Combination therapy with nirmatrelvir and molnupiravir improves the survival of SARS-CoV-2 infected mice

Abstract

As the SARS-CoV-2 pandemic remains uncontrolled owing to the continuous emergence of variants of concern, there is an immediate need to implement the most effective antiviral treatment strategies, especially for risk groups. Here, we evaluated the therapeutic potency of nirmatrelvir, remdesivir, and molnupiravir and their combinations in SARS-CoV-2-infected K18-hACE2 transgenic mice. Systemic treatment of mice with each drug (20 mg/kg) resulted in slightly enhanced antiviral efficacy and yielded an increased life expectancy of only about 20–40% survival. However, combination therapy with nirmatrelvir (20 mg/kg) and molnupiravir (20 mg/kg) in lethally infected mice showed profound inhibition of SARS-CoV-2 replication in both the lung and brain and synergistically improved survival times up to 80% compared to those with nirmatrelvir (P= 0.0001) and molnupiravir (P= 0.0001) administered alone. This combination therapy effectively reduced clinical severity score, virus-induced tissue damage, and viral distribution compared to those in animals treated with these monotherapies. Furthermore, all these assessments associated with this combination were also significantly higher than that of mice receiving remdesivir monotherapy (P= 0.0001) and the nirmatrelvir (20 mg/kg) and remdesivir (20 mg/kg) combination (P= 0.0001), underscored the clinical significance of this combination. By contrast, the nirmatrelvir and remdesivir combination showed less antiviral efficacy, with lower survival compared to nirmatrelvir monotherapy, demonstrating the inefficient therapeutic effect of this combination. The combination therapy with nirmatrelvir and molnupiravir contributes to alleviated morbidity and mortality, which can serve as a basis for the design of clinical studies of this combination in the treatment of COVID-19 patients.

Combined Molnupiravir and Nirmatrelvir Treatment Improves the Inhibitory Effect on SARS-CoV-2 in Rhesus Macaques

“…As the mode of action for MK-4482 and PF-07321332 are distinct, the former being a nucleoside analog and the latter an inhibitor of viral protease inhibitor, combined therapy may provide a potential benefit over monotherapy. This was supported by recent in vitro data demonstrating a synergistic antiviral effect of MK-4482 and PF-07321332 against Delta and Omicron VOCs in comparison to individual drug treatment [27,28], and in vivo for a Korean strain isolated early in the pandemic [29] using a transgenic mouse model [30]. In our present study, combined twice daily oral treatment (1600mg in total) within 5 days of symptom onset [31].…”

“…Since SARS-CoV-2 Delta infection likely shows the most severe infection in a NHP model [26], this could be addressed in lethal rodent models or clinical trials. A suggestion of such efficacy against more severe disease is indicated in the recent study using a lethal transgenic COVID-19 mouse model [30]. Second, we only tested the efficacy of the current human dose for monotherapy.…”

Severe COVID-19 caused by persistent SARS-CoV-2 infection successfully treated with dual direct acting antivirals.

“…Another study showed synergistic inhibition of viral replication by Paxlovid and molnupiravir in vitro [7]. Synergy was also seen with these two agents in a murine model of survival after infection with the SARS-CoV-2 Beta variant [8]. One other case report exists which corroborates our experience with dual DAAs [9].…”

Rethinking treatment paradigms for the deployment of SARS-CoV-2 antiviral drugs on the shifting landscape of new variants

“…Preclinical data have clearly demonstrated that virological efficacy is higher for combinations of existing antiviral drugs than single agents (Abdelnabi et al, 2021 ; Jeong et al, 2022 ; Li et al, 2022 ). To achieve the goal of changing the treatment guidelines in SARS-CoV-2-infected immunocompromised individuals, independent and academic clinical trials for drug combinations should be considered as an urgent, unmet research priority.…”

“…With few drugs currently available, the opportunity must be seized prior to the emergence of resistance to drugs deployed widely as monotherapies. Combinations of polymerase inhibitors and polymerase/protease inhibitors have proven highly successful for other viruses and in animal models for SARS-CoV-2 (Abdelnabi et al, 2021 ; Jeong et al, 2022 ). Thus, as drugs that are appropriate to combine are available, there is no good reason not to study them clinically.…”