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.

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 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 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 < .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. CLINICAL TRIALS REGISTRATION: Japan Registry of Clinical Trials: jRCT2031210350 (https://jrct.niph.go.jp/en-latest-detail/jRCT2031210350).

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

BACKGROUND: Limited treatment options exist for patients with mild-to-moderate coronavirus disease 2019 (COVID-19), irrespective of vaccination history or risk status. Ensitrelvir is a novel oral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3C-like (3CL) protease inhibitor. While phase 2 studies of ensitrelvir have demonstrated promising results in treating mild-to-moderate COVID-19, evaluation of its clinical efficacy due to shifting vaccination status and emergence of the Omicron variant represents significant challenges. Here, we describe the protocol for a phase 3 study designed to evaluate the efficacy and safety of ensitrelvir in patients with mild-to-moderate COVID-19, regardless of risk status or vaccination history. METHODS: This is a multicenter, randomized, double-blind, placebo-controlled, phase 3 study. Patients with mild-to-moderate COVID-19 within 120 hours from onset will be randomized in a 1:1:1 ratio into 3 treatment arms-ensitrelvir 125 mg (375 mg loading dose on Day 1), ensitrelvir 250 mg (750 mg loading dose on Day 1), and placebo. The study interventions will be administered orally, once-daily, for 5 days. The primary endpoint will be the time to resolution of 5 symptoms of COVID-19 (stuffy or runny nose, sore throat, cough, feeling hot or feverish, and low energy or tiredness), and the key secondary endpoints will include the change from baseline on Day 4 in the amount of SARS-CoV-2 viral ribonucleic acid (RNA) and the time to first negative SARS-CoV-2 viral titer. The primary population for the primary and key secondary endpoints will be patients with <72 hours from COVID-19 onset to randomization and, subsequently, patients in entire patient population (<120 hours) in the ensitrelvir 125 mg group. Closed testing procedure will be used for the primary and key secondary endpoints in both the primary and entire patient populations. All safety assessments and adverse events (AE) will be reported. DISCUSSION: In a post hoc analysis of the phase 2b study, compared with placebo, ensitrelvir demonstrated a reduced time to resolution of 5 symptoms in patients with mild-to-moderate COVID-19. Through this study, we intend to validate and establish the efficacy and safety of ensitrelvir in patients with mild-to-moderate COVID-19.

A Randomized Phase 2/3 Study of Ensitrelvir, a Novel Oral SARS-CoV-2 3C-Like Protease Inhibitor, in Japanese Patients with Mild-to-Moderate COVID-19 or Asymptomatic SARS-CoV-2 Infection: Results of the Phase 2a Part.

This multicenter, double-blind, phase 2a part of a phase 2/3 study assessed the efficacy and safety of ensitrelvir, a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3C-like protease inhibitor, in Japanese patients with mild-to-moderate coronavirus disease 2019 (COVID-19) or asymptomatic SARS-CoV-2 infection. Sixty-nine patients were randomized (1:1:1) to orally receive 5-day ensitrelvir fumaric acid (375 mg on day 1 followed by 125 mg daily, or 750 mg on day 1 followed by 250 mg daily) or placebo and followed up until day 28. The primary outcome was the change from baseline in the SARS-CoV-2 viral titer. A total of 16, 14, and 17 patients in the ensitrelvir 125 mg, ensitrelvir 250 mg, and placebo groups, respectively, were included in the intention-to-treat population (mean age: 38.0 to 40.4 years). On day 4, the change from baseline in SARS-CoV-2 viral titer (log10 50% tissue culture infectious dose/mL) in patients with positive viral titer and viral RNA at baseline was greater with ensitrelvir 125 mg (mean [standard deviation], -2.42 [1.42]; P = 0.0712) and 250 mg (-2.81 [1.21]; P = 0.0083) versus placebo (-1.54 [0.74]); ensitrelvir treatment reduced SARS-CoV-2 RNA by -1.4 to -1.5 log10 copies/mL versus placebo. The viral titer and viral RNA were similar across groups on and after day 6. The median time to infectious viral clearance decreased by approximately 50 h with ensitrelvir treatment. All adverse events were mild to moderate. Ensitrelvir treatment demonstrated rapid SARS-CoV-2 clearance and was well tolerated (Japan Registry of Clinical Trials identifier: jRCT2031210350).