Multiple Sclerosis (MS)


Copaxone (glatiramer acetate) is an approved disease-modifying therapy for the treatment of relapsing forms of multiple sclerosis (MS) including clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and active secondary progressive MS (SPMS).

Copaxone was originally approved by the US Food and Drug Administration (FDA) in 1996 for a 20 mg/mL daily subcutaneous injection in patients with RRMS.1 A new, higher dose of 40 mg/mL given 3 times per week, at least 48 hours apart,1 was approved in January 2014.2

Copaxone was originally developed and marketed by Teva Neuroscience, a subsidiary of Teva Pharmaceuticals. A number of generic forms of Copaxone are also available.

Copaxone’s Mechanism of Action

MS is caused by autoimmune inflammation that attacks the myelin sheath surrounding neurons in the central nervous system (CNS). Over time and during disease flare-ups, the inflammation and demyelination ultimately lead to neurodegeneration.

The exact mechanism of action for glatiramer acetate in MS is not fully understood. Results from human and animal studies have shown that Copaxone appears to act through both anti-inflammatory and neuroprotective effects.3 Research has shown that antigen-presenting cells (APCs) in the periphery are the first targets of Copaxone which lead to an anti-inflammatory M2 shift in immune cell differentiation affecting several types of B- and T-cells.3

Copaxone has also shown neuroprotective effects through myelin repair visible on brain imaging. The neuroprotective effects appear to be driven by an increase in the production of several neurotrophins, including brain-derived neurotrophic factor (BDNF), and insulin-like growth factors (IGFs).3

Warnings, Precautions, and Adverse Reactions

Glatiramer acetate is given as subcutaneous injections and patients may experience a number of post-injection reactions including chest pain, flushing, heart palpitations, tachycardia, anxiety, dyspnea, throat constriction, or urticaria.1 These reactions can happen within seconds to minutes after injection.

There is not sufficient evidence to make decisions about the use of Copaxone in special patient populations including pediatric, geriatric, pregnant, or breastfeeding patients, as well as patients with impaired renal function. Studies in animals did not show any adverse effects on embryofetal development during pregnancy or lactation.1

The most common reactions reported (in greater than 10% of patients and 1.5x the amount seen in placebo groups) in clinical trials of the 20 mg dose of Copaxone included injection site reactions, vasodilation, rash, dyspnea, and chest pain.1 The most common reactions in studies of the 40 mg dose were injection site reactions.1

Get detailed prescribing information on the Copaxone monograph page at Rare Disease Advisor.

Efficacy in Trials and Trial Results

Copaxone has been evaluated in a number of clinical trials over the years. The initial approval of Copraxone was based on data from 2 clinical trials. First, a pilot trial of Copaxone involving 50 patients with RRMS tested daily injections of 20 mg/mL of Copaxone or a placebo for 2 years. The primary endpoint of the study showed Copaxone significantly reduced relapses,4 with 56% of patients in the treatment group being free from relapse after 2 years compared to only 28% of the placebo patients (P =0.085).1

Another study that was useful for the initial approval was a phase 3 randomized, double-blind, placebo-controlled trial (NCT00004814). In that trial, 251 patients with RRMS were recruited to receive either 20 mg of Copaxone or a placebo through daily subcutaneous injections for 2 years. The trial showed a 29% reduction in the 2-year relapse rate, from 1.68 in the placebo group to 1.19 in the Copaxone group.5 Patients in this study had the opportunity to roll over into an open-label extension study (NCT00203021).

An international double-blind, placebo-controlled trial investigated the effect of 20 mg/mL of Copaxone versus placebo on the number of gadolinium-enhancing lesions observed on T1-weighted MRI scans. A total of 239 patients were randomized between the 2 groups and received injections for 9 months. The study showed that patients who were given placebo had a median cumulative number of enhancing lesions of 17 compared to 11 in the Copaxone group, a difference of 35% (P =0.0030).6

Another international phase 3 trial (NCT00666224) investigated Copaxone versus placebo in 481 adult patients with CIS. Patients were given daily subcutaneous injections of either 20 mg/mL of Copaxone or a placebo for up to 3 years in the blinded portion of the study. Once patients completed the 3 years or were converted to a diagnosis of clinically definite multiple sclerosis (CDMS), they were moved to the open-label portion of the trial where every patient received Copaxone for up to an additional 24 months. Results showed that Copaxone reduced the risk of progressing to CDMS by 45%.7 The time for 25% of patients to convert was also much longer in the Copaxone group — 722 days compared to 336 days for placebo.7 The results of this trial were used to expand the approval of Copaxone to include patients with CIS in 2009.8

Another major study was the Phase 3 GALA trial (NCT01067521) which investigated the safety, tolerability, and efficacy of 40 mg injections 3 times a week compared to placebo. A total of 1404 patients received either 40 mg Copaxone or a placebo for 12 months. Study results showed that Copaxone resulted in a lower annualized relapse rate (ARR) of 0.331 compared to 0.505 for placebo (P <0.0001).9 Copaxone also showed a decrease in gadolinium-enhancing T1 lesions and new or enlarging T2 lesions.9 The 40 mg dose was also found to be safe and well tolerated. Based on the results of this trial, the FDA approved the new dosage of 40 mg/mL 3 times per week in 2014.2

References

1. Copaxone. Package insert. Teva Neuroscience; 1996. Updated July 2020. Accessed May 4, 2021.

2. Copaxone. National Multiple Sclerosis Society. Accessed May 4, 2021. 

3. Prod’homme T, Zamvil SS. The evolving mechanisms of action of glatiramer acetate. Cold Spring Harb Perspect Med. 2019;9(2):a029249. doi:10.1101/cshperspect.a029249

4. Bornstein M, Miller A, Slagle S, et al. A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis. N Engl J Med. 1987;317(7):408-414. doi:10.1056/NEJM198708133170703

5. Johnson K, Brooks B, Cohen J, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. Neurology. 1995;45(7):1268-1276. doi:10.1212/wnl.45.7.1268

6. Comi G, Filippi M, Wolinsky JS, European/Canadian Glatiramer Acetate Study Group. European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging-measured disease activity and burden in patients with relapsing multiple sclerosis. Ann Neurol. 2001;49(3):290-297. doi:10.1002/ana.64

7. Comi G, Martinelli V, Rodegher M, et al. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet. 2009;374(9700):1503-1511. doi:10.1016/S0140-6736(09)61259-9

8. Weinstock-Guttman B, Nair KV, Glajch JL, Ganguly TC, Kantor D. Two decades of glatiramer acetate: from initial discovery to the current development of generics. J Neurol Sci. 2017;376:255-259. doi:10.1016/j.jns.2017.03.0309. Khan O, Rieckmann P, Boyko A, Selmaj K, Zivadinov R, GALA Study Group. Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis. Ann Neurol. 2013;73(6):705-713. doi:10.1002/ana.23938

Reviewed by Kyle Habet, MD, on 7/1/2021.

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