The Safety of Fenebrutinib in a Large Population of Patients With Diverse Autoimmune Indications Supports Investigation in Multiple Sclerosis (MS)
Jiwon Oh1, Stanley Cohen2, David Isenberg3, Marcus Maurer4, Joshua Galanter5, Tom Chu5, Anastasia Teterina6, Alexandra Goodyear5, Corey Mandel5, Chin Lee5, Katie Tuckwell5, Jeremy Lim5, Konstantina Vanevski6, Gavin Giovannoni7
1St Michael's Hospital, 2Presbyterian Hospital, University of Texas Southwestern Medical School, 3University College Hospital, University College London, 4Allergy-Centrum-Charité, Charité University Medicine, 5Genentech, Inc., 6F. Hoffmann-La Roche Ltd, 7Queen Mary University of London
Objective:

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

Background:
Fenebrutinib is a potent, highly selective, reversible oral Bruton’s tyrosine kinase inhibitor (BTKi) being evaluated in Phase 3 clinical trials for MS. We analyzed safety data from Phase 2 RCTs and OLEs in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and chronic spontaneous urticaria (CSU).
Design/Methods:

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.

Results:

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.

Conclusions:

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.