Biosimilar Granulocyte Colony-stimulating Factor Research Articles

Biosimilar Granulocyte Colony-Stimulating Factor Uptakes in the EU-5 Markets: A Descriptive Analysis

Biosimilars are copies of biological reference medicines. Unlike generics (copies of chemical molecules), biologics are complex, expensive and complicated to produce. The knowledge of the factors affecting the competition following patent expiry for biologics remains limited. The aims of this study were to analyse the EU-5 Granulocyte-Colony Stimulating Factor (G-CSF) markets and to determine the factors affecting the G-CSF biosimilar uptakes, particularly that of biosimilar prices relative to originators. Data on medicine volumes, values, and ex-manufacturer prices for all G-CSF categories were provided by IMS Health. Volumes were calculated in defined daily doses (DDD) and prices in Euros per DDD. In the EU-5 countries, there is 5 years of experience with biosimilar G-CSFs (2007-2011). Two G-CSF market profiles exist: (1) countries with a high retail market distribution, which are the largest G-CSF markets with low global G-CSF biosimilar uptakes (5.4% in France and 8.5% in Germany in 2011); and (2) countries with a dominant hospital channel, which are the smallest markets with higher G-CSF biosimilar uptakes (12.4% in Spain and 20.4% in the UK). The more the decisions are decentralized, the more their uptakes are high. The price difference between G-CSF biosimilars and their reference plays a marginal role at a global level (price differences of +13.3% in the UK and -20.4% in France). The competition with G-CSF biosimilars varies significantly between EU-5 countries, probably because of G-CSF distribution channel differences. Currently, this competition is not mainly based on prices, but on local political options to stimulate tendering between them and recently branded second- or third-generation products.

Biosimilar G-CSF Based Mobilization of Peripheral Blood Hematopoietic Stem Cells for Autologous and Allogeneic Stem Cell Transplantation

The use of granulocyte colony stimulating factor (G-CSF) biosimilars for peripheral blood hematopoietic stem cell (PBSC) mobilization has stimulated an ongoing debate regarding their efficacy and safety. However, the use of biosimilar G-CSF was approved by the European Medicines Agency (EMA) for all the registered indications of the originator G-CSF (Neupogen®) including mobilization of stem cells. Here, we performed a comprehensive review of published reports on the use of biosimilar G-CSF covering patients with hematological malignancies as well as healthy donors that underwent stem cell mobilization at multiple centers using site-specific non-randomized regimens with a biosimilar G-CSF in the autologous and allogeneic setting.A total of 904 patients mostly with hematological malignancies as well as healthy donors underwent successful autologous or allogeneic stem cell mobilization, respectively, using a biosimilar G-CSF (520 with Ratiograstim®/Tevagrastim, 384 with Zarzio®). The indication for stem cell mobilization in hematology patients included 326 patients with multiple myeloma, 273 with Non-Hodgkin's lymphoma (NHL), 79 with Hodgkin's lymphoma (HL), and other disease. 156 sibling or volunteer unrelated donors were mobilized using biosimilar G-CSF. Mobilization resulted in good mobilization of CD34+ stem cells with side effects similar to originator G-CSF. Post transplantation engraftment did not significantly differ from results previously documented with the originator G-CSF. The side effects experienced by the patients or donors mobilized by biosimilar G-CSF were minimal and were comparable to those of originator G-CSF.In summary, the efficacy of biosimilar G-CSFs in terms of PBSC yield as well as their toxicity profile are equivalent to historical data with the reference G-CSF.

Use of a biosimilar granulocyte colony‐stimulating factor for peripheral blood stem cell mobilization: an analysis of mobilization and engraftment

Peripheral blood haematopoietic progenitor cell mobilization has become a standard procedure prior to autologous stem cell transplantation. Biosimilar granulocyte colony-stimulating factors (GCSF) have recently been awarded European Union (EU) licences for stem cell mobilization but data for their use in this context remain limited. The biosimilar GCSF, Ratiograstim(®) (Ratiopharm, Ulm, Germany) was granted an EU licence in September 2008 and incorporated into clinical practice in the Wessex Blood and Marrow Transplantation Programme in December 2008. Data were retrospectively collected for 154 consecutive patients undergoing peripheral blood stem cell harvest between January 2009 and December 2011 using the biosimilar GCSF. 131 consecutive patients from the preceding 3years, who had received Neupogen(®) , were used as a control. We analysed both parameters relevant to stem cell collection and engraftment data, where patients proceeded to transplantation. We found no statistically significant difference between the two groups when comparing CD34 predictors, total number of CD34(+) stem cells collected, number of days required for collection, or for time to engraftment. This is, to our knowledge, the largest direct comparison of a biosimilar GCSF with originator GCSF for stem cell mobilization. The use of biosimilar GCSF can produce a significant cost saving, allowing investment in other areas of stem cell transplantation.

A non-interventional study of biosimilar granulocyte colony-stimulating factor as prophylaxis for chemotherapy-induced neutropenia in a community oncology centre

Prophylaxis with granulocyte colony-stimulating factor (G-CSF) reduces the severity of chemotherapy-induced neutropenia. Biosimilar G-CSF is now approved for use, based on comparable efficacy, safety and quality with the originator product. We conducted a retrospective review of patients' charts following the switch from originator G-CSF (Neupogen(®)) to biosimilar G-CSF (Zarzio(®)/Filgrastim Hexal(®)) in a large community oncology practice. A total of 77 consecutive patients with cancer who received biosimilar G-CSF were reviewed, as were 25 patients who received originator G-CSF at the same centre. The median age of patients in the biosimilar G-CSF cohort was 67 years (range 20-83). In this cohort 48% had chemotherapy with a febrile neutropenia risk of >20%. Biosimilar G-CSF was given as primary prophylaxis in 52% and as secondary prophylaxis in 48% of patients. Age and febrile neutropenia in medical history or in previous chemotherapy were factors that triggered the use of G-CSF in patients with a febrile neutropenia risk of <20%. One patient developed febrile neutropenia. Neutropenia led to chemotherapy dose reductions in five patients (6.5%) and discontinuation in two patients (2.5%). No unexpected safety findings were observed. Patient characteristics were generally similar in the originator G-CSF cohort. Only 24% of patients had a febrile neutropenia risk >20% and 36% received primary prophylactic G-CSF. One patient developed febrile neutropenia. Neutropenia led to chemotherapy dose reductions in two patients (8%) and discontinuation in two patients (8%). Biosimilar G-CSF was effective and prevented dose reductions/discontinuation in the majority of patients. Biosimilar G-CSF was considered clinically comparable to its reference product.

Presently available biosimilars in hematology-oncology: G-CSF

Biopharmaceuticals were copies of endogenous human proteins developed in the mid-1990s that were characterized by complex three-dimensional, high-molecular weight compounds. What made them unique was that contrary to classical chemotherapeutical drugs, they were manufactured by living cells. One of these biopharmaceuticals was granulocyte-colony stimulating factor (G-CSF). Once their patent expired, generic versions appeared in pharmacies. They are now called biosimilars. There are several biosimilar G-CSFs approved in Europe: Biograstim®/Filgrastim ratiopharm/Ratiograstim®/Tevagrastim® (XM02); Zarzio® and Nivestim®. All these new products are manufactured in facilities with state-of-the-art technology. All products have passed the regulatory requirements for approval, mainly phase I and phase III, with the consequent PD/PK evaluations and studies on efficacy and safety. However, there are still some concerns regarding their long-term evaluation, in particular, the limited experience at the time of approval of these products in terms of efficacy, safety and immunogenicity. For this reason, pharmacovigilance should be rigorous. A lot of work remains to be done in terms of clarification with regard to substituting a biosimilar G-CSF for the innovator product and, finally, information must be provided to physicians, pharmacists and patients to allow for proper decision-making. Ultimately, only clinical trials and effective post-marketing pharmacovigilance will provide definitive evidence that a biosimilar is comparable to the originator-reference product in terms of efficacy and safety.

Follow-on biologics in oncology – the need for global and local regulations [Polish version: Leki bionastępcze w onkologii – potrzeba globalnych i lokalnych regulacji p. 467

The patent expiration for first-generation biological drugs has prompted the development of a new group of biopharmaceuticals – follow-on biologics. The extent of studies needed in the process of follow-on biologics approval is incomparably greater than in the case of generics but reduced in comparison to innovative biologics. The basis for the approval is to show the similarity sufficient to ensure the same quality, safety and efficacy as the reference medicine. In oncology, the most widely used among so far registered follow-on biologics are biosimilar granulocyte colony-stimulating factors, and in the hitherto clinical practice, there have been no concerns about their effectiveness and safety. It is expected that along with the patent expiry of next biologics, the number of follow-on biologics will increasingly grow, that implies the need to develop and implement specific regulations for this new class of medicine.

Use of Biosimilar G-CSF Is Effective After Autologous Bone Marrow Transplantation

Abstract 5321 OBJECTIVES:Granulocyte colony-stimulating factors (G-CSFs) are widely used to accelerate haematopoietic recovery after bone marrow transplantation (BMT). Regulatory approval of biosimilar G-CSFs in Europe has been on the basis of comparable efficacy, safety and quality as the originator product. However, data are not presently available for all G-CSF clinical settings. This is the first reported use of a biosimilar G-CSF for neutrophil recovery after BMT. METHODS:A total of 23 consecutive patients (12 male, 11 female; mean ± SD age 47 ± 13 years) with haematological malignancy (multiple myeloma, n=12; Hodgkin's lymphoma, n=6; non-Hodgkin's lymphoma, n=4; acute myeloid leukaemia, n=1) were recruited at a single-centre. Nineteen patients were receiving their first BMT while it was the second autograft for 4 patients. Mobilisation chemotherapy consisted of high-dose (HD) VEP (n=14), ESHAP (n=4), HD Ara-C (n=3), HD cyclophosphamide (n=2) or ICE (n=1). Patients received biosimilar G-CSF (EP-2006, Sandoz Biopharmaceuticals) after myeloablative chemotherapy (primarily BEAM or melphalan 140/200 mg/m2 +/− bortozemib) with or without radiotherapy followed by autologous BMT. G-CSF therapy was started when absolute neutrophil count (ANC) was <0.5 × 109/l and was continued until ANC reached >1.5 × 109/l for 3 consecutive days. Response was evaluated after BMT using International Uniform Response Criteria. RESULTS:Mean ± SD number of CD34+ cells collected before transplantation was 10.1 ± 4.0 x106/kg/body weight. After BMT, one patient had a stringent complete response (CR), 7 patients had a CR, one patient a near CR, one patient a very good partial response (PR), 12 patients a PR, and one patient had progressive disease (overall response 96%). Mean recovery to ANC >0.5 × 109/l was 13.0 ± 4.0 days. Mean duration until platelet recovery >20 000/ml was 16.1 ± 4.4 days (not achieved in 5 patients at last available assessment). Mean duration of treatment with biosimilar G-CSF was 14.4 ± 5.1 days (range 6−23). Patients required antibiotics on a median of 4 days (range 1−6). Five patients (22%) experienced neutropenic events (neutropenic fever, n=4 and neutropenic enterocolitis and sepsis, n=1). Mean number of days in hospital was 28 ± 6. CONCLUSION:Biosimilar G-CSF appears to be effective in reducing the duration of neutropenia in patients undergoing myeloablative therapy followed by autologous BMT. The use of biosimilar G-CSFs may result in cost savings in cancer supportive care budgets. Disclosures:Dmoszynska:Mundipharma: Advisory Board; Roche: Honoraria.

First Reported Use of a Biosimilar G-CSF in Allogeneic Stem Cell Mobilisation

Abstract 4571 OBJECTIVES:Biosimilar granulocyte colony-stimulating factor (G-CSF) has been approved on the basis of comparable quality, safety and efficacy as the originator product. Approval of biosimilar G-CSF is in the same indications as the originator, including autologous and allogeneic peripheral blood stem cell (PBSC) mobilisation, for which it is being used throughout our large hospital group in Paris, France. Concerns have been raised by professional bodies over use of biosimilar G-CSF in allogeneic transplants. To our knowledge, this is the first reported use of biosimilar G-CSF in healthy donors for allogeneic transplantation. METHODS:Healthy related donors received biosimilar G-CSF (EP-2006, Sandoz Biopharmaceuticals) 10 μg/kg/day for PBSC mobilisation. G-CSF was administered on days 1–4 with the first leukapheresis performed on day 5. If the required number of CD34+ cells per recipient body weight (4 × 106 CD34+ cells/kg) was not collected, G-CSF administration was continued and a second PBSC collection was performed on day 6. Further G-CSF administration and a third leukapheresis was done on day 7 if required. RESULTS:Twelve healthy donors (7 male, 5 female; mean ± SD age 61.0 ± 7.8 years, range 51–73) received biosimilar G-CSF for PBSC mobilisation. Median donor body weight was 82 kg (range 55–115 kg). Median CD34+ cell count on day 5 was 75/ml (range 23–140). A single leukapheresis after 4 injections of biosimilar G-CSF was sufficient to collect the CD34+ cell dose required in six donors with peripheral blood (PB) CD34+ counts ranging from 80–140 ml. Six donors underwent a second leukapheresis after 5 days of biosimilar G-CSF, one of whom (a 73-year old female) underwent a third leukaphereses on day 7 (PB CD34+ at first apheresis 23 ml). Median number of CD34+ cells per recipient bodyweight was 5.5 × 106 cells/kg (range 2.6–8.9). Five donors reported bone pain (4 mild, 1 moderate severity) which was effectively treated with paracetamol. No other adverse events were reported. Blood measurements were normal in all donors when assessed one week after the end of mobilisation. These findings are consistent with our previous use of originator G-CSF (Neupogen®) in allogeneic stem cell mobilisation. CONCLUSION:These preliminary findings suggest biosimilar G-CSF is effective and well-tolerated in allogeneic stem cell mobilisation. Further studies are required to assess longer-term safety outcomes. The use of biosimilar G-CSF may provide important cost-savings when compared with the originator product. Disclosures:No relevant conflicts of interest to declare.

Efficacy and Safety of Biosimilar G-CSF and Originator G-CSF for Haematopoietic Stem Cell Mobilisation: A Randomised Comparison

Abstract 4392 OBJECTIVES:Recombinant granulocyte colony-stimulating factor (G-CSF) is widely used to mobilise haematopoietic stem cells. Biosimilar filgrastim is now available in Europe. No differences were observed between biosimilar filgrastim (n=40) and a retrospective cohort of patients receiving originator filgrastim for stem cell mobilisation in a previous comparison, although no safety findings were reported (Lefrère et al. Adv Ther 2011;28:304−10). We compared the efficacy and safety of a biosimilar filgrastim (EP-2006, Sandoz Biopharmaceuticals) with originator filgrastim (Neupogen®, Amgen) in patients with haematological malignancies. METHODS:A total of 108 patients were included in this study, 59 of whom were female (49 male), with an overall median age of 51 years (range 19–69). Patients had multiple myeloma (n=46), Hodgkin's lymphoma (n=26), non-Hodgkin's lymphoma (n=28) or other diagnosis (n=8). Median time from diagnosis to mobilisation was 10 months (range 3−122). After administration of mobilising regimens (primarily high-dose etoposide, high-dose cyclophosphamide, intermediate-dose Ara-C or ESHAP), patients were randomised to a standard daily 10 μg/kg dose of EP-2006 (n=54) or originator filgrastim (n=54). RESULTS:Median duration of G-CSF administration was 8 days with both EP-2006 (range 4−17) and originator filgrastim (range 4−14). Both groups had a median of one apheresis with a median time until first apheresis of 11 days. There were no statistically significant differences between groups in the median (range) number of mobilised CD34+ cells/μL in peripheral blood (EP-2006, 62.0 [2−394]; originator filgrastim, 47.5 [2−370]) or the number of CD34+ cells/ kg body weight (EP-2006, 9.1 [0−23]; originator filgrastim, 9.4 [6−48]). Five patients (9%) in each group did not mobilise sufficient CD34+ cells. The adverse event profile was comparable between the EP-2006 and originator filgrastim groups, with similar occurrence of neutropenic fever (9 vs 11 patients) and bone pain (8 vs 6 patients). CONCLUSION:EP-2006 demonstrated similar efficacy and safety as the reference filgrastim in haematopoietic stem cell mobilisation in patients with haematological malignancies. Disclosures:Dmoszynska:Mundipharma: Advisory Board; Roche: Honoraria.

Concerns about the use of biosimilar granulocyte colony-stimulating factors for the mobilization of stem cells in normal donors: position of the World Marrow Donor Association

Concerns about the use of biosimilar granulocyte colony-stimulating factors for the mobilization of stem cells in normal donors: position of the World Marrow Donor Association

Presently available biosimilars in hematology-oncology — Part II: G-CSF

Biopharmaceuticals were copies of endogenous human proteins developed in the mid-nineties that were characterized by complex three-dimensional, high-molecularweight compounds. What made them unique was that contrary to classical chemotherapeutical drugs, they were manufactured by living cells. One of these biopharmaceuticals was granulocyte-colony stimulating factor (G-CSF). Once their patent expired, generic versions appeared in pharmacies. They are now called biosimilars. There are several biosimilar G-CSFs approved in Europe: Biograstim/Filgrastim ratiopharm/Ratiograstim/Tevagrastim (XM02); Zarzio and Nivestim. All these new products are manufactured in facilities with state-of-the-art technology. All products have passed the regulatory requirements for approval, mainly Phase I and Phase III, with the consequent PD/PK evaluations and studies on efficacy and safety. However, there are still someconcerns regarding their long-term evaluation, in particular, the limited experience at the time of approval of these products in terms of efficacy, safety and immunogenicity. For this reason, pharmacovigilance should be rigorous. A lot of work remains to be done in terms of clarification with regard to substituting a biosimilar G-CSF for the innovator product and, finally, information must be provided to physicians, pharmacists and patients to allow for proper decision making. Ultimately, only clinical trials and effective post-marketing pharmacovigilance will provide definitive evidence that a biosimilar is comparable to the originator-reference product in terms of efficacy and safety.

First experience of autologous peripheral blood stem cell mobilization with biosimilar granulocyte colony- stimulating factor

Mobilization techniques for autologous peripheral blood stem cell (PBSC) collection include chemotherapy followed by hematopoietic growth factors, such as granulocyte colony-stimulating factor (G-CSF). Biosimilar versions of G-CSF are now available in Europe. In this study, 40 patients with a hematological malignancy scheduled to receive biosimilar G-CSF (Zarzio(®) Sandoz Biopharmaceuticals, Paris, France) following first-cycle chemotherapy for treatment and autologous PBSC mobilization were prospectively included at a single center. These patients were compared with a historical control group who had been treated with G-CSF (Neupogen(®) Paris, France) at the same center according to the same clinical protocol. PBSC harvesting was considered successful if at least 3×10(6) CD34+ cells/kg were collected. If three consecutive CD34+ tests were below 10/μL then PBSC harvesting was not performed. Patient characteristics were similar in both groups with no significant differences in age, diagnosis, previous chemotherapy, or chemotherapy mobilization regimen. No significant differences were observed between groups in median CD34+ cells mobilized and collected, or the number of G-CSF injections and leukaphereses required to obtain the minimal CD34+ cell count. Proportion of failures was also similar in both groups. Zarziois(®) comparable to Neupogen(®) for PBSC mobilization and collection after chemotherapy and so may provide a more cost-effective strategy.

Biosimilar agents in oncology/haematology: from approval to practice

The regulation of biosimilars is a process that is still developing. In Europe, guidance regarding the approval and use of biosimilars has evolved with the products under consideration. It is now more than 3 years since the first biosimilar agents in oncology support, erythropoiesis-stimulating agents, were approved in the EU. More recently, biosimilar granulocyte colony-stimulating factors have received marketing approval in Europe. This review considers general issues surrounding the introduction of biosimilars and highlights current specific issues pertinent to their use in clinical practice in oncology. Information on marketing approval, extrapolation, labelling, substitution, immunogenicity and traceability of each biosimilar product is important, especially in oncology where patients are treated in repeated therapy courses, often with complicated protocols, and where biosimilars are not used as a unique therapy for replacement of e.g. growth hormone or insulin. While future developments in the regulation of biosimilars will need to address multiple issues, in the interim physicians should remain aware of the inherent differences between biosimilar and innovator products.

Physicochemical and Biologic Comparability of a Biosimilar Granulocyte Colony-Stimulating Factor with Its Reference Product

Development of biosimilars requires physicochemical and biologic characterization to show comparability with a reference product. Zarzio (filgrastim) is a biosimilar recombinant human granulocyte colony-stimulating factor (G-CSF) that has been approved in the EU using Neupogen as its reference product. The aim of this study was to compare the drug identity, purity, and bioactivity of Zarzio (300 and 480 μg/0.5 mL solution) with Neupogen, using a broad range of standard and advanced analytical methods. Peptide mapping with UV detection and mass determination, circular dichroism (CD) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry and liquid chromatography electrospray ionization (LC-ESI) mass spectrometry were among the analyses used to compare primary and higher-order protein structure. Cation-exchange chromatography (CEX) and reversed-phase high-performance liquid chromatography (RP-HPLC) were used to compare polarity and charge. Biologic characterization included comparison of G-CSF receptor binding affinity by surface plasmon resonance spectroscopy, an in vitro cell proliferation assay, and Western blot immunologic binding. The primary structures of Zarzio and Neupogen were shown to be identical by peptide mapping and other tests. CD and NMR spectroscopy demonstrated that the two products have comparable secondary and tertiary structures. RP-HPLC and other methods showed that the products have similar purity profiles. Comparable affinity with the G-CSF receptor GCSFR/CD114 was obtained using surface plasmon resonance spectroscopy, and comparable in vitro bioactivity was shown in a cell proliferation assay. These results show the physicochemical and biologic comparability of Zarzio and its reference product, Neupogen.

Incidence of Febrile Neutropenia and Myelotoxicity of Chemotherapy: A Meta-Analysis of Biosimilar G-CSF Studies in Breast Cancer, Lung Cancer, and Non-Hodgkin’s Lymphoma

Background: The aim of this meta-analysis of 3 clinical studies, conducted with breast cancer, lung cancer, and non-Hodgkin’s lymphoma patients, was to compare a new granulocyte colony-stimulating factor (G-CSF) biosimilar, XM02, with filgrastim in terms of its prophylactic effect on the development of febrile neutropenia (FN) during the first chemotherapy cycle in relation to the myelotoxic potency of the applied chemotherapy regimen. Patients and Methods: Overall, 608 patients (363 under XM02 and 245 under filgrastim) were included in the meta-analysis. The majority of patients were allocated to the chemotherapy categories docetaxel-doxorubicin (45.4%) and cyclophosphamide-hydroxy daunomycin (adriamycin)-oncovin (vincristine)-prednisolone (CHOP)/platinum(Pt)-vinorelbine or Pt-vinblastine/ Pt-etoposide (43.1%); another 11.5% were allocated to the category Pt-gemcitabine/Pt-docetaxel or Pt-paclitaxel. Results: FN in the XM02 and filgrastim groups was reported for 12.1 and 12.5% of patients, respectively, under docetaxeldoxorubicin, for 13.5 and 11.9% under CHOP/Pt-vinorelbine or Pt-vinblastine/Pt-etoposide, and for 15.6 and 12.0% under Pt-gemcitabine/Pt-docetaxel or Pt-paclitaxel. Conclusions: The incidence of FN in the first cycle of chemotherapy under primary G-CSF prophylaxis is low (in the range of 12–16%) and not directly correlated with the myelotoxic potency of the applied chemotherapy regimen. XM02 demonstrated to be non-inferior to filgrastim regarding the incidence of FN, irrespective of the myelotoxicity of the chemotherapy regimen.