Afternoon, everyone. Welcome back to Oppenheimer's Annual Healthcare Conference. I'm Jeff Jones. I'm one of the analysts here on the biotech team. I am delighted to be joined by Martin Babler and John Schroer, CEO and CFO of Alumis. Been a lot of excitement around the story. Really thrilled to be able to jump into a fireside chat with you gentlemen this afternoon. Thank you for having us. You guys obviously kicked off the year in a very big way with the announcement of positive top line Phase 3 data for envudeucitinib in psoriasis in January. Maybe if you would just highlight for us what you've shared to date. I know it's very top line, just in a press release, you know, why don't you set the stage for us there? Yeah. We've shared some information in a press release, and then also in a discussion in a webinar, and we've and in the Q&A, added a few bits of information. Let me just walk you through the most important things. We were very cautious on what we shared and very disciplined in what we shared, and the reason for that is that we wanted to submit a late breaker to the AAD. Given that the organization is quite strict, we wanted to give everybody enough information to get a picture of the molecule and the asset in psoriasis, and at the same time, really keep our chances high that we hopefully will get a late breaker at the AAD. The first set of data we disclosed was for PASI 75 and sPGA 0/1, at week 16. That is our primary endpoint, and we shared there that we achieved an average PASI 75 between the two trial of 74% and sPGA 0/1 of 59%. We did not share the placebo rate and the placebo-adjusted rate because of AAD. What we did share is that when it comes to this endpoint, specifically at week 16, we did see what you would expect in terms of the placebo rate from one trial. In the other trial, we did see an increased placebo rate, but also an increased active rate and an increased comparator rate. If you placebo or actively adjust those data set, the two trials were actually identical. We shared the PASI 90 and PASI 100 average numbers. For PASI 90 at week 24, we see about a 65% average. For PASI 100, just about over 40% on average. We shared that the placebo rate for those two were very much in line with what we've seen in the past. We also shared that we saw a rapid onset, and that at week 4, we already see a separation of PASI 75 and PASI 90, and that we see a deepening response over time between also week 16 and 24. That we have clinically meaningful improvements in quality of life, itch, and other patient-reported outcomes, and that the safety is consistent with what we've seen in the Phase II, with the four largest manifestations of safety and tolerability, being that we did see headaches, we did see upper respiratory tract infection, nasopharyngitis, and some acne in the patients. Overall, the safety is consistent, and we also said that we didn't see a malignancy signal, and that we didn't see any change in blood chemistry that would make us believe that we would have to do monitoring for those patients. Great. Now, obviously, you're in a tight competitive position with J&J being ahead on their IL-23 blocker and icotrokinra, and that's sort of where everybody has put the bar for the orals in psoriasis, and then also TYK2, Takeda's TYK2 inhibitors, zasocitinib. Obviously, lots more data coming, most likely at AAD in that late-breaking session, from yourselves and Takeda. I guess, what, in your view, what should folks be really focused on in trying to distinguish these products, be it, on the efficacy signals, on the safety signals? You know, there's been comment on itch, as this potentially distinguishing factor as well. Just what would you call attention to as we get ready in next month for the AAD conference? Our plan is if we get an accepted abstract, that we would share a lot of the numbers around the PASI scores, sPGA, 1 and 0, and 0. I think the expectation there is that you see numbers that are somewhat similar between the molecules. There are additional benefits of the TYK2 pathway, and we do believe they have to do with patient-reported outcomes, they have to do with age, they have to do with quality of life, et cetera, et cetera. I think, from an efficacy standpoint, we do believe that the TYK2 mechanism actually has possibly some additional benefits over the IL-23 only mechanism. The distinction within TYK2 is hard to speculate at this point because we just don't have enough data. I don't want to get into a lot of speculation here on how we're different from the Takeda molecule in terms of efficacy. We have shared that if we interpret their numbers right, that we believe we have a competitive molecule. On the safety side, we also will have to see. We know in the past at least, that when it came to maximum target inhibition, both deucravacitinib and Takeda had to dose reduce from Phase 1 to Phase 2 a little bit because if they really pushed the dose, they saw additional side effects. We will have to see how that pans out. Overall, we believe we have a very competitive molecule in this situation. The one piece we haven't talked about yet is that we do have, at this point at least, a twice a day. We're working on a once a day, but we have actually done some market research, especially when it comes to food effect, showing that when we ask over 400 patients, "Would you rather have a twice a day that has no food effect versus a once a day that actually has a fasting requirement?" At least two-thirds of the patients felt that they would rather have a twice a day in that situation. Overall, when you look at market research and twice a day versus once a day, but with no food effect, you see that there's a slight loss in market share, but we'll have to really see the full set of data until we decide how this is. I think the more important thing here is that we do believe with these 3 molecules, that the overall oral market will grow significantly. Even today, actually, when it comes to systemic therapy, the orals actually have a higher patient share than the injectables. It's not obvious because from a dollar share, that's not the case, but from a patient share, actually, there's more patients on oral drugs today than there is on biologics. I think the other piece that will happen is they will stay on orals a lot longer, and they probably get on orals earlier from the topicals, because systemic therapy for a systemic disease is something that the dermatology community is actually really pushing right now. That's really helpful. Maybe to drill down around potential challenges for TYK2s as a class, one of the things that's come up is deucravacitinib on the label does have monitoring for triglycerides and liver enzymes, and, you know, hard to say until you have a labeling discussion with the FDA. Was there anything that, you know, distinguishes what you've seen with envu versus what was seen with deucravacitinib to drive perhaps that labeling, that labeling, challenge? Yeah. Like, very often in these cross-molecule comparisons, we believe that actually is a molecule-specific issue and not a target issue. We haven't really seen any change in triglycerides or liver enzymes. There's really no reason that you would monitor if your blood chemistry is basically consistent, and it's been consistent into Phase two, and it's been consistent in Phase 3. We believe that's a lot more driven by the molecule specifically than it is actually a target issue. I also just want to reiterate that we have really not seen any JAK pharmacology, which is the other reason why that might be the case. You know, we have a high level of conviction that, and TYK2 really affects very different cytokines than some of the JAKs. Therefore, you should really look at the pharmacology of the specific cytokines that you affect and not at the class. Otherwise you would have to think about ITK and BTK the same way. They're both tech family members, and we would never assume that they're actually doing the same thing. Just because the protein have a lot of homology, doesn't necessarily mean that the target basically is behaving the same way. Okay. That's really helpful. Another thing that's, I guess, come up from some of the investor discussions we've had is asking about the malignancy warning that you see on Deucravacitinib, and obviously, some of the JAK inhibitors as well. I think you saw a few individual cases in your open-label extension from your Phase two, but individual cases, and so really hard to, for me, sitting on the outside, draw any conclusions from that. I guess, what's your comfort level on, you know, that as a, as a labeling issue? Yeah, let's start by saying there's always a certain background rate of malignancy in a trial of this size. What we have publicly stated is that we do not believe that we have a malignancy signal. The two cases that we had in our open label extension, one of them was a renal cancer, and this is actually, by the way, really well documented in our publication that came out earlier this year, for both the STRIDE trial and the open label extension. The first one was a renal cancer that is a slow-growing cancer and was so large that it must have been present before. The second one was actually a patient that had an EGFR mutation and lung cancer, where the brother, the sister, and the father also had exactly the same. Because the sister was just diagnosed, that patient went for a scan, and it was discovered that they, too, had lung cancer. There's clearly a familial history there, we do really not believe that that was related to drug in any way. We will disclose our safety data in more detail at the future medical meeting, hopefully at AAD, but we really don't see anything. I think part of that came also up because we've seen a couple of cases of Kaposi sarcoma in the context of the OX40 trials, and that's clearly an area where that is on target, and so therefore you look for it a lot more carefully. Remember also that the P1104A mutation that where is actually mimicking pharmacologically what we see with what we do with our drug, which is reducing the kinase function of TYK2, that if you look at that group of humans, and it's about 5% of the Caucasian population, a little bit less than other ethnicities, those people actually do not have a phenotype, and there doesn't seem to be an increased cancer risk for those. From a target risk perspective, we really would not expect to see a cancer risk here. Is the warning in the label for Sotyktu a remnant of JAK labeling or, how to interpret this is a key question because the ultimately, if you study more than 2,500 patients like we have now, you will find some cancers. That's just unavoidable, given the background rate that we have in humans. All right. Again, I appreciate the clarity there. As you noted earlier, you guys have done the Phase III with the BID formulation. Just if you could, obviously, you're working also on a QD formulation. What's your latest thinking in terms of timing and where you are in bringing that forward? Let me start by saying we actually have successfully accomplished developing a QD formulation with the PK/PD profile that we were looking for. The unique situation here is it's a little bit harder for this situation because remember, normally when you do that, you optimize for Cmax and AUC, and that's actually the measure that the FDA uses. One of the reasons why we believe that envu is been successful is because we believe that Cmin and trough levels are really, really important. In this situation, we actually had to optimize for Cmax, AUC, and Cmin, and we actually accomplished that. However, there were other features of the formulation that we didn't like, we decided to actually do some additional work. It will not be a formulation that we launch with. It will basically be a life cycle extension now for the molecule, and we will eventually have a once-a-day formulation. We just want to make sure we're solving this engineering problem, basically, in the best possible way to have the best possible formulation. That will take a little bit longer. As soon as we have identified what the engineering solution to the problem is, we can also then state a lot easier what the timeline looks like, et cetera, et cetera. All right. Obviously, we're talking about Phase 3 data. I guess, next steps, regulatory plans, and how are you thinking about how you might pursue commercial here? Obviously, a very large indication, and with J&J on the other side at this point, how then do you think about commercializing? On the filing, we plan on submitting our NDA in the second half of the year. The reason why that is the case is that in contrast to other programs, remember, we basically split the 24-week and the 52-week data into trial programs or the 48-week data. We already have the 24-week data. That's what we made public. We will get the 48-week data by the middle of the year, and part of that 48-week data will include a randomized withdrawal to get for the label, the data that is needed for durability and maintenance. Because of that's what actually defines the second half of the year submission date for the NDA. From our standpoint, the commercial efforts, the best way I can describe it to you is that we have a very strong commercial plan, given that I actually personally basically developed the commercialization plan for Genentech in the early 2000s, that really changed the way Genentech launched drugs. We have a very strong plan. We know what we need to do right now that is timely. We have a small but mighty commercial team in place. We will have to decide by the end of the year whether we're going to ramp up internally or externally. The question is actually not necessarily a psoriasis question. The question is actually a broader question, what it is that we're doing with our TYK2 franchise? The likelihood that we, as an organization, can launch this drug and develop this drug in up to 20 indications which we've identified, on a global level is close to zero. We do believe the more likely outcome is that we will partner, and the only question then becomes what that partnership looks like and what role we play in that partnership. Okay. You know, makes a lot of sense and some big decisions to come. Obviously, another big milestone for you guys will be in the SLE later this year as well. Maybe if you could talk a little bit about the SLE opportunity, what an oral looks like there, and what you're hoping to see from this data? It's very clear, and, you know, the unmet need in SLE is still extremely high. We have two molecules currently approved. Their efficacy rate is actually relatively low. There's no oral drug approved at this point. We do believe that there's a very significant opportunity for a efficacious oral drug in lupus. We have decided a couple of years ago to design a lupus program that consists of the trial we're currently running, which is a Phase 2b trial that is run as a pivotal trial. We have alignment with the agency, what it would have to entail to be a pivotal trial, and we implemented all of those pieces. It is a relatively large trial. It's more than 400 patients. It's a 48-week trial endpoint, we're testing 3 active doses on placebo, against placebo. That trial has completed enrollment last summer, and basically, we will read out the data for that trial in the third quarter of this year. The primary endpoint for the trial at 48 weeks is BICLA. The first secondary endpoint is SRI-4, and we do believe that there's a lot of validation for TYK2 in lupus. This comes from the genomics, and this comes from the fact that anifrolumab, which is an interferon inhibitor, it has been successful in this indication, and we know 1 of the 2 pathways that TYK2 affects quite significantly, and we've shown that in preclinical in Phase I and in psoriasis Phase II, is interferon. The third one is that there is actually positive data from a Phase 2 with Sotyktu in lupus. For us, the validation is very strong. The question is more an execution question: How do you keep the placebo rate as low as you possibly can, and how do you execute that trial with a high likelihood of success? We've put a couple of key things in place. The first one is really patient selection, where we paid a lot of attention. The second one is making sure that people know how to use the tools that are used because the tools we use in lupus are quite crude. They're questionnaires, they have many domains, et cetera. The third one is really also to making sure we are paying a lot of attention to the co-medications, especially steroids, because they're actually quite effective in lupus. We have a forced taper down to 5 milligrams or less that has to happen in a certain time frame. Overall, we believe those will all contribute ultimately to the de-risking the trial and hopefully see a successful outcome in the third quarter of this year. You mentioned, deucravacitinib a nd Galapagos recently announced sort of mixed, a mixed signal, if you will, in SLE. In just in terms of potency versus deucra, assuming deucravacitinib does show positive data here, what's the difference, potency-wise, in inhibiting TYK2 versus yourselves in deucravacitinib? It's actually really hard to say because we actually believe that deucravacitinib probably also has an active metabolite that messes a little bit with our understanding of how well deucravacitinib inhibits the target. What we know, at least from psoriasis and from some other data that we have, is that we do believe that we have a maximum inhibition of the target for 24 hours a day, and we do not believe that deucravacitinib accomplishes that. We do believe that there's a chance that we see some improved efficacy versus deucravacitinib. We also know from past trials, at least from the safety side, that we see a safety profile that should be enhanced over the safety profile of deucravacitinib. In terms of the Galapagos trial, that is, at this point, extremely hard to interpret for us. First of all, we don't have a lot of information, and it's hard to decipher the press release. It's also a trial that is relatively small and short, and we know as our CMO, Jörn, would tell you, in lupus, you want to go big or go home because you really want to make sure that you have sufficient information to make a clear conclusion of whether your drug works or not. That molecule is a TYK JAK, therefore, it's not 100% clear how much of the TYK effect is there versus how much of the effect is a JAK effect. It's just a little bit harder to really draw any clear conclusions from the data set at this point in time, and I think that the more likely better comparator is the fact that all three doses of deucravacitinib basically showed a benefit in lupus. While there was no dose response, there is many different other indicators where deucravacitinib also did not have a dose response because the PK is relatively variable and not linear. There's been some really interesting communications out of the FDA recently about the standard becoming a single trial for approval. Every time they comment on that, I see your stock jump. Folks are clearly paying attention to that messaging, and I think principally because of what it could mean for your SLE trial, given how you've designed it. Just, I guess, any thoughts on what that signal could mean for you guys? Yeah. We certainly will look at the data once we have it. It allows us to go to the FDA and really have a conversation whether that trial would be sufficient. The communication from the FDA actually was silent on one key thing, and that is what the safety database has to look like. The ICH guidelines are pretty clear what safety databases need to look like. While you might have one trial, it doesn't mean you have half the patients for the safety database. The key question for us is: how much can we use the psoriasis safety and the safety in other trials to shore up the safety for lupus? The best way that I can describe it to you is at this point, our base case assumption remains that we might have to do 1 additional Phase 3 trial, similar to the size we currently have, maybe slightly larger. And the upside case is that we can actually go to the agency if the dataset looks really good and basically make a case for having a conditional approval and a confirmatory Phase 3 in parallel. We do believe the key question here is actually not on the efficacy side, because we believe we should see a signal in 1 dose, maybe even in 2 doses, it's a lot more about what the safety requirement is. One of the challenges with lupus, of course, is that the safety profile for lupus patients often looks very different from psoriasis because those patients are more prone to infections, they're more prone to cardiovascular disease. They have a lot of concomitant meds, so it's a lot harder to tease out those elements, and that's the piece of information we need to have. We will certainly take advantage of every possibility here that the new guidance from the FDA at least provides us. I do believe that we also have to be realistic, that we have to also prepare for our base case that there is 1 additional Phase 3. Right. Appreciate that. Maybe switching over to the pipeline beyond envu. You know, you acquired lonigutamab from ACELYRIN, about a year ago now, or at least when the deal was announced. You know, any progress in how you're thinking about that program? Then obviously you have your CNS penetrant TYK2 and A-005 as well. Let me start with just the TYK2 franchise, because I think it's important for all of us to understand that while we have a CNS penetrant molecule, and the preferred place to go and take that molecule is CNS indications, we do believe with the latest data on the opportunity set, we have to think about this as a TYK2 franchise. As such, if you think about pricing, if you think about IRA, if you think about patent life, if you think about permeability of the molecule, et cetera, there might be some peripheral indications that we should also think about A five. I want to leave you with the notion is, we should probably not necessarily just separate this out as a totally separate thing, but it actually really is how we need to think about it now, and where else do we take our TYK2 franchise? We have to incorporate that. That's an ongoing process, and we're going to share more news about that in the not-too-distant future with everybody. On lonigutamab, we actually strongly feel that lonigutamab is a differentiated molecule, especially based on the mechanism. We've actually... We're doing ongoing work to really better understand that mechanism, because one of the most interesting things in the last couple of quarters has been some novel data that the IGF one molecule, actually a protein, actually might help shuttle things across the blood-brain barrier, but also across the blood inner ear barrier. The question really for us is that if you have a competitive inhibitor like TEPEZZA or vrselerotug, does that mean that you basically have more IGF that can help shuttle these molecules actually into the inner ear, and therefore the ototoxicity is partially related to the mechanism? That's really something that we're exploring. Then we have a couple other pieces that we're working on to ultimately create what is the right story for lonigutamab. Part of that is also what the competitive landscape looks like. Once we have that information, we said in the first half of this year, we will make a decision on how to best move forward. I think the most important thing here is we believe this is an asset, we believe it is an asset that has value, and at the same time, we have to figure out how that fits into the overall picture and what is the story we're coming to all of you with. As you know, there was a lot of dichotomy and understanding around lonigutamab. Some people felt like, we should not move forward, some people felt it should absolutely move forward. All right. Well, gentlemen, we are actually at time, so I just want to thank you very much for taking the time to sit down with us this afternoon. Deep dive into the story and positioning us ahead of the Derm conference. I hope you guys get that late breaker. It's gonna be an exciting weekend, in Denver in a couple of weeks. Look forward to seeing you all there. Yeah. We hope the same, and hope to see you there as well. Thank you for having us. All right.