Great. Good morning again, everyone. Happy to have the Vyne Therapeutics team here with David and Iain. I think Todd will be joining shortly as well. But maybe to kick things off with this fireside chat, kick it over to David to give a brief overview of Vyne, and then we'll jump right into a Q&A. So David, over to you. Yeah, thanks, Alex. Good morning. Thanks for having us here. We're really excited to be with you. So, briefly, obviously, we've been on quite a journey here at Vyne. We're an emerging biotech company focusing on developing our novel BET inhibitor platform for the treatment of various autoimmune conditions. You know, BET inhibitors have been around for a little bit. Most of the work with BET inhibitors has been predominantly focused in the oncology arena by large pharma, large biotech. We're doing really some of the first, you know, cutting-edge, formative work in developing BET inhibitors for the treatment of various I and I indications. We've got two major assets within our platform, which we refer to as our InhibET platform. The first is what we refer to as VYN-201. That's a locally administered, it's a tissue-specific pan-BD BET, BET inhibitor. It's a soft drug approach, in terms of drug delivery. Concept is, obviously, get the drug into the, the targeted tissue, whether it's the skin, or joint or lungs, and anything that would, get, out of the tissue would be rapidly, screened through the liver. That asset, has kind of morphed into somewhat of a pipeline within a product. Our most advanced, happens to be focused in the skin. It's a topical therapy, which we, have very good phase 1b results in vitiligo and, and are now in a phase 2b trial for the treatment of non-segmental vitiligo. I'm sure we'll talk more about that. So we're very excited about the prospects of, that particular part of our platform. The second is an oral, BET inhibitor. It's a highly selective BD2 BET inhibitor, which we've taken through a series of preclinical models. We're quite pleased with the results from that. We filed an IND earlier this year, and we are currently in a phase 1a SAD/MAD study, and we announced just last week that we completed the first portion of that, the single ascending dose portion of that study, and then now are in the multiple ascending dose portion of that study. Our approach for this is to be hyper-focused on the BD2 portion of the BET protein, which is where all the culprits of inflammation reside, and we believe that's the appropriate approach in terms of our drug design thesis. Assuming we get through the SAD/MAD portion of the study, again, we've completed the SAD, assuming the MAD portion goes well, we'll then quickly move into two proof-of-concept studies for our oral BET inhibitor, again, which we refer to as VYN-202. One of those studies would be in moderate to severe rheumatoid arthritis, and the other would be in moderate to severe psoriasis. With that, Alex, I think that's a pretty good overview, and we'll turn it back to you for whatever questions you would have. Yeah. So. Yeah, definitely. Thanks, David. And I guess maybe to kick things off, you know, I just wanna talk a little bit about, you know, the canonical role of BET protein family members and, and why they actually are interesting targets for inflammation. Maybe, maybe, Iain? Yeah. Go, Iain. Yeah, sorry, guys, I'm getting a terrible feedback here. Could you repeat that, Alex? Yeah. Just can you talk a little bit about the canonical role of the BET protein family members and why that makes them an interesting target for anti-inflammation drugs? Iain, you there? Yeah, I'm here. I'm sorry, guys. I'm getting- Yeah, can you hear me, Iain? I'm getting a terrible feedback. Great, we're back. David, I guess let's talk a little about the two oh one program, your soft drug approach. I guess kind of why, why vitiligo? What does the unmet need look like here still? And, you know, how does this mechanism make sense? Yeah, so when we developed VYN-201, we looked at it across several different preclinical models. We saw a pretty profound anti-inflammatory effect, regardless of what the model was, including conditions such as psoriasis. One of the preclinical models that we tested the drug in was vitiligo, and we were really, really pleased to see the type of impact that we had. This was not your typical animal model. This was actually reconstituted human epithelial skin cells. And so the results we saw were pretty profound in terms of the reduction in or the improvement in melanocyte regeneration, which gave us a lot of confidence in moving forward into the clinical trial. We initially designed our phase 1b. It was only eight weeks in design, because that's the amount of tox data that we had when we kicked that study off. Since we had that amount of time, we spoke with our KOLs and advisors, and we said, "Well, look, we've got this asset that we think could be really good for vitiligo, but we don't have a ton of time." We know these studies are usually six months in duration or longer, and so we asked our advisors: "Well, how can we determine whether or not we can get a signal?" And so they said, "Look, take the toughest patients that have vitiligo, those that have active or progressive disease. They're in this hyper state of inflammation. See if you can slow it down or arrest it. And if you get any signs of repigmentation, then you've really got something here." So when we announced the design of that study, it was initially eight weeks, because that's what we had in terms of tox data, but we were very clear that that would ultimately expand beyond that. So we ultimately had 16 weeks, a four-month study. The results from that trial, we were really pleased with. So it was about 30 patients that were in the study. It was an open label design. We had three doses, a 0.5 dose, a 1%, a 2% dose. It was once daily dosed, with just patients that had active or progressive disease. What we saw was a pretty profound effect in improvement on F-VASI score, Facial Vitiligo Severity Index score. The 0.5% dose was fine. We saw a modest improvement, but the 1% and 2% doses were pretty significant. We not only did we see basically none of the patients, only one had a slight worsening of their response, but all the other patients either did not get worse, or many of them saw a pretty significant improvement. On our 1% and 2% doses, 80% of the patients in the study actually improved. We were thrilled with those results. After only four months of study treatment, we saw the F-VASI reduction to be about 39% for our 2% dose, which was in the same area of some of the other comparable programs at six months, and again, that was in purely a patient population that had active or progressive disease. So we knew we had something there, and that gave us, Mm ... the excitement to move forward into our phase 2B. Yeah, I guess a couple, a couple digging in a little bit more. You alluded to the patient population. Can you maybe put a little finer point on, you know, how much more severe this population was than historical proof of concept studies for some of the agents out there, like Opzelura, some of the systemics, et cetera, and sort of what that means when you're interpreting the 16-week data relative to those agents? Yeah, sure. There's basically two types of disease states for vitiligo, stable disease and active disease. Active disease, again, they're in this hyper state of inflammation, and if there's no intervention, these patients will continue to lose pigmentation very rapidly, weeks and months. Those that have stable disease have underlying inflammation, but as the name suggests, they're somewhat in a stable state, and generally speaking, from all the literature and the feedback we've got from advisors, KOLs, patients with stable disease tend to respond more quickly- more quickly, as well as more deeply with interventional therapy. For those with active disease, if you don't give that patient something, they're going to rapidly lose their skin pigmentation. In terms of the percent split, there's more stable patients than there are active. For us, when we initiated that study, the phase 1b, we were hoping we could see any type of effect. And so by knowing that we didn't have six months or a year, we were just hoping we could slow down the loss of pigmentation. Mm. and any green shoots would be obviously a bonus. And obviously, we didn't just see a significant loss. We didn't see not just a significant, you know, arresting of that inflammation, but we saw, you know, pretty significant repigmentation. We were really thrilled. So let's talk about safety. I guess, can you talk about some of the potentially on-target tox that you were looking for, and the level of systemic exposure that you actually saw in this proof of concept study? Yeah, sure. I mean, for the BET inhibitor class, there's two adverse events of special interest, GI, stem cell tox, and thrombocytopenia. Obviously, for a topical route of administration, you know, GI issues really don't, you know, it's not something that you'd be concerned with, but thrombocytopenia we would be. And what we saw was, you know, really clean safety profile, both in terms of impact on platelets, and it was, you know, we saw nothing. And when it comes to local skin reactions, which is the other, you know, the other types of adverse events or side effects that you look for, really, really benign. So this, this drug was generally very well-tolerated. We were very, very pleased. Great. And I guess moving on to the phase IIb, can you talk about the design here, and I guess the rationale, too, for adding a higher dose based on what you saw in the IIa? And then maybe broadly, how this sort of looks relative to sort of standard phase IIs in this space. Yeah, this is a pretty, pretty meaty-sized phase IIb. It's a four-arm study. We have three doses. We took the 1% and the 2% into the phase IIb because we saw pretty, pretty profound results on our 1b. But we thought we had some headroom. We had you know certainly more headroom in terms of tox doses that we could push for the dose taken to the clinic. And again, we saw a really clean safety profile in our phase 1b, so ultimately we took the 1%, the 2%, and we also took a 3% dose into the clinic versus the placebo dose. And so well, we're looking at about 160 patients in total. About 40 patients per arm will be once daily dosed for six months. The primary endpoint is the static F-VASI 50, so 50% improvement in F-VASI score after six months. And then the key secondary will be F-VASI 75, as well as T-VASI. F-VASI 75 is the registrational endpoint, so assuming we get through the phase IIb, that would be the primary endpoint for phase II registrational studies. But the design of our phase IIb study very much mirrors Opzelura- Mm-hmm ... Incyte's phase IIb study as well. Coming back to the design, after six months, patients that are on the 1%, the 2%, and the 3% will continue for an additional six months. Patients that are on vehicle will be re-randomized to either the 1%, the 2%, or the 3% for an additional six months. Coming back to Alex, you talked about you asked about the market size. You know, there are about 3 million patients that have vitiligo in the U.S. Mm. A million are diagnosed. But historically, until Opzelura was approved for vitiligo, only about 10% have been actively seeking treatment. And the primary reason for that is that most of the historical treatment options out there really did not work that well or were quite burdensome to the patients. You know, steroids, calcineurin inhibitors, light therapy. Opzelura obviously is the first drug approved for that. It's a twice-daily dose drug. You know, we believe that our product, if approved, could have meaningful points of differentiation. One is that our drug is a once-daily dosed drug. Two, we've obviously seen a pretty rapid onset of action already, so hopefully that would hold in the phase IIb studies and beyond. And three, as you know, the JAK class is saddled with black box warnings, and our hope is that we obviously would not have any of those warnings, and we think those are meaningful points of differentiation. Yeah, I guess to that point, as you're thinking about the readout for the IIb, you know, what is kind of the bar for moving into phase III? Is comparable efficacy to Opzelura sufficient? Do you need to show that faster onset? Do you need to show a maximal effect that's greater? How are you thinking about that moving forward? Yeah, a couple thoughts. You know, obviously in our phase Ib, we looked at only patients that had active disease, progressive disease, and so they generally are harder to treat. Our hope is that in our phase IIb study, which is an all-comer study, we'll be enrolling and are enrolling patients that have stable disease as well as active. So by you know broadening that patient population, does a couple things. One, we'll have obviously a broader label. But two, we would hope that by including patients that have stable disease, which are the majority of the patients with vitiligo, that as I shared before, they tend to respond more quickly and more durably to therapy. So we hope that would help us in the results for our phase IIb study. Mm-hmm. In terms of how does success look? We've heard this over and over again over the last, you know, call it year and a half, two years, since the drug's been in development, is that we don't have to beat what's out in the market. The fact that, as I shared before, there's only one drug approved, it's a twice-daily dose drug. Ours is once daily. The fact that it's not a JAK, which is saddled with the black box warning, those are our meaningful points of differentiation. So if we're just in the same general vicinity as, you know, the other drugs that are in development, you know, we think that obviously, Mm ... gives us a pretty meaningful position. Obviously, if we see a faster onset of action, if we see better efficacy, all that's just upside for the patients. Mm-hmm. Last piece I would add, Alex, too- Yeah ... is when you take a look at patients that have vitiligo, the vast majority of them, 80%-85%, have less than 10% of their body surface area covered with these lesions, and so they are really candidates for localized therapy, and so we think our drug, if the data holds and the points that I was making before, we think that 201 could be a potential first-line therapy, and then for those that obviously have more widespread disease, highly unlikely they would get a systemic steroid, or let's just say one of the systemic JAKs is approved, plus a topical JAK. Yeah. So we think our drug would have utility for both, first-line therapy, but also as adjuvant therapy as well. Yeah. Okay, and then timing of top-line data? Yeah, yeah. So we began enrolling patients for the phase IIb in early June. We're pleased how things are progressing, and as we've communicated, we anticipate having top-line results for the phase IIb middle of next year. You know, we remain confident on those timelines. Great. And maybe shifting gears to 202, I guess, you know, how confident are we that, you know, being selective is going to help here, avoiding some of the systemic tox that we're worried about with that inhibition broadly? Yeah, yeah, as I shared earlier in my initial opening comments, BET's been around for a bit of time and almost exclusively developed in oncology. And our drug design thesis, you know, it appears that you know, the inflammatory culprits reside within the BD2 portion of the BET protein, and BD1 is really more to manage housekeeping genes and keep a level of homeostasis. And so the idea is be super selective on the BD2 portion of the protein and try not to touch BD1. Mm. We believe that we've validated that concept, and the reason why is, as I had shared, we intended to take VYN-202 into two proof of concept studies in psoriasis and rheumatoid arthritis. We obviously ran preclinical models, and we saw pretty, you know, pronounced effect in addressing inflammation and, you know, clinical signs of improvement. But we ran the same two preclinical models with VYN-201, which as you know, is a pan BD BET inhibitor and hits both BD1 and BD2. But it's a soft drug approach, and so anything that gets out of the tissue is rapidly- Mm ... created through the liver. For VYN-201, we ran the psoriasis study by applying it topically, and for the arthritis model, it was injected right into the joint. For VYN-202, obviously, it's a systemic route of administration. When you layer the results next to each other, they're almost identical. Mm-hmm. We saw the same type of improvement in the signs and symptom scores for both models, for VYN-201 and 202, which seems to validate this notion of if you're hyper-focused on the BD2 portion of that protein, that's gonna be your best opportunity to improve inflammation, especially for autoimmune diseases. How much read-through do your preclinical models have on broader systemic tox as you're thinking about human data? I know we have some phase 1 I want to talk about, but how much can you read into that? Yeah, I mean, we're certainly pleased by what we've seen, and encouraged by all the results to date. As you said, so now we're in our human studies. Yeah. We announced our SAD, or single ascending dose, results last week. We were pleased and encouraged by the results, you know, both from a safety perspective and a tolerability perspective. But we also saw, you know, impact on some of the key biomarkers that we were targeting. Yeah. HEXIM1, which is a target engagement biomarker for BETs. We saw impact there, as well as reduction in some of the key cytokines that are associated with these diseases, so what I would say is so far, so good. Yeah. Now we're obviously in the multiple ascending dose portion of the study, and we'll see how those results shake out over the next several weeks. And yeah, based on historical precedent, you know, how much does that data de-risk some of the on-target heme or GI tox elements already? Yeah, I mean, so how I would view it again is so far so good. Yeah. So- Certainly helpful. And so it's encouraging. Obviously, multiple ascending doses are going to be more informative. Yeah Both from a safety perspective, but also from a trial design for our POC studies, what doses we're going to take in. Again, so far so good. We're pleased. MAD data, you said a few weeks? Yeah, so we had the SAD. MAD results will be this quarter. Mm-hmm. And we're already on our way, so it'll be certainly this quarter. And then assuming everything goes well, our intent is to kick off the proof of concept studies in psoriasis and RA. Yeah ... by the end of the year, right around that time period, and then have the results for those studies, the back end of second half of next year. Yeah. Can you talk a little bit about, in closing, I guess, sort of the design of the psoriasis and RA studies? Yeah. Yeah, sure. So we would anticipate having a couple doses in this study. And a lot of these, you know, phase Ia/IIas, have a handful of patients, short duration, try to get a signal. And we'd like to think that we've learned from the lessons of others. And so we want these studies to be a bit more meaty. So there are going to be more patients in the study. We're gonna look at a couple doses, and they're gonna be longer in duration. So we would anticipate that both these studies to be twelve weeks in duration. And the reason is twofold. One, we want to get as much safety data as possible. Two, from a efficacy proof of concept perspective, again, when you're dealing with a small molecule asset, you want to give this as much time to see that efficacy mature and develop and evolve over time. Which again, would be informative for us in then move into standard dose ranging studies in 2B. And the last piece too, obviously, we want to make sure that hopefully the data we have is as conclusive- Yeah ... and much confident as possible. You know, some other companies that have done these POC studies with, you know, one dose or for a couple of weeks- Yeah ... they're one patient from it going either way, and it creates a lot of ambiguity. We're trying to avoid that. Yeah. No, totally understood, and I guess final question: Can you talk about cash runway and what your embedded assumptions are with that? Yeah, sure. So, at the end of last quarter, we had just shy of $80 million in cash. As you know, we did a pretty sizable capital raise last fall. It was a recapitalization of the company, and the cash that we have on hand gets us through the end of next year with some cushion. So that allows us to conduct all these programs. Obviously, we're right in the middle of the phase 2b and the for VYN-201. We're obviously now in the MAD portion of the phase 1a for VYN-202. And obviously, we would move into two phase 1b proof of concept studies. The cash we have on hand allows us to get through all these programs. Obviously, we've got some pretty meaningful milestones- Yeah ... this year, the balance of this year, and through next year, and we've got the cash to get through all that. Great. David, thanks so much for joining us. Appreciate it. Thanks, Alex. Appreciate your patience. Sorry about the technical difficulty. All good. All right. Talk soon. Bye. Thanks.