Immunosuppressants, selective immunosuppressants. ATC code:
Pharmacology: Pharmacodynamics: Mechanism of action:
Fingolimod is a sphingosine 1-phosphate receptor modulator. Fingolimod is metabolised by sphingosine kinase to the active metabolite fingolimod phosphate. Fingolimod phosphate binds at low nanomolar concentrations to sphingosine 1-phosphate (S1P) receptor 1 located on lymphocytes, and readily crosses the blood-brain barrier to bind to S1P receptor 1 located on neural cells in the central nervous system (CNS). By acting as a functional antagonist of S1P receptors on lymphocytes, fingolimod phosphate blocks the capacity of lymphocytes to egress from lymph nodes, causing a redistribution, rather than depletion, of lymphocytes. Animal studies have shown that this redistribution reduces the infiltration of pathogenic lymphocytes, including pro-inflammatory Th17 cells into the CNS, where they would be involved in nerve inflammation and nervous tissue damage. Animal studies and in vitro
experiments indicate that fingolimod may also act via interaction with S1P receptors on neural cells.
Within 4-6 hours after the first dose of fingolimod 0.5 mg, the lymphocyte count decreases to approximately 75% of baseline in peripheral blood. With continued daily dosing, the lymphocyte count continues to decrease over a two-week period, reaching a minimal count of approximately 500 cells/microlitre or approximately 30% of baseline. Eighteen percent of patients reached a minimal count below 200 cells/microlitre on at least one occasion. Low lymphocyte counts are maintained with chronic daily dosing. The majority of T and B lymphocytes regularly traffic through lymphoid organs and these are the cells mainly affected by fingolimod. Approximately 15-20% of T lymphocytes have an effector memory phenotype, cells that are important for peripheral immune surveillance. Since this lymphocyte subset typically does not traffic to lymphoid organs it is not affected by fingolimod. Peripheral lymphocyte count increases are evident within days of stopping fingolimod treatment and typically normal counts are reached within one to two months. Chronic fingolimod dosing leads to a mild decrease in the neutrophil count to approximately 80% of baseline. Monocytes are unaffected by fingolimod.
Fingolimod causes a transient reduction in heart rate and decrease in atrioventricular conduction at treatment initiation (see Precautions and Adverse Reactions). The maximal decline in heart rate is seen within 6 hours post dose, with 70% of the negative chronotropic effect achieved on the first day. With continued administration heart rate returns to baseline within one month. The decrease in heart rate induced by fingolimod can be reversed by parenteral doses of atropine or isoprenaline. Inhaled salmeterol has also been shown to have a modest positive chronotropic effect. With initiation of fingolimod treatment there is an increase in atrial premature contractions, but there is no increased rate of atrial fibrillation/flutter or ventricular arrhythmias or ectopy. Fingolimod treatment is not associated with a decrease in cardiac output. Autonomic responses of the heart, including diurnal variation of heart rate and response to exercise are not affected by fingolimod treatment.
S1P4 could partially contribute to the effect but was not the main receptor responsible for the lymphoid depletion. The mechanism of action of bradycardia and vasoconstriction were also studied in vitro
in guinea pigs and isolated rabbit aorta and coronary artery. It was concluded that bradycardia could be mediated primarily by activation of inward-rectifying potassium channel or G-protein activated inwardly rectifying K+
channel (IKACh/GIRK) and that vasoconstriction seems to be mediated by a Rho kinase and calcium dependent mechanism.
Fingolimod treatment with single or multiple doses of 0.5 and 1.25 mg for two weeks is not associated with a detectable increase in airway resistance as measured by FEV1
and forced expiratory flow rate (FEF) 25-75. However, 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. Subjects on fingolimod treatment have a normal bronchodilator response to inhaled beta-agonists.
Clinical efficacy and safety:
The efficacy of Gilenya has been demonstrated in two studies which evaluated once-daily doses of fingolimod 0.5 mg and 1.25 mg in patients with relapsing-remitting multiple sclerosis (RRMS). Both studies included patients who had experienced ≥2 relapses in the prior 2 years or ≥1 relapse during the prior year. Expanded Disability Status Score (EDSS) was between 0 and 5.5. A third study targeting the same patient population was completed after registration of Gilenya.
Study D2301 (FREEDOMS) was a 2-year randomised, double-blind, placebo-controlled Phase III study of 1,272 patients (n=425 on 0.5 mg, 429 on 1.25 mg, 418 on placebo). Median values for baseline characteristics were: age 37 years, disease duration 6.7 years, and EDSS score 2.0. Outcome results are shown in Table 1. There were no significant differences between the 0.5 mg and the 1.25 mg doses as regards either endpoint. (See Table 1.)
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Patients who completed the 24-month core FREEDOMS study could enter a dose-blinded extension study (D2301E1) and receive fingolimod. In total, 920 patients entered (n=331 continued on 0.5 mg, 289 continued on 1.25 mg, 155 switched from placebo to 0.5 mg and 145 switched from placebo to 1.25 mg). After 12 months (month 36), 856 patients (93%) were still enrolled. Between months 24 and 36, the annualised relapse rate (ARR) for patients on fingolimod 0.5 mg in the core study who remained on 0.5 mg was 0.17 (0.21 in the core study). The ARR for patients who switched from placebo to fingolimod 0.5 mg was 0.22 (0.42 in the core study).
Comparable results were shown in a replicate 2-year randomised, double-blind, placebo-controlled Phase III study on fingolimod in 1,083 patients (n=358 on 0.5 mg, 370 on 1.25 mg, 355 on placebo) with RRMS (D2309; FREEDOMS 2). Median values for baseline characteristics were: age 41 years, disease duration 8.9 years, EDSS score 2.5. (See Table 2.)
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Study D2302 (TRANSFORMS) was a 1-year randomised, double-blind, double-dummy, active (interferon beta-1a)-controlled Phase III study of 1,280 patients (n=429 on 0.5 mg, 420 on 1.25 mg, 431 on interferon beta-1a, 30 µg by intramuscular injection once weekly). Median values for baseline characteristics were: age 36 years, disease duration 5.9 years, and EDSS score 2.0. Outcome results are shown in Table 3. There were no significant differences between the 0.5 mg and the 1.25 mg doses as regards study endpoints. (See Table 3.)
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Patients who completed the 12-month core TRANSFORMS study could enter a dose-blinded extension (D2302E1) and receive fingolimod. In total, 1,030 patients entered, however, 3 of these patients did not receive treatment (n=356 continued on 0.5 mg, 330 continued on 1.25 mg, 167 switched from interferon beta-1a to 0.5 mg and 174 from interferon beta-1a to 1.25 mg). After 12 months (month 24), 882 patients (86%) were still enrolled. Between months 12 and 24, the ARR for patients on fingolimod 0.5 mg in the core study who remained on 0.5 mg was 0.20 (0.19 in the core study). The ARR for patients who switched from interferon beta-1a to fingolimod 0.5 mg was 0.33 (0.48 in the core study).
Pooled results of Studies D2301 and D2302 showed a consistent and statistically significant reduction in annualised relapse rate compared to comparator in subgroups defined by gender, age, prior multiple sclerosis therapy, disease activity or disability levels at baseline.
Further analyses of clinical trial data demonstrate consistent treatment effects in highly active subgroups of relapsing remitting multiple sclerosis patients.
The efficacy and safety of once-daily doses of fingolimod 0.25 mg or 0.5 mg (dose selected based on body weight and exposure measurements) have been established in paediatric patients aged 10 to <18 years with relapsing-remitting multiple sclerosis.
Study D2311 (PARADIGMS) was a double-blind, double-dummy, active-controlled study with flexible duration up to 24 months, with 215 patients 10 to <18 years old (n=107 on fingolimod, 108 on interferon beta-1a 30 μg by intramuscular injection once weekly).
Median values for baseline characteristics were: age 16 years, median disease duration 1.5 years and EDSS score 1.5. The majority of patients were Tanner stage 2 or higher (94.4%) and were >40 kg (95.3%). Overall, 180 (84%) of patients completed the core phase on study drug (n=99 [92.5%] on fingolimod, 81 [75%] on interferon beta-1a). Outcome results are shown in Table 4. (See Table 4.)
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Pharmacokinetic data were obtained in healthy adult volunteers, in renal transplant adult patients and in multiple sclerosis adult patients.
The pharmacologically active metabolite responsible for efficacy is fingolimod phosphate.
Fingolimod absorption is slow (tmax
of 12-16 hours) and extensive (≥85%). The apparent absolute oral bioavailability is 93% (95% confidence interval: 79-111%). Steady-state-blood concentrations are reached within 1 to 2 months following once-daily administration and steady-state levels are approximately 10-fold greater than with the initial dose.
Food intake does not alter Cmax
or exposure (AUC) of fingolimod. Fingolimod phosphate Cmax
was slightly decreased by 34% but AUC was unchanged. Therefore, Gilenya may be taken without regard to meals (see Dosage & Administration).
Fingolimod highly distributes in red blood cells, with the fraction in blood cells of 86%. Fingolimod phosphate has a smaller uptake in blood cells of <17%. Fingolimod and fingolimod phosphate are highly protein bound (>99%).
Fingolimod is extensively distributed to body tissues with a volume of distribution of about 1,200±260 litres. A study in four healthy subjects who received a single intravenous dose of a radioiodolabelled analogue of fingolimod demonstrated that fingolimod penetrates into the brain. In a study in 13 male multiple sclerosis patients who received Gilenya 0.5 mg/day, the mean amount of fingolimod (and fingolimod phosphate) in seminal ejaculate, at steady-state, was approximately 10,000 times lower than the oral dose administered (0.5 mg).
Fingolimod is transformed in humans by reversible stereoselective phosphorylation to the pharmacologically active (S)-enantiomer of fingolimod phosphate. Fingolimod is eliminated by oxidative biotransformation catalysed mainly via CYP4F2 and possibly other isoenzymes and subsequent fatty acid-like degradation to inactive metabolites. Formation of pharmacologically inactive non-polar ceramide analogues of fingolimod was also observed. The main enzyme involved in the metabolism of fingolimod is partially identified and may be either CYP4F2 or CYP3A4.
Following single oral administration of [14
C] fingolimod, the major fingolimod-related components in blood, as judged from their contribution to the AUC up to 34 days post dose of total radiolabelled components, are fingolimod itself (23%), fingolimod phosphate (10%), and inactive metabolites (M3 carboxylic acid metabolite (8%), M29 ceramide metabolite (9%) and M30 ceramide metabolite (7%)).
Fingolimod blood clearance is 6.3±2.3 l/h, and the average apparent terminal half-life (t1/2
) is 6-9 days. Blood levels of fingolimod and fingolimod phosphate decline in parallel in the terminal phase, leading to similar half-lives for both.
After oral administration, about 81% of the dose is slowly excreted in the urine as inactive metabolites. Fingolimod and fingolimod phosphate are not excreted intact in urine but are the major components in the faeces, with amounts representing less than 2.5% of the dose each. After 34 days, the recovery of the administered dose is 89%.
Fingolimod and fingolimod phosphate concentrations increase in an apparently dose proportional manner after multiple once-daily doses of 0.5 mg or 1.25 mg.
Characteristics in specific groups of patients:
The pharmacokinetics of fingolimod and fingolimod phosphate do not differ in males and females, in patients of different ethnic origin, or in patients with mild to severe renal impairment.
In subjects with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, and C), no change in fingolimod Cmax
was observed, but fingolimod AUC was increased respectively by 12%, 44%, and 103%. In patients with severe hepatic impairment (Child-Pugh class C), fingolimod-phosphate Cmax
was decreased by 22% and AUC was not substantially changed. The pharmacokinetics of fingolimod-phosphate were not evaluated in patients with mild or moderate hepatic impairment. The apparent elimination half-life of fingolimod is unchanged in subjects with mild hepatic impairment, but is prolonged by about 50% in patients with moderate or severe hepatic impairment.
Fingolimod should not be used in patients with severe hepatic impairment (Child-Pugh class C) (see Contraindications). Fingolimod should be introduced cautiously in mild and moderate hepatic impaired patients (see Dosage & Administration).
Clinical experience and pharmacokinetic information in patients aged above 65 years are limited. Gilenya should be used with caution in patients aged 65 years and over (see Dosage & Administration).
In paediatric patients (10 years of age and above), fingolimod-phosphate concentrations increase in an apparent dose proportional manner between 0.25 mg and 0.5 mg.
Fingolimod-phosphate concentration at steady state is approximately 25% lower in paediatric patients (10 years of age and above) following daily administration of 0.25 mg or 0.5 mg fingolimod compared to the concentration in adult patients treated with fingolimod 0.5 mg once daily.
There are no data available for paediatric patients below 10 years old.
Toxicology: Preclinical safety data:
The preclinical safety profile of fingolimod was assessed in mice, rats, dogs and monkeys. The major target organs were the lymphoid system (lymphopenia and lymphoid atrophy), lungs (increased weight, smooth muscle hypertrophy at the bronchio-alveolar junction), and heart (negative chronotropic effect, increase in blood pressure, perivascular changes and myocardial degeneration) in several species; blood vessels (vasculopathy) in rats only at doses of 0.15 mg/kg and higher in a 2-year study, representing an approximate 4-fold margin based on the human systemic exposure (AUC) at a daily dose of 0.5 mg.
No evidence of carcinogenicity was observed in a 2-year bioassay in rats at oral doses of fingolimod up to the maximally tolerated dose of 2.5 mg/kg, representing an approximate 50-fold margin based on human systemic exposure (AUC) at the 0.5 mg dose. However, in a 2-year mouse study, an increased incidence of malignant lymphoma was seen at doses of 0.25 mg/kg and higher, representing an approximate 6-fold margin based on the human systemic exposure (AUC) at a daily dose of 0.5 mg.
Fingolimod was neither mutagenic nor clastogenic in animal studies.
Fingolimod had no effect on sperm count/motility or on fertility in male and female rats up to the highest dose tested (10 mg/kg), representing an approximate 150-fold margin based on human systemic exposure (AUC) at a daily dose of 0.5 mg.
Fingolimod was teratogenic in the rat when given at doses of 0.1 mg/kg or higher. Drug exposure in rats at this dose was similar to that in patients at the therapeutic dose (0.5 mg). The most common foetal visceral malformations included persistent truncus arteriosus and ventricular septum defect. The teratogenic potential in rabbits could not be fully assessed, however an increased embryo-foetal mortality was seen at doses of 1.5 mg/kg and higher, and a decrease in viable foetuses as well as foetal growth retardation was seen at 5 mg/kg. Drug exposure in rabbits at these doses was similar to that in patients.
In rats, F1 generation pup survival was decreased in the early postpartum period at doses that did not cause maternal toxicity. However, F1 body weights, development, behaviour, and fertility were not affected by treatment with fingolimod.
Fingolimod was excreted in milk of treated animals during lactation at concentrations 2-3-fold higher than that found in maternal plasma. Fingolimod and its metabolites crossed the placental barrier in pregnant rabbits.
Juvenile animal studies: Results from two toxicity studies in juvenile rats showed slight effects on neurobehavioural response, delayed sexual maturation and a decreased immune response to repeated stimulations with keyhole limpet haemocyanin (KLH), which were not considered adverse. Overall, the treatment-related effects of fingolimod in juvenile animals were comparable to those seen in adult rats at similar dose levels, with the exception of changes in bone mineral density and neurobehavioural impairment (reduced auditory startle response) observed at doses of 1.5 mg/kg and higher in juvenile animals and the absence of smooth muscle hypertrophy in the lungs of the juvenile rats.