BG-12 Shows Clinical, Neuroradiologic Efficacy in U.S. Patients with Relapsing-Remitting Multiple Sclerosis

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Oral dimethyl fumarate (BG-12) is in development for the treatment of relapsing multiple sclerosis (MS), though experimental evidence already suggests it may provide anti-inflammatory and cytoprotective effects by activating the transcription factor Nrf2. BG-12 demonstrated both clinical and neuroradiologic efficacy over two years in the DEFINE and CONFIRM phase 3 clinical trials in patients with relapsing-remitting multiple sclerosis (RRMS). A pre-specified integrated analysis plan — which included analysis by region — was conducted to obtain more precise estimates of the treatment’s effects than what could be achieved by analyzing separate data from each study. In the Multiple Sclerosis: Clinical Trials Outcomes poster session at the American Academy of Neurology (AAN) 2013 Annual Meeting, Mariko Kita, MD, irectorVirginia Mason Multiple Sclerosis Center, Seattle, reported on the efficacy of BG-12 in U.S. patients with RRMS from the pre-specified integrated analysis of DEFINE and CONFIRM trial data. Kita and her collaborators in various U.S. centers outlined the eligibility criteria, which included ages 18 to 55 years old, a diagnosis of RRMS per revised McDonald criteria, and an Expanded Disability Status Scale (EDSS) score of 0 to 5.0. In both trials, patients were randomized to 240 milligrams of BG-12 twice daily (BID), BG-12 three times daily (TID) or placebo. In the DEFINE study, the primary endpoint was the proportion of relapsed patients, and in the CONFIRM trial, it was the annualized relapse rate at two years.

The overall, integrated intent-to-treat (ITT) population comprised of 2,301 patients. Of that study group, 403 U.S. patients were assigned either to BG-12 BID (N=130), to BG-12 TID (N=136) or placebo (N=137). They included a cohort of 193 patients at sites with MRI capabilities assigned to the treatment groups, as follows: TID (N=65), BID (N=60) or placebo (N=68). The baseline demographics and disease characteristics of the U.S. trial population were balanced across treatment groups and similar to those in the integrated analysis ITT population, with the exception that more U.S. patients had received prior MS treatment than patients in the overall ITT population (63 percent versus 35 percent). In the U.S. population at two years, BG-12 reduced the annualized relapse rate versus placebo by 44 percent (BID) and 27 percent (TID), and it reduced the proportion of relapsed patients by 42 percent (BID) and 40 percent (TID), Kita said in her presentation. Similarly, at two years, BG-12 consistently reduced the number of gadolinium-enhancing, new or enlarging T2 hyperintense lesions and new T1 hypo-intense MRI lesions compared to placebo. The difference between BG-12 and placebo effects ranged from 62 percent to 87 percent, depending on the BG-12 dose and the MRI procedure. Kita and the other U.S.-based investigators concluded that patients participating in the DEFINE and CONFIRM phase 3 studies derived clinical and neuroradiologic benefit from treatment with BG-12 relative to placebo. They pointed out that findings in the U.S. subgroup mirrored results from the integrated analysis of all data from the combined DEFINE and CONFIRM study populations. That suggests the efficacy of BG-12 is consistent across subpopulations of patients.