Fenebrutinib Demonstrates Superior Efficacy in Reducing Relapses and Brain Lesions in Pivotal Phase 3 MS Trials

New data from 2 large-scale phase 3 clinical trials, FENhance 1 and FENhance 2, reveal that the investigational drug fenebrutinib (Genentech) significantly outperforms the standard-of-care treatment, teriflunomide (Aubagio; Sanofi), in reducing disease activity for adults with relapsing multiple sclerosis (MS). The results, presented at the Consortium for Multiple Sclerosis Centers (CMSC) 2026 Annual Meeting, position fenebrutinib as a potential breakthrough in targeting the dual drivers of disability in MS: peripheral and central nervous system (CNS) inflammation.¹

A Unique Mechanism of Action

Fenebrutinib is a uniquely designed Bruton tyrosine kinase (BTK) inhibitor. Unlike some other treatments in this class, it is noncovalence and highly selective. Crucially, the drug is CNS-penetrant, meaning it can cross the blood-brain barrier to address inflammatory mediators within the CNS, which are major drivers of long-term disability accumulation.

The FENhance program follows successful phase 2 results from the FENopta trial and parity results in the phase 3 FENtrepid trial, which evaluated the drug in primary progressive MS.

Superior Reduction in Annualized Relapse Rates

The primary objective of the FENhance 1 and 2 trials was to evaluate the efficacy and safety of fenebrutinib (200 mg twice daily) against teriflunomide (14 mg once daily) over a minimum of 96 weeks. The studies enrolled 1497 participants with relapsing MS between the ages of 18 and 55, the majority of whom (66.5%) were female.¹

Fenebrutinib achieved superiority in the annualized relapse rate (ARR) across both studies. In FENhance 1, fenebrutinib reduced the ARR to 0.061, compared to 0.125 for teriflunomide. In FENhance 2, the efficacy was even more pronounced, with an ARR of 0.054 for fenebrutinib versus 0.130 for the control group. These results were statistically significant, with P-values of less than 0.001 in both instances.

Profound Impact on Brain Lesions

The secondary end points of the trial focused on MRI disease activity, which tracks new or active damage in the brain. Fenebrutinib demonstrated significant relative reductions in key MRI markers compared to teriflunomide.¹

For T1 gadolinium-enhancing (T1 Gd+) lesions, which indicate active inflammation, fenebrutinib showed a reduction of 70.7% in FENhance 1 and 77.6% in FENhance 2. Similarly, the drug significantly reduced new or enlarging T2 lesions, which measure overall disease burden, by 76% and 82.5%, respectively. All MRI results reached a high level of statistical significance (P < 0.0001).¹

Safety Profile and Clinical Observations

Safety data showed that the proportion of patients experiencing adverse events (AEs) was generally similar between the treatment arms. In FENhance 1, AEs were reported in 90.4% of the fenebrutinib group versus 88.7% for teriflunomide. In FENhance 2, the rates were 93.1% and 87.4%, respectively. Notably, liver enzyme elevations were found to be comparable between both treatment arms.¹

However, a pooled safety analysis identified 8 deaths in the fenebrutinib group compared to 1 in the teriflunomide group. These deaths were attributed to “various causes.”

A First in MS Treatment

With positive results now recorded in both primary progressive MS and relapsing MS trials, fenebrutinib has become the first oral BTK inhibitor to demonstrate efficacy across both relapsing and progressive disease biologies. This dual efficacy suggests that by targeting both peripheral B cells and CNS-resident cells, fenebrutinib may offer a more comprehensive approach to managing the complex nature of multiple sclerosis.

REFERENCE

1. Nicholas JA. Efficacy and safety of fenebrutinib vs teriflunomide in relapsing MS: results of the FENhance 1 and 2 studies. Presented at: Consortium for Multiple Sclerosis Centers (CMSC) 2026 Annual Meeting. May 29, 2026. Charlotte, NC.