Safety, pharmacokinetics, pharmacodynamics and target-mediated drug disposition modeling of TST002, a sclerostin antibody, in men and postmenopausal women with low bone mineral density.

BACKGROUND: TST002 is a humanized IgG4 monoclonal antibody targeting sclerostin for osteoporosis treatment. This first-in-human study investigated its safety, tolerability, immunogenicity, pharmacokinetics (PK) and pharmacodynamics (PD) after intravenous infusion in Chinese men and postmenopausal women with low bone mineral density (BMD). RESEARCH DESIGN AND METHODS: In a randomized, double-blind, placebo-controlled, dose-escalation trial, 32 subjects were assigned to four dose cohorts (3:1 ratio to receive single TST002 doses of 200, 400, 800, or 1200 mg or placebo) with 85 days of follow-up. PK, PD, safety, and immunogenicity were assessed. An exploratory population PK-PD model incorporating target-mediated drug disposition (TMDD) was developed. RESULTS: Among TST002 recipients (n = 24), most treatment-related adverse events were grade 1 in severity. Nonlinear PK was observed, with greater-than-dose-proportional exposure and a mean half-life of 4.38-8.06 days. Increases in serum sclerostin and lumbar spine BMD, and decreases in β-CTX were observed. An exploratory population TMDD-PD model was developed to describe the observed time courses of TST002, sclerostin, and β-CTX within the present phase I dataset. CONCLUSIONS: TST002 was well tolerated and showed preliminary PD activity. Exploratory TMDD-based PK/PD modeling provided preliminary insights into exposure-response relationships, limited by the sample size, single-dose design, and unavailable bone formation marker assessment. CLINICAL TRIAL REGISTRATION: This study was registered at Clinicaltrials.gov (NCT05391776).