Study: Concern SARS-CoV-2 variants and the biological sex of the patients influence the effectiveness of molnupiravir

Concerning SARS-CoV-2 variants and patients’ biological sex affect the effectiveness of molnupiravir, the first oral drug approved for outpatient use against COVID-19, according to a new study led by researchers at the Center for translational antiviral research in the Department of Biomedical Sciences at Georgia State University.

SARS-CoV-2, the virus that causes COVID-19, has been increasing due to the limited longevity of vaccine-induced immunity, the reluctance of various populations to vaccinate, and the worrisome variants (eg, alpha, beta, gamma, delta and omicron) that are increasingly contagious or not susceptible to vaccines. Omicron has quickly replaced Delta as the dominant circulating strain, having first emerged in November 2021.

While oral antivirals such as molnupiravir promise to improve disease management, the efficacy and potency of molnupiravir against variants of concern are either questioned or unknown. Although Omicron appears to be milder than previous variants, there is an urgent need for therapeutics to improve disease management due to record high daily infection rates and increased hospitalizations.

The study published in the journal Nature Communications tested molnupiravir against SARS-CoV-2 variants of concern in cultured cells, human airway epithelial organoids, ferrets and a dwarf hamster model of severe COVID-19-like lung injury. The analysis showed that molnupiravir inhibited variants of concern in cells and organoids alike, and the treatment reduced shedding and prevented transmission in ferrets.

Furthermore, the ability of SARS-CoV-2 to cause disease in dwarf hamsters was variant dependent and highest for the delta, gamma and omicron variants. All hamsters treated with molnupiravir survived and showed a reduction in lung viral load from one order of magnitude for delta to four orders of magnitude for gamma. The effect of treatment varied in individual hamsters infected with Omicron, and the reduction in viral load was significant in males but not females.

We have established in this manuscript a novel SARS-CoV-2 animal model that yields a high viral load of omicron, which is currently the variant of concern. None of the other models did that. We show that dwarf hamsters provide a robust experimental system to study the level of pathogenicity of different SARS-CoV-2 variants. Unexpectedly, the efficacy of molnupiravir against Omicron was variable between individual dwarf hamsters. The biological sex of the animals was found to correlate to the therapeutic benefit of using molnupiravir versus Omicron, with treated males doing better overall than females. In contrast, biological sex had no impact on treatment benefit when dwarf hamsters were infected with gamma or delta, consistent with the human study data reported for these variants of concern.”

Richard Plemper, senior author of the study, director of the Center for Translational Antiviral Research and Distinguished University Professor, Institute for Biomedical Sciences at Georgia State

Scientists lacked an efficacy model reflecting acute lung injury from the life-threatening COVID-19 and a relevant experimental platform to test molnupiravir’s effect on mitigating lung damage caused by different variants of concerns. This discovery could allow researchers to study the effects of treatment on disease progression.

“Without controlled clinical data to evaluate the efficacy of molnupiravir against Omicron, it is unclear to what extent the findings in dwarf hamsters translate to human therapy,” Plemper said. “However, our study shows that the pharmacological relief of severe COVID-19 is complex and attempts to predict drug efficacy based on an unchanged prognosis ex vivo Inhibitory concentrations alone may be premature. The results based on dwarf hamsters illuminate that there may be variant-specific differences in the magnitude of the treatment effect in vivoand draws attention to the need to continuously re-evaluate the therapeutic utility of approved antiviral drugs for individual patient subgroups as SARS-CoV-2 evolves and potential future variants of concern may emerge.”