Ensitrelvir Shows Promise Preventing COVID-19 Post Exposure

Oral ensitrelvir was significantly more effective than placebo for preventing COVID-19 infection in uninfected at-risk adults who had exposure to those infected, based on data from a phase 3 trial presented at the 2025 Conference on Retroviruses and Opportunistic Infections. 

Ensitrelvir, an oral SARS-CoV-2 3CL protease inhibitor, is approved in Japan for the treatment of mild-to-moderate COVID-19, wrote Akimasa Fukushi, MD, of Shionogi & Co., Ltd, the drug’s Japanese manufacturer, in the study abstract. 

The researchers randomized adults who were household contacts of confirmed COVID-19 patients but not yet infected themselves. The modified intent-to-treat population was confirmed negative for COVID-19 at baseline. Participants received ensitrelvir at doses of 375 mg on day 1 and 125 mg on days 2-5 or a placebo (1030 and 1011 individuals, respectively) within 72 hours of symptom onset in their household index patient. The mean age of the study population was 42.4 years, and 37% had at least one high-risk factor for severe COVID-19. 

The primary endpoint was the percentage of household contacts who developed COVID-19 at day 10, at which time 2.9% of the ensitrelvir group had developed COVID-19, compared to 9.0% of the placebo group, a 67% reduction in risk. 

“In addition to vaccination, post-exposure prophylaxis with timely use of an oral antiviral would be a valuable way to help prevent COVID-19 illness in people who have been exposed, especially people at high risk for severe disease,” said Frederick Hayden, MD, in a press release from the company. Hayden, professor emeritus of clinical virology and professor emeritus of medicine at the University of Virginia School of Medicine, Charlottesville, presented the study, known as SCORPIO-PEP (Stopping COVID-19 pRogression with early Protease InhibitOr treatment – Post-Exposure Prophylaxis), at the meeting. 

In a secondary analysis that included all household contacts regardless of confirmed uninfected status and in household contacts who had tested positive, the risk ratios for COVID infection in ensitrelvir groups were 0.43 and 0.75, respectively. 

The development of any treatment-emergent or serious treatment-emergent adverse events were similar between the ensitrelvir and placebo groups (15.1% vs 15.5% and 0.2% vs 0.2%, respectively). The most common treatment-emergent adverse events across both groups were headache, diarrhea, and influenza. No COVID-19-related fatalities or hospitalizations were reported during the study.

Additional data from a companion study known as SCORPIO-HR was recently published in Clinical Infectious Diseases. In that study, ensitrelvir failed to meet its primary endpoint of sustained symptom resolution (≥ 2 days) when given as an oral treatment for individuals already infected with COVID-19 within 3 days of symptom onset. 

However, no serious treatment-related adverse events were reported, and the drug showed antiviral activity, according to the study authors.

Cautious Enthusiasm for COVID Prevention

The lack of available medications in the United States for COVID post-exposure prophylaxis leaves household members in close contact with someone who is infected vulnerable to developing COVID themselves, said Shirin A. Mazumder, MD, an infectious diseases specialist in Memphis, Tenn, in an interview. 

“Access to a medication such as ensitrelvir may have a significant impact on preventing infections which in turn can also protect against some of the long term and more serious complications associated with COVID,” she said.

Mazumder was enthusiastic and “pleasantly surprised” by the significant study findings of a 67% risk reduction in infections among household contacts. “Given that there are no currently available options for COVID post-exposure prophylaxis, the findings of this study are very encouraging and has the potential to shift how we treat household members exposed to COVID,” she said.

Ensitrelvir’s Pros and Cons

An oral mediation option is convenient compared to other routes of administration, such as injections, said Mazumder. In addition, preventing COVID infections in the first place prevents days missed at school or work, complications such as long COVID, and more severe complications necessitating hospitalizations and even death, she said. “Postexposure prophylaxis along with vaccinations can significantly change the prevention landscape for COVID,” she added. 

If approved, some potential barriers to the use of ensitrelvir in clinical practice include cost and access, Mazumder told Medscape. “A 5-day course of Paxlovid [nirmatrelvir and ritonavir] for COVID treatment is approximately $1660, but it is covered by many insurance plans, which helps with patient access,” she said. “It will be interesting to see how ensitrelvir will be priced in this country if approved, and whether insurance will cover the cost,” she noted. The time delay before the new medication would be widely available through pharmacies could be another barrier affecting access, she added. 

Next Directions 

Ensitrelvir is a protease inhibitor that can have some significant drug interactions, and it would be helpful to know whether any participants were excluded from the study because of the potential for drug interactions, said Mazumder. “In addition, it would be useful to know if the severity of infection was reduced in those that developed COVID in the ensitrelvir group,” she said. 

Additional areas of research include evaluating ensitrelvir in those younger than 12 years as this may have an impact on the transmission of COVID in school settings, Mazumder noted. Evaluation of ensitrelvir’s efficacy in the immunocompromised and elderly populations is needed, given that these groups are at higher risk of COVID-related complications, and the impact of different circulating variants of the virus on ensitrelvir’s efficacy will need evaluation, she said. 

The study was funded by ensitrelvir manufacturer Shionogi. 

Mazumder had no financial conflicts to disclose.