Positive Phase 1 Results, Regulatory Progress Announced for 2 Therapeutics in ALS

Clinical data on the investigational therapeutics, DNL343 and SAR443820/DNL788, were presented at the 2021 Annual Northeast ALS Meeting this month.

Two investigational small molecule therapeutics have reported positive phase 1 clinical results, as well as regulatory progress, in the treatment of amyotrophic lateral sclerosis (ALS), Denali Therapeutics announced at the 2021 Annual Northeast ALS (NEALS) Meeting, held virtually October 6-7.

The receptor-interacting protein kinase 1 (RIPK1) inhibitor SAR443820/DNL788 (Sanofi) was granted fast track designation from the FDA and plans for the phase 2 HIMALAYA study of the treatment were outlined at NEALS. Following positive results from a phase 1 trial of eukaryotic translation initiation factor 2B (eIF2B) activator DNL343, which were also presented at the virtual conference, a phase 1b trial (NCT05006352) began in the third quarter of 2021. 

“Effective treatment options are a critical unmet medical need for people living with ALS,” Carole Ho, MD, chief medical officer, Denali Therapeutics, said in a statement. “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.”

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DNL343 Highlights

The phase 1 study of DNL3443 included a total of 95 healthy participants, with investigators analyzing the safety, pharmacodynamics (PD), and pharmacokinetics (PK) of both single and ascending doses of the treatment. The treatment had a PK profile that supported dosing once a day following predictable dose-related increases in exposure, and investigators found the investigational therapeutics to be generally well tolerated for up to 14 days. Distribution was also found to be robust in the central nervous system (CNS).

Investigators further confirmed pathway engagement in cellular integrated stress response (ISR), as samples of blood cells from healthy patients treated with DNL343 were subject to stress ex vivo, prompting robust changes in the ISR biomarkers. A mouse model of vanishing white matter disease also received treatment with DNL343, which was successful in normalizing both body weight and motor function. Peripheral tissues and the brain also had reductions in ISR gene expression and stress response protein levels, preclinical data presented at NEALS indicated. 

The ongoing phase 1b study of DNL343 is a multicenter, randomized, placebo-controlled, double-blind study further evaluated PK, PD, and safety of the treatment. A total of 30 patients with ALS were enrolled for a 28-day period, which will be by an 18-month open-label extension period. 

SAR443820 Highlights

Positive results were announced at NEALS from the phase 1 study of SAR443820 in healthy volunteers, with the treatment having received fast track designation from the FDA. Sanofi also presented plans for the phase 2 HIMALAYA study in patients with ALS, designed as multicenter, randomized, double-blind, placebo-controlled study with an open-label long-term extension.

“We’re very encouraged by the initial results of the Phase 1 study of SAR443820 for the treatment of ALS,” Nazem Atassi, MD, global head, early neurodevelopment, Sanofi, said in a statement. “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.”

The novel, CNS-penetrant small molecule inhibitor of RIPK1 also has the potential for development in multiple sclerosis (MS), and Alzheimer disease (AD), with Sanofi leading development in phase 1 and phase 2 of the treatment for ALS and MS, while co-developing alongside Denali in phase 3 clinical trials for ALS, AD, and MS.

REFERENCE
Denali Therapeutics announces positive clinical results and regulatory progress for development programs in amyotrophic lateral sclerosis (ALS). News release. Denali Therapeutics Inc. October 6, 2021. Accessed October 7, 2021. https://www.globenewswire.com/news-release/2021/10/06/2309876/0/en/Denali-Therapeutics-Announces-Positive-Clinical-Results-and-Regulatory-Progress-for-Development-Programs-in-Amyotrophic-Lateral-Sclerosis-ALS.html