Neuroprotection with glatiramer acetate: evidence from the PreCISe trial

Douglas L Arnold,Sridar Narayanan,Samson Antel

doi:10.1007/s00415-013-6903-5

Abstract

The phase III, multicenter, randomized, placebo-controlled PreCISe trial assessed glatiramer acetate (GA) effects in patients with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS). To assess the neuroprotective effect of GA in a subset of patients in the PreCISe trial, we used proton magnetic resonance spectroscopy (MRS) to measure N-acetylaspartate (NAA), a marker of neuronal integrity, in a large central volume of brain. Thirty-four CIS patients randomized to GA 20 mg/day (n = 19) SC or placebo (n = 15) were included. Patients who relapsed (developed clinically definite MS [CDMS]) were removed from the substudy. NAA/creatine (NAA/Cr) ratios were compared between GA-treated and placebo-treated patients. Twenty patients with CIS had not converted to CDMS and were still in the double-blind phase of the trial at 12 months of follow-up. Paired changes in NAA/Cr differed significantly in patients treated with GA (+0.14, n = 11) compared with patients receiving placebo (−0.33, n = 9, p = 0.03) at 12 months, consistent with a neuroprotective effect of GA in vivo. Patients with CIS who received GA showed improvement in brain neuroaxonal integrity, as indicated by increased NAA/Cr, relative to comparable patients treated with placebo, who showed a decline in NAA/Cr consistent with findings from natural history studies.

Highlights

The importance of neuroaxonal degeneration as the substrate of chronic irreversible disability in multiple sclerosis (MS) is being increasingly appreciated [1]
In the overall PreCISe study, patients treated with glatiramer acetate (GA) had a 45 % reduction in the risk of developing clinically definite MS (CDMS) compared to patients treated with placebo, and the time to the disease-defining relapse was delayed by approximately 1 year [12]
Analysis of covariance examining the effect of T2weighted lesions, categorized by the presence or absence of new T2-weighted lesions, showed that increased NAA/creatine and phosphocreatine (Cr) was significant in patients who developed new T2-weighted lesions over the course of the study

Summary

Introduction

The importance of neuroaxonal degeneration as the substrate of chronic irreversible disability in multiple sclerosis (MS) is being increasingly appreciated [1]. The neurological impairment that occurs with MS relapses results primarily from acute conduction block associated with demyelination and inflammation [2]. Resolution of inflammation, along with remyelination of axons that are not transected, and insertion of new sodium channels to allow conduction across segments of axons that remain demyelinated, can lead to reversal of the disability attributable to these factors. Axons are often transected in acute lesions, and axons that are not transected but remain demyelinated may degenerate due to increased influx of sodium and calcium, loss of trophic support by myelin, and impaired axonal transport and mitochondrial function. Chronic diffuse inflammation within the CNS [3] probably accelerates the loss of axons

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