Phase 2 Data Highlight Fenebrutinib’s Impact on Brain Lesions in Relapsing Multiple Sclerosis


Findings from the 12-week study showed a significant decrease in total number of new gadolinium-enhancing lesions in patients with relapsing MS on fenebrutinib relative to placebo.

Levi Garraway, MD, PhD, chief medical officer, head, Global Product Development, Roche

Levi Garraway, MD, PhD

Genentech has announced new data from its phase 2 FENtopa study (NCT05119569), demonstrating that treatment with fenebrutinib, its investigational Bruton tyrosine kinase (BTK) inhibitor, met its primary and secondary end points, showing a significant reduction in MRI markers of multiple sclerosis (MS) activity in the brain relative to placebo.1

FENtopa is a double-blind, placebo-controlled 12-week study that includes 109 adults with relapsing MS, aged 18-55 years. At the conclusion of the analysis, fenebrutinib demonstrated a significant reduction in total number of new gadolinium-enhancing T1 brain lesions, the primary end point, compared with placebo (P = .0022). Full detailed results of the data are expected to be shared at an upcoming medical meeting.

Secondary end points, which included the number of new or enlarging T2-weighted lesions, was significantly reduced through treatment of fenebrutinib. In addition, a higher proportion of patients treated with the agent were free from any new gadolinium-enhancing T1 brain lesions and new or enlarging T2-weighted brain lesions compared with placebo. Fenebrutinib continued to maintain a safe treatment profile, with findings that were consistent with previous and ongoing trials.

"I am encouraged by this clinical data for fenebrutinib, which is important news for people living with MS," Levi Garraway, MD, PhD, chief medical officer, head, Global Product Development, Roche, said in a statement.1 "Fenebrutinib’s mechanism of action, which can inhibit both B cells and microglia, has the potential to both reduce MS disease activity, such as relapses, and also impact disease progression."

Fenebrutinib is unique in that it is a noncovalent and reversible BTK inhibitor compared with other agents, such as ibrutinib (Imbruvica; AbbVie/Janssen), tolebrutinib (Sanofi), and evobrutinib (EMD Serono), which are all covalent and irreversible. It is currently being assessed in a large-scale phase 3 clinical trial program that included 2 identical phase 3 trials in relapsing MS, FENhance 1 (NCT04586023) and FENhance 2 (NCT045586010), and a separate phase 3 trial in primary progressive MS (PPMS), FENtrepid (NCT04544449).

READ MORE: Risk of Severe COVID-19 Infection in Pediatric Patients With MS on B-Cell-Depleting Therapies

FENtrepid, a multicenter, double-blind, double-dummy, parallel-group study, includes 946 patients with PPMS aged 18 to 65 years. Eligible patients are randomly assigned 1:1 to either daily oral fenebrutinib or placebo or intravenous ocrelizumab (Ocrevus; Genentech), the first and only approved therapy for progressive MS, for 120 weeks. An open-label extension may follow FENtrepid, depending on the observed benefits.

The BTK inihibitor was previously assessed in a double-blind, phase 1 study of healthy volunteers, with data published in 2018. All told, findings showed that fenebrutinib is well-tolerated and poses no safety concerns. Plasma concentrations peaked 1-3 hours after oral administration and declined thereafter, with a steady-state half-life ranging from 4.2-9.9 hours. The investigators concluded that based on pharmacokinetic/pharmacodynamic simulations, a once-daily dosing regimen (100 mg QD) was expected to maintain a high level of BTK inhibition over the dosing interval.2

More recently, at MSVirtual2020, the 8th Joint ECTRIMS-ACTRIMS Meeting, held in September 2020, data presented highlighted the drug’s mechanism and compared them with those of other BTK inhibitors. At the end of the presentation, the study authors concluded that fenebrutinib may be safer than less selective, covalent BTK inhibitors and that it has best-in-class potential in MS. Fenebrutinib’s safety profile was further examined and confirmed through an analysis that included data from phase 2 randomized, controlled clinical trials and open-label extensions in diverse autoimmune indications such as rheumatoid arthritis, systemic lupus erythematosus, and chronic spontaneous urticaria. Safety assessments included adverse events (AEs), laboratory results, electrocardiogram results, and vital signs.3

1. Genentech’s BTK inhibitor fenebrutinib significantly reduced brain lesions in people with relapsing forms of multiple sclerosis. News release. May 17, 2023. Accessed May 17, 2023.
2. Herman AE, Chinn LW, Kotwal SG, et al. Safety, pharmacokinectis, and pharmacodynamics in healthy volunteers treated with GDC-0835, a selective reversible Bruton’s tyrosine kinase inhibitor. Clin Pharmacol Ther. 2018;103(6):1020-1028. doi:10.1002/cpt1056
3. Roche expands its multiple sclerosis portfolio with investigational BTK inhibitor fenebrutinib and initiates novel clinical trials for OCREVUS (ocrelizumab). News release. September 9, 2020. Accessed May 17, 2021.
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