Last updated: 5 May 2013

Glatiramer acetate

Summary

Trade name:

Copaxone [[490]]

Class:

Immunomodulator [[343]]

Neuroprotector [[343]]

Target:

Immune cells [[343]]

Status for MS:

Approved in US (1996), EU, and other countries for RRMS [[487]] [[488]]

Approved in US (2009) and other countries for treating CIS patients in cases suggestive of MS [[487]] [[488]]

Administration:

Involves daily subcutaneous injection, according to information from the FDA [[492]]

Prefilled syringes contain 20 mg glatiramer acetate in solution [[489]] [[492]]

Nasal administration appears effective in experimental autoimmune encephalomyelitis mice [[5357]]

Commercial:

In North America, marketed by Teva Neuroscience, a subsidiary of Teva Pharmaceutical Industries [[487]]

In Europe, marketed by Teva Pharmaceutical Industries and Sanofi-aventis [[487]]

Sales and marketing rights in the EU have been taken back from Sanofi by Teva (May 2012) [[1768]]

Teva has attempted to delay marketing approval of generic versions of Copaxone through legal measures against other companies and regulatory channels; Teva's fourth petition to US Food and Drug Administration, asking that marketing for a generic version would not be approved without clinical trials, was denied, as the previous three had been (5 December 2012) [[4142]]

Application for a US patent for a Copaxone-Laquinimod mixed treatment (which would be administered via an injection) for MS has been filed by Teva (13 February 2013) [[4980]]

Application for US Food and Drug Administration approval for a three-times weekly dose of Copaxone has been filed by Teva (March, 2013) [[5913]]

Patent covering the use of a combination of estriol and glatiramer acetate for treating MS has been issued to the Regents of the University of California by the US Patent & Trademark Office (4 April 2013) [[5533]]

Names

Name:

Glatiramer acetate

Trade name:

Copaxone [[490]]

Synonyms:

COP-1 [[465]]

Copaxone [[490]]

Copolymer-1 [[465]]

GA [[343]]

L-Glutamic acid peptide with L-alanine, L-lysine and L-tyrosine, acetate (salt) [[465]]

UNII-5M691HL4BO [[465]]

Systematic name:

L-Glutamic acid polymer with L-alanine, L-lysine and L-tyrosine, acetate (salt) [[465]]

Physiology

Class:

Immunomodulator [[343]]

Neuroprotector [[343]]

Target:

Immune cells [[343]]

Properties:

Designed to mimic myelin basic protein [[343]]

Random polymer of four residues found in myelin basic protein (L-glutamic acid; L-alanine; L-lysine; L-tyrosine) [[408]]

Average MW 6.4 kDa [[343]]

Binds to class II MHC molecules on antigen-presenting cells [[343]]

Polar [[343]]

Not likely to cross blood-brain barrier [[343]]

Mechanisms/Effects

Human:

Exact mechanism unknown [[343]]

Is an immunomodulator that appears to normalize dysregulated immune system circuits in MS [[343]]

May act as a universal antigen (induces in vitro proliferation of naive T cell populations from both healthy controls and MS patients) [[403]]

Affects the function of many types of immune cells, including several types of T cells, dendritic cells, and natural killer cells [[343]]

Shifts CD4+ T cell response from Th1 (pro-inflammatory cytokine secreting T helper type 1) to Th2 (anti-inflammatory cytokine secreting T helper type 2) [[343]]

Upregulates cytotoxic CD8+ T cells to healthy levels [[343]]

Increases the capability of T regulatory cells (which suppress autoimmunity) [[343]]

Increases the frequency of naïve T cells, decreases the frequency of central memory T cells (which is increased in MS patients), and increases the frequency of T-suppressor cells in RRMS patients [[2099]]

Induces expression of interferon gamma and interleukin 4 mRNAs ex vivo in mononuclear cells from MS patients; expression above a certain threshold predicts a better response to glatiramer acetate in patients (a better chance of being relapse free and a better relapse-free survival rate) [[1684]]

Increases killing ability of natural killer cells from humans against dendritic cells [[343]]

Often increases the cytotoxic activity of natural killer (NK) cells (isolated from RRMS patients treated with glatiramer acetate) toward immortalized leukemia cells (an increased activity that correlates with increased expression of NK cell activating cytotoxicity receptors and reduced expression of CD158, an inhibitor molecule, on the NK cell surface); these NK cells can also lyse both autologous immature and mature dendritic cells [[5746]]

Reduces the percentage of dendritic cells expressing CD40 in MS patients; a higher percentage of such cells is associated with an increased risk of relapse [[1993]]

Downregulates the expression of the P2X7 purinergic receptor in peripheral blood monocytes from MS patients, as shown by PCR analysis [[2100]]

Increases the phagocytic activity of monocytes, based on a comparison of cells from treated versus non-treated MS patients or healthy controls and on in vitro experiments, an activity that appears to come from a CD14++CD16+ subset of monocytes [[4407]]

Decreases microglial activation, as determined by measuring uptake of [(11)C]-R-PK11195, a radiopharmaceutical for positron emission tomography, in MS patients before and after 1 year of treatment [[5776]]

Rapidly (within 4 to 12 hours after the first exposure) changes immune cell levels and function, such that the CD4/CD8 T cell ratio decreases, CD8+ T cell homeostasis alters, suppression by CD8+ T cells increases, and interleukin 10 and tumor necrosis factor alpha production increases [[5605]]

Attenuates the pro-migratory pattern of immune cell adhesion molecules [which includes upregulated LFA-1 (on certain T cells and B cells), VLA-4 (on certain T cells and natural killer cells), ICAM-1 (on B cells), and ICAM-3 (on natural killer cells)] in RRMS patients, but the effects are relatively slow and unselective [[5764]]

Displays neuroprotective functions [[343]] [[5629]]

Associated with increased levels of soluble thrombomodulin, which is released from the cell surface of cerebrovascular endothelial cells when they are damaged and promotes a protective response, in RRMS patients [[3108]]

Promotes production of brain-derived neurotrophic factor by T cells, which promotes nerve regeneration and remyelination [[343]]

Response induced in patients appears to be influenced by allelic combinations of immune-response genes [[2195]]

Probably does not play a large role in regulating Fcγ receptors on immune cells in RRMS patients [[4420]]

Not an immunosuppressor [[343]]

Animal:

Augments B cell activity in mice, suppressing experimental autoimmune encephalomyelitis (EAE), as shown by the finding that B cells from glatiramer acetate (GA)-treated mice suppress EAE in recipient mice [[343]]

Induces production of anti-GA antibodies that might enhance remyelination in EAE mice [[343]]

Developed to induce EAE, but surprisingly inhibited it [[343]]

Induces the secretion of CXCL13 (a chemoattractant for B cells) after administration to mice [[3011]]

Induces the secretion of CCL22 (a chemoattractant for Th2 cells) after administration to mice, and this effect is independent of the class II major histocompatibility complex, indicating involvement of an innate immune receptor [[3011]]

Induces the secretion of CCL22 (a chemoattractant for Th2 cells) in bone marrow-derived macrophages from mice [[3011]]

Reduces the expression of Toll-like receptor (TLR) 9, which plays a role in the activation of innate immunity and subsequent adaptive immunity, and Myd88, a universal adapter protein for TLRs, in EAE mice [[3892]]

Shifts dendritic cells toward an anti-inflammatory phenotype, reducing expression of the cytokine osteopontin, interleukin 17, and its mediator the nuclear receptor RORgamma, in dendritic cells of EAE mice [[3892]]

Enhances production of interleukin 10 by dendritic cells in EAE mice [[3892]]

Reduces the expression of pro-inflammatory, brain-specific chemokines that might attract antigen promoting cells to the central nervous system in EAE mice [[3892]]

Induces a strong neuroprotective response in mice who received a crush injury to the optic nerve after Copaxone treatment, but this response is absent if the mice are exposed to chronic mild stress before receiving Copaxone (and the response is regained if Copaxone is combined with Prozac) [[4478]]

Has a neuroprotective role against glutamate toxicity in EAE mice [[4802]]

Reverses the changes in striatal glutamate-mediated excitatory postsynaptic currents (which are induced by tumor necrosis factor-alpha) that occur in EAE mice [[4802]]

Reduces microglial activation and expression of tumor necrosis factor-alpha in EAE mice [[4802]]

Does not decrease damage when administered after cerebral ischemia in mice, despite an increase in neurogenesis (with induced permanent middle cerebral artery occlusion) and a decrease in microglial proinflammatory cytokines (with induced transient occlusion) [[3325]]

Significantly upregulates or downregulates 1,474 genes in mouse splenocytes [which were harvested after mice were treated with glatiramer acetate (GA), and then reactivated ex vivo with GA], as shown by gene expression profiling [[5198]]

Induces pathways involved with T and B lymphocyte proliferation and activation, antigen presenting cell stimulation, and effector T lymphocyte differentiation in mouse splenocytes, as shown by gene expression profiling and functional pathway analysis [[5198]]

Promotes maturation of oligodendrocytes in an animal model (involving cuprizone-induced demyelination) [[5788]]

Regulatory and Commercial Status

Status for MS:

Approved in US (1996), EU, and other countries for RRMS [[487]] [[488]]

Approved in US (2009) and other countries for treating CIS patients in cases suggestive of MS [[487]] [[488]]

Highest status achieved (for any condition):

Approved [[488]]

Other uses:

Had positive effects in a mouse model of Alzheimer disease [[383]]

Did not affect progression of amyotrophic lateral sclerosis (ALS) in a human trial, although it has positive effects in a mouse model of ALS [[358]] [[396]]

Reduces risk of developing cerebral malaria, a condition that appears to involve host immune responses, in an experimental mouse model [[366]]

Might be useful for controlling epileptic seizures, based on experiments in rats [[5763]]

Inhibits graft rejection in mice [[399]]

Reduces inflammation and neurodegeneration in a mouse model of HIV1 encephalomyelitis [[378]]

Had positive effects in mouse models of inflammatory bowel disease [[387]] [[3236]]

Weekly vaccination with GA decreased symptoms of dry age-related macular degeneration in a small human trial [[369]]

Administration:

Involves daily subcutaneous injection, according to information from the FDA [[492]]

Prefilled syringes contain 20 mg glatiramer acetate in solution [[489]] [[492]]

Nasal administration appears effective in experimental autoimmune encephalomyelitis mice [[5357]]

Negative effects:

Dyspnea (shortness of breath) [[354]]

May have contributed to the development of Guillain-Barré syndrome in one patient [[1747]]

Has been associated with severe acute hepatitis in one patient [[2752]]

Hypersensitivity [[354]]

Rarely, induces delayed-type hypersensitivity reactions, and this response involves T(H)1 cells that express skin-homing receptors, as shown by analysis of the responses of two patients [[3066]]

Injection-site reactions [[354]]

Urticaria (hives) [[354]]

Vasodilatation [[354]]

Exposure during pregnancy does not seem to be a major teratogenic risk, based on an analysis of 41 pregnancies [[3117]]

Exposure during pregnancy is not associated with an increased risk of spontaneous abortion or other negative pregnancy or fetal outcomes, based on a prospective observational study of 423 pregnancies, 17 of which involved glatiramer acetate exposure [[3681]]

Commercial:

In North America, marketed by Teva Neuroscience, a subsidiary of Teva Pharmaceutical Industries [[487]]

In Europe, marketed by Teva Pharmaceutical Industries and Sanofi-aventis [[487]]

Sales and marketing rights in the EU have been taken back from Sanofi by Teva (May 2012) [[1768]]

Application for a US patent for a Copaxone-Laquinimod mixed treatment (which would be administered via an injection) for MS has been filed by Teva (13 February 2013) [[4980]]

Application for US Food and Drug Administration approval for a three-times weekly dose of Copaxone has been filed by Teva (March, 2013) [[5913]]

Key Clinical Trials

Placebo-controlled Trials:

Trial name:

Glatiramer Acetate Low-Frequency Administration (GALA) (press releases, June 2012 and October 2012) [[2158]] [[3588]]

Phase:

Phase III trial [[2158]]

Study Design:

Company-sponsored, multinational, randomized, double-blind, placebo-controlled trial to study the safety and effect of glatiramer acetate injection (40 mg/1 ml, administered 3 times weekly) on reducing the number of confirmed relapses (primary endpoint) [the dose in this study is higher but less frequent than the marketed dose (20 mg/1 ml daily) at the time of this press release] [[2158]]

Disease Stage:

RRMS [[2158]]

Enrollment/Number of Patients:

>1400 [[2158]]

Duration:

12 months [[2158]]

Status/Outcome:

Drug at the 40 mg/1 ml dose reduced the annualized relapse rate by 34.4% as compared with placebo [[2158]]; additionally, the drug at this dose reduced the cumulative number of new and enlarging T2 lesions by 34.4% and the cumulative number of gadolinium-enhancing lesions by 44.8% as compared with placebo, but the drug did not affect the percent change of brain volume at 12 months [[3588]]

Trial name:

Comparator and aN oral Fumarate In RRMS (CONFIRM) (publ September 2012, press release April 2012) [[1793]] [[3222]]

Phase:

Phase III trial [[1793]] [[3222]]

Study Design:

Company-sponsored, global, randomized, double-blind, placebo-controlled, dose-comparison study to determine the safety and efficacy of oral BG-12 (dimethyl fumarate) (240 mg given either twice a day or three times a day) or glatiramer acetate (20 mg subcutaneous injection each day) in reducing the annualized relapse rate (ARR) (primary endpoint) and the proportion of patients who relapse at two years and the number of T2-hyperintense lesions (secondary endpoints); study was not designed to test whether BG-12 is superior or noninferior to glatiramer acetate [[1793]] [[3222]]

Disease Stage:

RRMS [[1793]] [[3222]]

Enrollment/Number of Patients:

1430 [[1793]] [[3222]]

Duration:

2 years [[1793]] [[3222]]

Status/Outcome:

BG-12 reduced the ARR by 44% (twice a day dose; ARR=0.22) or 51% (three times a day dose; ARR=0.20) and glatiramer acetate reduced this rate by 29% (ARR=0.29) as compared to placebo (ARR=0.40); BG-12 reduced the proportion of patients who relapsed at two years by 34% (twice a day dose) or 45% (three times a day dose) and glatiramer acetate reduced this rate by 29% as compared to placebo; BG-12 also had a significant effect on brain lesions [[1793]] [[3222]]

Trial name:

Early GA Treatment in Delaying Conversion to Clinically Definite Multiple Sclerosis in Subjects Presenting With a Clinically Isolated Syndrome (CIS) (PreCISe) (publ 2009; further analyses publ 2013) [[343]] [[360]] [[5629]]

Phase:

Phase III trial [[491]]

Study Design:

Randomized, double-blind, multicenter trial to study the effect of early glatiramer acetate (20 mg per day) on the time to clinically definite MS from clinically isolated syndrome (primary outcome measure) [[360]]

Disease Stage:

CIS [[360]]

Enrollment/Number of Patients:

481 [[360]]

Duration:

Up to 36 months [[360]]

Status/Outcome:

Drug reduced the risk of CIS converting to clinically definite MS by 45% as compared to placebo [[360]]; in a substudy (involving 34 patients, 20 of whom did not relapse and were in the study through 12 months of followup), the drug (versus placebo) appeared to exert a neuroprotective effect in a large central brain volume, based on measurements of the ratio of a marker of neuronal integrity (N-acetylaspartate) relative to creatine [[5629]]

Trial name:

Metz et al., Mult. Scler., Oct 2009 trial [[361]]

Phase:

Phase II trial [[361]]

Study Design:

Double-blind, placebo-controlled study to compare the effects of glatiramer acetate plus minocycline (100 mg twice daily) vs. glatiramer acetate plus placebo on the total number of T1 gadolinium-enhanced lesions [[361]]

Disease Stage:

RRMS (28)

Enrollment/Number of Patients:

44, with 40 completing study [[361]]

Duration:

9 months [[361]]

Status/Outcome:

Glatiramer acetate plus minocycline reduced the number of T1 gadolinium-enhanced lesions by 63% as compared to glatiramer acetate alone [[361]]

Trial name:

PROMiSe Trial [[381]]

Phase:

Phase III trial [[955]]

Study Design:

Multinational, multicenter, double-blind, placebo-controlled trial to test whether glatiramer acetate (20 mg per day) results in a delay in time to sustained progression of accumulated disability in PPMS (primary outcome) [[381]]

Disease Stage:

PPMS [[381]]

Enrollment/Number of Patients:

943 [[381]]

Duration:

3 years [[381]]

Status/Outcome:

Study was stopped prematurely when an interim analysis (at which time 757 patients had completed 2 or more years of the study or had ended participation prematurely) showed that there was no discernible effect of glatiramer acetate on the primary outcome [[381]]

Trial name:

Comi et al., Ann. Neurol., Mar 2001 trial [[400]]

Phase:

Phase of trial not stated in article [[400]]

Study Design:

Multicenter, double-blind, randomized, placebo-controlled European/Canadian trial to study the effects of glatiramer acetate (20 mg per day) on disease activity (primary outcome, the number of enhancing lesions on T1-weighted images), as measured with monthly MRI scans and clinical assessments [[400]]

Disease Stage:

RRMS [[400]]

Enrollment/Number of Patients:

239 [[400]]

Duration:

9 months [[400]]

Status/Outcome:

Drug was associated with a reduction in the total number of enhancing lesions (-10.8) as compared to placebo (primary outcome), as well as a reduction in the relapse rate (33%) in the treatment vs. placebo group [[400]]

Trial name:

Johnson et al., Neurology, July 1995 trial [[412]]

Phase:

Phase III trial [[412]]

Study Design:

Multicenter, double-blind, randomized, placebo-controlled trial to determine whether glatiramer acetate (20 mg per day) caused a difference in the relapse rate (primary end point) [[412]]

Disease Stage:

RRMS [[412]]

Enrollment/Number of Patients:

251 [[412]]

Duration:

2 years [[412]]

Status/Outcome:

Drug was associated with a reduction in the relapse rate (primary outcome measure) (1.19 vs. 1.68 over 2 years in the treatment vs. placebo group) [[412]]

Trial name:

Bornstein et al., N. Engl. J. Med., Aug 1987 trial [[414]]

Phase:

Pilot trial; phase II trial [[414]]

Study Design:

Single-center, double-blind, randomized, placebo-controlled trial to test the effects of glatiramer acetate (20 mg per day) on the number of exacerbations [[414]]

Disease Stage:

Exacerbating-remitting MS [[414]]

Enrollment/Number of Patients:

50 [[414]]

Duration:

2 years (2)

Status/Outcome:

Drug was associated with a reduction in the number of exacerbations (0.6 vs 2.7 average per patient in treatment vs. placebo group over 2 years) [[414]]

Head-to-Head Trials:

Trial name:

Calabrese et al., Mult. Scler., April 2012 trial [[3009]]

Phase:

Postmarketing [[3009]]

Study Design:

Randomized study to compare the effects of subcutaneous (sc) interferon beta-1a (44 mcg three times weekly), intramuscular (im) interferon beta-1a (30 mcg weekly), and glatiramer acetate (20 mg daily) on the development of cortical lesions and cortical atrophy [[3009]]

Disease Stage:

RRMS [[3009]]

Enrollment/Number of Patients:

165 treated patients and 50 untreated patients, with 141 treated patients completing the study [[3009]]

Duration:

24 months [[3009]]

Status/Outcome:

Interferon beta-1a and glatiramer acetate significantly decreased the development of new cortical lesions and the progression of cortical atrophy, with the most pronounced effects seen with sc interferon beta-1a, such that at 12 months, one or more new cortical lesions were seen in 26% of patients receiving sc interferon beta-1a, 64% of patients receiving im interferon beta-1a, 50% of patients receiving glatiramer acetate, and 74% of untreated patient [[3009]]

Trial name:

Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis (CombiRx) (results described at meeting, July 2012, publ February 2013) [[2567]] [[2566]] [[5011]]

Phase:

Phase III trial [[2567]] [[2566]]

Study Design:

NIH-funded, randomized, double-blind, controlled study to examine whether a combination of interferon beta-1a (30 microg, intramuscularly, per week) and glatiramer acetate (20 mg per day) is more effective than either treatment alone plus placebo, with a reduction in the annualized relapse rate (ARR) the primary endpoint; time to confirmed disability, the Multiple Sclerosis Functional Composite (MSFC) score, and MRI measures were among the secondary endpoints [[2567]] [[2566]] [[5011]] [[5364]]

Disease Stage:

RRMS [[2567]] [[2566]] [[5011]]

Enrollment/Number of Patients:

1008 [[2567]] [[2566]] [[5011]]

Duration:

3 years [[2567]] [[2566]] [[5011]]

Status/Outcome:

Combination therapy did not reduce the risk of relapse as compared to glatiramer acetate alone, but both of those treatments were superior to interferon beta-1a in this regard; combination therapy did not reduce confirmed progression of the Extended Disability Status Scale or MSFC score as compared to either therapy alone, but combination therapy was better than either therapy alone in reducing the accumulation of lesions and new lesion activity [[5011]]; the combination therapy resulted in a half-point benefit on the 22-point scale measuring bladder control [[2567]] [[2566]]

Trial name:

Rinaldi et al., Mult. Scler., May 2012 trial [[1697]]

Phase:

Postmarketing [[1697]]

Study Design:

Prospective study to determine the efficacy of natalizumab versus interferon beta-1a or glatiramer acetate in reducing the accumulation of new cortical lesions [[1697]]

Disease Stage:

RRMS [[1697]]

Enrollment/Number of Patients:

120 [[1697]]

Duration:

2 years [[1697]]

Status/Outcome:

Natalizumab reduced the accumulation of new cortical lesions and the progression of cortical atrophy as compared to interferon beta-1a, glatiramer acetate, or no treatment [[1697]]

Trial name:

BECOME (BEtaseron vs COpaxone in Multiple Sclerosis with Triple-Dose Gadolinium and 3-Tesla MRI Endpoints) (publ 2009) [[365]]

Phase:

Phase IV [[956]]

Study Design:

Trial to compare the ability of interferon beta-1b and glatiramer acetate to suppress signs of disease activity (primary outcome, number of combined active lesions per patient per scan in first year) as measured by monthly brain MRI [[365]]

Disease Stage:

CIS or RRMS [[365]]

Enrollment/Number of Patients:

75 [[365]]

Duration:

Up to 2 years [[365]]

Status/Outcome:

Patients taking either interferon beta-1b and glatiramer acetate showed similar numbers of combined active lesions per patient for first year (primary outcome) and similar numbers of relapses for 2 years [[365]]

Trial name:

BEYOND (Betaferon Efficiency Yielding Outcomes of a New Dose) (publ 2009) [[362]]

Phase:

Phase III trial [[957]]

Study Design:

Multicenter, randomised, prospective study to compare the efficacy, safety, and tolerability of interferon beta-1b (250 or 500 microg every other day) and glatiramer acetate (20 mg per day) (primary outcome, relapse risk) [[362]]

Disease Stage:

RRMS [[362]]

Enrollment/Number of Patients:

2447 [[362]]

Duration:

2.0 to 3.5 years [[362]]

Status/Outcome:

Relapse risk, expanded disability status scale progression, and T1-hypointense lesion volume were similar among all treatment groups [[362]]

Trial name:

REGARD (REbif vs Glatiramer Acetate in Relapsing MS Disease) (publ 2008) [[371]]

Phase:

Phase IV trial [[958]]

Study Design:

Multicenter, randomised, comparative, parallel-group, open-label study to compare effect of interferon beta-1a (44 microg 3 times a week) and glatiramer acetate (20 mg per day) on time to first relapse (primary outcome) or brain lesions (secondary outcomes) [[371]]

Disease Stage:

RRMS [[371]]

Enrollment/Number of Patients:

764 [[371]]

Duration:

96 weeks [[371]]

Status/Outcome:

Study showed no significant difference between interferon beta-1a and glatiramer acetate on the primary outcome or secondary outcomes, except that interferon beta-1a was associated with fewer gadolinium-enhanding lesions per patient per scan [[371]]

Other Trials:

Trial name:

Jokubaitis et al., PLoS One, March 2013 study [[5370]]

Phase:

Prospective cohort study [[5370]]

Study Design:

Multicenter Australian cohort study using the MSBase platform to characterize use of disease-modifying therapies (DMTs, which included interferon beta, glatiramer acetate, and natalizumab); specifically, treatment persistence, factors that predict treatment discontinuation, and rates of switching between DMTs were studied [[5370]]

Disease Stage:

RRMS [[5370]]

Enrollment/Number of Patients:

1113 [[5370]]

Duration:

4.2 years (median time patients were followed) [[5370]]

Status/Outcome:

Treatment persistence in this study was short, such that patients remained on their first DMT for 2.5 years (median) and on their next DMT for 2.3 years; annualized switch or cessation rates were 9.5 to 12.5% (interferon beta), 11.6% (glatiramer acetate), and 4.4% (natalizumab); younger age and higher disability scores predicted DMT discontinuation [[5370]]

Trial name:

CombiRx extension study (conference report, March 2013) [[5364]]

Phase:

Extension phase of Phase III trial [[5011]] [[5364]]

Study Design:

Extension of the CombiRx trial, comparing effectiveness of combination therapy (interferon beta-1a and glatiramer acetate) with either therapy alone in reducing the annualized relapse rate (primary endpoint) [[5364]]

Disease Stage:

RRMS (in original study) [[5011]] [[5364]]

Enrollment/Number of Patients:

687 [[5364]]

Duration:

90 months [[5364]]

Status/Outcome:

Combination therapy did not reduce the risk of relapsing or confirmed disability progression as compared to glatiramer acetate, and glatiramer acetate reduced the risk of relapse more than interferon beta-1a, over 90 months; combination therapy was associated with a higher proportion of patients who were free of disease activity (driven by results from MRI) as compared with either therapy alone, but this effect is reduced over time [[5364]]

Trial name:

Comparison of Patients Treated with Natalizumab and Interferon-Beta/Glatiramer Using Propensity-Matched Multiple Sclerosis Registry Data (press release, 18 March 2013) [[5315]]

Phase:

Retrospective medical record review [[5315]]

Study Design:

Data from two MS patient registries [TYSABRI Observational Program (TOP) and MSCOMET] were used in a propensity-matched analysis to compare the effects of natalizumab, interferon beta, and glatiramer acetate on relapses [[5315]]

Disease Stage:

MS [[5315]]

Enrollment/Number of Patients:

N/A [[5315]]

Duration:

N/A [[5315]]

Status/Outcome:

Natalizumab was associated with a lower rate of first relapse as compared to interferon beta and glatiramer acetate; relapses in patients treated with natalizumab also occurred more slowly than in those treated with the other drugs [[5315]]

Trial name:

Romeo et al., Eur. J. Neurol., February 2013 study [[5033]]

Phase:

Observational/open-label study [[5033]]

Study Design:

Observational study to determine clinical- and MRI-based predictors of response to glatiramer acetate and interferon beta; patients were considered "responders" if clinical and MRI activity were absent during treatment and "non-responders" in the presence of MRI activity or if the reduction in annualized relapse rate (ARR) was <50% of the ARR in the 2 previous years [[5033]]

Disease Stage:

RRMS [[5033]]

Enrollment/Number of Patients:

594 [[5033]]

Duration:

2 years [[5033]]

Status/Outcome:

Later age at disease onset, a lower level of disability, and a lower number of gadolinium-enhancing lesions at baseline were predictors of response, on the basis of a multivariate analysis [[5033]]

Trial name:

Brandes et al., J. Med. Econ., February 2013 study [[4902]]

Phase:

Observational study [[4902]]

Study Design:

Analysis to assess the effect of real-world adherence (estimated from a study of a single claims database of a national pharmacy benefit manager) on the cost-effectiveness (the cost per avoided relapse) of fingolimod, subcutaneous interferon beta-1b (Extavia or Betaseron) and interferon beta-1a, glatiramer acetate, and intramuscular interferon beta-1a [[4902]]

Disease Stage:

MS [[4902]]

Enrollment/Number of Patients:

N/A [[4902]]

Duration:

N/A [[4902]]

Status/Outcome:

Costs per relapse avoided were estimated at $90,566 (fingolimod), $127,024 (Extavia), $137,492 (Betaseron), $144,016 (subcutaneous inferferon beta-1a), $160,314 (glatiramer acetate), and $312,629 (intramuscular interferon beta-1a) [[4902]]

Trial name:

Comi et al., Mult. Scler., December 2012 study (analyses of results obtained during open-label phase of the PreCISe trial) [[360]] [[4203]]

Phase:

Open-label extension study [[4203]]

Study Design:

Industry-sponsored, open-label extension study to compare the effects of early treatment (at randomization during the placebo-controlled phase of the PreCISe trial; 20 mg daily subcutaneous dose) versus delayed treatment (in patients originally randomized to placebo and then switched to glatiramer acetate in the open-label phase) in CIS patients [[4203]]

Disease Stage:

CIS [[4203]]

Enrollment/Number of Patients:

409 (in open-label phase), with 289 completing the study [[4203]]

Duration:

Median time on drug was 1709 days (early-treatment group) versus 1260 days (delayed-treatment group) [[4203]]

Status/Outcome:

Early treatment reduced the risk of conversion to clinically definite MS by 41% versus delayed treatment; early treatment was associated with a 972-day delay in conversion [[4203]]

Trial name:

Lu et al., Neurology, August 2012 study [[2959]]

Phase:

Retrospective literature review [[2959]]

Study Design:

Systematic review of the literature for information about the effects of interferon beta, glatiramer acetate, or natalizumab on the offspring of MS patients who used these disease-modifying drugs (DMDs) during pregnancy [[2959]]

Disease Stage:

MS [[2959]]

Enrollment/Number of Patients:

97 glatiramer acetate-exposed pregnancies were identified [[2959]]

Duration:

N/A [[2959]]

Status/Outcome:

Glatiramer acetate exposure during pregnancy was not associated with preterm birth, spontaneous abortion, congenital anomalies, or lower mean birth weight, but discontinuing DMD use before conception continues to be recommended [[2959]]

Trial name:

Rossi et al., Eur. J. Neurol., June 2012 study [[2319]]

Phase:

Observational/open-label study [[2319]]

Study Design:

Multicenter, open-label, non-randomized, prospective, pilot study to determine if glatiramer acetate is effective and safe in patients who have discontinued natalizumab; glatiramer acetate treatment was initiated 4 weeks after natalizumab was discontinued [[2319]]

Disease Stage:

RRMS [[2319]]

Enrollment/Number of Patients:

40 [[2319]]

Duration:

12 months [[2319]]

Status/Outcome:

Twelve months after beginning glatiramer acetate treatment, 62.5% of patients were relapse-free; the annualized relapse rate and time to relapse were both lower than before natalizumab treatment, indicating that glatiramer acetate can reduce the possibility of MS rebound or early reactivation after natalizumab is discontinued [[2319]]

Trial name:

Roskell et al., Curr. Med. Res. Opin., May 2012 study [[3359]]

Phase:

Retrospective trial review [[3359]]

Study Design:

Meta-analysis of placebo-controlled and head-to-head trials, which evaluated the effects of one or more drugs (fingolimod, interferon beta-1a, interferon beta-1b, and/or glatiramer acetate), to compare the effects of fingolimod versus the other treatments on the annualized relapse rate (ARR) [[3359]]

Disease Stage:

RRMS [[3359]]

Enrollment/Number of Patients:

N/A [[3359]]

Duration:

N/A [[3359]]

Status/Outcome:

Meta-analyses indicated that fingolimod significantly reduced the ARR as compared to the other drugs; the relative ARRs for each drug versus fingolimod were 1.43 (glatiramer acetate, 20 mg dose), 1.51 (interferon beta-1b, 250 microg dose), 1.55 (interferon beta-1a, 44 microg dose), 1.67 (interferon beta-1a, 22 microg dose), 1.93 (interferon beta-1a, 30 microg dose), and 2.32 (placebo) [[3359]]

Trial name:

Del Santo et al., Eur. J. Clin. Pharmacol., April 2012 study [[2482]]

Phase:

Retrospective trial review [[2482]]

Study Design:

Review of 10 randomized trials that tested interferon, glatiramer acetate, natalizumab, or fingolimod in RRMS, such that the relapse-free rates at 12 months were compared, either directly or through network meta-analysis [[2482]]

Disease Stage:

RRMS [[2482]]

Enrollment/Number of Patients:

N/A [[2482]]

Duration:

N/A [[2482]]

Status/Outcome:

Fingolimod was determined to have the most favorable profile with respect to relapse-free rate at the follow-up assessment at 1 year [[2482]]

Trial name:

Meca-Lallana et al., J. Neurol. Sci., April 2012 study [[4248]]

Phase:

Observational study [[4248]]

Study Design:

Observational, multicenter study to evaluate changes in spasticity after a switch from interferon beta to glatiramer acetate treatment, with the primary endpoint made up of changes in the Penn Spasm Frequency Scale, Modified Ashworth Scale, Adductor Tone Rating Scale, and Global Pain Score at 3 and 6 months after the switch [[4248]]

Disease Stage:

RMMS, with spasticity [[4248]]

Enrollment/Number of Patients:

68 [[4248]]

Duration:

6 months [[4248]]

Status/Outcome:

Switching to glatiramer acetate led to statistically significant improvement in spasm frequence, muscle tone, and pain after 3 and 6 months [[4248]]

Trial name:

Khan et al., J. Neurol. Sci., January 2012 study [[3065]]

Phase:

Retrospective medical record review [[3065]]

Study Design:

Study to measure the effects of glatiramer acetate (20 mg, injected subcuraneously once a day; 121 patients), interferon beta-1a (30 mcg, injected intramuscularly once a week; 53 patients), and interferon beta-1b (250 mcg, injected subcutaneously every other day; 101 patients), with treatments given for five years, on the loss of brain volume in previously treatment-naïve patients with relatively early RRMS (of less than or equal to five years duration when the study began); patients received brain MRI scans on the same scanner with the same protocol at baseline and year 5 [[3065]]

Disease Stage:

RRMS [[3065]]

Enrollment/Number of Patients:

275 [[3065]]

Duration:

5 years [[3065]]

Status/Outcome:

The disease-modifying therapies were associated with an adjusted (for pseudoatrophy in the first year) percentage change in brain volume (PCBV) over five years of -2.27% (glatiramer acetate), -2.62% (interferon beta-1a), and -3.21% (interferon beta-1b), which were all significantly reduced as compared to the PCBV (-4.75%) for 34 patients who were untreated for 8 to 24 months [[3065]]

Trial name:

Jongen et al., Health Qual. Life Outcomes, November 2010 study [[4981]]

Phase:

Observational/open-label study [[4981]]

Study Design:

Investigator-initiated, prospective, observational, international, multicenter study to determine whether glatiramer acetate increases the health-related quality of life (HR-QoL), reduces fatigue, and/or reduces depression during the first 12 months of treatment [[4981]]

Disease Stage:

RRMS [[4981]]

Enrollment/Number of Patients:

197 (91 with previous immunomodulatory or immunosuppressive treatment and 106 without such treatment) [[4981]]

Duration:

12 months [[4981]]

Status/Outcome:

In the previously untreated group, glatiramer acetate increased the HR-QoL score (such that 43% of the patients had improved scores at 12 months) and decreased fatigue at 6 and 12 months, whereas these improvements did not occur in the previously treated group; neither group experienced changes in depression [[4981]]

Trial name:

US Glatiramer Acetate Trial (publ 2010) [[355]]

Phase:

Extension study [[355]]

Study Design:

Ongoing open-label trial to study up to 15 years of continuous glatiramer acetate as only disease-modifying therapy [[355]]

Disease Stage:

RRMS [[355]]

Enrollment/Number of Patients:

232 enrolled when study began in 1991 and 100 were continuing as of Feb 2008 [[355]]

Duration:

Beginning 20th year as of 2011 (K. Johnson, ECTRIMS, Oct 2011)

Status/Outcome:

Drug is associated with reduced relapse rates and decreased progression to disability and SPMS, with no long-term safety issues [[355]]

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Editors' Pick

Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis.

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Teva to present positive data for glatiramer acetate 40 mg/1 ml given three times weekly for relapsing-remitting MS

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FDA denies Teva Copaxone generic trials petition

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Effects of early treatment with glatiramer acetate in patients with clinically isolated syndrome.

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Glatiramer acetate increases phagocytic activity of human monocytes in vitro and in multiple sclerosis patients.

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Fcγ receptors in Norwegian multiple sclerosis patients and healthy controls.

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Chronic mild stress eliminates the neuroprotective effect of Copaxone after CNS injury.

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Glatiramer Acetate Protects Against Inflammatory Synaptopathy in Experimental Autoimmune Encephalomyelitis.

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J Neuroimmune Pharmacol. 2013 Jan 31. Epub 2013 Jan 31. PMID: 23370991. Abstract

Implications of Real-world Adherence on Cost-effectiveness Analysis in Multiple Sclerosis.

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BRIEF: Teva files for Copaxone-Laquinimod patent

Middle East North Africa Financial Network, 13 Feb 2013

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Clinical and MRI predictors of response to interferon-beta and glatiramer acetate in relapsing-remitting multiple sclerosis patients.

Romeo M, Martinelli-Boneschi F, Rodegher M, Esposito F, Martinelli V, Comi G, San Raffaele Multiple Sclerosis Clinical Group

Eur J Neurol. 2013 Feb 20. PMID: 23425504. Abstract

Editors' Pick

Randomized study combining interferon & glatiramer acetate in multiple sclerosis.

Lublin FD, Cofield SS, Cutter GR, Conwit R, Narayana PA, Nelson F, Salter AR, Gustafson T, Wolinsky JS, for the CombiRx Investigators.

Ann Neurol. 2013 Feb 19. Epub 1969 Dec 31. PMID: 23424159. Abstract

Glatiramer Acetate administration does not reduce damage after cerebral ischemia in mice.

Poittevin M, Deroide N, Azibani F, Delcayre C, Giannesini C, Levy BI, Pocard M, Kubis N

J Neuroimmunol. 2013 Jan 15; 254(1-2):55-62. Epub 2012 Sep 29. PMID: 23026222. Abstract

Gene expression analysis reveals functional pathways of glatiramer acetate activation.

Bakshi S, Chalifa-Caspi V, Plaschkes I, Perevozkin I, Gurevich M, Schwartz R

Expert Opin Ther Targets. 2013 Apr; 17(4):351-362. Epub 2013 Mar 08. PMID: 23469939. Abstract

New Tysabri data reaffirm substantial efficacy in treatment of people with MS and demonstrate stability of anti-JCV antibody status

Biogen Idec, 18 Mar 2013

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Extension CombiRx data show no benefit of combined MS drugs

Medscape Medical News, 21 Mar 2013

Accessed on 25 Mar 2013 from http://www.medscape.com/viewarticle/781153.

Nasal administration of drugs as a new non-invasive strategy for efficient treatment of multiple sclerosis.

Duchi S, Ovadia H, Touitou E

J Neuroimmunol. 2013 Mar 18. PMID: 23517929. Abstract

Editors' Pick

The Australian Multiple Sclerosis (MS) Immunotherapy Study: A Prospective, Multicentre Study of Drug Utilisation Using the MSBase Platform.

Jokubaitis VG, Spelman T, Lechner-Scott J, Barnett M, Shaw C, Vucic S, Liew D, Butzkueven H, Slee M, Slee M

PLoS One. 2013; 8(3):e59694. Epub 2013 Mar 19. PMID: 23527252. Abstract

Synthetic Biologics announces issuance of U.S. patent covering combination of estriol and Copaxone® for multiple sclerosis

Synthetic Biologics, 4 Apr 2013

Accessed on 8 Apr 2013 from http://www.syntheticbiologics.com/2013-04-04-Synthetic-Biologics-Announces-Issuance-of-U-S-Patent-Covering-Combination-of-Estriol-and-Copaxone-for-Multiple-Sclerosis.

Decreased microglial activation in MS patients treated with glatiramer acetate.

Ratchford JN, Endres CJ, Hammoud DA, Pomper MG, Shiee N, McGready J, Pham DL, Calabresi PA

J Neurol. 2012 Jun; 259(6):1199-205. Epub 2011 Dec 09. PMID: 22160466. Abstract

Glatiramer acetate ameliorates inflammatory bowel disease in mice through the induction of Qa-1-restricted CD8⁺ regulatory cells.

Yao Y, Han W, Liang J, Ji J, Wang J, Cantor H, Lu L

Eur J Immunol. 2013 Jan; 43(1):125-36. Epub 2012 Nov 07. PMID: 23002042. Abstract

Modulation of immune function occurs within hours of therapy initiation for multiple sclerosis.

Ayers CL, Mendoza JP, Sinha S, Cunnusamy K, Greenberg BM, Frohman EM, Karandikar NJ

Clin Immunol. 2013 May; 147(2):105-19. Epub 2013 Mar 06. PMID: 23578552. Abstract

Neuroprotection with glatiramer acetate: evidence from the PreCISe trial.

Arnold DL, Narayanan S, Antel S

J Neurol. 2013 Apr 16. PMID: 23589190. Abstract

Soluble thrombomodulin levels in plasma of multiple sclerosis patients and their implication.

Festoff BW, Li C, Woodhams B, Lynch S

J Neurol Sci. 2012 Dec 15; 323(1-2):61-5. Epub 2012 Sep 08. PMID: 22967748. Abstract

Glatiramer promotes oligodendroglial cell maturation in a cuprizone-induced demyelination model.

Rosato Siri MV, Badaracco ME, Pasquini JM

Neurochem Int. 2013 Apr 22. PMID: 23619394. Abstract

A One Year Follow-Up Study of Natural Killer and Dendritic Cells Activities in Multiple Sclerosis Patients Receiving Glatiramer Acetate (GA).

Høglund RA, Holmøy T, Harbo HF, Maghazachi AA

PLoS One. 2013; 8(4):e62237. Epub 2013 Apr 22. PMID: 23614042. Abstract

Glatiramer acetate attenuates the pro-migratory profile of adhesion molecules on various immune cell subsets in multiple sclerosis.

Sellner J, Koczi W, Harrer A, Oppermann K, Obregon-Castrillo E, Pilz G, Wipfler P, Afazel S, Haschke-Becher E, Trinka E, et al.

Clin Exp Immunol. 2013 Apr 24. PMID: 23611040. Abstract

UPDATE 1-Teva Pharmaceutical banks on thrice-weekly Copaxone

Cohen T, Reuters, 2 May 2013

Accessed on 5 May 2013 from http://www.reuters.com/article/2013/05/02/tevapharm-results-idUSL6N0DJ35O20130502.

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