Mid-Stage Trial Failure for Sanofi and Denali's ALS Drug

Denali Therapeutics, in collaboration with Sanofi, has recently announced the disappointing results from their Phase II HIMALAYA study, where their ALS treatment, SAR443820/DNL788, did not achieve the primary efficacy goal. The primary endpoint was based on the ALS Functional Rating Scale-Revised, a standard measure for assessing the severity and progression of ALS.

Although the specifics of the study were not disclosed in the SEC filing, it was mentioned that Sanofi intends to present the study's findings at an upcoming medical conference. While the future of SAR443820/DNL788 in ALS treatment remains uncertain, the drug is still under development for multiple sclerosis and holds the potential to be a first-in-class treatment.

SAR443820/DNL788 is a small molecule that targets the RIPK1 protein, which plays a significant role in inflammatory responses and cell death pathways. Designed to cross the blood-brain barrier, the drug aims to reduce neuroinflammation and cell necroptosis, processes implicated in neurodegenerative diseases.

The development of SAR443820/DNL788 is part of a broader partnership between Sanofi and Denali initiated in 2018, which provided Denali with an initial payment of $125 million. However, the partnership has encountered several setbacks, including the suspension of other clinical programs.

In June 2020, the companies reported unsatisfactory Phase Ib results for DNL747, another RIPK1 inhibitor, in Alzheimer's and ALS due to dose-dependent toxicities observed in preclinical studies. This led to the suspension of DNL747's development in favor of DNL788.

Additionally, in October 2023, Sanofi halted the development of another RIPK1 inhibitor, DNL758, for cutaneous lupus erythematosus after it failed to meet its primary endpoint in a Phase II trial. Sanofi continues to be responsible for DNL758's development and is also conducting a Phase II study for the drug in ulcerative colitis.

The setbacks highlight the challenges in drug development, particularly in targeting complex pathways such as RIPK1 in neurodegenerative diseases. Despite these hurdles, the ongoing research and development efforts underscore the commitment to finding effective treatments for ALS and other debilitating conditions.