Filgrastim - Zarzio; Granulocyte Colony Stimulating Factor, recombinant
Status - EU biosimilar approval in Sept. 2008
Organizations involved:
Sandoz AG – Manuf.; R&D; Tech.; Intl. mark.
Novartis AG – Parent.
Cross ref.: See the other G-CSF entries, particularly filgrastim (Neupogen), for G-CSF-related information. Description: Zarzio is a formulation of recombinant human G-CSF produced in transformed Escherichia coli (E. coli) bacteria. Its amino acid sequence is identical to that of natural human G-CSF, except for the addition of an N-terminal methionine necessary for the expression in E. coli; and it is not glycosylated. Zarzio composition matches that of Neupogen except for the use of glutamate rather than acetate for the buffer..
Two presentations of the medicinal product are available: 30MU (300 µg/0.5 ml) Solution for Injection/concentration for solution for infusion; and a pre-filled syringe with 48 MU (480 µg/0.5 ml) Solution for Injection/concentrate for solution for infusion. The reference product, Neupogen, is also available in these same two presentations. Each ml of solution contains 60 million units (MU; equivalent to 600 µg filgrastim). Each pre-filled syringe contains 30 MU (equivalent to 300 µg) filgrastim in 0.5 ml. Each ml of solution also contains 50 mg sorbitol. The product has a shelf life of shelf-life of 30 months at 5±3°C for both presentations.
Biological.: EMEA concluded, "The composition of filgrastim [Zarzio] and Neupogen is quantitatively similar except the buffer system for filgrastim is glutamate and for Neupogen it is acetate. The data presented confirm that filgrastim and Neupogen are comparable with respect to primary structure, secondary and tertiary structure, molecular mass, hydrophobicity, molecular size, charge, binding and (in vitro) bioactivity. Product related impurities were thoroughly investigated. Aggregates and truncated forms showed no significant differences. The data show a consistently lower level of deamidated and oxidised forms. These differences did not appear to impact on bioactivity (in vitro bioassay) or stability. In conclusion, the physicochemical and biological analysis of filgrastim fully supports its biosimilarity to Neupogen."
Nomenclature: G-CSF, rDNA/Sandoz [BIO]; Zarzio [TR]; Filgrastim [USAN INN BAN MESH]; colony-stimulating factor (human clone 1034) , N-L-methionyl- [CAS]; 135968-09-1 [CAS RN]; granulocyte colony stimulating factor, recombinant [SY]; r-metHuG-CSF [SY]; NSC 614629 [SY NCI]
Companies.: Zarzio was developed and is manufactured and marketed by Sandoz AG, the generics subsidiary of Novartis AG. Zarzio is manufactured and released at Sandoz GmbH, Kundl, Austria. The primary market is Europe, but the product may also be marketed in other countries worldwide.
Manufacture: Filgrastim is produced by recombinant DNA technology in bacteria (E.coli) from the full length human sequence for N-(L-methionyl) granulocytes colony-stimulating factor (r-metHuG-CSF), i.e., native human G-CSF with an added N-terminal methionine (to allow expresion in E. coli). E.coli are expanded in fermentors using human and animal-free growth media. Filgrastim is concentrated in E.coli inclusion bodies (IB) which are isolated by cell disruption and centrifugation and then solubilized to allow protein re-folding.
Downstream processing involves chromatographic purification steps to separate filgrastim from other contaminating proteins and impurities, followed by further polishing steps. A final buffer exchange is performed to yield the active substance solution. The E.coli are banked in a standard two tier banking system consisting of a master cell bank (MCB) and a manufacturers working cell bank (MWCB). Critical steps and intermediates are controlled by a range of critical process parameters (identified during development), process parameters, action limits and acceptance criteria. Filgrastim is stored in pre-sterilized non-pyrogenic bottles with screw caps. Further manufacturing consists of mixing active substance with excipients and adjustment of pH followed by filtration and filling.
During development, a number of buffer systems were tested for stability of the active substance. The final composition was optimised and matched to Neupogen except for the use of glutamate rather than acetate for the buffer.
No materials of animal or human origin are used to manufacture Zarzio active substance or final product. Some reagents derived from bovine milk protein are used in the manufacture of chromatography columns, but the suppliers certify these comply with EU requirements
Indications: [Full text of the "Therapeutic indications:" section of the EU SPC]:
- Reduction in the duration of neutropenia and the incidence of febrile neutropenia in patients treated with established cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes) and 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.
The safety and efficacy of filgrastim are similar in adults and children receiving cytotoxic chemotherapy.
- Mobilisation of peripheral blood progenitor cells (PBPC).
- In children and adults with severe congenital, cyclic, or idiopathic neutropenia with an absolute neutrophil count (ANC) of ≤ 0.5 x 109/l, and a history of severe or recurrent infections, long term administration of filgrastim is indicated to increase neutrophil counts and to reduce the incidence and duration of infection-related events.
- Treatment of persistent neutropenia (ANC ≤ 1.0 x 109/l) in patients with advanced HIV infection, in order to reduce the risk of bacterial infections when other therapeutic options are inappropriate..
Status: A MAA for biosimilar approval with Neupogen as the reference was filed on Sept. 6, 2007. The MAA was submitted by Sandoz GmbH (Austria) under 2001/83/EC Article 10(4) concerning biosimilar medicinal products. European Union biosimilar approval was granted on Feb. 13, 2009 (Procedure No. EMEA/H/C/000917).
Presumably, when relevant patents expire and, particularly, if favorable biosimilars legislation is implemented in the U.S., Sandoz/Novartis will seek biosimilar approval in the U.S.
Trials: Zarzio for EU approval was tested in healthy volunteers in four Phase I studies and in neutropenic patients in a Phase III study. In the open Phase III cross-over study different doses of Zarzio were evaluated for safety and efficacy in breast cancer patients undergoing doxorubicin and docetaxel (Taxotere) chemotherapy, and therefore at high risk for severe neutropenia, and compared to Neupogen. This study confirmed that the administration of Zarzio was efficacious and safe, triggering no immunogenicity. Phase I cross-over studies demonstrated also biosimilarity, with respect to the pharmacokinetics and pharmacodynamics (absolute neutrophil count and CD34+ cells), of various doses (1, 5 or 10 mg/kg,) of Zarzio and the reference product, Neupogen (Amgen GmbH), in healthy volunteers, administered via both the SC and IV routes.
EMEA concluded, "A direct comparison of the safety profile of the test and reference products is possible from the four studies in 146 healthy volunteers (data not shown). ADRs were consistent with those reported in normal donors as described in the Neupogen SmPC and were similar for both products. Overall, these data support the comparability of the products."
In four clinical studies none of the healthy volunteers or cancer patients developed anti-rhG-CSF antibodies (neither binding nor neutralising) upon treatment with Zarzio. The evaluation of the immune response after rhG-CSF administration was made by a three-step procedure comprising a validated radioimmunoprecipitation assay and a validated cell-based neutralization antibody assay. Serum samples for antibody analysis were taken at baseline (screening), one hour before the start of treatment period II and at follow-up. At these time points, the presence of active substance, which might interfere with the ability to detect anti- rhG-CSF antibodies, may be excluded because rhG-CSF levels would have returned to normal values. Samples were taken in Study EP06-102 – single iv dose, Study EP06-103 – repeated sc dose (2.5 and 5 µg/kg), and Study EP06-101 – repeated sc dose (10 µg/kg). None of the volunteers developed anti-rhG-CSF binding antibodies at any time-point of the studies.
The Phase III study EP06-301 enrolled 170 chemically naive, female, breast cancer patients, who received Zarzio at a dose of 300 mg or 480 mg administered via the SC route. Patients were undergoing four cycles of doxorubicin and docetaxel (Taxotere) chemotherapy, and were therefore at high risk for severe neutropenia (low white blood cell count in the blood causing reduced host defence). The study was primarily designed to assess the safety and immunogenicity of filgrastim in breast cancer patients. In terms of efficacy, the mean duration of severe neutropenia with Zarzio was 1.8 days in cycle 1, compared to (historically) up to 7 days without growth factor. Over the four cycles, this was comparable (or lower) than historical data with the reference product, Neupogen. The incidence of febrile neutropenia in cycle 1 was 7.6% compared with 17.5% without growth factor. This also compared well with the reference product. Overall, filgrastim was very well tolerated by these cancer patients, although their exposure to filgrastim was not consistent with the literature data for the reference product. Since the dose was not adjusted to bodyweight, only 22% of the patients received doses included between 4.5 and 5.5 µg/kg while 75% received higher doses up to 8 µg/kg. Immunogenicity data in healthy volunteers and in cancer patients showed no evidence of IgG antibody formation against rhG-CSF, a finding consistent with the known low immunogenicity of Neupogen. Since PK and PD results are considered sufficiently comparable to support the biosimilarity of the test and reference products, a robust (head to head) comparison of their long-term safety was considered less critical by EMEA.
Ongoing safety follow-up will be performed on healthy subjects having participated in various trials.
In line with CHMP Scientific Advice, pharmacodynamic data in healthy volunteers (absolute neutrophil and CD34+ cell counts) were used to establish the clinical efficacy. The data submitted supported the comparability of filgrastim and Neupogen.
A direct comparison of the safety profile of the test and reference products was possible based on studies in healthy volunteers. ADRs associated with filgrastim were consistent with those reported in normal donors as described in the Neupogen SPC. Overall, these data supported the comparability of the products. A small single-arm trial in cancer patients submitted allowed, to a certain extent, to rule out any unexpected safety issue and suggests low immunogenicity of the test product. Additional long-term safety and immunogenicity data will be collected post-marketing as described in the RMP.
Market: Zarzio competes against Neupogen and multiple other biosimilars and also against Neulasta (pegylated G-CSF).
With G-CSF biosimilars following the examples set by biosimilar EPO products, these products are only capturing relatively small market share in Europe. In 2009, total sales were only ~$8 million (in Germany, France, Spain, Poland and Austria).
Index Terms:
Companies involvement:
Full monograph
160.8 G-CSF, rDNA/Sandoz
Nomenclature:
G-CSF, rDNA/Sandoz [BIO]
Zarzio [TR]
Filgrastim [USAN INN BAN MESH]
colony-stimulating factor (human clone 1034) , N-L-methionyl- [CAS]
135968-09-1 [CAS RN]
granulocyte colony stimulating factor, recombinant [SY]
NSC 614629 [SY NCI]
r-metHuG-CSF [SY]
molecular weight (kDa) = 19
FDA Class: Biologic BLA
Annual sales (2011, $millions) = $52
Annual sales (2009, $millions) = $8
biopharmaceutical products
Biorex-70 resin
exempt from CBER lot release requirements
growth factors, hematopoietic
recombinant DNA
bacterial culture <!-- bacterialculture -->
Escherichia coli (E. coli)
glutamate
somatropin, recombinant
BHK-21 (C-13)
EU200 Currently Approved in EU EU777
UM999 Not Available/Not Marketed in US
US000 never filed/no plans
EM001 Marketed Product in EU
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