Long-term effects of fingolimod in multiple sclerosis

Abstract

Objective:To assess long-term safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS).Methods:Patients completing FTY720 Research Evaluating Effects of Daily Oral Therapy in MS (FREEDOMS) were eligible for this dose-blinded, parallel-group extension study, continuing fingolimod 0.5 mg/day or 1.25 mg/day, or switching from placebo to either dose, randomized 1:1. Efficacy variables included annualized relapse rate (ARR), brain volume loss (BVL), and confirmed disability progression (CDP). Between-group analyses were conducted in the intent-to-treat (ITT) population from FREEDOMS baseline to end of study. Within-group analyses compared years 0–2 (FREEDOMS) and years 2–4 (extension) in the extension ITT population.Results:Of 1,272 patients (FREEDOMS ITT population), 1,033 were eligible, and 920 enrolled in the extension study (continuous-fingolimod: 0.5 mg [n = 331], 1.25 mg [n = 289]; placebo–fingolimod: 0.5 mg [n = 155], 1.25 mg [n = 145]); 916 formed the extension ITT population (n = 330; n = 287; n = 154; n = 145) and 773 (84%) completed. In the continuous-fingolimod groups, ARR was lower (p < 0.0001), BVL was reduced (p < 0.05), and proportionately more patients were free from 3-month CDP (p < 0.05) than in a group comprising all placebo–fingolimod patients. Within each placebo–fingolimod group, ARR was lower (p < 0.001, both) and BVL was reduced after switching (p < 0.01, placebo–fingolimod 0.5 mg). Rates and types of adverse events were similar across groups; no new safety issues were reported.Conclusion:Efficacy benefits of fingolimod during FREEDOMS were sustained during the extension; ARR and BVL were reduced after switching.Classification of evidence:This study provides Class IV evidence that long-term fingolimod treatment is well-tolerated and reduces relapse rates, disability progression, and MRI effects in patients with RRMS.

Fingolimod: therapeutic mechanisms and ocular adverse effects

“…These studies found no further increased risk of FAME over a period of up to 4.5 years. 2,31 In a retrospective study by Ontaneda et al, 32 a similar incidence (3/317, 0.9%) of macular oedema at 3 months after therapy initiation was reported.…”

“…In vivo, fingolimod is phosphorylated to fingolimodphosphate and becomes structurally similar to a sphingolipid called sphingosine-1-phosphate (S1P), an extracellular mediator, preventing it from binding normally to the five types of S1P receptors (S1PR [1][2][3][4][5]. At the cellular level, it leads to internalisation and eventual degradation of these cell surface receptors and abnormal cellular function and communication.…”

“…1,2 These therapeutic effects in multiple sclerosis therapy are thought to be due to the action of fingolimod on preventing the egression of lymphocytes from lymphoid tissue into the circulation, thereby sparing the central nervous system from attack by myelin-reactive lymphocytes. 3,4 In vivo, fingolimod exerts this immunomodulating effect through a novel mechanism by binding sphingosine-1-phosphate (S1P) receptors on lymphocytes.…”

De novo ceramide synthesis is involved in acute inflammation during labor

“…fingolimod, amitryptiline) (Nahrlich et al, 2013;Kappos et al, 2015). Sphingolipid metabolic rate is enhanced in early pregnancy in the first inflammatory implantation phase (Kaneko-Tarui et al, 2007).…”

A 12-month, Open Label, Multicenter Pilot Study Evaluating Fingolimod Treatment in terms of Patient Satisfaction in Relapsing Remitting Multiple Sclerosis Patients - FINE Trial

“…Phase III, controlled clinical studies with large sample sizes and more than 1000 patients with RRMS demonstrated that fingolimod significantly reduced annualized relapse rates, MRI measures, and brain volume loss compared with placebo and IM interferon -β1a and that its beneficial properties were retained in long-term extension studies (11,12,13,14,15,16).…”