Oral multiple sclerosis drug fenebrutinib receives FDA priority review, with safety questions remaining alongside efficacy

For people with multiple sclerosis, the challenge of treatment lies not only in reducing repeated relapses but also in preserving physical function as it gradually declines. On September 29, Roche’s Genentech announced that the U.S. Food and Drug Administration (FDA) had accepted the new drug application for the investigational oral drug fenebrutinib and granted priority review for relapsing and primary progressive multiple sclerosis. This raises the prospect of a new oral option for both groups of patients, but acceptance of the application does not mean approval for marketing.

Fenebrutinib inhibits Bruton’s tyrosine kinase (BTK) through reversible, non-covalent binding. According to the company, it can cross the blood-brain barrier and act on B cells and microglia in the brain, seeking to address both the acute inflammation that triggers relapses and the chronic inflammation believed to contribute to long-term nerve damage. This design connects two aspects of the disease: some patients experience repeated relapses, while others continue to worsen without obvious relapses.

The application is primarily based on three Phase 3 trials. In FENhance 1 and FENhance 2, which enrolled patients with relapsing disease, fenebrutinib reduced annualized relapse rates by 51.1% and 58.5%, respectively, compared with the oral drug teriflunomide over 96 weeks. However, reducing relapses and slowing disability progression are distinct questions of efficacy. NeurologyLive noted that the company described only favorable trends in disability measures in these two trials, and the announcement did not provide formal statistical results. Its effect on slowing disability progression therefore cannot yet be confirmed on this basis.

The FENtrepid trial in patients with primary progressive disease directly compared fenebrutinib with ocrelizumab and met its primary endpoint of “non-inferiority” in slowing disability progression. This means it met the trial’s prespecified standard of being no worse than the comparator treatment by more than a defined margin. The hazard ratio for disability progression was 0.88, with a 95% confidence interval of 0.75 to 1.03. Although the numerical result favored fenebrutinib, the interval crossed 1, so it cannot be claimed to be superior to ocrelizumab. For an oral treatment, this remains important evidence, but it is not proof of superiority across the board.

Beyond efficacy, the safety results of all three trials also require individual examination. Roche reported that the proportions of serious adverse events with fenebrutinib and the comparator drug were both 9% in FENhance 1 and 11% and 6%, respectively, in FENhance 2; both groups in FENtrepid had a rate of 19%. Liver enzyme elevations were similar to those with teriflunomide in the relapsing disease trials but were more common than with ocrelizumab in the primary progressive disease trial. Similar overall rates cannot replace an analysis of specific serious events.

The differences in deaths between groups particularly need clarification. BioPharma Dive reported that, across two of the three Phase 3 trials, a total of 8 patients receiving fenebrutinib died, compared with 1 patient in the Aubagio (teriflunomide) comparator groups. Genentech acknowledged an imbalance in death counts across the three pivotal trials, stating that the timing and causes of the events varied, but this announcement did not list specific counts or causes of death. These numbers alone cannot prove that the drug caused the deaths, but they make complete case data essential to assessing safety.

Liver risks also have a history in the drug’s development. BioPharma Dive cited one case of abnormal liver test results that met Hy’s law criteria, a signal of potential serious drug-induced liver injury; the program had also previously been subject to an FDA partial clinical hold. Although the company stated that its safety database includes more than 2,700 participants and described the risks as manageable, more detailed data on liver events are still needed to support that assessment.

Roche has not yet announced the FDA’s target decision date. According to BioPharma Dive, priority review generally follows a six-month review timeline, but it does not guarantee approval. The review will now center on how much practical benefit oral treatment and the observed efficacy can deliver, and whether questions about liver events and deaths can be adequately answered. For patients who need long-term medication, both must be weighed together.