Discussion
PD
This randomized, double-blind, placebo-controlled, dose-escalation phase 1 trial is the first clinical evaluation of multiple doses of SHR-1222 for POP treatment. SHR-1222 was generally well tolerated and demonstrated an acceptable safety profile at different dosing regimens from 100 mg QM to 600 mg Q2M. The AE profile of the SHR-1222 group was comparable to that of the placebo group during the whole treatment and follow-up, except for six AEs that showed ≥ 5% higher incidences in subjects with SHR-1222 than in those with placebo. Of these, the bone-specific blood ALP level increased as expected in a dose-dependent manner, with no induction in activities of liver enzymes (such as ALT, AST, and gamma-glutamyl transferase). The increased blood ALP level may be associated with the powerful promotive effect of SHR-1222 on bone formation, which was also observed in our preclinical studies of SHR-1222 (data on file, Jiangsu Hengrui Pharmaceuticals) and is in agreement with the phase 1 trial of romosozumab (This phase 1 trial provided evidence that after multiple subcutaneous injections of SHR-1222 ranging from 100 mg QM to 600 mg Q2M, the serum exposures (CThe dose-dependent PD responses of SHR-1222 were observed in the bone turnover biomarkers P1NP, OST, BSAP, and β-CTx, suggesting that SHR-1222 simultaneously enhances bone formation and reduces bone resorption, leading to increased BMD. The peak P1NP level increased from baseline in the SHR-1222 dosing group of 200 mg QM, which was close to that reported in a Japanese population who received romosozumab 210 mg QM (Of the 83 subjects with SHR-1222 included in the immunogenicity analyses, six (7.2%) developed anti-SHR-1222 antibodies. Similar drug-related anti-drug antibodies were obtained after a single dose of SHR-1222 (10.0% of subjects) and romosozumab (11.1% of subjects) (In conclusion, in this dose-escalation phase 1 trial, multiple doses of SHR-1222 were safe and well-tolerated ranging from 100 mg QM to 600 mg Q2M. The serum SHR-1222 exposure (C