Fenebrutinib shows rapid reduction of new Gd+ T1 lesions

Fenebrutinib penetrates the cerebrospinal fluid (CSF) at sufficient levels to reduce activation of B cells and microglia in vitro. These early findings from the ongoing, phase 2 FENopta study suggest that this new drug may impact mechanisms underlying chronic progressive disease biology in MS. The study met its primary endpoint, with a 69% reduction in the number of new T1 lesions in weeks 4–12.

Bruton’s tyrosine kinase (BTK) is implicated in peripheral and CNS inflammation in MS and is a therapeutic target for relapsing as well as progressive disease. Fenebrutinib is a potent, highly selective, non-covalent, 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 MS and its early impact on MRI outcomes and soluble markers of disease activity and progression. The results were presented by Prof. Amit Bar-Or (University of Pennsylvania, PA, USA) [1].

The 106 relapsing MS patients who participated were 18–55 years of age and had an Expanded Disability Status Scale (EDSS) score between 0 and 5.5. They were randomised 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 gadolinium-enhancing (Gd+) T1 lesions at weeks 4, 8, and 12.

Fenebrutinib concentrations in CSF were measured in 11 patients. 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 half-maximal inhibitory concentration), 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 Gd+ T1 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 hypointense T1 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 Gd+ T1 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 favourable benefit/risk ratio of fenebrutinib.

1. Bar-Or A, et al. Cerebrospinal fluid and MRI analyses of fenebrutinib treatment in multiple sclerosis reveal brain penetration and early reduction of new lesion activity: results from the phase II FENopta study. O187, MSMilan 2023, 11–13 October, Milan, Italy.

 

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Posted on 4 December, 20234 December, 2023