Roche’s BTK inhibitor, fenebrutinib, cuts relapse rates in patients with relapsing multiple sclerosis (RMS), but safety concerns continue to cloud the data.
The Swiss-based pharma company previously announced data from the Phase III FENhance 1 (NCT04586010) and FENhance 2 (NCT04586023) studies, which met their primary endpoints. The studies showed that fenebrutinib, an investigational non-covalent Bruton’s tyrosine kinase (BTK) inhibitor, reduced the annualised relapse rate (ARR) by 51.1% in FENhance 1 and 58.5% in FENhance 2 compared with Sanofi’s Aubagio (teriflunomide) in patients with RMS over 96 weeks.
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This equates to patients having approximately one relapse every 17 years, the company said in results shared as a late-breaking presentation at the 2026 American Academy of Neurology (AAN) Annual Meeting, which took place from 18 to 22 April in Chicago. The greatest relapse reductions were observed in patients with more inflammatory disease characteristics, including active brain lesions, younger age, more recent diagnosis and less disability.
Dr Jiwon Oh, medical director of the Barlo Multiple Sclerosis Program at St. Michael’s Hospital, University of Toronto, said: “These results underscore that fenebrutinib has potential as a high-efficacy oral treatment for RMS. Its unique mode of action may offer a differentiated profile by targeting dual drivers of MS within the central nervous system and periphery to address disease mechanisms underlying both relapsing and progressive disease biology. For the first time, a BTK inhibitor has demonstrated superiority in reducing relapses and formation of new brain lesions with comparable rates of liver enzyme elevations to a long-standing first-line medication in multiple Phase III RMS trials.”
Despite the positive efficacy data, Roche highlighted an imbalance in reported fatalities across studies. In FENhance 1 and 2, there were seven deaths (0.9%) in the fenebrutinib arm during the reporting period compared with one in the Aubagio arm (0.1%). One additional death was observed after the study period.
Overall, in the fenebrutinib arm, deaths occurred at different timepoints and were caused by various causes, including infections (neuro cryptococcosis gattii and pneumonia), complications of type 1 diabetes, serious bleeding, suicide, injuries from an accident and death of unknown cause.
This adds to concerns with the drug in regard to liver toxicity, something which plagues the BTK inhibitor class, with liver enzyme elevations above three times the upper limit of normal being comparable between the two arms. The drug was previously placed on a clinical hold by the US Food and Drug Administration (FDA) after it triggered liver enzyme elevations in two patients during the FENhance study.
In the FENhance 1 study, there was one Hy’s Law case in the fenebrutinib arm, which occurred before biweekly liver monitoring was implemented, and one in the Aubagio arm. Both cases were asymptomatic and resolved after study drug discontinuation.
Despite this, Roche is still hoping to gain approval of the drug and will be approaching regulators with the Phase III data. If approved, GlobalData predicts the drug to reach blockbuster status by 2031, with sales due to reach $1.31bn. GlobalData is the parent company of Clinical Trials Arena.
Both Novartis and Sanofi are also seeking approval of their BTK inhibitors, Rhapsido (remibrutinib) and tolebrutinib, respectively, in RMS.
In a previous conversation with Clinical Trials Arena, three MS experts touted the future potential of BTK inhibitors in the MS market, noting that their efficacy in hard-to-treat subsets and capacity to target both central and peripheral inflammation could earn them a place in the treatment paradigm.
