Published results from two large, phase III clinical trials of BG-12 capsules (dimethyl fumarate, Biogen Idec) in people with relapsing-remitting MS
suggest that this experimental therapy significantly reduced relapses and disease activity as detected by MRI. In one trial, BG-12 also reduced disability progression. These results were previously reported at medical meetings, and lead authors Ralf Gold, MD (Ruhr-University Bochum) and Robert J. Fox, MD (Cleveland Clinic) and colleagues have now published complete results in The New England Journal of Medicine (2012; 367: 1087-97
). The U.S. Food and Drug Administration is currently reviewing an application for marketing approval for BG-12.
Multiple sclerosis involves immune system attacks against brain and spinal cord tissues. Although its exact mechanism of action is not known, BG-12, an oral drug, is thought to inhibit immune cells and molecules and may be protective against damage to the brain and spinal cord. A chemically related compound, called Fumaderm (dimethyl fumarate and fumeric acid esters), has been used for decades in Germany to treat psoriasis. Two large-scale phase III studies of the BG-12 capsule, called DEFINE and CONFIRM, were conducted in people with relapsing-remitting MS.
The DEFINE trial involved more than 1200 people and was designed to determine whether BG-12 could decrease the proportion of participants experiencing relapses compared to inactive placebo, and also looked its safety and tolerability. A total of 952 people completed the study. Secondary outcomes included the effects on the frequency of relapses, progression of disability, and disease activity detected by MRI.
Participants were randomly assigned to one of two treatment groups receiving different doses (240 mg twice each day and 240 mg three times each day), or a group receiving placebo. For both groups taking BG-12, the primary endpoint was met, meaning that there was a significant reduction in the proportion of people who experienced relapses at 2 years, compared with the placebo group (26% and 27% of those on BG-12, versus 46% on placebo, representing a 49% and 50% reduction in the risk of relapse versus placebo). All secondary endpoints were met as well in these groups, including significant reductions in annualized relapse rate (0.17 and 0.19 for BG-12 groups versus 0.36 for placebo, representing relative reductions of 48% and 53%), and reduction in the risk of confirmed progression of disability as detected by the EDSS, a standard scale that measures disability. The proportion of those who progressed over two years was 16% and 18% for BG-12 and 27% for placebo, representing a reduction of risk of disability of 38% (twice daily) and 34% (thrice daily) versus placebo. Both treatment groups also showed significantly fewer new, enlarging, or active (enhancing) MS lesions on MRI scans than those on placebo.
The primary goal of the CONFIRM study, which involved more than 1400 people, was to determine whether BG-12 could reduce the average annual MS relapse rate at two years. Secondary objectives included assessing effects on the proportion of people who had relapses, disability progression, and disease activity detected by MRI. Safety and tolerability were also assessed.
Participants were randomly assigned to one of two treatment groups receiving different oral doses (240 mg twice each day and 240 mg three times each day), a group receiving glatiramer acetate (Copaxone®, Teva Pharmaceutical Industries, an approved, injected therapy for MS) or a group receiving placebo. Both BG-12 groups and Copaxone were compared to the placebo groups, but the study was not designed to compare BG-12 and Copaxone.
Results showed that the primary endpoint was met; the average number of MS relapses in a year was reduced by 44% versus placebo in the twice daily group, 51% in the thrice daily group, and 29% in the Copaxone group (annual rates of relapses per year were 0.22 for the twice-daily group, 0.20 for thrice-daily group, 0.29 for Copaxone, and 0.40 for placebo). Results in secondary endpoints included significant reductions in disease activity on MRI and the proportion of patients experiencing relapses in the BG-12 groups versus placebo. Disability progression was not reduced significantly in the BG-12 groups compared to the placebo group.
Safety During BG-12 Trials:
The most common adverse events in the BG-12 groups were flushing and gastrointestinal events (such as diarrhea, nausea, and upper abdominal pain). BG-12 reduced blood lymphocyte (white blood cell) counts but no opportunistic infections were reported. Liver enzyme tests were elevated in the DEFINE study, but there were no reports of significant liver injury or liver failure.
Based on these positive studies, Biogen Idec has submitted an application to the U.S. FDA for marketing approval of BG-12 as a treatment for relapsing MS. The FDA’s review of these results and other data should help define the safety and promise of this as a potential new oral therapy for relapsing MS. A decision by the FDA is expected in spring of 2013.
Copaxone is a registered trademark of Teva Pharmaceutical Industries.