==COPAXONE FOR MS== Arch Neurol 1999 Mar;56(3):319-24 Neuropsychologic status in multiple sclerosis after treatment with glatiramer. Weinstein A, Schwid SI, Schiffer RB, McDermott MP, Giang DW, Goodman AD Department of Neurology, University of Rochester Medical Center, NY 14642, USA. aweinstein@mail.neurology.rochester.edu BACKGROUND: Glatiramer acetate (Copaxone) therapy reduces clinical disease activity in relapsing-remitting multiple sclerosis (MS). OBJECTIVE: To study the effect of glatiramer therapy on neuropsychologic function as part of a randomized, placebo-controlled, multicenter trial. METHODS: Two hundred forty-eight patients with relapsing-remitting MS and mild to moderate disability (Expanded Disability Status Scale score, <5.0) were tested before and 12 and 24 months after randomization to administration of glatiramer acetate, 20 mg/d, or matching placebo. Neuropsychologic tests examined 5 cognitive domains most often disrupted in patients with MS: sustained attention, perceptual processing, verbal and visuospatial memory, and semantic retrieval. RESULTS: Baseline neuropsychologic test performance was similar in both treatment groups and was within normal range, except for impaired semantic retrieval. Mean neuropsychologic test scores were higher at 12 and 24 months than at baseline, and no differences were detected between treatment groups over time. No significant interactions were detected between treatment and either time or baseline impairment. CONCLUSIONS: Our 2-year longitudinal study showed no effect of glatiramer therapy on cognitive function in relapsing-remitting MS. Although it is possible that glatiramer therapy has no effect on cognitive function, the lack of measurable decline in cognitive function in both patient groups for 2 years limits the opportunity for glatiramer to demonstrate a therapeutic effect by minimizing such decline. Emerging treatments for MS should continue to be examined for their effect on cognitive impairment because it can be a critical determinant of disability. A greater understanding of the natural history of cognitive decline in MS is essential for a rational design of these drug trials. Annu Rev Med 1999;50:291-302 Immunologic therapy of multiple sclerosis. Arnason BG Department of Neurology, Pritzker School of Medicine, Chicago, Illinois, USA. barnason@drugs.bsd.uchicago.edu Three interferon beta preparations (Betaseron, Avonex, and Rebif) have shown efficacy in the treatment of relapsing-remitting multiple sclerosis (MS). Attack frequency is reduced by 30% and major attacks to an even greater extent. Accumulating disease burden as measured by annual T2-weighted magnetic resonance imaging is markedly lessened, and disease activity as measured by serial gadolinium-enhanced MRI scanning is reduced by over 80%. A fourth preparation, Copaxone, a basic copolymer of four amino acids, lessens MS attack frequency by 30% and also lessens disease activity as measured by gadolinium-enhanced MRI. Betaseron lessens accumulation of disability in MS patients with secondary progressive disease regardless of the severity of disability at the time treatment is commenced. MS is now a treatable disease. J Neuroimmunol 1998 Dec 1;92(1-2):113-21 Treatment of multiple sclerosis with copolymer-1 (Copaxone): implicating mechanisms of Th1 to Th2/Th3 immune-deviation. Miller A, Shapiro S, Gershtein R, Kinarty A, Rawashdeh H, Honigman S, Lahat N Neuroimmunology Research Unit and Multiple Sclerosis Center, Lady Davis Carmel Medical Center, Haifa, Israel. The synthetic polypeptide copolymer-1 (Cop-1; Copaxone; Glatiramer Acetate) has been recently approved as an effective treatment in relapsing multiple sclerosis (MS). A large body of evidence demonstrates that Cop-1 induces active suppression of CNS-inflammatory disease in animal models. However, Cop-1-mediated suppressor mechanisms have not yet been elucidated in humans. A 12-month open study following clinical and immunological parameters of ten relapsing MS patients treated with Cop-1 is presented. Relapse rates and disability scores (EDSS) were evaluated prior to and after 12 months of treatment. The immunological parameters assessed prior to and at 3 months' interval during treatment included serum levels of soluble IL-2 receptor (sIL-2R) and IL-10 as well as leukocyte cytokine mRNA expression of TNF alpha, IL-4 and TGF-beta. Copaxone treatment was found to lead to a significant reduction in the mean annual relapse rate (from 1.4 prior to treatment to 0.6 during treatment) and stabilization of disability in 90% of the patients. The treatment was accompanied by an elevation of serum IL-10 levels, suppression of the pro-inflammatory cytokine TNF alpha mRNA, and an elevation of the anti-inflammatory cytokines TGF-beta and IL-4 mRNAs in PBLs. These results suggest that the beneficial clinical effects of Copaxone in MS patients may be attributed to changes in activation of T cell subsets and a shift from Th1 to Th2/Th3 cytokine profile, probably leading to Cop-1-driven mechanisms of bystander suppression. Neurology 1998 Mar;50(3):701-8 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. Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, Myers LW, Panitch HS, Rose JW, Schiffer RB, Vollmer T, Weiner LP, Wolinsky JS Department of Neurology, University of Maryland, Baltimore 21201, USA. When 251 relapsing-remitting patients with multiple sclerosis were randomized to receive daily subcutaneous injections of glatiramer acetate, previously called copolymer 1 (Copaxone; n = 125) or placebo (n = 126) for 24 months, there were no laboratory abnormalities associated with glatiramer acetate treatment and it was well tolerated with few side effects. Patients receiving glatiramer acetate had significantly fewer relapses and were more likely to be neurologically improved, whereas those receiving placebo were more likely to worsen. This study was extended for 1 to 11 months (mean of 5.2 months for the glatiramer acetate group and 5.9 months for the placebo group). The blinding and study conditions used during the core 24-month study were unchanged throughout the extension. The results of this extension study confirm the excellent tolerance and safety profile of glatiramer acetate for injection. The clinical benefit of glatiramer acetate for both the relapse rate and for neurologic disability was sustained at the end of the extension trial. Mult Scler 1996 Jul;1(6):325-6 Management of relapsing/remitting multiple sclerosis with copolymer 1 (Copaxone). Johnson KP Department of Neurology, University of Maryland Hospital, Baltimore 21201, USA. Copolymer I (Copazone) was evaluated in a multicenter, placebo-controlled, double-blind trial at 11 universities. Two hundred and fifty-one relapsing-remitting ambulatory MS patients were randomized to receive 20 mg of copolymer I or placebo by daily subcutaneous injection for approximately 30 months. At conclusion, the copolymer I group had 32% fewer relapses (P = 0.002) and significantly more were relapse-free (P = 0.035). Significantly, more patients were receiving copolymer I had improved during the study, while more patients on placebo showed neurological decline (P = 0.001). There were few side effects and no drug related laboratory abnormalities. Copolymer I is being considered by North American and European regulatory agencies for approval as commercially available agent for the control of multiple sclerosis. J Neurol 1996 Apr;243(4 Suppl 1):S3-7 A review of the clinical efficacy profile of copolymer 1: new U.S. phase III trial data. Johnson KP Department of Neurology, University of Maryland Hospital, Baltimore 21201, USA. 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 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 beta in ushering in a new era of well-tolerated treatments for multiple sclerosis. J Neurol 1996 Apr;243(4 Suppl 1):S23-6 Safety profile of copolymer 1: analysis of cumulative experience in the United States and Israel. Korczyn AD, Nisipeanu P Department of Neurology, Tel Aviv University Medical School, Israel. 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. Neurology 1995 Jul;45(7):1268-76 Copolymer 1 reduces relapse rate and 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 Department of Neurology, University of Maryland, Baltimore, USA. 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.