A phase II trial has shown oral fumarate (BG00012) substantially reduces the MRI-disease activity* associated with relapsing-remitting multiple sclerosis (RRMS), and the results of phase III studies are now awaited. The results are reported in an Article in this week's edition of The Lancet, written by Professor Ludwig Kappos, University Hospital Basel, Switzerland, and colleagues.
BG00012 is oral fumarate with an immunomodulatory but also possibly a direct neuroprotective effect. In this randomised placebo-controlled trial a group of European and North American researchers studied 257 RRMS patients, aged 18-55 years. They were randomly assigned to receive BG00012 120 mg once daily (64 patients), 120mg three times daily (64), or 240mg three times daily (64), or placebo (65), all for 24 weeks. 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 new or enlarging T2-hyperintense lesions, new T1-hypointense lesions**** at week 24, and annualised relapse rate. Safety and tolerability were also assessed.
The researchers found that treatment with BG00012 240mg 3 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). It also reduced the number of new or enlarging T2-hyperintense and T1-hypointense lesions at week 24. Whilst BG00012 reduced the annual relapse rate by 32% (0.44 vs 0.65 for placebo), this finding was not statistically significant — but the study was not designed or powered to meet this clinical endpoint. Adverse events more common in patients given BG00012 than in those given placebo included abdominal pain, and hot flush. Dose-related adverse events in patients on BG00012 were headache, fatigue, and feeling hot.
The authors conclude: "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. 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."
In an accompanying Comment, Professor Per Soelberg Sorensen and Dr Finn Sellebjerg, Danish Multiple Sclerosis Research Center, Rigshospitalet, Copenhagen, Denmark, say: "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."
See also linked Seminar on multiple sclerosis.
Professor Ludwig Kappos, University Hospital Basel, Switzerland T) +41612654464 E) lkappos@uhbs.ch
Professor Per Soelberg Sorensen, Danish Multiple Sclerosis Research Center, Rigshospitalet, Copenhagen, Denmark T) +45 4030 3545 /+45 3545 2080 E) pss@rh.dk
Notes to editors:
*The higher the disease activity in MS as measured by Magnetic Resonance Imaging (MRI) is, the higher the chances are for the patients to experience relapses and eventually to accumulate neurological disability
**gadolinium enhancing lesions: a marker of the inflammatory activity of multiple sclerosis. Gadolinium enhancement occurs only in new or reactivated MS lesions and lasts for a few days up to a maximum of 2-3 months
***New or enlarging T2-hyperintense lesions: these include both acute and chronic MS lesions
****T1-hypointense lesions are MS lesions with more destructive (mostly permanent) and not only inflammatory pathology
Full Article, Comment and Seminar: http://press.thelancet.com/multiplesclerosisfinal.pdf
Journal
The Lancet