All right. Hello, everyone, and welcome to the next session of the H.C. Wainwright 3rd Annual Autoimmune & Inflammatory Disease Virtual Conference. My name is Matt Keller. I'm a VP in the Equity Research Department. Today here with me, I have David Domzalski, CEO, and Tyler Zeronda, CFO of VYNE Therapeutics. For those of us joining us in the session, a reminder, VYNE is a leader in developing BET, or BET inhibitors, for a whole range of inflammatory indications. We're glad to have you both here. Welcome both.
Thanks, Matt, for having us.
Yeah, absolutely. To get this kind of getting started, for the sake of time, let's just jump right into it. I was wondering if either of you could just give us a general overview of VYNE and also possibly BET inhibitors in general. You know, where have they been and where are you guys taking them?
Yeah, sure. Thanks, Matt, again for having us. As you shared, we're developing our novel BET Inhibitor Platform. We refer to it as our InhiBET platform. We're a clinical stage biopharmaceutical company. We're focused on developing our platform for the treatment of a broad range of autoimmune and inflammatory disorders. We're specifically focused on developing our novel BET Inhibitor Platform. BET inhibitors have been around for a fair amount of time, a good 10 years-12 years. They've been developed by primarily large pharma and large biotech, and almost exclusively for the treatment of various oncology disorders, mostly hem-onc, some solid tumor work. We're doing some of the first real formative work in developing BET inhibitors for the treatment of autoimmune diseases, inflammatory disorders. We're really excited.
We've got two primary components to our platform: Repibresib, formerly known as VYN201, which is our locally acting tissue-specific pan-BD BET inhibitor, which is currently Phase IIb study for the treatment of non-segmental vitiligo. The second part of our platform is what we refer to as VYN202. That's our oral highly selective BD2 BET inhibitor, which we are currently in the clinic in a Phase Ib study, primarily looking at safety, but also some preliminary efficacy signals for the treatment of moderate to severe plaque psoriasis.
You already kind of got ahead of me, but that's fantastic. As you mentioned, you have two primary assets. Both, as you mentioned, are different types of BET inhibitors. One of the things I want to kind of touch on before we go into the specific assets themselves is a little bit about safety. BETs themselves have a bit of a history, as you mentioned, a history when it comes to safety. I was wondering if you could just broadly talk about how your assets are a little bit different, possibly from previously developed molecules in the space.
Yeah, sure. Thanks, Matt. Our platform was really specifically developed to address some of these dose-limiting toxicity issues associated with the class. There are really two, primarily. One is GI stem cell issues, really serious GI toxicities, nausea, vomiting, even bleeding challenges. The second is low platelet counts or thrombocytopenia. For our first, our most advanced drug, Repibresib, which again was formerly referred to as VYN201, that's a pan-BD BET inhibitor. As such, similar to earlier generation BET inhibitors, we hit both parts of the BET protein, BD1 and BD2. We address the safety concerns through Repibresib by limiting systemic exposure via both a tissue-targeted delivery as well as delivering the drug as a soft drug. By the drug being delivered into the tissue, you obviously are going to avoid some of the toxicities, such as GI stem cell issues, right?
You're not going to see this for a drug that's delivered topically. You could see issues such as thrombocytopenia if you get meaningful systemic absorption. The other way we address this is through a soft drug approach, which then allows for a very high first-pass metabolism. The combination of this tissue-target approach plus a soft drug approach really has led to very low systemic exposure for Repibresib. Correspondingly, we've seen no effect or known adverse events of special interest, such as thrombocytopenia. We believe our drug design thesis has been validated, at least so far for what we've seen in the clinic. You can't take a soft drug approach, if you will, and the tissue-target approach doesn't apply with VYN202.
We focused our chemistry effort on obtaining a very high selectivity towards the BD2 portion of the BET protein, with really negligible affinity towards the BD1 part of the BET protein. Previous work that we've done and others have shown that for anti-inflammatory applications, really the BD2 part of the BET protein, that it appears to be the primary target to reduce irregular inflammatory signaling common in all autoimmune diseases. We've also shown in some of our preclinical models that if you even antagonize BD1 part of the BET protein, it really doesn't have any material anti-inflammatory effect and explains some of the more challenging safety issues the class has shown over the years.
Again, we believe this approach of being hyper-focused on the BD2 portion of the BET protein really avoids any attachment to the BD1 portion of the BET protein, seems to be playing out quite well. So far, what we've seen in our preclinical work, as well as we just completed Phase Ia SAD-MAD study for VYN202, we announced those results at the end of the year. A really clear safety profile, no GI issues of any meaningful effect, no issues of thrombocytopenia whatsoever. Although it's early, we're off to a really good start.
Yeah, no, thank you for that, Tyler. You know, we get a lot of questions around safety when it comes to BET inhibitors. I appreciate that additional context. I think it's really helpful for kind of setting the stage for the assets that we're going to be talking about, obviously. That might be a good segue to talking about Repibresib. I guess the very straightforward question right first is, why vitiligo? That's the first indication you're going to be targeting. As you said, it's currently Phase IIb study in that indication. Why vitiligo?
Yeah, sure. When we obviously developed Repibresib, we took it through quite a broad series of various preclinical tests. The results were really, really encouraging across the board. Much of this data we've already disclosed. We saw really good preclinical work in safe conditions, such as psoriasis. The topical space for psoriasis is pretty crowded. Our sentiment was there are other conditions of significant unmet need that could be addressed. One of our preclinical programs was in vitiligo. That was actually not your typical animal model, but it was a really, we recreated, in essence, the human skin. It was reconstituted human epithelial skin cells. We were able to test our drug, literally apply our drug directly to these reconstituted human epithelial skin cells. We saw fantastic results.
We were really, really encouraged with the results of that preclinical work. Really significant unmet need. As you know, there's only one drug out there that's approved for the treatment of vitiligo. When we looked at our preclinical data, when we looked at what do patients and caregivers need, we thought with a high level of conviction that going into vitiligo was the right place to go. As you know, we conducted a Phase Ib proof of concept study. We tested three different doses in that study. We looked at 30 subjects. It was a relatively short study, four months. The data was quite encouraging. The results from that, we tested three different concentrations of 0.5% dose, a 1% dose, and a 2% dose. The 0.5% dose had modest effect in improvement from baseline and F-VASI score.
The 1% and the 2% doses were quite impressive and quite encouraging to us. That data, coupled with our preclinical data, gave us a lot of conviction to take it Phase IIb study, which is currently underway.
Yeah, I should comment that the preclinical and the proof of concept data is actually very fascinating. For people who haven't seen that data, go look at it. It's very interesting. Actually, it is, it's very compelling. Which, again, it's another great segue into the IIb. The IIb data should be coming out relatively soon. A question about how is enrollment going and what should we expect timeline-wise when it comes to the IIb?
Yeah, sure. I mean, we announced that last patient was enrolled in the study right at the turn of the year, just before heading into the big JP Morgan conference. We are pleased with obviously completing enrollment. We initially announced that the target was going to be about 160 patients enrolled. We were a bit over-enrolled. We should have about 180 patients enrolled, 45 patients per arm. This is a four-arm study. We have a vehicle arm and three active dose arms. We took the 1% dose and the 2% dose Phase IIb study. we also added a third arm, active arm rather, with a higher dose of 3% concentration. We have a 1% dose arm, a 2% concentration arm, and a 3% concentration arm. The study's ongoing. We have communicated that we anticipate having a top-line readout in the first part of this study.
I'll come back to the design in a moment. We should have a top-line readout for the first part of this study, call it mid this year. This is really a two-part study. The first part is double-blind vehicle controlled, again, three actives versus vehicle, once daily dosing for six months. After that six-month period, those patients that are on any of the active doses will continue in a blinded fashion for an additional six months. They could be on drug for up to a year. Those patients that are on vehicle will be re-randomized after six months to one of the active doses, either one or the 2% or 3% dose for the remaining six months. The initial double-blind vehicle portion of that study, again, we should have the results for that middle of this year.
I guess looking ahead towards that, I'm going to throw out kind of a general question to both of you. You know, how are you looking at success for this trial? I'm thinking particularly not only internally for your own metrics, but maybe how it compares or would compare possibly to other similar biologics on the market as well that use either similar mechanisms or similar indications. How are you benchmarking or what would you consider to assess the IIb?
Yeah, I'm always cautious about comparing studies at various stages, certainly up until you get to your pivotals. This is all part of drug Phase IIb study, it is a dose-arranging study. As I shared, prior to us initiating this study, we conducted one relatively small proof of concept study with 30 patients for four months. We were really pleased with those results. We took, again, the 1% and the 2% dose from that study, added another dose. Now we have obviously a much more Phase IIb study. our first and primary objective is we've got a clean safety profile for the drug. We hit our primary endpoint. Our primary endpoint Phase IIb study is a static endpoint F-VASI50. That's a 50% improvement in vitiligo lesions on the face. That's the primary endpoint.
That's also the same primary endpoint that Incyte's drug Opzelura had Phase IIb study. that is the primary endpoint. Key secondary endpoints, F-VASI75 and T-VASI scores. Our objective first and foremost, and how we define success, is we obviously want to hit our primary endpoint. We obviously hope to have at least one, if not multiple doses that hit the endpoint. Hopefully, we come out of this study with a clean safety profile and a clear winner, a clear dose for us that we say, "Okay, this is the dose that we want to take into pivotals." At that point, we will have enough data that will allow us to appropriately design the pivotal program, the phase threes, to really maximize efficacy and empowering around that.
Yeah, absolutely. It totally makes sense. In a similar vein too, thinking about the future as well, I mean, obviously, the initial data is looking good, particularly, again, in vitiligo. Have you thought about other indications or other applications for Repibresib and possibly other diseases, inflammatory diseases specifically?
I mean, we obviously view this as not a single indication asset. We think of a lot of different places that Repibresib could go. Some of these, obviously, I think are quite obvious. If you take a look at a drug like Opzelura and see where they have either approved indications or places that they're studying, our view is those could potentially apply there as well. I mean, we've obviously conducted a series of preclinical models. The vast majority, we've been very pleased with for this asset. Some of this we've not yet disclosed. We would anticipate we would at the appropriate time. We certainly believe that Repibresib has optionality, certainly well beyond vitiligo. We just think vitiligo, again, being a fairly wide-open opportunity with only one approved drug, makes a lot of sense for us to go there first.
I think one of the key things too, Matt, is if you think about vitiligo itself, just digress for a moment. There are about 3 million patients with vitiligo in the U.S. 2 million have been diagnosed. Historically, before Opzelura was approved, only about 10% were actively seeking treatment. Obviously, more patients are being mobilized since topical ruxolitinib was approved. We think that's great for patients. We think that's great for caregivers. We think that's great for us. In terms of drugs that are in development, other than ruxolitinib, which has been approved, and our drug, Repibresib, our topical BET inhibitor, pretty much everything else of any meaningful stage of development is a systemic JAK inhibitor.
When we think about the opportunity, I'd say 80%, the data suggests about 80% of patients with vitiligo really have what you would call localized disease, so less than 10% of their body surface area covered. For localized disease, they're really candidates for localized therapy, non-systemic therapy, such as a topical. The remaining 20% obviously have more widespread disease and would likely be a candidate for systemic therapy. As we look at our drug, the fact that if it continues through the development pathway, the fact that Repibresib is to be dosed once daily, we would not anticipate it would have the black box warning associated with the JAK class. We think those two key points of differentiation, and I can't underscore enough once daily dosing, especially for a topical therapy, huge benefit to patients. We think it's really, really meaningful point of differentiation.
As we look at that, we think that the opportunity for this drug could be quite substantial, could have the potential as a first-line therapy, certainly for those that have more localized disease, which is the majority of patients, but could also be used as adjuvant therapy for those that have more widespread disease. When you just think, again, if everything in development is a systemic JAK, at least at this stage, highly unlikely for a patient that would have, say, more widespread disease to get a systemic JAK, and then also as an adjuvant therapy, a topical JAK. Again, we think our drug could apply certainly as a first-line therapy, assuming the data holds, but also as an adjuvant therapy for those that have more widespread disease.
Yeah, absolutely. We agree. I know we talked about how differentiated this product is for all of the things that you just mentioned. We're definitely excited for not only the IIb results, but also for the future Repibresib as well. I would be remiss if we did not spend some time on your second asset, VYN201. Switching gears a little bit, you mentioned this previously, but VYN201, excuse me, had gone through a phase one MAD- SAD trial. I was wondering if you could quickly talk about that and possibly how it was or did educate your current clinical endeavors with the product.
Oh, sure. Just for clarity, I think you want to talk about 202, right? VYN202.
Oh, 202. I'm sorry. Yes, 202. Yes.
Yeah. No, we were thrilled with the results. For VYN202, our objective, again, as I shared initially, is to address the historical challenges with earlier generation systemic pan-BET inhibitors. Again, these earlier generation BET inhibitors, and even those that have claimed to be selective, really are not that selective. They hit both BD1 and BD2 portion of the BET protein. We spent two and a half years in lead optimization work to get to the point where we are now with VYN202, where we have the most potent BET inhibitor and by far the most selective to BD2 BET inhibitor of any drug in development. We are at least 10,000-fold more selective to the BD2 portion of the BET protein than the BD1 portion of the BET protein. That is really important, right? It does two things.
It locks in on where the inflammatory culprit is, which is on the BD2 portion of the protein, but also because we have no affinity or very negligible affinity to the BD1 portion of the protein. The thesis, the drug design thesis, is that we would be able to significantly reduce or mitigate those side effects associated with the class. So far, I'd say so good. We announced at the end of the year the completion of a phase one A SAD-MAD study. There were five doses in the SAD, three doses in the MAD, three cohorts, rather, in the MAD. What we saw were really a couple of things. We kind of completed the triangle. First, we saw a really clean safety profile. Again, no issues around GI toxicities. Platelets looked really good. We had no issues with thrombocytopenia.
What you get concerned about are really significant issues with thrombocytopenia, Grade 3, Grade 4. We did not get anywhere near even a Grade 1. Safety profile looked really good. We had really predictable PK. That was certainly encouraging. We got the steady states for the drug after seven doses. That was obviously encouraging. We have a long half-life, 36 hours-41 hours. All of that was really, really encouraging. Allows for us no reason we should have any more than once daily dosed drug in any program we would look at, potentially even shorter. We obviously looked at key biomarkers. There were two. One, we wanted to see our target engagement biomarker, which is HEXIM1. We clearly saw a positive impact on HEXIM1. That was important for us. Our drug operates in the nucleus.
We wanted to see is the drug getting into the nucleus. It clearly was. The other component is we wanted to take a look at some key inflammatory biomarkers. We saw a meaningful downregulation of some of these key biomarkers associated with the types of conditions we're looking at, whether it's TH17, TH1 myeloid cell-driven cytokines, IL-17, TNF alpha, IL-6, if you will, IL-23. We saw a really nice downregulation of these key cytokines that I think directionally give us a lot of energy in the conditions that we're looking to target. We're initially going into right now a proof of concept study in moderate to severe plaque psoriasis. We've talked about other conditions, joint conditions such as rheumatoid arthritis and the like.
As we think about this Phase Ib study that's currently underway for us for VYN202, we really view this as a gateway. Our objective here is obviously this is primarily a safety study. We want to get as much exposure data as possible. We want to come out of this with a clean safety profile, take any kind of halo effect out of the equation for our drug, and then obviously, hopefully, get some meaningful efficacy signals. Assuming we do that, I think the optionality for this product is quite substantial.
Yeah, it's very exciting. 202 also represents, we think, a huge opportunity for VYN in the space. I'm a wax a little philosophical. To ask you a question, we talk about safety. We talk, as you mentioned, the biomarker selection, patient selection. I was wondering if you could talk about the role of, I guess, careful trial design as a recipe for success. I think what is actually kind of a tricky molecule, a tricky space to work in, and how you guys have worked with that strategy or changed your strategy to make sure that you're de-risking or setting yourself up for success in current trials and also future trials as well.
Yeah, sure. Tyler, why don't you provide some thoughts on that?
Yeah, sure. Obviously, as Dave mentioned, for 202, in considering kind of the safety components of the trial, we looked at our MAD trial in particular. It was a 14-day MAD. Typically, you see these trials in the 7-10 days. Part of that thinking of extending this for a 14-day treatment window and a 7-day follow-up was really to mitigate some of those potential safety questions that we had. As Dave said, we were quite pleased with those results to date. Moving forward, as we think about the program in the moderate to severe psoriasis program, obviously, when you think about proof of concept studies, oftentimes you see these kind of being shorter in duration, four weeks, maybe eight weeks, etc.
Given that we are taking BET inhibition out of oncology and applying it into the I&I space for the first time as a systemic therapy, our intent really is to evaluate this over a longer course, a 12-week study, right, for that very purpose. Coming out of this, the hope is to have a clean safety profile over a long course of duration of treatment, 12 weeks of data with a four-week follow-up. That really should help inform us on moving forward as we think about both from a safety perspective, but as we look at three doses across that study and exposure, as well as some of the exploratory efficacy and biomarker response that Dave had mentioned, that'll inform kind of next steps on where we go.
We're obviously taking a step-by-step approach here, given that we're doing some of the first formative work in I&I. Obviously, we're very encouraged about what we've seen to date.
Yeah, absolutely. Thank you for the additional context. Gentlemen, it looks like we're about at the limit of time that we have for this fireside. I was wondering if there's anything else you guys would like to share or anything that we may have missed that you might want to briefly communicate to our audience before we log off.
Yeah. No, Matt, again, thanks again for having us. We were thrilled to be a part of this exciting program. Obviously, speaking of excitement, this is an exciting time for us. We've got some key catalysts and key milestones that can be value-creating and value inflection-driven for current and prospective shareholders. We obviously have the readout of the first part of our Phase IIb study in vitiligo middle of this year. We are obviously in the Phase Ib proof of concept study for VYN202. We should have a readout for that by the end of this year. We are excited. We are very much in execution mode right now. We hope to have good updates as the year progresses.
Yep. We're very excited. We can't wait for these updates as well from each one of those programs. Thank you again, both of you, for joining us. We appreciate your time and for speaking with us today. Thank you again, guys.
Thanks, Matt.