients and physicians and the payer. Okay? As we mentioned on number one there, we have the angiotensin II receptor agonist. It's working on the RAS, it's the AT2R on the alveolar epithelial type 2 cells, promoting the reparatory mechanism. Again, that's the phase II AIR study that we'll go through. Number two, as Carl-Johan Dalsgaard mentioned, you know, in the whole sea of digital apps that you might find on your iPhone, only a fraction of those are validated using a clinical study, just as you would with a medicine. They're coined digital therapeutics. They're recognized by regulatory authorities such as the FDA and many payer bodies as well. The aim is for us to have our own personalized cognitive behavioral therapy DTx. As Carl-Johan mentioned, we've started the pilot study. We're actually waiting for ethics approval there. The plan is that that will quickly evolve into the pivotal study this year. So it's really our trailblazer. I suppose in some ways, particularly with the pandemic, it's not hard to imagine the emergence of a very different healthcare system powered by DTxs over the next three to five years. Number three, there is VP02. It's tackling again the distressing and disabling IPF cough. I suppose the therapeutic proposition there is to increase the lung exposure, reduce the systemic exposure, and obviously then hopefully reduce the side effects as well. Number four is pulmonary hypertension too, and I'll talk about that in the next slide. Go to the next one. Pulmonary hypertension is defined as an increase in pulmonary arterial pressure. Not all pulmonary hypertension is the same. There's different groups based on different causes. We're particularly with C21 interested in Group 1 PAH, and Group 3, which is in interstitial lung diseases. Here you have the muscularization of the vessels. You have these plexiform lesions that are formed. You get the remodeling and obviously the impact on the right heart. It's coined sort of the precapillary pulmonary hypertension. There's a growing body of evidence that C21 can actually reverse this. This is preclinical evidence. Again, Gerry will share the Sugen/ hypoxic model data where we found that C21 reduced the pulmonary artery pressure at human equivalent doses and also had an impact on the remodeling. It obviously certainly places C21 in a very favorable position for the treatment of either Group 1 and Group 3. You go to the next slide. Therefore, we're working very closely with Gerry. We're also with Professor Chris Denton to really prove these clinical benefits in pulmonary arterial hypertension. Now, it's a diverse yet homogeneous group because again you get that muscularization in the pulmonary artery. Traditionally patients have a couple of hemodynamic touch points every year. This is invasive right heart catheterization. Obviously increasing the number of touch points makes logical and intuitive sense. Abbott have an approved device to prevent the progression of heart failure. They've shown that safety and utility and actually there's been a study in PAH patients. This device is called CardioMEMS. It's implanted in the pulmonary artery. It's calibrated with the right heart catheterization in terms of the traditional aspects, and then the patient goes home, and they upload the data daily. It's a very patient-centric and convenient aspect, particularly if you acknowledge what's been happening with the pandemic. Then the patient and the physician can actually then review the data and obviously make clinical decisions around it. From a clinical study perspective, you can actually get away with smaller numbers, much fewer numbers, as subjects can serve as their own baseline. We're actually fleshing out a design for this study, and the plan is to start study in this year in 2022. Go to the next slide. Switching gears onto COVID-19, and as I mentioned, we're not out of the woods here. The reality is that not one modality will end the pandemic, you know. Yet right now we have limited therapeutic options. We have still suboptimal vaccination levels. And we have a highly mutagenic virus. And this is where C21 is a promising medicine. It could speed up recovery times, it could be produced at scale, and it could be made available to patients quickly. Professor Maureen Horton will share with you the phase II data, which then really gave us the impetus to move forward, particularly the impact it had on hypoxia, which is sort of the hallmark of COVID-19 progression, and is an independent risk factor for mortality. That's where C21 really showed its racing stripes. From a phase III design perspective, it was important to stay close to that population. These are patients that have been hospitalized and in need of oxygen, but not too close to the cliff. These patients don't have moderate to severe ARDS, and they're not on invasive mechanical ventilation. There's still the opportunity for us, for C21, to turn the disease around. We've designed this study with very close, you know, engagement and obviously advice from the FDA. We've engaged with the EMA, and many experts and Maureen is the coordinating investigator, and she'll talk more about that. Actually, just the other point I wanted to make was, and Carl-Johan Dalsgaard just mentioned it, that we have an independent DMC as part of this study, and they've just had their first review of the unblinded safety data, and they recommended that the study proceed with no changes. That's great news actually for the study and obviously for patients. You'll see there on the right, obviously, you know, we're operational right now in five continents, and about 50 different sites. As Carl-Johan Dalsgaard mentioned, you know, screening has paused in Russia and Ukraine. But we've actually just had the go-ahead to recruit about 120 extra patients in India. And we're also opening up some new sites, some in the hotspots in India. Okay? The aim is to have the top line data in the second half of this year. Go to the next slide. Putting it all together, you know, the mode of action, the alveolar epithelial type 2 cell, the AT2R, the clinical results from the phase II in terms of the hypoxia. You know, where do we feel that C21 will have the greatest utility? You know, COVID has been sliced and diced in many different ways, and I've tried to artificially do this here, again in the pathogenesis into three stages. What we do know is that I suppose a patient could have one of these stages or all three at the same time. I suppose, you know, it's important to, I suppose, realize that it's about patients coming into hospital. They're hypoxic, they need oxygen, and it's really about that ordinal scale five or six. It's treating patients on top of standard of care here. As we know, we don't know really, you know, when a variant more transmissible, more deadly, and more capable evading vaccines is around the corner. There's nothing really to suggest there that C21 is specific to any mutation. Okay, to the next slide. This is my final slide now. To conclude, here is the dashboard, I suppose, or visually, this is a status slide. 2022 is set to be a busy year for Vicore. With IPF, you know, and DTx study, it's full throttle, the pilot and then the pivotal after that. With C21, the AIR study is continuing, top-line results in second half of this year and in parallel, we're fleshing out the design of the phase III. We'll be obviously talking to the FDA in second quarter of this year. With COVID-19, phase III readout second half of this year and obviously then the planning in parallel in terms of obviously, FDA and hopefully an EUA. Lastly on the right is PAH. You know, that we released a press release this week that both Gerry Coghlan and Chris Denton from UCL will join Vicore as senior clinical advisors. We look forward to starting the PAH study this year. I'll stop there and hand over to Professor Toby Maher. Thanks, Rohit. I guess if I can have my next slide. There we go. That introduces me. I'm Toby Maher. I'm Professor of Medicine and Director of ILD at the University of Southern California in Los Angeles. If I can have my next slide. My clinical and research interest is in the management of fibrotic lung diseases. I'll just take a few minutes to describe the challenge that is idiopathic pulmonary fibrosis because that helps to put the results with C21 into some context. I'll just go over some of the data that's already been shown to discuss the results that we've seen so far. Idiopathic pulmonary fibrosis is an inexorably progressive, destructive condition that causes progressively worsening scarring of the lungs. It typically occurs in older adulthood. As Rohit said, it can be considered in the same way that Alzheimer's or dementia can, which is to say that it in some ways represents premature aging of the lung in advance of the rest of the organs in the body. The typical patient with IPF is usually a male in their mid-60s. The disease will cause inexorably worsening breathlessness. At diagnosis, patients actually have relatively limited symptoms. They only notice breathlessness on heavy exertion. As the disease gets worse over time, the amount of effort required to become breathless becomes less and less until the point where patients slip into respiratory failure at rest and become oxygen dependent. As that happens, the disease has a massive impact on quality of life. Patients are unable to undertake activities of daily living because of breathlessness. Earlier on in the disease, they're unable to undertake hobbies or pastimes because they struggle because of their breathing. Before the advent of anti-fibrotic therapy, median survival for the disease was about three years from diagnosis. The vast majority, in excess of 80% of patients who develop idiopathic pulmonary fibrosis, die as a direct consequence of the disease. I can have the next slide. As Rohit's already alluded to, the disease is inexorably progressive. As you've already heard, actually, as all of us get older, once we pass the age of 35, all of us will be losing lung function every year. Normally, that's of the order of about 15-20 ml a year. The average untreated IPF patient, as we know well from the placebo arm of multitudes of trials now, will lose somewhere between 220-260 ml a year. These graphs that I've got on this slide here actually represent a study that we ran about five or six years ago now, where we gave patients with pulmonary fibrosis a spirometer, so a device to measure lung function, and asked them to measure lung function at home on a daily basis. The two graphs here represent two different patients. The dots on each graph represent a daily forced vital capacity measurement. That's a measurement of lung size, essentially. You can see in the left-hand graph that the patient has fairly consistent lung function over time, but there is, over the 18 months of the study, a clear loss of lung function. That patient has lost about 10% of their lung volume over the 18 months that they participated. On the right-hand side, we have a patient with much more rapidly progressive disease. This gentleman sadly died 220 days after entering the study, but you can see the rapidity with which his lung function is getting worse. Then if we have the next slide. This then just shows the third pattern that we see in IPF on the left-hand side, which is that of acute exacerbations. IPF patients are uniquely susceptible to developing acute lung injury. Acute lung injury is really what we've seen as the major cause of death in COVID patients. It's where the lung becomes damaged, and that triggers a widespread inflammatory response that leads to epithelial death. For whatever reason, patients with IPF are uniquely susceptible to that. In the case of this individual, he survived the episode of acute exacerbation, but you can see the dramatic loss of lung function. He lost about a quarter of his lung function in under two weeks that occurs and was never recovered thereafter. Then if we look at the graph on the right-hand side, this looks at all of the patients that we recruited into that study. We recruited 50 patients. Each line on that graph represents the lung function trajectory of patients with IPF. This becomes important when we look at the results of the AIR study later on. What we see is of that 50 patients, there were a small number, four of them or 8%, who had genuinely stable lung function over 52 weeks. It is possible for an IPF patient to be stable, but it's unusual. The majority of patients lost approximately 10% a year, but actually a quarter of patients, one in every four, lost more than 50% of their lung function over the 52 weeks. You can see that whilst IPF may be a little bit unpredictable between patients, on average, patients lose 10% a year, and over 90% of patients will lose some lung function. The loss of lung function is really the expectation, and stability is by far and away the exception. If we can move on to the next slide. As Rohit has told us, we already have treatments available for IPF, so both nintedanib and pirfenidone have been shown in pivotal studies to approximately halve the rate of FVC decline in patients with IPF. That comes at the cost of side effects. With pirfenidone, it tends to be gastrointestinal upset and photosensitive rash. With nintedanib, it tends to be diarrhea. Real-world data would suggest that upwards of a third of patients discontinue treatment within the first year due to side effects. If I can have the next slide. However, that slowing of lung function decline is important. Real-world studies now show us that life expectancy for patients on anti-fibrotic drugs is better than for those who do not receive them. The graph on the right-hand side just tries to illustrate what that benefit might be. The first line on the graph, with the gray shading underneath it, represents untreated IPF patients who are matched to patients who were in the pivotal studies for pirfenidone, who then went on to receive long-term treatment. The average patient was 67 years old. They had relatively well preserved lung function, and therefore median survival was about five years. The second line, with the dark blue shading under it, represents patients who were on long-term treatment with pirfenidone. These patients went into a rollover open label study and received pirfenidone for upwards of 10 years. You can see that the median survival in this patient group improves to about 7.5 years. A life expectancy gain of 2-2.5 years with treatment. However, the third line on that graph, with the pale blue shading under it, or represents the life expectancy for a 67-year-old drawn from the population at random. You can see that the median life expectancy for those individuals is 15 years greater than for untreated IPF patients, and is still 12.5 years greater than for treated patients. We have this massive gulf still that we need to fill in terms of restoring like normal life expectancy for a patient newly diagnosed with IPF. If I can have the next slide. We've come a long way in the last 20 years in our understanding of the pathogenesis of idiopathic pulmonary fibrosis. We recognize that it's an abnormal wound-healing response that occurs in genetically susceptible individuals following a lifetime of alveolar epithelial cell injury. The important trigger for the development of the disease seems to be exhaustion and senescence of the alveolar stem cell, and an inability of the lung to repair itself following repeated injury. Once that happens, it triggers the activation of multiple pathways involved in the normal wound healing response, and it leads to this imbalance between pro-fibrotic and anti-fibrotic mediators that results in activation of multiple cell types in the lung that leads to the deposition of collagen and extracellular matrix. Interestingly, that process becomes self-perpetuating. As the extracellular matrix changes in the IPF lung and the lung becomes stiffer, that in itself perpetuates the fibrotic response. If we go to the next slide, we've already seen this slide in one of the earlier talks. It just explains the role of the angiotensin II receptor in the wound-healing cascade. You see that it has both those arms in both the sort of anti-fibrotic and the pro-resolution phase that make it an attractive target for trying to modify the fibrotic response in a disease such as IPF. If we move to the next slide, Rohit has already shown this one. This is the schematic for the AIR study. Essentially, this is a multi-center open label study that is targeting up to 60 patients with a diagnosis of IPF. Patients are not on background treatment. They are receiving therapy with 100 mg of C21 twice daily for 24 weeks. As Rohit alluded to, this study was designed to really leverage our knowledge now of how untreated IPF patients behave. Rather than have a placebo arm and expose half the patients to no treatment, this study is an open label study, is made more attractive to patients. The goal is to compare the outcome of the treated patients with historic control groups where we would expect this 220-260 ml response loss of lung function over 52 weeks. If we move to the next slide, this just shows the data from the interim analysis. You've got the green line there, which is the expected lung function loss in an untreated population of patients with idiopathic pulmonary fibrosis. You've got there in orange the observed change in lung function in the patients in the AIR study. These are all IPF patients, all treated with C21. Granted, there are small numbers of patients, but you will see that actually, rather than losing lung function, there is at the very least stabilization and beyond 20 weeks, an apparent improvement in FVC. As I've shown you with the home spirometry data that we generated in IPF patients, it's relatively unusual for one patient with IPF to be stable over a prolonged period of time. It would certainly be incredibly unusual to select by accident a population of patients who show either stability or improvement in time. If one just takes a sort of Bayesian approach to analyzing this data, it is highly suggestive that C21 is having a positive effect in this patient group, and certainly, to my view, provides a strong rationale for moving this forward down the drug development pathway. If I can have my next slide. This is just my final slide, which brings everything to a close. Hopefully I've convinced you IPF is a really nasty disease. Although it's considered an orphan disease, it actually results in 1- in- 100 deaths in Western countries. It actually is a relatively common cause of death in Western society and is increasingly becoming so with an aging population. It is an important problem. We do have treatments available. These have been an important step forward. They give us a clear developmental pathway for new drugs coming through. As I've shown you, we've still got a long way to go before we restore normal life expectancy to our patients with IPF. As I've told you, the currently available drugs are often poorly tolerated, with more than a third of patients discontinuing them. We really need both more effective drugs and drugs that are better tolerated. The AT2 receptor makes an attractive target for treating IPF. It has all the characteristics of a target that we might expect would modify the fibrogenic response. As I've shown you the data from the AIR trial, although it's an open label study with relatively small numbers, actually, given our historic understanding of IPF behavior, actually demonstrates what might be considered some very promising efficacy. I look forward to being able to work with Vicore to take this drug further forward in the future, into sort of phase IIb and phase III trials. I will now hand over to Gerry. I forget who I'm supposed to hand over to. I apologize. I think it might be Gerry. It is Gerry. It is me indeed. Okay, thank you very much. Very interesting data. We move from Alzheimer's to cancer. This is the pulmonary arterial hypertension. We're talking about the lung vessels. Essentially, this is a disorder of rarefaction and loss of lumen in the very small lung vessels. These are less than a third of a millimeter in diameter. We tend to sort of lose these small vessels in this condition. Next slide, please. Busy slide. If you look at the top left-hand corner for starters, what I'd like to do is to start with the fact that there's been quite good news in this territory. We've developed 12 different agents that improve the outcome in this population through three different activity sites. If you look at this population, this is a median age of 50, people with idiopathic pulmonary hypertension. They've got no other comorbidity, so it's just the disease in their lung vessels. If you compare the observed data with an 80% five-year survival to the same population before therapy was available, that's the NIH-predicted outcome in this population, which was 45% five-year survival. A huge improvement in the outlook for this particular group of patients with pulmonary hypertension. This, however, is only about 2% of all the patients with pulmonary hypertension, so it's a very wide condition, very many different types of disease in it. Although it is very impressive to be able to show data like that, it doesn't represent the experience of the average patient. The second thing to say is that at an average age of 50, a 80% five-year survival is not very good. If you look at the top left-hand graph, this shows patients currently starting treatment on therapy with intravenous epoprostenol who have scleroderma associated with pulmonary arterial hypertension. If you're in the high-risk group, which about a third, just over a third of this population are, you've got a 50% one-year survival. If you're in the intermediate risk group, which is about 2/3 of the population, so most of the rest, you've got a 50% 2.5-year survival. You know, it's a very poor outlook for some patients. That's the other extreme. If we look at the bottom, we've got the average outcome for these populations. This is from the National Audit of Pulmonary Hypertension, so all the centers in the U.K. collect all their data and send it centrally to the NHS England on a monthly basis. That data is then collated, and it's been collated over the last decade. The light blue line in the middle there is pulmonary arterial hypertension, so that's the population we're discussing. You can see we've only got a 51% five-year survival. We've got this very nice group with idiopathic pulmonary hypertension who are young, but we also have lots and lots of patients who are older, who have got tiny bits of comorbidity and things like that. If we take Group 3, which if you go down to PH Group 3, this is the lung disease associated with pulmonary hypertension, so this is your lung fibrosis and other conditions where you now have pulmonary hypertension as well. You're talking about a 22% five-year survival. The outcome is dependent on the population, and it remains an area with a very large unmet need. All right, we go on to the next slide, please. All right. Because there are, you know, there's a huge unmet need still, and despite the progress that we've made, there are many new agents being tested in pulmonary hypertension. I'll just sort of take you through briefly some of the agents that are being looked at in phase II and phase III trials mainly. If we start on the right-hand side there, liposomal inhaled treprostinil. We know that treprostinil is effective. It's a good agent for treating pulmonary hypertension, works through the prostanoid pathway, which is one of our standard pathways. The inhaled therapy is what has worked in pulmonary fibrosis as well as pulmonary hypertension, but now they're changing the formulation to actually get it more into the vessels from the alveoli. If you look at the middle there, we're looking at the PDE5, so the sildenafil-type drugs. TPN171 has the advantage of being completely selective for PDE5. It doesn't have off-target effects on other phosphodiesterases, which will reduce the side effect burden. It is more selective. It binds to it more completely and blocks it more effectively. That's also being looked at in the phase II trial. On the left-hand side, we look at the endothelin receptor system, so that's the third system we currently use. We've got macitentan, which we currently use at 10 mg per day. It's now being trialed at 75 mg because it's shown that at 10 mg it does not completely neutralize the endothelin production. There's an antibody that completely obliterates ETA, so a selective approach, but of course by injection, which is also being looked at. Even within our current pathways, we think there is room for improvement. Go on to the next one. Thanks. In terms of brand-new approaches, because there are many, there's much more understanding about the pathways that are important in pulmonary hypertension now. Sotatercept, which you've already heard about, is obviously the new kid on the block. This rebalances the BMPR2 system. This is a gene that has been found in most patients with heritable pulmonary hypertension. It's also found to be suppressed in its activity, even people who don't have a genetic defect. It is something that balances against activin. If you can increase activin activity, you will suppress BMPR2. If you suppress activin, you increase BMPR2 activity. That's what sotatercept does. If we move down to the PDE5, the smooth muscle group there, the tyrosine kinase inhibitors were shown to be highly effective in treating pulmonary hypertension, but imatinib, which did this, had too many side effects. There's an aerosolized form of this that's now being trialed. If you look over across to the endothelial dysfunction, straight across from that, we can see that serotonin agents are being developed and trialed again in the phase II trial. Well, that's actually phase III. If you go down to the bottom, where we've got inflammation remodeling, we've got sort of non-specific methods of attacking that using cardiosphere stem cells, and then we've rather more specific bromodomain inhibitors and of course C21 will fit into this territory as well. You can see that there's a huge amount of investment and activity in trying to improve the outlook in this population. Go on to our next slide there, please. Okay. This is just to show you the why we're so excited by sotatercept. This is a population of 106 patients in the phase II trial, so it shows you the size of current phase II trials. The ambition here is to reduce the pulmonary vascular resistance, which is the amount or the difficulty of pushing blood through the lungs. In a normal person, the pulmonary vascular resistance is what we call one Wood unit or 80 in this territory in dynes as measured here. In this population, it was about 800, so about 10 Wood units. Sotatercept on top of max optimal therapy, which in 53% they were on three drugs already, it was still able to reduce the resistance by between 20%-30%. A very effective agent in terms of that. This also associated with increasing their ability to walk and reducing the strain on the right heart. Because of the efficacy in that trial, they're now running three phase III trials. The STELLAR study has already completed recruitment in the last year and a half. We've got two other large trials that are going to be time to clinical worsening trials. A huge investment because the, you know, it's clear that this is potentially a major way forward. It does have one big drawback, and that is that it's an injection that has to be given every three weeks. Shall we go on to the next slide? All right. You've seen this so many times, so I think we can more or less skip over it, but essentially the concept here is that we've known for a long time that the ACE system was involved in pulmonary hypertension. We've tried to use ACE inhibitors, but because of the amount of hypotension, that didn't turn out to be successful. Angiotensin receptors, we've tried a bit, but they've never really been a convincing trial. They've been badly designed as much as anything else. But again, we tend to run into hypotension with them. The idea here was that rather than trying to suppress ACE activity, you could increase ACE2 activity or the angiotensin II receptor, which then rebalances the equation towards the more sort of vasodilatory anti-fibrotic activity. You can do that without dropping blood pressure. We should be able to improve things. Thank you. Next slide. This is, as has been mentioned, the Sugen/ hypoxia trials. There have been trials in bleomycin lung and in monocrotaline lung, which were successful I understand. That was because of course the fibrosis side of things, but there's also pulmonary hypertension in those populations. Sugen/ hypoxia is a much better model of the vasculopathy we see in pulmonary arterial hypertension. Here you can see there was about a 50% reduction in the tendency towards obliteration of small lung vessels, which is what we're trying to achieve in pulmonary hypertension, and that this is associated with a reduction in pulmonary artery pressure. With this, there was also an increase in stroke volume, so the ability of blood to be pushed through the lungs. It did all the right things that we'd expect in this model to suggest that this may be an agent that would be beneficial in pulmonary arterial hypertension. It's not mentioned there, but the size of the population, so it's five in the controls, and then in each of the Sugen/ hypoxia groups, there were 10. This would be our standard model. If we see an effect here, that's when we begin to think a drug may be beneficial in pulmonary arterial hypertension. Can we go on to the next slides? All right. A slight change of tack now, because there's a second area that's being looked at with the C21, and that is in Raynaud's. Now, Raynaud's a very common condition. Lots of people get hands that go blue and white in the cold, but it can be quite extreme. There's the question of whether you can improve Raynaud's, which would be beneficial symptomatically, but there's also the question of whether you can improve Raynaud's that we see in scleroderma, where it's actually associated with a very profound vasculopathy of the fingers, and that leads to ulceration, gangrene, infection, and amputation. If you go on to the next slide, we can see just how prevalent this problem is. This is a study of looking at people with digital ulceration, looking at all comers over a period of a couple of years. What you can see here is that about half of the population either had recurrent, in green, or chronic ulceration, in brown. There's a very substantial burden of disease in this population. If you are in those two groups, then you have got about a 50% chance of being hospitalized in any two years and about a 10%-15% chance of having gangrene or needing an amputation. There's a big burden of disease here. If you can improve the perfusion of the fingers in these patients, in the same way that improving the vasculopathy in the lungs would be useful, there is actually a substantial gain for these individuals. If we go on to the next slide, please. Ooh, we're missing a slide, aren't we? Okay. So there was a small study of about 12 patients with scleroderma using thermography. What you do is you put these patients' hands into cold water at 18 degrees, you drop their temperature, give them bad Raynaud's, and then you see how rapidly you can recover from that. What they've done is looked, after 15 minutes, at the rate of recovery, and the rate of recovery in each individual compared to themselves was substantially better if they were given C21. There is clear evidence that there's potential benefits in Raynaud's, and there are further studies going to be done there. Rohit's already shown this study at this stage. This is what we propose in pulmonary hypertension. First is a proof of concept study to say, "Can you lower the pressures in these people?" Now, we know from many pieces of work that if you can lower the pulmonary artery pressure by about 5 mm of mercury, that is more than two standard deviations from what would normally happen. We can actually say, "Yes, this is an effect," but we want to do it with the CardioMEMS device because then you've got the advantage of being able to look at not just the pressure reduction, but the amount of time you can spend with a lower pressure. Therefore, you would have much more power to compare the placebo group with the treatment group. The idea would be if we can demonstrate this effect, we would be able to move on to a phase II trial very easily, and then show that this is actually something that is effective and is very likely to be beneficial in our population. I'll thank you very much, and I'll pass on to the, I'm terrible now as I've also forgotten, so the lady from Johns Hopkins. Cheers. Hi. Hello. How are you? Hi. I'm Maureen Horton, and I'll talk to you a little bit about COVID-19. It's bittersweet. It's two days ago was the two-year mark of our first patient at Johns Hopkins with COVID-19, and we still have patients in the hospital, going from taking over about 15 wards to back down to only one ward at the moment. This has been longer than we thought, and it is still present two years later. Next slide. Next slide. This is a little old. I made this slide about a week ago, but there was 435 million total cases. Of course, this is totally underestimated because in some places we're not measuring. And on the previous slide, you would have seen that there were 6 million. We're now over 6 million deaths from COVID-19. That's pretty remarkable. I'm not sure why these keep going. I don't need them to go as fast as that. But you know, the previous slide and this slide here does show that. Okay, let's stop moving. This slide shows that there, you know, we were just about under 6 million, but now we're over 6 million cases at the time. Next slide. Now, we can see this is from 2020 to 2021, and you can see that the top are weekly cases, the bottom are weekly deaths, and this is just in the United States. You can see that there's these bumps along the road. Those bumps show you that when the different variants were coming along, right? You saw the Delta variant, and then you saw the Omicron. What happens is that this has resulted. I'm not sure why this is going on a continuous loop here, but it's showing that there's a lot of unexpected deaths in IPF. Not IPF. Unexpected deaths due to COVID-19. There's many, many more deaths in COVID-19 than would be expected for the certain time of the year. This is looking global. Is there any way we can stop making my slides go forward before I want that to? Just stop here. All right. This one, it shows that this is the effect of COVID-19 on death rate. In the U.S., we typically have deaths are from cancer, from cardiovascular disease, and they just chug along. That you saw in the last previous slide was that the purple was showing the COVID-19 increasing the death over time. This has led to an excess in deaths worldwide. The darker the colors, the darker the reds, orange, and the blacks are showing that the amount of death, excess death, reported deaths over expected deaths for a given of time. This is all due to COVID-19. If you remember in the previous slides, which have been going by very quickly, that you can see that a lot of this is due to COVID-19, but it comes in these bouts. It is also after mid-2020, it is in the presence of remdesivir, dexamethasone, the monoclonal antibodies, all of the therapies we have to date. The therapies we have to date are great, but they're not completely effective. Is there another way we can look at it? In the next slide, it's just going back and showing you again how this virus came. We believe that the virus came from animals into humans in the Wuhan district. The SARS-CoV-2 virus has these little spike proteins on the end, and they then attach into the ACE2 receptor on the epithelial cells, and then that causes inflammation, as you can see from the innate and adaptive immune system and antibody formation. Clinically, it can affect all organs, but mostly we see it in the lungs, and it causes the lungs and pneumonitis. The pneumonitis leads to ARDS. Again, we have vaccine therapies. We have much better diagnosis. Yeah, if we all isolate, we can prevent the spread, but I don't know if that is economically or even socially feasible for long term, given that we are very social animals. We need new investigational drugs. The next slide, again, is just to recap. If you go forward one. Again, we're 435 million cases, over 6 million deaths. The problem is it can be asymptomatic to critical illness, and we have no way of knowing who's going to be asymptomatic or develop the critical illness. About a third of the people who get the pneumonia tend to go on to serious. Again, that's variant specific. Delta virus may be more than 1/3. Omicron, a little less than a third. Again, the incubation is about three to seven days. Initial symptoms, 80% are mild: loss of smell and taste, fevers, cough, headaches, and then it can progress to pneumonia and shortness of breath. The treatment guidelines for COVID, this is the NIH treatment guidelines. If we can go to the next slide. It's basically four pillars. Antiviral therapies like remdesivir. There's the SARS-CoV-2 antibody products. There's the monoclonal antibodies. You have immunomodulators like tocilizumab, and then you have to treat the thrombotic. We can go forward because I'm gonna try to keep up with how fast you're going. The next slide after this. Okay, this is your therapeutic management of non-hospitalized patients. Basically, when you're non-hospitalized, you don't need oxygen. It's antivirals or monoclonal antibodies in patients who have symptoms. This is the key. In hospitalized patients, again, if you're not on oxygen, nothing. If you're on oxygen, it's remdesivir, dexamethasone, maybe baricitinib or tocilizumab. Again, those don't necessarily work. The people then go on to become ARDS and critical. What we have isn't working. There has to be something else. There has to be something else that perhaps works by a different way. SARS-CoV-2 seems to be here to stay. Few effective treatments. They're all identified as antiviral or antibody. Nothing to do with how the virus is getting in, how it is affecting the normal type 2 alveolar epithelial cell reaction. We need novel treatments. The next slide. As I went before, the spike protein binds to the ACE2 receptor, right? That's how it injects its RNA into the cell, and then it multiplies, and then it goes out, and it causes damage. Pro-cytokine, microangiopathic changes, and specific antibody development. Next slide. Now, this is a picture of the alveolus. In the alveolus, what you can see is, again, this is infecting the AT2 cells, and they're causing all the damage, and then that's related. You can imagine by the time you get to that part, where you have an alveolus full of stuff, how are monoclonal antibodies going to work? Because, yes, the virus is there, but, you know, day seven, 10, when you're getting the pneumonia and ARDS, the virus is pretty much gone. The antivirals and the antibodies, how are they having an effect? We need something a little more direct. Next slide. Again, you've seen this in various forms. We have angiotensinogen from the liver. The kidney produces renin, turning to angiotensin I. Then you have angiotensin-converting enzyme turning to angiotensin II. That's what causes vasoconstriction and blood pressure problems usually, right? Your ACE inhibitors, the ACEIs, those are all your ACEIs, meaning your captopril, your ramipril, all of those for blood pressure medicine. The ARBs are also a form of blood pressure medicine that prevents the effect of the constriction on the angiotensin II. Now, if you look at the SARS-CoV-2 in the middle there, the SARS-CoV-2 binds to the ACE2 receptor, and what it does is it blocks that receptor, and it degrades that receptor. The ACE2 receptor is very important in trying to take angiotensin II to Ang-(1-7) or angiotensin I to Ang-(1-9). Angiotensin- (1-7) and angiotensin-(1-9), they have vasodilatory, anti-inflammatory, antioxidant effects. You can see you lose the vasodilatory anti-inflammatory effect aspect that should normally be happening at the same time. You know, if you have, let's say, pneumococcal pneumonia, you will still get a lot of the damage in the lung, but you won't have lost the anti-inflammatory aspect of the lung epithelial cell membrane. Next slide. You've seen this slide a dozen times before, and the only reason I'm bringing it up again is to reiterate in IPF, in pulmonary hypertension, and now in an acute inflammatory lung disease called SARS-CoV-2 or COVID-19. We can see that ACE2 receptor is very important in producing this angiotensin-(1-9) and angiotensin-(1-7). That specifically binds to the AT2, the angiotensin II type 2 receptor, and causes the resolution in the anti-inflammatory regenerative aspects. Whereas if you lose that aspect, if you lose ACE2, then you're gonna go more to the AT1 receptor, and that's gonna be causing the hypertension, the pro-fibrotic, pro-inflammatory, pro-oxidative, and a lot of the bad things that we're seeing. If we can bypass ACE2, 'cause we can't really do much with that now when it's getting consumed by the virus, and go straight to the AT2 R receptor, and that's where C21 comes in. Next slide. This was the first trial, a phase II trial, ATTRACT of C21 in COVID-19. It was a multicenter randomized double-blinded placebo-controlled trial, about 100 patients. Pretty good mix of age, sex, oxygen, and the vast majority, again, this was after dex was sort of recommended in that one study, dexamethasone was on the patients. They all had acute respiratory infection. They all had markers of inflammation. This is an elevated C-reactive protein or CRP. They followed CRP, disease severity, need for oxygen, and safety and biomarkers. You can see screening randomization, whether they got C21 or placebo, and the follow-up was 7-10 days. Next slide. Here are just three aspects that came out of the study. C21 reduced NT-proBNP. ProBNP is a marker of heart failure, volume overload, inflammation in the lungs. When the proBNP goes down, it probably means you're clearing excess fluid, pulmonary edema, the lungs are not as congested. You can see that the C21 markedly decreased the proBNP day one versus eight versus placebo. C21 in the middle panel also showed it promoted a faster recovery with less supplemental oxygen. In the beginning, day one, pretty even balance of oxygen in the placebo versus the C21 patients. By day eight, you had a marked decrease in the number of patients on C21 on oxygen, and only one patient on day 14 in the C21 group remained on oxygen. Then a post hoc kind of study looking at C21 reduced long-term injury, looking at CT scans, high-resolution CT scans, 3-6 months afterwards. You saw a marked decrease in the lung areas in the lung that had abnormalities in the patients treated with C21. This is very encouraging, very exciting, for COVID, but also for me, I'm thinking for other acute inflammatory lung diseases that we can harness the effect of that AT2 receptor. Next slide. So that led to ATTRACT-3, which is the phase III trial, which is ongoing. This is a global randomized double-blinded control, 600 subjects, 14 days, 14-day follow-up. 14-day treatment, 14-day follow-up. We're only getting hospitalized patients on oxygen. Primary endpoint, the proportion of subjects discharged from the hospital and free of supplemental oxygen by day 15. Secondary endpoint, invasive ventilation, recovery time, discharge, duration, mortality, safety. Again, FDA approved it in June 2021, ongoing recruitment. I know Rohit had talked about that slowed down a wee bit, given the current problems with Russia and Ukraine. Top-line data expected in the second quarter of 2022, and the data safety monitoring board just met, and they had no concerns. We're really happy about that. Next slide. Looking forward, what do I expect? I think COVID is here to stay. I really do believe COVID-19 is going to turn to be more endemic. I think we're gonna keep getting our vaccinations, but unfortunately, despite the vaccinations, I do a lot of interstitial lung disease like Toby, and we have a lot of patients who just don't mount immune responses to it. Monoclonal antibodies are great, all of these other treatments are great, but they're not really that effective. Again, if we have something more specific to counteract the damage that's done by the virus, but not necessarily directly by the virus, meaning your antiretrovirals and whatnot won't work. Next slide. That's it. Thank you. Thank you very much, Maureen. I would like to summarize a pretty hefty presentation of the opportunities for C21 and the coming angiotensin type 2 receptor agonists. If I can have the next slide, and if the slides are not on speed. I think we should very simply summarize that we have the core is rare lung disease still. It is IPF, and it's the core rare disease. I think with the truly exciting data that we've seen now in the IPF trials, there's no reason for us to do anything else but to aim for first-line therapy. That will, of course, be a cornerstone of our presence in this disease. Of course, anxiety and cough is important, and we're surely going after that as well. Adding pulmonary hypertension, I think, brings a new dimension. I think that's inherent both in the disease, but also to treat, vasculopathies inherent in C21. I think that we have demonstration both of vasculopathy effects and anti-fibrotic effects, I think makes the angiotensin type 2 receptor agonist and C21 unique in this space. Can we move to the next slide, please? What we haven't talked too much about is what kind of product protection we will have for C21 in IPF. I mean, there is ethically no way that we could wait for the follow-up compounds to catch up. We will of course move on with C21, given the good data that we have. We will have, of course, market exclusivity. We will have orphan drug designation status, and then give us, then, seven years in the U.S. and 10 years in Europe of market exclusivity. We have been, of course, aware of the shortcomings in the product protection of IPF. We have now several pending patents regarding formulation, manufacturing, use, et cetera, specifically covering C21, within an expiration of 2040 and beyond. It's really, without going into the details, our ambition to create a product protection that is as strong and as enforceable as a composition of matter patent. I think that's really a hard work that's been done by the team. This is, of course, an important ambition because we will move forward with C21. Can I have the next slide, please? Why is that so important with protection then? Yes, we're looking at a market now of $10 billion or even $11 billion on aggregate. Think about the potential untreated patients as well. With the current standard of care, there's still a huge medical need in IPF and aiming for a pole position there is, of course, also aiming for market leadership in this business. Also in pulmonary arterial hypertension and the hypertensive aspects of IPF is a huge market. As we just heard, with still medical needs in both the PH and PAH, the Group 1 and Group 3. Again, the combination of the effects that we've seen, I think give us a very good opportunity in this space. We need more effective treatments, that's for sure. Let's move on to the next slide, please. The emerging pipeline. COVID-19 is in phase III. Fibrosis is in phase II, but we will do our utmost to advance that into a pivotal phase III trial, based on the data that we have today. We do receive emails and messages from patients, and one is quoted. I can quote one that says, "As you can understand, time is of the essence in this terrible disease." That is, of course, important for us and inspiring us to really work hard to get there. The same is true for PAH. I think Acceleron, in a way, have paved the way for us because they've shown that now, if you can show the effect on pulmonary vascular resistance, which they've done in their mechanistic trial. I think you're very far away, very far down the road of a treatment for primary hypertension and pulmonary hypertension. That is, of course, the study that we're now going to undertake, and hopefully to do that in a shorter, smarter, and swifter way, with the device that we're using. If we can have the next slide, please. Again, looking into the new indications. Now, I'll just give you a glimpse of what that can be. I mean, we're now looking at Vicore more as a company with three different boxes and COVID and interstitial lung disease, of course, being the boxes that we're entertaining. Then there is another box that can be separated into a number of boxes. We can look a little bit into new indications that we are kind of considering and working with without starting clinical trials yet. That's preeclampsia. It's women's health and it's kidney disease, diabetic nephropathy. There's also other areas that we're exploring preclinically. Of course, we base this evaluation on the preclinical data that do exist already. The opportunity for smart clinical trials that gives you a proof of concept, and then, of course, also the medical need, what could an angiotensin II receptor agonist really accomplish in this area. I think Vicore has really the expertise both in biology and chemistry and unique position to pursue these opportunities. If I can have the next slide, please. I'll just give you a glimpse about how I want to think about diabetic nephropathy, and that's a severe diabetes complication. Of course, it's a chronic kidney disease, and there are many genesis of chronic kidney disease. We picked one where we think this the opportunities are the best for us. We have a number of animal models where C21 has shown effects in diabetic nephropathy, and not only that, also metabolic effects. I think that is something that we believe has a good opportunity and bodes well for the. We know that in IPF we can replicate what we've seen in animals. This bodes well for the future also in kidney disease. We've done now the human kidney that Johan talked about as well and looked at TGF-beta expression. We have a very nice dose-dependent decrease in TGF-beta expression in human fibrotic kidneys. That's those parts that we are working with. We also know that the receptor is present here. That is one area that we work in. Of course, it is something that is very, in a way, mechanistically a lot of similarities with IPF. It is fibrosis, and it's kind of a premature aging in the organ. If I can have the next slide, please. We change completely to preeclampsia, which is a disease which is not a matter of aging, but it's hypertension and organ dysfunction and also in many cases, death during pregnancy. It's actually the leading cause of death during pregnancy. This is a disease that we have no therapy for today. The only treatment that is given is to premature delivery of the baby, and that could be a very premature delivery. Of course, if there would be something that could restore the blood pressure and prevent the proteinuria and the other organ dysfunction to happen, this would of course be great. This is now also a disease where we have a lot of preclinical evidence, and here we have data in a standard model for preeclampsia. Now we use angiotensin- (1-7) of this publication, where we can restore systemic blood pressure, where we can restore endothelial NO synthase, and we can also bring back fetal weight to normal in these situations. Of course, we have a little bit more work to do. We do have a molecule that would fit very nicely into this or disease. We know that we have vasoregulatory effects directly of angiotensin type 2 agonists via NO release. We've seen also in the systemic sclerosis model, for instance, that we do have positive effects. That's also a disease where we can in a very short-term clinical study actually monitor blood flow during pregnancy. That's just to give you a glimpse. To continue to the next slide, how do we look at all these opportunities? Of course, we cannot do everything ourselves. The history of Vicore is the history of a company that have given away C21 to a number of scientists, that has given all this very useful information in understanding of the angiotensin type 2 receptor as a target in a number of disease. We think it would be a very interesting idea to promote clinical AT2R research by providing the tools now, not to treat animals, but to treat humans in indications where specific investigators have a specific knowledge and of course would like to explore the angiotensin type 2 receptor here. We are talking about a AT2R academy and where we can actually provide drug, placebo and documentation to investigator-initiated trials. That could then, of course, help us to shed light over new indication and new opportunities. This is something that we will work with during the year and also try to be more active, more present in scientific community, trying to move the focus from animals to humans, and of course, form the basis for ATTRACT as a new class of drugs. By that, I thank you and hand over to the moderator for questions and answers. Well, maybe the answers should come from us. Great. Thank you, Carl-Johan. At this time, we'll be conducting our question and answer session with our speakers. As a reminder, if you would 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. To our analysts, we now invite you to join via Zoom. Please hold for a brief moment while we pull for questions. Our first question comes from Dan Akschuti from Pareto. Dan, you may go ahead and unmute your line. Hello, everyone. Can you hear me? Yes. Perfect. Thank you very much for this very comprehensive presentation. Indeed a lot of material to digest. A few questions regarding the IPF trial and also looking a bit forward for the next steps. Considering also the effect size that has been demonstrated now that is quite somewhere else compared to what we've seen from Promedior, also United Healthcare and other companies, could we expect a fairly small pivotal trial, or would you like to wait maybe for three months later to see a bit how the effect is going in June for the patients that are yet to get to 24- weeks and where we see this increase and longer, and maybe then you have time till September as well to have another three months. If you're following that data like that, will we also get additional interim readouts in summer and then autumn? Yeah, that would be my first question. I don't know who is going to answer, but I can start and maybe you can let me know if you want to chip in. Thank you, Dan, for your question. It was not one question, but I know that when you pose questions, it's a number of questions. It's a string of questions. The next step, talking about the effect size, and I think we should also ask Toby to fill in. But of course, the pivotal trial will have two purposes. One is the safety database, so there needs to be a number of patients, if we can, to make sure that we have a good safety profile of the drug. Then of course, it's a sample size calculation that will determine the size of the study. We haven't done that homework yet. I don't think we'll see a extraordinary small pivotal trial. I mean, as a comparison, we can think about the Roche studies. That's one study, about 600 patients, and then the pamrevlumab study. I think they have two studies of about 340 patients. That's the size that they have taken. Of course, if we have a very good effect, we may not need larger studies than that for demonstrating effect, but then we also have the safety aspect that we need to cover. I think that's the answer to that. We will of course follow the patients that we do have right now. I would be very surprised if we didn't see the same picture of the data when we continue to follow them. The numbers will be different. I think I'll hand over to Toby to maybe give an answer to the question as well. I'll unmute myself. That works. It's a good question because obviously, what one sees will feed into the expectations of any powering of a study. Notwithstanding the need for the studies to be big enough to sort of convince the regulatory authorities that the drug is safe, you know, if this genuinely is a drug that has the potential to improve lung function, then of course that puts a very different spin on any phase III trial and trial design. I think if come the autumn when we've got a bigger data set, we're seeing the same thing, then I think it does open up opportunities in trial design that aren't possible when we're simply looking at a drug that slows FVC decline. I think in answer to the question, it is tantalizing, and I think if we see the same in October, then we could be having some interesting discussions about how we do the pivotal studies. Thank you very much for your answers. You mentioned also the safety aspect being a part in terms of that that might define a bigger patient population than needed from a effect size perspective and looking at the safety profile that so far has been shown by C21 in the various trials, and looking at the one of standard of care, wouldn't you think that there could be even a completely different problem there in the sense that the side effects of the standard of care could introduce some type of positive bias towards C21? The C21 arm, 21 arm, and so that people kind of that worry with the hair loss at the higher doses that you didn't see now, but that your patients get at least a hint based on GI side effects and absence thereof that. How would regulators look at something like that? It's in a way not your fault that the standard of care has these side effects, but how can we look at the kind of readout from such a randomized and blind trial then? Am I going to answer that one? Again, you throw up some important and interesting challenges that come with designing phase III studies in IPF. I think ever since the approval of the two existing drugs, it's become harder to know how to design an optimal study. Thus far, the majority of companies have taken the approach of adding their new drug on top of standard of care, which of course creates its own issues in terms of dealing with the side effects of the underlying treatment regimen and has issues related to the expectation of rates of change in FVC amongst other things. What we've not really seen is a true head-to-head study design. I think as you allude to, there are a number of considerations to be made, which includes unblinding by side effect, and that is certainly a challenge with the existing drug regimens. Similarly, the issues with sort of liver function abnormalities and everything else that comes with using the other drugs also makes the design of any trial where you have two blinded treatments difficult. I think there will be a lot of things to think about, and I think the agency's view on all of it will also be important because I think this will be new territory for them really as well in terms of defining how these studies should be delivered and interpreted. Okay. Thank you. The last question on the IPF side. The patients in Ukraine, Russia, as understood, they were just a few and two were already at week 24. Could you maybe give us a few more details on how big the population from these countries are in the trial? Well, I think the population in Ukraine and Russia is small in the IPF trial, so I don't think it will have a big impact on the trial. Of course, at least one have passed week 24. I cannot give more details than that off the top of my head. But they are few, and we're not dependent on those patients in the IPF trial. Here we have, of course, already secured some of the data. I mean, we've cleaned the database to do this interim analysis, which I think is also a big advantage because that could be a problem in a country during war. It is sad in many aspects, and we have a few patients, but it doesn't have a big impact on the study. Okay, thank you very much. One last question from me on the PAH side. We got some interesting data last year from United Healthcare there with treprostinil. Mm-hmm. If you look at it, you see that they are trying to do the opposite. They started it in the PAH, and now they are looking into IPF, where they had interesting effect, much weaker than what we saw now from C21. You're looking now into PAH. If looking at the preclinical models and especially the Sugen/ hypoxia model, you can see that treprostinil does not have a direct impact on vascular remodeling. Is that the kind of part where you would see that you're clearly differentiating here C21 towards that drug? Or do you see any other mechanistic reasons where C21 could be better than treprostinil or where a combination would make sense? Maybe we can pass that question to Johan and elaborate a little bit on treprostinil or Rohit. I think, yeah, I think this is better for Rohit, actually, since he worked on this. Sure. Yeah, I mean, as you've seen, you know, in the Sugen/ hypoxic model, there was, you know, effects on remodeling there in terms of that muscularization and those plexiform lesions that you see, you know, and the luminal opening. So the remodeling. So I think we really see that sort of as a disease-modifying effect. Gerry also shared with you some data we did, a study we did, mechanistic study, the single-dose in Raynaud's phenomenon secondary to systemic sclerosis. And there we saw, you know, in these tough resistant vessel, you know, vasodilation. And then obviously, there's the anti-fibrotic aspects. Yeah. Remodeling, perhaps some vasodilation there, anti-fibrotic, you know, I think is really we would see how C21 would be working here. I think you know I shared with you the design of the study, and I think really it's there a number of things there that we'd be obviously looking at. The CardioMEMS, we would look at the hemodynamics. We'd quite possibly do echo as well, looking up via the right heart, as Gerry has advised us. Maybe something like a functional endpoint as well from a patient perspective. If I make a quick comment, treprostinil does have some anti-remodeling or remodeling effects as well, does have some anti-inflammatory effects, but they are quite minor. This looks more impressive than that. We've learned over many years not to jump from animal data to human data. We need to do this in humans. Thank you very much. That's all from my side. Thank you. Thanks for the question, Dan. Our next question comes from Fredrik Thor from Redeye. Fredrik, you may go ahead and unmute your line. Hello, and thank you. I was just wondering if you could clarify a bit because in the press release for the interim analysis for the AIR study, you mentioned a potential for a phase IIb dose-finding study. Has this changed, or yeah, could you give some context to this, yeah, how this differs from the pivotal trial? Yeah, I can comment on that. That would have been the normal path. I think we were really surprised by these extraordinary data. I didn't. I think they didn't really sink in in the few days time that we had to think about this press release. I think we should look upon IPF as a cancer disease with a very poor outcome, with its, it's a very devastating disease and not very good standard of care. If you take them, you have the addition of side effects. There's really a huge medical need. In my mind, with a drug that has the safety profile that we've seen of C21 and with the efficacy that we demonstrated, I think we should move directly into pivotal trial. Of course, this has to be vetted and confirmed by regulatory authorities. Just as a quote, "Time is of essence in such a terrible disease for these patients." I think it's our obligation to try to get it to patients as fast as we can. In terms of how many patients you would want to get data on before you initiate the pivotal trial, you mentioned that a bit before, but maybe if you could elaborate a bit more. Like, would you want to see perhaps 30 patients or so? Yeah. When could you initiate the pivotal trial the earliest in your mind? The earliest our plan is to do it in the first half next year. I think we'll collect the data that we get alongside, but scientifically I think we will not learn so much more from this trial that we are conducting right now. We will get more data for our calculations, yes. That's about it. I mean, we will not let that stop us to move forward to the phase II trial. A final question for me about VP03 and can you elaborate a bit about the business strategy given that you want to target larger indications potentially and several at the same time? How would you work with partners, for example, compared to how you think of orphan indications? I think we're. Those little boxes kind of indicate that they're not business units in a strict sense. I mean, they function as kind of virtual business units and we could have a partner for one area and do another area ourselves. Clearly, a small company like Vicore should not entertain diabetic kidney disease, which is a large company indication. But I'm also sure that if we can show proof of concept in patients with the new mechanisms, we will be able to attract partners in such an area. That's kind of the thinking and I think we're open to discuss each and every of these little boxes, how do we move them forward. It could be spin-outs, it could be collaborations, it could be something that we do ourselves if it is an indication that is small enough for a small company. Yeah. Reflexive. Yeah. That's all from me. Great. Thank you for the questions, Fredrik. Our next question comes from Suzanna Queckbörner from Handelsbanken. Suzanna, you may go ahead and unmute your line. Hello, and thank you for this very interesting R&D day. I'm just a little bit curious about the historical control in the IPF trial. Perhaps you could tell me a little bit more about the patient demographic here and how it compares to those receiving treatment, and just the thought process here, as well as when it comes to the statistical evaluation. Of course, at this point, you're at the interim analysis, but some kind of read on it. Maybe we should ask Toby to describe the state of IPF in mild, moderate, severe disease and I mean the background there for the 240 mls. Yeah. We've learnt over the last 20 years of doing clinical trials in IPF that the disease behaves fairly consistently at the population level. That is irrespective of baseline disease severity. We would expect FVC loss to be linear across the course of a disease in a cohort of patients, whether it's sort of mild early stage disease or advanced late stage disease. The sort of critical component in clinical trials in ensuring consistency has been the central reading of CT. One of the advantages that IPF has over diseases perhaps like asthma or inflammatory bowel disease is that we can adjudicate the CT scan to ensure that the patient population being recruited into the trials is consistent and fairly homogeneous. You know, as such, that population reflects the real world, but by using the CT it allows us to filter out patients who might have other forms of fibrotic lung disease. I think with all of that in mind, we've seen incredible consistency across different clinical trials run across different territories in the world in terms of the behavior of IPF populations without treatments. That's been mirrored in real world registries. It's sort of amazingly consistent over time. I think one can be confident that with the average IPF patient who fits standard clinical trial criteria, that the disease will behave in a given way. Maybe we should add that we have been very strict on these criteria and use the central reader that has been doing this for a number of trials that has been published, and that's been then the basis for the calculations of the or the estimate of the 240 ml. So that is of course very important in any trial, but even more important maybe in an open label trial. Mm. The other thing to mention also is for the first three months, we were bringing the patient back every fortnight, next three months, every three weeks, and then the last three months, every four weeks, which is probably a lot more than what's been done in other studies. This is the spirometry here. We're also using market sort of leader ERT. You know, they're the best at providing the equipment, the training, and then also the overread. So it's really important. It's about that intra-patient variability, and it's about getting the data in and obviously, you know, following these patients up very regularly. That's what we did in the study. Okay. I'm also curious for a question for Maureen in terms of COVID-19 and the patients that would be ideal for the C21. You said these would be patients who've already received antivirals and monoclonal antibodies. Can you just explain that a little bit again? I think I missed something here. Just so that I have a better understanding of when the ideal patient would receive this treatment. Sure. I mean, you didn't get it when the slides were zooming past the screen. What I was trying to say is that currently we have a lot of things. We have antiretrovirals, right, which will get the virus and kill the virus, right? We have anti-inflammatories like dexamethasone that just broadly decreases inflammation. Tocilizumab, which gets rid of IL-6, which is a, you know, just an inflammation marker there, and baricitinib. Even with those drugs, people are still going into ARDS, they're still dying. Looking at it from a different perspective, is there some other mechanism of action in which we can use to help promote normal lung healing? That's where the, you know, the angiotensin II type 2 receptor comes in. In that the C21 can bind to that, and it can have this anti-inflammatory vasodilatory effect. What I was trying to say is that despite all of the drugs we have in our armamentarium now, many of which were in all those blips I showed you of the COVID-19 cases, people are still getting sick. Looking at it from a different perspective, is there something new we can do? C21, for me, I think would be most effective, not on the asymptomatic patients, but in patients who are already showing some epithelial lung injury. Those would be patients on oxygen. And that's what the ATTRACT-3 trial is. They're patients with ordinal five, six scales, so they're on low levels of oxygen or high flow nasal cannula, but not to the point where they're intubated. I think here, and even in IPF, this is my thought too, is that you wanna get to heal those epithelial cells early, not late. You don't wanna wait till the end stage IPF. You don't wanna wait till the end stage ARDS, because a lot of the, that time you already have damage and there's nothing you're gonna be able to do. Did that sort of answer what you asked? Yes. Yes, it did. Also just a final question. The idea here is that the C21 is very much a part of the actual wound healing process rather than the clearing or the clearing of the actual fibrotic stroma that is there. Or how am I supposed to think about this? As a regenerative mechanism or as a preventative of further fibrosis? The COVID-19, which is an acute lung injury model or, I mean, it's not a model, it's a disease. In an acute lung injury model or an infectious model, you damage the type 2 airway epithelial cells. With that damage, you don't get the normal regeneration and the normal effects of the anti-inflammatory effect. In the COVID-19, it would probably help to decrease the inflammation and the damage, and then going on to end-stage processes. I'll leave it to the IPF guys to say what they think it is. You know, I think it does the same thing, but I'll let Toby answer specifically for the IPF. Yeah, I know. I think with IPF that the epithelium is important both in sort of chronically progressive disease and in acute exacerbations. I think particularly the acute exacerbations of IPF mirror very closely what we see in the acute lung injury in COVID. I think there is a big overlap in the way that the drug potentially has a beneficial effect across a range of pulmonary diseases, but particularly when you think about COVID lung and some of the consequences of idiopathic pulmonary fibrosis. Okay. Thank you very much. Thank you for the question, Suzanna. I'll now turn the call over to Hans Jeppsson to read the remaining questions that came over the webcast. Yes, thanks, Tara. I've got a couple of questions. Let's start with the first one to maybe direct to Gerry Coghlan on PAH. What are your thoughts on the CardioMEMS device? Is it approved and validated? The answer to that is yes, it is approved and validated. It's not been specifically designed for use in pulmonary arterial hypertension. It was designed for use in heart failure with pulmonary hypertension, so Group 2 pulmonary hypertension. There it has shown itself effective, and it's now licensed in more or less any type of left heart failure with pulmonary hypertension. What you do there is use diuretics to lower the pressures, and you can demonstrate that if you lower the pressures, you're less likely to be hospitalized, less likely to have complications from pulmonary hypertension. Yes, we know that it works. Yes, we know that it's reliable and reproducible, that it's got a low complication rate. The purpose of it in this trial is to say that if we can lower, because we can measure both the pulmonary hypertension and the pulmonary pressures and the pulmonary vascular resistance, we can estimate somewhat indirectly, but it still works. We will be able to show not just that at one point in time, which is what normal studies do, that the drug works, but that it has an effect that is consistent over time, and that's what you need in order to allow the right ventricle to recover. Perfect. Thanks, Gerry. Another question for you. Assuming success in the PH proof of concept trial, what would be the next step in development? A phase IIb dose-finding study, what would be the comparator in such a trial? I think placebo would have to come in here somewhere along the line, unless you want to go head-to-head with some of the therapies we have, which I think is unlikely. We would normally consider a placebo-controlled trial, if you know like was seen in IPF. There was an absolutely massive effect, you could argue that. We would have people on background therapy, and it would be C21 versus placebo in that. Now, whether you need to do dose ranging is the question. I think one needs more scientific data to help us on that. You know, if the drug is relatively effective and has a low side effect burden, then one's not gonna get over concerned about doing dose ranging. Clearly, you know, we want to have a dose that is effective and the maximum effective dose, but that which causes minimum side effect, and it's getting the trade-off between those two things. That would be, I think, where you go next. I do think that, you know, the lessons of the past are that you do a phase II trial, but if you rush to a phase III, you can sometimes come a cropper. Thanks a lot, Gerry. Maybe next one for Johan. How does C21 compare to Acceleron's sotatercept in animal models of PH? Sure. sotatercept was described by Gerry, like we also heard from Gerry, C21 is effective in three different animal models of pulmonary hypertension. Of these, the most predictive is the Sugen/ hypoxia model. Only if you start treatment when PH, the pulmonary hypertension, is already established in the animals, so-called therapeutic treatment. As Gerry also described, the therapeutic treatment in this model with C21 doses that mimic the clinical exposure has very convincing effects on many important parameters, including vasculopathy, pulmonary artery pressure, and cardiac function. In contrast, in a recent publication, sotatercept was only effective in the Sugen model when given before and during the development of PH. The relevance of that is obviously a bit limited. When sotatercept was given when PH was already established in the animals, it apparently did not reduce pulmonary artery pressure. I would also say that the doses of sotatercept that we used in the rats was quite a bit higher than those used in clinical. I mean, there's no direct comparison between two drugs, but our view is that C21 definitely has a very competitive profile in preclinical PH models, and particularly in the Sugen/ hypoxia model. Perfect. Thanks, Johan. I think we're switching gears to IPF. I've got a couple of questions there. I think we start with Toby, who has to lead. First one for you. If Vicore is able to demonstrate the results again in the next trial, how will that change standard of care? I think, you know, if you have a drug that genuinely offers the opportunity to improve lung function, and it does so with a very good tolerability profile, then I think the answer to that one is very easy. It will change standard of care overnight because patients would obviously want to be both on the most effective and the best-tolerated treatment. You know, I think I've already highlighted the difficulty with current standard of care, which is that it is associated with significant tolerability issues. Secondly, all we're offering our patients at the moment is the opportunity to slow disease decline. We don't actually improve any of the symptoms that they present with. you know, if these results could be replicated in a phase III study, I think that would be a game changer for patients and clinicians. Thanks, Toby. Maybe next one for Rohit. What is the timeline for the pivotal trial in IPF? Sure. So I mean, yeah, we've started planning of the pivotal studies, study, I should say. I think really, if we look at it now and we compare it to what we'd previously said, really this sort of, I suppose in some ways takes us you know gives us a sort of a year ahead really, if we start the study in the first half of 2023. So if we're sort of working backwards then, the next step really is to engage with the FDA, and the plan is to do that in quarter two this year. Perfect. Thanks, Rohit. Maybe the next one for Carl-Johan. Do you think you have the right dose to proceed into phase III in IPF? The short answer is yes. We know that we have a dose that is the highest tolerable dose. I think with the data that we've seen with gaining lung function, it's more than you can ask for. I think when we also look at the binding curves and the clinical dose in relation to receptor occupancy that Johan showed, I think we're exactly where you want to be with your dose. I think that is as far as you get in this situation. Could a little bit lower dose be effective as well? Maybe that's true, but I don't think that is as important when you have a drug with so limited side effect profile that kind of prevents your dosing. If we know that if we increase the dose to the double 200 mg twice daily, we will encounter hair loss as a side effect. Of course, compared to a deteriorating lung, that is a small price to pay. But I also think that with the data that we've seen, let's see how it develops with further patients, but with an increased lung function as a result. I think it's difficult to get any further, but I'll stop there. I think we have the right dose. Okay, thanks, Carl-Johan Dalsgaard. We've got quite some similar questions from folks. I'm trying to combine them and try to pose them appropriately here. I think next up, next one would be, can you comment on the safety profile in the phase II IPF study so far? Any serious adverse events? Maybe Carl-Johan Dalsgaard or Rohit Batta. I think that's for Rohit. Yeah. I think the key aspect there is any related serious adverse events. No. That's what we categorize really as what we call SUSARs. So there haven't been any SUSARs and no new safety signals, really. And like I said, most importantly, no GI sort of signals there as well. So far that's good. Obviously, we had this COVID study, phase III. It's a two-week treatment, obviously much shorter. But obviously, you know, we're going, you know, halfway through the study there. And the DMC have had their safety review there, and there was no signals there as well. So far, so good. So reassuring. Perfect. Thanks, Rohit. Maybe a final question here is also for you, Rohit. Will Vicore allow patients in the AIR to continue with C21 if they would like to do so? Yeah. That's an insightful question. So, I mean, obviously, yeah, in the IPF study, the treatment period is for nine months. I think the question being asked here is that if patients, you know, after completing the study, would like to continue treatment further, you know, would we be able to make the drug available? And right now, as it stands, we, you know, we don't. I think that's something that we could, you know, speak to regulators, speak to other relevant authorities about in terms of sort of compassionate use or name patient program or whatever. Obviously, these are patients where, you know, there's a favorable benefit risk profile. Obviously, given the stage of development and where we are, you know, we wouldn't offer compassionate use to patients outside the clinical study, in terms of patients who haven't been in one of the, you know, the Vicore clinical study. You know, this is something very interesting, and it's something that we would obviously need to speak to the relevant authorities about. Perfect, Rohit. I think we have a few more questions, but I think we're running out of time, and I think most of the answers to those are covered in the separate interim results session we had a few weeks ago. Encourage those of you who have posted questions to look at that one. I think that's it from a Q&A perspective. I'll turn back to Carl-Johan Dalsgaard for some concluding remarks. Thank you very much, Hans, and I would like to thank everyone for listening in and for participating for questions. Of course, a special thanks to Maureen, Toby, and Gerry for their excellent presentations and engagement in the Q&A session. I think the enthusiasm for C21 is rather large from our side, and I think also the R&D day that is going over time kind of shows the excitement in the Q&A session as well. I thank everyone for listening in, and have a very good day.