An antiviral called ensitrelvir significantly reduced the risk of COVID-19 infection among household contacts, a randomized trial has shown. Currently, no antivirals are approved for post-exposure prophylaxis (PEP) in this setting. In the study, only 2.9% of household contacts who received ensitrelvir developed COVID-19 within 10 days, compared to 9% of those given a placebo. The U.S. Food and Drug Administration (FDA) is currently reviewing an application for the oral antiviral, with a decision anticipated in June.
The trial demonstrated a more than twofold reduction in the risk of developing COVID-19 for household contacts receiving ensitrelvir. Specifically, within a modified intention-to-treat (ITT) population of household contacts of COVID patients, 2.9% of those who took at least one dose of oral ensitrelvir as PEP developed COVID-19 within 10 days, compared to 9% of those assigned to placebo (P<0.001). This finding was reported by researchers, including Frederick Hayden, MD, of the University of Virginia in Charlottesville, and detailed in the New England Journal of Medicine. Across the study's full ITT population, 4.4% of ensitrelvir recipients developed COVID-19 within the same timeframe, versus 10.2% in the placebo group (P<0.001).
Dr. Hayden emphasized the significance of these findings, stating, "This is really the first clear demonstration in a well-performed phase III placebo-controlled, double-blind trial that we actually have an agent that is easily administered orally and effective if taken in a timely fashion for protecting individuals who are exposed to COVID-19 in the household setting." He added that beyond individual households, "the trial results point to likely effectiveness in other settings with COVID-19 outbreaks, such as nursing homes and chronic care facilities."
Dr. Hayden noted that while timely PEP with antivirals like oseltamivir (Tamiflu) effectively protects household contacts from influenza, previous efforts to replicate this success for COVID-19 have failed. Clinical trials that repurposed existing COVID treatments such as nirmatrelvir-ritonavir (Paxlovid) and molnupiravir (Lagevrio) for PEP did not show significant protection.
Currently, ensitrelvir is approved in Japan for treating mild to moderate COVID-19 and as COVID-19 PEP. Its manufacturer, Shionogi, has submitted the antiviral to the FDA for similar approval.
The phase III SCORPIO-PEP trial, conducted between June 2023 and September 2024 in Argentina, Japan, South Africa, the U.S., and Vietnam, enrolled 2,387 household contacts aged 12 years or older of individuals diagnosed with COVID-19. The study also involved 1,319 index patients with COVID-19, predominantly adults (83.8%) and female (56%), with most residing in the U.S. (55%) or Japan (39.3%). The study's ITT population consisted of participants who tested negative for SARS-CoV-2 and were enrolled within 72 hours of an index patient developing COVID-19 symptoms. The modified ITT population comprised 2,041 individuals who met these criteria, were randomized to treatment within 72 hours, and received at least one dose of ensitrelvir or placebo.
The trial's primary endpoint was the incidence of lab-confirmed COVID-19—defined as a positive PCR test and at least one symptom lasting at least 48 hours—in a household contact within 10 days of receiving ensitrelvir or placebo. Secondary endpoints included any lab-confirmed COVID-19, regardless of symptom presence, within the same timeframe.
Among the household contacts in the ITT population, 59.3% were female, with a mean age of 42.4 years, and 9.3% were aged 65 or older. A majority (71.1%) enrolled within 48 hours of an index patient's symptom onset, and over a third (37%) presented with risk factors for severe COVID-19, such as obesity, smoking, or advanced age. Notably, more than 98% of these contacts had tested positive for SARS-CoV-2 antibodies, indicating previous infection or vaccination.
Looking at all lab-confirmed COVID-19 infections, symptomatic or asymptomatic, by day 10, the rate was 14% in ensitrelvir recipients compared to 21.5% in the placebo group. Furthermore, even among participants who developed COVID-19 despite PEP, those taking ensitrelvir exhibited lower viral loads than those on placebo.
The safety profile of ensitrelvir was favorable, with similar adverse event rates between the ensitrelvir (15.1%) and placebo (15.5%) groups. Unlike other antivirals such as nirmatrelvir-ritonavir, ensitrelvir was not associated with a higher incidence of dysgeusia (distorted sense of taste) or gastrointestinal side effects compared to placebo.
Dr. Hayden also highlighted several considerations and study limitations. These include the exclusion of pregnant women from the trial and ensitrelvir's classification as a moderately strong cytochrome P450 3A inhibitor, which implies a potential for drug-drug interactions. Furthermore, the study did not measure behavioral factors like mask-wearing that could influence household transmission. Researchers noted that antiviral therapy used by 18.7% of index patients might have also reduced the overall risk of transmission within households.
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