Sanofi stumbles in HIMALAYA trial, chalking up phase 2 ALS fail in another blow to Denali alliance

Sanofi’s HIMALAYA adventure has ended in failure, dealing another blow to its RIPK1 collaboration with Denali Therapeutics.

The phase 2 study randomized 305 people with amyotrophic lateral sclerosis (ALS) to receive SAR443820, a RIPK1 inhibitor also known as DNL788, or placebo orally twice a day. After 24 weeks, Sanofi assessed the change from baseline on an ALS severity scale, ALSFRS-R. The clinical trial also features an open-label extension designed to measure the combined assessment of the function and survival score at Week 52.

In a financial filing, Denali revealed the HIMALAYA study failed to meet the ALSFRS-R primary endpoint. Sanofi will share detailed safety and efficacy results at an upcoming scientific forum. For now, the only information is that the study missed its primary endpoint.

Sanofi is continuing to study SAR443820 in a phase 2 multiple sclerosis trial. That study began dosing 13 months ago, triggering a $25 million milestone payment to Denali, and finished enrolling its 174 subjects by the end of 2023. The primary completion date is September 2025, according to

The multiple sclerosis study is part of a dwindling list of opportunities open to the Sanofi-Denali RIPK1 collaboration. Sanofi paid $125 million to buy into the program in 2018, 11 months after Denali raised $250 million in the biggest biotech IPO of 2017. However, the project hit an early bump in the road when the partners switched to a backup compound in response to chronic toxicity data on their lead asset.

In parallel, the partners worked on another RIPK1 inhibitor that, unlike SAR443820, is designed not to penetrate the central nervous system. That drug, eclitasertib, is being studied in peripheral inflammatory diseases but has suffered setbacks. Sanofi stopped work on cutaneous lupus erythematosus last year in response to phase 2 efficacy data, although it is continuing to run a midstage study in ulcerative colitis. 

Other companies have shared Sanofi’s interest in RIPK1. Eli Lilly paid Rigel Pharmaceuticals $125 million for an inhibitor of the kinase in 2021 and began a phase 2 rheumatoid arthritis study last year. GSK, which previously dropped a RIPK1 cancer candidate, offloaded an asset to Boston Pharmaceuticals in 2021. Bristol Myers Squibb removed a phase 1 RIPK1 inhibitor from its pipeline last year.

Shares in Denali fell 7.3% to $17.02 over the course of Friday's trading.