(S-106) Clinical PK characterization of EGT710, a novel coronavirus Mpro inhibitor, and simulation of target attainment rates for efficacious dose prediction

Swati Ghanshani – Novartis; Suzanne Gaudet – Novartis; Lidiya Bebrevska – Novartis; Jonathan Trolander – Novartis; Fernanda Duraes – Nouscom; Kamal Balavenkatraman – Novartis; Renee Bergeron – Novartis; Frederique Chaperon – Novartis; Elisabete Goncalves – Novartis; Stephanie Moquin – Novartis; Bhardwaj Sakshi – Novartis; Feng Gu – Novartis; Steven Kovacs – Novartis

Objectives: A novel coronavirus Mpro inhibitor EGT710 [1] was tested in humans to evaluate safety, tolerability, and pharmacokinetics. For the assessment of developability of EGT710 for patients with COVID-19, FIH PK data was analyzed, and used in population modeling, and simulations of various dose regimens to understand the target attainment of EGT710.

Methods: In the completed FIH study, a total of 70 healthy volunteers received EGT710, and 18 healthy volunteers received placebo, across 5 single dose levels and 4 multiple dose levels, and two different formulations. Non-compartmental analysis was performed to evaluate food effect, relative bioavailability differences between two formulations, and to assess dose-expose linearity. MonolixSuite was used to develop a compartmental population PK (popPK) model and to simulate dose-regimens for efficacious dose prediction.

Results: EGT710 treatment of single doses of up to 1100 mg, and multiple doses of up to 700 mg once daily (QD) for 7 days, were all safe and well tolerated in healthy adults. Two-compartment popPK model with linear elimination and first order absorption was developed to describe the observed FIH PK data. Food and formulation effects were added as covariates on the absorption parameters and relative bioavailability. The developed popPK model was used to simulate 7-day treatment of doses in 250-700 mg for BID, and in 300-1100 mg for QD. Simulation results suggest 700 mg BID EGT710 is expected to reach 3xEC90 in 99.5% of the population from first dose onwards.

Conclusions: The results support development of EGT710 without coadministration with ritonavir (a strong CYP3A4 inhibitor) as a treatment for coronavirus disease.

Citations: [1] Moquin SA, Lakshminarayana SB, Balavenkatraman KK, et al. Preclinical characterization of EGT710, an oral nonpeptidic reversible covalent SARS-CoV-2 main protease inhibitor.

Keywords: coronavirus, target attainment, antivirals