Good day, everyone, and welcome to the Vicore AIR interim results webcast. I'm Hans Jeppsson, CFO, and I'm very proud to be hosting today's event. This recorded webcast is accessible via the Vicore website and will be available for replay later on today. Today's speaker will be Carl-Johan Dalsgaard, CEO, who will go through the AIR study design and interim results. You'll see a PowerPoint presentation on screen while he's talking. We estimate that the presentation will take about 20 minutes, and this will be followed by a Q&A session. If you would like to submit a question, please use the form in the webcast. At this point, I would like to hand over to Carl-Johan to kick things off.
Thank you, Hans, and good afternoon and good morning for those of you who just woke up. I'm very pleased and excited to share with you the remarkable results of the interim analysis of the phase II study of C21, a first-in-class angiotensin type two agonist in patients with IPF. This is the forward-looking statement. First, we will go through the study design. We have an open label, multicenter, single-arm study in treatment-naive patients. This analysis will report the results of C21 alone without addition of any standard of care. This is important since we want the effects to genuinely be C21 effects and not carry the burden of standard of care, both the side effect profile or effect-wise.
It's important to point out that we have secured the correct diagnosis by having a central reader who've been through all the high-resolution computed tomographies, and that we measure forced vital capacity, which is an objective measure of lung function, and that's the endpoint that regulators ask for. Since we have no control group in this study, we compare with well-documented decline of about 120 mL per six months or 24 weeks in the untreated patients. If you look at this slide, in the graph to the right, you will see the green dotted line is a trajectory of an untreated patient when it comes to the decline in lung volume, in lung function.
Our standard of care, the yellow line, is somewhere in between the black line, which is only the reduction by age if you don't have the disease, and the untreated patient line. 50% reduction of the decline in forced vital capacity is achieved by standard of care. Our target had been to be either as good as or better than standard of care, and of course, we will also focus very much on safety. The study outline is that after a screening, we give patients for 24 weeks 100 milligram oral capsule of C21 twice daily. That is where we have the efficacy endpoint. Safety we measure all the way through because we have also added a 12-week treatment extension that is optional.
So far, we have enrolled 25 patients, and in this analysis we have 21 patients, of which seven have reached all the way through to 36 weeks, 9- 24 weeks, 13 - 12 weeks, and then 18 for four weeks, and 21- 2 weeks and we will use all the data in this analysis. We make slope analysis based on observed values, and we'll show that a little bit later, and the statistical values is based on the 24-week analysis. For missing values, we have done an imputation, and I will come back to that when I share the data with you. We have done, I would say, a very conservative imputation in our analysis. Now, to the remarkable results. First of all, we focus on safety.
There've been no related serious adverse events, no acute exacerbations, no gastrointestinal signs, so no side effects that we are so much aware of with the standard of care. The safety profile is then, I think, supported very well by the three phase I studies we've done, the mechanistic study in systemic sclerosis, the COVID study, and the ongoing phase III COVID study. To give you a understanding of how this disease develops in untreated patients, we looked at a number of large placebo-controlled studies in IPF. There we can see that patients lose about 100-150 ml of lung volume in a 24-week period. Our comparator is targeted at 120, we've said in our assumptions.
This rate of decline, I think, first of all, is very well established, and then it also explains the three- to five-year life expectancy after diagnosis if you don't have any treatment. On the effect side then, C21 actually stabilizes these patients during the first period in the study, and after that we can see an increase in lung capacity up to 36 weeks. This is truly remarkable and clearly significant from a clinical point of view. Now if we compare this slide or this graph with the expected mean for untreated patients, we get to even more astonishing numbers, 320-370 milliliters of difference at 24 weeks. We think this is something that is truly unexpected and really interesting to work with.
When we do the statistical analysis of the slope values, we have a statistical significance versus the untreated at week 28, 32, and 36 with a p-value of 0.016 at 36 weeks. If this is confirmed in a randomized controlled trial, it is a game changer for patients and for IPF. Now, I talked about imputation, and since some values are missing because patients have not reached to that week yet and some were only in week four, for instance, when we stopped for this analysis, we put in values for all the missing points that are taken from what you could expect by being untreated. The decline that you have on the green is put in all the missing values. Then we have 21 patients with values for each and every time point.
Even with this very conservative approach, looking at the data, saying that all missing values will be nothing, no treatment effect, we still have a positive slope, and we still have a positive FVC by the end of this analysis. I think this is very strong data. Now, how come that C21 can be effective in this way? We're now coming a little bit to the mode of action. I think we will share some data now that ties very much the preclinical efficacy data from more than 100 pre-publications in animal models, many of which also has been in lung models, to the clinical situation. This really is very much about now understanding the localization of the receptor. It is abundantly found in the human lung.
This AT2 receptor has been an enigmatic receptor, I would say. It has not lent itself to identification with conventional techniques. Immunocytochemistry, Western blot, mRNA, they have all been difficult to work with because of technical reasons, and the receptor has no turnover. It is not internalized. By labeling angiotensin II or C21 with a radioactive isotope, we can now detect binding in human tissue. On this bar, you will see to the left, radioactive angiotensin binding to sections of human lung tissue, and it's a genuine and strong binding. This binding is displaced with nonradioactive angiotensin II and with nonradioactive C21. C21 can actually take the place of angiotensin, the natural ligand.
When we check for the angiotensin II receptor, AT1 receptor, the blood pressure receptor, and take a receptor blocker, it does nothing to this binding. It's very specific for the angiotensin II. Now, we also labeled C21, and we could see a very nice binding in lung tissue again with one nanomolar, which is 40 times lower actually than what we expect to have in the humans during the study, the exposure that we have in our studies. We have, I think, thereby demonstrated nicely target engagement. It binds to a number of abundant receptors in the lung. This can, of course, be displaced then with cold or with unlabeled C21. We have by this demonstrated that we have target engagement in the lung in a very elegant way.
This we can, of course, do further analysis of. Now, we have multiple mechanisms that are mediating angiotensin type two receptor agonist effects. This is both from the literature and studies we have done ourselves. Of course, we do not know which one is most important. Is it a combination or possibly also other mechanisms? One is, of course, the alveolar integrity and the stimulation of the type two alveolar cell. That is a progenitor cell that repair and regenerate the lining of the alveoli. We believe that this is very important in the initiation of IPF. We have the vascular effects. We know that we can stimulate endothelial NO to be released, and that is doing two things. It's doing remodeling, so it prevents vasculopathy, and we also generate vasodilation in small vessels.
That could also be an important contributor. We have, I think, very well documented antifibrotic effects through TGF-β and a number of mediators. We have shown that in human IPF lung slices, for instance. Fourth, but maybe not least, we also have signs of fibrinolytic activity, meaning that you can dissolve the fibrosis in a way. That is through activating enzymes that normally does this, and we have seen that also in fibrotic lung tissue slices. There are multiple mechanisms that possibly could contribute to the effects we've seen in the clinic. Now to repeat how devastating the disease is and how much an effective therapy would mean, I would just summarize a little bit of the disease characteristics. In this disease, you have a worse prognosis than many.
Most of the cancers, and there is really no cure. The lung will display scarring as you can see on the slides, but we also have a diseased vasculature which together leads to both the incapacity to oxygenate your cells, so you get shortness of breath, but also to cardiac failure. It's a dreadful combination. Treatment today, as I said, reduce the rate by which you decline, the lung capacity decline by 50%. But it also comes at a price, and that's the serious gastrointestinal side effects. From the day the patient get the diagnosis, he will, it's most often a he, will never feel any improvement, but instead declining lung function and also, if you're unlucky with your standard of care therapy, have nausea, loss of appetite, vomiting, diarrhea.
All in all, it is a very poor quality of life. Despite this, as you see to the right, global sales of the existing drugs exceeds $4 billion in last year, and this market is growing. To me this says that this is a much larger market once you have an effective therapy, of course. There is certainly still a significant unmet medical need and an opportunity for market leadership if you have an effective and tolerable drug. You can imagine we're excited of these unprecedented results and we see the initial stabilization followed by an increase in lung function, never seen before, with a good tolerability and safety.
With these results, we have decided now to immediately start planning for a next trial, a randomized controlled dose-finding trial to confirm the results and to establish the effective dose for the pivotal phase III trial. For us, it's exciting times, and I would like to thank you for your attention. I can certainly confirm now that Vicore is well positioned to develop novel therapies for fibrotic lung disease. By that, I stop this presentation and open up for questions if there's any questions have come into the desk. So-
Great. Thanks. Thanks, Carl-Johan. If I could start off, we have got a handful of questions that already have come through. Let's start with the first one. Can you comment on patient demographics in the study?
Yeah. It is comparable to other studies. It's male predominance 90%. Mean age is 69 years. We have Asian and White. We have the mean FVC predicted, meaning that they are moderate disease, is 72%. So that's. It is not mild, it's not severe, but it's a moderate. So I think they're very much comparable to other studies.
Great. Next question. Why do you have a single-arm open-label study design?
Of course, you would like to have a controlled randomized trial. We found in the phase I study of healthy volunteers, at the high dose, that was twice the dose we're using right now, at 200 milligrams, that we encountered hair loss. Nothing else but hair loss. Of course this is not a big deal for a patient with IPF if they get an effective drug. It would have ruined a double blind study because you will suddenly not have a blinded study anymore. People would recognize whether they had hair loss or not. Therefore, we decided to start with a single arm study, open label, with the dosing, that was clean, without any hair loss in the phase I, and that was 100 milligrams twice daily.
I can say that we haven't seen any hair loss in this study nor in any other studies apart from the high dose in that phase I. I think that's fortunate. Second, we wanted to study naïve patients. We wanted to evaluate the drug on its own, and I think that's a very good principle if you can. Patients don't like to be part of a placebo lottery, so I think this has been a patient-friendly study in that way. They know that when they enter the study, they will get an active component and hopefully an active drug for their disease. Therefore, we were also very, I think, very...
We had very stringent criteria in qualifying patients, so that an independent reader was doing the high resolution CTs, and that was the same reader that I know Boehringer has used in their studies and has done a number of studies. We had very good reference there. Then again, gold standard endpoint FVC is also important. We try to make up for not being controlled in that way. We also know that the trajectories, 120 mL per six months on a cohort basis. I think that's a good compromise for us. I think we've managed to keep integrity in that way. Finally, I think what's also important, we have collected data now up to the nine-month.
This is really strong because I haven't seen any published data with increase in FVC after six month and up to nine months. I think that kind of also take care of the worry about a placebo effect in these studies.
Okay, very good. Thanks, Carl-Johan Dalsgaard. Next question, is there any data from other trials that supports the observed increases that it's not a chance finding?
Yeah, that's a good question. The best data I'm aware of is the analysis of the INPULSIS. That's the two phase III studies that Boehringer did with nintedanib. There they grouped all the placebo patients from INPULSIS-1 and INPULSIS-2, and they found only 9% were stable or increased. When you look at those data more closely, the patients had 84% FVC % predicted versus our 72%, so they were less sick than ours. They also showed a decline at week 36 and they were more on a downward progress, so to speak, than we have seen in our study. It's a huge difference.
I think, as we said before, the increase as we move to week 36, I think is a very strong signal there. That's the closest observation. Of course, we could have been extremely lucky and caught these patients that are on the upper limit. I think that's a very low chance that this is the case.
Great, thanks. Can you comment on what the data would look like if you use medians instead of means? Just trying to understand if there are any outliers that drove any of the performance on FVC.
It looks basically the same. Any way we have analyzed these data, we have the same picture, so there is no skewness. I think it's a small sample size and we have a variation. It is always a high variation in FVC measurements, and we do have a high variation. That high variation is on the positive side of the FVC trajectory. We're on the right side of the zero line, so to speak. Even if you make slope analysis on different time points, you will get the same picture. It is consistent, either way we do it.
Great. Next question. Have you assessed any biomarkers?
No, not yet. I'm not really aware of any biomarker that kind of predict treatment success. There's a lot of biomarkers around, but they've never been, I think, really validated. They are more validating the target, and I think we've done the target validation in the autoradiographies that I shared with you before. We haven't done that, but we do have samples, exploratory samples that we can use for biomarker analysis after the study. We can then see what the status is for novel predicted biomarkers at that time, and then analyze them.
Next question. With the data like this, how do you foresee the positioning in the market?
If we are able to repeat this data, and if they hold through, I mean, these data are incredible. We have always aimed for first line therapy since we believe that there's so much still to be met, and both from a safety and from an efficacy point of view. That's been our primary aim with C21. Here we have shown more than that. I mean, we have exceeded that. We haven't seen any GI intolerability, for instance. I think if we can stabilize disease without any further lung function decline, I think we are having a game changer for IPF.
Yeah. Great. Next question. How has the COVID-19 affected the trial?
Well, I guess COVID-19 have affected all clinical trials in several ways, ours as well. First of all, I think most importantly is that IPF patients in particular, they want to avoid COVID because they want to avoid upper airway infections because that can trigger an exacerbation. It's for them to visit hospital to participate in the study, to do all the visits and measure the FVC is a challenge. We have, of course, experienced that challenge like everyone else. We unfortunately, in a sense, have had very frequent visits in our study as well. What we do is, of course, we add on more centers and open countries and so forth.
Logistics, supply, turnaround time at regulatory bodies that was very easy in the beginning of COVID has become very slow in the aftermath of the second phase of COVID and customs and hospitals and staff. I mean, everything has been affected. That is clear. What we did during the study, we changed the inclusion criteria, so we required that patients should be fully vaccinated against COVID to be to enter the trial. Despite that, we have had patients who have had COVID and are out of the trial, and we have also had patient that has been withdrawing their consent because they don't want to go to the visits because of trying to avoid the infection.
Like everyone else, we have been affected, but of course, we've done a lot of means and measures to counteract that.
Very good. We're getting some great questions here. Next one, what percentage of patients that have reached 24 weeks have continued into the 12-week treatment extension?
I think all patients that got 24 weeks have continued into the extension. It could be one, and I'm not completely sure. It could be one that has lost because of moving, but there's no one that says, "I don't like this, so I don't want to continue," because they. The ones that are at the 24 weeks. They probably don't feel any improvement. They probably don't feel much change, and I think that's a great step for them. It's maybe hard to appreciate that early in the disease. I would say eight out of nine or nine out of nine. I will have to check that.
Great. We are getting some similar questions from folks here. I'll try to combine them and try to pose them appropriately here. Next up would be, what is the next step? How long will the phase IIb study take, and when can we expect start of phase III?
We have, of course, not really started to plan in detail. We start to plan absolutely for a controlled phase IIb study, and we will need to sit down with statisticians and I think to get the number of patients needed based on the data that we see here and the data that we will collect later on. We hope to be able to start the trial by the end of the year. I mean, there are many bits and pieces that should be in place. I mean, not only protocols and approvals and so forth. So also study drug, labeling, placebo. So I mean, there are many things that we need to get in place.
The target for now and is to be able to get going by the end of the year. That is that's really about one year ahead of the schedule if we wouldn't have had these good data in the interim. I think we're gaining a year here. For how long? I think it depends on. We haven't really decided how long the study should be. Should it be six months, nine months? I don't think we need to do 12 months in the dose finding, and then the number. Maybe it takes one and a half, two years to complete this trial, and I think that's pretty normal. These studies have a tendency to take time.
Start the phase III after that, and we can of course meanwhile prepare for the phase III.
Great. Thanks. Next one related to that one. Are you looking for FDA input on the design of the phase IIb?
Absolutely. I mean, this will be done under an IND, sure. Because we need to discuss this with the FDA for the pivotal trial, so that's absolutely so. We have a discussion with the FDA, and we are on their map with the COVID trial, so. This have to be a separate IND, of course.
Great. Getting some similar questions here. When will the study be complete, and when will you be able to update these data sets?
We haven't really decided on that yet. I mean, we were a little bit taken by surprise when we saw the data, and we haven't really planned in detail on how to proceed. I mean, we will proceed with the trial, and of course, all the patients that are in the trial will be offered to continue and participate according to the study protocol. That's the plan we have right now. In parallel, we will do the planning for the phase II and start that as fast as possible.
Next question. Were there any patient-reported outcomes, i.e., quality of life endpoints measured over the 24 weeks period?
We only analyzed the FVC data in this interim analysis and of course the safety. We have no other analysis done. I think quality of life may not be adequate in this small type of trial. I think the quality of life that we have measured is of course the lack of gastrointestinal side effects and/or other side effects and tolerance issues. I think that's part of the quality of life. Otherwise, we haven't done the formal quality of life scores.
Very good. Next one. Is there a mechanistic rationale for the increasing slope?
Well, this is speculation. That was really, again, a surprise. I think we sometimes think of the lung as very, you know, mechanical. It's a box, and it's hard, and it's stiff. With scarring, it becomes harder and stiffer. I think there's a lot of dynamics going on. I think if you can, for instance, improve blood flow, if you can open up alveoli, and you can get a better breathing, I think there is room for improvement of your lung capacity, even though you have IPF, especially if you can stop the build-up of fibrosis. I think there is a dynamic aspect to this. We think about it as FVC. That's a measure.
How big a volume do you have for gas exchange, basically? I think there's much more dynamics around that, and I think this is really an interesting question to understand better in the future. I certainly think that there is opportunities for increasing your capacity, maybe not back to your normal starting point before disease but definitely a bit on the way.
Very good. Another question on next steps. Would you have one or more arms to evaluate efficacy on top of standard of care in addition to placebo and monotherapy arms?
It's a complex question. I think we will do one simple trial. I think we will do two doses, and I think we will have a comparator, whether or not that is a standard of care drug or placebo remains to be seen. We haven't really studied that in detail. I will rather avoid standard of care as an add-on in this dose-finding study. I still like to see how my own drug works in its isolation without the extra input from other drugs, especially when we know their profile. That's the ideal profile of this study.
Of course, we have to think about it, we have to design, we have to propose, and we have to agree with the regulatory authorities that this is the right way to figure out the best dose. The intention is there.
Great. Next question. Given what you said regarding the AIR trial being patient-friendly and not including a placebo arm, will this data, given the strength of the data, cause problems for the recruitment into the AIR 2 trial?
First of all, I think recruitment will be very much easier when we have this data to present because this gives patients a real opportunity. It's a good lottery to be part of this trial. Of course, patients may have difficulties with the placebo arm, and that's also why we have been thinking about could we have a standard of care arm as the control because then we have a blinded trial, we have the control. It is not really conventional, but maybe that's the ethical thing to do in a trial like this. Again, we have to do the math, we have to do all those bits and pieces. I think for a...
Trials need to be at least six months to find the data, and especially if we look at our trial, and I think that's true for most trials. It's hard to rely on three months' data. Which means then that if you have a placebo arm, you will have six months of placebo, and that's really on the edge of what patients will tolerate. If you go further to one-year placebo arm, it will be much more difficult. We'll try to find a middle way, and we'll try to do the study as patient-friendly as possible. I think that is arguments that we can use for a little bit maybe different design than the conventional.
Great. Next one. What will patients that exit the study do? Stay on C21 or revert to Esbriet or Ofev?
They will go to standard of care after completing the full nine months. That's very normal in these types of studies. They may have the opportunity to participate in the next study. We will not have any extended use of C21 after the study.
Yeah. I think we have the last question here is, now when you have these data from the interim analysis, what more do you think that you will learn from completing the study?
Not much, I would say. I think we have the picture clear. The values may be different, but I think the overall impression will be the same. That's also why we right now just focus on starting the phase II to move forward to get this as fast as possible to patients and to the market. I think we will get a few more patients. I don't think we will learn much from the side effect point of view because side effects are 1 in 100, 1 in 1,000, and so forth, and we won't pick that up in a few patients. I think we will get a little bit more solid and robust data set, but I think the overall picture will be the same.
Okay. Very good. That's it from a Q&A perspective on the inbound questions. Maybe turn back to you, Carl-Johan, for some concluding remarks.
Thank you so much, and thank you for listening in. I think this has been a really thrilling to go through the data and to be able to share with you something that if we can repeat it will be a game changer for a devastating disease. Thank you so much.