“m Check for updates
`
`Review
`Therapeutic Advances in Neurologicai Disorders
`
`Current and emerging therapies in
`multiple sclerosis: a systematic review
`
`Wanda Castro-Barrera. Donna Graves. Teresa C. Frohman. Angela Bates Flores, Paula
`Herdsman. Diana Logan, Megan Orchard. Benjamin Greenberg and Elliot M. Frohman
`
`Thar Adv Naomi Disord
`{2012] Silt} 205—220
`DOI:'|D.11'17I
`l756285612lz50936
`© The Authoris], 2012.
`Reprints and permissions:
`hillewwwsagepubiCduk/
`journalsPermissionsnav
`
`Abstract: Multiple sclerosis [MS] is a potentially disabling chronic autoimmune neurological
`disease that mainly affects young adults. Our understanding of the pathophysiology of MS has
`significantly advanced in the past quarter of a century. This has led to the development of many
`disease-modifying therapies iDMTs] that prevent exacerbations and new lesions in patients
`with relapsing remitting MS iRRMS]. So far there is no drug available that can completely halt
`the neurodegenerative changes associated with the disease. it is the purpose of this review to
`provide concise information regarding mechanism of action. indications. side effects and safety
`of Food and Drug Administration and European Medicines Agency approved agents for MS.
`emerging therapies. and drugs that can be considered for off-label use in MS.
`
`Keywords: disease-modifying therapies. emerging therapies. fingolimod. glatiramer acetate.
`interferon B, multipte scterosis. natalizumab
`
`Introduction
`
`is a chronic autoim—
`Multiple sclerosis (MS)
`mune inflammatory disease of the central nerv-
`ous system (CNS) that mainly affects young
`adults and may lead to significant disability over
`time. Since the first documented case of MS in the
`nineteenth century the knowledge regarding the
`pathophysiology of the disease has significantly
`advanced. The inflammatory cells in MS have
`been well described and include CD4 and CD8
`
`T lymphocytes, microglia and macrophages
`{Govermam 2011]. Also humoral immunity has
`been described as an important component in
`the pathophysiology of MS [Boater et al. 2010].
`
`Within the past 30 years new and effective
`therapies have been developed that decreased
`clinical relapses, reduced newT2 and gadolinium—
`enhancing (Gad+) lesions and aim to halt the
`progression of disease. Since the US Food and
`Drug Administration (FDA) approval of the first
`disease-modifying therapy (DMT)
`in 1993,
`interferon (IFN)—i31b (Betaseron), which was
`also approved in Europe in 1995 under the name
`of Betaferon, we now have a total of eight FDA—
`approved therapies for MS, including an oral
`agent and a single agent approved for secondary
`progressive MS (SPMS) (Table 1). Of note, there
`
`are two agents approved by the European
`Medicines Agency (EMA) for the treatment of
`SPMS, mitoxantrone and iFN—Blb (Betaferon/
`Extavia). All first-line iniectable agents have
`been studied in clinically isolated syndrome
`(CIS) and have demonstrated decreased risk of
`conversion into clinically definite MS (CDMS)
`(Table 2) [Kappos er a]. 2006; Jacobs er al. 20003
`Comi et al. 2001, 2009, 2012a]. So far there is
`no effective therapy to halt progression of disease
`and reduce disability in primary progressive MS
`(PPMS).
`
`There are many new agents in the pipeline which
`will bring great choices into the MS pharmaco—
`logical armamentarium (Table 3).
`
`Correspondence to;
`Wanda Castro-Borrero, MD
`University of Connecticut
`Health Center.
`Neurology Associates,
`263 Farmington Ave.
`Farmington. CT 0603!]-
`5357. USA
`weastrolauchcmdu
`Donna Graves. MD.
`Teresa C.Frohrnal1. PAC,
`Angeta Bales Flores, MD,
`Paula Herdsman, PAC.
`Diana Logan. RN,
`FNP-C. BC, MSCN,
`Hagan Orchard. PAC.
`Ianjamtn Greenherg.
`MD. HHS
`Elliot M. Frohman.
`MD. PhD
`University of Texas
`Southwestern Medical
`Center, Mutlipte Scterosis
`Program. Dallas. TX. USA
`
`FDA- and EMA-approved therapies
`
`Interferon ,6
`IFNs are a family of proteins that play a role in
`the body’s natural defense against microbial, neo-
`plastic and viral insults and have a rote in regu—
`lating the immune response. IFN—B impacts the
`immune system in several ways, such as decreas—
`ing major histocompatibility complex (MHC)
`class II expression, upregulation of interleukin 10
`
`
`
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`Page 1 of 16
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`.Ireomgenqfig
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`a
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`Biogen Exhibit 2225
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`Mylan v. Biogen
`IPR 2018-01403
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`Biogen Exhibit 2225
`Mylan v. Biogen
`IPR 2018-01403
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`

`

`Therapeutic Advances in Neurological Disorders 5 (4]
`
`Table 1. Current Food and Drug Administration/European Medicines Agency approved therapies for multiple
`sclerosis [MS]
`Wanton
`y
`
`. (
`
`IL—10) production, and decreasedT helper (Tm-1
`and Thl'? production, which leads to an overail
`anti—inflammatory effect [Kieseien 2011; Kappos
`at al. 2007].
`
`Subcutaneous interferon [31b fBetaseron, Bayer
`Scherr'ng Pharma AG/Betaferon. Bayer Schering
`Pharma AG/Extavia, Novartis Pharmaceuticals
`Corp). The pivotal phase III trial using IFN—Blb
`was a randomized, double—blind, placebo—con—
`trolled, multicenter trial of 372 patients with
`RRMS over 2 years. This trial demonstrated a
`34% reduction in overall relapses compared with
`placebo. More specifically, there was a 50% reduc—
`tion in annuah'zed relapses classified as moderate
`to severe in the treatment group. Patients receiv-
`ing IFN—Blb were also found to have a lower T2
`
`lesion volume and decreased accumulation of new
`
`lesions [IFNB Multiple Sclerosis Study Group.
`1993]. Each of the IFN-B therapies, as well as
`glatiramer acetate, has been shown to delay conn
`version to CDMS in patients with C18 (Table 2).
`In the 5-year active treatment extension of the
`BENEFIT trial, the effects of early versus delayed
`treatment with IFN Blb were investigated. This
`study showed the risk of conversion to CDMS
`remained lower in the group receiving early treat—
`ment; 46% compared with 57% of patients con-
`verting from CIS to CDMS [hazard ratio (HR)
`0.63; 95% confidence interval (CI) 0.48—0.83; log
`rank test p = 0.003) [Kappos at (212009}.
`
`intramuscular interferon flia lAvonex, Biogen ldec,
`Inc).
`In the pivotal trial including 30} patients
`
`W 2
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`W Castro-Borrero, D Graves et at.
`
`
`Table 2. Pivotal tria
`
`
`
`
`
`yaw /.
`
`v .
`
`'
`
`a.
`
`
`
`with RRMS, IFN-Bla intramuscularly was shown
`to delay time to progression of disability with
`fewer treated subjects experiencing disability pro—
`gression (21.9% versus 34.9%; p = 0.02) com—
`pared with placebo. Annualized relapse rates
`(ARRs) over a 2-year period were also lower com—
`pared with placebo (ARR 0.61 versus 0.90; p =
`0.03).The accumulation of Gad+ lesions was also
`reduced; however, T2 lesion volume was not sig-
`nificantiy different between the two groups at 2
`years Uacobs at al. 1996].
`
`Subcutaneous interferon 131a {Rebifi EMD Serena,
`Inc). The Prevention of Relapses and Disabil-
`ity by Interferon B—la Subcutaneously in Mul—
`tiple Sclerosis
`(PRISMS)
`trial was a 2—year
`randomized, double-blind, placebo-controlled,
`multimcentered trial of 560 patients with RRMS.
`Subjects treated with either the 22 or 44 ug dose
`of IFN—Bla subcutaneously showed a significant
`reduction in ARRs compared with placebo, 27%
`and 33% respectively. Both treatment groups
`showed a significant reduction in the number of
`new or enlarging T2 lesions; 67% reduction in
`the 22 ug group and 78% reduction in the 44 ug
`group [PRISMS Study Group, 1998]. An exten-
`sion study utilizing a crossover design in which
`placebo-treated patients were randomized to
`
`either 22 or 44 ug of IFN~f31a subcutaneously
`after 2 years revealed patients in both active
`
`treatment groups for the entire 4 years contin—
`ued to show significantly lower number ofrelapses
`per year EPRISMS Study Group, 2001]. IFNs
`have immunogenic properties and treated indi-
`viduals may develop binding and neutralizing
`antibodies (NAbs) to these products. NAbs may
`develop with the use of all formulations of IFN—
`{3; however, they are found more commonly with
`the high-dose, high-frequency IFNs (IFN—Blb
`and IFN—Bla subcutaneously). The issue of
`NAbs is controversial; however, a panel of
`experts met at the Neutralizing Antibodies on
`Interferon Beta in Multiple Sclerosis (NABI-
`NMS) consortium in 2009 in attempts to for-
`mulate a practical approach to the evaluation
`and incorporation of information regarding
`NAbs in the treatment of MS. The group pro—
`posed that both the NAb titer and clinical status
`of the patient should be considered in the deci-
`sion regarding the impact of the presence of
`NAbs on changing DMTs. They also suggested
`reevaluation of the NAbs status prior to making
`a change in therapy unless patients were clearly
`performing poorly clinicaliy {Poiman er a1. 2010].
`
`Glatiramer acetate
`
`Glatiramer acetate (GA) (Copaxone,Teva Neuro-
`science North America / Teva Pharmaceuticals)
`is a first—line therapy for relapsing forms of MS
`
`W h
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`ttp:/Jtan.sagepub.com
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`207
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`W Castro-Borrero, D Graves et at.W
`
`
`
`blocking direct immunologic attack. It was in the
`late 1980s that the immunologic concept ofTh1
`(proinflammatory) and T112 (anti—inflammatory)
`lymphocytes gained momentum.These two types
`of lymphocytes can be identified by the chemicals
`that they manufacture and then secrete. These
`chemicals are known as cytokines, and can be
`divided into inflammatory and proinflammatory.
`In 1997, Aharoni and colleagues published a
`paper that described how GA could stimulate the
`production ofThZ (anti~inflammatory) cells that
`inhibited the inflammatory response by secret—
`ing anti—inflammatory cytokines [Aharoni er a1.
`1997]. The GAs’ effect begins in the peripheral
`tissues in a population of specific lymphocytes
`which circulate in the blood and are capable of
`migrating into the CNS tissue by crossing the
`blood—brain barrier (BBB). These cells then
`encounter fragments of several myelin proteins
`that stimulate the glatiramer cells to multiply and
`begin to produce anti—inflammatory cytokines.
`Since the glatirameruactivated lymphocytes can
`suppress inflammation under way in the diseased
`area of CNS tissue, this process has been given
`the name bystander suppression Uohnson, 2010}.
`To date, data suggest that GA treatment is associ—
`ated with a broader immunomodulatory effect on
`cells of not only the innate but also the adaptive
`immune system. Recent investigations indicate
`that GA treatment may also promote regulatory
`Bncell properties [Lalive er al. 2011].
`
`GA has a relatively narrow adverse effect profile.
`Most frequently patients complain of mild pain
`and pruritis at the injection site. Lipoatrophy and
`skin sire reactions are also seen and may lead to
`discontinuation of therapy. A transient reaction
`called immediate postinjection reaction consists
`of chest tightness, flushing and dyspnea begin—
`ning soon after the injection and lasting no longer
`than 20 min. If no history or evidence of coronary
`artery disease, the patient can be reassured that
`such a reaction is benign [DiPiro er al. 2005].
`
`Multicenter trials with GA have demonstrated
`statistically significant reducu'ons in mean ARR
`that are comparable to those of the IFNs {DiPiro
`er al. 2005]. In two recent studies the efficacy of
`GA was compared with high—dose/highnfi'equency
`IFN—B. In the Rebif versus Glatiratner Acetate in
`Relapsing MS Disease (REGARD) study [Mikol
`er al. 2008}, subcutaneous IFN—B 1 a was compared
`with GA, and in the Betaseron/Betaferon Efficacy
`Yielding Outcomes of a New Dose (BEYOND)
`study [O’Connor
`er al. 2009], subcutaneous
`
`IFN—Blb was compared with GA. In both trials,
`there was no significant difference between IFN
`and GA in the primary endpoints or in any clini—
`cal endpoints, although some differences in mag—
`netic resonance imaging (MRI) measures of
`disease activity have been claimed.
`
`The results from a 15—year analysis of the US
`prospective open-label study of GA indicate that
`long-term continuous use is safe. It also indicates
`that the majority of patients continuing on GA
`therapy in the study have had few relapses and
`minimal disease progression. Of the initial 232
`patients that received at ieast one GA dose since
`study initiation in 1991, only we (43%, ongoing
`cohort) patients continued. Of the 100 patients
`receiving continuous GA as sole immunornodula—
`tory therapy for 15 years (mean disease duration
`of 22 years and mean patient age of 50 years) have
`not transitioned to SPMS, 57% have retained sta-
`ble or improved the Expanded Disability Status
`Scale (EDSS) scores over the course of the study
`and 82% remain ambulatory without mobility aids.
`There was no occurrence of any unforeseen adverse
`events in patients receiving GA therapy.The study
`will continue for 20 years of prospective follow up
`[Ford er a1. 2010] .
`
`Mitoxantrone
`
`Mitoxantrone is an anthracenedione initially
`developed as an anti-neoplastic agent that reduces
`lymphocyte proliferation. Mitoxantrone interca—
`lates into DNA strands, inducing strand breakage
`and inhibition of the DNA repair enzyme topoi-
`somerase II. It is an immunosuppressive agent
`used as a second—line treatment for SPMS, pri—
`mary relapsing multiple sclerosis and worsening
`RRMS. Mitoxantrone was approved for the treat—
`ment of SPMS based on the study by Hartung
`and colleagues {Harmng er al. 2002].
`
`Several studies have shown it to be efficacious in
`reducing exacerbations and number of Gad-I-
`lesions on MRI, and it seems to have elfects on
`disease course up to 5 years after discontinuing
`therapy [Martinelli at al. 2009; Goodin er a1. 2003].
`Nlitoxantrone is given as an intravenous infusion
`over 30 min every 3 months at 12 mg/rn2 for a 2—
`to 3—year period with a maximum cumulative dose
`of 140 mymz. Common side effects include alo-
`pecia, nausea and vomiting, an increased risk of
`infection (particularly urinary and respiratory
`tracts infections) and amenorrhea. Mitoxantrone,
`though eiifective, remains second line due to its
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`Therapeutic Advances in Neurological Disorders 5 l4]
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`risk of two serious adverse efiects that can occur
`
`at any time after the first dose is given. The first,
`acute leukemia has an incidence of approximately
`0.81% [Marriott er a1. 2010}. Regular monitor—
`ing of complete blood counts is recommended.
`Mitoxantrone can also cause decreased left ven~
`
`tricular ejection fraction (LVEF) and congestive
`heart failure at a rate of approximately 12% and
`0.4%, respectively [Marriott at at. 2010]. To
`monitor cardiotoxicity, a baseline LVEF must be
`obtained and any patient with an ejection fraction
`less than 50% should not receive mitoxantrone.
`
`It was previously believed that cardiotoxicity could
`only occur with cumulative doses over 96-140
`m m3; however, several reports of cardiotoxicity
`below this threshold have caused the FDA to rec—
`
`ommend monitoring cardiac function before every
`infusion.The therapy must be discontinued if the
`LVEF ever falls below 50% or decreases by 10%
`[Martinelli er al. 2009].
`
`Natalizumab
`
`Migration of leukocytes from the vasculature
`into the parenchyma involves the interaction
`between leukocyte adhesion molecules and their
`complementary ligands on vascular endothelial
`cells. Leukocyte integrins are heterodimeric gly—
`coproteins
`that contain an or and {3 chain
`[Ransohoffi 2007].Vascular cell adhesion mole-
`cule 1 CVCAM—l) is expressed on the surface of
`vascular endothelial cells in the blood vessels
`
`within the CNS and interacts with 004431 integrin
`on lymphocytes to allow for extravasation across
`the BBB. Also, the interaction of ot4l31 integrin
`with fibronectin and osteopontin may modulate
`the survival, priming and activation of leukocytes
`that have entered into the parenchyma of the
`brain and spinal cord. Natalizumab (Tysabri,
`Biogen Idec, Inc.) contains humanized immuno—
`globulin G4K monoclonal antibodies against leu—
`kocyte d4 integrins, including Q40] and 0.407
`integrins, and blocks binding to their endothelial
`receptors (VCAM—1 and mucosal addressin cell
`adhesion molecule l, respectively) [Polman er al.
`2006]. By blocking d4 integrins, natalizumab
`inhibits the migration of leukocytes into the
`brain, which results in reduced inflammation.
`
`Natalizurnab was evaluated for the treatment
`of RRMS in two phase III clinical trials. The
`Natalizumab Safety and Efficacy in relapsing
`remitting multiple sclerosis (AFFIRM) study
`evaluated 942 patients who were randomly
`assigned to receive natalizumab versus placebo
`
`every 4 weeks for 2 years. The primary endpoints
`were the rate of clinical relapse at 1 year and
`the rate of sustained progression of disability,
`measured by the EDSS, at 2 years. Natalizumab
`reduced the risk of sustained disability by 42%
`over 2 years (HR 0.58; 95% CI 0.43—0.77; 13 <
`0.001). It reduced the rate of clinical relapse at
`1 year by 68% (p < 0.001). MRI scans were
`obtained at baseline, 1 year and 2 years.Treatment
`with natalizumab resulted in an 83% reduction of
`
`new or enlarging hyperintense T2 lesions over 2
`years (mean number of lesions 1.9 with natali—
`zumab and 11 with placebo; 13 < 0.001). There
`were 92% fewer Gad+ lesions in the natalizumab
`
`group than in the placebo group at 1 and 2 years
`(p < 0.001).There was also a significant effect on
`Gad+ lesions seen after 6 weeks of natalizumab
`
`treatment [Polman er al. 2006].
`
`The Safety and Eflicacy of Natalizumab in com—
`bination with IFN—fila in patients with RRMS
`(SENTINEL) trial was a 2—year phase III trial
`evaluating treatment with natalizumab or placebo
`in combination with IFN—Bla. The primary end"
`points were the rate of clinical relapse at 1 year
`and accumulative probability of disability pro«
`gression, measured by the EDSS, at 2 years. The
`study showed that treatment with both drugs was
`more effective than treatment with IFN—Bla
`alone. Patients on combination treatment were
`
`less likely to have sustained disability progression
`(23% oersus 29%) and were more likely to remain
`relapse free (61% versus 37%). Combination
`treatment resulted in fewer new or enlarging T2
`lesions (0.9 versus 5.45 p < 0.001) [Rudick er a1.
`2006].The study ended a month early due to the
`occurrence of progressive multifocal
`leukoen—
`cephalopathy (PML) in two patients who received
`natalizumab with IFN—Bla.
`
`The most notable potential adverse effect of natal—
`izumab treatment is the development of PML.
`Following the observation that
`three patients
`treated with natalizumab developed PML, it was
`withdrawn from the market in February 2005
`and reintroduced in July 2006 as monotherapy
`treatment for RRMS. The original risk of PML
`was estimated to be approximately one per 1000
`patients receiving nataliznmab [Berger, 2010]. As
`of 4 January 2012, approximately 96,582 patients
`have received natalizumab since it was marketed
`and there have been 201 confirmed cases of PML
`
`worldwide. Approximately 20% of patients who
`have developed PML have died. Those that sur-
`vived have varying levels of disability, ranging
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`W Castro~Borrero, D Graves et at.M
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`from mild to severe. Fewer patients treated and
`wide confidence intervals result in questionable
`estimates beyond 30 months of treatment.
`
`PML is a rare demyelinating disease of the
`brain due to the John Cunningham (JC) virus. It
`is almost always seen in association with an
`underlying immunosuppressive condition. The
`precise explanation for the increased risk ofPML
`with natalizumab therapy remains unknown.
`
`In the natalizumab clinical trials, there was a
`small increase in the rate of infections, including
`herpes infections, pneumonia and urinary tract
`infections. There were no other opportunistic
`infections or increase cases of cancer reported
`[Ransohoff, 2007]. Post—release monitoring dis—
`closed one case of fatal herpes encephalitis,
`one nonfatal case of herpes meningitis, crypto—
`sporidium gastroenteritis, pneumocystis carinii
`pneumonia, varicella pneumonia and mycobac—
`terium avium intracellular complex pneumonia
`[Ransohoff, 20075 Gorelik at 111.2010].
`
`Natalizumab infusions were complicated by seri-
`ous hypersensitivity reactions,
`including fever,
`rash and anaphylaxis, in less than 1% of patients
`and less serious infusion reactions in about 4% of
`patients [Ransohoff, 2007; Polman er al. 20065
`Rudick et al. 2006]. Patients with infusion reac—
`tions were more likely to have persistent NAbs.
`The presence of antibodies lessoned natalizum-
`ab’s clinical efficacy and resulted in clinical and
`radiographic disease activity equivalent to patients
`in the placebo group [Ransohofifi 2007].
`
`Natalizumab is an extremely effective therapy
`for RRMS and is licensed for highly active naive
`patients. Due to the potential risk of PML and
`other opportunistic infections,
`it
`is
`typically
`reserved for patients with clinically or radio-
`graphically extremely active disease either as
`initial therapy or when initial therapy has been
`ineffective or poorly tolerated. Treatment with
`natalizumab requires rigorous ongoing clinical
`surveillance. To minimize the risk of PML,
`patients beginning treatment should have no
`history of immunosuppressive medications in
`the preceding 3 months and should not have
`other conditions that may compromise cell—
`mediated immunity. The FDA and EMA recw
`cmmend the use of the IC virus antibody for
`risk stratification on all patients onTysabri.The
`risk of PML increases after 24 months on ther-
`apy, if there has been prior immunosuppressant
`
`use and the presence of JC virus antibody.
`Patients with positive IC virus antibody, prior
`treatment with an immunosuppressant and who
`have received more than 24 doses of Tysabri
`have an estimated risk of PML of 9—11/1000.
`However, patients without any of those risk fac-
`tors for PML have a risk of PML of less than
`0.1 per 1000 [Sorensen er al. 2012].
`
`Fingolimod
`Fingolimod is an oral sphingosine—l phosphate
`(SIP) receptor modulator. It was approved by the
`FDA in September 2010 as first-line therapy for
`RRMS. However, the EMA has recommended
`that its use be limited to those whose condition
`fails to respond to first—line therapy or only in
`cases of severe, rapidly developing cases of MS. It
`acts as a sphingosine analogue, binding to the
`SIP] receptor on lymphocytes leading to inter~
`nalization and downregulation of their expression
`and thereby preventing the egression of lympho-
`cytes from the lymph nodesAdditionally, through
`interactions with SIP receptors on neural cells,
`fingolimod has been shown to have potentially
`neuroprotective effects in the animal experimen—
`tal autoimmune encephalomyelitis model [Foster
`er al. 2007; Coelho er al. 2007; Miron et at. 2008].
`
`In the 24—month phase III FTY720 Research
`Evaluating Effects of Daily Oral
`therapy in
`Multiple Sclerosis (FREEDOMS) trial compar—
`ing placebo with oral fingolimod at doses of 1.25
`mg and the now FDA—approved 0.5 mg daily
`dose, there was a significant reduction in ARR
`with both doses of fingolimod (0.16 at 1.25 mg
`and 0.18 at 0.5 mg) compared with placebo
`(0.40) which represented a relative reduction of
`60% and 54%, respectively. Furthermore, fingoli—
`mod also reduced the risk of disability progres—
`sion with a probability of disability progression
`(confirmed after 3 months) of 17.7% at the 0.5
`mg dose and 16.6% at the 1.25 mg dose com—
`pared with 24.1% with placebo. Almost 90% of
`patients receiving fingolimod, at either dose, were
`free of enhancing lesions over the course of 2
`years and approximately 50% were free of new or
`enlargingTZ lesions [Kappos et a1. 2010].
`
`The Trial Assessing Injectable Interferon "versus
`FTY720 Oral in RRMS (TRANSFORMS) com—
`paring fingolimod with intramuscular INF-131a
`showed a 52% relative reduction in ARR in the
`patients treated with fingolimod 0.5 mg versus
`IFN. This study showed a similar beneficial
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`Therapeutic Advances in Neurological Disorders 5 {4!
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`effect on MRI markers compared with IFN-Bla;
`however,
`there was no statistically significant
`difference in the disability progression between
`the fingolirnod and IFN—Bla groups [Cohen et al.
`2010].
`
`Despite its eficacy, there are additional safety
`concerns compared with the injectable therapies.
`Data from the two pivotal
`trials showed an
`increased risk of infections, cardiovascular effects,
`including bradycardia and atrioventricular (AV)
`block (first and second degree) with initial dosing
`and macular edema. Each of these was more
`
`common with the higher 1.25 mg dose. Of note,
`there were two deaths related to infections in sub-
`
`jects receiving fingolimod at the 1.25 mg dose in
`TRANSFORMS. One death was secondary to a
`dissemination varicella zoster infection and the
`
`second was related to herpes simplex encephalitis.
`While herpes virus infection has been seen at
`the 0.5 mg dose, cases tended to be mild and
`were not found to occur at a higher rate than the
`control arm [Cohen er a]. 2010].
`
`The EMA recently recommended increased
`patient monitoring during the first dose of fin-
`golimod, including electrocardiogram monitor-
`ing before treatment and then continuously for
`the first 6 h after the first dose is administered,
`and measurement of blood pressure and heart
`rate every hour over the same 6 h.
`
`Off—label therapies
`Immunosuppressive agents, chemotherapies and
`various mAbs have been used off label for many
`
`years as DMTs in MS but the potential benefits
`of these therapies are limited by systemic adverse
`events, such as increased risk of malignancy and
`opportunistic infections. These agents have been
`used in patients who are refractory to or cannot
`tolerate the side efi‘ects of IFN—[i and GA, cannot
`afford FDA-approved therapies, or need intensifi-
`cation of therapy (is. used in combination with
`IFN-B or GA). Also limiting the use of these med»
`ications is the lack of large-scale, controlled trials,
`validating their eficacy.
`
`which is the active metabolite. MA is a potent,
`selective, noncompetitive and reversible inhibitor
`of inosine 5' monophosphate dehydrogenase type
`II. MA inhibits the de novo synthesis pathway of
`guanosine nucleotides without being incorporated
`into DNA. Because '1‘ and B lymphocytes are
`critically dependent for their proliferation on de
`now synthesis of purines, while other cell types
`can utilize salvage pathways, MA has potent cyto—
`static effects on lymphocytes. MA inhibits prolif-
`erative responses ofT and B lymphocytes to both
`mitogenic and allospecific stimulation. MA also
`suppresses antibody formation by B lymphocytes
`[Product information: Cellcept, 2009].
`
`Potential side effects include hypertension, back”
`ache, abdominal pain, diarrhea, nausea, elevated
`transaminases, vomiting, anxiety and tremor.
`Serious side effects include gastrointestinal bleed—
`ing, thrombocytopenia, skin cancer, opportunistic
`infection and PML. Increased susceptibility to
`infection and the possible development of lym—
`phoma may result from immunosuppression.
`
`A retrospective review of experience in treating
`79 patients with MS with MMF showed that
`this agent was well tolerated by the majority of
`patients. Patients were initiated on 500 mg twice
`a day, which was titrated up by 500 mg weekly
`to a maximum of 1000 mg twice a day.While the
`observations were uncontrolled, some of the
`
`patients demonstrated either stabilization or
`improvements in their activities of daily living,
`ambulation and relapse rate [Frohman er al.
`2004]. In a randomized, MRI-blinded, parallel
`group, pilot trial of MMF compared with IFN—
`[513, both drugs appeared safe and well toler—
`ated in the majority of patients. The trial also
`showed a trend toward a lower accumulation of
`combined active MRI lesions. MMF showed a
`
`nonstatistically significant increase in infections
`[Frohman er al. 2010].The dose generally used
`in patients with RRIVIS is 1000 mg twice daily.
`Large, randomized clinical trials are needed to
`better evaluate the safety and efficacy of this
`agent in patients with MS.
`
`Mycophenolate mofetil
`Mycophenolate mofetil (MMF; Cellcept, Roche
`Laboratories, Nutley, N], USA) is FDA and EMA
`approved for preventing rejection of cardiac, liver
`and renal transplants. MMF undergoes rapid and
`complete metabolism to mycophenolic acid (MA),
`
`Azathioprine
`Azathioprine is FDA approved for rejection proph—
`ylaxis (as monotherapy or adjunct) of renal trans—
`plant and rheumatoid arthritis (RA). Although
`not FDA approved, it has been used in the USA
`to treat MS since 1971 [La Mantia er al. 2007].
`Azathioprine is
`licensed for MS therapy in
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`W Castro—Borrero. D Graves at at.W
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`Germany. Azathioprine is an imidazole derivative
`of 6—mercaptopurine and acts as an immunosup—
`pressive antimetabolite. It is a purine antagonist
`and afl‘ects DNA replication. It impairs T~cell
`lymphocyte function and is more selective for
`T lymphocytes than for B lymphocytes [Casetta
`at al. 2009].The Cochrane MS Group concluded
`that azathioprine is an appropriate maintenance
`treatment for patients with MS and could be a fair
`alternative to IFN. It is recommended that cumu-
`
`fatigue, headache, muscle
`fever,
`leucopenia,
`spasms and diarrhea. Cases of PML, severe
`mucocutaneous reactions, tumor lysis syndrome
`and fatal infusion reactions have been docu-
`mented. Other severe adverse reactions include
`
`fulminant hepatitis, hepatic failure, bacterial,
`fungal or viral infections, cardiac arrhythmias,
`renal toxicity and bowel obstruction or perfora—
`tion [Prescribing information, 2010].
`
`lative doses do not exceed 600 g due to possibly
`increasing the risk of malignancies [Casetta et at.
`2009].
`
`In a 72—week, open-label phase I trial the safety
`and tolerability of rituxirnab were evaluated in 26
`patients with RRMS. The authors indicated that
`
`Methotrexate
`
`Methotrexate (MTX) is a chemotherapeutic agent
`used for the treannent of severe psoriasis, juvenile
`RA ORA), severe RA, acute lymphoid leukemia
`and other malignancies. MTX reversibly inhibits
`dihydrofolate reductase.Via this mechanism, MTX
`sodium interferes with DNA synthesis, repair
`and cellular
`replication [Product
`information:
`methotrexate, 2000, 2005].
`
`On a systematic review of oral MTX for M8, for
`the Cochrane Multiple Sclerosis Group,
`the
`authors do not recommend the use of MTX for
`
`progressive MS or RRMS due to a lack of high—
`quality evidence. Future trials need to be performed
`using standard outcome measures and objective
`measures, such as MRI [Gray et al. 2004].
`
`Rituximab
`
`Ritnximab is FDA approved for the treatment of
`nonuHodgkin’s lymphoma, chronic lymphocytic
`leukemia, refractory moderate to severe RA,
`Wegener’s granulomatosis and microscopic pol—
`yangiitis [Prescribing information, 2010]. It is
`EMA approved for diffuse large B—cell
`lym—
`phoma and autoimmune arthritis. Rituximab is
`a chimeric murine/human mAb that targets and
`selectively binds CD20, an antigen present on
`pre-B cells and B cells, but not on antibody-
`producing plasma cells or stem cells in the bone
`marrow. By binding CD20, rituximab depletes
`circulating Bucell populations (but not stem cells
`or plasma cells) through a combination of cell—
`mediated and complementmdependent cytotox—
`icity and possibly promoting apoptosis [Bar—Or
`er al. 2008].
`
`Common side effects ofrituximab include naso—
`
`pharyngits, urinary tract
`
`infections, nausea,
`
`no serious adverse events were reported in this
`small cohort with active RRMS and all
`the
`adverse events including infections were mild to
`moderate and did not lead to medication with—
`drawal. No efficacy conclusions were noted due
`to the absence of a control group but they noticed
`a reduction in relapses, Gad+ lesions, new T2
`lesion number and T2 lesion volumes through
`72 weeks [Bar—Or er of. 2008]. In a phase II
`randomized, placebo-controlled trial with 104
`patients there was a reduction in Gad+ lesions
`
`and relapses in patients on rituximab oersus pla—
`cebo [Hauser er a1. 2008]. Rituximab has shown
`efficacy in the treatment of patients with RRMS.
`A recently completed randomized clinical trial
`using a standard dose of rituximab in patients with
`RRMS demonstrated a 91% reduction in the
`
`number of Gad+ lesions on MRI, as we