AMSTERDAM – Treatment with the investigational oral drug dimethyl fumarate reduced the risk of relapse by up to 50%, compared with placebo, in patients with relapsing–remitting multiple sclerosis in a phase III trial.
In the multicenter, randomized, double-blind trial of 1,234 patients, placebo-treated patients had a cumulative probability of relapse of 46% at 2 years, which was significantly higher than the rates of 27% and 26% recorded in patients who received dimethyl fumarate at 240 mg twice daily or 240 mg three times daily, respectively. These rates for the primary end point of the trial corresponded to hazard ratios for relapse of 0.51 and 0.50, respectively.
Those 2-year relapse rates translated to annualized relapse rates of 0.364 for placebo and 0.172 for 240 mg dimethyl fumarate twice daily and 0.189 for 240 mg three times daily.
The possibly of using a fumaric acid ester (FAE) such as dimethyl fumarate (also known as BG-12) in the treatment for MS was first suggested about 10 years ago, although FAEs have been used for the treatment of psoriasis for some years in Europe, said Dr. Ralf Gold of St. Josef and St. Elizabeth Hospital in Bochum, Germany. He presented the results of the DEFINE (Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS) study at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).
BG-12 is thought to defend the brain against oxidative stress and recent experimental evidence suggests that it may have dual effects – acting as both an anti-inflammatory and as a neuroprotective agent (Brain 2011;134:678-92).
Findings from a phase II study of BG-12 showed that it reduced MRI-detected disease activity in MS by about 69% from week 12 to 24, compared with placebo (Lancet 2008;372:1463-72), but the current findings from DEFINE suggest a greater reduction in MRI lesions may be possible.
Dr. Gold reported data from an MRI substudy of DEFINE that involved 540 patients. BG-12 was associated with a 73%-98% reduction in gadolinium-enhancing (GdE) lesions and a 74%-85% reduction in new or newly enlarging T2 hyperintense lesions on MRI at 2 years, depending on the dosing regimen used.
Coinvestigator Dr. Douglas Arnold of the Montreal Neurological Institute and Hospital at McGill University commented in an interview that these MRI results are impressive if you consider what can be achieved with other therapies.
"I think everybody was pleasantly surprised at how effective [BG-12] was on the MRI," Dr. Arnold said. "The suppression of the GdE lesions is 90% – that’s a stronger effect than any medication that’s available currently for the treatment for MS." The reduction of GdE lesions is as low as 30% for some agents, although it as high as 89% for others such as natalizumab (Tysabri), he said.
BG-12 reduced the risk of disability progression at 12 weeks by 38% with twice daily dosing and by 34% with three times daily dosing as measured by scores on the Expanded Disability Status Scale.
The safety and tolerability of BG-12 did not appear to differ greatly from placebo. Serious adverse events were reported in fewer BG-12 than placebo-treated patients (16%-18% vs. 21%), with two deaths – both unrelated to treatment – occurring in the BG-12 groups.
Flushing and gastrointestinal adverse events were reported more frequently in the BG-12 groups, although Dr. Gold observed that most cases of flushing were mild or moderate in severity and their incidence decreased substantially after the first month of treatment. Opportunistic infections were seen only in placebo-treated patients, and there was no increased risk of other serious infections or malignancies with BG-12.
MS patients who took BG-12 also benefited from higher quality of life scores after 2 years on physical and mental functioning, as well as higher general well-being scores, than did patients who received placebo.
In addition to efficacy, the safety of BG-12 in the study is reassuring, Dr. Paul O’Connor, director of the MS Clinic at St. Michael’s Hospital in Toronto, said in an interview. He noted that data from a second ongoing phase III trial, called CONFIRM, would be needed before any firm conclusions could be drawn. CONFIRM is comparing BG-12 with an active comparator, glatiramer acetate (Copaxone).
"The safety data are very encouraging because there have been various new treatments over the past 4 or 5 years that looked to have a more powerful effect than our conventional treatments, but all of them have come with significant safety problems," Dr. Neil Scolding of the University of Bristol (United Kingdom), said in an interview.