Denali Therapeutics Announces Achievement of RIPK1 Milestone for Phase 2 Clinical Trial Initiation in ALS by Sanofi

Denali Therapeutics Inc. recently announced its partner Sanofi has commenced dosing in a Phase 2 study, named HIMALAYA, of SAR443820 (DNL788) in individuals with amyotrophic lateral sclerosis (ALS). SAR443820 is a central nervous system (CNS)-penetrant small molecule inhibitor of RIPK1.

“ALS is a devastating neurodegenerative disease for which effective treatment options are a critical unmet medical need,” said Nazem Atassi, MD, Sanofi’s Global Head of Early Neuro Development. “We are very encouraged by the results from the Phase 1 trial of SAR443820 in healthy volunteers in which robust target engagement was demonstrated at doses that were generally well tolerated. Based on these results, we are excited to start the HIMALAYA Phase 2 ALS study and look forward to working with Denali and the ALS community to advance the development of this novel investigational therapy.”

“The initiation of this Phase 2 study marks a significant milestone in the SAR443820 development program and our RIPK1 inhibitor collaboration with Sanofi,” said Denali’s Chief Medical Officer, Carole Ho, MD. “We are excited about the progression of Denali’s portfolio in ALS with this milestone. Denali is committed to collaborating with the ALS community as we work toward a unified goal of developing potentially life-saving therapeutics for people living with ALS.”

Denali and Sanofi entered into a broad partnership in October 2018 for the global development and commercialization of peripherally restricted and CNS-penetrant RIPK1 inhibitors. RIPK1 is a critical signaling protein in the tumor necrosis factor (TNF) receptor pathway and is a regulator of inflammation and cell death. Increased RIPK1 activity in the brain drives neuroinflammation and cell necroptosis, and has been implicated in several CNS and peripheral diseases. RIPK1 inhibition has been shown to attenuate disease progression in preclinical models in ALS and multiple sclerosis (MS).

SAR443820 is a CNS-penetrant RIPK1 inhibitor discovered and developed by Denali scientists. Sanofi leads Phase 1 and Phase 2 development of SAR443820 for ALS and MS and leads co-development of SAR443820 with Denali in Phase 3 clinical trials for ALS, MS and Alzheimer’s disease. Sanofi completed a Phase 1 trial of SAR443820 in healthy volunteers in which robust target engagement was demonstrated at doses that were generally well tolerated. Based on these results, Sanofi decided to initiate the HIMALAYA Phase 2 study in ALS and plans to initiate a Phase 2 study in MS.

The Phase 2 HIMALAYA trial is a multi-center, randomized, double-blind, placebo-controlled trial, followed by an open-label long-term extension, to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of SAR443820 in approximately 260 adult participants with ALS. Further information about HIMALAYA (study number NCT05237284) can be accessed here on the ClinicalTrials.gov website.

The US FDA has granted Fast Track designation to SAR443820 for the treatment of ALS. Fast Track is a FDA process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need. Fast Track designation may allow for early and frequent communication with the FDA regarding the development of SAR443820 for the treatment of ALS.

Under the collaboration agreement, Denali will receive a milestone payment of $40 million from Sanofi related to the Phase 2 HIMALAYA study with SAR443820. Denali is entitled to receive additional development and regulatory milestone payments. Denali will share profits and losses equally with Sanofi for CNS-penetrant products sold in the US and China, and Denali is entitled to receive royalties on net sales for CNS-penetrant products sold outside of the US and China.

Sanofi is also conducting a Phase 2 clinical trial of the peripherally restricted RIPK1 inhibitor SAR443122 (eclitasertib) (DNL758) in cutaneous lupus erythematosus and plans to initiate a Phase 2 clinical trial in ulcerative colitis. SAR443122 (eclitasertib) was discovered and developed by Denali scientists. Sanofi is responsible for the development and commercialization of SAR443122 (eclitasertib) and covers all costs related to the program. Denali is entitled to receive development, regulatory and sales milestone payments and royalties on product sales.

SAR443820 and SAR443122 (eclitasertib) are investigational therapeutics that have not been approved by any regulatory authority for any commercial use.

Denali Therapeutics is a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the BBB for neurodegenerative diseases. Denali pursues new treatments by rigorously assessing genetically validated targets, engineering delivery across the BBB and guiding development through biomarkers that demonstrate target and pathway engagement. Denali is based in South San Francisco. For more information, visit www.denalitherapeutics.com.