Okay. Nearly the end of Good morning. Thanks so much for joining our 45th Annual Healthcare Conference. I'm Stacy Ku, part of the biotech team with my colleague Vishal, and we're happy to be hosting VYNE Therapeutics. We have Dave Domzalski, CEO, and Iain Stuart, CMO, and Tyler Zeronda, CFO, in the audience. Real brief, just an introduction on VYNE, a little bit of a transformation over the last few years. Now, all eyes are on your BET inhibitors, VYN201, VYN202. Just give some brief background, and we'll dig into recent updates. Sure, sure. Thanks, Stacy, for having us. We're thrilled to be here. VYNE is a clinical- stage biotech company focusing on developing our novel BET inhibitor platform. BET inhibitors have been around for a bit of time, a dozen or so years, large pharma, large biotech, almost exclusively in the oncology setting. Some work in solid tumors, but a lot of it, obviously, in blood cancers. We're doing some of the first real formative work in developing BET inhibitors for the treatment of autoimmune diseases. We have two parts to our what we refer to as our InhiBET platform. First part, our most advanced drug is repibresib, formerly known as VYN201. That's a topical pan BD BET inhibitor that's currently in the clinic right now, a phase II-B study for the treatment of non-segmental vitiligo. We'll talk more about that. The second part of our platform is what we refer to as VYN202. That's a highly potent, highly selective oral BD2 BET inhibitor. We just completed a phase I-A SAD/MAD study. We announced those results at the end of last year, and we're currently in a phase I-B proof of concept study for the treatment of moderate to severe psoriasis. We'll have the readout for that study by the end of this year. Wonderful. We're going to stick with 201 just for the sake of my ability to pronounce. I will get it, I promise. As we think about the proof of concept results, we saw that phase I-B for 201 in vitiligo, we're approaching kind of the phase II, even bigger de-risking for the vitiligo program. Maybe just talk, remind us, talk about the results we've seen so far and kind of what level of conviction you have for phase II. Sure. Our phase I-B study was a three-arm study. We had about 30 patients in, in total, 10 patients per arm. We announced the results of that study about a year and a half ago. We had only about four months to actually conduct that study. That was just a function of tox data and time that we had. Our objective post what was some pretty compelling preclinical model data in vitiligo is, how could we design a study to get a signal in a relatively short amount of time? Our advisors and opinion leaders said, recruit patients that have the most advanced disease, progressive or active vitiligo. They are in this heightened state of inflammation. They are rapidly losing their skin pigmentation. See if your drug can show an effect. Can it slow down the loss of pigmentation, maybe see some signs of repigmentation? We did. We saw that. There was a pretty clear dose response. We looked at three doses. The two highest doses were quite strong in the results. That is really what gave us the confidence to move forward into our current phase II-B study. Okay. Do you want to talk about maybe the biomarker results that you disclosed so far? In addition to biomarker, I think the safety is key as we think about vitiligo and the competitive, let's say, market. Curious if you could cover both. Yeah, so let's start with the biomarker. In that phase I-B study that Dave kind of outlined there, we actually took punch biopsies from skin, from perilesional skin. We're primarily looking at specific gene signatures associated with a pathway called the Wnt beta-catenin pathway. The Wnt beta-catenin pathway is downregulated in many autoimmune diseases. Vitiligo is one of them. It's also downregulated in synovial fluid and diseases like rheumatoid arthritis. What's interesting with that pathway is it's almost impossible for melanocytes to differentiate, i.e., produce more melanocytes, and for melanocytes to ultimately start to produce color or melanin when you have a dysregulated Wnt beta-catenin pathway. We were looking at specific gene signatures right across the pathway, such as beta-catenin itself, all the way down to a master switch for melanocyte differentiation called MITF. In all cases, we saw for patients where we saw good response, you see an upregulation of these genes in the skin, which gave us great confidence that not only have we an anti-inflammatory effect, we're actually seeing a benefit, a recovering of the skin over the course of the time of the treatment. With respect to safety, the drug itself, repibresib, is designed as a soft drug. You're probably familiar with that concept. Aclaris has had a soft JAK inhibitor, for example, that they were developing for topical use in atopic dermatitis. What a soft drug is, is you're specifically designing in a metabolic liability. Anything you apply to the skin naturally is going to pass percutaneously through the skin, and you're going to get some level of blood level, okay? What we have done there with the molecule itself is it's rapidly detoxified by the liver. We actually looked at the pharmacokinetics and the exposure for repibresib, and it was de minimis. Even at our highest concentration of 2% in that study, we only had a handful of samples we could even quantify the drug. That is important because the adverse event of special interest associated historically with the class of BET inhibitors is thrombocytopenia. Clearly, we want to ensure that we minimize any impact there. Naturally, in that study, because we had such a low exposure, we did not see any evidence of thrombocytopenia. Wonderful. Let's talk about the ongoing phase II-B trial. You alluded a little bit to some of the differences that you're bringing forward for vitiligo, but let's discuss longer duration of treatment, different types of patients. I believe you're bringing forward change from ointment to gel. Maybe talk through those different phase II-B considerations. Sure. As Iain outlined, our phase I-B study in vitiligo was only up to four months, and we looked at patients that only had active or progressive disease. The drug that we took into that study was an ointment-based formulation. For our phase II-B study that is currently ongoing, this is actually in total a year long in duration. There are two phases to the study. The current phase that we are in is initially for 24 weeks or six months. It is once daily dosing, and we actually have four arms. There are three active doses, 1% and 2%, which were doses that we had in our phase I-B. We also added a third dose, which is a 3% concentration. We have three doses relative to vehicle. The formulation itself is actually a gel formulation. This is a water-based formulation. We chose this for a couple of reasons. One, patients that have vitiligo is a chronic condition. Ointments tend to be heavy. They can be greasy. They can be challenging for long-term use. Gel is a much more cosmetically appealing dosage form that works very well, especially for chronic indications and long-term treatments. We took a variety of different formulations through various skin penetration models, and we saw really, really good results. We wanted to make sure that it was not inferior to the ointment. Clearly, it was not. Anything was slightly better. We took the best one, and that's the formulation that's in our phase II-B study. The last part difference is that this study is all-comers. In the phase I-B, we looked at only patients with active or progressive disease. In the 2b study, we have patients that are enrolling patients that have active, but also patients that have stable disease. What we've seen and what's suggested in the literature is those that have stable disease tend to respond more durably over the course of time. We think all these things can be supportive to us and the potential outcome of the study. Okay. Wonderful. I believe you disclosed enrollment was completed in early January. It is for the first part, a six-month study. Is it fair to assume disclosures could come somewhere? I know you said middle of 2025, but could it maybe come sometime in, let's say, June, late June, early July timeframe? We said results are middle of this year, so I'm going to stick to that. We're on target to hit our timelines. We're highly confident of that. Okay. Wonderful. Obviously, as we're expecting the results to come, let's talk about the hurdle for success. What's the criteria, in your view, for efficacy and safety? Sure. This is a dose-ranging study. We always try to put things in perspective. We're testing three doses. Our first study, we only ran it for four months in duration. It's the first time we're actually stretching the timeline out to what is more normal for these vitiligo studies. Our aim, first and foremost, is to be statistically significant versus vehicle. I think if we do that, assuming we do that, and our hope is that we'll have a clear winner in terms of the doses that we're studying, that will inform us on what registrational studies should look like as we would move into broader global programs. We obviously want to see meaningful efficacy, meaningful durable response, and obviously also see a good safety profile in that as well. We'll see what the data shows. Okay. As a reminder, FASI 50, so the 50% reduction is going to be the primary endpoint. The key secondary endpoint, which is the regulatory approval, will be 75? That's right. That's right. In our phase I-B study, we only looked at the percentage change from baseline. In this particular study, the phase II-B, the primary endpoint's FASI 50, 50% improvement from baseline in score on the face, vitiligo severity score on the face. FASI 75 is a key secondary because that ultimately will be the registrational endpoint. I think important to note is that the design of our phase II-B very closely mimics the design of the Incyte study for Opzelura. Wonderful. Sounds like you are going to push forward a six-month additional open-label extension trial. Obviously, in vitiligo, slow-moving progressive disease, this will allow us to really get a good full sense of the efficacy for 201. As we think about maybe that primary endpoint at six months, Iain, how are we thinking about the hurdle of efficacy versus Opzelura? Do we have to be better? Do we have to be similar? Is safety enough? Yeah. Just the second part is not open- label. We maintain the blind in the second part. What happens as patients get to month six, patients who are on vehicle will be re-randomized and maintaining the blind data to 1%, 2%, or 3% gels. Patients that are already on 1%, 2%, and 3% will just continue out for a further six months. In relation to the barrier or the target as it were, I think in and around, I mean, when we look at our data from our phase I-B, it was interesting, and this was with the exclusively progressive disease, we saw comparable efficacy to the JAK inhibitors other than Litfulo, which tends to be a little bit of a step back. It's very similar to Opzelura, but it happened about two months further earlier in our slot. We're going to be cautious about doing literature comparisons also. We were dealing with a small, small study. I think in and around that area. I think one of the key differentiation points beyond just raw efficacy is once daily. It's very difficult to overstate the importance of a very convenient application experience for patients to maintain compliance. As we know, the indicated drug Opzelura is twice daily. Doing anything twice daily for many months, if not years, is more challenging than doing it once daily. I think that's particularly important. Obviously, we can't speak to ultimately what safety labeling will look like, but we certainly know what the labeling looks like for JAK inhibitors. That's black box. It's not, do we feel the physicians are particularly concerned about black box precautionary language for a topical JAK inhibitor? Probably not. They do have to explain it to patients. That takes time. It may give patients some pause because these are quite scary words that they have to communicate to a patient. Given the option of that versus something that doesn't have that, I think it's pretty clear where the interest would lie. Okay. Maybe let's stay a little bit big picture before we then move to your oral asset. Let's talk about the market for vitiligo. What are you seeing so far for Opzelura in terms of adoption? What's the size of the market? What level of penetration do you think you could expect? Yeah, sure. This is a pretty open space. There are 3 million patients just in the U.S. alone that have vitiligo. 2 million have been diagnosed. Until Opzelura was approved, only about 10% were actively seeking treatment. We think Incyte's done a nice job of mobilizing patients and creating awareness around it. That drug's off to a pretty strong start since its vitiligo indication was approved a little more than two years ago. I think the run rate just on vitiligo alone is $175 million plus. As we talked about, 80% of patients that have vitiligo have what you would refer to as localized disease, less than 10% of their body surface area. They are really candidates for localized therapy, such as the topical. Iain outlined some of the key points of differentiation for our drug, repibresib. Assuming it holds through the clinical development pathway, we think that really allows a drug like ours to potentially be a first-line choice of therapy for those that have localized disease, which is the majority of patients with vitiligo, but also as an excellent adjuvant therapy for those that have more widespread disease. I fully expect one of these oral JAKs, if not more, will get approved. It is highly unlikely that a patient who has widespread disease who will still need something for a region of the body, such as the face, would get an oral JAK as well as a topical JAK. I think, again, our drug would have applicability in both segments. Okay. Understood. Obviously, the vitiligo update is near term. We are going to get the oral VYN202 update for psoriasis by year-end. In general, we get more questions on the oral asset, I would say. Just as we drill down into kind of the nitty-gritty on the phase I results, just let's walk through the single ascending dose, multiple ascending dose results that you've seen so far. Again, talk about the design of the MAD study that really allowed you to interrogate the safety profile of oral BET inhibitors. Sure. We'll start with the side component. We evaluated doses from 0.5 milligrams up to 4 milligrams. Obviously, that's once daily. I think the safety was unremarkable. We had good linear PK, which obviously allowed us to select doses moving into the multiple ascending dose, which is probably the more interesting data set. Normally, MAD studies can be somewhere between seven and 10 days of repeat dosing. We decided to extend this out to about 14 days with a seven-day safety follow-up, primarily in order to capture, again, as I talked about earlier, one of the key adverse events of special interest associated with this class, which is thrombocytopenia. Thrombocytes or platelets, their lifespan is somewhere between seven and 10 days. Obviously, treating out for two weeks and obviously with an observational period for a week, you'd like to be able to catch that effect if there's going to be one. In the MAD component, as I say, it was 14 days with a seven-day safety follow-up. We evaluated 0.5 milligrams every other day, 5.5 milligrams once a day, and 1 milligram once a day. We also looked at our drug-drug interaction cohort because, as you know, one of our indications for the future is rheumatoid arthritis. Those patients tend to be on a background DMARD, such as methotrexate. We wanted to see if there was any drug-drug interaction there. In relation to the safety findings, obviously, we were hyper-focused on platelets. We really didn't see any movement in platelets relative to placebo. We didn't have any grades of thrombocytopenia, not even a grade 1. Again, this is one of the key theses around VYN202 is hyper-targeting to the BD2 binding domain and having a de minimis impact on the BD1 binding domain. Obviously, prior studies for phase I were done in oncology patients. But as you look through, I'm sure, very diverse data, when do kind of the neutropenia start showing up? Within the first week to two weeks, essentially how we'd expect. I mean, what's interesting, and it's one that people folks don't maybe realize, is even outside of the BET class, if you look at abrocitinib, which is Pfizer's JAK inhibitor, they also see thrombocytopenia. You see it within the first week or two, probably obviously an off-target effect there. Okay. As for GI toxicity, when would you expect something like that would show up as you interrogate the multiple ascending dose? It's difficult to say. I mean, it can happen pretty much within the first few days to the first few weeks. The only GI findings we saw was mild diarrhea, sorry, mild constipation, which is not unsurprising. These patients are coming into clinic for three weeks. Their diet changes. It's a little bit of a stressful environment. We think it's more iatrogenic than anything to do with the drug because we saw just as many on the placebo as we saw on the active. When we talk about GI toxicity issues and BETs historically, we're talking about very significant GI issues, diarrhea, flushing, maybe some bleeding events as well. Okay. Understood. We do get occasionally questions around genotoxicity. It sounds like you've done a series of kind of approaches to make sure you've addressed that question. Can you talk through that? Yeah. In order to support our IND for VYN202, we conduct a three-test battery for genotoxicity. We look at Ames. We look at micronucleus testing and chromosome aberration. For all three tests, it was negative. Okay. Understood. Again, just initiated the phase I-B trial for psoriasis guiding for results by year-end. Just talk about the clinical trial design and how comprehensive it might be for kind of a proof of concept study. Yeah. We cautiously went with quite a large sample size for this study because we want to ensure the coming out of this trial were quite definitive on the response rates we see for 202. We did not want to do a 20-patient study that others have done where you may get some kind of head-scratch or inconclusive findings because of maybe some artifacts within the data. It is a 12-week study with a 4-week safety follow-up. It is a four-arm study. We are evaluating the same doses that we looked at in the multiple ascending dose. Only this time, we have a 0.25 milligram. It is a 0.25 milligram, 0.5 milligram, and 1 milligram three active arms versus placebo. The inclusion-exclusion criteria for the more severe population for psoriasis is one that many, many people have seen in the past. There's really nothing there that's unusual in relation to comparing that to any other trial. We are controlling for biologic experience. So we're allowing patients with up to 30% of the population could have been on a biologic. As you know, there's a bit of a balancing act there because if you make it completely naive, it's difficult to enroll. If you don't control for it, you could be introducing biologic failures that could tip the data the other way. So we feel that 30% is appropriate. With respect to endpoints, so it's changed from baseline and PASI, PASI 75, and then secondaries as PASI 90, PASI 100. They're pretty typical endpoints you'd expect to see. Okay. How did you select the doses from the phase I single-ascending dose, multiple-ascending dose? I'll tack on one more question before you answer. Just given the safety, did you give any consideration to maybe increasing the dose? What are the different kind of thought process behind that? Yeah. I think we were quite impressed with the effect we had on inhibiting the expression of the cytokines from the study because what we did in the phase I-A, obviously, these patients, their basal cytokine levels are going to be very low. They're healthy volunteers. What we did was we had a modified blood collection tube that could provide the induced immunostimulant in the blood sample as we collected it so we could actually see substantial release of some of the key cytokines that are obviously relevant to the pathology of the diseases we want to explore. We could compare patients who have been on active versus placebo, different time points. We were quite impressed with the level of inhibition of the expression of these cytokines. When we did some work, because obviously, we then had the PK for the study, we actually did some ex vivo testing in a human whole blood, essentially the same experiment. It was not part of the trial. It was a laboratory experiment where we actually spiked in different concentration ranges of 202 and passed it through exactly the same immunostimulation system. What's interesting is that once you get to around 5 nanograms per mL blood level, you see a flattening off with respect to the inhibition of the release of these cytokines, which is not unexpected because that's actually approaching the IC90 against our target. You see kind of ticks and ties that you're kind of saturating your impact to the target, and you're seeing a flattening off. That really equates to around the Cmax of the 1 milligram dose. We really didn't see any rationale to so-called push the dose much higher than that. Also remembering that this is a two-week study. We're going to go into a 12-week study. We'll have to be mindful of how safety develops over time. We feel that this is the right doses to progress. Okay. Understood. Appreciate that explanation. Sounds like this is proof of concept trial, a little bit of a gateway approach, maybe first decision around selecting psoriasis versus rheumatoid arthritis for your first proof of concept. Then we'll follow up with some other questions. Yeah. We have studied VYN202 across a broad array of preclinical models, much of which we've not yet disclosed, but we intend to do in the relatively near term. We're pretty excited about what we've seen. We've looked at it across a wide array of target indications. We've obviously talked about skin, joint. We think it's got applicability in the gut as well as various fibrotic diseases. We think the optionality for the asset is quite significant, not to mention BETs have been studied in the oncology setting, and we would have no reason to believe it wouldn't apply there as well. Optionality for 202, we think, is quite vast. Our objective for this phase I-B study and why we chose psoriasis is we have pretty compelling preclinical data. We compare it against the TYK2 assets. The TYK2, the data laid right on top of it. This is an indication that is well validated, and it's an efficient study. We can do an 80-patient study and get results in about a year's time. Our objective is if we could show a clean safety profile and get meaningful efficacy, it opens the doors for us to take this into a wide array of potential indications. The point I'd make too is because we're going to have a significant number of patients enrolled in psoriasis, we should get a decent number of patients, 25%-30%, that should have psoriatic arthritis. We'll get a view on how it impacts on the joint. As you know, we've studied 202 across two different preclinical models in rheumatoid arthritis, which was quite compelling. One of them where we compared against abrocitinib, and the results were virtually identical. We chose psoriasis because it's efficient, it's quick, well validated. We love how it works in the joint. Those arthritis studies can be a bit more noisy, and so this gives us a chance to put our best foot forward, get a readout, and then go from there. Okay. Wonderful. As we think about the competitive landscape, maybe Iain, just remind us again the decision for BD2 selectivity for your oral BET inhibitor and then maybe some of the other assets that are in development as we think about BET inhibition. Yeah, BET inhibition. Probably the BET inhibitor making the biggest noise is obviously MorphoSys or obviously Novartis drug. It's not a selective BET inhibitor. Slightly more selective towards BD2, it's about fivefold. They're obviously developing that right now. Obviously, the primary focus, as Dave said at the top of the presentation, is basically hematological malignancies. Innovation looked at solid tumor programs as well. I think having looked at as much as we can see, VYN202 is the most potent selective BET inhibitor in clinical development. There are some preclinical assets that are coming through. One is from Deep Dive, and another one is from Mitsubishi Tanabe. They seem to be about the kind of early preclinical stage. Certainly, no clinical data for these guys yet, at least what we can see. We're really excited about the potential of having a hyper-targeted BD2 selective inhibitor. This is really the whole idea around our inhibitor platform was to fundamentally address some of the challenges from a safety perspective of the class itself. For repibresib, it is a soft drug approach, limiting systemic exposure to maximize benefit risk. For VYN202, it is about hyper-targeted to BD2. Okay. Understood. Obviously, a lot of applicability as we think about kind of I&I approaches for BET inhibition. In the last few moments, just as a quick reminder, do you want to talk about IP for VYN202 and 201? Sure. We have a broad patent estate. We've filed patents at the key jurisdictions around the globe. We would anticipate, assuming they're approved, we would have IP around composition matter patents for repibresib. That would be minimum 2040, if not longer. Obviously, all of the supported patents behind that. For VYN202, those patents would take us out to 2042 and beyond. Okay. Wonderful. Number of different catalysts expected this year. Really excited to get more data. Looking forward to it. Thanks for having us. All right. Thanks so much, everyone.