Fingolimod in multiple sclerosis: Mechanisms of action and clinical efficacy

Clinical Immunology (2012) 142, 15–24

available at www.sciencedirect.com

Clinical Immunology www.elsevier.com/locate/yclim

REVIEW

Fingolimod in multiple sclerosis: Mechanisms of action and clinical efficacy Jens Ingwersen a , Orhan Aktas a,⁎, Patrick Kuery a , Bernd Kieseier a , Alexey Boyko b , Hans-Peter Hartung a,⁎ a

Multiple Sclerosis Center, Department of Neurology, Heinrich-Heine-University of Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany b Department of Neurology and Neurosurgery, Russian State Medical University and Moscow MS Center, Moscow, Russia

Received 15 March 2011; accepted with revision 17 May 2011 Available online 26 May 2011

KEYWORDS Multiple sclerosis; Fingolimod; FTY720; Therapy; Immunomodulation

Abstract Fingolimod, also known as FTY720, has recently been approved by the regulatory authorities in the US, EU, Australia, Russia, among others, for the treatment of relapsing– remitting multiple sclerosis. Fingolimod therefore represents the first oral drug for the treatment of this autoimmune disease of the central nervous system. Fingolimod modulates sphingosine-1 phosphate receptors and has unique immunoregulatory properties. Mechanistic studies from animal models have shown that fingolimod prevents immune cells from exiting from the lymphoid tissue and reaching the inflammatory tissue. Indeed, two phase III studies that laid the basis for fingolimod's approval demonstrated that fingolimod efficiently improves the relapse rate compared to both placebo and one of the standard MS medications. In this review, we will summarize the immunological profile of fingolimod, discuss the possible direct neurobiological effects that have been suggested recently and present the clinical data regarding the efficacy and safety profiles of this promising new drug. © 2011 Elsevier Inc. All rights reserved.

Contents 1. 2. 3. 4. 5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . S1P and its biological effects . . . . . . . . . . . . . . . . . Mechanisms of action: inhibition of lymphocyte migration Fingolimod in animal models . . . . . . . . . . . . . . . . . Immunoregulatory properties of fingolimod . . . . . . . . .

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⁎ Corresponding authors. E-mail addresses: [email protected] (O. Aktas), [email protected] (H.-P. Hartung). 1521-6616/$ - see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.clim.2011.05.005

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16 6. Is neuroregeneration promoted by fingolimod? 7. Efficacy in multiple sclerosis: clinical studies 8. Safety profile . . . . . . . . . . . . . . . . . . . 9. Outlook . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . .

J. Ingwersen et al. . . . . . .

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1. Introduction Fingolimod (also called FTY720) is chemically derived from myriocin (ISP-1), an immunosuppressive metabolite obtained from Isaria sinclairii, a fungus used in traditional Chinese medicine [1]. Fingolimod defines a new class of substances, the sphingosine-1-phosphate receptor modulators, that seems to be useful in the treatment of inflammatory conditions of the central nervous system (CNS) because of their immunological and neurobiological effects [2]. Multiple sclerosis (MS) is the most common chronic inflammatory disease of the CNS and is the leading cause of disability in young adults in the Western hemisphere. In contrast to classical immunosuppressive substances already in use for immune-mediated disorders, fingolimod does not impair the activation and proliferation of immune cells, but rather selectively regulates lymphocyte trafficking among lymphoid tissues [3]. Furthermore, due to its lipophilic structure, fingolimod is able to cross the blood–brain barrier (BBB) and enter the CNS. In fact, current data suggest that fingolimod might exert a direct effect on glial cells and neurons in the context of neuroinflammation [4–7]. In this article, we use the recent decisions of the regulatory authorities regarding the approval of fingolimod for MS therapy as an opportunity to examine the mechanisms of action and the therapeutic potential of this substance.

2. S1P and its biological effects Sphingosine-1-phosphate (S1P) is generated from sphingosine, which is phosphorylated by sphingosine kinases (SphK) and irreversibly degraded by the S1P lyase. S1P belongs to the lysophospholipid group [8] and has recently been recognized as an important mediator of a wide variety of cellular processes, such as cell proliferation and survival, cell motility, tissue invasion, angiogenesis and the migration of immune cells [3,9,10]. These pleiotropic, yet tissue specific effects are a consequence of the characteristic distribution patterns of S1P receptors and their differential intracellular signal transduction pathways [11]. The S1P1–3 receptors are ubiquitously expressed, whereas S1P4 is exclusively found in lymphatic and hematopoietic tissues, and S1P5 is predominantly found in the central nervous system [11,12]. Recognition of this expression pattern is crucial for understanding the clinical effects of substances that influence the S1P system: fingolimod inhibits lymphocyte migration through S1P1, but its off target effects include transient bradycardia, a first dose effect mediated via S1P1 and S1P3 [13].

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19 20 20 21 21 21

3. Mechanisms of action: inhibition of lymphocyte migration FTY720 is an oral predrug. Upon ingestion, FTY720 is mostly converted by hepatic sphingosine kinase 2 (SphK2) to its phosphorylated form, FTY720-P. This active metabolite binds to four of the five receptor subtypes, namely S1P1, S1P3, S1P4, and S1P5. Early preclinical studies investigated the effect of FTY720 in models of tissue rejection after transplantation. Fingolimod dose-dependently prolonged allogenous skin-graft survival and showed synergy with the established therapeutics ciclosporin A and tacrolimus. In contrast, it did not affect the production of interleukin-2 (IL-2), which is one of the central messenger molecules contributing to T cell survival and T cell-dependent graft rejection [14]. Immunological follow-up studies in tissuespecific S1P1- and SphK2-deficient animals have shown that S1P regulates the complex migration patterns of lymphocytes. Experiments with fluorescent lymphocytes revealed that fingolimod sequesters these cells inside the lymphoid organs, which resulted in marked lymphopenia; however, lymphocyte survival was unaltered. This effect on lymphocyte distribution, however, seems to be fully reversible. The lymphocytes that were “trapped” in the lymph nodes resumed their migration patterns after discontinuation of fingolimod treatment. Mechanistically, it has been shown that fingolimod interacts with S1P1 and modulates its function [15,16], eventually leading to internalization of the receptor and down-regulation at the gene expression level [17,18]. This process deprives lymphocytes of the S1P signal that they need to egress from the lymph nodes into inflamed tissue (see Fig. 1) [2]. It is particularly noteworthy that naïve and memory T cells, which express the chemokine receptor CCR7 on their surface, are preferentially retained, while effector memory T cells capable of down-regulating their surface CCR7 do not depend on S1P signaling and can therefore freely migrate through lymph nodes (for a review see [19]). This information may be relevant when considering the potential risks associated with a profound impact on the immune system, such as those mediated by fingolimod, in particular infections and malignancies. In such situations, these effector T cells may be available to mount a protective immune response in the presence of fingolimod.

4. Fingolimod in animal models Following a histopathological study on the expression of S1P receptors in MS lesions [20] and early experiments in immunological animal models [21], Brinkmann et al. showed

Fingolimod in multiple sclerosis: Mechanisms of action and clinical efficacy

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Figure 1 A model of MS disease induction and neural repair: potential mechanisms of action of fingolimod. Fingolimod is an oral predrug and shows structural similarities to sphingosine. In their phosphorylated forms, fingolimod-P and S1P can both bind to S1P receptors. To elicit neuroinflammation, myelin-directed T helper cells are thought to undergo a process that begins with their activation by antigen-presenting cells (APC) in peripheral lymphoid organs, such as lymph nodes (left of picture). The activated T cells then leave the lymphoid tissue, following an S1P gradient. This lymphocyte egress is inhibited by the interaction of fingolimod with S1P receptors. It has been suggested that this retention effect especially applies to peripheral interleukin-17-producing T cells [94]. Myelin-directed T cells cross the blood–brain barrier, a process that seems to be controlled by local dendritic cells (DC). The influx of activated T cells triggers a cascade of inflammatory responses (the activation of B cells and plasma cells to produce antibodies, the recruitment of other immune cells, such as macrophages, the activation of microglia and the direct attack by T cells of the myelin sheath and the neuronal cell soma, which eventually leads to demyelination and neuronal cell death). This tissue damage evokes reactive processes, such as the recruitment and differentiation of oligodendrocyte progenitor cells (OPC), which are thought to be promoted by fingolimod. Astrogliosis or glial scarring may be inhibited by fingolimod. Thus, fingolimod may exert its clinical efficacy via immune-directed and direct CNS-mediated effects.

a marked impact of fingolimod in experimental autoimmune encephalomyelitis (EAE) [15], the most common animal model of multiple sclerosis. This model is characterized by an inflammatory attack on the myelin sheath of the CNS, leading to profound demyelination and loss of oligodendrocytes [22,23]. This experimental disease is induced by subcutaneous immunization of susceptible rodent strains with myelin antigens (so-called active EAE) [24]. Alternatively, EAE can be elicited by the transfer of myelin-specific CD4 + T cells into non-immunized animals (transfer EAE or passive EAE) [25]. The resulting neuroinflammatory process causes extensive collateral damage, including injury to axons, loss of neurons and astrogliosis [26]. However, the translation of results obtained from animal models into clinical practice is often limited [27]. Nevertheless, the various EAE models have been shown to serve as useful platforms for the testing of new therapeutic agents and have generated helpful insights into the mechanisms of the many

facets of autoimmune neuroinflammation, such as the early steps of lesion formation [28], the role of dendritic cells in the control of blood–brain barrier permeability [29] and the molecular mechanisms underlying collateral damage to neurons [30,31]. A number of studies have consistently demonstrated the efficacy of fingolimod in EAE (see Table 1). Oral fingolimod, when administered before the onset of disease, protected Lewis rats from acute and monophasic EAE, reduced the number of CNS-infiltrating T cells and diminished the expression of proinflammatory cytokines [32]. Furthermore, myelin-reactive lymphocytes from immunized mice that had been treated with FTY720 were not capable of inducing EAE after transfer. In several EAE models, the drug showed efficacy even when given after the peak of the first signs of disease [33,34]. Fingolimod reversed the impairment of neural conduction and prevented axonal damage [35,36]. Fingolimod was able to not only modulate lymphocyte

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Table 1

FTY720 effects in experimental autoimmune encephalomyelitis (EAE), an animal model of MS.

EAE model

Encephalitogenic antigen

Disease induction

Treatment approach/dose

Clinical outcome

Mechanistic findings: histopathology

Mechanistic findings: immunology

Citation

Wistar rats Lewis rats (male)

Bovine spinal cord MBP

Active Active Passive

Preventive; 0.3 mg/kg p.o. Preventive 1 mg/kg p.o.

N/A Decreased infiltration of T cells and decreased apoptosis in the spinal cord

N/A Decreased expression of IL Immune cells from FTY720

[15] [32]

SJL mice (female)

PLP139–151

Active Passive

Active EAE: therapeutic treatment at and after disease onset with 0.03 to 1 mg/kg i.p. Passive EAE: preventive

Complete disease prevention Near complete disease prevention Complete prevention of mortality Reduction of disease score Correlation of disease severity with treatment initiation and cessation Dose dependency

N/A

[34]

Lewis rats (male) SJL mice C57BL/6 mice

MBP from guinea pig MOG35–55 PLP139–151

Active

Preventive and therapeutic 0.1–1 mg/kg p.o.

Decreased inflammation and demyelination in all models Marked reduction of CNS-infiltrating CD4+ and CD8+ T cells

Dark agouti rats

MOG1–125

Active

Preventive and therapeutic (rescue) 0.4 mg/kg p.o.

Marked effect as a prophylactic and therapeutic treatment in all three models Dose dependency with complete disease prevention at the highest dose Efficacy superior to rmIFN-β and equal to prednisolone Amelioration of VEP and SEP impairment

Reduced downregulation of myelin compounds Reduced up-regulation of inflammatory cytokines at the RNA level Lymphopenia Decreased number of circulating T and B lymphocytes Decreased IFN-γ expression (mRNA) in the spinal cord

Dark agouti rats

Syngeneic CNS antigen

Active

Preventive, therapeutic and rescue approaches 0.3 mg/kg p.o.

Efficacy of preventive and therapeutic approaches Reverse of established neurologic deficits for late stage treatment

Conditional S1P1-deficient mice (Synapsin-cre, Nestin-cre, GFAP-cre, C57BL/6 background)

MOG35–55

Active

Rescue approach 1, 3 and 10 mg/kg i.p.

Amelioration of disease by FTY treatment Reduced efficacy of FTY treatment in conditional S1P deficiency in astrocytes The S1P1 agonist AUY954 also ameliorated EAE

No demyelination or axonal loss with the preventive approach Decreased demyelination and axonal loss with the rescue approach Decreased area and number of lesions in the spinal cord Complete absence of active lesions

N/A

[35]

Decreased expression of many immune Increased expression of myelin Restored expression of pathologically-regulated S1P receptors in the brain Astrocytic S1P1 may be involved in the regulation of proinflammatory cytokines in the CNS

[38]

[6]

Abbreviations: MBP, myelin basic protein; IL, interleukin; IFN, interferon; MOG, myelin oligodendrocyte glycoprotein; PLP, proteolipid protein; SEP, somatosensory evoked potentials; S1P, sphingosine-1-phosphate; VEP, visually evoked potentials. CNS, central nervous system. Entries are in chronological order.

J. Ingwersen et al.

Astrocytic S1P1 deficiency and FTY treatment reduced demyelination, axonal damage and astrogliosis FTY increased receptor internalization on astrocytes (functional antagonism)

[33]

Fingolimod in multiple sclerosis: Mechanisms of action and clinical efficacy

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migration [37] but also curtail the inflammation induced blood–brain barrier dysfunction, even when given at very low concentrations [38].

regulatory T cell function. The majority of reports, however, suggests that fingolimod promotes Treg activity.

5. Immunoregulatory properties of fingolimod

6. Is neuroregeneration promoted by fingolimod?

The development and maintenance of autoimmune diseases, such as multiple sclerosis, as well as the defense against autoimmune tissue destruction, are thought to be in part dependent on the interplay between auto-aggressive T cells and so-called regulatory T cells, which are CD4 +CD25 + and express the transcription factor FoxP3 [39]. Fingolimod has been shown to exert a differential effect on the trafficking patterns of regulatory CD4 +CD25 + T cells compared to other T cell subsets. Indeed, CD4 +CD25 + T cells express lower levels of S1P1 and S1P4, and their relative numbers in the spleen and lymph nodes of fingolimod-treated mice were increased [40]. Furthermore, several recent reports have shown a direct effect of fingolimod on CD4 +CD25 +FoxP3 + T cells. In a model of colitis, fingolimod efficiently ameliorated disease severity, which was accompanied by a substantial increase in the numbers of FoxP3 + T cells in the lamina propria of the colon and an increase in the levels of cytokines associated with Treg function (TGF-β, IL-10) [41]. This finding might be explained by a redistribution phenomenon. An alternative explanation, as suggested by Sehrawhat et al. using a viral model of inflammation, may be a direct effect of fingolimod on non-regulatory T cells that leads to their conversion into FoxP3 + Tregs [42]. Furthermore, immature bone marrow-derived dendritic cells (BMDC), which are able to induce tolerance in tissue transplant models, have been shown to induce greater numbers of Tregs and thus more efficiently prevent allograft rejection when generated in the presence of fingolimod [43]. An in vitro paradigm using the allogeneic mixed lymphocyte reaction demonstrated that fingolimod increases the number and function of FoxP3 + Tregs [44]. Several other reports have shown amelioration of autoimmune diseases and increased numbers of Tregs in inflamed tissue due to fingolimod treatment in models including experimental autoimmune uveitis [45], experimental autoimmune neuritis [46] and a model of autoimmune diabetes in IDDM rats [47]. However, one report on the in vivo and in vitro functions of Tregs suggests that fingolimod might instead abrogate the immunoregulatory properties of regulatory T cells. Fingolimod inhibited Treg cell proliferation without directly affecting immunosuppressive Treg function in vitro [48]. Ex vivo Tregs isolated from fingolimod-treated animals lost their immunosuppressive function when adoptively transferred in models of autoimmunity and graft-versus-host disease. At this point, it is not clear how these seemingly contradictory reports can be reconciled. A mechanism by which fingolimod might influence Treg function was provided by Liu et al., who showed that S1P1 induces selective activation of the Akt-mTOR pathway in regulatory T cells [49]. The authors relied on genetic systems rather than pharmacological modulation to elucidate the function of S1P1 because of fingolimod's very complex interactions with S1P1 and other receptors, which are still not fully understood. This complexity might, in part, explain the contradictory findings concerning the drug's influence on

In vitro findings have raised the possibility that oral fingolimod, which can pass the blood–brain barrier and access the CNS, may exert a neuroprotective effect (see Fig. 1) [4,50]. Expression of the FTY720 activating SphK2 and S1P receptors on neurons, oligodendrocytes and astrocytes and their progenitors has been described [12,51,52]. A recent report even suggested that S1P1 and S1P3 are upregulated in MS lesions [53]. The effect on myelinproducing oligodendrocytes is of particular interest. Due to a number of heterogeneous studies, it remains controversial whether fingolimod increases the survival of cultivated oligodendrocytes across species [52,54–57]. Miron et al. recently showed that very low concentrations of FTY720 promoted remyelination in an ex vivo model of cultivated cerebellar slices exposed to a myelin-toxic lysolecithin [5]. This finding could not be confirmed in a different model of demyelination (the so-called cuprizone model). Kim et al. found that remyelination was not affected by FTY720 and demonstrated that the compound could exert both salutary and detrimental effects on astrogliosis, depending on the timing of administration [7]. Another recent report by Choi and colleagues, using several different conditional knock-out models, provided evidence suggesting a beneficial neurobiological effect of FTY720, independent from immunedirected mechanisms, which appeared to be mediated primarily through the modulation of astrocytic S1P1 signaling [6]. Interestingly, in EAE-associated optic neuritis in rats, Rau et al. showed that fingolimod was effective at reducing motor symptoms, while apoptosis of retinal ganglial cells (RGC), i.e., neurons forming the axons of the optic nerve, was not prevented. These results indicate that in certain models, fingolimod exerts differential effects on the immune and the nervous system [58]. Mechanistically, FTY720 modulates a plethora of intracellular signaling pathways, including MAP kinase, adenylate cyclase and calcium signaling, via S1P1, S1P3 and S1P5 activation in oligodendrocytes and astrocytes [52,56,59,60]. The latter play an important role in the chronification of inflammatory lesions (astroglial scarring) [61], possibly due to a disturbed differentiation of oligodendroglial progenitor cells [62,63]. In vitro, FTY720 enhances the migration of astrocytes via S1P1 [59,64]. Because S1P induces proliferation of astrocytes and inhibits gap junction communication, an FTY720-mediated effect on reactive astrogliosis, independent of the immune system, was hypothesized to exist [60,65]. This effect has only recently been verified [7]. Finally, the S1P signaling pathway has been shown to regulate the homeostasis and function of neurons, including adult neurogenesis. Here, a complex and heterogeneous picture concerning dendrite outgrowth and survival emerges [12,66–69]. With respect to neurogenesis, FTY720 has been proposed to facilitate the proliferation of neural progenitor cells and to promote their migration to damaged brain tissue [70–73]. Consequently, mice that are rendered

20 genetically deficient in S1P or SphK1/2 exhibit severe neuronal developmental disorders [74].

7. Efficacy in multiple sclerosis: clinical studies The Food and Drug Administration (FDA) recently approved oral fingolimod (Gilenya®) for use as a first-line therapy in multiple sclerosis, and the European Medicines Agency (EMA) announced a positive vote for fingolimod as a therapy for breakthrough disease. These decisions were based on the efficacy and safety data obtained in phase II and III studies in patients with MS. In the first double-blind, placebocontrolled phase II study [75], 281 individuals with active relapsing MS were randomized to receive placebo or FTY720 over 6 months at a daily dose of either 1.25 mg or 5 mg. The number and volume of contrast-enhancing lesions were reduced following fingolimod treatment. Although they were only secondary endpoints, the clinical parameters also revealed an advantage for the fingolimod groups. The percentage of relapse-free patients was greater in the FTY720 group, and the relapse rate was reduced by approximately 55%. FTY720 strongly reduced the number of both circulating CD4 + cells and CD8 + cells. According to recent studies, however, FTY720 does not negatively influence the primary T cell response [76–79]. Results from a 3-year extension phase of the study, in which all patients received fingolimod after 6 months, showed sustained therapeutic efficacy with respect to relapse rate [80]. Some patients from this phase II study received the drug for a total of 6 years in an extension trial. In the subsequently initiated phase III study, TRANSFORMS, which together with the FREEDOMS study formed the basis for fingolimod's approval, the compound's efficacy (at doses of 0.5 mg and 1.25 mg) was examined in 1292 patients with relapsing–remitting multiple sclerosis and compared against an established first line therapeutic, intramuscular interferon-β1a (Avonex®, 30 μg/week) over a period of 12 months [81]. Fingolimod decreased the relapse rate by 52% (0.5 mg) and 38% (1.25 mg). The already low annual relapse rate of 0.33 in the group of patients that received interferon-β1a is remarkable and adds to the data's reliability. Furthermore, even in this active-comparator trial, both new and enlarging T2 lesions in the MRI analysis and brain atrophy progression significantly favored the fingolimod groups. However, changes in EDSS scores did not significantly differ. The trial was probably underpowered and too short to reach significance for this secondary endpoint. While it is clear that one cannot make comparisons across different studies, it may be worth noting that the annual relapse rates observed in the fingolimod groups in this trial are the lowest ever seen in an approval study. Parallel to the TRANSFORMS study, the placebo-controlled phase III study FREEDOMS investigated the effect of FTY720 on the relapse rate and progression of neurological disability in 1272 patients with relapsing–remitting MS over a period of 24 months [82]. The initial results from the phase II study were confirmed and extended. FTY720 yielded a comparable improvement in the relapse rate and MRIbased disease activity at both doses. In addition to the relapse rate reduction of 54% (0.5 mg/day) and 60% (1.25 mg/day), FTY720 delayed disability progression by

J. Ingwersen et al. 30% (0.5 mg/day) and 32% (1.25 mg/day). These results indicate that FTY720 is able to prevent increases in disability over time. Moreover, this observation is a major rationale for a third, ongoing study (INFORMS) that is investigating the efficacy of FTY720 on disease progression in patients with primaryprogressive multiple sclerosis. In this primarily neurodegenerative MS phenotype, FTY720 may show therapeutic advantages in comparison to recently investigated drugs, such as glatiramer acetate and rituximab, which are primarily used to treat aberrant immune responses [81,83].

8. Safety profile The patient exposure in the FTY720 study program amounts to well over 5000 patient years. In the control groups, exposure approximates 1600 patient years. Some patients took fingolimod for over 5 years. Thus, a fairly extensive body of safety data has been collected. Common cold, sinusitis, mild headaches, fatigue and gastrointestinal dysfunction were the most frequent adverse effects. Considering the mechanisms of action of fingolimod and the data gathered using the monoclonal anti-integrin antibody natalizumab (Tysabri®), the side effects of greatest concern are rare, but potentially lethal opportunistic infections and malignancies [84]. At this point, no studies have shown JC virus-mediated progressive multifocal leukoencephalopathy (PML) during fingolimod treatment. In this respect, it should be emphasized that fingolimod-mediated lymphopenia is thought to be primarily due to the retention of lymphocytes in lymphatic tissue and is fully reversible in most patients. (In a few patients, lymphopenia has been observed even months after therapy cessation [85].) It does not, however, seem to repress the function of lymphocytes in the context of the primary immune response [76,79]. In the initial phase II study with daily fingolimod doses of 1.5 mg or 5 mg, no severe infectious complications occurred in the placebo-controlled core phase (6 months). Two suspicious infections (one case of facial herpes zoster and one case of enterocolitis) were reported during the 6 month extension phase [75]. In the TRANSFORMS study, two lethal cases of viral infections occurred (herpes simplex and varicella zoster encephalitis). The case of varicella zoster encephalitis was considered a disseminated primary infection. Both cases occurred in the 1.25 mg study, i.e., not at the dosage that received approval. However, because lymphocyte drops were similar at both dosages [81], one may speculate that there might not be a relevant difference in immune competence impairment between the two dosages. Although most of the infection-related adverse effects were more frequent at the 1.25 mg dose, thorough pharmacovigilance should be implemented when administering fingolimod at the 0.5 mg dose. A recent, small study on the efficacy of influenza vaccinations in 14 fingolimod-treated patients did not reveal an impaired immune response to the vaccine compared to healthy controls, which may indicate that fingolimod-treated individuals are generally able to mount virus-specific immune responses [77]. One should not, however, directly extrapolate from this vaccine study to primary viral infections. As long as the significance of varicella zoster infection during fingolimod treatment is

Fingolimod in multiple sclerosis: Mechanisms of action and clinical efficacy unclear, a determination of varicella zoster virus titers and, if negative, vaccination prior to treatment with fingolimod should be performed. Clearly, in addition to primary varicella zoster infection, one has to pay attention to patients with recurrent zoster episodes prior to fingolimod therapy. In both cases with lethal virus infections, treatment with high doses of intravenous steroids was initiated based on the assumption that neurological worsening was due to an MS relapse. It is therefore especially important to pay close attention to differential diagnostics when initiating relapse therapy with steroids in patients being treated with fingolimod. Furthermore, one patient with focal hemorrhagic encephalitis of unknown etiology and one patient with a critical brachial artery vasospasm were reported [86,87]. Infections of the lower respiratory tract seemed to be increased in the fingolimod groups when compared to intramuscular interferon administration in the TRANSFORMS study. This result was not, however, detected in the placebocontrolled FREEDOMS trial. Moreover, some cases of cancer have been observed. In the TRANSFORMS study, three cases of melanoma occurred in the 0.5 mg fingolimod group, while no cases were observed in the 1.25 mg group or the placebo group. Furthermore, four cases of breast cancer occurred in the fingolimod groups, and none occurred in the placebo group. In the placebo-controlled FREEDOMS study, however, only one case of breast cancer was observed in the fingolimod groups, and three cases were observed in the placebo group. The overall incidence of neoplasms was higher in the placebo group than in both fingolimod groups. The significance of these observations and the causative relationship to fingolimod-mediated interference with immune responses currently remain elusive. It is conceivable that fingolimod may compromise immune surveillance and weaken the defense against neoplasms and primary viral infections, especially in combination with high doses of corticosteroids. Mechanistically, as discussed above, immune responses designed to combat infectious agents may be fully operative because effector T cells are not trapped in lymph nodes following modulation of S1P signaling. A recent study reported that the relative numbers of various types of immune cells in cerebrospinal fluid (CSF) are altered in fingolimod-treated patients; this effect, in some respects, resembles the changes seen in patients treated with natalizumab [88]. The authors speculate that long-term fingolimod therapy might lead to a similarly compromised immune response in the CNS. Therefore, it is clear that even after fingolimod's successful approval, thorough pharmacovigilance is warranted. In addition to these adverse effects, which may be explained by the immunomodulatory actions of fingolimod, other side effects that appear to be due to “off-target” S1P signaling in other organ systems have been observed. Since the first studies on FTY720 in the transplantation program, a transient reduction of heart rate at the onset of therapy has been noticed [89], which appears to be mediated via S1P1 and S1P3 receptors [90,91]. This effect has been confirmed in healthy study participants and appears predominantly after the first administration of FTY720. In some patients, this adverse effect has become symptomatic, but no serious complications have been recorded. Due to a reactive adaptation response, this bradycardia is self-limiting. An additional observation made in the first studies and

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confirmed in the phase III studies was the appearance of a usually reversible macular edema during FTY720 treatment. Of note, the risk for developing macular edema may be increased in diabetics. The cardiac as well as the ophthalmological side effects of FTY720 are at the center of currently ongoing complementary study programs. Finally, it must be noted that the clearance of fingolimod can be reduced in patients with middle- or high-grade hepatic dysfunction [92].

9. Outlook In multiple sclerosis therapy, the development of more effective and orally applicable therapeutic approaches has long been awaited. Fingolimod is a capsule that is taken once a day and has greater efficacy compared to a standard medication (interferon-β1a). Head-to-head studies with other approved medications (e.g., natalizumab) are lacking. However, with the approval of fingolimod, an interesting and encouraging new therapy has been added to the MS therapeutic arsenal. Fingolimod acts through a unique mechanism of action by activating an endogenous control pathway that inhibits lymphocyte migration and leads to a distinct lymphocyte redistribution. Furthermore, fingolimod may bridge immunomodulatory approaches on the one hand and direct neurobiological effects on the other hand. Data from phase II and phase III studies prompted the FDA and its European counterpart, EMA, to approve fingolimod (Gilenya®) for the treatment of relapsing– remitting MS (though with different labels). It is, however, not unreasonable to expect that the established injection medications will continue to retain their central status as a mainstay treatment for basic MS patient care for some time. With respect to fingolimod, close continuous and rigorous patient monitoring will be required to reach a final conclusion concerning the drug's risk-benefit profile [93].

Acknowledgments HPH and OA received honoraria for consulting and speaking, with approval by the rector of HHU, from Bayer Healthcare, Biogen Idec, Merck Serono, Novartis and Teva Sanofi Aventis as well as research funding from the German Research Council (DFG). AB received honoraria for consulting and speaking from Bayer Healthcare, Biogen Idec, Merck Serono, Novartis and Teva Sanofi Aventis. The MS Center at the Department of Neurology, HHU, is supported in part by the Walter-and-Ilse-Rose Foundation. The Department of Neurology is a member of the German Competence Network Multiple Sclerosis (KKNMS), supported by the German Ministry for Education and Research (BMBF).

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