Fingolimod Exposure Research Articles

Pregnancy Outcomes in Multiple Sclerosis patients with or without exposure to Disease Modifying Therapies during pregnancy (N2.003)

Pregnancy Outcomes in Multiple Sclerosis patients with or without exposure to Disease Modifying Therapies during pregnancy (N2.003)

Real-world evidence on the safety and effectiveness of fingolimod in patients with multiple sclerosis from Taiwan

Multiple sclerosis is classified as a rare disease in Taiwan. This study evaluated the safety and effectiveness of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS) from routine clinical practice in Taiwan. In this retrospective, multicentre, observational study, we collected clinical data of patients treated with fingolimod 0.5mg/day in routine clinical practice between September 2012 and December 2015. Primary outcome was the overall safety of fingolimod; secondary outcome was the annualized relapse rate (ARR). Overall, 62/69 (86.1%) patients were on fingolimod by the end of data collection period. Mean age (±standard deviation [SD]) at inclusion was 37.7±10.10 years; mean duration of MS was 5.4±4.52 years and mean duration of fingolimod exposure was 135.8 patient-years. The most common adverse events (AEs) were bradycardia (21.7%; first-dose related), upper respiratory tract infection, dizziness, and hypoaesthesia (numbness) (11.6% each), followed by urinary tract infection and back pain (7.2% each). Seven patients had liver enzyme-related AEs. Eight patients had absolute lymphocyte counts <0.2×103/uL over the study period. One patient developed second degree AV block after first-dosing. Serious AEs were observed in 11 patients (15.9%; mild-to-moderate). No newly developed macular oedema was detected. The ARR was 0.3±0.74 in fingolimod-treated patients and 66.7% of patients were relapse-free. The mean (SD) change from baseline in expanded disability status scale score was -0.30±1.353. Fingolimod 0.5mg/day treatment with an average of 2 years of exposure was associated with a manageable safety profile, and maintained/improved effectiveness in RRMS patients from Taiwan.

Pregnancy outcome following first-trimester exposure to fingolimod: A collaborative ENTIS study

This prospective multicentre cohort study investigated pregnancy outcomes after fingolimod use for multiple sclerosis during pregnancy. Pregnancy outcomes of 63 fingolimod and 62 interferon-β-exposed pregnancies were compared. Rates of major congenital anomalies (MCA) were 4.8% (2/42) in the fingolimod group versus 2.3% (1/44) in the interferon-β group (odds ratio, 2.2; 95% confidence interval, 0.2–24.6). The adjusted hazard ratio for spontaneous abortion in fingolimod versus interferon-β-exposed pregnancies was 0.6 (95% confidence interval, 0.2–1.8). Further studies are needed to definitely rule out a moderately increased MCA risk after fingolimod exposure during pregnancy.

The ACROSS study: Long-term efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis.

BackgroundIn chronic diseases such as multiple sclerosis requiring lifelong treatment, studies on long-term outcomes are important.ObjectiveTo assess disability and magnetic resonance imaging-related outcomes in relapsing multiple sclerosis patients from a Phase 2 study of fingolimod 10 or more years after randomization and to compare outcomes in patients who had a higher fingolimod exposure versus those with a lower fingolimod exposure.MethodsACROSS was a cross-sectional follow-up study of patients originally enrolled in a Phase 2 fingolimod proof-of-concept study (NCT00333138). Disability and magnetic resonance imaging-related outcomes were assessed in patients grouped according to fingolimod treatment duration, based on an arbitrary cut-off: ≥8 years (high exposure) and <8 years (low exposure).ResultsOverall, 175/281 (62%) patients participated in ACROSS; 104 (59%) of these were classified “high exposure.” At 10 years, patients in the high-exposure group had smaller increases in Expanded Disability Status Scale (+0.55 vs. +1.21), and lower frequencies of disability progression (34.7% vs. 56.1%), wheelchair use (4.8% vs. 16.9%), or transition to secondary progressive multiple sclerosis (9.6% vs. 22.5%) than those in the low-exposure group. The high-exposure patients also had less progression in most magnetic resonance imaging-related outcomes.ConclusionAfter 10 years of fingolimod treatment, disability progression was lower in the high-exposure group than in the low-exposure group.

Extended treatment with fingolimod for relapsing multiple sclerosis: the 14-year LONGTERMS study results.

Background:Multiple sclerosis (MS) is a chronic disease that may require decades of ongoing treatment. Therefore, the long-term safety and efficacy of disease-modifying therapies is an important consideration.Methods:The LONGTERMS study evaluated the safety and efficacy of fingolimod in patients with relapsing MS (RMS) with up to 14 years of exposure. This phase IIIb, open-label extension study included patients aged ⩾ 18 years with confirmed RMS diagnosis who completed previous phase II/III/IIIb core/extension studies of fingolimod. Patients received fingolimod 0.5 mg orally once daily; safety and efficacy (clinical and magnetic resonance imaging) were the main outcomes.Results:Of 4086 patients from the core studies who entered LONGTERMS, 3480 (85.2%) completed the study. The median age (range) was 38 (17–65) years and median fingolimod exposure was 944.5 (range 75–4777) days. Overall, 85.5% of patients experienced at least one adverse event (AE); most common AEs (⩾10%) were viral upper respiratory tract infection (17.3%), headache (13.3%), hypertension (11.0%) and lymphopenia (10.7%). Among patients with serious AEs (12.6%), basal cell carcinoma and MS relapse (0.9% each) were most frequently reported. The aggregate annualized relapse rate decreased from 0.22 (in years 0–2) to 0.17 (years 0–10); 45.5% of patients remained relapse free after 10 years. At year 10, 63.2% of patients were free from 6-month confirmed disability worsening.Conclusion:This long-term observational study of patients treated for up to 14 years with fingolimod confirmed its established safety profile with no new safety concerns. Patients with RMS receiving fingolimod had sustained low levels of disease activity and progression.Trial Registration:ClinicalTrials.gov identifier: NCT01201356.

Evaluation of pregnancy outcomes in patients with multiple sclerosis after fingolimod exposure.

Background and Methods:Limited data are available on the safety of fingolimod in pregnant women. We estimated the risk of adverse pregnancy outcomes in women with multiple sclerosis (MS) exposed to fingolimod either shortly before or during pregnancy in prospectively collected cases from clinical trials, observational studies, surveillance programs, and spontaneous reports.Results:The prevalence of major malformations among live births does not appear to be significantly higher than those in the general population and the unexposed MS population. Similarly, the prevalence of cardiac malformations observed in this analysis was not significantly different from that of the general population. Proportions of miscarriage were in line with those of the general and unexposed MS population and no specific pattern of birth defects was identified.Conclusions:These data can help inform healthcare professionals and women with MS exposed to fingolimod during conception.

Immune thrombocytopenic purpura associated with fingolimod

Fingolimod is an oral sphingosine-1-phosphate receptor modulator which causes lymphocyte sequestration in lymph nodes and is approved for relapsing multiple sclerosis. The Therapeutic Goods Administration of Australia is aware of...

P.068 Real world experience with Fingolimod in Canada

Background: The Gilenya® Go ProgramTM offers education and support services, including coordination of first dose observation (FDO) and follow-up contact to reinforce monitoring recommendations and compliance in fingolimod-treated relapsing-remitting multiple sclerosis (RRMS) patients. Methods: Data were analyzed for patients enrolled in the Canadian Gilenya® Go ProgramTM from March 2011 to January 2016. The retention to fingolimod therapy, reasons for treatment discontinuation and incidence of adverse events (AEs) during treatment are reported. Results: At data cut-off, 3956 patients had completed FDO; 3201 patients were being actively treated. Mean age at enrolment was 41.0 years; 74.9% patients were female. The overall fingolimod exposure was 7869 patient-years. Most recent previous therapies (n=3746) included interferons (43.3%) and glatiramer acetate (29.6%). Most common reasons for switching to fingolimod (n=3674) was lack of efficacy (31.8%). Retention to therapy at data cut-off was 81.3%. AEs (45.2%) were the most common reason (n=334) for treatment discontinuation and included low lymphocyte count/abnormal hematology values (13.8%), gastrointestinal disturbances (6.9%), and elevated liver enzyme levels (7.8%). Adherence to recommended ophthalmic examination was 92.4%. Conclusions: In real-world clinical practice in Canada, adherence to both fingolimod treatment and monitoring was high. The Gilenya® Go Program™ helps to meet the safety monitoring recommendations for fingolimod-treated RRMS patients.

P028 - The risk of short-term relapse in patients switching from natalizumab to fingolimod

Background Risk stratification is an important pillar in treating high-risk multiple sclerosis (MS) patients. In JC virus seropositive patients, switching natalizumab to fingolimod is often considered after analyzing the risk versus benefit ratio. Objectives To determine the short-term risk of relapse after switching natalizumab to fingolimod in MS patients, and to assess its association with demographic and clinical parameters. Methods Data of MS patients who were prescribed fingolimod and natalizumab were extracted from the national MS registry. Demographics, clinical characteristics and duration of disease modifying therapies were collected. The risk of relapse of patients who were switched from natalizumab to fingolimod was compared to non-switchers. A multivariate analysis of specific demographics and clinical characteristics was conducted. Results Twenty nine patients were switched from natalizumab to fingolimod due to JC virus seropositivity. The mean duration of fingolimod exposure was 8.8 months. Men were more likely to continue on natalizumab (20.7% versus 41.7%; P=0.04). The mean disease duration was significantly higher in the switcher group (10.9 versus 6.29; P Conclusions The short-term risk of relapse in patients switched to fingolimod was higher than those who continued natalizumab. Switchers were more likely to be women and had longer disease duration. Patients, who stayed longer on natalizumab before switching to fingolimod and had short washout periods, had lower rates of relapses. Further studies are needed to assess the long-term risk of relapses in patients who switched from natalizumab to fingolimod.

Fingolimod: A Review of Its Use in Relapsing-Remitting Multiple Sclerosis

Fingolimod (Gilenya(®)) is an orally administered disease modifying agent (DMA) for use in relapsing-remitting multiple sclerosis (RRMS). In placebo-controlled trials in patients with RRMS with active disease, fingolimod 0.5 mg/day significantly reduced the annualized relapse rate (ARR) by approximately one-half over 2-year trial periods. It also significantly increased the proportion of patients with no disability progression, reduced deterioration from baseline in the Extended Disability Status Scale score and reduced MRI markers of disease progression (new/newly enlarging brain lesions and percentage change in brain volume). In a 12-month, comparison with intramuscular interferon β-1a (IFNβ- 1a) 30 μg/week, the ARR in fingolimod 0.5 mg/day recipients was significantly lower than in IFNβ-1a recipients by one-half; fingolimod recipients also had significantly lower MRI markers of disease progression. In extensions to the pivotal clinical trials, fingolimod exposure for up to 4 years was associated with low relapse rates and continuing benefits in terms of disability and disease progression. In clinical trials, adverse events in fingolimod recipients were generally mild to moderate in severity. In the pivotal placebo-controlled trial, serious adverse events occurred in similar proportions of fingolimod 0.5 mg/day and placebo recipients. First-dose bradycardia and atrioventricular block, which are generally asymptomatic, were clinically important adverse events associated with fingolimod in placebo-controlled trials. The risk for serious cardiovascular adverse events at the approved fingolimod dosage appears to be low in patients without pre-existing cardiac conditions. Fingolimod is an efficacious therapy for RRMS that reduces relapses, disability progression, new brain lesions and loss of brain volume. It has an acceptable tolerability profile and provides a useful alternative treatment in patients with RRMS who have responded poorly to other DMAs.

Pregnancy outcomes in the clinical development program of fingolimod in multiple sclerosis.

To report outcomes of pregnancies that occurred during the fingolimod clinical development program. Pregnancy outcomes from phase II, phase III, and phase IV clinical studies (with optional extensions) were reported by clinical trial investigators. Fingolimod exposure in utero was defined as fingolimod treatment at the time of conception or in the 6 weeks before conception. As of October 31, 2011, 89 pregnancies were reported in completed or ongoing clinical studies, with 74 in fingolimod treatment arms. Of 66 pregnancies with in utero exposure to fingolimod, there were 28 live births, 9 spontaneous abortions, 24 elective abortions, 4 ongoing pregnancies, and 1 pregnancy with an unknown outcome (patient lost to follow-up). Two infants were born with malformations: 1 with congenital unilateral posteromedial bowing of the tibia and 1 with acrania. Elective abortions were performed for 1 case each of tetralogy of Fallot, spontaneous intrauterine death, and failure of fetal development. There were 5 cases (7.6%; 95% confidence interval 3%-17%) of abnormal fetal development in the 66 pregnancies that had in utero exposure to fingolimod. In all 5 cases, fetal exposure to the drug took place in the first trimester of pregnancy. The number of patients becoming pregnant during fingolimod therapy remains small and does not permit firm conclusions to be drawn about fetal safety of fingolimod in humans. Given the known risks of teratogenicity in animals and the present data, women of childbearing potential should use effective contraception during fingolimod therapy and for 2 months after discontinuation.

Disease-modifying drugs for multiple sclerosis in pregnancy

To systematically review the literature regarding safety of disease-modifying drug (DMD) use during pregnancy on perinatal and developmental outcomes in offspring of patients with multiple sclerosis (MS). A PubMed and EMBASE search up to February 2012 was conducted with a manual search of references from relevant articles. Selected studies were evaluated using internationally accepted criteria. Fifteen studies identified 761 interferon β-, 97 glatiramer acetate-, and 35 natalizumab-exposed pregnancies. Study quality ranged from poor to good; no study was rated excellent. Small sample sizes limited most studies. Compared with data for unexposed pregnancies, fair- to good-quality prospective cohort studies reported that interferon β exposure was associated with lower mean birth weight, shorter mean birth length, and preterm birth (<37 weeks), but not low birth weight (<2,500 g), cesarean delivery, congenital anomaly (including malformation), or spontaneous abortion. Fewer studies of fair quality were available for glatiramer acetate and natalizumab. Glatiramer acetate exposure was not associated with lower mean birth weight, congenital anomaly, preterm birth, or spontaneous abortion. Natalizumab exposure did not appear to be associated with shorter mean birth length, lower mean birth weight, or lower mean gestational age. No studies examined mitoxantrone or fingolimod exposure. One study of paternal DMD use during conception found no effect on gestational age or birth weight. Few studies examined longer-term developmental outcomes. Further studies are needed to determine the potential risks associated with preconceptional and in utero DMD exposure in patients with MS. Discontinuation of DMDs before conception is still recommended.

Assessment of Potential Risk of PML with Fingolimod in MS Treated for at Least 24 Months (P04.137)

Objective: Assess the potential risk of PML with fingolimod in patients with Multiple Sclerosis (MS). Background A rare but serious risk of natalizumab treatment is progressive multifocal leukoencephalopathy (PML), with an overall incidence of 1.8/1000, rising to 3.4/1000 for patients with exposure of ≥24 months and who are positive for antibodies to JCV (JCV Ab+ve). As fingolimod is also an immuno-modulating therapy, questions arise about the potential risk for PML with fingolimod. Design/Methods: The fingolimod safety database was explored for confirmed PML cases. Given that duration of therapy increases PML risk with natalizumab, we evaluated risk in patients with at least 24 months fingolimod exposure. CIs were calculated based on the Exact (Clopper-Pearson) formula. Results: As of Aug 2011 >25,000 patients (>20,000 pt-yrs) have been treated with fingolimod. No PML case has been reported with fingolimod (incidence 0/1,000, 95%CI; 0-0.15/1,000, vs. 1.8/1,000, 95%CI 1.6-2.1 for natalizumab) 1 . There have been 2,300 patients with > 24 months of fingolimod (incidence 0/1,000 (95%CI 0-1.6) vs. 3.4/1,000 (95%CI, 2.8-4.0) for natalizumab >24months). Assuming a single case did occur in long-term patients, incidence would be 0.4/1,000 (95%CI 0.01-2.4) vs. 3.4/1,000. Assuming 50% of fingolimod patients (n=1150) are JCV Ab+ve, incidence is 0/1000 (95%CI; 0-3.2) vs. 2.8 (2.0/3.8) or 8.1 (5.4/11.6) 2 for those natalizumab patients without/with, respectively, prior immunosuppressant use and positive for JCV Ab and with >24-month-exposure. Assuming a PML risk 5-fold less for fingolimod than for natalizumab, no cases of PML would occur with only ∼20% probability. Conclusions: The absence of cases of PML with fingolimod (Aug 2011) suggests an important difference in mechanism of action between fingolimod and natalizumab exists regarding risk for PML. Assuming a case occurred subsequently on fingolimod, the risk of PML would nevertheless be several-fold less than with natalizumab. 1. Tysabri PML Monthly Update, Oct 2011. 2.Kappos et al Lancet Neurol 2011. Supported by: Novartis Inc. Disclosure: Dr. Francis has received personal compensation for activities with Novartis as an employee. Dr. Francis holds stock and/or stock options in Novartis, which sponsored research in which Dr. Francis was involved as an investigator. Dr. Dahlke has received personal compensation for activities with Novartis Pharma AG 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. Sfikas has received personal compensation for activities with Novartis as an employee.

Background and rationale for mechanism of action, efficacy, and safety of fingolimod (Gilenya), the first oral therapy for remitting-relapsing multiple sclerosis

Background and rationale for mechanism of action, efficacy, and safety of fingolimod (Gilenya), the first oral therapy for remitting-relapsing multiple sclerosis