Glatiramer therapy

Allie R, Hu L, MuUen KM, Dhib-Jalbut S, Calabresi PA (2005) Bystander modulation of chemokine receptor expression on peripheral blood T lymphocytes mediated by glatiramer therapy. Arch Neurol 62 889-894... 

Suhayl D-J. Glatiramer acetate (Copaxone) therapy for multiple sclerosis. Pharmacol Ther 2(X)3 98 245-55. 

While no cure for MS is known, the FDA approves four immunotherapies for RR-MS. All shorten attacks and lengthen the time between attacks by 30% (Arnason, 1999a, 1999b). The therapies include variations of IFN (3 IFN (3-la, (Avonex and Rebif) and IFN (3-lb (Betaseron). The second type of immunotherapy, glatiramer acetate is a copolymer of four amino acids termed Copaxone. All approved therapies involve self... 

Most common adverse effects in controlled trials include injection site reactions, vasodilatation, chest pain, asthenia, infection, pain, nausea, arthralgia, anxiety, and hypertonia. About 10% of patients experience an immediate post-injection reaction (flushing, chest pain, palpitations, anxiety, dyspnea, throat constriction, and urticaria). The symptoms are hansient and self-limited, and usually do not require specific heatment. Transient chest pain was noted in 21% of Copaxone patients versus 11% in the placebo group with no long-term sequelae. Unlike therapy with the IFNps, glatiramer acetate is not associated with flu-like symptoms. 

Follow up studies on glatiramer acetate show that the relapse rate continues to be lower after 6 years on therapy (Johnson et al., 2000). The last 3 years of the lohnson study were open label with the initial study a double-blinded protocol. 

Published head to head trials of the FDA approved therapies for RR MS still involve relatively small numbers and relatively short time periods but they provide important information on efficacy and side effect profiles. The first such study was a retrospective review by Kahn that was followed by a prospective open label 18-month study comparing IFBp-la IM, IFNp-lb and glatiramer acetate (Khan et al., 2001a). The subcutaneous form of IFNp-la (Rebif) was not FDA approved at the time. At the end of the 18-month prospective trial, 122 of 156 participants remained on their original therapy (79%). Relapse rate was the primary outcome measure. Participants on Glatiramer acetate had a significant reduction in relapses (P < 0.0001), as did those on IFNp-lb (p < 0.001) compared to untreated patients. There was not a significant difference in the relapse rate for the control patients and those on IF[3-la IM. 

Almost three hundred patients enrolled in the Haas (2003) prospective head to head study of all four FDA approved therapies for RR-MS. All four therapies show a significant reduction in relapse rate (p < 0.02 for the IFNs) with gladramer acetate showing the most significant reduction (p <. 001). Discontinuation rates were also higher on the IFNps 20-30% by 6 months compared to 8% for those on glatiramer acetate by the end of the 2 year study. 

Preliminary studies evaluating an oral version of glatiramer acetate did not prove effective in changing the clinical outcome measures related to RR MS. Early trials of ingested IFN-alpha did have some biological effect (Brod et al., 1997) but have not shown the promised efficacy. CuiTendy two other oral therapies have shown positive results in phase II clinical trials (NMMS, 2005). 

Klran OA, Tslis AC, Kamholz JA, Gai bem JY, Lewis RA, Lisak RP (2001b) A prospective open-label ti eatment trial to compare the effect of IFN beta-la (Avonex), IFN beta-lb (Betaseron) and glatiramer acetate (Copaxone) on tire relapse rate in relapsing-remitting multiple sclerosis Results after 18 mondis of therapy. Mult Scler 7 349-353. 

Pollmann W, Erasmus LP, Feneberg W, Then Bergh F, Straube A. Interferon beta but not glatiramer acetate therapy aggravates headaches in MS. Neurology 2002 59(4) 636-9. 

Treatment with interferon-/ or glatiramer acetate (Avonex, Betaseron, Copaxone, and Rebif, or ABC-R, therapy) can reduce annual relapse rate, slow progression of disability, slow cognitive decline, and slow changes seen on the brain MRIs. 

Intriguingly, in vitro data suggest a potential synergism between glatiramer acetate and interferon-/ . Given the cost of these therapies, as well as the potential for additive adverse effects, this therapeutic combination cannot be recommended until clinical evidence demonstrating benefit is available. A study that will compare glatiramer acetate alone with interferon-/ - a (Avonex) alone versus a combination of the two has just been funded by NIH and is underway, with results expected in several years. 

As with many therapeutic decisions, economic cost both to the individual and to society mnst be considered. Currently, the annual cost of the new potentially disease-modifying therapies is considerable. The cost to the pharmacist of glatiramer and both currently available interferons is between 10,000 and 17,000 per patient per year. Given this expense, it must be remembered that these therapies are not curative and that individual patients may experience variable results. Future investigations evaluating these therapeutic modahties clearly will need to address not only chnical but also economic and humanistic outcomes. 

For relapsing-remitting attacks, immunomodulatory therapies are approved beta-1 interferons (interferon beta-la, interferon beta-lb, and glatiramer acetate [Copaxone]). The interferons suppress the proliferation of T-lymphocytes, inhibit their movement into the CNS from the periphery, and shift the cytokine prohle from pro- to antiinflammatory types. 

Munari L, Lovati R, Boiko A. Therapy with glatiramer acetate for multiple sclerosis. Cochrane Database Syst Rev 2004 (1)... 

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