All right, good morning, everyone. I think we'll get started here with the next fireside discussion. My name is Derek Archila. I'm one of the Senior Biotech Analysts here at Wells . Very excited to have next here for the fireside Alumis from the company. We have Martin Babler, President and CEO. We also have John Schroer, the Chief Financial Officer. Gentlemen, thank you so much for joining us.
Thanks for having us.
Maybe, Martin, if you want to just start off, just kind of give us the high-level view of Alumis, what you guys are working on, and then we can kind of dig into some of the specific questions around your programs.
Yeah, so we're a precision immunology company. Started about four years ago. The company basically is focused on immunology, and mostly there on TYK2 inhibitors. Our two lead molecules basically are in the TYK2 space. We have a Phase 3 readout in psoriasis that will come in the early first quarter of next year. We have a Phase 2b readout in systemic lupus erythematosus (SLE) that will come in the third quarter of next year. Quite some important milestones that will really be transformative for the company. We have an additional program with lonigutamab that we just got through the acquisition and the merger of Accelerin. We have a research organization that is creating a pipeline behind all of this. The goal really for the company is to figure out a way to get treatments to patients, mostly oral medicines, that are not broad immunosuppressants and are very precise.
We're using a data analytics approach. That's actually where TYK2 was identified as a really, really interesting target, given the genomic richness of that target.
Got it. Perfect. Maybe there's been a lot of activity in the TYK2 space over the last couple of years. I think one of the key questions that we always get is, how do you guys differentiate and why you think yours could be better than maybe Deucra and some of the other molecules out there from like Takeda? I guess where do you kind of think you're differentiated and where does it speak to it in the data that you've already generated?
Yeah, I think the most important thing is to first establish why TYK2 is such an interesting target. TYK2 is genetically very rich, as I just mentioned. There's actually quite a few mutations that we have in TYK2 that humans have. One of those mutations actually mimics very much what we do pharmacologically. It's called the P1104A mutation. That mutation basically just down-regulates the kinase function of TYK2. The interesting aspect about that mutation, which is present in about 5% of Caucasians and about 3% in the general population, is that people who have that mutation have no phenotype, but at the same time, a really nice protective effect for autoimmune diseases. That's really been the basis for what we have established with our programs.
Interestingly, when you look at that data set, and that's actually where our differentiation comes in, we learned early on in that data set that if people have a heterozygous mutation, they get about a 20%- 30% protective effect. When they actually have a homozygous mutation, they have two alleles, they actually have about an 80%- 90% protection. That told us that this is a target where we have to down-regulate the kinase function really strongly to get the maximum beneficial effect. From the get-go, our goal was to have a stronger and better inhibition of TYK2 with our molecule.
It turns out that when you compare our molecule to the other molecules in the field that have been studied ahead of us, they all actually had to dose reduce from phase one to phase two because they got too many side effects and had to basically use lower doses that did not achieve maximal target inhibition. Our molecule currently is the only one that is in the phase 3 study, at least in the Western Hemisphere, that basically can inhibit the target above IC90 24 hours a day. If you look at our genomic data, that actually translated into in vitro data where we saw that ability. We took it into phase one, and we actually demonstrated in phase one by showing that we are above IC90 24/7. We actually did biomarker assessment that also showed that we are able to further inhibit the target.
That actually translated between the second highest and the highest dose in the clinic then to a 20% jump in efficacy across PASI-75, PASI-90, and PASI-100. We have basically shown all the way from the genomic end of the spectrum to the clinical end of the spectrum that more inhibition gets you a better outcome. That's really the key differentiator that we have. We actually have a better safety profile even at our maximum dose than some of our competitors when it comes to some of the key tolerability issues that you've seen with these other molecules. We didn't, we're the only ones that did not have to dose reduce.
Gotcha. Maybe you can kind of tee up for us the Phase 3 readout in the first quarter of next year for psoriasis. Give us a little bit of color on the trial design, how it compares to other trials, maybe even other TYK2 trials. Ultimately, where do we need to net out in terms of efficacy to really see this be a competitive molecule in the competitive landscape here?
Yeah, so there's two kind of ways to think about this from an outcome standpoint, if you so want. The key outcome for us is to look at the long-term efficacy of the molecule. Because we found in our discussions with thought leaders and with physicians that they really care about how many of their patients will ultimately respond to a drug. The way we designed our program was really to catch up with the competition in terms of timing. When we started this program, Deucravacitinib was basically in the approval phase, but everybody else was behind. We were actually the fourth in the ranking at the time. Our goal was to basically read out Phase 3 about the same time that our competitors read out.
Our Phase 3 design is slightly different from a standard Phase 3 design in that it's a six-month trial rather than a 12-month trial because we have a lot of long-term data from our Phase 2 long-term extension. What you will see early next year is basically 16- and 24-week data. Sixteen-week data that is placebo-controlled and 24-week data that is active-controlled. In two trials, we have a total of about 1,700 patients. Basically, those trials were read out. All those patients then have moved into a long-term extension. We will get additional durability data from that at a slightly later stage. That will not be part of this presentation. What you get is basically this 16-week placebo-controlled and the 24-week active-controlled data set.
In terms of what we believe we need to see, given the safety profile, given the convenience of this drug, because it has no fasting requirement or anything, we believe that if we are as competitive, if we're competitive with others, we're actually well served. For us, that means probably somewhere in the 55% 60% placebo-controlled PASI-75 at week 16. At week 24 to week 52, those measurements, what we've seen in our Phase 2 is we were about at 80/60/40, which means we were at about 80% PASI plus PASI-75. We were about 60% plus PASI-90 and about 40% PASI-100. If we're in that range where we were in Phase 2, we believe we have a highly competitive molecule based on the data we've seen so far from the others.
Gotcha. How do you think, again, about the competitive landscape with J&J's oral IL-23, as well as even Takeda's TYK2, which, again, we're supposed to get data from fairly soon? I guess how do you think this will all kind of play out and where's that differentiation maybe against those molecules?
Yeah, we have limited data information on those. What we've seen, the data set that we've seen so far from the oral IL-23 molecule is that it's a molecule that data set actually included adolescent patients, so that skews the data set slightly. We believe that our 80/60/40 and what I just said, between 55% and 60% for a PASI-75 at week 16, will make our molecule very competitive with that molecule. We do have the advantage, and this has already been remarked by the dermatology community, that we have an oral small molecule that can be taken independent of food. The oral peptide nature of that molecule makes it a little bit harder because you have to basically fast two hours before and sometime after you take it. If you are not compliant with that, the efficacy of that molecule might come down a little bit.
We do believe from an efficacy standpoint, we're competitive if we can repeat our Phase 2 data. From a safety standpoint, we have a very clean safety profile and have really not seen any major safety signal. From a convenience standpoint, we might have a slight advantage. With other TYK2 so far, what we've seen is that we have a safety profile that is highly competitive because we don't have as many skin reactions as we've seen with others. At the same time, we have a molecule that has shown efficacy at least across multiple doses and time points, so we have a very competitive molecule there as well.
Gotcha. I guess we've hooked the cards on this and it's positive. What are kind of the next steps for you? Is this something that you plan to commercialize yourself or is this something you partner large indication? What's kind of the commercial plans or if there are commercial plans post Phase 3 data?
We are certainly doing commercial preparation. At the same time, I would say the likelihood that we're going to commercialize a molecule of that potential on our own on a global basis is not very high. We've been very thoughtful about how we think about partnerships and what to do and how to do that. I think the data set will also partially define how we best do that. We are in a fortunate situation that we have basically cash that we can read out both psoriasis and lupus and possibly actually make strategic decisions only post a lupus readout and don't have to make that right after the psoriasis readout. We have put a commercial organization in place that takes care of all the steps that need to happen in a timely manner prior to launch. How exactly the strategy is for launching the molecule will be decided.
Got it. Maybe that's a good segue to lupus and what we should expect there. There's going to be another external catalyst with Bristol Myers Squibb's lupus trial reading out. I guess obviously we have a good proof of concept from the original trial. What are your expectations around that data given the molecule and some of the weaknesses around that specific molecule? What should we take from that and read through to your Phase 2?
Yeah, so you know I just shared with you that we have a very strong belief that more inhibition is better for TYK2. When you actually look in lupus, there is precedent data with Anifrolumab that shows that you really want to inhibit the interferon signature quite strongly in lupus because there was a clear dose-response relationship in the anifrolumab data. We do believe more inhibition of interferon and the interferon signature could read through to some better outcome. We'll have to see. I do believe that the unmet need in lupus is significant enough that we believe that having a molecule or two that are oral therapies, well tolerated and efficacious, is an important progress for those patients. We're very excited about this program. We believe that actually there's really two parts to the success of trials in lupus. One is the clinical and scientific evidence.
There's really good validation from anifrolumab for interferon. There's good validation genomically. There's good validation from other TYK2 inhibitors. In addition to that, we do believe actually trial execution is absolutely critical in lupus. We incorporated a lot of elements in our trial and our trial execution to really make sure that the placebo rate is hopefully as low as we can possibly get it. We believe those two combined actually increase the PTS for our lupus program.
Maybe elaborate on that. Also, just the fact that, again, a lot of these lupus trials tend to fail. It's maybe because of the heterogeneousness of the population. I guess, again, what are you doing to kind of control for some of these items?
Yeah, so fortunately, our CMO Jörn Dröpp, actually calls himself a lupologist and has been involved with many lupus trials and actually has seen what works and what doesn't. He was the one who helped with anifrolumab getting through approval. One of the key learnings, or several of the key learnings, are first of all that it's really critical that you have patients with active disease. Instead of just having the physicians decide that, we actually put an adjudication panel in place that looks at every patient that enrolled in the trial to make sure that they truly have active disease. The other one is that co-medications often play a key role in the placebo effect. We've controlled that quite dramatically, not just from co-medications that we basically banned from the trial, but also the steroid use is limited, and you have to taper the steroids.
The third one is that we believe that the use of the tools is a critical element. These tools are complicated and they're not ideal. It really requires that the sites are well trained and that you actually monitor very carefully that there's not mistakes happening in how these tools get utilized. What we did is we kind of built a crawler that basically runs over the data as it comes in. We do believe that actually addressing any discrepancies in the data as you go when it's still fresh in the minds of the investigator is critical. Instead of doing a lot of testing at the end and looking at things at the end, we are doing as the data comes in, we're watching very carefully.
We've had a team basically traveling around the world, not just educating those folks, but re-educating sites in case we saw some issues that popped up. We do believe that we've done a lot to at least help reduce the risk of having a very high placebo rate, because if you look at the last couple of trials, that often was actually the key issue in those trials.
Gotcha. I guess what do you think you need to show in terms of efficacy here? I mean, obviously, this would be an oral. That's kind of a little bit differentiating. Where do you think the bar is? Is it still pretty low or is there higher expectations now?
Right now we're between 8% and 15% placebo-adjusted benefit. We do believe that if we're at the higher end of that, we're actually totally fine. Is there a possibility to go higher? Yes. Would that be fantastic? Absolutely. We do believe that if you get to that, towards that 15% of placebo-adjusted benefit, you're actually in a good spot as an oral therapy. You have a lot of patients that have waxing and waning disease, but really need something that is safe and effective. The one piece about TYK2 compared to other therapies is that you're getting relief from the disease, but you don't get burdened from other things. If you just think about the trial enrollment, once we've been able to really show people what the drug did in psoriasis, and once people had some experience with it, we actually saw a really, really nice uptake with the molecule.
We do believe that there's a real unmet need for a simple, safe therapy in lupus that is oral and that is easy to administer. We believe that you don't have to exceed that bar dramatically to actually have a successful molecule.
Gotcha. Can you maybe talk about the regulatory alignment you have on this trial in terms of can it serve as a pivotal, and what would be needed to kind of actually get this through to registration?
Yeah, that's a really important point. When we set up this program, we made the decision that we are going to do a very robust trial. Often in lupus, to your point earlier, the trials were too small and were really not definitive. What you saw in lupus a lot was there was a smaller early trial that actually had success and then the Phase 3 actually failed. We basically decided that we're going to do a robust trial. If we do a robust trial, why not figure out whether we can make it a pivotal trial? We went to the agency here in the U.S. at least and had a conversation and said, if we wanted to make this into a pivotal trial, what would be the things that you would want to see? The agency gave us significant feedback and we incorporated that.
We are running this Phase 2b as a pivotal trial. That could possibly enable us to only have to run one additional Phase 3 trial. That's something we will have to discuss. It's at least set up in that way. Whether ultimately we're running one or two Phase 3s, I can't predict right now. For us, I think the most important thing is that we have an opportunity that we could possibly just have one additional trial about the same size. That would basically finalize the program.
Would it be pretty much a replication of the patient population, or would there be any differences there?
The patient population probably would be the same. The difference is that we have three active dose groups under placebo currently, and you would just have basically active in one dose.
Gotcha. How much follow-up data do you need to file on that? Is that something that you can use also from the psoriasis experience?
We can use some of it from psoriasis. We are actually enrolling the lupus patients in a long-term extension, so we will also learn additional information there.
Gotcha. How much data will you share at the top line? Is it just kind of like the primary endpoint, or will you have more of a robust data set of some of the key secondary measures?
At top line, we haven't fully decided yet, but we are using BIC class as the primary. We're using SRI-4 as a secondary endpoint. What exactly we're going to reveal, we haven't fully decided yet.
Got it. Maybe you could just talk about the market opportunity that you see within lupus. Obviously, still underserved, but where do you think a TYK2 can actually play a role? Is it early? Is it late? Or kind of just all the above?
The best way I can describe this, there was a really interesting session at EULAR earlier this year in Barcelona. There was a lot of discussion about cell therapies, et cetera, et cetera. Basically, every patient that was shown was under 30 years old. The first slide that one of the lupus thought leaders put up when they gave a presentation was like, our patient is on average 49 years old, female, and has had the disease for X amount of time. I think this is really a drug that we believe is likely going to be more on the first line, earlier side. People will get on a drug like this first, and if that benefits them, then they will stay on it. We also believe a lot of people get methotrexate or they get melphalan or steroids right now.
It could really be a situation where you try something like this because you're not having a huge burden of side effects that comes with the drug. So far, the drug has been shown to be very safe. I think that actually having a targeted therapy for lupus with limited side effects could really put that in a very good position early in the treatment algorithm.
Gotcha. I mean, anything else that we should be focused on or where you kind of feel like investors underappreciate the lupus story here?
I think one of the most important things is that lupus is opening up quite a bit of other opportunities. We've purposefully went after more of the IL-23 angle with psoriasis and the interferon angle with lupus. If lupus is positive, we do believe it really shows that we can go after many interferon-driven diseases. That's actually quite a large group of indications, including Sjogren's disease and others. I think for us, that's an important part. Ultimately, the other piece is that as an organization, because we have several molecules and we have several formulations, that also enables us to be a little bit more basically strategic on how we think about launching these molecules.
Gotcha. The other two assets in the pipeline, so A-005 and lonigutamab, maybe with the first one with 005, another TYK2 brain penetrant, like again, very interesting properties here. Maybe just, I mean, your time at Principia, maybe just kind of compare and contrast your excitement around with the BTK versus the TYK2 penetrant molecules.
Many of our team came from Principia. We actually had two BTK inhibitors, one that was brain penetrant, the other one not. We did follow that playbook a little bit, especially because we were intrigued originally mostly about the opportunity to combine a BTK inhibitor and a TYK2 inhibitor. That was the original plan. What we've learned since from really understanding the biology better and better is that basically TYK2 is a BTK plus in the brain. We did a lot of work on the microglia at Principia. We did work on TYK2 and realized that we have a very similar effect on the microglia. When you look at tolebrutinib, we now know that the microglial effect really has a benefit on the disability side. In parallel, when we did the EAE models with TYK2 and specifically with our molecule, we were literally able to prevent inflammation from happening.
TYK2, actually our specific molecule, A-005, is the only molecule so far that in an EAE model, in a prophylactic EAE model at least, could prevent the induction of inflammation. It mimics literally a genetic knock-in of when you prevent inflammation. It's actually better than in that model. It's better than fingolimod, which has been the standard in that model in terms of inflammation. If you think about the benefit that tolebrutinib had on the disability, and at the same time having the strongest anti-inflammatory effect, we really believe that combination could be very, very interesting for MS patients and for neurodegenerative diseases where we now understand more and more that inflammation plays a key role. For us, that double function is really intriguing. We created that molecule.
That molecule we have now shown in humans with spinal taps that we have a one-to-one ratio between the periphery and the blood and the brain. At the same time, we've also shown that not only do we get a one-to-one ratio, but we also saw that we can maximally inhibit the target in both settings. I think that for us was the most important thing to figure out.
Gotcha. What are the kind of the next steps there? I guess if MS is going to be kind of the opportunity that you pursue, what's the quickest path to like a proof of concept?
Yeah, so in MS, we plan to do something very similar to tolerectinib. The reason why we chose MS is because it's the fastest way to understand what a clinically relevant dose is. You can do a three-month imaging study and basically look at lesion reduction. You can do an extension, and in that extension, you can then look at other factors such as basically reduction in exacerbations or in relapse rate. From our standpoint, it was the easiest indication to do that, and that's why we chose MS. That's why we chose that kind of approach. That will then simplify if you go into other indications that require longer studies such as Parkinson's or others.
Gotcha. How fast are those types of trials enrolled? Also, what are the benchmarks in terms of lesion reduction we should be thinking about?
Yeah, the small challenge of those studies is that the lesion reduction, we don't have an N big enough to now translate really what does it mean in terms of relapse rates, et cetera, et cetera. At least from the data set we have, we know that we need to get to 80%- 90% lesion reduction to have a viable drug at this point in time. I think that's the bar that we should think about. That's what we've seen with tolerant nib. The study is actually relatively easy to perform. We did it for tolerant nib quite fast. I think things have changed a little bit, but we still believe that it's a three-month study in terms of study duration, but that you can get a study like this done in probably about 12 months.
What are the timelines? You guys reiterated some timelines here, but.
Yes, we did. We made two changes. The first one was on this program. The reality is, remember, we originally thought we would read out our psoriasis study in the second quarter. The enrollment and the velocity at which we were able to enroll was very high. We just did not have the internal resources to reallocate to this. Psoriasis was more important to us, so we basically pushed it from the end of this year into the first half of next year. Our plan is to start that study sometime in the first half of next year. The other adjustment we made is we actually have another program that we plan to put into the clinic relatively soon. That program we switched basically, we said instead of saying we're having it in a clinic by the end of this year, we will have phase one readout next year.
The reason why we did that is because we do not want to, we're not going to disclose what the target is. In today's environment, we believe that it's not very wise to tell everybody what you're doing, basically.
Makes sense. On , I know this is an asset that you gained through the acquisition of Accelerin. Where does this kind of fit among all the current portfolio? What's needed at this stage in terms of moving it forward in development?
Yeah, so lonigutamab is a really interesting molecule. I think it's actually a misunderstood molecule. Lonigutamab is an IGF-1R molecule. Basically, the key difference is the molecule compared to other TED assets, and this is where the molecule was originally studied, is that it internalizes rather than is a competitive inhibitor of IGF-1. What you have, and you have a lot less floating IGF-1. That could have a differentiation. That feature could translate into a key benefit. The key benefit could be that you actually have a lot less hearing loss and a lot less safety signals related to IGF-1. When you talk to patients today, a lot of them do not get on an IGF-1R like Tepezza because they already lose their eyesight and now they're at risk of losing their hearing. We do believe that there's a huge opportunity for a molecule that has an improved safety profile.
The question is, how can you assess that improved safety? If you do that in the most efficient manner, and if you do that, what does it do to the timelines? When will you launch, et cetera, et cetera? We pull on a couple of strings since we've got this molecule. We're fortunate that we have an entire research organization. Accelerin actually did not have a research organization per se. They had a mostly development focus, but they had some really great scientists that really dug through some of this stuff. We pulled on a couple of strings. We're just continuing to evaluate what is the best way within the current portfolio dynamics that we have to go after to utilize such a molecule. Is it TED? Is it something else? What do we do there? We haven't finished that evaluation yet.
We will let everybody know once we know what we do. For us, the interesting aspect here really is that there is an interesting hypothesis. The question is, can you evaluate that hypothesis in the most efficient way in the context of the entire portfolio?
Do you think, obviously, we covered Accelerin prior, but do you think there was enough dose work done to really understand? Do you think what I'm trying to get at is, is this like a Phase 3 ready asset, or do we have to do some mulling around in dose ranging again to really understand what we need to move forward in a pivotal?
Our opinion is that we need to really understand that. Whether you can do that on a piece of paper and calculate, or whether you actually have to do it, I'm not going to disclose at this point in time. You raise a good point, which is really you have to be very thoughtful about if you're optimizing for a safety and efficacy outcome in parallel, you have to really figure out what is the optimal way to do that.
Gotcha. Maybe just in terms of funding strategy and cash, just a lot of programs. I guess just in terms of allocation, you made some comments in terms of just like timing things for A-005. I guess, yeah, how do you think about future cash allocation? Obviously, there are some inflection points here that might dictate what you're going to be focusing on maybe in the next six months, whether it be psoriasis or lupus and things like that. How does this all kind of inform the funding strategy?
Yeah, I'm going to start and I'm going to hand it over to John. My only comment to you is that for us, the most critical thing is that we can read out psoriasis and lupus and still have money left in the buffer. We want to make strategic decisions based on those two data sets. That is the most important thing. I'll let John talk about how we think about it.
Thank you. We ended the, just to set a baseline, we ended the second quarter with $486 million of cash and cash equivalents. That provides us runway into 2027. As Martin said, as we read out these two meaningful trials, both psoriasis and lupus, with that information, I think that will also create opportunities for us to revisit what our current cash needs are and also availability.
Gotcha. Just one last question. I know I asked this specifically for the lupus trial, but maybe for the whole Alumis story, where do you think that the story is underappreciated by investors right now? Where do they maybe not believe or they need to see data? What's the pushback that you get and where you think maybe you're underappreciated?
I think the most important thing is that we are a TYK2 company first and foremost. Unfortunately, you know, there's a rule in this country, three strikes and you're out. You have three molecules that have disappointed. What I shared with you in the beginning is that none of these molecules actually got to maximum target inhibition. We actually believe that we don't know what the potential of TYK2 is. Because what we see in the data is that there is a very steep curve in terms of drop-off efficacy if you fall below a certain level. We believe that has to do likely with amplification of the kinase. We actually believe that we don't know yet what TYK2 can do. There was a judgment based on previous data that was done with molecules that all had the dose reduced.
I think the biggest underappreciation is the fact that there's a huge opportunity here that genomically has very strong support, that clinically has very strong support. We will just have to basically show the data to make sure people understand that there is a very significant opportunity. There are data sets out there besides ours that actually support that hypothesis. There's a couple of Chinese companies that have had data in patients that, yes, they had smaller body mass index, et cetera, et cetera. They saw some pretty amazing data that's better than anything we've seen with oral drugs. There's also data in CLE, for example, from even from Deucravacitinib, where basically TYK2 showed better responses than any other mechanism has shown so far. There are data sets that support the fact that TYK2 actually is a very, very interesting target.
I think it's just underappreciated because people were disappointed with the performance of other molecules. It's explainable, basically.
All right, we'll look forward to that data in the first quarter. All right, we'll leave it there. Thanks, Martin. Thanks, John.
Thank you.
Thank you.
All right.
Good to see you, guys.
Thank you.