Aclaris Therapeutics, Inc. (ACRS) Earnings Call Transcript & Summary

Good day, and thank you for standing by. Welcome to the Aclaris Therapeutics ATI-2138 Phase IIa Top line Results and ITK Franchise Update Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your host for today's conference, Will Roberts, Head of Communications.

Good afternoon, everyone, and welcome to the Aclaris Therapeutics conference call to review the positive results from our ATI-2138 Phase IIa clinical trial. The press release on these clinical results was issued this afternoon and can be found in the Press Releases subpage of the Investor Relations section of our corporate website, aclaristx.com. Please note that we have provided slides as part of the discussion now available in the webcast window and as a downloadable PDF document. We'll reference the slide numbers throughout, and a Q&A session will follow the prepared remarks. Before we begin, I'd like to remind you that today's webcast contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements represent management's judgment as of today and may involve risks and uncertainties that could cause actual results to differ materially from those expressed in or implied by these statements. More information on such risks and uncertainties, please refer to our filings with the Securities and Exchange Commission, which are available from the SEC or on our corporate website, www.aclaristx.com. Any forward-looking statements represent our views as of today, July 29, 2025. Joining me on the call today are Neal Walker, our Chief Executive Officer; and Joe Monahan, our Special Scientific Adviser to the CEO. In addition, Jesse Hall, our Chief Medical Officer; and Kevin Balthaser, our Chief Financial Officer, are also available for questions following their prepared comments. With that, I'll turn the call over to Neal.

Thanks, Will. Good afternoon, everyone, and thanks for joining us on our call to discuss the positive results from our open-label single-arm Phase IIa clinical trial of our investigational compound, ATI-2138 in moderate to severe atopic dermatitis. Hopefully, you have seen this afternoon's press release already. As a reminder, there are 2 components to our ITK franchise to keep in mind. First, 2138 is our ITK/JAK3 inhibitor that is the subject of this top line data announcement. Second, our pipeline includes next-gen ITK inhibitors where the JAK3 component has been engineered out, and as we have communicated, a 2026 IND is anticipated. These results represent a significant achievement for our ITK franchise by providing additional clinical evidence to help confirm the mechanism and validating our work on next-generation ITK selective compounds. Starting with Slide 3. 2138 is our investigational oral compound that interrupts T cell receptor signaling by inhibiting both ITK and JAK3. It's highly potent for both receptors. And due to its unique dual pharmacology, we believe it has best-in-class potential. Although it doesn't have a direct mechanistic comp in the market, it is most similar to ritlecitinib, which is approved for alopecia areata. And as we'll discuss momentarily, data to date suggests that 2138 is considerably more potent than ritlecitinib with the potential for a better tolerability profile. The crystal structure of 2138 is shown on Slide 4. Importantly, other oral drugs target the same positional cysteine, namely ritlecitinib and ibrutinib, a BTK inhibitor, to name a few. However, 2138 differs from reversible JAK inhibitors in that unlike approved JAK inhibitors, 2138 is specific for JAK3. It does not inhibit other JAKs, including JAK2, which can affect the bone marrow. And while both 2138 and ritlecitinib are selective for JAK3, 2138 is significantly more potent on ITK. Diving into 2138's potency advantage further on Slide 5. 2138 is 44x more potent than ritlecitinib for inhibiting ITK-dependent anti-CD3-induced interferon-gamma production and 5x more potent for inhibiting JAK3-dependent IL-2-induced interferon gamma production in human whole blood. We've also conducted preclinical work to compare the potency of 2138 to that of CPI-818, Corvus' small molecule ITK inhibitor. You can see this on Slide 6. In these assessments, 2138 is up to 38x more potent than CPI-818 in inhibiting the ITK enzyme activity and also significantly more potent than CPI-818 in blocking the Th2-derived cytokines. All of our next-gen compounds in development demonstrate similar potency advantages in head-to-head preclinical work. 2138 has also demonstrated robust anti-inflammatory activity in multiple industry standard animal models of disease, examples of which are shown on Slide 7. Chow administered 2138 reduced ilium and colon inflammation in a mouse IBD model on the left and reversed depigmentation in a vitiligo model on the right. These results, along with preclinical data in rodent RA and psoriasis models support a broad indication potential for this molecule. Slide 8 summarizes the SAD/MAD results that preceded the Phase IIa trial. This trial confirmed that 2138 was generally well tolerated with no serious adverse events reported. We saw linear PK and dose-dependent increases in exposure and at 10 to 30 milligrams daily, plasma concentrations of 2138 reached the targeted level. Finally, we observed dose-dependent inhibition of ITK and JAK3 markers and the 5- to 40-milligram BID doses inhibited up to 50% to 90% of both ITK and JAK3 PD functional markers. Now moving to the top line results of the Phase IIa trial. Atopic dermatitis is the right place to start for a variety of reasons, including that it provides an efficient means of assessing quick clinical response. As we have previously indicated, our next indication of interest for this drug is alopecia areata. Regarding the trial design on Slide 9, this was a Phase IIa open-label single-arm trial designed to assess 10 milligrams of ATI-2138 administered twice daily for 12 weeks in patients with moderate to severe atopic dermatitis. The primary endpoints were safety-related parameters. Secondary objectives included pharmacodynamic endpoints to help clarify the contribution of ITK to the results and assessments of efficacy, including the eczema area and severity or EASI score, and peak pruritus numerical rating Score or PP-NRS, which is a measure of worst itch over 24 hours. 26 patients were screened for inclusion, 14 were enrolled and included in the safety analysis and 12 completed treatment. Excluding 2 protocol violations, one for compliance and the other for prohibited concomitant meds use, 10 patients were included in the per protocol analysis, which is the analysis used for the efficacy results presented. Some of the PD results were generated in a subset of those due to availability of samples from a small number of patients. As you see on Slide 10, the average age was 36, ranging from 19 to 56. The enrolled population was split evenly between male and female participants. Consistent with published demographics, half of the enrolled population self-identified as African-American. Half of the enrolled population had a baseline EASI score above 21, which is considered severe. The rest were towards the top end of the 7.1 to 21 moderate range. The mean baseline EASI score was 23 ranging from 17 to 34. The average time since diagnosis was 14 years. We look to accomplish a lot with this small trial before moving into the next stage of clinical testing beyond confirming the SAD/MAD results. First, we need to understand the safety profile, given this was the first trial of multiple doses of 2138 over 12 weeks. Second, we wanted to help confirm the mechanism of 2138 across several efficacy measures. Third, we used a variety of pharmacodynamic assessments to validate ITK as a therapeutic target and clarify the contribution of ITK to the results. I'm happy to say that we achieved all 3. We'll now take them in order. First, the tolerability profile of 2138 continues to be very clean. In the safety analysis informing the primary endpoint, we did not see any of the side effects typically associated with JAK inhibition, including those resulting in the black box warning. As you see on Slide 11, 2138 was very well tolerated. No severe adverse events or treatment-emergent adverse events were observed in the trial. Most adverse events were mild and resolved spontaneously during treatment. And importantly, there were no discontinuations due to adverse events. Three patients experienced a combined total of 4 adverse events determined to be related to study drug, all but one, which was moderate muscle pain starting on day 24 with no elevation in CDK were mild, transient and resolved during treatment. No safety signals were observed in this trial. Second, in addition to the strong safety results, we saw consistently positive efficacy results with this low dose of 2138 across the predefined secondary efficacy endpoints. In the press release, we called out EASI and PP-NRS, though the other efficacy assessment showed similar consistent and rapid improvements starting at the first office visit. As shown on Slide 12, at week 12, patients in the per protocol population receiving 10 milligrams BID of 2138 experienced a mean EASI score improvement of 61% and a median improvement of 77%. The response was rapid and sustained. At week 4, we observed a mean 71% improvement in EASI score and a median improvement of 72%. And at week 8, the mean improvement in EASI score was 71%, with a median improvement of 76%. In fact, it was also notable that there were measurable improvements observed starting at the first office visit at week 1. This is exactly what we expected to see, an average EASI improvement from a low dose of 2138 that is very much in line with the average EASI improvement of 62% seen across the clinical studies that supported the approvals of JAK and IL-4 and IL-13 inhibitors in this indication. It is important to note that the week 12 mean EASI results in the per protocol population were skewed by a single outlier shown on Slide 13 in red, who demonstrated systemic findings inconsistent with AD, including significant nonlesional inflammation on the biopsy and tape strip data. This was further compounded by compliance issues with the study drug. In the Guttman Lab and independent of the clinical study, this patient was identified as an obvious statistical molecular outlier by more than 4 standard deviations compared to the others. Other than that patient, you see a consistent and rapid response to 2138 across the population of patients in the per protocol population. Excluding this outlier, as you can see on Slide 14, the mean improvement in EASI score at week 12 was 77% and the median improvement was 82%. At week 4 in this population, we observed a mean 77% improvement in EASI score with a median improvement of 73%. And at week 8, the mean improvement in EASI score was 81% with a median improvement of 77%. We also assessed the percentage of patients experiencing a greater than or equal to 4-point improvement in worst itch as measured by PP-NRS, which has been long held as a sign of clinical meaningfulness. And we observed a similar positive response to 2138. In this trial, as you can see on Slide 15, at week 12, 63% of per protocol patients experienced a greater than 4-point improvement. This result is considerably better than the 43% average of patients achieving that level of improvement across clinical studies of the approved drugs I mentioned before. Literature suggests that inhibiting ITK can reduce itch in diseases, including AD. In this trial, given the low dose and the strong anti-itch response, we believe we may be seeing that effect. Given the efficacy signals, combined with the PD data and tolerability results, we believe we have ample room to increase the dose of 2138 in future trials in additional indications. Finally, the PD results were important in this trial and that they further validated not only 2138, but also ITK as a target and the relative contribution of ITK inhibition to the results. Across the board, the PD results were consistently corroborative in that regard, and we want to appropriately spend time on them this afternoon. I will turn the call over to Joe for this section. Joe?

Thanks, Neal, and good afternoon, everyone. The goal of the PD analysis we conducted, as you can see on Slide 16, was to help confirm the mechanism of ATI-2138, understand the PK/PD relationship and to support the clinical results with PD data that help clarify the contribution of ITK inhibition. We performed a variety of in-house analysis, including ITK and JAK3 functional assays, ITK target occupancy determination and immunophenotyping in patient blood. Additional analysis with skin tape strips and punch biopsies were performed by Dr. Emma Guttman's lab at Mount Sinai. Moving to Slide 17. Ex vivo stimulated ITK analysis was carried out on blood from 8 of the 10 per protocol patients, and we observed approximately 90% inhibition of IL-2 and interferon gamma message 1 hour post dose and 40% to 60% inhibition at trough. These data demonstrate significant inhibition of ITK function across the dosing interval and throughout the 12 weeks of dosing. The impact of ATI-2138 on ITK was extended to target occupancy analysis as shown on Slide 18. We looked at target occupancy to assess the extent to which ATI-2138 covalently engages the ITK enzyme in a majority of the per protocol patients. Near complete ITK target occupancy was observed with ATI-2138 at 1 hour post dose, near the Tmax and 60% to 70% occupancy at trough. The ITK occupancy and functional data are consistent with strong and persistent inhibition of the enzyme. Moving to Slide 19. We also conducted ex vivo stimulated JAK3 human whole blood assays to evaluate the impact of ATI-2138 on this pathway. On the left-hand side of the slide, we observed approximately 80% inhibition of JAK3-dependent interferon gamma production 1 hour post dose, which decreased to about 20% inhibition at trough. The exposure response on the right indicates a consistent PK/PD pattern in the AD study in yellow compared with the MAD Phase I study in blue. These data demonstrate that while a strong inhibition of both ITK and JAK3 was observed at the 10-milligram BID dose, the potential exists for an incremental increase in inhibition of both pathways with higher dosing in subsequent studies. We also collected immunophenotyping data on 6 of the 10 per protocol patients as shown on Slide 20. No significant changes in the B cell, T cell or NK cell populations were observed throughout the study, consistent with the lack of global immune suppression and providing further evidence that we can push the dose higher. The subsequent PD analysis focuses on understanding the impact of ATI-2138 on endogenous immune inflammatory protein and mRNA signatures, both systemically and in lesional skin. The O-link immune protein marker subset in plasma is shown on Slide 21. The heat map on the right demonstrates an overall reduction in this set of markers at week 12 relative to baseline. These changes include markers for ITK-dependent Th2, Th17 and T cell activation pathways. Turning to Slide 22. We performed proteome and transcriptome lesional skin tape strip analysis, a minimally invasive method to study changes in gene and protein expression in skin affected by diseases like atopic dermatitis. These analysis were carried out at trough drug levels to better represent steady state. The graph on the right demonstrates significant reduction in the O-link protein immune marker subset across 12 weeks of dosing relative to baseline. This includes an ATI-2138 dependent reduction in multiple inflammatory pathways associated with ITK. For example, we saw downregulation of ITK-dependent Th2, Th17 and T cell activation pathway markers as well as the Th1 and fibrotic pathways. Importantly, as you see on Slide 23, these tape strip data were confirmed with skin biopsies from a subset of per protocol patients, where we saw ATI-2138 induced downward directional trends in the mRNA markers associated with key immunological pathways in lesional skin at week 12, along with the downregulation of both the ITK and JAK3 pathway markers. Once again, with data not shown, we see an impact on fibrotic markers in these biopsies. On Slide 24, we can visualize the impact of ATI-2138 on both the ITK and JAK3 pathways. The second and third columns in each of the 2 heat maps show a similar pattern of reduction of these pathway-related mRNA markers consistent with the expected ITK and JAK3 dual pharmacology. So in conclusion, on Slide 25, we believe that these PD analysis clearly demonstrate modulation of the ITK and JAK3 pathways as evidenced by inhibition of ex vivo pathway-specific stimulation of patient whole blood and sustained ITK target engagement. A significant and consistent ATI-2138 dependent reduction in markers of multiple inflammatory pathways associated with ITK was observed across multiple analysis in plasma, skin tape strips and skin biopsies in addition to a strong downregulation of key ITK-dependent markers. Furthermore, an interesting impact on fibrosis-related markers was observed. We have started to investigate the antifibrotic mechanism of ATI-2138 and how we may utilize this finding in selecting future indications. As Neal mentioned at the outset, these results help confirm the mechanism of ATI-2138 and validate our work on next-generation ITK selective compounds. I'll turn the call back over to Neal.

Thanks, Joe. As I mentioned at the start, although the trial didn't include a placebo control, these results represent a significant achievement for 2138 and our ITK franchise. They provide continued evidence of the strong safety and tolerability profile of 2138, efficacy results in line, if not better, than that of approved products and clear and convincing evidence of the strong contribution of ITK inhibition to these results. As such, they provide validation of 2 programs, which you can see on Slide 26. First, these results provide additional conviction in further pursuing the development of 2138 and other I&I disorders, starting with alopecia areata. Second, these results help confirm our conviction in ITK as a target in the pursuit of our next-generation ITK selective compounds for which we expect to provide the basis for new INDs starting in 2026. I'll remind you that we've executed well in 2025 to date, achieving the milestones we set forth earlier this year, as you can see on Slide 27. Clearance of our 052 IND and initiation of the Phase Ia/Ib program, first; second, initiation of the Phase IIa/b trial of bosakitug; and third, completing the 2138 Phase IIa trial and today communicating the top line results. We expect to complete the SAD/MAD healthy volunteer portion of the 052 Phase Ia/Ib bispecific program later this year as well with data expected soon thereafter. We also expect to conduct an R&D Day with investors in the fall to provide additional information on each of our primary clinical and preclinical programs. We'll communicate time lines and content as the date approaches. Looking forward, we expect that 2026 will be another important year for Aclaris with a number of opportunities to drive additional value. These are expected to include 052 SAD/MAD results early in the year, 052 POC data in up to 2 indications, bosakitug Phase II top line data in atopic dermatitis and as I mentioned earlier, initiation of the Phase II trial with 2138 in another indication being alopecia areata. In addition, we are planning a submission of an IND in the start of a Phase I program with an ITK selective compound. Importantly, we have the cash to execute on all this, with an expected cash runway that takes us into the second half of 2028 and potential opportunities to increase that runway further without dilution. We'll provide an update on our cash position in a couple of weeks on our second quarter financial results as well as a business update. Thanks for your time today. Let's open up the call to Q&A, though I'll remind you that we may be limited to what we can discuss beyond what we've disclosed. Operator, are there any questions?

[Operator Instructions] Our first question comes from Louise Chen with Scotiabank.

Congratulations on the data. First question I have for you is if you could provide more color on EASI and the statistical outlier that you mentioned?

Sure. So Louise, thanks, this is Neal. So in that particular -- with that particular patient, it was independently identified at the Guttman Lab while they were doing the PD analysis of all the work they were doing, whether it was O-link or the biopsies or tape strips that they were about a 4 standard deviation molecular outlier, which essentially means in layman's terms that there was such vibrant and diverse inflammation that it was not typical of what one would see in AD. Now certainly, you can see in non-lesional skin, some inflammation. It's more typical, though, in atopic to see just robust inflammation in the lesional area. So it was interesting because clearly, you can see in that spaghetti plot, we decided to provide you with the actual curves from all the patients to show you the stark contrast and mainly to show why the week 12 migrated up a little bit from the 70% response rate at weeks 4 and 8 is very consistent that it migrated up. And it was because that particular patient not only didn't get better, they got markedly worse. So I think there are some phenotypic things that we saw in the pictures that look like there's more than AD going on, and we're actually still tracking that down just out of interest and definitely to the patient, quite frankly, to make sure that the diagnosis is correct.

And I just had another question really quickly here. What drives the rapid onset of action seen for ATI-2138?

I think it's the combination of -- I mean, we're hypothesizing on this, but I think it's the combination of the JAK3 and the boost you get from ITK. ITK is very potent on Th2, Th17 cells. It hits basophils, mast cells. It does a whole host -- has a whole host of effects. And I really think that this was a great demonstration of that in action because all the data correlated. If you look at all the PD data and there's a mountain of it, I think we received about close to 200, 300 slides. So it was a lot to go through. But when you look at the tape strips, the biopsy, the plasma work, our ex vivo stim work and then you marry that up with the clinical effect, it all makes sense. And the itch effect was great. And we do plan to disclose some additional data in a poster at a scientific meeting and/or at our R&D Day that's coming up. But I can tell you that we did -- we mentioned this in the press release that all the efficacy parameters were rather consistent -- and just as an illustration of that, on EASI-50, we hit 90%, and that was from early on all the way through. And then on EASI-75, we hit 50%. So again, just all very consistent and the itch data was fantastic. I mean I just haven't seen itch response like that in any AD study, quite frankly.

Our next question comes from Raghuram Selvaraju with H.C. Wainwright.

Congrats on this data. Just in a general sense, can you comment on 2 aspects of the positioning for ATI-2138? Do you see atopic dermatitis as being principally a proof-of-concept indication for this candidate and not something that you would be likely to return to in the future at any point in its development? And by extension, is this also applicable to future ITK inhibitors? Or would you consider atopic dermatitis to be a lead indication for one or another of the future ITK inhibitors in the portfolio? And also, could you maybe comment on the potential positioning of 2138 within the alopecia areata indication specifically? Because my understanding is that when we look at traditional JAK inhibitors and their applicability in AA, effectively, patients are forced to keep taking those molecules as long as they want continued efficacy because as soon as those medications are withdrawn, the issue arises again. In that context, do you expect a similar mechanistic situation with 2138? And in that context, would you anticipate that given the expectation of a significantly improved safety and tolerability profile and the avoidance of some of the most troublesome issues associated with the broader spectrum JAK inhibitors that 2138 would be better suited to long-term chronic dosing in alopecia areata?

Yes. Thank you. I'll take that in order, Ram. And it's a great question because I will admit that it's a little bit confusing when we're talking about doing a POC indication with one asset and then saving that indication for potentially a later asset. So let's start with your first aspect of that. Yes, this was designed to be a proof of concept in AD. AD has a lot -- obviously, it's skin disorder. So it comps nicely to what we might expect in alopecia areata just from a skin penetration perspective. So 2138, I think the profile where you have another JAK entrant in a market that JAK inhibitors are not first line in AD, I don't think makes a lot of sense. And so we definitely view this as POC, and we've been very consistent from the day we initiated this study that the next place that we're going to go is alopecia areata. And so we will -- for an ITK selective, and this is important, we can't study AD and everything. The ITK selective with the JAK engineered out would be a very elegant oral solution in a market that doesn't have a great oral solution just yet and has the opportunity to be a first-line oral treatment very convenient. And so we think the ITK selective would be very well positioned, not only in AD, but think of all the Th2 diseases that are the hot areas that other biologics are actually chasing after in respiratory. It would be very relevant for all those sorts of things like asthma, COPD, and the like. And then finally, the positioning in AA that I think you described it well, makes a lot of sense. So the only approved products in alopecia areata are JAK inhibitors. And so those are first-line therapies. They work exceedingly well. Others have been looking at biologics, but the efficacy isn't even close to that of JAK inhibitors. And even with the black box warnings on JAKs, patients don't have another option. So they take these medications over the long term. It's well accepted within the dermatology community, but there are differences. So we know baricitinib, we know deuterated RUX or JAK1/2s. We know ritlecitinib, which is Pfizer's drug, which we talk about a lot, is a JAK3, but it also hits a number of the other TEC kinases. And very, very little on ITK at its actually prescribed dose. So we think there's a wonderful opportunity here to have ITK since we're 44x more potent on ITK than ritlecitinib to serve as a nice booster and differentiate in the market. And so that's kind of how we would think about the positioning. And certainly, given the safety profile that we've already seen, we're encouraged by that. So the next step is to do an alopecia areata study with 2138, much better target product profile for that indication. And then ITK will be reserved for AD, and that could be a real game changer in that space.

And then just 2 other quick questions, if I may. Firstly, given all the pharmacodynamic information you now have about 2138 and how that might guide what you would expect as core characteristics from a pharmacological profile of the next-generation ITK inhibitors, do you feel as though you have a clear sense of how you might position the small molecule elements of the portfolio relative to the biologic elements of the portfolio? And if there is likely to be any overlap or any combinatorial regimen exploration with these 2 categories of medications? And then just with respect to the future for 2138, are you considering vitiligo as a potential additional indication beyond alopecia areata for this molecule at this time?

Yes, we are. And you may have caught that in the deck that we included new data in vitiligo that was done at the Harris Lab up in Boston and just wonderful data there. So we -- and we know ritlecitinib has shown -- has been shown in their Phase II work to be quite strong in vitiligo. Another area where you get a lot of long-term use, huge unmet need and JAK inhibitors really rule the day there. And so people are obviously willing to take those over the long term. So in terms of the small molecule positioning, it's an interesting question. Maybe there's overlap, maybe there's combination strategy down the road. I know there's a lot of talk in the market these days of combining mechanisms and to get through efficacy ceilings and things. So you never rule that out. I do think, though, there are -- they're seemingly distinct populations of patients that tend -- some patients like orals, some patients like biologics and sometimes they cross over, sometimes they don't. But in my experience, having practiced in the past, those patients who like orals tend to like orals. So that's -- I think it's a false narrative when people talk about having to win the entire market. It never works that way, and there's plenty of room in large and growing markets for both orals and biologics.

Our next question comes from Biren Amin with Piper Sandler.

Congrats on the data. Maybe just your thoughts on the alopecia indication. What type of a trial design would you be looking at? Is it more of like a Phase IIb? Or would it be more like a Phase IIa? And can you maybe just talk about time lines around the next study for alopecia? And lastly, on the dosing for alopecia, would you look to going higher than 10 milligrams BID? Or do you feel like that's the appropriate dose for alopecia based on this data set?

Yes. No, good question. So I think right now, the way we're thinking about alopecia is doing something in line with an 80-, 90-patient study, 2:1 randomization, something in that regard. The placebo effect is not really a concern in this indication. And I think for us, we do want to push dose. We think very strongly that -- I mean, we just didn't see anything on the safety side here. So we think it makes sense to push dose, and we think we can drive an even more robust effect. So to me, that makes sense to do in the alopecia study. Time line-wise, we're just finishing up the long-term tox in life, and that's completing imminently. The rat work is already done. The monkey work is done in about the next couple of weeks or so. So just given some -- a few months to get reports together, et cetera, we should be starting that study perhaps in the December time frame, more likely in the January time frame. And these are quick enrollers. We haven't even started yet, so I don't want to give you a time frame. But if anything can be done within a pretty quick time period, it's an alopecia areata study. And these are 6-month studies. You have to really go out to 6 months to get a good idea how it's working. So that's the way I would look at it. But we're excited about it. It's -- I think it's pretty clear when you look at us comping to ritlecitinib, it gives me comfort knowing how much more potent we are on ITK. And we do know, and this is published out there at a poster that Angela Christiano, their group presented about a year ago where they looked into the effect of ITK in their mouse model and sure enough. It didn't demonstrate exactly a JAK effect, but it was a pretty robust effect. So we think that provides a nice, I guess, free boost, if you will, to the molecule's efficacy.

Our next question comes from Martin Fan with Wedbush Securities.

Congrats on the data. Two questions from me with regards to the planned development in alopecia. First, to follow up on the timing. Are there any manufacturing or logistical bottlenecks? Or is it mostly confirming that we're waiting on the NHP data? And then second, on the mechanism. So we have proof of mechanism with ritlecitinib. Is there a reason to believe that hitting ITK might give you extra efficacy? Or are you expecting most of the differentiation to come from the increased potency for JAK3?

Yes. I'll start with the second question first. It's a good question. And I think certainly, 5x potency helps on JAK3, but we are quite a bit more differentiated on ITK. And we also tickle TXK as well. So I think all of it will matter. And I think the encouraging thing is kind of coupling together the work done out of Columbia on ITK, and then looking at the data with ritlecitinib and saying, well, if I'm 5x more on one hand and 44x more on the other, then I ought to be able to drive a better effect. And so that's what we're hoping, and we're going to obviously push dose as well. In terms of the bottleneck, nothing CMC related. It's all just kind of waiting for the long-term tox. Quite frankly, if I would have had all that done last year, I likely would have started with alopecia, but I just didn't have the tox coverage for 6 months.

Our next question comes from Roger Song with Jefferies.

Congrats for the data. Two quick ones. One is related to the dosing and since you have more data to share. So how -- what's the high-level comment on the PK profile and then any potential for QD dosing? And the other one is, I believe on the call, you say EASI-75 is about 50%. And is that the data without the outlier or that's with the outlier?

That's with the outlier in that. So it's actually higher if you exclude the outlier. But it's still -- look, it's a 10-patient study, I think. The data, again, was so good and consistent across the board that -- and I think if you take that outlier out, it's like 55% or something like that at week 12. And so we're very happy with that. On your PK/PD question, if I'm thinking about that correctly, you asked about QD. There is a possibility for QD. And certainly, we'll explore that at the right time. I mean the first job is obviously to demonstrate efficacy. And if one could do that with BID, we do have some other thoughts on higher doses at a QD level and can certainly go there. But that's definitely in the cards, just not probably out of the gate.

Our next question comes from Alex Thompson with Stifel.

This is Seth on for Alex. Maybe 2 questions from us. First, just curious if patients were allowed to use TCS in the trial protocol. And then if you could provide any more color on the trial deviations. Are these coming from patients from the same trial site or different trial sites? I'd just like to know a little bit more there.

Yes. So thanks for the question. No topical corticosteroids in the study. And just -- I know you didn't exactly ask this, but anybody with prior JAK exposure was excluded. However, we did have 1 of the 10 per protocol patients was on 2 different biologics and had failed those Dupixent and tralokinumab. So yes, it was a good subset of severe patients. In terms of the deviations, I think if you're referring to 14 enrolled and then 10 per protocol, we had 2 patients who moved early on in the study. One was actually displaced by the LA fires. So they only got through a few weeks and then were out. We had one patient who violated the protocol by taking a con-med that was prohibited and had a surgery along the way as well. And then we also had the fourth patient that was excluded to get to the 10 in the per protocol was compliance. They just were not taking the drug up to the level that they needed to be. And it was a little confusing for patients out of the gate because we had in the study, it's 10 milligrams BID, but we had 2 pills, 25 milligrams that were supposed to take twice a day. And I think that particular patient just didn't quite understand that. So anyway.

Our next question comes from Thomas Smith with Leerink Partners.

Congrats on the nice data. First on 2138 safety, overall, it's clean in the study, but can you just disclose the other treatment-related AEs beyond the myalgia? And then coming back to the potential for 2138 to differentiate for the other JAKs, can you just clarify, do you think there's a path to avoiding the JAK class labeling with this compound? And when do you think we'll get clarity on that aspect of the competitive positioning?

Yes. I'd love to tell you that, that would be -- because that would be great that we could do that. I go into this just believing that, that's probably going to be a difficult hill to climb. However, I think we've seen this over time that the labeling is a little bit nuanced depending on the JAK inhibitor and where you're at in the class. And I mean obviously, we've all seen SOTYKTU that has really just a slight warning, and that's about it. So I'd like to believe that someone might take a data-driven approach, but there's no way to know that until you get to the NDA review time, unfortunately. But I think that's another reason why I think it just makes sense to position this particular asset in indications where JAK inhibitor use is accepted over the long term and docs are comfortable with it. I haven't run into a dermatologist yet who is squeamish about prescribing these sorts of things long term in alopecia areata patients, vitiligo patients. Certainly, in AD, they're used a little bit differently. But that's what I'd say on that. On the -- your first question on the possibly related AEs that we mentioned. So the first one was the moderate myalgia, and that just continued from, I think, a few weeks into the study, patient finished the study. They didn't discontinue, no CPK elevations. The other 3 were -- one was vomiting and that, I think, was -- lasted a day and again, was mild and -- but was deemed possibly related. And then the 2 other ones were in the same patient, and they were slight -- it was slight lymphopenia and leukopenia just below the lower limit of normal by like 0.1. So they were grade 1. And that was at one time point around week 4 or so. And just as a reminder, these patients had blood draws every week for 12 weeks and normalized on every subsequent blood draw. So I can't quite understand why they even call that possibly related because it was so minute, and there was no other trend in any other patients.

Got it. That makes sense. Super helpful. And then if I could just ask a follow-up question. Just on the itch improvement, really interesting signal. Could you just comment on the time course of that benefit and how early you saw that improvement? And then how are you thinking about potentially incorporating that into your alopecia program? I don't think ritlecitinib has any data on the label for pruritus, but is there potential for you to design your program to maybe get that on the label and provide another differentiating point?

Perhaps it's not a big feature of that particular condition, but it was right out of the gate. And you would expect that with this mechanism that it was robust and deep starting at week 1, week 2 and just carrying through. In fact, at some point, we're getting north of 70% in terms of the number of patients getting greater than or equal to 4. And so it was quite remarkable. And again, I think it's one of the higher itch parameters ever reported, albeit it's 10 patients, of course. But that was quite a strong feature, and it makes sense with the mechanism. So we weren't surprised.

Congrats again on the data.

That concludes today's question-and-answer session. I'll turn the call back over to Dr. Walker for his concluding comments.

Well, thank you, everybody. We're really excited about these results, not only because it validates 2138 specifically in certain indications, but also because it validates the ITK franchise, which we view as a potential game changer in Th2-driven diseases like atopic dermatitis and various respiratory diseases. Certainly, more to come throughout this year, and we'll give some guidance on our expected R&D Day later in the fall and really appreciate your time today, and we'll speak again soon. Thank you.

This concludes today's conference call. Thank you for participating. You may now disconnect.