The FDA has accepted for priority review a new drug application for fenebrutinib, an experimental oral treatment developed by Genentech. If approved, it would become the first Bruton tyrosine kinase (BTK) inhibitor to address both relapsing multiple sclerosis (RMS) and primary progressive MS (PPMS), two forms of the disease that currently lack targeted therapies.
Genentech’s submission is backed by three phase 3 trials: FENhance 1 and 2, which tested fenebrutinib against teriflunomide in RMS, and FENtrepid, which compared it directly to ocrelizumab—the only approved therapy for PPMS—in a head-to-head study. The filing marks a milestone for BTK inhibitors, which have struggled to gain traction in MS despite their potential to modulate immune-driven inflammation.
How the drug performed in clinical trials
In FENhance 1 and 2, fenebrutinib cut annualized relapse rates by 51.1% and 58.5%, respectively, compared to teriflunomide over 96 weeks. The drug also reduced active and chronic brain lesions, though formal statistical results on disability progression were not disclosed. In PPMS, FENtrepid met its primary goal of noninferiority to ocrelizumab, showing a 12% numerical risk reduction in confirmed disability progression, though the confidence interval crossed 1, meaning superiority was not proven.
The data suggest fenebrutinib may slow disease progression in PPMS, where ocrelizumab remains the sole option since 2017. However, the trial’s design leaves open questions: it did not demonstrate superiority over ocrelizumab, and its effect on disability in RMS has not been confirmed. The company also noted an imbalance in deaths across studies, though causes and timing were not specified.
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A different approach to BTK inhibition
Unlike most BTK inhibitors in development, fenebrutinib binds the enzyme reversibly, rather than irreversibly. This distinction could reduce long-term safety risks, though it has not yet been proven. The drug is designed to target both B cells, which drive acute inflammation in relapses, and microglia, which are implicated in chronic inflammation linked to disability. However, liver safety remains a concern: the FDA paused enrollment in 2023 after two cases of drug-induced liver injury in early trials, though both resolved after discontinuation.
Serious adverse events occurred in 9% of RMS patients on fenebrutinib versus 9% on teriflunomide in one trial, and 11% versus 6% in another. In PPMS, serious events were 19% for both fenebrutinib and ocrelizumab. Liver enzyme elevations were more common with fenebrutinib than with ocrelizumab, highlighting a key safety trade-off.
Regulatory hurdles ahead
The FDA’s decision to accept the application under priority review reflects urgency, but the drug’s path to approval is not guaranteed. The agency will weigh fenebrutinib’s efficacy against its liver and mortality signals, particularly given the recent setback for tolebrutinib, another BTK inhibitor developed by Sanofi. In December 2025, the FDA rejected tolebrutinib’s submission for nonrelapsing secondary progressive MS, citing unresolved safety concerns despite earlier positive feedback.
