Early molnupiravir use benefits unvaccinated COVID-19 outpatients

Early administration (ie, within 5 days after symptom onset) of the oral, small-molecule antiviral prodrug molnupiravir slashed the risk of hospitalization or death in at-risk, unvaccinated, nonhospitalized adults with mild-to-moderate COVID-19, findings from the phase III component of the phase II/III MOVe-OUT trial have shown.

“Molnupiravir met the prespecified superiority criterion at the time of the interim analysis,” said the researchers. At day 29, the risk of hospitalization for any cause or death was lower with molnupiravir vs placebo, both at the interim analysis (7 percent vs 14 percent; p=0.001) and in the all-randomized modified intention-to-treat population (7 percent vs 10 percent).

In a prespecified analysis, 6 percent of individuals receiving molnupiravir were hospitalized or died owing to reasons deemed COVID-19-related. The corresponding rate in the placebo arm was 9 percent. [N Engl J Med 2022;386:509-520]

“[These data represent] improvement in an outcome that is potentially meaningful for patients, healthcare systems, and public health,” said the researchers.

There were similar percentages of patients in the molnupiravir and the placebo arms with at least one adverse event (AE; 30 percent vs 33 percent), the most frequent (occurring in ≥2 percent of patients in either arm) being COVID-19 pneumonia, diarrhoea, and bacterial pneumonia.

Similarly, the rates of participants with AEs considered by investigators as related to the trial regimen were similar (8.0 percent vs 8.4 percent), the most frequent (occurring in ≥1 percent of participants in either arm) being diarrhoea and nausea.

“As in previous trials, no safety concerns with molnupiravir were identified, and there was no evidence of a pattern of clinically meaningful abnormalities in laboratory test results,” said the researchers.

There was only one death reported in the molnupiravir arm, representing an 89-percent lower risk of death compared with the placebo arm, which had nine deaths.

New tool in the COVID-19 treatment arsenal

MOVe-OUT involved 1,433 individuals with COVID-19 who were unvaccinated and nonhospitalized (median age 43 years, 51 percent female). They were randomized 1:1 to receive either oral molnupiravir 800 mg (delivered as four 200-mg capsules) or identical placebo BID for 5 days. 

“[C]linical progression to severe disease has a considerable impact on patients and on healthcare systems, increasing a patient’s risk of receiving mechanical ventilation and of death, and potentially overburdening local and regional hospital capacity during COVID-19 surges,” said the researchers. “Reducing COVID-19-related hospitalizations, and potentially also reducing community transmission by helping patients clear infectious virus more rapidly, are therefore critical.”

Antiviral therapies that cut the risk of COVID-19 progression are thus warranted, they continued. However, the monoclonal antibodies authorized for treating outpatients with COVID-­19 are mostly administered via infusions or injections in a medical setting.

“[O]ral agents such as molnupiravir that can be administered by the patient at home shortly after diagnosis may be more practical and patient-friendly for nonhospitalized persons. Such agents would be important new tools in the COVID-19 treatment armamentarium,” they said.

Dr Richard Whitley from the University of Alabama, Birmingham, Alabama, US, echoed similar thoughts in a separate editorial. “[While] vaccines must be the primary mode of protection against SARS-CoV-2 … orally bioavailable medications will become an essential tool for physicians in the management of this horrible disease,” said Whitley. [N Engl J Med 2022;386:592-593]

Molnupiravir is less beneficial when given late in the disease course (ie, after having symptoms for more than 3–5 days or after hospitalization), added Whitley. “[As such,] we must strive … to begin [therapy] within 72 hours in all patients, as shown in studies of influenza … Since SARS-CoV-2 infection must be confirmed, a point-of-care companion diagnostic test would be of value.”