NEJM articles on MS drugs Fingolimod and Cladribine
Published at www.nejm.org January 20, 2010 (10.1056/NEJMoa0909494)
A Placebo-Controlled Trial of Oral Fingolimod in Relapsing Multiple Sclerosis
Ludwig Kappos, M.D., Ernst-Wilhelm Radue, M.D., Paul O'Connor, M.D., Chris Polman, M.D., Reinhard Hohlfeld, M.D., Peter Calabresi, M.D., Krzysztof Selmaj, M.D., Catherine Agoropoulou, Ph.D., Malgorzata Leyk, Ph.D., Lixin Zhang-Auberson, M.D., Ph.D., Pascale Burtin, M.D., Ph.D., for the FREEDOMS Study Group
ABSTRACT
Background 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.
Methods 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).
Results 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 T2 -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.
Conclusions 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 [ClinicalTrials.gov] .)
Source Information
From the Departments of Neurology and Biomedicine (L.K.) and the Medical Image Analysis Center (E.-W.R.), University Hospital, University of Basel; and Novartis Pharma (C.A., M.L., L.Z.-A., P.B.) — both in Basel, Switzerland; St. Michael's Hospital, Toronto (P.O.); Free University Medical Center, Amsterdam (C.P.); Institut für Klinische Neuroimmunologie, Munich, Germany (R.H.); Johns Hopkins Hospital, Baltimore (P.C.); and the Medical University of Lodz, Lodz, Poland (K.S.).
This article (10.1056/NEJMoa0909494) was published on January 20, 2010, at NEJM.org.
Address reprint requests to Dr. Kappos at the Departments of Neurology and Biomedicine, University Hospital, Petersgraben 4, CH 4031, Basel, Switzerland, or at lkappos@uhbs.ch.
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Published at www.nejm.org January 20, 2010 (10.1056/NEJMoa0907839)
Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis
Jeffrey A. Cohen, M.D., Frederik Barkhof, M.D., Giancarlo Comi, M.D., Hans-Peter Hartung, M.D., Bhupendra O. Khatri, M.D., Xavier Montalban, M.D., Jean Pelletier, M.D., Ruggero Capra, M.D., Paolo Gallo, M.D., Guillermo Izquierdo, M.D., Klaus Tiel-Wilck, M.D., Ana de Vera, M.D., James Jin, Ph.D., Tracy Stites, Ph.D., Stacy Wu, M.D., Shreeram Aradhye, M.D., Ludwig Kappos, M.D., for the TRANSFORMS Study Group
ABSTRACT
Background Fingolimod (FTY720), a sphingosine-1-phosphate–receptor modulator that prevents lymphocyte egress from lymph nodes, showed clinical efficacy and improvement on imaging in a phase 2 study involving patients with multiple sclerosis.
Methods In this 12-month, double-blind, double-dummy study, we randomly assigned 1292 patients with relapsing–remitting multiple sclerosis who had a recent history of at least one relapse to receive either oral fingolimod at a daily dose of either 1.25 or 0.5 mg or intramuscular interferon beta-1a (an established therapy for multiple sclerosis) at a weekly dose of 30 µg. The primary end point was the annualized relapse rate. Key secondary end points were the number of new or enlarged lesions on T2-weighted magnetic resonance imaging (MRI) scans at 12 months and progression of disability that was sustained for at least 3 months.
Results A total of 1153 patients (89%) completed the study. The annualized relapse rate was significantly lower in both groups receiving fingolimod — 0.20 (95% confidence interval [CI], 0.16 to 0.26) in the 1.25-mg group and 0.16 (95% CI, 0.12 to 0.21) in the 0.5-mg group — than in the interferon group (0.33; 95% CI, 0.26 to 0.42; P<0.001 for both comparisons). MRI findings supported the primary results. No significant differences were seen among the study groups with respect to progression of disability. Two fatal infections occurred in the group that received the 1.25-mg dose of fingolimod: disseminated primary varicella zoster and herpes simplex encephalitis. Other adverse events among patients receiving fingolimod were nonfatal herpesvirus infections, bradycardia and atrioventricular block, hypertension, macular edema, skin cancer, and elevated liver-enzyme levels.
Conclusions This trial showed the superior efficacy of oral fingolimod with respect to relapse rates and MRI outcomes in patients with multiple sclerosis, as compared with intramuscular interferon beta-1a. Longer studies are needed to assess the safety and efficacy of treatment beyond 1 year. (ClinicalTrials.gov number, NCT00340834 [ClinicalTrials.gov] .)
Source Information
The authors' affiliations are listed in the Appendix.
This article (10.1056/NEJMoa0907839) was published on January 20, 2010, at NEJM.org.
Address reprint requests to Dr. Cohen at Mellen Center U-10, Neurologic Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, or at cohenj@ccf.org.
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Published at www.nejm.org January 20, 2010 (10.1056/NEJMoa0902533)
A Placebo-Controlled Trial of Oral Cladribine for Relapsing Multiple Sclerosis
Gavin Giovannoni, M.B., B.Ch., Ph.D., Giancarlo Comi, M.D., Stuart Cook, M.D., Kottil Rammohan, M.D., Peter Rieckmann, M.D., Per Soelberg Sørensen, M.D., D.M.Sc., Patrick Vermersch, M.D., Ph.D., Peter Chang, Ph.D., Anthony Hamlett, Ph.D., Bruno Musch, M.D., Ph.D., Steven J. Greenberg, M.D., for the CLARITY Study Group
ABSTRACT
Background Cladribine provides immunomodulation through selective targeting of lymphocyte subtypes. We report the results of a 96-week phase 3 trial of a short-course oral tablet therapy in patients with relapsing–remitting multiple sclerosis.
Methods We randomly assigned 1326 patients in an approximate 1:1:1 ratio to receive one of two cumulative doses of cladribine tablets (either 3.5 mg or 5.25 mg per kilogram of body weight) or matching placebo, given in two or four short courses for the first 48 weeks, then in two short courses starting at week 48 and week 52 (for a total of 8 to 20 days per year). The primary end point was the rate of relapse at 96 weeks.
Results Among patients who received cladribine tablets (either 3.5 mg or 5.25 mg per kilogram), there was a significantly lower annualized rate of relapse than in the placebo group (0.14 and 0.15, respectively, vs. 0.33; P<0.001 for both comparisons), a higher relapse-free rate (79.7% and 78.9%, respectively, vs. 60.9%; P<0.001 for both comparisons), a lower risk of 3-month sustained progression of disability (hazard ratio for the 3.5-mg group, 0.67; 95% confidence interval [CI], 0.48 to 0.93; P=0.02; and hazard ratio for the 5.25-mg group, 0.69; 95% CI, 0.49 to 0.96; P=0.03), and significant reductions in the brain lesion count on magnetic resonance imaging (MRI) (P<0.001 for all comparisons). Adverse events that were more frequent in the cladribine groups included lymphocytopenia (21.6% in the 3.5-mg group and 31.5% in the 5.25-mg group, vs. 1.8%) and herpes zoster (8 patients and 12 patients, respectively, vs. no patients).
Conclusions Treatment with cladribine tablets significantly reduced relapse rates, the risk of disability progression, and MRI measures of disease activity at 96 weeks. The benefits need to be weighed against the risks. (ClinicalTrials.gov number, NCT00213135 [ClinicalTrials.gov] .)
Source Information
From Queen Mary University London, the Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, London (G.G.); the Institute of Experimental Neurology, Università Vita-Salute San Raffaele, Milan (G.C.); the University of Medicine and Dentistry, New Jersey Medical School, Newark (S.C.); Ohio State University, Columbus (K.R.); the University of British Columbia and Vancouver Coastal Health, Vancouver, BC, Canada (P.R.); Copenhagen University Hospital, Rigshospitalet, Copenhagen (P.S.S.); the University of Lille–Nord de France, Lille, France (P.V.); and Merck Serono, Geneva (P.C., A.H., B.M., S.J.G.).
This article (10.1056/NEJMoa0902533) was published on January 20, 2010, at NEJM.org.
Address reprint requests to Dr. Giovannoni at the Neuroscience Centre, Blizard Institute of Cell and Molecular Science, 4 Newark St., Whitechapel, London E1 2AT, United Kingdom, or at g.giovannoni@qmul.ac.uk.
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