Multiple sclerosis disease activity reduced after taking oral fumarate

An article published in The Lancet reports successful results from a phase II trial for oral fumarate (BG00012). The drug was found to significantly reduce disease activity linked to relapsing-remitting multiple sclerosis (RRMS) that was detected by Magnetic Resonance Imaging (MRI). A phase III trial is underway and the researchers are awaiting the results.

Multiple sclerosis (MS) is an autoimmune disease characterised by the immune system's attacking of the central nervous system. This usually leads to the deterioration of the myelin sheath (the electrically-insulating protective layer that surrounds the axons of neurons) followed by physical and cognitive disability. One marker of inflammatory activity in MS patients, on which this recent study focused, is gadolinium enhanced (GdE) lesions in the brain. In addition, researchers looked at T2-hyperintense and T2-hypointense lesions.

Professor Ludwig Kappos (University Hospital Basel, Switzerland) and colleagues studied the immunomodulatory (immune system changing) and direct neuroprotective effect of the oral fumarate BG00012. A sample of 257 RRMS patients (18 to 55 years old) participated in the randomised placebo-controlled trial. The patients were randomly assigned such that 65 patients received placebo and 64 patients each were assigned to a group that received BG00012 120 mg once daily, 120 mg three times daily, or 240 mg three times daily for a 24 week period. The main focus of the researchers was the total number of new GdE lesions on brain MRI scans after 12, 16, 20, and 24 weeks. In addition, the researchers monitored new or enlarging T2-hyperintense lesions, new T1-hypointense lesions after 24 weeks, and the patients' annualised relapse rates. Finally, the researchers included an analysis of safety and tolerability.

Kappos and colleagues report a 69% lower average total number of new GdE lesions from week 12 to 24 in participants who received BG00012 240 mg 3 times compared to those who received placebo. Similarly the fumarate treatment lowered the number of new or enlarging T2-hyperintense and T1-hypointense lesions after 24 weeks. The difference in relapse rate was lower but not significant for participants who received BG00012. Although the treatment seemed to reduce the number of lesions, patients who received BG00012 experienced more adverse events such as abdominal pain and hot flush. Higher doses of BG00012 led to more headaches, fatigue, and hot feelings.

"Longer-term (phase III) studies of BG00012 in larger patient populations are underway to define its place in the future of relapsing-remitting multiple sclerosis treatment," conclude the researchers. "If these studies show similar relapse rate reductions with BG00012, interferon beta, and glatiramer acetate, BG00012 could be a suitable initial treatment for relapsing-remitting multiple sclerosis. Because of the convenience of an orally administered product, BG00012 could also be an alternative for patients who cannot tolerate or choose not to initiate injectable therapies because of injection-related effects or anxiety. The potentially unique mode of action of BG00012 could also be valuable as a monotherapy or combination therapy."

Professor Per Soelberg Sorensen and Dr Finn Sellebjerg (Danish Multiple Sclerosis Research Center, Rigshospitalet, Copenhagen, Denmark) write in an accompanying comment that: "The balance between efficacy, safety, and convenience will be decisive for the choice of drug. Oral formulations have advantages in convenience and will be preferred by most patients, as long as efficacy and safety are similar to that of injectable alternatives. Although comparison of drugs tested in different placebo-controlled trials is difficult and should be done cautiously, BG00012 might have a favourable benefit-to-risk ratio profile compared with its oral competitors and the currently available first-line injectable drugs. However, we will have to await the results from the ongoing large phase III trials to establish the place of BG00012 and of other oral drugs in the treatment of relapsing-remitting multiple sclerosis."

(Source: The Lancet: University Hospital Basel: October 2008)