Managing Multiple Sclerosis: New Data on Copaxone and Prognostic Value of Brain MRI
ABSTRACTS & COMMENTARY
Sources: Johnson KP, et al. Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Neurology 1998;50:701-708; Mancardi GL, et al. Effect of copolymer-1 on serial gadolinium-enhanced MRI in relapsing-remitting multiple sclerosis. Neurology 1998;50:1127-1133; O'Riordan JI, et al. The prognostic value of brain MRI in clinically isolated syndromes of the CNS. Brain 1998;121:495-503.
Extension data on the safety and efficacy of glatiramer acetate (Copaxone) were presented in this study of 251 relapsing remitting multiple sclerosis (RRMS) patients for up to 35 months (125 treated, 126 placebo, with a mean of 29 months of therapy). There were no laboratory abnormalities associated with the drug, and there were few side effects, such as transient flushing, chest tightness, and palpitations. Patients receiving Copaxone had significantly fewer relapses and were more likely to experience neurological improvement.
In the extended period of study, the mean relapse rate for the Copaxone group was 1.34 (95% CI, 1.06-1.63) vs. 1.98 (95% CI, 1.70-2.26) in the placebo group, representing a 32% reduction in the relapse rate with treatment (P = 0.002). While most patients in both groups were clinically unchanged over the study period (54% Copaxone vs 57% placebo), 27% of Copaxone patients compared to 12% of control patients showed improvement by one or more EDSS steps in their neurologic status (P = 0.001). In a time to increased disability analysis determined by 1.5 EDSS steps or more, 41.6% of placebo patients worsened during the extended trial vs. 21.6% Copaxone patients. No MRI data were presented.
In a small MRI study out of the University of Genoa, 10 patients with RRMS had monthly gadolinium-enhanced MRI (gad-MRI) scans in a 9-27 month pre-treatment period, followed by 10-14 months during Copaxone treatment. There was about a 50% decrease in new gad-MRI lesions, both in number and in area, in the Copaxone period compared to the pre-treatment period (0.92 vs 2.20 lesions/month; 22 mm2 vs 43 mm2 area/month; P = 0.1). Percentage change in the area of lesion load on T2-weighted images showed a decrease in the rate of accumulation during treatment. For all 10 patients, there was approximately a 14% increase in T2 lesions in the pretreatment period that slowed to a 2% increase during the Copaxone treatment period (P = 0.14).
In a 10-year, follow-up study of 81 patients by O'Riordan and colleagues at the National Hospital in Queen Square, London, the prognostic value of brain MRI was examined in clinically isolated syndromes of the optic nerve, brainstem, or spinal cord suggestive of demyelinating disease. Initial brain MRI was abnormal in 67% of patients, of which 83% went on to develop clinically definite MS. There was a strong correlation with more lesions conferring a worse pattern of disease activity with a higher disability score. In contrast, of those patients with a normal MRI at presentation, only 11% went on to develop MS in what was a milder pattern of disease.
COMMENTARY
Copaxone (glatiramer acetate) is a mixture of synthetic polypeptides composed of four amino acids-alanine, glutamic acid, lysine, and tyrosine-represented in myelin basic protein. The exact mechanism of action is unknown, but Copaxone is thought to interfere with normal MHC class II antigen binding on the antigen presenting cell to affect T cell recognition. Early human trials started over a decade ago with FDA approval for use in RRMS coming only last year. Both glatiramer acetate and interferon-beta have now shown modest benefits in reducing the attack rate in RRMS by about one-third. It is reassuring that the trial extension data for Copaxone further support a benefit. Also, perhaps more important are data indicating a corresponding reduction in demyelination on serial brain MRI scans. The small numbers of patients in this brain MRI study by Mancardi and colleagues, however, limits the statistical significance of the results. A much larger multicenter MRI study is in progress which should be complete by September 1998. The results will be crucial in confirming this important objective and quantitative measure of drug efficacy.
In addition to the above, ongoing studies of interferon-beta (both Betaseron and Avonex) are being tested in the treatment of secondary progressive (SP) MS. A European study of Betaseron treatment in SPMS concluded prematurely this year following early favorable results.
As reported in a recent Neurology Alert (1998;16:41-42), the greatest single predictor of future development of clinically definite MS following an attack of optic neuritis was the number of lesions on brain MRI at time of presentation (Neurology 1997;49:1404-1313). The 10-year, follow-up study by O'Riordan et al supports the predictive value of the initial MRI in determining the subsequent pattern of disease activity. This and other studies would support early therapeutic intervention with interferon-beta or Copaxone for patients with multiple lesions on brain MRI, since this appears to indicate a worse prognosis. -ba
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