New Oral Agent for Multiple Sclerosis Shows Benefit
November 1, 2006 3 minutes read
New Oral Agent for Multiple Sclerosis Shows Benefit
Abstract & Commentary
By Brain R. Apatoff, MD, PhD, Director, Multiple Sclerosis Clinical Care and Research Center, Department of Neurology and Neuroscience, NewYork-Presbyterian Hospital, Cornell Campus. Dr. Apatoff is on the speaker's bureau for Biogen and Teva.
Synopsis: Fingolimod, a novel immunomodulating agent that can be taken orally, reduces the number of clinical relapses and MRI lesions in patients with multiple sclerosis.
Source: Kappos L, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med. 2006;355:1124-1140.
In this phase II clinical trial, 281 patients with multiple sclerosis (MS) from centers in Europe and Canada were randomized to treatment with the immune modulator, fingolimod, at a dose of 1.25 mg or 5.0 mg daily, or to a placebo, once daily for 6 months. The baseline characteristics of the patients were similar in all 3 groups — mean age was approximately 38 years, mean disease duration was 8.5 years, and mean EDSS score was 2.5. The majority of patients had relapsing-remitting MS, with a small percentage (approximately 10%) categorized as secondary progressive MS.
Patients were monitored with blinded, monthly clinical assessments and brain MRI scans for 6 months. At the end of 6 months, 255 patients completed the core study. For the primary end point, the median total number of gadolinium-enhancing lesions on MRI was lower with fingolimod 1.25 mg (1 lesion, P < 0.001) and fingolimod 5.0 mg (3 lesions, P < 0.006) than with placebo (5 lesions). The annualized relapse rate in the placebo group was 0.77, compared with a rate of 0.35 in the 1.25 mg fingolimod group (P < 0.01) and a rate of 0.36 in the 5.0 mg fingolimod group (P < 0.01).
In a blinded extension study, patients in the placebo group were randomly assigned to one of the fingolimod doses for months 7 through 12. For the 227 patients completing the extension phase, there was a sustained benefit in the original fingolimod groups, and reductions in the clinical measures and brain MRI activity of patients who switched from placebo to fingolimod.
Adverse events included nasopharyngitis, dyspnea, headache, diarrhea, and nausea. Asymptomatic elevations of liver enzymes were seen in 10-12% of fingolimod patients vs 1% of placebo patients. Fingolimod was also associated with a transient reduction in heart rate and a slight decrease in the forced expiratory volume in one second. There was one case of posterior reversible encephalopathy syndrome (PRES) in the 5 mg. per day fingolimod group.
Commentary
Fingolimod is derived from a fungus that has been used in Chinese traditional medicine for thousands of years. Its lymphopenic effect has been shown to be caused by its blockade of sphingosine-1-phosphate receptors (S1P) that are expressed on T-lymphocytes and regulate lymphocyte migration. The S1P receptor is necessary for extravascular lymphocytes to migrate from lymph nodes and enter the vascular compartment and, ultimately, the central nervous system compartments. Thus, fingolimod's ability to induce lymphopenia results from T-cell sequestration rather than the cytotoxic effects seen with other immunosuppressive drugs. Because the S1P receptor is also expressed in cardiac and pulmonary tissue, some adverse effects were seen on heart rate and pulmonary function. The presence of S1P receptors in the brain may also explain the case of PRES that was observed in the high-dose fingolimod group.
This proof of concept study shows that oral fingolimod causes a significant and relatively rapid reduction of disease activity based on brain MRI lesions and clinical relapse rate. A larger, long-term Phase III study is being organized in the United States, and will hopefully provide more complete safety and efficacy data for this promising, novel, immune-modulating drug.
Fingolimod, a novel immunomodulating agent that can be taken orally, reduces the number of clinical relapses and MRI lesions in patients with multiple sclerosis.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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