Abstract
Herein we compared 40 mg/mL lots of the active ingredient, glatiramer acetate, manufactured by Mylan/Natco to the active ingredient, glatiramer acetate in Copaxone (Teva Pharmaceuticals, Ltd., Netanya Israel) using physicochemical (PCC) methods and biological assays. No differences were seen between the Mylan/Natco and Teva lots with some low resolution release PCC assays (amino acid analysis, molecular weight distribution, interaction with Coomassie Brilliant Blue G-250). Changes in polydispersity between Mylan/Natco and Copaxone lots were found using size exclusion chromatography and the high resolution PCC method, known as Viscotek, and suggestive of a disparity in the homogeneity of mixture, with a shift towards high molecular weight polypeptides. Using RPLC-2D MALLS, 5 out of 8 Mylan/Natco lots fell outside the Copaxone range, containing a high molecular weight and high hydrophobicity subpopulation of polypeptides not found in Copaxone lots. Cation exchange chromatography showed differences in the surface charge distribution between the Copaxone and Mylan/Natco lots. The Mylan/Natco lots were found to be within Copaxone specifications for the EAE model, monoclonal and polyclonal binding assays and the in vitro cytotoxicity assay, however higher IL-2 secretion was shown for three Mylan/Natco lots in a potency assay. These observations provide data to inform the ongoing scientific discussion about the comparability of glatiramer acetate in Copaxone and follow-on products.
Highlights
Copaxone, a safe and effective treatment option for multiple sclerosis (MS), was approved by the United States Food and Drug Administration (FDA)in 1997 as a once daily 20 mg/mL injection, and in 2014 as a 40 mg/mL thrice weekly injection.MS is a neurodegenerative disease mediated by highly reactive lymphocytes which cross the blood brain barrier into the central nervous system (CNS), and cause widespread inflammation resulting demyelination, cell apoptosis and axonal loss [1]
The active ingredient of Copaxone is glatiramer acetate (GA), a non-biological complex drug (NBCD) composed of a heterogeneous mixture of nano-sized polypeptide components derived from the copolymerization of four synthetic amino acids (l-glutamic acid, l-alanine, l-tyrosine, and l-lysine), and was discovered to mimic myelin basic protein (MBP), an autoantigen involved in MS pathology as an altered peptide of MBP p82-100 [2,3]
While the composition of GA is defined by the specifics of multiple stages in the manufacturing process, the consistent quality of its active ingredient relies on the robustness of these manufacturing stages
Summary
Copaxone (glatiramer acetate, Teva Pharmaceuticals), a safe and effective treatment option for multiple sclerosis (MS), was approved by the United States Food and Drug Administration (FDA)in 1997 as a once daily 20 mg/mL injection, and in 2014 as a 40 mg/mL thrice weekly injection.MS is a neurodegenerative disease mediated by highly reactive lymphocytes which cross the blood brain barrier into the central nervous system (CNS), and cause widespread inflammation resulting demyelination, cell apoptosis and axonal loss [1]. The active ingredient of Copaxone is glatiramer acetate (GA), a non-biological complex drug (NBCD) composed of a heterogeneous mixture of nano-sized polypeptide components derived from the copolymerization of four synthetic amino acids (l-glutamic acid, l-alanine, l-tyrosine, and l-lysine), and was discovered to mimic myelin basic protein (MBP), an autoantigen involved in MS pathology as an altered peptide of MBP p82-100 [2,3]. The therapeutic effects of Copaxone are thought to be related to the presentation of Copaxone’s yet unidentified epitopes as antigens binding to various major histocompatibility complex Class II molecules on antigen-presenting cells and T-cells [3]. While the composition of GA is defined by the specifics of multiple stages in the manufacturing process, the consistent quality of its active ingredient relies on the robustness of these manufacturing stages
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