Exactly. We've gotten started.
Thanks, Katie.
Awesome. Well, thanks so much, everyone, for joining us here for the last session of the day, and thanks to the team from Aclaris. Maybe I'll turn it over to you guys to introduce yourself and give us a brief overview of the company.
Great. Let's start with Kevin.
Kevin Balthaser, CFO. I've been at Aclaris now for six years. The first five of that predominantly spent running, finance accounting operations for our former CFO. I took over for him in January.
Joe Monahan, CSO of the company. Started with Aclaris in 2017, when they bought the company that I started back in 2010 called Confluence Life Sciences.
Douglas Manion, CEO. I joined as COO in July of last year, with the intent of having an orderly transition of Neal Walker, our founder, to become chairman, and that occurred in January. Quick story about us. Neal and Frank Ruffo, who was Kevin's predecessor, founded the company in 2012 to be kind of a spec derm play, and they have a long history of launching companies, finding products that they can sell and then being taken out. That was plan A, you know, for version 1.0 of Aclaris. They actually did acquire a couple of assets that were being sold in the mid, you know, 2010s. During that time, they actually were looking to have a topical JAK to develop.
They actually reached out to Joe and his friends at Confluence to begin developing that. As a hedge, they bought Confluence in 2017. Then by 2019, we realized that the derm products were just not selling well enough. They were divested. Of course, Joe brought with him not just unbelievable discovery prowess, both biology and chemistry, but also a stable of assets, the topical JAK, as well as others, including ATI-450, our lead MK2 inhibitor. We pivoted from being a derm company to an I&I company, focusing on clever ways to impact the human kinome, to impact serious diseases with serious unmet medical need. Our lead asset, the MK2 ATI-450, is in phase IIb testing for rheumatoid arthritis after a successful phase IIa that read out last year.
Our topical soft JAK, ATI-1777, is in phase IIb research for atopic dermatitis. That should read out in the second half of this year. A novel approach to blocking ITK/JAK3, a drug called ATI-2138, is completing a healthy volunteer MAD study. We'll have PK/PD data on it in the coming month or so. Lastly, our backup MK2, ATI-2231, is initially being validated in solid tumors. In partnership with an academic institution, we're about to have first patient dosed in an all-comer Phase IIa solid tumor study. The goal of it in cancer would be metastatic breast cancer or pancreatic cancer. ATI-2231, we're also fast-tracking to get an I&I IND. It could actually be tested for other indications in line with what we do with 450.
Extremely busy year. I think we punch way above our weight class in terms of discovery and development.
Great. Maybe we'll start with ATI-450 or zunsemetinib. First, let's just start with the structure of the drug. It inhibits MK2. That's been traditionally pretty difficult to target. What are the challenges that you had to overcome as a discovery team, and could you walk us through some of those features?
The p38 pathway, of which MK2 is part of, has been of interest to drug companies for the last 25 years, particularly focused on p38 as a target. p38 turns out to be a non-optimal target for two main reasons. One is that inhibitors tend to have some safety liabilities, in part due to the fact that p38 has over 70 different substrates. Secondly, in phase II studies, p38 inhibitors demonstrated a lack of sustained efficacy, particularly in RA studies. In a 12 week RA study across a number of different companies with a number of different chemotypes of p38 inhibitors, they all saw the same thing, with an initial reduction in inflammation in RA patients. After continued dosing, after two to four to six weeks, you see that reduction in inflammation come back to baseline levels.
It had transient effect on the anti-inflammatory effect in RA patients. MK2 is one step downstream from p38. It is the kinase that is specifically associated with the pro-inflammatory cytokine modulation of the pathway. It's a positive impact there, and it's much more selective than a p38 inhibitor that has all these different substrates. The problem is, as you said, MK2 inhibitors historically have been very difficult to develop because MK2 is a difficult target to drug. For 10 years, a lot of drug companies were involved in MK2 inhibitor development, yet none actually even made it into the clinic, much less through the clinic. We started the work when we started Confluence back in 2010, and it was based on a co-crystal structure that was published on a p38/MK2 complex.
The two proteins form a complex prior to p38 phosphorylating MK2, and there's the interface of that complex that we targeted. By targeting that interface, we're able to generate molecules that specifically bound to the complex, didn't bind to p38 by itself or MK2 by itself, and also didn't bind to p38 when in a complex with other substrates. It's very specific for the p38 and MK2 complex, and in binding to this interface, it locked MK2 to an inactive conformation. It blocked the signal transduction at the MK2 level, allowing p38 to continue to do the things that it does, except for regulating these pro-inflammatory cytokines. The result of that was ATI-450, and we demonstrated pre-clinically in a number of different cellular studies, that we maintain the ability to knock down these key cytokines, such as TNF, IL-1, IL-6, IL-8, and IL-17.
We had efficacy in a number of different disease models, inflammatory disease models, including those for IBD, RA, CAPS, for example. We took it into clinical study, as Doug said in the phase IIa RA study, the two things we wanted to demonstrate is ATI-450 safe in RA patients over a 12 week dosing? Does it, or does it have some liability similar to p38? We demonstrated that it was safe, didn't have the p38 liabilities. Most importantly, does it inhibit inflammation sustained over 12 weeks? We demonstrated with a number of readouts, including CRP reduction, cytokine reduction, measures of clinical efficacy, that we had a reduction in inflammation. That reduction was maintained for 12 weeks.
That's where we are now, and now we're getting the readout later this year in the phase IIb study.
Great. Maybe let's just quickly do a refresher on the clinical studies we've seen so far. One in rheumatoid arthritis that was successful, another in hydro... I'm not even going to try to say it at this time of the day.
It's-
In HS, that didn't pan out. Can you just remind us what we saw and how you interpret that as it relates to the coming study?
As mentioned, you know, the initial kind of de-risking indication was RA, for the reasons that Joe mentioned. The study was very successful, relatively modest in size, the point estimates for ACR20, ACR50, and ACR70 were in line with what you see with JAK and TNF. You know, we saw a good safety profile. That was the impetus for us to go into phase IIb in it. My predecessors decided to also go into two additional indications. Psoriatic arthritis, which is another spondyloarthropathy. Typically, things that work in RA work in PSA, they decided to do that study anyways. They took a bit of a flyer going into hidradenitis suppurativa.
Nice job.
I have, I've had way less work than you today. There it was all based on the theoretical thinking that, you know, we hit TNF, we hit IL-17, we hit IL-1, we hit IL-8. IL-17s and TNFs have been shown to work. IL-1 and IL-8, you would think would be useful in terms of HS. The challenge with HS is that there's no validated efficacy model, predictive efficacy models. Unlike RA and IBD, where you have a pretty good idea that at least there is a reason to believe it's gonna work based on in vivo efficacy models, that is not the case with HS. They took a bit of a flyer. It turned out that, you know, the study was well executed.
It was a phase IIa study of 95 patients. It read out in March of this year. What we saw was minimal activity in terms of the primary outcome, which is a decrease in active nodules from baseline compared to placebo. There's two reasons for that. One of them is that placebo had an unbelievably good day. If we did a single arm study just with placebo, it would've been the best drug ever in HS, even though we know it doesn't work. Comparing to that very high placebo rate, nothing, you know, even if we, if we had tested 1,000 people, it would not have mattered. Also, we looked at individual results and compared it to PK and PD results for the people who were on active drug.
You'd expect, if we had any impact, that the higher the systemic exposures to our drug and the bigger the decrease in cytokine, endogenous cytokines, the more activity you would see. It was a complete flat line. There was zero correlation. There's a disconnect between the good effect that we have on cytokines systemically and what's actually going on in the skin of this disease, which we don't fully understand. I don't think anyone really understands this disease, but it's very clear that we don't have enough activity to continue prosecuting for it. The good news, though, in the study, is that the PK was exactly as predicted, based on healthy volunteer studies in the phase IIa RA study. The PD was exactly what we predicted in terms of ex vivo simulation, and Joe can elaborate on that, as well as endogenous cytokine knockdown.
Most importantly, the safety profile was clean. You know, we have a very, very clean non-human preclinical tox package, including six and nine month mammal studies that showed no dose-limiting toxicities, which is great. There's yet to be a signature toxicity that we're worried about in phase IIb, and I've developed scores of drugs. I've never had a drug look this clean. All that is kind of positive, we feel, read-through for the phase IIb RA, and we don't see any negative efficacy read-through from the lack of efficacy. Anything you want to kind of elaborate on regarding the cytokines?
Just with the HS study, similar to the RA study, the ex vivo stimulated cytokines from blood were inhibited by ATI-450 on day one and day 84. The pathway was maintained as far as the dependence of the pathway, cytokines on the pathway. The endogenous cytokines, they weren't elevated as much in HS patients as they were in RA patients. In both cases, the endogenous cytokines were reduced to healthy donor levels. Very similar systemic effect on cytokines in both studies.
Great.
Just an important, I think, data point that might contribute to understanding this is what we saw with HUMIRA's HS program. They did a phase IIb of standard dose HUMIRA, versus placebo, versus double frequency dosing HUMIRA, and only with double frequency dosing did they see a clinically significant impact, and even then, it was relatively modest compared to the placebo effect. It probably works. It doesn't work gangbusters, but at least for the TNF pathway, you got to hit it with a sledgehammer to have activity. The value proposition behind our approach is that we knock down multiple pathways, including TNF, but sub maximally. We think that there'll be synergy, additivity to synergy from an efficacy perspective, but we think that there'll be enough residual function of each cytokine pathway that hopefully will have a better safety profile.
Most importantly, we won't see the issues that you see with TNFs, for instance, in terms of increased incidence of lymphomas or opportunistic infection. Thus far, the safety database in humans bears out our value proposition on both fronts, and we're hoping that's going to carry forward.
Yeah. You mentioned the pretty clean profile. A couple other things that we've seen are headaches, dizziness, CPK. Maybe you could just contextualize those events to help us understand the mechanism.
Yep. The mechanism is always tough, but the one thing that we're seeing that we think is probably drug attributable, is this very transient, mild headache and dizziness that's seen after the first dose or two, but which basically goes away. It was seen in well-controlled, healthy volunteer studies, SAD and MAD. These are patients who are basically hospitalized for one to 14 days. It was seen fairly consistently, and it was seen kind of in a dose-related effect, and it's at a higher rate than placebo. That appears to be real, but it is just a nuisance toxicity. In the MAD, where everybody goes through, in every instance, it appeared and disappeared within a day or two. We did see some headache in the RA phase IIa study. Similarly, it kind of went away.
In the HS study, there was an incidence of someone who had a headache day one, who actually left the study. It's unfortunate that they did that because if they had dosed through, they probably would have been fine. That is the one toxicity that we're aware of, where we have basically instructed the investigators for ongoing studies like the RA and psoriatic arthritis studies, to be looking for this and to pre-warn their patients. If there's kind of an anticipatory expectation that they know if it occurs, it's going to be transient and mild, and it may mean they were randomized to active as opposed to placebo, we're expecting to see much less drop off because of it, if any. That's good. CPK is different. With CPK, we've seen zero preclinical signals.
In short term and longer term, now six to nine month non-human mammalian tox studies, we've seen zero impact on muscle. No, you know, symptomatic toxicity of the animals, you know, not ambulating or moving around properly. No indication of biochemical toxicity, so no elevations of CPK or other muscle-relevant enzymes. Most importantly, zero evidence of muscle toxicity on histopath. It would be hard to understand if you had that clean a profile preclinically at exposures in excess of that seen in humans, that you would have an issue in humans. In the RA study, there was no CPK signal. In the HS study, what we saw were blips of CPK seen both in active and placebo.
In fact, if you looked, there were 26 patients who actually had an increase in CPK at at least one visit, 11 in placebo, 15 on active. In no instance was it symptomatic, so no muscle weakness, no muscle pain. In every instance where people dosed through, it went away at the next study visit. All the synthesis of all of this information convinces me that we don't have an issue with CPK. It's bolstered by the fact that we have a DSMB that oversaw the HS study, and it's also the same DSMB overseeing the RA study. They're looking at ongoing, unblinded safety data, and they have not raised any concerns.
You know, we did a Q1 earnings call to basically share with everybody more detail on everything we learned from the HS study in terms of PK/ PD, and safety. If you go to our website, there's a very detailed slide deck that kind of goes through this stuff in even more detail, but we think that this is, there's no there on CPK.
Great. As we look ahead to the phase IIb trial, which I think you just announced completion of enrollment. Maybe remind us what the trial design looks like, any key aspects in terms of inclusion, criteria, powering, assumptions, et cetera.
Yep. It's a phase IIb study, three arms, 280 patients. It's a one to one to one randomization, placebo, 20 mg BID, 50 mg BID. The 50 mg BID dose was the one that was used in the successful phase IIa study. We designed the phase IIb to be as close to the phase IIa as possible, with one major exception, well, there's two major exceptions. One of them is that we're testing two doses, but the second one is, whereas it was an all-comer U.S.-based study in phase IIa, that resulted in half the patients having JAK and/or TNF experience, and half being naive to anything but methotrexate. The phase IIb, we proscribed that there could not be more than 20% of the patients who had JAK and/or TNF experience, and 80% were on methotrexate, but not exposed to other systemics.
That is going to skew, obviously, towards the naive population that tends to do better. They did do better in our phase IIa study, those are the differences. In the U.S., most of the experienced patients came from U.S. sites, the experienced strata was actually completed a couple of months ago, we just completed the naive study with most of the patients coming from Eastern Europe, notably Poland.
Okay, great. As you think about success scenarios for that study, first of all, like, what do you need to show in terms of in comparison to JAKs and the antibodies that are already there?
Three things we're looking for. One of them would be a replication of the good efficacy we saw in phase IIa, and if anything, with a skewing towards more naive patients, the point estimate in terms of, for instance, ACR20, which is the primary endpoint on which the study was powered, should go up. I think that you want to be in the ballpark of TNFs and JAKs. By the way, on that, if you have read the ACR guidelines in terms of treatment for RA, they're now moving towards a thing called Treat to Target, which is basically cycling through mechanisms until you find one that gets people down to very, very low active joint count.
Whereas before you'd put somebody on it for a year and then kind of look for evidence of, for instance, radiographic improvement, now the new way to do it is find, you know, get this symptomatic joint count down as low as possible just by trying stuff. Having efficacy that's in the range of JAK and TNFs, coupled with good safety, which should put us, you know, easily within the arm and terrain drugs that we're going to cycle through. Number one is competitive efficacy. Number two is a continuation of the good safety profile and a reason to believe that we'll not have a black box warning. If you look at our profile currently, it would defy logic that we'd have, you know, any onerous safety labeling.
Third, and people kind of miss this, is we'd love to have dose clarity coming out of the phase IIb, such that unlike the JAKs, we could take a single dose into phase III. That would save, you know, a lot of money and probably a year in terms of phase III execution.
Great. That's a great segue to my next question, which is pending good results, what do you view as the next steps for this program?
Part of bringing me on board, and we also brought in a rheumatologist, Gail Cawkwell, as our CMO last summer, we wanted to be able to design and prosecute phase III for all of our programs internally. The one caveat with that is that we don't have the cash currently, so we'd have to raise money somehow, our CFO can elaborate on how we're going to do that. We have all of the internal capability to design and execute our studies. We're already in the process of drafting protocols for phase III, for 450. You know, we're not public on where we're going to go, but if we hit as big in RA as we would like, the obvious thing to do would be to go big in phase III for spondyloarthropathies.
RA, psoriatic, ankylosing spondylitis, juvenile idiopathic arthritis, all kind of co-migrate. We could go straight to phase III with all of those, and then we expand into other areas where we may need to do additional POC and/or dose ranging. The rheumatologic vascular disease, like PAN, as an example, and going into IBD, and we have really good evidence that we work in IBD based on validated predictive animal models. That would be the hope.
Great. Maybe we'll touch on psoriatic arthritis then. We'll also see data for that program in the next couple of months, later this year or early next. First, you talked to it, but, like, the rationale for selecting this indication, let's start there.
Purely just validation. You know, it's kind of like a check-the-box exercise. If you work in RA, you do this. I think the initial idea was that psoriatic was going to read out before the phase IIb for RA, but that just isn't how things worked out. That was in part because of geopolitics. When all hell broke loose in Ukraine, we were actually going to be in Ukraine big time for both of these programs. We pivoted to Poland. Poland was inundated with similar requests-
Not the only one.
From much bigger companies than us.
Yeah.
I think everyone would be glad to hear we prioritize getting regulatory approval for the phase IIb RA study over the psoriatic, and that explains the delay.
Mm-hmm.
I think all of the sites that we plan on having have been initialized, so we're just starting to see screening increase. We're hoping to be able to refine the delivery of data date. Right now, we're just saying first half of 2024, but we should be refining that in the coming couple of months.
Yeah. Where do you see the opportunity for new agents in this particular space?
Psoriatic is different than RA. Methotrexate is not used as much. TNF is kind of first line, there is significant unmet medical need. Psoriatic arthritis is probably not a single disease. It's probably a commission of diseases where you have a, you know, a spondyloarthropathy coupled with skin sensitivity. It is very different. There is a large unmet medical need. There are drugs that are active in skin, so for instance, the IL-23s and IL-12s, that are being tested. It's not clear how much activity they're going to have on the underlying arthritis. We think mechanistically, it makes a lot of sense for us to be there, and I think that, you know, we're going to be a nice foil to the TNFs in that disease.
Great. Maybe we'll spend some time then on the funding side, cash runway today, and how you think about funding the large slew of programs you just outlined.
Sure. We ended the first quarter with $204 million of cash. As some of you may have seen, we did do a transaction off our ATM with Bain Capital that brought in an additional $27 million. Think about our end of Q1 cash balance is $230 million. We think that gives us a lot of flexibility to execute on the programs that we currently have running. As Doug mentioned, obviously, we caveat that by saying that cash balance doesn't give us enough to get through a phase III program for RA or a phase III program for ATI-1777.
As we approach these data readouts, we will be having discussions and looking best alternatives to provide that funding, and that may be a mix of dilutive and non-dilutive funding, and we'll see what that looks like as we approach the data readouts.
Just to add, we, and this predates me, but we've really been parsimonious in terms of how we spend our investors' money. Our burn rate's about $25 million a quarter. With that low level of spend, we have three and two and four drugs in the clinic. In the last five years, since we acquired Confluence, we're pumping out an IND candidate every year and an IND-enabled drug every 18 months. The idea here would be to keep a relatively low burn rate. We have 120 employees. We're not planning on going much bigger than that. The dream would be that we monetize the phase IIb drugs, so the, you know, the drug for atopic derm in 450, and then that gets pumped back into the model.
We never intend on being a commercial phase study, a company, rather. We don't want to have a sales and marketing infrastructure. We'll let other people do that. We want to keep discovering clever drugs very cleverly and inexpensively, de-risk them, and then find a partner.
Yeah. Let's talk about some of these other drugs, maybe starting with ATI-1777. It's a soft JAK inhibitor. What does that mean?
By the way, this is why Aclaris began our relationship with Confluence, which resulted in us buying the company. Joe, take it away.
ATI-1777 was specifically designed as a topical JAK inhibitor. The three things we wanted to incorporate into that molecule was, one, JAK1/3 selectivity, so to avoid interaction with JAK2 and inhibition of JAK2, because we don't feel that JAK2 adds anything to the efficacy and could bring in some safety liabilities. Second, the ability of the compound to traverse the skin intact and have a local effect in the skin. Importantly, number three, when the drug does get into the circulation, the plasma esterases, we built in soft spots into the molecule, which means they're metabolically labile spots. Plasma esterases and then liver enzymes would rapidly degrade the molecule. It gives us the opportunity for a best-in-class type approach, where we would have efficacy locally in the skin, but we have no systemic availability, so efficacy with limited safety liabilities.
Great. What have you seen thus far in terms of systemic exposure?
In the two-way study that we did in atopic dermatitis, we tested all patients, a number of time points with each patient, and we saw a total of about six values out of about 150 values that we looked at that were above the lower limit of quantitation. These levels were in 3 different patients. It wasn't consistent, it was just a point in time with each of these three patients. The level that we attained there was below the IC50 for JAK1/3 and way below the IC50 for JAK2. We did clearly achieve this lack of systemic availability to have less than pharmacologically relevant concentrations across that whole study with all the patients.
Great.
Just to add, that was with a 2% BID approach for the phase IIa. In phase IIb, and it's a 240 patient study that we'll be reading out later this year, as we just said, there are four active arms, the 2% BID, right, that had almost no exposure, 1% BID, 0.5% BID, and 2% QD. Obviously, you know, the three that aren't 2% BID will have lower exposures. Yet the goal here would basically to have zero detectable drug in the blood after phase IIb. We think that's gonna be compelling to the U.S. FDA to want to see this product in phase III and without the eventual black box warning that you have with topical JAKs.
Can you expand a little bit on the design of the phase IIb and what you expect to see with respect to, you know, what's a good outcome here?
Six arms, 40 patients per arm, three BID arms with a BID placebo, one 2% QD arm against a QD placebo. The goal would be to see a replication of the good results we saw in phase IIa in terms of efficacy, but as I mentioned, to find one or more doses that had zero exposure, and then we'd make a decision as to which one we progress to phase III.
Understood. How do you think about the landscape for topical dermatology products now? I know you obviously pivoted away from this a little while ago. There's been some progress there. What do you see now?
And it's too bad that Neal Walker, our founder, former CEO and chairman, isn't here because he taught me everything I know about this. Topical derm products are tough from a, from a gross to net perspective. When Incyte launched, you know, they took systemic RUX and made a topical formulation with it, and they got it approved, and then they had a sales force with only one product in the bag. We were very, very skeptical in terms of what they projected to be their top-line sales. I think they were projecting something north of $1.5 billion, but also the gross to net, because it just made no sense.
The good news is, in fact, though they're not hitting the top line, revenue that they had projected to, they are actually selling a lot of drug. Even with their, I think, imperfect single product sales force model, they're actually conferring decent gross to net, which could only be improved upon if a drug like that or like ours, was in the hand of a company that already has a sales force with a bag full of products for derm, for dermatologists. They're creating a market that we're gonna fit into very nicely. I mean, I think that they're tracking to hit maybe north of $500 billion of peak sales with acceptable gross to net. That's gonna help us in our discussions with big pharma.
We don't intend to commercialize products, so we are looking for someone who wants to take it off our hands to commercialize. The sooner that we, that is kind of nailed down, the sooner then we'll know how to finance phase III. We can do this through dilutive means, although we think that's unlikely. More likely, we'll look for a partner to pay for it, possibly off their P&L, which would be a good way for them to go. Lastly, we're talking to royalty pharma companies in terms of subsidizing it. We'll see where it takes us.
Understood.
It's a very compact phase III. Unlike RA, that could cost north of $500 million, AD would be a small fraction of that. You'd have to do a relatively small sample size from a safety database perspective. We could easily prosecute this if we had the funding.
Okay, great. Maybe we can move on to the ITK/JAK inhibitor. Let's just talk about why that mechanism of action and where you expect it to fit?
Yeah. ATI-2138 is a covalent inhibitor of ITK and JAK3. Takes advantage of a cysteine residue that's in the same place in both ITK and JAK3. JAK3 is the only isoform of the JAK family that has this cysteine, this compound is exquisitely selective for JAK3 across the JAK family.
What this compound would be good for is T-cell driven diseases. A number of different T-cell driven diseases that we're looking at, but it'll block both cytokine production, it'll block T-cell function. Really excited about the possibility here. As currently, we completed a phase I single ascending dose study. We're near completion, as Doug said, of a phase I multiple ascending dose study. We'll pull those data together, look for doses that we want to move into phase II, and rapidly move this into a T-cell driven phase II disease.
Great. When should we expect to see the next kind of clinical updates from that program, and what would we look for in terms of success?
We'll see top line from the MAD in July, and final results from the MAD in September. We intend to be initializing phase II this year, with first patient dose early next year.
Okay. How are you thinking about indication selection?
It's a great question. A way to look at this mechanism is it's in the same space as the S1Ps. The S1P basically is a T-cell trafficking approach. A bunch of drugs have been approved or are being developed among the S1P class, including the etrasimod, that was the lead asset for Arena Pharmaceuticals, where I used to work, that was purchased by Pfizer last year. The S1Ps were initially validated, ozanimod was initially validated in multiple sclerosis. Ozanimod, by the way, is the drug that Receptos developed with Celgene, bought, and now BMS is commercializing. It was developed for UC. The etrasimod is being developed for UC and for AD. The universe of T-cell driven diseases is really broad, and includes, for instance, asthma and COPD.
Right.
I think UC is the right first step for us, because it'll be a compact phase IIa, where there's lots of precedent, there's reliable animal models in which we work spectacularly. It's the right way to go initially, but we'll kind of see where we pivot after that.
Great. You mentioned the kind of pace of INDs and IND-enabling studies. How should we expect, like, the focus of those programs?
Mechanistically, our expertise is really on perturbing the human kinome to impact areas of serious unmet medical need. If you look at 450, if you look at ATI-1777, ATI-2138, and we haven't mentioned it yet, ATI-2231, another MK2, we've been way more clever than the average bear in attacking kinases, including JAKs, in a way that should be safer than what others have done. That's kind of our lifeblood in terms of chemistry. Where we go in terms of diseases, you know, is a little bit less constrained. Obviously, I&I indications have been where we are, derm, rheum, and soon GI. 2231 is being initially developed for oncologic applications, for mechanistic reasons and financial reasons that make a lot of sense for us.
We don't really want to take anything off the table. I think, again, where we have a secret sauce is in picking robust targets that can be addressed by hitting the human kinome, and in some cases, there'll be pleuro potential, and we'll kind of figure things out.
Great. You talked a little bit about cash runway in terms of these programs. As you think about sources of capital for funding the rest of these, I guess, how should we think about cash runway today? Yeah, I don't know.
Sure, yeah. I mean, what I mentioned earlier, we guide to our cash runway being through the end of 2025, with the caveats I mentioned. In terms of capital allocation, I think the way we would describe it is, until we see otherwise, ATI-450 is gonna get the incremental dollar. Something like ATI-1777, we could use as a funding mechanism for ATI-450, but we will also allocate some capital to those discovery programs to help backfill the pipeline, and give us a future-
Yeah.
Beyond 450.
I'd be remiss not to mention, I mean, we're, I think we're fishing in the right pond. If you look at M&A in the I&I space of late, there was Pfizer taking out Arena for $6.7 billion. There was Takeda buying the Nimbus TYK2 for ultimately $6 billion, and then there was just the Prometheus deal with Merck.
Yeah.
There's an awful lot of interest in big pharma. A lot of them have got revenue or LOE you know, IP cliffs that they need to kind of fill, I think having an oral non-JAK pleuro potential I and I agent puts us in a very good place.
Great. Awesome. Well, that takes us to time. Thanks so much to the team for joining us today.
Well, thank you, Brad.
Thank you.
It's a great meeting, as always.