Welcome back, everyone. Good afternoon. Welcome to our Inaugural Healthcare Innovation Conference. My name is Yatin Suneja. I am one of the biotech analysts here at Guggenheim. Our next presenting company is Alumis, and from the company, we have here with me President and CEO Martin Babler. We also have the Chief Financial Officer John Schroer here with me. Martin, young company, relatively new, recent IPO. Why don't you orient our audience what Alumis is all about, what are some of the upcoming catalysts, and then we'll go into the Q&A discussion. Okay. Thank you. Well, first of all, Yatin, thanks for having us. Certainly appreciate to be here, and thank you for joining us here. So Alumis is about three-year-old, not three years old now, and actually that tells you a little bit about the fact that we are in phase III. We was our lead program, which we acquired originally at the stage where it just went into the clinic about three years ago. And so, we have a phase III in psoriasis ongoing right now. We have a phase II-B, which is actually run as a pivotal trial in lupus, with our lead program ESK001. And ESK001 is a unique TYK2 inhibitor because it actually is so far the only one that can really safely maximally inhibit the target. There are some implications of that, certainly in terms of our expected efficacy and the pharmacology around it. We have a second program that we put in the clinic earlier this year. That's A-005. A-005 is a brain-penetrating TYK2 inhibitor. Then behind that, we're building a pipeline right now, that includes other mechanisms outside of TYK2. The premise of the company, however, is actually started out as a precision immunology company, really with the goal to figure out ways to move from broad target inhibition to very precise inhibition, of patients with immune-mediated diseases. The company actually originally started out by doing a broad assessment of many, many targets that are associated with autoimmune diseases. Out of those, we basically picked TYK2 as one of the leads. We did that because when you look at the genomics of many of these targets, TYK2 is actually quite a unique target because there are some mutations that exist in humans. In the case of TYK2, actually, a specific mutation, the 1104 mutation, that mutation leads to the loss of the function of TYK2 just on the kinase function. It turns out that about 5% of the Caucasian population actually have that mutation, and there is no phenotype. In other words, these patients actually live amongst us without realizing that they have this mutation. So that's a really great predictor ultimately of what you should see about safety and tolerability of that target and that specific inhibition of the kinase function. Those patients not only don't have a phenotype or that mutation doesn't have a phenotype, but it also actually has a protective effect from autoimmune diseases, and the reason why we picked lupus and the reason why we picked psoriasis is actually because that protective effect of that mutation is about 50%. So in other words, you, you have a 50% reduced risk of having psoriasis or lupus, compared to the general population, and so that those kind of data sets are what we're using in our precision approach to then select targets, select indications, and ultimately, hopefully, also select, patients, as we go forward. Very good, Martin. Maybe if you could put in perspective the pharmacology of your molecule, because I think there are three molecules that everybody sort of focuses on, obviously. One is your molecule, that is the Takeda molecule, and then obviously Sotyktu, which is already approved. So what is the unique feature about your molecule? How are you able to get to the coverage that other people might not be able to? And what is the relevance of that? So we are strong believers in pharmacology, especially when it comes to kinase inhibitors, because one of the things about kinase inhibitors is you'd want to be relatively precise on what you hit, but you also want to be able to dial in the perfect kind of way that you can get the maximum clinical effect with the least side effects or tolerability issues possible. And I think that's where the molecule really is unique. The key features of this molecule are twofold. The first one is the selectivity, not just of the actually parent molecule, but the fact that we have inactive metabolites. And so therefore, you can really focus in terms of the selectivity on the parent molecule. And this molecule truly is just hitting TYK2 and really nothing else. And it does it through the JH2 domain, which means really it's an allosteric inhibitor. And so we see very little off-target effects of any sort and really don't see any JAK pharmacology. That leads to the fact that we actually, as we dial up the dose and if we try to go towards that maximum target inhibition, we really don't see some of the side effects that have to date been associated with TYK2, like the skin rash or maybe triglycerides, etc., etc., triglyceride increase. The other aspect is that the molecule is extremely tight in its PK. So it has actually a variability coefficient of less than 20% of most of the PK parameters. In other words, if we give this to 100 people, their likelihood of their exposure to the drug is actually very, very tight. And there's only a variability of about ±20%, which is very, very good for a small molecule. That allows you to really dial up without having outliers that mess with the safety or that mess with the tolerability of the molecule. Got it. How has that pharmacology played out in the clinical setting? Obviously, you generated the STRIDE data, right? And that was the study was in itself unique that not many companies do a 52-week study, right? You guys did that as a phase II. So how, what did you learn in that study if you can put the data in perspective relative to not only the other TYK2s, but just in general in the psoriasis, oral psoriasis space? Yeah. So for the oral psoriasis space, what you basically see is actually very consistent with what you see with the injectable space, which is there's mechanisms that are a little faster in action, a little slower in action, but the critical pathways that we're trying to target is really the IL-17 pathway and the IL-23 pathway. And so what you see is that actually when you inhibit the IL-23 pathway, that the better your inhibition level is, the more efficacy you get. And so when we look at an inhibition level with TYK2 of, let's say, 80% to 90% or almost complete inhibition, you get about a 70% PASI 90, PASI 75, or and about 40% to 50% PASI 90. When we dial up from our dose where we get those levels to a dose where we get actually maximum inhibition, which is our 40 milligram BID dose, we see about a 20% jump in efficacy. So the delta between almost complete inhibition and complete inhibition or almost complete inhibition and maximum inhibition really is a quite significant delta in terms of efficacy. And so we do believe that, based on all the experiments where we had, where we didn't just see that in STRIDE, but then in the open label extension, we moved every patient now to that 40 milligram BID dose. And every time we do this experiment, whether they come from 20 milligrams QD, whether they come from 40 milligrams QD or 20 milligrams BID and move to that dose, they always have the same outcome. They get to basically a PASI 75 of about 90-plus%. So we know not just from STRIDE, but from the follow-on now that really there is a very consistent and internally consistent outcome that we should see a better inhibition level and therefore a better clinical outcome, and with a factor of about 20% delta between the highest dose and the second highest dose. Second highest dose. Could you also put in perspective the onset of action as it relates to the mechanism? Because some of the features of that STRIDE study or the data were interesting that you were seeing a little bit of a delaying of an onset. Why is that? I actually don't believe we have the answer to that question yet. The reason is because we haven't treated enough patients for 16 or 20 weeks in a row. Remember, our design was that we actually stopped after 12 weeks and that we had a break. What we see in terms of the performance in terms of speed of onset, we actually have an interruption. Therefore we actually don't know exactly what the speed of onset of our molecule is. We are now running this in phase III and we'll see. What we know historically though, and what we've seen in our own analysis, we actually did an analysis of most of the relevant clinical trials that were run, with many different targets over the last 10, 15 years is that when you, IL-17 is actually the pathway that has the fastest onset. Yes. IL-23 is the second fastest onset. IL-12/23 is somewhere close to IL-23, but there is a hypothesis out there that maybe hitting IL-12 in parallel might be just slightly slower. This is not yet clear, and it is a hypothesis that's still out there, but not necessarily proven. If you wanted the speed of onset, you would go for an IL-17 probably. However, that actually is not the dominant mechanism used in the clinic today. The reason for that really is because we keep comparing 12-week data in psoriasis in phase II and to try to figure out who's ultimately gonna be the best. We believe that speed of onset is a critical thing. When you actually talk to physicians, they actually believe that the ultimate clinical outcome and the level of maximum clinical effect that you see is more important because for them, the most critical thing is, can I tell my patient, hey, take this drug, it's gonna work for you? Or am I gonna say, well, you know what, it's gonna work somewhat at week 12, but this one would be just slightly better at week 12? That is, the 12-week endpoint is actually not a clinical endpoint. It's for us comparing efficacy a little bit. So we believe that, while the IL-23 pathway is a little bit slower than IL-17, ultimately the long-term efficacy is really what drives decision-making at the physician level, and so we believe we will have even against the IL-17s a competitive profile. Got it. Then now can you talk about your phase III onward program, like, how it is, what does it comprise of, how many studies, where is the enrollment? I think what we are hearing from the field is that there has been, the other competitors like J&J have been able to enroll a little bit faster. So I just love to understand where, where we stand on the enrollment curve. Yeah. So, the most important thing about our entire program is that we started this process in psoriasis later compared to our competitors. Our goal always was to design a program that is as aggressive time-wise as it possibly can be so we could actually catch up with our competitors so we would not launch significantly after them. Our phase II actually enrolled faster than any other phase II in psoriasis. For our phase III, we actually designed a program that could possibly give us the opportunity to submit faster. We actually broke precedent with our program in phase III because we actually have agreement with the FDA that we can file with a six-month package rather than a 12-month package. The reason for that is that in our phase II, we basically did this open label extension, and that gives us a lot of the requirements for the safety package that we need from the ICH guidelines. Our phase III program consists of two parallel identical phase III trials that will run for six months. They will have a placebo control that runs for four months. People basically from the placebo arm will move to the active arm of ESK001. We will also have an active control with, basically Otezla to get a six-month readout because we believe that six-month readout is also critical for the label. So we'll have a four-month placebo, against placebo, we'll have a six months against the Otezla, and then everybody rolls over into an open label extension, which will give us the durability and the maintenance, data to also then ultimately put in a label. And we can combine that with the three-year data that we get from the open label extension from phase II, and that really gives us a very comprehensive package. Got it. Got it. Then in terms of enrollment, you're absolutely right. One of the things that I think we've learned now is that it is easier to handle in a clinical trial an oral drug, whether that ultimately is a market preference as well, we'll find out. But at least from a performance of a clinical trial standpoint, we've seen this in our phase II. As I said, we enrolled that faster than any other psoriasis trial of that size before. So our hope is that we can do the same as our competitors can. Our trials are both global trials. They're currently enrolling. We're certainly on track for our own internal projections. As we stated before, we, the readout for that will be in the first half of 2026 at the latest. Half 2026. Why choose, or Otezla as a competitor? Why not Sotyktu, Sotyktu? The most important thing for us really was to make sure that we have a six-month data endpoint that is controlled. Yes. And from a PASI standpoint, of course, using Otezla as a competitor, is a higher likelihood of success. At the same time, it is also the most relevant competitor right now, because we actually don't know at this point whether Sotyktu ultimately is going to be a relevant competitor. And we will run additional head-to-head trials. The question for us is, will it be Sotyktu or deucravacitinib, or would it be something else that we're going to use? And that's really gonna depend on what are the most relevant molecules that will be in the market. We do believe that we have enough time to basically run those trials so that at the time of launch, we'll actually have some, or shortly thereafter, we'll have some competitive data as well against other competitors and not just, or Otezla. Got it. So for these, for the onward program, you have buy-in from the Europeans? We have shared this program with both the U.S. and the European agencies, and there were requests that both of those agencies made, and we tried to accommodate as many aspects of that as we could. In the study. Okay. Actually no, a few more questions. How should I think about the baseline for these phase III that you're targeting? Because in your phase II, you actually had a higher number with more and more severe disease, right? So like a third of, I'm just curious to understand, like how many biologic-exposed versus non-exposed patients you might have? Yeah, that's a really good question. One of the things about our phase II trial is that it was mostly run in the U.S. and Canada. So we had about a third of patients, a little bit more than a third of patients that actually were bio-experienced. We also had basically about 40% that were basically severe patients and about 60% that were moderate patients. As we expand the global footprint of our trials, we do believe the likelihood that that will come down a little bit is actually quite high. We're not basically enrolling, have specific criteria for the enrollment. I think it's more a matter of fact that we, with a lot of U.S. and Canadian patients, in our phase II, the likelihood to have a lot of bio-experience was higher. If you ran that trial just outside the U.S., you probably would see a lower number. Got it. So what is the expectation for this study? I mean, is there a particular delta over either Otezla or even Sotyktu and, sort of, cross-trial comparison that we need to look at on PASI 75 when you produce these data? So for us, I think the most important question really is where does the efficacy plateau. Our expectation right now, because we, as I mentioned, ran this experiment multiple times now with the phase II, moving all the different doses to that highest dose, our expectation would be that our molecule would perform very similarly in the phase III. We have not made any changes in dose. We have not made any changes in terms of enrollment criteria, et cetera, et cetera. Our assumption is that we will be in the 80% to 90% for PASI 75, hopefully between 60% and 75% for PASI 90, which actually would be nicely competitive even with some of the injectables. And so that's really what we expect. That is different from what we've seen so far in the label and from the long-term reporting from competitive molecules such as deucravacitinib, where the PASI 75 was in the 60% to 70% range, the PASI 90 was more in the 40% range. So we hope to be able to repeat that there is this really 15% to 20% jump actually, from the maximum target inhibition. Got it. Okay. Maybe just one, like a short comment on the competition. Obviously there is an IL-23 oral. Let's see what happens with the Takeda molecule. Like how do you think the competition is gonna shake out and how are you positioned? So I think I wanna start by making a comment about the market overall. One of the most fascinating things that we often forget when we look at this very crowded corner of the psoriasis is that these injectables currently make up only the treatment of about 10% of the patients. Actually, it's less than 10% of patients with psoriasis that get an injectable biologic today. 90% of patients that are diagnosed in the U.S. do not get that. We do believe that there's room for a lot of opportunity here on a market-making standpoint. Even our comp, one of our competitors recently stated that there's about 5 million patients basically waiting for an oral therapy. I think there's the market taker opportunity and there's the market maker opportunity. I think in the market taker opportunity where it is about how competitive are you, et cetera, that's one segment that we likely are gonna play in where we will take some patients away that prefer an oral or an injectable. Then there's the second segment, which is probably the largest segment, which is that segment where you actually make the market. And that is that patients and physicians are really now talking a lot more about treating patients earlier and harder. In other words, let's not go from watch and wait to a topical, then to methotrexate, then maybe to an Otezla, then to a biologic, but let's actually move an efficacious oral drug or convenient drug up as much as we can. And so that's the market maker opportunity. Then there's the third segment, which is actually also an interesting which we discovered in our market research with patients, is a lot of patients tell us, yes, I'll go on a biologic to get clear, but I would love to maintain myself on an oral. So that's the third segment that we believe is an opportunity as well. And so in terms of our competitors, we believe that we have a very competitive profile, in that we have so far demonstrated a really good efficacy profile. We have actually the largest database of patients on the phase III dose now with about 150 patients that have been treated for more than a year at that dose. And we really haven't seen any safety issues. So we are assuming that we actually have a very competitive safety profile. And then, as you know, we've basically announced that we currently are in phase III with twice a day, but we actually are developing a once-a-day formulation that we'll introduce likely shortly after the launch. From a convenience standpoint, given that this can be taken with or without food, we actually believe that we're also going to be competitive there, given that some of our competitors basically have to be taken on an empty stomach and have to be taken in a fasting mode. Overall, our assessment is that we have a very competitive molecule that actually enters a relatively large market and where we believe we can get our fair share. Got it. Very good. Moving on to the other indications. So outside of psoriasis and psoriatic arthritis, where do you think there is the highest, I would say, applicability or potential of success for this mechanism? And if you wanna touch on your SLE program briefly. Yeah. So, so as you know, we started originally picking TYK2 as part of our genomic analysis. We then moved on to assess all the indications that might be possible. And, at the top of that list was actually SLE, psoriasis, PBC, sarcoidosis, and, and, juvenile RA or something in the highest level, psoriatic arthritis in there as well. Sorry. So, so we, we certainly have a lot of other opportunities from a genomic standpoint. We're already pursuing lupus because that's one of the other large indications that, that was up there. That's a current ongoing trial. It will read out in 2026. It is designed as a pivotal phase II. So if that trial is successful, then we can just run one additional phase III, and if the agency agrees to that. So that would be a slightly faster program that way. We believe that that actually has a high likelihood of success compared to what maybe the market perception is because we have genomic data to support it. We have the success of Sotyktu in their phase II. And we also have the data from anifrolumab, which is inhibiting the same interferon pathway that actually showed that the maximum inhibition of the interferon pathway actually leads to a positive outcome. So, three to four really key indicators on why this should work. And then on top of that, we really designed this trial really to minimize the placebo effect, which we believe is actually the most important thing in a lupus trial. So, a program that we're very excited about. And then we have made a list, a priority list of what might be next. Certainly high on those that list are the IBD indications, psoriatic arthritis, and there's some other indications, and that's really more just a matter of resources on when and how to start these programs. Then maybe the last couple minutes on A-005, so it's the CNS penetrant TYK2 inhibitor. What, and the data are gonna come relatively soon, right? So what are we looking at? Like what should we be looking at and what are some biomarkers or anything that we can glean from? Yeah. So we've done a lot of biomarker work on ESK001. And so we, you know, we will have interferon, we'll have Siglec-1, which we actually presented at EADV as a key marker for TYK2 activity. We'll have IL-17, IL-23, et cetera. We actually will have PKPD data, we'll have biomarker data, and then we actually are doing a spinal tap. In a bunch of healthy volunteers to really show what the concentration is in the CSF. And the outcome we really would like to see is we'd like to see very strong inhibition of the biomarkers in the periphery. We'd like to see very good linear PK if possible, and tight PK. And then we would like to see the similar concentration in the CSF so that we can understand what it will take to get maximum target inhibition also in the brain and not just in the periphery. So those are the elements, and ultimately that will lead then to a phase II program in MS, which is going to be likely a three-month imaging study that will start next year and read out in 2026. Is there a way to measure target engagement in this? So we will measure target engagement in many different ways, but only in the periphery. Nobody volunteered to have a hole drilled in their brain. Okay. In this study. So, but it's gonna be a little bit of math, one plus one equals two. So take the peripheral concentration, peripheral inhibition, and then translate it into the brain. Got it. John, maybe on the financial, you know, if the phase III studies accelerate from a timeline perspective, like how are you positioned? So what we've shared with people is that we have cash runway to carry us into 2026. And if there's an acceleration, obviously that would bring that readout further into the near term for us. And so we think that the extra investment that would be involved if that would be required would be a NPV positive for investors. I see. Yeah. Very, very good. Well, very good. I think that's all I had for you guys. Thank you so much. Thank you. Thank you. Certainly appreciate the time. Thank you. The opportunity.