PF-06881893 (Nivestym™), a Filgrastim Biosimilar, Versus US-Licensed Filgrastim Reference Product (US-Neupogen®): Pharmacokinetics, Pharmacodynamics, Immunogenicity, and Safety of Single or Multiple Subcutaneous Doses in Healthy Volunteers

Abstract

Background Three comparative clinical studies assessed the pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity and safety of PF-06881893 (filgrastim-aafi; Nivestym™), a filgrastim biosimilar, versus US-licensed reference product (filgrastim; US-Neupogen ® ) in healthy volunteers (HVs). Methods Two separate open-label, crossover-design PK/PD studies were conducted: a single-dose study ( n = 24) and a multiple-dose study ( n = 60). In each study, HVs were randomized to Nivestym followed by US-Neupogen, or vice versa. Study drug (5 μg/kg) was administered subcutaneously as a single injection or as five consecutive daily injections. Primary PK and PD endpoints were area under the filgrastim serum concentration–time curve, maximum observed concentration, area under the effect curve (AUEC) for absolute neutrophil count (ANC), maximum observed ANC, AUEC for cluster of differentiation (CD)-34 + count, and maximum observed CD34 + count. In an open-label, parallel-design, non-inferiority, comparative immunogenicity study, HVs were randomized ( n = 128/treatment) to Nivestym or US-Neupogen. The primary endpoint was the proportion of subjects with a negative baseline antidrug antibody (ADA) test result and one or more confirmed post-dose positive ADA result. Results Overall demographics were as follows: female ( n = 162/340); White ( n = 274/340), Black ( n = 58/340), and other ( n = 8/340); age (18–65 years); and weight (50.8–96.5 kg). All primary PK and PD endpoints met the pre-specified criteria for PK and PD equivalence. The primary endpoint in the comparative immunogenicity study met pre-specified criteria for non-inferiority. Conclusions Nivestym demonstrated PK and PD equivalence in single and multiple subcutaneous-dose settings and non-inferiority for immunogenicity to US-Neupogen, with a comparable safety profile, supporting the demonstration of biosimilarity. Trial registration ClinicalTrials.gov C1121002 (NCT02766647); C1121003 (NCT02766634); C1121012 (NCT02923791). Electronic supplementary material The online version of this article (10.1007/s40259-019-00343-8) contains supplementary material, which is available to authorized users.

Biosimilarity Assessment of 2 Filgrastim Therapeutics in Healthy Volunteers

“…The inclusion of patients may make the comparison nonsensitive due to the interference of disease and comedication. The selected dose of 300 µg was close to a daily dose of 5 mg/kg/day of most therapeutic indications 9‐12,14‐19 . The method for quantification of filgrastim in serum was adequately validated.…”

“…Tinagrast, a proposed biosimilar filgrastim, was developed by AryaTinaGene Biopharmaceutical Company, and extensive comparability studies, including physicochemical characterization, cell‐based biological activity, and nonclinical studies, have suggested a high similarity to the originator product. As the study of pharmacokinetic and pharmacodynamic profile of a new filgrastim product in healthy volunteers is routinely performed in support of biosimilarity, 9‐12 the objective of the present study was to evaluate the similarity of 2 filgrastim products after a subcutaneous administration of a 300‐µg single dose, comparing their pharmacokinetic and pharmacodynamic and safety properties in healthy subjects.…”

Analysis of the Regulatory Science Applied to a Single Portfolio of Eight Biosimilar Product Approvals by Four Key Regulatory Authorities

“…They are also key to guiding the requirement for, and nature of, subsequent comparative clinical studies [ 31 ]. The proportion of PK/PD queries was unaffected whether the study was conducted in patients (such as for PF-rituximab [ 32 ]) or in healthy subjects (PF-infliximab [Ixifi ™ ] [ 33 ], PF-epoetin [ 34 , 35 ], PF-filgrastim [ 36 ], PF-trastuzumab [ 37 ], PF-bevacizumab [ 38 ], PF-adalimumab [Abrilada ™ /Amsparity] [ 39 ], PF-pegfilgrastim [Nyvepria ™ ] [ 40 ]). The generally low focus on PK information across RAs may reflect the proactive engagement of the applicant with the relevant RA during the study design process, the transparency of the data disclosure and interpretation.…”

Intercambialidade de produtos biológicos no Sistema Único de Saúde (SUS): principais desafios regulatórios

“…Embora estudos comparativos entre produtos biológicos inovadores e suas respectivas cópias venham demonstrando semelhança quanto ao perfil de imunogenicidade 25,26,27,28,29,30 , a avaliação da imunogenicidade é recomendada para todos os medicamentos biológicos, inovadores e cópias, durante todo o ciclo de vida dos produtos 22 .…”