Novartis drug Gilenya showed positive clinical outcomes

Once-daily oral MS medicine showed a 48% relative reduction in annualized relapse rate, meeting primary endpoint in Phase III placebo-controlled study

Significant reduction in brain volume loss demonstrated, reinforcing strong efficacy benefit in key secondary endpoint

Basel, December 15, 2011 - Novartis announced today new data from the Phase III 2309 study showing patients with relapsing-remitting multiple sclerosis (RRMS) treated with Gilenya (fingolimod) had a statistically significant 48% reduction in annualized relapse rates (ARR) at 24 months compared to placebo. Study 2309 is the third Phase III clinical trial 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 MRI (magnetic resonance imaging) measure compared to control.

"Study 2309 confirms the efficacy of Gilenya across several key measures, including reductions in annualized relapse rate and reductions in brain volume loss," said David Epstein, Head of the Pharmaceuticals Division at Novartis Pharma AG. "With more than 20,000 patient years of fingolimod exposure to date, Gilenya continues to demonstrate its value to patients and the MS community. We are looking forward to presenting the full data to the clinical community at a scientific congress next year."

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 characterized 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 randomized 1:1:1 to fingolimod 1.25 mg, fingolimod 0.5 mg or placebo. Patients who were randomized 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.

About Gilenya (fingolimod)
Gilenya, licensed from Mitsubishi Tanabe Pharma Corporation, is the first in a new class of compounds called sphingosine 1-phosphate receptor (S1PR) modulators. It has demonstrated superior efficacy compared to Avonex (interferon-beta-1a IM), a commonly prescribed treatment, showing a 52% relative reduction in annualized relapse rate (primary endpoint) and a 40% relative reduction in the rate of brain atrophy (secondary endpoint) at one year in a pivotal head-to-head trial in patients with relapsing-remitting multiple sclerosis.1 In a recent sub-analysis, Gilenya showed a 61% relative reduction in annualized relapse rate compared to interferon-beta-1a (IM) at one year in subgroups of patients with highly active relapsing-remitting MS not responding to interferon treatment.

Gilenya is generally a highly effective once-daily oral MS treatment without label restrictions specific to treatment duration. In clinical trials it was generally well tolerated with a manageable safety profile, and there is increasing experience of Gilenya’s long-term effectiveness and safety profile, with more than 25,000 patients having been treated as of mid October 2011 in clinical trials and in a post-marketing setting. Currently, there is more than 20,000 patient years of exposure. In clinical trials, the most common side effects were headache, liver enzyme elevations, influenza, diarrhea, back pain, and cough. Other Gilenya-related side effects included transient, generally asymptomatic, heart rate reduction and atrioventricular block upon treatment initiation, mild blood pressure increase, macular edema, and mild bronchoconstriction. ,

The rates of infections overall, including serious infections, were comparable among treatment groups, although a slight increase in lower respiratory tract infections (primarily bronchitis) was seen in patients treated with Gilenya. The number of malignancies reported across the clinical trial program was small, with comparable rates between the Gilenya and control groups. ,

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