A double-blind, randomized, two-arm, single-dose, parallel-group study in healthy participants to compare the pharmacokinetics, pharmacodynamics, and immunogenicity of FKS518 proposed biosimilar to denosumab with the originator (LUMIADE-1 study).

Abstract

e15097 Background: Denosumab is a RANKL inhibitor used in patients with bone metastases from solid tumors. FKS518 is a proposed biosimilar to denosumab originator product. Biosimilars offer similar efficacy, quality, safety, and favorable economic impact. Once the analytical and functional similarity of a biosimilar has been shown, a comparative human pharmacokinetics (PK) study is conducted to demonstrate that there are no clinically meaningful differences between the biosimilar and the reference product. The present study assessed the PK equivalence of FKS518 to the originator product and provided data on the similarity of the pharmacodynamic, safety and immunogenicity profiles. Methods: A randomized, controlled, double-blind, parallel-group study in healthy volunteers was performed to compare denosumab biosimilar candidate FKS518 versus the originator product. Subjects received a single subcutaneous denosumab 60 mg injection and were followed up for 40 weeks. Primary endpoints PK parameters (Cmax, AUC0-last and AUC0-inf) were natural log transformed and analyzed using analysis of covariance methods; results were then transformed back to the original scale. Safety data were collected throughout the study and analyzed descriptively. Results: 213 male subjects 28-55 years of age, with a baseline BMI between 18.2 and 31.7 kg/m2, were randomized to the originator denosumab (n = 106) or FK518 (n = 107). Results of the primary PK analysis demonstrated bioequivalence between FKS518 and the originator denosumab product since the 90% confidence intervals (CIs) for the geometric least squares mean (LSM) ratios for the 3 primary PK parameters were completely included within the predefined 80.00% to 125.00% equivalence margin (point estimate [90%CI for the ratio]): Cmax: 104.79% [97.04%,113.15%], AUC0-last: 112.29% [104.17%,121.04%] and AUC0-inf : 112.65% [104.27%,121.70%]. Secondary PK parameters were similar as well between FKS518 and the originator: tmax (median: 217.45 hrs. vs. 216.03 hrs. respectively), t1/2 (median: 235 hrs. vs 337 hrs. respectively). The nature, frequency, severity, or resolution of adverse events were comparable across treatments. For immunogenicity, there was no difference between the 2 treatment groups in ADA and Nab incidence at each timepoint. Conclusions: PK equivalence of FKS518 and denosumab originator product was demonstrated with similar PD, safety and immunogenicity profile for the two products. This study adds to the totality of evidence supporting FKS518 as a proposed biosimilar to denosumab.