Nov. 10, 2022
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Fingolimod, first synthesized in 1992, is derived from myriocin, a metabolite of the fungus Isaria sinclairii, found to have immunosuppressive properties. Fingolimod belongs to a class of disease-modifying agents called sphingosine 1 phosphate (S1P) receptor modulators. It was originally tested in clinical trials on renal transplant patients but not found to be superior to the conventional immunosuppressant agents and, hence, not developed further for this indication. In 2010, the FDA's Peripheral and Central Nervous System Drugs Advisory Committee recommended approval of fingolimod as an oral therapy for the treatment of patients with relapsing-remitting multiple sclerosis. It is now approved for this indication in the United States, Canada, the European Union, Russia, and Australia. It is 1 of the first orally active drug therapies to be made available for the treatment of relapsing-remitting multiple sclerosis.
Fingolimod is a prodrug that is phosphorylated by sphingosine kinase to active metabolite fingolimod-phosphate (S1P).
Pharmacodynamics. Fingolimod, an S1P receptor modulator, has an immunosuppressant effect in patients with multiple sclerosis. On phosphorylation, fingolimod can bind with high affinity to 4 out of 5 sub-types of S1P receptor – an extracellular lipid mediator whose major effects are mediated by G protein-coupled receptors. Persistent modulation of S1P receptor subtypes with subsequent internalization of these by fingolimod inhibits lymphocyte egress from the lymph nodes and prevents these cells from infiltrating inflammatory lesions in the CNS (01). Data from another experimental study have identified nonimmunological CNS mechanisms of fingolimod efficacy and implicate S1P signaling pathways within the CNS as targets for fingolimod therapy (06).
Fingolimod therapy affects immune cells in CSF differently from those in the blood of patients with multiple sclerosis. Fingolimod decreases the proportion of CSF CD4+ T cells but to a lesser extent than in the peripheral blood (29).
Lymphopenia produced by fingolimod differs from that caused by immunosuppressants such as azathioprine, which inhibit lymphocytes from forming, whereas fingolimod simply sequesters lymphocytes in the lymph nodes.
Prophylactic administration of fingolimod to animals with experimental autoimmune encephalitis, a model of multiple sclerosis, completely prevents development of pathological features (08). Preclinical studies suggest that fingolimod might promote neural repair in vivo (45). Fingolimod modulates multiple neuroglial cell responses, resulting in enhanced remyelination in cerebellar slice cultures with lysolecithin-induced demyelination (34).
Fingolimod attenuates ceramide-induced blood-brain barrier dysfunction in multiple sclerosis by targeting reactive astrocytes, which are the primary cellular source of enhanced ceramide production (44). Retrospective analysis of patients with relapsing-remitting multiple sclerosis with high serum levels of biomarker Sema4A who were resistant to interferon-β therapy showed that they responded with improvement on switching to fingolimod, and this correlated with lowering of Sema4A levels (27). Similar action was observed after administration of recombinant Sema4A-Fc in mice with experimental allergic encephalitis followed by fingolimod treatment. These data suggest that fingolimod can be used as a disease modifying personalized therapy for management of multiple sclerosis patients with high Sema4A levels.
Neuroprotective effect of fingolimod in vivo may result from its inhibitory action on key activation steps of astrocytes, which contribute to neuroinflammation and neurodegeneration by participating in glial scar formation as well as nitric oxide production (10). Neuroprotective effect of fingolimod on relapsing-remitting multiple sclerosis may be due to its modulatory effect on oligodendroglial cells and astrocytes as well as its direct effect on cortical neurons (36). Clinical studies including in vivo measurement of grey matter damage are required to confirm this effect.
Pharmacokinetics. After oral administration of 1 oral dose, blood concentrations of fingolimod increase steadily over the first 12 hours and remain elevated during the 24-hour period until the next dose. Pharmacokinetic profile in human patients shows a linear, dose-dependent relationship for the maximum concentration and the area under the curve. Time to maximum concentration, half-life, and clearance do not vary as the dose increases. Fingolimod has a half-life of 6 to 9 days, and steady-state pharmacokinetics are reached after 1 to 2 months of daily dosing. The phosphorylation of fingolimod to fingolimod-phosphate is reversible in plasma. As a stable equilibrium is reached between the 2, fingolimod-phosphate concentration is 2- to 4-fold higher than concentration of the parent drug. Fingolimod is also partially metabolized in the liver by cytochrome P450 to metabolites that are devoid of immunosuppressive activity and are excreted in urine and feces. Fingolimod has a predictable pharmacokinetic profile that enables effective once-daily oral dosing (11).
Local concentrations of both phosphorylated and nonphosphorylated fingolimod are much higher in lymphoid tissues than in blood, generating a reservoir in thymus and secondary lymphoid organs, which leads to sustained fingolimod production and activation of S1P within tissues. Lipophilicity of fingolimod enables crossing of the blood-brain barrier, which enhances its activity.
Pharmacogenetics/pharmacogenomics. No information is available yet.
Several preliminary and phase I/II clinical trials have been conducted on fingolimod since 2006. Recommendation for approval was based on the results of 2 clinical trials.
FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis) was a phase III, 24-month, placebo-controlled, double-blind, randomized study, conducted on patients who had relapsing-remitting multiple sclerosis and received oral fingolimod at a dose of 0.5 mg or 1.25 mg daily (24). As compared with placebo, both doses of oral fingolimod improved the relapse rate, the risk of disability progression, and end points on MRI. The investigators pointed out that these benefits will need to be weighed against possible long-term risks based on adverse events reported during the trial. A subgroup analysis of primary outcome in the FREEDOMS trial showed that patients with relapsing-remitting multiple sclerosis with a wide spectrum of clinical and MRI features can potentially benefit from treatment with 0.5 mg fingolimod (12). Findings of FREEDOMS II, a placebo-controlled, double-blind phase III study, substantiated the beneficial profile of fingolimod as a disease-modifying agent in relapsing-remitting multiple sclerosis and provided a detailed analysis of adverse effects (04). Pooling of the results of FREEDOMS I and II trials showed that over a period of 2 years the annual rates of brain volume loss was like that expected in healthy adults and was achieved in proportionately more patients with multiple sclerosis who received fingolimod than those who received placebo. Incidence of adverse events was slightly higher with fingolimod therapy than with placebo.
TRANSFORMS (Trial Assessing injectable interferon vs. FTY720 Oral in Relapsing-remitting Multiple Sclerosis) was a phase III, 12-month, double-blind, double-dummy study, in which patients with relapsing-remitting multiple sclerosis were randomly assigned to receive either oral fingolimod (0.5 mg or 1.25) daily or intramuscular interferon beta-1a weekly (09). Results showed the superior efficacy of oral fingolimod with respect to relapse rates and MRI outcomes. According to 1 comment on this study, it is still uncertain whether oral fingolimod could be used as first-line treatment or as an alternative treatment for patients who have failed immunomodulating therapy (37). Another commentary on these clinical trials suggested that only the lower dose of fingolimod (0.5 mg), which possibly has less toxicity, should be considered for prevention of relapses in relapsing-remitting multiple sclerosis (13). A randomized extension of the TRANSFORMS study showed that switching from interferon beta-1a to fingolimod led to enhanced efficacy, which was sustained with continuous use of fingolimod for 2 years (26). Within the framework of this study, measurements of the brain volume by MRI showed that fingolimod reduced brain volume loss over 12 months as compared to interferon β-1a IM in all patient subgroups, and baseline gadolinium-enhancing T1 lesion count was most predictive of change in percentage brain volume change (02).
A double-blind, randomized, parallel-group, phase II study on Japanese patients with relapsing multiple sclerosis showed clinical efficacy of fingolimod in Japanese patients that is consistent with the established effects of fingolimod in clinical trials on Caucasian patients (39).
An open-label study on patients in the real-world clinical practice setting, such as those with co-existing diseases and other medications, confirmed that the first dose of fingolimod is safe and well tolerated (31).
In INFORMS (FTY720 in Patients with Primary Progressive Multiple Sclerosis), a multicenter, double-blind, placebo-controlled parallel-group study, anti-inflammatory effects of fingolimod did not slow disease progression in patients with primary progressive multiple sclerosis (32).
A systematic review of randomized trials has shown that treatment with fingolimod compared to placebo in patients with relapsing-remitting multiple sclerosis is effective in reducing inflammatory disease activity, but it may make little or no difference in preventing worsening of disability (30). Evidence of effectiveness of fingolimod is provided by a systematic review of studies of fingolimod in the real-world practice beyond clinical trials, but some gaps remain to be investigated further due to diversity of methods used for assessing treatment benefits (47).
Fingolimod is indicated for use in relapsing-remitting multiple sclerosis.
(1) Fingolimod inhibits angiogenesis and may provide a novel therapeutic approach for pathologic conditions with dysregulated angiogenesis such as cancer.
(2) Beyond the autoimmune indications, some studies suggest that short-term, low-dose administration of fingolimod could help treat chronic viral infections.
(3) Clinical severity, electrophysiological, and histological findings were ameliorated in oral fingolimod given to rats with spontaneous autoimmune polyneuropathy.
(4) Hemorrhagic focal encephalitis.
(5) Fingolimod rapidly reduces ocular infiltrates in experimental autoimmune uveoretinitis in rats and has the therapeutic potential of an acute rescue intervention for human noninfectious posterior-segment intraocular inflammatory disease.
(6) Administration of oral fingolimod to patients within 72 hours of intracerebral hemorrhage onset is reported to be safe, reduces cerebral edema, and attenuates neurologic deficits (15).
(7) An experimental study identified neuroprotective effects of fingolimod on astrocytes, ie, induction of neurotrophic mediators and inhibition of tumor necrosis factor–induced inflammatory genes, supporting the view that the effects of fingolimod may be partly mediated via astrocytes (19).
(8) Fingolimod improves incorporation and survival of transplanted neural stem cells in the CNS and drives their differentiation into more oligodendrocytes but fewer astrocytes, thus, promoting remyelination and CNS repair processes in situ (46). Therefore, neural stem cell-based therapy has potential application in the secondary progressive stage of multiple sclerosis.
(9) Fingolimod has shown neuroprotective effect in rat models of neurodegenerative disorders such as Alzheimer disease (reduction of amyloid-β production) and Huntington disease, as well as enhancement of cognitive function in multiple sclerosis patients. The neuroprotective effects exerted by fingolimod in these preclinical studies support the translation of fingolimod into clinical trials as treatment for neurodegenerative diseases beyond neuroinflammatory conditions (03).
(10) In animal models of epileptogenesis, fingolimod has shown antiinflammatory and neuroprotective effects, which are hypothesized to be key players in the development of epilepsy. The ameliorating effects of fingolimod shown in these studies support its further evaluation as an antiepileptogenic treatment, whether alone or in combination with other drugs.
No contraindications have been defined yet.
The aim is to stop the progression of multiple sclerosis and prevent relapses. The longest reported use of fingolimod in clinical trials so far is 3 years. Efficacy benefits of fingolimod during the FREEDOMS clinical trial were sustained during the extension study; annualized relapse rate and brain volume loss were reduced after switching (23). There is a case report of possible rebound of multiple sclerosis disease activity after discontinuation of fingolimod due to development of malignant melanoma (17). A real-world study in routine clinical practice has confirmed the effectiveness of fingolimod previously shown in clinical trials on multiple sclerosis patients and the practicality of quantifying clinical and MRI data collected from multiple centers using a systematic approach (48). Although fingolimod lowers the number of relapses in multiple sclerosis, it causes several side effects. This led to a study for estimating the benefit-harm balance of fingolimod using individual patient data from FREEDOMS trial, which compared 2 different dosages of fingolimod to placebo (41). Results showed that fingolimod’s net benefit did not reach the clinical relevance but the decreased risk for a decline in health over 2 years was significant and provides an objective evidence base for guideline recommendations.
Based on clinical trials, the recommended daily oral dose of fingolimod is 0.5 mg.
The pharmacokinetics of fingolimod are unaffected by renal impairment or mild-to-moderate hepatic impairment. However, for patients with severe hepatic impairment, a standard first dose of fingolimod could be given followed by a maintenance dose that is reduced by half from the normal maintenance dose.
Pediatric. In a phase 3 randomized trial on pediatric patients with relapsing multiple sclerosis, fingolimod was associated with a lower rate of relapse and less accumulation of lesions on MRI over a 2-year period than interferon beta-1a, but it was associated with a higher rate of serious adverse events (05).
Geriatric. Use of fingolimod has not been tested in geriatric patients, as there were none in clinical trials. Earlier trials in renal transplant patients included older patients, but there were no specific precautions.
Pregnancy. No information is available, as pregnant and nursing women were excluded from clinical trials of fingolimod for multiple sclerosis. The number of pregnancies reported in women exposed to fingolimod in completed or ongoing clinical studies is small and does not allow firm conclusions to be drawn about fetal safety of fingolimod in humans. Because of the known risks of teratogenicity in animals, contraception is recommended in women on fingolimod therapy and for 2 months after discontinuation (25).
Anesthesia. No information is available.
Fingolimod is not expected to interact with other drugs used for the treatment of multiple sclerosis, as most of these do not metabolize via P450 4F2/3 enzyme pathway. However, ketoconazole increases fingolimod blood levels in a drug interaction via CYP4F2 inhibition (28).
Immune checkpoint inhibitors such as pembrolizumab are effective anticancer agents and antitumor immune responses are associated with a stronger presence of tumor-infiltrating lymphocytes in solid tumor tissue (21). In cancer patients with relapsing-remitting multiple sclerosis who are under continuous treatment with fingolimod, which inhibits lymphocyte egress from secondary lymphatic organs, the efficacy of immune checkpoint inhibitors may be reduced. In patients with relapsing-remitting multiple sclerosis who developed various cancers during fingolimod treatment, histology of all tumors consistently showed low numbers of tumor-infiltrating lymphocytes but a second biopsy taken from 1 of the tumors showed a significant increase of tumor-infiltrating lymphocytes after stopping fingolimod and starting pembrolizumab, indicating a surge in the number tumor-infiltrating lymphocytes (16).
Adverse events during clinical trials include bradycardia and atrioventricular block, respiratory and herpesvirus infections, increased liver enzyme levels, hypertension, and macular edema (20). Paroxysmal atrial fibrillation has been reported after initiating fingolimod therapy (38).
Cerebral vasospasm has been reported during fingolimod treatment in a patient with multiple sclerosis (40). Animal experimental studies show that S1P induces vasoconstriction in coronary arteries by directly activating S1P-3 receptor and through a subsequent increase in calcium ions and Rho activation in vascular smooth muscle cells. Vasoconstriction can be counteracted by TY-52156, which is an S1P-3 receptor-specific antagonist (35).
Macular edema was reported in 0.5% of patients treated with fingolimod in the FREEDOMS and TRANSFORMS trials (22). Macular edema appears to be dose-dependent as it occurred in only 2 patients taking the lower 0.5 mg dose and resolved following discontinuation of therapy. Macular edema has been reported to be successfully managed in a case by topical antiinflammatory drugs (07). Retinal hemorrhages and retinal vein occlusion have also been reported, which may not resolve with discontinuation of fingolimod alone but may require intravitreal therapy (33).
Of the 19 cases of fingolimod-associated progressive multifocal leukoencephalopathy reported worldwide by the end of 2017, 4 cases were from Japan, and there is a suspicion of dose sensitivity in Japanese multiple sclerosis patients, as recovery of lymphocyte counts in the peripheral blood after reduction of dosage of fingolimod is worse in patients who receive long-term fingolimod treatment than in patients who receive short-term fingolimod treatment (42).
Fingolimod therapy markedly reduces lymphocyte counts in peripheral blood of multiple sclerosis patients, and subgroup analysis of T cells showed that naïve and central memory T helper cells are the most severely affected (18). Long-term treatment with fingolimod is associated with a small increase in the risk of herpes virus reactivation and respiratory tract infections. A patient with a relapsing remitting multiple sclerosis under fingolimod treatment developed a severe COVID-19 infection with bilateral interstitial pneumonia but improved following discontinuation of fingolimod and intensive care (14).
Macular edema has been reported in a multiple sclerosis patient who presented with an acute decrease in vision in the left eye during treatment with fingolimod, and the diagnosis was confirmed on fluorescein angiogram and optical coherence tomography (43). Macular edema resolved completely after discontinuation of fingolimod and treatment with a topical corticosteroid.
A patient in Europe with a diagnosis of possible multiple sclerosis has been reported to have developed progressive multifocal leukoencephalopathy following fingolimod therapy. According to an alert issued by the FDA in 2013, physicians in the United States are requested to report any similar adverse event.
K K Jain MD†
Dr. Jain was a consultant in neurology and had no relevant financial relationships to disclose.See Profile
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