Fenebrutinib Shows Efficacy in Both Relapsing and Progressive MS, but Safety Signals Raise Questions
核心洞察
The Phase III FENtrepid trial showed fenebrutinib was non-inferior to ocrelizumab on 12-week confirmed disability progression in primary progressive MS, with a higher but mostly unrelated fatality incidence.
In the FENhance 1 and 2 Phase III trials, fenebrutinib demonstrated superiority over teriflunomide in reducing annualized relapse rate and MRI disease activity in relapsing MS.
Across all three trials, fenebrutinib was associated with reversible liver enzyme elevations and an imbalance of fatalities, with only two of seven deaths in FENhance considered treatment-related.
The 2026 American Academy of Neurology (AAN) Annual Meeting featured pivotal Phase III data on fenebrutinib, an investigational Bruton's tyrosine kinase (搜索) (BTK) inhibitor, across both relapsing and primary progressive multiple sclerosis (搜索) (MS). The results position fenebrutinib as a potential first-in-class BTK inhibitor for MS, while also raising important safety considerations that will likely shape regulatory review.
FENtrepid: Fenebrutinib in Primary Progressive MS
Amit Bar-Or of the Perelman School of Medicine at the University of Pennsylvania presented the primary results of the Phase III FENtrepid study, which compared the efficacy and safety of fenebrutinib versus ocrelizumab in primary progressive MS. The trial met its primary endpoint, with fenebrutinib demonstrating non-inferiority to ocrelizumab on composite confirmed disability progression at 12 weeks.
This represents a notable finding, as ocrelizumab remains the only disease-modifying therapy (DMT) approved for primary progressive MS. If fenebrutinib gains regulatory approval, it would become only the second DMT to demonstrate efficacy in this difficult-to-treat population.
However, the safety profile warrants scrutiny. Fenebrutinib was associated with a higher incidence of fatalities compared to ocrelizumab, though investigators deemed these fatal events unrelated to the study drug. Additionally, the trial identified an increased rate of liver enzyme elevations with fenebrutinib, all of which were reversible.
FENhance 1 and 2: Fenebrutinib in Relapsing MS
Jiwon Oh of the University of Toronto presented results from the FENhance 1 and 2 Phase III trials, which evaluated fenebrutinib against teriflunomide in relapsing MS. The primary endpoint was annualized relapse rate, and fenebrutinib demonstrated superiority over teriflunomide in reducing relapses and disease activity on MRI.
The safety findings in FENhance 1 and 2 mirrored those in FENtrepid. An imbalance of fatalities was observed with fenebrutinib, though only two of seven deaths were considered related to the study drug by investigators. Reversible liver enzyme elevations were again noted.
A Novel Mechanism of Action for MS
BTK inhibitors represent a distinct therapeutic approach in MS, with the potential to penetrate the central nervous system and target inflammation localized within that compartment. Marwa Kaisey of Cedars-Sinai Medical Center highlighted BTK inhibitors as an "untapped treatment target" for progressive MS, expressing excitement about their ability to address CNS-compartmentalized inflammation.
The fenebrutinib program is part of a broader pipeline of investigational therapies for MS discussed at the meeting, including CAR-T cell therapy, hematopoietic stem cell transplant, anti-CD40L, anti-CD3, anti-CD20 "brain shuttle" approaches, and mRNA vaccines targeting Epstein-Barr virus.
Context: The Evolving MS Treatment Landscape
The fenebrutinib data arrive alongside significant changes in MS diagnosis. The 2024 McDonald Criteria, reviewed at the meeting by Aaron Miller of the Icahn School of Medicine at Mount Sinai, now incorporate the optic nerve as the fifth topographical region for evaluating dissemination in space, as well as biomarkers such as the central vein sign (CVS), paramagnetic rim lesions (PRLs), and kappa free light chains. Notably, individuals previously diagnosed with radiologically isolated syndrome may now be diagnosed with MS under the updated criteria.
The meeting also underscored the growing emphasis on high-efficacy DMTs early in the disease course. Veronica Cipriani of the University of Chicago Medicine presented data supporting the association of higher-efficacy treatments with delayed development of secondary progressive MS. This treatment philosophy extends to pediatric-onset MS, where Leslie Benson of Harvard Medical School and Vaishnavi Vaidyanathan of UC Davis recommended initial treatment with high-efficacy DMTs.
Ongoing trials such as TREAT-MS and DELIVER-MS are expected to provide further evidence on the optimal approach to DMT selection—whether to start with lower-efficacy treatment and escalate, or to begin with high-efficacy therapy from the outset.