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..
References
Alpizar, Accini, Anderson, Eysa, Medina-Piñón et al., Molnupiravir for intra-household prevention of COVID-19: The MOVe-AHEAD randomized, placebo-controlled trial, J. Infect,
doi:10.1016/j.jinf.2023.08.016Ando, Noshi, Sato, Ishibashi, Yoshida et al., Pharmacokinetic and pharmacodynamic analysis of baloxavir marboxil, a novel cap-dependent endonuclease inhibitor, in a murine model of influenza virus infection, J. Antimicrob. Chemother,
doi:10.1093/jac/dkaa393Fukao, Nobori, Kuroda, Baba, Matsumoto et al., Pharmacokinetic and pharmacodynamic analysis of the 3CL protease inhibitor ensitrelvir in a SARS-CoV-2 infection mouse model, Viruses,
doi:10.3390/v15102052Hayden, Gubareva, Monto, Klein, Elliot et al., Inhaled zanamivir for the prevention of influenza in families. Zanamivir Family Study Group, N. Engl. J. Med,
doi:10.1056/NEJM200011023431801Ikematsu, Hayden, Kawaguchi, Kinoshita, De Jong et al., Baloxavir marboxil for prophylaxis against influenza in household contacts, N. Engl. J. Med,
doi:10.1056/NEJMoa1915341Kashiwagi, Watanabe, Ikematsu, Awamura, Okamoto et al., Laninamivir octanoate for post-exposure prophylaxis of influenza in household contacts: a randomized double blind placebo controlled trial, J. Infect. Chemother,
doi:10.1007/s10156-013-0622-9Kawashima, Matsui, Adachi, Morikawa, Inoue et al., Ensitrelvir is effective against SARS-CoV-2 3CL protease mutants circulating globally, Biochem. Biophys. Res. Commun,
doi:10.1016/j.bbrc.2023.01.040Kuroda, Nobori, Fukao, Baba, Matsumoto et al., Efficacy comparison of 3CL protease inhibitors ensitrelvir and nirmatrelvir against SARS-CoV-2 in vitro and in vivo, J. Antimicrob. Chemother,
doi:10.1093/jac/dkad027Martins-Filho, Ferreira, Heimfarth, De Souza Araújo, Quintans-Júnior, Efficacy and safety of hydroxychloroquine as pre-and post-exposure prophylaxis and J o u r n a l P r e -p r o o f treatment of COVID-19: A systematic review and meta-analysis of blinded, placebocontrolled, randomized clinical trials, Lancet Reg. Health Am,
doi:10.1016/j.lana.2021.100062Matsuyama, Nao, Shirato, Kawase, Saito et al., Enhanced isolation of SARS-CoV-2 by TMPRSS2-expressing cells, Proc. Natl. Acad. Sci. U. S. A,
doi:10.1073/pnas.2002589117Mukae, Yotsuyanagi, Ohmagari, Doi, Imamura et al., 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, Antimicrob. Agents Chemother,
doi:10.1128/aac.00697-22Mukae, Yotsuyanagi, Ohmagari, Doi, Sakaguchi et al., Efficacy and safety of ensitrelvir in patients with mild-to-moderate COVID-19: the phase 2b part of a randomized, placebocontrolled, phase 2/3 study, Clin. Infect. Dis,
doi:10.1101/2022.06.22.22276792Nobori, Fukao, Kuroda, Anan, Tashima et al., Efficacy of ensitrelvir against SARS-CoV-2 in a delayed-treatment mouse model, J. Antimicrob. Chemother,
doi:10.1093/jac/dkac257Ouyang, Zaongo, Harypursat, Li, Routy et al., SARS-CoV-2 pre-exposure prophylaxis: A potential COVID-19 preventive strategy for high-risk populations, including healthcare workers, immunodeficient individuals, and poor vaccine responders, Front. Public Health,
doi:10.3389/fpubh.2022.945448Pfizer, Pfizer Shares Top-Line Results from Phase 2/3 EPIC-PEP Study of PAXLOVID™ for Post-Exposure Prophylactic Use
Shimizu, Sonoyama, Fukuhara, Kuwata, Matsuo et al., A phase 1 study of ensitrelvir fumaric acid tablets evaluating the safety, pharmacokinetics and food effect in healthy adult populations, Clin. Drug Investig,
doi:10.1007/s40261-023-01309-zUemura, Nobori, Sato, Toba, Kusakabe et al., 2-Thiouridine is a broad-spectrum antiviral nucleoside analogue against positive-strand RNA viruses, Proc. Natl. Acad. Sci. U. S. A,
doi:10.1073/pnas.2304139120Unoh, Uehara, Nakahara, Nobori, Yamatsu et al., Discovery of S-217622, a Noncovalent Oral SARS-J o u r n a l P r e -p r o o f CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19, J. Med. Chem,
doi:10.1021/acs.jmedchem.2c00117Vangeel, Chiu, De Jonghe, Maes, Slechten et al., Remdesivir, molnupiravir and nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern, Antiviral Res,
doi:10.1016/j.antiviral.2022.105252Welliver, Monto, Carewicz, Schatteman, Hassman et al., Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial,
doi:10.1001/jama.285.6.748
