FDA Approves First Oral Drug Indicated to Treat Dermatomyositis in Adults

FDA Approves Lisraya as First Oral Treatment for Dermatomyositis

The U.S. Food and Drug Administration (FDA) has approved Lisraya (brepocitinib) tablets for the treatment of dermatomyositis in adults, effective August 27, 2026. This marks the first FDA-approved oral treatment option for this rare autoimmune disease, addressing a significant unmet need. Lisraya, a once-daily Janus kinase (JAK/TYK2) inhibitor, demonstrated superior efficacy in a Phase 3 study involving 241 adults, showing a higher average Total Improvement Score (TIS) at week 52 for the 30 mg dose compared to placebo, alongside improvements in physical function and skin disease activity.

• The efficacy and safety of Lisraya were evaluated in a randomized, double-blind, multicenter, placebo-controlled Phase 3 study (NCT05437263) involving 241 adult patients with dermatomyositis. Participants were randomized to receive either Lisraya (brepocitinib) 30 mg once daily, 15 mg once daily, or placebo over a 52-week treatment period.
• The study's primary measure, Total Improvement Score (TIS) at week 52, showed that participants treated with Lisraya 30 mg achieved a higher average TIS score, indicating greater clinical response and disease control, compared to the placebo group. Additionally, patients on Lisraya 30 mg demonstrated improvements in physical function and skin disease activity, and were more likely to reduce corticosteroid use by week 48.
• Common adverse reactions included upper respiratory tract infection, headache, fatigue, urinary tract infection, and nausea. Discontinuation due to adverse reactions was lower in the Lisraya 30 mg group (6%) compared to placebo (11%). Lisraya carries a boxed warning for serious infections, increased all-cause mortality, malignancies, major adverse cardiovascular events, and thrombosis.
• The FDA granted Lisraya both Orphan Drug and Priority Review designations, underscoring the significant unmet medical need for dermatomyositis and the potential for this new treatment to offer substantial improvements over existing therapies.

Addressing the Significant Unmet Need in Dermatomyositis

Dermatomyositis remains a therapeutically challenging condition, with management strategies largely shaped by clinical experience rather than robust trial evidence. The absence of standardized, evidence-based guidelines—compounded by disease heterogeneity and the risk of serious treatment-related complications—leaves significant gaps in care for a meaningful proportion of patients.

• Lack of evidence-based treatment guidelines: Current treatment strategies rely predominantly on uncontrolled studies, with no established placebo-controlled trial data to support them. Despite this evidentiary gap, glucocorticoids remain the cornerstone of initial management by clinical consensus rather than validated protocol.

• Refractory disease presentation: A substantial subset of patients fails to respond to sequential immunosuppressive regimens. Refractory dermatomyositis is defined by lack of improvement following two distinct immunosuppressive agents in combination with corticosteroids, with or without intravenous immunoglobulins. Severe juvenile dermatomyositis with peripheral nervous system involvement may pursue a refractory course despite aggressive, guideline-directed immunosuppression, and inclusion body myositis remains broadly resistant to corticosteroids and multiple immunomodulatory therapies.

• Treatment-related complications: Aggressive multi-combination therapy carries significant safety burdens, including opportunistic infections, leukopenia, and osteoporosis. JAK inhibitors, while increasingly utilized, introduce additional risks of thromboembolic events and heightened infection susceptibility, requiring careful ongoing monitoring.

• Rapidly progressive interstitial lung disease (RP-ILD): Anti-MDA5 antibody-positive dermatomyositis with RP-ILD represents a particularly high-risk phenotype. Infectious risk frequently delays initiation of effective immunosuppression, likely accelerating pulmonary deterioration. Cases of anti-MDA5 antibody-positive RP-ILD without classical dermatomyositis or clinically amyopathic dermatomyositis signs have demonstrated uniformly poor outcomes, with reported cases succumbing to respiratory failure within two months.

• Limited therapeutic options for severe and refractory cases: Steroid-sparing agents such as cyclosporine and cyclophosphamide are generally reserved for patients intolerant of or refractory to first-line therapy, given their more adverse safety profiles. Evidence supporting the use of biological agents in juvenile dermatomyositis remains limited, and their application continues to be regarded as investigational.

Lisraya's Pivotal Phase 3 Trial Design and Efficacy

The pivotal trials evaluating therapies in dermatomyositis (DM) have employed rigorous randomized, controlled designs anchored to validated composite response criteria, most notably the 2016 ACR/EULAR Myositis Response Criteria and Total Improvement Score (TIS). Across studies, the six core set measures (CSMs) — encompassing physician and patient global disease activity, MMT-8, Health Assessment Questionnaire, extra-muscular disease activity, and muscle enzymes — serve as the foundational efficacy endpoints.

Understanding Lisraya's Safety Profile and Regulatory Path

Clinical trials in dermatomyositis have identified a consistent set of safety signals spanning multiple therapeutic modalities, including IVIg, JAK inhibitors, and conventional immunosuppressive regimens. Infection risk and thromboembolic events represent the most clinically significant concerns, with severity influenced by baseline patient characteristics and treatment-specific factors.

• Thromboembolic events (TEEs) with IVIg: In the ProDERM phase 3 trial, eight TEEs occurred in six patients receiving high-dose IVIg, with six events in five patients deemed possibly or probably treatment-related. Patients who experienced TEEs had 2.4- to 15.2-fold higher baseline thromboembolic risk factors compared to those who did not, underscoring the importance of pre-treatment risk stratification. Reducing infusion rate attenuated TEE incidence, and no events were observed at the lower IVIg dose.

• High overall TEAE burden with IVIg: During the first 16 weeks of the ProDERM trial, 113 treatment-emergent adverse events (TEAEs) possibly or probably related to IVIg were recorded across 30 of 52 patients (57.7%), compared with 38 TEAEs in 11 placebo patients (22.9%). Eight patients discontinued therapy due to IVIg-related TEAEs, though no haemolytic transfusion reactions or deaths were reported.

• Severe infections in PM/DM populations: In a series of 279 polymyositis/dermatomyositis patients, 104 severe infections were documented (37.3%), comprising pyogenic infections (n=71) and nonpyogenic or opportunistic infections (n=33). Causative opportunistic pathogens included Candida albicans, Pneumocystis jiroveci, Aspergillus fumigatus, cytomegalovirus, and herpes simplex and zoster virus. Esophageal dysfunction, ventilatory insufficiency, malignancy, and lymphopenia were significantly more prevalent in patients who developed infections.

• Infection and thromboembolic risk with JAK inhibitors: JAK inhibitors carry a class-level risk of opportunistic infections — particularly viral reactivation — as well as thromboembolic events, consistent with signals observed across the JAK inhibitor class in other autoimmune indications and relevant to ongoing evaluation in dermatomyositis.

Pivotal Oral Therapy Emerges for Dermatomyositis Patients

The recent FDA approval of Lisraya (brepocitinib) for dermatomyositis (DM) marks a significant milestone, ushering in a new era for patients grappling with this rare and often debilitating autoimmune condition. For years, treatment options have been limited, relying on broad immunosuppressants and glucocorticoids that often come with significant side effects and inconsistent efficacy. Brepocitinib, as the first oral, targeted therapy, directly addresses this substantial unmet need.

At its core, brepocitinib is a dual TYK2/JAK1 inhibitor, a mechanism that precisely targets the inflammatory pathways central to DM pathogenesis. Research has consistently highlighted the role of type I interferon and other pro-inflammatory cytokines like IL-12, IL-23, and IFNγ in driving the muscle weakness, skin lesions, and other systemic manifestations of DM. By inhibiting these key signaling molecules, brepocitinib offers a more refined approach to disease management.

The Phase 3 clinical trial data underscored this promise, demonstrating superior efficacy for the 30 mg dose of brepocitinib compared to placebo. Patients experienced significant improvements in the Total Improvement Score, a composite measure of myositis activity, alongside notable benefits in skin disease activity, physical function, and the crucial ability to reduce glucocorticoid use. These improvements were observed remarkably early, within four weeks of treatment initiation.

However, as with any potent therapeutic, careful consideration of the risk-benefit profile is paramount. The Phase 3 trial identified a higher incidence of serious infections in the 30 mg brepocitinib group, a known concern with JAK inhibitors, underscoring the need for vigilant patient monitoring. Furthermore, efficacy was dose-dependent, with only the 30 mg dose showing significant benefit, suggesting that precise dosing will be critical. Given its mechanism, brepocitinib will also be subject to ongoing scrutiny regarding class-specific safety concerns associated with JAK inhibitors, such as potential cardiovascular events and venous thromboembolisms, necessitating robust post-marketing surveillance.

Despite these considerations, brepocitinib's approval represents a transformative step. It not only offers a much-needed, convenient, and effective oral option for DM patients but also validates the TYK2/JAK1 inhibition pathway, potentially paving the way for its broader application across other autoimmune diseases where brepocitinib has shown promise in earlier trials. This development sets a new benchmark for targeted therapies in rare autoimmune conditions.