MS Therapies in the Pipeline:

     Rocky Mountain MS Center, eMS News, June 2009

  BG-12 (dimethyl fumarate) is the fifth emerging oral therapy in our eMS series and, similar to the agents previously mentioned, is also poised to change the landscape of MS treatment.  Now in late stage (Phase III) clinical trials, BG-12 has thus far demonstrated encouraging results and minimal side affects. It could, along with laquinimod and oral cladribine, soon be headed to the FDA for approval.

     BG-12, an oral fumarate derivative, has been shown to activate the Nrf2 transcriptional pathway – the first compound to do so.  This pathway is thought to defend against oxidative-stress induced neuronal death, protect the blood-brain barrier, and support maintenance of myelin integrity in the central nervous system – all key elements to treating MS. According to Dr. Vollmer, in addition to its use as individual therapy, the activation of this pathway may make BG12 – if approved – a potential candidate for combination therapy as well.

     In October 2008, results from a Phase II study were published.  The study concluded in 2006 and involved 257 participants with relapsing remitting MS in 10 European countries.  For six months, patients received a 120 mg, 360 mg, or 720 mg dose per day of BG-12, or a placebo.

    The recently published study results are encouraging.  Those receiving the 720 mg dose had much less disease activity compared with those receiving placebo as measured by MRI changes.  Those receiving a lower dose did not differ from those receiving placebo.

     More specifically, between weeks 12 and 24, study participants who received the 720 mg dose (240 mg three times a day) demonstrated a 69 percent reduction in new active gadolinium-enhancing lesions compared to placebo; cumulatively, a 44 percent reduction in new active lesions was demonstrated versus placebo.  The data also showed a 53 percent reduction in T1-hypointense lesions ("black holes"), which are generally thought to represent areas of axonal damage.

     Additionally, those participants who received the 720 mg dose demonstrated 48 percent reduction in new or newly enlarging T2-hyperintense lesions, and 63 percent of BG-12 patients showed no new T2 lesions. T2 lesions are generally considered to be markers of overall disease activity.

     Clinically, the group receiving the higher dose of BG-12 had fewer relapses than the group receiving placebo, but this trial was not designed to be definitive in measuring clinical outcomes.  The larger studies that are currently underway should clarify whether BG-12 produces meaningful reductions in relapses or disability progression.

     Study side-effects included flushing, gastrointestinal disorders, headache, nausea and nasal inflammation.  The infection rate among those on BG-12 was the same as among participants on placebo, and thus far the emerging safety profile is rather positive.

     BG-12 is now in the midst of two Phase III trials known as the DEFINE study and the CONFIRM study, both of which will last two years.  The studies aim to evaluate the efficacy of BG-12, specifically its effect on measurements of clinical relapse and disability progression.  The DEFINE study involves 1,011 patients at 160 different sites in North America, Europe and other parts of the world.

     The other study, CONFIRM, will compare two different doses of BG-12 or injections of Copaxone, against placebo.  The goal is to assess the efficacy of the oral therapy compared to currently used injectable therapies, in this case Copaxone.  The study involves1,232 patients at 175 sites in North America, Europe and other parts of the world. 

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