流感帽依赖性核酸内切酶抑制剂ZX-7101A治疗非复杂性流感成人患者的疗效和安全性：一项随机、双盲、安慰剂对照的2/3期试验
Efficacy and safety of ZX-7101A, an inhibitor of influenza cap-dependent endonuclease, in adults with uncomplicated influenza: a randomized, double-blind, placebo-controlled phase 2/3 trial.
作者信息
Wang Hongyu, Wang Gang, Gao Yan, Qu Lihong, Wang Hong, Deng Min, Gao Hainv, Li Yilin, Yang Nan, Wang Baogui, Liu Rongge, Ma Xuzhu, Tao Zhen, Zhang Guoqiang, Wang Qian, Zhao Weifeng, Yu Yunsong, Chen Lin, Liang Lianchun, Wang Shengyu, Shao Lei, Yang Tao, Cao Jinglei, Cao Yuan, Qin Xiaoli, Ai Jingwen, Zhu Huadong, Zhang Wenhong
机构信息
Department of Infectious Diseases, National Medical Center for Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Department of Infectious Disease, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Shandong, China.
出版信息
Clin Microbiol Infect. 2025 Feb;31(2):274-281. doi: 10.1016/j.cmi.2024.10.020. Epub 2024 Oct 26.
OBJECTIVES
To evaluate the efficacy and safety of ZX-7101A: an inhibitor of influenza viral cap-dependent endonuclease, in adults with uncomplicated influenza and explore treatment-emergent resistance.
METHODS
We conducted a randomized, double-blind, placebo-controlled, adaptive-design phase 2 and phase 3 studies (ZX-7101A-202) in adults with uncomplicated influenza. Eligible patients were randomized 1:1:1 to receive a single dose of 40 or 80 mg ZX-7101A or placebo, stratified by body weight and baseline composite symptom score. The primary efficacy endpoint was time to alleviation of influenza symptoms (TTAS) in intention-to-treat infected population.
RESULTS
The phase 2 trial suggested significantly shorter TTAS for ZX-7101A compared with placebo: the median TTAS of 40 or 80 mg ZX-7101A groups were 34.7 hours (95% CI, 22.8-43.4; p 0.005) and 45.8 hours (95% CI, 32.0-66.3; p 0.020), compared with 63.6 hours (95% CI, 43.9-93.4) in the placebo group. In the phase 3 trial, the TTAS of both ZX-7101A dose groups was significantly shortened relative to the that of placebo group: the median TTAS was shortened to 48.4 hours (95% CI, 40.5-55.6) for 40 mg group and 39.4 hours (95% CI, 35.8-49.3) for 80 mg group, compared with 62.9 hours (95% CI, 56.4-69.3) for placebo group (p 0.003 and p < 0.001, respectively). In the safety population, ZX-7101A treatment was associated with fewer adverse events, with 41.8% (100/239) in the 40 mg group, 44.2% (106/240) in the 80 mg group, and 53.8% (129/240) in the placebo group. The majority of adverse events were mild or moderate. Emergence of resistance to ZX-7101A through I38T amino acid substitution was detected in 5/278 (1.8%) patients.
DISCUSSION
ZX-7101A was an effective treatment for influenza with a single dose of either 40 mg or 80 mg, with more rapid alleviation of influenza symptoms vs. placebo. No safety concerns were identified with single dose treatment of ZX-7101A.
目的
评估流感病毒帽依赖性核酸内切酶抑制剂ZX - 7101A治疗无并发症流感成年患者的疗效和安全性，并探索治疗中出现的耐药性。
方法
我们对无并发症流感成年患者进行了一项随机、双盲、安慰剂对照、适应性设计的2期和3期研究（ZX - 7101A - 202）。符合条件的患者按体重和基线综合症状评分分层，以1:1:1的比例随机接受单剂量40或80 mg ZX - 7101A或安慰剂。主要疗效终点是意向性治疗感染人群中流感症状缓解时间（TTAS）。
结果
2期试验表明，与安慰剂相比，ZX - 7101A的TTAS显著缩短：40或80 mg ZX - 7101A组的中位TTAS分别为34.7小时（95%CI，22.8 - 43.4；p<0.005）和45.8小时（95%CI，32.0 - 66.3；p<0.02），而安慰剂组为63.6小时（95%CI，43.9 - 93.4）。在3期试验中，两个ZX - 7101A剂量组的TTAS相对于安慰剂组均显著缩短：40 mg组的中位TTAS缩短至48.4小时（95%CI，40.5 - 55.6），80 mg组为39.4小时（95%CI，35.8 - 49.3），而安慰剂组为62.9小时（95%CI，56.4 - 69.3）（p分别为<0.003和<0.001）。在安全性人群中，ZX - 7101A治疗的不良事件较少，40 mg组为41.8%（100/239），80 mg组为44.2%（106/240），安慰剂组为53.8%（129/240）。大多数不良事件为轻度或中度。在5/278（1.8%）的患者中检测到通过I38T氨基酸替代对ZX - 7101A产生耐药性。
讨论
单剂量40 mg或80 mg的ZX - 7101A是治疗流感的有效药物，与安慰剂相比，能更快缓解流感症状。单剂量治疗ZX - 7101A未发现安全问题。
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