Fenebrutinib penetrates cerebrospinal fluid at sufficient enough levels to reduce activation of B-cells and microglia in vitro.

Bruton’s tyrosine kinase (BTK) is implicated in peripheral and central nervous system inflammation in MS and is a therapeutic target for relapsing as well as progressive disease. Fenebrutinib is a potent, highly selective, noncovalent, reversible BTK inhibitor that is being evaluated for MS. The aim of the phase 2 FENopta trial (NCT05119569) was to establish the safety and efficacy of fenebrutinib in relapsing multiple sclerosis (RMS) and its early impact on MRI outcomes and soluble markers of disease activity and progression. The results were presented by first author Prof. Amit Bar-Or (University of Pennsylvania, United States) [1].

The 106 patients with RMS who participated were between 18 and 55 years of age and had an Expanded Disability Status Scale score between 0 and 5.5. They were randomly assigned 2:1 to fenebrutinib (200 mg, twice daily; n=70) or placebo (n=36) for 12 weeks. The primary efficacy endpoint was the total number of new T1 gadolinium-enhancing (Gd+) lesions at weeks 4, 8, and 12.

In 11 participants, fenebrutinib concentrations in CSF were measured, and after 12 weeks of continuous administration, the median concentration was 47.4 ng/mL. According to Prof. Bar-Or, all 11 patients had values within the active range (above IC50), and the CSF-to-plasma ratio indicated CSF-penetration.

The study met its primary endpoint, with a 69% reduction in the adjusted rate of new T1 Gd+ lesions at weeks 4, 8, and 12 combined (P=0.0022). The reduction in the adjusted rate of new or enlarging T2-weighted lesions at weeks 4-12 combined was 74% (P=0.0004). The adjusted rate of new T1 hypointense lesions (an exploratory endpoint) at weeks 4-12 combined was 64% lower. A rapid onset of action was observed, with relative reductions of 92% and 90% in T1 Gd+ lesions at week 4, and relative reductions of 90% and 95% in T2 lesions at week 8 and 12, respectively.

Prof. Bar-Or added that no new safety concerns were identified. Results were consistent with previous findings, indicating a potentially favorable benefit-risk ratio of fenebrutinib.

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