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).

Conflict of interest statement

Conflict of interest

TBM, SM, MS, H-MY, and JZ are employees of and own stock or options in Pfizer Inc. FDO was an employee of and held stock or options in Pfizer Inc at the time of study conduct. TB, SH, and JL are employees of Quotient Sciences, formerly Seaview Research Inc., which received funding from Pfizer Inc to perform the studies described in the manuscript.

Ethical approval and informed consent

The protocol and all amendments for each study were approved by the institutional review board at each of the investigational centers participating in the studies. All studies were conducted in compliance with the protocol, International Conference on Harmonization guidelines, all applicable regulatory requirements, and the Declaration of Helsinki. Subjects provided written informed consent prior to the performance of any study-specific procedures. Volunteers were free to withdraw from the study at any time.

Data availability

Upon request, and subject to certain criteria, conditions and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines, and medical devices (1) for indications that have been approved in the USA and/or EU or (2) in programs that have been terminated (i.e., development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.

Figures

Fig. 1

Nivestym biosimilar clinical development program in healthy volunteers. a C1121002: single-dose PK/PD study of Nivestym vs. US-Neupogena. b C1121003: multiple-dose PK/PD study of Nivestym vs. US-Neupogenb. c C1121012: comparative immunogenicity study of Nivestym vs. US-Neupogenc. aPK samples were collected 1 h before and 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, and 48 h after dose administration in each TP. PD samples were collected 1 h before and 0.5, 1, 2, 4, 6, 8, 24, 48, 72, 96, and 120 h after dose administration in each TP. Immunogenicity samples were collected before dose administration on day 1 and on day 12 ± 2 days of each TP, on day 28 of TP1, and at the final visit (day 28 of TP2). Day − 1 is technically part of the screening period. However, there are day − 1 activities that are related to the TP. Therefore, in the study design, day − 1 is included in the TP rather than in the screening period. bPK samples were collected 1 h before dose administration on days 1–5 and at 0.5, 1, 2, 3, 4, 6, 9, 12, 16, and 24 h after dose administration on day 5 of each TP. PD samples were collected 1 h before dose administration on days 1-5 and at 24, 48, 72, 96, and 120 h after dose administration on day 5 of each TP. Immunogenicity samples were collected before dose administration on day 1 and on day 12 of each TP, on day 33 of TP1, and at the final visit (day 33 of TP2). Day − 1 is technically part of the screening period. However, there are day − 1 activities that are related to the TP. Therefore, in the study design, day − 1 is included in the TP rather than in the screening period. cImmunogenicity samples were collected on days 0 and 10 of each TP, on day 26 (± 1) of TP1, and at the final visit (day 31 ± 2 of TP2). PD pharmacodynamic, PK pharmacokinetic, SC subcutaneous, TP treatment period, US-Neupogen filgrastim reference product licensed in the USA

Fig. 2

PK and PD parameter-over-time profiles for Nivestym and US-Neupogena. a Single-dose PK/PD study: mean ± SD filgrastim serum concentration-over-time profiles (semi-log) for Nivestym and US-Neupogenb. b Single-dose PK/PD study: mean ± SD ANC-over-time profiles (linear) for Nivestym and US-Neupogen. c Multiple-dose PK/PD study: mean ± SD CD34+-over-time profiles (linear) for Nivestym and US-Neupogen. d Multiple-dose PK/PD study: mean ± SD filgrastim serum concentration-over-time profiles (linear) for Nivestym and US-Neupogen post-dose administration on day 5. aPK and PD analyses were conducted using the PK and PD populations, respectively. bConcentrations below BQ occurring after Tmax were treated as missing values and BQ before Tmax (including pre-dose concentrations) were set to zero. ANC absolute neutrophil count, BQ lower limit of quantitation, CD cluster of differentiation, PD pharmacodynamic, PK pharmacokinetic, SD standard deviation, Tmax time to maximum observed concentration, US-Neupogen filgrastim reference product licensed in the USA