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Ensitrelvir for COVID-19
10 studies with >6,000 patients
Serious outcome risk
Ensitrelvir
Control
Significantly lower risk for recovery, cases, and viral clearance.
9 studies from 5 independent teams (all from the same country) show significant benefit.
COVID-19 Ensitrelvir studies · October 2026
Variants may be resistant to ensitrelvir1,2. Ensitrelvir was adopted in 2 countries. Recent:
Nakano
Mukau
Chen
Baker.
Covid Analysis Ensitrelvir for COVID-19: real-time meta-analysis of 10 studies (Version 17)
Significantly lower risk is seen for recovery, cases, and viral clearance. 9 studies from 5 independent teams (all from the same country) show significant benefit. Meta-analysis using the most serious outcome reported shows 12% [1..
Aug 19
 Nakano et al., Journal of the Pediatric Infectious Diseases Society, doi:10.1093/jpids/piag071 A Phase 3 Study of Ensitrelvir in Japanese Participants Aged 6-11 Years with SARS-CoV-2 Infection
4% faster recovery (p=0.84) and 28% improved viral load (p=0.0002). RCT 117 pediatric outpatients (6-11 years) with mild-to-moderate COVID-19 in Japan showing improved viral clearance, but no significant difference in time to symptom resolution with ensitrelvir vs. placebo.
Apr 27
 Chen et al., Journal of Virology, doi:10.1128/jvi.02223-25 SARS-CoV-2 3CLpro mutations T21I and E166A confer differential resistance to simnotrelvir, bofutrelvir, and ensitrelvir
In vitro and mouse study showing differential resistance of SARS-CoV-2 3CLpro T21I/E166A mutations to simnotrelvir, bofutrelvir, nirmatrelvir, and ensitrelvir. The resistant isolate SARS2-T21I/E166A showed 4.3-9.2-fold resistance to simno..
Apr 22
 Baker et al., Clinical Infectious Diseases, doi:10.1093/cid/ciag272 Ensitrelvir for the treatment of hospitalized adults with COVID-19: an international phase 3 randomized placebo-controlled trial
40% higher mortality (p=0.36) and 22% worse recovery (p=0.17). RCT 589 hospitalized patients showing no significant benefit for clinical outcomes with ensitrelvir treatment.
Apr 2
 Henrich et al., NCT06161688 Placebo-Controlled, Randomized Trial of Ensitrelvir (S-217622) for Viral Persistence and Inflammation in People Experiencing Long COVID (PREVAIL-LC)
RCT 40 long COVID patients in the USA, showing no significant improvement with ensitrelvir.
Mar 20
 Mukau et al., Kansenshogaku Zasshi, doi:10.11150/kansenshogakuzasshi.e25012 Effectiveness and Safety of Ensitrelvir Fumaric Acid in Patients with Risk Factors for Severe COVID-19: A Randomized Controlled Trial of Ensitrelvir Compared with Molnupiravir
RCT 150 outpatients with risk factors for severe COVID-19 showing no significant differences in viral clearance between ensitrelvir and molnupiravir. There was no control group.
Oct 14
2025
 Zhou et al., Emerging Microbes & Infections, doi:10.1080/22221751.2025.2552716 SARS-CoV-2 Mpro inhibitor ensitrelvir: asymmetrical cross-resistance with nirmatrelvir and emerging resistance hotspots
In vitro study showing that SARS-CoV-2 develops high-fitness resistance to ensitrelvir through Mpro mutations. Authors found asymmetrical cross-resistance, with ensitrelvir-resistant variants showing minimal cross-resistance to nirmatrelv..
Sep 29
2025
 Ikeuchi et al., BMC Infectious Diseases, doi:10.1186/s12879-025-11651-6 Comparative effectiveness of antiviral treatment on household transmission of SARS-CoV-2: a retrospective cohort study using administrative data
Retrospective 5,398 married couples in Japan showing no significant difference in household transmission rates between molnupiravir, ensitrelvir, and paxlovid. Hospitalized patients receiving antivirals showed a trend toward lower transmi..
Jul 31
2025
 Ul Haq et al., Infection, doi:10.1007/s15010-025-02582-0 Efficacy and safety of Ensitrelvir in asymptomatic or mild to moderate COVID-19: a systematic review and meta-analysis of randomized controlled trials
Meta-analysis of 6 RCTs with 2,793 participants showing significantly lower viral load with ensitrelvir. However, treatment was associated with significant adverse effects including decreased HDL levels, elevated triglycerides, increased ..
May 21
2025
 Schilling et al., The Lancet Infectious Diseases, doi:10.1016/S1473-3099(25)00482-7 (date from preprint) Antiviral efficacy of oral ensitrelvir versus oral ritonavir-boosted nirmatrelvir in COVID-19
8% faster recovery (p=0.006) and 49% improved viral clearance (p<0.0001). RCT 604 low-risk adults with early COVID-19 symptoms showing significantly improved SARS-CoV-2 viral clearance with both ensitrelvir and paxlovid. Inclusion criteria selected for low-risk patients with high viral loads which may not gener..
Apr 30
2025
 Katsuta et al., Journal of Infection and Chemotherapy, doi:10.1016/j.jiac.2025.102669 The time to return-to-work in healthcare workers with COVID-19 treated with ensitrelvir, a novel oral inhibitor of 3C-like protease of SARS-CoV-2: An observational study utilizing pre-existing data from a single hospital
10% faster recovery (p=0.02). Retrospective 102 healthcare workers in Japan showing shorter time to return-to-work with ensitrelvir treatment for COVID-19.
Mar 9
2025
 Hayden et al., New England Journal of Medicine, doi:10.1056/NEJMoa2509306 (results released 3/9/2025) Ensitrelvir for Covid-19 Postexposure Prophylaxis in Household Contacts
68% fewer symptomatic cases (p<0.0001) and 58% fewer cases (p<0.0001). RCT 2,041 household contacts showing significantly lower symptomatic COVID-19 cases with ensitrelvir post-exposure prophylaxis. Some results are from the registry (posted September 16, 2026). Concerns with this trial include: CRITICAL 1. ..
Feb 17
2025
 Luetkemeyer et al., Clinical Infectious Diseases, doi:10.1093/cid/ciaf029 Ensitrelvir for the Treatment of Nonhospitalized Adults with COVID-19: Results from the SCORPIO-HR, Phase 3, Randomized, Double-blind, Placebo-Controlled Trial
203% higher hospitalization (p=0.37), 5% faster recovery (p=0.14), 2% higher long COVID (p=0.8), and 19% improved viral clearance (p=0.02). RCT 2,093 outpatients with mild-to-moderate COVID-19 showing improved viral clearance but no significant difference in time to symptom resolution with ensitrelvir. Participants were randomized to receive ensitrelvir or placebo within five..
Aug 12
2024
 Nair et al., The Journal of Infectious Diseases, doi:10.1093/infdis/jiae385 Persistence of an infectious form of SARS-CoV-2 post protease inhibitor treatment of permissive cells in vitro
In vitro study showing the persistence of an infectious form of SARS-CoV-2 after treatment with 3CLpro inhibitors nirmatrelvir and ensitrelvir, which may explain the rebound often seen with paxlovid. 3CLpro is crucial for processing viral..
Jul 6
2024
 Zhao et al., Quantitative Biology, doi:10.1002/qub2.60 Assessing the inhibition efficacy of clinical drugs against the main proteases of SARS‐CoV‐2 variants and other coronaviruses
In vitro study showing that leritrelvir and GC376 remained effective against some nirmatrelvir- and ensitrelvir-resistant Mpro mutants. Leritrelvir showed better broad-spectrum activity against other pathogenic coronaviruses compared to e..
Jun 28
2024
 Takazono et al., Infectious Diseases and Therapy, doi:10.1007/s40121-024-01010-4 Real-World Effectiveness of Ensitrelvir in Reducing Severe Outcomes in Outpatients at High Risk for COVID-19
24% higher mortality (p=0.84), 158% higher ventilation (p=0.2), 36% lower need for oxygen therapy (p=0.33), and 37% lower hospitalization (p=0.02). Retrospective 167,310 high-risk COVID-19 outpatients in Japan showing significantly lower hospitalization with ensitrelvir treatment.
Jun 24
2024
 Lopez et al., Current Clinical Microbiology Reports, doi:10.1007/s40588-024-00229-6 SARS-CoV-2 Resistance to Small Molecule Inhibitors
Review of resistance mutations in SARS-CoV-2 3CLpro and nsp12 that could reduce efficacy of antiviral therapies including nirmatrelvir, ensitrelvir, remdesivir, and favipiravir. Authors identify 39 single mutations across 17 critical resi..
Feb 29
2024
 Nobori et al., Antiviral Research, doi:10.1016/j.antiviral.2024.105852 Prophylactic effect of ensitrelvir in mice infected with SARS-CoV-2
Mouse study showing protective effects against SARS-CoV-2 infection in aged mice with the 3CL protease inhibitor ensitrelvir. A single subcutaneous dose of ensitrelvir at 64, 96, or 128 mg/kg given 24 hours before a lethal SARS-CoV-2 chal..
Feb 29
2024
 Bouzidi et al., Antiviral Research, doi:10.1016/j.antiviral.2024.105814 Generation and evaluation of protease inhibitor-resistant SARS-CoV-2 strains
In vitro and animal study showing that SARS-CoV-2 can develop resistance to nirmatrelvir and ensitrelvir. Authors generated resistant viral strains through repeated passaging with both drugs. For nirmatrelvir, they identified three differ..
Feb 6
2024
 Yoshida et al., Cureus, doi:10.7759/cureus.61048 (date from preprint) Real-World Efficacy of Ensitrelvir in Hospitalized Patients With COVID-19 in Japan: A Retrospective Observational Study
Retrospective 154 hospitalized COVID-19 patients in Japan showing faster viral clearance and shorter hospitalization with ensitrelvir treatment compared to remdesivir or molnupiravir. There was no significant difference for fever resoluti..
Dec 31
2023
 Bischof, E., Aging and disease, doi:10.14336/AD.2023.0318 Mitigating COVID-19 Mortality and Morbidity in China's Aging Population: A Focus on Available Medications and Future Developments
Review focusing on 3CL protease inhibitors. First generation inhibitors like paxlovid and simnotrelvir require boosting with ritonavir, which can cause drug-drug interactions and other issues. Second generation inhibitors like ensitrelvir..
Nov 30
2023
 Uraki et al., iScience, doi:10.1016/j.isci.2023.108147 Antiviral efficacy against and replicative fitness of an XBB.1.9.1 clinical isolate
In vitro and animal study showing that the SARS-CoV-2 omicron subvariant XBB.1.9.1 has similar antigenicity, antiviral susceptibility, and replicative ability compared to XBB.1.5. Casirivimab, imdevimab, tixagevimab, cilgavimab, sotrovima..
Aug 20
2023
 Moghadasi et al., npj Antimicrobials and Resistance, doi:10.1038/s44259-023-00009-0 Rapid resistance profiling of SARS-CoV-2 protease inhibitors
In vitro study of SARS-CoV-2 main protease (Mpro) variants showing distinct resistance profiles for the Mpro inhibitors nirmatrelvir, ensitrelvir, and FB2001. Results show significant resistance for multiple variants for nirmatrelvir and ..
Jul 13
2023
 Yotsuyanagi et al., JAMA Network Open, doi:10.1001/jamanetworkopen.2023.54991 (date from preprint) Efficacy and Safety of 5-Day Oral Ensitrelvir for Patients With Mild to Moderate COVID-19: The SCORPIO-SR Randomized Clinical Trial
11% faster recovery (p=0.3) and 49% improved viral clearance (p=0.001). RCT 1,821 COVID-19 outpatients in Japan, Vietnam, and South Korea, showing improved viral clearance and improved recovery (significant for patients treated within 3 days of onset) with ensitrelvir. Only 2 hospitalizations were reported, w..
Mar 31
2023
 Moghadasi et al., Science Advances, doi:10.1126/sciadv.ade8778 Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors
Analysis of naturally occurring SARS-CoV-2 main protease variants for resistance to nirmatrelvir and ensitrelvir. Authors identified multiple single amino acid mutations that confer significant resistance to these drugs. Phylogenetic anal..
Feb 10
2023
 Kuroda et al., Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkad027 Efficacy comparison of 3CL protease inhibitors ensitrelvir and nirmatrelvir against SARS-CoV-2 in vitro and in vivo
In vitro and animal study comparing nirmatrelvir and ensitrelvir, showing similar efficacy in vitro, and equal or better efficacy of ensitrelvir in vivo (with similar unbound-drug plasma concentrations).
Dec 7
2022
 Mukae et al., Clinical Infectious Diseases, doi:10.1093/cid/ciac933 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
9% improved recovery (p=0.28) and 32% faster viral clearance (p=0.0001). RCT 428 COVID-19 patients in Japan showing faster viral clearance and improved recovery with ensitrelvir.
May 17
2022
 Mukae et al., medRxiv, doi:10.1101/2022.05.17.22275027 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
45% improved viral clearance (p=0.002). RCT 69 patients in in Japan, showing faster viral clearance with ensitrelvir. 5-day ensitrelvir (375mg on day 1 followed by 125 mg daily or 750mg on day 1 followed by 250mg daily).
References