Vincent Racaniello

Multiple vaccines have been developed that have made substantial contributions to controlling the COVID-19 pandemic, but where are the antivirals? Only repurposed drugs have been used and not with much success. That situation seems about to change with the authorization of drugs that target the RNA polymerase (Molnupiravir) and a viral protease (Paxlovid).

Molnupiravir is an orally available pro-drug of the nucleoside analog N4-hydroxycytidine (NHC). The latter is a nucleoside analogue which is incorporated into RNA by the viral RNA-dependent RNA polymerase. Once incorporated into RNA, NHC is recognized as either C or U by the RNA polymerase. As a consequence, many mutations are introduced into the viral genome, causing lethal mutagenesis and inhibition of infectivity. NHC has been shown to block SARS-CoV-2 transmission in ferrets.

Interim results in 775 patients of a phase 3 clinical trial with molnupiravir show that the drug reduced hospitalization or death about 50% compared with placebo in patients with mild to moderate COVID-19: 7.3% of patients who received molnupiravir were either hospitalized or died through Day 29 (28/385), compared with 14.1% of placebo-treated patients (53/377). No deaths were reported in patients who received molnupiravir, as compared to 8 deaths in patients who received placebo, through day 29. The trial required that all patients have laboratory-confirmed COVID-19 with symptom onset within 5 days of assignment to control or drug group. Patients were recruited from multiple countries and included those with risk factors for poor disease. Merck expects to produce 10 million doses of the drug in 2021 and has submitted an application for emergency use authorization (EUA).

Paxlovid is an inhibitor of the 3CL or main protease of SARS-CoV-2, an essential viral enzyme that is required to process precursor proteins into functional products. The drug works by binding to the active site of the protease. Such inhibitors have been successfully developed and are approved for the treatment of AIDS and hepatitis C. Paxlovid inhibits viral reproduction in cell culture and in virus-infected mice when given orally. In a phase I trial in 4 participants, the drug was safe and well tolerated and reached levels greater than needed to inhibit reproduction in cell culture.

Interim analysis of a phase 2/3 randomized, placebo-controlled study of Paxlovid showed that the drug reduced the risk of hospitalization or death by 89%. This study enrolled non-hospitalized patients with COVID-19 who were at risk for severe illness. The patients were treated with Paxlovid within 3 days of symptom onset. Of the patients who received the drug, 3/389 were hospitalized through day 28 (0.8%) compared with 27/385 in the placebo group hospitalized and 7 deaths (7%). Similar results were obtained in a group of patients treated within 5 days of symptom onset. Based on these results, Pfizer plans to submit an application for EUA.

The only antiviral repurposed for SARS-CoV-2 that had any efficacy is remdesivir, whose widespread adoption is limited by the need to administer the drug intravenously. Because they are taken orally, Molnupiravir and Paxlovid should have a far greater impact on the pandemic, especially for people who refuse to be vaccinated. If these drugs had been available before the pandemic – which was certainly possible – it might have been largely prevented.