Back-to-back clinical failures have dealt further blows to efforts to treat Parkinson’s disease by targeting alpha-synuclein. Days after UCB reported the failure of its Novartis-partnered program, Roche has shared details of its own flop while clinging onto signs of clinical benefit that could still save the candidate.
Roche’s trial randomized 586 people with early-stage Parkinson’s to receive monthly intravenous doses of the Prothena-partnered anti-alpha-synuclein antibody prasinezumab or placebo. Time to confirmed motor progression of Parkinson’s was statistically no better on prasinezumab than placebo, causing the study to miss its primary endpoint. The p-value was 0.0657.
Roche said the drug candidate showed “potential clinical efficacy” on the primary endpoint, despite the lack of statistical significance, and shared further analyses to make the case that prasinezumab may have a future. The nominal p-value was 0.0431 in a prespecified analysis of the 75% of participants who also received the approved Parkinson's drug levodopa.
Consistent positive trends were seen across multiple secondary and exploratory endpoints, Roche said. Prothena went further in its press release, providing p-values for the levodopa subpopulation and data from prespecified supplementary covariate-adjusted analyses. After the adjustments, the nominal p-values in the primary and levodopa populations were 0.0334 and 0.0175, respectively.
Roche is continuing to track patients in a phase 2 trial and an open-label extension to the phase 2b. The Swiss drugmaker is still evaluating the data and will decide the next steps after talking to regulators.
Prothena could benefit financially if Roche takes the antibody forward. Roche licensed the candidate 11 years ago for $30 million upfront and has paid $105 million in milestones tied to the start of phase 1, 2 and 2b trials. The deal is still worth up to $290 million in development, regulatory and “various first commercial sales milestones.” Later commercial milestones are worth up to $330 million.
Still, today's failure extends the losing streak of alpha-synuclein candidates. Novartis paid UCB $150 million upfront for rights to two assets that target alpha-synuclein, one small molecule and one antibody, three years ago. The small molecule flunked a midphase test this week, prompting the partners to terminate an extension study. A phase 1 trial of UCB’s antibody wrapped up last year.
UCB is continuing to study an inhibitor of extracellular alpha-synuclein spread, but the precedents are poor. The setbacks at UCB and Roche follow the phase 2 failure of a program in development at Biogen.