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Copolymer-1

A Review of its Pharmacological Properties and Therapeutic Potential in Multiple Sclerosis

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Summary

Copolymer-1 is a mixture of synthetic random polypeptides composed of 4 amino acids. In a variety of animal species, including primates, it suppresses experimental allergic encephalomyelitis, an approximate model of multiple sclerosis. In vitro experiments using murine and human T cell lines demonstrate that copolymer-1 inhibits the binding of some myelin proteins to the major histocompatibility complex.

Although reactive antibodies to copolymer-1 were observed in most patients receiving the drug in a trial, available evidence suggests that these antibodies do not neutralise the clinical effectiveness of copolymer-1.

In monkeys, subcutaneous copolymer-1 is quickly absorbed with a time to maximum plasma concentration of 2 to 4 hours. Therapeutic doses of subcutaneous copolymer-1 are unlikely to produce detectable plasma concentrations in patients because of rapid metabolism to smaller peptide fragments.

Compared with placebo (n = 126), subcutaneous copolymer-1 20mg once daily (n = 125) for up to 2.5 years significantly reduced the annual relapse rate by 30% and slowed the progression of disability in patients with relapsing-remitting multiple sclerosis. Copolymer-1 was more beneficial to patients with little initial accumulated neurological disability than more severely affected patients. In a smaller trial, also involving patients with relapsing-remitting multiple sclerosis, copolymer-1 20mg once daily (n = 25) caused a 76% reduction in the annual relapse rate compared with placebo (n = 23). However, in patients with secondary progressive multiple sclerosis, subcutaneous copolymer-1 15mg twice daily (n =51) for 2 years was not shown to be effective in slowing disease progression in comparison to placebo (n = 55).

In clinical trials, injection site reactions were the most common adverse effects associated with copolymer-1 treatment, with 90 and 59% of copolymer-1 (n = 125) and placebo (n = 126) recipients reporting ≥1 reaction from an average of about 730 injections in 1 trial. A transient benign systemic reaction characterised by flushing, chest tightness, dyspnoea, palpitations or anxiety occurred more frequently with copolymer-1 than placebo. Nine to 15% of patients receiving copolymer-1 20mg once daily reported this reaction at least once, compared with 0 to 3% of placebo recipients.

Overall, copolymer-1 causes few serious adverse effects and appears to be effective in slowing the relapse rate and progression of disability of patients with relapsing-remitting multiple sclerosis. However, it has not been shown to be effective for the treatment of the secondary progressive form of the disease. Copolymer-1 can thus be considered a significant addition to the limited armoury of drugs for the treatment of patients with multiple sclerosis.

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    Andrew P. Lea & Karen L. Goa

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Various sections of the manuscript reviewed by: R. Arnon, Department of Chemical Immunology, The Weizmann Institute of Science, Rehovot, Israel; D. Buljevac, Department of Neurology, University Hospital Dijkzigt Rotterdam, Rotterdam, The Netherlands; A. Coles, Department of Neurology, Addenbrooke’s Hospital, Cambridge, England; L. Durelli, Clinica Neurologica, Università di Torino, Turin, Italy; A. Goonetilleke, Department of Neurology, Middlesbrough General Hospital, Middlesbrough, England; J.W. Hadden, Department of Internal Medicine, University of South Florida, Tampa, Florida, USA; H.P. Hartung, Neurologische Universitätsklinik, Julius-Maximilians-Universität, Würzburg, Germany; E. McDonald, Multiple Sclerosis Society of Victoria, Toorak, Victoria, Australia; P.K. Newman, Department of Neurology, Middlesbrough General Hospital, Middlesbrough, England; H. Panitch, Department of Neurology, University of Maryland Hospital, Baltimore, Maryland, USA; C.H. Polman, Department of Neurology, Free University Hospital, Amsterdam, The Netherlands.

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Lea, A.P., Goa, K.L. Copolymer-1. Clin. Immunother. 6, 319–331 (1996). https://doi.org/10.1007/BF03259096

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