Bit early, but we can get started. Welcome back to the Cantor Conference, everyone. My name is Eric Schmidt. Delighted to be hosting our next presenting company, Alumis. We've got Martin, the CEO, and Jörn, the CMO. I know we've got a lot to talk about coming off some data just last week. Before we get into envudeucitinib, the company's next generation TYK2 inhibitor, and the Alumis phase II-B results in lupus that came out, let's start with the high level, Martin, and just remind everyone what the key attributes of the company are and how you're going to create some shareholder value going forward. Thank you, Eric, and thanks for having us. We're a precision immunology company based in the Bay Area. We're about five years old now, and our two clinical assets are actually TYK2 inhibitors. We do have a pipeline behind that that we haven't shared yet, but it's also focused on precision immunology. Our lead program is envudeucitinib, and envudeucitinib just reported basically one-year data in psoriasis. We're planning on presenting some additional data at EADV in a couple of weeks, and then also file an NDA for envudeucitinib in plaque psoriasis for moderate to severe plaque psoriasis in the fourth quarter of this year. That is a business that we believe is already in itself quite valuable. I believe, to be honest with you, it's not really reflected in our stock price today. What we've shown with envudeucitinib is very good activity in plaque psoriasis for an oral drug. There's a couple of features that probably are unique and differentiating for what we've shown, and that is that we have very strong effects, not just on plaque psoriasis and the plaques themselves, but also on quality of life, on itch and other factors that we believe play a key role in the well-being of psoriasis patients. The second indication we started envudeucitinib in is lupus. We reported out last week that while we did not hit the primary endpoints, we learned a lot in this trial. It was a Phase II trial in terms of how we might move forward, and we certainly spend a little bit more time discussing about that. We have a second TYK2 inhibitor in A-005. This is a brain-penetrant TYK2 inhibitor that we intend to take into a Parkinson's biomarker study in 2027. Maybe before we get too deep into the applications for TYK2 inhibition, just high level, why TYK2 inhibition? What does this solve in I&I indications that others can't do? Yeah. So our initial interest actually was really piqued by a lot of really strong genomic data. TYK2 has a couple of key mutations that are very telling actually about the mechanism itself. One of those mutations specifically, it's a P1104A mutation. Actually, it's a mutation where you down-regulate the kinase function of TYK2, very similar to what we do in the clinic. When people are carriers of that mutation, actually, they're highly protected against autoimmune disease. In the case of many of these indications, especially those patients who have two copies of these alleles, so have a very strong down-regulation of TYK2, they have about an 80% reduced chance to have psoriasis or lupus or other autoimmune disease. On average, these protections, even with a single copy of this mutation, is between 20% and 40% protective effect. So we've always felt that that would be a good indicator for what we might see in the clinic. The second piece is that there's actually no phenotype when you have this mutation. So most people don't know that they have this mutation. So we felt if you down-regulate the kinase function of TYK2, you should actually have a very safe drug, and you should have a very effective drug. We certainly have shown that in psoriasis, and other people have shown that in psoriatic arthritis, in CLE, in SLE. Currently, the TYK2 inhibitors are actually studied in about 10 other indications, or 10 indications in total. So we believe that there's a broad opportunity for TYK2 across many autoimmune diseases that are affected by either the IL-23 or the interferon pathway. Okay, let's start with SLE, and then we can progress to some of the pre-commercial preparations around psoriasis and your strategy there. But the data last week, as you mentioned, Martin, weren't what you had hoped. What are the key learnings from that story? Yeah. So this was a phase II-B dose-ranging trial that tested three active doses of envudeucitinib against placebo. Primary endpoint was BICLA at week 48. Bottom line was that the primary as well as key secondary endpoints were not met in the overall population. The key learning was that there is a well-understood subpopulation that, in fact, many other trials have looked at, which is characterized by elevated expression of type I interferon-regulated genes, or the so-called interferon signature. In this subpopulation, we saw a very robust response. The obverse subpopulation to type I interferon signature negative was, as had previously been reported, characterized by very high placebo responses and really no observable treatment effect. As we set out to design and conduct this trial, we decided not to exclude type I interferon negative patients, because at that time, there was no a priori evidence that these patients would not at least derive some benefit from the treatment, even though it was already known from the anifrolumab experience that they were likely to have higher placebo responses. So instead, we decided to stratify and analyze it. Unfortunately, it did turn out that we enrolled an unexpectedly high proportion of these interferon negative or interferon signature negative patients. Typically, they constitute roughly 30% of the overall moderate to severe lupus population. In our trial, they were close to 40%. Among this subpopulation that constituted 40%, there were very high placebo response rates and no observable treatment response, and that was an effect that was sufficiently large to render the overall all-comers population negative. What was startling about the data as I saw it, Jörn, is just the high placebo response rate in that interferon negative- Yeah. population, and much higher than the drug arm in terms of response rate. Yes. Is there any viable explanation having pondered the data now for probably several days? Yeah. We're still basically in the process of digging through the data to see whether for example, any particular ethnicities, any races, any geographies contributed disproportionately to this. I think to some extent it is randomness and bad luck, as we have seen this in prior trials, including in the PAISLEY trial of deucravacitinib where there was a negative treatment effect in the subgroup in one arm, a positive in the other arm, and a neutral effect in the third arm. So there's just a lot of variability and randomness specifically in this subpopulation. And it appears that the type I IFN negative population is just a very heterogeneous sort of Gemisch of different underlying disease pathophysiologies. This isn't your first lupus study. Given what you know about the indication and this IFN negative subpopulation, did you consider making this trial LUMUS-focused in terms of the statistical considerations on the IFN, interferon gene signature high patient population? Could that have been an option? That could have been an option, and in hindsight, which is 20/20, that would have probably been a smart thing to do. But like others, we basically elected to have the overall population as the primary endpoint and then a secondary analysis by interferon signature. But yeah, had we done it the other way around, we would have had a different headline. What is the path forward here as you think about it, and maybe timeline forward as well? I think the path forward is to really hone in on this type 1 interferon positive subpopulation that has a very good chance of responding to therapies that target this pathway, and to stay away from the type 1 interferon negative subpopulation that has little or no chance of deriving any benefit from this type of therapy. You can achieve that in a variety of different ways. You can either, again, do an all-comers trial, but with a cap on the proportion of interferon negative patients and the primary analysis being in the positive subpopulation with the overall all-comers as the secondary analysis. Or you can basically select based on the biomarker to begin with and only study patients with the type 1 interferon signature. All of these are possibilities. Which one of those is most appealing will in part also depend on regulatory feedback that we hope to obtain towards the end of this year. If you start to use the IFN gene signature assay to either enroll or stratify patients, do you need to validate that assay for use as a clinically validated study? Yeah, that's exactly one of the topics we need to discuss with the agency. This is not an assay that's developed by us. It's an off-the-shelf, CLIA-certified assay that is available in major central labs such as PPD and Covance. It's not our invention, but if we use it as a biomarker that we base enrollment on, there may be additional validation and qualification requirements, and that is one of the topics we need to find out. What does the timeline look like toward making a decision on next steps? I think we want to get ready to define a path forward to phase III. The FDA interaction is a part of that. The next several weeks, we'll still spend digging through the data in a great amount of detail and depth, and answer some of the questions that we don't have certainty about at this point, including dose response, why did the SRI-4 perform better than the BICLA counter to our expectations, and other questions along these lines. We will then propose a phase III protocol design and submit a data package as well as the draft protocol to the agency for comment and feedback, and hope that we can get this feedback towards the end of the year. The agency always does get busy in December. Whether or not we can get this meeting this year or early next year, I cannot predict, but we'll certainly work expeditiously to submit the package. This may be more of a question for Martin, but how do you think about capital allocation to another SLE study knowing that this is a difficult indication, at least for clinical trial development? Yeah, I think we're definitely going to do additional analysis to really understand some of those data that we actually have in hand. My view is that data has to give us more conviction than before, that we should really go ahead. We'd certainly have alternatives. I think for us, the key question now in the next couple of months is whether our base business is psoriasis and we'll build everything on top of that, or whether our base business is the interferon-driven diseases, and we'll build on top of that. Then it's really more a question of what can we do in terms of capital allocation to these businesses, and that will really define the path forward to a large degree. We continue to believe very strongly that the interferon hypothesis per se has actually only been reinforced by these results and not negated. We do believe TYK2 remains a very attractive target for both interferon-driven diseases and IL-23-driven diseases. But we also learn not just internally, but we'll get some additional external validation or at least data from our competitors on some of those indications that might also define additionally where we are going to put our efforts. I think you're probably referencing Bristol's SOTYKTU in part with that answer. They're going to have a phase III readout in SLE later this year. Yeah. Should that succeed or fail, how would that influence your thinking? I think there's a couple of scenarios, right? If it fails for very similar reasons that we failed, then I think the hypothesis remains intact and the path forward remains possible. If it fails for other reasons, the drug didn't work, then that would substantially increase the risk, obviously, and would certainly lead us to reconsider. Conversely, if they have a spectacularly great outcome where they can replicate their 28% delta that they saw at the 3 mg BID level in the PAISLEY study, then that would also make a path forward much more challenging and would lead us to reconsider prioritizing other indications. Competitively challenging, not saying- Competitively. Exactly, yeah. Okay. We'll talk about. Let's move to psoriasis, and we'll come back to partnerships. Okay. If that works for you. Obviously, you had much better success in the phase III psoriasis studies. Yes. We're expecting a little bit more data later this year. So maybe first frame the next update, and then we can talk about the filing strategy. Yeah. In psoriasis, we had really great results for the six months dataset in January, and we showed that we actually had the highest PASI 100 rates of any oral drug in psoriasis across our two trials, with a PASI 100 of about 40%. That means basically 40% of patients were in a clinical cure kind of state. We also showed very, very strong data on quality of life and other metrics, patient-reported outcomes, and itch. Overall, actually, the key measurement, the PSSD, that evaluates how many patients feel like the psoriasis is not impacting their life at all at 24 weeks was actually 35%. That compares very, very favorably with our competitors so far. A couple of weeks ago, we reported then the 12 months data or the 48-week data for the ONWARD1 and ONWARD2 study that the patients are enrolled in ONWARD3. ONWARD3 itself saw a PASI 100 rate of 55%. If we follow every single patient that enrolled in the trial in an intent-to-treat analysis from the very beginning to the very end, at 48 weeks, we're still above 47% in terms of PASI 100. That's a really, really strong number, actually stronger than what we've seen from competitors so far at week 48. Overall, we feel like we have a very strong molecule, not just from the plaque reduction standpoint, but also from the quality of life and other factors that matter to patient standpoint. We'll see some additional data, especially about some of these other aspects. We also are presenting data related to how well do people actually stay on drug and how good the durability of the effect is. That's coming later this year, and then we will finish with the NDA filing. We're planning to file that in the fourth quarter of this year. Importantly, we also observed a continued excellent safety and tolerability profile, really with no signals relating either to MACE or lipid excursions or other hypothetical risks or malignancy signals or anything like that. Really strongly reinforced the safety profile that we had observed in the ONWARD1 and ONWARD2 trials. With the withdrawal study that you're completing, is that just a check-the-box exercise, or is that going to be informative at all of the drug's profile? I think that's mostly a check-the-box exercise at this point, given that we've already reported that 90% of patients maintain their PASI 90, 80% of patients maintain their PASI 100 as well. So from a maintenance and durability standpoint, I think it's more a check-the-box than anything else. You've talked about filing in the fourth quarter. What's limiting to that? The only thing that we were actually waiting for is because we have to submit safety data across all indications that we're studying. The last piece actually was the safety data from the LUMUS trial. That one also was very good safety, and we shared that we have not seen any major malignancies there in that trial or anything. So we believe it just actually complements the safety profile. Does that mean if you are able to get that safety data set into usable, submittable form that you could be filing in the earlier part of Q4? We just basically guided to fourth quarter, and there is a lot that needs to happen for a filing. At this point, it is in the fourth quarter, but we are not going to be more specific than that. Okay. Psoriasis obviously has been a competitive market, a large and certainly very expanding population that is being treated. But you do have a couple of competitors in the oral space. What key labeling considerations are you hoping to obtain in order to be competitive there? I think the most important things are that we make sure that those pieces that ended up in the DUPIXENT label or in the JAK labels are not going to necessarily show up in our label. We believe we have a very strong case to be made that we should have similar basically TB labeling as you have seen with SOTYKTU and as you have now seen with [Repro]. We do believe that there is really no malignancy signal. There should not be any monitoring requirement. Those are certainly the pieces where we aspire to in the label just based on the data. What we are likely going to have, like every immunosuppressant, is a warning for infections, but that should be relatively overall, the label should be a relatively clean label based on the data that we have seen. So maybe specifically, you don't think you'll have the class JAK warning? We don't see a reason that we should have a class JAK warning because this is not a JAK inhibitor. It's a member of the JAK family, but we really don't inhibit, and we don't see any JAK pharmacology. Are there regulatory discussions you've had that make you believe you can kind of get around that class warning that was instituted on SOTYKTU? No. Label discussions and then warnings occur later in the process after NDA submission. But we intend to very strongly present our view that the data that we are presenting, which is a large data set comprising 1,600-plus patients, does not really warrant this warning because we did not see any lipid excursions nor any other suggestions of JAK-like activity. Is there something different from your data relative to SOTYKTU that makes you think it's safer, or did Bristol just negotiate a lesser label? Well, Bristol did see a little bit of an elevation in triglycerides that I think is very debatable whether or not this is of any clinical significance, but it did end up in their label. J&J's deucravacitinib is launching as we speak. What are you learning and watching for in that launch? I think the first and most important piece of that launch is that we always said, and I think so did our competitors, that this market is ripe for a high-efficacy oral. I think what we're seeing very much is the adoption of that drug is very rapid, and patients really would like to have an oral option that is efficacious. So I think actually just looking at the new patient starts and how actually that launch is really affecting others, especially the biologics, is very encouraging to us. I think one of the key pieces that we will have to see is that whether the drug performs in a similar way in the commercial setting or the real-world setting as it behaved in the clinical trials. Because one question always was with drugs that require fasting, whether they behave the same way. I think that's one of the aspects that we will watch very closely. Can you get a sense of that objectively, or is it just sort of feedback subjectively from the field? I think we will have to rely on what the impressions are that physicians report back to us. Ultimately, those impressions will affect their prescribing behavior as well. Maybe the one liability of envudeucitinib in the competitive psoriasis indication is a BID formulation. I do not know if you feel that way. Maybe I feel that way. You have been working on a QD for a while. What gives you confidence you are going to get there? We actually have three approaches that we've been working on. We are entering the clinic with those approaches in the near future. We do believe that we have a path forward going there. We had a formulation. We basically didn't like one aspect of it and ultimately decided to basically dismiss that approach. But we will get to once a day. Our market research suggests that we basically will lose some market share due to the BID, but it is not a huge impact. It's in the 10%-20% impact. What would you need to show from your formulation QD in order to get that to commercialization? The reason why we've been relatively quiet about it is exactly that question, because we don't have that answer. Depending on the solution, we will have to run either a clinical trial or might have to possibly do it in a different way. But the most likely outcome is that we have to run a phase II-like trial for that formulation to show some equivalence and then move into the commercial realm. Okay. Maybe let's come back now that we've kind of fully vetted the two leading indications, psoriasis and SLE, come back to strategy partnerships, collaborations, and how this all kind of fits together in your mind. Yeah. I think we've been very clear for a long time now that we believe that the best way to maximize the opportunity across all the different indications for a TYK2 franchise like we have is with a partner that shares the same vision. There are certainly other ways to do this, and we're reviewing that, and we're talking to people about that. You could also partner just one aspect like we've done in Japan, where we basically gave away the rights just for dermatology. So in our minds, there's an opportunity here to think about how you make the pie so much bigger that our share of that bigger pie is bigger than if we did it alone. There is a way to do this alone, and I think there's good examples now where people have done it alone. But that is not necessarily the path that we believe will actually maximize value. Is the time right now to investigate and sign a partnership or fully vet this, or what is your thinking on timing? The lupus data, to a certain degree, is a clearing event. It's not exactly the absolute clearing event that we were hoping for, because if the trial was positive, it would be more clearing than where we are right now because there's still a question on the path forward. But at least it is now clear that there is an opportunity in the interferon-driven diseases. So it's now easier for people to value that aspect. And so we believe that now is a good time, as we predicted that it would be, compared to where we were before, to have these conversations. What type of deal structure do you think does make sense such that your share of the pie can be substantial enough relative to going at it alone? Ultimately, this is all about do we share the vision? If we don't share the vision necessarily, how do we retain enough value in a collaboration that we basically can ultimately realize that vision? What's your vision? Well, ultimately, I think the best way would be to have a global partnership where somebody believes that there's five, six, seven, eight, 10 indications here that could be developed and ultimately launched in partnership. Do you have a vision? What is your vision for the molecule? Based on the data we have to date, I would say we have already seen that TYK2 actually has very good efficacy, best oral efficacy so far in psoriasis, in CLE, in psoriatic arthritis. SLE is still outstanding. We will find out. Ultimately, there are many other indications where it could be used. We believe the most important thing is that we really have a chance to realize the possibilities for TYK2 across many different diseases for patients who really have very few options right now. We have talked before about interferon-driven indication. That includes many more there. The question is really what is TYK2's role in IBD as well. Is it worth talking about what might come after SLE, or is that all still TBD in conjunction with a partnership? I think a lot of it is ultimately a matter of what can we finance. We said earlier that our intended focus before we saw the SLE data was to focus on interferon-driven diseases, the next two that we suggested that we would pursue were CLE and were Sjögren's. I think we are still in the evaluation phase at this point, what exactly we are going to do and whether there should be a shift or not. You mentioned the stock price was in the [toilet], for lack of a better word, and maybe below fair value in the psoriasis indication alone. What do you think you need to do to regain confidence in the share price and see share price improvement? Yeah. I think the most important thing is people need to understand what they're actually valuing. Right now, it's a little bit harder because we just had this event. So I think the most important thing for us is to basically re-articulate once we are clear how we're moving forward, re-articulate what the strategy is for the company, and basically make the case for why we're allocating the resources where we're allocating them. I think ultimately that we have a very solid molecule with great safety and great efficacy in the indications where it has worked. I think ultimately you can build on that, and people just need to understand how we're going to spend the capital that we have very wisely and invest capital to maximize the value of this franchise. But then also, I think the next piece is what's behind the pipeline and how we maximize that as well. Well, it sounds like capital allocation is a key deliverable on your end then. Absolutely. When do you think we'll get that information? We'll have to see whether we can do this in a two-step process or whether we just have to wait until we have all the pieces together. If we can do it in a two-step process, we might start to articulate that before the end of the year. Otherwise, we probably want to make sure we have the interaction with the FDA and have that understanding. But we certainly, in the meantime, are very judicious in how we're spending the capital that we have and where we can make sure that we're basically allocating capital and where we're not allocating capital right now. We didn't talk about your other molecule, A-005, Parkinson's. Expecting that to maybe go into a trial next year. Is that a priority for capital allocation, or is that less of a priority? The top priority for this year is submitting the NDA. Certainly, A-005 is an asset that is important to us, and it is an important priority. But at the end of the day, we will have to see what is our ability to start and to finish this trial. We, under no circumstance, want to start something that we cannot finish. We'll determine our overall strategy and then make a decision as to what is within strategy and what is beyond strategy. At that point, I think we can provide an update there. Terrific. Martin, Jörn, thank you for coming out so quickly after the news last week and sharing your latest thoughts with us. Really appreciate it. Thank you. Thank you. Thanks for having us.