New results presented at ACTRIMS showed that in the phase 3 FENtrepid study, fenebrutinib was noninferior to ocrelizumab in reducing disability progression in primary progressive multiple sclerosis.
New data from phase 3 FENtrepid study (NCT04544449) showed that fenebrutinib (Genentech), an investigational Bruton’s tyrosine kinase (BTK) inhibitor, met its primary end point of noninferiority compared with ocrelizumab (Ocrevus; Roche) in reducing disability progression in patients with primary progressive multiple sclerosis (PPMS).1 These results were presented as a late breaker at the recently concluded
Findings showed that fenebrutinib was associated with a 12% reduction in the risk of disability progression compared with ocrelizumab, as measured by time to onset of 12-week composite confirmed disability progression (cCDP12; HR, 0.88; 95% CI, 0.75–1.03). Researchers also observed a separation between treatment curves as early as 24 weeks and reported a consistent treatment effect on the primary end point across patient subgroups and throughout the duration of treatment.
"I was delighted that fenebrutinib indeed emerged as non-inferior to ocrelizumab, and in fact at least nominally appeared to be a little better at limiting progression of disability in PPMS. It’s exciting to imagine a single agent that might have an important impact on both relapsing and progressive biologies of MS,” lead author
The FENtrepid trial is a phase 3 multicenter, randomized, double-blind, double-dummy, parallel-group study to assess the efficacy and safety of fenebrutinib compared with ocrelizumab in 985 adult patients with PPMS. In FENtrepid, participants were randomized 1:1 to receive either daily oral fenebrutinib once daily plus an intravenous (IV) ocrelizumab–matched placebo or IV ocrelizumab plus an oral fenebrutinib–matched placebo for a minimum of 120 weeks.
The cCDP12 primary end point included confirmed disability progression based on the Expanded Disability Status Scale (EDSS), the timed 25-foot walk (T25FW), and the 9-hole peg test (9HPT). Results revealed that the strongest treatment effect in the composite was observed for upper limb function, with fenebrutinib reducing the risk of worsening on the 9HPT by 26% compared with ocrelizumab (HR, 0.74; 95% CI, 0.56–0.98).
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In addition to the primary analysis, a post-hoc analysis demonstrated that fenebrutinib was superior to ocrelizumab on a composite end point that included 2 of the 3 cCDP12 components, including EDSS and 9HPT. All told, this analysis showed a 22% reduction in the risk of disability progression among patients with PPMS treated with fenebrutinib (HR, 0.78; 95% CI, 0.64–0.95).
The safety profile of fenebrutinib was reported to be generally comparable to ocrelizumab, with common adverse events (AEs) occurring in at least 10% of patients including infections (67.0% vs 70.9%), nausea (12.0% vs 7.1%), and haemorrhage (10.2% vs 8.1%). Transient and reversible elevations in liver enzymes were observed more frequently in patients receiving fenebrutinib (13.3% vs 2.9%). All cases resolved following discontinuation of study treatment, and no cases meeting Hy’s law criteria, an indicator for potential severe liver injury, were reported.
Serious AEs occurred in 19.1% of patients treated with fenebrutinib and 18.9% of those receiving ocrelizumab, leading to treatment withdrawal in 4.3% and 3.0% of patients, respectively. Fatal events were reported in 1.4% of patients in the fenebrutinib arm and 0.2% in the ocrelizumab arm. Investigators assessed all fatal cases as unrelated to study treatment, with no consistent pattern in timing or cause.
In November 2025,
Findings from the FENhance 2 study showed that treatment with fenebrutinib led to significant reductions in annualized relapse rate, the primary outcome, compared with teriflunomide over at least 96 weeks. The company noted that results from FENhance 1 are expected in the first half of 2026, after which data from all phase 3 fenebrutinib trials are planned for submission to regulatory authorities.
"In addition to the efficacy results of FENtrepid in PPMS, fenebrutinib demonstrated a robust effect on limiting new acute inflammatory lesions by MRI in the phase 2 FENopta study and the top line results of the FENhance 2 phase 3 trial in RMS noted that fenebrutinib met it’s primary endpoint of reducing the ARR compared to active comparator terifluomide,” Bar-Or added. "If this efficacy data in RMS is borne out in the pending FENhance 1 trial, fenebrutinib would have a unique profile on impacting both relapsing and progressive biologies, together the key drivers of disability progression in MS. We eagerly await the full efficacy as well as safety data from the fenebrutinib program."
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