Hey, everyone. We're back now with Alumis for a Fireside Chat. We have CEO Martin Babler and CFO John Schroer for a F ireside. Maybe I'll start off by sending it back to Martin for a quick company overview, and then we'll jump into Q&A. Martin, over to you. Thank you, Alex. We're Alumis. We are about a four-year-old company. We're a precision immunology company, with a focus on our lead asset being a TYK2 inhibitor. We have three clinical molecules and a research pipeline behind that. To start with, our lead asset is ESK-001. That's a TYK2 inhibitor that we're studying for psoriasis and lupus. We will have the readout for psoriasis in early Q1 of next year. We will actually, at that point, read out both our phase III trials. Each trial has about 850 patients in it. We will read out both the 16-week endpoint, which is against placebo and active drug, and then the 24-week endpoint, which is against active drug. This positions us well, time-wise, with the competitors. As you might remember, we started way behind the competitors, but we were able to catch up. I think that team did a really fantastic job in terms of execution. Behind that, we have the readout for lupus, which will happen in the third quarter of next year. In lupus, we are in a phase II-B right now. This is a trial that was designed as a pivotal trial, and if that has a good outcome, we have the opportunity potentially to just have to run one more phase III trial. Then we have A-005, which is going to go into phase II for MS. A-005 is a brain-penetrant TYK2. We have been able to show that we have a one-to-one ratio between the plasma and the brain, so a very well-behaved molecule as well. Then we have lonigutamab that came in with the merger from Acceleron, and we have multiple planned assets, and one of those actually will have phase I data sometime next year. I think the most important other aspect is we have, with the merger with Acceleron, enough cash to read out both psoriasis and lupus and still have cash beyond that into 2027. The team here actually has quite some experience. Many of us on the leadership team came from Principia and MyoKardia, and we've basically had successful development programs before. I'm going to stop here and hand it back to you, Alex. Yeah, I think the first question I have is just kind of like a high-level one on TYK2 as a mechanism and a class generally. If in 10 years or so, the TYK2 class is this multi-blockbuster class, like the next JAK class what would you look back at now and point to as evidence for that happening? I think right now a lot of investors are skeptical of that, just maybe given the way TYK2 has been launching. What would you point to to give your confidence in this being a huge class in the future? Yeah, so I think the most important thing is that when you look at the original thesis that we had based on the genomics and how that translates to the clinic, we have always known that for TYK2 to get the real effect of the target, you actually have to hit the target really hard. When you actually start with the genetics, and there's a TYK2 is one of the richest targets when it comes to genetics and genomics and the mutations. There's one specific mutation, which is this 1104 mutation, that just down-regulates the kinase function. There's two features of that. The first one is that there's no phenotype, so it should be really a safe mechanism. The other one is that when you look at the effect that it has, a lot of people have highly protective effects against autoimmune diseases. That would suggest that there should be a good therapeutic effect. The one twist that a lot of people have not necessarily understood is that when you look at the patients that have one allele, so the heterozygous carriers, they actually have a 20%- 30% protective effect and less kinase function reduction. Those that have the homozygous variant with two alleles, they have a very strong kinase reduction, and they actually have about an 80%- 90% protective effect. That already told us that inhibiting this target really hard is important. Unfortunately, the first couple of molecules in this class have not really delivered on that promise, but there actually have now been a total of four molecules that have delivered on that promise and actually have shown really, really good results. There's our own molecule. There is a molecule that a second-generation molecule that Bristol Myers Squibb had, and then there's two molecules that are developed in China only from Incyte and InnoCare that actually also show that better inhibition actually leads to a better outcome. I think the challenge that we really have is that the class has been a little bit, gotten a bad rap because of the first couple of molecules that maybe just weren't that effective at that as the target. When you actually look at the data and you look at nuances of the data, you already know from our phase II data, from the CLE data with DUCKRA, from the psoriatic arthritis data, and that TYK2 actually is a very viable target that really instills a benefit for patients. I think we will look back at this and think about, you know, it was not the target, it was not the mechanism, it was actually the molecule that led to the perception. I do believe that in the next 12 months, we will really change the view of TYK2 as a target. Yeah, specifically for your molecule, like DUCKRA, what are the key design aspects or otherwise that you think are differentiating versus even these next-gen molecules? Yeah, so amongst all these next-generation molecules, I believe, or we believe that ESK-001 actually stands out because we've already shown from a safety profile that we do not have, for example, to dose reduce because of those skin reactions that others have seen. The first three molecules in this class all had to dose reduce when they went from phase 1 to phase II. We did not have to do that. We could literally push the dose to above IC90, for 24 hours a day. That is the key differentiator. We know that some of the newer molecules besides ours actually have the same feature. Whether that is TYK2 driven or whether that actually is a metabolite issue is to be seen, but we do believe actually the one molecule where we get a sense that it might be a metabolite issue is actually the case of, of, so TYK2 versus its second-generation follow-up molecule, which basically was a little bit more optimized for the metabolic profile. We do believe that actually is some credence to that hypothesis that this is really, if you have active metabolites and they might not be as selective, you might actually have a different side effect profile. Yeah, yeah, makes sense. I want to talk about your phase III design, et cetera, but we're going to get, before your phase II reads out, the final phase III, at least top-line data from Takeda, the NIMUS molecule, later this year. What are your expectations for that readout? And what are the important read-throughs for Alumis? If you look across the board of all phase II data so far with this molecule, most endpoints show an efficacy that is probably better than TYK2. Where exactly it's going to fall, we don't know. What we know is that that molecule is not at the dose at least tested in, and that we understand that they test in psoriasis, able to be above IC90 24 hours a day in patients. Where that exactly comes at, we don't know. Our assumption is that we have three molecules that are in late-stage development in psoriasis, and they will have better efficacy than what's out there right now. How they ultimately stack up compared to each other, we will see. The one thing we know is that, at least from the data, in the two phase IIs that have read out for the molecule from Takeda, there is a little bit more skin reaction than we've seen in our trials. The question really is on the efficacy and safety, is the molecule going to set a new standard, or is this molecule going to fall slightly below the expectations? We'll have to see that. The other molecule I want to talk about is ixekizumab, the IL-23 receptor antagonist, oral as well. Where does that fit into the conversation around next-gen orals and psoriasis? We do believe that that is probably the molecule that we all have to reckon with. However, we actually have not seen a pure adult population data set yet. We will see that sometime later this week, and it will be interesting to see because the data we've seen so far was always actually slightly, you know, probably biased by the fact that they had adolescent patients in there who normally actually have a better outcome, and that has been shown. I think really the bar will be set by the data that doesn't include the adolescents, and we'll see that later this week. We do believe it's a competitive molecule. The big question for that molecule is whether the clinical efficacy is going to translate into the commercial market. When you talk to dermatologists, there is a suspicion that patients will not be fully compliant with the fact that you have to fast two hours before and sometime after. We know from other oral protein molecules, for example, in the GLP-1 space, that when they were ultimately in the market, the efficacy was not quite as high because patients just were not compliant. It's a safe molecule. It's a very well understood mechanism. It is an efficacious molecule. I think there will be nuances here that will differentiate those different molecules and those different classes. For example, we see that at least in when it comes to a reduction of itch, for example, that our molecule has so far shown in phase II a faster and deeper response. We do believe that there's an opportunity in plantar disease, for example, where IL-23 pure mechanisms actually don't work that well. There will be preferences and there will be differentiation, but we do believe all of these molecules have a competitive profile that we need to reckon with. Also, if you look at right now, there's actually more patients on oral therapies than there are on oral systemic therapies than there are on injectables. It's just that from a patient share, there's more, but from a dollar share, basically, the injectables are dominant. They actually, less than 10% of all diagnosed psoriasis patients actually are getting an injectable at this point. There's a huge market opportunity for these orals that we believe leaves room for everybody. On your own phase III program, can you talk about the design of the trials and really what you think good looks like here? I guess, like, do you need to replicate what you saw in phase II? We actually might not even need to replicate what we saw in phase II because I think the bar currently is set that at 16 weeks, you need to be somewhere between 50% and 60%. At week 24 through 52, what we've heard from the dermatologists that looked at our phase II data is that they believe if you're somewhere in the range of 80% for PASI 75, somewhere in the range of 60% for PASI 90, and somewhere in the range of 40% for PASI 100 during that time period, you have a highly competitive molecule. We believe that that is achievable. Our design is such that we have a 16-week primary endpoint against placebo. We also have active control at 16 and 24 weeks, and then patients go into long-term extension, which will give us the durability and the maintenance language for the label. You will have a table in the label with 16- and 24-week data, and you probably will have text in the label on the rest. We believe we will have a very competitive label, very comparable to others. Our design is such that we can submit with the six months data. We don't have to run all the way out to the 12 months data, and that gives us a little bit of timing advantage. That's how we were able to catch up, basically, with the other TYK2 inhibitors that were in the market. Yeah, I guess sort of fast forward successful phase IIIs, you know, can you launch this drug on your own? You know, can a biotech like Alumis be a competitive player in this market? I would say the likelihood that we're going to launch a drug like this on a global level by ourselves is relatively low, but we do believe that there is an opportunity. There's actually a precedent now in the psoriasis market with Sun Pharma having launched their drug, and they found a creative way to basically be a player in the market. Is it going to be the same size product as if you had a partner? Probably not. Could we possibly do this on our own? Yes, that is not necessarily our intent to do so. Is it a possibility? We do believe we've done a lot of thinking about this and a lot of work on it, and we do believe there is that possibility certainly to do so. Are you going to, you know, go through the necessary prep to launch this drug on your own, or are you going to look for a partner immediately following positive phase III data? I can't really just declare what our strategy is here, but what I can tell you is that given that we have a commercial organization in-house that has a lot of experience with launching drugs, myself included, we are doing all the things that need to be done in a timely manner, in preparation for the launch. I think that's the most important part, that even if we have a partner, the things that need to be done at a certain point in time prior to the launch will actually have been done for the launch of the molecule. For, you know, moving on from psoriasis, why is SLE such an exciting, you know, market opportunity for a TYK2 inhibitor? Yeah, so we decided on SLE for really two key reasons. The first one is when you look at most programs that are run with TYK2 right now, they're actually focused on the IL-23 mechanism. The second mechanism where TYK2 is actually very strong is the interferon pathway. We've shown in our phase I and then in the phase II in psoriasis patients that both systemically and in the periphery in the skin, we actually reduce interferon levels down to normal levels with our molecule. We do believe that there is really good data that validates interferon as a mechanism. The first one is that we have genomic information that shows that. The The second one is enofrilimab basically goes after the interferon pathway. The Biogen molecule, also, one of the Biogen molecules also goes after the interferon pathway. Those both had actually successful clinical data. The third one is really that there is already positive data in phase II with the TYK2 inhibitor in the case of deucravacitinib. We have three key pieces of validation that TYK2 actually is a really interesting mechanism for lupus. We decided to pursue that also to open up the entire path of the interferon mechanism because there's a lot of indications, especially in rheumatology, where that mechanism plays a key role. For us, the readout next summer, in the third quarter, is not just about lupus, but it's also about opening up that opportunity set of interferon-driven diseases. Yeah, makes sense. I guess beyond room, you know, IB has always been a question for the TYK2 class. What's your level of confidence that that could be unlocked with this higher exposure strategy with these next-gen TYK2s? Yeah, so I have one key question there. As you know, if you think about gut restriction, restricted drugs didn't necessarily work very well in IBD. The biologics need to dose really, really high because you actually have to get some drug into the gut for them to work well. For me, the question actually is not necessarily about whether the IL-23 mechanism works, and I think it will if you appropriately dose and inhibit it. The question is how much drug do you need to have in the luminal side and how much do you need to have on the systemic side. That's more a drug property question. What we've seen clearly with the IC90 data is that IL-23 as a mechanism will work in that disease. Whether it's going to be the best one, we don't know. I think the other piece here that is very interesting and where we have a little bit of an edge over our competitors because of our PK profile is that we do believe one interesting approach for IBD is combination. We have a molecule that is really easily combinable because it's so controlled, and has such a small% CV. We will wait to see what other people show in IBD, and that certainly could trigger for us to move forward in that direction. For right now, we believe that there's as much opportunity on the interferon-driven diseases side and some other indications, but it's certainly an area where, besides CLE, lupus, and psoriatic arthritis and psoriasis, you could possibly go and see a decent effect. You obviously have a lot of experience in MS. You know, what gets you excited about TYK2 as a brain-penetrant molecule with your next gen here and where that could go? Yeah, so the very original idea was actually to really enhance what we've seen with BTKs in MS. One of the most fascinating things, and we probably as a company, as our former company, Principia, spent more than most other people really understanding the gut-brain axis and the whole question about the microglial function. One of the best ways to describe it to you is that when we started to do work on TYK2, it became very obvious to us that not only do we affect microglia really well and very similar to BTK, which we know is a key driver of the BTK response in MS, but we're also affecting the astrocytes. The other thing is that we are actually a better, TYK2 is a better anti-inflammatory. The way we think about it now is that TYK2 really could be a BTK plus. Because when you look at our preclinical data in the EAE model, which is basically a model of inflammation, when you look at especially the prophylactic data, we literally can flatline that model. In other words, you cannot induce any inflammation if our drug is on board. That's actually better than the gold standard in that model, which is [Sengalimod] In the therapeutic model, the same thing. We actually beat the S1P1, which are the strongest anti-inflammatory drugs in MS, in that model. You get the effect that we've seen with BTK, which is basically the effect on disability more than anything. Then you get the effect on the relapse rate, which really comes a lot from the anti-inflammatory side. I think that combination is a really intriguing combination of effects that could really benefit MS patients. Makes sense. You mentioned in the upfront that with this Acceleron deal, you've obviously extended cash runway into 2027, but you've also got this new drug lonigutamab for thyroid eye disease. Where do you see, if any, path forward for that drug here at Alumis? Yeah, so I think the most important thing here to understand is that lonigutamab is a differentiated asset. It has a differentiated mechanism. The mechanism of lonigutamab is such that instead of actually competing at the receptor site against IGF-1, you basically internalize the receptor and IGF-1. The systemic circulation of IGF-1 is very different from what you see with other TED assets currently. The question is, does this feature translate into a valuable patient benefit on the safety side and therefore something that people really care about? The key question is, how do you best test that hypothesis in a way that you don't have to run a full phase III to find out? We are working through that aspect. We are also working through the fact that the TED market has a dynamic that people did not well understand in the past, but I think we start to understand better, which is that the re-treatment rate is actually very low. There seems to be some durable benefit from the treatment of these patients. The number of patients that come into the pool versus the one that leaves through treatment is actually almost smaller. What you've seen is basically a flattening or maybe even a slight decline of the number of patients available. The question really in that context is, what do you do and what do you actually have to accomplish to really get a dominant share in that market for it to be worth doing? In our minds, those are some of the factors that we're working through and eventually we'll make a decision whether we move forward. There's also some new biology around IGF-1 that might make other things attractive or interesting. Certainly, as an organization, we do believe that lonigutamab is a drug. Fundamentally, the question just is where and how to best develop it. Your current runway doesn't include any lonigutamab development at the moment? The current runway actually does include some money for (LONI), but we haven't spent any, or spent very minimal on it. Fundamentally, there is some money in there. We also want to be very judicious on whether, and how to best spend that money. I did want to touch on, you know, before we wrap up on your newly disclosed IRF5 program, it seems to be an emerging target, currently. I guess, you know, curious what you can say about where you think you might be differentiated versus others in the space. We haven't disclosed which molecule we'll have phase I data for next year. We have an IRF5 program, that is correct. From our standpoint, this is a very interesting target that we've done a lot of genomic work on, but at this point, that is about as much as we're disclosing on that program. Great. I appreciate you both taking the time, and thanks for joining us. Thanks for having us. Thank you. Thank you.