Outcomes of switching directly to oral fingolimod from injectable therapies: Results of the randomized, open-label, multicenter, Evaluate Patient OutComes (EPOC) study in relapsing multiple sclerosis

Fox, Edward J.; Edwards, Keith R.; Burch, Gordon; Wynn, Daniel; LaGanke, Chris; Crayton, Heidi; Hunter, Samuel F.; Huffman, Cynthia; Kim, Edward; Pestreich, Linda; McCague, Kevin; Barbato, Luigi

doi:10.1016/j.msard.2014.06.005

Cited by 76 publications

(83 citation statements)

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“…In fact, the antidepressant effects of fingolimod (3 mg/Kg, i.p. once a day for 4 weeks) have been reported in mice exposed to chronic unpredictable stress and in mice chronically treated with corticosterone, both of which represent models of depression [21] and in patients with relapsing-remitting multiple sclerosis, who switched from injectable disease-modifying therapy to fingolimod [73,74]. In our study, fingolimod did not affect anxiety-like behavior in the EPM test, similar to the findings by di Nuzzo et al [21] in mice.…”

Section: Discussionsupporting

confidence: 90%

Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model

et al. 2017

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One of the major challenges in the epilepsy field is identifying disease-modifying drugs in order to prevent or delay spontaneous recurrent seizure onset or to cure already established epilepsy. It has been recently reported that fingolimod, currently approved for the treatment of relapsing-remitting multiple sclerosis, has demonstrated antiepileptogenic effects in two different preclinical models of acquired epilepsy. However, to date, no data exist regarding the role of fingolimod against genetic epilepsy. Therefore, we have addressed this issue by studying the effects of fingolimod in WAG/Rij rats, a well-established genetic model of absence epilepsy, epileptogenesis, and neuropsychiatric comorbidity. Our results have demonstrated that an early-long term treatment with fingolimod (1 mg/Kg/day), started before absence seizure onset, has both antiepileptogenic and antidepressant-like effects in the WAG/Rij rats. However, these effects were transitory, since 5 months after treatment discontinuation, both absence seizure and depressive like-behavior returned to control level.Furthermore, a temporary reduction of mTOR signaling pathway activity, indicated by reduced p-mTOR and p-p70S6k levels and by an increased p-AKT in WAG/Rij rats of 6 months of age accompanied the transitory antiepileptogenic fingolimod effects. Surprisingly, fingolimod has demonstrated longer-lasting positive effects on cognitive decline in this strain. This effect was accompanied by an increased acetylation of Lysine 8 of histone H4 (both 6 and 10 months of age). In conclusion, our results support the antiepileptogenic effects fingolimod. However, these antiepileptogenic effects were transitory. Moreover, fingolimod might also have a positive impact on animal behavior and particularly in protecting the development of memory decline.

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Section: Discussionsupporting

confidence: 90%

Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model

et al. 2017

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“…Due to differences in study design and included populations, the results could not be meta-analysed and are reported narratively. Three of the studies were RCTs; 85,112,113 five were retrospective cohorts; [114][115][116][117][118] and one was a prospective cohort. 119 Before switching drugs, all participants had been receiving interferon beta-1a, interferon beta-1b or glatiramer acetate and were described as having had a treatment failure, although this term was not always defined 115,117 or was assessed subjectively by the neurologist.…”

Section: Review Questionmentioning

confidence: 99%

“…118 Two studies included specific treatment failure definitions combining relapses (more than one or more than two) and sustained disability worsening (defined as increase in at least 0.5 points or increase in at least 1 point in the EDSS score compared with the year prior to therapy). 114,119 In four studies, participants who switched drugs received fingolimod; [112][113][114][115][116] in two studies, participants switched to natalizumab; 118,119 in one study, participants switched to natalizumab; 117 and in one trial, participants switched to alemtuzumab. 85 Further study characteristics are presented in Supplementary Appendix 4 -Tables 37 and 38.…”

Section: Review Questionmentioning

confidence: 99%

“…115,116 All these studies reported consistent results of a higher proportion of participants discontinuing the study due to any reason in the interferon/ glatiramer acetate group than in the fingolimod group. [113][114][115][116] Switching to natalizumab resulted in a longer time to relapse and to disability worsening (HR = 0.42, 95% CI: 0.24-0.71; HR = 0.38, 95% CI: 0.20-0.71) at 2 years' post-switch, according to evidence with a serious risk of bias. 119 The impact on annualized relapse rate, which held at 2, 3 and 4 years, was confirmed by a later study with a moderate risk of bias (annualized relapse rate of 0.20 vs 0.58), but there was a disproportionately higher drop-out rate in the natalizumab group, which warrants caution when interpreting findings.…”

Section: Review Questionmentioning

confidence: 99%

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ECTRIMS/EAN Guideline on the pharmacological treatment of people with multiple sclerosis

et al. 2018

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Background and scopeMultiple sclerosis (MS) is an inflammatory-demyelinating disease of the central nervous system (CNS) that is characterized by inflammation, demyelination and degenerative changes. MS usually begins around the age between 20 and 40 years and affects two to three times as many women as men; it also constitutes the most frequent cause of non-traumatic disability in the young adult population. 1 The incidence of MS varies across regions, with rates as high as 8 to 10 new cases per 100,000 in high latitudinal regions. 2,3 Current estimates suggest that over 700,000 people are affected in Europe, with over 2.5 million cases worldwide, 4 which represent a significant burden in terms of impact on quality of life, societal costs and personal expenses. 5,6 Most patients (85%-90%) have a relapsing course from onset that is characterized by relapses and remissions of neurological symptoms Methods: This guideline has been developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology and following the updated EAN recommendations. Clinical questions were formulated in Patients-Intervention-Comparator-Outcome (PICO) format and outcomes were prioritized. The quality of evidence was rated into four categories according to the risk of bias. The recommendations with assigned strength (strong and weak) were formulated based on the quality of evidence and the risk-benefit balance. Consensus between the panelists was reached by use of the modified nominal group technique. Results: A total of 10 questions were agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease-modifying drugs approved by the European Medicine Agency (EMA) at the time of publication. A total of 21 recommendations were agreed by the guideline working group after three rounds of consensus. Conclusion:The present guideline will enable homogeneity of treatment decisions across Europe. associated with areas of CNS inflammation, and over the course of two decades, more than half of untreated patients transition to a phase of gradual worsening independent of acute attacks. 7,8 Progressive forms of MS can be present as the initial disease course (primary-progressive MS) in approximately 10%-15% of patients. 9,10 There is no curative treatment available for MS, and the current therapeutic strategy is aimed at reducing the risk of relapses and potentially disability progression. The treatment era for MS began in 1993, when the first interferon became available, and recent years have seen a large expansion in the therapeutic options for MS, with 11 disease-modifying therapies (DMTs) approved by the European Medicine Agency (EMA) in both injectable and oral formulations by the beginning of 2017. 11 The growing armamentarium of therapies brings new opportunities for individualized therapy where patients and providers must balance considerations around efficacy,...

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“…In order to reflect real-world clinical practice, patients did not undergo a washout period before the switch in therapy. The impact of the switch was assessed using a series of patient-and physician-reported outcomes, which included treatment satisfaction, side effects, convenience, fatigue and depression, but the primary analysis did not differentiate according to factors such as patient demographics or previous therapy type [10,11].…”

Section: Introductionmentioning

confidence: 99%

Outcomes of a Switch to Fingolimod to Treat Relapsing Multiple Sclerosis: A Patient Subgroup Post Hoc Analysis

Gudesblatt¹,

Agashivala²,

Simrat³

et al. 2014

J Mult Scler

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Objective: The EPOC study assessed the effects of switching from an injectable disease-modifying therapy (glatiramer acetate or one of three interferon beta drugs) to once-daily, oral fingolimod 0.5 mg in patients with relapsing MS. Outcomes were assessed in several patient subgroups at 6 months between patients who switched to fingolimod and those who continued on iDMT.Methods: Differences in study endpoints between those who switched to fingolimod and those who continued on an iDMT were evaluated by age, gender, baseline Expanded Disability Status Scale score, MS duration, number of relapses in the previous year, previous treatment, previous treatment duration, and reason for switching. The primary endpoint was the change from baseline to month 6 in the Treatment Satisfaction Questionnaire for Medication Global Satisfaction score. Secondary endpoints were changes in scores for the TSQM Effectiveness, Side Effects and Convenience subscales, Beck Depression Inventory-II, Fatigue Severity Scale, Patient-Reported Outcome Indices for Multiple Sclerosis Activities subscale and the 36-item Short-Form Health Survey. Physician-assessed Clinical Global Impressions of Improvement score at 6 months was also recorded.Results: Switching to fingolimod from iDMT significantly improved scores in all subgroups for TSQM Global Satisfaction at month 6 (all comparisons p≤0.001). Switching to fingolimod significantly improved secondary endpoint scores across all scales for most subgroups (p<0.05) with a few exceptions: switching to fingolimod improved PRIMUS Activities scores only in patients with baseline EDSS scores of greater than 2.5 (p<0.05), and did not improve FSS scores in patients who were male, switched for efficacy reasons, received previous glatiramer acetate, or in whom MS symptom onset had occurred less than 3 years ago. For SF-36 scores, the benefit of switching to fingolimod was highly variable. Conclusion:Switching to fingolimod from iDMT improved outcomes versus continuing on iDMT, including for overall treatment satisfaction, in patients with MS with wide-ranging baseline characteristics.

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Outcomes of switching directly to oral fingolimod from injectable therapies: Results of the randomized, open-label, multicenter, Evaluate Patient OutComes (EPOC) study in relapsing multiple sclerosis

Cited by 76 publications

References 30 publications

Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model

Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model

ECTRIMS/EAN Guideline on the pharmacological treatment of people with multiple sclerosis

Outcomes of a Switch to Fingolimod to Treat Relapsing Multiple Sclerosis: A Patient Subgroup Post Hoc Analysis

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