It’s early days, but a phase 2 trial has found support for a selective tyrosine kinase 2/Janus kinase 1 inhibitor in adults with the condition.
Adults with cutaneous sarcoidosis may not need to rely on off-label treatments for much longer, new research suggests.
The interim analysis for BEACON, an international placebo-controlled phase 2/3 clinical trial exploring the effects of the selective TYK2/JAK1 inhibitor breprocitinib in adults with cutaneous sarcoidosis, are the first to demonstrate the efficacy of a targeted therapy in CS.
“Current treatment of CS relies on off-label antimalarials, tetracycline antibiotics, conventional disease-modifying antirheumatic drugs, and/or tumour necrosis factor inhibitors, often in combination with topical or systemic glucocorticoids,” said the researchers behind the study.
“Despite the frequent use of multiple concurrent therapies, complete and durable disease control remains uncommon. Poor tolerability and the cumulative toxic effects of standard therapies further complicate long-term disease management.
“Together, these limitations underscore the urgent need for novel, targeted treatment options for CS.”
The findings were published in JAMA Dermatology.
Thirty-one patients (mean age 53 years, 58% female participants, 74% Black participants, average disease duration 8.1 years) were randomised to 45mg of oral brepocitinib, 15mg oral brepocitinib, or placebo in a 3:2:2 fashion, with group allocation stratified according to oral glucocorticoid use at baseline.
All participants had a Cutaneous Sarcoidosis Activity and Morphology Instrument–Activity score ≥10. Treatment was administered once daily for 16 weeks.
The primary efficacy outcome for this prespecified interim analysis was the change in CSAMI-A score from baseline to week 16. The average CSAMI-A score at baseline across all participants was 33.6. After 16 weeks of treatment, the average reduction in CSAMI-A score was 22.3 points in the 45mg brepocitinib group, 22.2 in the 15mg breprocitinib group, and 0.7 in the placebo group.
Several secondary efficacy outcomes were also met. A greater proportion of patients in the 45mg breprocitinib group achieved a CSAMI-A score less than five at week 16 compared to placebo (61.5% versus 0%), and a greater proportion achieved a ≥10-point reduction in their CSAMI-A score (100% versus 14.3%).
Similarly, patients in the 45mg group reported greater improvement in the Skindex-16 (a measure of how skin disease affect their quality of life, mean change from baseline 23.5 versus -8.9) and King’s Sarcoidosis Questionnaire – Skin Domain (a sarcoidosis-specific measure of how skin manifestations affect their quality of life, 34.6 versus 1.8).
The researchers claimed the improvements in patient-reported outcomes were a valuable addition to the changes in clinician-assessed disease activity.
“These findings underscore the persistent physical and psychosocial burden of CS with currently available treatment approaches and highlight the potential for rapid, sustained control of skin disease activity to translate into clinically meaningful improvements in symptoms, functioning, and quality of life in patients with CS,” they wrote.
Adverse events were common across all groups (92% in the 45mg brepocitinib group, 82% in the 15mg breprocitinib group, and 86% in the placebo group) but were mostly mild in severity.
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The adverse events that occurred in four or more participants were a worsening or exacerbation of CS (two patients in the 45mg brepocitinib group, three in the 15mg breprocitinib group, and three in the placebo group), pruritus (four, one, and one), and nasopharyngitis (one, four, and one).
There were no recorded deaths, serious adverse events, viral reactivations, cancers, major adverse cardiovascular events, venous thromboembolic events, or liver enzyme elevations.
“Collectively, these findings provide convergent evidence that selective TYK2/JAK1 inhibition produces broad clinical benefit in CS. Brepocitinib was well tolerated, with no serious adverse events and low rates of study drug discontinuation in all treatment groups,” the researchers wrote.
The findings give promise to a cohort of patients with next to no other viable treatment options, according to the researchers.
“Current management relies exclusively on off-label immunomodulatory therapies that are associated with variable efficacy, cumulative toxic effects, and frequent treatment failure,” they wrote. “Given the penchant for CS to cause irreversible tissue injury and permanent disfigurement, treatment goals extend beyond partial clinical improvement to include early and sustained suppression of disease activity.”
“The high rates of deep clinical response (CSAMI-A score <5) and achievement of clear or almost clear disease observed with brepocitinib, 45mg, suggest that cutaneous remission-oriented treatment goals may be achievable for a condition with no currently approved therapies.”
Additional efficacy and safety data will be provided as part of the ongoing phase 3 part of the BEACON trial.
