The Integrated Stress Response Is Modulated by eIF2B Agonist DNL343: Results From Phase 1 Healthy Subject and Phase 1b ALS Patient Studies.
Linus Sun1, Richard Tsai1, Ernie Yulyaningsih1, Melania Fanok1, Maurits Vissers2, Jules Heuberger2, Brittany Flores1, Fen Huang1, Lesley Kane1, Isaac Cohen1, Shyeilla Dhuria1, Meng Fang1, Anthony Estrada1, Maksim Osipov1, Brent Willman-Yoswa1, Romeo Maciuca1, Sarah Dobbins1, Ronnie Chau1, Timothy Earr1, Hoang Nguyen1, Isabel Lopez1, Kimberly Scearce-Levie1, Tommy Bunte3, Leonard Van den Berg3, Carole Ho1, Geert-Jan Groeneveld2, Matthew Troyer1
1Denali Therapeutics, 2Centre for Human Drug Research/Leiden University Medical Center, 3University Medical Centre Utrecht
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.