Tselis et al matter with those seen in the gray matter are not clear (Kidd et al 1999; Peterson et al 2001; Kutzelnigg et al 2005) Glatiramer acetate (GA) is an immunomodulating agent approved by the FDA for the treatment of RRMS. The drug was originally prepared as an analog of myelin basic protein (MBP), and consists of a random copolymer of L-alanine, L-lysine, L-glutamic acid, and L-tyrosine, in a molar ratio 4.2:3.4:1.4:1.0, respectively, as a string of 40–100 amino acid residues. The compound was used in research on experimen- tal allergic encephalomyelitis (EAE), an animal model of MS, in which the injection of myelin antigens (whether puriﬁed in adjuvant or crude extracts of white matter) triggers inﬂam- matory demyelination, with some parallels to MS. The drug was found to strongly inhibit the inﬂammatory demyelination which occurs in EAE (Arnon 1996). Clinical studies and trials Open label studies The success of GA in preventing and ameliorating EAE suggested its potential for beneﬁt in MS, and preliminary studies were initiated early on. In the ﬁrst published report of the use of GA in humans, Abramsky et al (1977) gave GA to 3 patients with acute dis- seminated encephalomyelitis (ADEM) (2 mg intramuscularly daily) and 4 patients with severe MS (2–3 mg intramuscularly every 2–3 days). The drug was well tolerated. An open label study of 12 patients with CPMS and 4 with RRMS examined the effect of GA given intramuscularly, origi- nally intended to be given at decreasing doses over a 6-month period. However, there were hints of efﬁcacy and many of the patients continued the drug at doses of up to 20 mg a day, for 18 months to more than 2 years. None of the patients deteriorated and a few seemed to improve (Bornstein et al 1981). Controlled trials In an important pilot trial of GA, 50 RRMS patients were divided into treatment and placebo groups, with patients in- dividually matched for gender, relapse frequency and degree of disability before entering the study (Bornstein et al 1987). The degree of disability was measured by the Kurtzke ex- tended disability status score (EDSS) (Kurtzke 1983). The treatment group received GA 20 mg daily for 2 years. The primary outcome variable was the proportion of relapse-free patients, while secondary outcomes consisted of frequency of exacerbations, change in disability and time free of pro- gression. The results showed clear beneﬁt with GA. The proportions of relapse-free patients in the treatment and placebo groups were 56% and 26% (p = 0.045) respectively. 260 The number of relapses in the treatment and placebo groups was 16 and 62. Interestingly, the less disabled patients had more beneﬁt in the relapse rate than the more disabled patients, in the treatment group, suggesting a greater ef- ﬁcacy the earlier treatment is started (Tselis and Khan 2004). The next trial examined the efﬁcacy of GA in CPMS. In this study 106 “chronic progressive” patients, at 2 sites (Albert Einstein, Bronx, NY and Baylor, Houston, Texas), were randomized to either placebo or GA 15 mg twice daily for 2 years (Bornstein et al 1991). The primary endpoint was the proportion of patients with conﬁrmed progression. Conﬁrmed progression was deﬁned as a change in EDSS by 1.0 or 1.5 steps (for those with baseline EDSS greater or less than 5.0 respectively) sustained for 3 months. As previously stated, “chronic progressive” MS is not a homogeneous entity and included both SPMS and PPMS, which dilutes the patient groups and makes valid comparisons difﬁcult. Overall, there was no statistically signiﬁcant (in the sense of p ≤ 0.05) difference in the primary outcome between the two groups at the 24 month time point. Interestingly, there was a trend (in the sense of 0.05 ≤ p ≤ 0.10) to beneﬁt from GA at both the 12- and 24-month time points, with progres- sion in 20.4% of treatment and 29.5% of placebo subjects at two years, p = 0.086 (Bornstein et al 1991). When the results were analyzed by center, however, some interesting observa- tions were made. At the Einstein site there was a statistically signiﬁcant beneﬁcial effect, with a probability of progression of 21.4% in treated patients and 38.5% in placebo patients, p = 0.041. At Baylor there was no difference, with 19% of both treated and placebo patients progressing. The placebo patients at Einstein had a much higher rate of progression (with 34% progressing) than the Baylor patients (only 14.8% progressing). The reason for this is unknown, but may have to do with the relative proportions of SPMS and PPMS patients at each center. The pivotal trial, leading to the approval of GA by the Food and Drug Administration (FDA) for RRMS, consisted of 251 patients randomized to GA 20 mg subcutaneously once a day or placebo, for 24 months (Johnson et al 1995). The patients had EDSS scores between 0 and 5.0, at least 2 relapses within the preceding 2 years, and no recent cortico- steroid or immunomodulatory therapy. The primary endpoint was the mean number of relapses per patient during 2 years of treatment, with a comparison between the treatment and placebo patients. A number of secondary outcomes were studied, including proportion of patients relapse-free, time to ﬁrst relapse after initiation of therapy and proportion of Neuropsychiatric Disease and Treatment 2007:3(2)