Critical appraisal of biosimilar filgrastim (Nivestim™) for febrile and chemotherapy-induced neutropenia

Abstract:

Recombinant granulocyte colony-stimulating factor (filgrastim) stimulates the proliferation and differentiation of hematopoietic stem and progenitor cells committed to neutrophil and granulocyte lineages. Filgrastim has been used as an adjunct to chemotherapy for ameliorating neutropenia, one of the major side effects of chemotherapy in cancer patients. Its use has led to reduction of infections and hospital admissions for patients with cancer undergoing chemotherapy. In addition, filgrastim has multiple other indications in hematology and oncology. Following the European Union patent expiry of Neupogen® (filgrastim; Amgen Inc) in 2006, a biosimilar filgrastim has been developed (Nivestim™; Hospira). In accordance with the requirements of the European Medicines Agency, Nivestim has been studied in a development program that included preclinical studies, two Phase I clinical trials, and one Phase III clinical study. Preclinical studies showed pharmacodynamic as well as pharmacokinetic bioequivalence with the original product, Neupogen. Two randomized, single-center, Phase I trials compared both the pharmacokinetic, pharmacodynamic, and safety profiles of Nivestim and Neupogen in healthy volunteers. In both studies, 90% confidence intervals for the primary endpoints were within the predefined range (0.80–1.25) necessary to demonstrate bioequivalence. Nivestim was well tolerated, with no additional safety concerns over Neupogen. Bioequivalence was demonstrated in a randomized, double-blind multicenter Phase III trial of 279 patients with breast cancer receiving myelosuppressive chemotherapy. The mean duration of severe neutropenia in cycle 1, the primary endpoint, was similar between Nivestim (1.6 days, n = 165) and Neupogen (1.3 days, n = 85), meeting predefined criteria for bioequivalence. Secondary endpoints supporting bioequivalence included the mean time to recovery of absolute neutrophil count and incidence of febrile neutropenia. The most common treatment-related adverse event with Nivestim was grade 1–2 bone pain. As a result of these preclinical and clinical trials, Nivestim was approved by the European Medicines Agency and in Australia for prevention of febrile neutropenia and treatment of neutropenia in cancer patients treated with cytotoxic chemotherapy (except in patients with myelodysplastic syndromes and chronic myelogenous leukemia). Nivestim is also indicated for the treatment of myelosuppression after bone marrow transplantation, of neutropenia in patients with human immunodeficiency virus, and of severe congenital, cyclic, or idiopathic neutropenia.

Keywords::

• filgrastim
• biosimilar
• granulocyte colony-stimulating factor
• neutropenia
• Nivestim™