Full data from the FENhance studies of fenebrutinib will be presented at the 2026 American Academy of Neurology Annual Meeting and submitted for regulatory review along with FENtrepid data in multiple sclerosis.
Genentech has reported that its pivotal phase 3 FENhance 1 study assessing investigational Bruton’s tyrosine kinase (BTK) inhibitor fenebrutinib against teriflunomide (Aubagio; Sanofi), an approved treatment for relapsing forms of multiple sclerosis (RMS), met its primary end point in reducing annualized relapse rate.1
All told, findings showed that treatment with fenebrutinib reduced the ARR by 51% compared with teriflunomide over at least 96 weeks, which was consistent with results from the previously completed FENhance 2 (NCT04586023) study, which showed a 59% reduction in ARR among patients with RMS. The company also reported that secondary end points in both FENhance studies displayed statistically significant reductions in brain lesions and that all progression end points showed favorable trends for fenebrutinib.
“The positive phase 3 results of FENhance 1 are exciting and validating for the BTK inhibitor class, particularly given the long pursuit of therapies that can meaningfully impact both relapsing and progressive MS. Seeing consistent efficacy in a large program suggests fenebrutinib may represent a true advance rather than a signal limited to early-phase data,”
FENhance 1 and 2 are both phase 3 multicenter, randomized, double-blind, double-dummy, parallel-group trials investigating the efficacy and safety of fenebrutinib compared with teriflunomide in 1497 adult patients with RMS. Participants in the studies were randomized 1:1 to receive either oral fenebrutinib twice daily with a placebo matched to oral teriflunomide once daily, or oral teriflunomide once daily with a placebo matched to oral fenebrutinib twice daily, for at least 96 weeks.
The primary end point is ARR, and the secondary end points include total number of T1-gadolinium-enhancing MRI lesions, total number of new and/or enlarging T2-weighted MRI lesions, time to onset of 12-week composite confirmed disability progression (cCDP) and 24-week cCDP. After the double-blind treatment period, participants have the option to enter an open-label extension phase, in which all would receive fenebrutinib treatment.
In this latest Peer Exchange video program, multiple sclerosis (MS) experts Stephen Krieger, MD, Benjamin Greenberg, MD, Jiwon Oh, MD, PhD, FRCPC, Barry Singer, MD, and Ann Bass, MD, discussed the complexities of identifying and monitoring disease progression in MS.
“The results of FENhance 1 study are great news for the MS community as it confirms what FENhance 2 found earlier, which is a benefit on active inflammation in relapsing MS. Clearly, fenebrutinib is different from the other BTK inhibitors with Phase 3 trials results in MS – evobrutinib and tolebrutinib – in that it has robust and persistent reduction in disease activity,”
Regarding the safety findings, liver transaminase elevations were noted as comparable with teriflunomide in both FENhance studies. In the FENhance 1 study, 1 Hy law case occurred in the fenebrutinib arm and 1 in the teriflunomide arm; both cases were asymptomatic and resolved after study drug discontinuation. Moreover, 1 fatal case was reported in the teriflunomide arm and 8 fatal cases with various causes and at different points in treatment in the fenebrutinib arms for the RMS studies. The company stated that further analyses are ongoing to better understand these safety findings.
“The higher rate of death in the relapsing trials mirrors that recently reported in the primary progressive trials and are concerning; the rate of severe elevation in liver enzymes – 20x upper limit normal – is similar in the fenebrutinib arm of the primary progressive MS trial as other BTK inhibitors in MS, so merits careful examination in the relapsing trials; and the lack of a benefit on disability progression in the relapsing trials is surprising and somewhat disappointing,” Fox added. “All of these deserve further detailed examination of the data. In short, the benefit of fenebrutinib on focal inflammation is clear, but there are concerning safety signals that require close examination of the data as well as a greater understanding of why fenebrutinib didn’t slow disability progression.”
The fenebrutinib phase 3 program not only includes the FENhance 1 and 2 studies, but also the FENtrepid study (NCT04544449) of primary progressive MS (PPMS), where the BTK inhibitor is evaluated against ocrelizumab (Ocrevus; Roche), the only approved therapy for PPMS. These positive FENhance 1 data follows positive results for FENhance 2 and for FENtrepid, both of which were announced in
“Fenebrutinib is a highly selective, non-covalent BTK inhibitor designed to modulate B-cell and microglial signaling without broad B-cell depletion. This dual targeting of peripheral and compartmentalized CNS immune activity may differentiate it from existing anti-CD20 therapies and could be particularly relevant for patients with progressive disease,” Hersh, who is also president-elect of the
“Fenebrutinib was engineered to be both highly potent and highly selective, demonstrating markedly greater affinity for BTK compared with other kinases, which supports more precise target engagement,” Hersh added. “Unlike most BTK inhibitors that bind irreversibly, fenebrutinib attaches in a reversible, non-covalent manner, binding to BTK without permanently inactivating it. This combination of selectivity and reversibility may reduce unintended off-target activity while maintaining effective pathway modulation.”
Editor’s Note: Fox disclosed that although he was not involved in the fenebrutinib trials, he has received consulting fees from the study sponsor Genentech.
