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Drug for MS Reduces Lesions and Extends Time to Relapse

By Neil Osterweil, MedPage Today Staff Writer
Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University of Pennsylvania School of Medicine.
September 13, 2006


BASEL, Switzerland, Sept. 13 -- An investigational oral drug for relapsing multiple sclerosis reduced the number of lesions seen on MRI, produced rapid reductions in clinical disease activity, ,and significantly prolonged the time to relapse, found researchers here.

Patients who were switched to the drug, fingolimod (FTY720), after being on placebo also had a reduction in MS lesions and improvement of MS symptoms, reported Ludwig Kappos, M.D., from University Hospital in Basel, and colleagues, in the Sept. 14 issue of the New England Journal of Medicine.

Nearly 80% of patients who had received the drug continually for a year were free of relapses during that time, compared with about 66% of patients who received placebo for the first six months, then fingolimod for the next six months.

"Our results demonstrate that oral fingolimod given once daily provides significant and rapid improvement in MRI measures of inflammation and in relapse-related clinical end points in patients with relapsing multiple sclerosis," the authors wrote.

In an accompanying perspective article, Steffen Massberg, M.D., Ph.D., and Ulrich H. von Andrian, M.D., Ph.D., both of Harvard Medical School, wrote that "the results of the current proof-of-concept study by Kappos et al. are certainly promising and should provide a strong incentive for long-term follow-up trials on a large scale."

Fingolimod is an immuomodulating agent, developed by Novartis, that appears to work by trapping inflammatory lymphocytes in lymph nodes, thereby preventing their migration into the central nervous system. It's a chemical derivative of a metabolite produced by a fungus used in traditional Chinese medicine.

The drug's development pathway was illuminated by the mechanism of action of another drug for MS, Dr. Massberg and Dr. von Andrian suggested "The clinical importance of T-cell migration in patients with multiple sclerosis has been impressively demonstrated by the therapeutic effects of natalizumab [Tysabri], a monoclonal antibody that blocks the α4 integrin-dependent adhesion of blood-borne encephalitogenic T cells and macrophages to microvessels in the CNS," they wrote.

"Fingolimod also interferes with T-cell migration," they continued, "but at a different step; the drug prevents lymphocytes from leaving lymph nodes and other tissues. The sequestration of T and B lymphocytes in lymphoid tissues results in the nearly complete disappearance of lymphocytes, but not myeloid leukocytes, from the blood."

Fingolimod does not kill lymphocytes, and the process is reversible, Dr. Massberg and Dr. Andrian noted.

In the core proof-of-concept study, Dr. Kappos and colleagues in centers in Europe and Canada randomly assigned 281 patients to placebo or oral fingolimod at a dose of either 1.25 mg or 5.0 mg once daily.

The patients were followed with gadolinium-enhanced MRI monthly for six months, and again at 12 months.

The primary study endpoint was the total number of gadolinium-enhanced MS lesions recorded on T1-weighted MRI. Clinical end points included the number of patients remaining free of relapse, the annualized relapse rate, and the time to the first relapse.

The investigators also conducted a six-month extension study in which both they and their patients remained unaware of the dose assignments, with patients who were originally assigned to placebo being randomized to receive fingolimod in one of the two doses used in the core study.

Among the 255 patients who completed the core study, the median total number of gadolinium-enhanced lesions on MRI was significantly lower on both drug doses than placebo. Patients on the 1.25 mg dose of fingolimod had a median of one lesion (P<0.001) and those on the 5.0 mg of fingolimod had a median of three lesions (P =0.006). In contrast, patients on placebo had a median of five lesions.

At six months, 47% of patients were free of gadolinium-enhanced lesions, compared with 77% of those in the 1.25 mg group, and 82% of those in the 5.0 mg group (P<0.001 for both).

The annualized relapse rate was 0.77 in the placebo group, compared with 0.35 in the 1.25 mg group (P=0.009) and 0.36 in the 5.0 mg group (P=0.01).

"Although the study was not powered to detect a treatment effect on the relapse end points," the authors wrote, "significant improvements over placebo were observed in the fingolimod groups, including a relative reduction in the annualized relapse rate (by 53% in the 5.0-mg group and by 55% in the 1.25-mg group)."

They also found that the estimated time to a first relapse was significantly prolonged in the fingolimod groups, and when they included data on unconfirmed relapses, the results were similar.

There were, however, no significant differences at 12 months between the fingolimod and placebo group at 12 months in terms of disability, as measured by the Expanded Disability Status Scale.

Among the 227 patients who completed the extension study, the number of gadolinium-enhanced lesions and relapse rates remained low in the groups that received continuous fingolimod, and both measures decreased in patients who switched from placebo to fingolimod.

At 12 months, the median number of lesions among patients who received six months of placebo and six of 1.25 mg fingolimod was 1, compared with 0 for all other groups (placebo plus 5.0 mg fingolimod, and 12-months 1.25 mg or 5.0 mg fingolimod).

In all 86% of those on placebo/1.25 mg were lesion-free at 12 months, compared with 69% of those on placebo/5.0 mg, 85% of those on 1.25 mg for a year, and 88% of those on 5.0 mg fingolimod for a year.

Adverse events included nasopharyngitis, dyspnea, headache, diarrhea, and nausea. Clinically asymptomatic elevations of alanine aminotransferase levels occurred in the core study in 10% of patients on the 1.25 mg dose and 12% on the 5.0 mg dose, compared with 1% of those on placebo.

There was one case of the posterior reversible encephalopathy syndrome in the 5.0-mg group, and fingolimod was also associated with an initial reduction in heart rate within six hours after the first dose, followed by a gradual return toward baseline.

Patients on fingolimod also had an initial reduction in mean blood pressure (5 to 6 mm Hg lower than the baseline value) within 4 to 5 hours after the administration of fingolimod, followed by a sustained elevation (4 to 6 mm Hg higher than baseline) after two months of treatment, although there was no further increase during the extension study, the authors reported.

Patients on fingolimod also experienced a modest decrease in pulmonary function, as measured by forced expiratory volume in one second (FEV1).

"Our results show that oral fingolimod may be a treatment option for relapsing multiple sclerosis," the authors wrote. "Before these findings can be considered clinically directive, the benefits and risks of fingolimod need to be further evaluated in larger-scale, longer-term clinical studies."

In their perspective, Dr. Massberg and Dr. von Andrian cautioned that because it's an immunosuppressant, fingolimod will need to be evaluated for its potential to increase susceptibility to infections.

In addition, the drug's ability to prevent lymphocytes from reaching the CNS could have unwelcome consequences. They pointed to Tysabri, a highly effective MS drug that has been associated with three cases of progressive multifocal leukoencephalopathy caused by the JC polyomavirus.

"The development of this disorder in a small number of natalizumab recipients was unexpected, but it might have been due to the drug-induced absence of immune surveillance of the CNS," they wrote. "Whether long-term inhibition of lymphocyte migration caused by fingolimod treatment might carry a similar risk is not known and will require further investigation."

The study was supported by Novartis. Many of the authors reported receiving consulting fees and/or research support from Novartis, as well as many other drug companies.
Primary source: New England Journal of Medicine
Source reference:
Kappos L et al. "Oral Fingolimod (FTY720) for Relapsing Multiple Sclerosis." N Engl J Med 2006;355:1124-40

Additional source: New England Journal of Medicine
Source reference:
Massberg S and von Andrian UH. "Fingolimod and Sphingosine-1-Phosphate-Modifiers of Lymphocyte Migration." N Engl J Med 2006;355:1088-1091.

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New Drug Reduces MS Symptoms

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