RIP kinase 1 regulates inflammation, cytokine release, and necroptotic cell death and is implicated in pathogenic cellular pathways in ALS, AD and MS. Inhibition of RIPK1 activity protects against inflammation and cell death in multiple animal models. DNL104 is a selective, brain-penetrant inhibitor of RIPK1 phosphorylation in clinical development for AD and ALS. DNL104 was tested in 68 healthy volunteers to investigate safety and tolerability, pharmacokinetic profile in plasma and CSF, and pharmacodynamic effects of RIPK1 inhibition in PBMCs in a first-in-human, placebo-controlled, double-blind, randomized single- and multiple- ascending dose study. DNL104 was well tolerated in the SAD and during the dosing period of the MAD. However, post-dose liver toxicity in 37.5% of subjects was observed in the MAD, and assessed to be drug related. We demonstrate that DNL104 leads to RIP1 kinase inhibition, and this is not associated with CNS toxicities, supporting future development of CNS penetrant RIPK1 inhibitors. This article is protected by copyright. All rights reserved.