A second phase 3 study of Roche’s fenebrutinib in relapsing multiple sclerosis (RMS) has hit its primary endpoint, positioning the company to submit the BTK inhibitor for approval. But the discovery that more patients died on fenebrutinib than on the control drug has spurred further analyses by Roche.
The Swiss drugmaker reported a phase 3 win for fenebrutinib over Sanofi’s Aubagio in RMS in November. In that study, Roche linked its drug candidate to a 59% reduction in the annualized relapse rate (ARR) compared to Aubagio. Roche replicated the success on Monday, reporting a 51% reduction in ARR over Aubagio in its other phase 3 RMS trial.
Both studies linked fenebrutinib to statistically significant reductions in brain lesions, and all progression endpoints trended in favor of the BTK inhibitor. With Roche posting a phase 3 win in primary progressive MS last year, the company believes it has the data to support filings with regulatory authorities.
Safety will be a focus once fenebrutinib is in front of regulators. The FDA rejected Sanofi’s request for approval of another BTK inhibitor, tolebrutinib, late last year over the risk of severe drug-induced liver injury. After reviewing the FDA decision, Guggenheim Securities analysts said in a note to investors that Roche will “face a high bar in establishing a favorable risk/reward” for fenebrutinib.
Related
The prediction reflected potential cases of Hy’s Law—which relates to liver injury—and elevated liver enzymes. Roche said there was one Hy’s Law case each in the fenebrutinib and Aubagio arms in the newly reported RMS trial. Both cases were asymptomatic and resolved after study drug discontinuation. Roche hasn’t seen any other Hy’s Law cases across the fenebrutinib clinical development program.
In guidance on drug-induced liver injury, the FDA said “finding one Hy’s Law case in the clinical trial database is worrisome.” A second case would cause deeper concerns. The FDA views two Hy’s Law cases as highly predictive that a therapy has the potential to cause severe drug-induced liver injury when given to a larger population.
Across the two RMS trials, eight patients on fenebrutinib died compared to one death in the Aubagio arms. Roche said the fenebrutinib deaths had various causes and happened at different points in treatment. The drugmaker is analyzing the data to better understand the findings. Roche will share full data from the RMS trials at an event in April.
The safety concerns facing Roche’s fenebrutinib and Sanofi’s tolebrutinib create potential opportunities for Novartis, which is developing a rival BTK inhibitor. Novartis has won approval for the drug, Rhapsido, in chronic spontaneous urticaria without triggering liver safety concerns. The drugmaker is now closing in on data from phase 3 trials comparing its candidate to Sanofi’s Aubagio in RMS.