Good afternoon, everyone. Thanks for joining us here at the Leerink Partners Global Healthcare Conference. My name's Tom Smith. I'm one of the senior biotech analysts here at Leerink, and happy to be joined by our next company here up on stage, Aclaris Therapeutics, represented today by Chairman CEO Neal Walker, President and COO Hugh Davis, and CSO Roland Kolbeck. Gentlemen, thanks for joining us.
Thank you.
Mm-hmm.
Thank you.
Neal, it's been a busy last 12 months for you guys. A lot of execution, some new data points on kind of on both sides of the house. Maybe for those who are a little bit less familiar with the story, like just give us a little bit of background on the company, current focus, what you guys have done over the last 12 months, and what we're excited for here in 2026.
Sure. Aclaris is a clinical stage biotech company focused on both large and small molecule therapeutics in the I&I space. Currently, we have 3 clinical stage assets, and 1 asset that's quickly heading to the clinic will be in IND in the back part of the year. You can broadly think of the company in two big buckets, I guess. One is large molecule therapeutics, which is represented by our TSLP mAb, which is ATI-045. That is currently in a phase II study in moderate to severe AD that will read out in the back part of the year. ATI-052 is a bispecific construct utilizing the same ATI-045 TSLP mAb combined with an IL-4R. That is currently in SAD/MAD work, but also headed to 1b work.
We're enrolling actively in those two 1b studies, one in moderate asthma, the other in severe AD. Both of those will read out at the end of the year. Finally on the oral small molecule side, we have ATI-2138, which we're down selecting to a lead indication that has a full phase II ready package, including long-term tox. We have the next-gen ITK, where we've engineered out the JAK component, and that is headed towards an IND in the back part of the year. Certainly a lot going on. I think, you know, we get asked mostly about the bispecific and the next-gen ITK.
Yeah. Exposure to a lot of hot areas of biology.
Yep.
Certainly the ITK franchise has come in vogue here over the last.
Yep
3-6 months. Yeah, why don't we start with the antibody and I guess the most advanced program, the bosakitug, which is the TSLP-targeted compound. Maybe just talk through and kind of level set us, like why you believe this is a differentiated TSLP, attributes of the compound and like what drives your confidence that you will have something that's like differentiated.
Sure. I'll hand that to Hugh.
Yeah, hi. TSLP is differentiated in a couple of ways. One is the retention time that it has on TSLP, and so over 400 hours of binding relative to other compounds that we've tested against that are in the clinic currently, and tezepelumab were about 20 times stronger binding in terms of time. They're about 20 hours, we're 400. Then that retention time has really translated into potency. The potency that we measured against again some of these other clinical development candidates as well as Tezspire, we're the most potent in all of those that we've tested.
We believe that the retention time and the potency are really two key attributes when you're trying to bind an alarmin like TSLP, which is highly potent in and of itself, and present at picogram per ml quantities. You need to be able to bind it and maintain that binding inhibition for a long period in order to really allow that Th2 pathway to turn around and have keratinocyte healing in the dermis and in asthma as well, where you need to have reduction in asthma exacerbations. We're excited because the phase II-A data showed a really great EASI response with 94% EASI response and EASI-75, and then we also had 88% of the subjects with an IGA 0/1.
That was at 7 sites around the U.S., but it was a 2A. It was open label, so it was enough information for us to move into a full phase II, and we're excited about the data readout that we'll see at the end of this year, where we have a 96-subject trial, 2-to-1 randomization. Obviously, it's double-blind and placebo-controlled, and we're really excited about seeing those data. If they recapitulate any of the 2A, we'll be extremely happy.
Yep. Trying to confirm the open-label phase II-A dataset now in the phase II-B. Just remind us on the dosing, I guess similarity of dosing that you're using between the two studies, and then when you talk about time on target, I guess how that might translate to longer-term, kind of like TPP, ideal dosing interval, like how infrequently do you think we might be able to dose this once we've confirmed the signal?
Yeah. Great question. The antibody itself, just the naked antibody is 23-day half-life, so it's naturally long half-life. In the 2A, we showed that after the last dose, we still saw 12 weeks of EASI-75 response. We think that with this study and with the other data that we have in hand, we could get out to a 3-month dosing interval. What we did with the study was we dosed at a 300 mg every two weeks, but only because we wanted to really show whether TSLP was a valid target in AD, and everyone seems to
You know, maybe be coming around to that now more that we've seen some recent data. You know, we wanted to make sure that we had a trial that was really had greatest possibility of success.
Right. You are evaluating the endpoint here at 24 weeks?
Yes.
Right. We're giving a little bit more time, the target. Maybe just put, I guess, your phase II-A data set in the context of, like, there have been other TSLP antibodies. You brought up tezepelumab, like Tezspire had a phase II program in AD. Just put this open label data into context versus what they saw and I guess, like, learnings from their program, how you're able to incorporate those into your phase II-B.
Yeah. The exposure response is the key, and again, we have the long retention time. When we look at Tezspire that dosed every 4 weeks, that was only of course in the asthma studies and CRSwNP. We think when you go into AD, you may need to have more exposure in order to show a deeper response. That's because there's only 15% bioavailability in the skin from blood. At the end of the day, out of that phase II-A and our phase II now, we'll have a great exposure response profile that we'll be able to move right into a phase II-B/III if the data you know, support that.
Maybe just give an update on enrollment. We're on track for data towards the end of the second half.
Yep. We'll have it by the end of the year.
Yep.
You know, since it's six months of therapy, you know, the math would show that we're getting close to enrolling that.
Got it. I feel like we've had a couple of recent AD data readouts that maybe restored confidence, at least among investors, about the ability to, like, design and execute these AD studies and minimize placebo variability. But you guys have also taken pretty extensive steps in not just this study, but all of your AD studies to try to minimize that variability. Just remind us of what you're going through to try to mitigate placebo response here.
Yeah. We're pretty intensively screening all the patients in on pictures. So both myself, who's a board-certified dermatologist and an independent medical reviewer, are both looking at the pictures and making sure that not only do they have the diagnosis, which can be a problem in these studies, but also that they meet the proper inclusion criteria. Just as an example, if somebody has a baseline EASI 16, you wanna look at the pictures and make sure that that is reflected in what we see. So, you know, it's pretty stringent. I think it's worked actually very, very well, and feel confident that, you know, this molecule's actually testing AD.
When we look forward to the top-line results, this increasingly competitive field, I guess just help frame for us how you think about bar for success. Like the responses you saw in the phase II-A were deep.
Yeah
Durable, quite impressive. Do we need to see the same thing from the phase II-B? Or just like how do we think about like a really competitive data set and
Yeah. I think each of these assets has their place and, you know, although we've got a lot of development stage compounds that are working their way through the cascade and really only 5 approved therapeutics in atopic dermatitis. I think one of the keys for me, particularly in a disease that skews young is, you know, you gotta be safe. I think TSLP checks that box, you know, over and over and over again. I think that's why it's of interest and a part of a lot of these bispecific constructs. From an efficacy standpoint, love to be on par with Dupixent. I think it would have a home in that regard as an orthogonal way to treat these patients.
I mean, Dupixent obviously, you know, goes down the IL-13 path, and TSLP is a pleiotropic molecule that hits mast cells, basophils, dendritic cells, stimulates IL-13 through hitting ILC2s and, you know, regulates through STAT5. So completely kinda different mechanism. I do believe that would have a place depending on the data. First job is it stat sig? Second job is what's the responder rate and where does it fit? Now we have the bispecific coming down the pike. Obviously, Pfizer put out, you know, really wonderful data, kind of just buttressing some of the arguments we've been making with our bispecific. I think we have to weigh those out and see what the data tells us at the end of the day.
If the bispecific's moving along quite nicely, you know, that's also another consideration.
If I could just double-click on that point. Yeah, the Pfizer phase II. This is the IL-4 TSLP-
Yep
Multispecific. Don't have all the details.
Yep.
However, yeah, very impressive, placebo-adjusted EASI responses. Safety looks generally clean. A couple SAEs. We're a couple things that we're interested in, when we see the detailed data. How does seeing something like that, I guess, impact your level of conviction in your bispecific IL-4 TSLP?
I think there's a couple layers to this. One is, you know, we haven't seen too many large data sets about the whole just bispecific thesis in general, right? It has to be one plus one equals three, or why do it? So far the data sets we've seen are out of J&J, and that's an IL-4R IL-31. Didn't work out. Everybody is waiting for the Sanofi data kind of midyear. So this kinda came a little early to me, but it's a direct read-through to us and validates, number one, that you can get synergy with the right bispecific constructs. It's certainly a direct read-through on the targets we're going after, for sure.
I also think it showed the art of the possible with TSLP in AD. You know, Sanofi's gone on record talking about TSLP and its efficacy in AD. You know, certainly, again, it's part of a lot of these bispecific constructs. You can imagine whatever incremental pop you're getting above a Dupixent response rate is likely due to the TSLP as part of that pathway, right? To us, it's very exciting and I think, you know, checks a big box in terms of de-risking the program.
Yep.
Um-
Let's talk more about your program. You generated and reported initial phase I data in January this year. Maybe just, like, what were the kinda two or three, like, major hitting points that give you confidence in taking this forward into the two phase I-B cohorts?
Yeah. I'll start and then maybe Hugh can layer in. Just as a reminder, we only presented the first three SAD doses, the three lowest up to 360. What's to come is we have the last of the SAD cohorts, which is at 720, double the last dose that you saw, and then we have two MAD cohorts at 240 and 480. You know, we would expect to continue to see the same improving PK and PD profile, and that's why we're excited about it because the PD we showed you, again, is 100% inhibition, and no matter how you slice it, 100's 100. Whether I'm cross-trial comparing to, whoever I'm cross-trial comparing to, they better be at 100%.
We would expect in this next layer of data to show an extending kind of PD effect curve, you know, with higher doses. I think that's typically what you see with biologics, and we'll be reporting the rest of that data out in the early second quarter.
The only two things I would add is, you know, we used all of the PK data that we had in the trial so far to calculate a half-life, and a 26-day half-life is substantially, you know, better than most that go against a receptor. So we're, you know, three times longer half-life than Dupixent, for instance. We also saw a duration of PK that took us out for 8 weeks after the last dose so far in the 240, and I'm expecting we'll get out to 3 months with the 480.
you know, we also not only have the opportunity for really great efficacy in terms of target engagement being at 100% for 3-6 weeks, but also, we have the opportunity to show maybe even a longer dosing interval of every, you know, 2 or 3 months.
On the dosing interval, and this applies to the TSLP antibody, but, I mean, Neil, you're a dermatologist. Like, there are other companies that are angling for once every 6 months, 12 months. Like, what do you think of as actually, like, the optimal dosing interval for a therapeutic in atopic dermatitis?
Yeah, I think it depends on the indication. It depends on a lot of factors, but how mature the market is, you know, what the actual efficacy, max out efficacy rates are. You know, to me, anything in the 2-3-month window is plenty. You know, when we talk about going from, like, 26 injections to 4, all right, that's meaningful, but 4-8, it just starts to get squishy, right? I think we've seen this time and time again. Efficacy, any market research anybody does, efficacy matters most. You know, if I was back practicing to a dermatologist, I wanna make sure they're getting better. You know, if that treatment effect is waning between now and month 6, it's not a good thing.
That means you're getting a call from a patient, that means now you gotta maybe administer another drug in between, and that has safety implications. I'm not sure if people saw the CRL that the long-acting IL-5 from GSK just got with the severe CRSwNP with NP, but, you know, they called out, you know, be careful about doing simulations and modeling as a surrogate for dose ranging studies and raise the issue of safety and efficacy that might have a higher bar when you're looking at these lower in dose or longer dosing intervals. Those are the practical applications in addition to payer and everything else. I think, you know, when we think about broad-based adoption of those types of constructs, it's likely not to be broad-based.
It's gonna be in the very small handful of patients who are exceedingly well controlled. I do think that, you know, we should go back to, like, over-indexing on efficacy and safety first.
Fair to say, like, psoriasis experience is the blueprint?
Yeah. I think that's a great blueprint and, you know, it's, you know, drugs like SKYRIZI aren't doing well just because they have a three-month dosing interval, it's because it works really well.
Yep.
That's a much different market, much more mature market. If I have a very stable psoriasis patient that I don't need to see very often, then I'm happy to put them on something that's a little bit extended. They're kind of experienced. They've been there, done that. You know, AD is a treat the flare disease.
Yeah.
It's characterized by waxing and waning. It's not indolent and smoldering like psoriasis. Again, I think some indications would lend itself to that. You know, it is to me more max out the efficacy than worry about the dosing interval later.
Yep, that makes sense. For 052 on immunogenicity, what have we seen so far? Obviously, I think we're looking forward to seeing more data here as you alluded to, early Q2. But what are the expectations on immunogenicity, ADA rates?
Yeah. You know, when you have ADA, usually it's the consequences, not the incidents. We've looked at the consequences so far, and you don't see enhanced clearance at day 15 or 20. You don't see neutralization, you know, like if you had neutralizing antibody with those kind of 100% inhibition rates on IL-4 and TSLP activation. We're quite confident that the ADA impact isn't being seen. We'll do the analysis at the end of the healthy volunteer study.
Yep. Okay. Then you have these two phase I-B cohorts. Maybe just help frame expectation, like starting with AD. I guess expectations for, like what would you consider a compelling signal where, you know, we advance this and it like how do we think about advancement in AD and asthma together?
Yeah, I think the first study out of the gate will be asthma. That's what we're planning for right now, a 2b in asthma. That just makes sense, right? You know, looking at combining tezepelumab and dupilumab in that population I think is wise. I don't know, Roland, do you wanna speak to it?
Yeah, certainly in asthma I think it makes a lot of sense because Tezspire works in T2-low and T2-high patients that has been clearly demonstrated in clinical studies. Whereas dupilumab is really effective in the T2-high population in asthma. We believe that combination with the mechanistic differentiation between TSLP and IL-4 receptor biology, that should be a great indication for all comers in asthma.
Yeah. For the AD study, you know, we're doing both of these 1b studies to help inform how we design the 2bs. On the AD side, it'll be a 8-week primary endpoint. It's the last dose will be 4 weeks preceding that, so we'll get an idea of kind of dose response. Then we also will have 10 weeks post that last time period to measure, you know, a variety of things like PD, you know, PK, et cetera. It'll really help inform the next layer and it really mimics, if you think about it, induction dosing that we see with that is common in AD.
We'll learn a lot on that study, leading in and, you know, look, I expect if I believe in the synergy like I do, the one plus one equals three, then I expect to see, you know, somewhere on the order of like a 10% bump on responder rates like that that you might see with dupilumab. You know, if you kind of dissect through at least what Pfizer's disclosed already, it seems they're seeing the same thing.
Yep. Will you be taking measures of clinical efficacy during the follow-up period?
Yeah.
Like, are we gonna get a sense for persistency of potential EASI reductions?
Correct.
Yep. Okay. Cool. Let's shift gears to the ITK franchise. You've generated phase II data for ATI-2138, and now we are in basically like an indication selection process. We're gonna advance that into a phase II. I think you've with your R&D event last year, lichen planus was one that we kind of highlighted, but you've also generated data in a number of models, one of them an alopecia model.
Mm-hmm.
Like, maybe just hit the high points on the data that you generated and then current thoughts on what's the right indication to advance this.
Yeah. Well, the data we generated out of Angela Christiano's lab was phenomenal. We actually took a hard-to-treat mouse model more so than is historically true, and she's tested every drug that's either been approved or been in development for alopecia and basically their commentary, you could see it in the curves, that this was the most rapid and robust effect that they've seen out of any molecule. From our perspective, I think the decision comes down to going into maybe a more crowded marketplace where there's more drugs approved versus trying to carve out our own niche, perhaps a little bit like the Roivant model, which I think they've done quite well at that. You know, it is an embarrassment of riches.
There's a ton of indications that you could utilize this molecule in, and it's just on us to pick the right lead, that we can push along within the confines of Aclaris. That decision will be forthcoming very soon.
Great. That model, that was, versus ritlecitinib?
That was head-to-head versus ritlecitinib and, which is a good comp because it's a JAK3 covalent inhibitor, you know, just like ours, except we have that extra ITK boost. I mean, we're just showing an amazing result even at week two.
Right.
Pretty encouraged by that.
Right. You've already run a phase II atopic dermatitis study, so we've already generated a fair amount of safety data.
Correct. We have 6- and 9-month full chronic tox, all looked clean, and very clean profile in the AD clinical study.
Great. Okay. Then coming behind that, we have basically a portfolio of selective ITK inhibitors. You've nominated ATI-9494, and we're going to put an IND in here in the second half of the year. Seen some really interesting data from a competitor who has an ITK inhibitor, ritlecitinib. Maybe just contextualize like that data point, I guess what we've seen from cohort 3 and cohort 4 from ritlecitinib, and then how you think with a more selective ITK you could maybe improve on that.
Yeah, I think, look, we've tested their molecule against ours in-house for probably the last three years and feel pretty comfortable with the profile relative to improved potency that's orders of magnitude more potent. You know, what that allows is lower drug burden for a covalent drug. It also allows more flexibility in dosing and, you know, thinking about ITK occupancy at the end of the day. I think the final thing is we've optimized that program for an extended half-life, meaning that QD dosing is 100% on the table. I'm not sure that they can get there with that.
Look, we're excited about that molecule just like they are and about theirs and, you know, we're anxious to get into the clinic and get moving.
Just help us think through, like, the timeline, you know, from IND filing later this year to perhaps catching up to them. Are there certain things that you can do to streamline your development process now that we have what looks to be a pretty good signal in the class that will allow you to potentially close that gap?
There are. We can do more of the MAD within the MAD cohorts. You know, derm patients are generally healthy, so we can add those into the mix into those cohorts, and we know a lot about the molecules already, and I think ATI-2138 went a long way to kind of informing us about what appropriate dose levels might look like. We're gonna get up the curve pretty quickly and run through that signal finding study very quickly and then just jump right into a phase II II-B program. You know, I think as we sit here today, we're probably 12 months behind, but I'm not really worried about that.
I worry more about having, you know, a superior molecule, better efficacy, better profile, QD, a better safety profile, and you know, we'll catch up.
Just building on the last part of that, like I mentioned this portfolio of ITK inhibitors because you have spent the time, run the preclinical studies. When we think about optimizing it, like you've called out the half-life and I think with a more potent compound, like the ability to generate potentially better efficacy, but on safety and selectivity, I guess what specifically would you be looking to improve upon there out of the cycle?
Well, there's various ways that we've thought about tuning in and tuning out effect and, you know, the first thing was to get rid of the JAK3 piece, and then what you can do is you can toggle off of a pure ITK selective or toggle in some Th1 effect through TXK and, you know, in our internal work, we do think that that's important. Some of it we've published, some of it we haven't and will be down the road. You know, there's a reason we're moving forward with that as kind of the lead. You know, time will tell. We're gonna run, you know, two POC studies with each and then make our selection, you know, based on that data.
Maybe taking a step back and just kind of level set. I mean, you guys did a great job of this with your R&D event last year, but just kinda walk us through mechanistically applications, biology, and settings outside of atopic dermatitis and then how you mentioned like running a couple POCs potentially. Like what else is kind of high on the list of-
Literally, I think you go into every Th2-driven disease that's currently has biologics like ADBRY or Dupixent approved. I mean, that's I think the promise of an oral in that indication. I think it's similar in that regard to STAT6, although I think with an ITK, we have more breadth and, you know, we know that there's a lot of heterogeneity, particularly in diseases like AD and asthma, and it's important to address the various inflammatory endotypes, not just Th2, but Th1 and Th17 to really increase that efficacy ceiling. I think, the opportunity is vast there and the kind of pathway's been painted already for us.
I would, you know, right out of the gate with something like an ITK oral, I'd do AD, I'd do asthma, think about COPD, and just start clicking off of those.
For you guys, because you have this breadth of portfolio optionality, like how should we think about the investment, I guess the split between the two houses, where kind of where we started out, right? Antibodies and small molecule. Then it would seem to make sense to me that we would have multiple ITK inhibitors kind of running after each of these indications potentially, but how do you think about it?
Yeah. I mean, it's funny, the cadence of spend, you know, was heavier weighted on the oral small molecule side to ATI-2138, but now that we've got more conviction around the next gen ITK, the spend shifts there. Same thing has happened on the large molecule side, you know, heavier investment on TSLP mAb, and now that we know that the bispecific has checked a lot of the de-risking boxes, it'll be heavier spend there. But they're two very different markets, and I think people like to.
You know, I've seen a lot of market research these days that say, "Hey, if I deliver an oral, there's 90-some odd% switch of patients, and similarly, on the other side, if I deliver a long-acting biologic, 90% shift of patients." I can tell you as a former practitioner, I've never seen that in my life, like, and I don't think we will ever see that in our lives. I think both pieces of research are incorrect. There's always gonna be opportunities for orals or just patients who just like orals better, and there's always gonna be opportunity for biologics. If I have two of these great assets to go after, you know, I'm not gonna choose between one or the other. I'm gonna invest in both 'cause I'm targeting a much broader swath of the market that way.
Turns out these are massive end markets.
Yes.
that can easily support both options.
Well, just look at psoriasis. Fascinating, right? Everything went to biologics. Now all of a sudden we're investing back in orals, right? That is because exactly what I said. The biologics or the orals never take over the whole market.
Yep. Just in the last, you know, 15, 30 seconds, we talked about a lot of things today. Just remind us on cash runway, kind of like what's funded and, obviously we ran through the milestones, but kind of, yeah, hit the highlights.
Runway. I think as of today, we're into Q4 2028. We recently disclosed additional capital that came in. Basically that allows us to deliver everything we've been talking about, but now importantly adds in the phase II-B asthma study for the bispecific. Gives us a good runway to continue. It gives us good incremental runway, but also more importantly allows us to do more now that we know that we've de-risked the programs.
Yep. Great. All right. Well, we're a little bit over time, but, thank you Aclaris team.
Sure
For joining us. Thanks for the insights. A lot to look forward to this year.
Thank you so much.
Thank you.
Thanks.