Efficacy and Safety of Rilzabrutinib in Pemphigus: PEGASUS Phase 3 Randomized Study

Area of Science:

• Immunology
• Dermatology
• Pharmacology

Background:

• Pemphigus is a severe autoimmune blistering disease requiring long-term management.
• Current treatments aim to minimize corticosteroid (CS) exposure while maintaining disease control.
• Rilzabrutinib, an oral Bruton tyrosine kinase inhibitor, has shown efficacy in Phase 2 pemphigus studies.

Purpose of the Study:

• To evaluate the efficacy and safety of rilzabrutinib in patients with moderate-to-severe pemphigus vulgaris/pemphigus foliaceus.
• To assess the potential of rilzabrutinib to reduce corticosteroid dependence.
• To determine if rilzabrutinib provides consistent disease control with improved safety.

Main Methods:

• A Phase 3, randomized, double-blind, placebo-controlled trial (PEGASUS study) involving 131 adult patients.
• Patients were randomized 1:1 to receive either 400 mg of rilzabrutinib or placebo twice daily for 37 weeks.
• Concomitant corticosteroid use was limited to ≤ 0.5 mg/kg/day.

Main Results:

• The primary endpoint (complete remission at weeks 29-37 with CS ≤ 10 mg/d) was not statistically significant (24% rilzabrutinib vs. 18% placebo).
• Secondary endpoints showed numerical improvements in reduced CS use, remission duration, and time to remission with rilzabrutinib, but these were not significant.
• Rilzabrutinib was generally well-tolerated, with similar adverse event profiles between the treatment and placebo groups.

Conclusions:

• Rilzabrutinib was well-tolerated in patients with pemphigus.
• The primary efficacy endpoint was not met under the specified conditions (CS ≤ 10 mg/d).
• A prespecified sensitivity analysis (CS ≤ 5 mg/d, all observations) suggested that Bruton tyrosine kinase inhibition is a viable therapeutic strategy for pemphigus.