Tselis et al (p < 0.002). There was also a reduction in re-enhancing le- sions by 59% when comparing the treated patients with those in the placebo group. Patients in this trial were recruited into an open-label extension phase lasting another 9 months, with the placebo subjects getting open label GA and the treatment subjects continuing on their medication (Wolinsky et al 2002). It was found that the number of enhancing lesions decreased by 54% in those who went from placebo to GA, and further decreased by 24.6% in those who continued on GA from the double- blind to the open label phase (Wolinsky et al 2002). Interest- ingly, the difference in T2 lesion burden persisted over the 18 months of the study, suggesting that early treatment may preserve tissue, which was not regained in the switch from placebo to open label (Wolinsky et al 2002). Imaging studies have been used to detect the extent of “neurodegeneration” by various surrogate measures. One possibility would be to use brain atrophy as a surrogate for the effects of degeneration. In a substudy of the original pivotal GA study, 27 patients were randomized to GA or placebo, and the number of enhancing T1 and T2 lesions, as well as brain parenchymal volume measured over 2 years. There was less atrophy in the GA group than in the placebo group (Ge et al 2000). In another study comparing two different methods of measuring brain atrophy, using data from the E-C study, there was a signiﬁcant decrease in the development of brain atrophy in the GA group compared with the placebo group, when using the more sensitive measure (Sormani et al 2004). Magnetic resonance spectroscopy (MRS) measurements of brain chemistry have been very useful in understanding the pathogenesis of neurological diseases, and MS has been extensively studied. Various markers of neuronal and myelin structure have been measured and correlated with pathol- ogy and disability. N-acetyl aspartate (NAA) is a marker of neuronal structure and axonal integrity. Its decrease in MS plaques indicates axonal injury, which may be only partly reversible (Arnold et al 2001). In a pilot study of the effect of GA on axonal injury in RRMS, 22 patients were recruited, 18 of whom were treated with GA and 4 of whom declined treatment because of aversion to needles (Khan et al 2005). The patients were followed for 2 years. MRS measured NAA in a volume of interest (VOI) containing abnormal signal as well as in normal-appearing white matter (NAWM). In the GA group, the NAA-to-creatinine ratio (NAA/Cr, easily measured for technical reasons) had increased in the VOI by 10.7% in the treated group, while it had decreased by 8.9% in the untreated group. Similarly, in the NAWM, the 262 NAA/Cr was increased by 7.1% in the treated group, while it decreased by 8.2% in the untreated group. Anti-glatiramer antibodies The issue of the generation of antibody to GA is an important one since antibodies can theoretically abrogate the beneﬁcial effect of the drug, as seems to be the case for interferon-beta and natalizumab therapy. Antibodies to GA acetate have been detected in the sera of patients treated with the drug (Brenner et al 2001). In this study, sera from 217 patients who participated in the treatment and placebo arms of several GA acetate trials were tested for antibodies to GA using an ELISA method. Antibodies to GA were of the IgG (more IgG1 than IgG2) but not IgM or IgE isotypes. They were detected in all of the active treatment patients but not in the placebo patients. The titers of these antibodies increased to a maximum at 3 months after initiation and slowly decreased thereafter. There was no change in antibody titers to myelin basic protein. Another study showed the presence of IgG4 antibodies, detected by ELISA, in all 20 MS GA-treated patients, and in a minority of MS patients not treated with GA and normal controls (Farina et al 2002). There was no evidence of adverse effect of the antibodies, and indeed patients with higher antibody titers seemed to be more likely to be relapse-free (Brenner et al 2001). In vitro correlates of GA effect were observed either not affected or enhanced by antiGA antibodies in one study (Teitelbaum et al 2003) but not in another (Salama et al 2003). In the latter study it was proposed that some of the patients had antibodies that blocked the therapeutic effects but the in vitro immunologic endpoints were not necessarily measures of all of the mechanisms of action of GA, the clinical observations were not blinded and the number of patients was small. Glatiramer acetate in primary progressive MS A phase 3 trial of GA acetate in primary progressive MS (PPMS) was initiated in 1999 (Wolinsky 2004). The study randomized 943 patients to either GA or placebo for 36 months, with a placebo-controlled extension phase. The primary endpoint was progression of disease as ascertained by a sustained (3 month) increase in EDSS by 1 point for baseline EDSS 3.0–5.0 (low tier) and by 0.5 point for baseline EDSS 5.5–6.5 (high tier). Secondary endpoints included proportion of progression-free patients, changes in EDSS scores, number and volume of various lesions on MRI, black hole lesion burden, and brain volume loss. The study was discontinued early (at Neuropsychiatric Disease and Treatment 2007:3(2)