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Prophylactic effect of ensitrelvir in mice infected with SARS-CoV-2

Nobori et al., Antiviral Research, doi:10.1016/j.antiviral.2024.105852
Feb 2024  
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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 challenge significantly increased 14-day survival rates and reduced body weight loss compared to control mice. Ensitrelvir plasma concentrations of 2.99 μg/mL or greater at the time of infection conferred significant protection. Viral titers were suppressed in the lungs of ensitrelvir-treated mice, suggesting ensitrelvir exerts its prophylactic effect by inhibiting viral replication.
3 preclinical studies support the efficacy of ensitrelvir for COVID-19:
In Vitro studies demonstrate efficacy in VeroE6/TMPRSS2 Note A, Kuroda, HEK293T/ACE2-TMPRSS2 Note B, Kuroda, and MucilAir Note C, Kuroda cells. Animal studies demonstrate efficacy in BALB/c mice Note D, Nobori, Kuroda and Syrian hamsters Note E, Kuroda. Preclinical studies demonstrate efficacy for the ancestral Note F, Kuroda, delta Note G, Kuroda, and omicron Note H, Kuroda variants.
Nobori et al., 29 Feb 2024, Japan, peer-reviewed, 10 authors. Contact:,,,,,,,,,
This PaperEnsitrelvirAll
Prophylactic effect of ensitrelvir in mice infected with SARS-CoV-2
Haruaki Nobori, Keiko Baba, Takayuki Kuroda, Kaoru Baba, Kazumi Matsumoto, Shinpei Yoshida, Ryosuke Watari, Yuki Tachibana, Teruhisa Kato, Keita Fukao
Antiviral Research, doi:10.1016/j.antiviral.2024.105852
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological cause of coronavirus disease 2019 and continues to be a major health concern worldwide. Strategies to protect individuals at high risk of COVID-19 are critical but are currently a largely unmet need. We evaluated the oral antiviral drug ensitrelvir, which specifically targets the SARS-CoV-2 3CL protease, for its efficacy as a pre-exposure prophylactic treatment. Aged BALB/c mice were subcutaneously treated with various doses of ensitrelvir 24 h prior to a lethal SARS-CoV-2 challenge infection. Mouse body weight changes, survival rates, and viral titers in the lungs were evaluated, and plasma concentrations of ensitrelvir were determined. A single subcutaneous administration of ensitrelvir at 64 mg/kg or greater 24 h prior to SARS-CoV-2 challenge infection significantly protected aged mice against lethality and inhibited body weight loss. Pharmacokinetic analysis of ensitrelvir in the aged mice suggested that plasma concentrations ≥ 2.99 µg/mL resulted in a significant prophylactic effect against SARS-CoV-2 infection. In the aged mouse prophylaxis model, SARS-CoV-2 titers were suppressed in the lungs of mice treated with ensitrelvir 24 h prior to challenge infection, suggesting that the prophylactic administration of ensitrelvir exerted its prophylactic effect by suppressing viral proliferation. These findings suggest that ensitrelvir is a candidate drug for pre-exposure prophylactic treatment of individuals at high risk of COVID-19.
Effect of prophylactic ensitrelvir on body weight in aged mice infected with SARS-CoV-2 The prophylactic effect of S-217622 against lethal infection with the SARS-CoV-2 MA-P10 strain in mice was evaluated by monitoring body weight loss for 14 d post-challenge infection. A single dose of ensitrelvir administered subcutaneously at 64, 96, or 128 mg/kg 24 h prior to infection significantly suppressed body weight loss due to SARS-CoV-2 infection (Fig. 3 and Supplementary Figure S2 ). A single subcutaneous dose of 32 mg/kg ensitrelvir failed to provide significant prophylactic protection compared to that of vehicle (P ≥ 0.3039). The 64 mg/kg and 96 mg/kg ensitrelvir treatment provided significant protection from weight loss compared to that of vehicle from day 3 through day 7 post-infection (P < 0.05 -P < 0.001). Significant protection was also observed for ensitrelvir doses 128 mg/kg from day 2 through day 7 post-infection (P < 0.001). Effect of prophylactic ensitrelvir on viral load in the lungs of aged mice infected with SARS- CoV-2 To evaluate the prophylactic effect of ensitrelvir against lethal infection with the SARS-CoV-2 MA-P10 strain, lung virus titers were measured at 1, 2, 4, and 9 d post-challenge infection. A single prophylactic subcutaneous administration of 64 or 128 mg/kg ensitrelvir 24 h before infection significantly suppressed the lung viral load in mice (Fig. 4 , Supplementary Table S1 ). The lung viral titers peaked at 2 d post-infection and..
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