Multiple doses of SHR-1222, a sclerostin monoclonal antibody, in postmenopausal women with osteoporosis: A randomized, double-blind, placebo-controlled, dose-escalation phase 1 trial

Frontiers in Endocrinology

Endocrinology

Guoping Yang¹  Jianzhong Shentu²  Wenhua Wei³  Kai Shen³  Chang Shu³  Wei Lu³  Hong Chen³  Chong Zou⁴  Guijun Qin⁵  Lijuan Wang⁶  Ping Jin⁷  Xianghang Luo⁸  Qin Zhang⁹  Danhong Peng^1,10  Yanxiang Cheng^1,11  Liping Li^1,12  Zhe Zhang^1,13  Qun Qin^1,14  Zhifeng Sheng^1,15  Xiang Yan^1,16  Rongrong Cui^1,16  Bo Wu^1,16  Xiyu Wu^1,16  Wei Liu^1,16  Yuting Xie^1,16  Zhiguang Zhou^1,16  Lingfeng Yang^1,16  Zhijie Dai^1,16  Chunli Song^1,17  Ronghua Zhu^1,18  Pingfei Fang^1,18  Xiao Fan^1,18  Qiangyong Yan^1,18 

[1] Center of Clinical Pharmacology, The Third Xiangya Hospital of Central South University, Changsha, China;Clinical Pharmacy, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China;Clinical Research & Development, Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China;Department of Clinical Pharmacology, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China;Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China;Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China;Department of Endocrinology, The Third Xiangya Hospital of Central South University, Changsha, China;Department of Endocrinology, Xiangya Hospital of Central South University, Changsha, China;Department of Geriatrics, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China;Department of Gynaecology and Obstetrics, Zhongda Hospital Southeast University, Nanjing, China;Department of Gynecology, Renmin Hospital of Wuhan University, Wuhan, China;Endocrine Department, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China;Endocrinology and Metabolism, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China;National Agency for Clinical Trial of Medicines, Xiangya Hospital of Central South University, Changsha, China;National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Metabolism and Endocrinology, and Health Management Center, The Second Xiangya Hospital of Central South University, Changsha, China;National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China;Orthopedics Department, Peking University Third Hospital, Beijing, China;Phase I Clinical Trial Center and Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China;

关键词: sclerostin;    postmenopausal osteoporosis;    pharmacokinetics;    pharmacodynamics;    bone mineral density;   

DOI  :  10.3389/fendo.2023.1168757

 received in 2023-02-18, accepted in 2023-03-22,  发布年份 2023

来源: Frontiers

【 摘 要 】

SHR-1222, a novel humanized monoclonal antibody targeting sclerostin, has been shown to induce bone formation and decrease bone resorption at a single dose ranging 50–400 mg in our previous phase 1 trial. This study was a randomized, double-blind, placebo-controlled, dose-escalation phase 1 trial, which further investigated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of multiple ascending doses of SHR-1222 in women with postmenopausal osteoporosis (POP). A total of 105 women with POP were enrolled and randomly assigned. Twenty-one received placebo and eighty-four received SHR-1222 sequentially (100 mg QM, n=4; 200 or 300 mg QM, n=20; and 400 or 600 mg Q2M, n=20). The most common adverse events included increased blood parathyroid hormone, increased low-density lipoprotein, increased blood alkaline phosphatase, increased blood cholesterol, back pain, and arthralgia, the majority of which were mild in severity without noticeable safety concerns. Serum SHR-1222 exposure (Cmax,ss and AUC0-tau,ss) increased in a greater than dose-proportional manner. Following multiple doses of SHR-1222, the bone formation markers (terminal propeptide of type I procollagen, bone-specific alkaline phosphatase, and osteocalcin) increased in a dose-dependent manner, whereas the bone resorption marker (β-C-telopeptide) was downregulated. Accordingly, BMD gains in the lumbar spine, total hip, and femoral neck were observed. The maximum BMD increase from baseline at the lumbar spine was detected in the 300 mg QM cohort (14.6% vs. 0.6% in the placebo group on day 169). Six (6/83; 7.2%) subjects developed anti-SHR-1222 antibodies with no discernible effects on PKs, PDs, and safety. Thus, multiple doses of SHR-1222 showed an acceptable safety profile and dose-dependent plasma exposure in women with POP, and could improve their BMD rapidly and prominently by promoting bone formation and inhibiting bone resorption. These findings further support SHR-1222 as a potential alternative agent for the treatment of POP.

【 授权许可】

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Copyright © 2023 Dai, Zhu, Sheng, Qin, Luo, Qin, Song, Li, Jin, Yang, Cheng, Peng, Zou, Wang, Shentu, Zhang, Zhang, Yan, Fang, Yan, Yang, Fan, Liu, Wu, Cui, Wu, Xie, Shu, Shen, Wei, Lu, Chen and Zhou