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Setback for phase II multiple sclerosis trials

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Electronicjuice Vol 265 No 7117 p508
October 07, 2000 Clinical

Setback for phase II multiple sclerosis trials

Two phase II trials that were investigating treatment of multiple sclerosis with altered peptide ligands (APLs) have had to be stopped because of adverse reactions (Nature Medicine 2000;6:1167 and 1176).
In the first study, Dr Bibiana Bielekova (neuroimmunology branch, National Institute of Neurological Disorders and Stroke, US) and colleagues developed CGP77116, an APL of myelin basic protein (MBP), a component of myelin, in the hope that it would alter relapsing-remitting MS activity in humans. Seven volunteers with relapsing-remitting MS were given 50mg of CGP77116 subcutaneously weekly but all but one of the subjects discontinued treatment. Three suffered exacerbations of their MS, one had a systemic hypersensitivity reaction to the drug and the remaining three discontinued for other reasons. A further patient was given a lower dose of CGP77116 but also suffered an adverse reaction. All patients suffered injection-site reactions.
The authors say that two of the three exacerbations were related to the administration of APL therapy. The third was not caused by CGP77116, which they say suggests that not all MS attacks might be caused by the same antigen.

A better understanding of autoimmune responses is needed, authors say

MBP-specific T-cells may still be valid targets for treating MS but a better understanding of autoimmune diseases in individuals is needed before they can be used effectively and safely, the authors conclude.
In the second study, Dr Ludwig Kappos (department of neurology, University hospitals, Basel, Switzerland) and colleagues looked at the effect of an MBP-specific APL and placebo on magnetic resonance imaging (MRI) scans of the central nervous system. However, halfway through the study, the trial was stopped because 13 of the 142 patients had had a hypersensitivity reaction. Symptoms included itching, paraesthesiae, rash and dyspnoea. In addition, one patient suffered a hypotensive episode and another, syncope. The authors note that, in general, there was no worsening of MRI scans in patients who had suffered a reaction. They conclude that APL induces T-cell activity against autoimmune antigens but at the price of causing hypersensitivity reactions.
In a commentary on the two studies, Drs Claude Genain and Scott Zamvil (department of neurology, University of California) say that “one should not conclude that APL therapy is either good or bad”. The observations made in the studies should stimulate further research into which patients are most likely to benefit from APL therapy, they say (ibid, p1098).

MS aetiology and altered peptide ligands

The aetiology of MS is not understood but animal data suggest that it is an autoimmune disease mediated by myelin-specific T-cells. Specific therapies for T-cell autoimmune diseases in animal models have been developed where the target antigen is known. Thus, there has been a great deal of interest in finding similar approaches for human autoimmune diseases.
One approach is to use altered peptide ligands. These affect T-cell responses in one of three ways — by acting either as partial agonists or as antagonists at T-cell receptors or by inducing the production of T-cells that suppress the inflammatory response.

Citation: Electronicjuice URI: 20003162

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