21 A first-in-human phase 1 study of SIM0417, a 3CL-like protease inhibitor for treatment of COVID-19, in healthy adult subjects

Introduction Safe and efficacious antiviral therapeutics are in urgent need for treatment of coronavirus disease 2019. SIM0417 is a selective 3C-like protease inhibitor that can effectively inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methodology We evaluated the safety, tolerability, and pharmacokinetics of dose escalations of SIM0417 alone or with ritonavir (SIM0417 or SIM0417/ritonavir) in healthy subjects, as well as the food effect. Results The overall incidence of adverse events (AEs) was 22.2% (17/72) and 6.3% (1/16) in intervention and placebo group, respectively. The SIM0417 apparent clearance was 135–369 L/h with SIM0417 alone, and decreased significantly to 19.5–29.8 L/h with SIM0417/ritonavir. The SIM0417 exposure increased in an approximately dose-proportional manner between 250–750 mg when co-administered with ritonavir. After consecutive twice daily dosing of SIM0417/ritonavir, SIM0417 had a low accumulation index ranging from 1.39 to 1.51. The area under the curve of SIM0417 increased 44.0% and 47.3% respectively, after high fat and normal diet compared with fasted status. Conclusion SIM0417 has adequate safety and tolerability. Its pharmacokinetics indicated a trough concentration above the level required for 90% inhibition of SARS-CoV-2 in vitro at 750 mg/100 mg SIM0417/ritonavir twice daily under fasted condition, supporting further development using this dosage as the clinically recommended dose regimen.