Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis.

Abstract

BACKGROUND:

BG-12 (dimethyl fumarate) is in development as an oral treatment for relapsing-remitting multiple sclerosis, which is commonly treated with parenteral agents (interferon or glatiramer acetate).

METHODS:

In this phase 3, randomized study, we investigated the efficacy and safety of oral BG-12, at a dose of 240 mg two or three times daily, as compared with placebo in patients with relapsing-remitting multiple sclerosis. An active agent, glatiramer acetate, was also included as a reference comparator. The primary end point was the annualized relapse rate over a period of 2 years. The study was not designed to test the superiority or noninferiority of BG-12 versus glatiramer acetate.

RESULTS:

At 2 years, the annualized relapse rate was significantly lower with twice-daily BG-12 (0.22), thrice-daily BG-12 (0.20), and glatiramer acetate (0.29) than with placebo (0.40) (relative reductions: twice-daily BG-12, 44%, P<0.001; thrice-daily BG-12, 51%, P<0.001; glatiramer acetate, 29%, P=0.01). Reductions in disability progression with twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate versus placebo (21%, 24%, and 7%, respectively) were not significant. As compared with placebo, twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate significantly reduced the numbers of new or enlarging T(2)-weighted hyperintense lesions (all P<0.001) and new T(1)-weighted hypointense lesions (P<0.001, P<0.001, and P=0.002, respectively). In post hoc comparisons of BG-12 versus glatiramer acetate, differences were not significant except for the annualized relapse rate (thrice-daily BG-12), new or enlarging T(2)-weighted hyperintense lesions (both BG-12 doses), and new T(1)-weighted hypointense lesions (thrice-daily BG-12) (nominal P<0.05 for each comparison). Adverse events occurring at a higher incidence with an active treatment than with placebo included flushing and gastrointestinal events (with BG-12) and injection-related events (with glatiramer acetate). There were no malignant neoplasms or opportunistic infections reported with BG-12. Lymphocyte counts decreased with BG-12.

CONCLUSIONS:

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. (Funded by Biogen Idec; CONFIRM ClinicalTrials.gov number, NCT00451451.).

• Authors: Robert J Fox, David H Miller, J Theodore Phillips, Michael Hutchinson, Eva Havrdova, Mariko Kita, Minhua Yang, Kartik Raghupathi, Mark Novas, Marianne T Sweetser, Vissia Viglietta, Katherine T Dawson, CONFIRM Study Investigators
• Journal: The New England journal of medicine (N Engl J Med) Vol. 367 Issue 12 Pg. 1087-97 (Sep 20 2012) ISSN: 1533-4406 [Electronic] United States
• PMID: 22992072 (Publication Type: Clinical Trial, Phase III, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Fumarates
• Immunosuppressive Agents
• Peptides
• Glatiramer Acetate
• Dimethyl Fumarate

Topics

• Administration, Oral
• Adult
• Brain (pathology)
• Dimethyl Fumarate
• Double-Blind Method
• Female
• Fumarates (administration & dosage, adverse effects, therapeutic use)
• Glatiramer Acetate
• Humans
• Immunosuppressive Agents (administration & dosage, adverse effects, therapeutic use)
• Infections (etiology)
• Intention to Treat Analysis
• Magnetic Resonance Imaging
• Male
• Middle Aged
• Multiple Sclerosis, Relapsing-Remitting (drug therapy, pathology)
• Peptides (adverse effects, therapeutic use)