DNL343 in amyotrophic lateral sclerosis: results from the doubleblind, placebo controlled, randomized HEALEY ALS platform trial

Document Type

Conference Proceeding

Publication Date

11-12-2025

Publication Title

Amyotroph Lateral Scler Frontotemporal Degener

Keywords

evetifator, guanine nucleotide exchange factor, placebo, adult, amyotrophic lateral sclerosis, Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised, breathing muscle, clinical trial, conference abstract, controlled study, double blind procedure, drug therapy, female, human, incidence, light chain, major clinical study, male, multicenter study, muscle strength, neurofilament, neuroprotection, randomized controlled trial, side effect

Abstract

Background: 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 (ISR). Persistent ISR activation has been associated with ALS and inhibition of the ISR has been shown to be neuroprotective in preclinical models of both ALS and other neurodegenerative diseases. Objectives: To evaluate the safety and efficacy of DNL343 200 mg once daily oral formulation in people living with ALS. Methods: DNL343 was evaluated as a regimen (regimen G) of the HEALEY ALS Platform Trial, a randomized, doubleblind, multi-regimen, placebo-controlled trial conducted at 74 Northeast ALS Consortium (NEALS) centers in the US. Eligible participants were randomized in a 3:1 ratio to receive DNL343 or matching placebo for a planned placebocontrolled duration of 24 weeks. 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 on DNL343 relative to control. The model had components for function (measured by the ALSFRS-R) and survival linked through an integrated estimate of disease slowing in treatment relative to controls across the two end points (denoted as the disease rate ratio [DRR]). A DRR of 1 corresponded to no difference between treatments, whereas values of less than 1 indicated a slowing in disease progression on treatment relative to control. Several safety, secondary and exploratory endpoints were also collected. Results: A total of 254 participants were randomly assigned to this regimen; 249 met eligibility and were randomized to DNL343 (n=186) or regimen-specific placebo (n=63). An additional 76 unique participants were randomized to placebo on other concurrently enrolling regimens within the master protocol bringing the total placebo group to 139 participants. The estimated median DRR common to ALSFRS-R and survival was 1.05 (95% Credible Interval (CrI); 0.84, 1.35). The mean 24-week change in ALSFRS-R total score and measures of limb and respiratory muscle strength using repeatedmeasures analyses were not statistically different between the DNL343 and placebo group. Results from the supportive joint rank analysis and neurofilament light chain analyses indicated no evidence of benefit. Overall, the incidence rates of adverse events were similar between DNL343 and placebo, and no unexpected treatment-related risks were identified. Discussion: DNL343 200 mg once daily oral formulation tested as a regimen of the HEALEY ALS Platform Trial did not meet its prespecified primary efficacy endpoint and was not significantly different than placebo for secondary endpoints. DNL343 was generally well tolerated. The design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources. Trial Registration: Clinical Trial Identifier NCT04297683 NCT05842941).

Volume

26

First Page

10

Last Page

11

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