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DENALI Denali Therapeutics Announces Positive Clinical Results and Regulatory Progress for Development Programs in Amyotrophic Lateral Sclerosis ( ALS ) October 6 , 2021 8:01 PM PDT • elF2B activator DNL343 achieved safety and biomarker goals in a Phase 1 study in healthy volunteers ; a Phase 1b study began in individuals with ALS in Q3 2021 • Fast Track designation granted by the U.S. Food and Drug Administration ( FDA ) to SAR443820 / DNL788 , a RIPK1 inhibitor , for the treatment of ALS ; Sanofi to initiate Phase 2 study in individuals with ALS in Q1 2022 • Denali to host webinar for analysts and investors today , October 6 , at 4:30 p.m. Eastern Time SOUTH SAN FRANCISCO , Calif . , Oct. 06 , 2021 ( 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 positive Phase 1 clinical results and regulatory progress for two investigational small molecule therapeutics in development for the treatment of amyotrophic lateral sclerosis ( ALS ) at the 2021 Annual Northeast ALS ( NEALS ) Meeting being held virtually , October 6-7 . " Effective treatment options are a critical unmet medical need for people living with ALS , " said Carole Ho , M.D. , Denali's Chief Medical Officer . “ DNL343 and SAR443820 are designed to modulate distinct biological pathways implicated in ALS , including the integrated stress response and inflammation , respectively . We are pleased that the data generated preclinically and in Phase 1 studies support clinical investigation of both molecules as potential treatments for individuals with ALS . " " We're very encouraged by the initial results of the Phase 1 study of SAR443820 for the treatment of ALS , " said Nazem Atassi , M.D. , Sanofi's Global Head of Early Neurodevelopment . " ALS is a devastating disease for patients and their families , with no available cure or effective treatment for slowing its progression . We look forward to launching the Phase 2 HIMALAYA trial in adults with ALS in early 2022 and to achieving our ultimate goal of helping people living with ALS . " Highlights from elF2B activator DNL343 clinical and preclinical data presented at NEALS Denali presented positive results from a Phase 1 study in healthy volunteers ( n = 95 ) in which safety , pharmacokinetics ( PK ) and pharmacodynamics ( PD ) of single and multiple ascending doses of DNL343 were evaluated . The results demonstrated that DNL343 was generally well tolerated for up to 14 days of dosing , with robust distribution in the central nervous system ( CNS ) and predictable dose - related increases in DNL343 exposure with a PK profile supporting once daily dosing . Biomarker assessments were also made as related to the cellular integrated stress response ( ISR ) . The ISR is a biological pathway implicated in ALS and other diseases . After healthy volunteers were treated with DNL343 , samples of their blood cells were subjected to stress ex vivo , and robust changes in biomarkers of the ISR were observed , confirming pathway engagement . Denali also presented preclinical data in a mouse model of vanishing white matter ( VWM ) disease , a genetic and progressive disorder that causes severe neurological symptoms after exposure to certain stressors . elF2B activity is reduced in the VMW disease model leading to chronic activation of the ISR , making this a relevant model for demonstrating target engagement and ISR modulation by DNL343 . After treatment with DNL343 , body weight and motor function were normalized in these mice . Furthermore , ISR gene expression and stress response protein levels were reduced in both peripheral tissues as well as the brain . A similar PK / PD relationship was observed in mice and in humans , supporting DNL343 dose selection in the ongoing Phase 1b study in participants with ALS . The Phase 1b study ( NCT05006352 ) is a multicenter , randomized , placebo - controlled , double - blind , 28 - day study followed by an 18 - month open - label extension , designed to evaluate the safety , PK and PD of DNL343 in approximately 30 participants with ALS . Dosing in this study began in the third quarter of 2021 . Highlights from RIPK1 inhibitor SAR443820 clinical trial design presentation at NEALS and Fast Track Designation Denali's partner Sanofi presented plans for a Phase 2 study of RIPK1 inhibitor SAR443820 in participants with ALS based on positive results of a Phase 1 study in healthy volunteers . In that study , robust target engagement was demonstrated at doses that were generally well tolerated . The Phase 2 study , named HIMALAYA , is a multi - center , randomized , double - blind , placebo- controlled study , followed by an open - label long - term extension , to evaluate the efficacy and safety of SAR443820 in adult participants with ALS . This Phase 2 study is expected to commence in the first quarter of 2022 . The U.S. FDA has granted Fast Track designation to SAR443820 for the treatment of ALS . Fast Track is an 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 . This designation also enables rolling review of the marketing application . About the elF2B activator DNL343