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Clinical Trial
. 2025 Apr:236:106097.
doi: 10.1016/j.antiviral.2025.106097. Epub 2025 Jan 30.

Ensitrelvir treatment-emergent amino acid substitutions in SARS-CoV-2 3CLpro detected in the SCORPIO-SR phase 3 trial

Takeki Uehara  1 , Hiroshi Yotsuyanagi  2 , Norio Ohmagari  3 , Yohei Doi  4 , Masaya Yamato  5 , Takumi Imamura  6 , Hiroki Sakaguchi  6 , Akimasa Fukushi  6 , Yosuke Takeda  6 , Keiko Baba  7 , Haruaki Nobori  7 , Tadashi Miyamoto  7 , Shuhei Arita  7 , Reiko Dodo  7 , Alice Shimba  7 , Keita Fukao  7 , Takao Shishido  7 , Yuko Tsuge  6 , Hiroshi Mukae  8
Affiliations
Clinical Trial

Ensitrelvir treatment-emergent amino acid substitutions in SARS-CoV-2 3CLpro detected in the SCORPIO-SR phase 3 trial

Takeki Uehara et al. Antiviral Res. 2025 Apr.

Abstract

The impact of treatment-emergent amino acid substitutions (TEAASs) in severe acute respiratory syndome coronavirus 2 (SARS-CoV-2) 3C-like protease (3CLpro) on clinical and virologic outcomes was evaluated in patients with mild-to-moderate coronavirus disease 2019 (COVID-19) who received ensitrelvir 125 mg in the SCORPIO-SR trial. Individuals were randomised to ensitrelvir or matched placebo once daily for 5 days (first dose <72 h after disease onset). 3CLpro-TEAASs were identified by sequencing nsp5 encoding 3CLpro from pre- and post-treatment nasopharyngeal swabs. Time to resolution of a composite of five characteristic COVID-19 symptoms (TTR) was compared between patients with and without the most common 3CLpro-TEAASs in the ensitrelvir arm. The ensitrelvir and placebo intention-to-treat populations comprised 345 and 341 patients, respectively. 3CLpro-TEAASs were detected in 19/204 (9.3%) ensitrelvir-treated and 3/137 (2.2%) placebo-treated patients with paired sequence data. The most common 3CLpro-TEAASs in the ensitrelvir arm were M49L (n = 12), M49I (n = 3) and S144A (n = 2). In the placebo arm, all 3CLpro-TEAASs occurred in ≤1 patient. Median (95% confidence interval) TTR was comparable between patients with and without those TEAASs (158.8 h [112.1-281.9] vs 189.7 h [151.4-234.4]). Mean viral RNA levels declined more slowly in patients with M49L/I or S144A versus those without. Reductions in viral titre were unaffected by these TEAASs. The characteristics of recombinant SARS-CoV-2 with 3CLpro mutations were explored in vitro. Recombinant viruses with some 3CLpro mutations had reduced susceptibility to ensitrelvir in vitro, with limited effects on viral and competitive fitness. Continued surveillance is warranted to monitor the spread of viruses with 3CLpro mutations.

Keywords: Antiviral resistance; COVID-19; Ensitrelvir; SARS-CoV-2; Treatment-emergent amino acid substitutions; nsp5.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: Hiroshi Yotsuyanagi has received honoraria for lectures from Shionogi, MSD, Pfizer and ViiV Healthcare; received travel and meeting support from Shionogi; serves as an advisory board member of Shionogi; and is President of the Japanese Society of Infectious Diseases. Yohei Doi has received grants from Entasis and Shionogi; consulting fees from GSK, Moderna, Gilead Sciences, Shionogi, Fujifilm, Meiji Seika Pharma, Pfizer and AbbVie; and lecture fees from Gilead and Shionogi. Masaya Yamato has received lecture fees from Shionogi. Takeki Uehara, Takumi Imamura, Hiroki Sakaguchi, Akimasa Fukushi, Yosuke Takeda, Keiko Baba, Haruaki Nobori, Tadashi Miyamoto, Shuhei Arita, Reiko Dodo, Alice Shimba, Keita Fukao, Takao Shishido and Yuko Tsuge are full-time employees of Shionogi & Co., Ltd. and may hold stock in the company. Hiroshi Mukae has received support for the present manuscript from Shionogi; consulting fees from Shionogi and MSD; and lecture fees from Shionogi, MSD, Gilead Sciences, AstraZeneca, Pfizer and GSK. Norio Ohmagari has no conflict of interest to declare.

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