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

Good morning, and welcome to the Vicore Pharma R&D Day. [Operator Instructions] 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.

Thanks 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 on the arterial 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 and Gilman's, you will find a chapter that is at price 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. And can I have the next slide, please? And then the next slide. That, together with myself, our CSO, Johan Raud; and CMO, Rohit Batta, will present today. And that is Toby Maher, Gerry Coghlan, Maureen Horton. They would 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? So first, I will give you a little bit of an update on the key programs that are ongoing. And when we start with COVID-19, I can tell you that about half the study is enrolled. But I will also tell you that recruitment in Ukraine and Russia has been stopped for obvious reasons. And this will have an impact on time lines and the population that we are reviewing. So we have already announced that top line data will not be first half 2022 but second half 2022. And 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 hot spots 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, then again, about half the study's enrolled. And again, recruitment in Ukraine and Russia stopped for the same reason. And this has not as big impact on the recruitment. But of course, we will do the utmost post 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 Phase II IPF, we recently reported an interim analysis with some unprecedented data in terms of not only stabilizing disease but increasing lung function. And 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. So 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 from 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 new -- first new molecule has passed the preclinical evaluation, is being prepared now for a Phase I trial starting the next quarter, so quarter 2. And in addition to that, we actually have 4 more compounds, 3 of which are [ pre-CDS ] and will be evaluated during this year in the final tox studies, and one is already being selected in favor of the 106 that is now being forwarded. So all in all, I think we have made great progress, and this will be a good starting point for the next step, which is an -- can I have the next slide, please, that we are looking into this receptor, then the angiotensin type 2 receptor as a new drug target. And 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. And 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. So can I have the next slide, please? There is more than 100 scientific publication on C21 and its effects in various and a variety of animal models, and this is really amazing what kind of background there is for this work. But until recently, there were really no clinical data. So we were -- we didn't really know if we were dealing with another asthma drug for guinea pigs or if this was for real. But I think we can say now with the 3 Phase I studies we've done, the 3 Phase II studies we have done and is 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 all through for -- also for clinical treatment. So this is, I think, also something very important that if we believe that this represents a new class of drugs, there is certainly a huge unmet need and a huge opportunity in a number of diseases. And 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 by which mechanisms angiotensin type 2 receptor agonist may work. And you will hear more about this later in this presentation. But one important thing is that we do have this receptor on the progenitor cell in the alveolar type 2 cell. And this type 2 cell is really keeping up the integrity of the alveolar, which is important for preventing fibrosis to start and also itself 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 artery hypertension, but I think this is also inherited in all IPF patients and their pathology. We have shown anti-fibrotic effects. But not only that, we've also shown fibrolytic effects. So it means that we can actually resolve some of the fibrosis that's already been generated with these mechanisms. So 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. And 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 a Phase II trial, and the data were very good. So that represents one opportunity. Interstitial lung disease where we now are focusing and 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. Then I will give you a little bit of glimpse later on in the end of the presentation of 2 areas that we are kind of investigating and that is preeclampsia and diabetic nephropathy. But there is several other areas that could be of interest for this class of drug. So with that, I'm very happy to kick off this event and hand over to Johan Raud, CSO of Vicore.

Thank you. So 10 minutes of some scientific background on the renin-angiotensin system, and in particular, about angiotensin type 2 receptor and Vicore's drug candidates. Take the next slide. So 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. So it's fundamentally an ancient rescue system in a way. But the main pathway for this is the hormone angiotensin 2, which binds to the angiotensin 1 type 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 [ AT1R ] receptor pathways is a bit, so to say, trigger happy and can overshoot and cause [indiscernible] hypertension. As most of you probably know, there are several antihypertensive blood pressure drugs that block either the formation of angiotensin 2 or block the AT1 receptor. This system also has a parallel pathway. Basically, that's the opposite via angiotensin type 2 receptor, which is also the target of Vicore's drugs. So activating this type 2 receptor, basically, it triggers resolution and repair, which includes things like vasodilation, immune motivation [indiscernible]. This receptor has been known for quite some time. But at least from a clinical point of view, it's certainly another target. C21, like Carl-Johan said, this is first AT2R agonist to reach the chemical stage. I would also like to briefly mention the angiotensin peptides, Ang(1-7) and Ang(1-9), which are suggested to be endogenous into our agonist. There has been some contradictory both views and findings in this area where involvement of the so-called Mas receptor is suggestive. You can take the next slide. As you can see in this table, we have done some work with this enterprise. Most of this is Vicore's unpublished data. So 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 peptides have a profile that's actually very similar to C21. And they are potent AT2R ligands and don't seem to bind AT2R. And they didn't activate the Mas receptor in this system. So next slide. C21 was first [indiscernible] almost 20 years ago. And since then, a very large number of labs around the world have done quite impressive -- have shown quite impressive effect to C21 in the range of the animal models like Carl-Johan mentioned. And this includes models for pulmonary fibrosis, pulmonary hypertension, kidney fibrosis, preeclampsia, just to name a few. And to the right is a published example showing that C21 can effectively protect against experimental pulmonary fibrosis. And 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. The next slide. So if we switch to the human lung, this slide shows that we can visualize both angiotensin and C21 by [ removing ] thin sections of fresh human lung tissue. So in upper-left image, you see binding of isotope-labeled angiotensin 2 alone. One step to the right, you'll see that the one receptor blocker, valsartan, does not block this angiotensin to bind it. While the next image shows that adding C21 completely displaces angiotensin This altogether suggest quite strongly that the value 2 receptor very little AT1 receptor. And current to direct, it's also interesting. It simply shows how increasing concentrations of C21 displace this Ang II binding, and with an inhibitor concentration 50 of 4.5 nanomolar, which is almost identical to the receptor binding data that we have. This is, of course, very encouraging. And also importantly, the red asterisks that you can see on the curve is showing the concentration of free C21 that patients with the doses that we are using in the past. If you look at the 2 images below, the left one shows binding of the very low concentration of C21 isotope in the lung tissue. And to the right, you see displacement of this C21 binding with so-called target engagement of C21 in the lung. Take the next slide. So if you continue with C21, and this slide shows the [indiscernible] activity and fresh IPF tissue transplants with dose-dependent inhibition of both the prophylactic back to PDF and the collagen 1, alpha 1, which is the major component of type 1 collagen, which the major collagen entirety fibrotic tissue. This asset is obviously more specific than animal models. And importantly, the concentrations that we have used are in the range. I can also mention that we see similar effects in human fresh kidney tissue and also with our new AT2R agonist. So if we move to the next slide, if we all go outside the lung, the AT2R receptor is also present in other human tissues, which, together with all the preclinical studies I mentioned before, makes targeting this receptor interesting in the 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 in a few minutes. We'll take to next slide. So you've seen this already. Carl-Johan said a few words about this. So if we dig a little bit deeper, the effects of the AT2R receptor is to be mediated by at least these 4 mechanisms. If we start with the first box, Johan briefly the AT2R receptor is highly expressed on these type 2 epithelial cells. And these are then important for repairing alveolar. They also produce -- secrete surfactant, which helps expand the lungs. Secondly, in box 2, the activation of AT2 is known to stimulate vascular epithelial cells to release nitric oxide, which is a vasodilator and important molecule for keeping blood vessels healthy. Thirdly, as Carl-Johan shown before, C21 is antifibrotic and at least in part due to inhibition of TGF, but also there is direct inhibition of myofibroblast, which uses fibrotic components. And as shown in the fourth box, C21 has some very interesting fibrolytic activities in that it increase so-called matrix metalloproteinase enzymes that can break down fibrotic tissue that has already been formed. And I also would like to emphasize that all of these mechanisms that I described have experimental support. Two more slides describing our new molecules. So if you move to the next slide. As I mentioned before, C21 was developed quite a while ago, and we have worked extensively to develop new improved [indiscernible] this compound C106 is the most advanced so far. These new candidates all have improved stability and metabolism compared to C21 where AT2R affinity and selectivity is similar to or often better than C21, and they all suppress TGF in human tissues, also often better than C21, as you can see below in the graph for C106 in IPF tissue. Then we can take the last slide. These are currently our most advanced drug candidates with C106 expected [indiscernible] this year and with C111, C112 and C103 also progressing very well. C21, as Carl-Johan indicated, is very similar to C106 and this past some lower priority right now. These new compounds can all be used in new indications [indiscernible] but they have slightly different profiles, and we will provide more details about this at a later stage. All in all, we made a large number of compounds, several within 7 classes, and these compounds have pending patents projected to Vicore's protection to 2040 and beyond. Now I will stop here and pass the word on to Dr. Batta, our CMO.

That's great. Thank you very much, Johan. So yes, just -- I mean, I'm Rohit Batta. I'm the Chief Medical Officer for Vicore. And so our core focus really is to bring novel therapeutic solutions to patients with severe lung diseases like idiopathic pulmonary fibrosis. And I was on an IPF patient conference not too long ago. And the motto there was living well. And unfortunately, that's not really what's happening today with approved anti-fibrotics. They haven't impacted mortality. But on the flip side, they have negatively impacted quality of life. And we've made great progress with our clinical programs, and I'm going to take you through some of these successes today and the key milestones for the year ahead. Go to the next slide. So 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. So instead of here's a visual display of our clinical programs led by C21, our pathfinder medicine. And if I start on the left-hand side, idiopathic pulmonary fibrosis, we're looking at the disease in the 360 way. We're really positioning ourselves as a one-stop shop. With C21 or VP01, the project name, we aim to stop the progression of the disease. VP02, which is not shown here, it's an inhaled version of Thalidomide. The aim is to alleviate the disabling and distressing IPF cough. And then VPO4 with the DTx is addressing the mental health burden of IPF. And 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. And sadly, we're not at the end of this crisis. I mean, yes, things have improved in the short term with vaccinations. But the virus is still very much in control, and we only have a handful of therapies for patients that are hospitalized and hypoxic. And I'll take you through our Phase III design there. And then on the right, we have pulmonary hypertension. And it's coined the cardiologist's cancer because it's due to the high morbidity and mortality that's seen there. And 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. And we'll be sharing some of our preclinical data with the Sugen-Hypoxic model, which shows that C21 has a remodeling effect. And it's similar, if not better than what was seen with -- what's been seen in Sotatercept studies. And we've recently heard about the Merck acquiring Acceleron for sort of eye-watering amounts there. So we're moving expeditiously into a Phase II proof-of-concept study, and I'm going to take you through the design. Go to next slide. So you'll hear from Toby about the disease IPF and the unmet need. And instead, I'm going to 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. So 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 and RCTs. We have a reliable endpoint change in FVC, which regulators seem to favor, and we can make an impact here. There's a large gap to fill. Again, we have the 2 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. So we've really taken all of these learnings and applied them to our Phase II study. Go to the next slide. And 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 mLs per year much faster. And this is, again, being described in many studies time and time again. So we designed the AIR study based on this carefully applied historic 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. And the white space or, in this case, orange space is our C21 target. Our target product profile is to demonstrate better efficacy and better safety. Go to the next slide. So the interim analysis data is hot off the press, and Toby will run through it during his presentation. And I suppose despite the relatively small numbers and open label design, the results are unexpected and unprecedented. It suggests that we're stabilizing the disease with C21. And that between 6 and 9 months, actually, there's an increase in FVC. So 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. And 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. And I suppose you don't need sort of a clunky expensive ID clinic set up for it, which can be fraught with challenges, particularly during a pandemic. And the fourth point here is that the mode of action is working, as Johan mentioned in the epithelial and in the endothelial cells, so it has this dual anti-fibrotic and remodeling effect. So with these results, there's obviously a heightened sense of urgency from our side. And the next stop is 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. So another business or buzzword is differentiation. And what we mean by that is how will C21 be different and add value if we consider sort of the long game here. And at the top here, you have the likes of, again, the pirfenidone and nintedanib. Yes, they are approved. Yes, they're oral, but they don't appear to stabilize the disease. And obviously, then you have the compliance issues. And given this profile of C21, we'll share again the data, obviously, with the approved therapies, the lack of the documentation of mortality benefits, 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 FibroGen, Pamrevlumab. And looking at the eligibility criteria of the Phase III study, it seems to suggest that they're really more positioning in third line, actually, where patients either cannot tolerate or failed anti-fibrotics or refused it, which is obviously a smaller piece of the pie and then also acknowledging that it's an intravenous therapy. Next you have Roche there. It's human Pentraxin2. It's on top of standard of care, and it's IV, okay? And then you have the inhaled treprostinil. And that's been with recent successes in PH. But however, it's up to about 12 breaths 4 times a day, and that may not be then obviously consistent with living well. So from a C21 perspective, yes, we're in Phase II, so I suppose chronologically we're a bit behind there. But there's opportunities now to speed up and obviously then deliver improvements -- these improvements to patients. Go to the next slide. So this is my final slide on IPF. And IPF is a complex disease. And it's important not to be single-threaded. Instead, you need to really sew together an effective recipe that sort of creates value for patients and physicians and the payer, okay? And as we mentioned on #1 there, we have the angiotensin 2 receptor group is working on the RAS. It's the AT2R on the alveolar epithelial type 2 cells, promoting the respiratory mechanism. And again, that's the Phase II AIR study that we'll go through. Number two, as Carl-Johan mentioned, 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 the medicine. And they're coined digital therapeutics. They're recognized by regulatory authorities such as the FDA and many payer bodies as well. And the aim is for us to have our own personalized cognitive behavioral therapy, DTx. And as Carl-Johan mentioned, we've started the pilot study. We're actually waiting for its approval there. And the plan is to then -- that will quickly evolve into the pivotal study this year. So it's really our trailblazer. And I suppose in some ways, particularly with the pandemic, it's not hard to imagine the emergence of a very different health-care system powered by DTxes over the next 3 to 5 years. Number three, there is -- DT02 is tacking again the distressing and disabling IPF cough. And 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. And number 4 is pulmonary hypertension too, and I'll talk about that in the next slide. Go to the next one. So pulmonary hypertension is defined as an increase in pulmonary artery's pressure. But not all pulmonary hypertension is the same. There's different groups based on different causes. And we're particularly with C21 interested in Group 1 PAH and Group 3, which is in interstitial lung diseases. And 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, and it's going sort of the precapillary pulmonary hypertension. And there's a growing body of evidence that C21 can actually reverse this. This is preclinical evidence. And again, we'll -- Gerry will share the Sugen-hypoxic model data, which where we found that C21 reduced the pulmonary artery pressure at human equivalent doses and also have an impact on the remodeling. So obviously, then that's certainly places C21 in a very favorable position for the treatment of either Group 1 and Group 3. You go to the next slide. So therefore, we're working very closely with Gerry but also with Professor Chris Denton to really prove these clinical benefits in pulmonary artery hypertension. Now it's a diverse yet homogeneous group because, again, you get that muscularization in the pulmonary artery. And traditionally, patients have a couple of hemodynamic touch points every year. This is invasive right-heart catheterization. But obviously increasing the number of touch points makes logical and intuitive sense. And Abbott have an approved device in -- to prevent the progression of heart failure. And they've shown that safety and utility, and actually, there's been a study in PAH patients. And 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. And it's a very patient-centric and convenient aspect, particularly if you acknowledge what's been happening with the pandemic. And then the patient and the physician can actually then review the data and obviously make clinical decisions around it. So from a clinical study perspective, you can actually get away with smaller numbers, much more very fewest numbers as subjects can serve as their own baseline. So 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. So switching gears on to 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. Yet right now, we have limited therapeutic options. We have suboptimal still 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. And 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. So from a Phase III design perspective, it was important to stay close to that population. So these are patients that have been hospitalized and in need of oxygen but not too close to the [indiscernible]. So these patients don't have moderate to severe ARDS, and they're not on invasive mechanical ventilation. So there's still the opportunity for us -- for C21 to turn the disease around. And we've designed the study with very close engagement and, obviously, advice from the FDA. We've engaged with the EMA and many experts, and Maureen is the coordinating investigator, and she will talk more about that. Go to -- then actually just -- the other point I wanted to make was, and Carl-Johan 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. So that's great news actually for the study and obviously for patients. You see there on the right, obviously, we're operational right now in 5 continents and about 50 different sites. And as Carl-Johan mentioned, 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 in the hot spots in India, okay? And the aim is to have the top line data in the second half of this year. Go to the next slide. So pulling it all together, the mode of action, the alveolar epithelial type 2 cell, the AT2R, the clinical results from the Phase II in terms of the hypoxia, where do we feel that C21 will have the greatest utility? And Corvid has been sliced and diced in many different ways. And I've tried to artificially do this here again in pathogenesis into 3 stages. And what we do know is that I suppose a patient could have 1 of these stages or all 3 at the same time. But I suppose it's important to -- I suppose to realize that it's about patients coming into hospital. They're hypoxic. They need oxygen, and they -- it's really about the ordinal scale of 5 or 6, and it's treating patients on top of standard of care here. As we know, we don't know really when a variant more transmissible, more deadly and more capable evading vaccines is around the corner. And there's nothing we need to suggest that C21 is specific to any mutation, okay? Go to the next slide. This is my final slide now. So to conclude, here is the dashboard I suppose or visually display slide. And 2022 is set to be a busy year for Vicore. With IPF and DTx study, it's full throttle, the pilot and then the pivotal after that With C21, the AIR study is continuing with 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 in the EUA. And then lastly, on the right is PH. We released a press release this week, both Gerry Coghlan and Chris Denton from UCL will join Vicore a senior clinical adviser. So we look forward to starting the PAH study this year. And I'll stop there and hand over to Professor Toby Maher.

Thanks, Rohit. So I guess if I can have my next slide. There we go. So that introduces me. So I'm Toby Maher, Professor of Medicine and Director of ILD at the University of Southern California in Los Angeles. And if I can have my next slide. So my clinical and research interest is in the management of fibrotic lung diseases. And so 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. And then I'll just go over some of the data that's already been shown to discuss the results that we've seen so far. So idiopathic pulmonary fibrosis is an inexorably progressive, destructive condition that causes progressively worsening scarring of the lungs. It typically occurs in older adulthood. And 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, it represents premature aging of the lung in advance of the rest of the organs in the body. And the typical patient with IPF is usually a male in their mid-60s. The disease will cause inexorably worsening breathlessness. So at diagnosis, patients actually have relatively limited symptoms. They only notice breathlessness on heavy exertion. But as the disease gets worse over time, that -- 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. And 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 and past times because they struggle because of their breathing. And before the advent of antifibrotic therapy, median survival for the disease was about 3 years from diagnosis. And the vast majority in excess of 80% of patients who've developed idiopathic pulmonary fibrosis die as a direct consequence of the disease. If I can have the next slide. So as Rohit's already alluded to, the disease is inexorably progressive. And 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. But normally, that's of the order of about 15 to 20 milliliters a year. The average untreated IPF patients, as we know well from the placebo arm of multitudes of trials now, will lose somewhere between 220 to 260 milliliters a year. And these graphs that I've got on this slide here actually represent a study that we ran about 5 or 6 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. And so the 2 graphs here represent 2 different patients. The dots on each graph represent a daily forced vital capacity measurement. That's a measurement of lung size, essentially. And 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. And 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. And 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. So IPF patients are uniquely susceptible to developing acute lung injury. And acute lung injury is really what we've seen as the major cause of death in COVID patients. So it's where the lung becomes damaged, and that triggers a widespread inflammatory response that leads to epithelial death. And 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 1/4 of his lung function in under 2 weeks that occurs and was never recovered thereafter. And 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. And 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, 4 of them or 8%, who had genuinely stable lung function over 52 weeks. So 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 1/4 of patients, 1 in every 4, lost more than 50% of their lung function over the 52 weeks. So 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. So it -- the loss of lung function is really the expectation and stability is by far and away the exception. So if we can move on to the next slide. So 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 half 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. And real-world data would suggest that upwards of 1/3 of patients discontinued 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 antifibrotic drugs is better than for those who do not receive them. And 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. So the average patient was 67 years old. They had relatively well-preserved lung function, and therefore, median survival was about 5 years. The second line with the dark blue shading under it represents patients who were on long-term treatment with pirfenidone. So these patients went into a rollover, open-label study and received pirfenidone for upwards of 10 years. And you can see that the median survival in this patient group improves to about 7.5 years. So a life expectancy gain of 2 to 2.5 years with treatment. However, the third line on that graph with the pale blue shading under it is the median life -- or represents the life expectancy for a 67-year-old drawn from the population at random. And 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. So we have this massive gulf still that we need to fill in terms of restoring normal life expectancy for a patient newly diagnosed with IPF. So if I can have the next slide. So 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. And 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 [ routine ] response and it leads to this imbalance between profibrotic and antifibrotic mediators that results in activation of multiple cell types of the lung that leads to the deposition of collagen in extracellular matrix. And interestingly, that process becomes self-perpetuating as the extracellular matrix changes in the IPF lung and the lung becomes stiffer, that in itself perpetrates the fibrotic response. And if we go to the next slide, we've already seen this slide in one of the earlier talks, but it just explains that -- the role of the angiotensin II receptor in the wound-healing cascade. And you see that it has both those arms in both the sort of antifibrotic and the pro-resolution phase that make it an attractive target for trying to modify the fibrotic response in a disease such as IPF. And 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 multicenter, open-label study that is targeting up to 60 patients with the diagnosis of IPF. Patients are not on background treatment. They are receiving therapy with 100 milligrams of C21 twice daily for 24 weeks. And as Rohit's 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 patient -- this study as an open-label study is made more attractive to patients. And the goal is to compare the outcome of the treated patients with historic control groups where we would expect this 220 milliliter to 260 milliliter loss of lung function over 52 weeks. And so if we move to the next slide, this just shows the data from the interim analysis. So you've got the green line there, which is the expected lung function loss in an untreated population of patients with idiopathic pulmonary fibrosis. And you've got there, in orange, the observed change in lung function in the patients in the AIR study. So 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 isn't the very least stabilization and beyond 20 weeks and apparent improvement in FVC. And 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. And so 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. So if I can have my next slide. This is just my final slide, which brings everything to a close. So 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. So it's actually a relatively common cause of death in Western society and is increasingly becoming so with an aging population. So 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. But 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. And as I've told you, the currently available drugs are often poorly tolerated with more than 1/3 of patients discontinuing them. So we really need both more effective drugs and drugs that are better tolerated. And 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. And 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. So 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. So I will now hand on -- I forget who I'm supposed to hand on to, I apologize. I think it might be Gerry. It is Gerry.

[ It is me, indeed. ] Okay. Thank you very much. Very interesting data. So we move from Alzheimer's to cancer. So that's the pulmonary arterial hypertension, so we're talking about the lung vessels. And essentially, this is a disorder of rarefaction and loss of lumen in the very small lung vessels. So these are less than 1/3 of a millimeter in diameter. So we tend to sort of lose these small vessels in this condition. Next slide, please. So a busy slide. So 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 3 different activity sites. And if you look at the -- this population, this is the median age of 50, people with idiopathic pulmonary hypotension. They've got no other comorbidities, so it's just the disease in their lung vessels. And if you compare it to the observed data with an 80% 5-year survival to the same population before therapy was available, that's the NIH predicted outcome in this population, which was 45% 5-year survival. So 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 big -- it's a very wide condition, very many different types of disease. And 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, 80% 5-year survival is not very good. If you look at the left-hand -- top left-hand graph, this shows patients currently [ trip ] starting on therapy with intravenous epoprostenol, who have scleroderma-associated pulmonary arterial hypertension. And if you're in the high-risk group, which about 1/3 -- just over 1/3 of this population are, you've got a 50% 1-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. So it's a very poor outlook for some patients. That's the other extreme. Then if you look at the bottom, we've got the average outcome for these populations. So 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. And that data is then collated. And it's been collated over the last decade. So the light blue line in the middle there is pulmonary arterial hypertension. So that's the population we're discussing. And you can see, we've only got a 51% 5-year survival. So 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 bits of -- 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 pulmonary hypertension. So this is your lung fibrosis and other conditions where you would now have pulmonary hypertension as well, you're talking about a 22% 5-year survival. So the outcome is dependent on the population and it remains an area with a very large unmet need. All right. So we go on to the next slide, please. All right. Because there are -- there's a huge unmet need still and despite the progress that we made, there are many new agents being tested in pulmonary hypertension. So 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. So if we start on the right-hand side there, liposomal inhaled treprostinil. So we know that treprostinil is effective. It's a good agent for treating pulmonary hypertension, works through [ the prostanite ], the 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 they're [ sildenafil-type drugs ]. And 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. And this is more [ a selective fit ]. It binds to it more completely and blocks it more effectively. So that's also being looked at in the Phase II trial. And then on the left-hand side, look at the endothelin circulations on our system. So that's the third system we currently use. We've got macitentan, which we currently use at 10 milligrams per day. It's now being trialed at 75 milligram because it's shown that as a 10 milligram, it does not completely neutralize the endothelin production. And then there's an antibody that completely obliterates ETA. So a selective approach, but of course, by injection, which is also being looked at. So even within our current pathways, we think there is room for improvement. Move on to the next slide. Thanks. And then in terms of brand-new approaches because there are many -- much more -- there is 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. And this rebalances the BMPR2 system. So this is a gene that has been found in most patients [ with heritage ] pulmonary hypertension. It's also found to be suppressed in its activity, even people who don't have a genetic defect. And it is something that balances against activin. So if you can increase activin activity, you would suppress BMPR2. If you suppress activin, you increase BMPR2 activity. So that's what Sotatercept does. If we move down to the PDE5, so the smooth muscle group there, the trials in kinase inhibitors were all shown to be highly effective, increasing pulmonary hypertension, but imatinib, which did this, had too many side effects. So 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 -- it's actually Phase III. And then if you go down to the bottom where we've got [ information and remodeling ], we've got sort of nonspecific methods of attacking that using cardiosphere stem cells. And then we have all the more specific bromodomain inhibitors and, of course, C21 will fit into this territory as well. So you can see that there's a huge amount of investment in activity in trying to improve the outlook in this population. Move on to our next slide there, please. Okay. And 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 trials, [ to choose ] the size of current Phase II trials. The ambition here is to reduce the pulmonary vascular resistance, which is the amount of the difficulty of pushing blood through the loans. So in a normal person, the pulmonary vascular resistance is what we call 1 Wood unit or 80 in this territory in dynes dines as measured here. In this population, it was about 800, so about 10 Wood units. And Sotatercept on top of optimal therapy, which in 53%, they were on 3 drugs already, it was still able to reduce the resistance by between 20% and 30%. So a very, very effective agent in terms of that. And this also was associated with increasing their ability to walk and reducing the strain on the right heart. Because of the efficacy in that trial, they are now running 3 Phase III trials. The seller study has already completed recruitment in the last couple -- last 1.5 years. And then we've got 2 other large trials that are going to be tied to clinical worsening trials. So a huge investment because it's clear that this is potentially a major way forward. It does have 1 big drawback, and that is that it's an injection that has to be given every 3 weeks. Should we go on to the next slide? All right. You've seen this so many times, I think we can more or less skip over. 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 of -- and badly designed that was, as much 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 [indiscernible], dilatory, antifibrotic activity. And with -- if you can do that without dropping blood pressure, we should be able to improve things. Thank you. Next slide. So this is, as been mentioned, the Sugen-Hypoxia trial. So 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 and Hypoxia is a much better model of the vasculopathy we see in pulmonary arterial hypertension. And 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. And with this, there was also an increase in stroke volume, so the ability of blood to be pushed through the lungs. So it did all the right things that we'd expect in this model to suggest that this may be an agent that will be beneficial in pulmonary arterial hypertension. It's not mentioned there, but the size of the population, so there's 5 in the controls and then in each of the Sugen-Hypoxia groups, there was 10. So 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. We move on to the next slides. All right. So 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 is a very common condition, lots of people get their hands that go blue and white in the cold, but it can be quite extreme. So there's a 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. And if you go on to the next slide, we can see just how prevalent this problem is. So this is a study of looking at people with duodenal ulceration formation, looking at all-comers over a period of a couple of years. And what you can see here is that about half of the population either had recurrent in green or chronic ulceration in brown. So there's a very substantial burden of disease in this population. And if you are in those 2 groups, then you've got about a 50% chance to have been hospitalized in 2 years and about a 10% to 15% chance of having gangrene or needing an amputation. So 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 approving vasculopathy in the lungs will be useful, there is actually a substantial gain for these individuals. And if we go on to the next slide, please. Oh, we're missing a slide, don't we? Okay. So there's an also small study of about 12 patients at scleroderma using thermography. And 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. And what they've done is looked after 15 minutes, looked at the rate of recovery and the rate of recovery in each individual compared to themselves was substantially better if they were given C21. So there is clear evidence that there's potential for this in Raynaud's and there are further studies that are going to be done there. Rohit's already shown this study at the stage, so 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 minutes in mercury ], that, that's more than 2 standard deviations from what would normally happen, so 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 reduction pressure, 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. So the idea would be if we can demonstrate this effect or 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. And thank you very much. And I'll pass on [ to -- so to -- I have -- I'm terrible now. Sorry, folks, I've forgotten. ] Sorry. The lady from Johns Hopkins. Cheers.

Hi, hello. Hi, I'm Maureen Horton, and I'll touch a little bit about COVID-19. And it's bittersweet. It's -- 2 days ago was the 2-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 1 ward at the moment. But -- so this has been longer than we thought, and it is still present 2 years later. Next slide. Again, next slide. So this is a little old. I've made this slide a week ago, but there was 435 million total cases. Of course, this totally underestimates it because in some places, we're not measuring. And on the previous slide, you would have seen that there is 6 million, we're now over 6 million deaths from COVID-19. So that's pretty remarkable. I'm not sure why these keep going. I don't need them to go as fast as that. But at the previous slide and this slide here does show that -- okay, let's stop moving. So this slide shows that there -- we're -- 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 United States. And you can see that there's these bumps along the road. And those bumps show you that when the different variants were coming along, right? So then you saw the Delta variant, then you saw the Omicron. And 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 -- and not IPF, unexpected deaths due to COVID-19. So there's many, many more deaths in COVID-19 than would be expected for this certain time of the year. And this is looking global. Is there any way we can stop making my slides go forward before I go on that, too? So stop here. All right. And this one, it shows that this is the effect of COVID-19 on death rate. So in the U.S., we typically have -- deaths are from cancer, from cardiovascular disease, and they just chug along. And what you saw in the last -- previous slide was that the purple was showing the COVID-19 increasing the death over time. And so this has led to an excess in deaths worldwide. And the darker the colors, the darker the reds, the orange and the blacks are showing that the amount of death, excess death, reported deaths over expected death [ for a given of time ]. And this is all due to COVID-19. And if you remember in the previous slides, which have been going by very quickly, that you can see that a lot of this was -- is due to COVID-19, but it comes in these bouts. And it is also after mid-2020, it is in the presence of resdemivir (sic) [ remdesivir ], dexamethasone, the monoclonal antibodies, all of the therapies we have to date. So the therapies we have to date are great, but they're not completely effective. So is there another way we can look at it? So in the next slide, it's just going back and showing you again how this virus came. And we believe that the virus came from animals into humans in the Wuhan district and 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, then pneumonitis leads to ARDS. And again, we have vaccine therapies. We have much better diagnosis. Yes, 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. So we need new investigational drugs. So the next slide, again, is just to recap. If you go forward one, again, we're 435 million cases, over 6 million deaths. And 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 a critical illness. About 1/3 of the people who get the pneumonia tend to go on to serious. And again, that's variant-specific. Delta virus, maybe more than 1/3. Omicron, a little less than 1/3. And again, the incubation is about 3 to 7 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 4 pillars, antiviral therapies. This is 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. So we can go forward because I'm going to try to keep up with how fast you're going. So the next slide after this. Okay. So this says the therapeutic management of nonhospitalized patients. So basically, when you're not 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 [indiscernible]. But again, those don't necessarily work. The people then go on to become ARDS in clinical. So what we have isn't working, so there has to be something else. There has to be something else that perhaps works by a different way. So 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 or the epithelial cell reaction. So we need novel treatments. So the next slide. Oh, so as I meant before, the spike protein binds to the ACE2 receptor, right? Then 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. And in the alveolus, what you can see is, again, this is infecting the AT2 cells and they're causing all the damage and [ then naturally ]. So you can imagine by the time you get to that part where you have an alveolus full of stuff, how are monoclonal antibody is going to work? Because yes, the virus is there. But day 7, 10, when you're getting the pneumonia and ARDS, the virus is pretty much gone. So the antivirals and the antibodies, how are they having an effect? We need something a little more direct. Next slide. So again, you've seen this in various forms. We have angiotensinogen from the liver. The kidney produces renin, turning to angiotensin 1. Then you have angiotensin-converting enzyme, turning to angiotensin 2. And then that's what causes vasoconstriction and blood pressure problems usually, right? And then your ACE inhibitors, the [ ACEis ] , those are all your ibs, like your -- our ils, meaning your captoprils, your ramipril, all of those for blood pressure medicine. And then the [ arbs ] are also a form of blood pressure medicine that prevents the effect of the construction on the angiotensin 2. Now if you look at the SARS-CoV-2, in the middle there, that -- okay. Everything's gone. Well, the SARS-CoV-2 binds to the ACE2 receptor. And what it does is it blocks that receptor and it degrades that receptor. Now the ACE2 receptor is very important in trying to take angiotensin 2 to Ang (1-7) or angiotensin 1 to (1-9). And angiotensin (1-7) and (1-9), they have vasodilatory, anti-inflammatory, antioxidant effects. So you can [ see, you ] lose the vasodilatory, anti-inflammatory effect aspect that should normally be happening at the same time. 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. So 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 inflammatory -- acute inflammatory lung disease called SARS-CoV-2 or COVID-19, we can see that, that ACE2 receptor is very important in producing this angiotensin (1-9) and (1-7) and that specifically binds the [ AT2, the angiotensin 2 -- type 2 receptor ] and causes a resolution in the anti-inflammatory regenerative aspects. Whereas if you lose that aspect, if you lose ACE2, then you're going to go more to the AT1 receptor, and that's going to be causing the hypertension, the profibrotic, [ co-inflammatory for oxidative ] and a lot of the bad things that we're seeing. So if we can bypass ACE2 because we can't really do much with that now when it's getting consumed by the virus and go straight to the [ AT to our ] receptor, and that's where C21 comes in. Next, side. So 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 we -- dex was a -- sort of recommended in that one study, dexamethasone is on the patients. So they all had acute respiratory infection. They all had markers of inflammation. So this is an elevated C-reactive protein or CRP. And then they even followed a CRP disease severity, a need for oxygen and safety and biomarkers. And you can see screening randomization, if they got C21 or placebo and the follow-up was 7 to 10 days. Next slide. So here are just 3 aspects that came out of the study. So C21 reduced NT-proBNP. So proBNP is a marker of heart failure, volume overload, inflammation in the lungs. And so when the proBNP goes down, it probably means you're clearing excess fluid, pulmonary edema, the lungs are not as congested. And you can see that the C21 markedly decreased the proBNP day 1 versus 8 versus placebo. C21 in the middle panel also showed it promoted a faster recovery with less oxygen -- supplemental oxygen. In the beginning, day 1, pretty even balance of oxygen in the placebo versus the C21 patients. But by day 8, you had a marked decrease in the number of patients on C21 on oxygen and only 1 patient on day 14 in the C21 group remained on oxygen. And then a post-hoc kind of study, looking at 21 -- C21-reduced long-term injury, looking at CT scans, high-resolution CT scans 6 to -- 3 to 6 months afterwards. And you saw a marked decrease in the lung -- areas in the lung that had abnormalities in the patients treated with C21. So 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 then that led to ATTRACT-3, which is the Phase III trial, which is ongoing. This is a global randomized double-blinded, controlled, 600 subjects, 14 days, 14-day follow-up. 14-day treatment, 14-day followup. And 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 and secondary endpoint in 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 concern. So we're really happy about that. Next slide. So 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 going to 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 want immune responses to it. The monoclonal antibodies are great, all of these other treatments are great, but they're not really that effective. And again, if we have something more specific to counteract the damage that's done behind the virus, but not necessarily directly by the virus meaning antiretrovirals and what not wont work. Next slide. That's it. Thank you.

So thank you very much, Maureen. I would like to summarize a pretty hefty presentation of the opportunities for C21 and the incoming angiotensin type 2 receptor agonist. And 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 is still. It is IPF and it's the core rare disease. And 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. And 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. And I think that's inherited both in the disease, but also to treat vasculopathies, inherited in C21, and I think that we have demonstration both of vasculopathy effects and the 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 -- or status and then give us the 7 years in the U.S. and then 10 years in Europe of market exclusivity. But we have been, of course, aware of the shortcomings in the product protection of IPF. And we have now several pending patents regarding formulation manufacturing use, et cetera, specifically covering C21 within an expiry of 2040 and beyond. And it's really -- without going into the details, our ambition to create a product protection that is as strong and as reinforceable, as a composition of matter patent. And I think that's really a hard work that's been done by the team. And this is, of course, an important ambition because we will look forward C21. Can I have the next slide, please? So why is that so important with protection then, yes, we're looking at a market now of USD 10 billion or even USD 11 billion on aggregate, think about the potential untreated patients as well. And 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. And also in pulmonary artery hypertension and the hypertensive aspects of IPF it's a huge market. And as we just heard, with still medical needs in both the PH and PAH, Group 1 and Group 3. So again, the combination of the effects that we've seen, I think, give us a very good opportunity in this space. And we need more effective treatments. That's for sure. So let's move on to the next slide, please. So 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. And we do receive e-mails and messages from patients. And 1 is quoted -- I can quote 1 and says, "as you can understand, time is of essence in this terrible disease." And that is, of course, important for us and inspiring us to really work hard to get there. The same is true for PAH. And I think Acceleron have paid the way for us because they've shown that now with -- if you can show the effect on pulmonary vascular resistance, which is done in the mechanistic trial, I think you're very far away, very far down the road of a treatment for pulmonary hypertension and pulmonary artery hypertension. And 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. So if we can have the next slide, please. Again, looking into the new indications, I will not -- I'll just give you a glimpse of what that could be. I mean, we're now looking at Vicore company with 3 different boxes and COVID and interstitial lung disease, of course, being the boxes that we're entertaining. But then there is another box that can be separated into a number of boxes and we can look a little bit into new indications that we are kind of considering and working without starting clinical trials yet. And that's Preeclampsia, so women's cells and it's kidney disease, diabetic nephropathy, but there's also other areas that we're exploring preclinically. And 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 type 2 agonist is really accomplishing in this area. And I think Vicore has really the expertise both in biology and chemistry and unique position to pursue these opportunities. So if I can have the next slide, please. I'll just give you a glimpse about I want to think about diabetic nephropathy, and that's a severe diabetes complication. But of course, it's a chronic kidney disease, and there are many genesis of chronic kidney disease, and we picked 1 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. So I think that is something that we believe has a good opportunity and bodes well from the -- now we know that in IPF, we can replicate what we've seen in the animals. This bodes well for the future also in kidney disease. And we've done now the human kidney that Joanna talked about as well and look at TGF-beta expression, and we have a very nice dose-dependent decrease in TGF-beta expression in human fibrotic kidney. So that's -- those parts that we are working with. And we also know that the receptor is present here. So -- that is 1 area that we work in. And of course, this 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 order. If I can have the next slide, please. We changed completely to preeclampsia, which is a disease, which is not a matter of aging, but it's hypertension and organ dysfunction in -- and also in many cases, death during pregnancy. It's actually the leading cause of death during pregnancy. And 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. And 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. And now we use Ang 1-7 or on this publication, where we can restore systemic blood pressure where we can restore endothelial NO synthase and we can also bring back fetal weights to normal in these situations. And of course, we have a little bit more work to do. We do have a molecule that will fit very nicely into this disease, and we know that we have base of regulatory effects directly of angiotensin type 2 agonists by NO release. And we've seen also in this [ Indiscernible ] model for instance that we do have positive effect. So that's also a disease where we can, in a very short-term clinical study actually monitor blood flow during pregnancy. So that's just to give you a glimpse and 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 is given all this very useful information in understanding of angiotensin II type 2 receptor as a target in a number of diseases. And we think it would be a very interesting idea to promote clinical ATRAG 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 II type 2 that receptor here. And we are talking about a ATRAG Academy and where we can actually provide drug, placebo and documentation to investigator-initiated trials. And that could then, of course, help us to shed light over new indication and new opportunities. And 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 ATRAG as a new class of drugs. And by that, I thank you and hand over to the moderator for questions and answers. Well, maybe the answer should come from us.

[Operator Instructions] So our first question comes from Dan Akschuti from Pareto.

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. So could we considering also the effect size that has been demonstrated now that is quite somewhere else compared to what you've seen from Promedior, also UnitedHealthcare and other companies. Could we expect a fairly small pivotal trial? Or would you like to wait maybe for 3 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 longer and maybe then you have time until September as well, they have another 3 months. And if you're following that data like that, will we also get additional interim readouts in summer and then autumn. That would be my first question.

I don't know who's going to answer, but I can start and maybe you can -- let me know if you want to chip in. And thank you, Dan, for your question. It was not 1 question, but I know that when you pose questions, it's a number of questions. String of pearls. The next step, talking about the effect side, and I think we should also ask Toby to fill in. But of course, the pivotal trial will have 2 purposes. One, it's a 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. And then, of course, it's a sample-size calculation that will determine the size of the study. And we haven't done that homework yet. So I don't think we will see a extraordinarily small pivotal trial. But I mean as a comparison we can think about the -- there are studies that's 1 study, about 600 patients, and then the pamrevlumab study, I think they have 2 studies of about 340 patients. So that is kind of 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. So I think that's let's say that's the answer to that. And 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. And I think I'll hand over to Toby to maybe give an answer to the question as well.

It's a good question because, obviously, what one sees will feed into the expectations of any powering of a study. And notwithstanding the need for the studies to be big enough to sort of convince that the regulatory authorities that the drug is safe. 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. So 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. So 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. So you mentioned also the safety aspect being a part in terms of that might find a bigger patient population than needed from an effect size perspective. And -- but looking at the safety profile that so far has been shown by C21 in the various trials. And looking at the one-off standard of care wouldn't you think that there could be even a completely different problem there in the sense that the side effect of the standard of care could introduce some type of positive bias towards C20, the C20 arm -- C21 arm. And so that people kind of that worry with the hair loss at the higher doses that we didn't see now, but that you -- patients at least a hint based on GI side effects and absence thereof that -- and how would regulators look at something like that. It's in a way, not your fault that the standard of care has the side effects, but how can we look at the kind of readout from such a randomized and blinded trial.

I am 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 2 existing drugs, it's become harder to know how to design an optimal study. And 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 rate of change in FVC amongst other things. What we've not really seen is a true head-to-head study design. And I think as you alluded 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 2 blinded treatments difficult. So 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 a new territory for them really as well in terms of defining how these studies should be delivered and interpreted.

Okay. And the last question on the IPF side. So the patients in Ukraine, Russia, as I understood, there were just a few and 2 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?

I think the population in Ukraine and Russia, it's small in the IPF tries I don't think it will have a big impact on the trial. And of course, at least 1 have passed week 24, I cannot give more details than that on top of my head, but there are a few, and we are not dependent on those patients in the IPF trial. And here, we have of course, already secured some of the data. I mean we'll clean 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. So it is sad in many aspects, we have a few patients, but it doesn't have a big impact on the study.

One last question from me on the PAH side. So we got some interesting data last year from UnitedHealthcare there with treprostinil and -- then if you look at [ Indiscernible ] they are trying to do the opposite. So they started it in the PAH and now they are looking into IPF, where they had an interesting effect, much weaker than what we saw now from C21. You're looking now into PAH. 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 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 Joanna and elaborate a little bit on to treprostinil or Rohit.

I think this is about reduction.

Yes. I mean, as you've seen in the Sugen-Hypoxia-model, there was effects on remodeling there in terms of that muscularization and those plexiform lesions that you see and the luminal opening. So the remodeling. So I think we really see that as sort of as a disease-modifying effect. Gerry also shared with you some data we did in the study we did mechanistic study, the single dose in Raynaud's phenomenon secondary systemic sclerosis. And there, we saw in this tough resistant vessel vasodilatation. So -- and then obviously, there's the antifibrotic aspects. So yes, so remodeling perhaps as a location there, antifibrotic I think is really -- we would see how C21 would be working here. And I think I shared with you the design of the study, and I think really -- there's a number of things there that we'll be obviously looking at the cardioMEMS. We look at the hemodynamic. We quite possibly do echo as well, looking at the right heart as Gerry has advised us and maybe something like a functional end point as well from a patient perspective.

I make a quick comment. Treprostinil does have some anti-remodeling or remodeling effects as well. It does have some anti-inflammatory effects, but they are quite minor. This looks more impressive than that. But we've learned over many years not to jump from animal data to human data. We need to do this in humans.

Our next question comes from Fredric from Redeye.

I was just wondering if you could clarify a bit because in the press release for the interim analysis for the IPF study, you mentioned of potential for a Phase IIb dose-finding study. Has this changed or can you give some context to this how this differs from the pivotal trial?

Yes, I can comment on that. And that would have been the normal path. I think we were really surprised by these extraordinary data, and I didn't -- I think they didn't really sink in, in a few days' time that we have to think about this press release. And I think we should look upon IPF as a cancer disease with a very poor outcome, it's a very devastating disease and not very good standard of care if you take them, you have the addition of side effects. And there's really a huge medical need and -- and in my mind, with a drug that has a safety profile that we've seen of C21 and with the efficacy that we demonstrated, I think we should move directly into pivotal trial. And of course, this has to be better than and confirmed by regulatory authorities. But again, just as a quote, time is of essence in such a terrible disease for these patients. And I think it's our obligation to try to get it to patients as fast as we can.

And in terms of how many patients you would want to get it on before you initiate the pivotal trial? You mentioned that a bit more, but maybe elaborate a bit more like would you want to see perhaps 30 patients or so to finalize the full study? Or yes, when could you initiate pivotal trial the earliest in your mind?

The earliest our plan is to do it in the first half next year. And 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, but that's about it. But I mean we will not let that stop us to move forward to the pivotal trial.

And a final question for me about VPO 3 and -- can you elaborate a little bit about the business strategy, given that you want to target larger indications potentially and several at the same time, does it -- how would you work with partners, for example, compared to how you think of orphan incisions.

I think we -- those little boxes kind of indicate that they are not -- I mean, they're not business unit in strict sense, but I mean they function as kind of virtual business units. And I mean, we could have a partner for 1 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. So 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 out, it could be collaboration. It could be something that we do ourselves if it is a an indication that is small enough for a small company.

Our next question comes from Suzanna Queckborner from Handelsbanken.

Hello and thank you for this very interesting R&D Day. I'm just a little bit curious about the historic 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 more severe disease. And I mean, the background there for the 240 mls.

Yes. So we've learned over the last 20 years of doing clinical trials in IPF, the disease behaves fairly consistently at the population level. and that is irrespective of baseline disease severity. So we would expect FVC loss to be linear across the course of the disease in a cohort of patients, whether it's sort of mild early-stage disease or advanced late-stage disease. And the sort of the critical component in clinical trials and ensuring consistency has been the central reading of CT. So 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. And 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. And 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 treatment. And that's been mirrored in real-world registries and it's sort of amazingly consistent over time. So 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.

And maybe we should add that we have been very strict on these criteria and use a central leader that has been doing this for a number of trials that has been published, and that's been then the basis for the calculations 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.

The other thing to mention also is -- for the first 3 months, we were bringing the patient back every fortnight, next 3 months, every 3 weeks and then the last 3 months every 4 weeks, which is probably a lot more than what's been done in other studies, and this is the spirometry here. We're also using a market sort of leader ERT, they're the best at providing the equipment, the training and then also the overread. So it's really important. It's about the intra-patient variability and it's about getting the data in. And obviously, following these patients up very regularly, and that's what we did in the study.

Okay. And then 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 -- 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 this -- 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 you to IL-6, which is just an in-plane marker there and baricitinab. But even with those drugs, people are still going into ARDS they're still dying. So 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. And that's where the angiotensin II type 2 receptor comes in. In that the C21 combined to that, and it can have this anti-inflammatory vasodilatory effect. So what I was trying to say is that despite all of the drugs we have in our armamentaria now, many of which were in all those blips I showed you of the COVID-19 cases, people are still getting sick. So looking at it from a different perspective, is there something new we can do? So C21, for me, I think, would be most effective, not in the asymptomatic patients. but in patients who are already showing some epithelial lung injury. So those would be patients on oxygen. And that's the -- what the ATTRACT-3 trial is there are patients with ordinal 5, 6 scale, so they're on low levels of oxygen or high flow nasal cannula but not to the point where they're incubated. So I think here -- and even in IPF, this is my thought, too, is that you want to get to heal those epithelial cells early, not late. You don't want to wait to the end-stage IPF. You don't want to wait to the end-stage ARDS. Because a lot of at that time, you already have damage and there's nothing you're going to be able to do. Did that sort of answer what you asked?

Yes, yes, it did. So then also just a final question. Then 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? How am I supposed to think about this as a regenerative mechanism or as a preventative of further fibrosis?

So I'll let this the COVID-19, which is an acute lung injury model -- I mean, it's not a model. It's a disease. But in an acute lung injury model or an infectious model, you damage the type 2 -- you damage the airway epithelial cells. And with that damage, then you don't get the normal regeneration and the normal effects of the anti-inflammatory effect. So 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. I won't give my -- I think it does the same thing, but I'll let Toby answer specifically for the IPF.

Yes. I think with IPF, 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. So I think that's there is a big overlap in the way that the drug potentially has a beneficial effect in -- across a range of pulmonary diseases, but particularly when you think about COVID lung and some of the consequences of idiopathic pulmonary fibrosis.

I'll now turn the call over to Hans Jeppsson to read the remaining questions that came over the webcast.

Yes. Thanks, Tara. We have got a couple of questions. I start with the first 1 to maybe direct to Gerry on PAH. What are your thoughts on the CardioMEMS device? Is it approved and validated?

So 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 hypertension. And there, it has shown itself effective. And it's now licensed in more or less any type of left heart failure with pulmonary hypertension. And what you do there is diuretics to lower the pressures, and you can demonstrate that if you lower the pressure, you're less likely to be hospitalized, less likely to have complications from pulmonary hypertension. So yes, we know that it works, yet we know that it's reliable and reproducible that it's got a low complication rate. And 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 pressure and the pulmonary vascular resistance, we can estimate somewhat indirectly, but it still works. We will be able to show not just that at 1 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. And -- assuming success in the PAH proof-of-concept trial, what would be the next step in development of Phase IIb dose finding study what would be the competitor in such a trial?

So I think placebo would have to come in here somewhere on the line. Unless you want to go head-to-head with some of the therapies we have, which I think it's unlikely. So we would normally consider a placebo-controlled trial. Like we've seen in IPF, there was an absolutely massive effect, you could argue that. But so we would have people on background therapy and it would be C21 versus placebo in that. Now whether you need to do dose ranging as a question, I think one needs more scientific data to help us on that. But if the drug is relatively effective and has a low side effect burden, then one is not going to get overconcerned about dose ranging. But clearly, we want to have a dose that is effective and the maximum effective dose, but that which causes minimal side effect and it's getting the trade-off between those 2 things. So that will be, I think, where you go next. I do think that. trade-off between those 2 things. So that would be, I think, where you go next. I do you think that the lessons of the past are did you do a Phase II trial that if you rush to a Phase III, you can sometimes come on proper.

Thanks a lot Gerry. And maybe next one for Johan. How does C21 compared to Acceleron setting animal models of PAH.

Sure. As placebo was described by Gerry and like also certain are secret one. is effective in 3 different models of hypertension. And of these, the most predictive is the Sugen-Hypoxia-model, but only if you start treatment when PH pulmonary hypertension is already establishing the so-called therapeutic treatment. And as Gerry also described the therapeutic treatment in this model with C21 doses that many think is popular has very convincing effects from many important parameters, including vasculopathy, pulmonary artery [ Indiscernible ]. In contrast, in a recent publication. So placebo was only effective in the Sugen model when given before and during the development of PH. -- But the relevance of that is so to speak, a bit limited. And as Placebo, was given when PH was already established in the articles, it apparently did not reduce pulmonary artery pressure. And I would also say that the doses of [ Indiscernible ] that were used in the rats was quite a bit higher than those used in clinical. So I mean, there's no direct comparison between 2 drugs. But our view is that C21 definitely has a very competitive profile in preclinical PH models in particular in the Sugen-Hypoxia-model.

Okay. Thanks, Johan. I think we're switching gears to IPF. I've got a couple of questions there. I think we'll start with Toby, which has to lead. So first one for you. If Vicore is able to demonstrate the results again in the next trial? How will that change standard of care?

Well, I think 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. I think I've already highlighted the difficulty with current standard of care, which is that it is associated with significant tolerability issues. And secondly, all we're offering our patients at the moment is the opportunity to slow disease decline. So we don't actually improve any of the symptoms that they present with. So if these results could be replicated in a Phase III study, I think that would be a game changer for patients and clinicians...

Toby. Maybe next one for Rohit. What is the time line for the pivotal trial in IPF?

Sure. So I mean, yes, we've started planning of the pivotal studies study, I should say. And I think really, if we look at it now and we compare to what we previously said, really the sort of, I suppose, in some ways, takes us -- 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, then the next step really is to engage with the FDA and the plan is to do that in quarter 2 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 the 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. And 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 milligrams twice daily, we will encounter hair loss as a side effect. And 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. We've got quite some similar question from folks. I'm trying to combine them and try to post them appropriately here. I think next one would be, can come on the safety profile in the Phase II IPF study so far, any serious adverse events maybe Carl Johan or Rohit?

I think that's for Rohit.

Yes. I think the key bit aspect there is any related serious adverse events. And no, that's what we categorize as what we call [ sesars ]. So there haven't been any [ sesars ] and no new safety signals, really. And like I said, most importantly no GI sort of signals there as well. So, so far, that's good. And obviously, we have this COVID study Phase III, it's a 2-week treatment, obviously, much shorter. But obviously, we're going halfway through the study there. And the DMC had a safety review there, and there was no signals there as well. So, so far, so good, so reassuring.

Perfect. Thanks, Rohit. Maybe a final question here is also for Rohit. Will Viper allow patients in the air to continue with C21 if they would like to do so.

Yes, that's an insightful question. So I mean, obviously, in the IPF study, the treatment period is for 9 months. But I think the question being asked here is that if patients after completing the study, would like to continue treatment further, would we be able to make the drug available. And right now, as it stands, we don't. But I think that's something that we could 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 there's a favorable benefit risk profile. But obviously, given the stage of development and where we are, we wouldn't offer compassionate use to patients outside the clinical study in terms of patients who haven't been in one of the BioCore clinical study. But this is something very interesting, and there's something that we would obviously need to speak to the relevant authorities about.

Perfect. I think we have a few more questions, but I think we're running over 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. So encourage those of you who have posted questions to look at that one. So I think that's it from a Q&A perspective. I'll turn it back to Carl Johan for some conclusion remarks.

Thank you very much, Hans. And I would like to thank everyone for listening in and for participating for questions. And of course, a special thanks to Maureen, Toby and Gerry for their excellent presentations and engagement in the Q&A session. And 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. So I thank everyone for listening in and have a very good day.