ABSTRACT
Background: The 3CL protease (3CLpro) of coronaviruses (CoV) is responsible for essential & early steps of viral replication. Early treatment of SARS-CoV2 infection with a 3CLpro inhibitor has shown to substantially reduce the rate of hospitalization & death from COVID-19. There is a need for a protease inhibitor that can be used as a stand-alone agent to treat and prevent SARS-CoV-2 infection globally, in the setting of remote testing & healthcare delivery, and as unsupervised outpatient use by a significant number of people who take other medications. Methods: PBI-0451 was assessed in cultures of inducible pluripotent stem cell-derived alveolar type II (iPS-AT2) cells, in nonclinical PK and toxicity studies, and an ongoing randomized, double-blind first-in-human (FIH) study evaluating the tolerability, safety, and PK of single and multiple doses administered as an oral suspension to healthy adult subjects. The effect of food and the potential for a drug-drug interaction (DDI) with ritonavir were also explored. Results: PBI-0451 potently inhibited SARS-CoV-2 replication in iPS-AT2 cells with multi-log reductions in viral titer and mean (SD) IC50 & EC90 values of 32 (25) & 106 (90) nM, respectively. No clinically relevant adverse effects of PBI-0451 were observed in 14-day GLP toxicity studies in mice and dogs, including on the cardiovascular, CNS, or respiratory systems. PBI-0451 was not genotoxic in Ames and micronucleus tests. In the ongoing FIH study to date, study treatments were generally well tolerated with no study drug or study discontinuations. No Grade 2, 3, 4, or severe adverse events were reported. Preliminary single-dose concentration-time profile of PBI-0451 following administration with food demonstrated a 2-compartment PK profile with a median terminal elimination t1/2 ranging from 11-14 hours. PBI-0451 demonstrated good oral bioavailability and a linear increase in exposure over a 10-fold dose range when administered with food, achieving concentrations >1-, 3-& 10-fold the plasma protein binding-adjusted EC90 value (374 ng/mL) against SARS-CoV-2 at doses of 100, 300 & 1050 mg, respectively. The PK of PBI-0451 was unaffected by coadministration with ritonavir. Conclusion: PBI-0451 has shown favorable nonclinical properties and early clinical safety & PK that supports its continued evaluation as a stand-alone agent. Ongoing multiple-dose evaluation will further elucidate its clinical profile and inform the dose & dosing regimen selection for potential Phase II/III studies.