Hey, good morning, everyone. Kicking off the next fireside chat here with Bernt van den Blink, CMO of Vicore Pharma, and Hans Jeppsson, CFO. We're going to do a formal fireside chat here. I'll kick it over to them to give a brief overview of Vicore, and then we'll get into a Q&A. With that, over to you guys.
Thanks, Alex. Pleasure to be here. Vicore is a clinical stage listed on U.S. Nasdaq since July this year, developing buloxibutid, which is a first-in-class oral angiotensin II type 2 receptor agonist for idiopathic pulmonary fibrosis, a fatal disease with no truly disease-modifying therapy today. Unlike most other IPF approaches, buloxibutid acts upstream, which is how we believe this disease needs to be targeted. Bernt will share more on our very encouraging phase II-A trial data later on. We're now fully enrolled in our global phase II-B ASPIRE trial targeting top-line data mid-2027. Finally, I think on the intro to Vicore, we have a very strong shareholder base, including Sanofi, and we also have a partnership with Nippon Shinyaku for Japan.
Great. I guess I wanted to kick things off talking about the current state of the IPF landscape, sort of the trend towards recent positive trials after sort of a stretch of a lot of failures, and then some feedback for the sort of newer launch here from Boehringer Ingelheim with nintedanib.
Yeah, maybe I can comment on that, Alex. I think everyone has been hugely encouraged that finally, after more than 10 years, it has proven possible to develop a next generation of IPF drugs. We've seen initial, I think, large enthusiasm for nintedanib. I think the main driver of that is the better tolerability. That's what we're hearing from investigators and KOLs because we must acknowledge that the effect size is rather limited. On the other hand, of course, we've now seen recent triple therapy data look a little bit better in terms of effect size, although we need to be cautious because analysis methods differ between these trials, but obviously have quite some tolerability issues.
I think what we're learning from here is that there is a large unmet need for drugs that are really better tolerated and have a decent effect size. And what we're also seeing still in these studies, of course, is that this remains a deadly disease for patients. Despite these therapies, they are still unfortunately burdened with a lethal disease.
Yep.
I think the most recent insight that we also, I think, would be good to share is that I think the enthusiasm for a first-line or a monotherapy that's well-tolerated remains. Real-life experience combining pirfenidone with nintedanib has really dwindled. Patients suffer from lots of diarrhea, and in real practice, nintedanib is often dose reduced or stopped. I think it highlighted that people want to do combination therapy, it makes a lot of sense, but are looking for a drug that can be well combined and is well tolerated with other IPF drugs.
Great. I think that's a good transition to buloxibutid. I guess maybe could you talk a little about kind of the discovery here and the mechanism of action?
Yeah.
Then we get to the data that you generated to date.
Yeah, of course. Buloxibutid is an oral small molecule angiotensin type two receptor agonist. Folks on the line may be well familiar with the angiotensin type one receptor. It is targeted by ARBs and ACE inhibitors in the past to reduce hypertension. This receptor is really evolutionary, very well conserved to prevent you dying from a large bleed out if you have a large wound. Basically, it constricts your vessels, it closes your wound with the fibrotic and inflammatory process. The angiotensin type two receptor, less known, is the evolutionarily also well conserved counterpart of that. It is vasodilatory, anti-inflammatory, and importantly, anti-fibrotic. It clears sort of excess collagen in the wound. buloxibutid is targeting precisely that pathway to resolve fibrosis.
I think the really intriguing bit is that this receptor is constitutively expressed in the lung, in the part of the lung that is usually exposed to a lot of damage, the alveolus, and then in the type two cell that actually normally replenishes a damaged alveoli. It is this cell that is also at the start of the pathogenesis of the disease we are targeting, which is IPF. In IPF, this cell is dysfunctional, and we are targeting sort of upstream effects in this cell.
You have done a lot of preclinical work here looking at sort of that anti-fibrotic mechanism. Can you walk through that and sort of how that, again, sort of adds conviction to IPF as an indication here?
Yeah, absolutely. Maybe sort of as tagging on sort of this crucial cell in IPF pathogenesis, we know that in IPF, what happens is cell is dysfunctional and then starts producing TGF-beta, which has downstream fibrotic effects on fibroblasts and myofibroblasts. The cell itself become mesenchymal cells, and they also stop producing normal surfactant protein D, which also is a source of normal alveolus health. Even in the end, also leads to vascular dysregulation, leading to pulmonary hypertension that we increasingly recognize an important part of the pathogenesis. Our preclinical data, both from preclinical mouse models, both translational position of lung slices, and even in vivo clinical data, show that, one, with buloxibutid, we increase viability of this type II alveolar cell, increases function by increased production of surfactant protein D.
Two, decreases the pro-fibrotic signal, decreases TGF-beta production, collagen deposition, and also has a beneficial effect on the vascular part. We see reduced signs of pulmonary hypertension in our models. Finally, I think intriguingly, we see that these cells, these type two cells, are a source of a matrix metalloproteinases. Basically, the enzyme that chew up excess collagen, and we are seeing that that function is restored with buloxibutid. We even see that in our clinical study, in the phase II-A study we run, and we may talk about it in a bit.
Yeah.
We see that patients have increased levels of the MMP-13.
Yeah. This is a good transition to talk about your II-A. Maybe if you could walk through sort of the design and-
Yeah.
Kind of an overview of the data there. We can get into some additional questions, too.
Yeah, absolutely. The AIR study was a single-arm, open-label phase II-A study in treatment-naïve patients with IPF. Patients were centrally reviewed for their diagnosis using the HRCTs, and they were treated up to nine months with the buloxibutid. This was primarily a safety tolerability study, but obviously this gave us the opportunity also to assess efficacy. The rationale was that, in IPF, we know this is a relentless disease, and you can sort of expect what patients in a placebo group do in terms of FVC decline. First of all, I think an important learning was the drug's overall really well-tolerated, particularly-
Yeah.
From a gastrointestinal effect, right? We're not seeing really any signal on diarrhea and vomiting, making really a different type of potential drug than nintedanib and pirfenidone. But I think the really intriguing bit was that when we looked at patients who completed the 36-week treatment period, patients had an increase in their FVC up to a mean of 216 ml. That's really unprecedented, right?
Yeah.
I don't think we've seen that in IPF. Really very encouraging. We've sort of course, sliced and diced the data, pressure tested it, imputing missing data-
Yeah.
Assuming everyone who dropped out had declined. Even when we do that, we see, I think, stabilization, which is still far beyond expectation in this relentless disease. Really very encouraging data driving our progress-
Yeah.
In the space.
Yeah, I think to that point, you mentioned we had more than a decade of high-profile failures in IPF, right? I think the key question here is just, how confident can you be in the realness of this data set, right? Can you talk through some-
Yeah.
More detail, some of the sensitivity analyses that you did and why you think that this is a signal that can be replicable on a phase II-B?
Yeah, absolutely. No, and the failures resonates with some of us in the company have been close to those, and there's lots of learning. Yeah, I think that one of the, I think, really interesting experiments we've done is we've used a large external control cohort matching patients with similar characteristics as in AIR, looked at the probability that you just by random chance would find a group of approximately 50 patients that show stabilization or improvement like we saw in our AIR data. Basically, what this experiment told us is that the probability is really very, very small.
We generated 408 placebo arms with similar characteristics as in AIR, what we saw is that overall, their mean decline was about 115 ml in FVC. When we looked at how often does it happen that patients increase, there was only one out of 408 placebo arms that had an increase similar to conservatively imputed AIR data. Basically, that tells us that in this experiment, the probability just by random chance, you find a group of patients that have stabilization or increase is really small.
One in 408. If you put a P-value on it's a P-value of 0.0025.
Beyond FVC, can you talk a little about other biomarker, other efficacy endpoints that are orthogonal or at least supportive here, too?
Yeah, I think some of the story here comes from the biomarkers. We saw a trend in TGF-beta going down these patients. Not an easy biomarker, as everyone knows from also other fields. I think the most important piece of the puzzle here was again, this MMP-13 that we saw significantly increase over time at several time points in patients. Since then, we've been able to show in lung slices that the type two alveolar cell is actually the source of this matrix metalloproteinase. I think the interesting part here is that together with surfactant protein D, it supports our hypothesis that maybe we not only reduce fibrotic progression, but also have an ability maybe to even reverse some of the early abnormalities that you see in all IPF patients, right?
Yeah.
Even in late stage, you see still early damage, and we really hope we have a beneficial effect that goes beyond just tuning down the progress.
You alluded to you not seeing the GI issues of standard of care, but can you walk through the rest of the safety profile you've seen-
Yeah.
So far?
Yeah, absolutely. Indeed, so overall, the A profile was really very mild. No GI issues. The only expected tolerability issue was hair loss. We had seen in healthy volunteer study with very high doses, we saw hair loss. One of the reasons, I think, also to do this study, to assess that, and we saw hair thinning in about 10% of patients in the AIR trial. Only one of those patients discontinued the study, and we're seeing similar sort of trends in the current, very large global placebo-controlled study that we're currently running. I think what we're seeing is that, one, it does not impede recruitment, right? We recruited ahead of schedule.
Yeah.
And what we are also seeing is that patients really overall, it does happen, but these are older male patients generally, so hair loss usually is not a big issue. And it is well-tolerated in the sense that patients also usually do not discontinue. Only very few patients abort the trial because of that.
Yep. So maybe moving forward, can you talk about the design of the phase II-B study, and how it is similar or different than other contemporary studies in the space?
Yeah. I think, many things are, I think, quite standard for our study.
Yeah.
But some are exceptional for a phase II study. So this is a placebo-controlled randomized global study, and we have a high dose, low dose versus placebo, stratifying on background therapy, allowing nintedanib and pirfenidone. I think what is special about our study, it is a relatively large study, almost 380 patients, and it is a relatively long study. It is not 24 weeks, but it is a 52-week study. And the reason for that is, I think, one, there have been many failures in this space, unfortunately, and particularly the phase II to phase III transition has proven to be a high-risk transition.
We think that with this design, we will be able to come to a very confident assessment of the treatment benefit of buloxibutid, really de-risking future investments in this field.
You just presented baseline characteristics of ERS, so how does the trial population compare to contemporary studies as well, like the pirfenidone or tocilizumab studies?
Overall, I think it compares quite well. I think we have enrolled a population that is very similar to many of the late stage phase III studies.
It is predominantly, again, older white male population with clear lung function impairments. There are a few small differences. One is our FVC and DLCO is slightly higher, very well understandable. Also, our lower threshold for FVC and DLCO are about 5% higher than phase III studies. This is by intent. We know that FVC and DLCO are one of the strongest predictors for mortality.
And while mortality is sort of an important signal in phase III, it is not a realistic signal in phase II. We want to have as complete data as possible. The other, I think, important bit in our baseline characteristics is we have targeted to have at least 30% of patients not on background therapy.
Yeah.
One, to get, again, a very clean signal in that population, but also to set us up for first-line or monotherapy.
Yeah.
We really met the threshold nicely at 40%. That is a little bit higher than [Fibrinogen and COMPANION. It is very much in line with the ALOFT data. Finally, 25% is actually treatment naive, which is-
Yeah.
Quite a substantial number, I think really helpful when we think about future treatment paradigm.
Yeah.
And think about potentially early treatment. Let me pause there and see if you.
Yeah, no. A lot there. I guess like it is one of the questions here in particular is what does the modern placebo response look like. On FVC and-
Yeah
Imagine that including naive and then also patients that are not on background therapy probably ensure that you are probably seeing a clear reduction in placebo FVC. How are you thinking about, or how did you think about powering the study just given that context?
Yeah. It is a little bit counterintuitive, but what we have learned over the last five, six years is that actually patients on background therapy do much worse than we expected.
Yeah.
They have much larger decline. There are some hypothesis, including self-selection. I think that plays a role. Patients who are not doing well on background therapy go into trials, and part of that might be, again, not tolerating drugs well and maybe less compliance with the drugs they are on.
Those patients give us a relatively large window to measure treatment benefits, because what we've seen in all the studies that they decline with about 180 ML. And then a little bit counterintuitive, patients not on background therapy do a little bit better than you would expect. Based on the older studies, you would maybe expect about 200 ML, and they decline with 150, 250 ML. Maybe also that's a little bit more difficult to understand. It's a heterogeneous group of patients who had treatment in the past and those who are treatment naive. I think generally what we're seeing, these are patients a little bit earlier in their disease and may have chosen, "I don't want these drugs that are ill-tolerated. Let me first do a trial.
Yep.
The overall message is that when you combine these groups, the overall decline is still clearly large enough to measure a treatment benefit, right? We would estimate somewhere around 170 ML, something like you would see in Fibrinogen, which gives us a very large window to measure a treatment benefit compared to the 75 of Fibrinogen or about 100 in [DICO]. We're really confident that that will work out well.
Yep. Again, we've been dancing around this for a while, but obviously there's been a lot of failures in IPF. I guess, what gives you the most confidence that this trial won't fail your drug in general, and how are you thinking about that?
Yeah. I think the difficulty, of course, with early development IPF is what gives you confidence to move forward.
Yeah.
It is, of course, the totality of the data. I think our preclinical package is really strong. We have shown multiple effects, beneficial effects in multiple animal models. Precision-cut lung slices have a relatively good grasp on the mechanism. Importantly, I think moving away from just fibroblast focus to really an upstream marker. I think the biology is really there. Then we are building, I think, on data from a phase II-A study that we acknowledge the limitations of not being controlled. But even if you are doing really very conservative imputation matching with external control arms, you still, I think, see a signal that is hugely encouraging. Then I think the setup of our trial really lends itself to come also to a confident answer about the treatment benefits, both the sample size as well as the duration, but also I think how we operate as a company.
We are a biotech company, but with that said, our outsourcing model is to be very close to sites and investigators. We have people on the ground in all continents and investigators and study coordinators we have direct relationship with. That is important not just for recruitment, but also for the quality of the study, particularly for the primary endpoint, which we really have been driving very hard towards getting really high quality. I think we are seeing that coming in. We monitor and track that closely. I am quite confident that we will have a really reliable readout.
Then for you, what does a good outcome look like to support pivotal development?
Yeah. I think that the bar is really not very high in IPF, right? I think that we can see that if we develop something that has nintedanib like effect size is better tolerated.
Yeah.
We already bring huge value to a patient via IPF. Obviously, we hope to see something with a larger effect size. I think we have reasons to believe that based on our mechanism and the AIR data, but that's why we're doing this study to really determine that. Then the second thing is being able to combine well with other IPF therapies. I think that's going to be important, and we also have every reason to believe that will be the case. Yeah.
Do you expect to see a dose response? Do you plan to pool doses if you're not seeing a dose?
Yeah.
How does that play into the assumptions here?
Yeah. We chose to include a lower dose to have more optionality also for hair loss mainly, right?
Yeah.
If there are patients who do not want to experience hair loss, we would have an idea of the dose response. I think based on the data we have with 100 mg, we are pretty close to the maximum effect we can sort on the receptor.
Okay.
We will have to see whether our 50 mg really gives a clear dose response signal. We think it really might, and I think will help us both determine optimal dose for phase III, but even beyond that may give us optionality in selecting the right dose for certain patients. Yeah.
Makes sense. Then just obviously, there is a lot of next-gen agents in development in IPF as well. I guess, where do you see buloxibutid fitting in kind of within the broader landscape of other new targets out there?
Yeah. I think that interesting unknown is admilparant at the moment, right?
Yeah.
We're expecting the readout, I think momentarily, somewhere in October, is the word on the street. I think the expectations are modest in admilparant based on the phase II study. But it might be a well-tolerated drug, and I think that is maybe where this is going. We are looking for drugs that are well-tolerated, might not Some of these drugs that will be available might not have a great effect. But what I think we're seeing is that the field is figuring out what is the new treatment paradigm. There's no consensus. The assessments of these modest effect size makes everyone think, "Okay, should we really switch? Should we add? Should we maintain what we had?" And we are now seeing both in the E.U. and the U.S. initiatives to do academic trials to really assess that.
I think that the paradigm for combination therapy will play out in the next couple of years, but I think we will be well-positioned to put ourselves both as a first line, but also as a combination therapy that could be with nintedanib, but also I think in the longer run also, for example, with buloxibutid or admilparant, drugs that probably combine really well and that give really hopefully combined a fantastic benefit to patients.
Great. Then maybe, Hans, to wrap things up, do you want to talk a little about your current cash runway and what's embedded in those assumptions?
Absolutely. We ended June with $93 million in cash, which funds us into the second half of 2028, so well past our phase II-B ASPIRE top line data expected mid-2027. That runway includes phase III preparatory costs like CMC, but not phase III clinical trial costs.
I guess, would you expect, if this trial is successful, that it could count as a pivotal trial? Is that the expectation?
Yeah. We think this trial as it is a substantial trial, 52 weeks will be part of the substantial evidence package.
Yeah.
Our assumption is that we would need one pivotal phase III trial. Yeah.
Great. Well, Bernt, Hans, really appreciate you joining us this morning, and thanks a lot.
It was our pleasure, Alex. Thanks for having us.
Yep.
Thanks. Bye