DNL343

DNL343 is a potent, selective, and brain-penetrant small molecule activator of eukaryotic translation initiation factor 2B (eIF2B), developed as an investigational therapy for neurodegenerative diseases, primarily amyotrophic lateral sclerosis (ALS). By activating eIF2B, DNL343 modulates the integrated stress response (ISR), restoring protein synthesis, dispersing TDP-43 aggregates, and promoting neuronal survival. The drug has demonstrated robust inhibition of ISR biomarkers such as ATF4 protein and CHAC1 mRNA in both healthy volunteers and ALS patients. It is orally administered with a long half-life supporting once-daily dosing and shows extensive distribution into cerebrospinal fluid. Despite promising pharmacodynamic effects and good tolerability in early-phase studies, DNL343 did not meet primary or secondary efficacy endpoints in a Phase 2/3 trial for ALS but was found to be safe and well tolerated[3][4][5][8][10].