Emerging therapy review
`FTY720 in multiple sclerosis: the emerging evidence
`of its therapeutic value
`Andrew Thomson
`
`Core Medical Publishing, Knutsford, UK
`
`Abstract
`
`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.
`
`Key words: evidence-based review, FTY720, immunomodulator, multiple sclerosis
`
`Core emerging evidence summary for FTY720 in multiple sclerosis
`
`Outcome measure
`
`Patient-oriented evidence
`Disease relapse rates
`
`Convenient administration
`
`Tolerability
`
`Disease-oriented evidence
`Disease progression determined by
`magnetic resonance imaging
`Immunomodulation
`
`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
`
`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
`
`SUN - IPR2017-01929, Ex. 1005, p. 1 of 11
`
`

`

`FTY720 | emerging therapy review
`
`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.
`
`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.
`
`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 and
`included. Thus, a total of eight publications (six full papers and two
`meeting abstracts) were included in the evidence base.
`
`Disease overview
`
`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
`
`Table 1 | Evidence base included in the review
`
`Category
`
`Number of records
`
`Full papers
`
`Abstracts
`
`Initial search
`
`records excluded
`
`records included
`
`Additional studies identified
`
`Level 1 clinical evidence
`
`Level 2 clinical evidence
`
`Level ≥3 clinical evidence
`
`trials other than RCT
`
`case reports
`
`Economic evidence
`
`Total records included
`
`14
`
`14
`
`0
`
`6
`
`0
`
`5
`
`1
`
`0
`
`0
`
`0
`
`6
`
`2
`
`1
`
`1
`
`1
`
`0
`
`2
`
`0
`
`0
`
`0
`
`0
`
`2
`
`For definition of levels of evidence, see Editorial Information on inside back cover.
`RCT, randomized controlled trial.
`
`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
`
`158
`
`© 2006 Core Medical Publishing Limited
`
`SUN - IPR2017-01929, Ex. 1005, p. 2 of 11
`
`

`

`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
`
`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.
`
`FTY720 | emerging therapy review
`
`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).
`
`Classification
`
`Type of incidence
`at presentation
`
`Schematic typical
`of clinical course
`
`Relapsing remitting
`multiple sclerosis
`(RRMS)
`
`~85%
`
`Secondary progressive ~50% of patients
`multiple sclerosis
`with RRMS will
`(SPMS)
`progress to this
`subform
`
`Primary progressive
`multiple sclerosis
`(PPMS)
`
`~10%
`
`Progressive relapsing
`multiple sclerosis
`(PRMS)
`
`~5%
`
`Diagnosis
`
`The typical stimulus for patients to seek medical help is the first
`acute attack. An accurate clinical history and a thorough
`
`Fig. 1 | Classification, incidence, and examples of clinical
`courses of subtypes of multiple sclerosis (adapted with
`permission from Kieseier & Hartung 2003)
`
`Core Evidence 2006;1(3)
`
`159
`
`Time
`
`Time
`
`Time
`
`Time
`
`Severity
`
`Severity
`
`Severity
`
`Severity
`
`Time
`
`Time
`
`Time
`
`Time
`
`Severity
`
`Severity
`
`Severity
`
`Severity
`
`SUN - IPR2017-01929, Ex. 1005, p. 3 of 11
`
`

`

`FTY720 | emerging therapy review
`
`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).
`
`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).
`
`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
`(Rebif®) or
`interferon beta-1a
`for either subcutaneous
`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 agent may only be used up to a cumulative
`lifetime dose of ≥140 mg/m2 (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
`
`Table 2 | Disease course characteristics associated with the prognosis of multiple sclerosis
`
`Poor prognosis
`
`Good prognosis
`
`Motor involvement, in particular disturbed coordination or balance
`
`Sensory or visual symptoms dominate
`
`Onset of disease in older males
`
`Complete recovery from individual attacks
`
`Frequent and prolonged relapses with incomplete recovery within 2 years of disease onset
`
`Short interval between the initial episode and first relapse
`
`Onset of progressive phase
`
`160
`
`© 2006 Core Medical Publishing Limited
`
`SUN - IPR2017-01929, Ex. 1005, p. 4 of 11
`
`

`

`FTY720 | emerging therapy review
`
`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 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).
`
`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.
`
`Core Evidence 2006;1(3)
`
`161
`
`SUN - IPR2017-01929, Ex. 1005, p. 5 of 11
`
`

`

`FTY720 | emerging therapy review
`
`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.
`
`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, S1P1–5. Distribution of
`these receptors shows that S1P1–3
`receptors are widely
`
`Fig. 2 | Structure of FTY720 and related compounds (adapted
`with permission from Brinkmann et al. 2002)
`
`expressed whereas the S1P4 receptor is specific to lymphoid
`tissue and S1P5 is found in the spleen and white matter tracts of
`the central nervous system (Brinkmann & Lynch 2002). FTY720-P
`interacts as a high-affinity agonist at four of the five S1P receptors
`(S1P1 and S1P3–5) (Brinkmann et al. 2002).
`
`Evidence of activity in animal models of multiple sclerosis
`
`Orally administered FTY720 is effective in a 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.
`
`Pharmacodynamic outcomes
`
`Results from a number of clinical studies have shown that FTY720
`produces 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.
`
`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
`
`162
`
`© 2006 Core Medical Publishing Limited
`
`NH2
`
`HO
`
`HO
`
`NH2
`
`HO
`
`Sphingosine
`
`Sphingosine 1-phosphate
`
`HO
`
`O
`
`P
`O OH
`
`HO
`
`HO
`
`NH2
`
`O
`
`P
`
`HO
`
`OH
`
`O
`
`HO
`
`NH2
`
`FTY720
`
`FTY720-P (rac)
`
`SUN - IPR2017-01929, Ex. 1005, p. 6 of 11
`
`

`

`FTY720 | emerging therapy review
`
`Table 3 | Summary of pharmacodynamic and pharmacokinetic outcomes for FTY720
`
`Level of
`evidence
`2
`
`2
`
`2
`
`2
`
`3
`
`Outcomes
`
`FTY720 dosage
`
`Study design and population
`
`Reference
`
`1.25 (n=20) or 5 mg
`(n=20), or placebo
`(n=20) once daily for
`7 d
`
`Randomized, double-blind,
`placebo-controlled,
`multiple-dose study
`in 60 healthy volunteers
`(age range 18–44 y)
`
`Kovarik et al.
`2004a
`
`1 mg under fasting
`conditions or with
`a high-fat meal
`
`Randomized, two-period,
`crossover, single-dose
`study in 14 healthy male
`volunteers (age range
`20–39 y)
`
`Kovarik et al.
`2004b
`
`0.25 (n=6), 0.5 (n=6),
`0.75 (n=3), 1 (n=3),
`2 (n=3), or 3.5 mg
`(n=3), or placebo (n=8)
`
`Randomized, double-blind,
`placebo-controlled, two-center,
`single-dose study in 20 stable
`renal transplant patients (mean
`age 43.2 y)
`
`Budde et al.
`2002;
`Budde et al.
`2003
`
`Drug exposure on d 7 was dose proportional for Cmax (5.0±1.0
`vs 18.2±4.1 ng/mL)