Sanofi has ended a Phase 2 clinical trial for oditrasertib, a drug developed in partnership with Denali Therapeutics, intended for the treatment of multiple sclerosis (MS), after the drug failed to meet its primary and key secondary endpoints. This decision effectively halts the development plan for this particular therapeutic approach to MS.
The trial's disappointing results mark another setback in the collaboration between Sanofi and Denali. Oditrasertib is designed to inhibit RIPK1, a signaling protein that, when overstimulated, can drive neuroinflammation and cell death, processes implicated in the pathogenesis of MS. Sanofi, according to a spokesperson, does not have any further studies planned for the drug.
The collaboration between Sanofi and Denali began with Sanofi paying Denali $125 million upfront in 2018, with potential milestone payments exceeding $1 billion, reflecting a significant investment in the RIPK1 target. However, the partnership has faced a series of disappointing outcomes. In February, oditrasertib failed to demonstrate efficacy in a Phase 2 amyotrophic lateral sclerosis (ALS) study, failing to improve patient symptoms as measured by the ALS Functional Rating Scale.
Another asset from the 2018 deal, DNL747, was discontinued in 2020 after Phase 1b data in Alzheimer’s and ALS patients proved unfavorable. A third asset, DNL758, is currently undergoing a Sanofi-led Phase 2 study for ulcerative colitis, though an earlier study in cutaneous lupus erythematosus was discontinued in October 2023 due to lack of efficacy.
Despite the challenges faced by the collaboration, Denali reported a strong financial position at the end of June, with $1.35 billion in cash, equivalents, and marketable securities. This funding is expected to support the advancement of Denali’s mid- to late-stage pipeline, including a potential treatment for Hunter syndrome, for which Denali is preparing an accelerated approval application based on a successful meeting with the FDA regarding a surrogate endpoint, with plans to submit the application in early 2025.
RIPK1 Inhibition as a Therapeutic Target
Receptor-interacting protein kinase 1 (RIPK1) is a signaling protein involved in inflammation and cell death pathways. Overstimulation of RIPK1 has been implicated in various neurodegenerative diseases, including multiple sclerosis and amyotrophic lateral sclerosis. The rationale behind targeting RIPK1 is to modulate neuroinflammation and prevent neuronal cell death, potentially slowing disease progression.
Current MS Treatment Landscape
The current treatment landscape for multiple sclerosis includes a range of disease-modifying therapies (DMTs) that aim to reduce the frequency and severity of relapses and slow the accumulation of disability. These therapies include injectable medications, oral medications, and infusions. While these treatments can be effective in managing MS, they are not curative and may have significant side effects. There remains a need for new therapies that can provide more effective disease control with fewer side effects.
Trial Details
The Phase 2 trial that was discontinued was designed to evaluate the safety and efficacy of oditrasertib in patients with multiple sclerosis. The primary endpoint of the trial was to assess the impact of oditrasertib on disease activity, as measured by MRI and clinical assessments. Secondary endpoints included measures of disability progression and patient-reported outcomes. The specific dosing regimen and administration route for oditrasertib were not disclosed in the provided source material.
