The following brief reports summarize some of the findings presented at the 5th Joint Triennial Congress of the European Committee for Treatment and Research in Multiple Sclerosis/Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS). Additional coverage of the ECTRIMS/ACTRIMS meeting can be found online at www.neurologyreviews.com and in upcoming issues of Neurology Reviews.
BG-12: Data From the Phase 3 DEFINE Trials
AMSTERDAM—Results from a large phase 3 trial support the potential of BG-12 (dimethyl fumarate) as an effective oral treatment for patients with relapsing-remitting multiple sclerosis (MS). According to researchers, BG-12 may have dual anti-inflammatory and neuroprotective effects via the Nrf2 pathway.
DEFINE was a randomized, double-blind, placebo-controlled, multicenter trial that evaluated the efficacy and safety of BG-12 over two years in patients with relapsing-remitting MS. Patients ages 18 to 55 with relapsing-remitting MS and an Expanded Disability Status Scale (EDSS) score of 0 to 5 (inclusive) were randomly assigned to placebo, BG-12 240 mg BID, or BG-12 240 mg TID.
All patients underwent clinical assessments at screening, baseline, and every four weeks for up to two years. The primary end point was proportion of patients relapsing at two years. Secondary efficacy end points at two years were annualized relapse rate and disability progression as measured by EDSS score.
A total of 1,234 patients were randomized—408 received placebo, 410 received BG-12 BID, and 416 received BG-12 TID. All primary and secondary end points were met. BG-12 BID and TID reduced the risk of relapse by 49% and 50%, respectively, compared with placebo at two years. Annualized relapse rate was 0.36 with placebo, and 0.17 and 0.19 with BG-12 BID and TID, corresponding to reductions of 53% and 48% for BG-12 BID and TID. The risk of confirmed 12-week disability progression was reduced by 38% for the BID dosing and by approximately 34% with TID dosing.
The overall incidence of adverse and serious adverse events was similar among the three groups.
Alemtuzumab: Phase 3 CARE-MS I Data Released
Results of a head-to-head comparison of alemtuzumab and interferon beta-1a have shown that 78% of patients with relapsing-remitting MS treated with alemtuzumab remained relapse-free for two years, compared with 58% of patients taking interferon beta-1a.
The phase 3 CARE-MS I trial compared alemtuzumab (12 mg/d IV for five days with a second 3-day IV administration one year later) to treatment with interferon beta-1a (44 mcg SC injection 3 times per week) in 581 patients with relapsing-remitting MS who had had no previous MS treatment except steroids.
Additional findings include other secondary end points that suggest positive outcomes with alemtuzumab. Improvement in the Multiple Sclerosis Functional Composite (MSFC) score was observed in alemtuzumab-treated patients compared with interferon beta-1a–treated patients (0.12 vs 0.05, mean change from baseline at year 2). Reduction in T2-hyperintense lesion volume with alemtuzumab compared to interferon beta-1a was -9.3 versus -6.5 (median percent change at year 2). Statistically significant improvement was observed for alemtuzumab versus interferon beta-1a in the percentage of patients with new enlarging T2-hyperintense lesions (49% vs 58%), with new gadolinium-enhancing lesions (15% vs 27%), and with new T1-hypointense lesions (24% vs 31%). Alemtuzumab-treated patients also experienced less change in brain parenchymal fraction compared to interferon beta-1a (-0.87 vs -1.49, median change from baseline).
Common adverse events associated with alemtuzumab in the CARE-MS I trial were infusion-associated reactions that were mild to moderate. The incidence of infection was increased, with the most common infections involving the upper respiratory and urinary tract and oral herpes. Infections were mild to moderate, and none were life-threatening or fatal.
Serious adverse events were similar between both groups (18.4% for alemtuzumab and 14.4% for interferon beta-1a). Just over 18% of alemtuzumab-treated patients developed an autoimmune thyroid-related adverse event, and 0.8% developed immune thrombocytopenia during the two-year study period. Cases of autoimmunity were detected and managed using conventional therapies.
Daclizumab: Phase 3 SELECT Trial Results Released
Monthly subcutaneous daclizumab monotherapy demonstrated a robust and clinically meaningful effect on MS activity, including evidence for early impact on disability progression, according to phase 3 data that were presented.
Researchers randomized 600 patients with relapsing-remitting MS and at least one MS relapse in the prior 12 months or one new gadolinium-enhancing lesion in the prior six weeks to receive low-dose daclizumab (150 mg), high-dose daclizumab (300 mg), or placebo as a subcutaneous injection once every four weeks for 52 weeks.
A total of 559 patients (93%) completed the treatment period. Annualized relapse rate, the study’s primary end point, was 0.21 for low-dose daclizumab, 0.23 for high-dose daclizumab, and 0.46 for placebo. The proportion of relapse-free patients was 81% in the low-dose group, 80% in the high-dose group, and 64% in the placebo group. There were significant reductions in the mean number of new or newly enlarging T2 lesions at one year (2.4 for low dose, 1.7 for high dose, and 8.1 for placebo). Among 309 patients in an MRI substudy, the mean number of new gadolinium-enhancing lesions between weeks 8 through 24 was 1.5 for low-dose daclizumab, 1.0 for the high-dose group, and 4.8 for placebo. The risk of three-month sustained disability progression at one year was reduced by 57% in the low-dose group and by 43% in the high-dose group.