Vera Weinstein

Compositional differences between Copaxone and Glatopa are reflected in altered immunomodulation ex vivo in a mouse model

Copaxone (glatiramer acetate, GA), a structurally and compositionally complex polypeptide nonbiological drug, is an effective treatment for multiple sclerosis, with a well‐established favorable safety profile. The short antigenic polypeptide sequences comprising therapeutically active epitopes in GA cannot be deciphered with state‐of‐the‐art methods; and GA has no measurable pharmacokinetic profile and no validated pharmacodynamic markers. The study reported herein describes the use of orthogonal standard and high‐resolution physicochemical and biological tests to characterize GA and a U.S. Food and Drug Administration–approved generic version of GA, Glatopa (USA‐FoGA). While similarities were observed with low‐resolution or destructive tests, differences between GA and USA‐FoGA were measured with high‐resolution methods applied to an intact mixture, including variations in surface charge and a unique, high‐molecular‐weight, hydrophobic polypeptide population observed only in some USA‐FoGA lots. Consistent with published reports that modifications in physicochemical attributes alter immune‐related processes, genome‐wide expression profiles of ex vivo activated splenocytes from mice immunized with either GA or USA‐FoGA showed that 7–11% of modulated genes were differentially expressed and enriched for immune‐related pathways. Thus, differences between USA‐FoGA and GA may include variations in antigenic epitopes that differentially activate immune responses. We propose that the assays reported herein should be considered during the regulatory assessment process for nonbiological complex drugs such as GA.

Physicochemical, biological, functional and toxicological characterization of the European follow-on glatiramer acetate product as compared with Copaxone

For more than 20 years, Copaxone (glatiramer acetate, Teva), a non-biological complex drug, has been a safe and effective treatment option for multiple sclerosis. In 2016, a follow-on glatiramer acetate product (FOGA, Synthon) was approved in the EU. Traditional bulk-based methods and high-resolution assays were employed to evaluate the physicochemical, functional, and bio-recognition attributes, as well as the in vivo toxicity profile of the active substances in Copaxone and Synthon EU FOGA lots. These tests included quality control tests applied routinely in release of Copaxone lots, as well as additional characterization assays, gene expression studies and a rat toxicity study. Even though the Synthon FOGA was designed to copy and compete with Copaxone, the active substances were found to be similar in only 7 of the tested 14 (50%) methods (similar is defined as within approved specifications or within the inherent microheterogeneity range of tested Copaxone batches, or not showing statistically significant differences). With additional methods applied, consistent compositional differences in attributes of surface charge distribution, molecular size, and spatial arrangement were observed. These marked differences were concordantly observed with higher biological activity of some of the Synthon EU FOGA lots compared with Copaxone lots, including potency and cytotoxicity activities as well as gene expression of pathways that regulate apoptosis, IL-2, and inflammation signaling. These observations raise concerns for immunogenicity differences, particularly in (repeated) substitution settings. Another orthogonal finding demonstrated increased frequency of injection-site local toxicity observations for the Synthon EU FOGA in an in vivo daily dosing rat study, thus warranting further qualification of the link between compositional and functional differences in immunogenicity, and potential impact on long-term efficacy and safety.