TORONTO—Annualized relapse rates in patients with relapsing-remitting multiple sclerosis (MS) were more than 50% lower in subjects taking oral fingolimod (FTY720) than in those taking a placebo, according to research presented at the 62nd Annual Meeting of the American Academy of Neurology. The medication also reduced the risk of disability progression by 30% and significantly decreased the number of new or enlarged T2 lesions and gadolinium-enhancing lesions, per 24-month results of the phase III FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS) trial.
Oral fingolimod, a sphingosine 1-phosphate receptor (S1PR) modulator, is the first in a novel class of drugs under evaluation for the treatment of relapsing and progressive forms of MS. S1PR modulators work to retain circulating lymphocytes in the lymph nodes, thereby reducing the recirculation of autoreactive lymphocytes and preventing penetration of these lymphocytes into the CNS.
Fingolimod Versus Placebo
The double-blind, placebo-controlled multicenter FREEDOMS study randomized 1,083 patients (mean age, 40.5) to receive once-daily doses of either 1.25-mg fingolimod, 0.5-mg fingolimod, or a placebo. For the primary end point of annualized relapse rate, both doses of fingolimod were superior to placebo, with a 54% reduction in relapses for the lower dose and a 60% reduction in the higher dose. For the key secondary end point of time to three-month confirmed disability progression, measured by a 1-point increase in the Expanded Disability Status Scale (EDSS), a 30% risk reduction was reported in the 0.5-mg dose, and 32% in the 1.25-mg dose, compared with placebo.
“Overall, 1.25-mg fingolimod did not offer any advantages regarding efficacy, and it had a slightly higher array of side effects; therefore, 0.5 mg is the dosage that we will submit an application for [FDA] approval at this time,” announced Ludwig Kappos, MD, of the Department of Neurology, University Hospital, University of Basel, Switzerland.
The second phase of the study, which was presented in 2006, showed a “clear cut effect on inflammatory outcomes on MRI,” Dr. Kappos noted. “Five years of follow-up support these effects…. Approximately 99.5% of patients remaining in the study do not show MRI activity and have a low annualized relapse rate at approximately 0.2, [which is equivalent to] one relapse every five years.”
The phase III, 24-month MRI inflammatory activity results favored fingolimod over placebo, with 50.5% of the 0.5-mg fingolimod group and 51.9% of the 1.25-mg group free from new or newly enlarged T2 lesions, compared with 21.2% of the placebo group, reported Ernst-Wilhelm Radue, MD, Director of Medical Image Analysis Center, University Hospital Basel, Switzerland. In addition, more patients were free from gadolinium-enhanced lesions with fingolimod (89.7% and 89.8%), compared with placebo (65.1%).
Fingolimod Versus Interferon
A second study, the Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS), compared both doses of fingolimod to intramuscular interferon beta-1a and found that the oral medicine reduced annualized relapse rates by up to 50%, compared with injectable interferon.
The 12-month phase III study of 1,153 patients also found that fewer patients experienced relapses requiring steroid treatment and/or hospitalization when treated with fingolimod than when treated with interferon beta-1a. Patients in both fingolimod groups also had significantly less deterioration of the ability to perform daily activities, based on the Patient-Reported Indices for Multiple Sclerosis (PRIMUS)–Activities scores, compared with the interferon group.
A 24-month optional extension study to assess the safety and efficacy—both clinically and on MRI—is under way and involves 89% of the patients who completed the core TRANSFORMS study. Patients who were taking weekly interferon beta-1a injections have been switched to daily oral fingolimod, and those who took fingolimod in the earlier phase of the trial have continued on the medication. Following the results of the FREEDOMS II trial, all subjects in the TRANSFORMS extension study are taking the 0.5-mg dose.
Safety and Tolerability
Of the 1,272 patients initially enrolled in the FREEDOMS trial, 81% completed the study. Those who discontinued the trial were proportionately lower in the 0.5-mg fingolimod group (19%), compared with the 1.25-mg dose (31%) or placebo (28%) groups.
The percentages of patients reporting any adverse events were similar for both fingolimod groups (94%) and placebo (93%). Serious adverse events were reported in 10% of patients taking 0.5-mg fingolimod, 12% of those taking 1.25-mg fingolimod, and 13% of the placebo group. Serious infectious adverse events occurred in 1.6% of the 0.5-mg group, 2.6% of the 1.25-mg group, and 1.9% of the placebo group.
Malignant neoplasms were reported in 10 patients in the placebo group and four patients in each active group. Seven cases of macular edema occurred, all in patients on the 1.25-mg dose. A transient heart rate decrease at the beginning of treatment, minor increases in blood pressure, and increases in liver enzymes were also observed.