Integrated Transcriptomic and Physicochemical Characterization of Glatiramer Acetate Products (Copaxone and Glatopa) Available in the United States

Objective: Characterize glatiramer acetate products available in the United States (Copaxone and Glatopa) using an expanded set of physicochemical and gene expression assays. Background: Glatiramer acetate (Copaxone; GA) a complex polypeptide mixture that cannot be fully characterized, is a safe, effective treatment for relapsing forms of multiple sclerosis. In 2015, a generic Glatiramer acetate (Glatopa) became available in the US. The FDA approved Glatopa based on active substance sameness as defined by four step criteria, including traditional physicochemical methodologies, and structural signatures for polymerization and depolymerization, with no requirement for in vivo clinical bioequivalence studies. Design/Methods: An expanded set of physicochemical methods was applied to characterize compositional properties of both Copaxone and Glatopa. Gene expression profiles were used to characterize functional effects in splenocytes from mice pre-treated with Copaxone or Glatopa, then activated ex-vivo with either drug; qRT-PCR was used for confirmation. Results: When a subset of low resolution physicochemical assays were applied, consistency between drugs was observed; however, an expanded high resolution set of physicochemical assays showed differences between Glatopa and Copaxone. Glatopa had higher surface positivity compared to Copaxone across multiple orthogonal methods. Genomic analyses demonstrated similarities and differences: in splenocytes, thousands of probesets were modulated similarly; however, hundreds were differentially modulated (7–11% of Copaxone-affected probesets), including immune pathways. Consistent with literature linking surface positivity to immunomodulation, including over-expression of Ccl2, Glatopa (but not Copaxone) upregulated Ccl2 (adj p Conclusions: When an expanded state of the art, high resolution set of physicochemical and gene expression assays are utilized to characterize Copaxone and Glatopa, significant differences are observed. Gene expression differences include altered immunomodulation of inflammation-relevant genes, consistent with physicochemical observations of altered surface charge. These observations provide additional data to inform the ongoing scientific discussion about whether sameness of GA in Copaxone and in follow on GA products can be established. Study Supported by: Teva Pharmaceutical Industries Disclosure: Dr. Komlosh has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Laifenfeld has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Kolitz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Immuneering. Dr. Fowler has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Immuneering. Dr. Hasson has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Konya has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Bakshi has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Zeskind has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Immuneering. Dr. Zhang has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Immuneering. Dr. Wells-Knecht has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Molotsky has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Krispin has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Papir has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Pinkert has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Cooperman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Weinstein has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Sahly has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Loupe has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Melamed-Gal has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Teva. Dr. Grossman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Hayden has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries.