Fingolimod Effect on Relapse Rate in Young Adult Patients with Multiple Sclerosis

Background: Relapse frequency has been reported to be higher in multiple sclerosis (MS) patients with younger age. To date, no controlled studies have been completed to evaluate disease modifying treatments in pediatric MS patients. 

Objectives: To estimate and compare annualized relapse rates (ARR) for fingolimod 0.5mg, placebo or intramuscular interferon-beta-1a (IFN-beta) in young adult MS patients from Phase 3 pivotal studies, in order to inform sample size requirements for a study of fingolimod in pediatric MS patients.

Methods: A post-hoc analysis of ARR was conducted in the ITT populations of FREEDOMS (2-year study vs placebo) and TRANSFORMS (1-year study vs IFN-beta). A negative binomial regression model with adjustments for treatment, age at baseline (continuous) and a treatment-by-age interaction estimated ARR’s at age 20 years (yrs.) and at age 30 yrs. 

Results: Of all randomized patients in FREEDOMS and TRANSFORMS, respectively, 28/1272 (2.2%) and 40/1292 (3.1%) were aged 20 yrs. or younger; 325/1272 (25.6%) and 355/1292 (27.5%) were aged 30 yrs. or younger at baseline. The estimated ARRs in young patients treated with fingolimod 0.5mg were low irrespective of age and similar to those in the overall fingolimod 0.5mg treatment groups (20 yrs., 30 yrs., overall: ARR=0.16, 0.19, 0.18 in FREEDOMS;  ARR=0.14,  0.17, 0.16 in TRANSFORMS). The estimated ARRs in the control groups were higher in young patients compared to those in the overall control groups (20 yrs., 30 yrs., overall: ARR=0.73, 0.57, 0.40 for placebo in FREEDOMS; ARR=0.60, 0.48, 0.33 for IFN-beta in TRANSFORMS). The estimated relative reduction in ARR in patients aged 20 yrs., 30 yrs. and in the overall population, respectively, was 79%, 67% and 54% vs placebo in FREEDOMS and 77%, 64% and 52% vs IFN-beta in TRANSFORMS (all p<0.001).   

Conclusions:

ARRs in fingolimod 0.5mg treated patients were low and independent of age. The relative treatment effects of fingolimod vs placebo or IFN-beta was higher in the young adult patients compared to the overall population in the fingolimod Phase 3 studies.  For a randomized, double-blind study to evaluate the efficacy of fingolimod vs IFN-beta in pediatric MS patients aged 10 to <18 years (PARADIGMS), a sample size of 190 patients in total was determined to be required to detect a 50% treatment effect on ARR for fingolimod vs IFN-beta. The PARADIGMS study is currently recruiting worldwide.