Abstract Details

Title The Integrated Stress Response Is Modulated by eIF2B Agonist DNL343: Results From Phase 1 Healthy Subject and Phase 1b ALS Patient Studies.

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P8 - Poster Session 8 (11:45 AM-12:45 PM)

Poster/Presentation
Number 10-010

Objective DNL343 is being investigated as a potential therapeutic agent for Amyotrophic Lateral Sclerosis (ALS).

Background 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.

Design/Methods 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 CHAC1 gene expression and ATF4 protein in stimulated peripheral blood mononuclear cells (PBMCs).

Results 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 (CHAC1 [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.

Conclusions

DNL343 is generally safe and well-tolerated at doses that demonstrate robust inhibition of ISR through CHAC1 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.

Authors/Disclosures
Linus D. Sun, MD, PhD (Denali Therapeutics) PRESENTER	Dr. Sun has received personal compensation for serving as an employee of Denali Therapeutics. Dr. Sun has stock in Denali Therapeutics.
Richard M. Tsai, MD (Denali Therapeutics)	Dr. Tsai has received personal compensation for serving as an employee of Denali Therapeutics. Dr. Tsai has stock in Denali Therapeutics.
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Brent A. Willman-Yoswa (Denali Therapeutics)	Mr. Willman-Yoswa has received personal compensation for serving as an employee of Denali Therapeutics.
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Leonard van den Berg, MD (University Medical Centre Utrecht)	The institution of Dr. Van den Berg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Amylyx. The institution of Dr. Van den Berg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for ferrrer. The institution of Dr. Van den Berg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. The institution of Dr. Van den Berg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. The institution of Dr. Van den Berg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Takeda. The institution of Dr. Van den Berg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. The institution of Dr. Van den Berg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BMS. The institution of Dr. Van den Berg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for ArgenX. The institution of Dr. Van den Berg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Projenx. Dr. Van den Berg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Corcept. The institution of Dr. Van den Berg has received research support from Netherlands ALS Foundation.
Carole Ho, MD (Denali Therapeutics)	No disclosure on file
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Matthew D. Troyer, MD (Denali Therapeutics)	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.

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