REVIEW ARTICLE
`
`Drugs 2008; 68 (17): 2445-2468
`0012-6667/08/0017-2445/$53.45/0
`
`© 2008 Adis Data Information BV. All rights reserved.
`
`Disease-Modifying Agents for
`Multiple Sclerosis
`Recent Advances and Future Prospects
`
`Til Menge,1 Martin S. Weber,2,3 Bernhard Hemmer,2 Bernd C. Kieseier,1
`Hans-Christian von B ¨udingen,4 Clemens Warnke,1 Scott S. Zamvil,3 Aaron Boster,5
`Omar Khan,6 Hans-Peter Hartung1 and Olaf St ¨uve7,8,9
`1 Department of Neurology, Heinrich Heine-University, D ¨usseldorf, Germany
`2 Department of Neurology, Klinikum rechts der Isar, Technical University,
`M ¨unchen, Germany
`3 Department of Neurology, University of California, San Francisco, California, USA
`4 Department of Neurology, University of Z ¨urich, Z ¨urich, Switzerland
`5 Department of Neurology, The Ohio State University, Columbus, Ohio, USA
`6 Department of Neurology, The Multiple Sclerosis Clinical Research Center, Wayne State
`University School of Medicine, Detroit, Michigan, USA
`7 Neurology Section, VA North Texas Health Care System, Medical Service, Dallas, Texas, USA
`8 Department of Neurology, University of Texas Southwestern Medical Centre at Dallas, Dallas,
`Texas, USA
`9 Department of Immunology, University of Texas Southwestern Medical Centre at Dallas,
`Dallas, Texas, USA
`
`Contents
`Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2445
`1. Pathogenesis of Multiple Sclerosis (MS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2447
`1.1 Genetic and Environmental Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2447
`1.2 Activation and Migration of Immune Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2447
`1.3 Lesion Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2448
`1.4 Neurodegeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2448
`2. Testing the Efficacy of Pharmacological Agents in MS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2449
`3. Current Treatment Regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2449
`4. Overview of Future Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2452
`4.1 Suppressing the Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2452
`4.2 Modulating the Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2454
`4.2.1 Compounds with Broad Modes of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2454
`4.2.2 Compounds with Selective Modes of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2455
`4.2.3 Compounds with Highly Selective and Monospecific Modes of Action . . . . . . . . . . . . . 2456
`5. Protection and Repair of the CNS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2458
`6. Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2459
`7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2459
`
`Abstract
`
`Multiple sclerosis (MS) is a chronic autoimmune disease of the CNS. Current-
`ly, six medications are approved for immunmodulatory and immunosuppressive
`treatment of the relapsing disease course and secondary-progressive MS. In the
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`first part of this review, the pathogenesis of MS and its current treatment options
`are discussed.
`During the last decade, our understanding of autoimmunity and the pathogene-
`sis of MS has advanced substantially. This has led to the development of a number
`of compounds, several of which are currently undergoing clinical testing in phase
`II and III studies. While current treatment options are only available for parenteral
`administration, several oral compounds are now in clinical trials, including the
`immunosuppressive agents cladribine and laquinimod. A novel mode of action
`has been described for fingolimod, another orally available agent, which inhibits
`egress of activated lymphocytes from draining lymph nodes. Dimethylfumarate
`exhibits immunomodulatory as well as immunosuppressive activity when given
`orally. All of these compounds have successfully shown efficacy, at least in
`regards to the surrogate marker contrast-enhancing lesions on magnetic resonance
`imaging.
`Another class of agents that is highlighted in this review are biological agents,
`namely monoclonal antibodies (mAb) and recombinant fusion proteins. The
`humanized mAb daclizumab inhibits T-lymphocyte activation via blockade of the
`interleukin-2 receptor. Alemtuzumab and rituximab deplete leukocytes and
`B cells, respectively; the fusion protein atacicept inhibits specific B-cell growth
`factors resulting in reductions in B-cells and plasma cells. These compounds are
`currently being tested in phase II and III studies in patients with relapsing MS.
`The concept of neuro-protection and -regeneration has not advanced to a level
`where specific compounds have entered clinical testing. However, several agents
`approved for conditions other than MS are highlighted. Finally, with the advent of
`these highly potent novel therapies, rare, but potentially serious adverse effects
`have been noted, namely infections and malignancies. These are critically
`reviewed and put into perspective.
`
`efficacy and good safety profiles. Over the past 10
`Multiple sclerosis (MS) is a chronic disease con-
`years, specific anatomical, cellular and molecular
`fined to the CNS. Its pathological hallmarks are
`targets have become the focus of drug development.
`neuroinflammation, de- and remyelination, neurode-
`A more in-depth understanding of the inflammatory
`generation and astrogliosis. To date, the aetiology of
`cascade underlying MS disease activity will allow
`MS remains unknown; however, growing evidence
`the development of increasingly specific, and hope-
`supports an autoimmune pathogenesis triggered by
`fully safe and effective, pharmacological agents for
`environmental factors in genetically susceptible in-
`all clinical MS phenotypes. As a consequence, fu-
`dividuals. Perhaps not surprisingly, immunomodu-
`ture treatments will have to be designed to tackle the
`latory therapies have been the mainstay of pharma-
`neurodegenerative processes inherent to MS.
`cotherapy for many decades. Currently, clinicians
`On the basis of the current pathogenetic concepts
`have access to two distinct treatment strategies. In
`of MS, we provide an overview of future com-
`the past, our limited knowledge of MS pathogenesis
`pounds, describe the mechanisms by which they
`allowed only general modulation or suppression of
`immune responses. During the last decade, several modulate the immune system in patients with MS,
`agents belonging to the class of immunomodulators
`known adverse effects and their stages of clinical
`were shown to be effective in clinical trials, and
`development. Publications were retrieved by search-
`were approved. All of these agents have modest
`ing PubMed Entrez provided by the National Center
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`for Biotechnology Information. The search strategy
`consisted of a combination of
`the following
`keywords: multiple sclerosis OR experimental
`autoimmune encephalomyelitis AND therapy, clin-
`ical trial(s), drug development, experimental, drug
`efficacy, drug safety. Latest search dates assessed
`were June 2008. The National Institute of Health’s
`website and the website of the National Multiple
`Sclerosis Society (http://www.nationalmssociety.
`org/research/clinical-trials/index.aspx) have been
`utilized to screen for clinical trials of compounds
`related to MS.
`
`1. Pathogenesis of Multiple
`Sclerosis (MS)
`
`In order to highlight current advances in the
`treatment of MS, one must appreciate the current
`pathogenic concepts of the disease. Typically, MS
`becomes clinically apparent during early adulthood.
`The disease is more prevalent in females than males.
`It is very likely that in many patients, CNS inflam-
`mation starts many years before the onset of clinical
`signs and symptoms.[1] Despite tremendous progress
`in our understanding of the disease and in the devel-
`opment of specific therapies, MS remains one of the
`leading causes of neurological disability among
`young individuals, second only to trauma.[2-4] Fol-
`lowing a period of monophasic disease, termed clin-
`ically isolated syndrome (CIS), the disease in the
`majority of patients enters a relapsing-remitting MS
`(RRMS) disease course. After another 10–15 years,
`the disease enters a chronic progressive phase in
`about 30–50% of patients, termed secondary-pro-
`gressive MS (SPMS).[2,5] Approximately 10–20%
`are affected by a primary-progressive MS (PPMS)
`disease course[4] and a rather small group of patients
`(<5%) experience a progressive-relapsing disease
`course that most rapidly progresses, resulting in loss
`of ambulation in a median of 7 years.[6]
`
`1.1 Genetic and Environmental Factors
`
`The aetiology of MS remains unknown. How-
`ever, there is strong evidence emerging that suggests
`a complex interplay of multiple genes and environ-
`mental factors.[7-9] The identification of specific sus-
`
`ceptibility genes has been difficult. Until recently,
`the only strong and consistent linkage identified has
`been at chromosome 6p21, the location of the major
`histocompatibility complex (MHC).[10-13] For pa-
`tients with MS of Northern European ethnicity,
`there is widespread consensus on the role of one
`common HLA allele: DRB1*1501. One allele of
`this gene increases the disease risk by an odds ratio
`of about 3.[14,15] More recently, it was shown by an
`international collaborative efforts that predominant-
`ly single nucleotide polymorphisms in the genes that
`encode parts of the interleukin (IL)-2 and -7 recep-
`tors appear to be associated with an increased risk of
`developing MS.[16,17] Interestingly, these genes play
`a critical role in inflammatory immune responses
`and neurodevelopment. In addition, a number of
`microbial agents, bacterial and viral, have been im-
`plicated in the pathogenesis of MS, of which Ep-
`stein-Barr virus, human herpesvirus (HHV)[6] and
`varicella zoster virus are currently being extensively
`studied.[18-22]
`It is conceivable that in an individual carrying
`such disease susceptibility genes, an infection or
`sequential infections may eventually lead to an aber-
`rant response of the immune system against self-
`antigens.[23,24]
`
`1.2 Activation and Migration of
`Immune Cells
`
`Both the innate and the adaptive immune systems
`play a role in the pathogenesis of MS. Structural
`homology of microbial antigens with CNS epitopes
`may lead to chronic activation of the immune sys-
`tem against self-antigens. This phenomenon is
`termed molecular mimicry. Animal studies have
`demonstrated that acquired immune responses to
`CNS antigens are initiated in the lymph nodes and
`spleen, where antigen-specific T and B cells become
`activated and clonally expand.[25] Activation enables
`these cells to cross biological membranes, including
`the blood-brain barrier (BBB). This is essential to
`physiological immune surveillance, including the
`CNS.[26] Unfortunately, it leads to autoimmunity if
`the antigen recognized in the lymph nodes resem-
`bles an autoantigen in the CNS. During the early
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`sion.[40-43] Some of these maturation steps may also
`phase of MS, microglia activation and an amplifica-
`take place in the CNS within lymphoid follicle-like
`tion of immune cell infiltration into the brain and
`structures found in late stages of MS.[44-46] The ulti-
`spinal cord are seen.[27] The physiologically tightly
`sealed BBB likely becomes compromised, and the mate target specificities of these B cells still remain
`enigmatic.[47] Subsets of memory B cells and plasm-
`transmigration of additional immune cells, includ-
`ing macrophages and dendritic cells, is facilitated.
`ablasts, which are attracted to the intrathecal space
`and parenchymal lesions,[48] produce antibodies that
`Cell migration from the periphery into the CNS
`are detectable in MS lesions and are likely to be the
`involves a complex sequential interaction of adhe-
`cause of demyelination via complement activation
`sion molecules, matrix metalloproteinases (MMPs)
`in most MS patients.[49,50]
`and chemokines.[28] Namely, the firm contact be-
`There is emerging evidence that in the progres-
`tween leukocytes destined to enter the CNS and
`endothelial cells of the BBB activated by cytokines
`sive stages of MS, immune responses are further
`is, amongst others, mediated by α4-integrins on
`compartmentalized (see earlier in this section[44-46])
`and locally sustained,[51] thus impeding the access of
`leukocytes and vascular cell adhesion molecule-1
`(VCAM-1) on endothelial cells.[29] Other potentially
`a number of immunoactive therapeutic compounds
`relevant adhesion molecules and chemokine recep-
`to the lesion site, including monoclonal antibodies,
`tors are also expressed by lymphoid and myeloid
`neurotrophic and gliotrophic factors, and cell thera-
`cells.[30]
`pies.
`
`1.3 Lesion Formation
`
`1.4 Neurodegeneration
`
`While demyelination is the hallmark characteris-
`It was demonstrated by several investigators that
`tic of MS and occurs most prominently in areas of
`macrophages and T cells (both CD4+ and CD8+)
`infiltrate the CNS parenchyma in MS.[31-33] In addi-
`acute inflammation within the white matter, the
`neurodegenerative and neuroregenerative features
`tion, clonotypic CD8+ T cells were also detected in
`cerebrospinal fluid (CSF).[31,32] CD4+ T cells and
`of MS have only recently been rediscovered after
`their initial description by Charcot.[52-54] Damage to
`B cells appear to be more prominent in the perivas-
`cular spaces adjacent to lesions.[27] Macrophages
`or even loss of axons occurs in early disease stages
`and appears to correlate with the degree of neuro-
`and T cells within the lesion secrete a wide range of
`logical disability.[55,56] Axonal injury is evident both
`molecules toxic to the myelin sheath, including pro-
`at sites of inflammatory infiltrates and also in their
`teases, reactive oxygen species, nitric oxide deriva-
`conspicuous absence.[53] In the context of inflamma-
`tives and cytokines, that orchestrate the inflamma-
`tory damage.[34] Whereas some studies suggested a
`tion, the underlying mechanisms may be quite simi-
`pro-inflammatory T helper (Th)-1 and Th17 cyto-
`lar to those of demyelination: a direct attack on the
`kine signature in MS lesions,[33,35,36] other investiga-
`axon by CD8+ T cells, complement-mediated anti-
`tors demonstrated that both Th1 and Th2 cytokines,
`body-dependent phagocytosis of axons after binding
`of antibodies to neuronal membrane antigens,[57] T-
`and their receptors are up-regulated in the CNS of
`MS patients.[37] More recently, it has also been dis-
`cell-dependent recruitment and activation of macro-
`phages that express inflammatory mediators and
`cussed whether cytokines may be an essential com-
`toxic molecules all may lead to acute axonal trans-
`ponent of CNS repair mechanisms, for example,
`remyelination after an acute attack.[38] In addition, it
`section. In contrast, the gradual loss of oligodendro-
`cytes and axo-glial disconnection may eventually
`was proposed that the inflammatory milieu itself
`may support neuroprotection.[39] B cells in the CSF
`deprive axons of trophic support and further aug-
`and MS plaques are oligoclonally expanded, expres- ment their insidious damage; once denuded, axons
`sing somatically mutated B-cell receptor genes that
`appear to be particularly vulnerable to noxious med-
`are compatible with an antigen-driven expan-
`iators, including nitric oxide metabolites and ex-
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`ing lesions on T1-weighted images, and the number
`citotoxic molecules, and hence undergo degenera-
`tion.[58] In these denuded axons, the redistribution
`of newly emerging lesions. However, there is a
`general notion that the use of these MRI disease
`and enhanced activities of sodium channels can lead
`to mitochondrial energy failure and calcium over- makers may correlate insufficiently with histopa-
`flow, ultimately activating proteases capable of dis-
`thology and clinical disease progression; hence,
`integrating the axonal cytoskeleton.[57,59]
`MRI may never substitute for clinical outcome mea-
`sures.[68] Biomarkers that unequivocally correlate to
`Up to 50% of all demyelinating lesions remye-
`disease parameters have not yet been established.[69]
`linate spontaneously.[60] Remyelination occurs in all
`The animal model of MS, experimental autoim-
`disease subtypes and takes place even late during the
`mune encephalomyelitis (EAE), has been extensive-
`disease course.[61] It appears to be initiated by
`ly studied to investigate CNS autoimmunity, but
`oligodendrocyte progenitor cells (OPCs), which
`does not faithfully reflect and model the hetero-
`proliferate within the lesion, differentiate into pre-
`geneity and insidious onset of the human disease
`myelinating oligodendrocytes and finally into ma-
`and its pathogenetic hallmarks.[70] EAE represents
`ture oligodendrocytes. This orderly process requires
`some of the characteristic features of MS (CNS
`an appropriately permissive microenvironment,
`damage mediated by CD4+ T cells and macro-
`such as growth factors and support of neurons.[62]
`phages), while others are largely missing or incom-
`Even
`in chronic MS
`lesions, premyelinating
`plete (CNS damage mediated by CD8+ T cells and
`oligodendrocytes are present, but seem to be im-
`B cells, neurodegeneration in the absence of inflam-
`paired in their remyelinating activity.[62,63] As yet, it
`mation).[70-72] This may explain why compounds
`remains enigmatic as to why remyelination occurs in
`shown to be highly efficacious in EAE have failed in
`some patients, but is absent or fails in other pa-
`clinical trails.[73,74] Perhaps even more problematic
`tients.[64,65] Possible mechanisms include ongoing
`is the fact that many pharmaceutical companies do
`destruction of OPCs, or the compromise of other
`not pursue drug development of compounds that fail
`glia cells and neurons that may support remyelina-
`to show a benefit in the EAE model.
`tion.[66,67]
`Novel EAE models, including transgenic human-
`Figure 1 illustrates the current concept of MS
`ized models, have been generated to better replicate
`pathogenesis. Compounds that selectively interfere
`B-cell- and CD8+ T-cell-mediated demyelination
`with certain pathogenic pathways are depicted in
`and axonal damage, and may be applied to preclini-
`figure 1 to highlight their mode of action.
`cal testing of novel compounds in the future.[72,75-80]
`Animal models of virus-induced autoimmunity
`or demyelination may add relevant information
`when evaluating pharmaceuticals for patients with
`Clinically, pathogenetically and histopathologi- MS.[23,70,71,81]
`cally, MS is a complex and highly heterogeneous
`disease with an often unpredictable disease
`course.[4,49,50] Thus, clinical trials would have to
`enrol very large numbers of patients (and controls)
`and would have to last many years to attain mean-
`ingful results if they only relied on clinical out-
`comes. In the past two decades, disease surrogate
`markers on brain magnetic resonance images
`(MRIs) have been used to substitute for clinical
`outcomes. These paraclinical tests aim to capture
`subclinical disease activity. Conventional imaging
`sequences include T2 lesion load, contrast enhanc-
`
`Acute relapses are managed by intravenous corti-
`costeroids: typically 3–5 days of methylpred-
`nisolone 1 g with or without oral tapering. This
`regimen was shown to shorten the duration of the
`relapse, mediated through a number of genomic and
`non-genomic actions.[82-84]
`Two classes of agents are currently approved as
`first-line treatment for the prevention of clinical
`relapses. These drugs are considered first-line thera-
`
`2. Testing the Efficacy of
`Pharmacological Agents in MS
`
`3. Current Treatment Regimens
`
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`Periphery
`
`T helper cell
`
`Th2 and
`FoxP3+ Treg
`
`Adhesion
`
`B cells
`
`Proliferation
`
`Migration
`
`Neuron
`
`Menge et al.
`
`CNS
`
`Plasma cell
`
`Secretion of
`myelin-specific
`antibodies
`
`Astrocyte
`
`Ag presentation
`
`Proliferation
`Th1 and Th17
`differentiation
`
`Adhesion
`
`T cells
`
`Peripheral APC
`(e.g. dendritic cell)
`
`BBB
`
`Myelin
`sheath
`
`Migration
`
`Oligodendrocyte
`
`Secretion of
`inflammatory cytokines
`
`Local or
`recruited
`APC
`(e.g. microglia)
`
`Fig. 1. Mechanisms of action of currently approved treatments for multiple sclerosis. Interferon-β (IFNβ, yellow) reduces leukocyte
`proliferation, expression of adhesion molecules and secretion of matrix metalloproteinases required for leukocyte migration. Glatiramer
`acetate (GA, green) alters presentation of antigen (Ag) by antigen-presenting cells (APC) and promotes development of T helper (Th)-2 and
`FoxP3+ regulatory T cells (Treg). Through inhibition of cell replication, mitoxantrone (red) reduces proliferation and activation of leukocytes.
`Natalizumab (purple) blocks the adhesion molecule very late activating antigen (VLA)-4 inhibiting leukocyte adhesion to the blood-brain-
`barrier (BBB).
`
`pies based predominantly on their safety record, not
`their efficacy. Recombinant interferon-β (IFNβ) is
`available in three formulations for subcutaneous or
`intramuscular administration. All three formulations
`were approved on the basis of successful phase III
`trials in CIS, RRMS and at least for IFNβ-1b in
`SPMS.[85-91] There is now overwhelming evidence
`that early disease initiation with IFNβ slows down
`disease progression (recently reviewed in this jour-
`nal by St¨uve et al.[92]). IFNβ exerts a plethora of
`effects at multiple critical checkpoints of MS patho-
`genesis (see figure 1).[93,94] It induces the expression
`
`of a number of gene products, including 2′,5′-
`oligoadenylate synthetase, neopterin, tryptophan,
`β2-microglobulin and human Mx protein, and some
`of these markers are used in assays that assess the
`bioavailability of these drugs in individual pa-
`tients.[82] Treatment with IFNβ results in MHC class
`I gene expression, antiviral and antiproliferative ac-
`tions, and monocyte activation, to name a few. How-
`ever, the way that IFNβ mediates its beneficial
`effects in MS is not completely understood. There is
`convincing evidence that several different mechan-
`isms of action may play a role, although some have
`
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`only been demonstrated in vitro. These include the
`inhibition of leukocyte proliferation, the decrease of
`antigen presentation by microglia, a modulatory ef-
`fect on the IgG synthesis of plasma cells, the reduc-
`tion of T-cell MMP expression, as well as the
`downregulation of adhesion molecules that allow T-
`cell migration into the brain.[95,96]
`
`decreased expression of MMPs.[107,108] Because of
`its potential cumulative cardiotoxicity, the individu-
`al maximal dosage is limited and the timepoint of
`treatment initiation has to be carefully consid-
`ered.[109] Mitoxantrone may slow down disease pro-
`gression in some patients with SPMS.[91,104,105]
`
`Another second-line treatment option for escalat-
`ing therapy in RRMS patients who do not respond to
`The second first-line compound, glatiramer ace-
`IFNβ or GA has been approved only recently. The
`tate (GA), is a random polypeptide made up of four
`highly specific humanized monoclonal antibody
`amino acids (L-glutamic acid, L-lysine, L-alanine
`(mAb) natalizumab is a novel compound that is the
`and L-tyrosine) in a specific molar ratio that resem-
`first product of rational drug design for this disease
`bles myelin basic protein (MBP). Interestingly, ser-
`in that it targets a molecule that propagates CNS
`endipity has led to its discovery as a MS treatment
`inflammation. Specifically, natalizumab targets the
`option, because initially it was developed to induce
`α4-integrin of the adhesion molecule very late acti-
`rather than ameliorate EAE.[97] While not all mech-
`vating antigen (VLA)-4 on leukocytes, an adhesion
`anisms of action of GA are fully understood, the
`following immunomodulatory effects of GA in MS molecule crucial for the initial contact between leu-
`may be attributed mainly to altered T-cell activation
`kocytes and endothelial cells of the BBB. The adhe-
`and differentiation:[93] (i) induction of GA-reactive
`sion molecule VLA-4 binds to VCAM-1 on brain
`vascular endothelium (figure 1).[29] By specific
`Th2-like regulatory suppressor cells; (ii) restoration
`blockade of the subunit α4-integrin, natalizumab
`of CD4+CD25+FoxP3+ regulatory T cells; and (iii)
`direct
`immunomodulatory activity on antigen- was designed to prevent egress of T cells from the
`presenting cells (APCs), which participate in innate
`blood into the brain. Proof-of-concept was demon-
`immune responses (figure 1).[98-100] GA is approved
`strated in the EAE model.[110] After several mainly
`for the treatment of RRMS.[101,102] A phase III trial in MRI-centred phase II studies,[111-114] some 7 years
`CIS (preCISe) was prematurely terminated in late
`later clinical efficacy was successfully explored in
`2007 as primary endpoints were already met in the
`two of the largest phase III trials conducted at the
`interim analysis.[103]
`time, enrolling over 2000 MS patients.[115,116] This
`led to US FDA fast-track approval of natalizumab in
`the US in 2004 after reviewing the 1-year data of the
`AFFIRM (Natalizumab Safety and Efficacy in Re-
`trial.[115]
`lapsing Remitting Multiple Sclerosis)
`Natalizumab reduced relapse rates by more than
`two-thirds and slowed disease progression during
`the 2-year observation period.[115-118]
`
`Because of its problematic safety profile, the
`alkylating chemotherapeutic agent mitoxantrone is
`only considered a second-line treatment option for
`patients with relapsing forms of MS who do not
`respond to IFNβ or GA.[104,105] Mitoxantrone inter-
`calates into DNA, resulting in cross-links and strand
`breaks.[106] In addition, mitoxantrone interferes with
`the enzyme topoisomerase II,[106] an enzyme that
`Inhibition of immune cell migration to the CNS
`had rare but serious adverse effects;[119] progressive
`transiently forms double-strand breaks that occur
`when DNA is altered during replication or transcrip- multifocal leucencephalopathy (PML) occurred in
`tion (figure 1). Consequently, mitoxantrone affects
`0.1% of patients, and subsequently led to the death
`replication predominantly in rapidly dividing cells.
`in two patients and severe disability in another pa-
`tient.[120] PML is a deadly opportunistic CNS infec-
`Predominantly as a result of this effect, there are a
`number of secondary effects on the immune system,
`tion for which specific treatment is not available. It
`including interference with antigen presentation, re-
`is caused by reactivation of a clinically latent JC
`duction in the expression of pro-inflammatory cyto-
`polyomavirus infection. As of March 2008, approxi-
`kines and attenuation of leukocyte migration via a mately 32 000 patients worldwide have received
`
`© 2008 Adis Data Information BV. All rights reserved.
`
`Drugs 2008; 68 (17)
`
`Page 7 of 24
`
`YEDA EXHIBIT NO. 2077
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`2452
`
`Menge et al.
`
`4. Overview of Future Compounds
`
`MS is a chronic inflammatory autoimmune dis-
`ease. Therefore, it is not surprising that the majority
`of current and proposed treatment options are direct-
`ed towards the modulation or suppression of the
`immune system. However, as more and more know-
`ledge is gathered regarding the potential of neurore-
`generation in MS, therapeutic avenues aiming to
`support neuroregeneration are becoming increasing-
`ly more popular. Therapies can be discerned in
`regards to their specificity (i.e. broad-based vs spe-
`cifically interfering with certain pathways). Most of
`the established therapies can be considered broad-
`based, including IFNβ and GA, while newer drugs
`are rather specific, including natalizumab. The spe-
`cific advantages and disadvantages of broad-based
`and highly specific agents that are currently in de-
`velopment or in clinical trials are discussed in this
`section, and table I summarizes the information
`provided for novel and only recently approved bi-
`opharmaceuticals.
`
`natalizumab in the post-marketing setting, 3600 of ment trials at the time were not unequivocal.[131] The
`benefit-risk ratio of azathioprine is considered un-
`whom have been exposed for at least 18 months,
`favourable, given the efficacy of IFNβ and GA, and
`with three further reported cases of PML to date.[121]
`the increased risk for malignancy in long-term treat-
`Further cases of PML have not yet been made pub-
`ment in an adolescent patient population.[130,132]
`lic. Notably, the two MS patients had received com-
`bination therapy with IFNβ, while the third patient
`As yet, treatment options for the progressive
`phases of MS are limited. There is currently no
`with Crohn’s disease had been pretreated with other
`agent approved for PPMS (i.e. none has shown
`immunomodulators and immunosuppressants. It is
`sustained efficacy).[133]
`thus tempting to speculate that effective global sup-
`pression of immune reactions may compromise
`immune surveillance of the CNS towards potentially
`noxious agents such as JC virus.[122,123] In fact, natal-
`izumab treatment of patients was shown to lead to
`the reactivation of HHV-6.[123] Additionally, since
`natalizumab was shown
`to mobilize CD34+
`haematopoietic stem cells from the bone marrow, it
`may be argued that potentially JC virus-bearing cells
`may also be sequestered systemically.[124]
`It remains to be further evaluated whether natal-
`izumab differentially impacts on migration of the
`various immune cell subsets, and whether additional
`effects (e.g. co-stimulation, cell maturation, apopto-
`sis, virus reactivation) play a role in its mode of
`action.[123,125] Sensitive enrolment procedures, in-
`cluding identification of compromised immunocom-
`petence prior to natalizumab initiation and height-
`ened awareness of possible complications during
`treatment, have been recommended.[126,127] Open
`questions remain concerning the long-term and ad-
`verse effects in patients receiving natalizumab, and
`the generation of biomarkers to a priori identify
`patients at risk for PML.
`In addition to the drugs listed in this section, all
`of which are approved for the treatment of patients
`with MS, a number of experimental agents have
`been used extensively in clinical practice. Cyclo-
`phosphamide is an alternative option when mitoxan-
`trone is not indicated or has failed, for instance, in
`patients with rapidly worsening MS.[128,129] There is
`no inherent risk of cardiotoxicity but there is for
`bladder toxicity. Oral immunosuppressants, such as
`azathioprine, methotrexate and ciclosporin, do not
`play a role in current MS treatment.[130] In the pre-
`IFNβ era, azathioprine was used to treat a larger
`percentage of patients with RRMS, although treat-
`
`4.1 Suppressing the Immune System
`
`New immunosuppressive drugs with less serious
`adverse effects than mitoxantrone have been devel-
`oped and are currently being evaluated in clinical
`trials. Laquinimod (ABR-215062) is an orally
`bioavailable quinoline-3-carboxamide. It is an ana-
`logue of linomide (roquinimex), which was chemi-
`cally modified after serious adverse effects occurred
`in patients with MS, including endocarditis and ser-
`ositis.[155] After demonstration o