Sanofi, in partnership with Denali Therapeutics, has halted the Phase 2 clinical trial of oditrasertib (SAR443820), an investigational RIPK1 inhibitor, for the treatment of multiple sclerosis (MS). The decision was based on the drug's failure to meet its primary endpoint of reducing serum neurofilament light chain (NfL) levels, a key biomarker of neurodegeneration, as well as other key secondary endpoints.
The K2 study (NCT05630547) was a randomized, double-blinded, placebo-controlled trial involving over 170 patients with relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), or primary progressive MS (PPMS). The trial aimed to evaluate the efficacy and safety of oditrasertib over a 48-week treatment period, followed by a 48-week open-label extension.
Mechanism of Action and Prior Clinical Experience
Oditrasertib is an orally available, brain-penetrant inhibitor of receptor-interacting protein kinase 1 (RIPK1), a protein involved in inflammatory and cell death pathways. RIPK1 is implicated in the pathogenesis of neurodegenerative diseases, including MS, where its overactivation contributes to inflammation and neuronal damage. By inhibiting RIPK1, oditrasertib was intended to reduce inflammation and protect against neurodegeneration.
However, oditrasertib has faced previous setbacks in clinical development. In February 2024, Sanofi and Denali announced the failure of the Phase 2 HIMALAYA study of oditrasertib in amyotrophic lateral sclerosis (ALS), where it did not significantly improve disease severity as measured by the ALS Functional Rating Scale-Revised. Consequently, Sanofi discontinued the development of oditrasertib for ALS in April 2024.
Impact on Multiple Sclerosis Treatment Landscape
Multiple sclerosis is a chronic, degenerative disease affecting approximately 2.8 million people worldwide. The global market for MS treatments was valued at $21.3 billion in 2023 and is projected to reach $38.9 billion by 2032. Developing effective therapies for MS remains a significant challenge, with recent failures also observed for other investigational drugs, such as Sanofi's BTK inhibitor tolebrutinib, which initially missed endpoints in two Phase 3 studies before showing positive results in a third trial for non-relapsing SPMS.
Future Directions for Sanofi and Denali
Despite the discontinuation of the oditrasertib MS trial, Sanofi and Denali continue to collaborate on other RIPK1 inhibitors. Eclitasertib (SAR443122), a peripherally restricted RIPK1 inhibitor that does not cross the blood-brain barrier, is currently in Phase 2 development for the treatment of ulcerative colitis. The companies hope to find success in other indications with alternative RIPK1 inhibition strategies.
