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.
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. eIF2B 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.
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.
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