Experimental COVID-19 drug shows promising antiviral efficacy in Asians

The oral SARS-CoV-2 3C-like protease inhibitor ensitrelvir fumaric acid helps speed up recovery time for COVID-19 symptoms in patients with mild-to-moderate infection, according to the phase III data from the phase II/III SCORPIO-SR study conducted in Asia.

Time to resolution of the composite of five characteristic symptoms of SARS-CoV-2 Omicron infection (ie, stuffy or runny nose, sore throat, cough, feeling hot or feverish, and low energy or tiredness)—the primary endpoint—was shorter by 24.3 hours among patients who received ensitrelvir 125 mg within 72 hours of disease onset than among those who received placebo (167.9 vs 192.2 hours; p=0.04). [JAMA Netw Open 2024;7:e2354991]

Furthermore, ensitrelvir treatment led to a significant reduction in the time to virus clearance, with the first negative SARS-CoV-2 titre occurring 29.1 hours earlier relative to placebo (median, 36.2 vs 65.3 hours; p<0.001). By day 4, patients on ensitrelvir had a 2.48-log₁₀ copies/mL reduction in their viral RNA level as compared with a 1.01-log₁₀ copies/mL reduction in the placebo group.

Outcomes with 250-mg ensitrelvir were comparable but slightly inferior to those observed with 125-mg ensitrelvir.

“The current SCORPIO-SR study met the primary endpoint and demonstrated clinical efficacy of ensitrelvir in the resolution of COVID-19 symptoms (sustained for at least 24 hours) irrespective of the presence of risk factors for severe disease,” the investigators said.

“Moreover, a significant reduction compared with placebo was observed in the two key secondary endpoints representing antiviral efficacy,” they noted.

No major safety concerns

In terms of safety, ensitrelvir was generally well tolerated. Adverse events (AEs) occurred in 44.2 percent of patients in the 125-mg ensitrelvir group, 53.6 percent in the 250-mg ensitrelvir group, and 24.8 percent in the placebo group. These AEs were mild in general, and most treatment-related adverse events resolved without sequelae.

Serious adverse events were documented in two patients (heavy menstrual bleeding in one patient on 125-mg ensitrelvir group on day 14 and acute cholecystitis in one patient in the placebo group on day 9), both of which were deemed to be unrelated to treatment. 

The most frequent adverse event was a decrease in high-density lipoprotein levels (31.1 percent in the 125-mg group, 38.6 percent in the 250-mg group, and 3.8 percent in the placebo group), consistent with the findings of previous clinical studies of ensitrelvir. [Antimicrob Agents Chemother 2022;66:e0069722;

Ensitrelvir-treated patients showed a transient change in high-density lipoprotein cholesterol, triglyceride, total bilirubin, and iron levels was at day 6, all of which resolved without additional treatment. None of the patients had clinical jaundice during the study.

Asian population

The primary analysis population included 1,030 patients (53.6 percent men) between 12 and 69 years of age (mean 35.2 years) with mild-to-moderate COVID-19. Enrolled from multiple sites in Japan, Vietnam, and Korea, these patients were randomly assigned to receive treatment with 125 mg of ensitrelvir (375 mg on day 1; n=347), 250 mg of ensitrelvir (750 mg on day 1; n=340), or placebo (n=343). Treatment was administered within 72 hours of disease onset, once daily for 5 days, with a 28-day follow-up period.

The study was limited by the inclusion of mostly Asian patients, as SCORPIO-SR was conducted only in Asian countries. Also, while ensitrelvir shortened the COVID-19 symptom duration, the absolute difference in median time to resolution was approximately 1 day relative to placebo.

The investigators shared that ensitrelvir is being explored further through various clinical trials, which involve patients with and without risk factors (SCORPIO-HR), those who are hospitalized (STRIVE), and children.