- Jennifer Middleton, MD, MPH
The U.S. Food and Drug Administration (FDA)'s advisory committee voted last week in favor of approving molnupiravir, Merck's oral antiviral medication for COVID-19. The FDA is expected to follow the committee's recommendation and authorize use of the drug this week under an Emergency Use Authorization (EUA). Pfizer is also preparing an EUA application for its antiviral medication, ritonavir. While the development of additional treatments to combat COVID-19 is cause for some optimism, it may be too early to celebrate given the limited, preliminary nature of both medications' efficacy to date.
Data from molnupiravir's phase 2a trial has not yet been peer reviewed; outcomes demonstrated reasonable tolerability and a substantial reduction of viral load. Merck also announced phase 3 data demonstrating a nearly 50% reduction in death and hospitalization for outpatients with laboratory-confirmed COVID-19 infection who began taking it within 5 days of symptom onset. This data came from an interim analysis of 775 trial participants with "mild to moderate COVID-19" and "one risk factor associated with poor disease outcome." The trial's independent data review committee recommended terminating the trial early given these findings, but continued follow-up of study participants has demonstrated a lower efficacy of about 30%. That trial's data is not yet available for public review but was reportedly considered by the FDA advisory committee. The advisory committee vote was close (13-10); committee members who voted "yes" despite molnupiravir's modest efficacy cited the lack of other antiviral treatments available, with some suggesting that approval could be later rescinded if better treatments are developed. Members voting "no" raised concerns about the drug's risk of teratogenesis as well as its potential to induce dangerous mutations into the SARS-CoV-2 virus:
“Even if the probability is very low, 1 in 10,000 or 100,000, that this drug would induce an escape mutant from which the vaccines we have do not cover, that could be catastrophic...” Dr. James Hildreth, CEO of Meharry Medical College in Nashville, Tenn., told the panel.
Pfizer's ritonavir has had more promising results. Its phase 2/3 trial enrolled just over 1200 "non-hospitalized adults aged 18 and older with confirmed COVID-19 who are at increased risk of progressing to severe illness" who were randomized to either receive placebo or ritonavir within 5 days of laboratory-confirmed COVID-19 infection. Pfizer reported an 85% reduction in the risk of hospitalization or death in enrolled participants with a no significant difference of adverse events between groups (21% placebo vs 19% ritonavir). This study was also stopped early due its positive interim findings; it remains to be see whether these positive findings will persist with further analysis.
While oral antiviral medications may be "another tool in our toolbox" as touted by U.S. President Biden, vaccination remains the most critical element to stem the development of new SARS-CoV-2 mutations as well as the pandemic. The worldwide vaccine supply is adequate to meet the World Health Organization's ambitious vaccination goals if "distributed equitably."
In the meantime, the AFP By Topic on COVID-19 continues to be regularly updated, with sections on Prevention (including this Lown Right Care article on "Helping Ambivalent Patients Make Healthy Decisions About COVID-19") and Treatment.
