Safety Profile of Fenebrutinib in MS Similar to Other Autoimmune Conditions


Phase 2 study analysis of Roche's fenebrutinib reveals similar safety profiles across multiple autoimmune indications, including relapsing multiple sclerosis.

Jiwoh Oh, MD, PhD, staff neurologist and medical director of the Barlo Multiple Sclerosis Program at St. Michaels Hospital

Jiwoh Oh, MD, PhD

In an analysis of phase 2 studies assessing Roche’s fenebrutinib, an oral Bruton tyrosine kinase (BTK) inhibitor, results showed that the safety profile of the agent was similar in both patients with relapsing multiple sclerosis (MS) and other previously studied automimmune indications.1

Led by Jiwoh Oh, MD, PhD, staff neurologist and medical director of the Barlo Multiple Sclerosis Program at St. Michaels Hospital, the data included 73 patients with relapsing MS and 577 patients with autoimmune indications who received fenebrutinib 200 mg BID across phase 2 studies. The previously studied indications included rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), chronic spontaneous urticaria (CSU). In addition, investigators also included 36 patients with relapsing MS and 278 with autoimmune indications who received placebo or standard of care.

Presented at the 2024 Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, held February 29 to March 2, in West Palm Beach, Florida, adverse events (AEs) reported at least 5% of fenebrutinib-treated patients with relapsing MS were abnormal hepatic transaminase elevation and urinary tract infection (5.5% each). For more context, in December 2023, the FDA placed a hold on the development program of fenebrutinib for MS based on 2 cases of hepatic transaminase elevations in conjunction with elevated bilirubin suggestive of drug-induced liver injury identified in the phase 3 FENhance studies of relapsing MS. Both patients were asymptomatic and had elevations returned to normal levels following the discontinuation of fenebrutinib.2

Between the treatment arms, there was no imbalance in rate of infections, nor were there any reported serious or fatal AEs across any of the indications. Hepatic transaminase elevations of at least grade 2 were more frequent in fenebrutinib groups over placebo. For relapsing MS, these occurred in 8.2% of patients on active treatment vs 2.8% of those on placebo. Similarly, these occurred in 4% of those with autoimmune conditions on the drug vs 1.4% of those on placebo (RA: 1.9% vs 1.3%; SLE: 4.5% vs 2.4%; CSU: 9.6% vs 0.0%).1

READ MORE: Neurofilament Light Levels Predict Future MS Disease Activity Regardless of Race or Ethnicity

Additional data from the analysis showed that nonserious grade 1 bleeding/bruising AEs were reported in 1.4% of fenebrutinib-treated patients with relapsing MS and 7.7% of those with autoimmune conditions treated with the agent. In comparison, these occurred in 3.2% of patients with autoimmune indications on placebo and in no patients with relapsing MS on placebo. Furthermore, irrespective of the condition, there were no cases of major hemorrhage or cardiovascular events in patients who received fenebrutinib.

Fenebrutinib, a BTK inhibitor that blocks the function of BTK, is also a dual inhibitor of both B-cell and microglia activation. As a result of the December 2023 clinical hold, new enrollment for the FENhance 1 trial (NCT045865023) in the US was paused, while enrollment in countries outside the US continued. In addition, participants in the US who received the therapy for more than 70 days continued treatment in all studies, which comprise the ongoing, fully enrolled FENhance 2 (NCT045586010) and FENtrepid trial (NCT04544449).2

Prior to the FENhance trials, fenebrutinib was evaluated in the phase 2 FENtopa study (NCT05119569), a double-blind, placebo-controlled study comprised of 109 adults with relapsing MS, aged 18-55 years. The study met its primary, with fenebrutinib demonstrating a significant reduction in the total number of new gadolinium-enhancing T1 brain lesions compared with placebo (P = .0022). Secondary end points, which included the number of new or enlarging T2-weighted lesions, was significantly reduced through treatment of fenebrutinib. Furthermore, more patients treated with the agent were free from any new gadolinium-enhancing T1 brain lesions and new or enlarging T2-weighted brain lesions compared with placebo.3

Click here for more coverage of 2024 ACTRIMS Forum.

1. Oh J, Raievska A, Sierzega M, et al. The safety profile of fenebrutinib in patients with multiple sclerosis is consistent with those in previously studied autoimmune indications. Presented at: ACTRIMS Forum; February 29 to March 3, 2024; West Palm Beach, FL. Abstract P094
2. Fenebrutinib multiple sclerosis clinical trial program update. News release. Genentech/Roche. November 30, 2023. Accessed March 1, 2024.
3. Genentech’s BTK inhibitor fenebrutinib significantly reduced brain lesions in people with relapsing forms of multiple sclerosis. News release. May 17, 2023. Accessed March 1, 2024.
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