Sanofi and Denali Halt Multiple Sclerosis Study Due to Disappointing Data

Sanofi has decided to halt a Phase II study of its RIPK1 blocker oditrasertib for multiple sclerosis after the drug did not achieve its primary and key secondary goals. This decision was disclosed in an SEC filing by Denali Therapeutics, Sanofi’s partner in the study.

The Phase II K2 study was a randomized, double-blind, placebo-controlled trial that included over 170 participants who had various forms of multiple sclerosis, such as relapsing-remitting MS, secondary progressive MS, and primary progressive MS. The central aim of the study was to assess the impact of oditrasertib on serum neurofilament light chain levels.

While the SEC filing did not provide specific details about which secondary outcomes oditrasertib failed to meet, or address the drug’s safety profile, the results were sufficiently unfavorable for Sanofi to discontinue the trial.

Oditrasertib is designed as an investigational inhibitor that targets the RIPK1 protein, which plays a significant role in inflammation and cell death processes. In neurodegenerative diseases, RIPK1 and related proteins are often overactivated, resulting in extensive inflammation and cell death in the brain. By inhibiting RIPK1, oditrasertib aims to disrupt these harmful pathways, thus preserving brain function.

Despite the potential of its mechanism, oditrasertib has faced significant hurdles in clinical trials. Earlier in 2024, Sanofi decided to stop a Phase II trial of oditrasertib for amyotrophic lateral sclerosis (ALS) after it did not show meaningful results in reducing disease severity, as measured by the ALS Functional Rating Scale-Revised. This decision followed a similar failure in February 2024, when Sanofi and Denali reported that oditrasertib did not meet the necessary endpoints in the Phase II HIMALAYA study for ALS.

Developing successful treatments for multiple sclerosis has been notably challenging. In another instance, in September 2024, Sanofi's BTK inhibitor tolebrutinib did not significantly reduce relapse rates in two Phase III studies. However, it showed promise a few weeks later by significantly delaying disability onset in patients with non-relapsing secondary progressive MS in a separate Phase III trial.

In the same month, a study published in Neurology questioned the efficacy of anti-CD20 antibodies in multiple sclerosis. The research found no significant difference in relapse rates or disability progression between patients treated with these therapies and those who were untreated. This study focused on primary progressive multiple sclerosis, for which the only approved anti-CD20 therapy is Roche’s Ocrevus (ocrelizumab). Other drugs in this class, such as Novartis’ Kesimpta (ofatumumab) and TG Therapeutics’ Briumvi (ublituximab), are approved for relapsing forms of MS.

Sanofi’s recent setbacks underscore the difficulties in developing effective therapies for neurological disorders like MS and ALS. Despite promising scientific hypotheses and mechanisms of action, translating these into successful clinical outcomes remains a formidable challenge. These failures highlight the need for ongoing research and development to find more effective treatments for these debilitating diseases.