BIOEQUIVALENCE of a BIOSIMILAR FILGRASTIM and REFERENCE FILGRASTIM: IMPACT ON the MOBILIZATION of CD34+ PERIPHERAL BLOOD PROGENITOR CELLS in a RANDOMIZED, PHASE I STUDY.

Granulocyte colony-stimulating factor (G-CSF) stimulates the proliferation and differentiation of hematopoietic stem and progenitor cells. Recombinant human G-CSF (filgrastim) was developed by Amgen to enhance mobilization of peripheral blood progenitor cells (PBPCs) prior to autologous or allogeneic hematopoietic stem/progenitor cell transplantation. After the patent expiry of Amgen filgrastim (Neupogen^®), Hospira developed a biosimilar filgrastim. Preclinical and phase I studies supported the bioequivalence of Hospira filgrastim and Amgen filgrastim in terms of their physicochemical, pharmacokinetic and pharmacodynamic characteristics (Skrlin A, et al. EHA 2009, Abstract 0568; Waller CF, et al. EHA 2009, Abstract 0562). Here we compare the impact of Hospira filgrastim and Amgen filgrastim on CD34+ PBPC mobilization in a randomized, double-blind phase I study.

To demonstrate the bioequivalence of Hospira filgrastim and Amgen filgrastim with respect to the mobilization of CD34+ PBPCs.

Healthy, male or female volunteers aged 18–50 years were enrolled at Charles River Clinical Services, Edinburgh, UK, between 2 November 2006 and 24 January 2007. Using a computer-generated randomization list, volunteers were first randomized to 5μg/kg or 10μg/kg dose groups, before further randomization to order of agent administration. Subcutaneous injections of Hospira filgrastim or Amgen filgrastim were administered under double-blind conditions on five consecutive days (days 1–5), with crossover to the alternative agent after a washout period of ≥13 days. Blood samples were taken at day 1 (pre dose), day 3 (6 hours [h] post dose), day 5 (6 h post dose), day 7 (48 h post dose) and day 10 (120 h post dose). Mean CD34+ cell counts were evaluated by flow cytometry and bioequivalence was assessed using a mixed effects analysis of variance model. Bioequivalence was concluded if the 90% confidence intervals (CI) for the ratio of ‘test’ (Hospira filgrastim) to ‘reference’ (Amgen filgrastim) mean CD34+ cell counts at day 5 were completely within the conventional bioequivalence limits of 0.80–1.25.

Twenty-four volunteers were randomized to the 5μg/kg group and 26 to the 10μg/kg group. At both doses, CD34+ cell counts were similar with Hospira filgrastim and Amgen filgrastim across all time points. Regardless of agent or dose, mean CD34+ cell count at day 1 was 2.2–2.8 cells/μl, increasing to a maximum count at day 5. In the 5μg/kg group, mean CD34+ cell count at day 5 (n=24) was 47.2 cells/μl (95% CI: 36.1, 61.7) with Hospira filgrastim and 46.0 cells/μl (95% CI: 33.6, 63.0) with Amgen filgrastim. In the 10μg/kg group, mean CD34+ cell count at day 5 (n=23) was 81.9 cells/μl (95% CI: 64.5, 104.0) with Hospira filgrastim and 77.5 cells/μl (95% CI: 59.4, 101.3) with Amgen filgrastim (Figure 1). At both doses, 90% CIs for the ratios of test to reference mean CD34+ cell counts at day 5 were within the predefined range required to demonstrate bioequivalence. The incidence of adverse events (AEs) was slightly lower with Hospira filgrastim than with Amgen filgrastim at both doses (5μg/kg, 79 vs 83%; 10μg/kg, 77 vs 92%). The most frequently reported AEs of any severity (mild/moderate/severe) with each agent at each dose were back pain (38–62%) and headache (44–58%), which could be treated with standard analgesics.

Hospira filgrastim and Amgen filgrastim are similar in their ability to stimulate mobilization of CD34+ PBPCs. These data add to a growing body of evidence in support of the bioequivalence of these agents. Hospira filgrastim may provide a useful alternative to Amgen filgrastim as a growth factor to support PBPC mobilization and transplantation. The bioequivalence of these agents may enable Hospira filgrastim to be used without the need to adapt PBPC harvesting protocols. The continued clinical development of Hospira filgrastim is warranted.

Medical writing support provided by Hannah FitzGibbon (GeoMed) with financial support from Hospira.

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Bronchud:Hospira UK Ltd: Consultancy. Waller:Hospira UK Ltd: Consultancy. Off Label Use: Hospira filgrastim is a biosimilar filgrastim that is in clinical development for the treatment of neutropenia associated with cytotoxic chemotherapy.. Mair:Charles River Clinical Services: Employment. Challand:Hospira UK Ltd: Employment.