Early Development of Ocadusertib, a Selective Receptor-Interacting Serine/Threonine-Protein Kinase 1 Inhibitor.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) inhibitors are being investigated for chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis. Ocadusertib is a potent and selective allosteric inhibitor of RIPK1 and is currently being studied in clinical trials. Here, we present data on the development of ocadusertib, including preclinical studies and pharmacokinetic, safety, and target engagement results from phase 1 trials. Preclinically, ocadusertib inhibited RIPK1 enzymatic activity with high potency (half-maximal inhibitory concentration [IC50] = 12-38 nM) and inhibited necroptotic responses in multiple cell-based assays. Ocadusertib was highly selective for RIPK1, showing no significant inhibition of more than 100 other kinases representative of the full kinome. In mouse studies, ocadusertib treatment prevented RIPK1-dependent hypothermia in response to tumor necrosis factor (TNF) challenge and significantly reduced disease severity in a model of chronic proliferative dermatitis. In a first-in-human study of ocadusertib in healthy participants, single oral doses exhibited linear pharmacokinetics and dose-proportional exposure, with a time to maximum concentration of 1-4 h and a half-life of 13-15 h. Steady state was attained at 4-6 days after multiple once-daily dose administrations. Ocadusertib was well tolerated, with no deaths, serious adverse events, or significant treatment-emergent adverse events reported. In a phase 1, double-blind, randomized, multiple-dose study in healthy participants, greater than 90% RIPK1 target engagement was achieved at Day 14 with ocadusertib treatment. Taken together, these findings support further assessment of ocadusertib for the treatment of chronic inflammatory diseases.