Belimumab

The Phase IIb LUMUS trial of envudeucitinib in systemic lupus erythematosus (SLE) failed to meet its primary and secondary endpoints in the overall patient population, Alumis Inc. (Nasdaq: ALMS) reported on September 1. The miss affects Alumis' multi-indication ambitions for the oral TYK2 inhibitor, though the company said responses in a prespecified interferon gene signature-high (IFNGS-high) subgroup support advancing to Phase III in an enriched population. The 408-patient LUMUS trial evaluated three doses of envudeucitinib against placebo over 48 weeks in adults with moderately-to-severely active, autoantibody-positive SLE. The primary endpoint was British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response at Week 48. Neither BICLA nor key secondary endpoints — including CLASI-50, SRI-4, and Lupus Low Disease Activity State — were met in the overall population. Alumis attributed the failure partly to an unexpected under-representation of IFNGS-high patients in the enrolled cohort. Because this subgroup typically shows lower placebo response rates and greater sensitivity to interferon pathway-targeted agents, its dilution in the overall population reduced detectable treatment effects. In IFNGS-high patients — who Alumis said represent the majority of moderate-to-severe SLE cases — robust responses were observed across BICLA and the key secondary measures. No specific response rates were disclosed. Pharmacodynamic data confirmed dose-dependent interferon-pathway suppression, with maximal effect at the highest dose of 40 mg twice daily. Envudeucitinib is a highly selective oral allosteric inhibitor of tyrosine kinase 2 (TYK2) that blocks signaling downstream of the type I interferon, IL-23, and IL-12 receptors. The SLE result arrives as Alumis prepares to submit an NDA for envudeucitinib in moderate-to-severe plaque psoriasis in Q4 2026, following positive Phase III ONWARD1 and ONWARD2 data reported in January 2026 and long-term ONWARD3 extension data in August 2026 showing 54% of patients achieving complete skin clearance (PASI 100) after 48 weeks of continuous treatment. The psoriasis program remains the company's near-term commercial anchor. The SLE setback narrows but does not close the oral TYK2 path in lupus. No targeted oral therapy is currently approved for SLE; the two approved targeted biologics — AstraZeneca's Saphnelo (anifrolumab), a type I interferon receptor antagonist, and GSK's Benlysta (belimumab), a BLyS inhibitor — are both injectable. Alumis said it plans to engage regulators to discuss a Phase III design enriched for IFNGS-high patients. Whether regulators accept a biomarker-selected trial based on a subgroup from a failed Phase IIb — without a prospectively powered Phase IIb in that subgroup — will be a central question for that discussion. The company also cited cutaneous lupus erythematosus and Sjögren's disease as potential indications within the type I interferon-driven disease space. In the psoriasis arena, envudeucitinib faces direct oral competition from Bristol Myers Squibb's Sotyktu (deucravacitinib), the first approved TYK2 inhibitor, and Johnson & Johnson's Icotyde (icotrokinra), an oral IL-23 receptor antagonist approved in March 2026. Takeda's zasocitinib, another oral allosteric TYK2 inhibitor that demonstrated superiority over deucravacitinib in a head-to-head Phase III trial, is also targeting an NDA filing. Alumis reported PASI 90 rates of approximately 65% at Week 24 on average across its two Phase III psoriasis trials, with the twice-daily dosing schedule a potential disadvantage against once-daily competitors. Spot something wrong? Report an issue with this article