Fingolimod Shows Benefit in RRMS in a Third Phase 3 Trial

Emma Hitt, PhD

December 15, 2011

December 15, 2011 — Fingolimod (Gilenya, Novartis), the first daily oral medication indicated for relapsing remitting multiple sclerosis (RRMS), showed a 48% relative reduction in annualized relapse rate (ARR) at 24 months compared with placebo, meeting the primary endpoint of the phase 3 trial.

The study also demonstrated a significant reduction in the secondary endpoint of brain volume loss. In addition, safety and tolerability were broadly consistent with previous clinical trials, a media release from the company notes.

No deaths were reported in the trial. However, earlier this week, Novartis confirmed that it is investigating a death that occurred the day after the patient received a first dose of fingolimod, as reported by Medscape Medical News. A statement from the company noted that this was the first reported death to occur within 24 hours of taking a first dose of fingolimod in the more than 28,000 patients who have received the drug to date.

The current trial, called the 2309 study, included 1083 patients with RRMS across 126 sites in 8 countries. Most of patients were enrolled in the United States. Patients were randomly assigned in a ratio of 1:1:1 to receive fingolimod 1.25 mg, fingolimod 0.5 mg, or placebo.

Patients who were assigned to the fingolimod 1.25 mg control group were switched to 0.5 mg during the course of the study in a blinded manner on the basis of a determination of a superior benefit-risk profile for the 0.5-mg dose in a phase 3 study reported by Medscape Medical News.

Fingolimod-treated patients showed a 48% reduction in ARR at 24 months compared with patients receiving placebo. The trial findings support positive results from two previous studies that compared fingolimod with interferon-beta-1a. In those studies, both agents showed more than a 50% reduction in ARR.

"Study 2309 confirms the efficacy of Gilenya across several key measures, including reductions in annualized relapse rate and reductions in brain volume loss," noted David Epstein, head of the pharmaceuticals division at Novartis Pharma AG, in a company written release.

"With more than 20,000 patient years of fingolimod exposure to date, Gilenya continues to demonstrate its value to patients and the MS community,” he said. “We are looking forward to presenting the full data to the clinical community at a scientific congress next year."

Patients receiving fingolimod had a nonsignificant 17% and 28% reduction in 3-month and 6-month confirmed disability progression compared with patients receiving placebo, as measured by the Expanded Disability Status Scale (EDSS), respectively. According to the authors, the lack of a significant benefit in this measure might result from a high variability in EDSS measurements among patients with low baseline scores.

“A subsequent analysis that applied a more rigorous definition of EDSS disability progression reduced the impact of this variability,” they note.

Safety and tolerability were comparable to that observed in previous phase 3 clinical trials. Symptomatic bradycardia and associated atrioventricular conduction block were rare, and no episode required symptomatic treatment for patients receiving 0.5-mg doses of fingolimod. Fingolimod was also associated with an increase in the incidence of liver transaminase elevations, hypertension, and lymphopenia.

Infection rates were comparable between fingolimod- and placebo-treated patients. Although herpes viral infections were reported more frequently in patients treated with fingolimod in the study 2309 trial, this was not seen in all trials combined. Basal cell carcinomas of the skin were rare but were more frequently reported in fingolimod-treated patients.

"The results of this third phase 3 study of Gilenya confirm data from the previous 2 studies that this drug is highly effective in relapsing forms of MS," said Peter Calabresi, MD, professor of neurology at Johns Hopkins University School of Medicine in the Novartis media release.

Media release from Novartis Pharma AG, December 15, 2011.

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