BG-12: New Oral Medication for Relapsing-remitting MS
BG-12: New Oral Medication for Relapsing-remitting MS
Abstract & Commentary
By Jai S. Perumal, MD. Assistant Professor of Neurology, Weill Cornell Medical College. Dr. Perumal is a consultant for Biogen Idec and Genzyme, and is on the speakers bureau for Teva and Biogen Idec.
Synopsis: Two recently reported Phase 3 trials for BG-12 demonstrated efficacy and safety in the treatment of relapsing-remitting multiple sclerosis.
Sources: Gold et al, for the DEFINE Study Investigators. Placebo-controlled Phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012;367:1098-1107.
Fox et al, for the CONFRIM Study Investigators. Placebo-controlled Phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012;367:1087-1097.
Bg-12, an oral immunomodulating agent, is a fumaric acid ester, the active compound of which is dimethyl-fumarate. Fumaric acid esters have been used for many years in Germany for the treatment of psoriasis. Although the exact mechanism of action is unclear, BG-12 is believed to have anti-inflammatory and antioxidative effects. After potential benefits in preclinical experiments and subsequent clinical trials in multiple sclerosis (MS), BG-12 underwent investigation in two large Phase 3 trials.
DEFINE (Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS Study) was a 2-year, placebo-controlled, double-blind, multicenter trial in which 1237 patients were randomized to BG-12 240 mg twice a day, BG-12 240 mg three times a day, or placebo in a 1:1:1 fashion. The study population was relapsing-remitting MS patients between the ages of 18 and 55 years who met the inclusion/exclusion criteria. The primary endpoint was the proportion of patients who had a relapse by 2 years. Twenty-seven percent of the patients in the BG-12 twice daily group and 26% in the BG-12 three times daily group had a relapse at 2 years compared to 46% in the placebo group (P < 0.001 for both comparisons). BG-12 met several secondary endpoints as well. The relative risk reduction for disability progression compared to placebo was 38% for the BG-12 twice daily group and 34% for BG-12 three times a day group, respectively. Both BG-12 groups were significantly superior to placebo in all the MRI endpoints, including new or enlarging T2-weighted lesions and number of gadolinium-enhancing lesions at 2 years.
CONFRIM (Comparator and Oral Fumarate in Relapsing-Remitting Multiple Sclerosis) was a 2-year multicenter, double-blind trial where patients were randomized in a 1:1:1:1 manner to BG-12 240 mg twice a day, BG-12 240 mg three times a day, glatiramer acetate 20 mg SQ once a day, or placebo. The glatiramer acetate arm was a reference comparator and the study was not designed to show a superiority or noninferiority of BG-12 over glatiramer acetate. In this study, 1430 patients were randomized and the primary endpoint was the annualized relapse rate (ARR) over 2 years. The ARR was 0.22 in the BG-12 twice daily, 0.20 in the BG-12 three times a day group, 0.29 in the glatiramer acetate group, and 0.40 in the placebo group. The ARR reduction was statistically significant for all treatment arms when compared to placebo (P < 0.001). The reduction in disability progression was not statistically significant in this study. All the treatment groups had a significantly reduced number of new or enlarging T2-weighted lesions, odds of having more gadolinium enhancing lesions, and new T1-weighted lesions on MRI when compared to placebo.
The overall incidence of adverse events was similar in the treatment arms and placebo in both studies. Adverse events that were more frequent with BG-12 were predominantly flushing and gastrointestinal symptoms including diarrhea, nausea, and abdominal pain seen in about 40% of patients on BG-12. The incidence of these events was highest in the first month with a significant decrease after that. There were no instances of life-threatening or opportunistic infections or malignancies. There was a mean drop in white blood cell counts and lymphocyte count in the BG-12 groups that plateaued at first year, but the mean values remained within the normal range. There was also an increased incidence of elevated liver enzymes within the first 6 months of starting BG-12.
Commentary
BG-12 is an oral agent that has continued to demonstrate significant efficacy in the treatment of relapsing-remitting MS. There were no major safety concerns and no life-threatening or opportunistic infections or malignancies. BG-12 appears to have a good benefits-risk profile. As an oral medication, it also offers ease of administration and potentially increased adherence to recommended dosing. However, the incidence of flushing and gastrointestinal symptoms was about 40%, so tolerability within the first few weeks of use would need to be considered. Measures to mitigate the frequency and severity of flushing and gastrointestinal symptoms associated with its use are being explored. Overall, BG-12 has demonstrated a good safety profile, shows significant efficacy in relapsing-remitting MS, and will be an exciting new addition to the armamentarium. It is currently under FDA review and is expected to be available by early 2013.
Two recently reported Phase 3 trials for BG-12 demonstrated efficacy and safety in the treatment of relapsing-remitting multiple sclerosis.Subscribe Now for Access
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