DNL343 Falls Short of Primary End Point in Phase 2/3 HEALEY-ALS Platform Trial

Carole Ho, MD

Newly announced data from the phase 2/3 HEALEY-ALS Platform trial revealed that DNL343 (Denali Therapeutics), an investigational eIF2B agonist in development for amyotrophic lateral sclerosis (ALS), did not meet its primary end point of overall function and survival in this patient population. Further analyses, including neurofilament light (NfL), other fluid biomarkers, subgroup evaluations, and active treatment extension data, are anticipated in late 2025.¹

DNL343, a novel treatment, is designed to activate eIF2B and thereby restore protein synthesis, disperse TDP-43 aggregates, and improve neuronal survival. In the primary analysis, treatment with the agent failed to distinguish itself from placebo on the primary end point of change in ALS Functional Rating Scale-Revised and survival at 24 weeks. At this time, investigators also observed no statistical difference in key secondary end points of muscle strength and respiratory function between the 2 groups.

HEALEY-ALS is a patient-centric trial designed in collaboration with the Northeast ALS Consortium (NEALS) to accelerate the development of breakthrough treatments for persons with ALS by testing multiple drugs (regimens) at the same time with efficient use of patient, scientific, and operational resources. In the latest update to the DNL343 regimen, 186 patients received the investigational product while 139 participants were randomized to placebo from this regimen (n = 63) or shared from a concurrently enrolling regimen (n = 76). Overall, DNL343 was considered safe and well tolerated, according to Denali.

"Better treatment options for individuals with ALS are critically needed,” Carole Ho, MD, chief medical officer at Denali, said in a statement.¹ "We are deeply grateful to the study participants, investigators, and the broader community for their collective support of the HEALEY study, which has provided an efficient and innovative platform for evaluating the therapeutic potential of DNL343 in addressing this critical unmet need. We look forward to a more comprehensive analysis of the study results as additional analyses, including pre-specified subgroup analyses and treatment effects on NfL, become available later in 2025."

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Prior to HEALEY-ALS, DNL343 was studied in both a phase 1, randomized, placebo-controlled trial of healthy volunteers (NCT04268784) and a 28-day, phase 1b randomized controlled trial of patients with ALS (NCT05006352) with an ongoing 18-month open-label extension (OLE). An analysis of both studies was presented at the 2023 American Academy of Neurology Annual Meeting, with results showing that the therapy was safe and well-tolerated at doses that demonstrate robust inhibition of integrated stress response (ISR).²

Merit Cudkowicz, MD, MSc

In the phase 1 study, 95 healthy participants were randomized to either single-ascending dose (SAD; n = 48) or multiple ascending dose (MAD; n = 47) cohorts. All told, treatment with the therapy resulted in no serious adverse events or discontinuations related to the 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. Furthermore, DNL343 attenuated 2 ISR biomarkers across the dosing period and at through 2-hours after the last dose (CHAC1: 66-94%; ATF4: 50-73%) in all MAD cohorts.

"Though the initial top-line clinical results of this trial were not what we hoped, the data collected is valuable in helping to understand the next stage of ALS research," Merit Cudkowicz, MD, MSc, principal investigator and sponsor of the HEALEY-ALS Platform Trial, and director of the Sean M. Healy & AMG Center for ALS at Harvard Medical School, said in a statement.¹ "We have additional pre-specified subgroup analyses and biomarker work, including NfL, pending from this regimen, as well as long term efficacy data from participants who continued in the active treatment extension period. We remain deeply committed to fully understanding the effects of DNL343 in ALS and will further evaluate the data before determining next steps."

REFERENCES
1. Denali Therapeutics Announces Topline Results for Regimen G Evaluating eIF2B Agonist DNL343 in the Phase 2/3 HEALEY ALS Platform Trial. News release. January 6, 2025. Accessed January 7, 2025. https://www.globenewswire.com/news-release/2025/01/06/3005002/0/en/Denali-Therapeutics-Announces-Topline-Results-for-Regimen-G-Evaluating-eIF2B-Agonist-DNL343-in-the-Phase-2-3-HEALEY-ALS-Platform-Trial.html
2. Sun LD, Tsai RN. The Integrated Stress Response Is Modulated by eIF2B Agonist DNL343: Results From Phase 1 Healthy Subject and Phase 1b ALS Patient Studies. Presented at: 2023 American Academy of Neurology Annual Meeting. POSTER 10-010