Date: 2011-12-15
Type of information: Initiation of preclinical development
phase: 3
Announcement: results
Company: Novartis (Switzerland)
Product: Gilenya® (fingolimod)
Action
mechanism: Gilenya®, licensed from Mitsubishi Tanabe Pharma Corporation, is the first in a new class of drugs called sphingosine 1-phosphate receptor (S1PR) modulators. In multiple sclerosis, the immune system damages the covering that protects nerve fibers in the central nervous system which includes the brain and spinal cord. Fingolimod reduces the ability of T cells to move from the lymph nodes towards the brain and spinal cord thus limiting the damage they cause in multiple sclerosis. It does this by blocking the action of a receptor on the T cells called the sphingosine-1-phosphate receptor, which is involved in regulating the movement of these cells in the body.
Disease: relapsing-remitting multiple sclerosis (RRMS)
Therapeutic area: Autoimmune diseases - Neurodegenerative diseases
Country: USA
Trial
details: 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 FDA 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.
Latest
news: Novartis has announced 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.
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.
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.
