FDA Places Clinical Hold on Roche’s BTK Inhibitor Fenebrutinib for Multiple Sclerosis

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The clinical hold is in reference to safety concern observed in the phase 3 FENhance studies of patients with relapsing forms of multiple sclerosis.

According to a recent announcement, the FDA has placed a clinical hold on the development program for fenebrutinib (Roche), an investigational oral, reversible, and noncovalent Bruton tyrosine kinase (BTK) inhibitor in development for patients with multiple sclerosis (MS).1

The decision was based on 2 recent cases of hepatic transaminase elevations in conjunction with elevated bilirubin suggestive of drug-induced liver injury that was documented in the blinded phase 3 FENhance studies of relapsing MS. Both patients were asymptomatic and had elevations returned to normal levels following the discontinuation of fenebrutinib.

As a result of the hold, new enrollment for the FENhance 1 trial (NCT04586023) in the US will be paused, while enrollment in countries outside of the US will continue. Participants in the US who received fenebrutinib for more than 70 days will continue treatment in all studies, which comprise the ongoing, fully enrolled FENhance 2 (NCT045586010) and FENtrepid trial (NCT04544449). Roche noted that only a small number of participants in the US who received the treatment for 70 days or less will discontinue treatment.

Fenebrutinib, a BTK inhibitor that blocks the function of BTK, is also a dual inhibitor of both B-cell and microglia activation. Despite the number of BTK inhibitors in the clinical pipeline increasing in recent years, fenebrutinib remains the only reversible inhibitor with this mechanism of action.

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In addition to the FENhance and FENtrepid trials, fenebrutinib was assessed in the phase 2 FENtopa study (NCT05119569), a double-blind, placebo-controlled 12-week study of patients with relapsing MS, aged 18-55 years. Data announced earlier this year showed that the agent met its primary end secondary end points, demonstrating a significant reduction in MRI markers of MS activity in the brain relative to placebo.2

At the conclusion of FENtopa, fenebrutinib-treated patients showed amelioration in the total of new gadolinium-enhancing T1 brain lesions, the primary end point, compared with placebo (P = .0022). Additional findings showed that 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. The investigational therapy also maintained a safe treatment profile, with findings that were consistent with previous and ongoing trials.

FENtrepid, a multicenter, double-blind, double-dummy, parallel-group study, compares the efficacy and safety of fenebrutinib with ocrelizumab (Ocrevus; Genentech), the only currently approved therapy for progressive MS. In the study, patients with primary progressive MS are assigned 1:1 to either daily oral fenebrutinib or placebo or intravenous ocrelizumab for 120 weeks, with change in 12-week confirmed disability progression (CDP) as the primary outcome measure. Time to onset of composite 24-week CDP, the percentage change in total brain volume assessed by MRI, and change from baseline in participant-reported physical impacts of MS will all comprise secondary end points.3

Because of its noncovalent and reversible mechanism of action, fenebrutinib remains unique from other BTK inhibitors such as ibrutinib (Imbruvica; AbbVie/Janssen), tolebrutinib (Sanofi), and evobrutinib (EMD Sorono), which are all covalent and irreversible.

REFERENCES
1. Fenebrutinib multiple sclerosis clinical trial program update. News release. Genentech/Roche. November 30, 2023. Accessed December 5, 2023. https://www.gene.com/media/statements/ps_113023
2. Genentech’s BTK inhibitor fenebrutinib significantly reduced brain lesions in people with relapsing forms of multiple sclerosis. News release. May 17, 2023. Accessed December 5, 2023. https://www.businesswire.com/news/home/20230516005196/en/Genentech%E2%80%99s-BTK-Inhibitor-Fenebrutinib-Significantly-Reduced-Brain-Lesions-in-People-With-Relapsing-Forms-of-Multiple-Sclerosis
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 December 5, 2023. https://www.globenewswire.com/news-release/2020/09/09/2090572/0/en/Roche-expands-its-multiple-sclerosis-portfolio-with-investigational-BTK-inhibitor-fenebrutinib-and-initiates-novel-clinical-trials-for-OCREVUS-ocrelizumab.html
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