A Randomized Phase 1 Study Comparing the PK , PD , Safety, and Immunogenicity of Proposed Biosimilar RGB ‐14‐X and Denosumab in Healthy Adult Males

ABSTRACT Denosumab is a monoclonal antibody targeting the receptor activator of nuclear factor kappa‐b ligand widely used for the prevention of skeletal‐related events in patients with bone metastases. This Phase 1 randomized, double‐blind, two‐arm, parallel‐group study assessed the equivalence in pharmacokinetics (PK) and compared the pharmacodynamics (PD), safety, and immunogenicity of the proposed biosimilar RGB‐14‐X and reference denosumab in healthy males. Participants were randomized 1:1 to a single subcutaneous 60 mg dose of RGB‐14‐X or reference denosumab, with 252 days of follow‐up. Primary PK endpoints were maximum observed serum concentration (C max ) and area under the concentration‐time curve from time 0 to last quantifiable concentration (AUC 0‐last ) and extrapolated to infinity (AUC 0‐inf ). Secondary objectives were to compare additional PK parameters, safety and tolerability, PD and immunogenicity between groups. Of 165 participants randomized, 162 (98.2%) completed the study. The geometric mean ratios and corresponding 90% confidence intervals of RGB‐14‐X versus reference denosumab for C max , AUC 0‐last , and AUC 0‐inf were within the pre‐specified range of 0.80–1.25, demonstrating equivalence. No notable differences were observed in secondary PK or PD parameters between groups; maximum reduction in concentration of the bone resorption marker serum C‐terminal telopeptide of type I collagen (CTX) and the extent and duration of reduction in CTX levels over time were similar. RGB‐14‐X was well tolerated with a similar safety profile to reference denosumab. No anti‐drug or neutralizing antibodies were detected in either group. RGB‐14‐X demonstrated biosimilarity to reference denosumab, with equivalent PK and similar PD, safety, and immunogenicity outcomes in healthy males.