Two decades of glatiramer acetate: From initial discovery to the current development of generics.

Multiple sclerosis (MS) is a chronic, incurable, inflammatory disease of the central nervous system (CNS). In the United States, several US Food and Drug Administration (FDA)-approved disease-modifying treatments (DMTs) are available, including glatiramer acetate (GA; Copaxone®), one of the most longstanding treatments. GA was discovered serendipitously in the late 1960s/early 1970s while attempting to produce a synthetic antigen capable of inducing experimental autoimmune encephalomyelitis (EAE), an animal model of autoimmune inflammatory CNS disorders, including MS. Instead, GA was found to be protective in EAE models. Subsequent clinical evaluations resulted in GA's FDA approval for relapsing-remitting MS in 1996, followed by a change to the current indication of relapsing forms of MS along with approval of a higher dose and less frequently administered version in 2014. The cost of DMTs including GA remains high, highlighting the potential value of generic therapies for MS. A rigorous scientific approach may be undertaken to demonstrate equivalence between the generic and innovator drug. The introduction of generic versions of GA into the MS treatment landscape has the potential to reduce treatment costs, improving access to these much-needed treatments.

Equivalent Gene Expression Profiles between Glatopa™ and Copaxone®.

Glatopa™ is a generic glatiramer acetate recently approved for the treatment of patients with relapsing forms of multiple sclerosis. Gene expression profiling was performed as a means to evaluate equivalence of Glatopa and Copaxone®. Microarray analysis containing 39,429 unique probes across the entire genome was performed in murine glatiramer acetate--responsive Th2-polarized T cells, a test system highly relevant to the biology of glatiramer acetate. A closely related but nonequivalent glatiramoid molecule was used as a control to establish assay sensitivity. Multiple probe-level (Student's t-test) and sample-level (principal component analysis, multidimensional scaling, and hierarchical clustering) statistical analyses were utilized to look for differences in gene expression induced by the test articles. The analyses were conducted across all genes measured, as well as across a subset of genes that were shown to be modulated by Copaxone. The following observations were made across multiple statistical analyses: the expression of numerous genes was significantly changed by treatment with Copaxone when compared against media-only control; gene expression profiles induced by Copaxone and Glatopa were not significantly different; and gene expression profiles induced by Copaxone and the nonequivalent glatiramoid were significantly different, underscoring the sensitivity of the test system and the multiple analysis methods. Comparative analysis was also performed on sets of transcripts relevant to T-cell biology and antigen presentation, among others that are known to be modulated by glatiramer acetate. No statistically significant differences were observed between Copaxone and Glatopa in the expression levels (magnitude and direction) of these glatiramer acetate-regulated genes. In conclusion, multiple methods consistently supported equivalent gene expression profiles between Copaxone and Glatopa.