Oral Fingolimod (FTY720) for Relapsing Multiple Sclerosis
Ludwig Kappos, M.D., Jack Antel, M.D., Giancarlo Comi, M.D., Xavier Montalban, M.D., Paul O'Connor, M.D., Chris H. Polman, M.D., Tomas Haas, Ph.D., Alexander A. Korn, Ph.D., Goeril Karlsson, Ph.D., Ernst W. Radue, M.D., for the FTY720 D2201 Study Group
Background Fingolimod (FTY720) is a new oral immunomodulatingagent under evaluation for the treatment of relapsing multiplesclerosis.
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, andwe followed these patients for 6 months with magnetic resonanceimaging (MRI) and clinical evaluations (core study, months 0to 6). The primary end point was the total number of gadolinium-enhancedlesions recorded on T1-weighted MRI at monthly intervals for6 months. In an extension study in which the investigators andpatients remained unaware of the dose assignments (months 7to 12), patients who received placebo underwent randomizationagain to one of the fingolimod doses.
Results A total of 255 patients completed the core study. Themedian total number of gadolinium-enhanced lesions on MRI waslower with 1.25 mg of fingolimod (1 lesion, P<0.001) and5.0 mg of fingolimod (3 lesions, P=0.006) than with placebo(5 lesions). The annualized relapse rate was 0.77 in the placebogroup, 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, thenumber of gadolinium-enhanced lesions and relapse rates remainedlow in the groups that received continuous fingolimod, and bothmeasures decreased in patients who switched from placebo tofingolimod. Adverse events included nasopharyngitis, dyspnea,headache, diarrhea, and nausea. Clinically asymptomatic elevationsof alanine aminotransferase levels were more frequent with fingolimod(10 to 12%, vs. 1% in the placebo group). One case of the posteriorreversible encephalopathy syndrome occurred in the 5.0-mg group.Fingolimod was also associated with an initial reduction inthe heart rate and a modest decrease in the forced expiratoryvolume in 1 second.
Conclusions In this proof-of-concept study, fingolimod reducedthe number of lesions detected on MRI and clinical disease activityin patients with multiple sclerosis. Evaluation in larger, longer-termstudies is warranted. (Clinicaltrials.gov numbers, NCT00333138
[ClinicalTrials.gov][core study] and NCT00235430
[ClinicalTrials.gov]
[extension].)
Source Information
From the Departments of Neurology and Research, University Hospital, Basel, Switzerland (L.K.); Le Centre Universitaire de Santé McGill, Montreal Neurological Institute, McGill University, Montreal (J.A.); Neurology Clinic, San Raffaele Hospital, University Vita e Salute, Milan (G.C.); Neuroimmunology Unit, Hospital Vall d'Hebron, Barcelona (X.M.); Division of Neurology, St. Michael's Hospital, Toronto (P.O.); Department of Neurology, Vrije Universiteit Medical Center, Amsterdam (C.H.P.); Biostatistics and Statistical Reporting (T.H.) and Clinical Development and Medical Affairs (G.K.), Novartis Pharma, Basel, Switzerland; Clinical Development and Medical Affairs, Novartis Pharmaceuticals, East Hanover, NJ (A.A.K.); and Neuroradiology and MS-MRI Evaluation Center, University Hospital, Basel, Switzerland (E.W.R.).
Address reprint requests to Dr. Kappos at the Departments of Neurology and Research, University Hospital, Petersgraben 4, 4031 Basel, Switzerland, or at lkappos{at}uhbs.ch.
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