Demonstration of equivalence of a generic glatiramer acetate (Glatopa™)

Abstract

Glatiramer acetate (GA) has been available under the brand name Copaxone® for nearly two decades. Recently, the US Food and Drug Administration (FDA) approved the first generic GA, Glatopa™, as fully substitutable for all indications for which Copaxone 20mg is approved; Glatopa also represents the first FDA-approved "AP-rated," substitutable generic for treating patients with MS. Glatiramer acetate is a complex mixture of polypeptides and, consequently, its characterization presented challenges not generally encountered in drug development. Despite its complexity, and without requiring any clinical data, approval was accomplished through an Abbreviated New Drug Application in which equivalence to Copaxone was evaluated across four criteria: starting materials and basic chemistry; structural signatures for polymerization, depolymerization, and purification; physicochemical properties; and biological and immunological properties. This article describes the rigorous overall scientific approach used to successfully establish equivalence between Glatopa and Copaxone, and presents key representative data from several of the comprehensive sets of physicochemical (structural) and biological (functional) assays that were conducted.

Acute liver injury in a Glatopa-treated patient with MS

“…Sandoz demonstrated Glatopa's equivalence with Copaxone by similarities in chemistry, polymerization, biological, and immunologic properties. 5,6 In a study by the US-FDA using 3 different analytic measures, distinct physicochemical differences were found between Copaxone and commercially available copolymer-1. 7 Teva Pharmaceuticals also found differences in charge distribution, molecular density, monomolecular size, and the existence of a novel polypeptide group in Glatopa compared with Copaxone.…”

Biomaterial strategies for generating therapeutic immune responses

“…Since publication of this finding in 1971, GA has been developed over the ensuing decades, was approved in multiple countries for the treatment of relapsing-remitting MS in 1995, and is now a widely prescribed drug [73]. Recently a generic version marketed as Glatopa was approved by the US-FDA [74], and other generics have been marketed and administered worldwide. Glatimer by Natco Pharma is sold in India and the Ukraine, Probioglat by Probiomed is sold in Mexico, and both Escadra (Raffo Laboratories) and Polimunol GTR (Synthon) are sold in Argentina [75].…”

“…One consequence of the diminished inflammatory phenotype of innate cells elicited by GA is a resultant skewing of T cells away from inflammatory pathways such as Th1 towards the anti-inflammatory Th2 and Th3 pathways [71,74,85]. Th2 cells produce IL4, IL5, IL10, and IL13, resulting in a non-inflammatory phenotype and strong antibody (IgG1 and IgG4) production.…”

Considerations in the development of generic disease therapies for multiple sclerosis

“…Following submission of an ANDA in December 2007, a generic GA (GLATOPA; Momenta/Sandoz, Cambridge, MA) was approved by the FDA in April 2015, based on demonstration of equivalent physicochemical characteristics plus immunologic and clinical effects in EAE. 15 A clinical trial was not requested. Mylan/NATCO (Pittsburgh, PA) and Synthon/Pfizer (Nijmegen, the Netherlands) also filed ANDAs for generic GA products, in September 2009 and November 2011, respectively.…”