Alumis NASDAQ: ALMS said its Phase II LUMUS trial of envudeucitinib in systemic lupus erythematosus, or SLE, did not meet its primary or key secondary endpoints in the overall study population. However, the company said pre-specified analyses showed clinically meaningful responses among patients with a high interferon gene signature, a subgroup it plans to emphasize in future development discussions with regulators.
The randomized, double-blind, placebo-controlled LUMUS study enrolled 408 adults with moderately to severely active, autoantibody-positive SLE. Participants received one of three envudeucitinib doses or placebo for 48 weeks in the trial's Part A. The primary endpoint measured improvement in overall disease activity using the BICLA composite endpoint at week 48.
“The LUMUS Phase II study trial did not meet the primary and secondary endpoints,” President and Chief Executive Officer Martin Babler said. “This was clearly not the outcome we expected.”
Chief Medical Officer Jörn Drappa said the study also did not achieve statistical significance on SRI-4 and other key secondary endpoints in the overall population.
Safety and pharmacodynamic findings
Despite the efficacy miss in the broad population, company executives said envudeucitinib was well tolerated through 48 weeks, with no new safety signals. Drappa said treatment-emergent adverse events, serious adverse events and adverse events of clinical interest occurred at lower rates in active-treatment groups than in the placebo group.
There were no reports of major adverse cardiovascular events, extended major adverse cardiovascular events or malignancies in any treatment arm, according to the company.
Alumis also said pharmacodynamic results indicated that the TYK2 inhibitor engaged its intended target. The 40-milligram twice-daily dose produced maximal downregulation of the Type I interferon pathway based on SIGLEC-1 expression and a four-gene interferon-regulated gene panel, Drappa said.
Babler said the safety data add to the company’s broader dataset for envudeucitinib as Alumis continues to expect a new drug application submission for moderate-to-severe psoriasis in the fourth quarter.
High-signature subgroup showed treatment effect
The company attributed part of the overall trial outcome to enrollment of a lower-than-expected proportion of patients with a high interferon gene signature, referred to as IFNGS-high. Approximately 60% of LUMUS participants were IFNGS-high, versus an approximately 80/20 split between high- and low-signature patients in some other Phase II and Phase III lupus studies, according to Drappa.
IFNGS-high patients are generally associated with greater disease activity and may respond more favorably to therapies directed at the interferon pathway, while IFNGS-low patients tend to have higher placebo response rates, Drappa said. He noted that the LUMUS protocol stratified patients by interferon gene signature but did not require high-signature status for enrollment.
In the pre-specified IFNGS-high subgroup, Alumis reported separation from placebo across BICLA, SRI-4 and Lupus Low Disease Activity State, or LLDAS, measures. The company said separation from placebo appeared as early as 24 weeks in the high-signature group. No apparent clinical benefit was observed in the IFNGS-low subgroup.
Drappa said the results were consistent with envudeucitinib’s mechanism, which acts by modulating downstream Type I interferon signaling. He also said the company’s comparisons with published data for upacitinib and anifrolumab were subject to the usual limitations of cross-trial comparisons.
Regulatory planning and Phase III considerations
Alumis is preparing for an end-of-Phase II meeting with regulatory authorities and expects to seek an interaction as soon as possible, potentially by the end of the year. Babler said the company does not foresee significant changes to its overall development timeline.
The company has not finalized a Phase III enrollment approach. Drappa said Alumis could either focus entirely on IFNGS-high patients or cap the proportion of IFNGS-low patients, with further analyses planned to determine the preferred strategy. He said commercially available assays can identify interferon gene signature status and were already used at screening in LUMUS.
Questions also remain around dose selection. Drappa said 40 milligrams twice daily produced strong pharmacodynamic suppression of the interferon signature, but clinical dose-response patterns varied by endpoint. The company plans further dose-response and exposure-response modeling before selecting a Phase III dose. He said a higher dose did not appear likely to be necessary based on the pharmacodynamic findings.
Alumis will also continue evaluating envudeucitinib in other interferon-driven diseases. Drappa said the data strengthened the company’s conviction in the target for patients with a confirmed interferon signature and supported continued evaluation in cutaneous lupus and Sjögren’s disease.
About Alumis (NASDAQ:ALMS)
Our mission is to significantly improve the lives of patients by replacing broad immunosuppression with targeted therapies. Our name, Alumis, captures our mission to enlighten immunology, and is inspired by the words "allumer"-French for illuminate-and "immunis"-Latin for the immune system. We are a clinical stage biopharmaceutical company with an initial focus on developing our two Tyrosine Kinase 2 (TYK2) inhibitors: ESK-001, a second-generation inhibitor that we are developing to maximize target inhibition and optimize tolerability, and A-005, a central nervous system (CNS) penetrant molecule.
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