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Glatiramoids

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Non-Biological Complex Drugs

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 20))

Abstract

Glatiramoids are non-biologic complex drugs (NBCDs) comprising four naturally occurring amino acids in a complex copolymeric mixture. The first and most thoroughly studied glatiramoid, glatiramer acetate (Copaxone®, Teva Pharmaceutical Industries, Ltd.) is approved for treatment of relapsing-remitting forms of multiple sclerosis, an autoimmune disorder characterized by neuroinflammation and progressive neurodegeneration. Glatiramoid mixtures comprise a potentially incalculable number of structurally closely related active peptide moieties that cannot be isolated, quantified, or identified using even the most sophisticated available multidimensional separation techniques. Numerous studies have demonstrated that the glatiramer acetate in Copaxone® modulates innate and adaptive immune cell responses to promote antiinflammatory and neuroprotective activities; however, the active epitopes in Copaxone® are unknown and the precise mechanisms of immunomodulatory activity responsible for its therapeutic efficacy are not entirely elucidated. The identity, quality, and consistency of a glatiramoid are inexorably linked to its own manufacturing process. Several manufacturers now market glatiramoids in various countries that are purported to be generic or follow-on versions of Copaxone®; at this writing, no full set of peer-reviewed long term safety and efficacy data for these products is available in the medical literature. Sophisticated analysis techniques, though unable to completely characterize glatiramoid mixtures can differentiate among them based on physicochemical features and biological activities. Comparative gene expression studies have demonstrated important differences between the reference drug (Copaxone®) and purported generic glatiramer acetate products that may have significant implications for the safety and efficacy of the purported generic products. Currently, there is no globally agreed defined pathway for regulatory approval of follow-on and generic glatiramoid products. In the interest of patient safety and well-being, there is an urgent need for regulatory agencies to come to consensus regarding criteria needed to establish therapeutic equivalence among members of the glatiramoid class. Scientific approaches discussed in this chapter may be helpful when evaluating glatiramoid formulations in the framework of equivalence testing.

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Abbreviations

AA:

Amino acids

ACTRIMS:

Americas committee for treatment and research in multiple sclerosis

AFM:

Atomic force microscopy

ALA:

L-alanine

APC:

Antigen-presenting cells

APL:

Altered peptide ligand

APP:

Amyloid precursor protein

ARR:

Annual relapse rate

BBB:

Blood Brain Barrier

BDNF:

Brain-derived neurotrophic factor

CCR7:

Chemokine receptor type 7

CDMS:

Clinically definitive multiple sclerosis

CNS:

Central nervous system

Co-stim:

Costimulatory

DLS:

Dynamic light scattering

EAE:

Experimental autoimmune encephalomyelitis

ECTRIMS:

European committee for treatment and research in multiple sclerosis

GA:

Glatiramer acetate

GdE:

Gadolinium-enhancing

GLU:

L-glutamic acid

HLA:

Human leukocyte antigen

IEF:

Isoelectric focusing

IL:

Interleukin

IMMS:

Ion mobility mass spectrometry

IFN-γ:

Interferon gamma

LYS:

L-lysine

MBP:

Myelin basic protein

MHC:

Major histocompatibility complex

MOG:

Myelin oligodendrocyte glycoprotein

MRI:

Magnetic resonance imaging

MRS:

Magnetic resonance spectroscopy

MS:

Multiple sclerosis

MW:

Molecular weight

NBCD:

Non-biological complex drug

NK:

Natural killer

PBMC:

Peripheral blood mononuclear cells

PD:

Pharmacodynamic

PD1:

Programmed death receptor 1

PFS:

Pre-filled syringe

PK:

Pharmacokinetic

PLP:

Proteolipid protein

RP-HPLC:

High-performance liquid chromatography

RRMS:

Relapsing-remitting multiple sclerosis

SC:

Subcutaneous

SEC:

Size exclusion chromatography

TCR:

T cell receptor

TGF-β:

Transforming growth factor beta

TIV:

Total intensity value

TNBS:

2,4,6-trinitrobenzenesulfonic acid

TNF-α:

Tumor necrosis factor alpha

TYR:

L-tyrosine

UV:

Ultraviolet

WFI:

Water for injection

YFP:

Yellow fluorescent protein

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Acknowledgement

The authors sincerely wish to thank the following persons for their advice and contribution to this book chapter and especially the help of those at CMC and R&D departments of Teva Pharmaceuticals: Arthur Komlosh, Tal Hasson, Tatiana Molotsky, Anna Kogan, Revital Krispin, Dalia Pinkert, Galia Papir, Kevin Wells-Knecht, Mehran Yazdanian, Jill Conner, Shlomo Bakshi, Olga Beriozkin and Wim Weyenberg.

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Authors and Affiliations

  1. Teva Pharmaceutical Industries, Ltd., Petach Tikva, Israel

    Dr. Vera Weinstein, Dr. Rivka Schwartz & Dr. Iris Grossman

  2. Immuneering Corporation, Cambridge, USA

    Dr. Benjamin Zeskind

  3. Teva Pharmaceuticals, Kansas City, MO, USA

    Dr. J. Michael Nicholas

Authors
  1. Dr. Vera Weinstein
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  2. Dr. Rivka Schwartz
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  3. Dr. Iris Grossman
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  4. Dr. Benjamin Zeskind
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  5. Dr. J. Michael Nicholas
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Corresponding author

Correspondence to Vera Weinstein .

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Editors and Affiliations

  1. Utrecht University, Utrecht, Utrecht, The Netherlands

    Daan J.A. Crommelin

  2. Top Institute Pharma NBCD Working Group, Leiden, The Netherlands

    Jon S. B. de Vlieger

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Weinstein, V., Schwartz, R., Grossman, I., Zeskind, B., Nicholas, J. (2015). Glatiramoids. In: Crommelin, D., de Vlieger, J. (eds) Non-Biological Complex Drugs. AAPS Advances in the Pharmaceutical Sciences Series, vol 20. Springer, Cham. https://doi.org/10.1007/978-3-319-16241-6_4

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