Safety, Pharmacokinetics and Target Engagement of a Novel Brain Penetrant <scp>RIPK1</scp> Inhibitor (<scp>SIR9900</scp>) in Healthy Adults and Elderly Participants

Receptor-interacting serine/threonine kinase 1 (RIPK1) regulates inflammatory signaling and induces apoptosis and necroptosis. Pharmacological inhibition of RIPK1 kinase activity has demonstrated efficacy in animal models of neurodegenerative, autoimmune and inflammatory diseases. SIR9900 is a potent and selective novel small molecule RIPK1 inhibitor. This first-in-human, phase I, randomized, double-blind, placebo-controlled study evaluated the safety, pharmacokinetics, and pharmacodynamics of single (3-200 mg) and multiple (3-60 mg daily for 10 days) ascending oral doses of SIR9900 in healthy adult (18-64 years, n = 80) and elderly participants (≥ 65 years, multiple doses 30 mg, n = 8). The study included a food effect component. Overall, SIR9900 was safe and well tolerated with no concerning dose-dependent trends in safety observed. SIR9900 was rapidly absorbed with a plasma maximum concentration time (T_max) of 3.0-4.0 h and plasma half-life (t_1/2) of 31.92-37.75 h following single doses. Similar T_max and t_1/2 results were observed following multiple doses. Systemic exposure to SIR9900 increased in a dose-proportional manner and was similar between adult and elderly participants. No appreciable food effect was observed. The cerebrospinal fluid to unbound plasma ratio was 1.15. A robust pharmacodynamic effect was demonstrated with approximately 90% peripheral target engagement at 3 h post-dose, and sustained RIPK1 inhibition over the 10-day treatment period. The promising safety, pharmacokinetic, and pharmacodynamic profile of SIR9900 with central nervous system penetrating potential in healthy adult and elderly participants supports its further clinical development in patients with inflammatory and degenerative diseases, particularly in the central nervous system.