Abstract P4-16-14: Meta-analysis of Phase I pharmacokinetic/pharmacodynamic results of proposed biosimilar pegfilgrastim

Abstract

Abstract Background The long-acting granulocyte colony-stimulating factor (G-CSF) pegfilgrastim is widely used to prevent chemotherapy-induced neutropenia (CIN). Biosimilars could potentially improve sustainability of cancer care. Sandoz proposed biosimilar pegfilgrastim is under development and has been evaluated in Phase I and III studies.1,2 The current meta-analysis uses data from two Phase I studies in healthy volunteers (HVs) comparing pharmacokinetic (PK)/pharmacodynamic (PD) properties of Sandoz proposed biosimilar and EU-reference (Neulasta®) pegfilgrastim. Methods Data from two studies were included: a single-dose, double-blind, parallel-group study (study 1, data on file) and a single-dose, double-blind, crossover study (study 2),3 both in HVs randomized to receive proposed biosimilar or reference biologic (PK/PD analysis populations: study 1, n=93 per arm; study 2, n=169 per arm). Primary PK and PD parameters were AUC0–inf, AUC0–last, Cmax and ANC AUEC0–last, ANC Emax, respectively. For each parameter, geometric mean ratios and confidence intervals (CIs) for treatment comparisons (proposed biosimilar vs reference biologic) from the two studies were combined using meta-analytical techniques with a fixed-effects model. The 90% (PK) or 95% (PD) CIs were calculated and PK/PD biosimilarity was demonstrated if all CIs fell within equivalence margins of 80% to 125%. Non-baseline corrected PD parameters were used. Results The combined CIs of the geometric mean ratios for primary PK and PD parameters were all contained within the predefined equivalence margins. Safety, tolerability and immunogenicity were found to be similar between proposed biosimilar and EU-reference biologic in HVs (data not shown). Combined geometric mean with 90% (PK)/95% (PD) CICombined ratio with 90% (PK)/95% (PD) CI Proposed biosimilarEU-referenceProposed biosimilar vs EU-referencePK parametersAUC0–last (ng×h/mL)N93+16993+169 Geometric mean 90% CI6823 [6122, 7603]6034 [5404, 6738]1.1385 [1.0606, 1.2221]AUC0–inf (ng×h/mL)N92+168a93+168a Geometric mean 90% CI6973 [6268, 7757]6183 [5560, 6876]1.1335 [1.0570, 1.2156]Cmax (ng/mL)N93+16993+169 Geometric mean 90% CI196 [178, 216]180 [163, 198]1.0994 [1.0265, 1.1774]PD parametersAUEC0–last (109×h/L)N93+16993+169 Geometric mean 95% CI4986 [4855, 5121]4952 [4816, 5093]1.0119 [0.9959, 1.0281]Emax (109/L)N93+16993+169 Geometric mean 95% CI36.4 [35.3, 37.5]36.2 [35.1, 37.2]0.9981 [0.9790, 1.0175]AUC=area under serum-concentration curve; AUEC=area under effect curve; CI=confidence interval; Cmax=maximum observed serum concentration; Emax=maximum effect attributable to investigational medicinal product; PD=pharmacodynamic; PK=pharmacokinetic. aOne subject in study 2 had AUC0–inf extrapolated >20% and was excluded from AUC0–inf analysis Conclusions This meta-analysis of two Phase I studies supports PK/PD similarity of Sandoz proposed biosimilar to EU-reference pegfilgrastim. Also, no clinically meaningful differences in safety, tolerability and immunogenicity were found. Sandoz proposed biosimilar pegfilgrastim presents as a sustainable option to manage CIN in patients with cancer. References 1Blackwell et al. Oncologist 2016;21:789–94 2Harbeck et al. Future Oncol 2016;12:1359–67 3Nakov et al. Cancer Res 2018;78:P3-14-10 Citation Format: Nakov R, Wang J, Chen Y, Bellon A, Gattu S, Krendyukov A, Li Y. Meta-analysis of Phase I pharmacokinetic/pharmacodynamic results of proposed biosimilar pegfilgrastim [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-16-14.