Roche recently released results from the Phase III FENtrepid study evaluating its Bruton’s tyrosine kinase (BTK) inhibitor fenebrutinib in patients with primary progressive multiple sclerosis (PPMS). The data indicate that the study met its primary endpoint, demonstrating non-inferiority to the approved therapy ocrelizumab (Ocrevus) in delaying disability progression. This represents a notable development in the PPMS treatment landscape, where therapeutic advances have been limited in recent years. The company stated that it plans to compile Phase III data in both PPMS and relapsing multiple sclerosis (RMS) and submit regulatory filings in the first half of this year.

FENtrepid was a multicenter, randomized, double-blind, double-dummy, parallel-group Phase III trial enrolling 985 adult patients with PPMS. Participants were randomized 1:1 to receive either oral fenebrutinib plus intravenous placebo or intravenous ocrelizumab plus oral placebo for a minimum of 120 weeks. The primary endpoint was time to 12-week composite confirmed disability progression (cCDP12). This composite endpoint incorporated three measures: Expanded Disability Status Scale (EDSS)-confirmed disability progression, the Timed 25-Foot Walk (T25FW), and the Nine-Hole Peg Test (9HPT). Compared with EDSS alone, this multidimensional endpoint is considered more sensitive and capable of capturing earlier changes across different functional domains.

Using cCDP12 as the metric, fenebrutinib reduced the risk of disability progression by 12% relative to ocrelizumab (HR=0.88; 95% CI: 0.75–1.03), with separation of the Kaplan–Meier curves observed as early as Week 24. Treatment effects were consistent across prespecified subgroups and throughout the study period. Among individual components, the most pronounced effect was seen in upper limb function as assessed by 9HPT, with a 26% risk reduction (HR=0.74; 95% CI: 0.56–0.98). EDSS-related progression risk was reduced by 22% (HR=0.78; 95% CI: 0.64–0.95).

The overall safety profile was comparable between groups. In the fenebrutinib arm, the most common adverse events (≥10%) included infections (67.0%), nausea (12.0%), and bleeding (10.2%), with similar rates observed in the ocrelizumab group. Transient and reversible elevations in liver enzymes were more frequent with fenebrutinib (13.3% vs. 2.9%), resolving upon treatment discontinuation, and no signal of severe drug-induced liver injury was identified. Serious adverse events occurred in 19.1% and 18.9% of patients in the fenebrutinib and ocrelizumab groups, respectively, leading to treatment discontinuation in 4.3% and 3.0%. Reported deaths in both groups were deemed unrelated to study treatment and showed no consistent temporal or etiological pattern.

Fenebrutinib is an oral, brain-penetrant, reversible, non-covalent BTK inhibitor with approximately 130-fold selectivity for BTK over other kinases. Unlike most irreversible covalent BTK inhibitors, fenebrutinib dissociates from its target enzyme after binding, a design feature that may reduce off-target effects. The agent inhibits activation of both peripheral B cells and central nervous system microglia, aiming to address acute inflammatory activity associated with relapses as well as chronic neuroinflammatory processes implicated in progressive disability.

Currently, therapeutic options for PPMS remain limited. Epidemiological estimates suggest that worldwide patient populations include approximately 910,000 with RMS, 170,000 with non-relapsing secondary progressive MS (nrSPMS), and 120,000 with PPMS. If the RMS program is successful, fenebrutinib could potentially serve a broad MS population and provide a new oral option for patients with progressive disease.

The compound patent for fenebrutinib was filed as PCT application WO2013067274A1 and has entered national phase in 47 countries or regions, including China, the United States, the European Union, Japan, South Korea, Australia, and Canada. At least one patent has been granted in each of these jurisdictions. In China, two patents have been granted (CN104125959B and CN107011348B, the latter being a divisional of the former). The family has a filing date of November 2, 2012, with an estimated expiry date of November 2, 2032. Given the breadth of international grant, the patent family appears to possess relatively strong inventiveness and stability. However, assuming regulatory submission in the first half of this year and even under expedited review, the effective patent term remaining after potential market approval is unlikely to exceed six years. In jurisdictions providing patent term extension or supplementary protection mechanisms for pharmaceuticals, the patentee may seek term restoration to secure a longer period of market exclusivity.