Drug Safety Evaluation
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Overview and safety of fingolimod hydrochloride use in patients with multiple sclerosis 1.
Introduction
2.
Mechanism of action
3.
Pharmacokinetics
4.
Clinical applications/efficacy data
5.
Safety in clinical trials
6.
Post-marketing events
7.
Conclusion
8.
Expert opinion
Melanie D Ward, David E Jones & Myla D Goldman† †
University of Virginia, Department of Neurology, Charlottesville, VA, USA
Introduction: Fingolimod (Gilenya, FTY720) is an oral sphingosine-1-phosphate analogue that was approved by the FDA in 2010 for the treatment of relapsing forms of multiple sclerosis (MS). Fingolimod’s mechanism of action is primarily related to lymphocyte sequestration in primary and secondary lymphoid tissues. Phase III trials demonstrated a reduction in annualized relapse rate and MRI progression in fingolimod-treated subjects compared with both placebo and IFN-b-treated subjects. Frequent adverse effects include fatigue, gastrointestinal disturbance, headache and upper respiratory tract infection. More serious, but rare, adverse events associated with fingolimod include atrioventricular block, symptomatic bradycardia, herpetic viral infections and macular edema. Areas covered: We discuss the mechanism of action, pharmacokinetics, clinical efficacy and safety profile of fingolimod in patients with relapsing MS. Expert opinion: Fingolimod is an effective treatment for relapsing MS and its oral route of administration may be preferred by some. Fingolimod is generally well tolerated but requires diligence in patient selection and monitoring. Additional information is needed regarding risk of infection, malignancy and rebound disease with long-term use of fingolimod. Keywords: fingolimod, FTY720, multiple sclerosis, sphingosine-1-phosphate Expert Opin. Drug Saf. (2014) 13(7):989-998
1.
Introduction
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS in part mediated by autoreactive T cells, which also has a neurodegenerative component [1]. The majority of patients with MS have a relapsing--remitting course with disease onset in the second or third decade of life [2]. MS is a leading cause of neurologic disability, particularly among young adults [1]. Current disease-modifying therapies primarily target the inflammatory component of the disease. Fingolimod (Box 1) is a sphingosine-1-phosphate (S1P) analogue initially identified during the derivation of myriocin, an immunosuppressant isolated from the fungus Isaria sinclairii [3]. Fingolimod was initially studied in renal transplant, but trials demonstrated only modest efficacy [4,5]. Fingolimod was the first FDAapproved oral therapy for MS [6,7]. Fingolimod’s mechanism of action is thought to be primarily mediated by lymphocyte sequestration in primary and secondary lymphoid tissue, but it may also have neuroprotective effects [8]. 2.
Mechanism of action
Sphingolipids have long been recognized as important cell membrane components but also play an important role in cell signaling through interaction with G-protein-coupled receptors [9]. S1P is a lysophospholipid involved in a multitude of physiologic processes including lymphocyte trafficking, modulation of heart rate 10.1517/14740338.2014.920820 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name Phase Indication Pharmacology description Routes of administration Chemical structure
Fingolimod (Gilenya, FTY720) IV, approved Relapsing forms of multiple sclerosis Sphingosine-1-phosphate analogue Oral H 3C HCI
OH
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OH H2N
Pivotal trials
FREEDOMS, TRANSFORMS
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and regulation of both smooth muscle tone and endothelial cell barriers. There are five identified G-protein-coupled S1P receptors: S1P1, S1P2, S1P3, S1P4 and S1P5 [8,10]. S1P and S1P1 regulate migration of cells between the vascular and lymphatic compartments. Naive T cells, central memory T cells (TCM), effector memory T cells (TEM) and B cells express C-C chemokine receptor 7 (CCR7) receptors that induce lymphocyte retention in the lymph nodes. Signaling mediated by S1P and S1P1 can overcome CCR7 retention signals, allowing lymphocyte egress from lymphoid tissue. Under normal circumstances within lymphoid tissue, naive cells have a downregulation of cellular S1P1, allowing CCR7 signal-directed retention in lymphoid tissue. After activation and clonal expansion, cellular S1P1 expression is upregulated, allowing cells to overcome CCR7 retention signals and migrate out of lymph nodes. Unique from other cells, TEM cells can down modulate CCR7 independently and do not require S1P1 to exit [10-12]. Fingolimod is reversibly phosphorylated to fingolimod phosphate (its active moiety), which is a S1P analogue. Fingolimod phosphate binds all S1P receptor subtypes except S1P2 [13]. Fingolimod phosphate binds the S1P receptor but acts as a functional antagonist due to abnormal receptor phosphorylation, internalization and degradation [14]. Downregulation of the S1P1 receptor results in inability of naive cells and TCM to overcome CCR7 retention signals, resulting in sequestration within lymphoid tissue [8,10]. Even in the absence of fingolimod, the majority of cells are found within lymphoid tissue at any given time; thus, fingolimod does not cause lymphadenopathy [15]. There is evidence that fingolimod may reduce peripheral blood levels of a subset of IL-17-producing TCMs (Th17 cells) known to play a predominant role in the pathogenesis of MS [16,17]. Fingolimod may also affect migration of certain populations of natural killer cells [18,19]. S1P is involved in several CNS cellular processes, offering the potential for direct neuroprotective effects of fingolimod (Table 1) [8]. 990
3.
Pharmacokinetics
Blood levels of fingolimod peak within 6 h of a single oral dose, remain at a plateau for 6 -- 48 h and then slowly decline. The half-life of fingolimod is ~ 6 -- 9 days, and steady state is reached after daily dosing in 1 -- 2 months. Fingolimod is > 90% bioavailable, > 99% protein bound in the circulation and has a large volume of distribution. Food intake does not appear to affect the pharmacokinetics of fingolimod. Fingolimod is ultimately excreted through urine. No dosing adjustments are recommended in renal or hepatic impairment [20-22].
4.
Clinical applications/efficacy data
Fingolimod 0.5 mg was FDA-approved in 2010 for the treatment of relapsing forms of MS, after two large Phase III trials confirmed a significant reduction in the annualized relapse rate (ARR) and MRI progression. FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS) was a 2-year, Phase III trial comparing two doses of fingolimod (0.5 or 1.25 mg) to placebo. Subjects included in the study were 18 -- 55 years old with relapsingremitting MS, ‡ 1 relapses in the year prior to enrollment or ‡ 2 relapses in the 2 years prior to enrollment and Expanded Disability Status Scale of 0 -- 5.5. Exclusion criteria included relapse or steroid administration within 30 days of enrollment, use of IFN-b or glatiramer acetate within 3 months, infection at the time of enrollment, diabetes mellitus (DM), clinically significant systemic disease, macular edema (ME) and medication-induced or disease-related immunosuppression. The primary end point was ARR, and the secondary end points included time to disability progression. FREEDOMS enrolled 1272 subjects in the three-arm study. No significant differences were found in outcome measures between 1.25 and 0.5 mg dosing; therefore, we
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Fingolimod (Gilenya, FTY720)
Table 1. Roles of S1P/fingolimod in the CNS. Cell type
S1P effects
Fingolimod effects
Astrocytes
Reactive astrocytes in MS lesions have been found to have significantly increased expression of S1P1 and S1P3 [75]; S1P injected intracranially in mice results in astrogliosis [76] Modulation of migration, differentiation and survival [77,78]
Human astrocytes treated with fingolimod-P in vitro had decreased production of inflammatory cytokines [75]
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Oligodendrocytes
Neurons
Likely contributes to regulation of multiple processes (survival, differentiation, growth and function), may play a role in spinal cord injury by contributing to migration of neural stem cells to site of injury [82]
In animal studies, induced differentiation of oligodendrocyte precursor cells to oligodendrocytes (at low concentrations, at high inhibited) [78] and inhibited apoptosis of oligodendrocytes [79,80]. In human cells, induced membrane elaboration and process extension [81] Effect unclear
MS: Multiple sclerosis; S1P: Sphingosine-1-phosphate.
discuss only the results from the approved 0.5 mg dose. The relative reduction in ARR of 0.5 mg fingolimod compared with placebo was 54% (p < 0.001). The proportion of subjects remaining relapse free was 70% with fingolimod versus 46% with placebo (p < 0.001). The hazard ratio for disability progression was 0.70 compared with placebo (p = 0.02). In addition, fingolimod demonstrated significant benefit (p < 0.001) on imaging measures including the number of new lesions, number of enhancing lesions and brain atrophy [6]. FREEDOMS II was a 24-month Phase III trial comparing fingolimod (1.25 or 0.5 mg) to placebo. There were 1083 subjects randomized with similar inclusion criteria. Exclusion criteria were also similar, except notably history of malignancy was an exclusion criterion in FREEDOMS II. The primary end point was ARR reduction, and the secondary end points included brain atrophy and time to 3-month disability progression. At 0.5 mg dosing, ARR and atrophy decreased by 48 and 33%, respectively (p < 0.001 for both values). Significant differences in 3- and 6-month disability progression were not seen [23]. The Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS) was a 12-month, Phase III trial comparing 1.25 mg fingolimod, 0.5 mg fingolimod and IFN-b1a in the treatment of relapsing MS. Inclusion and exclusion criteria were similar to FREEDOMS, except DM and recent treatment with IFN-b and glatiramer acetate were not exclusion criteria in TRANSFORMS. Of note, 47.6% of subjects randomized to the IFN-b1a arm of the study had been previously treated with an IFN-b product. The primary end point was ARR, and secondary end points included the number of new or enlarging T2 lesions and disability progression. TRANSFORMS enrolled 1292 subjects with a demonstrated relative reduction in ARR compared to IFN-b1a of 52% in the 0.5-mg group (p < 0.001). Patients treated with either dose
of fingolimod had decreased new or enlarged T2-weighted lesions and decreased reductions in brain volume (p = 0.004 and p < 0.001, respectively). The decrease in disability progression seen in FREEDOMS was not demonstrated in TRANSFORMS, possibly attributable to the shorter duration of the study or use of an active comparator [7]. In a TRANSFORMS extension study in which IFN-b1a-treated subjects were transitioned to fingolimod, improvement in ARR and MRI measures were seen after transition to fingolimod [24]. An on-going study is currently evaluating fingolimod’s effect in primary progressive MS [25]. 5.
Safety in clinical trials
Overall, the incidence of reported adverse events was similar in all groups in FREEDOMS and TRANSFORMS. Adverse effects occurring in > 10% of patients in the fingolimod groups included back pain, diarrhea, fatigue, gastrointestinal disturbance, headache and upper respiratory tract infections [6,7]. The incidence of selected adverse effects in the Phase III trials is summarized in Table 2, and below we discuss adverse effects of particular concern. Cardiovascular events Dose-dependent decreases in heart rate were observed in the fingolimod groups within 2 h of drug administration. Nadir occurred within 4 -- 5 h and improved after ~ 6 h. Presumably, the effect of fingolimod on heart rate is due to the known cardiac effects of S1P, with return of baseline heart rate following receptor internalization and degradation. Mean maximum decrease in heart rate was 8 -- 12 beats/ min, and most subjects who developed bradycardia were asymptomatic. In an integrated analysis of the Phase III clinical trials and their respective extension studies, the rate of symptomatic bradycardia in 0.5-mg fingolimod groups was 0.5% [26]. First-degree (prolongation of the PR interval > 0.2 s) or second-degree 5.1
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Table 2. Selected adverse events in fingolimod (0.5 mg) versus control in pivotal clinical trials (percentage).
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Event
Any adverse event Event leading to drug discontinuation Serious adverse event Death Infectious Herpes virus infection* Influenza Nasopharyngitis* Upper respiratory tract infection* Nervous system Headache Fatigue Gastrointestinal Elevated LFTs* Diarrhea Nausea Musculoskeletal Back pain* Blood and lymphatic system Lymphopenia* Cardiovascular Atrioventricular block (first degree) Atrioventricular block (second degree) Bradycardia* Hypertension Ophthalmologic Macular edema* Neoplasms Basal-cell carcinoma Melanoma Breast cancer
FREEDOMS [6]
TRANSFORMS [7]
Fingolimod
Placebo
Fingolimod
IFN-b1a
94.4 7.5 10.1 0
92.6 7.7 13.4 0.5
86.0 5.6 7.0 0
91.6 3.7 5.8 0
8.7 12.9 27.1 49.9
7.9 9.8 27.5 50.5
2.1 6.8 20.5 7.2
2.8 7.4 20.4 6.3
25.2 11.3
23 10.8
23.1 10.3
20.4 10.4
15.8 11.8 8.9
5.0 7.4 8.6
6.5 7.5 9.3
1.9 4.9 6.7
11.8
6.9
6.1
5.3
3.5
0.5
0.2
0
0.5 0 2.1 6.1
0.5 0.2 0.7 3.8
0.2 0.2 0.5 3.7
0 0 0 1.9
0
0
0.5
0
0.9 0 0
0.7 0.2 0.7
0.7 0.7 0.5
0.2 0 0
*The most relevant side effects.
(conduction block between the atria and ventricles) atrioventricular (AV) block each occurred in 0.1% of subjects in Phase III studies [26]. Mild increases in systolic (3 mmHg) and diastolic (1 mmHg) blood pressures were seen in fingolimod-treated subjects [6,7,26]. Infection The overall incidence of infection was similar in fingolimod and control (placebo or IFN-b1a) groups; however, bronchitis and pneumonia occurred more frequently in the fingolimodtreated groups in FREEDOMS and mild respiratory infections were more frequent in fingolimod groups in TRANSFORMS [6,7]. Two serious herpetic infections were reported in FREEDOMS: one case of genital herpes in a subject treated with 1.25 mg of fingolimod, and one case of herpes simplex labialis in a subject in the 0.5-mg group. The overall incidence of herpes infection was similar between fingolimod and placebo groups [6]. In FREEDOMS II, herpes zoster infections were more commonly reported in the fingolimod groups (2.5% of patients treated with 0.5-mg fingolimod compared with 0.8% in placebo) [23]. In
TRANSFORMS, herpes infections occurred most frequently in the 1.25-mg fingolimod group. Two subjects in the 1.25-mg group died from viral infections. One subject died from disseminated varicella, while receiving concomitant corticosteroids for a MS relapse, and another due to herpes simplex encephalitis [7].
5.2
992
Laboratory abnormalities As expected, lymphocyte counts begin declining within several hours of the first dose of fingolimod and decreased between 73 and 77% of baseline within 1 month [6,7,27]. Fingolimod results in 80% reduction in peripheral blood CD4+ cells due to the selective retention of naive and TCM cells in lymphoid tissue. Despite CD4+ cell reduction, there did not appear to be a significantly increased infection risk at 0.5 mg dosing in clinical trials, postulated to be because these cells are not eliminated permanently [12]. Lymphocyte counts typically return to normal within 6 weeks of discontinuation of fingolimod [6,7], but prolonged lymphopenia has been reported in two patients [28]. Asymptomatic elevations in alanine aminotransferase levels to 2 -- 3 times the upper 5.3
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Fingolimod (Gilenya, FTY720)
limit of normal were more common in the fingolimod groups, which resolved spontaneously with or without discontinuation of fingolimod [6,7].
diffusion capacity for carbon monoxide. These did not worsen through the duration of treatment [6,7]. 6.
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5.4
ME is caused by fluid accumulation in the central retina or macula. Symptoms include decreased acuity and metamorphopsia, but ME is frequently asymptomatic. Primary modalities for detecting ME include fundus examination, optical coherence tomography and intravenous fluorescein angiography [29]. In TRANSFORMS, six subjects (four in 1.25-mg group and two in 0.5-mg group) developed ME, five of which did so within four months of starting fingolimod and four of which resolved after stopping fingolimod [7]. In FREEDOMS, seven patients developed ME, all in the 1.25-mg group. Six out of seven cases resolved after stopping fingolimod [6]. Pooled data from FREEDOMS, TRANSFORMS and FREEDOMS II indicated the overall incidence of ME was 0.4% in the 0.5-mg group. There is an increased risk of fingolimod-associated macular edema (FAME) in patients with DM or uveitis, and most cases of ME in the trials occurred in patients older than age 41. The mechanism of development of FAME is felt to be related to effects of S1P on vascular permeability [29]. Malignancies Several malignancies were reported in the 0.5-mg fingolimod groups in FREEDOMS and TRANSFORMS: seven basal cell carcinomas, two breast cancers and three melanomas [6,7]. In FREEDOMS II, basal cell carcinoma occurred in 2.8% of patients treated with 0.5 mg fingolimod compared with 0.6% of placebo-treated patients [23]. Data has failed to identify a significant increase in rate of malignancy between 0.5-mg fingolimod and control groups, although amongst all Phase III studies there was a trend towards increased incidence of basal cell carcinoma in fingolimod-treated patients [26]. One case of melanoma developing 57 months after initiation of treatment with fingolimod has been reported, in a subject who was initially treated with 1.25 mg dosing [30]. Three cases of lymphoma (one each of cutaneous T-cell lymphoma, Epstein--Barr virus-positive B-cell lymphoma and large B-cell non-Hodgkin lymphoma) were reported in the clinical development programs, which was higher than expected in the general population [26]. Studies in mouse models have suggested an increased rate of development of myeloma and B-cell lymphoma with fingolimod treatment, although doses administered were higher than those used in humans [31]. At this point, the association between fingolimod and lymphoma remains uncertain. 5.5
Pulmonary events A mild (2 -- 3%) decrease in one-second forced expiratory volume was seen in the fingolimod groups in both FREEDOMS and TRANSFORMS, in addition to a mild decrease in 5.6
Post-marketing events
Macular edema Cardiac events and relabeling In December 2011, there was a reported death of a patient within 24 h of the first dose of fingolimod [32]. Another patient died of suspected ventricular arrhythmia ~ 5 months after beginning treatment with fingolimod [33]. The FDA subsequently reviewed a total of 31 deaths in patients treated with fingolimod from 2003 to 2012. There were no deaths that could be definitively attributed to fingolimod, and number of cardiovascular deaths or deaths from an unknown etiology did not appear to be higher in fingolimod-treated patients compared to other MS patients not treated with fingolimod. However, the FDA did revise monitoring guidelines and contraindications in the product label [34]. Revised guidelines recommended cardiac monitoring for 6 h following the first dose of fingolimod, with extended monitoring in patients who developed significant bradycardia following the first dose and in those on medications known to prolong QT interval. Contraindications included myocardial infarction, stroke, transient ischemic attack, unstable angina or decompensated or class III/IV heart failure within 6 months prior to treatment; sick sinus syndrome or Mobitz II or higher AV block unless pacemaker has been placed; baseline QTc > 500; and use of class Ia or class III antiarrhythmics [34-36]. Administration of atropine can successfully reverse fingolimod-associated bradycardia [37]. In post-marketing studies, bradycardia occurred more often in patients treated with beta or calcium channel blockers [38]. There is one reported case of delayed asystole occurring 21 h after fingolimod administration in a patient on risperidone; asystole lasted for 7.5 s and recovered spontaneously [39]. Risperidone has been independently associated with prolonged QT interval, conduction block, bradycardia, asystole and sudden cardiac death. One case of prolonged bradycardia in a patient with baseline vagotonia and one case of paroxysmal atrial fibrillation following a first dose of fingolimod have also been reported [40,41]. 6.1
Extensive demyelinating lesions during fingolimod treatment
6.2
There have been several reported cases of extensive demyelinating lesions in fingolimod-treated patients [42-45]. Additional reports of severe demyelinating lesions specifically following transition from natalizumab to fingolimod have also been reported. In all cases, there were at least 8 weeks between cessation of natalizumab and initiation of fingolimod [46-48]. There has been an isolated report of extensive demyelination in a fingolimod-treated patient later determined to have neuromyelitis optica, for which fingolimod is not approved [49]. It has been postulated that in certain individuals, fingolimod may
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alter immunopathology and predispose to extensive demyelinating lesions [42], although the association remains unclear. Rebound disease after fingolimod discontinuation
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6.3
There are several case reports of patients who developed multiple new demyelinating lesions within several months of fingolimod discontinuation [50-55]. Reasons for discontinuation included patient decision [54], disease progression [50,55], desire to conceive [52], superficial melanoma [51], genital human papillomavirus infection [55] and herpes zoster infection [53,54]. Immune reconstitution causing increased influx of cells into the CNS has been proposed as a possible mechanism for rebound activity after fingolimod discontinuation [54]. Other reported events Three cases of posterior reversible encephalopathy syndrome have been reported in fingolimod-treated patients; one during clinical trials [56] and two in the post-marketing period [26]. Other vascular events reported include branch retinal vein occlusion [57] and critical vasospasm of left forearm arteries [58]. Recently, three cases of amenorrhea within the first 6 months of fingolimod treatment have been reported. In all three cases, menses returned to baseline following discontinuation of fingolimod [59]. Progressive multifocal leukoencephalopathy (PML) is caused by the John Cunningham (JC) virus and has been reported with natalizumab treatment in MS. In natalizumab-treated patients, PML risk is increased in those with detected serum JC virus antibodies, with > 24 infusions, and/or previous immunosuppressant use [60,61]. A single case of PML has been reported in a fingolimod-treated patient; however, this patient had been treated with natalizumab in the recent past [62]. In August 2013, the FDA reported a patient diagnosed with PML after taking fingolimod for 8 months. This was the first reported case of PML in a natalizumab-naive, fingolimod-treated patient, and further details are pending [63]. Other infectious complications reported in the post-marketing period include a case of hemorrhaging focal encephalitis presumed to be either autoimmune or viral in etiology [64] and a case of varicella encephalitis with vasculopathy in a patient who had not previously been vaccinated against varicella [65]. Two cases of fatal hemophagocytic syndrome during fingolimod treatment have recently been reported, although details regarding these cases are currently limited [66]. Hemophagocytic syndrome is characterized by marked hyperinflammation resulting in prolonged fevers, hepatosplenomegaly and cytopenias and can be triggered by viral infections [67]. 6.4
Monitoring guidelines Prior to initiating fingolimod, baseline electrocardiogram, complete blood count, liver function tests, bilirubin, varicella 6.5
994
antibody titers and ophthalmologic examination should be obtained. Patients with negative varicella antibody serology should be vaccinated (with a two-dose regimen) at least one month prior to initiation of fingolimod. There are no recommended guidelines for repeating antibody titers postvaccination. Live attenuated virus vaccinations should be avoided during treatment with fingolimod. Cardiac monitoring is recommended for at least 6 h after the first dose of fingolimod, with extended monitoring in special populations as previously detailed. Patients treated with b-blockers, diltiazem or digoxin should consider transitioning to alternative medications before starting fingolimod. For patients in whom fingolimod is discontinued for > 14 days and then restarted, first-dose monitoring should be repeated. Repeat ophthalmologic examination should be performed within 4 months of initiation of treatment, and periodically thereafter in patients with diabetes or uveitis [22]. Discontinuation should be considered in patients who develop ME [29]. Repeat liver and pulmonary function testing may be obtained as indicated clinically after initiation of treatment [22]. Use in pregnancy and breastfeeding Fingolimod is pregnancy category C, with teratogenicity (primarily cardiac abnormalities) demonstrated in rodents. In humans, there were nine spontaneous abortions and five cases of abnormal fetal development amongst 66 pregnancies occurring in fingolimod-exposed patients in the clinical development programs. Abnormalities included one case each of acrania, failure of fetal development, spontaneous intrauterine death, tetrology of Fallot and unilateral posteromedial bowing of the tibia. The combined frequency of congenital anomalies amongst pregnancies with in utero exposure to fingolimod (live births and elective abortions performed due to abnormalities) was 7.6%, higher than an expected rate of 3% [68,69]. Due to the overall low number of pregnancies in fingolimod-treated patients, caution is advised in interpreting these results. Contraception use is recommended during fingolimod treatment and for 2 months after cessation of therapy, and breastfeeding during fingolimod treatment is not recommended [22,70]. There is a fingolimod pregnancy registry [71]. 6.6
7.
Conclusion
Fingolimod is an effective treatment for relapsing MS and is generally well tolerated. The overall incidence of adverse events was similar in fingolimod and control groups in clinical trials. Of notable concern in fingolimod-treated patients is the risk of cardiac events, specifically transient symptomatic bradycardia and AV block after the first dose. Although most cases of bradycardia are transient and asymptomatic, a post-marketing unexplained death in a fingolimod-treated patient prompted a comprehensive FDA review and revision of monitoring guidelines and selection criteria. Clinical trials also suggested a potential risk of herpes virus and varicella
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Fingolimod (Gilenya, FTY720)
infections in patients treated with fingolimod, especially in those treated with concomitant steroids. Other serious adverse events include ME, which is likely to resolve with cessation of treatment. These complications occurred more frequently in the 1.25-mg-treated group than with the approved 0.5 mg dose. Additional post-marketing reports have raised concern for risk of extensive demyelinating lesions during treatment, rebound disease after cessation of treatment or development of certain malignancies with fingolimod, but these associations remain unclear. Appropriate patient selection, baseline evaluations, cardiac monitoring and surveillance monitoring are needed during treatment. 8.
Expert opinion
At the time of its approval in 2010, fingolimod offered important benefit in patients who preferred an oral route of medication administration or had disease progression on alternative treatments. In addition, fingolimod has demonstrated superior efficacy compared to at least one standard treatment for MS, intramuscular IFN-b1a. Fingolimod would significantly alter the treatment of primary progressive MS should ongoing trials reveal benefit in outcomes, as mitoxantrone is currently the only approved disease-modifying therapy for progressive disease. Most cardiac events during fingolimod treatment are asymptomatic and resolve spontaneously, and the risk of adverse cardiac outcomes can be mitigated with appropriate patient selection and monitoring following the first dose of medication. Although the overall risk of infection does not appear to be significantly increased, appropriate pretreatment screening and monitoring for infectious complications (especially herpesvirus and varicella) during fingolimod treatment are prudent. Steroid administration in the setting of fingolimod-induced lymphopenia may predispose to viral infections or reactivation, and this should be considered in treatment decisions for patients on fingolimod [72]. Of additional note, patients treated with fingolimod may have
decreased immune response to seasonal influenza and tetanus toxoid vaccines, although this is of uncertain significance [73]. As seen in the delayed recognition of increased risk of leukemia with mitoxantrone treatment, cumulative risk of malignancy with any new therapy may not become clear until several years post-marketing [74]. Although Phase III clinical trials did not reveal an increased risk of malignancy in fingolimod-treated groups, the risk of malignancy with longterm use is not yet defined. In addition, further data is needed to evaluate the potential risk for severe relapses or tumefactive demyelination during fingolimod treatment, transition from other treatments (e.g., natalizumab) and the risk of rebound disease following discontinuation of fingolimod. Although fingolimod offers the convenience of an oral route of administration, we reserve fingolimod for secondline treatment in patients who do not tolerate or who have disease progression on first-line disease-modifying therapies (e.g., IFN-b1a or glatiramer acetate) until longer term post-marketing data is available.
Acknowledgement MD Ward prepared the first draft version and reviewed the manuscript. DE Jones and MD Goldman prepared the manuscript and reviewed.
Declaration of interest M Goldman has received consulting fees from Novartis, Biogen Idec and Concert Pharma and has also received research funding from Biogen Idec and Novartis. D Jones has received consulting fees from Biogen Idec, Novartis and Genzyme. He has also received research funding from Genzyme. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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Affiliation Melanie D Ward1 MD, David E Jones2 MD & Myla D Goldman†2 MD MSc † Author for correspondence 1 Resident Physician, University of Virginia, Department of Neurology, PO Box 800394, Charlottesville, VA 22908, USA 2 Assistant Professor, University of Virginia, Department of Neurology, PO Box 800394, Charlottesville, VA 22908, USA Tel: +1 434 982 3936; Fax: +1 434 982 1726; E-mail: [email protected]
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Overview and safety of fingolimod hydrochloride use in patients with multiple sclerosis 1.
Introduction
2.
Mechanism of action
3.
Pharmacokinetics
4.
Clinical applications/efficacy data
5.
Safety in clinical trials
6.
Post-marketing events
7.
Conclusion
8.
Expert opinion
Melanie D Ward, David E Jones & Myla D Goldman† †
University of Virginia, Department of Neurology, Charlottesville, VA, USA
Introduction: Fingolimod (Gilenya, FTY720) is an oral sphingosine-1-phosphate analogue that was approved by the FDA in 2010 for the treatment of relapsing forms of multiple sclerosis (MS). Fingolimod’s mechanism of action is primarily related to lymphocyte sequestration in primary and secondary lymphoid tissues. Phase III trials demonstrated a reduction in annualized relapse rate and MRI progression in fingolimod-treated subjects compared with both placebo and IFN-b-treated subjects. Frequent adverse effects include fatigue, gastrointestinal disturbance, headache and upper respiratory tract infection. More serious, but rare, adverse events associated with fingolimod include atrioventricular block, symptomatic bradycardia, herpetic viral infections and macular edema. Areas covered: We discuss the mechanism of action, pharmacokinetics, clinical efficacy and safety profile of fingolimod in patients with relapsing MS. Expert opinion: Fingolimod is an effective treatment for relapsing MS and its oral route of administration may be preferred by some. Fingolimod is generally well tolerated but requires diligence in patient selection and monitoring. Additional information is needed regarding risk of infection, malignancy and rebound disease with long-term use of fingolimod. Keywords: fingolimod, FTY720, multiple sclerosis, sphingosine-1-phosphate Expert Opin. Drug Saf. (2014) 13(7):989-998
1.
Introduction
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS in part mediated by autoreactive T cells, which also has a neurodegenerative component [1]. The majority of patients with MS have a relapsing--remitting course with disease onset in the second or third decade of life [2]. MS is a leading cause of neurologic disability, particularly among young adults [1]. Current disease-modifying therapies primarily target the inflammatory component of the disease. Fingolimod (Box 1) is a sphingosine-1-phosphate (S1P) analogue initially identified during the derivation of myriocin, an immunosuppressant isolated from the fungus Isaria sinclairii [3]. Fingolimod was initially studied in renal transplant, but trials demonstrated only modest efficacy [4,5]. Fingolimod was the first FDAapproved oral therapy for MS [6,7]. Fingolimod’s mechanism of action is thought to be primarily mediated by lymphocyte sequestration in primary and secondary lymphoid tissue, but it may also have neuroprotective effects [8]. 2.
Mechanism of action
Sphingolipids have long been recognized as important cell membrane components but also play an important role in cell signaling through interaction with G-protein-coupled receptors [9]. S1P is a lysophospholipid involved in a multitude of physiologic processes including lymphocyte trafficking, modulation of heart rate 10.1517/14740338.2014.920820 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name Phase Indication Pharmacology description Routes of administration Chemical structure
Fingolimod (Gilenya, FTY720) IV, approved Relapsing forms of multiple sclerosis Sphingosine-1-phosphate analogue Oral H 3C HCI
OH
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OH H2N
Pivotal trials
FREEDOMS, TRANSFORMS
Pharmaprojects - copyright to Citeline Drug Intelligence (an informa business). Readers are referred to Informa-Pipeline (http://informa-pipeline.citeline.com) and Citeline (http://informa.citeline.com).
and regulation of both smooth muscle tone and endothelial cell barriers. There are five identified G-protein-coupled S1P receptors: S1P1, S1P2, S1P3, S1P4 and S1P5 [8,10]. S1P and S1P1 regulate migration of cells between the vascular and lymphatic compartments. Naive T cells, central memory T cells (TCM), effector memory T cells (TEM) and B cells express C-C chemokine receptor 7 (CCR7) receptors that induce lymphocyte retention in the lymph nodes. Signaling mediated by S1P and S1P1 can overcome CCR7 retention signals, allowing lymphocyte egress from lymphoid tissue. Under normal circumstances within lymphoid tissue, naive cells have a downregulation of cellular S1P1, allowing CCR7 signal-directed retention in lymphoid tissue. After activation and clonal expansion, cellular S1P1 expression is upregulated, allowing cells to overcome CCR7 retention signals and migrate out of lymph nodes. Unique from other cells, TEM cells can down modulate CCR7 independently and do not require S1P1 to exit [10-12]. Fingolimod is reversibly phosphorylated to fingolimod phosphate (its active moiety), which is a S1P analogue. Fingolimod phosphate binds all S1P receptor subtypes except S1P2 [13]. Fingolimod phosphate binds the S1P receptor but acts as a functional antagonist due to abnormal receptor phosphorylation, internalization and degradation [14]. Downregulation of the S1P1 receptor results in inability of naive cells and TCM to overcome CCR7 retention signals, resulting in sequestration within lymphoid tissue [8,10]. Even in the absence of fingolimod, the majority of cells are found within lymphoid tissue at any given time; thus, fingolimod does not cause lymphadenopathy [15]. There is evidence that fingolimod may reduce peripheral blood levels of a subset of IL-17-producing TCMs (Th17 cells) known to play a predominant role in the pathogenesis of MS [16,17]. Fingolimod may also affect migration of certain populations of natural killer cells [18,19]. S1P is involved in several CNS cellular processes, offering the potential for direct neuroprotective effects of fingolimod (Table 1) [8]. 990
3.
Pharmacokinetics
Blood levels of fingolimod peak within 6 h of a single oral dose, remain at a plateau for 6 -- 48 h and then slowly decline. The half-life of fingolimod is ~ 6 -- 9 days, and steady state is reached after daily dosing in 1 -- 2 months. Fingolimod is > 90% bioavailable, > 99% protein bound in the circulation and has a large volume of distribution. Food intake does not appear to affect the pharmacokinetics of fingolimod. Fingolimod is ultimately excreted through urine. No dosing adjustments are recommended in renal or hepatic impairment [20-22].
4.
Clinical applications/efficacy data
Fingolimod 0.5 mg was FDA-approved in 2010 for the treatment of relapsing forms of MS, after two large Phase III trials confirmed a significant reduction in the annualized relapse rate (ARR) and MRI progression. FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS) was a 2-year, Phase III trial comparing two doses of fingolimod (0.5 or 1.25 mg) to placebo. Subjects included in the study were 18 -- 55 years old with relapsingremitting MS, ‡ 1 relapses in the year prior to enrollment or ‡ 2 relapses in the 2 years prior to enrollment and Expanded Disability Status Scale of 0 -- 5.5. Exclusion criteria included relapse or steroid administration within 30 days of enrollment, use of IFN-b or glatiramer acetate within 3 months, infection at the time of enrollment, diabetes mellitus (DM), clinically significant systemic disease, macular edema (ME) and medication-induced or disease-related immunosuppression. The primary end point was ARR, and the secondary end points included time to disability progression. FREEDOMS enrolled 1272 subjects in the three-arm study. No significant differences were found in outcome measures between 1.25 and 0.5 mg dosing; therefore, we
Expert Opin. Drug Saf. (2014) 13(7)
Fingolimod (Gilenya, FTY720)
Table 1. Roles of S1P/fingolimod in the CNS. Cell type
S1P effects
Fingolimod effects
Astrocytes
Reactive astrocytes in MS lesions have been found to have significantly increased expression of S1P1 and S1P3 [75]; S1P injected intracranially in mice results in astrogliosis [76] Modulation of migration, differentiation and survival [77,78]
Human astrocytes treated with fingolimod-P in vitro had decreased production of inflammatory cytokines [75]
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Oligodendrocytes
Neurons
Likely contributes to regulation of multiple processes (survival, differentiation, growth and function), may play a role in spinal cord injury by contributing to migration of neural stem cells to site of injury [82]
In animal studies, induced differentiation of oligodendrocyte precursor cells to oligodendrocytes (at low concentrations, at high inhibited) [78] and inhibited apoptosis of oligodendrocytes [79,80]. In human cells, induced membrane elaboration and process extension [81] Effect unclear
MS: Multiple sclerosis; S1P: Sphingosine-1-phosphate.
discuss only the results from the approved 0.5 mg dose. The relative reduction in ARR of 0.5 mg fingolimod compared with placebo was 54% (p < 0.001). The proportion of subjects remaining relapse free was 70% with fingolimod versus 46% with placebo (p < 0.001). The hazard ratio for disability progression was 0.70 compared with placebo (p = 0.02). In addition, fingolimod demonstrated significant benefit (p < 0.001) on imaging measures including the number of new lesions, number of enhancing lesions and brain atrophy [6]. FREEDOMS II was a 24-month Phase III trial comparing fingolimod (1.25 or 0.5 mg) to placebo. There were 1083 subjects randomized with similar inclusion criteria. Exclusion criteria were also similar, except notably history of malignancy was an exclusion criterion in FREEDOMS II. The primary end point was ARR reduction, and the secondary end points included brain atrophy and time to 3-month disability progression. At 0.5 mg dosing, ARR and atrophy decreased by 48 and 33%, respectively (p < 0.001 for both values). Significant differences in 3- and 6-month disability progression were not seen [23]. The Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS) was a 12-month, Phase III trial comparing 1.25 mg fingolimod, 0.5 mg fingolimod and IFN-b1a in the treatment of relapsing MS. Inclusion and exclusion criteria were similar to FREEDOMS, except DM and recent treatment with IFN-b and glatiramer acetate were not exclusion criteria in TRANSFORMS. Of note, 47.6% of subjects randomized to the IFN-b1a arm of the study had been previously treated with an IFN-b product. The primary end point was ARR, and secondary end points included the number of new or enlarging T2 lesions and disability progression. TRANSFORMS enrolled 1292 subjects with a demonstrated relative reduction in ARR compared to IFN-b1a of 52% in the 0.5-mg group (p < 0.001). Patients treated with either dose
of fingolimod had decreased new or enlarged T2-weighted lesions and decreased reductions in brain volume (p = 0.004 and p < 0.001, respectively). The decrease in disability progression seen in FREEDOMS was not demonstrated in TRANSFORMS, possibly attributable to the shorter duration of the study or use of an active comparator [7]. In a TRANSFORMS extension study in which IFN-b1a-treated subjects were transitioned to fingolimod, improvement in ARR and MRI measures were seen after transition to fingolimod [24]. An on-going study is currently evaluating fingolimod’s effect in primary progressive MS [25]. 5.
Safety in clinical trials
Overall, the incidence of reported adverse events was similar in all groups in FREEDOMS and TRANSFORMS. Adverse effects occurring in > 10% of patients in the fingolimod groups included back pain, diarrhea, fatigue, gastrointestinal disturbance, headache and upper respiratory tract infections [6,7]. The incidence of selected adverse effects in the Phase III trials is summarized in Table 2, and below we discuss adverse effects of particular concern. Cardiovascular events Dose-dependent decreases in heart rate were observed in the fingolimod groups within 2 h of drug administration. Nadir occurred within 4 -- 5 h and improved after ~ 6 h. Presumably, the effect of fingolimod on heart rate is due to the known cardiac effects of S1P, with return of baseline heart rate following receptor internalization and degradation. Mean maximum decrease in heart rate was 8 -- 12 beats/ min, and most subjects who developed bradycardia were asymptomatic. In an integrated analysis of the Phase III clinical trials and their respective extension studies, the rate of symptomatic bradycardia in 0.5-mg fingolimod groups was 0.5% [26]. First-degree (prolongation of the PR interval > 0.2 s) or second-degree 5.1
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Table 2. Selected adverse events in fingolimod (0.5 mg) versus control in pivotal clinical trials (percentage).
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Event
Any adverse event Event leading to drug discontinuation Serious adverse event Death Infectious Herpes virus infection* Influenza Nasopharyngitis* Upper respiratory tract infection* Nervous system Headache Fatigue Gastrointestinal Elevated LFTs* Diarrhea Nausea Musculoskeletal Back pain* Blood and lymphatic system Lymphopenia* Cardiovascular Atrioventricular block (first degree) Atrioventricular block (second degree) Bradycardia* Hypertension Ophthalmologic Macular edema* Neoplasms Basal-cell carcinoma Melanoma Breast cancer
FREEDOMS [6]
TRANSFORMS [7]
Fingolimod
Placebo
Fingolimod
IFN-b1a
94.4 7.5 10.1 0
92.6 7.7 13.4 0.5
86.0 5.6 7.0 0
91.6 3.7 5.8 0
8.7 12.9 27.1 49.9
7.9 9.8 27.5 50.5
2.1 6.8 20.5 7.2
2.8 7.4 20.4 6.3
25.2 11.3
23 10.8
23.1 10.3
20.4 10.4
15.8 11.8 8.9
5.0 7.4 8.6
6.5 7.5 9.3
1.9 4.9 6.7
11.8
6.9
6.1
5.3
3.5
0.5
0.2
0
0.5 0 2.1 6.1
0.5 0.2 0.7 3.8
0.2 0.2 0.5 3.7
0 0 0 1.9
0
0
0.5
0
0.9 0 0
0.7 0.2 0.7
0.7 0.7 0.5
0.2 0 0
*The most relevant side effects.
(conduction block between the atria and ventricles) atrioventricular (AV) block each occurred in 0.1% of subjects in Phase III studies [26]. Mild increases in systolic (3 mmHg) and diastolic (1 mmHg) blood pressures were seen in fingolimod-treated subjects [6,7,26]. Infection The overall incidence of infection was similar in fingolimod and control (placebo or IFN-b1a) groups; however, bronchitis and pneumonia occurred more frequently in the fingolimodtreated groups in FREEDOMS and mild respiratory infections were more frequent in fingolimod groups in TRANSFORMS [6,7]. Two serious herpetic infections were reported in FREEDOMS: one case of genital herpes in a subject treated with 1.25 mg of fingolimod, and one case of herpes simplex labialis in a subject in the 0.5-mg group. The overall incidence of herpes infection was similar between fingolimod and placebo groups [6]. In FREEDOMS II, herpes zoster infections were more commonly reported in the fingolimod groups (2.5% of patients treated with 0.5-mg fingolimod compared with 0.8% in placebo) [23]. In
TRANSFORMS, herpes infections occurred most frequently in the 1.25-mg fingolimod group. Two subjects in the 1.25-mg group died from viral infections. One subject died from disseminated varicella, while receiving concomitant corticosteroids for a MS relapse, and another due to herpes simplex encephalitis [7].
5.2
992
Laboratory abnormalities As expected, lymphocyte counts begin declining within several hours of the first dose of fingolimod and decreased between 73 and 77% of baseline within 1 month [6,7,27]. Fingolimod results in 80% reduction in peripheral blood CD4+ cells due to the selective retention of naive and TCM cells in lymphoid tissue. Despite CD4+ cell reduction, there did not appear to be a significantly increased infection risk at 0.5 mg dosing in clinical trials, postulated to be because these cells are not eliminated permanently [12]. Lymphocyte counts typically return to normal within 6 weeks of discontinuation of fingolimod [6,7], but prolonged lymphopenia has been reported in two patients [28]. Asymptomatic elevations in alanine aminotransferase levels to 2 -- 3 times the upper 5.3
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Fingolimod (Gilenya, FTY720)
limit of normal were more common in the fingolimod groups, which resolved spontaneously with or without discontinuation of fingolimod [6,7].
diffusion capacity for carbon monoxide. These did not worsen through the duration of treatment [6,7]. 6.
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5.4
ME is caused by fluid accumulation in the central retina or macula. Symptoms include decreased acuity and metamorphopsia, but ME is frequently asymptomatic. Primary modalities for detecting ME include fundus examination, optical coherence tomography and intravenous fluorescein angiography [29]. In TRANSFORMS, six subjects (four in 1.25-mg group and two in 0.5-mg group) developed ME, five of which did so within four months of starting fingolimod and four of which resolved after stopping fingolimod [7]. In FREEDOMS, seven patients developed ME, all in the 1.25-mg group. Six out of seven cases resolved after stopping fingolimod [6]. Pooled data from FREEDOMS, TRANSFORMS and FREEDOMS II indicated the overall incidence of ME was 0.4% in the 0.5-mg group. There is an increased risk of fingolimod-associated macular edema (FAME) in patients with DM or uveitis, and most cases of ME in the trials occurred in patients older than age 41. The mechanism of development of FAME is felt to be related to effects of S1P on vascular permeability [29]. Malignancies Several malignancies were reported in the 0.5-mg fingolimod groups in FREEDOMS and TRANSFORMS: seven basal cell carcinomas, two breast cancers and three melanomas [6,7]. In FREEDOMS II, basal cell carcinoma occurred in 2.8% of patients treated with 0.5 mg fingolimod compared with 0.6% of placebo-treated patients [23]. Data has failed to identify a significant increase in rate of malignancy between 0.5-mg fingolimod and control groups, although amongst all Phase III studies there was a trend towards increased incidence of basal cell carcinoma in fingolimod-treated patients [26]. One case of melanoma developing 57 months after initiation of treatment with fingolimod has been reported, in a subject who was initially treated with 1.25 mg dosing [30]. Three cases of lymphoma (one each of cutaneous T-cell lymphoma, Epstein--Barr virus-positive B-cell lymphoma and large B-cell non-Hodgkin lymphoma) were reported in the clinical development programs, which was higher than expected in the general population [26]. Studies in mouse models have suggested an increased rate of development of myeloma and B-cell lymphoma with fingolimod treatment, although doses administered were higher than those used in humans [31]. At this point, the association between fingolimod and lymphoma remains uncertain. 5.5
Pulmonary events A mild (2 -- 3%) decrease in one-second forced expiratory volume was seen in the fingolimod groups in both FREEDOMS and TRANSFORMS, in addition to a mild decrease in 5.6
Post-marketing events
Macular edema Cardiac events and relabeling In December 2011, there was a reported death of a patient within 24 h of the first dose of fingolimod [32]. Another patient died of suspected ventricular arrhythmia ~ 5 months after beginning treatment with fingolimod [33]. The FDA subsequently reviewed a total of 31 deaths in patients treated with fingolimod from 2003 to 2012. There were no deaths that could be definitively attributed to fingolimod, and number of cardiovascular deaths or deaths from an unknown etiology did not appear to be higher in fingolimod-treated patients compared to other MS patients not treated with fingolimod. However, the FDA did revise monitoring guidelines and contraindications in the product label [34]. Revised guidelines recommended cardiac monitoring for 6 h following the first dose of fingolimod, with extended monitoring in patients who developed significant bradycardia following the first dose and in those on medications known to prolong QT interval. Contraindications included myocardial infarction, stroke, transient ischemic attack, unstable angina or decompensated or class III/IV heart failure within 6 months prior to treatment; sick sinus syndrome or Mobitz II or higher AV block unless pacemaker has been placed; baseline QTc > 500; and use of class Ia or class III antiarrhythmics [34-36]. Administration of atropine can successfully reverse fingolimod-associated bradycardia [37]. In post-marketing studies, bradycardia occurred more often in patients treated with beta or calcium channel blockers [38]. There is one reported case of delayed asystole occurring 21 h after fingolimod administration in a patient on risperidone; asystole lasted for 7.5 s and recovered spontaneously [39]. Risperidone has been independently associated with prolonged QT interval, conduction block, bradycardia, asystole and sudden cardiac death. One case of prolonged bradycardia in a patient with baseline vagotonia and one case of paroxysmal atrial fibrillation following a first dose of fingolimod have also been reported [40,41]. 6.1
Extensive demyelinating lesions during fingolimod treatment
6.2
There have been several reported cases of extensive demyelinating lesions in fingolimod-treated patients [42-45]. Additional reports of severe demyelinating lesions specifically following transition from natalizumab to fingolimod have also been reported. In all cases, there were at least 8 weeks between cessation of natalizumab and initiation of fingolimod [46-48]. There has been an isolated report of extensive demyelination in a fingolimod-treated patient later determined to have neuromyelitis optica, for which fingolimod is not approved [49]. It has been postulated that in certain individuals, fingolimod may
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alter immunopathology and predispose to extensive demyelinating lesions [42], although the association remains unclear. Rebound disease after fingolimod discontinuation
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6.3
There are several case reports of patients who developed multiple new demyelinating lesions within several months of fingolimod discontinuation [50-55]. Reasons for discontinuation included patient decision [54], disease progression [50,55], desire to conceive [52], superficial melanoma [51], genital human papillomavirus infection [55] and herpes zoster infection [53,54]. Immune reconstitution causing increased influx of cells into the CNS has been proposed as a possible mechanism for rebound activity after fingolimod discontinuation [54]. Other reported events Three cases of posterior reversible encephalopathy syndrome have been reported in fingolimod-treated patients; one during clinical trials [56] and two in the post-marketing period [26]. Other vascular events reported include branch retinal vein occlusion [57] and critical vasospasm of left forearm arteries [58]. Recently, three cases of amenorrhea within the first 6 months of fingolimod treatment have been reported. In all three cases, menses returned to baseline following discontinuation of fingolimod [59]. Progressive multifocal leukoencephalopathy (PML) is caused by the John Cunningham (JC) virus and has been reported with natalizumab treatment in MS. In natalizumab-treated patients, PML risk is increased in those with detected serum JC virus antibodies, with > 24 infusions, and/or previous immunosuppressant use [60,61]. A single case of PML has been reported in a fingolimod-treated patient; however, this patient had been treated with natalizumab in the recent past [62]. In August 2013, the FDA reported a patient diagnosed with PML after taking fingolimod for 8 months. This was the first reported case of PML in a natalizumab-naive, fingolimod-treated patient, and further details are pending [63]. Other infectious complications reported in the post-marketing period include a case of hemorrhaging focal encephalitis presumed to be either autoimmune or viral in etiology [64] and a case of varicella encephalitis with vasculopathy in a patient who had not previously been vaccinated against varicella [65]. Two cases of fatal hemophagocytic syndrome during fingolimod treatment have recently been reported, although details regarding these cases are currently limited [66]. Hemophagocytic syndrome is characterized by marked hyperinflammation resulting in prolonged fevers, hepatosplenomegaly and cytopenias and can be triggered by viral infections [67]. 6.4
Monitoring guidelines Prior to initiating fingolimod, baseline electrocardiogram, complete blood count, liver function tests, bilirubin, varicella 6.5
994
antibody titers and ophthalmologic examination should be obtained. Patients with negative varicella antibody serology should be vaccinated (with a two-dose regimen) at least one month prior to initiation of fingolimod. There are no recommended guidelines for repeating antibody titers postvaccination. Live attenuated virus vaccinations should be avoided during treatment with fingolimod. Cardiac monitoring is recommended for at least 6 h after the first dose of fingolimod, with extended monitoring in special populations as previously detailed. Patients treated with b-blockers, diltiazem or digoxin should consider transitioning to alternative medications before starting fingolimod. For patients in whom fingolimod is discontinued for > 14 days and then restarted, first-dose monitoring should be repeated. Repeat ophthalmologic examination should be performed within 4 months of initiation of treatment, and periodically thereafter in patients with diabetes or uveitis [22]. Discontinuation should be considered in patients who develop ME [29]. Repeat liver and pulmonary function testing may be obtained as indicated clinically after initiation of treatment [22]. Use in pregnancy and breastfeeding Fingolimod is pregnancy category C, with teratogenicity (primarily cardiac abnormalities) demonstrated in rodents. In humans, there were nine spontaneous abortions and five cases of abnormal fetal development amongst 66 pregnancies occurring in fingolimod-exposed patients in the clinical development programs. Abnormalities included one case each of acrania, failure of fetal development, spontaneous intrauterine death, tetrology of Fallot and unilateral posteromedial bowing of the tibia. The combined frequency of congenital anomalies amongst pregnancies with in utero exposure to fingolimod (live births and elective abortions performed due to abnormalities) was 7.6%, higher than an expected rate of 3% [68,69]. Due to the overall low number of pregnancies in fingolimod-treated patients, caution is advised in interpreting these results. Contraception use is recommended during fingolimod treatment and for 2 months after cessation of therapy, and breastfeeding during fingolimod treatment is not recommended [22,70]. There is a fingolimod pregnancy registry [71]. 6.6
7.
Conclusion
Fingolimod is an effective treatment for relapsing MS and is generally well tolerated. The overall incidence of adverse events was similar in fingolimod and control groups in clinical trials. Of notable concern in fingolimod-treated patients is the risk of cardiac events, specifically transient symptomatic bradycardia and AV block after the first dose. Although most cases of bradycardia are transient and asymptomatic, a post-marketing unexplained death in a fingolimod-treated patient prompted a comprehensive FDA review and revision of monitoring guidelines and selection criteria. Clinical trials also suggested a potential risk of herpes virus and varicella
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Fingolimod (Gilenya, FTY720)
infections in patients treated with fingolimod, especially in those treated with concomitant steroids. Other serious adverse events include ME, which is likely to resolve with cessation of treatment. These complications occurred more frequently in the 1.25-mg-treated group than with the approved 0.5 mg dose. Additional post-marketing reports have raised concern for risk of extensive demyelinating lesions during treatment, rebound disease after cessation of treatment or development of certain malignancies with fingolimod, but these associations remain unclear. Appropriate patient selection, baseline evaluations, cardiac monitoring and surveillance monitoring are needed during treatment. 8.
Expert opinion
At the time of its approval in 2010, fingolimod offered important benefit in patients who preferred an oral route of medication administration or had disease progression on alternative treatments. In addition, fingolimod has demonstrated superior efficacy compared to at least one standard treatment for MS, intramuscular IFN-b1a. Fingolimod would significantly alter the treatment of primary progressive MS should ongoing trials reveal benefit in outcomes, as mitoxantrone is currently the only approved disease-modifying therapy for progressive disease. Most cardiac events during fingolimod treatment are asymptomatic and resolve spontaneously, and the risk of adverse cardiac outcomes can be mitigated with appropriate patient selection and monitoring following the first dose of medication. Although the overall risk of infection does not appear to be significantly increased, appropriate pretreatment screening and monitoring for infectious complications (especially herpesvirus and varicella) during fingolimod treatment are prudent. Steroid administration in the setting of fingolimod-induced lymphopenia may predispose to viral infections or reactivation, and this should be considered in treatment decisions for patients on fingolimod [72]. Of additional note, patients treated with fingolimod may have
decreased immune response to seasonal influenza and tetanus toxoid vaccines, although this is of uncertain significance [73]. As seen in the delayed recognition of increased risk of leukemia with mitoxantrone treatment, cumulative risk of malignancy with any new therapy may not become clear until several years post-marketing [74]. Although Phase III clinical trials did not reveal an increased risk of malignancy in fingolimod-treated groups, the risk of malignancy with longterm use is not yet defined. In addition, further data is needed to evaluate the potential risk for severe relapses or tumefactive demyelination during fingolimod treatment, transition from other treatments (e.g., natalizumab) and the risk of rebound disease following discontinuation of fingolimod. Although fingolimod offers the convenience of an oral route of administration, we reserve fingolimod for secondline treatment in patients who do not tolerate or who have disease progression on first-line disease-modifying therapies (e.g., IFN-b1a or glatiramer acetate) until longer term post-marketing data is available.
Acknowledgement MD Ward prepared the first draft version and reviewed the manuscript. DE Jones and MD Goldman prepared the manuscript and reviewed.
Declaration of interest M Goldman has received consulting fees from Novartis, Biogen Idec and Concert Pharma and has also received research funding from Biogen Idec and Novartis. D Jones has received consulting fees from Biogen Idec, Novartis and Genzyme. He has also received research funding from Genzyme. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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Affiliation Melanie D Ward1 MD, David E Jones2 MD & Myla D Goldman†2 MD MSc † Author for correspondence 1 Resident Physician, University of Virginia, Department of Neurology, PO Box 800394, Charlottesville, VA 22908, USA 2 Assistant Professor, University of Virginia, Department of Neurology, PO Box 800394, Charlottesville, VA 22908, USA Tel: +1 434 982 3936; Fax: +1 434 982 1726; E-mail: [email protected]
