Belumosudil in diffuse cutaneous systemic sclerosis: a randomized, double-blind, open-label extension,...

Area of Science:

• Rheumatology and Immunology
• Pharmacology and Therapeutics
• Dermatology

Background:

• Diffuse cutaneous systemic sclerosis (dcSSc) is a severe autoimmune disease characterized by widespread skin thickening and internal organ involvement.
• Current treatments for dcSSc have limited efficacy and significant side effects.
• Belumosudil, a ROCK2 inhibitor, is being investigated for its potential immunomodulatory and anti-fibrotic effects in autoimmune diseases.

Purpose of the Study:

• To evaluate the efficacy, safety, and pharmacodynamics of belumosudil in patients with dcSSc.
• To assess the impact of belumosudil on the CRISS score, a measure of systemic sclerosis severity.
• To explore the mechanism of action of belumosudil through RNA-sequencing and biomarker analysis.

Main Methods:

• A randomized, double-blind, placebo-controlled trial with an open-label extension.
• Patients with dcSSc received belumosudil (200 mg QD or BID) or placebo for 28 weeks.
• Primary endpoint was CRISS score ≥0.60 at week 24; secondary endpoints included safety and pharmacodynamic markers.

Main Results:

• The study was terminated prematurely; target enrollment was not met.
• Belumosudil did not demonstrate a significant efficacy signal compared to placebo for the primary endpoint (CRISS score).
• Belumosudil was well-tolerated with similar safety profiles across groups. RNA-sequencing showed FOXP3 upregulation and STAT3, IL23A, TGF-β downregulation, supporting the drug's mechanism. A trend of decreased fibrosis biomarkers was observed.

Conclusions:

• Belumosudil did not show detectable efficacy in this dcSSc patient cohort.
• Pharmacodynamic analyses supported belumosudil's mechanism of action.
• A trend towards reduced fibrosis biomarkers suggests potential therapeutic benefits warranting further investigation.