Clinical and Demographic Profile of Patients Receiving Fingolimod in Clinical Practice in Germany and the Benefit–Risk Profile of Fingolimod After 1 Year of Treatment: Initial Results From the Observational, Noninterventional Study PANGAEA

Neurotherapeutics https://doi.org/10.1007/s13311-017-0595-y ORIGINAL ARTICLE Clinical and Demographic Profile of Patients Receiving Fingolimod in Clinical Practice in Germany and the Benefit–Risk Profile of Fingolimod After 1 Year of Treatment: Initial Results From the Observational, Noninterventional Study PANGAEA Tjalf Ziemssen 1 & Michael Lang 2 & Björn Tackenberg 3 & Stephan Schmidt 4 & Holger Albrecht 5 & Luisa Klotz 6 & Judith Haas 7 & Christoph Lassek 8 & Jennie Medin 9 & Christian Cornelissen 10 & on behalf of the PANGAEA study group # The Author(s) 2017. This article is an open access publication Abstract The population with multiple sclerosis receiving treatment in clinical practice differs from that in randomized controlled trials (RCTs). An assessment of the real-world benefit–risk profile of therapies is needed. This analysis used data from the large, noninterventional, observational German study Post-Authorization Non-interventional German sAfety study of GilEnyA (PANGAEA) to assess prospectively baseline characteristics and outcomes after 12 months (± 90 days) of fingolimod treatment. Patients were divided into 2 cohorts: fingolimod starter [first received fingolimod in PANGAEA (n = 3315)] and previous study [received fingolimod before enrollment in PANGAEA in RCTs (n = 875), some of whom also had baseline data at entry into RCTs (n = 505)]. At PANGAEA baseline, patients in the fingolimod starter versus the previous study cohort had a higher annualized relapse rate [ARR (95% confidence interval): 1.79 (1.75–1.83) vs 1.32 (1.25–1.40)] and Expanded Disability Status Scale score [3.11 (3.04–3.17) vs 2.55 (2.44–2.66)]. A greater proportion in the fingolimod starter versus previous study cohort had diabetes (2.0% vs 0.7%). After 12 months of fingolimod, ARRs were lower than in the 12 months before PANGAEA enrollment in the fingolimod starter [0.386 (0.360–0.414)] and previous study [0.276 (0.238–0.320)] cohorts. Expanded Disability Status Scale scores were stable versus baseline. Adverse events were experienced by similar proportions in both cohorts during fingolimod treatment. Relevant differences exist in disease activity and comorbidities between patients receiving fingolimod in clinical practice versus RCTs. Irrespective of baseline differences indicating a higher proportion at an advanced stage of multiple sclerosis in the real world versus RCTs, fingolimod remains effective, with a manageable safety profile. Keywords Multiple sclerosis . Fingolimod . Real-world evidence . Benefit–risk profile . Observational study Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13311-017-0595-y) contains supplementary material, which is available to authorized users. * Tjalf Ziemssen 1 2 3 Center of Clinical Neuroscience, Neurological University Clinic Carl Gustav Carus, University of Technology, Dresden, Germany NeuroPoint Patient Academy and Neurological Practice, Ulm, Germany Department of Neurology, Clinical Neuroimmunology Group, Philipps-University, Marburg, Germany 4 Bonn Neurological Practice, Bonn, Germany 5 Neurological Practice, Munich, Germany 6 Department of Neurology, University Hospital Münster, Münster, Germany 7 Center for Multiple Sclerosis, Jewish Hospital Berlin, Berlin, Germany 8 Kassel and Vellmar Neurological Practice, Vellmar, Germany 9 Novartis Pharma AG, Basel, Switzerland 10 Novartis Pharma GmbH, Nuremberg, Germany T. Ziemssen et al. Introduction Randomized controlled trials (RCTs) of disease-modifying therapies (DMTs) in multiple sclerosis (MS) are designed to evaluate treatment efficacy. In order to minimize the influence of confounding factors, such as concomitant diseases, RCTs often include a highly selected population of patients who are treated in specialist environments under optimal, restricted conditions [1–3]. RCTs generate high-quality data required for regulatory approval, but the experimental conditions under which they are conducted and the specific population that they often investigate mean that results may not be generalizable to the clinical use of DMTs in the real world [1, 4]. Following marketing authorization, robust real-world studies are needed to assess the safety and effectiveness of DMTs in the population of patients being treated in clinical practice, including those with characterized comorbidities and using concomitant medications [4–6]. In light of the need for robust real-world data following RCTs, the large, prospective, observational 5-year real-world Post-Authorization Non-interventional German sAfety study of GilEnyA (PANGAEA) has been initiated to investigate the effectiveness and safety of fingolimod 0.5 mg (Gilenya; Novartis Pharma AG, Basel, Switzerland) in clinical practice [7]. Real-world data can also be collected retrospectively from existing data sources, such as MS registries, including the international patient registry MSBase. However, such registries tend to focus on treatment effectiveness, and provide limited safety information, whereas PANGAEA has been designed to collect robust data for both safety and effectiveness [1, 7–9]. In the European Union (EU), fingolimod is indicated for patients with highly active MS, despite previous treatment with at least 1 DMT, and for individuals with rapidly evolving severe relapsing–remitting MS [10]. In contrast, the pivotal phase III RCTs included in the marketing authorization application to the European Medicines Agency for fingolimod [FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS), FREEDOMS II, and Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing–Remitting Multiple Sclerosis (TRANSFORMS)] were designed to investigate fingolimod as a first-line DMT, which was the original intended label for fingolimod (see Table S1 for the eligibility criteria of these RCTs) [11–13]. Individuals in clinical practice who are eligible to receive fingolimod according to the EU label are therefore likely to have more advanced disease than those in the pivotal fingolimod RCTs, and PANGAEA will provide data with which to assess fingolimod in this real-world population [11–13]. Patients aged over 55 years with comorbidities such as diabetes mellitus and specified cardiovascular, pulmonary, hepatic, or autoimmune conditions, and those receiving certain concomitant medications were excluded from the 3 pivotal RCTs [11–13]. For PANGAEA, the only exclusion criteria were the contraindications listed in the European fingolimod Summary of Product Characteristics [10]. PANGAEA will therefore provide data for assessing the long-term benefit–risk profile of fingolimod in subgroups of patients with comorbidities or receiving concomitant medications who can receive the drug according to the EU label but who would have been excluded from clinical trials [7]. PANGAEA investigates all patients receiving fingolimod in clinical practice according to the EU (...truncated)