Could an oral targeted therapy finally change the treatment landscape in dermatomyositis?

A first-in-class oral, selective inhibitor of tyrosine kinase 2 (TYK2)/Janus kinase 1 (JAK1) achieved clinically meaningful improvements in adults with dermatomyositis who had failed prior therapies in the phase 3 VALOR trial (NCT05437263). The agent also successfully improved dermatologic manifestations, supporting its potential as a targeted treatment option in this difficult-to-treat disease.

To date, no targeted therapies are approved for dermatomyositis; current standards, such as conventional disease-modifying anti-rheumatic drugs (DMARDs) and intravenous immunoglobulin, are limited by modest efficacy, burdensome administration, and significant toxicity. Against this backdrop, Prof. Ruth Ann Vleugels (Brigham and Women’s Hospital, MA, USA) presented results from the randomised, double-blind, placebo-controlled phase 3 VALOR trial, with simultaneous publication in the New England Journal of Medicine [1,2]. Brepocitinib targets both TYK2 and JAK1, key mediators of proinflammatory cytokines signalling implicated in the pathogenesis of dermatomyositis.

The trial enrolled adults aged 18–75 years with active muscle and skin involvement, randomising them to brepocitinib 30 mg daily (n=81), 15 mg daily (n=81), or placebo (n=79). The mean age was 50.6 years, and 81.3% had moderate-to-severe disease activity at baseline. Stable background therapy with a single antimalarial, a single DMARD, or both was permitted. Patients receiving systemic glucocorticoids were required to taper to ≤20 mg prednisone-equivalent per day before randomisation, although short rescue courses were allowed during the first 12 weeks.

At week 52, the mean Total Improvement Score, defined as the primary endpoint, was 46.5 with brepocitinib 30 mg, compared with 37.5 with brepocitinib 15 mg and 31.2 for placebo. The difference versus placebo was 15.3 points for the higher dose (P<0.001), whereas the 6.3-point difference for the 15 mg arm did not reach statistical significance. All 9 key secondary endpoints favoured brepocitinib 30 mg over placebo.

Cutaneous outcomes were assessed using the Cutaneous Dermatomyositis Disease Area and Severity Index–Activity (CDASI-A) in participants with moderate-to-severe skin disease at baseline (CDASI-A >14). Cutaneous clinical remission, defined as CDASI-A ≤5 at week 52, was achieved in 44% of patients on the 30 mg dose (n=46) and 32% on the 15 mg dose (n=47), compared with 21% in the placebo group (n=53).

Overall adverse event rates were comparable across arms (90%, 86%, and 91%, respectively). However, serious infections occurred more frequently with brepocitinib 30 mg (10%) than with placebo (1%). According to the investigators, these events resolved with appropriate medical management, and most affected patients completed the treatment. Overall trial completion was 87.1%, although discontinuation was more common in the 30 mg arm (25%) than in the placebo group (11%). Notably, 32% of participants receiving the higher dose did not achieve even moderate improvement.

For dermatologists managing refractory dermatomyositis, brepocitinib may offer an opportunity to intervene earlier with a targeted oral agent, potentially reducing reliance on prolonged systemic corticosteroid use and the toxicities associated with conventional DMARDs. An ongoing 52-week open-label extension will further evaluate the long-term efficacy and safety of brepocitinib in this population.

Vleugels RA, et al. Brepocitinib achieves rapid and sustained control of cutaneous disease activity, itch, and skin-related quality of life in dermatomyositis: Results from the phase III VALOR trial. S034: Late-breaking Research Session 2. AAD 2026, 27–31, March, Denver, CO, USA.
Vleugels RA, et al. New Engl J Med 2026; 394: Published March 28, DOI: 10.1056/NEJMoa2503531.