Quantitative Systems Pharmacologist Pfizer, United States
Objective: A key challenge in the development of novel antivirals is establishing preclinical metrics of pharmacological activity that can be objectively translated to clinically relevant treatment scenarios [1]. As evidenced during the COVID-19 pandemic, rapid preclinical and clinical development of antiviral therapeutics (eg. SARS-CoV-2 Mpro inhibitors) is crucial to prevent the overwhelming of healthcare systems and is integral to future pandemic preparedness strategies. Given the need to expedite clinical development due to the COVID-19 pandemic, most Mpro inhibitor development programs investigated doses that feasibly maximized the clinical exposure of these agents. Thus, without characterization of the clinical exposure-response in dose-ranging studies, this strategy did not inform an understanding of how preclinical metrics of pharmacology would quantitatively translate to clinical antiviral activity. Consequently, the development of a number of investigational Mpro inhibitors has been hampered due to the inadequate virological efficacy in patients despite exhibiting pharmacological activity in vitro [2]. Here, we use a model-based framework to validate the relationship between preclinical pharmacological activity and virological response in COVID-19 outpatients for this class of antivirals.
Methods: We identified Mpro inhibitors [3-7] with publicly available information on in vitro antiviral potency from human airway epithelial (HAE) assays, preclinical in vivo characterization of antiviral activity [8, 9], steady state clinical plasma drug concentrations and nasopharyngeal viral load reductions in COVID-19 outpatients (a key endpoint in proof-of-concept clinical trials of COVID-19 antivirals). We integrated this disparate information using a previously published QSP model of COVID-19 [10] to enable head-to-head comparisons between clinical trials for different Mpro inhibitors and predicted the relationship between their clinically reported antiviral activity and target coverage, defined as the ratio of steady state clinical plasma exposures to in vitro potency in HAE assays.
Results: The model-predicted relationship between in vitro pharmacological activity (from HAE) and clinical antiviral activity in COVID-19 outpatients closely recapitulated the observations for the Mpro inhibitors across a clinically relevant range of reported target coverage. The model prediction was prospectively validated against virological efficacy data from the dose ranging study of ibuzatrelvir. Additionally, we identified a threshold of target coverage that corroborated in vivo antiviral activity in preclinical animal models of SARS-CoV-2 infection and was predictive of clinical response.
Conclusions: We developed a quantitative metric for the clinical translation of Mpro inhibitors, which can be used to establish go/no-go criteria and accelerate pivotal dose selection decisions for novel Mpro inhibitors. We propose that key learnings from our analysis have broader implications for preclinical to clinical translation of antivirals for the treatment of other respiratory viruses.
Citations: 1. Dudal, S., et al., Translating pharmacology models effectively to predict therapeutic benefit. Drug Discov Today, 2022. 27(6): p. 1604-1621. 2. Pardes Biosciences Announces Top-line Results from Phase 2 Trial Evaluating Pomotrelvir for the Treatment of COVID-19. Available from: https://www.biospace.com/pardes-biosciences-announces-top-line-results-from-phase-2-trial-evaluating-pomotrelvir-for-the-treatment-of-covid-19. 3. Borroto-Esoda, K., et al., SARS-CoV-2 viral dynamics in a placebo-controlled phase 2 study of patients infected with the SARS-CoV-2 Omicron variant and treated with pomotrelvir. Microbiol Spectr, 2024. 12(2): p. e0298023. 4. Mortezavi, M., et al., Virologic Response and Safety of Ibuzatrelvir, A Novel SARS-CoV-2 Antiviral, in Adults With COVID-19. Clin Infect Dis, 2025. 80(3): p. 673-680. 5. Hammond, J., et al., Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19. New England Journal of Medicine, 2022. 386(15): p. 1397-1408. 6. Pharmaceuticals, E. Enanta Pharmaceuticals Reports Positive Topline Results from Phase 2 SPRINT Trial Evaluating EDP-235 in Standard Risk Patients with COVID-19 | Enanta Pharmaceuticals, Inc. 2023; Available from: https://ir.enanta.com/news-releases/news-release-details/enanta-pharmaceuticals-reports-positive-topline-results-phase-2/. 7. Yotsuyanagi, H., et al., Efficacy and Safety of 5-Day Oral Ensitrelvir for Patients With Mild to Moderate COVID-19: The SCORPIO-SR Randomized Clinical Trial. JAMA Netw Open, 2024. 7(2): p. e2354991. 8. Owen, D.R., et al., An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19. Science, 2021. 374(6575): p. 1586-1593. 9. Allerton, C.M.N., et al., A Second-Generation Oral SARS-CoV-2 Main Protease Inhibitor Clinical Candidate for the Treatment of COVID-19. J Med Chem, 2024. 67(16): p. 13550-13571. 10. Rao, R., C.J. Musante, and R. Allen, A quantitative systems pharmacology model of the pathophysiology and treatment of COVID-19 predicts optimal timing of pharmacological interventions. NPJ Systems Biology and Applications, 2023. 9(1): p. 13.
Keywords: Preclinical to clinical translation, antiviral development, COVID-19, QSP modeling
