Phase 3 Data Support Oral TYK2 Inhibitor Envudeucitinib for Psoriasis

Although biologic therapies targeting cytokines such as interleukin (IL)-23 and IL-17 have demonstrated high levels of efficacy in psoriasis, many patients and clinicians continue to seek effective oral treatment options with comparable outcomes.¹ The phase 3 ONWARD clinical program evaluated envudeucitinib, a next-generation, highly selective oral tyrosine kinase 2 (TYK2) inhibitor, as a potential therapy for adults with moderate to severe plaque psoriasis.²

Today, Alumis Inc announced positive topline results from ONWARD1 and ONWARD2, 2 parallel, global, randomized, double-blind phase 3 trials designed to assess the efficacy and safety of envudeucitinib over 24 weeks. Together, the trials enrolled more than 1,700 patients who were randomized in a 2:1:1 ratio to receive envudeucitinib 40 mg twice daily, placebo, or the active comparator apremilast. Both studies included placebo and active control arms, allowing assessment of efficacy relative to an established oral therapy as well as to placebo.

"With envudeucitinib's strong phase 3 data, dermatology once again sees the high efficacy of next-generation TYK2 inhibition on reducing pathologic IL-23, IL-17, and type I interferon activity in plaque psoriasis,” said Christopher Bunick, MD, PhD, associate professor of dermatology at Yale School of Medicine in New Haven, Connecticut, and Dermatology Times Editor in Chief, in an exclusive statement. “The clinical landscape of oral therapies for plaque psoriasis is changing rapidly, and for the better for patients and clinicians."

The co-primary endpoints for ONWARD1 and ONWARD2 were the proportion of patients achieving at least a 75% improvement from baseline in the Psoriasis Area and Severity Index (PASI 75) and a static Physician’s Global Assessment (sPGA) score of 0 or 1 (clear or almost clear skin) at week 16. According to the topline results, envudeucitinib met all primary and secondary endpoints in both trials with high statistical significance compared with placebo (p < 0.0001).

“Patients with moderate to severe psoriasis have to choose between oral and biologic therapies,” said Andrew Blauvelt, MD, MBA, an investigator on the trials, in a release. “And for individuals seeking the best chance for clearance, biologics have long been superior to oral therapies. But now, with these new data on envudeucitinib, we’re seeing an exciting possibility of a new oral drug for psoriasis that can deliver high levels of efficacy in a safe manner.”

Across ONWARD1 and ONWARD2, an average of 74% of patients treated with envudeucitinib achieved PASI 75 at week 16, and 59% achieved sPGA 0/1. The placebo-adjusted response rates for both co-primary endpoints were reported to be consistent between the 2 studies, supporting reproducibility of the findings. Investigators also observed that treatment responses continued to deepen over time beyond the primary endpoint assessment.

Higher levels of skin clearance were evaluated as secondary outcomes. At week 24, approximately 65% of patients achieved PASI 90, and more than 40% achieved complete skin clearance (PASI 100), on average across the 2 trials. Notably, separation from placebo on PASI 90 responses was evident as early as week 4, suggesting a relatively rapid onset of clinical effect.

“We believe envudeucitinib demonstrates the full promise of TYK2 inhibition,” said Jörn Drappa, MD, PhD, Chief Medical Officer of Alumis in the release. “By maximally inhibiting TYK2, envudeucitinib blocks both IL‑23 and IL‑17 to deliver comprehensive disease control. In phase 3, this translated into rapid onset of action, high rates of skin clearance, and meaningful symptom improvements that rank among the strongest reported for an oral therapy. We are deeply grateful to the patients, families, and investigators whose commitment made this milestone possible.”

In addition to physician-assessed outcomes, the trials included patient-reported measures related to itch and dermatology-specific quality of life. Treatment with envudeucitinib was associated with consistent and clinically meaningful improvements in these domains, indicating that objective skin clearance was accompanied by symptomatic benefit from the patient perspective.

Envudeucitinib was also compared directly with apremilast, an approved oral therapy for psoriasis. In both ONWARD1 and ONWARD2, envudeucitinib demonstrated superior efficacy versus apremilast across all PASI endpoints at week 24, with statistical significance reported for these comparisons (p < 0.0001).

From a safety standpoint, investigators found envudeucitinib was generally well tolerated through 24 weeks of treatment. The overall frequency and severity of treatment-emergent adverse events were similar across the 2 trials and were consistent with findings from earlier phase 2 studies, including long-term extension data. Most adverse events were mild to moderate in severity, transient, and manageable with standard care. The most commonly reported adverse events included headache, nasopharyngitis, upper respiratory tract infection, and acne. Importantly, no new safety signals were identified during the phase 3 program.

ONWARD1 and ONWARD2 are part of a broader ONWARD clinical program that includes ONWARD3, an ongoing long-term extension study designed to assess durability of response, maintenance of skin clearance, and long-term safety. Beyond psoriasis, envudeucitinib is also under investigation in systemic lupus erythematosus in the phase 2b LUMUS trial, reflecting interest in its potential activity across multiple immune-mediated diseases.

Based on the phase 3 results, Alumis plans to submit a New Drug Application to the US FDA in the second half of this year and to present more detailed trial data at an upcoming medical meeting. If approved, envudeucitinib may expand the range of oral therapeutic options available for patients with moderate to severe plaque psoriasis.

References

1. Ferrara F, Verduci C, Laconi E, Mangione A, Dondi C, Del Vecchio M, Carlevatti V, Zovi A, Capuozzo M, Langella R. Therapeutic advances in psoriasis: From biologics to emerging oral small molecules. Antibodies (Basel). 2024 Sep 14;13(3):76. doi: 10.3390/antib13030076.
2. Alumis’ envudeucitinib delivers leading skin clearance among next-generation oral plaque psoriasis therapies in phase 3 program. News release. Alumis Inc. Published January 6, 2026. Accessed January 6, 2026. https://www.biospace.com/press-releases/alumis-envudeucitinib-delivers-leading-skin-clearance-among-next-generation-oral-plaque-psoriasis-therapies-in-phase-3-program