nach oben

CNS Drugs

Erschienen in:

01.12.2002 | Adis Drug Evaluation

Glatiramer Acetate

A Review of its Use in Relapsing-Remitting Multiple Sclerosis

verfasst von: Dene Simpson, Stuart Noble, Caroline Perry

Erschienen in: CNS Drugs | Ausgabe 12/2002

Einloggen, um Zugang zu erhalten

Summary

Glatiramer acetate is a synthetic copolymer composed of a random mixture of four amino acids that modifies the immune response that results in the CNS inflammation, demyelination and axonal loss characteristic of relapsing-remitting multiple sclerosis (RRMS).

In three randomised, double-blind trials in patients with RRMS, subcutaneous glatiramer acetate 20 mg/day was significantly more effective than placebo for the primary outcome measure of each trial (mean relapse rate, proportion of relapse-free patients and number of gadolinium-enhancing lesions on magnetic resonance imaging [MRI] scans). The mean relapse rate was significantly reduced at endpoint (approximately one-third less) in the two larger trials (the US pivotal trial [primary endpoint] and the European/Canadian study [tertiary endpoint]) in patients receiving glatiramer acetate compared with those receiving placebo. The rate was 78% less for glatiramer acetate than placebo patients in the pilot trial that investigated a slightly different patient population. Glatiramer acetate significantly decreased disease activity and burden of disease, as assessed in the European/Canadian study using a range of MRI measures. Patients with RRMS treated with glatiramer acetate in the US trial were significantly more likely to experience improved disability (whereas placebo recipients were more likely to experience worsening disability) and their overall disability status was significantly improved compared with placebo recipients. Data from the active-treatment extension of the US trial suggest that glatiramer acetate has sustained clinical benefits up to 8 years.

Glatiramer acetate was generally well tolerated; the most commonly reported treatment-related adverse events were localised injection-site reactions and transient post-injection systemic reactions. Both reactions were generally mild and self limiting but were responsible for the majority of withdrawals from treatment (up to 6.5 and 3.5%, respectively). Glatiramer acetate is not associated with the influenza-like syndrome or neutralising antibodies that are reported in patients treated with interferon-β for RRMS.

The cost effectiveness of glatiramer acetate has yet to be definitively determined as assessment of available data is confounded by very different models, data sources and assumptions.

Conclusion.

Glatiramer acetate has shown efficacy in well controlled clinical trials in patients with RRMS; it reduces relapse rate and decreases MRI-assessed disease activity and burden. It is generally well tolerated and is not associated with the influenza-like symptoms and formation of neutralising antibodies seen with the interferons-β. Based on available data and current management guidelines, glatiramer acetate is a valuable first-line treatment option for patients with RRMS.

Pharmacological Properties

The proposed mechanism of action of glatiramer acetate in modulating the autoimmune response in relapsing-remitting multiple sclerosis (RRMS) consists of two components. The first is the induction of glatiramer acetate-specific suppressor T cells (i.e. type 2 helper T lymphocytes [T_h2]) that are capable of directly and indirectly downregulating the inflammation in the CNS associated with multiple sclerosis (MS). Human studies have shown that these glatiramer acetate-reactive T cells are initially and predominantly T_h1 type (pro-inflammatory), but with exposure to glatiramer acetate there is a shift to a T_h2/T_h3-type response (anti-inflammatory). It is these glatiramer acetate-specific suppressor T cells, not glatiramer acetate itself, that may migrate into the CNS and downregulate the inflammation that is triggered by the antigenic products of demyelination (myelin basic protein [MBP] and other myelin antigens). In a small study involving patients with RRMS, this shift from T_h1- to T_h2-type T cells induced by glatiramer acetate was accompanied by clinical benefits.

The second feature of glatiramer acetate’s mechanism of action is the inhibition of the autoreactive MBP- and other myelin antigen-specific T cells that would otherwise be stimulated to proliferate and release inflammatory cytokines. Current hypotheses include glatiramer acetate acting as an altered peptide ligand and engaging various T-cell receptor (TCR)s, and glatiramer acetate engaging the TCR and downregulating the MBP-specific T-cell response possibly by delivering a non-activating signal (anergy).

Recent research suggests that neuroprotection may be another mechanism of action accounting for the beneficial clinical effects of glatiramer acetate in RRMS. p ]Antibodies stimulated by glatiramer acetate treatment are non-neutralising and do not affect the clinical efficacy of the drug.

Few pharmacokinetic data are available for glatiramer acetate; following subcutaneous administration, the drug is rapidly degraded in the periphery, resulting in very low or undetectable serum concentrations. Glatiramer acetate is not required to be present in the serum to exert its anti-inflammatory action but absorption in proportion to the dose administered was rapid.

Therapeutic Efficacy

Glatiramer acetate has shown efficacy in treating patients with RRMS. In three randomised, double-blind trials (including a 2-year pilot trial and the larger US pivotal [2-year] and European/Canadian [9-month] studies) glatiramer acetate 20mg once daily, administered subcutaneously in patients with RRMS, was significantly more effective than placebo for the respective primary endpoint of each trial (proportion of relapse-free patients, relapse rate and number of enhancing lesions on magnetic resonance imaging [MRI] scans).

For patients receiving glatiramer acetate compared with those receiving placebo in the two larger comparative studies, the mean relapse rate (covariate adjusted) at study endpoint was 29% lower in the large US trial (where relapse rate was the primary endpoint) and 33% lower in the European/Canadian study (where relapse rate was the tertiary endpoint). In the pilot trial, glatiramer acetate recipients had a mean relapse rate 78% lower, and they were more than twice as likely to be relapse free, than placebo recipients. Relapse-related results in this pilot trial have not been reproduced in larger trials, possibly due to the patient population’s having a shorter duration of disease and a higher baseline relapse rate than those in subsequent studies.

Glatiramer acetate decreased disease activity and burden of disease, as assessed by analysis of MRI scans, in patients enrolled in the European/Canadian study where certain MRI measures were the primary and secondary endpoints. For the primary outcome measure, patients in the glatiramer acetate-treated group demonstrated 29% fewer gadolinium-enhancing CNS lesions (areas of acute inflammation representing disruption of the blood-brain barrier) than patients in the placebo group. For secondary MRI outcomes, glatiramer acetate showed significantly greater lesion reductions (ranging from 30 to 82.6%) than placebo. Although this 9-month trial period was considered too short to demonstrate a significant reduction in the volume of hypointense T1 lesions (representing areas of demyelination and axonal loss), further analysis of these scans has shown that, after 8 months, the proportion of new T2 lesions evolving into these hypointense T1 lesions (‘black holes’) in patients receiving glatiramer acetate was half that shown in patients receiving placebo.

Progression to sustained disability, as measured by the Kurtzke Expanded Disability Status Scale (EDSS), was a secondary endpoint in the two long-term trials. Patients with RRMS treated with glatiramer acetate in the pivotal US trial were significantly more likely to experience improved disability, and placebo recipients were more likely to experience worsening disability. The overall disability status was also significantly improved in this trial, although the change was modest. The pilot trial showed positive trends in delaying the onset or worsening of disability, although it did not have adequate statistical power to evaluate this outcome.

Preliminary results data from the active-treatment extension of the US trial suggest that glatiramer acetate has sustained clinical benefits up to 8 years.

Pharmacoeconomics

Two studies conducted in 2000 and 2001 investigating the cost effectiveness of glatiramer acetate in the treatment of RRMS are difficult to compare as they used different models and data sources and led to different conclusions.

According to a cost-utility analysis based on the clinical outcomes of a large placebo-controlled trial (the US pivotal trial) and its extensions, glatiramer acetate is cost effective compared with best supportive care alone for RRMS, from the perspective of the UK National Health Service. Cost-utility ratios improved with a longer duration of treatment for all three cost variables. At 8 years, cost per relapse avoided was £11 000, cost per disability unit avoided was £8 862 and cost per quality-adjusted life-year (QALY) gained was £22 586 (year 2000 costs).

An analysis conducted by the National Institute of Clinical Excellence used longer term modelling and concluded that neither glatiramer acetate nor the interferons-β were cost effective in the treatment of RRMS. The best mean cost per QALY gained (i.e. at 20 years of treatment and including MS Research Trust data on quality of life), expressed as a range covering all the agents under investigation, was between £35 000 and £104 000, which was more than the value considered favourable in the UK (£30 000).

Given the complexities of cost-effectiveness assessments in RRMS, a lifelong, disabling disease (for which clinical benefits of long-term treatment have only recently been published) and the limited amount of information available at present, it is impossible to draw a single definitive conclusion regarding the cost effectiveness of glatiramer acetate, and further data and evaluations in this field would be useful.

Tolerability

Subcutaneously administered glatiramer acetate 20mg is generally well tolerated. The most commonly reported treatment-related adverse events (data from three placebo-controlled clinical trials and pooled results from two of these and other trials) are localised injection-site reactions and transient post-injection systemic reactions. The incidence of injection-site reactions (manifesting mainly as pain and erythema) was 64 and 73% with glatiramer acetate versus 37 and 38% with placebo (no p value reported).

Post-injection systemic reactions occurred with an incidence of 10–38% with glatiramer acetate versus <1–13% with placebo (no p value reported) and manifested as one or more symptoms (facial flushing, chest tightness, dyspnoea, palpitations, tachycardia, anxiety and/or sweating) occurring within minutes of an injection and lasting for 30 seconds to 30 minutes. Both reactions were generally mild and self limiting but accounted for the majority of withdrawals from treatment. Overall withdrawal rates ranged from 6–8% with localised injection-site reactions accounting for up to 6.5% and post-injection systemic reactions for up to 3.5% (vs 0.8% with placebo, no p value stated).

Serious treatment-related events occurred in ≤2% of patients enrolled in clinical trials and, although no anaphylaxis was reported during the trials, three non-fatal cases of allergic reaction have since been recorded. Glatiramer acetate is not associated with the influenza-like syndrome reported in patients treated with interferon-β.

Dosage and Administration

Glatiramer acetate is indicated for the long-term management of RRMS and is currently approved in numerous countries worldwide including the USA, Canada, the UK and many other European countries. Glatiramer acetate is administered once daily by subcutaneous injection at a standard dose of 20mg. Data on the use of glatiramer acetate in pregnant and nursing women, the elderly, patients younger than 18 years and those with impaired renal function are limited. Contraindications include intravenous administration and hypersensitivity to glatiramer acetate or mannitol (which is included in the injection formulation).

Goodin DS. Therapeutic developments in multiple sclerosis. Expert Opin Investig Drugs 2000 Apr; 9(4): 655–70PubMed

Compston A. The ‘nature’ of multiple sclerosis. J Neurol 2002 Jun; 249 Suppl. 1: 1–3

Weilbach FX, Gold R. Disease modifying treatments for multiple sclerosis: what is on the horizon? CNS Drugs 1999 Feb; 11: 133–57

Lucchinetti C, Bruck W, Noseworthy J. Multiple sclerosis: recent developments in neuropathology, pathogenesis, magnetic resonance imaging studies and treatment. Curr Opin Neurol 2001 Jun; 14(3): 259–69PubMed

Ben-Nun A, Mendel I, Bakimer R, et al. The autoimmune reactivity to myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis is potentially pathogenic: effect of copolymer 1 on MOG-induced disease. J Neurol 1996 Apr; 243(4 Suppl. 1): S14–22PubMed

Polman CH, Uitdehaag BMJ. Drug treatment of multiple sclerosis. BMJ 2000 Aug 19; 321: 490–4PubMed

Noseworthy JH. Progress in determining the causes and treatment of multiple sclerosis. Nature 1999 Jun 24; 399 Suppl.: A40–7PubMed

Keegan BM, Noseworthy JH. Multiple sclerosis. Annu Rev Med 2002; 53: 285–302PubMed

Goodin DS, Frohman EM, Garmany GP, et al. Disease modifying therapies in multiple sclerosis. Neurology 2002 Jan; 58: 168–78

10.

Schechter G. Therapeutic strategies for multiple sclerosis: success, failure — what next? Drug Mark Dev 1997 Dec 1; 8: 275–80

11.

Lea AP, Goa KL. Copolymer-1: a review of its pharmacological properties and therapeutic potential in multiple sclerosis. Clin Immunother 1996; 6(4): 319–31

12.

Giovannoni G, Miller DH. Multiple sclerosis and its treatment. J R Coll Physicians Lond 1999 Jul 31; 33(4): 315–22PubMed

13.

van Oosten BW, Truyen L, Barkhof F, et al. Choosing drug therapy for multiple sclerosis: an update. Drugs 1998 Oct; 56(4): 555–69PubMed

14.

Bitsch A, Bruck W. Differentiation of multiple sclerosis subtypes: implications for treatment. CNS Drugs 2002; 16(6): 405–18PubMed

15.

Rudick RA. Disease-modifying drugs for relapsing-remitting multiple sclerosis and future directions for multiple sclerosis therapeutics. Arch Neurol 1999 Sep; 56(9): 1079–84PubMed

16.

Stinissen P, Raus J, Zhang J. Autoimmune pathogenesis of multiple sclerosis: role of autoreactive T lymphocytes and new immunotherapeutic strategies. Crit Rev Immunol 1997; 17(1): 33–75PubMed

17.

Rolak LA. Multiple sclerosis treatment 2001. Neurol Clin 2001 Feb; 19(1): 107–18PubMed

18.

Teitelbaum D, Meshorer A, Hirshfield T, et al. Suppression of experimental allergic encephalomyelitis by a synthetic polypeptide. Eur J Immunol 1971; 1: 242–8PubMed

19.

Arnon R. The development of Cop 1 (Copaxone), an innovative drug for the treatment of multiple sclerosis: personal reflections. Immunol Lett 1996 Apr; 50(1–2): 1–15PubMed

20.

Teitelbaum D, Fridkis-Hareli M, Arnon R, et al. Copolymer 1 inhibits chronic relapsing experimental allergic encephalomyelitis induced by proteolipid protein (PLP) peptides in mice and interferes with PLP-specific T cell responses. J Neuroimmunol 1996 Feb; 64(2): 209–17PubMed

21.

Teitelbaum D, Sela M, Arnon R. Copolymer 1 from the laboratory to FDA. Isr J Med Sci 1997 Apr; 33(4): 280–4PubMed

22.

Sela M, Teitelbaum D. Glatiramer acetate in the treatment of multiple sclerosis. Expert Opin Pharmacother 2001; 2(7): 1149–65PubMed

23.

Teva Pharmaceutical Industries. Copaxone: prescribing information [online]. Available from URL: http://www.copaxone.com/newpi/copaxonepi.pdf [Accessed 2000 Nov 9]

24.

Bornstein MB, Miller A, Slagle S, et al. A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis. N Engl J Med 1987 Aug 13; 317(7): 408–14PubMed

25.

Aharoni R, Teitelbaum D, Leitner O, et al. Specific Th2 cells accumulate in the central nervous system of mice protected against experimental autoimmune encephalomyelitis by copolymer 1. Proc Natl Acad Sci U S A 2000 Oct 10; 97(21): 11472–7PubMed

26.

Hohlfeld R. Therapeutic strategies in multiple sclerosis. I: immunotherapy. Philos Trans R Soc Lond B Biol Sci 1999 Oct 29; 354(1390): 1697–710PubMed

27.

Gran B, Tranquill LR, Chen M, et al. Mechanisms of immuno-modulation by glatiramer acetate. Neurology 2000 Dec 12; 55(11): 1704–14PubMed

28.

Dhib-Jalbut S. Mechanisms of action of interferons and glatiramer acetate in multiple sclerosis. Neurology 2002 Apr 23; 58(8 Suppl. 4): S3–9PubMed

29.

Neuhaus O, Farina C, Wekerle H, et al. Mechanisms of action of glatiramer acetate in multiple sclerosis. Neurology 2001 Mar 27; 56(6): 702–8PubMed

30.

Teitelbaum D, Milo R, Arnon R, et al. Synthetic copolymer 1 inhibits human T-cell lines specific for myelin basic protein. Proc Natl Acad Sci U S A 1992 Jan 1; 89(1): 137–41PubMed

31.

Comi G, Filippi M, Wolinsky JS, et al. 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: European/Canadian Glatiramer Acetate Study Group. Ann Neurol 2001 Mar; 49(3): 290–7PubMed

32.

Ziemssen T, Neuhaus O, Hohlfeld R. Risk-benefit assessment of glatiramer acetate in multiple sclerosis. Drug Saf 2001; 24(13): 979–90PubMed

33.

Lobel E, Riven-Kreitman R, Amselem A, et al. Copolymer-1. Drugs Future 1996; 21(2): 131–4

34.

Aharoni R, Teitelbaum D, Sela M, et al. Copolymer 1 induces T cells of the T helper type 2 that crossreact with myelin basic protein and suppress experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 1997 Sep 30; 94(20): 10821–6PubMed

35.

Fridkis-Hareli M, Teitelbaum D, Pecht I, et al. Binding of copolymer 1 and myelin basic protein leads to clustering of class II MHC molecules on antigen-presenting cells. Int Immunol 1997 Jul; 9(7): 925–34PubMed

36.

Fridkis-Hareli M, Strominger JL. Promiscuous binding of synthetic copolymer 1 to purified HLA-DR molecules. J Immunol 1998 May 1; 160(9): 4386–97PubMed

37.

Fridkis-Hareli M, Teitelbaum D, Gurevich E, et al. Direct binding of myelin basic protein and synthetic copolymer 1 to class II major histocompatibility complex molecules on living antigen-presenting cells: specificity and promiscuity. Proc Natl Acad Sci U S A 1994 May 24; 91(11): 4872–6PubMed

38.

Fridkis-Hareli M, Neveu JM, Robinson RA, et al. Binding motifs of copolymer 1 to multiple sclerosis- and rheumatoid arthritis-associated HLA-DR molecules. J Immunol 1999 Apr 15; 162(8): 4697–704PubMed

39.

Racke MK, Martin R, McFarland H, et al. Copolymer-1-induced inhibition of antigen-specific T cell activation: interference with antigen presentation. J Neuroimmunol 1992 Mar; 37(1–2): 75–84PubMed

40.

Duda PW, Schmied MC, Cook SL, et al. Glatiramer acetate (Copaxone) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis. J Clin Invest 2000 Apr; 105(7): 967–76PubMed

41.

Neuhaus O, Farina C, Yassouridis A, et al. Multiple sclerosis: comparison of copolymer-1-reactive T cell lines from treated and untreated subjects reveals cytokine shift from T helper 1 to T helper 2 cells. Proc Natl Acad Sci U S A 2000 Jun 20; 97(13): 7452–7PubMed

42.

Farina C, Then Bergh F, Albrecht H, et al. Treatment of multiple sclerosis with Copaxone (COP): Elispot assay detects COP-induced interleukin-4 and interferon-γresponse in blood cells. Brain 2001 Apr; 124 (Pt 4): 705–19PubMed

43.

Chen M, Gran B, Costello K, et al. Glatiramer acetate induces a Th2-biased response and crossreactivity with myelin basic protein in patients with MS. Mult Scler 2001 Aug;7(4): 209–19PubMed

44.

Miller A, Shapiro S, Gershtein R, et al. Treatment of multiple sclerosis with copolymer-1 (Copaxone): implicating mechanisms of Th1 to Th2/Th3 immune-deviation. J Neuroimmunol 1998 Dec 1; 92(1–2): 113–21PubMed

45.

Brenner T, Arnon R, Sela M, et al. Humoral and cellular immune responses to Copolymer 1 in multiple sclerosis patients treated with Copaxone. J Neuroimmunol 2001 Apr 2; 115(1–2): 152–60PubMed

46.

Aharoni R, Teitelbaum D, Amon R, et al. 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. Proc Natl Acad Sci U S A 1999 Jan 19; 96(2): 634–9PubMed

47.

Duda PW, Krieger JI, Schmied MC, et al. Human and murine CD4 T cell reactivity to a complex antigen: recognition of the synthetic random polypeptide glatiramer acetate. J Immunol 2000 Dec 15; 165(12): 7300–7PubMed

48.

Milo R, Kerlero-de-Rosbo N, Mendel I, et al. Copolymer-1 suppresses the T-cell proliferative response to myelin oligodendrocyte glycoprotein. Ann Neurol 1996 Sep; 40: 551

49.

Qin Y, Zhang DQ, Prat A, et al. Characterization of T cell lines derived from glatiramer-acetate-treated multiple sclerosis patients. J Neuroimmunol 2000 Aug 1; 108(1–2): 201–6PubMed

50.

Aharoni R, Teitelbaum D, Sela M, et al. Bystander suppression of experimental autoimmune encephalomyelitis by T cell lines and clones of the Th2 type induced by copolymer 1. J Neuroimmunol 1998 Nov 2; 91(1–2): 135–46PubMed

51.

Ziemssen T, Kuempfel T, Klinkert W, et al. Glatiramer acetatespecific T cell lines produce brain-derived neurotrophic factor (BDNF) after activation upon antigen challenge in vitro: a novel mechanism of action? Neurology 2002; 58 Suppl. 3: A326

52.

Chen M, Dhib-Jalbut S. Glatiramer acetate (GA)-reactive T-cells produce brain-derived neurotrophic factor (BDNF) [abstract no. P328]. European/American Committee for Treatment and Research in Multiple Sclerosis (Ectrims/Actrims); 2002 Sep 18–21; Baltimore (MD)

53.

Chen M, Johnson KP, Martin R, et al. Glatiramer acetate treatment induces a Th1 to Th2 cytokine shift in multiple sclerosis [abstract no. 224]. Ann Neurol 2000 Sep; 48: 475

54.

Wee Yong V. Differential mechanisms of action of interferon-b and glatiramer acetate in MS. Neurology 2002 Sep; 59:802–8PubMed

55.

Chen M, Conway K, Johnson K, et al. Sustained immunological effects of glatiramer acetate in patients with multiple sclerosis treated for over 6 years. J Neurol Sci 2002 Sep 15; 201(1–2): 71–7PubMed

56.

Chabot S, Yong FP, Le DM, et al. Cytokine production in T lymphocyte-microglia interaction is attenuated by glatiramer acetate: a mechanism for therapeutic efficacy in multiple sclerosis. Mult Scler 2002 Aug; 8(4): 299–306PubMed

57.

Kipnis J, Yoles E, Porat Z, et al. T cell immunity to copolymer 1 confers neuroprotection on the damaged optic nerve: possible therapy for optic neuropathies. Proc Natl Acad Sci U S A 2000 Jun 20; 97(13): 7446–51PubMed

58.

Stadelmann C, Kerschensteiner M, Misgeld T, et al. BDNF and gpl45trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells? Brain 2002; 125: 75–85PubMed

59.

Johnson KP, Teitelbaum D, Arnon R, et al. Antibodies to copolymer 1 do not interfere with its clinical effect: US Phase III Copolymer-1 Study Group. Ann Neurol 1995 Dec; 38:973

60.

Ure DR, Rodriguez M. Polyreactive antibodies to glatiramer acetate promote myelin repair in murine model of demyelinating disease. FASEB J 2002 Jun 7; 16(10): 1260–2PubMed

61.

Farina C, Vargas V, Heydari N, et al. Treatment with glatiramer acetate induces specific IgG4 antibodies in multiple sclerosis patients. J Neuroimmunol 2002 Feb; 123(1–2): 188–92PubMed

62.

Teitelbaum D, Tamar BY, Rebeca T-H, et al. Specificity of the suppressive effect of copolymer 1. J Neurol 1996; 243 Suppl. 2: S85–6

63.

Teitelbaum D, Webb C, Meshorer A, et al. Suppression by several synthetic polypeptides of experimental allergic encephalomyelitis induced in guinea pigs and rabbits with bovine and human basic encephalitogen. Eur J Immunol 1973; 3: 273–9PubMed

64.

Brosh N, Zinger H, Moses E. Copolymer-1 (Copaxone) does not affect the induction and development of experimental systemic lupus erythematosus (SLE) [abstract no. P573]. J Neurol 1997; 244 Suppl. 3: S113

65.

Johnson KP, Brooks BR, Cohen JA, 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 Jul;45: 1268–76PubMed

66.

Bornstein MB, Miller AI, Slagle S, et al. Clinical trials of copolymer I in multiple sclerosis. Ann N Y Acad Sci 1984; 436: 366–72PubMed

67.

Johnson KP, Brooks BR, Cohen JA, et al. Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability: Copolymer 1 Multiple Sclerosis Study Group. Neurology 1998 Mar; 50(3): 701–8PubMed

68.

Johnson KP, Brooks BR, Ford CC, et al. Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 years: Copolymer 1 Multiple Sclerosis Study Group. Mult Scler 2000 Aug; 6(4): 255–66PubMed

69.

Johnson KP, Brooks B, Ford CC, et al. Results of the long-term (eight-year) prospective, open-label trial of glatiramer acetate for relapsing multiple sclerosis. Neurology 2002 Apr; 58 Suppl. 3: A458

70.

Wolinsky JS, Comi G, Filippi M, et al. Copaxones’s effect on MRI-monitored disease in relasping MS is reproducible and sustained. Neurology 2002; 59: 1284PubMed

71.

Filippi M, Comi G, Wolinsky JS, et al. Glatiramer acetate and relapse rate in multiple sclerosis: meta-analysis of three double-blind, placebo-controlled clinical trials. J Neurol Sci 2001; 187 Suppl.: 1316

72.

Khan OA, Tselis AC, Kamholz JA, et al. A prospective, open-label treatment trial to compare the effect of IFNβ-1a (Avonex), IFNβ-1b (Betaseron), and glatiramer acetate (Copaxone) on the relapse rate in relapsing-remitting multiple sclerosis: results after 18 months of therapy. Mult Scler 2001 Dec; 7(6): 349–53PubMed

73.

Firzlaff M, Schroder M, Schmid M, et al. Comparison of immunomodulatory treatment of relapsing remitting multiple sclerosis (RRMS): prospective open study in 304 MS patients treated with interferon-β (IFN-β) 1-b, IFN-β 1-a i.m., IFN-β 1-a s.c, glatiramer acetate (Copaxone) or immunoglobulins [poster]. Tenth Meeting of the European Neurology Society (ENS); 2000 Jun 18–22; Jerusalem

74.

Sormani MP, Bruzzi P, Comi G, et al. MRI metrics as surrogate markers for clinical relapse rate in relapsing-remitting MS patients. Neurology 2002 Feb 12; 58(3): 417–21PubMed

75.

Waubant EL, Goodkin DE. Assessing efficacy in clinical trials of treatments for multiple sclerosis: issues and controversy. CNS Drugs 1996; 6(6): 462–73

76.

Filippi M, Horsfield MA, Ader HJ, et al. Guidelines for using quantitative measures of brain magnetic resonance imaging abnormalities in monitoring the treatment of multiple sclerosis. Ann Neurol 1998 Apr; 43: 499–506PubMed

77.

Wolinsky J. Glatiramer acetate. In: Hawkins C, Wolinski J, editors. Principles of treatments in multiple sclerosis. Oxford: Butterworth-Heinemann, 2000: 71–94

78.

Calabresi PA. Considerations in the treatment of relapsing-remitting multiple sclerosis. Neurology 2002 Apr 23; 58(8 Suppl. 4): S10–22PubMed

79.

Filippi M, Rovaris M, Rocca MA, et al. Glatiramer acetate reduces the proportion of new MS lesions evolving into “black holes”. Neurology 2001 Aug 28; 57(4): 731–3PubMed

80.

Ge Y, Grossman RI, Udupa JK, et al. Glatiramer acetate (Copaxone) treatment in relapsing-remitting MS: quantitative MR assessment. Neurology 2000 Feb 22; 54(4): 813–7PubMed

81.

Rovaris M, Comi G, Rocca MA, et al. Short-term brain volume change in relapsing-remitting multiple sclerosis: effect of glatiramer acetate and implications. Brain 2001 Sep; 124 (Pt 9): 1803–12PubMed

82.

Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983 Nov; 33: 1444–52PubMed

83.

Greenstein JI. Extended use of glatiramer acetate (Copaxone) for MS [letter]. Neurology 1999 Mar 10; 52(4): 897–8PubMed

84.

Liu C, Blumhardt LD. Disability outcome measures in therapeutic trials of relapsing-remitting multiple sclerosis: effects of heterogeneity of disease course in placebo cohorts. J Neurol Neurosurg Psychiatry 2000 Apr; 68(4): 450–7PubMed

85.

Comi G. Why treat early multiple sclerosis patients? Curr Opin Neurol 2000 Jun; 13(3): 235–40PubMed

86.

Metz LM, Patten SB, Rose SM, et al. Multiple sclerosis fatigue is decreased at six months by glatiramer acetate (Copaxone) [abstract no. P431]. 11th Meeting of the European Neurological Society; 2001 Apr 21–25; Paris

87.

Metz LM, Patten SB, Rose SM, et al. Multiple sclerosis fatigue is decreased at six months by glatiramer acetate (Copaxone) [poster]. 11th Meeting of the European Neurological Society; 2001 Apr 21–25; Paris

88.Bose

U, Ladkani D, Burrell A, et al. Cost-effectiveness analysis of glatiramer acetate in the treatment of relapsing-remitting multiple sclerosis. J Drug Assess 2002; 5 (Pt 1): 67–79

89.

Beta interferon and glatiramer acetate for the treatment of multiple sclerosis [Technology Appraisal Guidance No. 32]. London: National Institute for Clinical Excellence, 2002 Jan: 1-22

90.

Korczyn AD, Nisipeanu P. Safety profile of copolymer 1: analysis of cumulative experience in the United States and Israel. J Neurol 1996 Apr; 243(4 Suppl. 1): S23–6PubMed

91.

Bayerl C, Bohland P, Jung EG. Systemic reaction to glatiramer acetate. Contact Dermatitis 2000 Jul; 43(1): 62–3PubMed

92.

Milo R, Panitch H. Glatiramer acetate or interferon-β for multiple sclerosis? A guide to drug choice. CNS Drugs 1999; 11(4): 289–306

93.

Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 1996 Mar; 39(3): 285–94PubMed

94.

PRISMS Study Group (Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis). Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet 1998 Nov 7; 352: 1498–504

95.

The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I: clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993 Apr; 43: 655–61

96.

Hwang L, Orengo I. Lipoatrophy associated with glatiramer acetate injections for the treatment of multiple sclerosis. Cutis 2001 Oct; 68(4): 287–8PubMed

97.

Drago F, Brusati C, Mancardi G, et al. Localized lipoatrophy after glatiramer acetate injection in patients with remitting-relapsing multiple sclerosis [letter]. Arch Dermatol 1999 Oct; 135(10): 1277–8PubMed

98.

Windhagen A, Maniak S, Marckmann S, et al. Lymphadenopathy in patients with multiple sclerosis undergoing treatment with glatiramer acetate [letter]. J Neurol Neurosurg Psychiatry 2001 Mar; 70(3): 415–6PubMed

99.

Vollmer T. Safety and tolerability of glatiramer acetate for injection (formerly known as copolymer-1) in the treatment of multiple sclerosis patients previously treated with interferon β-1b. Ann Neurol 1998 Sep; 44: 505

100.

Aventis. New Copaxone® prefilled syringe introduced [online]. Available from URL: http://aventis.custservices.com/news.asp?up=113 [Accessed 2002 Oct 18]

101.

Teva Pharmaceutical Industries. FDA issues approvable letter on prefilled syringe for Copaxone® [online]. Available from URL: http://www.tevapha/musa.com [Accessed 2001 Oct 2]

102.

Lyseng-Williamson KA, Plosker GL. Management of relapsing-remitting multiple sclerosis. Defining the role of subcutaneous recombinant interferon-β-1a (Rebif®). Dis Manage Health Outcomes 2002; 10(5): 307–25

103.

Freedman MS, Blumhardt LD, Brochet B, et al. International consensus statement on the use of disease-modifying agents in multiple sclerosis. Mult Scler 2002; 8: 19–23PubMed

104.

Weinstock-Guttman B, Jacobs LD. What is new in the treatment of multiple sclerosis? Drugs 2000 Mar; 59(3): 401–10PubMed

105.

Herndon RM. Treatment of multiple sclerosis with the interferon-βs: comparative risks and benefits. Biodrugs 1998 Dec; 10(6): 462–70

106.

Walther WD, Hohlfield MD. Multiple sclerosis: side effects of interferon beta therapy and their management. Neurology 1999 Nov; 53: 1622–7PubMed

107.

Grudzinski AN, Hakim Z, Cox ER, et al. The economics of multiple sclerosis: distribution of costs and relationship to disease severity. Pharmacoeconomics 1999 Mar; 15: 229–40PubMed

108.

National Multiple Sclerosis Society (NMSS). Disease management consensus statement. [online]. Available from URL: http://www.nationalmssociety.org/Sourcebook-Early.asp [Accessed 2002 Jun 12]

109.

Wingerchuk DM, Noseworthy JH. Randomized controlled trials to assess therapies for multiple sclerosis. Neurology 2002 Apr 23; 58(8 Suppl. 4): S40–8PubMed

110.

Rudge P. Are clinical trials of therapeutic agents for MS long enough? Lancet 1999 Mar 27; 353: 1033–4PubMed

Titel: Glatiramer Acetate
A Review of its Use in Relapsing-Remitting Multiple Sclerosis
verfasst von: Dene Simpson
Stuart Noble
Caroline Perry
Publikationsdatum: 01.12.2002
Verlag: Springer International Publishing
Erschienen in: CNS Drugs / Ausgabe 12/2002
Print ISSN: 1172-7047
Elektronische ISSN: 1179-1934
DOI: https://doi.org/10.2165/00023210-200216120-00004

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Neurologie

Schützt Olivenöl vor dem Tod durch Demenz?

10.05.2024 Morbus Alzheimer Nachrichten

Konsumieren Menschen täglich 7 Gramm Olivenöl, ist ihr Risiko, an einer Demenz zu sterben, um mehr als ein Vierten reduziert – und dies weitgehend unabhängig von ihrer sonstigen Ernährung. Dafür sprechen Auswertungen zweier großer US-Studien.

Bluttest erkennt Parkinson schon zehn Jahre vor der Diagnose

10.05.2024 Parkinson-Krankheit Nachrichten

Ein Bluttest kann abnorm aggregiertes Alpha-Synuclein bei einigen Menschen schon zehn Jahre vor Beginn der motorischen Parkinsonsymptome nachweisen. Mit einem solchen Test lassen sich möglicherweise Prodromalstadien erfassen und die Betroffenen früher behandeln.

Darf man die Behandlung eines Neonazis ablehnen?

08.05.2024 Gesellschaft Nachrichten

In einer Leseranfrage in der Zeitschrift Journal of the American Academy of Dermatology möchte ein anonymer Dermatologe bzw. eine anonyme Dermatologin wissen, ob er oder sie einen Patienten behandeln muss, der eine rassistische Tätowierung trägt.

Wartezeit nicht kürzer, aber Arbeit flexibler

Psychotherapie Medizin aktuell

Fünf Jahren nach der Neugestaltung der Psychotherapie-Richtlinie wurden jetzt die Effekte der vorgenommenen Änderungen ausgewertet. Das Hauptziel der Novellierung war eine kürzere Wartezeit auf Therapieplätze. Dieses Ziel wurde nicht erreicht, es gab jedoch positive Auswirkungen auf andere Bereiche.

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen