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

Abstract

For the treatment of coronavirus disease 2019 (COVID-19), antiviral agents that can achieve rapid severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reduction are warranted. This double-blind, phase 2a part of a phase 2/3 study assessed the efficacy and safety 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. Sixty-nine patients enrolled from 56 sites 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 change from baseline in 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: 38.8, 40.4, and 38.0 years, respectively). 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]), and ensitrelvir treatment reduced SARS-CoV-2 RNA by −1.4 to −1.5 log10 copies/mL versus placebo. All adverse events were mild to moderate. Ensitrelvir treatment demonstrated rapid SARS-CoV-2 clearance and was well tolerated in patients with mild-to-moderate COVID-19 or asymptomatic SARS-CoV-2 infection (Japan Registry of Clinical Trials identifier: jRCT2031210350).

Efficacy and safety of ensitrelvir in patients with mild-to-moderate COVID-19: the phase 2b part of a randomized, placebo-controlled, phase 2/3 study

“…In the current phase 2b part, virologic efficacy was assessed using the change in SARS-CoV-2 viral titer from baseline to day 4 (co-primary endpoint) and SARS-CoV-2 RNA (endpoint commonly used in clinical studies for anti–COVID-19 treatments 14, 16, 21 ). The rapid and significant reduction in the SARS-CoV-2 viral titer and viral RNA following ensitrelvir treatment is consistent with the findings of the previous phase 2a part 20 , but the level of viral titer reduction from baseline to day 4 was lower in the current phase 2b part (−1.49 log 10 TCID 50 /mL) than in the phase 2a part (−2.81 log 10 TCID 50 /mL with ensitrelvir 250 mg) 20 . These differences in findings may be attributed to the lower baseline titer recorded in the phase 2b part than in the phase 2a part (2.5–2.8 versus 3.3–3.7 log 10 TCID 50 /mL), as well as other unidentified differences in viral characteristics.…”

“…The current phase 2b part of the study found no clear dose response, which is consistent with the findings of the phase 2a part 20 . Pharmacokinetic data for 5-day ensitrelvir 125 mg treatment (375 mg on day 1) derived from the phase 1 study of ensitrelvir (maximum plasma concentration, 30.4 µg/mL; area under the curve, 598.3 µg•hr/mL) suggest that this regimen is sufficient to achieve a reduction in SARS-CoV-2 in humans (R. Shimizu et al, unpublished data).…”

“…Clinical efficacy, such as a symptom relief, is a pivotal part of COVID-19 clinical trials because patients present with diverse symptoms 25 and clinical symptoms may differ depending on the epidemic variants. Although the decreasing trend in the total 12 COVID-19 symptom scores is consistent with the findings from the phase 2a part 20 , the results of the current phase 2b part indicate differences in the symptom characteristics between the Omicron and Delta variant infections. Among the 12 symptoms assessed, respiratory symptoms and feverishness were recorded in many patients enrolled in the phase 2b part, whereas systemic and digestive symptoms were relatively less observed at baseline.…”

“…This phase 2b part of a randomized, double-blind, placebo-controlled, phase 2/3 trial of ensitrelvir in patients with mild-to-moderate COVID-19 was conducted in early 2022 during the SARS-CoV-2 Omicron epidemic. Based on the results of the phase 2a part conducted during the SARS-CoV-2 Delta epidemic 20 , which showed a statistically significant reduction in the SARS-CoV-2 viral titer and an improving trend in the total score of the 12 COVID-19 symptoms after ensitrelvir treatment, we used these outcomes as the co-primary endpoints. On day 4, ensitrelvir treatment significantly reduced the SARS-CoV-2 viral titer versus placebo.…”

“…A multicenter, randomized, double-blind, placebo-controlled, phase 2/3 study is also underway to assess the efficacy, safety, and pharmacokinetics of ensitrelvir administered as a 5-day oral regimen. In its phase 2a part, although the sample size was small, ensitrelvir treatment led to a reduction in the SARS-CoV-2 viral titer and viral RNA versus placebo with an acceptable safety profile 20 . Herein, we present the antiviral and clinical efficacy and safety of ensitrelvir derived from the phase 2b part of this phase 2/3 study.…”