Comparison of Molnupiravir Exposure-Response Relationships for Virology Response and Mechanism of Action Biomarkers With Clinical Outcomes in Treatment of COVID-19

Abstract

Molnupiravir, an orally administered drug for the treatment of mild-to-moderate COVID-19, is a prodrug of the ribonucleoside β-D-N4-hydroxycytidine (NHC). NHC incorporation in the SARS-CoV-2 RNA strand causes an accumulation of deleterious errors in the genome, resulting in reduced viral infectivity and replication. Exposure-response (E-R) analyses for viral RNA mutation rate and virologic outcomes were conducted using data from three phase 2/3 studies of molnupiravir (P006, MOVe-IN, and MOVe-OUT). Three dose levels (200, 400, and 800 mg every 12 hours [Q12H]) and placebo were evaluated. E-R datasets were generated for SARS-CoV-2 RNA mutation and longitudinal SARS-CoV-2 RNA viral load. E-R models were defined for RNA mutation rate and viral load change from baseline at days 5 and 10. The models supported plasma NHC AUC_0-12 as the appropriate pharmacokinetic driver for assessing E-R relationships. The highest percentage of participants with > 20 low-frequency nucleotide substitutions (LNS) per 10,000 bases, a measure of likely meaningful drug effect, was predicted in the 800 mg Q12H treatment group. A strong drug effect on the reduction of viral load was observed on days 5 and 10. E-R relationships were best represented by an E_max structural model with reasonable consistency in the estimated AUC₅₀s (~2.3-fold), across the models, of 10,260 and 4390 nM*hr. for day 5 viral load change from baseline and LNS error rate, respectively. These biomarker E-R curves support the choice of 800 mg Q12H as providing near-maximal drug effect, consistent with findings from the previously published molnupiravir E-R model of clinical outcomes.

Keywords: NHC; SARS‐CoV‐2; exposure‐response; low‐frequency nucleotide substitutions; pharmacokinetics‐pharmacodynamics; viral load; virologic outcomes; β‐D‐N4‐hydroxycytidine.

FIGURE 1

Model‐predicted probability of > 20, > 35, and > 50 LNS errors per 10,000 nucleotides relative to baseline. Error bars represent a 95% confidence interval. AUC, area under the concentration‐time curve; LNS, low‐nucleotide substitution; NHC, β‐D‐N4‐hydroxycytidine.

FIGURE 2

Change from baseline SARS‐CoV‐2 RNA over time in the phase 3 population. NP, nasopharyngeal; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2; VL, viral load.

FIGURE 3

Model‐predicted VL change from baseline on days 5 and 10 vs. NHC AUC. A total of 1000 simulations were conducted and summarized to report the median and 2.5th and 97.5th percentiles. The patients were resampled from the analysis dataset, preserving the correlation between exposure and other covariates (baseline disease severity, baseline viral load). Parameter estimates were sampled from the model‐estimated variance–covariance matrix to account for uncertainty in estimation. AUC, area under the concentration‐time curve; CFB, change from baseline; E‐R, exposure‐response; NHC, β‐D‐N4‐hydroxycytidine; NP, nasopharyngeal; VL, viral load.

FIGURE 4

Normalized E_max E‐R relationships established for day 5 VL CFB (phase 2 and phase 3) LNS error count (phase 2) and phase 3 clinical outcomes (hospitalization/death) compared with AUC distribution at 800 mg Q12H from results of the PopPK model. The y‐axis is a relative scale (0–1) and reflects the predicted drug effect relative to the model estimated E_max value for each E‐R model. Three different efficacy responses were simulated for a range of exposures using their corresponding E‐R models. The efficacy was normalized to a [0, 1] scale using a min‐max normalization method where the corresponding E_max value is considered maximum efficacy. The red, green, and blue lines and shaded regions show the mean and 90% CI of the drug effect for various efficacy measures. The shaded area corresponds to the 90% prediction interval of NHC AUC values following a 800 mg dose of molnupiravir given Q12H. AUC, area under the concentration‐time curve; CFB, change from baseline; E‐R, exposure‐response; LNS, low‐frequency nucleotide substitutions; MOV, molnupiravir; NHC, β‐D‐N4‐hydroxycytidine; PopPK, population pharmacokinetic; Q12H, every 12 hours; VL, viral load.