Elsevier

The Lancet

Volume 372, Issue 9648, 25–31 October 2008, Pages 1463-1472
The Lancet

Articles
Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study

https://doi.org/10.1016/S0140-6736(08)61619-0Get rights and content

Summary

Background

Oral fumarate (BG00012) might have dual anti-inflammatory and neuroprotective effects. Our aim was to assess the efficacy and safety of BG00012 in patients with relapsing-remitting multiple sclerosis.

Methods

257 patients, aged 18–55 years, with relapsing-remitting multiple sclerosis were randomly assigned to receive 120 mg once daily (n=64), 120 mg three times daily (n=64), or 240 mg three times daily (n=64) BG00012, or placebo (n=65) for 24 weeks. During an extension period of 24 weeks for safety assessment, patients treated with placebo received BG00012 240 mg three times daily. The primary endpoint was total number of new gadolinium enhancing (GdE) lesions on brain MRI scans at weeks 12, 16, 20, and 24. Additional endpoints included cumulative number of new GdE lesions (weeks 4–24), new or enlarging T2-hyperintense lesions, new T1-hypointense lesions at week 24, and annualised relapse rate. Analysis was done on the efficacy-evaluable population. Safety and tolerability were also assessed. This study is registered with ClinicalTrials.gov, number NCT00168701.

Findings

Treatment with BG00012 240 mg three times daily reduced by 69% the mean total number of new GdE lesions from week 12 to 24 compared with placebo (1·4 vs 4·5, p<0·0001). It also reduced number of new or enlarging T2-hyperintense (p=0·0006) and new T1-hypointense (p=0·014) lesions compared with placebo. BG00012 reduced annualised relapse rate by 32% (0·44 vs 0·65 for placebo; p=0·272). Adverse events more common in patients given BG00012 than in those given placebo included abdominal pain, flushing, and hot flush. Dose-related adverse events in patients on BG00012 were headache, fatigue, and feeling hot.

Interpretation

The anti-inflammatory effects and favourable safety profile of BG00012 warrant further long-term phase III studies in large patient groups.

Funding

Biogen Idec, Inc.

Introduction

BG00012, an oral formulation of dimethyl fumarate, might have novel and complex effects on the pathobiology of multiple sclerosis. Preclinical experiments have shown that dimethyl fumarate and its primary metabolite monomethyl fumarate can activate the nuclear-factor-E2-related factor-2 (Nrf2) transcriptional pathway,1 which controls phase-2 detoxifying enzyme gene expression, and is crucial for oxidative stress response and immune homoeostasis.2, 3, 4 Activation of the Nrf2 pathway defends against oxidative-stress-induced neuronal death,5, 6, 7, 8 protects the blood–brain barrier,9 and supports maintenance of myelin integrity10 in the CNS. Dimethyl fumarate induces expression of phase-2 detoxification enzymes in astroglial and microglial cells.11 It also inhibits expression of cytokines and adhesion molecules implicated in the inflammatory response in vitro.11, 12, 13 These data suggest that BG00012 could have dual neuroprotective and anti-inflammatory effects.

An oral formulation of fumaric acid (Fumaderm, Biogen Idec Gmbh, Ismaning, Germany) showed effectiveness in patients with chronic plaque psoriasis, a disorder associated with immune dysfunction.14 In a pilot study in patients with relapsing-remitting multiple sclerosis, this formulation also reduced the number and volume of gadolinium enhancing (GdE) lesions on brain MRI scans compared with baseline.15 On the basis of these preliminary findings, we have tested the efficacy and safety of three doses of BG00012 versus placebo in a multicentre, randomised, double-blind, placebo-controlled, dose-ranging, phase IIb study in patients with relapsing-remitting multiple sclerosis.

Section snippets

Patients

257 patients were recruited from 43 centres in the Czech Republic, Germany, Hungary, Netherlands, Poland, Russia, Sweden, Switzerland, Turkey, and UK, between Nov 24, 2004, and March 31, 2005. Participants were aged 18–55 years with a diagnosis of relapsing-remitting multiple sclerosis by McDonald criteria,16 a baseline Expanded Disability Status Scale (EDSS) score between 0 and 5,17 and either at least one relapse within 12 months of randomisation and a previous cranial MRI scan showing

Results

257 patients were randomly assigned to receive BG00012 120 mg once daily, or 120 mg or 240 mg three times daily, or placebo. One patient, who was randomly assigned to the highest dose of BG00012, withdrew before receiving the drug (figure 2). Patients were well-matched for demographic and baseline disease characteristics (table 1). The mean number of baseline GdE lesions was higher for the BG00012 120 mg three times daily group than for all other treatment groups (table 1).

During the first 24

Discussion

We showed that treatment with BG00012 240 mg three times daily reduces brain MRI activity in patients with relapsing-remitting multiple sclerosis. Treatment with the highest BG00012 dose studied reduced by 69% the mean number of new GdE lesions from scans at weeks 12 to 24 compared with treatment with placebo. Patients in the BG00012 120 mg three times daily group had a higher baseline GdE lesion count compared with other treatment groups, which explained the absence of a more pronounced

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