Fingolimod Treatment Initiation Research Articles

Ocrelizumab experience in treatment-resistant warts associated with Fingolimod: A case report

Fingolimod is a sphingosine 1-phosphate (S1P) analogue that has antagonistic effects on S1P receptors. It creates an immunosuppressive effect by decreasing the number of circulating lymphocytes by preventing the exit of lymphocytes from lymphoid tissues. The causal link between fingolimod treatment and warts has not yet been proven. Herein, we report a case of relapsing–remitting multiple sclerosis in which multiple warts developed on the right hand over the years after the initiation of fingolimod treatment and disappeared completely after discontinuation of treatment. Conclusions: The temporal relationship between discontinuation of treatment and healing of lesions, as in our case, supports a possible causal role of fingolimod and new warts did not form while receiving ocrelizumab treatment.

Fingolimod treatment modulates PPARγ and CD36 gene expression in women with multiple sclerosis.

Fingolimod is an oral immunomodulatory drug used in the treatment of multiple sclerosis (MS) that may change lipid metabolism. Peroxisome proliferator-activated receptors (PPAR) are transcription factors that regulate lipoprotein metabolism and immune functions and have been implicated in the pathophysiology of MS. CD36 is a scavenger receptor whose transcription is PPAR regulated. The objective of this study was to evaluate whether fingolimod treatment modifies PPAR and CD36 gene expression as part of its action mechanisms. Serum lipoprotein profiles and PPAR and CD36 gene expression levels in peripheral leukocytes were analysed in 17 female MS patients before and at 6 and 12 months after fingolimod treatment initiation. Clinical data during the follow-up period of treatment were obtained. We found that fingolimod treatment increased HDL-Cholesterol and Apolipoprotein E levels and leukocyte PPARγ and CD36 gene expression. No correlations were found between lipid levels and variations in PPARγ and CD36 gene expression. PPARγ and CD36 variations were significantly correlated during therapy and in patients free of relapse and stable disease. Our results suggest that PPARγ and CD36-mediated processes may contribute to the mechanisms of action of fingolimod in MS. Further studies are required to explore the relation of the PPARγ/CD36 pathway to the clinical efficacy of the drug and its involvement in the pathogenesis of the disease.

Treatment satisfaction and quality of life in patients treated with fingolimod.

BackgroundThe development of oral treatments for relapsing–remitting multiple sclerosis (RRMS) may alter patient satisfaction and quality of life (QoL). The aim of this survey was to evaluate treatment satisfaction and QoL in patients treated with fingolimod in everyday clinical practice in France.MethodsNeurologists treating MS in France were invited to participate in the survey by telephone. Each physician was expected to recruit up to six patients with RRMS currently being treated with fingolimod. Enrolled patients were asked to complete the Treatment Satisfaction Questionnaire for Medication (TSQM), the 3-level 5-dimension EuroQoL instrument, as well as specific questions on change in QoL since starting fingolimod. Factors associated with the TSQM score were evaluated using multiple logistic regression analysis.ResultsTwo hundred and fourteen patients were recruited by 54 neurologists. The mean age of the patients was 41.6±10.0 years, and 73.4% of them were women. During the hospitalization for initiation of fingolimod treatment, 70.1% of patients had received information on MS, 76.6% had received information on fingolimod, and 20.7% had participated in a therapeutic education program. The two variables with the strongest associations with high TSQM scores (≥75) were a positive perception of initial hospitalization (hazard ratio: 10.27) and receiving information on MS during hospitalization (hazard ratio: 5.70). The mean EQ-visual analog scale score was 71.6±16.8. The mean EQ-visual analog scale score was significantly higher in patients satisfied with their treatment (75.8±15.2) compared to those unsatisfied with treatment (66.6±17.2). The proportion of patients who reported an improvement in their capacity to plan for the future was higher in satisfied (72.6%) than in unsatisfied patients (49.5%).ConclusionThe majority of patients treated with fingolimod are satisfied with their treatment. Treatment satisfaction is associated with better self-rated QoL and an improvement of QoL since starting treatment.

Patient initiation of fingolimod treatment: comparison of cardiac monitoring in-clinic and in the Gilenya@Home program (P5.347)

Patient initiation of fingolimod treatment: comparison of cardiac monitoring in-clinic and in the Gilenya@Home program (P5.347)

Real-World Outcomes in Fingolimod-Treated Patients with Multiple Sclerosis in the Czech Republic: Results from the 12-Month GOLEMS Study.

Background and ObjectiveOnce-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.MethodsGOLEMS 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.ResultsOf 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.ConclusionThe results confirm the favourable safety and efficacy profile of fingolimod under real-world conditions, consistent with phase III trials.

Early safety and efficacy of fingolimod treatment in Denmark.

Initiation of fingolimod treatment is associated with a transient decrease of heart rate, and atrioventricular (AV) conduction block may occur. To evaluate the therapeutic effect and safety of fingolimod treatment in MS patients in Denmark with focus on cardiac and pulmonary side effects at treatment onset. We analysed data from the first 496 fingolimod-treated Danish patients, observed for at least 3 months. In a subset of 204 patients, we monitored cardiac and pulmonary adverse effects following treatment initiation. The overall annualized relapse rate (ARR) was 0.37 (95% CI 0.31-0.44); 0.22 (95% CI 0.03-0.81) in de novo-treated patients, 0.29 (95% CI; 0.23-0.37) in patients switching from IFN-beta or GA and 0.46 (9 5% CI 0.34-0.60) after natalizumab. In the subset of 204 patients, 8 (3.9%) required prolonged cardiac monitoring due to bradycardia and/or second-degree AV block type I. All patients recovered spontaneously. Two patients discontinued fingolimod. Eleven (5.4%) patients reported respiratory complaints and two of these patients discontinued treatment. Fingolimod appears to be safe and effective in MS patients in a clinical setting. Mild cardiac adverse effects occurred at a similar rate as in clinical trials.

Onset of clinical and MRI efficacy occurs early after fingolimod treatment initiation in relapsing multiple sclerosis.

To minimize the clinical burden associated with multiple sclerosis (MS), early control of focal and diffuse CNS disease activity is a treatment priority. A post hoc analysis was conducted to evaluate the onset of efficacy of fingolimod treatment in patients with relapsing MS. Data from patients who received fingolimod 0.5 mg or placebo during either of two 24-month, double-blind, randomized, parallel-group clinical trials (FREEDOMS and FREEDOMS II) were pooled for analysis. Efficacy outcomes were: time to first confirmed relapse; annualized relapse rate (ARR); proportions of patients free from T1 gadolinium-enhancing lesions or new/newly enlarged T2 lesions; percentage brain volume loss (BVL); and change in Multiple Sclerosis Functional Composite (MSFC) z-score from baseline to 6 months. An early benefit was seen with fingolimod (N = 783) vs. placebo (N = 773) for ARR at both 3 and 6 months (3 months, 0.32 vs. 0.52, p = 0.0015; 6 months, 0.21 vs. 0.45, p < 0.0001). Time to first relapse was also delayed with fingolimod vs. placebo from day 48 onwards. At 6 months, more patients in the fingolimod group than in the placebo group were free from new MRI activity (65.3 vs. 40.5 %, p < 0.0001) and had less BVL (37.1 % reduction vs. placebo, p < 0.001). MSFC z-score favored fingolimod over placebo at 6 months, with improvements noted in 9-Hole Peg Test and Paced Auditory Serial Addition Test scores. Improvements in outcomes related to relapses, MRI, disability, cognition, and BVL occurred within 6 months of treatment initiation with fingolimod.Electronic supplementary materialThe online version of this article (doi:10.1007/s00415-015-7978-y) contains supplementary material, which is available to authorized users.

Assessment of immune functions and MRI disease activity in relapsing-remitting multiple sclerosis patients switching from natalizumab to fingolimod (ToFingo-Successor).

BackgroundIn light of the increased risk of progressive multifocal encephalopathy (PML) development under long-term treatment with the monoclonal antibody natalizumab which is approved for treatment of active relapsing remitting multiple sclerosis (RRMS), there is a clear need for alternative treatment options with comparable efficacy and reduced PML risk. One such option is fingolimod, a functional sphingosin-1-receptor antagonist that has been approved as first oral drug for treatment of active RRMS. However, the optimal switching design in terms of prevention of disease reoccurrence is still unknown. Moreover, potential additive effects of both drugs on immune functions, especially with regard to migration, have not yet been evaluated.Methods/designThis is an exploratory, open-label, monocentric, investigator-initiated clinical trial. Fifteen RRMS patients under stable treatment with natalizumab will receive one last natalizumab infusion followed by a wash-out period of 8 weeks before fingolimod treatment initiation for a period of 24 weeks. Disease activity under natalizumab and during switching will be closely monitored by assessment of relapse rate and disease severity as well as high-frequent high-resolution magnetic resonance imaging including quantitative diffusion tensor imaging. Immunological assays include longitudinal assessment of adhesion molecule expression, functional evaluation of the migratory capacity of immune cells in an in-vitro model of the blood–brain-barrier, and the quality of cellular antiviral immune responses.DiscussionOur trial represents the first detailed and longitudinal functional analysis of key immunological parameters in the process of switching from natalizumab and fingolimod, especially with regard to potential additive effects of both drugs on trafficking and immune surveillance. Moreover, our study will generate valuable information about even subtle disease exacerbations as consequence of natalizumab cessation, which will help to understand whether a switching protocol containing a wash-out period of 8 weeks before fingolimod treatment is appropriate in terms of disease stability.

Fingolimod first-dose effects in patients with relapsing multiple sclerosis concomitantly receiving selective serotonin-reuptake inhibitors

Selective serotonin-reuptake inhibitors (SSRIs), commonly administered for depression and anxiety in patients with multiple sclerosis, are associated with QT interval prolongation. Fingolimod (FTY720; Gilenya®, Novartis Pharma AG) is a first-in-class sphingosine 1-phosphate receptor modulator approved for relapsing forms of multiple sclerosis. Fingolimod first-dose administration is associated with a transient, generally asymptomatic, slowing of heart rate, which may also prolong QT interval. This posthoc analysis compared cardiac outcomes in over 3300 patients with relapsing multiple sclerosis who were or were not receiving SSRIs during fingolimod treatment initiation, including a subset of patients receiving citalopram or escitalopram. Vital signs were recorded hourly for 6h, and electrocardiograms were obtained pre-dose and 6h post-dose. Changes in mean hourly heart rate from baseline (pre-dose) to 6h post-dose were similar among patients not receiving SSRIs (fingolimod 0.5mg, –7.5bpm; placebo, 0.0bpm) and those receiving SSRIs (fingolimod 0.5mg, –6.6bpm; placebo, 0.3bpm). In patients treated with fingolimod 0.5mg, the mean change in corrected QT interval from baseline to 6h after treatment initiation was under 10ms, and few patients had absolute corrected QT intervals of over 450ms (men) or 470ms (women), calculated according to Bazett׳s or Fridericia׳s correction methods, irrespective of whether or not they were receiving an SSRI; similar findings were reported in the placebo group. Co-administration of SSRIs and fingolimod was not associated with an increased incidence of any electrocardiogram findings compared with fingolimod therapy alone, and the majority of patients receiving fingolimod (83–86%) were discharged from first-dose monitoring at 6h irrespective of whether they were also receiving SSRIs. These analyses provide reassurance that concomitant use of SSRIs does not affect cardiac outcomes associated with fingolimod treatment initiation.

A Swiss real world best practice experience in three different clinical settings of the 6 hour fingolimod first dose observation procedure.

BackgroundThe Swiss label of oral fingolimod (0.5 mg once daily) requires a 6-hour first dose observation (FDO) including an ECG prior to and 6 hours after the first intake but in comparison to other countries such as Austria, Australia and Canada there are no restrictions regarding the clinical settings of the FDO procedure in Switzerland. We present here our real-world experience of the 6 hour FDO procedure in three different clinical settings, following fingolimod treatment initiation. This is the first report on the FDO of fingolimod in these real-world clinical settings in Swiss patients with multiple sclerosis (MS).MethodsThis was a retrospective, multi-clinic, observational study of 136 patients with relapsing-remitting multiple sclerosis. Summary statistics have been used to present the data.ResultsOnly two patients (<1.5% [2/136]) experienced symptoms after the first dose of fingolimod. Atrioventricular conduction abnormalities were reported in 3% (4/136) of patients, which resolved spontaneously within 24 hours of treatment initiation. During the average 6.8 months follow-up, 96% (131/136) of the patients remained on therapyConclusionsThese findings support the safety and feasibility of FDO and tolerability of fingolimod in real-world clinical settings.

P040 - Good cardiac safety in patients with relapsing remitting multiple sclerosis upon first fingolimod dose

Background/objective Fingolimod, a sphingosine 1-phosphate receptor (S1PR) modulator, is approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Following treatment initiation, fingolimod activates S1PR at the surface of cardiac myocytes, resulting in transient pulse rate reduction, and in rare cases in atrioventricular conduction blocks. The START-study characterizes the cardiac safety profile of fingolimod treatment initiation in a RRMS patient population. Design/methods The START study is a prospective, 1-week, open-label study enrolling up to 7000 RRMS patients in >250 centers in Germany, according to the EU label criteria of fingolimod. The study consists of a screening period, a baseline visit, and a final visit after one week. The procedure at baseline is as follows: prior to the first intake of fingolimod, a 12-lead ECG is recorded. After the first dose, a continuous 6 h Holter ECG is carried out, while pulse and blood pressure are measured simultaneously, every hour. A final 12-lead ECG is performed afterwards. In 200 patients, diagnostics include a 24 h ECG during screening and at baseline. All ECG recordings are centrally evaluated by cardiologists. Results In a first, interim analysis based on 599 patients, there was no Mobitz type II 2nd degree AV-block. Only 1.4% and 0.3% of patients developed a Mobitz type I 2nd degree block and a 2:1 2nd degree AV block, respectively. Additionally, data regarding QT intervals after fingolimod treatment initiation will be available. The new data set will also be analyzed with regard to the potential impact of co-medications frequently prescribed in RRMS-patients, as symptomatic treatments upon occurrence of cardiac events. Conclusion This national study confirms the good cardiac safety profile of fingolimod, which has already been documented in the previous pivotal multicenter trials, leading to approval. Additionally, the possible impact of comedication on AV-conduction, relevant for sub-groups of RRMS patients, is addressed.

P032 - Consistent reduction in the annualized rate of brain volume loss across phase 3 core and extension trials of fingolimod in relapsing multiple sclerosis

Background/objective In phase 3 trials, fingolimod 0.5 mg or 1.25 mg daily reduced brain atrophy versus placebo over 2 years (FREEDOMS and FREEDOMS II), and versus interferon beta-1a IM (IFNβ-1a) over 1 year (TRANSFORMS). Rates of brain atrophy on continuous fingolimod treatment were sustained in extension studies, but diminished number of completers might limit interpretability. We estimated the continuous effect of fingolimod treatment on brain volume (BV) loss, using all data from phase 3 and extension trials. Design/methods We determined annualized percentage BV change (PBVC) for all patients individually, to account for variable treatment-time exposures. During phase 3 studies and extensions, annualized PBVC was calculated for each patient from fingolimod treatment initiation until last available scan. Descriptive analyses included cohorts of patients receiving fingolimod 0.5 mg continuously, and all patients receiving fingolimod (combined-dose group) continuously, for up to 60 months from phase 3 baseline. Further analyses, using these dose-group definitions, were also conducted for up to 24 months from extension baseline to compare annualized PBVC among patients after switching to fingolimod from placebo or IFNβ-1a, with that determined on long-term fingolimod treatment. Results Respectively, mean annualized PBVC in the long-term continuous fingolimod 0.5 mg and combined-dose groups was FREEDOMS, ?0.45% ( n =372), ?0.42% ( n =718); FREEDOMS II, ?0.41% ( n =279), ?0.38% ( n =553); TRANSFORMS, ?0.31% ( n =379), ?0.31% ( n =728); and after switching was FREEDOMS, ?0.49% ( n =135), ?0.44% ( n =259); FREEDOMS II, ?0.47% ( n =47), ?0.43% ( n =103); TRANSFORMS, ?0.25% ( n =130), ?0.19% ( n =267). Conclusion Annualized PBVC during fingolimod phase 3 and extension studies demonstrate a consistent low rate of brain atrophy, supporting previous observations from individual studies. After switching to fingolimod from the comparator, patients exhibited similar atrophy rates to those initially randomized to fingolimod. Annualized PBVC calculation incorporates all available PBVC data, despite varying treatment-time exposures, and partly addresses discontinuation bias that may occur in long-term analyses.

Efficacy and safety of fingolimod in Hispanic patients with multiple sclerosis: pooled clinical trial analyses.

The disease characteristics of multiple sclerosis (MS) appear to differ between Hispanic and Caucasian patients, with Hispanic patients having a younger age at onset, and a higher prevalence of optic nerve and spinal cord involvement. Fingolimod, the first-in-class oral sphingosine 1-phosphate receptor modulator approved for the treatment of relapsing MS, has been shown to significantly reduce annualized relapse rates (ARRs), lesion-based magnetic resonance imaging (MRI) activity, confirmed disability, and brain volume loss, compared with placebo or intramuscular interferon beta-1a (IFNβ-1a IM) in randomized, double-blind, controlled clinical studies. Here, the efficacy and safety profile of fingolimod in Hispanic patients was compared to that observed in the overall study populations. This was a post hoc analysis of relapses and safety data for Hispanic patients with relapsing-remitting MS (RRMS) randomized to receive daily fingolimod 0.5 mg, weekly IFNβ-1a IM (30 mg) or placebo, in the phase 3, controlled FREEDOMS, FREEDOMS II, and TRANSFORMS fingolimod studies. The ARR was estimated for each treatment group; only relapses that were confirmed by an independent examining neurologist were included in these analyses. Safety assessments included the incidence of adverse events and serious adverse events. Eligible Hispanic patients aged 18-55 years (n=181) had been treated as follows: fingolimod 0.5 mg (n=89), IFNβ-1a IM (n=65), and placebo (n=27). Hispanic patients treated with fingolimod for up to 2 years had lower ARRs (ARR: 0.22, 95% confidence interval [CI]: 0.14-0.35) than those receiving placebo (ARR: 0.46, 95% CI: 0.24-0.88) or IFNβ-1a IM (ARR: 0.34, 95% CI: 0.18-0.63), with relative reductions of 52% and 35%, respectively. A transient decrease in heart rate that started to attenuate 6 h after fingolimod administration was observed, consistent with the well-characterized pharmacologic effect following fingolimod treatment initiation. No cases of symptomatic bradycardia were reported in Hispanic patients. The incidence of first-degree atrioventricular block was low and similar across all treatment groups (3.1-4.5%). The safety profile of fingolimod in Hispanic patients was consistent with that reported in the overall population of each study. Overall, this study demonstrates that fingolimod is efficacious and well tolerated in Hispanic patients with RRMS.

First-dose effects of fingolimod after switching from injectable therapies in the randomized, open-label, multicenter, Evaluate Patient OutComes (EPOC) study in relapsing multiple sclerosis

BackgroundIn pivotal phase 3 studies, fingolimod treatment initiation was associated with a transient reduction in heart rate (HR). Atrioventricular (AV) conduction delays, which were typically asymptomatic, were detected in a small minority of patients. ObjectiveWe report the first-dose effects of fingolimod in patients who switched from injectable therapies during the Evaluate Patient OutComes (EPOC) study (ClinicalTrials.gov Identifier: NCT01216072). MethodsThis was a phase 4, 6-month, randomized, active-comparator, open-label, multicenter study. It included over 900 fingolimod-treated patients with relapsing multiple sclerosis, with subgroups of individuals who were receiving common concomitant HR-lowering medications or had pre-existing cardiac conditions (PCCs). Vital signs were recorded hourly for 6h post-dose. A 12-lead electrocardiogram was obtained at baseline and at 6h post-dose. ResultsA transient decrease in mean HR and blood pressure occurred within 6h of the first fingolimod dose. The incidence of symptomatic bradycardia was low (1%); eight patients reported dizziness and there was one case each of fatigue, palpitations, dyspnea, cardiac discomfort, and gait disturbance. These symptomatic events were typically mild or moderate in severity and all resolved spontaneously, without intervention or fingolimod discontinuation. ConclusionFirst-dose effects in patients with PCCs and in those receiving concomitant HR-lowering medications were consistent with effects observed in the overall study population and with results from previous clinical trials. The EPOC study provides additional data demonstrating the transient and generally benign nature of fingolimod first-dose effects on HR and AV conduction in a large population that is more representative of patients encountered in routine clinical practice than in the pivotal trials.

First-dose effects of fingolimod: Pooled safety data from three phase 3 studies

Fingolimod treatment initiation is associated with a transient slowing of heart rate and atrioventricular conduction. This report presents first-dose fingolimod effects (0.5mg or 1.25mg) on cardiac parameters using phase 3 FREEDOMS, FREEDOMS II and TRANSFORMS pooled study data (n=3635 patients). Vital signs were recorded hourly for ≥6h; 12-lead electrocardiogram (ECG) was obtained at baseline and at 6h post-dose. Clinical events were graded at the first-dose administrator׳s discretion. At screening, on day 1 and at month 3, 1073 patients underwent 24-h ambulatory electrocardiogram monitoring. A transient decrease in mean measured heart rate occurred 4–5h after the first dose, with a maximum reduction of 8 (fingolimod 0.5mg) and 11 beats per minute (fingolimod 1.25mg) below baseline. Symptomatic bradycardia at treatment initiation was reported in 0.6% (fingolimod 0.5mg) and 2.1% (fingolimod 1.25mg) of patients; events were typically mild or moderate in severity, and most resolved spontaneously. Atrioventricular (AV) conduction delays were observed in a few patients (Wenckebach (Mobitz type I) second-degree AV block, fingolimod 0.5mg, 0.2%; 1.25mg, 1%: 2:1 AV block fingolimod, 0.5mg, 0%; 1.25mg, 0.2% on ECG 6-h post-dose). These were usually well tolerated and first occurred within 6h of dosing. Consistent with its effects on atrial myocytes, fingolimod treatment initiation induced a transient slowing of heart rate and AV conduction. However, symptomatic bradycardia and second-degree AV block were uncommon and did not require intervention.

Erratum to: Assessment of cardiac safety during fingolimod treatment initiation in a real-world relapsing multiple sclerosis population: a phase 3b, open-label study

Erratum to: Assessment of cardiac safety during fingolimod treatment initiation in a real-world relapsing multiple sclerosis population: a phase 3b, open-label study

PML-IRIS during Fingolimod Diagnosed after Natalizumab Discontinuation

Background. Natalizumab treatment is frequently discontinued and replaced by alternative medication in multiple sclerosis (MS) patients having a high risk of progressive multifocal leukoencephalopathy (PML). Case Presentation. We report a PML case that was missed on magnetic resonance imaging (MRI) at the time Natalizumab treatment was discontinued. The patient subsequently developed a PML-immune reconstitution inflammatory syndrome after the initiation of Fingolimod treatment, suggesting that immune reconstitution may occur even during Fingolimod induced lymphopenia. Conclusion. This report highlights the need for strict drug surveillance using MRI of Natalizumab-associated MS patients at the time of drug discontinuation and beyond. This is important with respect to pharmacovigilance purposes not only for Natalizumab, but also for alternative drugs used after Natalizumab discontinuation.

Early Initiation of Fingolimod Treatment Reduces the Recurrence of Disease Activity after Natalizumab Discontinuation in Multiple Sclerosis (P01.199)

Early Initiation of Fingolimod Treatment Reduces the Recurrence of Disease Activity after Natalizumab Discontinuation in Multiple Sclerosis (P01.199)

Evaluation of efficacy, safety and tolerability of fingolimod in patients with the relapsing form of multiple sclerosis – 12-month observation. A preliminary report

Background and purposeOral fingolimod 0.5 mg daily was approved in the European Union in 2011 for the treatment of relapsing multiple sclerosis in the aggressive form and as a second line treatment in patients with high disease activity despite interferon beta therapy. The aim of this study was the evaluation of efficacy, safety and tolerance of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS) during a 12-month observation period. Material and methodsThe investigated group consisted of 11 patients aged between 23 and 63 years. All patients underwent immunomodulatory treatment (disease modifying drugs – DMD) or immunomodulatory treatment in combination with mitoxantrone (Mx) without a positive effect for 3–5 years. Patients received oral fingolimod 0.5 mg daily during 12 months. Disability was evaluated with Kurtzke Expanded Disability Status Scale (EDSS) scale. Safety and tolerability of fingolimod were evaluated by adverse events monitoring, laboratory tests, and ophthalmological and skin assessment. ResultsBefore the initiation of fingolimod treatment all the patients progressed in disability and in MRI changes including five cases with gadolinium-enhancing lesions. During fingolimod treatment there was no new relapse in any patient and no patient stopped the treatment because of any adverse event. During the 12-month treatment, EDSS improvement was observed in seven patients, three patients were stable, and one patient progressed by 0.5 point in the EDSS. ConclusionsIn our study patients fingolimod was effective, safe and well tolerated independently of disease activity and previous treatment.

Cardiac Safety of Fingolimod 0.5 mg during the First Dose Observation in 4-Month, Open-Label, Multi-Center FIRST Study in Patients with Relapsing MS (S41.003)

Objective: To report the safety results of fingolimod 0.5 mg focusing on cardiac events during the first dose observation in relapsing MS patients both without cardiac risk factors and with cardiac conditions not included in fingolimod clinical trials. Background Fingolimod (FTY720) is an S1PR modulator approved for the treatment of relapsing MS. The initiation of fingolimod treatment results in generally asymptomatic and transient bradycardia and may be associated with atrioventricular blocks (AVB). Prescribing information recommends 6 hours on-site observation for signs and symptoms of bradycardia. Design/Methods: 2417 patients were enrolled. Preliminary results are reported for 2289 patients. Unless patients met pre-defined cardiac risk criteria the first dose administration was permitted off-site. Heart rate and ECG abnormalities were assessed by ambulatory Holter-ECG for 24 hours at screening and for 6 hours after administration of the first dose. Results: In the post-dose Holter ECGs the incidence of Mobitz I second degree AVBs was 1.4% and the incidence of 2:1 AVBs was 0.5%. One patient had a finding of >3 sec pause in both screening and post dose Holter-ECG. Incidence of conduction abnormalities was similar in patients monitored on-site (n=1162) and off-site (n=1127) and in patients with or without cardiac risks. One patient discontinued study drug due to the second degree AVB. No patient had a HR Conclusions: Overall incidence of AVBs on Holter-ECGs was low, irrespective of on- or off-site first dose administration or the presence of potential cardiac risk factors. These results are similar to those observed in fingolimod trials and confirm the benign nature of the cardiac effects of treatment initiation with fingolimod. Supported by: Novartis Pharma AG, Basel, Switzerland. Disclosure: Dr. Comi has received personal compensation for activities with Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals, Inc., Merck Serono, Bayer Schering, and Biogen Dompe. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Palace has received personal compensation for activities with Teva Neuroscience, Biogen Idec, Merck Serono, and Bayer Schering Pharma. Dr. Palace has received research support from GlaxoSmithKline, Inc. Dr. Gottschalk has received personal compensation for activities with Novartis as an employee. Dr. Bijarnia has received personal compensation for activities with Novartis Healthcare Pvt Ltd as an employee. Dr. Keil has received personal compensation for activities with Novartis as an employee. Dr. Tomic has received personal compensation for activities with Novartis as an employee. Dr. von Rosenstiel has received personal compensation for activities with Novartis Pharma AG. Dr. von Rosenstiel holds stock and/or stock options in Novartis Pharma AG, which sponsored research in which Dr. von Rosenstiel was involved as an investigator. Dr. Gold has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Teva Neuroscience. Dr. Gold has received personal compensation in an editorial capacity for Therapeutic Advances in Neurological Disorders. Dr. Gold has received (royalty or license fee or contractual rights) payments from Biogen Idec. Dr. Gold has received research support from Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novartis and Teva Neuroscience.