Demonstration of Pharmacokinetic and Pharmacodynamic Equivalence in Healthy Volunteers for B12019, a New Proposed Pegfilgrastim Biosimilar

B12019 is being developed as a biosimilar to Neulasta^® (INN pegfilgrastim), a long-acting, pegylated form of recombinant human granulocyte-colony stimulating factor (r-metHuG-CSF, INN filgrastim) for the prevention of chemotherapy-induced neutropenia. A comprehensive analytical, functional and preclinical comparability program has already demonstrated a high degree of similarity of B12019 as compared to Neulasta^®. In order to confirm the similarity on the clinical level, a pharmacokinetics/pharmacodynamics (PK/PD) study was conducted with B12019 in comparison to EU-authorised Neulasta^®.

The study was designed as a single-dose, randomized, double-blind, two-way crossover study. The study statistics were based on a two-stage design derived from to Potvin et al, 2007 to address potential high variability for the PK endpoints. 172 healthy male volunteers were enrolled in stage 1 of the study, whereas stage 2 would allow the recruitment of additional 102 subjects. The subjects received B12019 as well as Neulasta^®. The primary PK endpoints were the Area Under the Curve for concentration (AUC_0-last) and maximum concentration (C_max). The primary PD endpoint was the Area Under the Effect Curve (AUEC) for Absolute Neutrophil Count (ANC). PK endpoints were assessed with a 94.32% confidence interval (CI) accounting for the two-stage study design, whereas the PD endpoint was assessed with a 95% CI. Furthermore, safety and immunogenicity were investigated.

161 subjects were eligible to contribute to the model-based PK and PD comparison based upon the first stage of the study. For the PK endpoints, the 94.32% CIs for the geometric mean ratios were 86.60-104.73% for AUC_0-last and 84.36-102.18% for C_max. Both PK endpoints fulfilled the predefined acceptance criteria of being within the range of 80-125%. For the PD endpoint, the 95% CI for the geometric mean ratio of the ANC AUEC was 98.67-101.75%, also falling within the predefined acceptance criteria of 80-125%. Since the primary PK endpoints were met in stage 1 of the study, stage 2 was not required. The safety profile of B12019 did not show any clinically meaningful difference as compared to Neulasta^®. Neither anti-G-CSF nor neutralising antibodies were detected for both, B12019 and Neulasta^®.

The study demonstrated PK and PD comparability as well as comparable safety and immunogenicity profiles of B12019 as compared to EU-authorised Neulasta^®. No clinically meaningful differences were detected between B12019 and Neulasta^®. The high analytical and functional similarity of B12019 was confirmed on clinical level.