Alumis Inc. Common Stock 12th Annual Cantor Fitzgerald Global Healthcare Conference

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.

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.

Yeah. So this was a Phase 2b 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.

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.