Introduction
cardiovascular death, fracture, pain, PD, osteoporosis, Osteoporosis, systemic skeletal disease, arthralgia
MYOCARDIAL INFARCTION, STROKE, ADVERSE EVENTS, FRAGILITY, POSTMENOPAUSAL OSTEOPOROSIS, OSTEOPOROSIS, EVENTS, OSTEOPOROSIS
Edited by: Kok Yong Chin, National University of Malaysia, MalaysiaReviewed by: John Krege, Eli Lilly, United States; Jan Josef Stepan, Charles University, Czechia†These authors have contributed equally to this work and share first authorshipThis article was submitted to Bone Research, a section of the journal Frontiers in EndocrinologySHR-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 (COsteoporosis is defined as a progressive systemic skeletal disease characterized by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture by the NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy (Medications used to treat osteoporosis are classified as either antiresorptive or anabolic in action (Mechanistically, as a negative regulator of the Wnt signaling pathway, sclerostin binds low-density lipoprotein receptor-related protein 5/6 (LRP5/6) co-receptors, further inhibiting bone formation and promoting bone resorption (Romosozumab is the only humanized therapeutic antibody against sclerostin that has been authorized for use in the United States, the European Union, Japan, Korea, and Canada. However, a safety warning for romosozumab for the risk of cardiovascular (CV) events (myocardial infarction, stroke, and cardiovascular death) should be noted (SHR-1222 is a novel humanized monoclonal antibody targeting sclerostin that was developed for the treatment of osteoporosis. Preclinical studies have demonstrated that SHR-1222 exhibits high affinity for human sclerostin (data on file, Jiangsu Hengrui Pharmaceuticals). Moreover, our first-in-human clinical trial (NCT03870100) indicated that single doses of SHR-1222 ranging 50–400 mg were generally well tolerated and promoted bone formation, inhibited bone resorption, and increased BMD in healthy men and postmenopausal women with low bone mass (