Utilize gene expression to compare the biological impact of proposed generics from different manufacturers with each other and with branded glatiramer acetate (GA).
Since the 1990s, Copaxone has provided a safe and effective treatment option for MS patients. GA, the active substance of Copaxone, is a copolymer of L-alanine, L-lysine, L-glutamic acid and L-tyrosine. The specific composition of polypeptides in solution comprising GA cannot be fully characterized with available assays. While various physicochemical tests show complete consistency between GA batches, they identify significant differences between GA and proposed generics, as well as amongst proposed generics from different manufacturers. Gene expression provides a means to investigate the biological impact of these differences, particularly given the absence of PK/PD markers for GA. This represents a test case for the broader challenge of assessing biosimilars/biogenerics and generics for non-biological-complex-drugs.
Splenocytes from GA-primed mice were reactivated ex-vivo with GA or proposed generics. Expression data were measured using microarrays, and analyzed to identify differentially expressed genes and elucidate underlying biology.
Differentially expressed genes induced by proposed generic vs. GA were associated with activation of inflammatory responses and increased cell adhesion and migration. GA also upregulated FOXP3 and other genes associated with tolerance-inducing regulatory T cells (Tregs) more consistently and to a greater extent than proposed generic. Proposed generic upregulated inflammatory monocyte-related genes to a greater extent than GA. Additional genes differentially expressed between GA vs. proposed generic, and amongst proposed generics from different manufacturers, also may play a role in MS pathology and therapeutic response. Studies in human monocytes are ongoing and will be reported accordingly.
Gene expression studies identify differences between GA and proposed generics, and differences amongst proposed generics from different manufacturers. These findings warrant further investigation to ensure that MS patients receive safe and effective medicines.