DNL343 and Disease Progression in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.

Importance: DNL343 is a brain-penetrant small molecule that acts as an activator of eukaryotic translation initiation factor 2B (eIF2b), designed to inhibit the integrated stress response. A prior phase 1B trial of DNL343 in amyotrophic lateral sclerosis (ALS) provided evidence of a favorable safety profile, central nervous system penetrance, and target engagement based on integrated stress response biomarkers in blood and cerebrospinal fluid. Objectives: To evaluate the safety and efficacy of a 200-mg formulation of DNL343 given once daily in individuals living with ALS. Design, Setting, and Participants: DNL343 was evaluated as a regimen of the HEALEY ALS Platform Trial, a double-blind, multiregimen, placebo-controlled randomized clinical trial conducted at 74 centers in the US between May 24, 2023, and May 22, 2025. Eligible participants were randomized in a 3:1 ratio to receive DNL343 or matching placebo, with both groups enrolling concurrently. The analysis included shared randomized participants receiving placebo from an additional regimen. Intervention: The study drug was administered for a placebo-controlled duration of 24 weeks. Main Outcomes and Measures: The primary analysis was a bayesian shared parameter model of function and survival that provided an integrated estimate of the relative rate of disease progression among participants receiving DNL343 relative to placebo. The model had components for function and survival linked through an integrated estimate of disease slowing in treatment relative to controls across the 2 outcomes (denoted as the disease rate ratio [DRR]). Several safety, secondary, and exploratory end points were also evaluated. Results: A total of 259 screenings were completed in this regimen; 249 participants met eligibility and were randomized to DNL343 (n = 186) and regimen-specific placebo (n = 63), with an additional 76 participants from a concurrent regimen receiving placebo included for a total of 139 shared placebo participants (325 participants, with 196 (60.3%) male and mean [SD] age of 59.3 [11.5] years). The estimated median DRR common to the ALS Functional Rating Scale-Revised and survival was 1.04 (95% credible interval, 0.83-1.32; probability of DRR <1, 0.37). Secondary outcome measures were not statistically different between the DNL343 and placebo groups. Overall, the incidence rates of adverse events were similar in participants receiving DNL343 and placebo. Conclusions and Relevance: In this randomized clinical trial, despite the relevance of the eIF2b activation pathway in ALS disease biology and supporting evidence of proof of mechanism and optimal dose selection in a prior phase 1B ALS clinical trial, 200-mg/d DNL343 did not show evidence of slowing disease progression in ALS, highlighting the need for alternative therapeutic approaches. Trial Registration: ClinicalTrials.gov Identifier: NCT05842941.