Megan Brooks and Susan Jeffrey

October 21, 2011

October 21, 2011 (Amsterdam, the Netherlands) — A phase 3 study of oral BG-12 (dimethyl fumarate, Biogen Idec) in relapsing-remitting multiple sclerosis (MS) found that the drug reduced by roughly half the proportion of patients who relapsed at 2 years compared with placebo.

The findings, from the Determination of the Efficacy and safety of oral Fumarate IN rElapsing-remitting MS (DEFINE) trial were released today here at the 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS). The study was supported by Biogen Idec.

"We conclude that these results may provide a therapeutic option for patients with relapsing MS, with robust efficacy, a good tolerability, and excellent safety profile for this oral drug," study presenter Ralf Gold, MD, professor and chair, Department of Neurology, St. Josef-Hospital/Ruhr-University, Bochum, Germany, told attendees here.

Dr. Ralf Gold

The BG-12 results are "big news," at the conference, Jeffrey Cohen, MD, from the Cleveland Clinic in Ohio, told Medscape Medical News. "BG-12 showed good efficacy, safety, and tolerability. These results are very encouraging," added Dr. Cohen, who was not involved in the study.

Novel Mechanism of Action

BG-12 is believed to have dual anti-inflammatory and neuroprotective effects via the Nrf2 pathway. In a phase 2b trial, it reduced inflammatory activity in patients with relapsing-remitting MS. BG-12 received fast-track designation from the US Food and Drug Administration in 2008.

Top-line results from the study were released in April and reported by Medscape Medical News at that time.

DEFINE was a global, randomized, double-blind, placebo-controlled, dose-comparison study to determine the efficacy and safety of oral BG-12 in more than 1234 patients aged 18 to 55 years with McDonald criteria diagnosis of relapsing-remitting MS and an Expanded Disability Status Scale score of 0.0 to 5.0.

The patients were randomly assigned to receive placebo (n = 408), BG-12 twice daily (n = 410), or BG-12 3 times daily (n = 416).

The results showed that both BG-12 twice or 3 times daily met the primary and all secondary study endpoints, demonstrating a highly statistically significant reduction (P < .0001) in the proportion of patients who relapsed at 2 years compared with placebo.

Treatment with BG-12 also reduced annualized relapse rates and the risk for disability progression, as measured by the Expanded Disability Status Scale score at 2 years.

Table 1. Outcomes With BG-12 vs Placebo

Outcome BG-12 Twice Daily BG-12 Three Times Daily
Cumulative probability of relapse (95% confidence interval [CI]) 0.51 (0.40 - 0.66) 0.50 (0.39 - 0.65)
Annualized relapse rates (% reduction vs placebo) 53% 48%
Time to 12-week confirmed disability progression (95% CI) 0.62 (0.44 - 0.87) 0.66 (0.48 - 0.92)

Imaging and Safety Data

As part of the DEFINE study, magnetic resonance imaging (MRI) scans were obtained at baseline, 24 weeks, 1 year, and 2 years to determine the number of T2 hyperintense lesions, gadolinium-enhancing lesions, and T1 hypointense lesions (a tertiary endpoint).

At 2 years, BG-12 twice daily and 3 times daily reduced the mean number of new or newly enlarging T2 hyperintense lesions by 85% and 74%, respectively; reduced the mean number of gadolinium-enhancing lesions by 90% and 73%, respectively; and reduced the mean number of new T1 hypointense lesions by 72% and 63%, respectively (P < .0001 for all comparisons).

The overall incidence of adverse events, serious adverse events, and adverse events leading to study discontinuation was similar among the BG-12 and placebo groups, the investigators report.

Adverse events were reported by roughly 95% of study participants, irrespective of group. The most frequently reported adverse events across the 3 study groups were flushing, MS relapse, nasopharyngitis, headache, diarrhea, and fatigue. These events were more common with BG-12 than with placebo, with the highest incidence in the first 30 days of treatment and decreasing thereafter.

Table 2. Adverse Events

Adverse Event BG-12 Placebo
Flushing (%) 35 5
Diarrhea (%) 17 13
Nausea (%) 13 9
Upper abdominal pain (%) 11 7
Abdominal pain (%) 10 5

Serious adverse events were reported in 21% of patients receiving placebo and 17% of patients receiving BG-12. The most frequently reported serious adverse event across all treatment groups was MS relapse (15% placebo; 9% BG-12). There were no deaths related to study treatment. There was no increase in infections, serious infections, opportunistic infections, or malignancies.

"Based on patient-reported measures, BG-12 significantly improved physical functioning and general well-being," the investigators say.

Top-line data from a second phase 3 study of BG-12 called CONFIRM are expected later this year. This study compares BG-12 and an active comparator, glatiramer acetate, against placebo on clinical relapse, MRI measures of MS, progression of disability, and safety.

Different Pathways

Asked for comment on these findings, Giancarlo Comi, MD, PhD, director of the Department of Neurology and Institute of Experimental Neurology at the Scientific Institute and University Vita-Salute San Raffaele in Milan, Italy, pointed out that because the data are new, they will take some time to digest.

"Nevertheless, what we have seen is very good effects on relapses, on lesions — so the ability to protect from the new lesions — and this is translated into an effect on disability," he told Medscape Medical News.

Dr. Comi pointed out, however, that although there was about a 50% reduction in relapses with BG-12, the reduction of disability was about 30%. Laquinimod, another oral agent that his own group has been involved with investigating, and new data on which are also being presented here tomorrow, appears to have about a 20% reduction of relapses, but a 30% reduction in disability, so the 2 groups of patients end up in a comparable condition at 2 years from the point of view of disability. It may be, then, that the drugs are taking "2 different pathways to reach the same final pathway."

"What we don't have now is information about the MRI burden," he noted. BG-12 had a very good effect on relapse rates and lesions, but it is not clear what is happening outside the lesions in the normal brain tissue, which, it is becoming more and more clear, is critical to maintaining function in the face of the disease course. "We don't have atrophy measures, so for the complete picture, we have to wait."

The DEFINE study was supported by Biogen Idec Inc. Dr. Gold has disclosed having received honoraria from Bayer Health Care, Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience and research support from Bayer Health Care, Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience. Several of the authors are employees of Biogen Idec. Dr. Cohen has disclosed financial relationships with Sanofi-Aventis and other companies that make therapies for MS. Dr. Comi reports receiving consulting fees and honoraria from Serono Symposia International Foundation, Merck Serono, Novartis, Teva Pharmaceutical Industries Ltd, Sanofi-Aventis, Bayer Schering, and Biogen Dompé.

5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS): Abstracts 95, P1071, P831, P994. Presented October 21, 2011.

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