Inhibition of cap-dependent endonuclease in influenza virus with ADC189: a pre-clinical analysis and phase I trial.
10.1007/s11684-024-1115-1
- Author:
Jing WEI
1
;
Yaping DENG
2
;
Xiaoyun ZHU
1
;
Xin XIAO
2
;
Yang YANG
2
;
Chunlei TANG
3
;
Jian CHEN
4
,
5
Author Information
1. Jiaxing Andicon Biotech Co., Ltd., Jiaxing, 314006, China.
2. Department of Clinical Pharmacology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, 311202, China.
3. School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, 214122, China. tangcl@jiangnan.edu.cn.
4. Department of Clinical Pharmacology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, 311202, China. cj21_0503@
5. com.
- Publication Type:Clinical Trial, Phase I
- Keywords:
ADC189;
cap-dependent endonuclease inhibitor;
efficacy;
influenza virus;
phase I trial
- MeSH:
Humans;
Antiviral Agents/therapeutic use*;
Animals;
Male;
Adult;
Mice;
Female;
Endonucleases/antagonists & inhibitors*;
Influenza, Human/drug therapy*;
Young Adult;
Dibenzothiepins/pharmacology*;
Oseltamivir/pharmacology*;
Middle Aged;
Triazines/pharmacology*;
Thiepins/pharmacology*;
Influenza B virus/drug effects*;
Influenza A Virus, H1N1 Subtype/drug effects*;
Pyridines/pharmacology*;
Morpholines;
Pyridones
- From:
Frontiers of Medicine
2025;19(2):347-358
- CountryChina
- Language:English
-
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 preclinical 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 (T1/2) 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.
