Envudeucitinib

Alumis is forging ahead with late-stage development of envudeucitinib in systemic lupus erythematosus (SLE), even though the oral TYK2 inhibitor missed its primary and secondary endpoints in the Phase IIb LUMUS trial. Shares in the biotech plummeted 56% on Tuesday.The trial randomised 408 patients with moderate-to-severe SLE to receive one of three envudeucitinib doses, or placebo, for 48 weeks.While envudeucitinib failed to elicit responses in the overall trial population, Alumis pointed to data from a subgroup of patients who achieved "robust clinical responses" as measured by the British Isles Lupus Assessment Group–based Composite Lupus Assessment (BICLA), the primary endpoint.   Those participants had a high interferon gene signature (IFNGS‑high), which makes up the majority of SLE cases. The subgroup also performed well on additional efficacy measures, including Cutaneous Lupus Erythematosus Disease Area and Severity Index 50 (CLASI-50), SLE Responder Index 4 (SRI-4), and Lupus Low Disease Activity State (LLDAS).According to the drugmaker, IFNGS-high patients typically respond better to interferon pathway-targeted therapies, but were "unexpectedly under-represented" in LUMUS, which reduced response rates overall."Although envudeucitinib did not meet its primary objective in the overall trial population, the magnitude of effect observed in the prespecified IFNGS-high subgroup is highly compelling in a disease with no targeted oral therapies currently available," said Chief Medical Officer Jörn Drappa. "We plan to engage regulators to discuss Phase III development for envudeucitinib."Alumis also reported "robust dose-dependent interferon-pathway target engagement" based on pharmacodynamic findings, which support "its potential in interferon-driven immune-mediated diseases." The highest level of suppression was seen with the high, 40-mg dose of envudeucitinib, given twice daily.  There were no new safety signals, the company said, with envudeucitinib demonstrating a favourable safety profile.Psoriasis filing remains 'on track'Outside of SLE, Alumis is developing envudeucitinib for moderate-to-severe plaque psoriasis, though it trails behind other oral options, like Bristol Myers Squibb's Sotyktu (deucravacitinib) and Johnson & Johnson's Icotyde (icotrokinra). Takeda is also developing an oral TYK2 inhibitor, zasocitinib, which recently bested Sotyktu in a head-to-head Phase III psoriasis study.Alumis reiterated Tuesday that it's on track to submit an application with the FDA in the fourth quarter for envudeucitinib in moderate-to-severe plaque psoriasis.For more on the oral psoriasis landscape, see – KOL Views Q&A: Label and access will dictate threat level of Takeda's zasocitinib to J&J's Icotyde in psoriasis.

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