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Published on 15 December 2011

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Gilenya® ‘positive for relapsing-remitting MS’

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Patients with relapsing-remitting multiple sclerosis (RRMS) treated with Gilenya® (fingolimod) recorded a 48% reduction in annualised relapse rates (ARR) at 24 months compared to placebo, according to the results of a Phase III clinical trial.

Study 2309 is the third of its kind to demonstrate a significant reduction of relapse rates with Gilenya treatment in patients with RRMS.

The two previous Gilenya studies involved a two-year, placebo-controlled trial and a one-year, head-to-head trial against interferon-beta-1a (IM) in which the once-daily oral medicine showed a 54% and a 52% relative reduction in ARR, respectively.

A reduction of brain volume loss, a pre-defined key secondary endpoint for study 2309, also achieved statistical significance for Gilenya-treated patients compared to placebo.

Brain volume loss is valued as a predictor of long-term disability and study 2309 is the third Phase III clinical trial where Gilenya demonstrated high efficacy in this magnetic resonance imaging (MRI) measure compared to control.

Gilenya-treated patients had a 17% and 28% reduction in three-month and six-month confirmed disability progression, compared to placebo as measured by EDSS (expanded disability status scale), respectively, which were not statistically significant.

A post-hoc analysis of the data showed that this result is likely due to a high variability in EDSS measurements among patients with low baseline scores (i.e. 0.0 and 1.0).

A subsequent analysis that applied a more rigorous definition of EDSS disability progression reduced the impact of this variability.

Specifically, Gilenya-treated patients showed approximately a 34% reduction of six-month confirmed disability progression compared to placebo when a 1.5 point increase in EDSS was used to define progression in patients with baseline EDSS scores of zero, rather than the pre-specified 1.0 point increase.

This disability reduction outcome is in range with what was seen in previous clinical trials.

Further, study 2309 showed a statistically significant difference from placebo in the Multiple Sclerosis Functional Composite (MSFC), an alternative disability scale pre-defined in the clinical trial.

“The results of this third Phase III study of Gilenya confirm data from the previous two studies that this drug is highly effective in relapsing forms of MS,” said Peter Calabresi, M.D., Professor of Neurology, Johns Hopkins University.

“The absence of an effect on disability in this trial is in contrast to the previous placebo comparison trial and seems to relate to inaccuracies of the EDSS scale at the low end where there is known to be quite a bit of variability.

“Nonetheless, there was a reduction of disability in line with previous trials if one employs a more rigorous definition of change, which is in keeping with the observed reduction in brain atrophy as well as other functional outcome measures of disease progression.”

Safety and tolerability were broadly consistent with the safety profile of fingolimod as characterised in the previous Phase III clinical trials.

There were no deaths in fingolimod treated patients in the trial. Symptomatic bradycardia and associated AV-conduction blocks were rare and none required symptomatic treatment at the fingolimod 0.5 mg dose.

As in previous studies, other adverse events which were observed more frequently in fingolimod-treated patients included liver transaminase elevations, hypertension and lymphopenia.

The overall rate of infections was similar between fingolimod- and placebo-treated patients.

Although herpes viral infections were reported more frequently with fingolimod in this trial, updated integrated analyses of all controlled clinical trials from the fingolimod development program show no differences in the incidence of herpes viral infections between fingolimod and placebo treatment groups.

Malignancies were equally distributed across treatment groups in this study with the exception of basal cell carcinomas of the skin which, although of low incidence, were more frequently reported in fingolimod treated patients.

Study 2309 was a two-year placebo-controlled, parallel-group, multi-center Phase III clinical trial evaluating the efficacy and safety of Gilenya (fingolimod) 0.5 mg in patients with relapsing-remitting multiple sclerosis (RRMS).

Study 2309 was primarily performed to provide specific safety data for the Gilenya New Drug Application (NDA) that was submitted to the US Food and Drug Administration in December 2009.

The study included 1083 patients across 126 sites in eight countries with most of patients enrolled in the United States, and had a central MRI review and independent EDSS raters.

The study included three arms and patients with RRMS were randomised 1:1:1 to fingolimod 1.25 mg, fingolimod 0.5 mg or placebo. Patients who were randomised to the fingolimod 1.25 mg arm were switched to 0.5 mg during the course of the study in a blinded manner based on a determination of superior benefit-risk profile for the 0.5 mg dose in the Phase III studies FREEDOMS and TRANSFORMS.



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