To analyze the large fenebrutinib safety database of prior autoimmune randomized clinical trials (RCTs) and open-label extensions (OLEs).

Safety assessments included adverse events (AEs), laboratory results, ECGs and vital signs. Patients who received fenebrutinib at the highest dose (200 mg) or placebo were included.

In the RCTs and OLEs, 792 patients were exposed to fenebrutinib (523 RA, 194 SLE, 75 CSU). Of these, 493 patients were exposed for ≥48 weeks. AEs reported in >5% of fenebrutinib-treated patients in RCTs (n=299) were nasopharyngitis (6%), nausea (5.7%), and headache (5.4%). Serious infections were reported in 6 patients (2%) receiving fenebrutinib and 5 patients (1.8%) receiving placebo. Asymptomatic, reversible grade 2 and 3 alanine aminotransferase elevations were reported in 11 patients (3.7%) receiving fenebrutinib and 3 (1.1%) receiving placebo; there were no Hy’s law cases. No patients in the RCTs experienced atrial or ventricular tachyarrhythmias. Bleeding or bruising (multiple AE terms combined) was reported in 23 patients (7.7%) receiving fenebrutinib vs 3.2% receiving placebo, with no cases of major hemorrhage (Grade ≥3, serious, or neurological). AEs generally became less frequent with prolonged exposure during OLEs and were consistent with the RCT high dose.

Fenebrutinib at the highest dose tested was generally well tolerated in Phase 2 RCTs and OLEs, without increases in infection rates. Liver function test elevations were reversible upon discontinuation. Fenebrutinib’s enhanced selectivity may result in few off-target AEs associated with less specific BTKis. Fenebrutinib’s safety profile supports testing in Phase 3 clinical trials in MS.