BTK Inhibitor Reduces Brain Lesions in Relapsing MS

MILAN — Investigational fenebrutinib reduced brain lesions in relapsing multiple sclerosis (MS) patients and showed evidence of central nervous system (CNS) penetration, data from the phase II FENopta study showed.

Compared with placebo, oral fenebrutinib led to a 69% reduction in the total number of new T1 gadolinium-enhancing (Gd+) lesions at weeks 4, 8, and 12 combined (P=0.0022), reported Amit Bar-Or, MD, of the University of Pennsylvania Perelman School of Medicine in Philadelphia.

Rapid onset of lesion reduction was observed by week 4, Bar-Or said at the joint meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the American Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

At weeks 8 and 12, respectively, relative reductions of 92% and 90% in T1 Gd+ lesions and 90% and 95% in T2 lesions were seen.

Brain penetrance was measured in cerebrospinal fluid (CSF). In a subgroup of 11 participants, fenebrutinib was present in CSF at levels sufficient to reduce activation of B cells and microglia in vitro, suggesting the drug may affect mechanisms underlying chronic progressive disease biology in MS, Bar-Or said in his late-breaking presentation.

Fenebrutinib is a reversible, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor that blocks the function of BTK. BTK regulates B cell development and activation; it is also involved in the activation of innate immune system myeloid lineage cells, such as macrophages and microglia.

A BTK inhibitor has the dual capacity to inhibit B cell and myeloid cell activation. The prospect is that this will contribute to decreases in both relapsing activity worsening and progression independent of relapse activity, Bar-Or said.

FENopta randomized 109 people with relapsing MS 2:1 to fenebrutinib 200 mg twice daily (73 participants) or placebo (36 participants). The primary endpoint was the total number of new T1 Gd+ lesions on MRI at weeks 4, 8, and 12.

This study population was “a relatively active relapsing MS population,” Bar-Or noted. Participants had either two relapses within the last 2 years or one documented clinical relapse within 12 months of screening, or documented evidence of one or more T1 Gd+ lesions on MRI in the 6 months before randomization.

Nearly 72% were women. At baseline, participants had a mean age of 30, and about a third had used a prior disease-modifying therapy. Expanded Disability Status Scale (EDSS) scores ranged from 0 to 5.5; the median EDSS was 2.5.

Importantly, T1 Gd+ lesions at baseline were balanced between the fenebrutinib and placebo arms — 0.74 in the fenebrutinib group and 0.72 for placebo — Bar-Or pointed out.

Of 11 participants whose CSF was sampled at week 12, the mean level of fenebrutinib was 43.1 ng/mL. “All participants had values within the active range, above IC₅₀ [half maximal inhibitory concentration],” Bar-Orr observed.

Overall, 38.4% of people in the fenebrutinib group and 33.3% in the placebo group had one or more adverse events. No serious adverse events occurred. “All adverse events were grade 1 or 2, with the exception of two grade 3 asymptomatic liver transaminase level elevations,” Bar-Or said. “The rate of infection appeared balanced between the fenebrutinib-treated and placebo-treated cohorts.”

The phase III program for fenebrutinib is underway and includes two identical trials in relapsing MS (FENhance 1 and FENhance 2) with an active teriflunomide (Aubagio) comparator, and one trial in primary progressive MS (FENtrepid) of fenebrutinib versus ocrelizumab (Ocrevus).

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