Regulatory Decision Summary for Gilenya

The efficacy and safety of oral fingolimod in the treatment of Relapsing Remitting Multiple Sclerosis (RRMS) in pediatric patients aged 10 years to less than 18 years was established on the results of a pivotal Phase III study (D2311; PARADIGMS). PARADIGMS was a randomized, double-blind, double-dummy, multi-center, active-controlled study evaluating the efficacy/safety of fingolimod once daily (weight-based dosing; 0.25 mg ≤40 kg or 0.5 mg >40 kg) vs. Interferon beta-1a (IFN β-1a) 30 µg i.m. once/week in pediatric patients with MS aged 10 to <18 years. In total, 215 patients were randomized: 107 patients to the fingolimod arm and 108 patients to the IFN β-1a arm.

The primary efficacy endpoint, annualized relapse rate (ARR) up to 24 months, was met, demonstrating statistically superior efficacy of fingolimod vs. IFN β-1a in the treatment of pediatric patients with MS. Treatment with fingolimod for up to 24 months corresponded to a reduction of 81.9% in ARR compared with IFN β-1a, which is statistically significant (p<0.001). The key secondary endpoint was also met showing a statistically significantly lower annualized rate of the number of new or newly enlarged T2 lesions in fingolimod compared with IFN β-1a in the 24 month period (52.6% reduction; p<0.001). For other pre-specified secondary endpoints, fingolimod demonstrated efficacy over IFN β-1a.

The safety profile of oral fingolimod in the pediatric MS population (aged 10 to <18 years) displayed an overall similar safety profile to the adult MS population with exception of increased incidence of events related to seizures and depression/suicidal ideation, which have been risk managed through labeling in both the Warnings and Precautions and Adverse Reactions sections of the Gilenya product monograph. The major limitation and uncertainty in the safety assessment of the pediatric MS study is the relatively smaller safety population when compared to the larger population sizes for the adult MS registration trials. Consistent with recommendations for adult MS patients being treated with fingolimod, upon initiating fingolimod treatment it is recommended that all pediatric MS patients be observed, with hourly pulse and blood pressure measurements, for a period of 6 hours for signs and symptoms of bradycardia. All patients should have an electrocardiogram performed prior to dosing and at the end of the 6-hour monitoring period; these first dose monitoring procedures also apply when switching from a 0.25 mg to a 0.5 mg daily dose. Information regarding drug interactions, contraindications and warnings and precautions for pediatric MS patients reflects the approved labeling for adult MS patients where applicable. In addition, pediatric MS patients are recommended to have completed all immunizations in accordance with current immunization guidelines prior to initiating fingolimod treatment.

The study duration may not have allowed for a complete characterization of late-onset adverse events that may or may not be related to chronic treatment such as effects on growth, bone development, infections, etc. Vigilance of adverse events collected through the long-term extension phase study (still ongoing) should help address this concern.

At this point in time, considering the above safety issues identified during the review, the benefit-risk-uncertainty profile for oral fingolimod in the treatment of pediatric RRMS is favourable when Gilenya is used in accordance with recommendations outlined in the Product Monograph.