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

• Partner Sanofi has commenced dosing in a Phase 2 clinical trial of SAR443820 (DNL788) in individuals with amyotrophic lateral sclerosis (ALS)
• Denali to receive a milestone payment of $40 million from Sanofi for Phase 2 clinical trial initiation
• Development of RIPK1 inhibitor program continues in a broad range of CNS and peripheral inflammatory indications 
  

SOUTH SAN FRANCISCO, Calif., May 02, 2022 (GLOBE NEWSWIRE) -- Denali Therapeutics Inc. (NASDAQ: DNLI), a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier (BBB) for neurodegenerative diseases, today announced that 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, M.D., 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, M.D. “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.”

About SAR443820 and Sanofi RIPK1 Inhibitor Collaboration

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 U.S. Food and Drug Administration (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 United States and China, and Denali is entitled to receive royalties on net sales for CNS-penetrant products sold outside of the United States 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.

About Denali Therapeutics 

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 additional information, please visit www.denalitherapeutics.com.   

Cautionary Note Regarding Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements expressed or implied in this press release include, but are not limited to, statements regarding both Denali’s and Sanofi’s plans, timelines, expectations, and milestones related to SAR443820 (DNL788) and SAR443122 (DNL758); the ongoing Phase 2 studies of SAR443820 (DNL788) in ALS and SAR443122 (DNL758) in cutaneous lupus erythematosus; Denali’s priorities, regulatory approvals, timing and likelihood of success and expectations regarding its collaborations; Denali's expectations regarding milestone payments and royalties on product sales; expectations regarding Denali’s product candidates and the therapeutic potential of SAR443820 (DNL788) and SAR443122 (DNL758); statements made by Denali’s Chief Medical Officer; statements made by Sanofi’s Global Head of Early Neuro Development; and Sanofi's plans to initiate a Phase 2 study of SAR443820 (DNL788) in MS and a Phase 2 study of SAR443122 (DNL758) in ulcerative colitis. Actual results are subject to risks and uncertainties and may differ materially from those indicated by these forward-looking statements as a result of these risks and uncertainties, including but not limited to, risks related to: any and all risks to Denali’s business and operations caused directly or indirectly by the ongoing COVID-19 pandemic; Denali’s early stages of clinical drug development; Denali’s dependence on successful development of its BBB platform technology and TV-enabled product candidates; Denali’s and its partners’ ability to enroll patients in its ongoing and future clinical trials; the potential for clinical trial results of Denali’s product candidates to differ from preclinical, early clinical, preliminary or expected results; Denali’s reliance on third parties for the manufacture and supply of its product candidates for clinical trials; Denali’s and its partners' ability to conduct or complete clinical trials on expected timelines; the risk that the expected benefits of Fast Track designation for SAR443820 (DNL788) will not materialize; the risk that SAR443820 (DNL788) and SAR443122 (DNL758) may cause serious adverse events, toxicities or other side effects; the risk that SAR443820 (DNL788) and SAR443122 (DNL758) may not in the future receive regulatory approval as a treatment for ALS, MS, Alzheimer’s disease, cutaneous lupus erythematosus, ulcerative colitis, or other indications necessary to be commercialized; risk of the occurrence of any event, change or other circumstance that could give rise to the termination of Denali’s collaboration agreements; Denali’s and its partners’ ability to complete the development and, if approved, commercialization of its product candidates on expected timelines; developments relating to Denali’s competitors and its industry, including competing product candidates and therapies; Denali’s ability to obtain, maintain, or protect intellectual property rights related to its product candidates; implementation of Denali’s strategic plans for its business, product candidates and BBB platform technology; and other risks and uncertainties. In light of these risks, uncertainties, and assumptions, the forward-looking statements in this press release are inherently uncertain and may not occur, and actual results could differ materially and adversely from those anticipated or implied in the forward-looking statements. Accordingly, you should not rely upon forward-looking statements as predictions of future events. Information regarding additional risks and uncertainties may be found in Denali’s Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC) on February 28, 2022, and Denali’s future reports to be filed with the SEC. The forward-looking statements in this press release are based on information available to Denali as of the date hereof. Denali disclaims any obligation to update or revise any forward-looking statements, to conform these statements to actual results or to make changes in Denali’s expectations, except as required by law.

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