DNL104

DNL104 is an investigational oral small molecule inhibitor of receptor-interacting serine/threonine-protein kinase 1 (RIPK1), developed by Denali Therapeutics. RIPK1 is a key mediator in the tumor necrosis factor (TNF) receptor pathway, regulating inflammation and necroptosis (programmed cell death). Dysregulation of RIPK1 is implicated in the pathogenesis of neurodegenerative and inflammatory diseases, including amyotrophic lateral sclerosis (ALS). DNL104 was the lead candidate in Denali's RIPK1 program and underwent Phase 1 clinical testing in healthy volunteers to evaluate safety, pharmacokinetics, and pharmacodynamics. However, development was discontinued following the observation of liver toxicity (elevations in liver enzymes) in the Phase 1 study. Denali subsequently pivoted to successor molecules with improved safety profiles, such as DNL747 and DNL788 (SAR443820).