Oral fingolimod, a sphingosine-1-phosphate-receptor modulator that prevents the egress
of lymphocytes from lymph nodes, significantly improved relapse rates and end points
measured on magnetic resonance imaging (MRI), as compared with either placebo or intramuscular
interferon beta-1a, in phase 2 and 3 studies of multiple sclerosis.
In our 24-month, double-blind, randomized study, we enrolled patients who had relapsing-remitting
multiple sclerosis, were 18 to 55 years of age, had a score of 0 to 5.5 on the Expanded
Disability Status Scale (which ranges from 0 to 10, with higher scores indicating
greater disability), and had had one or more relapses in the previous year or two
or more in the previous 2 years. Patients received oral fingolimod at a dose of 0.5
mg or 1.25 mg daily or placebo. End points included the annualized relapse rate (the
primary end point) and the time to disability progression (a secondary end point).
A total of 1033 of the 1272 patients (81.2%) completed the study. The annualized relapse
rate was 0.18 with 0.5 mg of fingolimod, 0.16 with 1.25 mg of fingolimod, and 0.40
with placebo (P<0.001 for either dose vs. placebo). Fingolimod at doses of 0.5 mg
and 1.25 mg significantly reduced the risk of disability progression over the 24-month
period (hazard ratio, 0.70 and 0.68, respectively; P=0.02 vs. placebo, for both comparisons).
The cumulative probability of disability progression (confirmed after 3 months) was
17.7% with 0.5 mg of fingolimod, 16.6% with 1.25 mg of fingolimod, and 24.1% with
placebo. Both fingolimod doses were superior to placebo with regard to MRI-related
measures (number of new or enlarged lesions on T(2)-weighted images, gadolinium-enhancing
lesions, and brain-volume loss; P<0.001 for all comparisons at 24 months). Causes
of study discontinuation and adverse events related to fingolimod included bradycardia
and atrioventricular conduction block at the time of fingolimod initiation, macular
edema, elevated liver-enzyme levels, and mild hypertension.
As compared with placebo, both doses of oral fingolimod improved the relapse rate,
the risk of disability progression, and end points on MRI. These benefits will need
to be weighed against possible long-term risks. (ClinicalTrials.gov number, NCT00289978.)
Copyright 2010 Massachusetts Medical Society