Proof‐of‐concept for clinical effects of oral rilzabrutinib, the first Bruton tyrosine kinase inhibitor for pemphigus vulgaris: the phase 2 BELIEVE study

Background Bruton tyrosine kinase (BTK) inhibition targets B-cell and other non-T-cell immune cells implicated in pemphigus pathophysiology, an autoimmune disease driven by anti-desmoglein autoantibodies. Rilzabrutinib is a new reversible, covalent BTK inhibitor demonstrating preclinical efficacy as monotherapy in canine pemphigus foliaceus. Objectives Evaluate efficacy and safety of oral rilzabrutinib in pemphigus vulgaris patients in a multicenter, proof-of-concept, phase 2 trial. Methods Patients with PDAI severity scores 8-45 received 12 weeks of oral rilzabrutinib 400-600 mg bid and 12 weeks follow-up. Patients initially received between zero and ≤0·5 mg/kg prednisone-equivalent corticosteroid (CS, ie, "low-dose"), tapered after Control of Disease Activity (CDA; no new lesions, existing lesions healing). The primary endpoints were CDA within four weeks on zero-to-low-dose CS and safety. Results 27 patients with pemphigus vulgaris were included: nine newly diagnosed (33%) and 18 relapsing (67%); 11 with moderate disease (41%) and 16 moderate-to-severe (59%). The primary endpoint CDA was achieved in 14 patients (52%; 95% CI: 32%-71%): 11 using low-dose CS, three using no CS. Over 12 weeks of treatment, mean CS doses reduced from 20·0 to 11·8 mg/day for newly diagnosed patients and 10·3 to 7·8 mg/day for relapsing patients. Six patients (22%) achieved complete response by week 24, including four (15%) by week 12. Treatment-related adverse events were mostly mild (grade 1/2); one patient experienced grade 3 cellulitis. Conclusions Rilzabrutinib alone, or with much lower CS doses than usual, was safe with rapid clinical activity in pemphigus vulgaris. These data suggest that BTK inhibition may be a promising treatment strategy and supports further investigation of rilzabrutinib for the treatment of pemphigus.