SAN DIEGO — Results from two phase 3 trials offer mixed findings on the potential of experimental Bruton tyrosine kinase (BTK) inhibitors for primary progressive multiple sclerosis (PPMS).

Findings for both studies were presented on February 7 at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2026.

Available treatment for PPMS is limited, and interest for new disease-modifying therapies (DMTs) is high. BTK inhibitors, which can cross the blood-brain barrier, are among the most promising contenders.

In the first trial, investigators found that fenebrutinib was noninferior to ocrelizumab, the only approved treatment for PPMS. Treatment with the drug was associated with a 12% decrease in risk for disability progression, making fenebrutinib the first oral therapy to show efficacy in PPMS.

“Here’s a BTK inhibitor that is no less good — and maybe better — than the only approved therapy,” said Amit Bar-Or, MD, of the University of Pennsylvania, Philadelphia, lead investigator of the FENtrepid trial.

This is important, he added, because not all patients with PPMS may be candidates for anti-CD20 monoclonal antibodies such as ocrelizumab or have access to them.

Results of the second trial were not as promising, with the investigational BTK inhibitor tolebrutinib showing no significant benefits over placebo in the PERSEUS trial.

The Challenge of Treating PPMS

PPMS accounts for about 10% of MS cases and is especially difficult to treat, Robert J. Fox, MD, PERSEUS co-investigator and neurologist with the Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, told Medscape Medical News.

“We have more than 20 FDA-approved therapies for MS, and all of them work best on the relapsing MS component,” he said.

It’s been almost a decade since the FDA approved ocrelizumab as the first — and still the only — treatment for PPMS, “but it actually doesn’t slow down progression very much,” Fox said.

Drugs such as fenebrutinib and tolebrutinib inhibit tyrosine kinase, an enzyme involved in B-cell activation and immune response. The enzyme is also expressed in other immune cells, including microglia, Fox explained.

Microglia activation is believed to trigger an immune response that may be driving progressive MS, he said.

“Our currently approved therapies don’t seem to modulate microglia, and maybe that’s why they don’t really do much on progression.”

Promising Results in FENtrepid Trial

For the FENtrepid trial, investigators enrolled 985 patients with PPMS aged 18-65 years (mean age 48.9; 49.5% female) and randomly assigned them to receive either oral fenebrutinib 200 mg twice daily or intravenous ocrelizumab 600 mg every 24 weeks.

Median baseline scores for Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk Test, and Nine-Hole Peg Test (9HPT) were similar between groups.

The experimental treatment met the primary endpoint of noninferiority on 12-week composite confirmed disability progression (cCDP, 58.8% for fenebrutinib vs 66.1% for ocrelizumab), with fenebrutinib associated with a 12% decrease in disability progression (hazard ratio [HR], 0.88; 95% CI, 0.75-1.03).

In a post hoc analysis, investigators also found that fenebrutinib was associated with a 22% lower risk of worsening EDSS and 9HPT scores at 12 weeks.

The treatment effect of the investigational drug was generally consistent across age, sex, time since system onset, prior DMT use, and other subgroups.

Adverse events were reported in 96.3% vs 93.7% of patients in the fenebrutinib group vs the ocrelizumab group, with serious events occurring in 19.1% and 18.9%, respectively.

Fatalities (1.4% vs 0.2% with fenebrutinib vs ocrelizumab) were not linked to the trial medications. Adverse events leading to withdrawal from treatment, mainly liver enzyme elevations, were at 14.1% and 5.1%, respectively.

"Fenebrutinib is the first oral and second-ever therapy to demonstrate efficacy in PPMS, potentially providing a unique (central nervous system)-penetrant treatment option,” researchers wrote.

A similar phase 3 trial is currently underway testing fenebrutinib vs teriflunomide for relapsing MS.

PERSEUS Trial Misses Mark

For the PERSEUS trial, investigators enrolled 767 patients with PPMS aged 18-55 years (mean age 45; 53%-55% male). Participants were randomly assigned 2:1 to either oral tolebrutinib 60 mg daily once daily or placebo.

The primary endpoint was time to onset of 6-month cCDP. Secondary outcomes included time to onset of 6-month CDP (for EDSS only), time to 3-month cCDP, new or enlarging T2 lesions, and brain volume loss.

The trial failed to meet the primary endpoint, with cCDP rates at 6 months not statistically different between groups (66.1% vs 61.9% with tolebrutinib vs placebo; HR, 1.01; P = .94), which prompted investigators to cancel an open-label extension trial.

Tolebrutinib was associated with a 14% reduction of risk for EDSS progression in the drug group vs placebo, although it wasn’t statistically significant.

The drug was also associated with significantly fewer new or enlarged T2 lesions vs placebo (adjusted rate ratio, 0.54; P = .005) and less brain loss (least squares mean, 0.17; P = .01). But findings for other secondary outcomes were not significantly different between groups.

Treatment-emergent adverse events were common in both groups (84.3% vs 81.3% with tolebrutinib vs placebo), with higher rates of COVID and falls in the tolebrutinib cohort. Deaths were the same in both groups at 0.8%.

The next step, Fox said, is to review data to see if subgroups benefited.

Fox co-authored the HERCULES trial, which linked tolebrutinib to a reduction in time to onset of 6-month confirmed disability progression by 31% vs placebo in nonrelapsing secondary progressive MS. But in January, the FDA rejected the drug due to liver toxicity.

F. Hoffmann-La Roche AG funded the FENtrepid trial, and PERSEUS was funded by Sanofi. Bar-Or, co-author of both trials, disclosed having relationships with AstraZeneca, Biogen, Bristol Myers Squibb, Cabaletta Bio, Inc., Capstan Therapeutics, EMD Serono, F. Hoffmann-La Roche/Genentech and Gilead Sciences, GlaxoSmithKline, Immunic Therapeutics, Moderna, Neuron23, Novartis, Oculis, Sanofi, Sudo, Zenas, Biogen Idec, Merck/EMD Serono, and Novartis. Fox disclosed having a relationship with Sanofi.