Roche has shared details of fatalities in its phase 3 relapsing multiple sclerosis (RMS) trials, revealing that deaths from infections, diabetes complications and an accident contributed to an imbalance between its fenebrutinib and control cohorts.
Last month, Roche reported that fenebrutinib, a BTK inhibitor, had beaten Sanofi’s Aubagio in a phase 3 RMS study for the second time. The trials linked fenebrutinib to a 51.1% and 58.5% drop, respectively, in annualized relapse rate (ARR) compared with Aubagio. But an imbalance in fatalities across the two trials, with eight patients dying on fenebrutinib compared to one on Aubagio, cast a shadow over the readout.
Roche shared more information about the deaths at the American Academy of Neurology (AAN) Annual Meeting Wednesday. People taking fenebrutinib died at different times and of various causes, including infections, Type 1 diabetes complications, bleeding, suicide, injuries from an accident and an unknown cause. Roche listed neurocryptococcosis gattii—a fungal disease—and pneumonia as deaths from infections.
The Swiss drugmaker previously reported (PDF) an imbalance in the death rate in a phase 3 fenebrutinib trial in primary progressive MS (PPMS). In that trial, seven people died in the fenebrutinib arm, compared to one patient in the Ocrevus cohort. Investigators ruled all the PPMS deaths unrelated to the study drug and Roche saw no pattern in the timing or cause of the fatalities.
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The deaths add another element to the scrutiny of the safety of fenebrutinib, which, like other BTK drugs, has been linked to liver toxicity. Rates of liver enzyme elevations above three times the upper limit of normal were comparable with Aubagio in the RMS trials, Roche said. One patient each on fenebrutinib and Aubagio met Hy’s Law, a liver injury framework, across the two RMS studies.
Roche, which included the primary ARR endpoint data in its earlier press releases, used the AAN meeting to share results on secondary endpoints. Fenebrutinib reduced markers of active inflammation by 70.7% and 77.6% in the two RMS trials, replicating the result seen in phase 2. Chronic disease burden fell 76% and 82.5% on fenebrutinib in the phase 3 studies.
Those results were statistically significant, but fenebrutinib only achieved a numerical advantage over Aubagio on a disability assessment. The risk of 12-week composite confirmed disability progression in the two studies was 20% and 13% lower, respectively, on fenebrutinib than Aubagio. The PPMS trial found fenebrutinib was noninferior to Ocrevus on a disability endpoint.
The disability endpoint in Roche’s RMS trials looked at overall disability, walking speed and upper limb function. Roche presented a post-hoc analysis from the studies that removed walking speed from the assessment, linking fenebrutinib to a 20% and 26% reduction in the risk of worsening on the other two measures of disability.
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Roche plans to submit data from the RMS and PPMS trials to regulators. At an investor event last month, Bruno Eschli, head of investor relations at Roche, said the consensus estimate for fenebrutinib revenues in 2030 was 1.1 billion Swiss francs ($1.4 billion). Eschli said the figure reflected a small increase after the top-line phase 3 readouts and predicted the full data could drive “additional upside.”
Novartis’ BTK inhibitor could challenge Roche for the RMS market. While Sanofi dropped plans to bring its BTK inhibitor to market in RMS after flunking phase 3, Novartis is still moving toward pivotal data on a molecule that so far has demonstrated a potentially differentiated safety profile.
