Journal Article

HSK21542 in patients with postoperative pain: two phase 3, multicentre, double-blind, randomized, controlled trials

Wang, Liangrong, Hu, Xiaoling, Xia, Zhongyuan, Zhang, Peng, Li, Lin, Zhong, Yinbo, Yan, Min, Qin, Zhong, Wang, Haiying, Cheng, Zhigang, Xu, Younian, Yang, Mengchang, Lei, Qian, Jiang, Ke, Wang, Zhiping, Xie, Haihui, Zhao, Zhibin, Wu, Jinglei, Li, Yalan, Jiang, Huayong, Wang, Guonian, Wang, Saiying, Wang, Yuexin, Chen, Jingli, Gu, Zhengfeng, Chen, Xiangdong, Zhang, Jiaqiang, Ming, Yue, Zhai, Haoyu

2025

Overview

HSK21542, a peripherally restricted kappa opioid receptor agonist, was evaluated for efficacy and safety in patients with postoperative pain following abdominal surgery. This was assessed in two phase 3, multicentre, randomized, double-blind, controlled trials (HSK21542-301 [ClinicalTrials.gov identifier, NCT04738357] and HSK21542-303 [ClinicalTrials.gov identifier, NCT05390905]) in China. HSK21542-301 was a dual-arm study comparing HSK21542 1.0 μg/kg with placebo, while HSK21542-303 involved three arms comparing HSK21542 1.0 μg/kg with tramadol 50 mg/dose and placebo. All treatments were administered intravenously. The primary endpoint was the time-weighted summed pain intensity differences over 24 h (SPID 0-24 h ). Both HSK21542-301 (least squares [LS] mean [± standard error], −39.1 [1.88] vs −27.4 [1.89]; P  < 0.001) and HSK21542-303 (−64.0 [2.25] vs −45.9 [2.25]; P  < 0.001) demonstrated superiority of HSK21542 over placebo in terms of SPID 0-24 h , while HSK21542-303 showed non-inferiority to tramadol (LS mean difference, −1.1; 95% confidence interval, −7.4 to 5.1; P  < 0.001). Furthermore, HSK21542 had a comparable safety profile to placebo, inducing fewer gastrointestinal adverse events compared with tramadol. Grade ≥3 treatment-emergent adverse events occurred in eight (5.9%) and three (2.3%) patients in the HSK21542 arm of HSK21542-301 and HSK21542-303, respectively. In conclusion, HSK21542 showed potent analgesic effect and was well tolerated in patients who underwent abdominal surgery and experienced postoperative pain. Commonly used opioids for pain management primarily target the mu opioid receptor. However, mu opioid receptor agonists often come with harmful side effects. Here, the authors report the results of two phase 3 trials of HSK21542 (anrikefon), a highly selective activator of peripheral kappa opioid receptor agonists, for postoperative pain treatment following abdominal surgery.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 692/308/153 / 692/698/1688/1366/64 / 692/698/1688/1959/1315/1951 / 692/700/565/411 / Abdomen / Abdominal surgery / Adult / Adverse events / Aged / Agonists / Analgesics / Analgesics, Opioid - administration & dosage / Analgesics, Opioid - adverse effects / Analgesics, Opioid - therapeutic use / Clinical trials / Double-Blind Method / Female / Humanities and Social Sciences / Humans / Male / Middle Aged / multidisciplinary / Narcotics / Opioid receptors (type kappa) / Opioid receptors (type mu) / Pain / Pain Measurement / Pain, Postoperative - drug therapy / Patients / Placebos / Receptors / Receptors, Opioid, kappa - agonists / Science / Science (multidisciplinary) / Side effects / Standard error / Surgery / Tramadol / Tramadol - administration & dosage / Tramadol - therapeutic use / Treatment Outcome