Contributions
Abstract: EP1652
Type: ePoster
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Objective: Copaxone (Teva, glatiramer acetate), has provided a safe and effective treatment option for multiple sclerosis for 20+ years. The European regulatory assessment of follow-on-glatiramer acetate (FOGA) relied on establishing similarity rather than sameness of the active substance, and followed a biosimilar type approach. Copaxone release tests, high resolution physicochemical tests and biological assays were employed to evaluate compositional characteristics and their associated and functional ramifications, when comparing European FOGA relative to Copaxone specifications or inherent variability ranges.
Methods: The characterization methods included molecular weight distribution (MWD), Coomassie Brilliant Blue G-250 (CBBG), Viscotek TDAmax, cation exchange chromatography (CEX), Atomic Force microscopy (AFM), 2D-RPLC MALLS, cell-based potency, cytotoxicity, and ELISA assays using monoclonal (MAb) and polyclonal (PAb) antibodies for bio-recognition of glatiramer acetate.
Results: The FOGA batches (n=6) were within the Copaxone specification or variability ranges for the following methods; MWD, CBBG, AFM, 2D-RPLC MALLS, potency, and bio-recognition by MAb and PAb antibodies. Several compositional attributes were consistently different between the FOGA and Copaxone, including molecular size, hydrodynamic radius, and intrinsic viscosity (Viscotek). Charge distributions of the FOGA batches were outside the Copaxone value range for negatively charged and weak positively charged subpopulations, and for 4 out of 6 batches, also for the strongly positively charged subpopulation (CEX). Biological tests showed distinctly higher potency of all FOGA batches as compared to Copaxone although results were within the potency specification range. Furthermore, a third of the FOGA batches demonstrated higher in vitro cytotoxicity activity than the established Copaxone specification range.
Conclusion: When applying state-of-the-art methodologies, consistent differences were observed in compositional characteristics of the European FOGA product. Altered surface charge distribution has previously been associated with cytotoxicity and potency alterations (Bhattacharjee et al. 2010; Fromen et al. 2016) and was confirmed herein experimentally. Associated immunogenicity risks warrant investigation.
Disclosure: All authors are employees of Teva Pharmaceutical Industries who sponsored the research described in this report
Abstract: EP1652
Type: ePoster
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Objective: Copaxone (Teva, glatiramer acetate), has provided a safe and effective treatment option for multiple sclerosis for 20+ years. The European regulatory assessment of follow-on-glatiramer acetate (FOGA) relied on establishing similarity rather than sameness of the active substance, and followed a biosimilar type approach. Copaxone release tests, high resolution physicochemical tests and biological assays were employed to evaluate compositional characteristics and their associated and functional ramifications, when comparing European FOGA relative to Copaxone specifications or inherent variability ranges.
Methods: The characterization methods included molecular weight distribution (MWD), Coomassie Brilliant Blue G-250 (CBBG), Viscotek TDAmax, cation exchange chromatography (CEX), Atomic Force microscopy (AFM), 2D-RPLC MALLS, cell-based potency, cytotoxicity, and ELISA assays using monoclonal (MAb) and polyclonal (PAb) antibodies for bio-recognition of glatiramer acetate.
Results: The FOGA batches (n=6) were within the Copaxone specification or variability ranges for the following methods; MWD, CBBG, AFM, 2D-RPLC MALLS, potency, and bio-recognition by MAb and PAb antibodies. Several compositional attributes were consistently different between the FOGA and Copaxone, including molecular size, hydrodynamic radius, and intrinsic viscosity (Viscotek). Charge distributions of the FOGA batches were outside the Copaxone value range for negatively charged and weak positively charged subpopulations, and for 4 out of 6 batches, also for the strongly positively charged subpopulation (CEX). Biological tests showed distinctly higher potency of all FOGA batches as compared to Copaxone although results were within the potency specification range. Furthermore, a third of the FOGA batches demonstrated higher in vitro cytotoxicity activity than the established Copaxone specification range.
Conclusion: When applying state-of-the-art methodologies, consistent differences were observed in compositional characteristics of the European FOGA product. Altered surface charge distribution has previously been associated with cytotoxicity and potency alterations (Bhattacharjee et al. 2010; Fromen et al. 2016) and was confirmed herein experimentally. Associated immunogenicity risks warrant investigation.
Disclosure: All authors are employees of Teva Pharmaceutical Industries who sponsored the research described in this report