Neurology · 2023 · 10 citations · 0 references
<h3>Objective:</h3> DNL343 is being investigated as a potential therapeutic agent for Amyotrophic Lateral Sclerosis (ALS). <h3>Background:</h3> ALS is a fatal neurodegenerative disease with TDP-43 inclusion pathology in 95% of patients. Chronic activation of the integrated stress response (ISR) may contribute to ALS by blocking translation, altering RNA and endosomal trafficking, and increasing formation of TDP-43-containing stress granules. DNL343 is a small molecule that activates a key ISR regulator, eIF2B, which inhibits ISR stress granule formation in cellular models and promotes neuroprotection in animal models. <h3>Design/Methods:</h3> The safety, pharmacokinetics (PK) and pharmacodynamics (PD) of DNL343 were evaluated in a Phase 1 randomized, placebo-controlled trial (RCT) in healthy volunteers (NCT04268784) and a 28-day Phase 1b RCT in ALS participants (NCT05006352), with an ongoing 18-month open label extension (OLE). ISR inhibition was evaluated by measuring <i>CHAC1</i> gene expression and ATF4 protein in stimulated peripheral blood mononuclear cells (PBMCs). <h3>Results:</h3> In the Phase 1 study, ninety-five healthy participants were randomized (n=48 SAD, n=47 MAD). DNL343 was generally safe and well-tolerated with no serious adverse events (SAEs) or discontinuations related to study drug. DNL343 plasma concentrations were dose-dependent, with a plasma half-life of 38–46 hours and CSF-to-unbound plasma concentration ratio of 0.66–0.92. DNL343 attenuated two ISR biomarkers across the dosing period and at trough 24-hours after the last dose (<i>CHAC1</i> [66–94%] and ATF4 [50–73%]) in all MAD cohorts. Safety, pharmacokinetics and ISR pharmacodynamics from the 28-day Phase 1b study in ALS participants will be presented. <h3>Conclusions:</h3> DNL343 is generally safe and well-tolerated at doses that demonstrate robust inhibition of ISR through <i>CHAC1</i> and ATF4 inhibition. The pharmacokinetic profile supports once daily oral dosing and there is extensive CSF distribution. Data from these early-stage studies in HV and ALS patients support further development of DNL343 as a potential therapeutic for the treatment of ALS. <b>Disclosure:</b> Dr. Sun has received personal compensation for serving as an employee of Denali Therapeutics. Dr. Sun has stock in Denali Therapeutics. Dr. Tsai has received personal compensation for serving as an employee of Denali Therapeutics. Dr. Tsai has stock in Denali Therapeutics. Dr. Yulyaningsih has received personal compensation for serving as an employee of Denali Therapeutics. Dr. Yulyaningsih has stock in Denali Therapeutics. Dr. Yulyaningsih has stock in 23 & ME. Dr. Yulyaningsih has stock in Ardelyx. Dr. Yulyaningsih has stock in Amylyx. Dr. Fanok has received personal compensation for serving as an employee of Denali Therapeutics . An immediate family member of Dr. Fanok has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for Cincor Pharma. Dr. Fanok has stock in Denali Therapeutics. Mr. Vissers has received personal compensation for serving as an employee of Centre for Human Drug Research. Dr. Heuberger has received personal compensation for serving as an employee of Centre for Human Drug Research. Dr. Flores has nothing to disclose. Fen Huang has nothing to disclose. Dr. Kane has received personal compensation for serving as an employee of Denali Therapeutics. Dr. Kane has stock in Denali Therapeutics. Dr. Cohen has received personal compensation for serving as an employee of Denali. Dr. Cohen has stock in Denali. Dr. Dhuria has received personal compensation for serving as an employee of Denali Therapeutics. Dr. Dhuria has stock in Denali Thereapeutics. Dr. Fang has received personal compensation for serving as an employee of Denali Therapeutics. Dr. Fang has stock in Denali therapeutics. Dr. Estrada has stock in Denali Therapeutics . Dr. Osipov has received personal compensation for serving as an employee of Denali Therapeutics. Dr. Osipov has stock in Denali Therapeutics. Dr. Osipov has received intellectual property interests from a discovery or technology relating to health care. Mr. Willman-Yoswa has received personal compensation for serving as an employee of Denali Therapeutics. Mr. Maciuca has received personal compensation for serving as an employee of Denali Therapeutics. Mr. Maciuca has received stock or an ownership interest from Denali Therapeutics. Ms. Dobbins has received personal compensation for serving as an employee of Denali Therapeutics. Ms. Dobbins has stock in Denali Therapeutics. Miss Chau has received personal compensation for serving as an employee of Denali Therapeutics. Miss Chau has stock in Denali Therapeutics. Timothy Earr has received personal compensation for serving as an employee of Denali Therapeutics. Timothy Earr has stock in Denali Therapeutics. Ms. Nguyen has received personal compensation for serving as an employee of DENALI THERAPEUTICS. Ms. Nguyen has stock in Denali Therapeutics. Mrs. Lopez has nothing to disclose. Kimberly Scearce-Levie has received personal compensation for serving as an employee of Denali Therapeutics. Kimberly Scearce-Levie has stock in Denali Therapeutics. Mr. Bunte has nothing to disclose. Dr. Van den Berg has nothing to disclose. Carole Ho has nothing to disclose. Geert-Jan Groeneveld has nothing to disclose. Dr. Troyer has received personal compensation for serving as an employee of Denali Therapeutics Inc. Dr. Troyer has stock in Denali Therapeutics Inc. Dr. Troyer has stock in Merck & Co., Inc. Dr. Troyer has stock in Eli Lilly.