Efficacy and Safety of Ensitrelvir in Patients With Mild-to-Moderate Coronavirus Disease 2019: The Phase 2b Part of a Randomized, Placebo-Controlled, Phase 2/3 Study

Abstract

Background This phase 2b part of a randomized phase 2/3 study assessed the efficacy and safety of ensitrelvir for mild-to-moderate coronavirus disease 2019 (COVID-19) during the Omicron epidemic. Methods Patients were randomized (1:1:1) to orally receive ensitrelvir fumaric acid 125 mg (375 mg on day 1) or 250 mg (750 mg on day 1) or placebo once daily for 5 days. The co-primary endpoints were the change from baseline in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) titer on day 4 and time-weighted average change from baseline up to 120 hours in the total score of predefined 12 COVID-19 symptoms. Safety was assessed through adverse events. Results A total of 341 patients (ensitrelvir 125 mg group, 114; ensitrelvir 250 mg group, 116; and placebo group, 111; male, 53.5%–64.9%; mean age, 35.3–37.3 years) were included in the efficacy analyses. The change from baseline in the SARS-CoV-2 titer on day 4 was significantly greater with both ensitrelvir doses than with placebo (differences from placebo: -0.41 log10 50% tissue-culture infectious dose/mL, P < 0.0001 for both). The total score of the 12 COVID-19 symptoms did not show a significant difference between the ensitrelvir groups and placebo group. The time-weighted average change from baseline up to 120 hours was significantly greater with ensitrelvir versus placebo in several subtotal scores, including acute symptoms and respiratory symptoms. Most adverse events were mild in severity. Conclusions Ensitrelvir treatment demonstrated a favorable antiviral efficacy and potential clinical benefit with an acceptable safety profile.

A phase 2/3 study of S-217622 in participants with SARS-CoV-2 infection (Phase 3 part)

“…Based on the results of the phase 2a [ 30 ] and 2b [ 31 ] studies, patients will be orally administered a once-daily dosage of ensitrelvir 125 mg, ensitrelvir 250 mg, or a matching placebo. Two types of placebo doses will be administered: placebo-B, which is identical in appearance and packaging to ensitrelvir 125 mg, and placebo-D, which is identical in appearance and packaging to ensitrelvir 250 mg. For patients assigned to the placebo group, 3 tablets each of placebo-B and placebo-D will be administered on Day 1, followed by 1 tablet each of placebo-B and placebo-D administered on Days 2 to 5.…”

“…The phase 2a [ 30 ] and 2b [ 31 ] studies demonstrated decreased viral load with ensitrelvir treatment. In the phase 2a and 2b studies, time to improvement of COVID-19 symptoms was used for clinical assessment, similar to the assessment of influenza treatment, and a significant difference was not observed between ensitrelvir and placebo arms.…”

“…[ 29 ] Promising results have been observed in the ongoing phase 2/3 study comprising several components—phase 2a, phase 2b, phase 2b/3, and phase 3 (SCORPIO-SR) studies—designed to assess the antiviral efficacy of ensitrelvir. The phase 2a [ 30 ] and 2b [ 31 ] studies showed that once-daily ensitrelvir administered for 5 days demonstrated a significant reduction in viral titer and viral RNA compared with placebo in mild-to-moderate COVID-19. In the phase 2b study, while there was no significant difference between ensitrelvir and placebo in the time-weighted average change in total score corresponding to the 12 COVID-19 symptoms (with the exception of smell or taste disorder; Supplemental Table 1, http://links.lww.com/MD/I511 ), planned and post hoc analyses demonstrated that ensitrelvir produced favorable improvements in a subtotal of 4 respiratory symptoms (planned) or in the composite of respiratory symptoms and feverishness (post hoc).…”

“…In the phase 2b study, while there was no significant difference between ensitrelvir and placebo in the time-weighted average change in total score corresponding to the 12 COVID-19 symptoms (with the exception of smell or taste disorder; Supplemental Table 1, http://links.lww.com/MD/I511 ), planned and post hoc analyses demonstrated that ensitrelvir produced favorable improvements in a subtotal of 4 respiratory symptoms (planned) or in the composite of respiratory symptoms and feverishness (post hoc). [ 31 ] Both studies demonstrated that ensitrelvir was safe and well tolerated. [ 30 , 31 ] The phase 2b study was conducted when Omicron was the dominant variant, and most patients had been vaccinated.…”

“…[ 31 ] Both studies demonstrated that ensitrelvir was safe and well tolerated. [ 30 , 31 ] The phase 2b study was conducted when Omicron was the dominant variant, and most patients had been vaccinated. [ 31 ] These studies suggested the need to evaluate efficacy in endpoints that reflect clinical features of SARS-CoV-2 strains in circulation at the time.…”