Ensitrelvir (Shionogi) administered within 72 hours of household COVID-19 exposure reduced the number of people contracting COVID-19, according to research presented at CROI 2025.
Investigator Frederick G. Hayden, MD, an emeritus professor at the University of Virginia, in Charlottesville, sat down with Infectious Disease Special Edition to talk about the study, which saw a 67% reduction in spread when taking ensitrelvir, he said.
The study, conducted in Japan—where ensitrelvir is approved for use—the United States and other countries, included 2,041 individuals 1:1 in the intention-to-treat population. The mean age was 42 years, and 37% had at least one high-risk factor for severe COVID-19. Nearly three-fourths of household contacts were randomized within 48 hours of the index patient’s symptom onset.
The researchers found that the overall proportion of household contacts developing confirmed COVID-19 was significantly lower in the intervention group than the placebo arm (2.9% vs. 9.0%, respectively; risk ratio, 0.33; 95% CI, 0.22-0.49; P<0.0001).
For treatment-emergent adverse events (TEAEs), the proportions were similar in both groups: 15.1% for ensitrelvir and 15.5% for the placebo group. Serious TEAEs were 0.2% for both groups. The most common TEAEs were headache (ensitrelvir, 2.9%; placebo, 2.5%), diarrhea (ensitrelvir, 1.8%; placebo, 2.5%) and influenza (ensitrelvir, 1.1%; placebo, 1.6%). There were no COVID-19–related hospitalizations or fatalities during the study.
The following was transcribed by Temi.
Frederick Hayden, MD (00:09):
This is Frederick Hayden. I’m an emeritus professor at the University of Virginia.
Frederick Hayden, MD (00:18):
Happily, and thanks for your interest. So we presented the results of a phase three international trial on a drug called ensitrelvir used for post-exposure prophylaxis in household contacts of a case of COVID-19. It tested the question of whether this drug, which is a SARS-CoV-2, 3C-like protease inhibitor, could protect contacts in the household setting from acquiring COVID. There was an unmet need for this problem because two prior studies of oral antivirals did not meet their primary end points. Hence there’s no currently approved oral antiviral to protect household contacts in this circumstance. So the trial then was randomized, placebo-controlled, double-blinded in its overall design. The groups were well balanced with regard to demographic characteristics overall, and notably about 9% were older adults. We had fully 37% in each of the active and placebo groups that had risk conditions for more severe COVID and its complications. These included obesity; smoking, either current or previous; older age; diabetes; and heart disease. This was a group of particular interest because these are the individuals that we most want to protect.
Frederick Hayden, MD (02:08):
In the placebo group, there was rapid development of new cases of COVID, and this was reduced markedly in the ensitrelvir group, so that by day 10, fully 9% of the placebo group had developed COVID compared to 2.9% in the ensitrelvir groups. This represented a 67% reduction. And this, again, is the first time that an oral SARS-CoV-2 inhibitor has been shown to be protective under these circumstances.
Frederick Hayden, MD (02:53):
Well, I thought that there was a high likelihood of success because we have a historical experience with influenza, which is also readily transmitted in the household setting, and has even a somewhat shorter incubation period, so we know that several different influenza drugs—including oral oseltamivir [Tamiflu, Roche], oral baloxavir [Xofluza, Genentech] and inhaled zanamivir [Relenza, GlaxoSmithKline]—can protect household contacts from flu, and so this study really was designed in part on the basis of those prior studies.