Oral fingolimod in relapsing multiple sclerosis

Fingolimod is an oral drug that acts as a sphingosine-1-phosphate-receptor modulator. It may act by preventing the release of lymphocytes from lymph nodes, with consequent reduced central nervous system invasion by lymphocytes. Modulation of sphingosine-1-phosphate receptors on neural cells may also play a part. Preliminary studies have suggested that it might be effective treatment for multiple sclerosis. Now, it has been shown to give better results than either placebo or interferon.

In the placebo-controlled study a total of 1,272 patients with relapsing-remitting multiple sclerosis were randomized at 138 centres in 22 countries to oral fingolimod (0.5 or 1.25 mg daily) or placebo, for 24 months, and 1,033 completed the study. The annualized relapse rate was 0.18 (fingolimod 0.5 mg), 0.16 (fingolimod 1.25 mg) and 0.40 (placebo), a highly significant improvement with either dose compared with placebo. The risk of progression of disability over the 24 months was reduced significantly by 30% and 32% with the two doses of fingolimod compared with placebo. The cumulative probability of progression in the three groups respectively was 17.7%, 16.6%, and 24.1%. Both doses of the drug were significantly better than placebo as regards new or progressive lesions on MRI. Adverse events with fingolimod included bradycardia and atrioventricular conduction block on starting the drug, macular oedema, raised liver enzymes, and mild hypertension.

In the interferon-controlled study a total of 1,292 patients were randomized at 172 centres in 18 countries to the above doses of fingolimod, or intramuscular interferon beta-1a (30 ?g weekly), for 12 months, and 1,153 completed the study. The annualized relapse rates were 0.16 (fingolimod 0.5 mg), 0.20 (1.25 mg), and 0.33 (interferon). Both doses of fingolimod were significantly better than interferon. The MRI results were similar. Progression of disability did not differ significantly in the three groups. There were two deaths from infection on the higher dose of fingolimod: one from disseminated primary varicella zoster infection, and one from herpes simplex encephalitis. Fingolimod was also associated with non-fatal herpes virus infections, bradycardia and atrioventricular block, hypertension, macular oedema, skin cancer, and raised liver enzymes.

Fingolimod gave better results than either placebo or interferon. More and longer studies are needed to assess toxicity and long-term efficacy.

Kappos L et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. NEJM 2010; 362:387–401; Cohen JA et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. Ibid: 402–415; Carroll WM. Oral therapy for multiple sclerosis – sea change or incremental step? Ibid: 456–458 (editorial).