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CHARLOTTE — The investigational oral Bruton tyrosine kinase inhibitor (BTKi) fenebrutinib significantly outperformed teriflunomide on relapse and MRI outcomes, marking the first potential win breakthrough for a drug class that has faced repeated setbacks in multiple sclerosis (MS).

Results of two randomized phase 3 trials showed fenebrutinib, which penetrates the central nervous system and is credited with novel mechanisms of action, provided greater clinical and radiological protection than teriflunomide. 

Already associated with benefit in relapsing-remitting MS, “fenebrutinib is the first and only oral treatment option to demonstrate efficacy across the MS disease continuum,” said study investigator Jacqueline A. Nicholas, MD, director of the MS Research and Neuroimmunology Fellowship program for OhioHealth, Toledo, Ohio.

The two identical active-comparator trials, FENhance 1 and 2, represent the second set of data evaluating fenebrutinib in relapsing MS. The FENtrepid trial, presented earlier this year at the 2026 ACTRIMS Forum, showed fenebrutinib was noninferior to ocrelizumab, the only therapy with an indication for relapsing MS. 

The updated studies were presented as late breakers May 29 at the Consortium of Multiple Sclerosis Centers (CMSC) 2026 Annual Meeting. Top-line results were presented a month earlier in the 2026 annual meeting of the American Academy of Neurology. 

Efficacious, Manageable Safety Signals

In the two trials, patients between the ages of 18 and 55 with a diagnosis of relapsing MS and any Expanded Disability Status Scale (EDSS) score of 5.5 were randomly assigned to receive 200 mg twice-daily fenebrutinib or 14 mg once-daily teriflunomide, an immunomodulatory pyrimidine synthesis inhibitor. The double-blind was preserved with matching placebos.

Employing a 1:1 randomization to the study arms, FENhance 1 enrolled 346 patients and FENhance 2 enrolled 351. The groups in both arms were well balanced for age, disease activity on imaging, EDSS score at baseline, and other meaningful characteristics. The median time since onset of symptoms and diagnosis were approximately 3.5 years and 1 year, respectively.

The primary endpoint was annualized relapse rate (ARR) after a minimum of 96 weeks of follow-up. Fenebrutinib reduced relapses by 51.1% relative to teriflunomide in FENhance 1 (0.061 vs 0.125; P < .001) and by 58.5% in FENhance 2 (0.054 vs 0.13; P < .00001). 

There was a greater treatment effect in patients younger than 40 years and in those with gadolinium-enhancing lesions at baseline, a marker of higher inflammatory disease activity. 

Fenebrutinib also significantly suppressed MRI disease activity. Relative to teriflunomide, the drug reduced new T1 gadolinium-enhancing lesions by 70.7% in FENhance 1 and 77.6% in FENhance 2, while reducing annualized new or enlarging T2 lesions by 76.0% and 82.5%, respectively (all P < .0001). 

When data from the two trials were pooled, fenebrutinib was associated with a 16% relative reduction in the risk of 12-week confirmed disability progression compared with teriflunomide (hazard ratio [HR], 0.84; 95% CI, 0.71-0.99). Among the individual components of disability progression, the strongest treatment effect was observed on the Nine-Hole Peg Test, Nicholas reported. 

Although Nicholas described the overall safety profiles of fenebrutinib and teriflunomide as comparable, citing similar rates of overall and serious infections, she reported that more patients discontinued treatment because of adverse events in the fenebrutinib group than in the teriflunomide group (54 vs 41). 

There were seven fatal adverse events in the fenebrutinib arm vs one in the teriflunomide arm. However, an event-by-event review did not identify an obvious common mechanism, with deaths attributed to a mix of causes, including preexisting medical conditions, infections, accidents, and suicides. 

“When we looked at adverse events that have been associated with BTK inhibitors in the past, event rates in the two treatment arms of this study were similar,” said Nicholas, with comparable rates of infection, hemorrhage, neoplasms, and nausea.

At the 2026 ACTRIMS Forum, investigators from the FENtrepid trial reported that the drug met the predefined threshold for noninferiority to ocrelizumab on 12-month confirmed disability progression. At that time, principal investigator Amit Bar-Or, MD, said the findings suggest the drug could provide an oral alternative to ocrelizumab if approved for relapsing MS. 

Fenebrutinib may be distinguishing itself from other BTKis. Nicholas noted that a post hoc analysis of FENtrepid suggested superiority to ocrelizumab on a modified composite disability endpoint based on the EDSS and Nine-Hole Peg Test, while FENhance delivered the first clear demonstration of efficacy against an active comparator in relapsing MS.

“Fenebrutinib is a uniquely designed CNS-penetrant, noncovalent, highly selective BTK inhibitor with an optimized PK/PD profile,” she said. 

Nicholas added that BTK signaling is believed to contribute to both relapsing and progressive MS biology but that previous studies of BTKis have yielded mixed and often disappointing results. 

One recent example was the PERSEUS trial of tolebrutinib, presented at the 2026 ACTRIMS Forum. The study failed to meet its primary endpoint of 6-month confirmed disability progression vs placebo, prompting investigators to discontinue the open-label extension.

Cautious Optimism

Against that backdrop, the FENhance findings exceeded expectations, said Amy Perrin Ross, APN, MSN, CNRN, an independent MS specialist at Loyola University Medical Center who was not involved in the study. Ross chaired the Scientific Program Committee for the 2026 CMSC meeting.

“I think many of us have been very surprised about the limited efficacy we have seen with BTK inhibitors up until now,” Ross told Medscape Medical News.

With positive results from two phase 3 trials in relapsing disease, “I think we will now see a BTK inhibitor approval,” she said.

Despite the encouraging results, Ross urged caution, noting that expectations for BTKis have been high since the pathway first emerged as a promising target in MS. 

“I think we have had to reset our expectations for the BTK inhibitors, but fenebrutinib looks promising if we remain realistic about how it will perform.”

The fenebrutinib studies were funded by Bristol-Myers Squibb. Nicholas reported financial relationships with Alexion, EMD Serono, Genentech, Greenwich Biosciences, Hoffmann-La Roche, Horizon, Novartis, Sanofi Aventis, and TG Therapeutics. Ross reported financial relationships with Alexion, BMS, EMD Serono, Horizon, Novartis, Roche, Sanofi, and TG Therapeutics.