Hello, everyone, and welcome to this latest in a series of fireside chats here at H.C. Wainwright's Inflammatory Skin Diseases Conference. My name is Ram Salvaraju, and I am a Managing Director and Senior Equity Research Analyst in Wainwright's Equity Research Department. I'm joined here by a Clarice Therapeutics, a company that trades under the ticker symbol ACRS on the NASDAQ, and which we cover with a buy rating and 12-month price target of $16 per share. It's a pleasure to have members of the Claris Therapeutics Senior Management Team here with us today. Folks, welcome. So I think it would be helpful, Neil, you're the CEO of the company. Perhaps you can just give us a brief overview of the company's lead candidate, ATI052, and the rationale for the buy-specific approach that you've taken here, particularly in the context of the utilization, broad utilization, one might say, in inflammatory skin disease, particularly atopic dermatitis, of established monotherapies, and how the company hit upon the specific targets that are being addressed with ATI-052.
Sure. Well, I'll start and I'll hand it off to Hugh. But we're really excited about 052. Two, we obviously have already put out SAD-MAD data that show potential for three-month dosing interval and PD effect that would put it in a best-in-class category. We have two additional cohorts that we will be putting out, or three additional cohorts that we'll be putting out later this month as a final update to the SAD-MAD work. and we already have two 1B studies in flight, one in severe atopic dermatitis and one in asthma. And we already messaged earlier this year that we'll be rolling into a 2B in asthma as the first larger study with that construct. As to the specifics around the bispecific construct,
I'll pass that to Hugh. Thanks, Neil. So yeah, as you pointed out, We think it's a best-in-class approach because not only do we have a T-slip antibody that is a very long retention time with the best potency in the class that we tested against other candidates and 70 times more potent than tezopelumab, and on the IL-4R side, the reason that was chosen in building this construct is because IL-4 and IL-13 both drive Th2 disease. And we feel it's important to neutralize the impact of both of those cytokines on the immune path or portion of this pathway, rather than leaving IL-4 on the table that we've seen in other constructs that have been built. And so in the end, our molecule, which is a T-slip IL-4R bispecific, has really the potential, as we saw in the healthy volunteers that Neil mentioned, 100% inhibition of T-slip activity and IL-4 and IL-13 activity downstream from inhibiting chemokine secretion. So we believe that this is a best-in-class approach that has synergy relative to the monotherapies that have been on the market, TESI and DUPI in this case. But in AD, of course, only DUPI is approved, not tezopelumab. So that's the rationale for going after the targets that we did and why we believe it's going to be better than monotherapy alone because of the increased synergy that we saw with the potency that we put out a while back where our bispecific is four times more potent than the combination of DUPI plus TESI combined.
So to that point, given the nature of the differentiation that you see pharmacologically, pharmacodynamically, what would you anticipate, Hugh, might be the impact clinically on efficacy
parameters like IgA and EZ? Yeah, so the nice thing about hitting this at the top of the Th2 cascade with T-slip, as we know, T-slip is pleiotropic in its activity. Dendritic cells and ILCs, mast cells, and etc. We believe we'll be able to show activity in T2 low, as TESI does. And at the same time, we would expect even greater activity than what we're seeing with DUPI in AD, for instance, where they show two-thirds of patients with a 75% response in EZ, and IGA's zero ones of 35 to 40 percent, we're expecting to see a much more enhanced activity profile. So we would expect early and late durability of activity that would exceed either DUPI in AD or TESI and DUPI in asthma. And on the, you know, dose and convenience side,
that clearly is a significant factor in the context of deployment of biologics for treatment of chronic inflammatory diseases like atopic dermatitis. So perhaps you could talk about the phase 1a interim results that have been generated with ATI052, and in particular also the function of the molecule as this pertains to the possibility of significantly less frequent injection schedule and how this plays into the commercial opportunity. Maybe, Hugh, you can talk about the pharmacodynamic profile and the potential dosing frequency reduction, and then maybe, Neil, you can comment on what implications this might have commercially. Yeah, so what we showed and
put out recently was that this bispecific has 26-day half-light as a minimum, and in fact, the accumulation ratios that we saw after the fifth dose in the MAD portion of the study actually predicts more of a 40, greater than 40-day half-life. So we're at least three times maybe longer half-life than DUPI. And so that allows us to think about from a pharmacokinetic perspective going out at least two to three months in dosing interval. But also the pharmacodynamic half-life is also considerable here and needs to be taken into consideration. And as Neil pointed out initially, we were seeing up to three weeks of 100% inhibition of IL-4 stimulated or T-slip stimulated TARC. And in order to have max effect, we don't need 100% inhibition. And we believe with our MAD cohorts that we can actually get out to three-month dosing with substantial inhibition of both the top T-slip and the bottom of the cascade with IL-4 and 13 inhibition as well.
Yeah, and to your question, Ram, on the commercial prospects, you know, certainly there's a big jump going from, you know, let's say a dupy dosing interval of every two weeks and other flavors of that to now talking about every month, every two months, three months. You know, we really feel like the sweet spot for INI diseases, particularly diseases that tend to have flare and quiescent periods in between is really in the three-month time period. There's a lot of practical issues that from a practitioner standpoint and also just patient differences in terms of whether somebody is going to break through. When you start talking about six months or longer in some of these indications, you know, I can get my head around perhaps psoriasis and very, very stable patients when you're talking about six and even 12 months. But, you know, for a lot of these diseases, I think Q3 months makes sense. And there's really not a practical difference between four injections and two. So, you know, we have designed this program to make sure that we're concentrating on optimizing the efficacy and safety first. And then, you know, certainly the dosing interval plays into that. But the reason that patients, you know, go on and stay on medications is because it works, right? So I think that that's the key. And we're happy that our biospecific construct will support three-month dosing?
I think it's important to emphasize for our audience just how important focusing on validated targets, both scientifically and clinically, happens to be in immunology, which is a very complex area, and the degree to which there has been notable success in the INI space for an extended period of time, particularly when we look at, you know, biologic drug development in terms of focusing on validated targets. And I think that's an important feature of the ATI052 platform, which clearly focuses on targets that have been well-validated by previous work and validated also commercially. I also wanted to touch upon something that you just mentioned, Neil, which is the safety aspect. There was no conjunctivitis observed in the SADMAD Healthy Volunteer cohorts. And since the mechanism of action of Dupixin in particular is often associated with ocular surface treatment emergent adverse events, you know, maybe you could comment on the specific engineering in the ATI052 molecule or the FC region in particular that could reduce the risk of these off-target effects. And if you could perhaps also comment on how this construct could stack up against DUPI in the context of recent emergent reports of a small but measurable elevation and risk of development of cutaneous T-cell lymphoma in patients who have been treated with DUPI for an extended period of time.
yeah i so i maybe i'll comment and you can speak to the specifics of the molecule but um you know i think so far so good we haven't seen uh any conjunctivitis and i think if we go back and try to compare ourselves to maybe the most similar molecule out there which would be pfizer's tri-specific it seems to me that they also alluded to um having either no conjunctivitis or very low amount of it in their study. We don't know the exact number, but I mean, if I were to look at it from a biologic standpoint, it could be that hitting two parts of that pathway, you know, or again, not only working synergistically, but also maybe being helpful on the safety side. Those are just guesses. You know, we hope that as we proceed, we see no conjunctivitis or very little. Um, and in terms of the, uh, um, you know, the, the cutaneous lymphoma, um, I, I'm just not aware of, you know, a very high risk in that regard. Um, I'm sure there are some, some case reports there, but again, we, we just have a different construct. The bispecific's very different than, then dupie and um q do you want to comment on the construct yeah you know it's interesting
because when you look at the conjunctivitis um in terms of the etiology it's really hard to nail down and there's a lot of review out there around il-13 being a driver of that and causing tears and the like and we're inhibiting tears um but at the end of the day we think that the t-slip molecule portion of the molecule is actually helping to offset some of that at the top end of the cascade. But because the etiology is not quite known, it's still more of a measured value. And we were happy at least initially not to see any conjunctivitis. And we'll be seeing output from our 1Bs and AD, you know, by the end of the year. So we'll have some good patient data there
as well. Maybe we could shift just briefly to thinking about endpoint sensitivity and specific endpoints that you will look to use to evaluate 052 and potentially bench in the context of the competitive landscape in atopic dermatitis. And in particular, I was wondering about the easy outcome measure in comparison to endpoints that specifically address itch, like PPNRS. So maybe you could talk a little bit about which of these types of outcome measures you expect to be particularly pertinent in evaluating and elucidating the efficacy profile of a drug like
ATI-052? Well, you hit the nail on the head. I mean, the itch component is a key one for us. You know, we think obviously that's the main symptom and it's kind of the early, if you can get rid of itch early, then you start allowing the skin to heal and just decrease inflammation. So for us, you know, looking at both EZ and itch in tandem and, you know, wanting to see not just a small benefit, but, you know, something on the 10% side, you know, just a lift in terms of that efficacy. And I also want to, by the way, see something that's, you know, hopefully more rapid, you know, because that's another need in the market. Again, you know, these AD in particular to treat the flare disease. So the quicker you can get rid of that flare, the better off the patient is. So I think, you know, we'll be paying close attention to the itch scores early on, and this is an eight-week primary, but we'll be following the patients out 10 weeks post that day 57 primary. And, you know, we chose that because we think we can see something that early, which I also think will be a pretty nice advantage. And just as a reminder, We're treating all severe patients in this first study.
Also, just wanted to revisit one thing regarding the dosing and administration. Clearly, since Dupixen has been on the market for an extended period of time, you know, there are now both pre-filled syringes as well as these, you know, invisible needle pens. And I'm assuming that ultimately formulation work with ATI052 would enable the drug to be amenable to be presented in all of these types of forms from an injector presentation standpoint.
Is that correct? Yes, it's exactly what we're pursuing. Yep. Okay. Again, going into, you know,
now the kind of more complicated aspect of the competitive landscape, you know, bispecifics versus trispecifics. You know, this is a canonical, you know, kind of ongoing discussion, But I think 052 presents a particularly unique way to address this debate for, you know, elucidating purposes for our audience. You know, there are multiple competing multi-specific time modal constructs out there currently in the clinic. Perhaps the most notable one, which reported favorable mid-stage results only recently, was Pfizer's Tilrecamig. Sanofi has Linsecamig. These are multispecific antibodies targeting T-slip and IL-4 and IL-13. But I think it would be helpful for you to point out to our audience how a bispecific construct can both emulate and indeed overhaul a trispecific construct and the manner in which the specific uniqueness of your bispecific construct might actually provide advantages that cannot be achieved with existing trispecific constructs.
yeah so yeah we um you know the way our molecule was designed is it's a two plus two design and uh and so uh we actually have uh two binding you know fabs that bind tslp and each of those fabs buying tslp across the entire tslp molecule so it completely binds at the nnc terminus and that's why we have that 400 hour residence time on t-slip by the t-slip part of the molecule On the bispecific, to your point, Ram, is, you know, by inhibiting IL-4R, we also then inhibit IL-4 and IL-13. So in effect, it is a trispecific in terms of its inhibitory activity. But we have the advantage of the IL-4R binding portions, the two single-chain FVs. We also have two binding sites there that combine IL-4R. And so we have a bispecific that has four independent binding sites, two to T-slip and two to IL-4 receptor, and they all operate independently and can be fully saturated, and they don't affect the affinity of the binding to the other target when the first target is bound. And so a molecule like Pfizer is monovalent to each of those three targets, whereas, again, we're divalent with biparatopic approaches on T-slip and independent binding at all four binding sites. So we really have a very highly optimized molecule along with the enhanced half-life with the YTE extension that, as I mentioned, exceeds 40 days if you look at the accumulation factor. And that's also a big advantage over the Pfizer molecule, which basically in their PR said that they could dose up to one month. And so I'm assuming that their half-life is much shorter than that. So many different advantages to this construct.
I think it might be helpful for you to also comment on how you're looking at the overall biologics portfolio inside a CLARIS. Clearly, ATIO52 looks to be positioned as the flagship, but maybe you can talk a little bit about how you see ATIO52 relative to both Sacitug, which was obviously the predecessor and that informed a lot of the work that you're now doing, as well as how you see the overall biologics portfolio being built out. Another aspect, of course, is that Claris is very unique among biotech companies in having both an active biologics development portfolio as well as a small molecule portfolio and longstanding discovery expertise in the small molecule world, particularly from a kinase modulation standpoint. So I think it would be helpful for you to talk a little bit about how you see sort of the two halves of the whole, so to speak, coming together, potentially allowing you to evaluate combinatorial regimens, whether sequential or applied concomitantly in the context of inflammatory skin disorders, as this pertains to elements of your biologics portfolio, as well as the small molecules that you have in your pipeline.
Yeah, no, those are great questions and points. And, you know, so I think simply, you know, we look at how the biologics portfolio has evolved. Of course, we have a study ongoing with the T-slipmab. And, you know, if that's positive, we do believe that a very safe T-slip might have a place in the treatment of AD patients across the spectrum, just as background therapy. And, you know, we'll see that readout, you know, towards the back part of the year. But certainly as the buy specific keeps generating good data, I think you'll see us investing more there, particularly if we generate the data we expect, which is that boost in efficacy and we get that one plus one. And so I think that's where the dollars will flow mainly, and that's what we're planning already, at least the first 2B study in asthma that would kick off kind of at the turn of the year. So that's how we think about the biologic side. On the oral small molecule side, we have a couple of assets there. One is the next-gen ITKs that are headed towards IND, and then we have 2138, which is quite an interesting molecule. It inhibits the T cell receptor function like a cyclosporine might, and it also inhibits downstream cytokines that are driven by JAK3. So there's a lot of indications one could go after there. And I think you bring up, as usual, a great point, you know, in this world where you're hearing a lot about combination approaches and therapy, and certainly dermatologists use polypharmacy all the time. And I think it's a great way to think about things where if you really want to get somebody across the finish line, let's say an AD quickly, you put out the fire with a hammer like 2138, and then perhaps you have the bispecific or the T-slipmab or combinations thereof that could be more baseline kind of maintenance therapy. And those approaches 100% exist in dermatology and many other therapeutic areas. And I think it's something that we've been thinking about and makes a lot of sense if you can develop regimens that take care of the acute and then handle the durability or maintenance over the course of the year.
Yeah, I think it's important to emphasize for our audience that not only is this a unique aspect of the eclaris value proposition the ability to potentially pair and combine mix and match biologics with small molecules but it's also appropriate to maybe think about a more comprehensive and holistic approach to symptom management and indeed the underlying disease pathophysiology when one thinks about potential combinatorial regimens or sequential regimens that involve, you know, as you pointed out, Neil, you know, a hammer-like approach with a small molecule combined with an upstream approach like an anti-T-slip. I was also wondering just, you know, before we leave the biologics topic and talk a little bit more in depth about the small molecule portfolio, you know, more directly, with respect to the biologic lead candidate, are you thinking about a specific clinical readout that might be a core triggering mechanism for a future business development transaction or partnership that would further optimize the value of this asset? And if so, what kind of clinical readout do you think is likely to achieve critical mass, so to speak, in the eyes of potential strategic
partners? Yeah, you know, I would say that we've post putting out the sad, mad data and showing the wonderful PK and PD that Hugh already mentioned has generated interest. And, you know, certainly I think we always have to be aware of that as smaller companies, because once you know that you've proved out the concept, then the whole effort revolves around stepping on the gas and putting up multiple indications. And we, of course, have already messaged, you know, doing a phase 2B in asthma, but, you know, with a bigger kind of balance sheet or a large partner, you know, one might, you know, endeavor to go after four indications or five indications at once, and then it just becomes kind of a speed to market. So that's always in the back of our mind, like how to stay once you generate a POC, how to continue to maintain your lead if you feel like
you have best in class potential. And I would, of course, draw folks attention to the fact that the INI space has been one of the most avidly sought after areas by strategic acquirers. You know, we all remember the examples of companies like Prometheus and Televent. So clearly it will be very interesting to see what happens next with ATI052. If we could just switch gears for a second and touch upon some salient features of the small molecule portfolio, I think it would in particular be helpful to educate our audience on three aspects. How you see 9494, which is a JAKS-bearing ITK inhibitor versus ATI-2138, which you mentioned earlier, effectively has a dual mechanism targeting ITK and JAK3, and how you're thinking about indication prioritization and overall development prioritization of these two molecules. And then also, if you could talk a little bit about how you see the differential indications of things like alopecia areata and vitiligo on the one hand versus lichen planus on the
Yeah. Roland, do you want to comment on that?
Yeah, sure. I can start talking a little bit about the distinction of the ITK-specific and the dual ITK-CHK3 inhibitor. So ATI-2138, that's our furthest advanced small molecule inhibitor. That's an ITK-CHK3 dual inhibitor, as you're pointing out, has a very unique pharmacology. The way to think about it is probably like a bispecific antibody. It includes, you know, the JAK3 inhibition part, which, again, the closest competitor is Ritlacitinib, and includes the ITK inhibition, and the closest is Zoccalitinib from Corvus. And so, by inhibiting ITK, what 2138 does, it inhibits T-cell receptor signaling on CD8, cytotoxic T-cells, and CD4 T-cells, which is antigen-driven, and then with JAK3 inhibits the cytokines, which really, to drive the T-cell survival, you know, proliferation, differentiation, and activation. So, we believe, again, this is a great molecule, has that dual activity. And because CHAC3 and ITK are really restricted to the immune system, it's also quite different from the other CHAC isoforms, which are CHAC1, CHAC2 are widely expressed in many different tissues. So, we have a very potent and powerful molecule here. It's way more potent than Ritlacitinib on Shag3, about five-fold more potent than on ITK, about 50-fold more potent than the Corvus compound. So, and then we have, Neil, you want to jump in here?
Yeah, sure. So, and in terms of indications, Ron, the way we think about it, that, you know, we're trying to pick indications that can leverage the unique pharmacology in 2138. We've taken a while to kind of down select to that. We'll be going live with that towards the end of this month, but you are correct. We've talked about alopecia, some scarring alopecia, vitiligo, you know, tougher to treat diseases that would benefit from having a dual mechanistic approach that will be very different from just an ordinary JAK because we are going through the TCR pathway as well as JAK3, but also indications like lichen planus. We put out a fair amount of data on that indication back last October during our R&D day. I think, you know, what's exciting to us about lichen planus is that it really is a great mechanistic fit for the dual mechanism of 2138, and there's kind of a spectrum of diseases that one can tackle within that category. They're basically lichenoid dermatitis under the microscope when you look at it histologically, And that would be both oral and cutaneous lichen planus, which are in the same category, but kind of different, a little bit different diseases. And then, you know, lichen planopilaris, which is a scarring alopecia. So one can do a study where you look at all three of those indications and they're distinct opportunities within the market and there's nothing approved for any of them. So, you know, I think that's where we're leaning, but we'll be formalizing all that at the end of the month. And I think, you know, relative to 94-94, when you're talking about engineering out the Jack-3, the whole goal is to get Jack-like efficacy in a pill without the safety baggage, right? And, you know, just like somebody with an oral stat 6 may say I have an oral dupie, well, we'll have an oral jack with jack-like efficacy that tackles the heterogeneity. So I would go after every indication that dupie's in with that molecule.
Very exciting. So I think we're going to have to leave it there, unfortunately, but really appreciate all of you taking the time to talk through the salient aspects of the Aclara story with our audience. Clearly a very exciting company with multiple future clinical outcomes and data readouts coming up and clearly additional information that we can look forward to with regard to the small molecule side of things. So definitely want to thank all of you and thank you to our audience for their attention.
Thank you. Thank you.