Long-term safety and real-world effectiveness of fingolimod in relapsing multiple sclerosis

Patient Related Outcome Measures Dovepress open access to scientific and medical research REVIEW Patient Related Outcome Measures downloaded from https://www.dovepress.com/ by 51.68.7.205 on 12-Jul-2018 For personal use only. Open Access Full Text Article Long-term safety and real-world effectiveness of fingolimod in relapsing multiple sclerosis This article was published in the following Dove Press journal: Patient Related Outcome Measures Charlotte Druart Souraya El Sankari Vincent van Pesch Neurology Department, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium Introduction Correspondence: Vincent van Pesch Neurology Department, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, 10 Avenue Hippocrate, Brussels 1200, Belgium Email Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS).1 It affects over 2.3 million people worldwide, and is the most common cause of atraumatic disability in young adults. Its most common clinical presentation is relapsing–remitting MS (RRMS; 85%–90%), in which subacute bouts of neurological worsening seem to be driven at least partly by invasion of the CNS by adaptive immune cells.2,3 As the disease evolves over time, there is disability progression (DP), resulting in reduced quality of life (QoL).4 There is an increasing armamentarium of disease-modifying treatments (DMTs), both injectable and oral, with different mechanisms of action approved for relapsing MS. It is now recognized that the overall objective in treating MS includes preventing relapses, DP, and increase in CNS-lesion burden as seen on magnetic resonance imaging (MRI). These outcomes are included in the composite measure of no evidence of disease activity (NEDA).5,6 NEDA 4 also includes follow-up of brain-volume loss as surrogate marker for neurodegeneration and disability worsening. Phase III randomized controlled trials assess the short-term efficacy and safety of DMTs in a strictly preselected patient population. Real-world evidence (RWE) is defined as data regarding a treatment that are not collected in a randomized controlled trial.7 RWE is gathered in unselected patient populations and can provide more generalizable data and also long-term evidence on a wide variety of end points such 1 submit your manuscript | www.dovepress.com Patient Related Outcome Measures 2018:9 1–10 Dovepress © 2018 Druart et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). http://dx.doi.org/10.2147/PROM.S122401 Powered by TCPDF (www.tcpdf.org) Abstract: With a growing number of disease-modifying therapies becoming available for relapsing multiple sclerosis, there is an important need to gather real-world evidence data regarding long-term treatment effectiveness and safety in unselected patient populations. Although not providing as high a level of evidence as randomized controlled trials, and prone to bias, realworld studies from observational studies or registries nevertheless provide crucial information on real-world outcomes of a given therapy. In addition, evaluation of treatment satisfaction and impact on quality of life are increasingly regarded as complementary outcome measures. Fingolimod was the first oral disease-modifying therapy approved for relapsing multiple sclerosis. This review aims to summarize current knowledge on the long-term effectiveness and safety outcomes of multiple sclerosis patients on fingolimod. Impact on treatment satisfaction and quality of life will be discussed according to available data. Keywords: multiple sclerosis, fingolimod, quality of life, safety, effectiveness, long-term, realworld evidence, patient-reported outcomes Dovepress Patient Related Outcome Measures downloaded from https://www.dovepress.com/ by 51.68.7.205 on 12-Jul-2018 For personal use only. Druart et al as effectiveness, safety or other outcomes, such as patientreported outcomes (PROs). Despite existing bias, due to the non-randomized setting in which data is collected, RWE can still provide evidence that can be used for post-marketing decision making by health care providers or regulatory authorities.8 There is however an unmet need for RWE data, regarding long-term outcomes on more recently introduced DMTs, to understand their comparative benefits in this complex and evolving landscape. PROs are increasingly recognized as complementary outcomes measures to classical end points not captured by classical measures, such as the Expanded Disability Status Scale (EDSS). They can provide additional insight on disease status by evaluating mood, fatigue, treatment satisfaction, and QoL.9 In the setting of MS, a large-scale European survey recently showed that reported decreases in QoL were correlated with increasing disease severity in the domains of mobility, self-care, usual activities, and pain/discomfort.10 Traditional injectable DMTs, such as IFNβ and glatiramer acetate, have been the mainstay of first-line RRMS treatment for the past two decades and have overall good safety profiles. However, the efficacy of these agents may be limited in some patients.11,12 In addition, the need for long-term self-administration of injections imposes a significant burden on patients, because of tolerability issues and injection-site-related side effects.13,14 This can be responsible for reduced treatment persistence in the long run and potentially affects QoL.15 Fingolimod (Gilenya; Novartis International AG, Basel, Switzerland) is a sphingosine 1 phosphate-receptor modulator that selectively and reversibly retains naïve and central memory T-lymphocytes within lymph nodes, thereby preventing them from circulating to other tissues, including the CNS.16 It was the first oral therapy approved to treat relapsing MS by the US Food and Drug Administration (FDA) in September 2010. The European Medicines Agency approved fingolimod for rapidly evolving severe MS or failure of first-line therapy in RRMS in January 2011. In total, three Phase III studies – FREEDOMS, FREEDOMS II, and TRANSFORMS – demonstrated the efficacy of fingolimod in reducing the annualized relapse rate (ARR) and improving MRI outcomes, including slowing of brain-volume loss compared with placebo or intramuscular IFNβ1a.17–19 By May 31, 2017, it was estimated that over 213,000 patients worldwide had been treated with fin (...truncated)