Status - EU biosimilar approval in Sept. 2008; BLA (full, not biosimilar) approved in Aug. 2012

Organizations involved:

Teva Pharmaceutical Industries Ltd.– R&D; Tech.; Parent

Hospira - World mark.

Sicor Pharmaceuticals – Manuf.; R&D; Tech.

Lemery SA de CV, Mexico – Manuf. other

BioGenerIX AG - R&D ; Tech.

ratiopharm AG – Parent

Cross ref.: See also the entries for G-CSF, rDNA/BiogenerIX (Ratiograstim), G-CSF, rDNA/CT Arzneimittel (Biograstim), and G-CSF, rDNA/ratiopharm (Filgrastim Ratiopharm), which are the same product as this, with the active agent manufactured by SICOR and packaged by Lemary, but marketed and with EU approval held by a different company. See the other G-CSF entries, particularly filgrastim (Neupogen), for G-CSF-related information.

Description: TevaGrastim/Neutroval refers to aqueous formulations of XM02, recombinant human granulocyte-colony stimulating factor produced in transformed E. coli K802, yielding a non-glycosylated protein with an N-terminal methionyl extension (INN filgrastim). The protein is expressed in inclusion bodies followed by renaturation of protein and chromatographic purification steps. The formulation contains sodium acetate buffer, sorbitol, polysorbate and water for injections, and is similar to Neupogen with only slight differences exist in the concentration of polysorbate and in the pH value.

TevaGrastim is supplied as solution for injection or infusion in 1 ml glass, single-use, pre-filled syringes in two strengths:

- 30 MIU/0.5 ml dosage strength containing 300 µg of filgrastim active substance, to give a 0.5 ml extractable volume

- 48 MIU/0.8 ml dosage strength containing 480 µg of filgrastim active substance, to give a 0.8 ml extractable volume.

Each strength is to be supplied in packs of one, five, two x five, or ten pre-filled syringes.

TevaGrastim is supplied in pre-filled syringes containing 0.5 (for the lower strength) or 0.8 ml (for the higher strength) of sterile, preservative-free solution for injection consisting of 30 or 48 MIU (corresponding to 300 and 480 µg respectively) XM02 together with acidic sodium acetate buffer, sorbitol, polysorbate and water for injections.

Note, Sicor had previously developed, manufactured and marketed a Grasalva, a similar G-CSF product, in Lithuania starting in 2003, in collaboratin with BiogenerIX. The active substances for Grasalva and Tevagrastim are the same and they are manufactured using to the same process. However, there are some differences on the level of the drug product, and the EU concluded that the two products are not the same. Regarding safety experience with Grasalva, EMEA noted, "As details in the Grasalva dossier were limited in some areas, a thorough assessment of these adverse events was difficult... The CHMP concluded that the data provided in the Grasalva dossier do not affect the opinion for Tevagrastim... The CHMP concluded that the Applicant had demonstrated satisfactorily that the clinical development for Tevagrastim was clearly separate from the clinical development of Grasalva and conducted by two separate companies, i.e. Biogenerix for Tevagrastim and Sicor Biotech for Grasalva. In conclusion, the CHMP concluded that data generated for the medicinal product Grasalva did not affect the benefit-risk balance of Tevagrastim."

Nomenclature: G-CSF, rDNA/Teva [BIO]; Neutroval [TR US]; TevaGrastim [TR EU]; Granix [TR fro tbo version]; filgrastim [USAN INN BAN MESH]; tbo-filgrastim [FDA]; 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]; none [CAS; according to Amgen]; NSC 614629 [SY NCI]; XM02 [SY]

Companies.: XM02, the active substance, is manufactured by SICOR Biotech UAB, Vilnius, Lithuania. SICOR is a subsidiary of Teva Pharmaceuticals. Clinical development was handled by BioGenerIX, a subsidiary of ratiopharm. TevaGrastim is marketed in Europe by Teva.

Manufacture of prefilled syringes takes place at Lemery SA de CV, Mexico and employs a straightforward process, including compounding, sterile filtrations and aseptic filling

In Sept . 2009, Hospira acquired exclusive worldwide marketing rights. Hospira previously had been collaborating on the product with Barr Pharmaceuticals, which was bought by Teva.

Manufacture: After a predefined growth time, inductor is added to fermentation media. This induces the start of the production phase, which continues for a predefined growth time. The cells are harvested and disrupted, and inclusion bodies are washed with buffer for removal of contaminants. The inclusion bodies are dissolved in a chaotropic agent and refolded by reducing-oxidizing system. After refolding, a series of orthogonal chromatographic purification steps are applied. Following purification, the active substance is filtered, filled into bottles and stored at 2-8°C (refrigerated). The concentration of medicinal product bulk solution is 0.6 mg/ml and the difference in the two strengths is achieved by the different fill volumes.

No major changes were introduced into the manufacturing process during development. All batches of active substance manufactured at the developmental and commercial scales were produced using the same Working Cell Bank (WCB). The developmental scale batch was used only during Phase I trials. Throughout process development, fermentation was conducted at the same scale, but the site of fermentation and purification was changed when the manufacturing was transferred to a GMP production facility.

Three materials of biological origin are used in routine production; bacterial host strain E. coli, casamino acids used as a fermentation medium component, and polysorbate 80 (Tween 80) used as a component of the formulation. The starting material of the casamino acids is bovine milk deemed fit for human consumption from healthy animals of New Zealand origin. This material is compliant with EU requirements to minimise TSE risks laid out in the Note for Guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products (EMEA/410/01). The hydrolysis process involves acid treatment at pH ≤1.0, 120°C for a minimum of six hours. It is expected that these conditions should be more than sufficient to inactivate any adventitious viruses. The polysorbate 80 used as an excipient is of vegetable origin, and therefore does not constitute a virus safety risk. Because the fermentation of E. coli does not support growth of viruses, no viral clearance studies were performed.

FDA class: BLA (biosimilar; bBLA); Biologic

Indications: [Full text of the "Therapeutic indications:" section of the EU SPC]:

Tevagrastim is indicated for the 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 for the 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.

Tevagrastim is indicated for the mobilisation of peripheral blood progenitor cells (PBPC).

In patients, children or 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 Tevagrastim is indicated to increase neutrophil counts and to reduce the incidence and duration of infection-related events.

Tevagrastim is indicated for the treatment of persistent neutropenia (ANC less than or equal to 1.0 x 109/l) in patients with advanced HIV infection, in order to reduce the risk of bacterial infections when other options to manage neutropenia are inappropriate.

Status: Tevagrastim was developed (for the EU) as a “similar biological medicinal product” according to Article 10 (4) and Annex 1, Part II, Chapter 4 of Directive 2001/83/EC as amended. The chosen reference medicinal product was Neupogen sourced from Amgen, Germany.

The MAA was submitted by Teva Generics GmbH (Germany) on Jan. 29, 2007 under 2001/83/EC Article 10(4) concerning biosimilar medicinal products. European Union biosimilar approval was granted on Sept. 18, 2009 (Procedure No. EMEA/H/C/827).

During its EU review, a major objection was raised regarding the source of the reference medicinal product, as the applicant appeared to have used Neupogen from three different sources: Amgen Germany; Amgen Lithuania and Roche Lithuania. The reference medicinal product must be a medicinal product authorised in the Community on the basis of a complete dossier and at the time of the study, Lithuania was not a member of the EU. It was unclear whether an EU authorized medicinal product was used as reference in the analyses for product-related impurities by RP-HPLC and IE-HPLC. In Teva's responses, the company provided both a summary of the data provided in the original dossier and new data regarding the product-related impurity profile as detected by RP-HPLC and IE-HPLC. The data confirmed that the XM02 medicinal product contains comparable or fewer product-related impurities compared to Neupogen sourced from Amgen, Germany. Together with the comparability exercise submitted in the original dossier, the comparability between XM02 medicinal product and Neupogen was fully demonstrated using an EU authorised medicinal product as reference (i.e. Neupogen sourced from Amgen, Germany). All data produced with Neupogen from Lithuania were regarded as supportive.

On Dec. 2 2009, Teva filed the BLA for XM02 for the reduction in the duration of severe neutropenia and the incidence of febrile neutropenia in patients treated with established myelosuppressive chemotherapy for cancer. Note, this was for a full BLA approval, not a biosimilar approval.

On Sept. 30, 2010, FDA issued Teva a complete response letter requesting some additional information for the BLA,

Tech. transfer:      In Feb. 2010, Amgen filed a patent infringement suit against Teva concerning XM02. Amgen's main European patents on Neupogen expired in 2006, allowing the sale of biosimilars, but Amgen has U.S. patents it claims cover it until 2013. [With Amgen having won a patent dispute with Roche concerning Mircera (see related entry), it seems doubtfult that Teva will win this suit.]. The U.S. district of Pennsylvania in summer 2011 ordered that Teva must wait to market Neutroval until 10 November 2013, unless the courts decide the Amgen patents are not infringed.

Trials: In order to show the biosimilarity between XM02 and Neupogen, the clinical program was composed of 5 clinical studies and focused on showing the clinical equivalence of XM02 and Neupogen in all respects, i.e. clinical pharmacology in 2 phase I studies, efficacy and safety in 3 phase III studies.

Randomized, single-blind, single dose, crossover studies in 196 healthy volunteers showed that the pharmacokinetic profile of XM02 was comparable to that of the reference product, Neupogen (filgrastim), after subcutaneous and intravenous administration.

Clinical efficacy was investigated in one pivotal study (Study XM02-02-INT) performed in patients with breast cancer. Two other studies in patients with lung cancer and non-Hodgkin lymphoma focused on safety. All three studies were blinded.

The product related impurity profiles between XM02 medicinal product and Neupogen were shown to be similar. The conclusion is based on impurity testing in stability studies as well as on the experimental evidences from comparability studies.

Market: Teva progressively began marketing the product throughout Europe in 2009. TevaGrastim will have to compete against Neupogen and multiple other biosimilars and also against Neulasta (pegylated G-CSF). If G-CSF biosimilars follow the examples set by biosimilar EPO products, these products will only capture relatively small market share in Europe.