Ensitrelvir: A COVID-19 Antiviral That Remains Effective Against New Variants


Ensitrelvir is an investigational 3CL protease inhibitor that reduced COVID-19 illness duration by 1 day.

COVID-19 vaccines have been indispensably vital in mitigating the burden of the coronavirus pandemic. However, as Simon Portsmouth, MD, points out, severe and fatal COVID-19 infections are still occurring, particularly among immunocompromised or otherwise vulnerable populations.

Portsmouth is the head of clinical development for the United States division of the pharmaceutical company Shionogi & Co., Ltd. He is on the front lines of Shionogi’s efforts to develop the investigational oral COVID-19 antiviral, ensitrelvir fumaric acid (ensitrelvir; S-217622).

Ensitrelvir is a 3CL protease inhibitor, and targets COVID-19 viral replication. This method of action helps ensitrelvir remain effective against new and emerging variants.

“It retains activity,” said Portsmouth, “which is not surprising since we considered that most of these changes are in the spike protein, and we haven’t seen any changes in the 3CL protease.” This contrasts with treatments like monoclonal antibodies, which target the virus’s ever-evolving spike protein and have not proven effective against the latest variants.

A recent phase 3 trial, conducted in 3 Asian countries, found that ensitrelvir reduced COVID-19 recovery time by 1 day compared to placebo. “That was statistically significant,” Portsmouth said. “It doesn’t sound like a large difference but, in fact, these are very insensitive endpoints, so to be able to show any difference at all I think is really remarkable.”

Ensitrelvir may be particularly beneficial for patients with highly symptomatic COVID-19 infection. When Portsmouth and his team analyzed recovery in patients who presented with a symptom score of 9 or higher for COVID-19, they found an approximate 50% reduction in insomnia and 45% reduction in difficulty concentrating.

These are still exploratory findings, but Portsmouth emphasized, “It is the first prospective study of an antiviral that did show that treating the acute episode seems to have effects 6 months later.”

Other trials of ensitrelvir are ongoing, including one in hospitalized COVID-19 patients and another in a global mix of standard-risk and high-risk patients. The trials recruit participants within 3 days of COVID-19 symptom onset and treat them with either ensitrelvir or placebo.

Portsmouth also noted plans to test the efficacy of ensitrelvir as post-exposure prophylaxis of COVID-19. “At the moment, there isn’t an agent available for post-exposure prophylaxis, and so we’re planning a study where we will treat household members of an indexed case of COVID-19 to see if either ensitrelvir or placebo will affect the incidence of symptomatic COVID onset.”

After the positive results of the phase 3 trial conducted in Japan, ensitrelvir was granted emergency approval in the country. The priority now is completing the upcoming ensitrelvir trials, but Portsmouth added Shionogi is in conversation with global agencies about future approval.

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