Eclitasertib

Shares in Denali Therapeutics fell 7.3% to $17.02 Friday. 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 ClinicalTrials.gov. 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.

Pictured: Sanofi distribution center in Canada/iStock, JHVEPhoto Sanofi-partnered Denali Therapeutics reported on Friday that its investigational amyotrophic lateral sclerosis therapy fell short of its primary efficacy endpoint in the Phase II HIMALAYA study. The announcement, made in an SEC filing, was scarce with details or data. The companies only said that the candidate, dubbed SAR443820/DNL788, “did not meet the primary endpoint of change in ALS Functional Rating Scale-Revised,” which is a validated tool to assess the severity of amyotrophic lateral sclerosis (ALS) and monitor a patient’s functional performance. Sanofi plans on presenting findings from HIMALAYA at an upcoming medical congress, according to the SEC document. The partners did not reveal their plans for SAR443820/DNL788 in ALS but the candidate remains in development for multiple sclerosis, where it has first-in-class potential. In October 2023, Sanofi presented data for SAR443820/DNL788 at the 9th Joint European and Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) Meeting. SAR443820/DNL788 is a small molecule blocker of the RIPK1 protein, which is a crucial player in the signaling cascade involved in inflammation and cell death. According to Denali’s website, SAR443820/DNL788 is designed to be able to penetrate the central nervous system, where heightened RIPK1 activity is believed to contribute to neuroinflammation and cell necroptosis driving neurodegeneration. Sanofi and Denali are developing SAR443820/DNL788 under a 2018 partnership, which gave Denali $125 million upfront. However, the partnership has run into several clinical hurdles that have led to suspended development programs. In June 2020, Sanofi and Denali posted disappointing Phase Ib data for DNL747—which was the initial highlight of the 2018 pact—in Alzheimer’s disease and ALS. DNL747, also a RIPK1 inhibitor, showed dose- and duration-dependent toxicities in monkey studies that would make it difficult to scale dosing in humans. The companies were forced to suspend the development of DNL747 and instead channel their resources into DNL788. In October 2023, Sanofi also discontinued the development of the second RIPK1 inhibitor under the 2018 agreement—dubbed DNL758—in cutaneous lupus erythematosus. The decision came after a Phase II proof-of-concept trial fell short of its primary endpoint. Sanofi holds the sole responsibility for DNL758’s development and is still currently running a Phase II study of the candidate in ulcerative colitis. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.