Investigational Oral Antiviral Shows Promise in COVID Outpatients

SEATTLE -- Patients with mild to moderate COVID-19 treated with the oral antiviral ensitrelvir within 5 days of symptom onset saw their symptoms resolve a day earlier, according to data from a phase II/III randomized trial.

Median time to symptom resolution was 24.3 hours earlier for patients treated with 125-mg ensitrelvir compared with those receiving placebo (P=0.04), reported Takeki Uehara, PhD, senior vice president of drug development and regulatory science at Shionogi and Co. in Osaka, Japan, during the Conference on Retroviruses and Opportunistic Infections.

In addition, SARS-CoV-2 viral titers were negative within a median of 36.2 hours in the treatment group compared with 65.3 hours in the placebo group (P<0.0001), with an 87% reduction of infectious virus at day 4 with the oral drug.

"We shortened the resolution of symptoms," Uehara said. "We showed statistical significance for time to cessation of the viral shedding."

He also noted that patients treated with 250-mg ensitrelvir had similar -- though slightly inferior -- outcomes.

Ensitrelvir is a novel 3C-like protease inhibitor that targets the SARS-CoV-2 virus. "Because of its mode of action, ensitrelvir maintains antiviral activities across various different types of variants, including recently circulating Omicron variants," Uehara said.

Of note, follow-up of patients continued out to 3 months and 6 months to evaluate the drug's effectiveness on long COVID.

In this exploratory analysis, Uehara reported an overall 25% reduction in risk for at least one long COVID symptom among 14 commonly reported long COVID symptoms compared with placebo. For four neurological symptoms, the 125-mg dose demonstrated a 26% risk reduction.

"This is the first prospective placebo-controlled study to see if the antiviral has the potential to reduce the risk of patients developing long COVID symptoms," Uehara noted.

The 125-mg dose further decreased risk in a subpopulation of patients who had higher scores for 14 COVID symptoms at baseline. In these patients, the overall risk reduction was 45% for the 14 symptoms, and 33% for neurological symptoms.

"A treatment addressing the symptoms of long COVID remains one of the largest unmet needs of the pandemic," said Amesh Adalja, MD, of Johns Hopkins Center for Health Security in Baltimore, in a Shionogi press release. "An antiviral for this condition would be a welcome addition to the tools we have to care for patients with COVID-19. As these data are from an exploratory analysis, this promising signal will hopefully be followed up with further evaluation of ensitrelvir for long COVID."

Ensitrelvir recently received emergency regulatory approval for the treatment of SARS-CoV-2 from the Ministry of Health, Labour and Welfare in Japan. The NIH also plans to study the drug in hospitalized patients.

"We hope results from this trial can be applied to improve the standard of care for people with COVID-19, which still causes hundreds of deaths each day in the United States, as well as to strengthen our pandemic preparedness," said H. Clifford Lane, MD, deputy director for clinical research and special projects at the National Institute of Allergy and Infectious Diseases, in a press release.

Uehara presented data from the phase III portion of the trial. Overall, 1,798 patients were enrolled within 120 hours of onset of symptoms and randomized to 125-mg ensitrelvir (n=603), 250-mg ensitrelvir (n=595), or placebo (n=600) for 5 days.

Patients were followed for clinical symptoms and safety data to day 28, and to 3 months and 6 months for long COVID symptoms.

Over half of the participants were men, mean age was 35-36, and almost all were Asian. Most patients (90%) were vaccinated, and Omicron infection was confirmed in more than 87% of participants, with about 70% infected with the BA.2 variant.

Ensitrelvir was well tolerated, with no serious treatment-related adverse events or deaths. Among the most common treatment-related adverse events were temporary decreases in high-density lipoprotein levels and increased blood triglyceride levels.

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