FDA Grants Priority Review for Roche's MS Pill Fenebrutinib
The FDA has accepted Roche's application for fenebrutinib, an oral BTK inhibitor for multiple sclerosis, initiating a six-month priority review.
The FDA has accepted Roche's application for priority review of fenebrutinib, an investigational oral BTK inhibitor, for both relapsing and primary progressive multiple sclerosis. Genentech, part of the Roche Group, received the priority review designation. The evaluation covers both forms of the disease and is based on data from three Phase III trials. The regulator now has a six-month timeline to complete its review.
Fenebrutinib's mechanism and potential significance
Fenebrutinib is an investigational non-covalent Bruton's tyrosine kinase (BTK) inhibitor. It is designed to cross the blood-brain barrier and act within the central nervous system. The drug aims to address both acute inflammation, which causes relapses, and chronic brain inflammation, which drives disability progression. If approved, fenebrutinib would become the first BTK inhibitor and the first high-efficacy oral treatment for both relapsing MS (RMS) and primary progressive MS (PPMS).
Efficacy data from Phase 3 trials
The filing acceptance is based on data from the phase 3 FENhance 1 and 2 RMS studies and the phase 3 FENtrepid PPMS study. In the RMS trials, fenebrutinib significantly reduced annualized relapse rates compared to the older drug teriflunomide. It also showed a consistent, positive trend in delaying disability progression in those studies.
| Trial Name | Patient Population | Comparator Drug | Key Efficacy Result | Statistical Significance (p-value) |
|---|---|---|---|---|
| FENhance 1 | Relapsing MS | Teriflunomide | 51.1% reduction in annualized relapse rate | < 0.001 |
| FENhance 2 | Relapsing MS | Teriflunomide | 58.5% reduction in annualized relapse rate | < 0.00001 |
| FENtrepid | Primary Progressive MS | Ocrevus | 12% numerical reduction in disability progression risk (HR 0.88) | Met primary endpoint of non-inferiority |
In the FENtrepid trial for PPMS, fenebrutinib met the primary endpoint of non-inferiority to Ocrevus for disability progression. The hazard ratio of 0.88 corresponds to a numerical 12% reduction in the risk of 12-week composite confirmed disability progression compared to Ocrevus. The 95% confidence interval for this ratio was 0.75 to 1.03, which included 1.0. Fenebrutinib became the first investigational medicine in more than a decade to slow disability progression in a phase 3 PPMS trial.
Safety considerations and regulatory context
While the drug met its goals in late-stage testing, its approval path was slowed by a partial clinical hold. Regulators have pre-existing concerns about the liver safety of BTK inhibitors. Development of candidates from Merck KGaA and Sanofi was previously slowed by liver-related side effects. Sanofi’s medicine Cenrifki was rejected in the U.S. Due to safety concerns, though it was cleared in Europe in June for a narrower group of MS patients.
Additional safety concerns emerged during testing of fenebrutinib. In one trial, Roche reported a case of liver enzyme elevations meeting Hy’s law threshold, which indicates an increased risk of death or liver transplantation. There was an imbalance in the number of deaths between treatment recipients and comparator groups. There were eight deaths among fenebrutinib recipients in two of the three Phase 3 studies, compared to one death in a participant who received the comparator drug Aubagio. Roche stated that the deaths occurred at different timepoints and had various causes. The company described fenebrutinib’s safety profile as manageable across its development program, which includes a large safety database with more than 2,700 study participants.
Current MS treatment landscape and need
Ocrevus is currently the only approved treatment for PPMS. Until its FDA approval, there had been no FDA-approved treatments for that debilitating form, which is marked by steadily worsening symptoms without distinct relapses. Nearly one million Americans and more than three million people worldwide live with MS. Approximately 85% are initially diagnosed with relapsing-remitting MS, while about 15% have PPMS. Despite available options, over a third of all people with MS still receive lower-efficacy treatment.
The FDA has six months to complete its priority review, after which a decision on approval will be made based on the submitted data from the three Phase 3 studies.
