Comparing the Biological Impact of Glatiramer Acetate with the Biological Impact of a Generic

Abstract

For decades, policies regarding generic medicines have sought to provide patients with economical access to safe and effective drugs, while encouraging the development of new therapies. This balance is becoming more challenging for physicians and regulators as biologics and non-biological complex drugs (NBCDs) such as glatiramer acetate demonstrate remarkable efficacy, because generics for these medicines are more difficult to assess. We sought to develop computational methods that use transcriptional profiles to compare branded medicines to generics, robustly characterizing differences in biological impact. We combined multiple computational methods to determine whether differentially expressed genes result from random variation, or point to consistent differences in biological impact of the generic compared to the branded medicine. We applied these methods to analyze gene expression data from mouse splenocytes exposed to either branded glatiramer acetate or a generic. The computational methods identified extensive evidence that branded glatiramer acetate has a more consistent biological impact across batches than the generic, and has a distinct impact on regulatory T cells and myeloid lineage cells. In summary, we developed a computational pipeline that integrates multiple methods to compare two medicines in an innovative way. This pipeline, and the specific findings distinguishing branded glatiramer acetate from a generic, can help physicians and regulators take appropriate steps to ensure safety and efficacy.

The regulator’s perspective: How should new therapies and follow-on products for MS be clinically evaluated in the future?

“…Each of the rows within the Treg, macrophage and monocyte sections represents a gene with a high cell-type specificity score for each cell type. Overall, GA induces higher expression of Treg-associated genes than Glatimer ® , while Glatimer ® induces higher expression of macrophage and monocyte-associated genes than GA. 50 (b) Glatimer ® induces significantly higher expression of CD14 (p = 0.0203). 50 The box for the T cells with more green/white included represents low expression, whereas the boxes for the macrophaes and monocytes with more red/less white included represents high expression.…”

Complexity in the making: non-biological complex drugs (NBCDs) and the pharmacopoeias

“…Studies comparing gene expression profi les of Copaxone ® to purported 'generic' glatiramoids, e.g. Glatimer ® (India), Probioglat ® (Mexico) and Escadra ® (Argentina) revealed essential differences between the originator and the follow-on drugs [14,15]. It was therefore suggested by Teva that follow-on glatiramoids should not receive marketing authorization by the generic drug pathway.…”

Non-Biological Complex Drugs Concept in Generic Drugs Development

“…Разнообразие этой смеси и вариантов соотношений неидентичных видов полипептидных структур определяет высокую сложность состава активного компонента препаратов глатирамера [8]. В ходе исследований препаратов глатирамера ацета-та было продемонстрировано существенное разли-чие биологической активности препаратов с одним международным непатентованным наименованием (МНН), не прошедших исследований сопоставимо-сти с референтным препаратом [9,10].…”