Envudeucitinib demonstrates biologic-like efficacy in moderate-to-severe plaque psoriasis

The novel tyrosine kinase 2 (TYK2) inhibitor envudeucitinib (ESK-001) produced high levels of skin clearance with a reassuring tolerability profile in the phase 3 ONWARD 1 and 2 trials. By week 24, Psoriasis Area and Severity Index (PASI) 90 was achieved by approximately 65% of patients with moderate-to-severe plaque psoriasis, and complete clearance (PASI 100) by 40% of patients, approaching response levels typically associated with biologic therapy.

TYK2 inhibition has emerged as an attractive oral strategy in psoriasis, as it enables selective modulation of interleukin-23 (IL-23) and type I interferon signalling without broader inhibition of the Janus kinase (JAK) pathway, which is associated with known adverse effects. As Dr Andrew Blauvelt (University of Maryland School of Medicine, MD, USA) noted, envudeucitinib achieves sustained TYK2 inhibition throughout the 24-hour dosing interval. But does this translate into clinical benefit? This question was now answered by the ONWARD 1 (NCT06586112) and ONWARD 2 (NCT06588738) pivotal trials, presented in a late-breaking research session [1].

Both randomised, double-blind studies enrolled more than 1,700 adults with moderate-to-severe plaque psoriasis and compared envudeucitinib 40 mg twice daily with apremilast and placebo. Co-primary endpoints at week 16 were PASI 75 and a Physician’s Global Assessment (PGA) score of 0/1. Both trials met all primary and secondary endpoints, demonstrating clinically meaningful separation from comparators; approximately 75% of patients receiving envudeucitinib achieved PASI 75 at week 16, compared with substantially lower response rates in the apremilast and placebo groups. At the same time point, 59% of patients achieved PGA 0/1.

Response depth continued to increase through week 24, consistent with the delayed efficacy often observed with agents modulating the interleukin-23 (IL-23) pathway. At week 24, approximately 80% of patients achieved PASI 75, around 65% reached PASI 90, and 40% attained complete PASI 100. Envudeucitinib outperformed apremilast across all PASI endpoints at week 24 (P<0.0001). Dr Blauvelt emphasised the clinical relevance of achieving a 40% PASI 100 rate with an oral therapy, a level of efficacy historically associated with biologic agents.

The safety signal was favourable and consistent with prior experience with TYK2. The most frequently reported adverse events were nasopharyngitis and upper respiratory tract infections. No signals were observed for major adverse cardiovascular events, tuberculosis reactivation, or laboratory abnormalities, including lipid elevations.

Looking ahead, Dr Blauvelt suggested that the typical regulatory timeline for late-breaking phase 3 dermatology data may apply, with potential market entry within the following year. A long-release once-daily formulation is under development to replace the current 40 mg twice-daily regimen, and paediatric studies are planned.

With PASI 100 achieved in approximately 40% of patients at week 24 and no new safety concerns identified, envudeucitinib, described by Dr Blauvelt as a “next-generation or second-generation TYK2 inhibitor,” may expand the oral treatment landscape for moderate-to-severe plaque psoriasis, offering a biologic-like efficacy profile for patients who prefer oral therapy.

Blauvelt A. Envudeucitinib (ESK-001) in moderate-to-severe plaque psoriasis: 24-week results from the randomised, double-blind, active comparator- and placebo-controlled, phase 3 ONWARD 1 and 2 studies. AAD 2026, 27–31 March, Denver, CO, USA.