Sanofi and Denali Therapeutics have reported that their investigational drug, SAR443820 (also known as DNL788), failed to meet the primary endpoint in a Phase 2 clinical trial for amyotrophic lateral sclerosis (ALS). The drug, a brain-penetrating RIPK1 inhibitor, did not demonstrate a significant change in the ALS Functional Rating Scale-Revised (ALSFRS-R), a key measure of symptom progression in ALS patients.
The Phase 2 trial enrolled 305 participants who were randomly assigned to receive either SAR443820 or a placebo twice daily for 24 weeks. Denali disclosed the results in a regulatory filing, noting that Sanofi intends to present detailed efficacy and safety data at an upcoming scientific meeting. The collaboration between Sanofi and Denali, initiated in 2018, focused on developing therapies for neurological and inflammatory diseases, with Sanofi paying Denali $125 million upfront and potential milestone payments reaching $1 billion.
RIPK1 Inhibition in ALS: A Questionable Approach?
SAR443820 is a small molecule designed to inhibit RIPK1, a signaling protein involved in inflammation and cell death throughout the body. Phase 1 results in healthy volunteers showed that the drug was safe and engaged its target. However, the Phase 2 failure in ALS raises concerns about whether RIPK1 inhibition is an effective therapeutic strategy for this disease. Leerink Partners analyst Marc Goodman noted that the trial was well-powered and the drug showed strong target engagement in Phase 1, making the Phase 2 failure particularly disappointing.
Ongoing Studies and Future Directions
Despite the negative results in the Phase 2 ALS trial, a 52-week open-label extension study is underway to further assess the drug's safety and efficacy. All participants who choose to continue in the extension study will receive SAR443820, with the primary goal being a combined assessment of function and survival. Additionally, the Phase 2 study of SAR443820 in multiple sclerosis (MS) has completed enrollment of 174 patients and is continuing.
Implications for Other RIPK1 Inhibitor Programs
The failure of SAR443820 in ALS may have broader implications for other companies developing RIPK1 inhibitors. Eli Lilly, for example, has a partnership with Rigel Pharmaceuticals to develop RIPK1-blocking small molecules, with a lead program in Phase 2 testing for rheumatoid arthritis and a preclinical molecule targeting neurodegenerative diseases like Alzheimer's and ALS. The results from the Sanofi and Denali trial could prompt a reassessment of the potential of RIPK1 inhibition in neurodegenerative diseases.
ALS Treatment Landscape
The ALS treatment landscape saw a recent approval with Amylyx Pharmaceuticals' Relyvrio, a drug targeting two pathways crucial for neuron survival. This approval was based on Phase 2 data, and a larger Phase 3 trial is ongoing, with topline data expected in the second quarter of this year.
