Two of the most highly anticipated presentations in the 2026 ACTRIMS Late-Breaking Session were the FenTrepid and PERSEUS studies for the treatment of Primary Progressive Multiple Sclerosis (PPMS).
The Phase 3 FENtrepid trial evaluated fenebrutinib, an oral CNS-penetrant BTK inhibitor, against ocrelizumab in 985 patients with PPMS. The results showed that fenebrutinib achieved noninferiority to ocrelizumab in reducing 12-week composite confirmed disability progression (cCDP12), with a 12% overall risk reduction (HR 0.88), and the most pronounced benefit was seen with the 9-Hole Peg Test (26% risk reduction). None of the predefined subgroup analyses (including age, sex, disease duration, prior DMT use, baseline EDSS, Gd+ lesion status, and B-cell count) demonstrated statistically significant differences in the treatment effect of fenebrutinib versus ocrelizumab on cCDP12, as all hazard ratio confidence intervals crossed 1. Safety profiles were generally comparable between the two treatments, though fenebrutinib showed a much higher incidence of transient reversible liver enzyme elevations (13.3% vs 2.9% with ALT >3x ULN) and more treatment withdrawals due to these elevations. There was also an imbalance in fatal adverse events (seven in the fenebrutinib arm vs one in ocrelizumab). While these deaths were assessed as unrelated to the study drug by investigators, the 7:1 ratio represents a potential safety signal that warrants continued monitoring and evaluation in larger populations with longer follow-up.
The Phase 3 PERSEUS trial evaluated tolebrutinib, an oral, brain-penetrant BTK inhibitor, against placebo in 767 patients with PPMS. The study did not meet its primary endpoint, showing no significant reduction in 6-month composite confirmed disability progression (cCDP) compared to placebo (HR 1.01, p=0.94). While tolebrutinib showed no benefit on disability outcomes (including EDSS progression and functional measures), it did demonstrate nominally significant effects on MRI markers: a 46% reduction in new/enlarging T2 lesions (p=0.005) and less brain volume loss (p=0.01) versus placebo. Tolebrutinib was associated with a slightly higher incidence of liver enzyme elevations (ALT >3× ULN) compared to placebo (4.9% vs 3.2% of patients), with most cases being mild to moderate in severity and all resolving without long-term consequences.
The negative results of the PERSEUS trial came as a surprise. Unlike its success in non-relapsing secondary progressive MS (31% risk reduction) and relapsing MS (29% risk reduction), tolebrutinib showed no clinical benefit in PPMS, suggesting that perhaps disability accumulation in this population may be less responsive to BTK inhibition than in other forms of MS.
Several additional factors may help explain why FENtrepid met its primary endpoint while PERSEUS did not. One factor may be placebo-controlled versus active comparator, which may introduce patient selection bias. In the PERSEUS trial, the use of a placebo comparator (rather than an active comparator like ocrelizumab in FENtrepid) may have introduced selection bias toward enrolling more stable, slower-progressing patients. Clinicians and patients may have been hesitant to enroll individuals with more aggressive disease into a trial where they could receive a placebo, potentially resulting in a population less likely to demonstrate measurable disability progression over the study period.
Another factor is the requirement for evidence of disease progression. FENtrepid required patients to have evidence of disability progression in the 12 months before screening, ensuring enrollment of an actively progressing population more likely to experience disability worsening events during the trial. PERSEUS did not have this requirement, which may have resulted in a more heterogeneous population that included patients with stable or slowly progressing disease who were less likely to reach disability endpoints regardless of treatment assignment. These design differences may have contributed to a lower event rate or reduced ability to detect treatment effects in PERSEUS. When a trial population includes a substantial proportion of patients who would not progress even on placebo, it becomes more difficult to demonstrate a statistically significant treatment benefit — potentially explaining why tolebrutinib did not meet its primary endpoint in PPMS despite showing efficacy in relapsing and non-relapsing secondary progressive MS populations.
In terms of baseline characteristics, the PERSEUS population appears to represent patients who had more prior treatment exposure (40.9% vs 23.6%) but were younger (45.2 vs 48.9 years) with shorter disease duration (7.6 vs 9.0 years since symptom onset), while FENtrepid enrolled patients with longer-standing disease but less prior treatment experience. These differences may have influenced the respective trial outcomes and treatment responses.
Based on the results from the FENhance 2 study in relapsing MS, the GEMINI 1/2 studies demonstrating effects on progression independent of relapse activity (PIRA), the HERCULES study in non-relapsing SPMS, and the FENtrepid study in PPMS, the BTK inhibitor class shows promise across the MS disease spectrum. Nevertheless, careful consideration of the individual patient benefit-risk profile remains essential.
Dr. Berkovich has served on advisory boards for both Genentech and Sanofi.
Collage by Jennifer Bogartz
