DNL343 to be Assessed in HEALEY ALS Platform Trial Following Positive Phase 1 Findings

Author(s):

After showing robust inhibition of biomarkers associated with integrated stress response, the eIF28 modulator will be assessed alongside several other potential agents in the HEALEY ALS Platform trial.

Carole Ho, MD

Newly announced interim results from a phase 1b study of Denali Therapeutics’ eIF2B agonist DNL343 showed that the agent was well tolerated and demonstrated robust blood-brain barrier penetration in patients with amyotrophic lateral sclerosis (ALS). Denali also announced the design of a phase 2/3 study for entry into the HEALEY ALS Platform trial, the first such study assessing multiple agents for ALS.¹

In the double-blind, multicenter, placebo-controlled trial, the mean ratio of DNL343 in cerebrospinal fluid compared with unbound drug in plasma ranged from 1.02-1.23, suggesting that the agent effectively crossed the BBB and was extensively distributed in the central nervous system. Additionally, following treatment with DNL343, biomarkers associated with integrated stress response (ISR)—ATF4 and CHAC1—were attenuated.

"These initial Phase 1b results with DNL343 in ALS are consistent with our previously reported Phase 1 healthy volunteer data and are an important milestone for the program,” Carole Ho, MD, chief medical officer, Denali, said in a statement.¹ "The data continue to support late-stage development plans for DNL343, and we are excited to be collaborating with the HEALEY ALS Platform Trial team in our unified effort to advance potential treatment options for people living with ALS."

Denali noted that the results will be presented at the 33rd International Symposium on ALS/MND, held virtually December 6-9, 2022. The interim analysis included 20 of the expected 29 patients with ALS in the trial who were on either DNL343 or placebo. Like many early-stage trials, the study’s main goal was safety, with incidence of treatment-emergent adverse events as the primary outcome. Other outcome measures included maximum concentration of DNL343 in plasma, time to reach maximum concentration, and CSF fluid-to-plasma concentration ratio following multiple doses.

Duchenne Gene Therapy SRP-9001 Wins Priority Review

The PDUFA date for SRP-9001, developed in partnership between Sarepta and Roche, is set for May 29, 2023. The BLA was submitted for accelerated approval.

DNL343, designed to activate eIF2B and thereby restore protein synthesis, disperse TDP-43 aggregates, and improve neuronal survival, will be assessed in one of the most notable trials across the country. The HEALEY ALS Platform trial is the first of its kind for the neurodegenerative disorder, and aims to test multiple investigational products in parallel, thus reducing the cost of research, decreasing the trial time, and increasing patient participation. Therapeutic candidates that enter the trial are chosen by a group of expert ALS scientists and members of the Healey & AMG Center.

"ALS is a devastating progressive disorder with very few treatment options,” Merit Cudkowicz, MD, MSc, principal investigator and sponsor of the HEALEY ALS Platform trial, director, Sean M. Healey & AMG Center for ALS, and chief of the Department of Neurology, Massachusetts General Hospital, said in a statement. “Given the strong collective data from the DNL343 program to date, we are looking forward to working with Denali to develop DNL343 for the HEALEY ALS Platform Trial, bringing us closer to our goal of finding more effective treatments for ALS through collaboration."

Previously, at the 2021 Annual Northeast ALS (NEALS) Meeting, Denali presented data from a phase 1 study of DNL343 in healthy participants. All told, the treatment demonstrated a pharmacokinetic profile that supported dosing once a day following predictable dose-related increases in exposure, and investigators found the investigational therapeutic to be generally well-tolerated for up to 14 days. Pathway engagement in cellular ISR was also identified, as samples of blood cells from healthy patients treated with DNL343 were subject to stress ex vivo, prompting robust changes in the ISR biomarkers.²

REFERENCES
1. Denali Therapeutics announces DNL343 interim phase 1b data in ALS and entry into the HEALEY ALS Platform trial. News release. December 5, 2022. Accessed December 5, 2022. https://www.globenewswire.com/news-release/2022/12/05/2567244/0/en/Denali-Therapeutics-Announces-DNL343-Interim-Phase-1b-Data-in-ALS-and-Entry-into-the-HEALEY-ALS-Platform-Trial.html
2. 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 December 5, 2022 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