Positive Results Published on Clinical Trials of Oral FTY720 (Fingolimod) for Relapsing MS - Novartis Applies to FDA and European Regulatory Agency for Approval
Positive results from two large-scale phase III clinical trials of oral fingolimod (FTY720) have been published showing it significantly reduced multiple sclerosis relapse rates, and one of the trials also suggested it could slow the progression of disability. The sponsor, Novartis International AG, has announced that it applied for marketing approval in the U.S. and European Union in December 2009. There are currently no approved oral disease-modifying therapies for MS. The papers were published early online in the New England Journal of Medicine on January 20, 2010, along with a separate paper that describes results from a clinical trial of another orally administered experimental therapy, cladribine.
This is a new class of therapy in development for treating multiple sclerosis. FTY720 binds to a docking site (sphingosine-1-phosphate receptor, or S1P receptor) on immune cells, including T cells and B cells, that have been implicated in causing nervous system damage in MS. The drug appears to induce immune cells to remain in lymph nodes, where they can do little harm, preventing them from migrating into the brain and spinal cord. NEJM epub Jan 20, 2010
Details
1 . A Placebo-Controlled Trial of Oral Fingolimod in Relapsing Multiple Sclerosis
Oral fingolimod, a sphingosine-1-phosphate–receptor modulator 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.
This 24-month, double-blind, randomized study, enrolled patients who had relapsing–remitting multiple sclerosis, who 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 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.
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.
2. Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis
In this 12-month, double-blind, double-dummy study, 1292 patients with relapsing–remitting multiple sclerosis who had a recent history of at least one relapse were randomly assigned 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.
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.
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.
With information from the National MS Society (USA)
National Research and Programs
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