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Biosimilar Product Is Equivalent to Neupogen, FDA Staff Says
A biosimilar drug product from Sandoz/Novartis is “highly similar” to Amgen’s blockbuster cancer treatment Neupogen (filgastrim), according to a briefing document compiled by staff members of the FDA’s Oncologic Drugs Advisory Committee (ODAC).
The staff report will be considered at a January 7 meeting of ODAC, at which time the committee will decide whether the biosimilar product EP2006 should be approved for all five of Neupogen’s indications. These indications include:
- to decrease the incidence of infections, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever
- to reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of adults with acute myeloid leukemia
- to reduce the duration of neutropenia and neutropenia-related clinical sequelae, such as febrile neutropenia in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by marrow transplantation
- to mobilize hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis
- to reduce the incidence and duration of the sequelae of neutropenia (e.g., fever, infections, and oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia
Sandoz submitted comparative data on the EP2006 lots used in clinical studies intended to support a demonstration of biosimilarity with Neupogen. Based on its review of the data, ODAC ruled that the EP2006 clinical product lots were “highly similar” to the reference product (Neupogen), notwithstanding minor differences in clinically inactive components. The committee also found that the proposed commercial EP2006 drug product was analytically “highly similar” to Neupogen with the exception of protein content, which was slightly lower than that of Neupogen. The lower protein content of the proposed commercial EP2006 product appeared to be a manufacturing issue, which could be resolved by manufacturing and control strategies, the committee noted.
“The results of the clinical development program suggest that the applicant’s data meet the requirement for a demonstration of ‘no clinically meaningful differences’ between the proposed product and the reference product in terms of safety, purity, and potency,” the committee announced.
This conclusion was supported by data from a comparative clinical study that enrolled patients with breast cancer receiving TAC (Taxotere [docetaxel], Adriamycin [doxorubicin], and Cytoxan [cyclophosphamide]) chemotherapy. The subjects were randomly assigned to treatment with either EP2006 or Neupogen. The FDA’s analysis of the efficacy and safety results from this trial provided additional support for the finding that there are no clinically meaningful differences between EP2006 and Neupogen.
Neupogen contains recombinant methionyl granulocyte colony-stimulating factor (met-G-CSF). The drug’s approved indications generally fall under the categories of neutropenia and mobilization of hematopoietic stem cells.
The biologic activity of G-CSF is initiated by the binding of G-CSF to the G-CSF receptor on myeloid progenitor cells and mature neutrophils. This binding initiates transduction signals that lead to the proliferation and differentiation of neutrophil-committed progenitor cells, to an increase in mature neutrophils in the blood (an acceptable pharmacodynamic marker for neutropenia), and to enhanced neutrophil function. These activities are all relevant to the neutropenia indications for Neupogen.
EP2006 (met-G-CSF) is produced by recombinant technology in Escherichia coli. The manufacturing process of the EP2006 drug substance consists of various steps intended to isolate and purify met-C-GSF.
The FDA gained the authority to approve biosimilars through the 2010 Patient Protection and Affordable Care Act.
Sources: FDA; January 5, 2014; and Bloomberg News; January 5, 2015.