Fenebrutinib trials show success in treating both relapsing and progressive multiple sclerosis

Genentech announced results of two phase 3 studies examining the effectiveness of fenebrutinib, an investigational Bruton’s tyrosine kinase (BTK) inhibitor, for the treatment of both relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS), according to a recent news release. These findings position fenebrutinib as the potential first and only BTK inhibitor approved for both major forms of MS.

Multiple sclerosis is a chronic autoimmune disease that affects more than 2.9 million people worldwide. Relapsing multiple sclerosis is the most common type of MS, accounting for approximately 85% of all MS diagnoses. Patients with RMS experience periods of relapse, while PPMS patients just experience a steady worsening of symptoms. Primary progressive multiple sclerosis is much rarer than RMS, accounting for approximately 15% of MS cases.

In the first study, FENhance 2, results showed that fenebrutinib reduced relapses compared with teriflunomide over at least 96 weeks of treatment. A total of 1,497 patients were randomized 1:1 to receive either oral fenebrutinib twice a day or oral teriflunomide once a day. Full data from FENhance 2 will be presented at an upcoming medical meeting, while results from FENhance 1 are expected in the first half of 2026.

In the second study, FENtrepid, fenebrutinib slowed disability progression as effectively as Ocrevus, which is currently the only approved treatment for PPMS. Effectiveness was measured by a delay in confirmed disease progression over at least 120 weeks of treatment. Patients treated with fenebrutinib saw symptom improvement as early as week 24. A total of 985 patients with PPMS were randomized 1:1 to receive either daily oral fenebrutinib or IV Ocrevus. The 12-week composite confirmed disability progression (cCDP12) was used as the primary endpoint. The cCDP12 measures walking speed, upper limb function and total functional disability.

Safety findings for fenebrutinib were consistent with previous studies, and liver safety remained stable. Additional long-term data will be gathered through open-label extension phases of both trials, in which all participants can receive fenebrutinib.

Fenebrutinib works by targeting B cells and microglia, two types of immune cells involved in MS disease activity and progression. By modulating both cell types, the therapy aims to reduce acute inflammation that triggers relapses and address chronic brain inflammation that drives long-term disability. Unlike covalent BTK inhibitors, fenebrutinib is non-covalent, reversible and highly selective, allowing it to cross the blood-brain barrier and act directly within the central nervous system. It has also been shown to be more than 130 times more selective for BTK than other kinases.

“Fenebrutinib substantially reduced the number of relapses in RMS and slowed disability progression in PPMS. These unprecedented results suggest that fenebrutinib could potentially become a best-in-disease medicine as the first high-efficacy, oral treatment for people with RMS or PPMS,” Levi Garraway, M.D., Ph.D., Genentech’s chief medical officer and head of Global Product Development, said in the news release. "Therefore, these pivotal results for fenebrutinib may offer new hope for people living with MS, and they reaffirm our enduring commitment to the MS community.”

Genentech and its parent group, Roche, are currently investigating more than a dozen potential therapies across neurological conditions, including Alzheimer’s, Parkinson’s and Huntington’s diseases.