Journal of Personalized Medicine Article The Change of Fingolimod Patient Profiles over Time: A Descriptive Analysis of Two Non-Interventional Studies PANGAEA and PANGAEA 2.0 Tjalf Ziemssen 1,* and Ulf Schulze-Topphoff 2 1 Zentrum für Klinische Neurowissenschaften, Universitätsklinikum Carl Gustav Carus, D-01307 Dresden, Germany 2 Novartis Pharma GmbH, D-90429 Nuremberg, Germany; [email protected] * Correspondence: [email protected] Abstract: (1) Background: Fingolimod (Gilenya®) was the first oral treatment for patients with relapsing-remitting multiple sclerosis (RRMS). Since its approval, the treatment landscape has changed enormously. (2) Methods: Data of PANGAEA and PANGAEA 2.0, two German real-world studies, were descriptively analysed for possible evolution of patient profiles and treatment behavior. Both are prospective, multi-center, non-interventional, long-term studies on fingolimod use in RRMS in real life. Data of 4229 PANGAEA patients (recruited 2011–2013) and 2441 PANGAEA 2.0 patients (recruited 2015–2018) were available. Baseline data included demographics, RRMS characteristics and disease severity. (3) Results: The mean age of PANGAEA and PANGAEA 2.0 patients was similar (38.8 vs. 39.2 years). Patients in PANGAEA 2.0 had shorter disease duration (7.1 vs. 8.2 years) and fewer relapses in the year before baseline (1.2 vs. 1.6). Disease severity at baseline estimated by Citation: Ziemssen, T.; EDSS and SDMT was lower in PANGAEA 2.0 patients compared to PANGAEA (EDSS difference Schulze-Topphoff, U. The Change of 1.0 points; SDMT difference 3.3 points). (4) Conclusions: The results hint at an influence of changes in Fingolimod Patient Profiles over the treatment guidelines and the label on fingolimod patients profiles over time. Patients tended to Time: A Descriptive Analysis of Two have lower disease activity at fingolimod initiation, suggesting an earlier intervention. This indicates Non-Interventional Studies increased experience in using fingolimod for sub-optimally treated RRMS patients and a change in PANGAEA and PANGAEA 2.0. J. Pers. Med. 2021, 11, 561. https:// mindset towards an early treatment optimization. doi.org/10.3390/jpm11060561 Keywords: fingolimod; real-world evidence; patient profiles Academic Editors: Massimiliano Mirabella and Davide Quaranta Received: 21 April 2021 1. Introduction Accepted: 10 June 2021 Fingolimod (Gilenya®, Novartis AG) was first approved in 2011 as a once-daily oral Published: 16 June 2021 treatment for patients with highly active relapsing-remitting multiple sclerosis (RRMS). Since its approval, the treatment landscape has changed enormously and the label wording Publisher’s Note: MDPI stays neutral of fingolimod has been adapted several times, which might have altered the profile of with regard to jurisdictional claims in patients starting fingolimod treatment. Two large real-world studies were conducted in published maps and institutional affil- Germany, which could give insight into how patient characteristics might have changed iations. over time. The PANGAEA study recruited patients from 2011 to 2013. At that time, fingolimod was approved for use in RRMS patients fulfilling specific disease activity criteria despite beta interferon pretreatment and in rapidly progressing RRMS. The German guidelines Copyright: © 2021 by the authors. published by the DGN (German Society for Neurology) recommended beta interferons and Licensee MDPI, Basel, Switzerland. glatiramer acetate for first-line RRMS treatment as well as fingolimod and natalizumab for This article is an open access article escalation therapy. Second-line options were azathioprine, intravenous immunoglobulin, distributed under the terms and mitoxantrone or cyclophosphamide, which are rather unspecific immunosuppressive conditions of the Creative Commons or cytotoxic drugs mainly used in oncology or organ transplantation settings. In 2013, Attribution (CC BY) license (https:// teriflunomide and alemtuzumab emerged as new treatment alternatives for RRMS patients creativecommons.org/licenses/by/ (Figure1). 4.0/). J. Pers. Med. 2021, 11, 561. https://doi.org/10.3390/jpm11060561 https://www.mdpi.com/journal/jpm J. Pers. Med. 2021, 11, x FOR PEER REVIEW 2 of 10 J. Pers.2013, Med. 2021 teriflunomide, 11, 561 and alemtuzumab emerged as new treatment alternatives for RRMS2 of 10 patients (Figure 1). Figure 1. Changes in the treatment landscape during recruitment into PANGAEA and PANGAEA 2.0. Figure 1. Changes in the treatment landscape during recruitment into PANGAEA and PANGAEA 2.0. The consecutive real-world study PANGAEA 2.0 recruited patients from 2015 to 2018. By this time, the label of fingolimod had already been extended to the use in patients with The consecutivedisease real- activityworld despitestudy anyPANGAEA DMT and without 2.0 recruited the need topatients fulfil specific from activity 2015 criteria. to An updated version of the DGN guideline published in 2014 no longer distinguishes be- 2018. By this time, thetween label baseline of fingolimod and escalation had therapy, already but been classifies extended treatments to bythe their use efficacy in patients for use in with disease activitymild/moderate despite any andDMT in (highly)and without active forms the ofneed RRMS. to Betafulfil interferons, specific glatirameractivity acetate,cri- teria. An updated versiondimethylfumarate of the DGN and guideline teriflunomide published have since in been 2014 recommended no longer as distinguishes first-line treatment between baseline andoptions escalation for mild/moderate therapy, but RRMS, classifies while fingolimod, treatments alemtuzumab, by their efficacy and natalizumab for use are recommended as first-line treatments for (highly) active RRMS [1]. Furthermore, new MS in mild/moderate andtherapies in (highly) have gained active approval, forms of i.e., RRMS. dimethylfumarate Beta interferon (2014),s, daclizumab glatiramer (2016, ace- with- tate, dimethylfumaratedrawn and 2018 teriflunomide due to safety concerns), have cladribinesince been (2017) recommended and ocrelizumab (2018)as first (Figure-line1). treatment options for mild/moderateIn this analysis, RRMS, we compared while baseline fingolimod, data from alemtuzumab, PANGAEA and and PANGAEA natali- 2.0 in order to evaluate the change in the clinical profile of RRMS patients who switched to zumab are recommendedfingolimod as betweenfirst-line 2011–2013 treatments (PANGAEA) for (highly) and 2015–2018 active (PANGAEA RRMS [1]. 2.0) Further- [2,3]. more, new MS therapies have gained approval, i.e., dimethylfumarate (2014), daclizumab (2016, withdrawn 20182. Materials due to andsafety Methods concerns), cladribine (2017) and ocrelizumab (2018) (Figure 1). PANGAEA 2.0 and PANGAEA were prospective, multi-center, non-interventional, long-term studies of fingolimod (0.5 mg) for the treatment of patients with RRMS. The In this analysis,studies we compared were conducted baseline in Germany data from including PANGAEA office-based and neurologists PANGAEA and neurology2.0 in order to evaluate theclinics. change Patients in the who clinical received profile fingolimod of RRMS according patients to the summary who switched of product characteris-to fin- golimod between 2011tics– were2013 eligible. (PANGAEA) Treatment and followed 2015– common2018 (PANGAEA clinical routine. 2.0) The [2,3]. observation period was up to 36 months in PANGAEA 2.0 and up to 60 months in PANGAEA. Follow-up visits were documented about every three months. While PANGAEA 2.0 only included 2. Materials and Methodspatients naive to fingolimod treatment with a focus on patients with disease activity (i.e., PANGAEA 2.0 relapses,and PANGAEA MRI activity) were despite prospective, current treatment multi with-cente any DMT,r, non PANGAEA-interventional, also recruited patients who had already been treated with fingolimod in a clinical study setting before. long-term studies ofFor fingolimod the purpose (0.5 of this mg) analysis, for onlythe treatment data of PANGAEA of patients patients with treated RRMS. with fingolimod The studies were conductedfor the in first Germany time were consideredincluding to office allow for-based comparison neurologists between both and study neurology populations. clinics. Patients who receivedThis post fingolimod hoc analysis according of the data of to PANGAEA the summ 2.0ary and of PANGAEA product was character- conducted to istics were eligible. Treatmentgain insight onfollowed the clinical common profile of patientsclinical initiating routine. fingolimod The observation nowadays and period patients who started fingolimod in the first years after marketing approval. Therefore, baseline data was up to 36 monthsof in RRMS PANGAEA patients who 2.0 started and onup fingolimod to 60 months during thein yearsPANGAEA. 2011 to 2013 Follow in PANGAEA-up visits were documented about every three months. While PANGAEA 2.0 only included patients naive to fingolimod treatment with a focus on patients with disease activity (i.e., relapses, MRI activity) despite current treatment with any DMT, PANGAEA also re- cruited patients who had already been treated with fingolimod in a clinical study setting before. For the purpose of this analysis, only data of PANGAEA patients treated with fingolimod for the first time were considered to allow for comparison between both study populations. J. Pers. Med. 2021, 11, 561 3 of 10 and baseline data of patients who initiated treatment between 2015 to 2018 in PANGAEA 2.0 were descriptively analysed. Before 2011, treatment alternatives for patients