Wednesday, October 29, 2008
By Crystal Phend, Staff Writer, MedPage Today
Published: October 23, 2008
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco
Patients given oral fumarate at the highest dose had 69% fewer new inflammatory lesions enhanced by gadolinium on brain MRI scans at 12 to 24 weeks of treatment compared with placebo (P<0.0001), reported Ludwig Kappos, M.D., of University Hospital Basel, and colleagues in the Oct. 25 issue of The Lancet.
In the phase IIb dose-ranging trial, the experimental drug also reduced the annualized relapse rate by 32% compared with placebo, although the difference was not significant (P=0.272).
Fumarate, also known as BG00012, may have dual neuroprotective and anti-inflammatory effects by activating a pathway that defends against neuronal death from oxidative stress, protects the blood-brain barrier, and supports myelin integrity in the central nervous system, the researchers said.
If the longer-term phase III studies now underway show the agent to be as effective as the currently available injection- or infusion-only drugs, fumarate may have an advantage as initial treatment based on convenience alone, Dr. Kappos' group said.
"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," they said.
However, fumarate will have to compete with a number of other oral agents being developed, commented Per Soelberg Sorensen, M.D., and Finn Sellebjerg, M.D., Ph.D., both of Rigshospitalet in Copenhagen, in an accompanying commentary.
Phase III studies of at least four other oral agents -- cladribine (Leustatin), fingolimod, teriflunomide, and laquinimod -- are in progress for relapsing-remitting multiple sclerosis.
"Within the next four to five years neurologists may be able to choose between up to five new oral drugs for relapsing-remitting multiple sclerosis," Drs. Sorensen and Sellebjerg wrote.
The decisive factor in which drug wins out will be the balance between efficacy, safety, and convenience, they said.
But the findings of this study suggest fumarate may have a better benefit-to-risk profile than these oral competitors or approved first-line injectable drugs, they suggested.
The trial included 257 patients ages 18 to 55 with relapsing-remitting multiple sclerosis treated at 43 centers across Europe and Russia.
Participants were randomized to receive double-blind treatment for 24 weeks with oral fumarate at a dose of 120 mg once daily, 120 mg three times daily, or 240 mg three times daily, or to placebo.
The highest dose group had significantly fewer total new gadolinium-enhancing lesions on MRI at weeks 12, 16, 20, and 24 combined -- the primary endpoint -- compared with the placebo group (1.4 versus 4.5, P<0.0001).
This type of lesion indicates blood-brain barrier breakdown and continued inflammatory activity within the central nervous system, the researchers noted.
Gadolinium-enhancing lesions have been linked to acute clinical relapses and cerebral atrophy, although the short follow-up precluded atrophy as an outcome in the study, they said.
The highest-dose group also had a 48% reduction in the mean number of new or enlarging T2-hyperintense lesions over 24 weeks (P=0.0006) and a 53% reduction in new T1-hypointense lesions compared with placebo (P=0.014).
Lower doses of the experimental agent were also associated with fewer total new enhancing lesions, although there were no significant differences compared with placebo (3.3 with 120 mg once daily and 3.1 with three times daily versus 4.5).
Although the study was not powered for relapse endpoints, annualized relapse rates were reduced by 32% with the highest dose of fumarate over the first 24 weeks (0.44 versus 0.65 with placebo, P=0.272).
In an extension period of 24 weeks for safety assessment, during which patients continued on their assigned dose and the placebo group switched to the highest fumarate dose, relapse rates dropped further.
The reductions compared with the first 24 weeks were 43% for the lowest dose group, 40% for the intermediate dose group, and 64% for the highest dose group, and 60% for those who switched to fumarate after placebo.
"This result could indicate a delayed and increasing effect of BG00012 over time," Dr. Kappos' group suggested.
The researchers said the experimental drug was safe and generally well tolerated.
The most common adverse events included flushing, multiple sclerosis relapse, and headache. Abdominal pain was also significantly more common with the highest dose than with placebo.
The editorialists noted, however, that it was worrying that 25% of patients on the highest dose of fumarate withdrew from the study, with 13% of patients in this group discontinuing because of adverse events.
The study was funded by Biogen Idec.
Dr. Kappos reported participating as principal investigator, member, or chair of planning and steering committees or advisory boards in multiple sclerosis clinical trials sponsored by Allozyne, Amgen, Bayer HealthCare Pharmaceuticals, Bayer-Schering Pharma, Bayhill, Biogen Idec Inc, Eisai, Elan Pharmaceuticals Inc, Genmab, Genzyme, Merck-Serono, Medicinova, Novartis, sanofi-aventis, Shire, Roche, Teva, UCB, and Wyeth.
He also reported giving lectures on the diagnosis and management of multiple sclerosis sponsored by non-restricted educational grants from one of the sponsors and receiving research and clinical operations funding at his center supported by non-restricted grants from one or more of the sponsors and by grants from the Swiss MS Society, the Swiss National Research Foundation, the European Union, and the Gianni Rubatto Foundation.
Co-authors reported conflicts of interest for Biogen Idec, GlaxoSmithKline, Schering AG, Novartis, Bayer Schering, and the US National Institutes of Health, Serono, Teva, Octapharma, sanofi-aventis, Teva, Antisense Pharmaceuticals, Janssen Cilag, Johnson & Johnson, Orion, UCB, AstraZeneca, and Roche.
Dr. Sorensen reported receiving honoraria for lecturing and advisory councils, trial steering committees, travel expenses for attending meetings, or research grants from Biogen Idec, Bayer Schering, Merck Serono, TEVA, Biopartners, sanofi-aventis, and Genmab. Dr. Sellebjerg has received honoraria for lecturing and advisory councils, travel expenses for attending meetings, or research grants from Biogen Idec, Bayer Schering, Merck Serono, and TEVA.
Primary source: Lancet
Kappos L, et al "Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study" Lancet 2008; 372: 1463-72.
Additional source: Lancet
Sorensen PS, Sellebjerg F "Oral fumarate for relapsing-remitting multiple sclerosis" Lancet 2008; 372: 1447-48.