BACKGROUND AND OBJECTIVE: Once-daily oral fingolimod is approved in the EU as escalation treatment for adult patients with highly active relapsing multiple sclerosis (MS). The efficacy and safety profiles of fingolimod have been well established in a large clinical development programme and several papers reflecting the experience with fingolimod in real-world settings have been published to date. The GOLEMS study was designed to evaluate the efficacy, safety and tolerability of fingolimod and the impact of fingolimod treatment on disability progression and work capability in patients with MS in routine clinical practice in the Czech Republic. METHODS: GOLEMS was a national, multicentre, non-interventional, single-arm study conducted to analyse the outcomes of a minimum of 12 months of fingolimod therapy on primary and secondary endpoints. The primary endpoint was to assess the proportion of relapse-free patients and severity of MS relapses in patients treated with fingolimod for 12 months. Secondary endpoints included assessment of changes in disability progression evaluated by the Expanded Disability Status Scale (EDSS) score and work capability assessment measured through voluntary completion of the WPAI-GH questionnaire. The predictive factors for relapse-free status during fingolimod treatment were also analysed. RESULTS: Of the 240 enrolled patients, 219 completed the 12-month treatment period at the time of final analysis. In the efficacy set (N = 237), the proportion of relapse-free patients increased from 47 patients (19.6 %; 95 % confidence interval [CI] 14.8-25.2) in the year before fingolimod initiation to 152 patients (64.1 %; 95 % CI 58.0-70.2) after 1 year of fingolimod treatment. Of the 85 patients who experienced at least one relapse after 1 year of fingolimod treatment, 53 (62.4 %; 95 % CI 51.7-71.9) reported only one relapse, while 25 (29.4 %; 95 % CI 20.8-39.8) and seven (8.2 %; 95 % CI 4.0-16.0) patients had ≥2 relapses, respectively. No significant changes were observed in EDSS scores over the 12-month treatment period compared with baseline. The absolute number of relapses during 2 years before initiation of fingolimod treatment and baseline EDSS scores were identified as significant independent predictors for 'being relapse-free' during the 12-month fingolimod treatment period. No trend was established in work capability or number of missed days at work due to the large proportion of missing data. Of 240 enrolled patients, 27 (11.3 %) patients discontinued the study at or before the 12-month visit, 16 (6.7 %) discontinued because of adverse events related to study drug. Only six (2.5 %) patients reported serious adverse events related to the study drug. CONCLUSION: The results confirm the favourable safety and efficacy profile of fingolimod under real-world conditions, consistent with phase III trials.

Aprova s r o Brno Czech Republic

MS Center Department of Neurology and Center of Clinical Neuroscience 1st Faculty of Medicine and General University Hospital Prague Charles University Katerinska 30 120 00 Prague Czech Republic

Novartis s r o Na Pankraci 1724 129 14000 Prague Czech Republic

Zobrazit více v PubMed

European Medicines Agency: Gilenya (fingolimod) Product information EMEA/H/C/002202 -II-26-G. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002202/human_med_001433.jsp&mid=WC0b01ac058001d125. Accessed 21 Oct 2016.

Pelletier D, Hafler DA. Fingolimod for multiple sclerosis. N Eng J Med. 2012;366(4):339–347. doi: 10.1056/NEJMct1101691. PubMed DOI

Brinkmann V, Billich A, Baumruker T, Heining P, Schmouder R, Francis G, Aradhye S, Burtin P. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov. 2010;9:883–897. doi: 10.1038/nrd3248. PubMed DOI

Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, Burtin P, FREEDOMS Study Group A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Eng J Med. 2010;362:387–401. doi: 10.1056/NEJMoa0909494. PubMed DOI

Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, Tiel-Wilck K, de Vera A, Jin J, Stites T, Wu S, Aradhye S, Kappos L; TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Eng J Med. 2010;362:402–15. PubMed

Calabresi PA, Radue EW, Goodin D, Jeffery D, Rammohan KW, Reder AT, Vollmer T, Agius MA, Kappos L, Stites T, Li B, Cappiello L, von Rosenstiel P, Lublin FD. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): A double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13:545–556. doi: 10.1016/S1474-4422(14)70049-3. PubMed DOI

Novartis Pharmaceuticals Q2 2016 Condensed Interim Financial Report; Data as of second quarter of 2016. https://www.novartis.com/sites/www.novartis.com/files/2016-07-interim-financial-report-en.pdf. Accessed 04 Sep 2016.

Laroni A, Brogi D, Morra VB, Guidi L, Pozzilli C, Comi G, Lugaresi A, Turrini R, Raimondi D, Uccelli A. Mancardi GL; EAP Investigators. Safety of the first dose of fingolimod for multiple sclerosis: results of an open-label clinical trial. BMC Neurol. 2014;14:65. doi: 10.1186/1471-2377-14-65. PubMed DOI PMC

McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sandberg-Wollheim M, Sibley W, Thompson A, van den Noort S, Weinshenker BY, Wolinsky JS. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol. 2001;50:121–127. doi: 10.1002/ana.1032. PubMed DOI

Panitch H, Goodin DS, Francis G, Chang P, Coyle PK, O’Connor P, Monaghan E, Li D, Weinshenker B; EVIDENCE Study Group. EVidence of Interferon Dose-response: Europian North American Compartative Efficacy; University of British Columbia MS/MRI Research Group Randomized, comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE Trial. Neurology. 2002;59:1496–1506. doi: 10.1212/01.WNL.0000034080.43681.DA. PubMed DOI

Kappos L, Antel J, Comi G, Montalban X, O’Connor P, Polman CH, Haas T, Korn AA, Karlsson G, Radue EW, FTY720 D2201 Study Group Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med. 2006;355:1124–1140. doi: 10.1056/NEJMoa052643. PubMed DOI

Ziemssen T, Fuchs A, Schwarz HJ. 24-month PANGAEA: a 5-year non-interventional study of safety, efficacy and pharmacoeconomic data for fingolimod patients in daily clinical practice. Mult Scler. 2014;20(S1):67–284.

Achiron A, Sarova-Pinhas I, Magalashvili D, Dolev M, Raz H, Chapman J. Clinical factors predicting better outcome of acute multiple sclerosis relapses. Mult Scler. 2007;13:S7–S273.

Ramo-Tello C, Tintore M, Rovira A, Ramió-Torrenta L, Brieva L, Saiz A, Cano A, Carmona O, Hervás JV, Grau-López L. Baseline clinical status as a predictor of methylprednisolone response in multiple sclerosis relapses. Mult Scler. 2016;22:117–121. doi: 10.1177/1352458515590648. PubMed DOI

Hoepner R, Havla J, Eienbröker C, Tackenberg B, Hellwig K, Meinl I, Hohlfeld R, Gold R, Kümpfel T, Kleiter I. Predictors for multiple sclerosis relapses after switching from natalizumab to fingolimod. Mult Scler. 2014;20:1714–1720. doi: 10.1177/1352458514533398. PubMed DOI

Devonshire V, Havrdova E, Radue EW, O’Connor P, Zhang-Auberson L, Agoropoulou C, Häring DA, Francis G, Kappos L, FREEDOMS study group Relapse and disability outcomes in patients with multiple sclerosis treated with fingolimod: subgroup analyses of the double-blind, randomised, placebo-controlled FREEDOMS study. Lancet Neurol. 2012;11:420–428. doi: 10.1016/S1474-4422(12)70056-X. PubMed DOI

Baldi E, Guareschi A, Vitetta F, Senesi C, Curti E, Montepietra S, Simone AM, Immovilli P, Caniatti L, Tola MR, Pesci I, Montanari E, Sola P, Granella F, Motti L, Ferraro D. Previous treatment influences fingolimod efficacy in relapsing-remitting multiple sclerosis: results from an observational study. Curr Med Res Opin. 2014;30:1849–1855. doi: 10.1185/03007995.2014.921144. PubMed DOI

Ziemssen T, Kern R, Cornelissen C. The PANGAEA study design—a prospective, multicenter, non-interventional, long-term study on fingolimod for the treatment of multiple sclerosis in daily practice. BMC Neurol. 2015;15:93. doi: 10.1186/s12883-015-0342-0. PubMed DOI PMC

Al-Hashel J, Ahmed SF, Behbehani R, Alroughani R. Real-world use of fingolimod in patients with relapsing remitting multiple sclerosis: a retrospective study using the national multiple sclerosis registry in Kuwait. CNS Drugs. 2014;28:817–824. doi: 10.1007/s40263-014-0185-z. PubMed DOI

Totaro R, Costantino G, Bellantonio P, Danni M, Carmine CD, Fantozzi R, Cerqua R, Fuiani A, Carrocci C, Mundi C, Ruggieri S, Marini C, Provinciali L, Carolei A. Efficacy of natalizumab and fingolimod in relapsing remitting multiple sclerosis in real world clinical setting. J Neurol Neurophysiol. 2015;6:337.

Baroncini D, Zaffaroni M, Annovazzi PO, Baldini S, Bianchi A, Minonzio G, Comi G, Ghezz A. 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. Multiple Sclerosis Demyelinating Disord. 2016;1:4.

Rasenack M, Rychen J, Andelova M, Naegelin Y, Stippich C, Kappos L, Lindberg RL, Sprenger T. Derfuss T efficacy and safety of fingolimod in an unselected patient population. PLoS One. 2016;11:e0146190. doi: 10.1371/journal.pone.0146190. PubMed DOI PMC

Yamout BI, Zeineddine MM, Tamim H, Khoury SJ. Safety and efficacy of fingolimod in clinical practice: The experience of an academic center in the Middle East. J Neuroimmunol. 2015;289:93–97. doi: 10.1016/j.jneuroim.2015.10.015. PubMed DOI

Correia I, Batista S, Marques IB, Sousa M, Ferreira R, Nunes N, Macário MC, Sousa L. The effectiveness of fingolimod in a Portuguese real-world population. Mult Scler Rel Dis. 2016;6:41–48. doi: 10.1016/j.msard.2016.01.003. PubMed DOI

Cornelissen C, Albrecht H, Haas J, Klotz L, Lang M, Lassek C, Schmidt S, Tackenberg B, Ziemssen T. 4 Years PANGAEA: a 5-year non-interventional study of safety, effectiveness and pharmacoeconomic data for fingolimod patients in daily clinical practice—effectiveness update. Neurology, 2016;86(Suppl):P3.072.

Real-world effectiveness and safety of fingolimod in patients with multiple sclerosis in the Czech Republic: results from core and extension parts of the GOLEMS study up to 48 months