Core Evid. 2006; 1(3): 157–167.
`Published online 2006 Mar 31.
`
`PMCID: PMC3321664
`
`FTY720 in multiple sclerosis: the emerging evidence of its therapeutic value
`Andrew Thomson
`
`Core Medical Publishing, Knutsford, UK
`Correspondence: Andrew Thomson, Core Medical Publishing, Mere House, Brook Street, Knutsford, Cheshire WA16 8GP, UK or at ; Email:
`editor@coreevidence.com
`
`Copyright © 2006 Dove Medical Press Limited. All rights reserved
`
`This article has been cited by other articles in PMC.
`
`Abstract
`
`Go to:
`
`Introduction:
`Multiple sclerosis is a demyelinating disease of the central nervous system which can cause severe disability and
`has profound effects on patients’ quality of life over several decades. Although there is no cure for the disease,
`recently developed disease-modifying agents have modest effects on the impact of disease progression. There is
`therefore a need for a new, effective, and well-tolerated treatment for multiple sclerosis and FTY720 (an orally
`administered immunomodulatory compound with a novel mechanism of action) is one of a number of agents
`being evaluated for the treatment of this disease.
`
`Aims:
`The objective of this article is to assess the therapeutic potential for FTY720, now in phase II clinical trials, for
`the treatment of multiple sclerosis through a review of the published evidence.
`
`Emerging evidence:
`There is good evidence that FTY720 achieves immunomodulation as shown by a reversible redistribution of
`peripheral blood lymphocytes after oral administration. Two meeting abstracts have been published showing
`results obtained with FTY720 in a 12-month phase II clinical trial in patients with active relapsing multiple
`sclerosis. There is modest evidence that FTY720 significantly improves both patient-oriented (relapse rate) and
`disease-oriented outcomes (inflammatory disease activity). There is good evidence that FTY720 is well tolerated.
`
`Profile:
`Based on these early results from the clinical development program, FTY720 has the potential to be an effective
`disease-modifying agent for the treatment of multiple sclerosis. Further results from ongoing multinational phase
`III studies are awaited.
`
`Keywords: evidence-based review, FTY720, immunomodulator, multiple sclerosis
`
`Core emerging evidence summary for FTY720 in multiple sclerosis
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`Outcome measure
`Patient-oriented evidence
`Disease relapse rates
`
`Convenient administration
`
`Tolerability
`
`Emerging evidence
`
`Reduction in relapse rates and time to first relapse
`Likelihood that patients will at least have longer intervals between relapses
`Daily oral dosing with or without food
`No dose alterations necessary with hepatic impairment
`Well tolerated. No serious adverse events noted. Most common adverse event is
`asymptomatic, mild, and transient reduction in heart rate
`No evidence of increased risk of infections associated with drug-related lymphocyte
`sequestration
`
`Disease-oriented evidence
`Disease progression determined by
`magnetic resonance imaging
`Immunomodulation
`
`Reduction of new and existing inflammatory lesions responsible for subclinical disease
`progression
`Reversible lymphocyte sequestration, a characteristic of the mode of action of FTY720, is
`a convenient surrogate marker of immunomodulation
`
`Scope, aims, and objectives
`Multiple sclerosis is one of the most common chronic neurologic diseases causing progressive disability in young
`adults. The life expectancy of patients with multiple sclerosis is at least 25 years following the first onset of
`symptoms and most patients will die from unrelated causes. In recent years there has been great progress in
`understanding the pathogenic mechanisms associated with the disease and imaging techniques have been
`developed to monitor the effects of treatment on neurologic lesions. However, although recently developed
`disease-modifying agents have improved the management of multiple sclerosis, there is still no treatment that
`stops the development of disability.
`
`Go to:
`
`FTY720 is a novel immunomodulatory compound in clinical development for use in the prevention of organ
`rejection in transplant patients and for multiple sclerosis.
`
`The objective of this review is to evaluate the evidence for the potential of FTY720 as a treatment for multiple
`sclerosis.
`
`Methods
`The English language medical literature was reviewed for relevant articles on FTY720 for the treatment of
`multiple sclerosis. An initial search of PubMed, BIOSIS, and EMBASE was conducted on June 13, 2005 using
`the search terms “FTY720 OR FTY720 AND multiple sclerosis” for articles published between January 1993
`and June 2005 (inclusive). In addition, relevant abstracts were identified from the annual scientific sessions of the
`European Neurological Society, the American Society for Neurochemistry, and the International Society of
`Neuroimmunology, held during 2002 and 2005. The online database, www.clinicaltrials.gov was searched for
`information on ongoing phase II and phase III studies with FTY720 in multiple sclerosis. A hand search of
`reference lists in selected publications was carried out to ensure that no relevant articles were omitted.
`
`Go to:
`
`A total of 16 articles (14 full papers and two abstracts) was identified from the initial search strategy after any
`animal, in-vitro, or other nonrelevant publications were omitted (Table 1). All of the full papers identified
`initially were excluded from the evidence evaluation. Only one meeting abstract was included for analysis as it
`reported pertinent clinical outcomes with FTY720. Following the initial search strategy a further six full papers
`were identified from reference lists in the excluded full publications for inclusion in the review of evidence. The
`search strategy was also repeated on January 10, 2006 when one further relevant meeting abstract was identified
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`and included. Thus, a total of eight publications (six full papers and two meeting abstracts) were included in the
`evidence base.
`
`Table 1
`Evidence base included in the review
`
`Disease overview
`
`Go to:
`
`Signs and symptoms
`Multiple sclerosis is one of the most common neurologic diseases affecting young adults. It is usually a disease
`with sporadic episodes and is characterized as a variably progressive disorder of the nervous system in which
`patchy degenerative inflammatory changes occur within the brain and spinal cord (Compston & Coles 2002). The
`symptoms of multiple sclerosis are diverse and can include tremor, paralysis, loss of bladder or bowel control,
`fatigue, pain, loss of cognitive function, disturbances in vision and speech, emotional changes, and nystagmus.
`These symptoms can have a profound effect on patients’ quality of life and can also lead to significant reliance
`on their family, dependents, and carers.
`
`The severity and prognosis of multiple sclerosis can vary greatly. In about a quarter of all patients the disease
`does not affect activities of daily living. However, severe disability can affect about 15% of patients within a
`relatively short period of time (Compston & Coles 2002) and approximately half of all patients will require a
`cane for walking short distances within about 15 years of first onset of the disease (Weinshenker 1994). Attacks
`can occur randomly, with an initial incidence of about one per year followed by a steady increase in subsequent
`years.
`
`Epidemiology
`The incidence of multiple sclerosis is estimated to be seven cases per 100 000 per annum, and the prevalence is
`approximately 120 cases per 100 000. The lifetime risk of the disease is one in 400 (Compston & Coles 2002).
`There are about 2.5 million individuals with multiple sclerosis in the world, and in the USA alone there are about
`350 000 affected patients (Lutton et al. 2004). Multiple sclerosis develops in twice as many women as men and
`age at onset of the disease is usually 20–30 years. About 5% of all cases occur in patients under the age of 16
`years.
`
`Etiologic, genetic, and environmental factors
`The relationship between genetic and environmental factors in determining the susceptibility of patients to
`develop multiple sclerosis is complex and poorly understood. However, it is clear that there is an uneven
`geographic distribution of the disease in populations of northern European origin and an increased prevalence in
`geographically temperate areas (Dyment et al. 1997). Thus it is a disease that predominantly affects northern
`Europeans.
`
`To date the major histocompatibility complex (MHC) is the only area of the human genome with a clear
`association with the disease. Results from three genomic searches imply that a number of genes with interacting
`effects will ultimately be found; however, to date no single genetic region has been identified with a major
`influence on familial risk (Dyment et al. 1997). In addition, attempts to implicate specific environmental agents
`as responsible for the disease have been unsuccessful. Possible, but as yet unsubstantiated, candidate agents
`include Chlamydia pneumoniae and human herpes virus 6 (Compston & Coles 2002).
`
`Pathophysiology
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`Multiple sclerosis is characterized by acute focal inflammatory demyelination and the loss of axons with limited
`remyelination (Noseworthy et al. 2000). This leads to the presence of characteristic multifocal sclerotic plaques
`in the white matter of the central nervous system. These lesions are particularly common in the optic nerves, and
`white matter tracts of the periventricular regions, brain stem, and spinal cord (Hafler 2004). Typically T and B
`lymphocytes, macrophages, and antibodies can be found at the site of white matter destruction.
`
`A number of fundamental questions remain regarding the pathophysiology of multiple sclerosis. For example,
`what initiates the inflammation and what is the antigenic target driving the inflammation (Hafler 1999)? Possible
`triggers for the initial inflammatory insult include an autoimmune response (initiated by autoreactive T
`lymphocytes) or a structural alteration in the white matter as a result of microbial infection. It has also been
`hypothesized that multiple sclerosis is a spectrum of diseases and that some are initiated by an autoimmune
`response and others are induced by viral infections of the central nervous system (Hafler 1999). It is unlikely that
`the antigenic target driving the disease is due to a single antigen. The inflammatory process initiated by T-cell
`recognition of one myelin protein epitope subsequently leads to the activation of autoreactive T cells recognizing
`other epitopes of the same protein. This “epitope spreading” can lead to activation of T cells recognizing other
`myelin proteins that may get degraded and be presented on the MHC of local antigen-presenting cells (Hafler
`1999).
`
`It is known that trauma does not induce multiple sclerosis, nor does trauma activate a latent form of the disease or
`alter symptoms in a patient with the disease. However, the risk of an exacerbation in a patient with multiple
`sclerosis has been shown to be associated with stressful life events (Mohr et al. 2004). As yet, specific stressors
`cannot be linked to exacerbations and patients themselves should not be led to believe that they bear
`responsibility (through experiencing stress) for them.
`
`Diagnosis
`The typical stimulus for patients to seek medical help is the first acute attack. An accurate clinical history and a
`thorough neurologic examination are crucial for the accurate diagnosis of multiple sclerosis. At present there is
`no specific immunologic-based test for the disease. Results from imaging investigations should be used to
`support the clinical diagnosis and to rule out other pathologies. In the absence of clinical evidence, abnormalities
`detected by imaging are insufficient grounds for a diagnosis (Miller et al. 1998). Annual magnetic resonance
`imaging (MRI) scans are also recommended for the management of ongoing multiple sclerosis to monitor disease
`progression and to detect underlying pathology.
`
`MRI has both prognostic and diagnostic applications in multiple sclerosis. It has a pivotal role in the diagnosis of
`the disease and acts as a surrogate marker of drug efficacy in clinical trials. The use of imaging technology has
`been important in demonstrating that even during apparently stable periods between attacks the disease is still
`very active (Miller et al. 1998).
`
`Classification and clinical course
`At onset, multiple sclerosis can be categorized clinically as either relapsing remitting multiple sclerosis (RRMS)
`or primary progressive multiple sclerosis (PPMS). The most common form of the disease is RRMS, which is
`observed in about 85% of all patients (Fig. 1). RRMS is characterized by clearly defined disease relapses with
`full recovery or with sequelae and residual deficit upon recovery. On average about 1.5 attacks occur each year
`and approximately 10 new lesions are detected annually on MRI scan (Hafler 1999). Although RRMS is not
`classified as a progressive form of multiple sclerosis, residual deficits may occur after each exacerbation. At least
`half of all patients with RRMS will transition to secondary progressive multiple sclerosis (SPMS). This subform
`is characterized by disease progression with or without occasional relapses, minor remissions, and periods of
`stability. In contrast, PPMS is seen in far fewer patients (about 10%; Fig. 1).
`
`Fig. 1
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`Classification, incidence, and examples of clinical courses of subtypes of m
`(adapted with permission from Kieseier & Hartung 2003)
`
`It is characterized from the outset by the absence of acute attacks but demonstrates a worsening in disease
`severity.
`
`Progressive relapsing multiple sclerosis (PRMS) is the least common form of the disease, affecting about 5% of
`patients. From the outset it is progressive, with or without full recovery, and progression is continuous between
`relapse periods.
`
`Schematic representations of the courses of these four forms of multiple sclerosis are shown in Fig. 1. During a
`relapse, symptoms can develop over hours to days, persist for several days or weeks, and then gradually
`dissipate.
`
`Prognosis
`Patients with sensory or visual symptoms as the dominant feature, particularly those who experience complete
`recovery from attacks, generally have the best prognosis. This pattern is common in younger women (Compston
`& Coles 2002). Prognosis is particularly poor in males when disease onset occurs later in life, and in patients
`with frequent and prolonged relapses (particularly in the first 2 years) and in those with a short interval between
`the initial attack and the first relapse (Noseworthy et al. 2000) (Table 2).
`
`Table 2
`Disease course characteristics associated with the prognosis of multiple
`sclerosis
`
`Current therapy options
`The aim of treatment of multiple sclerosis is to reduce the frequency (and limit the lasting effects) of relapses,
`relieve symptoms, prevent disability arising from disease progression or incomplete recovery from relapses, and
`promote tissue repair (Compston & Coles 2002).
`
`Go to:
`
`The management of multiple sclerosis has greatly benefited from the availability of five disease-modifying
`agents which have been approved by the US Food and Drug Administration (FDA) since 1993 and are now
`widely available. However, there is no cure for the disease and available disease-modifying agents are lifelong
`therapies. Other therapies may be used to alleviate some of the chronic symptoms of the disease (spasticity,
`neuropathic pain, and fatigue), but by their nature they do not alter the course of the disease and there is a limited
`evidence base for symptomatic drug treatment for symptom control (Thompson 2001).
`
`Disease-modifying agents
`Of the five disease-modifying therapies approved by the FDA for the treatment of multiple sclerosis, four are
`immunomodulators (three preparations of interferon beta and glatiramer acetate) and one is an
`immunosuppressant (mitoxantrone). The disease-modifying agents that are indicated for the treatment of RRMS
`®
`include the immunomodulatory agents interferon beta-1b for subcutaneous administration (Betaseron ), two
`®
`®
`formulations of interferon beta-1a for either subcutaneous (Rebif ) or intramuscular administration (Avonex ),
`®
`and glatiramer acetate (Copaxone ). All four immunomodulators can be considered as first-line treatments for
`RRMS (Goodin et al. 2002; NMSS 2005).
`®
`Mitoxantrone (Novantrone ) is an inhibitor of the enzyme DNA topoisomerase II which is responsible for
`uncoiling and repair of DNA in both dividing and nondividing cells. Because of concerns over cardiotoxicity this
`2
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`2
`agent may only be used up to a cumulative lifetime dose of ≥140 mg/m (equivalent to about 11 doses) (Anon.
`2005b). It is administered intravenously and due to toxic adverse effects it is generally reserved for the more
`progressive forms of the disease. Thus it is indicated for the treatment of worsening RRMS, SPMS, and PRMS.
`Recently, marketing of natalizumab (a humanized alfa-4 integrin antagonist) has been suspended because of
`reports of two serious adverse events (two cases of progressive multifocal leukoencephalopathy, one proving
`fatal). This agent had previously received accelerated approval in the USA in November 2004 for reducing the
`frequency of exacerbations in patients with RRMS after 1 year of treatment (FDA 2005).
`
`The National Multiple Sclerosis Society (NMSS) has revised its consensus guidelines on the use of disease-
`modifying agents including interferon beta and glatiramer (NMSS 2005). The recommendations specify the use
`of the following four immunomodulators: interferon beta-1a (intramuscular), interferon beta-1a (subcutaneous),
`interferon beta-1b, and glatiramer acetate for all relapsing forms of multiple sclerosis and consideration of their
`use for selected patients with a first attack or who are at high risk of multiple sclerosis. Therefore, therapy is
`appropriate in all relapsing patients, those with SPMS, PPRS, and many patients experiencing a first attack,
`providing that no contraindication exists.
`
`All of the agents approved for the treatment of RRMS have been shown to reduce relapse rates in large-scale,
`randomized, double-blind, placebo-controlled, prospective trials (reviewed in Goodin et al. 2002). Both
`interferon beta-1a formulations have achieved reductions in sustained disability progression in relapsing multiple
`sclerosis when used during the early phase of the disease. For example, positive results have been obtained from
`a number of separate 2-year placebo-controlled clinical trials involving patients with RRMS treated with the
`three interferon beta agents. In summary, interferon-beta treatment significantly reduced the relapse rate by 30 to
`37% compared with placebo treatment (interferon beta-treated patient relapse rates ranged from 0.61 to 0.78 and
`placebo-treated rates from 0.9 to 1.2 relapses per year) (Compston & Coles 2002). This change in relapse rate
`was also associated with a reduction in the accumulation of disability with the two interferon beta-1a (but not the
`interferon beta-1b) preparations.
`
`In RRMS glatiramer acetate, mitoxantrone, and azathioprine all reduce relapse frequency and the accumulation
`of disability. Glatiramer acetate is a random polypeptide composed of four L-amino acids (glutamic acid, lysine,
`alanine, and tyrosine). Results from a placebo-controlled study involving 251 patients with RRMS showed that
`treatment with glatiramer acetate significantly reduced the clinical attack rate over a 2-year period by 27%
`(P=0.007 vs placebo) (reviewed in Goodin et al. 2002). The indications for the use of glatiramer acetate are
`comparable to those for interferon beta and it is appropriate to consider it for treatment in any patient with RRMS
`(Goodin et al. 2002). For those patients who fail to adequately respond to the disease-modifying agents, the only
`therapeutic option is to consider intensive immunosuppression with cytostatic agents or even autologous stem
`cell transplantation (Kappos et al. 2004).
`
`Disease-modifying agents that can be started and continued on a long-term basis are referred to as “platform
`therapies.” Key characteristics of an ideal agent used for platform therapy are maximal efficacy, safety,
`tolerability, convenience, and low rates of neutralizing antibody formation (neutralizing antibodies formed in the
`body may block or neutralize the biologic effects of the foreign protein or polypeptide, potentially decreasing the
`therapeutic effects of these agents) (Stuart et al. 2004). During periods of increased disease activity or instability
`other treatments (e.g. corticosteroids and immunosuppressants) may be used with platform therapy. Although
`almost all patients who recover from relapses do so spontaneously to some degree, most clinicians recommend
`treating a relapse if it has a significant effect on function (Polman & Uitdehaag 2000). Corticosteroids have been
`the first-choice agent for this role for a number of years and although they shorten the duration of relapse and
`hasten recovery it is unclear whether they affect the overall degree of recovery or alter the course of the disease.
`
`In summary, disease-modifying agents have beneficial effects on relapse rates, relapse-related disability, and MRI
`outcomes. These effects are more pronounced early in the course of the disease, are long lasting, and have no
`rebound effects (Kappos et al. 2004). Nevertheless these treatments are only partially effective; they are
`
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`administered parenterally and although they are generally well tolerated there are some safety issues to be aware
`of (e.g. potential cardiotoxicity with mitoxantrone).
`
`Unmet needs
`One of the most important objectives of successful therapy for multiple sclerosis is the prevention or
`postponement of long-term disability. Typically, disability may evolve slowly over many years; however, most
`clinical trials are conducted for relatively short periods and only short-term outcome measures (e.g. attack rates
`and MRI measures to establish that treatment at least reduces the biologic activity of multiple sclerosis) are used.
`Therefore, it is important that any short-term measure is validated based on actual long-term patient outcomes
`(e.g. reduction in disability). Indeed, there is some uncertainty as to the relationship between the attack rate and
`long-term disability. It has been suggested that reducing short-term attack rate measures may not be associated
`with a delay in the accrual of disability in multiple sclerosis (reviewed in Goodin et al. 2002).
`
`Go to:
`
`Based on results from a number of large, well-designed clinical trials it is generally accepted that interferon beta
`(1b or 1a) is the treatment of choice for patients with RRMS (Polman & Uitdehaag 2000; Stuart 2004; Stuart et
`al. 2004). Nevertheless, there are still some unresolved issues relating to its use including optimal timing for the
`initiation and cessation of treatment; optimal dose, frequency, and route of administration; long-term effects of
`treatment; occurrence and relevance of neutralizing antibodies; and cost (Polman & Uitdehaag 2000). In addition,
`up to 60% of patients experience influenza-like symptoms (including fever, chills, myalgia, and headache) with
`interferon beta (Calabresi 2004). The first-line choice for the treatment of SPMS is interferon beta; mitoxantrone
`or cyclophosphamide may be considered as second-line treatments for progressive disease. There are no
`established therapies for either PPMS or PRMS (Kieseier & Hartung 2003).
`
`Multiple sclerosis has a profound effect on patients’ quality of life and it is important to determine the effect of
`any treatment on this parameter. At present, no study has measured this as a specific outcome of treatment.
`Instead, because the disease has been shown to be modified by treatment (e.g. reduced relapse rates and
`improvements in disability) this has led to the inference that quality of life outcomes are likely to be improved by
`these agents (NMSS 2005). However, this issue may be addressed through the use of a suitably valid and reliable
`quality of life instrument [e.g. the Multiple Sclerosis Impact Scale (MSIS29)].
`
`Nevertheless, the management of multiple sclerosis has greatly benefited from the development of new disease-
`modifying agents such as interferon beta and glatiramer acetate as prior to their introduction there were no
`effective therapies. But, despite their widespread availability, they are still only partially effective (in terms of
`reductions in relapse rates, relapse-related disability, and imaging outcomes) in the treatment of multiple
`sclerosis, and all the currently available disease-modifying agents must be administered parenterally either by
`self-administration or under medical supervision. In addition, there is no agent currently available that is able to
`stop the disease process. Therefore, characteristics of an ideal agent for the treatment of multiple sclerosis would
`include oral administration (for convenience), clinically significant effects on disease- and patient-oriented
`outcomes, limitation of the disease process and reduced disability, and good tolerability.
`
`Drug review
`Much progress has been made on the immunopathogenesis of the disease and many new promising therapeutic
`agents are currently in development. In general, these agents can be broadly categorized into either nonselective
`(antigen-nonspecific) or selective (antigen-specific) therapies (Hohlfeld & Wekerle 2004). FTY720 (Fig. 2) is a
`new nonselective therapeutic agent in development for treatment of multiple sclerosis and will be reviewed in
`detail below. It is a novel, orally active compound derived from ISP-1 (myriocin), a fungal metabolite from
`Isaria sinclairii that was a remedy for “eternal youth” in traditional Chinese herbal medicine (Fujita et al. 1994).
`FTY720 is being developed by Novartis Pharma AG in the areas of transplantation and autoimmunity.
`
`Go to:
`
`Fig. 2
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`Structure of FTY720 and related compounds (adapted with permission from
`2002)
`
`Mode of action of FTY720
`FTY720 elicits lymphocyte sequestration by facilitating a reversible redistribution of lymphocytes from the
`circulation to secondary lymphoid tissues. This is a unique immunomodulation mechanism whereby T
`lymphocytes are effectively directed away from inflammatory sites toward the lymphatic system. Because of the
`structural similarity between FTY720 and sphingosine (a major component of the sphingolipids found in
`mammalian cell membranes; Fig. 2) it has been suggested that the drug may interact with sphingosine receptors
`(Brinkmann et al. 2002). Evidence suggests that FTY720 is phosphorylated in vivo via sphingosine kinase to give
`FTY720-phosphate (FTY720-P) which then participates in the sphingosine 1-phosphate (S1P) signaling cascade
`(Brinkmann & Lynch 2002; Brinkmann et al. 2002).
`
`S1P stimulates multiple cell signaling pathways by interacting with five (G-protein coupled) receptors, S1P
`1–5
`Distribution of these receptors shows that S1P
` receptors are widely expressed whereas the S1P receptor is
`1–3
`4
`specific to lymphoid tissue and S1P is found in the spleen and white matter tracts of the central nervous system
`5
`(Brinkmann & Lynch 2002). FTY720-P interacts as a high-affinity agonist at four of the five S1P receptors (S1P
`and S1P
`) (Brinkmann et al. 2002).
`3–5
`
`.
`
`1
`
`Orally administered FTY720 is effective in a
`Evidence of activity in animal models of multiple sclerosis
`number of preclinical models of transplant rejection and autoimmune disease. The experimental autoimmune
`encephalomyelitis (EAE) model is one of the most widely used animal models of multiple sclerosis mimicking a
`number of pathologic characteristics of the disease. In a rat model, orally administered FTY720 0.3 mg/kg per
`day prevented the development of EAE, as assessed by clinical disease score (Brinkmann et al. 2002). In another
`study using a rat model of EAE, oral FTY720 (0.3–1 mg/kg per day) completely eradicated inflammatory lesions
`in the central nervous system, as detected by either histology or MRI (Fujino et al. 2003; Rausch et al. 2004).
`Furthermore, when compared with control-treated animals in this study, FTY720 protected against both
`neurologic impairment and inflammatory lesions during the acute phase of the disease and subsequent first
`relapse (Rausch et al. 2004). These encouraging results suggest that FTY720 may be a promising candidate for
`clinical studies in the treatment of multiple sclerosis.
`
`Outcomes achieved with FTY720
`Pharmacokinetic and pharmacodynamic outcomes following single- or multiple-dose administration of FTY720
`have been determined in both healthy subjects and transplantation patients (Table 3). These data are included
`here as these outcomes are not affected by disease status and may be extrapolated to include those patients with
`multiple sclerosis.
`
`Table 3
`Summary of pharmacodynamic and pharmacokinetic outcomes for
`FTY720
`
`Results from a number of clinical studies have shown that FTY720 produces
`Pharmacodynamic outcomes
`profound and reversible immunomodulation following oral administration. The mechanism of action of FTY720
`leads to a reversible redistribution of lymphocytes from the circulation to secondary lymphatic tissue. The
`resulting lymphocyte sequestration is a convenient surrogate marker of the pharmacodynamic effect of FTY720
`and may be a useful parameter for monitoring the immunomodulatory effect of the drug in the clinic.
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`There is substantial evidence that lymphocyte sequestration develops in healthy volunteers and renal transplant
`patients treated with FTY720 (Table 3). Administration of a single oral dose of FTY720 1 mg to 14 healthy
`volunteers resulted in a 38% reduction in the number of peripheral blood lymphocytes 2 days postdose (Kovarik
`et al. 2004b). In another study, the same dose led to a 44% reduction in the number of blood lymphocytes in 32
`subjects with or without hepatic impairment (Kovarik et al. 2005). A similar effect was also seen in a phase I
`study after single-dose administration of FTY720 (0.25–3.5 mg) to 20 stable renal transplant patients receiving a
`cyclosporine-based regimen (Budde et al. 2002). Although the higher doses of FTY720 produced a more rapid
`and sustained lymphocyte sequestration, the actual degree of this property was similar across the range of doses
`used in the study and no clear dose–response relationship was detected. An analysis of the subsets of
`lymphocytes sensitive to FTY720 was also performed in this study. The effect of FTY720 was seen across all
`lymphocyte subsets except for natural killer cells. As early as 4 h postdose, profound effects on the different
`lymphocytes subsets were seen, with CD4+ and naïve T-lymphocyte counts decreasing to the greatest extent
`(Budde et al. 2003).
`
`The profound lymphocyte sequestration observed with multiple doses of FTY720 has also been shown to be
`reversible after cessation of drug treatment. For example, in a placebo-controlled study lymphocyte counts
`decreased by 80 and 88% in healthy subjects receiving orally administered FTY720 1.25 or 5 mg/day,
`respectively (Kovarik et al. 2004a). The lymphocyte counts were reduced at the first postdose sampling time
`point on day 2. During the washout phase (between days 9 and 35) the lymphocyte counts recovered towards
`baseline values. Similar outcomes were also seen in a study with patients treated with FTY720 0.25–2.5 mg/day
`for 12 weeks following renal transplantation (Park et al. 2005). FTY720-induced lymphocyte sequestration was
`observed during the first week of treatment and the nadir was reached by week 4. This effect was fully reversed
`4–8 weeks after stopping treatment.
`
`The pharmacokinetic parameters of FTY720 are not influenced by disease status
`Pharmacokinetic outcomes
`and therefore these outcomes that have been derived from studies in healthy volunteers and transplant recipients
`are valid for patients with multiple sclerosis.
`
`Results from a number of phase I studies with FTY720 have shown that the pharmacokinetic parameters
`following daily oral administration are predictable and are not influenced by food intake or impaired hepatic
`function (Table 3). Therefore, oral administration of FTY720 is likely to be convenient and require minimal dose
`adjustment when used in the clinic.
`
`There is substantial evidence to show that following oral administration the absorption phase of FTY720 is
`prolonged, characterized by a t
` of >12 h (Budde et al. 2002; Kovarik et al. 2004a,b, 2005). The
`max
`pharmacokinetic parameters of FTY720 are similar in healthy subjects and transplant recipients (Kovarik et a