Awesome. Good afternoon, everyone. It's my pleasure to introduce the Aclaris Therapeutics team. Hugh Davis, Roland Kolbeck, and Will Roberts here joining us this afternoon. Maybe we could start off with just a brief overview of the company. Maybe, Hugh, do you want to start with that? Sure. Yeah, hi. Thanks for having us. Aclaris is a clinical stage biotech. We have three assets in the clinic and another to come because we have an R&D group also that supports not only the discovery of new assets but also preclinical sciences around our current clinical assets. We have a world-class team. Many of us have come out of large pharma with many years of experience. That is both in our discovery group and our development side. We treat Aclaris as sort of a biotech where we're really bringing our knowledge and expertise across not only well-validated, targeted therapeutics but also innovative new assets that are coming through the pipeline. To date, what we have is both a small and a large molecule platform. We've been in the kinase arena now for many, many years with our group being expert in kinase inhibition, coming out of Pfizer initially and brought into Aclaris a number of years ago. Then on the large molecule side, we had an acquisition of a couple of assets, a licensing deal of a couple of assets from Biosion just about this time last year. We have both small and large molecule approaches to a number of important unmet medical indications that are, as I mentioned, currently being investigated in the clinic. Great. Yeah, I remember about during our health care conference last year was the Biosion deal. And maybe to start things off, it is something unique from a smaller biotech side to have both a large molecule vertical and a small molecule vertical. I guess, could you talk a little about the thinking behind the Biosion deal and how having both of those two types of assets together makes sense at a company like Aclaris? Sure. At the time, I actually came from the Biosion side along with the deal. Really, with Neal and Jim and John and the like, and Joe as well, they were really quite agnostic to where they would head in terms of supplementing the portfolio and looking for more near-term clinical assets that would have catalysts for the future of the company. There was a broad review of really just about everything, mRNAs and platform agnostic. With Biosion's antibody and bispecific antibody, it really gave Aclaris a chance to dive deeper into derm, but at the same time expand out into other immunological approaches in respiratory and even GI. It gave a broader opportunity to the company than in the past. Great. Yeah, so maybe let's start with Bosakitug, specifically how this antibody fits into the broader TSLP space. There's no lack of TSLP antibodies out there at the moment. Maybe if you could frame how this antibody is both similar and different than what else is out there today. Yeah, you're right. It's interesting because there are many approaches in the TSLP and now bispecifics with TSLP. Interestingly, I think Aclaris may be the only one going after atopic derm with the TSLP antibody and in phase two, as I mentioned. Really, it's a function of potency. I think that was one of the attractions of Bosakitug to Aclaris at the time because Bosakitug is about 70 times more potent than Tezepelumab. Again, kudos to the research team within Aclaris because during the due diligence, it wasn't just a matter of, oh, you're so much better than Tezi in potency and that's going to make all the difference in the world. They actually took it a step further, actually a few steps further, because they also brought the asset in and compared it to other clinical candidates. GSK, JP Morgan a year and a half ago, GSK for $1 billion bought in the Aiolos TSLP antibody. Merck put an antibody out as well against TSLP. Aclaris tested the Bosakitug against GSK clones, Merck, Upstream Bio, and they showed a couple of really key points that really differentiated the Bosakitug from the others. One of them is very long residence time on TSLP. The Bosakitug does not dissociate readily from TSLP. It binds and it stays bound. Four hundred hours of residence time relative to 3-20 hours of the Merck, the GSK, the Upstream, and the Tezopelumab compounds. In addition to that, they also looked at some of the rationale as to how this could be the case. It's been shown now that when you look at the binding of Bosakitug to TSLP, it binds to two epitopes on TSLP, both at the end and the C terminus. You have more of an avidity. The other part of that was we had a phase 2A ongoing at Biosion at the time. Aclaris was really smart to put us under exclusivity during the due diligence period. They got to see the phase 2A data come out throughout the summer. The deal closed in November. When we ended up showing 94% EASI-75 response and 88% IGA 01 response in atopic derm, and 12 weeks after the last dose, we're still seeing an EASI75 response, that I think was the clincher as to closing the deal at the time. Yep. I think the context around TSLP and atopic dermatitis is interesting. How much does potency make up for the fact that Tezopelumab did test a higher dose in AD and still did not show clear separation versus placebo? Can you in any way quantify how much that potency helps here? Yeah. Yeah, it's actually an excellent question. When you look at Tezi studies, and we did very closely at the time, they did 210 at two weeks, 420. There was basically a range of exposure of about fourfold. As I mentioned, we're showing 70-fold higher potency with Bosakitug to Tezi. You can't make up 70-fold in dose. On top of that, we also looked at the design. If you look at the phase 2A trial and even the phase 2B trials from Tezi, they were done on top of topical corticosteroid. When you have a baseline of TCS activity, it's really hard to show a differentiation of your own drug as monotherapy. With Bosakitug, we've shown that activity as monotherapy in the trial. That was the key differentiator at the time. Dose is important, but you can't make up that kind of potency difference. On the two A study itself, obviously, I want to talk about this in the context of your ongoing phase two B study. U.S. sites, placebo responses, looking at a more mild to moderate population, all of those things in the context of your two A, what gives you confidence that this is a real signal that can be replicated in the two B study? We thought long and hard about that because it takes a lot of really perspective to move into a phase 2B study with Bosakitug like Aclaris has done. When you look at the 2A, it was 24 weeks of therapy and the response was slow over time. Eventually, you achieved the maximum effect only after 24 weeks. At the same time, when you look at how some of these studies have been done with placebo rates of 75% and the like, to your point, in the 2A, we're looking at EASI scores of 16-24. In the trial that we're doing now, we're looking at moderate to severe again. We're really looking to minimize that placebo impact. We think that central reading and being able to really focus in on a population that's correct, which means that they have not only extent of disease but also intensity of disease and that they actually have atopic derm, which isn't always the case. Central readers and then Neal also being a dermatologist looking at those pictures too, we believe that we have a really appropriate population that's coming into the two B trial. If you're doing 88-90% in the two A and it's open label, you're looking at skin. It's not pain. It's not anxiety. You're looking at something very clearly that cleared and it cleared substantially. Even if we had a pullback with the double-blind placebo control pullback to 65% response, that would still be highly competitive and it would still be a best in class. Actually, it would be a first in class. We don't have a TSLP against or in a derm. Yeah, I guess that really anticipates my next question, which is looking at the data coming out of the phase 2B. What does a good outcome look like for you? Yeah. What we did was we have the same dosing regimen we had in 2A, so 300 milligram every two weeks. We did that because, again, we wanted to make sure that the data that we saw in 2A were real. We wanted to show max effect. That is what Aclaris is all about. If you look at Dupi, 2/3 of patients have a 75% response. That is not what we are looking to achieve. If we do that with Bosakitug, we will consider that a good response because we will also be able to have a much longer dosing interval with the same response as Dupi is able to achieve. It would be another molecule in the armamentarium of dermatologists, no other TSLP in derm. Again, we're really still hoping that we're going to be able to see extensive impact for patients in this trial. You talked about extending the dosing interval. How do you plan to move forward with that idea after the phase two? Ideally, we would do a 2B3 that would follow. The 2B3 would either have a couple of different doses or dosing intervals against placebo again. That would be a run-in then to the registration trial. When is the top line data? Top line's middle to end of next year. It's going to be an exciting year in 2026. How are you thinking about expansion beyond atopic derm here? Obviously, TSLP is well known in the respiratory space. Is that your plan or is it something beyond respiratory? For TSLP itself, we're looking at the derm play. Our partner, well, it's not our partner, it's Biosion's partner, CTTQ, is already investigating the respiratory indications. We have rights to data, seeing their data. At the same time, we would expect that we would partner that out if we wanted to take Bosakitug into both respiratory and derm indications. Aclaris is focused on derm for that asset. Yep. Okay. Maybe pivoting to 052, the TSLP IL-4 receptor bispecific. As you think about bispec partners out there in the INI space and dermatology or respiratory, what makes this combination attractive? Yeah, so it's a TSLP IL-4R. Again, 400 hours of residence time on TSLP. We're looking again to knock down TSLP as an alarm. We want to take it down to homeostatic levels. At the same time, by hitting it both at the top of the cascade, the TH2 cascade, and at the immune level of the cascade, we're looking for both a deep and a broad response. We have confidence in that in the trial as we move forward because in vivo, at least preclinically, we were able to show that we were four times more potent than Tezopelumab and Dupilumab combined in inhibiting CCL17 release from PBMCs. We're seeing a synergistic effect, not just an additive effect. I think that by showing with 052, the bispecific, we can have all four sites, the anti-TSLP and anti-IL-4R, fully saturated on a molecule. The affinity against those two targets doesn't change by having binding of the other target. We have a molecule that not only is able to inhibit TSLP and IL-4R, but it's able also to have an extended half-life because it has a YTE mutation in the Fc. It also has an AQQ mutation, which can limit some of that off-target toxicity binding the Fc gamma receptor. That's what we're thinking is the future across a more broad patient population relative to ATI-045 and Bosakitug. Heading into your phase one data set early, I think early next year, right? Yeah, for SAD/MAD. For SAD/MAD. I'm curious, in the context of the bispec, what would you expect from a PK perspective for a membrane-bound partner and a soluble partner? What does good look like in the phase one study before we get to a proof of concept? Yeah, you hit the target on the head there. Safety, first of all, right? You're inhibiting two targets in an immune cascade, so safety is utmost concern. Then pharmacokinetics. To your point, dupilumab has target-mediated drug disposition, which we would as well, binding to a receptor target. We have the opportunity with the YTE to extend the half-life, and we're expecting that we're going to be able to have something longer than every two weeks. The PK will be able to bear that out. That's going to be important as a readout in the healthy volunteers. How much can you de-risk from an immunogenicity perspective ahead of the phase one? Is that something obviously safety matters, but as a bispec, are you worried about immunogenicity at all? I'm never worried about immunogenicity unless there's safety risk to it. I've always looked at immunogenicity as a covariate to pharmacokinetics. If you don't see a safety risk with immunogenicity, anti-drug antibody, then the next question is, is it binding to your therapeutic and reducing the concentration enough that you will have a reduced efficacy? It's a covariate for PK. If you have low titer reasonable incidence, it's not usually a factor because you can dose through it. Yep. Yep. So then you're moving into proof of concept studies after that in both asthma and AD, correct? That's correct. What's the rationale for doing both simultaneously? First of all, we want to be able to see whether it has broad applicability. Obviously, we know Dupi and Tezi are both out there as validated targets. It is interesting, right? In asthma, are we going to see a better effect in a phase 2B study? This is just going to be a POC approach to seeing whether we have really great phenol response and FEV response with a single dose in a patient population, severe asthma. At the same time, we are doing five doses in atopic derm. In that case, we will also be able to see prolonged activity. We are going to get both on the respiratory and the derm side at the same time. Again, at the same time that 045, the Bosakitug, reads out in the 2B. We'll have a really full data set to be able to look at where we want to take each of the assets. Is there a strategic decision at that point as to whether you move forward with Bosakitug or really double down on the bispec in derm specifically? There will be strategic decisions, but I don't know that it's an either/or. Okay. Makes sense. You may be pivoting to the small molecule side of things with 2138. I guess maybe if you could start off with kind of where we are today with 2138, kind of what that molecule means for your broader ITK platform programs here and what the path forward looks like. Yeah, Roland, pick that up. Happy to pick that up. Great to be here. Yeah, 2138 is our lead compound of our ITK franchise. It's what we call the first generation small molecule inhibitor. It has a very unique dual pharmacology. It inhibits ITK, TXK. These are signaling molecules downstream of the T-cell receptor on CD4, CD8 T-cells and other cell types. Also, further downstream, it inhibits JAK3, which is an important signaling molecule of the common gamma chain cytokines. Cytokines like IL-2, IL-4, IL-7, 21, et cetera, IL-15. In that regard, I think this is a very unique molecule of our ITK franchise. Again, it's very potent. The way it inhibits both ITK and JAK3 is by covalent inhibition in the kinase pocket. We target a certain cysteine in each of the kinase pockets, which make it a very potent molecule. That also allows probably fairly low dosing. That is what we have seen in a small atopic dermatitis study in an open label study, but also in healthy volunteers. It turned out to be safe. The low dose and therefore the associated lower exposure, I think, has a higher potential for a better safety signal, better safety profile than other compounds. I mean, there is only one compound in that class, ritlecitinib, which also inhibits both ITK and JAK3. We are about 40-fold better potency on ITK and about 5-fold better potency on JAK3 in cellular potency assays. Yeah. I guess as it relates to kind of how you're thinking about the franchise, what's important about 2138 as you're thinking about developing more selective inhibitors in the future? Yeah, so as I was pointing out, I mean, our first-generation 2138 is a very broad reach. It's the gamma cytokines. It's the ITK T-cell receptor signaling. And we think that's a great start. What we are really interested in is also making compounds which are more specific for TCR signaling, so more specific for ITK/ TXK. We are trying to dial out the JAK3 component. We have a number of compounds already in the pipeline, which look very promising. They have great potency on ITK. We have shown that these compounds do not hit Jak3 in in vivo studies, for example. We are quite excited about this. That's the next generation of compounds in our portfolio. Sorry, when will those be ready for the clinic? We anticipate that by the end of 2026, we'll have an IND with one of these compounds. In the meantime, you've obviously generated data in atopic derm with 2138 shows activity. You've also made a strategic decision now to move that over to lichen planus versus alopecia areata. Can you talk about the rationale for that decision and maybe talk a little bit more about lichen planus as an indication? Great question. When we started the atopic dermatitis study, the goal was never to really stay in atopic dermatitis. At that point, we had three-month tox data, so we could do a three-month study in atopic dermatitis. We thought it is also a very good mechanistic fit for the compound a derm, so we did that study. We wanted to learn about the safety of the compound, but it also was a very rich data-driven study. We took skin biopsies and skin tape strips as well as blood, and we did transcriptomic and proteomic analysis. That was very important because this is the first time where we validated also ITK as a target in a disease indication. We got great reductions across the different biomarkers, T1, T2, T17, reduction in fibrosis markers, which I will come back to in a moment for other indications. That's probably quite important. With the safety profile and again, the very deep biomarker profiling, we're thinking about where else can we take that compound like lichen planus came up as a potential indication. Can you talk a little bit more about the underlying pathophysiology of lichen planus, how this mechanism fits in and what the commercial opportunity might be like? Yeah, sure. That's another dermatology indication. It affects mucous membranes, the skin, nails. You can get hair loss. It is associated with severe plaques, pruritus, scales, again, fatigue. I mean, it's a disease which is really undertreated. There is wide, wide, wide open space. There are no oral compounds approved in lichen planus. We believe that again, mechanistically, 2138 is a very good fit because it's known that in the disease, interferon gamma plays an important role. There are CD8 cytotoxic T-cells. There is significant pruritus activity, which is associated with IL-31 when we overheat that pathway. We think based on the mechanistic fit and the need in that indication, that's a great opportunity to test 2138. What does the clinical path look like there? We are, again, lichen planus, like many other indications, comes in different variations. It's just not one disease. There's a cutaneous form. There is a mucosal form. There is lichen planopilaris, which is again associated with significant hair loss. I mean, we are in the process of exploring what we really want to do in this phase two study. It could be that we look at maybe all three forms of the disease in that study. That's still under investigation internally. The readout would be IGA, for example, could be a primary readout. Pruritus reduction could be a secondary readout in the study. Again, as I said, we are just finishing the design of that trial internally. Great. Obviously, lots of catalysts for the next 12 months. Maybe, Will, can you talk a little about your current cash position, your runway, and what that gets you to in terms of readouts? Yeah, happy to, Alex. Thanks. Thanks for having us again. In the context of your questions, 2025 was a remarkable year for us from a foundational perspective. 2026 is a very, very different looking year that I think will be pretty exciting not only for us, but for investors. A ton of different milestones, a ton of different data readouts, not only from assets that are de-risked clinically and mechanistically like 2138 and 045, Bosakitug, but also from a couple of compounds that are further back in the pipeline that are no less exciting, but can certainly change the paradigm of how these diseases are treated, highly innovative drugs, 052, the bispecific, as well as the ITK franchise, right? A lot of data coming next year. Even beyond that, by the way, we've got a discovery platform that's going to allow us to bring forward additional multispecific antibodies, additional inhibitors, some ITK-like, some ITK-not. An awful lot to look forward to. In the context of your question, importantly, we have a cash runway now that takes us out into the back half of 2028. As such, it covers everything that we've already talked about today. We can do everything we've talked about. We can develop these drugs the way we need them developed with the cash runway we currently have. Importantly, we have some interesting opportunities for us ahead that can allow us to raise additional capital in a non-dilutive manner. We're in no rush to head out and raise capital, but are in full control of our pipeline. Great. Hugh, Roland, Will, thank you so much for joining us. Thank you. Thank you for having us. Appreciate it. Thank you.