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

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.