A real world experience with fingolimod in active RRMS patients naïve to second-line agents: a 2 years, intention-to-treat, observational, single center study

Background: Fingolimod is approved by EMA as a second-line treatment for relapsing-remitting multiple sclerosis (RRMS). Experience with fingolimod in real life is still limited. Aim of our study was to report data on fingolimod effectiveness in a real life cohort of Italian active RRMS patients, naïve to second-line agents, followed for 2 years. Fingolimod was a part of the patients’ regular treatment and is produced by Novartis. Methods: We included all consecutive RRMS patients starting fingolimod at our center according to EMA criteria before January 1st 2013. Exclusion criteria were a previous treatment with natalizumab or an immunosuppressant therapy in the previous 12 months. All patients were clinically evaluated quarterly, and performed brain MRI yearly. Definition of “no evidence of disease activity” (NEDA-3): no relapses, no brain MRI activity and no 6-months confirmed worsening in EDSS score. Results: We included 38 RRMS patients, 35 switched from first-line injectable therapies. Six patients were also previously treated with immunosuppressants (5 mitoxantrone, 1 cyclophosphamide). At 24 month 34 patients continued fingolimod treatment. Main adverse events were infections (18 %), liver-enzymes elevation (8 %), and leukopenia (8 %). After 12 and 24 months 79 and 63 % of patients were relapses-free. Fingolimod significantly reduced ARR compared to the previous year (0.3 ± 0.6 vs 1.2 ± 0.5; p < 0.001). After 12 and 24 months 63 and 37 % of patients had NEDA-3. Previous use of immunosuppressants and an ARR ≥1 in the 2 years predicted disease activity. Conclusion: Fingolimod significantly reduce disease activity in active RRMS patients, with no severe/ unexpected safety issues. Patients previously treated with immunosuppressants and with a higher ARR at baseline may respond less to fingolimod treatment. Background Fingolimod (FTY) is the first oral disease-modifying drug (DMD) approved for the treatment of relapsing remitting multiple sclerosis (RRMS). By acting as a functional antagonist on sphingosine-1-phosphate receptor, FTY blocks the capacity of lymphocytes to egress from lymph nodes, reducing their infiltration into the central * Correspondence: [email protected] Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Hospital, Milan, Italy Multiple Sclerosis Study Center, Sant’Antonio Abate Hospital, Via Eusebio Pastori 4, Gallarate, Italy Full list of author information is available at the end of the article © 2016 Baroncini et al. Open Access This arti International License (http://creativecommons reproduction in any medium, provided you g the Creative Commons license, and indicate if (http://creativecommons.org/publicdomain/ze nervous system (CNS) [1]. Once daily FTY 0.5 mg has demonstrated superior efficacy in reducing disease activity with respect to placebo [2, 3] and to intramuscular interferon (IFN) β-1a once/week [4] in randomized clinical trials (RCTs). Main adverse events (AEs) associated with FTY are herpes virus infections, first-dose induced bradycardia, arterial hypertension, macular edema, liverenzymes elevation, and lymphopenia [2–4]. The European Medicines Agency (EMA) approved FTY as a second-line treatment for patients with high disease activity despite treatment with first-line injectables DMDs (i.e. interferons and glatiramer acetate) cle is distributed under the terms of the Creative Commons Attribution 4.0 .org/licenses/by/4.0/), which permits unrestricted use, distribution, and ive appropriate credit to the original author(s) and the source, provide a link to changes were made. The Creative Commons Public Domain Dedication waiver ro/1.0/) applies to the data made available in this article, unless otherwise stated. Table 1 Baseline clinical and demographic characteristics Cohort (38 patients) Gender (male/female) 9/29 Age (y), mean ± SD (range) 39.6 ± 7.3 (26–53) Disease duration (y), mean ± SD (range) 12.0 ± 7.1 (2–31) EDSS score, median (range) 2.0 (0–6) Previous ARR (1y/2y before), mean ± SD 1.2 ± 0.5/0.8 ± 0.4 Previous use of ISs (yes/no) 6/32 Type of ISs (MTX/CTX) 5/1 Time from ISs suspension (y), mean ± SD (range) 7.2 ± 2.1 (4–10) Previous use of DMDs (yes/no) 35/3 Type of DMDs (IFNs/GA/both) 17/5/13 DMDs therapy duration (y), mean ± SD (range) 5.3 ± 3.9 (0.6–15) Legend: y year, SD standard deviation, ARR annual relapse rate, ISs immunosuppressants, MTX mitoxantrone, CTX cyclophosphamide, DMDs first-line disease modyfing drugs, IFNs interferons, GA glatiramer acetate, m months, FTY fingolimod Baroncini et al. Multiple Sclerosis and Demyelinating Disorders (2016) 1:4 Page 2 of 5 or with a rapidly evolving course in patients naïve to DMDs [5]. FTY confirmed its safety and efficacy also in RCTs extension studies [6–8] and in different subgroups of patients [9]. However, drugs efficacy and safety need to be assessed outside the context of RCTs, in real world less selected populations. Until now only few studies have addressed this topic [10–12]. The aim of our study was therefore to better delineate the effectiveness and safety of FTY in a real life set.