PF-06881894, a Proposed Biosimilar to Pegfilgrastim, Versus US-Licensed and EU-Approved Pegfilgrastim Reference Products (Neulasta®): Pharmacodynamics, Pharmacokinetics, Immunogenicity, and Safety of Single or Multiple Subcutaneous Doses in Healthy Volunteers

Abstract

Introduction: PF-06881894 is a proposed biosimilar to pegfilgrastim (Neulasta®). This study evaluated the pharmacodynamic/pharmacokinetic (PD/PK) equivalence, immunogenicity, and safety of PF-06881894 vs pegfilgrastim reference products (US- and EU-Neulasta®) in healthy volunteers.

Methods: A phase 1, open-label, randomized, crossover study was conducted to assess the pharmacologic equivalence and safety of a single 6-mg dose of PF-06881894, pegfilgrastim-US, and pegfilgrastim-EU. The primary PD endpoints were area under the effect-versus-time curve for absolute neutrophil count (ANC) from dose administration to 288 h postdose, and maximum observed ANC value among subjects confirmed negative for anti-pegfilgrastim antibodies. Primary PK variables included area under the serum pegfilgrastim-versus-time curve from the time of dose administration to time infinity and maximum observed serum pegfilgrastim concentration. A second phase 1, open-label, randomized (1:1), parallel-group, non-inferiority study was conducted to assess the immunogenicity and safety of multiple 6-mg doses of PF-06881894 versus pegfilgrastim-US. The primary endpoint for the immunogenicity study was the proportion of subjects with both negative baseline and confirmed positive postdose anti-pegfilgrastim antibodies at any time during the study.

Results: Across the single- and multiple-dose studies (N = 153 and N = 420 treated subjects, respectively), demographics for age (18-65 years), male gender (n = 264/573), and white race (n = 423/573) were similar. Three-way PD/PK equivalence of PF-06881894, pegfilgrastim-US, and pegfilgrastim-EU was demonstrated with the primary PD endpoints and primary PK variables being completely contained within the predefined 90% confidence interval acceptance limits (80-125%). The non-inferiority of PF-06881894 versus pegfilgrastim-US in terms of immunogenicity was established according to the prespecified non-inferiority margin (≤10%). Overall, there were no clinically meaningful differences in safety profiles among or between study groups.

Conclusions: Single-dose PF-06881894 demonstrated PD/PK equivalence and comparable safety with US- and EU-pegfilgrastim reference products. Multiple-dose PF-06881894 demonstrated immunogenicity non-inferiority to pegfilgrastim-US with comparable safety. Both studies contributed to the totality of evidence supporting biosimilarity.

Trial registration: ClinicalTrials.gov identifiers: NCT02629289; NCT03273842 (C1221005).

Keywords: Biosimilar; Immunogenicity; Myelosuppressive chemotherapy; Neulasta®; Neutropenia; PF-06881894; Pegfilgrastim; Pharmacodynamics; Pharmacokinetics; Safety.

Figures

Fig. 1

Clinical development program for PF-06881894 in healthy volunteers. a C1221001: a single-dose PD/PK study of PF-06881894 versus pegfilgrastim-US and pegfilgrastim-EUa. b C1221005: a multiple-dose comparative immunogenicity study of PF-06881894 versus pegfilgrastim-USb. a For the PD evaluations, blood samples (4.0 mL) for ANC were collected by either intravenous catheter or venipuncture into evacuated collection tubes within 1 h before dose administration and at 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, and 288 h postdose. A total of 14 samples were planned for PD analysis in each period. For PK evaluations, blood samples (5.0 mL) for the pegfilgrastim assay were collected within 1 h before dosing and at 1, 2, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, and 288 h postdose. Blood samples (7 mL) for ADA testing were collected within 1 h before dosing on days 1 and 13 of each period, at day 30 of the follow-up visit of each period, or early termination (if applicable). b Identical dosing procedures were performed on day 1 of phase 1 (first drug dose) and phase 2 (second drug dose) in this parallel-design study. Blood samples (7.5 mL) for ADAs were collected before dosing (day 1, phase 1 only) and after fasting for at least 4 h (on days 13 and 30 ± 2, phase 1 and on days 13, 30 ± 2, 60 ± 5 or at early withdrawal, phase 2). Early termination from the study required a subject to have completed the day 30 ± 2, phase 2 assessments. ISR data collection occurred up to 90 min postdose (days 1, 3, and 5 of phases 1 and 2); other ISR data were captured outside the ISR schedule during AE monitoring. ADA anti-drug antibody, AE adverse event, ANC absolute neutrophil count, ISR injection-site reaction, NAb neutralizing antibody, PDpharmacodynamic, pegfilgrastim-EUpegfilgrastim sourced from the European Union (reference product), pegfilgrastim-USpegfilgrastim sourced from the USA (reference product), PF-06881894 proposed biosimilar of pegfilgrastim (test product), PKpharmacokinetic, SCsubcutaneous

Fig. 2

Mean (SD) serum absolute neutrophil count concentration over time in the single-dose study (C1221001) (PD population). ANC absolute neutrophil count, PD pharmacodynamic, pegfilgrastim-EU pegfilgrastim sourced from the European Union (reference product),pegfilgrastim-US pegfilgrastim sourced from the USA (reference product), PF-06881894proposed biosimilar of pegfilgrastim (test product), SD standard deviation

Fig. 3

Mean (SD) serum pegfilgrastim concentration over time in the single-dose study (C1221001) (PK population).Pegfilgrastim-EU pegfilgrastim sourced from the European Union (reference product),pegfilgrastim-US pegfilgrastim sourced from the USA (reference product), PF-06881894proposed biosimilar of pegfilgrastim (test product), PK pharmacokinetic, SD standard deviation