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Copaxone

Copaxone (Copolymer-I) is made by Teva Pharmaceuticals, it was approved by the FDA in December 1996.


New England Journal of Medicine 317:408-414 (August 12), 1987
"Is synthesized by random polymerization of L-Alanine, L-Glutamic acid, L-Lysine, and L-Tyrosine. It was one of a series of prepared to simulate Myelin Basic Protein, a natural component of the Myelin sheath."



Back To: MS Medications



#0

Glatiramer Acetate (Copaxone)

Francis DA
Int J Clin Pract 2001 Jul-Aug;55(6):394-8
Queen Elizabeth Hospital, Queen Elizabeth NeuroScience Centre, Edgbaston, Birmingham B15 2TH, UK
PMID# 11501229; UI# 21393237
Abstract

Glatiramer Acetate (Copaxone) is a novel preparation of synthetic Peptides composed of four Amino Acids.

Laboratory studies have shown that it prevents, or modifies, Experimental Allergic EncephaloMyelitis, the animal model for Multiple Sclerosis (MS), in several mammalian species.

Its mode of action has not been fully elucidated but it is known to induce Suppressor T-Cells, known to be deficient in MS.

And competitively inhibits the effect of CNS Myelin Antigens, thought to be important in the PathoGenesis of MS, through MHC blockade.

Controlled clinical trials have shown it to improve the natural history of MS by reducing both the relapse rate and the resultant Disability.

GA shows similar efficacy to Interferon-beta (IFN-ß) but with fewer systemic side-effects and appears to be better tolerated by patients.

It has thus justified its place in the new era of disease-modifying treatments for MS.

While the evidence suggests GA should be considered as first-line therapy in selected patients, its differing mechanism of action also gives patients and doctors the option of an alternative agent.

When the efficacy of IFN-ß is waning or side-effects predominate.



#1

Glatiramer Acetate (Copaxone) Induces Degenerate, Th2-polarized Immune Responses In Multiple Sclerosis

Duda PW, Schmied MC, Cook SL, Krieger JI, Hafler DA
J Clin Invest 2000 Apr;105(7):967-76
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Laboratory of Molecular Immunology, Boston, Massachusetts 02115, USA
PMID# 10749576; UI# 20213446
Abstract

We examined the effect of Glatiramer Acetate, a random copolymer of Alanine, Lysine, Glutamic Acid, and Tyrosine, on Antigen-specific T-Cell responses in patients with Multiple Sclerosis (MS).

Glatiramer Acetate (Copaxone) functioned as a universal Antigen, inducing proliferation, independent of any prior exposure to the polymer, in T-Cell lines prepared from MS or healthy subjects.

However, for most patients, daily injections of Glatiramer Acetate abolished this T-Cell response and promoted the secretion of IL-5 and IL-13, which are characteristic of Th2 Cells.

The surviving Glatiramer Acetate-reactive T-Cells exhibited a greater degree of degeneracy as measured by cross-reactive responses to combinatorial Peptide libraries.

Thus, it appears that, in some individuals, in vivo administration of Glatiramer Acetate induces highly cross-reactive T-Cells that secrete Th2 Cytokines.

To our knowledge, Glatiramer Acetate is the first agent that suppresses human AutoImmune Disease and alters Immune Function by engaging the T-Cell Receptor.

This compound may be useful in a variety of AutoImmune Disorders in which Immune deviation to a Th2 type of response is desirable.



#2

Binding Motifs of Copolymer-1 To
Multiple Sclerosis & Rheumatoid Arthritis
Associated HLA-DR Molecules

Fridkis-Hareli M, Neveu JM, Robinson RA, Lane WS, Gauthier L, Wucherpfennig KW, Sela M, Strominger JL
J Immunol 1999 Apr 15;162(8):4697-4704
Harvard University, Dept of Molecular and Cellular Biology, and Microchemistry Facility, Cambridge, MA 02138; Harvard Medical School, Dana Farber Cancer Institute, Boston, MA 02115; and The Weizmann Institute of Science, Dept of Immunology, Rehovot, Israel
PMID# 10202010
Abstract

Copolymer-1 (Cop-1, poly (Y, E, A, K)) is a random synthetic Amino Acid. Copolymer-1 effective in the treatment of Relapsing forms of Multiple Sclerosis (MS).

Cop-1 binds promiscuously, with high affinity and in a Peptide -specific manner to purified MS-associated HLA-DR2 (DRB1*1501) and Rheumatoid Arthritis-associated HLA-DR1 (DRB1*0101) or HLA-DR4 (DRB1*0401) molecules.

In the present work at least 95% of added Cop-1 could be bound to recombinant "empty" HLA-DR1 and -DR4, and 80% could be bound to HLA-DR2 proteins.

Amino Acid composition, HPLC profiles, and sequencing patterns of Cop-1 eluted by acid extraction from HLA-DR molecules were similar to those of the unseparated Cop-1.

Protruding N-terminal ends of Cop-1 bound to HLA-DR1, -DR2, or -DR4 molecules were then treated with Aminopeptidase I, followed by Elution, HPLC, and pool sequencing.

In contrast to untreated or unbound Cop-1, this material exhibited distinct motifs at some positions.

With increases in levels of E at the first and second cycles, of K at the second and third cycles, and of Y (presumably at P1 of the bound Peptide) at the third to fifth cycles, regardless of the HLA-DR molecule employed.

No preference was seen at the following cycles that were mainly A.

These first pooled HLA-DR binding epitopes provide clues to the components of Cop-1 that are biologically active in suppressing MS and possibly Rheumatoid Arthritis.



#3

Copolymer 1 Acts Against The ImmunoDominant Epitope 82-100 Of Myelin Basic Protein By T-Cell Receptor Antagonism In Addition To Major Histocompatibility Complex Blocking

Aharoni R, Teitelbaum D, Arnon R, Sela M
Proc Natl Acad Sci USA 1999 Jan 19;96(2):634-639
The Weizmann Institute of Science, Dept of Immunology, Rehovot 76100, Israel
PMID# 9892685
Abstract

The synthetic random Amino Acid Copolymer Copolymer 1 (Cop-1, Copaxone, Glatiramer Acetate) suppresses Experimental AutoImmune EncephaloMyelitis, slows the progression of disability, and reduces relapse rate in Multiple Sclerosis (MS).

Cop-1 binds to various Class II Major Histocompatibility Complex (MHC) molecules and inhibits the T-Cell responses to several Myelin Antigens.

In this study we attempted to find out whether, in addition to MHC blocking, Cop-1, which is Immunologically cross-reactive with Myelin Basic Protein (MBP), inhibits the response to this AutoAntigen by T-Cell Receptor (TCR) antagonism.

Two experimental systems, "prepulse assay" and "split APC assay," were used to discriminate between competition for MHC molecules and TCR antagonism.

The results in both systems using T-Cell lines/clones from mouse and human origin indicated that Cop-1 is a TCR antagonist of the 82-100 Epitope of MBP.

In contrast to the broad specificity of the MHC blocking induced by Cop-1, its TCR antagonistic activity was restricted to the 82-100 determinant of MBP.

And could not be demonstrated for ProteoLipid Protein Peptide or even for other MBP Epitopes.

Yet, it was shown for all the MBP 82-100-specific T-Cell lines/clones tested that were derived from mice as well as from an MS patient.

The ability of Cop-1 to act as altered Peptide and induce TCR antagonistic effect on the MBP p82-100 ImmunoDominant determinant response elucidates further the mechanism of Cop-1 therapeutic activity in Experimental AutoImmune EncephaloMyelitis and MS.



#4

Effect of Copolymer-1
On Serial Gadolinium-Enhanced MRI
In Relapsing/Remitting Multiple Sclerosis

Mancardi GL, Sardanelli F, Parodi RC, Melani E, Capello E, Inglese M, Ferrari A, Sormani MP, Ottonello C, Levrero F, Uccelli A, Bruzzi P
Neurology 1998 Apr;50(4):1127-1133
Univ of Genoa, Dept of Neurological Sciences, Genoa, Italy
PMID# 9566406; UI# 98226057
Abstract

We examined the effect of Copolymer-1 (Cop-1) on Magnetic Resonance (MR) imaging changes in 10 patients with Relapsing/Remitting Multiple Sclerosis (RRMS).

Monthly Gadolinium (Gd)-enhanced MR imaging was performed for 9 to 27 months in the pretreatment period followed by 10 to 14 additional months during Cop-1 treatment.

MR images were evaluated by two radiologists (F.S. and R.C.P.) masked to the scan date.

We found a 57% decrease in the frequency of new Gd-enhancing Lesions and in the mean area/month of new Gd-enhancing Lesions in the Cop-1 treatment period.

Compared with the pretreatment period (0.92 versus 2.20 lesions per month and 22 mm2 versus 43 mm2 area/month; p = 0.1, Wilcoxon signed rank test).

Percentage change in Lesion load area on T2-weighted images showed a decrease in the accumulation of Lesion area during treatment, which was significant for the patient group with a longer pretreatment period (p = 0.05, Friedman test).

These results demonstrate a reduction in the number of new Gd-enhancing Lesions and in the Lesion load during Cop-1 treatment compared with the preceding period without therapy.

And are suggestive of an effect of Cop-1 on MR abnormalities observed in Multiple Sclerosis.



#5

Clinical Efficacy Review Of Copolymer-1:
New U.S. Phase III Trial Data

Johnson KP
J Neurol, 1996 Apr, 243:4 Suppl 1, S3-7
Univ of Maryland Hospital, Dept of Neurology, Baltimore, Maryland 21201, USA
UI# 96268554
Abstract

Copolymer-1 (Copaxone) is a mixture of synthetic Peptides composed of four Amino Acids.

It has been shown to alter positively the natural history of Multiple Sclerosis by both reducing the relapse rate and affecting disability.

A recently completed, large-scale, phase III, multicenter, double-blind study confirmed the therapeutic benefit shown in previous pilot studies.

Side effects were mild and the daily subcutaneous treatment was well tolerated.

Laboratory studies have shown that Copolymer-1 prevents or modifies Experimental Allergic EncephaloMyelitis (EAE) in several Mammalian species.

It induces Immunologic Suppressor Cells, which are deficient in Multiple Sclerosis, and competitively inhibits the effect of Central Nervous System Myelin Antigens, thought to be important in the PathoGenesis of Multiple Sclerosis.

Copolymer-1 joins Interferon-ß in ushering in a new era of well-tolerated treatments for Multiple Sclerosis.



#6

Copolymer-1
Reduces Relapse Rate & Improves Disability
In Relapsing/Remitting Multiple Sclerosis:

Results Of A Phase III Multicenter, Double-Blind Placebo-Controlled Trial.
The Copolymer-1 Multiple Sclerosis Study Group
Johnson KP; Brooks BR; Cohen JA; Ford CC; Goldstein J; Lisak RP; Myers LW; Panitch HS; Rose JW; Schiffer RB; et al
Neurology, 1995 Jul, 45:7, 1268-76
Univ of Maryland, Dept of Neurology, Maryland, Baltimore, USA
UI# 95342397
Abstract

We studied Copolymer-1 (Copaxone) in a multicenter (11-university) phase III trial of patients with Relapsing/Remitting Multiple Sclerosis (MS).

Two hundred fifty-one patients were randomized to receive Copolymer 1 (n = 125) or placebo (n = 126) at a dosage of 20 mg by daily subcutaneous injection for 2 years.

The primary end point was a difference in the MS relapse rate.

The final 2-year relapse rate was 1.19 +/- 0.13 for patients receiving Copolymer-1 and 1.68 +/- 0.13 for those receiving placebo, a 29% reduction in favor of Copolymer-1 (p = 0.007) (annualized rates = 0.59 for Copolymer-1 and 0.84 for placebo).

Trends in the proportion of relapse-free patients and median time to first relapse favored Copolymer-1.

Disability was measured by the Expanded Disability Status Scale (EDSS), using a two-Neurologist (examining and treating) protocol.

When the proportion of patients who improved, were unchanged, or worsened by > or = 1 EDSS step from baseline to conclusion (2 years) was evaluated, significantly more patients receiving Copolymer-1 were found to have improved and more receiving placebo worsened (p = 0.037).

Patient withdrawals were 19 (15.2%) from the Copolymer-1 group and 17 (13.5%) from the placebo group at approximately the same intervals.

The treatment was well tolerated. The most common adverse experience was an Injection-Site Reaction.

Rarely, a transient Self-Limited Systemic Reaction followed the injection in 15.2% of those receiving Copolymer-1 and 3.2% of those receiving placebo.

(Abstract Truncated At 250 Words)



#7

Safety profile of Copolymer-1: Analysis Of Cumulative
Experience In The United States & Israel

Korczyn AD; Nisipeanu P
J Neurol, 1996 Apr, 243:4 Suppl 1, S23-6
Tel Aviv Univ, Medical School, Dept of Neurology, Tel Aviv, Israel
UI# 96268557
Abstract

This paper summarizes the worldwide cumulative experience with Copolymer-1 (Copaxone) in 857 patients who were enrolled in open-label (n = 586), double-blind (n = 201), and compassioniate-use studies (n = 70).

The results of a phase III study, including previously unpublished information, are employed to delineate adverse events that occur more frequently among patients treated with Copolymer-1 than in placebo-treated controls, and to provide qualitative information.

In the cumulative database, patients usually had Relapsing/Remitting Multiple Sclerosis and typically received a dose of 20 mg by daily subcutaneous injection for at least 1 year, and occasionally for more than 10 years.

Withdrawal rates were 8% for Copolymer-1 and 2% for placebo. The most common adverse event was mild Injection-Site Reaction, manifested by Erythema, Inflammation, and Induration.

The most remarkable adverse event was a Systemic Post-Injection Reaction that occurred in 10% of patients. It was manifested by Flushing, Chest Tightness, Palpitations, Dyspnea, and Anxiety, and was acute and transient.

The incidence of adverse events associated with Interferon-beta, such as Flu-Like Syndrome, Depression, Hematologic Abnormalities, Cardiotoxicity, and Elevated Hepatic Enzymes, was not increased among patients treated with Copolymer-1.

Evaluation of the extensive experience with Copolymer-1 confirms that it is well tolerated and suitable for self-administration by patients with Multiple Sclerosis.

MeSH Heading (Major)
ImmunoSuppressive Agents|*AE; Peptides|*AE MeSH Heading Human;
Israel;
United States
Randomized Controlled Trial
ISSN 0340-5354
Germany
CAS Registry/EC Number
0 (Copolymer 1);
0 (Immunosuppressive Agents);
0 (Peptides)



Copaxone's Question & Answers

Copaxone's HomePage

~~~~~~~~~~~~~~~~~~

C1.What is Copaxone?

Copaxone, or Glatiramer Acetate, previously known as Copolymer-1, represents a different class of therapy for the treatment of patients with Relapsing/Remitting Multiple Sclerosis. Copaxone is an ImmunoModulator that appears to block Myelin specific AutoImmune Responses.

The active ingredient of Copaxone, Glatiramer Acetate, consists of the acetate salts of synthetic with a defined molecular weight range. Its structure resembles Myelin Basic Protein (MBP).

Copaxone is a sterile, white to off-white lyophilized (freeze-dried) powder containing 20 mg of Glatiramer Acetate and 40 mg of mannitol. Copaxone is supplied in single-use vials for subcutaneous administration after reconstitution with sterile water, the diluent that is supplied with the drug.

Research has shown that Copaxone is a unique, first-line therapy that reduces the frequency of relapses and is well tolerated.

~~~~~~~~~~~~~~~~~~~~~~

S1.What Side Effects Are Associated With Copaxone?

Copaxone is a well-tolerated therapy. Unlike other therapies, there is no clinically significant difference in such side effects as Flu-Like Symptoms, Depression, and Fatigue when compared with placebo.

The ten most common side effects in clinical trials that occurred more frequently than with placebo were: Injection Site Reactions, Vasodilatation, Chest Pain, Asthenia, Infection, Pain, Nausea, Arthralgia, Anxiety, and Hypertonia.

In clinical trials, about 10% of patients receiving Copaxone reported, at least once, an Immediate Post-Injection Reaction that could include Flushing, Chest Pain, Palpitations, Anxiety, Dyspnea, Constriction of the Throat, and Urticaria.

The symptoms generally appeared within minutes of an injection, lasted about 15 minutes, and did not require specific treatment. In the largest clinical trial, this side effect caused 3% of patients to discontinue taking the drug.

Transient Chest Pain was noted in 26% of Copaxone patients (vs 10% placebo); no long term sequelae.


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