Cornelius F Waller MD
Freiburg University Medical Centre,
Department of Haematology/Oncology, Hugstetter Strasse 55,
The patent expiration of several biopharmaceuticals, such as erythropoietin (erythropoiesis-stimulating agents; ESAs), granulocyte colony-stimulating factor (G-CSF; filgrastim) and others, has led to the development of biosimilar medicines. Biosimilar medicines are a subclass of biological medicines (biopharmaceuticals) defined as a copy version of an authorised biological medicinal product with demonstrated similarities in physicochemical characteristics, efficacy and safety, based on a comprehensive comparability exercise.(1) The European Medicines Agency (EMA) has introduced strict guidelines for the development of biosimilars, involving activities ranging from preclinical to phase III and post-marketing studies.(2) As a result, the term ‘biosimilars’ or ‘biosimilar medicines’ should only be used to describe follow-on biological medicines that have been approved following a rigorous comparability exercise, as is required in the European Union (EU) and other highly regulated markets, such as Japan, Australia and Canada.(1) Biosimilar medicines are manufactured according to the latest state-of-the-art technology, ensuring the highest quality standards available and are often better characterised than their reference products were at the time of their approval 10 or 20 years ago.(1) Biosimilars offer a number of potential advantages to pharmacists, physicians, payers and, ultimately, patients.(1)
Biosimilar G-CSFs and chemotherapy-induced febrile neutropenia
Recombinant human G-CSF (filgrastim; Neupogen®, Amgen) first received approval in both the United States and the EU in 1991 and has since become an important tool in preventing chemotherapy-related febrile neutropenia (FN), enabling patients to continue with planned dose-intensive chemotherapy regimens.(3) Filgrastim is a non-glycosylated protein, produced in genetically modified Escherichia coli. Its amino acid sequence is identical to that of human G-CSF, except for an additional N-terminal methionine. Filgrastim stimulates the proliferation and differentiation of haematopoietic stem and progenitor cells committed to the neutrophil lineages in a dose-dependent manner.(3) The originator filgrastim (Neupogen®) is indicated for reduction in the duration of neutropenia and the incidence of FN in patients treated with established cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes).(4) Indeed, European and other guidelines recommend prophylactic use of G-CSF when using a chemotherapy regimen associated with >20% risk of FN, or in lesser intensive chemotherapy regimens if certain patient-related risk factors, such as older age (>65 years), are present.(3) The benefits of G-CSF prophylaxis include significant reductions in infection-related complications and improvements in planned dose delivery.(3) Other current indications of Neupogen® are: reduction in the duration of neutropenia in patients undergoing myeloablative therapy followed by bone marrow transplantation considered to be at increased risk of prolonged severe neutropenia; mobilisation of peripheral blood progenitor cells (PBPC); treatment of severe congenital, cyclic or idiopathic neutropenia with an absolute neutrophil count (ANC) of ≤0.5×109/l, and a history of severe or recurrent infections; and treatment of persistent neutropenia (ANC ≤1.0 x109/l) in patients with advanced HIV infection.(4)
The patent expiration of Neupogen® has paved the way for development of biosimilar filgrastim and products currently on the market include Biograstim (CT Arzneimittel GmbH), Filgrastim Hexal (Hexal GmbH), Ratiograstim (Ratiopharm GmbH), Tevagastrim (Teva Generics GmbH) (XM02), Nivestim™ (Hospira UK Ltd) and Zarzio® (Sandoz Biopharmaceuticals GmbH).(1) Guidance issued by the EMA states that new biosimilar medicinal products containing filgrastim should demonstrate comparability with the reference product Neupogen® through extensive preclinical and clinical studies. These studies include pharmacokinetic, pharmacodynamic and safety investigations as well as a clinical trial demonstrating comparability between the test and the reference product for the prophylaxis of severe neutropenia after cytotoxic chemotherapy in a homogenous population of patients.(5) In addition, a risk-management programme/pharmacovigilance plan needs to be presented within the authorisation procedure.(5)
Clinical evaluation of NivestimTM
Nivestim , the biosimilar filgrastim marketed by Hospira Ltd,(6) has been developed with a thorough preclinical and clinical programme as recommended by the EMA. As a result, a series of rigorous preclinical analyses and clinical studies have demonstrated the bioequivalence of NivestimTM (7) and Neupogen®4 in terms of their physicochemical properties,(7) pharmacokinetic and pharmacodynamic characteristics(8,9) and clinical efficacy and safety profiles.(10) A phase III randomised, double-blind, therapeutic equivalence study evaluated the efficacy and safety of NivestimTM compared with Neupogen® for the prevention of neutropenia in patients receiving myelosuppressive chemotherapy for breast cancer.(10) The study was conducted in female patients with invasive breast cancer suitable for docetaxel and doxorubicin combination chemotherapy (a treatment associated with a high risk of developing FN). Patients (n=279) were randomised 2:1 to receive treatment with NivestimTM or Neupogen® (5µg/kg by subcutaneous injection for both treatments), administered at least 24 hours after chemotherapy, and continued once daily until the documented ANC nadir had passed and ANC was >3×109/l, or for 14 days, whichever occurred first. The primary objective of the study was to test the therapeutic equivalence of NivestimTM and Neupogen®, using the primary endpoint of duration of severe neutropenia (DSN) in days (ANC <0.5×109/L) during the first chemotherapy cycle. Secondary efficacy endpoints included DSN in cycles 2 and 3, time to ANC recovery (ANC >3×109/l) and incidence of FN (ANC <0.5×109/l and body temperature ≥ 38.5°C) in cycles 1–3, as well as safety of the treatment. NivestimTM- and Neupogen®-treated patients had a similar mean DSN (treatment cycle 1: NivestimTM:1.6 days, Neupogen®:1.3 days). The 95% confidence interval for difference in the adjusted mean DSN in treatment cycle 1 was within the predefined range (−1 to +1 day) required to demonstrate bioequivalence; therefore, the primary endpoint was met. Furthermore, the mean ANC in treatment cycle 1 was similar in both NivestimTM- and Neupogen®-treated patients and the mean time to ANC recovery in treatment cycle 1 was exactly the same in both groups.(10)
There was no difference in the frequency of hospitalisation owing to FN between NivestimTM and Neupogen® treatment groups, and no notable changes in laboratory parameters for any patient.(10) A similar percentage of patients in the two treatment groups experienced adverse events (AEs; 86.9% and 84.2% in the NivestimTM and Neupogen® groups, respectively) and the incidence of grade 3–4 treatment-emergent adverse events was almost identical with NivestimTM (12.57%) and Neupogen® (12.63%). In both treatment groups the most frequent treatment-related AEs were nausea, fatigue and bone pain. No neutralising antibodies to filgrastim were recorded in any patient. This led to the approval of NivestimTM by the EMA in June 2010 for all indications of the originator product Neupogen®. EMA guidelines support the extrapolation of clinical data from one therapeutic indication to another, assuming that reasonable justification can be made following consideration of clinical experience, current literature, similarity of the mechanisms of action and any possible safety issues in different patient subpopulations.(1)
Benefits of NivestimTM
The clinical efficacy of NivestimTM has been demonstrated in the phase III study of patients receiving myelosupressive chemotherapy for breast cancer.(10) Furthermore, the study demonstrated that NivestimTM is well tolerated and has an adverse event profile similar to other drugs in the class.(10) NivestimTM also offers a number of practical benefits to patients and physicians such as a range of pre-filled syringes supplied with a needle safety device, and individually wrapped blister packs.(6) Storage is also a practical consideration because protein-based biological medicines generally require careful handling and storage to ensure chemical stability and to maintain a long shelf-life. Therefore, it is particularly noteworthy that NivestimTM is unaffected by cyclical changes in temperature between the refrigerator and 25±2˚C, and is also unaffected by exposure either to room temperature for seven days or to freezing for three days.(11) This flexibility ensures that pharmacists, physicians and patients can be confident that NivestimTM remains active and stable during common environmental conditions encountered in transport and handling during general use.
Cost–benefits of biosimilar filgrastim
Although biological medicines have brought benefits to many patients with chronic or life-threatening diseases, they are often expensive and so access to these revolutionary treatments can be restricted in many parts of the world.(1) Biosimilars are likely to offer health-economic benefits because they should be more cost-effective than the branded reference product, owing to the reduced costs involved in the product development and clinical trials programmes. Therefore, biosimilars might give healthcare professionals more treatment options and increase patient access to previously expensive biological medicines.(1) Indeed, it has been postulated that, if biosimilar medicines were used as alternatives to only seven conventional biopharmaceuticals within the EU, savings of more than €2 billion could be achieved.(1) It is worth bearing in mind that the same degree of cost–benefits seen with generic small molecule drugs are unlikely with biosimilars because of the higher cost of manufacturing, extensive clinical trial studies and the comprehensive pharmacovigilance and drug safety programmes required for biosimilars.
The cost-efficiency of recombinant G-CSF was evaluated in a comparison of various regimens of filgrastim (Neupogen®), biosimilar filgrastim (ZarzioTM), and pegfilgrastim (Neulasta®), a second-generation filgrastim engineered for a sustained duration of action.(12) The comparison was against a period of 1–14 days and was across the European G5 countries (Germany, France, Italy, Spain and the UK). The cost-efficiency model included the direct costs a buyer or payer would incur when purchasing or covering any of the three agents in one patient during one chemotherapy cycle. Indirect costs were not included. The model also assumed that there were no significant differences in efficacy or safety between the three products. The analysis showed biosimilar filgrastim (ZarzioTM) was the most cost-efficient approach out of the three treatments analysed to reducing the incidence of FN in chemotherapy-treated patients, thus providing the best value for the prophylaxis and treatment of FN. Other biosimilar filgrastim products, such as NivestimTM, would be expected to provide similar cost-saving benefits. Within the UK (Scotland and Wales), NivestimTM has been recommended for use in the National Health Service (NHS) because it has demonstrated clinical equivalence to the reference product (Neupogen®) for reduction in duration of chemotherapy-induced neutropenia and incidence of FN at a lower cost than the reference product.(13,14) The cost–benefits associated with biosimilar filgrastim products could account for their increasing use in Europe since their first approval in 2008. In fact, market research conducted in December 2011 indicates that biosimilar filgrastim products now have a >50% share of the EU filgrastim market.(15)
Owing to patent expiration of originator products and approval based on rigorous processes including preclinical, clinical and post-marketing studies, biosimilar filgrastim products such as NivestimTM are an important addition to the range of treatment options available to clinicians. The safety and efficacy of NivestimTM has been demonstrated as comparable to the originator product in a phase III clinical trial. Biosimilars such as NivestimTM could provide cost-effective alternatives to their branded counterparts, potentially benefiting public health by improving access to these innovative medications.
The author has a consultancy agreement with Hospira UK Ltd. Editorial assistance was provided by ApotheCom ScopeMedical and funded by Hospira UK Ltd.
- The patent expiration of several biopharmaceuticals, such as erythropoietin and granulocyte colony-stimulating factor (G-CSF, filgrastim), has led to the emergence of biosimilar medicines.
- The European Medicines Agency (EMA) has introduced strict guidelines for the
- development of biosimilars, involving activities ranging from preclinical to phase III and post-marketing studies.
- A series of rigorous preclinical analyses as well as clinical studies have demonstrated the bioequivalence of NivestimTM (Hospira’s filgrastim) and its reference product Neupogen® (Amgen’s filgrastim).
- Biosimilars are likely to offer health-economic benefits as they should be more cost-effective than the branded reference product.
- Biosimilar filgrastim products such as NivestimTM are an important addition to the range of treatment options available and offer a number of potential advantages to pharmacists, physicians, payers and, ultimately, patients.
- European Generic Medicines Association. Biosimilars Handbook. 2nd ed. London;2011.
- European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP). Guidelines on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. London, 22 February 2006. www.emea.europa.eu/pdfs/human/biosimilar/4283205en_pdf (accessed 11 April 2012).
- Aapro MS et al. 2010 update of EORTC guidelines for the use of granulocyte colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours Eur J Cancer 2011;47:8–32.
- Neupogen. Summary of Product Characteristics, Amgen Europe BV. March 2011.
- European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP). Annex to guidelines on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. Guidance on similar medicinal products containing recombinant granulocyte-colony stimulating factor. London, 22 February 2006. www.emea.europa.eu/pdfs/human/biosimilar/3132905en.pdf (accessed April 2012).
- Nivestim. Summary of Product Characteristics, Hospira UK Ltd. November 2010.
- Skrlin A et al. Comparison of the physicochemical properties of a biosimilar filgrastim with those of reference filgrastim. Biologicals 2010;38(5):557–66.
- Waller CF et al. Pharmacokinetic profiles of a biosimilar filgrastim and Amgen filgrastim: results from a randomized, phase I trial. Ann Hematol 2010;89(9):927–33.
- Waller CF et al. Comparison of the pharmacodynamic profiles of a biosimilar filgrastim and Amgen filgrastim: results from a randomized, phase I trial. Ann Hematol 2010;89(10):971–8.
- Waller CF et al. A phase III randomized equivalence study of biosimilar filgrastim versus Amgen filgrastim in patients receiving myelosuppressive chemotherapy for breast cancer. Onkologie 2010;33(10):504–11.
- Burnett B, Krleža IR. Stability of Hospira filgrastim following changes to thermal and photic storage conditions. Eur J Hosp Pharm 2011;17(5):50–7.
- Aapro M, Cornes P, Abraham I. Comparative cost-efficiency across the European G5 countries of various regimens of filgrastim, biosimilar filgrastim, and pegfilgrastim to reduce the incidence of chemotherapy-induced febrile neutropenia. J Oncol Pharm Pract 2011;24:1–9.
- AWMSG Secretariat Assessment Report – Advice no. 0111 Filgrastim (NivestimTM) January 2011.
- Scottish Medicines Consortium. Advice 671_11 on Filgrastim (NivestimTM) February 2011. www.scottishmedicines.org.uk/SMC_Advice/Advice/671_11_filgrastim_Nivestim/filgrastim_Nivestim (accessed 11 April 2012).
- Hospira UK Ltd. Data on file.