Oral fingolimod (FTY720) for relapsing multiple sclerosis.
BACKGROUND
Fingolimod (FTY720) is a new oral immunomodulating agent under evaluation for the treatment of relapsing multiple sclerosis.


METHODS
We randomly assigned 281 patients to receive oral fingolimod, at a dose of 1.25 mg or 5.0 mg, or a placebo once daily, and we followed these patients for 6 months with magnetic resonance imaging (MRI) and clinical evaluations (core study, months 0 to 6). The primary end point was the total number of gadolinium-enhanced lesions recorded on T(1)-weighted MRI at monthly intervals for 6 months. In an extension study in which the investigators and patients remained unaware of the dose assignments (months 7 to 12), patients who received placebo underwent randomization again to one of the fingolimod doses.


RESULTS
A total of 255 patients completed the core study. The median total number of gadolinium-enhanced lesions on MRI was lower with 1.25 mg of fingolimod (1 lesion, P<0.001) and 5.0 mg of fingolimod (3 lesions, P=0.006) than with placebo (5 lesions). The annualized relapse rate was 0.77 in the placebo group, as compared with 0.35 in the group given 1.25 mg of fingolimod (P=0.009) and 0.36 in the group given 5.0 mg of fingolimod (P=0.01). For the 227 patients who completed the extension study, the number of gadolinium-enhanced lesions and relapse rates remained low in the groups that received continuous fingolimod, and both measures decreased in patients who switched from placebo to fingolimod. Adverse events included nasopharyngitis, dyspnea, headache, diarrhea, and nausea. Clinically asymptomatic elevations of alanine aminotransferase levels were more frequent with fingolimod (10 to 12%, vs. 1% in the placebo group). One case of the posterior reversible encephalopathy syndrome occurred in the 5.0-mg group. Fingolimod was also associated with an initial reduction in the heart rate and a modest decrease in the forced expiratory volume in 1 second.


CONCLUSIONS
In this proof-of-concept study, fingolimod reduced the number of lesions detected on MRI and clinical disease activity in patients with multiple sclerosis. Evaluation in larger, longer-term studies is warranted. (Clinicaltrials.gov numbers, NCT00333138 [core study] and NCT00235430 [ClinicalTrials.gov] [extension].).
Kappos
Ludwig
L
Department of Neurology, University Hospital, Basel, Switzerland. lkappos@uhbs.ch
Antel
Jack
J
Comi
Giancarlo
G
Montalban
Xavier
X
O'Connor
Paul
P
Polman
Chris H
CH
Haas
Tomas
T
Korn
Alexander A
AA
Karlsson
Goeril
G
Radue
Ernst W
EW
D000293:Adolescent; D000328:Adult; D001921:Brain / Q000473:pathology; D001927:Brain Diseases / Q000139:chemically induced; D004311:Double-Blind Method; D005260:Female; D000068876:Fingolimod Hydrochloride; D005682:Gadolinium; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000473:pathology; D011409:Propylene Glycols / Q000009:adverse effects / Q000627:therapeutic use*; D012141:Respiratory Tract Infections / Q000139:chemically induced; D013110:Sphingosine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018709:Statistics, Nonparametric
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D005682:Gadolinium; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine