By Marie Rosenthal, MS
If given within 72 hours after clinical onset of COVID-19 in a household, oral ensitrelvir was effective in protecting household contacts from SARS-CoV-2 infection, according to a presentation at ESCMID Global 2025, in Vienna (abstract 03159).
Protection was consistently seen in all at-risk groups studied, including older household contacts, according to Frederick G. Hayden, MD, the Stuart S. Richardson Professor Emeritus of Clinical Virology and a professor emeritus of medicine at the University of Virginia School of Medicine, in Charlottesville.
“As with other respiratory viruses, households are major sites for SARS-CoV-2 transmission with secondary attack rates that range quite high depending on the particular variant,” Dr. Hayden said.
While the omicron variant was circulating, the SCORPIO-PEP trial (Stopping COVID-19 pRogression with early Protease InhibitOr treatment – Post-Exposure Prophylaxis) evaluated the efficacy of post-exposure prophylaxis (PEP) with ensitrelvir in household contacts of index cases with confirmed COVID-19.
SCORPIO-PEP is a multicenter, double-blind, placebo-controlled study in household contacts of an index patient with laboratory-confirmed SARS-CoV-2 infection. The household contacts tested negative by antigen testing or real-time polymerase chain reaction (RT-PCR) and were randomly selected to either once-daily ensitrelvir or placebo within 72 hours of the index patient showing symptoms.
They enrolled 2,389 household contacts between June 2023 and August 2024. Those with a documented infection or who had received a vaccine in the prior six months were excluded from participation. A small number of patients had received vaccination six to 12 months before entering the trial, he said.
The median age of patients was 43 years, but about 9% were 65 years and older. Thirty-seven percent in both the intervention and placebo groups had at least one high-risk factor for severe COVID-19. About two-thirds of the participants were from the United States, he explained.
“Importantly, they had to be initiated on study drug within 72 hours of the symptom onset in the index patients. And then they were randomized 1:1 to ensitrelvir for a five-day course or placebo,” Dr. Hayden said. More than 71% were randomized within 48 hours of symptom onset.
In addition to recording their symptoms, participants had frequent nasal swabs done out to day 28 to detect infection. The primary population for analysis was the modified intent-to-treat population (mITT) with a negative result at baseline. About 10% of the household context were positive at the central laboratory, and they were included in the ITT population, but excluded from the mITT group, he explained.
The primary end point was the proportion of contacts who develop symptomatic COVID-19 that was confirmed by RT-PCR and who had at least one specific COVID-19 symptom by day 10, according to Dr. Hayden.
During the 10-day follow-up, 9% of those in the placebo group developed COVID-19 compared with 2.9% in the ensitrelvir group, a 67% relative risk reduction. “The placebo recipients, as indicated in this plot, started experiencing COVID onset rapidly after enrollment in the trial,” he said.
Those who were 65 and older saw a 75% relative risk reduction in the risk of developing COVID-19.
However, after days 10 to 12, there were no differences in the rates of COVID-19, which was “probably due to acquisition in the community environment,” he explained.
The most frequent risk factors for severe COVID-19 among the participants were obesity, smoking, older age, heart disease and diabetes. Those groups saw a significant reduction in the likelihood of developing COVID-19 with a relative risk ratio reduction of 76%.
The earlier PEP was prescribed, the better the effect, according to Dr. Hayden. “The efficacy of post-exposure prophylaxis was higher with earlier initiation in the contacts. This time treatment effect is an important one that’s been observed in prior post-exposure prophylaxis studies with influenza,” Dr. Hayden said.
Ensitrelvir was well tolerated in this study. “You’ll note that with regard to treatment-emergent adverse events, there were no differences in proportions across the two groups and that there were no study drug-related serious treatment-emergent adverse events, and very few discontinuations, nor were there any hospitalizations or mortality events noted in the study with regard to specifically emergent events,” Dr. Hayden said.
Headache was the most frequently reported adverse event.
Dr. Hayden said he thought these results could be extrapolated to other settings, where people have close contact with others. “These results, I think, suggest potential for protection in other settings, like outbreaks in acute care facilities, long-term care homes and the like,” Dr. Hayden said.
COVID-19 remains a major threat to public health, he reminded, and PEP could prevent the serious and long-term complications associated with the virus, according to Dr. Hayden. This could be an important option as COVID-19 vaccination rates are down, according to the CDC. The percentage of the population reporting receipt of the updated 2024-2025 COVID-19 vaccine is 13.1% (12.4%-13.7%) for children and 23.2% (22.6%-23.7%) for adults 18 and older, including 44.4% (42.8%-45.9%) among adults 65 and older.
Ensitrelvir, a 3CL protease inhibitor, works by selectively inhibiting the SARS-CoV-2 3CL protease, which is essential for the replication of the virus.
In related news, Shionogi initiated the rolling submission of a New Drug Application with the FDA for its investigational oral antiviral ensitrelvir based on positive results from the SCORPIO-PEP trial on April 1. With continually decreasing vaccination rates, waning immunity after vaccination and the potential for new variants to emerge, additional treatment and preventive options for COVID-19 are needed, the company said. If this application is approved, ensitrelvir is expected to be the first orally administered option for COVID-19 PEP. Ensitrelvir was granted Fast Track designation by the FDA in 2025 for PEP after contact with an individual who has COVID-19 and was granted Fast Track designation by the FDA in 2023 for the treatment of COVID-19.
Shionogi is also in discussions with FDA regarding a treatment indication for COVID-19 with ensitrelvir.
Dr. Hayden consults for Shionogi’s antiviral program.
