Oral BG-12 or Glatiramer Acetate for Multiple Sclerosis

Parenteral agents (interferon beta and glatiramer acetate) are common treatments for multiple sclerosis (MS), a chronic demyelinating and neurodegenerative disease of the central nervous system. According to researchers, oxidative stress and proinflammatory stimuli are important pathologic factors in MS. It has been suggested that BG-12, an oral formulation of dimethyl fumarate, has anti-inflammatory and cytoprotective properties that are mediated through activation of the nuclear factor-like 2 transcriptional pathway, among others.

Researchers recently conducted the CONFIRM (Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis) trial to assess the efficacy and safety of oral BG-12, at a dose of 240 mg two or three times daily, compared with placebo. Glatiramer acetate, an active agent, was included as a reference comparator. The researchers reported trial results in the New England Journal of Medicine [2012;367(12):1087-1097].

CONFIRM was a phase 3, randomized, multicenter, double blind, 2-year study. The primary end point was the annualized relapse rate over a 2-year period. The study was not designed to assess the superiority or noninferiority of BG-12 versus glatiramer acetate, the researchers noted. Funding support was provided by Biogen Idec.

Eligibility criteria included a diagnosis of relapsing-remitting MS, 18 to 55 years of age, a score of 0 to 5 on the Expanded Disability Status Scale (range 1-10, with higher scores indicating greater disability), and at least 1 clinically documented relapse in the previous 12 months or at least 1 gadolinium-enhancing lesion 0 to 6 weeks prior to randomization. Exclusion criteria included progressive forms of MS, other clinically significant illness(es), prespecified laboratory abnormalities, and prior exposure to glatiramer acetate or contraindicated medications.

Patients at 200 sites in 28 countries were randomly assigned in a 1:1:1:1 ratio to receive oral placebo, BG-12 at a dose of 240 mg 2 times daily, BG-12 at a dose of 240 mg 3 times daily, or subcutaneous daily injections of 20 mg of glatiramer acetate for 96 weeks. Patients in the glatiramer acetate group were aware of their assignment to that group.

In all, 1430 patients were randomized; of those, 1417 were included in the intent-to-treat population. At baseline, demographic and disease characteristics were similar among the 4 groups. Approximately 29% of patients had received an approved disease-modifying therapy prior to study entry.

The twice-daily and thrice-daily BG-12 dosages significantly reduced the frequency of MS relapses, with an adjusted annualized relapse rate at 2 years of -.22 and 0.20, respectively. The reductions relative to placebo were 44% and 51% (P<.001 for both comparisons). The annualized relapse rate was also reduced with glatiramer acetate (relative reduction 29% vs placebo; P=.01).

Compared with placebo, BG-12 (at both doses) and glatiramer acetate significantly reduced the risk of relapse by 34% (BG-12 twice daily, P<.001), 45% (BG-12 thrice-daily, P<.001), and 29% (glatiramer acetate, P=.01). There was no significant difference in disability progression among the 4 groups.

The overall incidence of adverse events was similar across study groups. Compared with placebo, there were more adverse events reported in the BG-12 groups, including flushing, gastrointestinal events, upper respiratory tract infections, and erythema. For flushing, including events of flushing and hot flush, the incidence was 35% with BG-12 twice daily, 28% with BG-12 thrice daily, 6% with placebo, and 3% with glatiramer acetate. For gastrointestinal events, the incidence was 36%, 41%, 26%, and 15%, respectively. Flushing and gastrointestinal events were of mild or moderate severity for most patients.

In conclusion, the researchers stated, “In patients with relapsing-remitting multiple sclerosis, BG-12 (at both doses) and glatiramer acetate significantly reduced relapse rates and improved neuroradiologic outcomes relative to placebo.”