Good morning, everyone. Thanks for joining us here at the Leerink Partners Global Healthcare Conference. My name is Tom Smith. I'm one of the senior biotech analysts here at Leerink. It's my pleasure to welcome our next company to the stage, Alumis, and happy to be joined up here by President and CEO Martin Babler. Martin, thanks for joining us.
Thank you, and thanks for having us.
Martin, why don't you just kick us off here with a little bit of a brief overview of Alumis, maybe for those in the audience who are a little bit less familiar with the story.
Yeah, so we're a company that's about four years old now, a precision immunology company. Really, with the goal to better understand the genomics, but also the biology behind a lot of autoimmune diseases. And our first two molecules are TYK2s. We decided to choose TYK2 as a target because we really believe the genomics are extremely interesting and actually have some good predictive value in terms of what you should see in the clinic. Specifically, there are mutations that mimic basically what we do pharmacologically. And they show that patients or people that have those mutations have a very strong protective effect, but don't have a phenotype, which really should translate in the clinic into a good safety profile and also good efficacy in autoimmune diseases. Lead indication for our first molecule, ESK-001, is psoriasis.
We are in Phase III that will read out in the first quarter of next year. We just presented long-term data for 52 weeks over the weekend at AAD. The second indication we're pursuing is lupus. That trial is ongoing and will also read out in 2026. Two weeks ago, we also announced data from Phase I for our second molecule. That's a brain-penetrant TYK2 inhibitor that we will take into an MS study. That data showed that the inhibitor basically gets into the brain at the same level that you see in the plasma. We believe that's really critical because one of the things we learned in TYK2 is that higher inhibition actually leads to a really better outcome. We are currently in the process of doing a merger with Xelora, and that will add lonigutamab to our portfolio.
We will really build a well-capitalized company with a broad portfolio and multiple readouts over the next two years.
Got it. Certainly a lot going on, a lot of data generation in progress, kind of a big execution year for Alumis. Maybe just take a step back and high level, just remind us of some of the differentiating aspects of ESK-001 relative to some of the other TYK2s. We have Sotyktu that's approved. We have the Takeda compound acquired from Nimbus. Just walk us through how you think about the differentiated profile for your compound.
I should probably start with what we see in the clinic. What we clearly see when we look at the higher we dosed and we have a really nice dose response, we really see more efficacy as you inhibit this target more. We do believe that there's probably some amplification or other mechanism that really requires dampening. Actually, the genomics support that because what you see in patients that have that mutation that reduces the kinase function of TYK2, the heterozygous patients actually have about 20%-40% protection. The homozygous individuals actually have about 80% protection, which really is a predictor that the more you actually reduce this kinase function, the better results you should get. That's actually what panned out in the clinic for us, where the highest dose gave us very, very high efficacy in psoriasis so far.
The second highest dose, while actually really covering the target quite well, a little bit less. I think the most important thing in this class is that we are fortunate that we did not have to dose reduce because we had a really good tolerability for our molecule. Our competitors often had to dose reduce because of the tolerability issues. Our risk-benefit profile is actually different. That has allowed us to really push the dose and push the target inhibition and has really resulted in better outcomes.
Great. Yeah, let's talk about the clinical data. Yeah, you had the late breaker at AAD over the weekend, 52-week data now from your Phase II STRIVE study. Talk about, I guess, sort of the evolution of the profile there as you've gone out now with extended duration of dosing at that 40 mg BID dose level that you think is giving you kind of optimal target coverage.
Yeah, I think the most important takeaway for us this weekend was that this molecule or this program moved in the eyes of the dermatologist from an interesting kind of program to a highly competitive program. The profile that we showed, and it was described by Dr. Blauvelt on stage, think about it, 40% PASI 100, 60% PASI 90, basically 80% PASI 75. That's very competitive with a great safety profile. I think what the dermatology community has now realized is that we have a molecule that is kind of an IL-23 plus molecule because we also have the interferon aspect. That actually has resulted in really great itch control for those patients as well.
A really interesting profile, and I think in the eyes of the derm community, a very competitive molecule that gives them more choices now, excuse me, to treat their patients, possibly as an oral molecule with a high efficacy oral that is close to where the biologics are. At the same time, also provides opportunity to go earlier and harder for patients because you can now give an oral that is highly efficacious and is likely going to work. I think the most important aspect of the oral therapy is that it can be very, very simple compared to a biologic. It has a lot of appeal, especially for those doctors that have high throughput needs where they really just want to write something for their patient and have a convenient way to do so.
That makes sense. I want to ask you about another late-breaking data set we saw at AAD over the weekend, which is the Phase III data, the first Phase III J&J's oral IL-23 inhibitor, also in psoriasis. Maybe you could just put your Phase II data in context versus J&J over the weekend. We will come back, we will talk about some of the other data updates around that. They also pressed really top lined some other data, not a lot of details, but maybe just put that into context.
Yeah. Maybe instead of giving you my impression, let me tell you what happened on stage. I think when our data was presented, the comment for, excuse me, the moderator was, "This is stunning data." I think when the J&J data was presented, it's really nice data. I think it's fantastic for patients. The one question that came out of the room was, this was actually a data set that included adolescent patients. We all know that adolescent patients normally do a little bit better in psoriasis. The first question actually was, what happens if you separate out the adolescent patients from the rest of the population?
J&J did a really good job, actually including adolescent patients in their first trial that they read out because that ultimately gives a really nice data set that might overstate slightly what would happen in the general population. At least that was the perception of the dermatologist. I think what happened in that very moment in the room is that people felt like we have two very comparable efficacy outcomes comparing those two molecules. On the safety side, I think they're very comparable. We have an advantage a little bit that we don't have a food effect and therefore don't need to do fasting for our molecule before and after. We do believe we have a competitive molecule on the safety and the efficacy side. We believe that we have a molecule slightly more convenient.
At the same time, we have to wait for our Phase III because that will ultimately be the proof. Given that we haven't really made any changes between Phase II and Phase III we believe that there's a possibility we can translate the Phase II results into Phase III.
Right. Okay. Yeah, I guess concurrent with the detailed data presentation, they also announced that there's more data. This was from a head-to-head study that included Sotyktu as a comparator. I guess when you think through the prospects of seeing detailed data from that data set later this year, perhaps at EADV, I guess what's your expectation in terms of how that will stack up relative to what you just saw as a late breaker at AAD?
I don't want to speculate on competitor data, but our expectation is that we will see a relatively consistent 40, 60, 80 across these, maybe slightly higher on some of the others. I think the most important thing is that we will ultimately have now very different options for patients in psoriasis with oral therapies. Ultimately, I think it will expand the oral market quite substantially. Some of this expansion actually just will come because the duration on these oral therapies will increase. As we know today with current oral therapies, a lot of patients don't respond to them, and so they'll switch ultimately to other drugs. We do believe that one of the key aspects here will be a longer duration on oral therapies and more patients on them because the response rates are very different from what earlier first-generation oral therapies have done.
Got it. That makes sense to me. I want to stick with psoriasis, but talk about your Phase III onward program. You did recently narrow and kind of accelerate the time to data. You were thinking first half 2026, you've moved it into, pulled it into Q1 2026. Maybe if you could just provide an update on what you're seeing out of the enrollment trends and I guess what gives you that confidence to move the timing forward.
Yeah. We have seen with our competitors that these trials enroll relatively fast. We had an expectation whether we could possibly also enroll a little bit faster. I think the most important thing is that it is actually just easier and simpler to do a trial with an oral drug because there is a lot less scheduling and things involved. I think that is actually a reflection of what we see. There is certainly a lot of interest from patients in the trial, and we have certainly seen an enrollment trend that was faster than we anticipated. That allowed us to basically now narrow it down for the first quarter and have a readout earlier than we originally anticipated. I think part of the aspect of our program always has been speed. When we actually started this program, we were significantly behind our competition.
Certainly, we're not catching up all the way with everybody, but we do believe that we are on a very competitive timeline now as well.
I guess on that point, can you maybe elaborate on how some of the design aspects from your Phase II study could allow you to narrow the gap versus some of the other competition who's also running pivotal Phase III studies?
Yeah, I think that's a very important point. When we started the program, we knew that we could not be far behind the competition. We decided to do this open label extension in the Phase II. We enrolled all of the patients in that open label extension now into the Phase III dose. All those patients moved to the 40 mg BID dose. Because of that, a lot of the ICH guideline requirements are actually met with our Phase II data set so that we could shorten our Phase III from a 12-month study to a six-month study. That part of catching up actually was the reality that we could get agreement with the agency that a six-month study or a six-month data set is sufficient to submit. We are going to enroll all these patients also in a long-term extension.
We will have the 12-month, et cetera, data set. I think one of the differentiating factors ultimately at the time of launch will be that we will have a data set, hopefully in the label, that already will have patients at three years at that point in time.
Got it. That makes sense. Maybe if you could just talk to your expectations and how you guys are thinking about internal bar for success for top line readout in Q1 and maybe relative to what J&J over the weekend.
Yeah. There is some variability in these scores. Certainly, one of the things that we always struggle in psoriasis is the placebo rate is normally between 0% and 15%. Do you look at placebo control or not kind of aspects? From our standpoint, what we are planning on setting the bar is we want to be competitive in efficacy, competitive in safety, and competitive, and certainly have a slight advantage in terms of convenience. There are certainly some subsets that we're going to be very interested in. One of the really emerging factors in psoriasis that a lot of the thought leaders now realize is that there is a role for interferon in psoriasis that actually contributes to certain aspects of psoriasis.
We will do a lot of also analyses around those aspects and believe that we might have an advantage there because we really have the IL-23 mechanism plus that interferon mechanism. It is kind of an IL-23 plus that we really see with TYK2. I think that is the piece that we want to make sure that we have clinical data ultimately to also support that. One initial aspect of that is probably the itch data that we have, which is really quite powerful, but there might be other ways to also differentiate.
Got it. You just mentioned kind of a convenience aspect. I know you're also working on a once-daily formulation for ESK-001. You just provide an update there, I guess, where you are in terms of data generation and then what a path to incorporating that into a label looks like. Is that something that could be available potentially with first launch, or is that something that comes a little bit down the line? What are the puts and takes there?
Yeah. So the best way to describe it is we actually do have a formulation and we're optimizing it. The question, what do you optimize it for? We know we have to optimize it for Cmin. We have to optimize it for AUC. If you have every aspect, including Cmax optimized, you could possibly run a bioequivalent study and you would not have to run a clinical bridging study. Where we are at right now, we know what the technology is, we know kind of what the formulation is, and the question is how long do you optimize to do that? If we are doing a clinical bridging study, we will have it within the first year of launch, and we will have the data of that study likely at the time of launch. As we talk to payers, et cetera, we will have the data available.
We also can share with physicians what that looks like. This is an ongoing project. We'll update everybody later this year as a part of our milestone to make sure people understand where we are on this. Fundamentally, this is a molecule that has about a 12-hour half-life in patients. To get to a once a day, we need to go to about 14. It is not that tricky to make that work. The ongoing effort really is how do we best optimize that formulation.
Got it. Okay. We'll stay tuned for an update on that later this year. Talking about this as an IL-23 plus, I think we could go a number of directions with that. I guess first I want to J&J data set that we saw top lined yesterday. They announced a success in a Phase II ulcerative colitis study with their oral IL-23. What sort of read-through, I guess, do you see from that study to TYK2, the pathway, and specifically ESK-001? And how are you thinking about opportunity in IBD?
Yeah, it's actually a really interesting question because to a certain degree, we actually believe that that data is probably more relevant for us to understand whether our molecule could benefit there. I have to give you a little bit more context for that. One of the most fascinating things about the 1104 mutation is that the heterozygous carriers that only have one allele have almost no protective effect. The homozygous carriers actually have about an 80% protective effect in IBD indication, which really means that for IBD, you have to hit this target very, very hard. We do believe that given that we have shown in psoriasis that we have similar outcomes where the IL-23 axis is actually critical to pure IL-23 inhibitors, there's probably some interesting read-through here that TYK2 could also be effective in IBD.
It is not an indication we're pursuing right now, but certainly an indication that we believe is worth exploring for TYK2 with the notion that you really have to hit the target hard to get a really good readout. At the same time, lupus certainly is an area where we see as much, if not more opportunity. There is also a readout of cutaneous lupus this weekend, which we believe reinforces our view that lupus could be a very interesting indication for the TYK2 pathway as well.
Yeah. No, that's great. Yeah, I wanted to double-click on your lupus program, got the Phase II Alumis study. You've got it to completing enrollment in that study by the middle of 2025. We hosted a rheumatology KOL panel yesterday, and I think the enthusiasm for the class is quite high on the back of the deucravacitinib and PAISLEY data and some of the data you alluded to over the weekend. Maybe you just provide us an update on enrollment, I guess your level of confidence in hitting that mid-2025 enrollment timeline. Are there particular subsets of lupus patients? We mentioned cutaneous lupus, but particular subsets of lupus patients where you think you could see outsized benefit where ESK-001 could have a particularly effective role?
Just to answer the last question, we do not know yet, but one of the reasons we chose BILAG as the key primary endpoint is actually because there is a bigger skin component in the BILAG. We do believe that that could be a possibility here that we see an additional benefit. Certainly, the cutaneous lupus data right now has confirmed that. We are actually very happy with the enrollment. I would say the hardest part in lupus right now is enrollment because not only do you have a relatively small portion of patients who are willing to go into a trial, especially in a placebo-controlled trial, you actually have to find active patients to enroll. The active subset of the overall lupus subset is actually a relatively small one.
In the context of that and the difficulty that we've seen with other folks, we're actually very happy where we are. Our enrollment is going really well, and we are certainly on target to enroll within the timeframe that we've said we wanted to enroll the trial by somewhere in the middle of this year. It is a 48-week endpoint after that. I would say in the difficult environment, we're probably doing better than many others. Certainly, the psoriasis data and the cutaneous lupus data is helping on that. We are very excited. As you know, one of the most important aspects that we have really focused on is what do we have to do to minimize the placebo effect because that's actually what breaks a lot of lupus trials.
There is a very significant effort that we've also put into that part to really de-risk that program and hopefully have a good outcome for patients.
Yeah. No, that's great. Yeah, certainly appreciate the competitive nature of trying to enroll the patients. We looked at that there's over 70 now, I think, active Phase II or Phase III SLE studies ongoing. Yeah, the competition for patients is quite high. Just on that last point, maybe if you could elaborate a little bit on some of the steps that you've taken to try to minimize the placebo effect. I guess thinking forward to your top line data next year, how should we think about bar for success there? Is it the PAISLEY data with DUCRA, or is there a different sort of bar that we should be thinking about?
Yeah. I think actually it's the original lupus data for DUCRA probably is where the bar is, not necessarily the subset of cutaneous lupus patients. In terms of what we've done, I think the key steps that our Chief Medical Officer basically really emphasizes, Jörn Drappa , who actually was the person who got anifrolumab through the approval process, is really that you have to have active patients. We do have basically a very strong review. There's a review panel that looks at every patient and makes sure that we really have active disease. It leads to a slightly higher screen failure rate, but we've gotten this message really out to the clinicians. That has helped. The second one is that you really have to be careful about concomitant medications.
We have very strict guidelines on what works and what does not in terms of concomitant medications. I think managing that is a really important aspect. The third one is really that we do a continuous control of looking at the data that comes in because we do believe educating, re-educating people on how to use these tools and are you actually assessing patients right is critical. There is a continuous control in the incoming data on if there are discrepancies between the data that we see and what we believe it should be. Basically, we are going immediately back to sites and make sure that we can actually make sure that all the tools are used appropriately, et cetera, et cetera. Those factors we believe should help us reduce the placebo rate and the placebo effect.
There are some additional things we do, but I think we have so far really had a good response on all of these. Despite those restrictions, we have been able to roll the trial quite nicely.
That's great. Yeah, that makes sense. Are there any other sorts of puts and takes in that comparison versus the original DUCRA SLE study that we should be contemplating here?
We believe actually that the DUCRA study is a good proof of concept study. One of the fascinating things about deucravacitinib, and we've seen it in the PAISLEY study again, is that there really is not a great dose response. We do believe that despite the fact that there's not always a great dose response, these trials are really actually predicting that there is an effect. Now it's just a matter of can we, with our stronger inhibition, basically see that there is a dose response or not like we've seen in psoriasis. In psoriasis, it was really a beautiful dose response. We know our PK is very linear. We know that the PK of our competitors is not quite as linear as ours. We do believe we started this program with really, really understanding PK/PD, and we believe that actually is a very important aspect.
That makes sense. We talked a little bit about potential in IBD, but I think especially if we're thinking about this as like an IL-23 plus sort of mechanism, potential in a whole host of other indications kind of comes to mind. Like how are you guys thinking about expansion opportunities into other areas besides psoriasis and lupus and maybe IBD?
Yeah. So we've done a very thorough portfolio analysis last fall, and we're actually going to update that now with the new data that came out over the weekend and in the last couple of months. I think it's really important to understand that for us, there are about four sets of opportunities that we're weighing and that we're looking at in terms of value creation. The first one is there are some additional things we can do in psoriasis to enhance our profile. The second one are these new indications for TYK2, whether that is actually with the ESK-001 or A-005, our brain penetrant molecule. And I do want to emphasize that we have an additional degree of freedom because we have two molecules.
It is not necessarily that we cannot use ESK-001 for brain indications, but we could use A-005 for peripheral indications and really have a differentiated set of indications for the different molecules. Fundamentally, expanding into these other indications is a key factor. The third one really is to look at the combination aspects of TYK2. We believe, especially with our molecule where you have such precise PK/PD, that actually lends itself. We know that these people that have this 1104 mutation, basically, they are on TNF inhibitors. They are on IL-17 inhibitors. They are on IL-23 inhibitors. We really do not see them having necessarily a very different outcome. The question is, is TYK2 actually a good combination partner? There are some of these combinations that lend itself more than others. Looking at that is another aspect.
We also, of course, now have hopefully the opportunity, once the deal is closed, to really look at lonigutamab as another aspect of our portfolio. In the context of that entire portfolio, we certainly will make decisions that are data-driven. That is really two sets of data. One is the scientific rationale. The other one is really what is the target profile that we can? Looking through those, really looking at what is the best value creation opportunity for us as a company.
Yeah, that is really interesting. I guess I want to expand a little bit on the combination potential. I guess, is there anything unique to the formulation of 001 or 005 that would preclude you from co-formulating with another mechanism? Have you started generating data preclinically in combination with other mechanisms, either in psoriasis or lupus or other disease models?
Yeah, we have started. We've actually had ongoing work. One of the premises actually originally for the company was that the research projects we would pursue could actually be potential combination partners for TYK2. We have done quite a lot of preclinical work and have some of our favorite potential combination partners. The good thing about both of these molecules, if you look, is it's very linear PK. The % CV of ESK-001 is actually for most parameters below 20%. That is really stunning for a small molecule and lends itself to being a good combination partner. Because the molecule is quite predictable in its PK, the same is true for A-005. If you look at that original data, it's linear PK. It actually has low variability. Those are ideal combination partners.
One aspect about the IRA actually that people do not necessarily think about is that your clock restarts if you have a fixed dose combination. We do believe that there is significant opportunity with combinations as well.
Yeah. Okay. No, that's great. I want to talk briefly about 005. You presented the detailed Phase I data at ACTRIMS. I guess what particularly stands out from the clinical profile there? What are the gating factors to getting this into the Phase II MS study?
Yeah. What stands out for us is really that we were able to confirm even in humans as a species that there's a one-to-one ratio blood to brain. The other piece that is really important is that we are at doses where we don't just get full inhibition in the brain, but also in the periphery. We do believe that we have a molecule that could be used both to peripherally fully inhibit the target and centrally fully inhibit the target. We have done additional work, and we've started to share some of that, that TYK2 basically is not just present in microglia, B cells and astrocytes. I think there's an emerging set of data now that really looks at not just neuroinflammation, but also neurodegeneration. We believe there's a broad opportunity there.
I think ultimately we're now at the stage where we are preparing for the Phase II. You ask what these aspects are that are critical. The two most important critical items for the Phase II start are basically the CMC aspect of it. Now that we know what the likely doses are, what do we make in terms of solid dose form? The other one is the tox study. We've already initiated the chronic tox, which really enables us to then not just have a three-month study, but potentially have a long-term extension for that three-month study. If there's anything we learned from tolebrutinib, we started the Phase II and then patients had to actually come off drug for a while until the chronic tox was completed for us to then restart them on a long-term extension.
If our plan is to actually have a long-term extension in that study, then having that tox study be completed would be very helpful.
Yeah, that makes a lot of sense. All right. Unfortunately, we're up against time here, but thank you, Martin, for joining us. Big year of execution for Alumis. We will stay tuned.
Absolutely.
Thank you.
Thank you so much.