B) Cheek for updates
`
`Review
`Therapeutic Advances in Neurological Disorders
`
`Current and emerging therapiesin
`multiple sclerosis: a systematic review
`
`Wanda Castro-Borrero, Donna Graves, Teresa C. Frohman, Angela Bates Flores, Paula
`Hardeman, Diana Logan, Megan Orchard, Benjamin Greenberg and Elliot M. Frohman
`
`Ther Adv Neurol Disord
`{2012] 5(4} 205-220
`DOM: 10,1177
`1756285612450934
`© The Authoris), 2012.
`Reprints and permissions:
`http./Avww.sagepub.ca.uk/
`journalsPermissions.nav
`
`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 {OMTs] that prevent exacerbations and new lesionsin patients
`with relapsing remitting MS (RRMS]. So far there is no drug available that can completely halt
`the neurodegenerative changes associated with the disease. it is the purposeof 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, multiple sclerosis, 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 maylead 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
`[Goverman, 2011]. Also humoral immunity has
`been described as an important component in
`the pathophysiology of MS [Boster et al. 2010].
`
`Within the past 30 years new and effective
`therapies have been developed that decreased
`clinical relapses, reduced new T2 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)-Blb (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-Bib (Betaferon/
`Extavia). All first-line injectable agents have
`been studied in clinically isolated syndrome
`(CIS) and have demonstrated decreased risk of
`conversion into clinically definite MS (CDMS)
`(Table 2) [Kapposet al, 2006; Jacobs et al. 2000;
`Comi ez 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 06030-
`9357, USA
`weastro@uchc.edu
`Donna Graves, MD,
`Teresa C. Frohman, PAC,
`Angela Bates Flores, MD,
`Paula Hardeman, PAC,
`Diana Logan, RN,
`FNP-€, BC, MSCN,
`Megan Orchard, PAC,
`Benjamin Greenberg,
`MD, MHS
`Elliot M. Frohman,
`MD, PhD
`Liniversity of Texas
`Southwestern Medical
`Center, Mullipie Sclerosis
`Program,Dallas, TX, USA
`
`FDA- and EMA-approved therapies
`
`interferon B
`IFNsare a family of proteins that play a role in
`the body’s natural defense against microbial, neo-
`plastic and viral insults and have a role in regu-
`lating the immune response, IFN-$ impacts the
`immune system in several ways, such as decreas-
`ing major histocompatibility complex (MHC)
`class IT expression, upregulation of interleukin 10
`
`
`
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`PE JoiG 8)bez F
`Zles
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`Biogen Exhibit 2225
`Mylanv. Biogen
`IPR 2018-01403
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`IPR 2018-01403
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`Therapeutic Advances in Neurological Disorders 5 (4)
`
`Table 1. Current Food and Drug Adrministration/European Medicines Agency approved therapies for multiple
`
`
`
`(IL-10) production, and decreasedT helper (Th)-1
`and Th17 production, which leads to an overall
`anti-inflammatory effect [Kieseier, 2011; Kappos
`et al. 2007].
`
`Subcutaneous interferon $1b ({Betaseron, Bayer
`Schering Pharma AG/Betaferon, Bayer Schering
`Pharma AG/Extavia, Novartis Pharmaceuticals
`Corp.). Thepivotal phaseIII trial using IFN-B1b
`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. Morespecifically, there was a 50% reduc-
`tion in annualized relapses classified as moderate
`to severe in the treatment group. Patients receiv-
`ing IFN-f1b 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-§ therapies, as well as
`glatiramer acetate, has been shown to delay con-
`version to CDMSin patients with CIS (Table 2).
`In the 5-year active treatment extension of the
`BENEFITtrial, the effects of early versus delayed
`treatment with IFN f1lb 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 CHR)
`0.63; 95% confidence interval (CI 0.48-0.83; log
`rank test p = 0.003) [Kapposet al.2009}.
`
`Intramuscularinterferon Bia [Avonex, Biogen Idec,
`Inc.).
`In the pivotal trial including 301 patients
`
`nmii
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`
`W Castro-Borrero, D Gravesef al,
`
`ee
`z
`ul Faas a
`
`
`
`with RRMS, IFN-$1a intramuscularly was shown
`to delay time to progression of disability with
`fewer treated subjects experiencingdisability 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 notsig-
`nificantly different between the two groups at 2
`years [Jacobs et al. 1996].
`
`Subcutaneous interferon Bla {Rebif, EMD Serono,
`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,
`multi-centered trial of 560 patients with RRMS.
`Subjects treated with either the 22 or 44 yp dose
`of FFN-B1a subcutaneously showed a significant
`reduction in ARRs compared with placebo, 27%
`and 33% respectively. Both treatment groups
`showeda significant reduction in the numberof
`new or enlarging T2 lesions; 67% reduction in
`the 22 pg group and 78% reduction in the 44 pg
`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-Bia 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 [PRISMS 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 ofall formulations of IFN-
`B; however, they are found more commonly with
`the high-dose, high-frequency IFNs (IFN-B1b
`and IFN-Sla 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
`NAbsin the treatment of MS. The group pro-
`posed that both the NAbtiter andclinical status
`of the patient should be considered in the deci-
`sion regarding the impact of the presence of
`NAbs on changing DMTs. Theyalso suggested
`reevaluation of the NAbsstatus prior to making
`a change in therapy unless patients were clearly
`performing poorlyclinically [Polmanet aj, 201 O}.
`
`Glatiramer acetate
`Glatiramer acetate (GA) (Copaxone, Teva Neuro-
`science North America / Teva Pharmaceuticals)
`is a first-line therapy for relapsing forms of MS
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`Therapeutic Advances in Neurological Disorders 5 (4)
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`W Castro-Borrero, D Graves et al,astro“borrero,DGravesetal,
`
`
`
`blocking direct immunologic attack. It was in the
`late 1980s that the immunologic concept ofThl
`(proinflammatory) and Th2 (anti-inflammatory)
`lymphocytes gained momentum.These twotypes
`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 ofTh2 (anti-inflammatory) cells that
`inhibited the inflammatory response by secret-
`ing anti-inflammatory cytokines [Aharoni er al.
`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 glatiramercells to multiply and
`begin to produce anti-inflammatory cytokines,
`Since the glatiramer-activated lymphocytes can
`suppress inflammation under way in the diseased
`area of CNStissue, this process has been given
`the namebystander suppression [Johnson, 2010}.
`‘To date, data suggest that GA treatmentis 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
`B-cell properties [Lalive et al, 2011].
`
`GA hasa relatively narrow adverseeffect profile.
`Most frequently patients complain of mild pain
`and pruritis at the injection site. Lipoatrophy and
`skin site reactions are also seen and maylead to
`discontinuation of therapy. A transient reaction
`called immediate postinjection reaction consists
`of chest tightness, flushing and dyspnea begin-
`ning soon after the injection andlasting no longer
`than 20 min.Ifno history or evidence of coronary
`artery disease, the patient can be reassured that
`such a reaction is benign [DiPiro et ai. 2005].
`
`Multicenter trials with GA have demonstrated
`statistically significant reductions in mean ARR
`that are comparable to those of the IFNs [DiPiro
`et al. 2005}. In two recent studies the efficacy of
`GA was compared with high-dose/high-frequency
`IFN-f. In the Rebif versus Glatiramer Acetate in
`Relapsing MS Disease (REGARD) study (Mikol
`et al. 2008}, subcutaneous IFN-B1a was compared
`with GA,and in the Betaseron/Betaferon Efficacy
`Yielding Outcomes of a New Dose (BEYOND)
`study [O’Connor et al. 2009], subcutaneous
`
`IFN-B1b was compared with GA.In both trials,
`there was no significant difference between IFN
`and GAin the primary endpointsorin anyclini-
`cal endpoints, although somedifferences in mag-
`netic resonance imaging (MRID 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 continuoususeis 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 least one GA dose since
`study initiation in 1991, only 100 (43%, ongoing
`cohort) patients continued. Of the 100 patients
`receiving continuous GA as sole immunomodula-
`tory therapy for 15 years (mean disease duration
`of 22 years and mean patientage 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 ne occurrence of any unforeseen adverse
`events in patients receiving GA therapy.The study
`will continue for 20 years ofprospective follow up
`[Ford et ai, 2010].
`
`Mitoxantrone
`Mitoxantrone is an anthracenedione initially
`developed as an anti-neoplastic agentthat reduces
`lymphocyte proliferation. Mitoxantrone interca-
`lates into DNA strands, inducing strand breakage
`and inhibition of the DNA repair enzyme topol-
`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 approvedfor the treat-
`ment of SPMS based on the study by Hartung
`and colleagues [Hartunget al. 2002}.
`
`Several studies have shownit to beefficacious in
`reducing exacerbations and number of Gad+
`lesions on MRI, and it seems to have effects on
`disease course up to 5 years after discontinuing
`therapy [Martinelli ez al. 2009; Goodin etai, 2003}.
`Mitoxantrone is given as an intravenous infusion
`over 30 min every 3 months at 12 mg/m? for a 2-
`to 3-year period with a maximum cumulative dose
`of 140 mg/m?. Commonside effects include alo-
`pecia, nausea and vorniting, an increased risk of
`infection (particularly urinary and respiratory
`tracts infections) and amenorrhea. Mitoxantrone,
`though effective, remains second line due to its
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`Therapeutic Advances in Neurological Disorders 5 (4)
`
`risk of two serious adverse effects that can occur
`at any time after the first dose is given. The first,
`acute leukemia has an incidence of approximately
`0.81% [Marriott et ai. 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 et ail. 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
`mg/m?; however, several reports of cardiotoxicity
`below this threshold have caused the FDAto 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 et 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 ao and f chain
`[Ransohoff, 2007]. Vascular cell adhesion mole-
`cule 1 (VCAM-1) is expressed on the surface of
`vascular endothelial cells in the blood vessels
`within the CNS and interacts with o4B1 integrin
`on lymphocytes to allow for extravasation across
`the BBB. Also, the interaction of a4B1 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 G4« monoclonal antibodies against leu-
`kocyte a4 integrins, including «481 and 0487
`integrins, and blocks binding to their endothelial
`receptors (VCAM-1 and mucosal addressin cell
`adhesion molecule 1, respectively) [Polman ez ai.
`2006}. By blocking a4 integrins, natalizuamab
`inhibits the migration of leukocytes into the
`brain, which results in reduced inflammation.
`
`Natalizumab 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. Natalizamab
`reduced the risk of sustained disability by 42%
`over 2 years (HR 0.58; 95% CI 0.43-0.77; p <
`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 numberoflesions 1.9 with natali-
`zumab and 11 with placebo; p < 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 ez ai. 2006].
`
`The Safety and Efficacy of Natalizamab in com-
`bination with IFN-Bla in patients with RRMS
`(SENTINEL)trial was a 2-year phase III trial
`evaluating treatment with natalizumab or placebo
`in combination with IFN-§1la. 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% versus 29%) and were morelikely to remain
`relapse free (61% versus 37%). Combination
`treatment resulted in fewer new or enlarging T2
`lesions (0.9 versus 5.4; p < 0.001) [Rudick etal.
`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 ofnatal-
`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 natalizumab (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
`
`ithtt
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`W Castro-Borrero, D Graves et al.reat~Borer,DGravesetal,
`from mild to severe. Fewer patients treated and
`wide confidence intervals result in questionable
`estimates beyond 30 monthsoftreatment.
`
`
`
`is a rare demyelinating disease of the
`PML.
`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 of PML
`with natalizamab therapy remains unknown.
`
`In the natalizumab clinical trials, there was a
`small increase in the rate ofinfections, including
`herpes infections, pneumonia and urinary tract
`infections. There were no other opportunistic
`infections or increase cases of cancer reported
`[Ranschoff, 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, 2007; Gorelik et af. 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 et al. 2006;
`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
`radiographicdisease activity equivalentto patients
`in the placebo group [Ransohoff, 2007].
`
`Natalizumab is an extremely effective therapy
`for RRMSandis licensed for highly active naive
`patients. Dueto 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 rec-
`ommend the use of the JC virus antibody for
`risk stratification on all patients on Tysabri. 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 JC 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 ofthoserisk fac-
`tors for PML have a risk of PML ofless than
`0.1 per 1000 [Sorensen er ai, 2012).
`
`Fingotimod
`Fingolimod is an oral sphingosine-1 phosphate
`(S1P) 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
`S1P, receptor on lymphocytes leading to inter-
`nalization and downregulation of their expression
`and thereby preventing the egression of lympho-
`cytes from the lymph nodes,Additionally, through
`interactions with S1P receptors on neural cells,
`fingolimod has been shown to have potentially
`neuroprotective effects in the animal experimen-
`tal autoimmune encephalomyelitis model [Foster
`et al, 2007; Coelho et al. 2007; Mironetal. 2008}.
`
`In the 24-month phase JI] 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 ofdisability 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
`enlarging T2 lesions [Kapposet al. 2010].
`
`The Trial Assessing Injectable Interferon versus
`FTY720 Oral in RRMS (TRANSFORMS)com-
`paring fingolimod with intramuscular INF-$la
`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 Advancesin Neurological Disorders 5 {4}
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`effect on MRI markers compared with IFN-B1a;
`however,
`there was no statistically significant
`difference in the disability progression between
`the fingolimod and IFN-Bla groups [Cohenetai.
`2010].
`
`Despite its efficacy, 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 wasrelated 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 et al. 2010].
`
`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 xovo synthesis pathway of
`guanosine nucleotides without being incorporated
`into DNA. Because T and B lymphocytes are
`critically dependent for their proliferation on de
`novo 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.
`Seriousside 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.
`
`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 6h.
`
`Off-label therapies
`Immunosuppressive agents, chemotherapies and
`various mAbs have been used off label for many
`years as DMTsin MS butthe 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 effects of IFN-B and GA, cannot
`afford FDA-approved therapies, or need intensifi-
`cation of therapy (i.e. used in combination with
`TFN-B or GA). Also limiting the use of these med-
`icationsis the lack oflarge-scale, controlled trials,
`validating their efficacy.
`
`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-
`Bla, 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
`(Frohmanet al. 2010]. The dose generally used
`in patients with RRMS 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, NJ, 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 approvedfor 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 et al. 2007].
`Azathioprine is
`licensed for MS therapy in
`
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`W Castro-Borrero, D Graveset al.ooinrEESES
`
`
`
`Germany. Azathioprine is an imidazole derivative
`fatigue, headache, muscle
`fever,
`leucopenia,
`of 6-mercaptopurine and acts as an immunosup-
`spasms and diarrhea, Cases of PML, severe
`pressive antimetabolite. It is a purine antagonist
`mucocutaneous reactions, tumorlysis syndrome
`and affects DNA replication. It impairs T-cell
`and fatal infusion reactions have been docu-
`lymphocyte function and is more selective for
`mented. Other severe adverse reactions include
`T lymphocytes than for B lymphocytes [Casetta
`fulminant hepatitis, hepatic failure, bacterial,
`et al, 2009], The Cochrane MS Group concluded
`fungal or viral infections, cardiac arrhythmias,
`that azathioprine is an appropriate maintenance
`renal toxicity and bowel obstruction or perfora-
`treatmentfor patients with MS and could beafair
`tion [Prescribing information, 2010].
`alternative to JFN.Itis recommended that cumu-
`lative doses do not exceed 600 g due to possibly
`increasing the risk of malignancies [Casetta et ai.
`2009].
`
`Methotrexate
`Methotrexate (MTX)is a chemotherapeutic agent
`used for the treatmentofsevere psoriasis, juvenile
`RA (JRA), 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 MS, for
`the Cochrane Multiple Sclerosis Group,
`the
`authors do not recommend the use of MTX for
`progressive MS or RRMS dueto a lack of high-
`quality evidence. Futuretrials need to be performed
`using standard outcome measures and objective
`measures, such as MRI [Gray et al, 2004].
`
`Rituximab
`Rituximab is FDA approved for the treatment of
`non-Hodgkin’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 B-cell populations (but not stem cells
`or plasma cells) through a combination of cell-
`mediated and complement-dependent cytotox-
`icity and possibly promoting apoptosis [Bar-Or
`et al, 2008).
`
`Commonside effects of rituximab inchide naso-
`pharyngits, urinary tract
`infections, nausea,
`
`In a 72-week, open-label phase I trial the safety
`and tolerability of rituximab were evaluated in 26
`patients with RRMS. The authors indicated that
`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 ez al. 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 versus pla-
`cebo [Hauseret ai. 2008]. Rituximab has shown
`efficacy in the treatmentof patients with RRMS.
`A recently completed randomized clinical trial
`using a standard dose of rituximabin patients with
`RRMS demonstrated a 91% reduction in the
`number of Gad+ lesions on MRI,as well as a sig-
`nificant reduction in the number ofclinical
`relapses (Hauser et al. 2008]. In a recenttrial of
`patients with PPMS,rituximab appeared to have
`efficacy only in young patients (primarily male)
`with signs of active inflammation on MRI scans
`{Hawk