Alumis Inc. Common Stock Study result

Good morning, and thank you for joining us today. Before we begin our formal comments, let me remind you that during today's webcast, we will be making forward-looking statements that represent the company's intentions, expectations, or beliefs concerning future events. These statements represent our views as of this date, are subject to risks and uncertainties, and should not be relied upon as representing our views as of any subsequent date in the future. With me on the call today are Martin Babler, our President and Chief Executive Officer, and Dr. Jörn Drappa, our Chief Medical Officer. Martin will open the call and then hand off to Jörn to walk through some of the data, including the pre-specified subgroup analyses. Martin will then review next steps before wrapping up the prepared remarks. Then we'll take questions. I would like now to turn the call over to Martin.

Thank you, John, and thank you all for joining us. Let me start by acknowledging that the LUMUS phase II study trial did not meet the primary and secondary endpoints. This was clearly not the outcome we expected. However, this phase II trial has provided important insights and a clear path forward for envudeucitinib in type 1 interferon-driven diseases, including SLE. The LUMUS data confirmed the favorable profile that we have seen to date. In LUMUS, envudeucitinib was well-tolerated with no unexpected findings and was comparable to placebo. These data strengthen the overall safety data set we have for envudeucitinib, especially as we continue to expect our NDA submission for moderate to severe psoriasis in the fourth quarter of this year. Robust clinical responses were observed in the pre-specified subgroup of patients with high interferon gene signature, which represents approximately 60% of the patients enrolled in LUMUS.

This analysis shows meaningful treatment effects across primary and key secondary efficacy endpoints. These results are consistent with the type 1 interferon target mechanism and confirm that envudeucitinib is working as designed. The subgroup of the population is an established and readily identifiable patient group and represents a large opportunity of moderate to severe SLE patients. Jörn will outline the factors we believe contributed to the overall outcome as well as the meaningful clinical benefit that we saw in the pre-specified subgroup of patients with high interferon gene signature. On this call, to simplify the lexicon, we will be abbreviating high interferon gene signature to IFNGS-high, and similarly, low interferon gene signature will be IFNGS-low. We believe that we have a clear path forward for regulatory engagement on phase III development for envudeucitinib in SLE, and we do not foresee significant changes to our overall development timeline.

I'll now turn the call over to Jörn to go into more detail on the LUMUS results.

Thank you, Martin. LUMUS was a phase II randomized, double-blind, placebo-controlled study that evaluated multiple doses of envudeucitinib in adults with moderately to severely active autoantibody positive SLE. The trial enrolled 408 patients who received one of three envudeucitinib doses or placebo for 48 weeks in Part A. The primary endpoint was the assessment of improvements in overall disease activity using the composite endpoint BICLA at week 48. Key secondary endpoints are listed on the slide. After week 48, patients had the option to roll over into the long-term open label extension portion of LUMUS, which is Part B. Let's now review the efficacy data. As Martin said, envudeucitinib did not achieve statistical significance with the primary endpoint in the overall population at week 48. The same was true for SRI-4 and other key secondary endpoints.

With respect to safety, we were pleased to see that in LUMUS, envudeucitinib treatment was well-tolerated through week 48 with no new safety signals. Overall, incidence rates were lower on active treatment compared with placebo for treatment-emergent adverse events, serious adverse events, and adverse events of clinical interest. Notably, there were no reports of MACE, extended MACE, or malignancies in any treatment arms. We were encouraged to see that the pharmacodynamic data from LUMUS confirms that envudeucitinib worked as intended. As a TYK2 inhibitor, it blocks downstream type I interferon signaling, and here we see that in a dose-dependent manner. On the left panel, you see expression levels of SIGLEC-1, a biomarker that is exquisitely sensitive to TYK2 inhibition. On the right panel, you see a four-gene panel that measures the expression of interferon-regulated genes.

By both of these measures, the top dose of 40 milligrams BID achieved strong target engagement with maximal downregulation of the type I interferon pathway. Before we go further into the LUMUS analyses, I would like to provide a little bit more context about the interferon gene signature characteristics in lupus patients, which play a key role in treatment response to type I interferon-targeted treatment. The distribution of interferon gene signature is bimodal with a natural separation into two distinct groups, high and low IGS groups. IGS high is an established patient group that represents approximately 70% of moderate to severe SLE patients, as reported in the SPOCS cohort study. As Martin mentioned, this subgroup is readily identifiable using commercially available assays. IGS high patients tend to have greater disease activity and typically respond more favorably to interferon pathway-targeted therapies with lower placebo response rates.

Conversely, IFNGS-low patients respond less favorably to interferon-targeted therapies and show higher placebo response rates. Now let's look at the key factors that affected the LUMUS study outcome. The baseline demographics were generally well-balanced across groups. There were two key factors that impacted the overall study outcome as follows. The first is the proportion of patients with the interferon signature. The second is the disease activity as measured by BILAG. BILAG stands for British Isles Lupus Assessment Group, which measures how active a patient's lupus is across nine organ systems. Symptoms are graded through a letter scale where A denotes severe disease activity, B denotes moderate disease activity, and C denotes mild disease activity. First, let's talk about the interferon signature. LUMUS enrolled a lower than expected proportion of IFNGS-high patients, and therefore also a lower than expected proportion of patients with severe disease.

For context, other phase II and phase III trials achieved approximately an 80/20 split between IFNGS-high and IFNGS-low patients. The Saphnelo study was closer to 60/40. As to why this occurred, one reason we hypothesize is that having more approved treatments available for SLE has reduced the pool of patients with severe disease activity that are available for clinical trials. In LUMUS, the interferon gene signature status was a stratification factor but was not a requirement for inclusion into LUMUS. The result was more IFNGS-low patients being enrolled than we had anticipated. Second, with regard to disease activity, the proportion of patients with severe disease activity, as indicated by a BILAG A, was slightly lower than the proportion of patients with moderate disease activity, as indicated by the presence of at least two BILAG Bs.

Patients with IFNGS-low respond less favorably to interferon pathway-targeted therapies and also show a higher placebo response rate, and both of these turned out to be true in our study. When we analyzed the LUMUS data for the pre-specified subgroup of IFNGS-high patients, we observed clinically meaningful benefit across primary and secondary treatment measures in these patients. I will now walk you through these compelling results. On the left side of the table, you'll see the IFNGS-high subgroup, and on the right side of the table, you see the IFNGS-low subgroup. In the green rectangle, you'll observe that for the IFNGS-high patients, on all endpoints, there are robust responses with clear separation from placebo. I'll also point you to impressive results, not only on BICLA, but as well on SRI4, and the LLDAS.

To achieve LLDAS, several criteria that incorporate both disease control and limitation of steroid exposure have to be satisfied. LLDAS is important because it answers the question of whether patients achieve a remission-like state of low disease activity, and it has a strong connection to long-term outcomes. Conversely, in the red rectangle, you'll see that there was no apparent clinical benefit from envudeucitinib in the IFNGS-low subgroup. These results are consistent with the TYK2 mechanism of action which primarily acts by down-modulating downstream type I interferon. On this slide in the top panel, the next slide, we show the response over time by dose in the IFNGS-high subgroup, with a clear separation from placebo shown in the yellow line as early as 24 weeks. In the bottom panel, you see the lack of response in the IFNGS-low subgroup.

I'll now walk you through several slides comparing our data to published data on upacitinib and anifrolumab in IFNGS-high and IFNGS-low subgroups. The usual caveats around cross-trial comparisons, of course, apply. Starting with slide 13 for the IFNGS-high subgroup, we see overall strong response rates for BICLA and envudeucitinib compared to placebo, and also compared to upacitinib and anifrolumab as well. In contrast, this slide shows that it's much more difficult to characterize responses in the IFNGS-low subgroup. Response rates are a lot more variable with no clear patterns. The same holds true if we look at the SRI4 endpoint. There was clear separation from placebo in the IFNGS-high subgroup. In contrast, this slide shows that for SRI4, it's more difficult to characterize responses in the IFNGS-low subgroup with variable response rates and no clear pattern.

Finally, on slide 17, we capture BICLA plus four key secondary endpoints, including CLASI-50 and SRI4 response, active joint count reduction, and glucocorticosteroid taper for envudeucitinib compared to anifrolumab. Again, there was clear separation from placebo on primary and these key secondary endpoints. To conclude, although LUMUS did not achieve its key objectives in the overall study population, the trial did provide us with deep insights that we can build upon moving forward and incorporate our findings into phase III development. Before I turn the call back to Martin, I would like to express our gratitude to the patients, families, and investigators whose participation made the LUMUS study possible.