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Optimal Dosing of Immunomodulating Drugs: A Dose-Comparison Study of GA in RRMS

Published online by Cambridge University Press:  22 October 2007

Daniel Wynn ,
Catherine Meyer ,
Neil Allen  and
Dennis O'Brien
Daniel Wynn
Affiliation:
Consultants in Neurology, Northbrook, IL, USA; Email: dwynnmd@dwynnmd.interaccess.com
Catherine Meyer
Affiliation:
Consultants in Neurology, Northbrook, IL, USA; Email: Research@CINLTD.com
Neil Allen
Affiliation:
Consultants in Neurology, Northbrook, IL, USA; Email: Research@CINLTD.com
Dennis O'Brien
Affiliation:
Billings Clinic, Billings, MT, USA
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Extract

ABSTRACT

Background: Though indications of a dose–response for glatiramer acetate (GA) were apparent during early drug development and clinical testing, no formal dose-comparisons of GA had been conducted before the present study. Design/Methods: This multicenter, randomized, double-blind study compared the safety and efficacy of two GA doses: 20 mg/day, the currently approved dose, versus 40 mg/day. Relapsing–remitting multiple sclerosis (RRMS) patients with active disease (1–15 gadolinium-enhancing (GdE) lesions on screening magnetic resonance imaging (MRI) and ≥1 relapse in the previous year) were eligible. The primary outcome was change from baseline in total number of GdE lesions at 7, 8, and 9 months. Other outcomes included effects on relapse, changes in expanded disability status scale (EDSS) scores, and responder analyses. Results: Benefits of the 40 mg GA dose versus the 20 mg dose on GdE lesions were evident by month 3. Additionally, significant advantages of the 40 mg dose were observed for time to first relapse and proportion of relapse-free patients. There was a trend for better outcomes with 40 mg/day GA for the primary efficacy measure, but the difference between doses was not statistically significant. Both GA doses were safe and similarly well tolerated. Interpretation: A 40 mg/day GA dosage may be more effective than the 20 mg/day recommended dosage for reducing disease activity, and appears to have an earlier onset of action. A large, phase III study is underway to confirm these findings.

Keywords

dose–responseglatiramer acetatemultiple sclerosisrelapsing–remitting.
Type
Research Article
Information
Progress in Neurotherapeutics and Neuropsychopharmacology , Volume 3 , Issue 1 , January 2008 , pp. 137 - 151
Copyright
© 2008 Cambridge University Press

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References

Abramsky, O., Teitelbaum, D., & Arnon, R. (1977). Effect of a synthetic polypeptide (COP 1) on patients with multiple sclerosis and with acute disseminated encephalomyelitis. Journal of the Neurological Sciences, 31, 433–438.Google Scholar
Aharoni, R., Kayhan, B., Eilam, R., Sela, M., & Arnon, R. (2003). Glatiramer acetate-specific T cells in the brain express T helper 2/3 cytokines and brain-derived neurotrophic factor in situ. Proceedings of the National Academy of Sciences of the United States of America, 100, 14157–14162.Google Scholar
Barkhof, F., Filippi, M., van Waesberghe, J.H., Molyneux, P., Rovaris, M., Lycklama, A., et al. (1997). Improving interobserver variation in reporting gadolinium-enhanced MRI lesions in multiple sclerosis. Neurology, 49, 1682–1688.Google Scholar
Berger, J.R., & Koralnik, I.J. (2005). Progressive multifocal leukoencephalopathy and natalizumab – unforeseen consequences. New England Journal of Medicine, 353, 414–416.Google Scholar
Bornstein, M.B., Miller, A.I., Teitelbaum, D., Arnon, R., & Sela, M. (1982). Multiple sclerosis: trial of a synthetic polypeptide. Annals of Neurology, 11, 317–319.Google Scholar
Bornstein, M.B., Miller, A., Slagle, S., Weitzman, M., Crystal, H., Drexler, E., et al. (1987). A pilot trial of Cop 1 in exacerbating–remitting multiple sclerosis. New England Journal of Medicine, 317, 408–414.Google Scholar
Clanet, M., Radue, E.W., Kappos, L., Hartung, H.P., Hohlfeld, R., Sandberg-Wollheim, M., et al. (2002). A randomized, double-blind, dose-comparison study of weekly interferon beta-1a in relapsing MS. Neurology, 59, 1507–1517.Google Scholar
Cohen, J.A., Rovaris, M., Goodman, A.D., Ladkani, D., Wynn, D., & Filippi, M. (2007). Randomized, double-blind, dose-comparison study of glatiramer acetate in relapsing–remitting MS. Neurology, 68, 939–944.Google Scholar
Comi, G., Filippi, M., Wolinsky, J.S., & European/Canadian Glatiramer Acetate Study Group (2001). 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. Annals of Neurology, 49, 290–297.Google Scholar
Ebers, G., & PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group (1998). Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet, 352, 1498–1504.Google Scholar
Filippi, M., Gawne-Cain, M.L., Gasperini, C., van Waesberghe, J.H., Grimaud, J., Barkhof, F., et al. (1998). Effect of training and different measurement strategies on the reproducibility of brain MRI lesion load measurements in multiple sclerosis. Neurology, 50, 238–244.Google Scholar
Ford, C.C., Johnson, K.P., Lisak, R.P., Panitch, H.S., Shifroni, G., & Wolinsky, J.S. (2006). A prospective open-label study of glatiramer acetate: over a decade of continuous use in MS patients. Multiple Sclerosis, 12, 309–320.Google Scholar
Hohlfeld, R., Kerschensteiner, M., Stadelmann, C., Lassmann, H., & Wekerle, H. (2000). The neuroprotective effect of inflammation: implications for the therapy of multiple sclerosis. Journal of Neuroimmunology, 107, 161–166.Google Scholar
Hughes, R.A.C., PRISMS (Prevention of Relapses and Disability by Interferon-β-1a Subcutaneously in Multiple Sclerosis) Study Group, & the University of British Columbia MS/MRI Analysis Group (2001). PRISMS-4: long-term efficacy of interferon-β-1a in relapsing MS. Neurology, 56, 1628–1636.Google Scholar
Jacobs, L., Rudick, R., & Simon, J. (2000). Extended observations on MS patients treated with IM interferon-beta1a (Avonex): implications for modern MS trials and therapeutics. Journal of Neuroimmunology, 107, 167–173.Google Scholar
Johnson, K.P., Brooks, B.R., Cohen, J.A., Ford, C.C., Goldstein, J., Lisak, R.P., et al. (1995). 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. Neurology, 45, 1268–1276.Google Scholar
Johnson, K.P., Brooks, B.R., Cohen, J.A., Ford, C.C., Goldstein, J., Lisak, R.P., et al. (1998). Extended use of glatiramer acetate (copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. The Copolymer 1 Multiple Sclerosis Study Group. Neurology, 50, 701–708.Google Scholar
Kipnis, J., & Schwartz, M. (2002). Dual action of glatiramer acetate (Cop-1) in the treatment of CNS autoimmune and neurodegenerative disorders. Trends in Molecular Medicine, 8, 319–323.Google Scholar
Kipnis, J., Aviden, H., Caspi, R.R., & Schwartz, M. (2004). Dual effect of CD4+CD25+ regulatory T cells in neurodegeneration: a dialog with microglia. Proceedings of the National Academy of Sciences of the United States of America, 101, 14663–14669.Google Scholar
Kurtzke, J.F. (1983). Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology, 33, 1444–1452.Google Scholar
Miller, D.H., Barkhof, F., Berry, I., Kappos, L., Scotti, G., & Thompson, A.J. (1991). Magnetic resonance imaging in monitoring the treatment of multiple sclerosis: concerted action guidelines. Journal of Neurology Neurosurgery and Psychiatry, 54, 683–688.Google Scholar
Poser, C.M., Paty, D.W., Scheinberg, L., McDonald, W.I., Davis, F.A., Ebers, G.C., et al. (1983). New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Annals of Neurology, 13, 227–231.Google Scholar
Rovaris, M., Filippi, M., Calori, G., Rodegher, M., Campi, A., Colombo, B., et al. (1997). Intra-observer reproducibility in measuring new putative MR markers of demyelination and axonal loss in multiple sclerosis: a comparison with conventional T2-weighted images. Journal of Neurology, 244, 266–270.Google Scholar
The IFNB Multiple Sclerosis Study Group (1993). Interferon beta-1b is effective in relapsing–remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology, 43, 655–661.Google Scholar
The Once Weekly Interferon for MS Study Group (1999). Evidence of interferon beta-1a dose response in relapsing–remitting MS: the OWIMS Study. Neurology, 53, 679–686.Google Scholar