Antiviral efficacy of oral ensitrelvir versus oral ritonavir-boosted nirmatrelvir in COVID-19

Abstract Background Ensitrelvir is an oral antiviral treatment for COVID-19 with the same molecular target as ritonavir-boosted nirmatrelvir - the current oral first-line treatment. There have been no direct comparisons between the two drugs. Methods In an open label controlled adaptive pharmacometric platform trial, low-risk adult patients aged 18-60 years with early symptomatic COVID-19 (<4 days of symptoms) were randomised concurrently to one of eight treatment arms including ensitrelvir, ritonavir-boosted nirmatrelvir, and no study drug. The primary endpoint was the rate of oropharyngeal viral clearance assessed in a modified intention-to-treat population (mITT), defined as patients with ≥3 days of follow-up. Viral clearance rate was derived under a Bayesian hierarchical linear model fitted to the log 10 viral densities in standardised duplicate oropharyngeal swab eluates taken daily over five days (14 measurements). This trial is registered at ClinicalTrials.gov ( NCT05041907 ). Findings Between March 2023 and April 2024 the three study arms randomised 604 patients concurrently in Thailand and Lao PDR (ensitrelvir 202; ritonavir-boosted nirmatrelvir 207; no study drug 195) among 903 patients enrolled. All patients recovered uneventfully. Ensitrelvir was very well tolerated and did not cause dysgeusia. Median (interquartile range) estimated SARS-CoV-2 clearance half-lives were 5.9 hours (4.0 to 8.6) with ensitrelvir; 5.2 hours (3.8 to 6.6) with nirmatrelvir; and 11.6 hours (8.1 to 14.5) with no study drug. Viral clearance following ensitrelvir was 82% (95% credible interval, CrI: 61 to 104%) faster than no study drug and 16% (95% CrI: 5 to 25%) slower than ritonavir-boosted nirmatrelvir. Viral rebound occurred in 15 (7%) of the nirmatrelvir group and 10 (5%) of the ensitrelvir group (p=0.4). Conclusions Both ensitrelvir and nirmatrelvir markedly accelerate oropharyngeal SARS-CoV-2 viral clearance. Ensitrelvir is an efficacious and well tolerated alternative to currently available antivirals in treating COVID-19. Funding “Finding treatments for COVID-19: A phase 2 multi-centre adaptive platform trial to assess antiviral pharmacodynamics in early symptomatic COVID-19 (PLAT-COV)” is supported by the Wellcome Trust Grant ref: 223195/Z/21/Z through the COVID-19 Therapeutics Accelerator. Research in context Evidence before this study We searched PubMed for studies published in English from Jan 1, 2020, to April 10, 2025, using the terms: “randomised” AND [“nirmatrelvir OR paxlovid”] AND “ensitrelvir”. Both ritonavir-boosted nirmatrelvir and ensitrelvir have shown in-vivo antiviral activity and clinical benefit, but there have been no direct randomised head-to-head comparisons. Comparisons between the preregistration studies are confounded by substantial differences in the study populations, and timing of the studies. Added value of this study Comparison of antiviral drug efficacy using clinical endpoints is difficult-‘hard endpoints’ such as hospitalisation or death require prohibitively large sample sizes due to their rarity, and classification of more frequently encountered milder symptoms are imprecise. By contrast, this pharmacometric approach provides a quantitative measure of antiviral effects in patients with tractable sample sizes. This randomised study provides the first direct comparison of the in-vivo antiviral effects of ritonavir-boosted nirmatrelvir and ensitrelvir. Both drugs markedly accelerate SARS-CoV-2 viral clearance. An individual patient meta-analysis of all drugs included in the study confirms these drugs to have the most potent anti-SARS-CoV-2 antiviral effect. Implications of all the available evidence Both ritonavir-boosted nirmatrelvir and ensitrelvir have potent in-vivo antiviral activity in patients with early COVID-19. Ensitrelvir can be considered an efficacious and well-tolerated alternative to currently available antivirals. Candidate antivirals and antiviral combinations for respiratory viruses (including COVID-19 and Influenza) should be assessed and compared using this method.