Glatiramer Acetate (DB05259) Approved and Investigational Drug Chemical Formula: C254H422N70O72 Molecular Weight: 5000-9000 Glatiramer acetate consists of the acetate salts of synthetic polypeptides, containing four naturally occurring amino acids: L-glutamic acid, L-alanine, L-tyrosine, and L-lysine with an average molar fraction of 0.141, 0.427, 0.095, and 0.338, respectively. The average molecular weight of glatiramer acetate is 5,000-9,000 daltons. It is an immunomodulator, licensed in much of the world for reduced frequency of relapses in relapsing-remitting multiple sclerosis Indication/Usage For reduction of the frequency of relapses in patients with Relapsing-Remitting Multiple Sclerosis. Pharmacodynamics Glatiramer acetate was originally designed to mimic a protein in myelin, called myelin basic protein, with the intention of inducing EAE (an animal model of MS). Quite to the contrary, it was found to suppress the disease and as a result came to be trialed in human MS. There is some evidence that Glatiramer acetate converts the body's immune response from a Th1 type to a Th2 one, promotes suppressor T cells or acts as an altered peptide ligand. Studies in animals and in vitro systems suggest that upon its administration, glatiramer acetate-specific suppressor T-cells are induced and activated in the periphery. Some fraction of the injected material, either intact or partially hydrolyzed, is presumed to enter the lymphatic circulation, enabling it to reach regional lymph nodes, and some may enter the systemic circulation intact.

Mechanism of Action Toxicity Metabolism Targets Glatiramer acetate (GA) exhibits strong and promiscuous binding to MHC molecules (HLA DRB1* variants) and consequent competition with various myelin antigens for their presentation to T cells. A further aspect of its action is potent induction of specific suppressor cells of the T helper 2 (Th2) type that migrate to the brain and lead to in situ bystander suppression. Furthermore, the GA-specific cells in the brain express the anti-inflammatory cytokines IL-10 and transforming growth factor beta, in addition to brain-derived neurotrophic factor, whereas they do not express the inflammatory cytokine IFN-gamma. Recent evidence also suggests that Glatiramer acetate directly inhibits dendritic cells and monocytes - both of which are circulating antigen presenting cells. Toxicity Adverse reactions include injection site reactions, vasodilatation, chest pain, asthenia, infection, pain, nausea, arthralgia, anxiety, and hypertonia. Metabolism Hydrolyzed by proteases Targets HLA class II histocompatibility antigen, DRB1-1 beta chain

General References Brands Weber MS, Hohlfeld R, Zamvil SS: Mechanism of action of glatiramer acetate in treatment of multiple sclerosis. Neurotherapeutics. 2007 Oct;4(4):647-53. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/17920545 Arnon R, Aharoni R: Mechanism of action of glatiramer acetate in multiple sclerosis and its potential for the development of new applications. Proc Natl Acad Sci U S A. 2004 Oct 5;101 Suppl 2:14593-8. Epub 2004 Sep 15. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/15371592 Francis DA: Glatiramer acetate (Copaxone). Int J Clin Pract. 2001 Jul-Aug;55(6):394-8. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/11501229 Li Q, Milo R, Panitch H, Swoveland P, Bever CT Jr: Glatiramer acetate blocks the activation of THP-1 cells by interferon-gamma. Eur J Pharmacol. 1998 Jan 26;342(2-3):303-10. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/9548401 Brands COPAXONE – Teva Neurosciences

Copaxone Chemical Name Formulation Used/Prescribed for Dosage Glatiramer acetate, the active ingredient of COPAXONE, consists of the acetate salts of synthetic polypeptides, containing four naturally occurringamino acids: L-glutamic acid, L-alanine, L-tyrosine, and L-lysine with an average molar fraction of 0.141, 0.427, 0.095, and 0.338, respectively. The average molecular weight of glatiramer acetate is 5,000 – 9,000 daltons. Glatiramer acetate is identified by specific antibodies. COPAXONE is a clear, colorless to slightly yellow, sterile, nonpyrogenic solution to be administered as subcutaneous injection Chemical Name L-glutamic acid polymer with L-alanine, L-lysine and L-tyrosine, acetate (salt) Formulation Each 1 mL of COPAXONE solution contains 20 mg or 40 mg of glatiramer acetate and the following inactive ingredient: 40 mg of mannitol. The pH of the solutions is approximately 5.5 to 7.0. Used/Prescribed for COPAXONE is indicated for the treatment of patients with relapsing forms of multiple sclerosis Dosage COPAXONE 20 mg per mL: administer once per day or COPAXONE 40 mg per mL: administer three times per week and at least 48 hours apart Contraindications COPAXONE is contraindicated in patients with known hypersensitivity to glatiramer acetate or mannitol. Side- effects Lymphadenopathy, Palpitations, Tachycardia, Eye Disorder, Nausea, Vomiting, Dysphagia, Asthenia, Pain, Edema, Local Reaction, Chills, Hypersensitivity, Infection, Influenza, Rhinitis, Bronchitis, Weight Increased, Benign Neoplasm of Skin, Laryngospasm, Dyspnea, cough

Drug Interactions References Interactions between COPAXONE and other drugs have not been fully evaluated. Results from existing clinical trials do not suggest any significant interactions of COPAXONE with therapies commonly used in MS patients, including the concurrent use of corticosteroids for up to 28 days. COPAXONE has not been formally evaluated in combination with interferonbeta. References http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aa88f583-4f5f-433b-80b4-1f4c9fb28357 http://www.rxlist.com/copaxone-drug.htm