Thanks Gisele for the introduction, thanks to the Cowen team for having us at the conference.
Refer to our typical forward-looking statement disclaimers. Vicore Pharma is a publicly listed company actually in Europe on Nasdaq Stockholm. We're about SEK 300 million market cap company currently with about SEK 130 million cash position as of the end of the year. We're fortunate to be backed by a number of excellent specialist investors in the United States and in Europe.
We have the bulk of our R&D team based out of the Nordics in Stockholm and in Copenhagen, and a growing team in the United States as well. I'm personally based in Boston.
What we're working on at Vicore is really heavily oriented towards our lead program, which is called buloxibutid, and it's being developed as the initial indication for idiopathic pulmonary fibrosis. It's currently in Phase 2b development for the disease, we're planning on completing enrollment of that study in the first half of this year, I'm excited to talk a little bit more about that trial. We've licensed Japanese rights to Nippon Shinyaku, a leading biopharmaceutical company in the country, otherwise are unencumbered.
In addition to this lead molecule, we have a number of preclinical candidates with similar biology that we're advancing for different fibrotic and inflammatory conditions. Since our focus is on IPF, I'll talk a little bit about why look at that disease in particular.
This is really a terrible disease with very limited survival after diagnosis. We're talking about a 3-4 year after diagnosis survival, and that's even in view of the available therapies. There are three therapies that are currently available. In addition to a relatively limited efficacy of those therapies, they're also quite poorly tolerated, so they tend to generate significant side effects, nausea, diarrhea, other gastrointestinal side effects, photosensitivity, and other side effects as well.
That combination of very limited efficacy and poor tolerability means that only a minority of patients in the United States, actually about a quarter, ever even initiate therapy after they have the conversation with their doctor about the disease, what they can expect and what the standard of care therapies would do about that. Even for that subset who do initiate therapy, they only stay on the therapy for a median of 10 months. Fairly quick time until they discontinue treatment.
Not with standing that super high unmet need, the unfortunate kind of drawbacks of the standard of care therapies, it's still a huge market commercially. It was over $4 billion in 2024. It's expected to grow to $10 billion-plus by 2030. There's.
The reasons for this are the combination of the fatality of the disease. It is an orphan disease, although a larger orphan disease.
It also is one where, of course, if we can have better-tolerated therapies and ones that are more efficacious, there's really incredible opportunity for patients and for the market. In addition to high unmet need, significant commercial opportunity, there's also limited late-stage development landscape. The three therapies that are shown here in addition to buloxibutid are the ones that are ahead of Vicore in development, and these therapies include one that's been approved. This is Boehringer Ingelheim's Jascayd or nerandomilast.
These therapies all have shown in development to date to have an incremental effect on lung function, i.e., the ability to slow the decline of lung function incrementally, and have different tolerability, or safety or convenience issues. For example, nerandomilast is one of those therapies that is known to drive GI, gastrointestinal side effects and tolerability issues. Inhaled treprostinil is known to drive cough, irritation, and other side effects.
Really there's a significant need both for something that would be disease-modifying or have a more significant impact on lung function, and we've certainly seen a signal of that with buloxibutid in our development to date, and I'll talk a little bit more about that, and also, therapies with a better tolerability profile.
We believe we have that as well, and I'll talk a little bit more about that as well. It's also nice that our drug is an oral small molecule, so it's very easy for patients to take and very convenient. Inhaled therapies can be a little bit more cumbersome for patients, particularly when you have to take them many times each day. What we have then in buloxibutid, I would say the most significant challenge with IPF, is ensuring that you have a therapy that can be efficacious. There have been a number of therapies that have been attempted in development, and they failed in a Phase II setting to Phase III setting, or they run a Phase 2a, and it doesn't pan out subsequently.
Really, we believe we have the right mechanism and the right data that reflects, you know, our confidence as we move forward in this space. First and foremost, you know, pulmonary fibrosis is a disease where you have injury to the lung, which drives a runaway wound healing or scarring process. Many companies that work in this space are trying to block that fibrotic cascade. Instead of doing that, we actually activate an endogenous tissue repair and fibrosis resolution system that sits well upstream of the fibrotic cascade, and we believe that's the right way to go after this disease.
That, mechanistic concept has been reflected in an excellent Phase 2a data set where we show actually the ability not just to slow the decline of lung function, not even just to stabilize lung function, but rather to improve it over an extended period of time, a 9-month Phase 2a study, and I'll talk a little bit more about that.
For our Phase 2b study, we're really looking to cement the demonstration of the activity of this molecule with a robust trial, 360 patients, which is relatively large for this disease state, a 52-week treatment period, so one year at the regulatory endpoint in the disease, which is the change in lung function over that 52-week period, and positioning the drug as a frontline therapy you can take on top of currently available standard of care or for patients who choose not to take the standard of care for various reasons as well. Maybe starting with the first piece of this puzzle, which is the mechanism, right? This is a schematic of the angiotensin II pathway, where the mechanism that we're going after sits.
What we're doing here is agonizing the angiotensin II type 2 receptor, which is shown in orange. This is a receptor whose activation drives anti-fibrotic, anti-inflammatory, and vasodilatory processes. It's a pleiotropic mechanism of action, and it drives a number of processes simultaneously. Again, we think that's the right way to go after this disease. The AT2 receptor actually functions in the body as the opposing force to the AT1 receptor, which is shown in gray on the left.
This is actually a receptor that drives then fibrosis, hypertension, and inflammation. It is the natural body's response to infection, injury, insult. It is a system that, you know, very quick to turn on and very quick to be activated. What also then exists in the body is this then response system that we're activating.
What's interesting about this mechanism is it is the pathway that's actually blocked by ARBs and ACE inhibitors. ARBs are losartan and the sartan class. They're commonly used not only for blood pressure control but for a number of other conditions. We believe that just as the ACE inhibitor and ARB class have been very fruitful in terms of yielding well-tolerated and active drugs in a number of therapeutic contexts, we believe that activation of the AT2 receptor can do the same, starting with IPF, but certainly going beyond that as well. Maybe since we're starting with IPF, we can take this into the context of the lung.
In particular, this AT2 receptor that we're activating is highly expressed on type II epithelial cells, which is a precursor cell that sit in the air sac of the lung, these alveoli that are shown here on the left-hand side. These type II epithelial cells that we're kind of activating with this mechanism of action, they play two key roles.
They differentiate into the type I or the gas exchange cells of the lung. That's actually the workhorse of the lung. The air sac is basically lined by these type I epithelial cells, and that's where oxygen comes out and carbon dioxide back through for the gas exchange function. In addition to that, these type II epithelial cells produce surfactant protein, which breaks up the natural surface tension of water.
On this slide, maybe we can talk a little bit about why that's important. This is a schematic of essentially the lung, and in the middle, you see the air sac. around the air sac, there's what's called an interstitial space, which is essentially the space between the air sacs and the pulmonary vasculature. At the bottom, you see the pulmonary vasculature.
The objective, you breathe in oxygen, it should come through into your air sacs, diffuse across these type I epithelial cells, these gas exchange cells, and then they kind of diffuse across that interstitial space into the pulmonary vasculature to oxygenate blood. Now, on the left-hand side, we're showing what happens in IPF.
IPF is a disease of basically injury to that epithelial layer of the air sac, that epithelial layer of the alveolus, and that injury is caused by a mix of genetic and environmental factors. Many folks who have IPF might have, been exposed to environmental exposures like working in industrial settings or military settings, plus, of course, some genetic component as well in many cases.
That injury then drives the death and dysfunction of that epithelial compartment. You have apoptosis and dysfunction of the type I and the type II epithelial cells. What that then does, even before any fibrosis, is causes an impaired gas exchange capability. Oxygen can't get out of the air sac and get into the pulmonary vasculature to oxygenate blood.
In addition to that, because the type II epithelial cells are becoming injured and dysfunctional, they can no longer then differentiate into type I to replace the injured cells or the apoptotic cells in that population. Beyond that, they also are no longer producing the same levels of surfactant protein to break up the surface tension of water.
What happens when you have a loss of surfactant production because of the dysfunction of these type II epithelial cells, is a phenomenon known as pre-fibrotic alveolar collapse. These alveoli collapse into a pancake, and they stop participating in the gas exchange function. This also then affects the ability of IPF patients to breathe even before any fibrosis builds up. Now we have actually the start of the fibrotic process.
The type II epithelial cells, when they become injured, they send out the wound-healing signal, right, the response to injury signal, that actually is TGF-beta 1 and other pro-fibrotic cytokines. That essentially causes fibroblasts. You see them on the lining of the type II epithelium. Or sorry, the epithelial layer. They start to build up, they start to activate, proliferate, migrate into the interstitial space, then they start depositing collagen.
That then causes a physical barrier to oxygen diffusion across of these air sacs. Further frustration of the ability, unfortunately, for IPF patients to breathe. As that collagen builds up, not only does it become harder for the oxygen to get out, it also starts to put pressure on the pulmonary vasculature, squeezing it down.
That causes what's called pulmonary hypertension, so a narrowing of the vessels in the pulmonary compartment, and also a thickening of the vessel walls. This causes even more disease kind of advancement and more difficulty in oxygenating blood. Now, on the right-hand side, we look at fundamentally what we believe we do about this disease by activating the Type II receptor on these Type II epithelial cells. That's driving a proliferation and a refunctionalization of these precursor cell population.
Now you can have differentiation into Type I gas exchange cells again, so you replenish your gas exchange capability. You can address pre-fibrotic alveolar collapse because these refunctionalized Type II epithelial cells are producing surfactant protein again. You also are able to attenuate that pathological pro-fibrosis drive, right?
When these type two cells become functional again, they're no longer releasing TGF-beta and other wound healing signals, and so you no longer have the activation build-up of fibroblasts transition to myofibroblasts and collagen deposition.
Not only does this mechanism stop the build-up of new fibrosis, it's also known to resolve fibrosis. That's what AT2 agonism does, and it does that by upregulating enzymes called collagenase matrix metalloproteinases, and these are enzymes that actually chop up existing fibrotic matrix. That then can facilitate better oxygen diffusion. Then when you go to the pulmonary compartment, this mechanism's also vasoactive, so it drives a vasodilation effect and addresses that vessel narrowing and the dysfunction in the pulmonary vasculature.
What we believe we have here with this mechanism of action is a comprehensive way to go after this disease state, which is distinguished from others that might be only involved in the interstitial space or that fibrotic cascade. Now maybe looking at then what we've seen clinically in terms of the ability of this mechanism of action to drive an effect.
What we did in our Phase 2a study in this disease was we looked at oral buloxibutid 100 mg twice daily over about 9 months in treatment-naive IPF patients in monotherapy. We of course, looked at safety and tolerability, but we also looked at the regulatory endpoint, which is this change in lung function as measured by forced vital capacity, which essentially is the, it's milliliters of capacity that are present in your lungs.
We enrolled in this open label Phase 2a study shown here on the left-hand side, it's called the AIR trial, a population that's very consistent with what other companies have enrolled for IPF trials. We have one of the sets of Phase IIIs that's led to approval of one of the standard of care INPULSIS on the right-hand side. This is a disease generally of older individuals. It tends to be more predominant in men. It also is a disease where there's impaired lung function. I would say that's one of the hallmarks of the disease.
You'll see there's an FVC percent predicted, and essentially that's the percent of total lung capacity expected for your age, weight, gender, and we have 75% predicted FVC at baseline for our enrolled population, which is in line with what you'd expect, 79% in the case of the INPULSIS studies.
In addition to enrolling a typical IPF population in this study, we also of course, looked initially at the safety and tolerability, and here we have treatment emergent adverse events shown on the right-hand side from that Phase 2a study. What we see here is a good GI tolerability, so we don't have that signal that you see with the standard of care. On the left-hand side we have a comparison again to standard of care in INPULSIS trials, which led to the approval of nintedanib, where there are significant GI side effects.
We also saw a low rate of exacerbation and cough worsening, which was very nice to see. No treatment-related serious adverse events were observed in this trial, so that was very nice to see as well.
We do observe 19% hair loss or hair thinning in the Phase 2a study, which is an expected side effect. This is an effect that was mild to moderate and that was reversible in the study. Patients, as they completed the study, had the hair regrow. This is something that we continue to look at, and in the Phase 2a study, we're looking at a 100 milligram dose only. In the Phase 2b, we'll actually look at a 100 milligram and 50 milligram to see if we can mitigate or even maybe eliminate this type of an effect.
Ultimately, because IPF is such a fatal disease and tends to be dominant in older men, we believe this is also an acceptable part of the tolerability profile. The exciting part of this story is really the efficacy profile that we see over this 9-month study. What we see here is in the green, you basically have the drug driving a stabilization in lung function initially, followed by improvement in lung function out to 36 weeks. Ultimately an improvement in lung function by over 200 milliliters, which is unseen before in IPF setting.
Really, an exciting data set and compares quite favorably to certainly what you'd expect an untreated population to experience, and that's shown in the dotted line. You'd expect about a 180 milliliter decline over that 36-week period based on the literature.
Certainly when you think about the standard of care, they would still be below zero, right? They're slowing the decline of lung function, but certainly not stopping it. What's also very nice about this data set is it's robust to outliers, which is one of the weaknesses of other and past IPF data sets. 65% of the patients at 36 weeks had improvement in lung function.
This is not a data set where you just have a couple of patients who are improving and pulling up the entire data set. 80% of patients performed better than expected untreated decline. We enrolled a number of patients out of India. The Indian patients had improvement in lung function, but so did the patients out of the United Kingdom and the other territories where we enrolled the patient population.
There's a nice consistency between geography, gender, and other features that we see at baseline having that improvement in lung function. In addition to that, it was nice to see that when you segment the disease state based on the high-resolution CT scan into probable UIP and typical UIP, which is a representation of, you know, more mild disease or more established disease, in both cases, you still have a modest improvement in lung function, even in the established disease, and then an outsized improvement in the maybe earlier stage patients or those who have a probable UIP.
W e believe that's explained by the mechanism of action and the ability to drive that epithelial repair, which can be more impactful at an earlier stage of disease.
Certainly, the ability to even then take the established disease patients and stabilize or modestly improve lung function is outstanding. Now, as you can see here, one of the features of this study was that it was an open label, and one thing we wanted to do is run a synthetic control arm analysis to really make sure that for patients who look like this, we confirm how they would have performed in terms of FVC trajectory over that 36-week period. We worked with a company called Qureight, who have a database of over 10,000 IPF patients.
We then narrowed that grouping of 10,000 patients by the ones who would meet the inclusion criteria for our Phase 2a study. For those then patients, we actually generated 30,000 randomly sampled placebo arms, so arms of 48 patients.
We basically took those placebo arms that most closely matched our placebo cohort across a number of different dimensions, including the lung function status, age, gender, and other features.
Essentially, we ended up with 408 kind of top matching placebo arms. What we then did is we looked at those 408 most closely matching placebo arms and what their trajectory would be over 36 weeks. That's shown here on the right-hand side. What you see is basically a mean decline in lung function of 115 milliliters over a 36-week period. It confirms that patients who look like this with IPF do have that decline in lung function over a 36-week period.
What's also nice is we show here a comparison via imputation to our Phase 2a dataset, we show a statistically significant difference between the placebo synthetic control arm decline and the treatment group, even when we do a relatively conservative imputation for some of the withdrawals from the study as well. Here, just recapping a couple of the points that I made, the improvement in lung function shown on the right-hand side, 65% of patients with buloxibutid at 36 weeks.
This is not the type of effect you would certainly see with standard of care therapy, where only a minority of patients would have any kind of improved FVC value.
Certainly, when you think about an untreated population, it would only be a single-digit number percentage of patients who would show, you know, a similar or slight, slightly better FVC value than at the outset.
Really kind of reflects that this is a very different dataset from what's been previously generated. From then here, what we've been working on is a Phase 2b study to really demonstrate the efficacy of this molecule in a randomized, you know, double-blind placebo-controlled study. We're enrolling 360 patients, as I mentioned, two different doses of buloxibutid, 100 milligram and 50 milligram, as well as then now enrolling patients who are on background standard of care, Nintedanib or nerandomilast, or not on background standard of care.
This helps to ultimately position this drug, as a frontline therapy that you can take, on top of available therapy or not on top of available therapy. Again, we'll look at the Phase III endpoint in this Phase 2b study, which is the change in lung function from baseline at 52 weeks.
The enrollment criteria are quite broad for this study, so materially similar to a number of the other Phase III studies, that are in development in this space. This is a study now that is going to complete enrollment in the first half of this year based on our projections, and we're well on track to achieve that. Of course, then, for a readout in mid-2027 after the 52-week enrollment period. Excellent.
That's our story, and I'm very happy to take any questions as well.