Practical NeurologyBTK Inhibitor Compared with Ocrelizumab for Primary Progressive MS

Fenebrutinib met non-inferiority to OCREVUS in reducing disability progression in PPMS, with a 12% numerical risk reduction and benefits emerging as early as 24 weeks. The oral, brain-penetrant BTK inhibitor showed its strongest effect on upper limb function, with a 26% risk reduction on the nine-hole peg test.

🧠 Clinical Considerations

• Post-hoc analysis showed 22% superiority over OCREVUS on a composite EDSS and upper limb endpoint, exceeding the primary non-inferiority result.
• Liver enzyme elevations occurred in 13.3% of fenebrutinib patients vs 2.9% on OCREVUS; all resolved after discontinuation with no Hy’s law cases.
• Fatal events were higher in the fenebrutinib arm (1.4% vs 0.2%), though investigators assessed all cases as unrelated to treatment.
• CNS penetration enables fenebrutinib to target both B cells and microglia, simultaneously addressing relapsing and progressive disease biology.

🎯 Practice Applications

• Monitor liver function tests in PPMS patients initiated on fenebrutinib following regulatory approval.
• Counsel patients on oral administration as a potential alternative to IV OCREVUS infusions.
• Anticipate regulatory submission mid-2026 and initiate formulary discussions with pharmacy teams.
• Document fenebrutinib’s investigational status in all patient conversations until FDA approval is granted.

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