The Phase II trial data showed that Fingolimod ( FTY720 ) taken once-daily during the initial six months of treatment for relapsing multiple sclerosis reduced the rate of inflammatory disease activity - as measured by magnetic resonance imaging ( MRI ) - by up to 80% and cut clinical relapses by more than 50% compared to placebo.

In patients who continued taking Fingolimod during the subsequent six-month extension, low levels of disease activity were maintained as measured by both MRI and relapses. Both these measures also decreased in patients who switched from placebo to Fingolimod.

The Phase II study was conducted at 32 centers in 11 countries ( in Europe and Canada ) to evaluate the effect of Fingolimod on disease activity as measured by MRI and clinical relapses as well as safety and tolerability.

In the initial placebo-controlled phase, 281 patients were randomized equally to receive Fingolimod ( 1.25 mg or 5 mg ) or placebo once-daily for six months.
Of the 255 patients who completed this part of the study, 98% volunteered to continue in the extension phase. Patients in the placebo group were then re-randomized to receive either 1.25 mg or 5 mg of Fingolimod and were blinded for an additional six months. Those already on Fingolimod continued with their original treatment.

The study showed that oral Fingolimod provided significant and rapid improvement in MRI measures of inflammation and in relapse-related clinical endpoints in patients with relapsing multiple sclerosis. Inflammatory disease activity as measured by the total cumulative number of gadolinium-enhancing MRI lesions was significantly reduced by up to 80% ( p<0.001 in Fingolimod 1.25 mg, p<0.006 in Fingolimod 5 mg ) compared to placebo over six months of treatment. At six months, the proportion of patients free of gadolinium-enhancing lesions was also greater in both Fingolimod groups compared to placebo ( p<0.001 for both groups ), with a separation between the curves becoming evident from two months onwards.

Relapse rates were reduced by 55% in the Fingolimod 1.25 mg group ( p=0.009 ) and by 53% in the Fingolimod 5 mg group ( p=0.014 ) compared to placebo. Time to first confirmed relapse was also significantly prolonged in both Fingolimod groups compared to placebo ( p=0.007 in Fingolimod 1.25 mg, p=0.01 in Fingolimod 5 mg ).

In both groups taking Fingolimod ( i.e. 1.25 mg or 5 mg ), patients who had experienced a reduction in their annualized relapse rate of more than 50% compared to placebo during the first six months of the study maintained this low relapse rate during the subsequent six months of the extension. More than 80% of patients who received Fingolimod for up to 12 months were free from lesions showing active inflammation on MRI at month 12, irrespective of their treatment dose.

In patients who switched from placebo to either dosage of Fingolimod after six months, the annualized relapse rate was reduced by at least 70% during the six-month extension compared to the period on placebo.

In the six month placebo-controlled phase of the study, the most frequent adverse events reported for Fingolimod were dose-dependent upper respiratory tract infections ( mainly nasopharyngitis ) and dyspnea, plus diarrhea, and nausea.
Fingolimod treatment was associated with initial dose-dependent decreases in heart rate and expiratory flow.
Clinically asymptomatic increases in alanine aminotransferase and increase in blood pressure were also observed. There were no unexpected safety findings during the six-month extension phase as compared to the six-month placebo-controlled phase.


Based on the positive Phase II results, Novartis launched a Phase III clinical trials program called FREEDOMS ( FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis ). This 24-month, randomized, double-blind, placebo-controlled study program is designed to include over 2,000 patients worldwide with the relapsing-remitting form of multiple sclerosis between ages 18 and 55.
Study participants will be randomized equally to either receive once-daily treatment with 1.25 mg or 0.5 mg of Fingolimod or placebo for up to 24 months.

Source:

1) The New England Journal of Medicine, 2006

2) Novartis, 2006


XagenaMedicine2006