Patients with clinically isolated syndrome who receive early treatment with glatiramer acetate have more than a 40% reduction in the risk of developing multiple sclerosis, compared with those whose treatment is delayed, according to findings from a prospectively planned 5-year follow-up of patient in the phase III PreCISe study.
After a 2-year extension phase of the 3-year double-blind, placebo-controlled study, 33% of 80 patients who had received early treatment with glatiramer acetate (GA) developed clinically definite multiple sclerosis (CDMS), compared with 50% of 118 patients who began treatment at the end of the initial 3-year double-blind phase. Each patient received 20 mg of GA daily by subcutaneous injection.
GA is marketed as Copaxone by Teva Pharmaceutical Industries Ltd. It is approved in 51 countries, including the United States, and is indicated for reducing the frequency of relapses in relapsing-remitting MS, including those who have experienced a first clinical episode and who have MS features on MRI.
In the Teva-sponsored study, disability progression, as measured by the Expanded Disability Status Scale, occurred in only 21% of patients over 5 years. No differences in disability progression were noted between the early and delayed treatment groups, according to the principal investigator, Dr. Giancarlo Comi, director of the department of neurology and Institute of Experimental Neurology at the University Vite Salute, San Raffaele, Italy.
“The long-term study results support the benefit of early GA treatment in delaying conversion to CDMS and in reducing MRI burden, including less accumulation of irreversible brain damage,” Dr. Comi said in an interview.
Patients in this 2-year extension phase were initially enrolled in the double-blind phase of PreCISe, and were randomized to receive active early treatment with GA or placebo. Findings from a planned interim analysis showed that treatment reduced the risk of CDMS by 44% versus placebo, and delayed disease progression by 722 days vs. 336 days. That phase was stopped after a mean exposure of 2.32 years, and patients were offered the opportunity to enter the open-label extension phase, during which all patients received treatment.
Early treatment reduced the risk of CDMS and delayed its onset when compared with placebo in the randomized phase of the trial but also was associated in the open-label extension phase with a delay of nearly 3 years in the time to conversion to CDMS when compared with delayed treatment.
MRI findings from the PreCISe study, which were presented in a separate session at ECTRIMS, also confirmed the importance of early treatment, according to the principal investigator for that portion of the study, Dr. Massimo Filippi, director of the Neuroimaging Research Unit and professor of clinical neurology at the Scientific Institute and University Ospedale San Raffaele, Milan, and his colleagues.
Early initiation of treatment with GA reduced disease activity and slowed the accumulation of brain atrophy over 5 years as demonstrated by MRI. The early treatment group had significantly fewer new T2 lesions – an indicator of disease activity – and lower T2 lesion volume – a predictor of disease progression – than did the delayed treatment group, the investigators found.
Percent brain volume change was also significantly lower over the entire study period in patients who received early treatment with GA (-0.99% vs. -1.27%), they said.
The drop-out rate in the 5 years of the PreCISe study was 33% among treated patients, which attests to the established long-term safety profile in patients with relapsing-remitting disease, Dr. Comi said.
“It is very difficult to compare Copaxone to other interferons studied in CIS due to the differences in the type of patients included in each study, but basically the results are comparable, although only Copaxone showed an effect on brain atrophy after 5 years,” Dr. Comi said. He added that the efficacy and safety results of this study establish the importance of early treatment with this drug in CIS patients presenting with positive brain MRI.
Chander Raman, Ph.D., an MS researcher and associate professor of clinical immunology and rheumatology at the University of Alabama at Birmingham, said the PreCISe findings confirm what neurologists have started to believe about managing CIS in adults – that treatment at the first clinical diagnosis of CIS is preferable for delaying full conversion.
“Hopefully in the near future there will be tools to determine if the patients with CIS should be treated with GA or interferon-beta,” he said.
In a study published earlier this year, Dr. Raman and his colleagues found that interferon-beta was effective in mice with experimental autoimmune encephalomyelitis, the animal model of MS, that was initiated by T helper type 1 cells. However, interferon-beta worsened disease that had been initiated by T helper type 17 cells (Nat. Med. 2010;16:406-12).