A new fenebrutinib MS trial may be the first win for BTK inhibitors (BTKis) in multiple sclerosis (MS). The oral drug beat teriflunomide on relapse and MRI in two phase 3 trials.

The fenebrutinib MS trial pair, FENhance 1 and 2, ran as late-breakers on 29 May at CMSC 2026 in Charlotte. Top-line data dropped at the 2026 American Academy of Neurology meeting a month earlier.

Why the fenebrutinib MS trial readout matters

The BTKi class has had a tough run in MS. Several candidates fell short. The PERSEUS trial of tolebrutinib at the 2026 ACTRIMS Forum missed its 6-month disability endpoint vs placebo. The team shut the open-label extension.

Fenebrutinib is built differently. It is CNS-penetrant, noncovalent, and highly selective. Study lead Jacqueline A. Nicholas, MD, put it plainly.

"Fenebrutinib is a uniquely designed CNS-penetrant, noncovalent, highly selective BTK inhibitor with an optimized PK/PD profile," she said. Nicholas runs the MS Research and Neuroimmunology Fellowship at OhioHealth in Toledo.

How the fenebrutinib MS trial was designed

Patients aged 18 to 55 with relapsing MS and an Expanded Disability Status Scale (EDSS) score up to 5.5 joined. They got 200 mg twice-daily fenebrutinib or 14 mg once-daily teriflunomide. The blind was kept with matched placebos.

The team used 1:1 randomization. FENhance 1 enrolled 346 patients. FENhance 2 enrolled 351. The arms matched on age, imaging, EDSS, and more.

The primary endpoint: annualized relapse rate (ARR) after 96 weeks of follow-up.

The relapse numbers were striking

The fenebrutinib MS trial delivered the best ARR result the BTKi class has seen in MS.

• FENhance 1: 51.1% relapse reduction vs teriflunomide (0.061 vs 0.125; P < .001).
• FENhance 2: 58.5% relapse reduction (0.054 vs 0.13; P < .00001).

The effect ran larger in patients under 40 and in those with baseline gadolinium-enhancing lesions. That group marks higher inflammatory disease activity.

MRI activity dropped sharply

The fenebrutinib MS trial radiology data tracked the clinical signal.

• New T1 gadolinium-enhancing lesions: 70.7% reduction in FENhance 1 and 77.6% in FENhance 2 vs teriflunomide.
• Annualized new or enlarging T2 lesions: 76.0% reduction in FENhance 1 and 82.5% in FENhance 2.

All MRI endpoints hit P < .0001.

Pooled fenebrutinib MS trial data showed the drug cut 12-week disability progression risk by 16% vs teriflunomide (HR 0.84; 95% CI, 0.71-0.99). The strongest effect was on the Nine-Hole Peg Test, Nicholas said.

Safety needs a careful read

Nicholas called the overall safety profiles comparable. Rates of overall and serious infections matched. But discontinuations for adverse events ran higher on fenebrutinib: 54 vs 41.

Fatal adverse events drew attention: 7 in the fenebrutinib arm vs 1 on teriflunomide. A review found no common cause. Causes spanned past health issues, 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," Nicholas said. She cited matching rates of infection, hemorrhage, neoplasms, and nausea.

What outside experts said

The trial result joins a broader data set. The FENtrepid trial at the 2026 ACTRIMS Forum found fenebrutinib non-inferior to ocrelizumab on 12-month disability. Ocrelizumab is the only approved relapsing MS drug now.

Principal investigator Amit Bar-Or, MD, said FENtrepid hints fenebrutinib could be an oral option to ocrelizumab once approved for relapsing MS.

A post hoc FENtrepid analysis even hinted at fenebrutinib beating ocrelizumab. The win was on a score built from the EDSS and Nine-Hole Peg Test.

Amy Perrin Ross, APN, MSN, CNRN, said the FENhance data beat hopes. Ross is an MS specialist at Loyola University Medical Center. Ross chaired the CMSC 2026 Scientific Program Committee.

"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.

"I think we will now see a BTK inhibitor approval," Ross said, citing the two positive phase 3 trials.

Ross still urged caution. "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."

Funded by Bristol-Myers Squibb. Coverage on Medigear.uk shows why neurology teams must track fenebrutinib MS trial findings.

Source: Originating coverage based on Medscape Medical News reporting on the FENhance 1 and FENhance 2 late-breaker presentations at the Consortium of Multiple Sclerosis Centers (CMSC) 2026 Annual Meeting in Charlotte. Study investigator Jacqueline A. Nicholas, MD, OhioHealth, Toledo, Ohio. Outside commentary from Amy Perrin Ross, APN, MSN, CNRN, Loyola University Medical Center. FENtrepid PI Amit Bar-Or, MD. Studies funded by Bristol-Myers Squibb.