Factors Influencing Covid-19 Risk: Insights from Molnupiravir Exposure-Response

ABSTRACT

Background: Exposure-response (E-R) models were developed for the primary endpoint of hospitalization or death in COVID-19 patients from the Phase 3 portion of the MOVe-OUT study (Clinicaltrials.gov NCT04577797). Beyond dose, these models can identify other determinants of response, highlight the relationship of virologic response with clinical outcomes, and provide a basis for differential efficacy across trials. Method(s) Logistic regression models were constructed using a multi-step process with influential covariates identified first using placebo arm data only. Subsequently the assessment of drug effect based on drug exposure was determined using placebo and molnupiravir (MOV) arm data. To validate the models, the rate of hospitalization/death was predicted for published studies of COVID-19 treatment. All work was performed using R Version 3.0 or later. Result(s) A total of 1313 participants were included in the E-R analysis, including subjects having received MOV (N=630) and placebo (N=683). Participants with missing baseline RNA or PK were excluded (79 from MOV and 16 from placebo arms). The covariates shown to be significant determinants of response were baseline viral load, baseline disease severity, age, weight, viral clade, and co-morbidities of active cancer and diabetes. Day 5 and Day 10 viral load were identified as strong on-treatment predictors of hospitalization/death, pointing to sustained high viral load as driving negative outcomes. Estimated AUC50 was 19900 nM*hr with bootstrapped 95% C.I. of (9270, 32700). In an external validation exercise based on baseline characteristics, the E-R model predicted the mean (95% CI) placebo hospitalization rates across trials of 9.3% (7.6%, 11.7%) for MOVe-OUT, 7.2% (5.3%, 9.8%) for the nirmatrelvir/ritonavir EPIC-HR trial, and 3.2% (1.9%, 5.5%) for generic MOV trials by Aurobindo and Hetero, consistent with the differing observed placebo rates in these trials. The relative reduction in hospitalization/death rate predicted with MOV treatment (relative to placebo) also varied with the above patient populations. Conclusion(s) Overall, the exposure-response results support the MOV dose of 800 mg Q12H for treatment of COVID-19. The results further support that many clinical characteristics impacted hospitalization rate beyond drug exposures which can vary widely across studies. These characteristics also influenced the magnitude of relative risk reduction achieved by MOV in the MOVe-OUT study.