Targeted TYK2–JAK1 inhibition improves muscle and skin disease activity while enabling glucocorticoid tapering in treatment-refractory dermatomyositis.
A first-in-class TYK2–JAK1 inhibitor has demonstrated significant clinical benefit in adults with dermatomyositis in a large phase 3 trial, offering a potential targeted therapy option for a disease with limited effective treatments.
In the multinational VALOR trial, once daily brepocitinib 30mg significantly improved overall disease activity compared with placebo over 52 weeks in patients with dermatomyositis that had not responded adequately to standard therapies.
The trial enrolled 241 adults across 90 sites in 20 countries, randomised to brepocitinib 30mg, brepocitinib 15mg, or placebo alongside background therapy.
Results have been published in The New England Journal of Medicine.
“In adults with dermatomyositis that was resistant to previous therapy, the use of brepocitinib at a dose of 30mg [but not at a dose of 15mg] resulted in significant benefits with respect to a composite myositis index, skin disease severity, glucocorticoid tapering, and functional disability,” the authors wrote.
Dermatomyositis is a systemic autoimmune inflammatory myopathy that affects muscle, skin and multiple organ systems, often resulting in chronic disability and reduced quality of life.
The researchers explained that although the use of systemic glucocorticoids has historically represented the cornerstone of therapy for dermatomyositis, chronic use was associated with substantial toxicity, including increased risks for infection, diabetes, cardiovascular disease, osteoporosis and glucocorticoid myopathy.
Even low doses have been linked to adverse effects, which made glucocorticoid reduction a key therapeutic goal in patients with dermatomyositis, they said.
“Current therapies, including combinations of systemic glucocorticoids, nonspecific disease-modifying antirheumatic drugs (DMARDs), and intravenous immune globulin, are associated with incomplete efficacy, treatment-related toxic effects, and challenges with administration,” the researchers wrote.
“As such, there is a substantial unmet need for safe and effective treatment options for patients with dermatomyositis.”
Brepocitinib targets tyrosine kinase 2 (TYK2) and Janus kinase 1 (JAK1), key signalling molecules involved in cytokine pathways implicated in dermatomyositis pathogenesis, including interferon and interleukin pathways.
At week 52, patients receiving brepocitinib 30mg achieved a mean Total Improvement Score of 46.5 compared with 31.2 in the placebo group, a statistically significant difference of 15.3 points. The lower 15mg dose did not meet the prespecified threshold for statistical significance versus placebo.
Clinical benefit extended across multiple disease domains. Moderate improvement or better was reported in 68% of patients receiving brepocitinib 30mg compared with 44% of those receiving placebo, while major improvement occurred in 46% versus 26% respectively.
Skin disease activity also improved significantly, with treatment effects emerging early. By week four, patients receiving brepocitinib 30mg had a greater reduction in Cutaneous Dermatomyositis Disease Area and Severity Index activity scores than those receiving placebo, with benefits sustained through week 52.
Importantly, the treatment also facilitated glucocorticoid tapering. Among patients taking glucocorticoids at baseline, 62% of those treated with brepocitinib 30mg reduced their prednisone dose to 2.5mg per day or less by week 52, compared with 34% in the placebo group, and 42% were able to discontinue steroids entirely.
Functional outcomes improved alongside disease activity, with patients reporting clinically meaningful gains in physical function as measured by the Health Assessment Questionnaire–Disability Index.
Safety outcomes were broadly similar between treatment groups, although serious infections occurred more frequently in the brepocitinib 30mg group (10%) than in the placebo group (1%).
The most common adverse events included upper respiratory tract infection, covid-19, urinary tract infection, nausea, diarrhoea and headache. No deaths occurred during the trial.
Investigators concluded that brepocitinib 30mg provided clinically meaningful improvements across muscle and skin disease activity, functional disability and glucocorticoid exposure in patients with dermatomyositis.
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However, the increased risk of serious infection highlighted the need for careful patient monitoring.
The researchers noted that a limitation of the trial was that the protocol required that background DMARD therapy remain stable throughout the blinded treatment period, even in patients who had marked clinical improvement.
Although this approach was necessary to ensure an equivalent intensity of background treatment for efficacy assessments, in clinical practice DMARD tapering is common after disease control has been achieved to limit polypharmacy and minimise toxic effects.
“Data from the ongoing 52-week open-label extension will help to characterise the use of brepocitinib under more flexible conditions as background therapy,” the researchers wrote.
If confirmed in longer-term follow-up studies, they said targeted TYK2–JAK1 inhibition could represent a new therapeutic strategy for dermatomyositis, particularly for patients whose disease remains active despite conventional immunosuppressive treatment.
