Drug Evaluation
Pharmacokinetic evaluation of fingolimod for the treatment of multiple sclerosis 1.
Introduction
2.
Overview of the market
3.
Introduction to the
Radu Tanasescu & Cris S Constantinescu† †
University of Nottingham, Queen’s Medical Centre, Academic Division of Clinical Neurology, Nottingham, UK
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compound 4.
Chemistry
5.
Pharmacodynamics
6.
Pharmacokinetics and metabolism
7.
Clinical efficacy
8.
Safety and tolerability
9.
Post-marketing surveillance
10.
Regulatory affairs
11.
Conclusion
12.
Expert opinion
Introduction: Fingolimod is a sphingosine 1-phosphate receptor modulator with a novel mechanism of action and the first oral drug approved for the treatment of relapsing forms of multiple sclerosis (MS). Fingolimod reduces relapses more effectively than intramuscular interferon b1a and delays disability progression. Associated safety risks are bradyarrhythmia and atrioventricular block following the initial dose, requiring monitoring. Areas covered: This article examines the characteristics of fingolimod, its pharmacokinetic properties and the efficacy and tolerability in MS. Information on the pharmacology and mechanisms of action is also provided. Expert opinion: Fingolimod is an effective therapy for relapsing forms of MS in a convenient oral dose. Fingolimod may target not only inflammation but potentially also neurodegeneration. Antagonizing astrocyte sphingosine signaling may help explain the reduction in cerebral atrophy observed in Phase III trials. Long-term data about the safety of fingolimod are needed. Keywords: fingolimod, multiple sclerosis, oral drugs, sphingosine phosphate Expert Opin. Drug Metab. Toxicol. (2014) 10(4):621-630
1.
Introduction
Multiple sclerosis (MS) is a chronic immune-mediated disease of the CNS. The pathological processes occurring in MS include T-cell-mediated and B-cellmediated mechanisms, demyelination, inflammatory injury of axons and glia, gliosis and neurodegeneration. In most cases, MS has a relapsing--remitting course (RRMS) followed by a progressive phase, with permanent disability (secondary progressive MS, SPMS). In RRMS, the progression of disability occurs mainly in the context of, but also independent from clinical relapses [1,2]. Acute pharmacological management of relapses involves the use of corticosteroids. Long-term disease-modifying treatments (DMTs) aim to decrease relapse rate (RR) and CNS inflammation. Initially approved DMTs were all injectable. The oral drugs emerged from the unmet needs for new mechanistic therapies tackling inflammation and disability progression and for easy and convenient administration regimens. Fingolimod (FTY720) 0.5 mg once daily (Gilenya, Novartis PharmaAG, Basel, Switzerland) is the first in a new class of therapeutic compounds named sphingosine 1-phosphate receptor (S1PR) modulators (Box 1). Fingolimod is the first oral therapy approved in a number of countries for the treatment of RRMS in patients with high disease activity, despite treatment with IFN-b or rapidly evolving RRMS. 2.
Overview of the market
The DMT approved prior to fingolimod are IFN-b, glatiramer acetate (GA), natalizumab and mitoxantrone. The first-line agents IFN-b and GA are the longest approved and commonly used DMTs in MS and are relatively safe. Depending on 10.1517/17425255.2014.894019 © 2014 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name Phase Indication
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Mechanism of action
Route of administration Chemical structure of fingolimod and fingolimod phosphate
FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol) III RRMS; patients with high disease activity despite treatment with IFN or patients with rapidly evolving severe RRMS The first approved sphingosine 1-phosphate receptor modulator Fingolimod inhibits egress of lymphocytes from lymph nodes and their recirculation, potentially reducing trafficking of pathogenic cells into the CNS Fingolimod also penetrates the CNS; fingolimod-P formed in situ may have direct effects on neural cells Oral NH2 HO HO
Fingolimod NH2
OH HO
P O
Pivotal trial(s)
O HO
the formulation, IFN-b is administered subcutaneously or intramuscularly, either on alternate days, three times per week, or once weekly. GA is given as a once-daily subcutaneous injection. IFN and GA have comparable efficacy, reducing RR by approximately 30% [3]. Common side effects include local injection-site reactions and postinjection systemic reactions. Formulation requiring less frequent injections has been recently evaluated for both drugs, in Phase III placebo-controlled trials [4,5]. As MS is a life-long disease and both IFN and GA require regular, long-term, selfinjection administration, the issues of tolerance and adherence to treatment reduce the likelihood of achieving durable treatment efficacy [3]. Second-line therapies such as the humanized antibody natalizumab and the cytostatic agent mitoxantrone are more effective and therefore reserved for highly active MS [6]. They are administered parenteraly and associated with potentially severe side effects (e.g., progressive multifocal leukoencephalopathy, PML for natalizumab; cardiotoxicity and acute leukemia for mitoxantrone [7-11]). Currently, four oral DMTs have completed Phase III clinical trials (fingolimod, laquinimod, dimethyl fumarate and teriflunomide) and have been or are currently being evaluated by medical agencies [12]. Teriflunomide, an immunomodulatory drug that inhibits de novo pyrimidine synthesis, reduces frequency of relapses by 30% and was recently approved by the US and European regulatory agencies. Its main side effects are increased hepatic enzymes, alopecia and teratogenicity [13]. Dimethyl fumarate inhibits expression of pro-inflammatory cytokines and adhesion molecules and reduces the annual RR in Phase III trials by 53% for the twice-daily dosing [14]. The drug has a good safety profile, but initial side effects include flushing and gastrointestinal symptoms. It has recently been approved by the FDA and is currently evaluated in Europe. Laquinimod reduces RR by ~ 25% compared with placebo and also reduces disability progression and brain 622
Fingolimod-P
[80,82]
volume loss [15,16]. Factors influencing placing of individual oral drugs within the therapy algorithm are clinical and radiological evidence, individual benefit-risk ratio, patient’s wishes and economic aspects [3]. 3.
Introduction to the compound
Fingolimod is a drug developed from fungus metabolite myriocin and initially studied in organ transplantation. Fingolimod is a prodrug phosphorylated in vivo to fingolimod phosphate (fingolimod-P) by sphingosine kinase-2 (Sphk2) [17,18]. Fingolimod-P is a high-affinity, nonselective agonist of four of the five known G protein-coupled sphingosine-phosphate receptors (S1PRs 1,3,4,5) and modulates their expression on lymphocytes and cells in the CNS and cardiovascular systems [17]. S1PRs have significant functions in the immune system and CNS, and S1P signaling is important in neuroinflammatory processes [19]. The main effect of fingolimod on the immune system is the down-modulation of S1P1 receptors on lymphocytes, preventing their egress from lymph nodes. This affects selectively naive and central memory T cells and B cells but spares effector memory T cells and therefore preserves their key immune functions [20]. Therefore, fingolimod acts through redistribution of lymphocytes to the lymphoid tissues rather than lymphocyte destruction, as seen with cytotoxic agents [21]. Early administration of fingolimod prevents development of the clinical features of the animal model of MS, experimental autoimmune encephalomyelitis (EAE) [22]. Fingolimod treatment at different stages of disease reduced clinical features, inflammatory infiltrates, axonal loss and demyelination [22]. Fingolimod effects were present even in late established disease, and a neuroprotective activity of the drug has been suggested [23]. The precise mechanisms underlying these effects remain to be determined.
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4.
Chemistry
Fingolimod (2-amino-2-[2-(4-octylphenyl) ethyl] propane1,3-diol) is composed of a polar head region, a phenyl ring and a hydrophobic alkyl chain [24]. Fingolimod-P is obtained by the phosphorylation of the symmetrical 2-alkyl-2-aminopropane-1,3-diol moiety from the polar head region of fingolimod. Both fingolimod and fingolimod-P share structural similarities with sphingosine and sphingosine 1-phosphate, respectively. Fingolimod-P interacts with S1PRs and exerts immunomodulatory properties [25,26] mainly through the hydroxymethyl group attached to the quaternary carbon [27]. The position of the phenyl group inserted within the alkyl chain determines the potency of the drug [28], and it was suggested that the most suitable length between the quaternary carbon and the phenyl ring corresponds to two carbon atoms [18] The phenyl ring confers increased agonist activity at S1PR5, loss of activity at S1PR2 and loss of the C2-stereospecificity at S1PR1 and S1PR3 [29].
to lymphoid organs and does not express the CD62L and CCR7 lymph-node-homing receptors [38]. This could help to retain desirable immunological functions [37]. Intrinsic lymphocyte functions are not affected by treatment with fingolimod, whereas local immune responses dependent on naive T cells and central memory T-cell migration to tissues are reduced or delayed. After stopping fingolimod, the average lymphocyte count exceeds the lower limit of normal range within 6 -- 8 weeks and at 3 months it reaches 80% of baseline values [39]. Discontinuations of the drug after long-term use is followed by reappearance of CD4+ CCR7+ T cells, which are implicated in MS pathogenesis and expected to be sequestered by fingolimod treatment [40]. The rapid reconstitution of CCR7+ cells raises caution about drug holidays and the period of transition to other therapies [40]. Chronic fingolimod treatment leads to a mild decrease in the neutrophil count to approximately 80% of baseline.
Effects of fingolimod on cells in the CNS Fingolimod is able to cross the blood brain barrier (BBB) [41-43]. By modulating the S1PRs receptors expressed on CNS cells [44-46], fingolimod may influence neurodegeneration, gliosis and repair mechanisms [17,42,45]. Fingolimod exposure in vitro can increase the number of progenitor and mature oligodendrocytes, protect oligodendrocytes from cell death induced by cytokines or by withdrawal of growth factors and modulate process outgrowth (both retraction and extension), thus influencing remyelination [47-49]. Fingolimod affects S1PR signaling and migration of astrocytes in vitro by both direct and indirect effects of receptor modulation [17,50]. Recent postmortem evidence suggests that reactive astrocytes represent a possible additional cellular target for fingolimod in MS by directly reducing the production of pro-inflammatory lipids and limiting subsequent transendothelial leukocyte migration [51]. Evidence from EAE studies suggests that beneficial effects of fingolimod are mediated not only through peripheral immune cells but also via direct CNS effects, by direct modulation of microvascular and/or glial cells [52-54]. EAE is attenuated and fingolimod efficacy is lost in mouse mutants lacking S1PR1 on glial fibrillary acidic protein (GFAP)expressing astrocytes but not on neurons [55]. A recent study on the focal delayed-type hypersensitivity (DTH) MS model in Lewis rats has studied fingolimod effects on lesion formation when the BBB is compromised; and on a chronic, active lesion occurring behind an intact, resealed BBB [42]. While the precise target cell population remains unclear, fingolimod continued to reduce demyelination behind an intact BBB, without reducing the number of lymphocytes within DTH lesions, thus suggests that the restorative effects of the drug at chronic disease stages may occur independently of effects on peripheral lymphocytes [42]. The mechanisms of fingolimod effects on CNS cells require further clarification, in particular, identification of the target cells and S1PRs [35]. 5.2
5.
Pharmacodynamics
Fingolimod effects on the immune system Fingolimod-P exerts its cellular effects through modulation of S1PRs (agonistic activation or internalization as a result of receptor potent stimulation, that is, receptor downregulation), which depends on the tissue or cell context, drug and endogenous ligand concentrations, and the receptor subtype [30]. S1PR1 and S1PR3 are ubiquitously expressed, whereas S1PR4 is primarily expressed in the lymphoid system and S1PR5 in the CNS [31,32]. Each S1PR is associated with different subtypes of heterotrimeric G proteins, which activate diverse intracellular signaling pathways [33,34]. Beneficial effects and side effects are the result of those pharmacodynamics interactions [35]. Fingolimod exerts its therapeutic effects in MS through receptor-mediated actions both on the immune system and in the CNS [33,34,36]. S1P and S1PR1 are major regulators of lymphocyte trafficking [28]. Fingolimod-P acts as an agonist at the S1PR1 on thymocytes and lymphocytes and induces its internalization. This renders these cells unresponsive to S1P, depriving them of an obligatory signal to exit lymphoid organs, thus reducing the infiltration of auto-aggressive lymphocytes into the CNS [34]. Blood lymphocyte count decreases to approximately 75% of baseline within 4 -- 6 h after the first dose of fingolimod 0.5 mg, then continues to decrease with continued daily dosing, reaching a nadir of approximately 500 cells/µl or 30% of baseline more than a 2-week period [34]. Low lymphocyte counts are maintained with daily dosing. Fingolimod selectively retains T cells that regularly traffic through lymph nodes and which express the homing receptor, CCR7 [37], including naive, central memory and Th17 cells [20]. Effector memory T cells are not affected by fingolimod because this lymphocyte subset typically does not traffic 5.1
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5.3
Cardiac, vascular and pulmonary effects
S1P regulates heart rate and conduction. S1PR1, S1PR2 and S1PR3 are the dominant receptors in the cardiovascular system [56]. Fingolimod binding to S1PR1s in atrial myocytes initially leads to activation of G-protein-gated cholinergic potassium channels (IKACh) eliciting an inward rectifying potassium current, membrane hyperpolarization, reduced cell excitability and decreased firing rate [56,57]. Receptor desensitization makes this effect self-limited [56]. Fingolimod causes a transient reduction in heart rate and atrioventricular conduction in the first 4 -- 5 h post-first dose, with 70% of the negative chronotropic effect achieved on the first day. Heart rate progressively returns to baseline values within 1 month of chronic treatment. Fingolimod increases the rate of new onset first-degree A-V heart block by 12% on first day of dosing; the incidence reduces to < 1% after 1 week of treatment [35]. Doses £ 1.25 mg were associated with a 7% incidence of heart block versus 3% on placebo. These blocks were usually asymptomatic and did not require treatment [35]. Autonomic responses of the heart are not affected by fingolimod treatment and the decrease in heart rate induced by fingolimod can be reversed by atropine, isoprenaline or salmeterol [35]. In the MS studies, there was no clinically relevant prolongation of QT interval [35]. Interestingly, FTY-720 alleviates existing cardiac hypertrophy/fibrosis through mechanisms involving negative regulation of NFAT activity in cardiomyocytes and reduction of periostin expression allowing for a more homeostatic extracellular compartment milieu [58]. Vascular and lymphatic endothelial cells express high levels of S1PR1 and lower levels of S1PR2 and S1PR3 [59,60]. The effects of S1P and fingolimod on endothelial cells are heterogeneous, augmenting tight junction and barrier function in some vascular beds and increasing permeability in other tissues [61,62]. Alveolar epithelium expresses S1PR3, and S1P administered in the airways disrupts alveolar epithelial barrier function [63]. Single fingolimod doses ‡ 5 mg (10-fold the recommended dose) are associated with a dose-dependent increase in airway resistance. Fingolimod treatment with multiple doses of 0.5, 1.25 or 5 mg is not associated with impaired oxygenation or oxygen desaturation with exercise or an increase in airway responsiveness to methacholine [35]. In a combined analysis of Phase III trials FREEDOMS and TRANSFORMS, minor fingolimod dose-dependent decreases in forced expiratory volume at 1 s and diffusing capacity for carbon monoxide seen at 1 month and were stable thereafter [64,65]. 6.
Pharmacokinetics and metabolism
The pharmacokinetics (PK) of fingolimod has been extensively evaluated in several patient groups and healthy people. PK parameters show slow and extensive absorption with no influence of food intake on absorption, steady-state exposure reached within 2 months after treatment initiation and extensive distribution to tissues [66]. Absorption of oral fingolimod 624
is relatively slow with a Tmax of 12 -- 16 h, with high oral bioavailability (93%) [67,68] and an average apparent clearance of 10.8 l/h [68]. The half-life of fingolimod following repeated administration is 6 -- 9 days [69]. Fingolimod and fingolimodP concentrations increase in an apparent dose-proportional manner after multiple once-daily doses of fingolimod 0.5 or 1.25 mg [69]. Steady-state blood concentrations are achieved within 2 months of daily administration are dose proportional and do not vary upon repeated administration (i.e., they are time independent and show constant clearance) [69]. Fingolimod-P Cmax and the AUC are approximately 50% lower than the parent drug on day 7 of seven daily doses of fingolimod [66]. A predictable relationship between dose and systemic exposure is seen. Results from multiple-dose studies of once-daily dosing with doses of 0.125 -- 5 mg administered for 7 days (in healthy volunteers) or 28 days (in renal transplant recipients and healthy volunteers) indicated that the Cmax and AUC of fingolimod at steady state are dose proportional, and intersubject variability is moderate to high (39 -- 79% for the Cmax and 21 -- 52% for the AUC) [69]. Furthermore, the fingolimod concentration profile after repeated dosing is remarkably flat, with peak-to-trough fluctuations of approximately 20% [69]. The half-life, Tmax and clearance were found to be largely independent of dose. The AUC and Cmax of fingolimod at steady state are dose proportional, with values for fingolimod 1.25 mg being approximately 2.9 times greater than those for fingolimod 0.5 mg [69]. PK studies in renal transplant patients [70], MS, hepatic impairment [25], children and different ethnic groups [71] have shown that, over a wide range of comorbidities, fingolimod and fingolimod-P PK do not vary and that the same dosing regimen can be used in White and Asian patients. No significant differences in apparent clearance according to sex were observed [69]. The metabolism of fingolimod is reduced in subjects with hepatic impairment, leading to increased exposure. Differences in exposure to fingolimod in patients with mild or moderate impairment are insufficient to necessitate dose adjustment [72,73]; however, in patients with severe hepatic impairment, fingolimod should either be used with caution [72] or should not be used [73]. In patients with severe renal impairment, fingolimod and fingolimod-P Cmax are increased by 32 and 25%, respectively, with no change in apparent elimination half-life. Based on these findings, the 0.5 mg dose is appropriate for use in patients with renal impairment [74]. Exposure to fingolimod is similar for patients with mild-to-moderate renal impairment (creatinine clearance 30 -- 80 ml/min) and patients with normal renal function. Comparison of fingolimod concentrations before and after each hemodialysis session, however, showed that hemodialysis led to a minor reduction of 14% in fingolimod concentrations [69]. Fingolimod is extensively metabolized, with biotransformation occurring via three main pathways. i) formation of
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Fingolimod
fingolimod-P by reversible phosphorylation. The phosphorylation of fingolimod is catalyzed by Sphk2, with a smaller contribution by Sphk1, whilst dephosphorylation of fingolimod-P is catalyzed by the lipid phosphate phosphohydrolases LPP1a and LPP3 and, by the specific sphingosine 1-phosphate phosphatase, SPP1 [75]. ii) oxidative biotransformation of fingolimod by hydroxylation at the methyl terminal of the octyl chain by cytochrome P450 (CYP) 4F2 and other enzymes of the CYP4F subfamily e [76]. iii) formation of nonpolar ceramide analogs of fingolimod by the action of (dihydro)ceramide synthase [75]. The major metabolites detected in blood (according to their contribution to the AUC during 0 -- 816 h) are fingolimod (23.3%), fingolimod-P (10.3%), the butanoic acid metabolite (8.3%) and the ceramide metabolites M29 (8.9%) and M30 (7.3%), and butanoic acid in urine (36%) [75]. Fingolimod and fingolimod-P are not detected in urine but are detected in faeces (2.4 and 1.7% of the dose, respectively) [75]. Following oral administration of [14C]-radiolabeled fingolimod, the radioactivity is excreted very slowly, with most of the dose being recovered in the urine (81%, compared with 11% in faeces); 62% of radioactivity is recovered within 10 days of administration and 89% within 34 days [69]. The distribution to blood cells is 86% for fingolimod and 17% for fingolimod-P [69]. Both compounds are extensively bound to plasma proteins (free fraction 0.15% for fingolimod and 0.3% for fingolimod-P). This binding is not altered by renal or hepatic impairment. Fingolimod binds extensively to serum albumin and lipoproteins, while fingolimod-P exhibits extensive binding to serum albumin and high-tomoderate binding to lipoproteins, a1-acid glycoprotein and g globulins [69]. Drug--drug interactions resulting from displacement from plasma proteins are not expected, given the very low concentrations of fingolimod and fingolimod-P at steady state under clinical conditions [69]. Fingolimod has a low potential for drug-drug interactions, as few drugs are known to be metabolized by CYP4F2. Ketoconazole, an inhibitor of CYP4F2, can increase the concentration of the drug [69]. Administration of fingolimod 0.5 mg does not alter the PK of oral contraceptives (levonorgestrel 150 mg or ethinylestradiol 30 mg), antihypertensive therapies (atenolol and diltiazem) or anti-bradycardic drugs (isoproterenol and atropine) [69]. Based on population PK analysis to date, there were no apparent clinically relevant effects when the following medications were co-administered with fingolimod: fluoxetine, paroxetine, carbamazepine, baclofen, gabapentin, oxybutynin, amantadine, modafinil, amitriptyline, pregabalin and corticosteroids [24,66]. 7.
Clinical efficacy
Clinical efficacy and safety of fingolimod in relapsing MS have been evaluated in one Phase II and two Phase III studies. The approval of fingolimod as MS treatment was based on the
largest Phase III clinical trial program in MS at the time of submission [77]. The Phase II study included 281 patients with active RRMS (having had at least two relapses during the previous 2 years or one relapse in the previous year or one gadolinium-enhancing (Gd+) lesion on MRI) and an Expanded Disability Status Scale (EDSS) of 0 -- 6.0, randomized to receive oral fingolimod 1.25 or 5 mg or placebo once daily [24]. Both dosages of fingolimod significantly reduced the total number of Gd+ lesions compared with placebo. Fingolimod-treated groups showed a greater proportion of patients free from Gd+ lesions, a reduced annualized relapse rate (ARR) and a greater proportion of patients (86%) who remained relapse-free when compared with the placebo group (66%). An open-label, active-drug extension study in which the previously placebo-treated patients were randomized to fingolimod showed a significant decrease in the number of Gd+ lesions and the ARR after fingolimod initiation [78,79]. During months 15 -- 24, patients receiving fingolimod 5 mg were switched to fingolimod 1.25 mg, which had fewer side effects and was as effective. These results were confirmed in two Phase III studies. In the FREEDOMS trial, active RRMS patients were randomized to receive oral fingolimod 0.5 mg, fingolimod 1.25 mg or placebo once daily for 24 months [80]. Approximately 60% of the patients were treatment-naive. The mean EDSS was 2.4. The ARR was reduced significantly by fingolimod when compared with placebo (fingolimod 0.5 mg: 0.18; fingolimod 1.25 mg: 0.16; placebo 0.4) and the relative risk from 54 to 60%. The time to confirmed disability progression after 3 and 6 months was prolonged significantly in fingolimod arms. MRI outcomes were favorable for fingolimod: number of Gd+ lesions, number of new or enlarged T2 lesions and volume of T1-hypointense lesions [80]. Subgroup analysis suggested that fingolimod 0.5 mg was effective in patients with breakthrough disease despite use of DMTs and in patients with highly active MS, however, the effect was attenuated in patients aged over 40 years [81]. The TRANSFORMS study compared fingolimod to intramuscular once weekly IFN-b1a. The patients were randomized in a double-blind design to oral fingolimod 0.5 mg, fingolimod 1.25 mg or IFN-b1a intramuscularly once weekly [82]. In the study, 1292 patients with active RRMS with EDSS between 0 and 5.5 were included. Average disease duration was 7.4 years. The patients had a mean EDSS of 2.2. The majority of patients had previous DMTs, mostly IFN-b or GA. Fingolimod reduced the ARR more than IFN-b1a (fingolimod 0.5 mg: 0.16; fingolimod 1.25 mg: 0.2; IFN-b1a: 0.33) [82]. The proportion of relapse-free patients was significantly higher in both fingolimod-treated groups (fingolimod 0.5 mg: 82.6%; fingolimod 1.25 mg: 79.8%; IFN-b1a: 69.3%). MRI outcomes were also significantly different (less Gd+ lesions, new or enlarged T2 lesions and brain atrophy). The TRANSFORMS patients who were treated with IFN-b1a were randomly assigned to receive 0.5 or 1.25 mg of fingolimod in an extension of the
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trial [83]. ARR, disability progression and MRI outcomes improved in the switched group from IFN-b1a to fingolimod. Patients receiving continuous fingolimod had unchanged benefits in the ARR and a significantly lower ARR and reduced inflammatory activity in brain MRI compared to the newly treated group [83]. Because initial data suggests that fingolimod may have an effect on nerve repair, the INFORMS study has been launched [84]. The purpose of INFORMS is to evaluate whether fingolimod (0.5 or 1.25 mg tablets taken daily for 3 years) is effective in delaying disability progression compared with placebo in 654 people with primary progressive MS. The INFORMS is due to end in September 2014.
8.
Safety and tolerability
Fingolimod was well tolerated in all clinical studies and had a favorable overall safety profile. The most common serious adverse events were transient bradycardia and atrioventricular block related to the first dose of the medication (within 6 h of first administration) [9]. Cutaneous neoplasias (basal cell carcinomas and melanomas in situ) were more often reported in the fingolimod group than in the control groups [80,82]. Macular edema occurred in 1% of the patients in the 1.25-mg group and 0.5% of the 0.5-mg group and resolved in most patients after treatment discontinuation. Up to 12.5% of patients had levels of liver enzymes three times the upper limit of the normal range or more. In all patients, liver enzyme abnormalities returned to normal after drug discontinuation. Hematologic side effects comprise lymphopenia (4%) and leucopenia (3%), and monitoring of fingolimod treatment should include complete cell counts at initiation, months 1, 3, 6, and periodically thereafter. In all clinical studies, the frequency of overall infections was comparable in fingolimod-treated patients and controls [82]. In the FREEDOMS study, lower respiratory tract infections (including bronchitis and pneumonia) were more frequent in patients treated with fingolimod. Vaccination during therapy with fingolimod may be less effective. Vaccination with live attenuated virus vaccines should be avoided during and 2 months after fingolimod therapy as it carries the risk of infections [9]. Patients without a history of chickenpox or vaccination against varicella zoster virus (VZV) should be tested for antibodies, and in those without (VZV) antibodies vaccination considered 1 month prior fingolimod initiation. Two fatal cases of disseminated VZV and herpes simplex encephalitis and a third case of a patient with a life-threatening HSV encephalitis were reported in the TRANSFORMS trial, in the group treated with the 1.25-mg fingolimod dose. Therefore, the lower dose of 0.5 mg was approved [9]. In October 2013, FDA warned that a MS patient taking fingolimod developed PML, without being previously treated with natalizumab [85]. 626
9.
Post-marketing surveillance
The European Medicines Agency and FDA reviewed the license for fingolimod after serious cardiovascular events in patients on the drug [86,87]. They recommended that the drug not be prescribed to patients with pre-existing cardiac or cerebrovascular disease or to those taking anti-arrhythmic drugs; if treatment was considered necessary, a prior cardiology opinion was advised. A baseline electrocardiogram (ECG) is required in all patients and continuous ECG monitoring for 6 h after the first dose to be extended to at least overnight in any patient developing a cardiac abnormality during the monitoring period. Other requirements include ophthalmic evaluations on commencing fingolimod and after 3 -- 4 months of therapy and baseline hematology and liver enzymes checks [12]. 10.
Regulatory affairs
Fingolimod is approved in the US, Switzerland and Australia as first-line drug for RRMS. In Australia, fingolimod is registered for the treatment of SPMS with superimposed relapses. In Europe, fingolimod is reserved to patients with high disease activity despite treatment with IFN (having at least one relapse in the previous year while on therapy, and have at least nine T2-hyperintense lesions in cranial MRI or at least one Gd+ lesion); or patients with rapidly evolving severe RRMS. Rapidly evolving severe RRMS is defined by two or more disabling relapses in 1 year and by one or more MRI Gd+ lesions or a significant increase in T2 lesion load as compared to a previous recent MRI. 11.
Conclusion
Fingolimod is the first member of the new class of S1PR modulators. Fingolimod represents a milestone in the treatment of RRMS, being the first approved oral therapy, offering patients a more convenient administration route. Fingolimod is effective in active RRMS. Two large Phase III clinical trials showed a superior efficacy of fingolimod compared to both placebo and IFN-b intramuscularly. Fingolimod is well tolerated and overall safe. Transient, generally asymptomatic bradycardia and infrequent atrioventricular block are seen with after first dose administration. Detailed cardiovascular risk stratification and adequate patient monitoring at treatment initiation are recommended. A Phase IV clinical program aims to assess tolerability and safety of the drug when used in patients under nonstudy condition. 12.
Expert opinion
Fingolimod is effective in active RRMS, after the first-line therapy IFN-b fails. According to expert opinion this would similarly apply to prior treatment with GA [88].
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Cost-effectiveness of fingolimod versus natalizumab for RRMS treatment is debated, and there is a current need to evaluate the relative value of newer therapies given healthcare resource constraints. Although data from decision analytic models show that natalizumab could dominate fingolimod in terms of incremental cost per relapse avoided, costminimizing analyses in different countries suggest that fingolimod use may result in considerable cost savings compared to natalizumab and that early treatment initiation is costeffective [89-95]. Whether and when fingolimod might be a therapeutic option following natalizumab needs to be evaluated, as well as the long-term risk for PML [96]. Fingolimod may target not only inflammation but potentially also neurodegeneration. The mechanism of antagonizing astrocyte S1PR1 signaling may help explain the improvement in cerebral atrophy scores relative to control groups observed during the FREEDOMS and TRANSFORMS trials, rarely seen with other MS treatments [97]. In vitro data suggesting that fingolimod affects oligodendrocyte precursors survival, recruitment and activation, and attenuates astrogliosis, needs supporting in vivo evidence. Fingolimod effects in function of particular MS pathological stages need further study. Effects on human oligodendrocytes, astrocytes and neurons are suggested to be time-, dose- and stage dependent, which may in part reflect the relative levels of expression of the relevant receptors. These effects could formally alter the myelination or remyelination processes [98]. Moreover, in vivo and in vitro studies with S1P have reported nervous system inflammatory responses that induce morphological changes Bibliography
in neural cells and astrocytes, and increase the expression of GFAP, a protein involved in astrocytosis which may impede regeneration [99-101]. Fingolimod has not been administered concomitantly with antineoplastic, immunosuppressive or other immunomodulatory therapies, but combined treatment with these agents is expected to increase the risk of immunosuppression. However, the unmet needs of MS treatments may lead in the future to the need for combined therapy. By its specific effect at targeting signaling through S1PR1 at the BBB, fingolimod and fingolimod-P can rapidly and reversibly reduce basal activity of the ATP-driven drug efflux pump P-glycoprotein and thus improve delivery of small-molecule therapeutics to the brain [98,102]. The PK profile of fingolimod has been extensively studied and a population PK predictive model exists [66]. However, long-term data about the safety of fingolimod, especially after cessation of natalizumab, are needed and should be further investigated.
Declaration of interest R Tanasescu has received travel support for meetings from Teva, Biogen-Idec, Lundbeck and Novartis. CS Constantinescu has received research support, travel support for meetings and honoraria for talks from Biogen-Idec, Bayer Schering, Teva, GW, Merck Serono, Novartis and MorphoSys. They did not receive funding or sponsorship for preparing this manuscript.
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Affiliation
Radu Tanasescu1,2 & Cris S Constantinescu†1 † Author for correspondence 1 University of Nottingham, Queen’s Medical Centre, Academic Division of Clinical Neurology, C Floor, South Block, Nottingham, NG7 2UH, UK Tel: +44 115 8754597/98; Fax: +44 115 823 1443; E-mail: [email protected] 2 University of Medicine and Pharmacy Carol Davila Bucharest, Colentina Hospital, Department of Neurology, Neurosurgery and Psychiatry, Bucharest, Romania
Pharmacokinetic evaluation of fingolimod for the treatment of multiple sclerosis 1.
Introduction
2.
Overview of the market
3.
Introduction to the
Radu Tanasescu & Cris S Constantinescu† †
University of Nottingham, Queen’s Medical Centre, Academic Division of Clinical Neurology, Nottingham, UK
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compound 4.
Chemistry
5.
Pharmacodynamics
6.
Pharmacokinetics and metabolism
7.
Clinical efficacy
8.
Safety and tolerability
9.
Post-marketing surveillance
10.
Regulatory affairs
11.
Conclusion
12.
Expert opinion
Introduction: Fingolimod is a sphingosine 1-phosphate receptor modulator with a novel mechanism of action and the first oral drug approved for the treatment of relapsing forms of multiple sclerosis (MS). Fingolimod reduces relapses more effectively than intramuscular interferon b1a and delays disability progression. Associated safety risks are bradyarrhythmia and atrioventricular block following the initial dose, requiring monitoring. Areas covered: This article examines the characteristics of fingolimod, its pharmacokinetic properties and the efficacy and tolerability in MS. Information on the pharmacology and mechanisms of action is also provided. Expert opinion: Fingolimod is an effective therapy for relapsing forms of MS in a convenient oral dose. Fingolimod may target not only inflammation but potentially also neurodegeneration. Antagonizing astrocyte sphingosine signaling may help explain the reduction in cerebral atrophy observed in Phase III trials. Long-term data about the safety of fingolimod are needed. Keywords: fingolimod, multiple sclerosis, oral drugs, sphingosine phosphate Expert Opin. Drug Metab. Toxicol. (2014) 10(4):621-630
1.
Introduction
Multiple sclerosis (MS) is a chronic immune-mediated disease of the CNS. The pathological processes occurring in MS include T-cell-mediated and B-cellmediated mechanisms, demyelination, inflammatory injury of axons and glia, gliosis and neurodegeneration. In most cases, MS has a relapsing--remitting course (RRMS) followed by a progressive phase, with permanent disability (secondary progressive MS, SPMS). In RRMS, the progression of disability occurs mainly in the context of, but also independent from clinical relapses [1,2]. Acute pharmacological management of relapses involves the use of corticosteroids. Long-term disease-modifying treatments (DMTs) aim to decrease relapse rate (RR) and CNS inflammation. Initially approved DMTs were all injectable. The oral drugs emerged from the unmet needs for new mechanistic therapies tackling inflammation and disability progression and for easy and convenient administration regimens. Fingolimod (FTY720) 0.5 mg once daily (Gilenya, Novartis PharmaAG, Basel, Switzerland) is the first in a new class of therapeutic compounds named sphingosine 1-phosphate receptor (S1PR) modulators (Box 1). Fingolimod is the first oral therapy approved in a number of countries for the treatment of RRMS in patients with high disease activity, despite treatment with IFN-b or rapidly evolving RRMS. 2.
Overview of the market
The DMT approved prior to fingolimod are IFN-b, glatiramer acetate (GA), natalizumab and mitoxantrone. The first-line agents IFN-b and GA are the longest approved and commonly used DMTs in MS and are relatively safe. Depending on 10.1517/17425255.2014.894019 © 2014 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name Phase Indication
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Mechanism of action
Route of administration Chemical structure of fingolimod and fingolimod phosphate
FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol) III RRMS; patients with high disease activity despite treatment with IFN or patients with rapidly evolving severe RRMS The first approved sphingosine 1-phosphate receptor modulator Fingolimod inhibits egress of lymphocytes from lymph nodes and their recirculation, potentially reducing trafficking of pathogenic cells into the CNS Fingolimod also penetrates the CNS; fingolimod-P formed in situ may have direct effects on neural cells Oral NH2 HO HO
Fingolimod NH2
OH HO
P O
Pivotal trial(s)
O HO
the formulation, IFN-b is administered subcutaneously or intramuscularly, either on alternate days, three times per week, or once weekly. GA is given as a once-daily subcutaneous injection. IFN and GA have comparable efficacy, reducing RR by approximately 30% [3]. Common side effects include local injection-site reactions and postinjection systemic reactions. Formulation requiring less frequent injections has been recently evaluated for both drugs, in Phase III placebo-controlled trials [4,5]. As MS is a life-long disease and both IFN and GA require regular, long-term, selfinjection administration, the issues of tolerance and adherence to treatment reduce the likelihood of achieving durable treatment efficacy [3]. Second-line therapies such as the humanized antibody natalizumab and the cytostatic agent mitoxantrone are more effective and therefore reserved for highly active MS [6]. They are administered parenteraly and associated with potentially severe side effects (e.g., progressive multifocal leukoencephalopathy, PML for natalizumab; cardiotoxicity and acute leukemia for mitoxantrone [7-11]). Currently, four oral DMTs have completed Phase III clinical trials (fingolimod, laquinimod, dimethyl fumarate and teriflunomide) and have been or are currently being evaluated by medical agencies [12]. Teriflunomide, an immunomodulatory drug that inhibits de novo pyrimidine synthesis, reduces frequency of relapses by 30% and was recently approved by the US and European regulatory agencies. Its main side effects are increased hepatic enzymes, alopecia and teratogenicity [13]. Dimethyl fumarate inhibits expression of pro-inflammatory cytokines and adhesion molecules and reduces the annual RR in Phase III trials by 53% for the twice-daily dosing [14]. The drug has a good safety profile, but initial side effects include flushing and gastrointestinal symptoms. It has recently been approved by the FDA and is currently evaluated in Europe. Laquinimod reduces RR by ~ 25% compared with placebo and also reduces disability progression and brain 622
Fingolimod-P
[80,82]
volume loss [15,16]. Factors influencing placing of individual oral drugs within the therapy algorithm are clinical and radiological evidence, individual benefit-risk ratio, patient’s wishes and economic aspects [3]. 3.
Introduction to the compound
Fingolimod is a drug developed from fungus metabolite myriocin and initially studied in organ transplantation. Fingolimod is a prodrug phosphorylated in vivo to fingolimod phosphate (fingolimod-P) by sphingosine kinase-2 (Sphk2) [17,18]. Fingolimod-P is a high-affinity, nonselective agonist of four of the five known G protein-coupled sphingosine-phosphate receptors (S1PRs 1,3,4,5) and modulates their expression on lymphocytes and cells in the CNS and cardiovascular systems [17]. S1PRs have significant functions in the immune system and CNS, and S1P signaling is important in neuroinflammatory processes [19]. The main effect of fingolimod on the immune system is the down-modulation of S1P1 receptors on lymphocytes, preventing their egress from lymph nodes. This affects selectively naive and central memory T cells and B cells but spares effector memory T cells and therefore preserves their key immune functions [20]. Therefore, fingolimod acts through redistribution of lymphocytes to the lymphoid tissues rather than lymphocyte destruction, as seen with cytotoxic agents [21]. Early administration of fingolimod prevents development of the clinical features of the animal model of MS, experimental autoimmune encephalomyelitis (EAE) [22]. Fingolimod treatment at different stages of disease reduced clinical features, inflammatory infiltrates, axonal loss and demyelination [22]. Fingolimod effects were present even in late established disease, and a neuroprotective activity of the drug has been suggested [23]. The precise mechanisms underlying these effects remain to be determined.
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4.
Chemistry
Fingolimod (2-amino-2-[2-(4-octylphenyl) ethyl] propane1,3-diol) is composed of a polar head region, a phenyl ring and a hydrophobic alkyl chain [24]. Fingolimod-P is obtained by the phosphorylation of the symmetrical 2-alkyl-2-aminopropane-1,3-diol moiety from the polar head region of fingolimod. Both fingolimod and fingolimod-P share structural similarities with sphingosine and sphingosine 1-phosphate, respectively. Fingolimod-P interacts with S1PRs and exerts immunomodulatory properties [25,26] mainly through the hydroxymethyl group attached to the quaternary carbon [27]. The position of the phenyl group inserted within the alkyl chain determines the potency of the drug [28], and it was suggested that the most suitable length between the quaternary carbon and the phenyl ring corresponds to two carbon atoms [18] The phenyl ring confers increased agonist activity at S1PR5, loss of activity at S1PR2 and loss of the C2-stereospecificity at S1PR1 and S1PR3 [29].
to lymphoid organs and does not express the CD62L and CCR7 lymph-node-homing receptors [38]. This could help to retain desirable immunological functions [37]. Intrinsic lymphocyte functions are not affected by treatment with fingolimod, whereas local immune responses dependent on naive T cells and central memory T-cell migration to tissues are reduced or delayed. After stopping fingolimod, the average lymphocyte count exceeds the lower limit of normal range within 6 -- 8 weeks and at 3 months it reaches 80% of baseline values [39]. Discontinuations of the drug after long-term use is followed by reappearance of CD4+ CCR7+ T cells, which are implicated in MS pathogenesis and expected to be sequestered by fingolimod treatment [40]. The rapid reconstitution of CCR7+ cells raises caution about drug holidays and the period of transition to other therapies [40]. Chronic fingolimod treatment leads to a mild decrease in the neutrophil count to approximately 80% of baseline.
Effects of fingolimod on cells in the CNS Fingolimod is able to cross the blood brain barrier (BBB) [41-43]. By modulating the S1PRs receptors expressed on CNS cells [44-46], fingolimod may influence neurodegeneration, gliosis and repair mechanisms [17,42,45]. Fingolimod exposure in vitro can increase the number of progenitor and mature oligodendrocytes, protect oligodendrocytes from cell death induced by cytokines or by withdrawal of growth factors and modulate process outgrowth (both retraction and extension), thus influencing remyelination [47-49]. Fingolimod affects S1PR signaling and migration of astrocytes in vitro by both direct and indirect effects of receptor modulation [17,50]. Recent postmortem evidence suggests that reactive astrocytes represent a possible additional cellular target for fingolimod in MS by directly reducing the production of pro-inflammatory lipids and limiting subsequent transendothelial leukocyte migration [51]. Evidence from EAE studies suggests that beneficial effects of fingolimod are mediated not only through peripheral immune cells but also via direct CNS effects, by direct modulation of microvascular and/or glial cells [52-54]. EAE is attenuated and fingolimod efficacy is lost in mouse mutants lacking S1PR1 on glial fibrillary acidic protein (GFAP)expressing astrocytes but not on neurons [55]. A recent study on the focal delayed-type hypersensitivity (DTH) MS model in Lewis rats has studied fingolimod effects on lesion formation when the BBB is compromised; and on a chronic, active lesion occurring behind an intact, resealed BBB [42]. While the precise target cell population remains unclear, fingolimod continued to reduce demyelination behind an intact BBB, without reducing the number of lymphocytes within DTH lesions, thus suggests that the restorative effects of the drug at chronic disease stages may occur independently of effects on peripheral lymphocytes [42]. The mechanisms of fingolimod effects on CNS cells require further clarification, in particular, identification of the target cells and S1PRs [35]. 5.2
5.
Pharmacodynamics
Fingolimod effects on the immune system Fingolimod-P exerts its cellular effects through modulation of S1PRs (agonistic activation or internalization as a result of receptor potent stimulation, that is, receptor downregulation), which depends on the tissue or cell context, drug and endogenous ligand concentrations, and the receptor subtype [30]. S1PR1 and S1PR3 are ubiquitously expressed, whereas S1PR4 is primarily expressed in the lymphoid system and S1PR5 in the CNS [31,32]. Each S1PR is associated with different subtypes of heterotrimeric G proteins, which activate diverse intracellular signaling pathways [33,34]. Beneficial effects and side effects are the result of those pharmacodynamics interactions [35]. Fingolimod exerts its therapeutic effects in MS through receptor-mediated actions both on the immune system and in the CNS [33,34,36]. S1P and S1PR1 are major regulators of lymphocyte trafficking [28]. Fingolimod-P acts as an agonist at the S1PR1 on thymocytes and lymphocytes and induces its internalization. This renders these cells unresponsive to S1P, depriving them of an obligatory signal to exit lymphoid organs, thus reducing the infiltration of auto-aggressive lymphocytes into the CNS [34]. Blood lymphocyte count decreases to approximately 75% of baseline within 4 -- 6 h after the first dose of fingolimod 0.5 mg, then continues to decrease with continued daily dosing, reaching a nadir of approximately 500 cells/µl or 30% of baseline more than a 2-week period [34]. Low lymphocyte counts are maintained with daily dosing. Fingolimod selectively retains T cells that regularly traffic through lymph nodes and which express the homing receptor, CCR7 [37], including naive, central memory and Th17 cells [20]. Effector memory T cells are not affected by fingolimod because this lymphocyte subset typically does not traffic 5.1
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5.3
Cardiac, vascular and pulmonary effects
S1P regulates heart rate and conduction. S1PR1, S1PR2 and S1PR3 are the dominant receptors in the cardiovascular system [56]. Fingolimod binding to S1PR1s in atrial myocytes initially leads to activation of G-protein-gated cholinergic potassium channels (IKACh) eliciting an inward rectifying potassium current, membrane hyperpolarization, reduced cell excitability and decreased firing rate [56,57]. Receptor desensitization makes this effect self-limited [56]. Fingolimod causes a transient reduction in heart rate and atrioventricular conduction in the first 4 -- 5 h post-first dose, with 70% of the negative chronotropic effect achieved on the first day. Heart rate progressively returns to baseline values within 1 month of chronic treatment. Fingolimod increases the rate of new onset first-degree A-V heart block by 12% on first day of dosing; the incidence reduces to < 1% after 1 week of treatment [35]. Doses £ 1.25 mg were associated with a 7% incidence of heart block versus 3% on placebo. These blocks were usually asymptomatic and did not require treatment [35]. Autonomic responses of the heart are not affected by fingolimod treatment and the decrease in heart rate induced by fingolimod can be reversed by atropine, isoprenaline or salmeterol [35]. In the MS studies, there was no clinically relevant prolongation of QT interval [35]. Interestingly, FTY-720 alleviates existing cardiac hypertrophy/fibrosis through mechanisms involving negative regulation of NFAT activity in cardiomyocytes and reduction of periostin expression allowing for a more homeostatic extracellular compartment milieu [58]. Vascular and lymphatic endothelial cells express high levels of S1PR1 and lower levels of S1PR2 and S1PR3 [59,60]. The effects of S1P and fingolimod on endothelial cells are heterogeneous, augmenting tight junction and barrier function in some vascular beds and increasing permeability in other tissues [61,62]. Alveolar epithelium expresses S1PR3, and S1P administered in the airways disrupts alveolar epithelial barrier function [63]. Single fingolimod doses ‡ 5 mg (10-fold the recommended dose) are associated with a dose-dependent increase in airway resistance. Fingolimod treatment with multiple doses of 0.5, 1.25 or 5 mg is not associated with impaired oxygenation or oxygen desaturation with exercise or an increase in airway responsiveness to methacholine [35]. In a combined analysis of Phase III trials FREEDOMS and TRANSFORMS, minor fingolimod dose-dependent decreases in forced expiratory volume at 1 s and diffusing capacity for carbon monoxide seen at 1 month and were stable thereafter [64,65]. 6.
Pharmacokinetics and metabolism
The pharmacokinetics (PK) of fingolimod has been extensively evaluated in several patient groups and healthy people. PK parameters show slow and extensive absorption with no influence of food intake on absorption, steady-state exposure reached within 2 months after treatment initiation and extensive distribution to tissues [66]. Absorption of oral fingolimod 624
is relatively slow with a Tmax of 12 -- 16 h, with high oral bioavailability (93%) [67,68] and an average apparent clearance of 10.8 l/h [68]. The half-life of fingolimod following repeated administration is 6 -- 9 days [69]. Fingolimod and fingolimodP concentrations increase in an apparent dose-proportional manner after multiple once-daily doses of fingolimod 0.5 or 1.25 mg [69]. Steady-state blood concentrations are achieved within 2 months of daily administration are dose proportional and do not vary upon repeated administration (i.e., they are time independent and show constant clearance) [69]. Fingolimod-P Cmax and the AUC are approximately 50% lower than the parent drug on day 7 of seven daily doses of fingolimod [66]. A predictable relationship between dose and systemic exposure is seen. Results from multiple-dose studies of once-daily dosing with doses of 0.125 -- 5 mg administered for 7 days (in healthy volunteers) or 28 days (in renal transplant recipients and healthy volunteers) indicated that the Cmax and AUC of fingolimod at steady state are dose proportional, and intersubject variability is moderate to high (39 -- 79% for the Cmax and 21 -- 52% for the AUC) [69]. Furthermore, the fingolimod concentration profile after repeated dosing is remarkably flat, with peak-to-trough fluctuations of approximately 20% [69]. The half-life, Tmax and clearance were found to be largely independent of dose. The AUC and Cmax of fingolimod at steady state are dose proportional, with values for fingolimod 1.25 mg being approximately 2.9 times greater than those for fingolimod 0.5 mg [69]. PK studies in renal transplant patients [70], MS, hepatic impairment [25], children and different ethnic groups [71] have shown that, over a wide range of comorbidities, fingolimod and fingolimod-P PK do not vary and that the same dosing regimen can be used in White and Asian patients. No significant differences in apparent clearance according to sex were observed [69]. The metabolism of fingolimod is reduced in subjects with hepatic impairment, leading to increased exposure. Differences in exposure to fingolimod in patients with mild or moderate impairment are insufficient to necessitate dose adjustment [72,73]; however, in patients with severe hepatic impairment, fingolimod should either be used with caution [72] or should not be used [73]. In patients with severe renal impairment, fingolimod and fingolimod-P Cmax are increased by 32 and 25%, respectively, with no change in apparent elimination half-life. Based on these findings, the 0.5 mg dose is appropriate for use in patients with renal impairment [74]. Exposure to fingolimod is similar for patients with mild-to-moderate renal impairment (creatinine clearance 30 -- 80 ml/min) and patients with normal renal function. Comparison of fingolimod concentrations before and after each hemodialysis session, however, showed that hemodialysis led to a minor reduction of 14% in fingolimod concentrations [69]. Fingolimod is extensively metabolized, with biotransformation occurring via three main pathways. i) formation of
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Fingolimod
fingolimod-P by reversible phosphorylation. The phosphorylation of fingolimod is catalyzed by Sphk2, with a smaller contribution by Sphk1, whilst dephosphorylation of fingolimod-P is catalyzed by the lipid phosphate phosphohydrolases LPP1a and LPP3 and, by the specific sphingosine 1-phosphate phosphatase, SPP1 [75]. ii) oxidative biotransformation of fingolimod by hydroxylation at the methyl terminal of the octyl chain by cytochrome P450 (CYP) 4F2 and other enzymes of the CYP4F subfamily e [76]. iii) formation of nonpolar ceramide analogs of fingolimod by the action of (dihydro)ceramide synthase [75]. The major metabolites detected in blood (according to their contribution to the AUC during 0 -- 816 h) are fingolimod (23.3%), fingolimod-P (10.3%), the butanoic acid metabolite (8.3%) and the ceramide metabolites M29 (8.9%) and M30 (7.3%), and butanoic acid in urine (36%) [75]. Fingolimod and fingolimod-P are not detected in urine but are detected in faeces (2.4 and 1.7% of the dose, respectively) [75]. Following oral administration of [14C]-radiolabeled fingolimod, the radioactivity is excreted very slowly, with most of the dose being recovered in the urine (81%, compared with 11% in faeces); 62% of radioactivity is recovered within 10 days of administration and 89% within 34 days [69]. The distribution to blood cells is 86% for fingolimod and 17% for fingolimod-P [69]. Both compounds are extensively bound to plasma proteins (free fraction 0.15% for fingolimod and 0.3% for fingolimod-P). This binding is not altered by renal or hepatic impairment. Fingolimod binds extensively to serum albumin and lipoproteins, while fingolimod-P exhibits extensive binding to serum albumin and high-tomoderate binding to lipoproteins, a1-acid glycoprotein and g globulins [69]. Drug--drug interactions resulting from displacement from plasma proteins are not expected, given the very low concentrations of fingolimod and fingolimod-P at steady state under clinical conditions [69]. Fingolimod has a low potential for drug-drug interactions, as few drugs are known to be metabolized by CYP4F2. Ketoconazole, an inhibitor of CYP4F2, can increase the concentration of the drug [69]. Administration of fingolimod 0.5 mg does not alter the PK of oral contraceptives (levonorgestrel 150 mg or ethinylestradiol 30 mg), antihypertensive therapies (atenolol and diltiazem) or anti-bradycardic drugs (isoproterenol and atropine) [69]. Based on population PK analysis to date, there were no apparent clinically relevant effects when the following medications were co-administered with fingolimod: fluoxetine, paroxetine, carbamazepine, baclofen, gabapentin, oxybutynin, amantadine, modafinil, amitriptyline, pregabalin and corticosteroids [24,66]. 7.
Clinical efficacy
Clinical efficacy and safety of fingolimod in relapsing MS have been evaluated in one Phase II and two Phase III studies. The approval of fingolimod as MS treatment was based on the
largest Phase III clinical trial program in MS at the time of submission [77]. The Phase II study included 281 patients with active RRMS (having had at least two relapses during the previous 2 years or one relapse in the previous year or one gadolinium-enhancing (Gd+) lesion on MRI) and an Expanded Disability Status Scale (EDSS) of 0 -- 6.0, randomized to receive oral fingolimod 1.25 or 5 mg or placebo once daily [24]. Both dosages of fingolimod significantly reduced the total number of Gd+ lesions compared with placebo. Fingolimod-treated groups showed a greater proportion of patients free from Gd+ lesions, a reduced annualized relapse rate (ARR) and a greater proportion of patients (86%) who remained relapse-free when compared with the placebo group (66%). An open-label, active-drug extension study in which the previously placebo-treated patients were randomized to fingolimod showed a significant decrease in the number of Gd+ lesions and the ARR after fingolimod initiation [78,79]. During months 15 -- 24, patients receiving fingolimod 5 mg were switched to fingolimod 1.25 mg, which had fewer side effects and was as effective. These results were confirmed in two Phase III studies. In the FREEDOMS trial, active RRMS patients were randomized to receive oral fingolimod 0.5 mg, fingolimod 1.25 mg or placebo once daily for 24 months [80]. Approximately 60% of the patients were treatment-naive. The mean EDSS was 2.4. The ARR was reduced significantly by fingolimod when compared with placebo (fingolimod 0.5 mg: 0.18; fingolimod 1.25 mg: 0.16; placebo 0.4) and the relative risk from 54 to 60%. The time to confirmed disability progression after 3 and 6 months was prolonged significantly in fingolimod arms. MRI outcomes were favorable for fingolimod: number of Gd+ lesions, number of new or enlarged T2 lesions and volume of T1-hypointense lesions [80]. Subgroup analysis suggested that fingolimod 0.5 mg was effective in patients with breakthrough disease despite use of DMTs and in patients with highly active MS, however, the effect was attenuated in patients aged over 40 years [81]. The TRANSFORMS study compared fingolimod to intramuscular once weekly IFN-b1a. The patients were randomized in a double-blind design to oral fingolimod 0.5 mg, fingolimod 1.25 mg or IFN-b1a intramuscularly once weekly [82]. In the study, 1292 patients with active RRMS with EDSS between 0 and 5.5 were included. Average disease duration was 7.4 years. The patients had a mean EDSS of 2.2. The majority of patients had previous DMTs, mostly IFN-b or GA. Fingolimod reduced the ARR more than IFN-b1a (fingolimod 0.5 mg: 0.16; fingolimod 1.25 mg: 0.2; IFN-b1a: 0.33) [82]. The proportion of relapse-free patients was significantly higher in both fingolimod-treated groups (fingolimod 0.5 mg: 82.6%; fingolimod 1.25 mg: 79.8%; IFN-b1a: 69.3%). MRI outcomes were also significantly different (less Gd+ lesions, new or enlarged T2 lesions and brain atrophy). The TRANSFORMS patients who were treated with IFN-b1a were randomly assigned to receive 0.5 or 1.25 mg of fingolimod in an extension of the
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trial [83]. ARR, disability progression and MRI outcomes improved in the switched group from IFN-b1a to fingolimod. Patients receiving continuous fingolimod had unchanged benefits in the ARR and a significantly lower ARR and reduced inflammatory activity in brain MRI compared to the newly treated group [83]. Because initial data suggests that fingolimod may have an effect on nerve repair, the INFORMS study has been launched [84]. The purpose of INFORMS is to evaluate whether fingolimod (0.5 or 1.25 mg tablets taken daily for 3 years) is effective in delaying disability progression compared with placebo in 654 people with primary progressive MS. The INFORMS is due to end in September 2014.
8.
Safety and tolerability
Fingolimod was well tolerated in all clinical studies and had a favorable overall safety profile. The most common serious adverse events were transient bradycardia and atrioventricular block related to the first dose of the medication (within 6 h of first administration) [9]. Cutaneous neoplasias (basal cell carcinomas and melanomas in situ) were more often reported in the fingolimod group than in the control groups [80,82]. Macular edema occurred in 1% of the patients in the 1.25-mg group and 0.5% of the 0.5-mg group and resolved in most patients after treatment discontinuation. Up to 12.5% of patients had levels of liver enzymes three times the upper limit of the normal range or more. In all patients, liver enzyme abnormalities returned to normal after drug discontinuation. Hematologic side effects comprise lymphopenia (4%) and leucopenia (3%), and monitoring of fingolimod treatment should include complete cell counts at initiation, months 1, 3, 6, and periodically thereafter. In all clinical studies, the frequency of overall infections was comparable in fingolimod-treated patients and controls [82]. In the FREEDOMS study, lower respiratory tract infections (including bronchitis and pneumonia) were more frequent in patients treated with fingolimod. Vaccination during therapy with fingolimod may be less effective. Vaccination with live attenuated virus vaccines should be avoided during and 2 months after fingolimod therapy as it carries the risk of infections [9]. Patients without a history of chickenpox or vaccination against varicella zoster virus (VZV) should be tested for antibodies, and in those without (VZV) antibodies vaccination considered 1 month prior fingolimod initiation. Two fatal cases of disseminated VZV and herpes simplex encephalitis and a third case of a patient with a life-threatening HSV encephalitis were reported in the TRANSFORMS trial, in the group treated with the 1.25-mg fingolimod dose. Therefore, the lower dose of 0.5 mg was approved [9]. In October 2013, FDA warned that a MS patient taking fingolimod developed PML, without being previously treated with natalizumab [85]. 626
9.
Post-marketing surveillance
The European Medicines Agency and FDA reviewed the license for fingolimod after serious cardiovascular events in patients on the drug [86,87]. They recommended that the drug not be prescribed to patients with pre-existing cardiac or cerebrovascular disease or to those taking anti-arrhythmic drugs; if treatment was considered necessary, a prior cardiology opinion was advised. A baseline electrocardiogram (ECG) is required in all patients and continuous ECG monitoring for 6 h after the first dose to be extended to at least overnight in any patient developing a cardiac abnormality during the monitoring period. Other requirements include ophthalmic evaluations on commencing fingolimod and after 3 -- 4 months of therapy and baseline hematology and liver enzymes checks [12]. 10.
Regulatory affairs
Fingolimod is approved in the US, Switzerland and Australia as first-line drug for RRMS. In Australia, fingolimod is registered for the treatment of SPMS with superimposed relapses. In Europe, fingolimod is reserved to patients with high disease activity despite treatment with IFN (having at least one relapse in the previous year while on therapy, and have at least nine T2-hyperintense lesions in cranial MRI or at least one Gd+ lesion); or patients with rapidly evolving severe RRMS. Rapidly evolving severe RRMS is defined by two or more disabling relapses in 1 year and by one or more MRI Gd+ lesions or a significant increase in T2 lesion load as compared to a previous recent MRI. 11.
Conclusion
Fingolimod is the first member of the new class of S1PR modulators. Fingolimod represents a milestone in the treatment of RRMS, being the first approved oral therapy, offering patients a more convenient administration route. Fingolimod is effective in active RRMS. Two large Phase III clinical trials showed a superior efficacy of fingolimod compared to both placebo and IFN-b intramuscularly. Fingolimod is well tolerated and overall safe. Transient, generally asymptomatic bradycardia and infrequent atrioventricular block are seen with after first dose administration. Detailed cardiovascular risk stratification and adequate patient monitoring at treatment initiation are recommended. A Phase IV clinical program aims to assess tolerability and safety of the drug when used in patients under nonstudy condition. 12.
Expert opinion
Fingolimod is effective in active RRMS, after the first-line therapy IFN-b fails. According to expert opinion this would similarly apply to prior treatment with GA [88].
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Cost-effectiveness of fingolimod versus natalizumab for RRMS treatment is debated, and there is a current need to evaluate the relative value of newer therapies given healthcare resource constraints. Although data from decision analytic models show that natalizumab could dominate fingolimod in terms of incremental cost per relapse avoided, costminimizing analyses in different countries suggest that fingolimod use may result in considerable cost savings compared to natalizumab and that early treatment initiation is costeffective [89-95]. Whether and when fingolimod might be a therapeutic option following natalizumab needs to be evaluated, as well as the long-term risk for PML [96]. Fingolimod may target not only inflammation but potentially also neurodegeneration. The mechanism of antagonizing astrocyte S1PR1 signaling may help explain the improvement in cerebral atrophy scores relative to control groups observed during the FREEDOMS and TRANSFORMS trials, rarely seen with other MS treatments [97]. In vitro data suggesting that fingolimod affects oligodendrocyte precursors survival, recruitment and activation, and attenuates astrogliosis, needs supporting in vivo evidence. Fingolimod effects in function of particular MS pathological stages need further study. Effects on human oligodendrocytes, astrocytes and neurons are suggested to be time-, dose- and stage dependent, which may in part reflect the relative levels of expression of the relevant receptors. These effects could formally alter the myelination or remyelination processes [98]. Moreover, in vivo and in vitro studies with S1P have reported nervous system inflammatory responses that induce morphological changes Bibliography
in neural cells and astrocytes, and increase the expression of GFAP, a protein involved in astrocytosis which may impede regeneration [99-101]. Fingolimod has not been administered concomitantly with antineoplastic, immunosuppressive or other immunomodulatory therapies, but combined treatment with these agents is expected to increase the risk of immunosuppression. However, the unmet needs of MS treatments may lead in the future to the need for combined therapy. By its specific effect at targeting signaling through S1PR1 at the BBB, fingolimod and fingolimod-P can rapidly and reversibly reduce basal activity of the ATP-driven drug efflux pump P-glycoprotein and thus improve delivery of small-molecule therapeutics to the brain [98,102]. The PK profile of fingolimod has been extensively studied and a population PK predictive model exists [66]. However, long-term data about the safety of fingolimod, especially after cessation of natalizumab, are needed and should be further investigated.
Declaration of interest R Tanasescu has received travel support for meetings from Teva, Biogen-Idec, Lundbeck and Novartis. CS Constantinescu has received research support, travel support for meetings and honoraria for talks from Biogen-Idec, Bayer Schering, Teva, GW, Merck Serono, Novartis and MorphoSys. They did not receive funding or sponsorship for preparing this manuscript.
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Affiliation
Radu Tanasescu1,2 & Cris S Constantinescu†1 † Author for correspondence 1 University of Nottingham, Queen’s Medical Centre, Academic Division of Clinical Neurology, C Floor, South Block, Nottingham, NG7 2UH, UK Tel: +44 115 8754597/98; Fax: +44 115 823 1443; E-mail: [email protected] 2 University of Medicine and Pharmacy Carol Davila Bucharest, Colentina Hospital, Department of Neurology, Neurosurgery and Psychiatry, Bucharest, Romania
