Molnupiravir for the treatment of COVID-19 in immunocompromised participants: efficacy, safety, and virology results from the phase 3 randomized, placebo-controlled MOVe-OUT trial

Abstract

Purpose: Immunocompromised patients have a potentially increased risk for progression to severe COVID-19 and prolonged replication of SARS-CoV-2. This post hoc analysis examined outcomes among immunocompromised participants in the MOVe-OUT trial.

Methods: In phase 3 of MOVe-OUT, non-hospitalized at-risk adults with mild-to-moderate COVID-19 were randomized to receive molnupiravir 800 mg or placebo twice daily for 5 days. Immunocompromised participants were identified based on prior/concomitant medications and/or medical history. All-cause hospitalization/death, adverse events, SARS-CoV-2 titers, infectivity, and RNA sequences were compared between immunocompromised participants who received molnupiravir or placebo and with non-immunocompromised participants.

Results: Fifty-five of 1408 participants were considered immunocompromised. Compared to placebo, fewer molnupiravir-treated immunocompromised participants were hospitalized/died through Day 29 (22.6% [7/31] vs. 8.3% [2/24]), with fewer adverse events (45.2% [14/31] vs. 25.0% [6/24]). A larger mean change from baseline in SARS-CoV-2 RNA was observed with molnupiravir compared to placebo in non-immunocompromised participants (least squares mean [LSM] difference Day 5: - 0.31, 95% confidence interval [CI] - 0.47 to - 0.15), while the mean change was comparable between treatment groups in immunocompromised participants (LSM difference Day 5: 0.23, 95% CI - 0.71 to 1.17). Molnupiravir treatment was associated with increased clearance of infectious virus. Increased errors in viral nucleotide sequences in post-baseline samples compared to placebo support molnupiravir's mechanism of action and were not associated with observation of novel treatment-emergent amino acid substitutions in immunocompromised participants.

Conclusion: Although the study population was small, these data suggest that molnupiravir treatment for mild-to-moderate COVID-19 in non-hospitalized immunocompromised adults is efficacious and safe and quickly reduces infectious SARS-CoV-2.

Gov registration number: NCT04575597.

Keywords: COVID-19; Immunocompromised; Molnupiravir; Treatment; Virology.

Fig. 1

Incidence of hospitalization or death through Day 29 by immunocompromised status (MITT population). 95% CIs were based on the Miettinen and Nurminen method. Unknown survival status at Day 29 was imputed as hospitalization or death. Abbreviations: CI confidence interval, MITT modified intention-to-treat

Fig. 2

Mean change from baseline in SARS-CoV-2 RNA over time (MITT population). Error bars represent 95% CIs based on constrained longitudinal data analysis model with RNA titer as the response variable and the following variables as covariates: treatment, study visit, treatment by study visit interaction, and time from symptom onset prior to randomization (≤ 3 days vs. > 3 days from randomization strata). Analysis includes participants with baseline SARS-CoV-2 RNA titer ≥ 500 copies/mL. Abbreviations: CI confidence interval, EOT end-of-therapy, LS least squares, MITT modified intention-to-treat, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2

Fig. 3

Proportion of participants with detectable infectious SARS-CoV-2 over time (MITT population). n = number of participants with detectable infectious titer at each timepoint among N. N = number of participants with positive baseline infectivity result and with available post-baseline SARS-CoV-2 RNA samples at the timepoint of analysis. Infectivity results were imputed as undetectable if the sample was not sent for infectivity testing due to SARS-CoV-2. RNA copies being lower than 10.⁵ copies/mL. Abbreviations: EOT end-of-therapy, MITT modified intention-to-treat, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2

Fig. 4

SARS-CoV-2 nucleotide error rates on Day 5 (MITT population). Viral nucleotide error rate was calculated as the number of nucleotide errors compared with the baseline sequence per 10,000 bases across the entire viral genome (30,000 bases). Abbreviations: MITT modified intention-to-treat, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2

Fig. 5

SARS-CoV-2 nucleocapsid antibody positivity over time (MITT population). n = number of participants with detectable SARS-CoV-2 nucleocapsid antibody at the corresponding visit; N = number of participants with an assay result of SARS-CoV-2 nucleocapsid antibody at the corresponding visit. 95% CI for the proportion of participants with detectable nucleocapsid antibody was based on the Clopper–Pearson method. The 95% CI for the difference in proportions was based on the Miettinen and Nurminen method stratified by randomization strata. Abbreviations: CI confidence interval, EOT end-of-therapy, MITT modified intention-to-treat, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2

Fig. 6

Mean change from baseline in SARS-CoV-2 spike protein neutralizing antibody titers on Days 10 and 29 (MITT population). n = number of participants with baseline and at least one post-baseline result at the time point assessed. The assay LLOQ was 40 copies/mL and ULOQ was 787,339 copies/mL. Post-baseline results below the LLOQ or above the ULOQ were included in the mean and mean change from baseline, with the imputed values 39 copies/mL and 787,340 copies/mL, respectively. Abbreviations: LLOQ lower limit of quantification, MITT modified intention-to-treat, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, ULOQ upper limit of quantification