The investigational Bruton’s tyrosine kinase (BTK) inhibitor fenebrutinib may curb chronic active lesions in multiple sclerosis (MS), data from phase III trials suggested.
Two MRI biomarkers in MS are slowly expanding lesions (SELs) and paramagnetic rim lesions (PRLs). “The field is quite interested in both SELs and PRLs because both are imaging biomarkers of chronic active lesions, which we know are a dominant driver of progressive disease biology,” said Jiwon Oh, MD, PhD, of the University of Toronto.
In both relapsing MS and primary progressive MS, fenebrutinib reduced the risk of SEL accumulation, Oh reported at a late-breaking session at MSToronto2026, the joint meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
In relapsing MS, fenebrutinib showed a 30.5% relative reduction in SEL volume compared with teriflunomide (Aubagio) over 96 weeks (P<0.0001), Oh said. In primary progressive MS, fenebrutinib showed a 27.5% relative reduction in SEL volume versus ocrelizumab (Ocrevus) over 120 weeks (P=0.0006).
Fenebrutinib-treated participants had a 62% lower odds of a net increase in PRLs in relapsing MS (OR 0.38, 95% CI 0.22-0.68, P=0.001), she added. In the primary progressive MS study, the PRL net increase difference was not significant (OR 0.64, 95% CI 0.22-1.83, P=0.405).
“Progressive MS biology occurs from disease onset in almost everybody with MS, regardless of the initial clinical presentation,” Oh said. “When PRLs have been evaluated, they seem to be present in most people early in the disease course,” she added. “Therapeutically, the greatest unmet need in the field are treatments that target mechanisms underlying progressive disease biology.”
Fenebrutinib is a non-covalent, reversible, and highly selective BTK inhibitor, Oh noted. Early research, including the phase II FENopta study, showed that fenebrutinib reduced brain lesions in relapsing MS.
Data for her analysis came from the phase III FENtrepid trial of fenebrutinib versus ocrelizumab in primary progressive MS, and the twin FENhance 1 and FENhance 2 phase III trials of fenebrutinib versus teriflunomide in relapsing MS. The analysis was designed to test whether BTK inhibition influenced imaging markers of progressive biology.
“In FENhance 1 and 2 in relapsing MS, as well as in FENtrepid in primary progressive MS, fenebrutinib met its primary endpoint,” Oh noted.
Pooled data from FENhance 1 and FENhance 2 presented at MSToronto2026 showed that fenebrutinib reduced annualized relapse rates — the trials’ primary endpoint — by 55% compared with teriflunomide (0.06 vs 0.13, P<0.001) over 96 weeks. Fenebrutinib also reduced annual total brain volume loss by 22.8% (P<0.001) and 12-week composite confirmed disability progression by 16% (P=0.04), according to Maria Pia Sormani, PhD, of the University of Genoa in Italy.
Transient and reversible liver enzyme elevations were comparable between pooled treatment arms. In FENhance 1, there was one case in the fenebrutinib arm and one in the teriflunomide arm that met criteria for Hy’s law, a prediction of fatal drug-induced liver injury risk. Both cases were asymptomatic and resolved after study drug discontinuation.
FENtrepid demonstrated that fenebrutinib was non-inferior to ocrelizumab in delaying disability progression in people with primary progressive MS over 120 weeks. Liver enzyme elevations occurred more frequently with fenebrutinib than with ocrelizumab (13.3% vs 2.9%), but all cases resolved after study drug discontinuation.
To assess SELs, T1 and T2 weighted sequences were evaluated in all patients from scans acquired during the studies, Oh said, but the PRL analysis was conducted in a subset of study participants. “This is because PRLs were able to be evaluated only at sites where there was the capacity to perform 3-Tesla MRIs and to get suitable susceptibility-sensitive images,” she noted. The PRL analysis set constituted about 45% of the full sample.
In September, the FDA accepted a new drug application for fenebrutinib to treat relapsing MS and primary progressive MS under priority review, developer Roche said. The drug is the first BTK inhibitor to receive FDA filing acceptance for both indications.
