Dramatic Improvement in Dermatomyositis Skin Symptoms With First Approved Oral Agent

Patients with previously treated dermatomyositis had significant improvement in skin-related symptoms and quality of life when treated with the selective TYK2/JAK1 inhibitor brepocitinib (Lisraya), data from a randomized trial showed.

Almost half of patients with moderate/severe skin disease at baseline had “clear” or “almost clear” skin after a year of treatment, compared with 22% of patients randomized to placebo. Twice as many patients in the brepocitinib arm achieved functional skin remission by a validated measure as compared with the placebo group. Three-fourths of patients with moderate itch at baseline had clinically meaningful improvement after 52 weeks versus a third of the placebo group.

The results support oral brepocitinib as a treatment that can effect rapid and clinically meaningful improvement in cutaneous manifestations of dermatomyositis, reported Ruth Ann Vleugels, MD, MPH, of Mass General Brigham in Boston, and colleagues in JAMA Dermatology.

“In this phase III randomized clinical trial in dermatomyositis, brepocitinib 30 mg was associated with early, sustained, and clinically meaningful improvements across multiple dimensions of cutaneous disease,” the authors stated. “These benefits were observed in a population with substantial baseline skin involvement despite ongoing use of standard-of-care therapies, underscoring the persistent, unmet need for more effective, targeted treatment options in dermatomyositis.”

“A notable finding of this analysis is the consistency of benefit observed across distinct clinician-reported and patient-reported outcome measures … . suggesting that targeted TYK2 and JAK1 inhibition with brepocitinib broadly modulates the underlying pathophysiology of cutaneous disease in dermatomyositis,” they added.

The analysis builds on and complements findings from the primary analysis of the VALOR trial, which Vleugels reported earlier this year at the American Academy of Dermatology meeting. The primary results showed a 50% improvement in total dermatomyositis score for the 30-mg dose of brepocitinib as compared with placebo. The results supported the recent FDA approval of brepocitinib as the first oral treatment option for dermatomyositis.

“We have never had a drug approved for use in the skin part of dermatomyositis, which is a major part of the disorder,” co-author Victoria Werth, MD, of the University of Pennsylvania in Philadelphia, told MedPage Today. “The only approved drug for dermatomyositis up until now has been IVIG [intravenous immunoglobulin], which is a pretty cumbersome treatment. This is a pill. It’s a lot easier, and it works rather quickly. Helps the components of the disease that are important to patients.”

Alternatives have included steroids and antimalarials, which help only a minority of patients, she continued. Immunosuppressives, such as methotrexate and mycophenolate mofetil, have been used but require continuous treatment.

“We’ve had pretty limited options and nothing on label in terms of any of the more recent biologics, like JAK inhibitors. It’s all off label and pretty unavailable,” said Werth.

The secondary outcomes in the current analysis showed that the targeted drug had a favorable impact on quality of life, including a “huge difference” in itch.

“These are all important aspects of the condition and we really need treatments,” said Werth. “These patients are all really miserable, so I think it’s really going to be a great advance.”

A rare autoimmune disorder, dermatomyositis arises from systemic inflammation leading to progressive tissue damage, including muscle, skin, lungs, joints, heart, and gastrointestinal tract. The condition often follows a chronic, unpredictable, and protracted disease course, associated with substantial morbidity, disability, and impaired quality of life. Current therapies offer incomplete efficacy and are associated with treatment-related toxicities.

Cutaneous manifestations are a key driver of dermatomyositis morbidity, as skin lesions involve cosmetically sensitive areas and are often chronic, pruritic, and disfiguring, Vleugels and colleagues noted in their introduction to the analysis. Pruritus is among the most debilitating and treatment-refractory symptoms and leads to substantial impairment in quality of life.

The VALOR trial included 241 patients who had received a median of four prior lines of therapy for dermatomyositis. Patients were randomized to two different doses of brepocitinib or placebo. The current analysis included 81 patients treated with the approved dose of brepocitinib (30 mg once daily) and 79 randomized to placebo.

The analysis focused on the secondary outcome of change in the Cutaneous Dermatomyositis Disease Area and Severity Index-Activity (CDASI-A) score at 4 and 52 weeks and the proportion of patients who achieved a clinically meaningful CDASI-A response (≥40% and ≥4 points from baseline).

The 4-week results showed significantly greater improvement in the brepocitinib arm (-6.4 vs -3.5 points, P<0.001). Almost twice as many patients in the brepocitinib group had a clinically meaningful CDASI-A response (33.3% vs 17.7%). Additionally, the treatment with the targeted agent led to higher rates of itch remission (38.3% vs 19.0%) and improvement in the Skindex-16 quality of life instrument (-12.9 vs -0.9).

The benefits associated with brepocitinib were maintained at all timepoints through week 52, including the proportion of patients with clear/almost clear skin (45.7% vs 21.8%) and functional skin remission (43.5% vs 20.8%).

As reported from the primary analysis, brepocitinib exhibited a safety profile consistent with approved JAK and TYK2 inhibitors.