Inhibition of cap-dependent endonuclease in influenza virus with ADC189: a pre-clinical analysis and phase I trial

Abstract

ADC189 is a novel drug of cap-dependent endonuclease inhibitor. In our study, its antiviral efficacy was evaluated in vitro and in vivo, and compared with baloxavir marboxil and oseltamivir. A first-in-human phase I study in healthy volunteers included single ascending dose (SAD) and food effect (FE) parts. In the pre-clinical study, ADC189 showed potent antiviral activity against various types of influenza viruses, including H1N1, H3N2, influenza B virus, and highly pathogenic avian influenza, comparable to baloxavir marboxil. Additionally, ADC189 exhibited much better antiviral efficacy than oseltamivir in H1N1 infected mice. In the phase I study, ADC189 was rapidly metabolized to ADC189-I07, and its exposure increased proportionally with the dose. The terminal elimination half-life (T_1/2) ranged from 76.69 to 98.28 hours. Of note, food had no effect on the concentration, clearance, and exposure of ADC189. It was well tolerated, with few treatment-emergent adverse events (TEAEs) reported and no serious adverse events (SAEs). ADC189 demonstrated excellent antiviral efficacy both in vitro and in vivo. It was safe, well-tolerated, and had favorable pharmacokinetic characteristics in healthy volunteers, supporting its potential for single oral dosing in clinical practice.

Keywords

ADC189 / cap-dependent endonuclease inhibitor / influenza virus / efficacy / phase I trial

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Acknowledgements

This study was sponsored by Jiaxing Andicon Biotech Co., Ltd. Jiaxing Andicon Biotech Co., Ltd. is responsible for the initiation, management, and funding of this study. We thank the investigators Shuming Sun and Jiehui Hu of Frontage Laboratories (Suzhou) Co., Ltd. for valuable experimental contributions. We also thank the collaborators of Hangzhou Tigermed Consulting Co., Ltd. for the help of data analysis, statistical analysis, and data interpretation.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-024-1115-1 and is accessible for authorized users.

Compliance with ethics guidelines

Conflict of interest Jing Wei, Yaping Deng, Xiaoyun Zhu, Xin Xiao, Yang Yang, Chunlei Tang, and Jian Chen declare that they have no conflict of interest.

All applicable institutional and/or national guidelines for the care and use of animals were followed. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The clinical trial was registered with ChinaDrugTrials.org.cn (No. CTR20213319). This study was designed by sponsor representatives and study investigators. The full protocol and its amendments were approved by institutional review board of Xiaoshan Hospital, Zhejiang. The current study was approved by the Hospital Ethics Committee of Zhejiang Xiaoshan Hospital (No. EC-2022080904). All patients provided written informed consent.

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