Future Research Directions in Multiple
`Sclerosis Therapies
`
`Benjamin M. Greenberg, inn, M.H.s.,1 and Peter A. Calabresi, ran.1
`
`ABSTRACT
`
`The success of presently available injectable immunomodulatozy therapies in
`treating multiple sclerosis has led to heightened interest in finding even more efficacious
`and better tolerated therapies. Severai oral agents have shown efficacy in phase-ll clinical
`trials and are now entering phasewill pivotal
`trials. in addition, monoclonai antibodies
`targeting,r surface receptors on various cells of the peripheral immune system have also shown
`efficacy in early studies and will soon be entering phase III. Ail of these approaches target
`immune molecules that are not specific for multiple sclerosis {MS and carry inherent risk of
`infection and systemic side effects. Novel immunotherapics in preclinical or phases I to Ila
`testing are attempting to more selectively target pathogenic effector cells and thereby block
`abnormal immune cell activation without compromising normal healthy immune responses.
`The induction of tolerance to self-proteins continues to he a goal ofMS immunorherapy, but
`as yet has not been accomplished outside of the laboratory. There is increasing awareness of
`the need to understand and modulate nonclassical immune targets as well as central nervous
`system degenerative processes. The roles ofvitamins, antimicrobials, and hormones continue
`to be studied. The mechanisms of neurodegeneration in MS are likely multilhctotiai and
`include direct damage hyT celis and Immoral immunity as well as oxidativc stress, glutamate-
`mediated excitotoxieity, and neuronal and oligodendrocyte apoptosis. Neuroproteetive drugs
`that were once only considered for classical degenerative diseases, such as amyotrophic lateral
`sclerosis and Parkinson’s disease, are now being considered in MS.
`
`KEYWORDS: Monoclonal antibodies. Immunosuppressm, neuroprotectlon, clinical
`trials, multiple sclerosis
`
`Despite the availahility of six immunomodulat—
`ing drugs, there remains a dire need for more effective,
`safer, and more tolerable therapeutic agents for multiple
`sclerosis (MS). MS is a heterogeneous disease with a
`variety of different clinical and pathological subtypes and
`stages, and it is iikcly that we wili need different combi-
`nations of therapeutic strategies to adequately treat all
`patients with MS."2 In this article, experimental immu—
`notherapeutic approaches, for which there are already
`positive phase—H clinical trial data, are considered first,
`
`immunotherapeutie strategies that
`followed hy novel
`offer hope For greater selectivity or safety. Finally, we
`consider strategies For neuroprotection and netn'orepair.
`
`IMMUNOTHERAPIES IN DEVELOPMENT
`
`Currently Available Therapies
`We are fortunate to have several treatment options for
`relapsing—remitting MS (RRMS). I'Iowever, the first-line
`
`EDepartrncnt 0?- Neurology. johns Hopkins Schooi of Medicine.
`Baltimore, tVIaryiaml.
`i’eter A.
`requests:
`Address
`for correspondence and reprint
`Calahresi. MD” Associate Professor, Department of Neurology,
`johns I'loplzins School of h’ledieinc,
`(:00 North Woife Street,
`Pathology (127, Bahitnorc, MD 21287 (ll-[1111“! calahresi@_i]3.rni.ecln].
`
`Multiple Scicrmis and the Spectrum oI'CNS Inflammatory Dcmye-
`limiting Diseases; Guest Editor, Claudia F. larccltinetli, Ml).
`Selnin Neural ZUUSQEJZIMZS. Copyright
`I
`2008 by 'I'hierne
`h'lcciiml Publishers,
`Inc., 333 Seventh Avenue, New York, NY
`10001, USA. Tel: 4 MEL?) 584-«Ihn2.
`DO] Ii).iUSstwlflll7-illl‘n33. ISSN 0271-8235.
`
`121
`
`Page 1 0f 8
`
`EXHIBIT
`13912 2 01 ‘33 ~03 9-03
`
`
`
`”LI—LL}
`._._.___________
`
`Biogen Exhibit 2224
`
`Mylan V. Biogen
`IPR 2018-01403
`
`Page 1 of 8
`
`Biogen Exhibit 2224
`Mylan v. Biogen
`IPR 2018-01403
`
`

`

`122
`2008
`SEMINARS IN NEUROLOGY/VOLUME 28. NUMBER 1
`MWmmmw—wwwmmmwmmuww
`
`inunttnomodttiatlug drugs (lths) approved for MS
`(glatiramcr acetate and interferon [5) are on average
`only one-third effective in reducing relapses ambhare
`only modest benefits on progression ofdisahiiity. H The
`shortcomings of these therapies likely relate to either
`potency of 1mmunosnppression or specificity for
`the
`pathological processes involved in MS pathogenesis. To
`this point, tttitoxantrone and other potent immunomo-
`dulating dmgs have shown increased efficacy compared
`with lMDs in reducing or abrogating relapses, bttt carry
`risk of significant toxicities and still have no benefits in
`pttrely progressive types or stages 11f1\=lS. Nataliaumab, an
`anti-Lv—s1 integrin monoclonal antibody, was designed to
`inhibit immune cell 111igration by interferinr'r with verv
`late activation (VLA)~4 interactions with endothelitnh
`and matrix proteins. lhis dtug suppresses relapses bv
`679’n, and after 2 years oftseatment 28% ofpatients were
`free ofany type of clinical or marrnetit resonance imacring
`(R’lRl) disease activity compared with only 69’11
`in the
`placebo group.n Unfortunately, despite hopes that
`it
`might selectively target pathogenic cells, three cases of
`progressive multifoeal leukoencephaloparhy (P3114) have
`occurred in patients on nzttalizumab in combination with
`other immunosuppressivc 111edications.7'3 At this time. it
`is unclear whether this rare side effect (3 out of 3000
`patients exposed in trials} is related to impaired immune
`surveillance of the central nen'ous system (CNS) or
`perhaps premature release (1ij virus—infected B cells
`from the bone marrow dtte to impaired interactions of
`these cells with the marrow sinusoidal vascular cell
`
`ligand):J
`(a VLA—4
`(VCAA’I)~I
`adhesion molecule
`Because VLA—4 is actually expressed on all activated T
`cells, B cells, and, to some extent, on monocytes. it may
`be too broad an immune cell target. Indeed, other CNS
`and systemic infections remain a concern in patients on
`this therapy. Thus. there remains a need for more specific
`therapies that could inhibit pathogenic WIS-related in—
`flammation without compromising the immune system’s
`ability to mount successful antimicrobial responses.
`
`Drugs in Clinical Trials
`
`The National Multiple Sclerosis Society(NMSS) \Veb site
`(“WMNIVISSorgl lists more than 300 different clinical
`trials of therapeutic approaches being tested for MS. The
`vast maioriry ofthcsc are small exploratoty trials or combi-
`nations of presentiy marketed drugs with experimental
`agents added on. in this article, we emphasize drugs in
`advanced clinical trials and neonagents that have promising
`resuits in phase-~11 studies. These me most simply
`divided into oral therapies and monoclonal antibodies.
`
`Oral lmmurtomodulatory Agents
`The i111munomodulator
`I‘ l Y720 (firtgolimod)
`sphingosintkllJ (5-1 F) receptor agonist that
`is given
`
`orally once per day. The S-ll’l receptor, which is the
`major target of fingolin‘lotl,
`is found predominantly 1111
`native and central memory lytnphocytcs; agonism of the
`receptor mediates down modulation, resulting in inbih»
`ition of lymphocyte egress from lymph nodes and thy-
`mus, but without any compromise of lymphocyte
`functionI{activation proliferation, and Lvtokine psodnt-
`tion). 111 in .1 1ece11t phase- I] clinical
`trial, 1””720,
`given either at 5 mg or 1.25 mg, resulted in an ~«SUQK1
`reduction in clinical relapse rate and 80% reduction in
`MRI activity at
`(1 months.” A 24-1111111th open label
`extension has shown sustained efficacy and a predictable
`side effect profile consisting of low-level
`increase in
`transa111inases, fitst- dose bzadtct'udia, and tare tepotts
`of pulmonary function changes and maL‘ulat edema. Two
`large phase-Ill trials are underway comparing fingoli-
`mod at 1.25 mg and at a lower dose of 0.5 mg to
`placebo.
`ECU. is a second generation fnmaric acid ester.
`The active ingredient, dimcthylfumaratc (DMF), has
`been shown to haye both antiinflammatmy and neuro-
`protective effectt.s Dbl]? decteascs proinfiammaton'
`cytoltines and has p101L11 efficacy in psoriasis.H in
`addition, preliminary data have implicated DMF in the
`regulation of a pathway for detoxification that is central
`to protection of cells from metabolic and inflammatory
`stress. A phase—II study designed to evaluate the efficacy
`and safety of B1612 in patients with RRR’IS met
`its
`primaty endpoint. Treatment with 13012 at the highest
`dose, 240 mg three times a day, led to :164‘ll1 reductionin
`the total numbe1 of gadolinium (Cd)-enhancing brain
`lesions measnred by MRI after (1 months of treatment
`versus placebo.
`In this small study,
`the reduction in
`telapse rate was 3.2311 and not significantly different
`compa1ed with placebo, but 12-month open—label ex—
`tension suggests continued deciine in the relapse rate.
`BG12 was generally safe and well tolerated. Common
`adverse events associated with 13012 included headache,
`gastrointestinal (GI) svmptoms, flushing, and elevated
`nan-1.1mmtses ‘5
`
`Laquinimod (AER-215062) is related to lino-
`n1icie, an oral drug that showed efficacy in MS but was
`abandoned due to cardiotoxicity (serositis, myocardial
`inlitrction).H Laquinimod has high oral b1oavulab1l1tv
`without the toxicity, and has demonstrated inhibitory
`activity on autoimmune attd inflammatoty diseases1n
`animai models." A tecent phase--11 study showed that
`laquinimod reduced the numbe1 ofactive MRI lesions by
`44%, but there was no significant reductiontn relapses or
`disability.‘8 llighe1 doses the being tested presently.
`Terifiunomide15 a dihydro-orotarc dehydrogen—
`ase inhibitor that has immtmomodttlatory effects,
`in—
`eluding the ability to suppiess experimental
`.tlL11_,1c
`anephalomvelitis HEAD.” A pltase——ll double—blinded
`study of 179 RRMS patients treated with either teri-
`flunomide at 7 mg and 14 mg versus placebo showed a
`
`Page 2 0f 8
`
`Page 2 of 8
`
`

`

`
`FUTURE RESEARCH DERECTIONS 1N MULTIPLE SCLEROSIS THERAPIESliziit"NE-Rig 1" :1 2131‘1-“81
`123
`
`significant reduction in combined unique active lesions
`seen on MR1 in both treatment arms alter 3(1 necks
`
`compared with placebo.”
`1111: hilrh dose group had a
`[lend tmvatd 1“edtzttion 111 relapses and showed signih-
`cant differences in their Expanded Disability Status
`Scale (151335) score compared with placcl1o Otttroinf'
`trials are
`investitrating 1111Lt§1L1 higher doses are toler-
`ated and 11111y increase efficacy.che11tl other oral arrents
`have 5111111111
`c1'1111' promise in open-11111131 pittasc1111
`studies.
`
`3-iiydroxy—3-1nethylg]utaryl-L'ocnzymc A
`The
`(l'lh’lG-CUA) rcdttctasc inhibitors cailed “statins” amel~
`
`iorate 13.9113 through a variety 111-immunological mech-
`anisms including T—helper type 2 (T113) cell deviation.3'
`Pilot data with siznvastarin showed a 449-11 reduction of
`
`Gd--enl1ancirtg MRI lesions}An Immune Tolerance
`NLtworli (ITN1~sponsored placebo-controlled trial of
`atorvastatin. 80 mg once a day. in patients with clinically
`isola1ed syndromes (Ciss) at high risk for conversion to
`MS is in progress. The oral antibiotic minoeycline has
`been shown to have antiinflammatorv and possibiv
`neur'opiotective effects? Pilot data from 11 small study
`of 10 MS patients suggest an effect111 reducingtMR1
`activity, and further testing is t111L1er11'11y.24 Caution is
`urged regarding widespread off-labei use of statins or
`minocyciine in MS before definitive clinical trial data are
`available because it is theoretically possible that these
`drugs could have deleterious e11eets.35'2" A recent epi~
`dcmiological study found that milittuy recruits with
`high—normai vitamin D levels were haif as likely to get
`MS as their counterparts with low-normai or deficient
`icvels.” Because Vitamin D not only plays a role in bone
`formation, but is also critical in suppressing interleukin
`(1L)-12 and inducintc‘r IL-IO, thereby allowing priming
`of'Thg eytoltinc responses, it eouiid hwe a role in disease
`UIISL‘I and Even PTOPEIgfltit}I].2
`Oral vitamin D supple—
`mentati'on is now being examined111 MS?” Esniol has
`been shown to have antiinflammaroty properties in EAR
`and efficacy on active MRI lesions in a pilot study 111‘MS,
`and is also being examined in MS as an adjunct
`to
`glatiratner acetatef‘”
`
`Monoclonal Antibodies
`
`The success of the monoclonal antibody nataiizumab
`has spurred testing of other monoclonal antibody
`therapies in 1\1.S 1The anti—~CD20 (B cells) monoclo—
`nal Ab (ritnximab)
`is
`a chimeric immunoglobulin
`(1g)G1 that rapidly depletes circulating B celis after
`ohc cycle (two doses taken 2 weeks apart)“ In a recent
`doubEe—blindcd placebo-controlled phase-II study, rit—
`uximab was shown to reduce Cid—enhancing lesions by
`919' and reduced the time to first relapse (hazard ratio
`[HR],003.23' 959’11 confidence interval [CI] 0.146 to
`{1.715). The drug was Well
`toierated, and pitasedll
`studies are pianned. The rapid MR1 response at
`
`lcveis
`3—1 weeks without significant changes in 11.10
`suggests that rather than depleting plasma cells and
`1g production, rituxiniab may inhibit pathogenic 13—cci1
`l'LlI‘lil'H'
`11131310515
`cytokines
`(lb-o and
`factor alpha
`[TNl‘qttD or antigen presentation to T ccllsfi'l‘i
`Because 13 cells are a
`reservoir for viral
`infections
`
`(Epstein-Barr virus 113.1311) this approach could then—
`reticaliy decrease presentation of viral epitopes that act
`as molecular mimics of myelin basic protein {M 131’).
`Cases of PML have been reported in lymphoma and
`lupus patients treated with rituxiinab, but this could be
`related to disease—specific mechanisms or combined
`exposure to other 111111111nosuppressive drugs. As with
`natalizumab (Tysabri), rituximab could promote pre-
`mature release of 1C viruswinfectcd Bmcell precursors
`from the bone marrow.
`
`Daclizumab is an anti-1L-2 receptor 11' chain
`(CD23) 1111111oc10nal antibody (h'lAb) that has proven
`eFficacy in preventing organ transplantation rejection
`and has shown promise in various autoimmune dis-
`eases.“ Two smail open-label studies have found a
`reduction in MRI activity and relapses with stable or
`improved EDSS compared with haseiine.‘l Platebo—
`controlled phase-11 dose-ranging studies are in progress.
`Daclizumab does not appear to deplete CD2S-positivc
`celis but
`rather actually increases
`the number of
`CD56 + naturai ltiller (NK) cells, which may have reg;
`ulat'o1y fitnctionsf’j
`The anti—CD52 MAI), aiemtnzuniab (CAMw
`PATi'lw'l), given in five 2041151 daily doses, causes
`coznple111ent-111ediated lysis of lymphocytes and pro-
`l'ound
`and longdastint.r depletion of
`ivmphocvtes
`(1 year). Pilot studies showed abrorration of V1 Rl activity
`and 92% reduction111 relapses compared with baseline.
`[3 ECCCnt Stildy COVEPHTilU" alcmluzumab t0 rilllCC “’Ccl'd)’
`subcutaneous intc1'1e1on- B (IFNB)- 111 showed a 75.11
`reduction oftelapses and (15‘!11 reductionIn the risk For
`progression of disability over 2 years. Six patients devel—
`oped idiopathic tlu'o1t1bt.1cytopenia (1311’), and one died
`of a brain hemorrhage. Also, a significantly greater
`proportion of patients had thyroid problems after 2 years
`ofalemtuzutuab treatment. These complications suggest
`that aberrant immune responses may occur in immuno—
`genetically predisposed hosts during the immune recon-
`stitution period-m
`Anti-11.4203 (1)40 chain) N11111:: have shown
`efficacy in psoriasis.“ 1L—12 is a potent 'lihi-driving
`cytokine produced by monocytes and dendritic cells.
`Laboratory data strongly support its role in Tin-medi~
`ated diseases. The shared use of P450 chain betwuen
`
`IL—12 and 1L~23 (implicated in T111L~17 celis in auto—
`immunity) makes it an attractive target
`in MS.”
`ltlowever, specificity may stiil be a prohiem because
`T111 and ThiL-l 7 ceils are needed to fight offinfection.
`No clinical data in MS have been reported to date, but
`trials are ongoing.
`
`Page 3 0f 8
`
`Page 3 of 8
`
`

`

`124
`
`SEMINARS IN NEUROLOGYIVOLUME 28, NUMBER 1
`
`2008
`
`
`
`Toward Antigen Specificity and Tolerance
`All of‘the previousiy described therapies stiller From lack
`ol'spccllicity for the pathogenic cells that are thought to
`mediate the autoimmune attack in MS. An alternative
`
`approach has been to selectively antagonize an antigen-
`speeific T—ccll clone by targeting,r
`its T-ccll
`receptor
`lTCR) directly or indirectiy by use or altered peptide
`ligands (Al.’f..s).“ APLs were designed with specific
`amino acid substitutions in key contact residues identi-
`fied in the MBP encephalitogenic peptide such that it
`could still he presented by human ienkocyt‘ antigen/
`major histocompatibility complex (HLA/h’lHC) mole—
`cules and recognized by the TCR specific for
`that
`peptide, but did not signal and activate the T celis fully,
`resultingI in deviation to a Th; response or even toler—
`ance.
`Initial clinical
`trials resulted in unpredictable
`results with a subtle trend toward improved outcomes
`in low dosages of the APL, but rare patients with
`unexpected disease activation at
`the higher dosta'l'l'45
`Concern regarding cpitope spreading as a means of the
`immune system recognizing alternative antigens as the
`disease process evolves has also been raised. 1 ‘onerhcless,
`interest in this approach persists using lower doses of
`Apia. Another antigen-specific treatment that involves
`loading,r antigen-presenting cells (APCs) with cocktails
`of relevant rnyeiin peptides and then fixed with ethylene
`carbodiimidc have shown promise in animals. and hu-
`man triais are planned.“ Several
`trials continue to
`address the possibility of vaccinating patients with irra—
`diated T cells expressing the disease—relevant TCR or
`delivery of myelin peptides as vaccinations to induce
`tolerance to specific T-cell subsets or myelin proteins. ‘7
`These approaches presuppose that we know the relevant
`antigen(s)/*I"CR that mediates disease in MS, that the
`disease is
`indeed autoimmune, and that
`the T-eeli
`response is restricted to one or a few antigens. An
`interesting approach being tried in several T-eeil—medi—
`ated diseases involves nonstimulatoty anti-CD3 anti—
`bodies, which bind T cells but induce anergyflS These
`have recently been shown to be effective orally in
`ameliorating BAH in mice.
`
`Novel immunomodulators in Preclinical
`Deveiopment
`
`Several novel alternative inununoiogicai approaches are
`being developed. Signal transduction inhibitors (for Th1
`cells}, either small molecule inhibitors or smail interfere
`ing (si)Ri\'A for T-bct, ameliorates EAR.” Similarly,
`there is interest in antagonizing the Thll.-]7 specific
`transcription Factor ROR'yt.“
`Blockade of the outward rectifying potassium
`channel Kv1.3 has been shown to selectively suppress
`T-effector memory cells, which are the costimulation
`independent, CCR7( -— )iCD/«lSRAl — } mommy cells
`implicated in MS by several groups and Found in MS
`
`l; Specific Kvl.3 inhibitors are being
`brain tissue}l
`developed that target chrrmically activated memory cells
`without compromising immediate and acute immune
`responses mediated by naive and central memory cells.
`FLT3 is a tyrosine kinasc receptor specifically
`expressed on mature dendritic cells (DCs) and perhaps
`mieroglia‘, and it is a potential
`target for autoimmune
`diseases.“ DCs are professional 2\i’Cs and may play a
`critical role in determining tolerance versus autoimmun—
`io’-“““ CEPml and other FLT} inhibitors block FLT":
`signaiing and DC nuituration, and have been shown to
`ameliorate EAR, presumably through inhibiting antigen
`presentation, but perhaps also by decreasing production
`of pathogenic cytoitines and other microglial cl‘l'cctor
`moieculess'l Several other approaches designed to intew
`Fete with APC Function or block costimulation of? cells
`
`are being investigated, including CTLA-sl-lg and sal-
`hutamol (antiwllml 2 rotten)?”H
`
`STRATEGIES FOR NEUROPROTECTION
`
`Neuroprotection can be defined as any approach that
`leads to the presewation oF neural
`tissue. In MS it is
`thought
`that permanent disability is associated with
`axonal damage that occurs both as a direct result oF the
`acute influx of inflammatoty cells duringr new lesion
`formation, as well as in chronic active lesions character-
`
`ized by CDBS -l— macrophages and microglia. l'lowevcr,
`it
`is also likeiy that chronically dentyelinated axons
`undergo degeneration as a result of loss of trophic
`support ol‘ the axons and increased susceptibility to the
`local
`inflammatory environment.“ The mechanisms
`underlying this process are likely multifactorial, hut
`include oxidative stress related to high levels of nitric
`oxide and its metaboiite pcroxynitrite, as well as gluta-
`mate—mediated excitotoxicity. Because these processes
`probably occur slowly over many years, MS may be an
`ideal disease in which to initiate therapies directed at
`these CNS processes ofdegeneration.“”"‘I
`
`Candidate Drugs
`Several Food
`and Drug Administration (FDA)«
`approved drugs have been shown to have neuroproteetivc
`properties in vitro or in animal models. h’linocycline has
`both antiinflammatoiy and putative antiapoptotic cliccts
`in a variety nit-different modci systems.“2 Etythtopoietin
`(EPO) has been shown to ameliorate EAE by several
`groups; the recent discovery of EPO receptors in the brain
`and the possibility of dissociating their hematopoietic
`effects from their neuroprotectivc effects have raised
`hopes that EPO derivatives could be designed for use
`in chronic disease without causing etythrocytosis."“‘;
`Short courses of EPO are being tested in ciinical trials
`of stroke, optic neuritis, and transverse myeliris. Several
`epilepsy drugs work by blocking sodium channels, and
`
`Page 4 0f 8
`
`Page 4 of 8
`
`

`

`
`FUTURE RESEARCH OIRE'CTEONS IN MULTIPLE SCLEROSIS THERAPIESItéiEc‘reta-Rt} (A £633.73]
`
`125
`
`thus could prevent influx of calcium into axons through
`the sodium calcium exchanger as well as having indirect
`effects on microgliafm Phenytoin, flecainidc, topirantate,
`and Lamictal are all being investigated in animal models
`of 3518.01!“ In addition to their antiinflamntatoty effects,
`estt‘ogcns have rtcut'oprotective properties and are being
`examined in KEPT”
`
`Antagonists of the glutamate receptor subtypes,
`N—methyl‘D—aspartate (NtViDA) and alphantn‘tino—fiw
`hydroayfi—isoxazolepropionic acid (AMP/'1), have been
`shown in models to be neuroproteetivc and are consid—
`ered candidates for MS triaisf}75 Potent NMDA
`antagonism is not tolerated; thus, only weak NMDA
`antagonists,
`such
`as memantine, may be
`feasible.
`Ab’lijA—receptor antagonists have shown efficacy in
`EAE, have been studied in amyotrophic lateral
`sclerosis (ALB), and could be tried soon in MS?“
`Downstream targets of cell death. such as nitric oxide
`and polyU‘tDP ribose)poEytnerase (PARP), may be
`amenable to intewention; inhibitors of these pathways
`have shown efficacy in animal modeis of nerve degen-
`Cl'ilt'it.)n.77'm
`
`Netti-optotection may also be mediated by remye—
`lination. Embtyonic stem cells offer the ultimate hope of
`reconstituting CNS tissue, but aiso the most risk because
`of their potential to differentiate into other tissue types
`or cancer cells as well as obstacles related to their
`
`isolation, delivery to the site ofinjury, and rejection after
`transplantation. h‘lesenehymal stem cells and bone mar~
`row—derived hematopoietic stem cells are being tried,
`may naturally migrate to CNS sites ofinfiammation, and
`may actualiy act by supporting or enhancing resident
`progenitor CNS ceils in initiating tissue repair. Stem
`cells can be differentiated into glittl restricted precursor
`cells, which may be much safer because of their restricted
`lineage potential, but methods of enhancing differentia—
`tion ofthcse cells into mature myelin-lorming oligoden”
`drocytes still need to be optimized. Partial remyelination
`occurs in the CNS in MS, and pathological studies Show
`an
`abundance of oligodendroeyte progenitor
`cells
`(Ol’Cs), but many appear to not successfully differ—
`entiate into mature oligodendrocytes. Much emphasis is
`now being placed on identifying the mechanisms respon-
`sible for inhibiting OPC maturation. One promising
`strategy that addresses this problem is the identification
`of LINGO, a natural b‘aite that turns off myelination
`during development. Recently, LINGO antagonists were
`shown to enhance OPC differentiation and to mediate
`
`they also
`myelination of axons in vitrof’s Remarkably,
`appear to enhance axon regeneration and thtts have the
`potential for dual benefits in MS.“
`
`CONCLUSION
`
`In the near future it is likely that one or more of the
`promising oral therapies will become available. in addi—
`
`Page 5 0f 8
`
`tion, potent MAhs offer promise for infrequent dosing
`and increased efficacy. The issue of specificity of our
`therapies remains a concern, and all of these successes
`will
`likely come with risks of infection related to im-
`paired function of healthy normal immune celis and/or
`other systemic side effects. Strategies aimed at inducing
`toicrance offer hope for avoiding this nonselective im~
`mtmosuppression, hut these also will ultimately require
`more knowledge regarding which are the pathogenic
`cells to be tolerizcd. Neuroprotection and rcmyclination
`are now r ".tlistic goals in MS. and promising approaches
`are beginning to be tested. There remains a critical need
`for developing novel clinical trial designs and biomarkers
`of axons and tnyelin that will ailow rapid testing ofsttch
`agents, tnttch in the way we have been able to screen
`immunosuppressivc drugs using Gd~enhanced MRI and
`relapses.
`
`ACKNOWLEDGMENTS
`
`The authors are supported by the National Institutes of
`Health, NSO41~333 (PAC), National MS Society
`(NMSS) Collaborative Center Award (PAC. and
`B.t\'l.G.), NMSS TR—3760-A—3 (PJLC. and B.t\"l.G.},
`The Nancy Davis Foundation (PAC). and The Accel-
`erated CURE project (B.\’I.G.}.
`
`REFERENCES
`
`5.1
`
`l.)
`
`l. Pittock S}. Lttcchinetti CF. The pathoiogy of MS: new
`insights and potential clinical applications. Neurologist 2007:
`13(2):45"5(1
`i'l,
`Kleimchnitz C. Mcuth SC. Kicscier BC, W'iendl
`lmmunotherapeutic apprt'iaches in MS: update on pathow
`physiology and emerging agents or strategies 2006. Endocr
`Metab lnnnune Disortl Drug Targets 2007;7(2}:35—a3
`littttmaun M. Rieckntann P. interferon-beta“) in multiple
`sclerosis. Expert Rev Neurother lii07;7(3):227~239
`\‘anifis‘iiy‘ls. The use of glariramer acetate in the treatment
`of multiple sclerosis. Adv Neurol 2006;98:273—292
`. W'ingercbuk DM. Multiple
`sclerosis discase-moditying
`therapies:
`adverse
`effect
`surveillance
`and management.
`Expert Rev Neurotitcr 20(}{);b(3)2333-—3-lo
`.ti. A
`'et
`6. Polman CH, O’Connor PW,
`l'lavrdova E,
`randomized, pEacebo-controlied trial of oataiizumah for
`relapsing multiple sclerosis. N Engl] Med 2t)!lo;354(9):3‘}‘}-
`910
`
`4.
`
`Ln
`
`‘ul
`
`. Berger JR. Natalianznab. Drugs 'l‘oday (Bare) 2306;42UO}:
`(139—655
`
`3. O'Connor P. Natalizumah and the role of alpha 4-integrin
`antagonism in the treatment of multiple sclerosis. Expert
`Opin Biol TllCl‘ 2UU7;7(l):133—136
`9. Ransohoff RM. Nataliaumab and PML. Nat Netnosci 2005;
`55(10):}.275
`10. Martini S, Peters H, Bohier T, Budde K. Current perspectives
`on PTYTZO. Expert Opin investig Drugs 200711660505»
`533
`11. Baumrnker T, Billich A, Brinknlann V. Fri-YTZO, an
`innnunontodulatory sphingolipid mimetic:
`translation of a
`
`Page 5 of 8
`
`

`

`126
`
`
`
`SEMINARS EN NEUROLOGWVOLUME 28, NUMBER 1 2008
`
`in multipie sclerosis.
`novel mechanism into clinical benefit
`Expert Opin investig Drugs 2|]ll?;ita(‘i}.2X3—28‘J
`Kappos l... Aurel J, Form (i. et .1]. Oral fiogoliirtod {lyl‘YUll}
`for reiapsing nntitipie sclerosis. N {Eng} J bled 2000:3350 i):
`l 1.2le i-lli
`
`i“llm:|.t'it'
`. Schilling; S. Goelv S. Linker R. Lot-inlet 1". Gold R.
`acid esters are effective in ciirouit experimental autoimmune
`cncepitalumyelitis and suppress macrophage infiltration. Clin
`Exp immuztnl 2005;]45liizlDim“)?
`iixtll'lflcis‘; do
`Shear NH. Fulfilling an unmet need in
`laiologicais hold the key to improved tolerabilirv? Drug Saf
`2i]flti‘.2‘}(1):-l‘3'—oo
`liunaric acid
`Schimriglc S. Brunt: N. l'ieliwig K. et .tl. Oral
`esters for the treatment of active multiple sclerosis: an open-
`laliei. baseline-controiled piiot study. Eur] Neurol 30%;
`13([))I(3D‘l—(11i]
`ion-won S, Anders-ton 0, Fee T, et ai. Synthesis and
`iiioiogical
`evaluation of new 1,l—dihvdror-lcitydrnxyv}
`two—3-t]uinoliuecarboxamides For treatment 0F autoimrmzoe
`disorders: structure-activity relationship. _l Med Chem .2004;
`-l7l8):2075—2088
`l..eandersou T. Ohlsson
`é‘txclsson B.
`L,
`Runstrom :‘\,
`inhibition of the development of chronic experimentai auto-
`immune encephalom)‘elitis by iaquinitnod (ARR-2150M) in
`lFNwheta lean. and wild type mice. ] Neuroimmuuol 3006;
`i 73(1»3):[1‘I~73
`Poiman C. Barkliof l7, Sandin:rg~\'Vo§lheiin M. Lindc A,
`Nordic O. Nederman T. Treatment with larptinimod reduces
`development
`oF active MR?
`iesions
`in
`relapsing MS.
`Neurology 2005314(6)?)87—991
`Zeyda M. Poglitsclt M. Ceyercggcr R, er al. Disruption of
`die interaction ofT cells with antigen-presenting cells by the
`active lefiuuotnide metabolite terifiunomide: involvement ol-
`
`14.
`
`it).
`
`18.
`
`1‘).
`
`synapse
`
`impaired integrin activation and immunologic
`formation. Arthritis Rheum 20l}5;52(‘?):2730—2739
`O’Connor l’W'. Li I). Freedman MS, et al. !\ Phase ll study
`()l—tilc safety and efficacy of‘terifiunomide in multiple Microsis
`with relapses. Neurology 2006;oo(6):894m960
`. Youssef S, Stuve O,
`i’atarroyo jC. et a]. The HMG~COA
`reductase inhibitor. aturvastatin. promotes a 'l'l12 bias and
`reverses paraiysis
`in centrai nervous system autoimmune
`disease. Nature 2002;420(6‘)11):73—84
`.ti. Orai simvastatiu
`. Vollmer T, Key L, Durkalski V. et
`treatment
`in reiapsingnremitting muitiple sclerosis. Lancet
`2004;36:5(9—12]):1607—it5i}3
`Giuliani F. Hader \‘V. Yong VVV. 1\-‘linr.icycline attenuates T
`cell and mierogiia activity to impair cytoltine production in
`T eeli-mieroglia interaction.
`j
`laetzitoc Biol 2t')05;78(i}:
`135~§~l3
`
`[\Jb:
`
`2-1.
`
`to'Jt
`
`26.
`
`t\'Iinoc}-'cline reduces
`Meta LM. Ziiang Y. i’cuog M, et al.
`gadolinium-enhaucing magnetic resonance imaging lesions
`in multipie sclerosis. Ann Neurol 2904;55(5):756
`. Miron VE, Raiaselthztrau 5,}arjout AA. Zamvil 55, Kennedy
`TE. Antel jl’. Simvastatin regulate: oligodendmglial process
`dynamics and survivai. Giia 2007;55(2):33i)—i~l3
`Yang l... Sugama S. Ciiirieiiigno j\*V, et al. A’Iinoeyclinc
`enhances MPTP toxicity to dopaminergic nettrons.] Neuro—
`sci Res 2003;74l2):273—235
`. Monger KL, Levin L1, Hollis BVV, Howard NS, Ascherio A.
`Serum 25~ltvtiroxyvimmin D levels and risk of multiple
`sclerosis. inle 2006;2‘io(23):2832—2833
`ll-—1(}
`Spach KNI, Nashold l-“E. Dittel BN, Hayes CE.
`signaling is essential for 1,ZS—diltytlroayvitamin IDS—mediated
`
`28.
`
`Page 6 0f 8
`
`inhibition of experimental .mtoimmuue cocephahnuyeiitis. _]
`ltiiniuzlol 30th.]T?(‘ll:hl]36vhl‘13?
`van der Mei M. Ponsonin' {\L. Divycr T. et .tl. Vitamin i)
`ievels
`in people \vttit multiple sclerosis and con‘mumit)’
`control»; in Tasmania. :‘tustralia. E Neural 3107;54:5314‘10
`. Vnt-iilllll RR.
`l’aiaszt'nskl K. Sex hormones in experimenta?
`autoimmune encephainmyelirls: unpiicatiom for multiple
`sclerosis. Neuroscientist 2001.7(3l:253m370
`. Cree l3. Emerging monoclonal antibody [ilcrdplllh {or multi-
`ple sclerosis. Neurologist 200(r;12(-i):171—178
`Rastetter W. Molina A. \Vhite CA. Rituximab: efipautiing
`role in therapy For
`lymphomas and .iutoirmmtne diseases.
`Aunu Rev Med 200-4551477503
`Cross AH. Starit _IL. Lattber _]. Ranishottozn M]. Lyons‘lA.
`Rituximab reduces B cells and T cells in ccreiirospinal fluid of
`multiple sclerosis patients. J Neuroimmunoi 20{)o;130fi~«2):
`{i340
`
`Stuve O. Cepolt S. Elias B. et a]. Clinical stabilization and
`effective Edginphocyte depletion in the Cereiirnspinal fluid and
`peripheral Hood of a patient with titlzninaot
`relapsing“
`remitting multiple sclerosis. Arch Neurol 2()05;62(10):1o20—
`H123
`
`va '41
`
`.
`
`3‘}.
`
`in the
`\‘Vaidmaon TA. Anti-Tac ((laclituimal), Zenapax)
`treatment of leukemia, autoininuine diseases. and in the
`prevention of aliograf‘t rejection: :1 25~year personal odyssey.
`.l Clin lmmunul 2007;27(1):1—i$
`Ruse JW'. \-V;itt i-lli. 'vVltite AT. Carlson NG. Treatment of
`multiple seierosis with an anti-inter]eukin~2 receptor mono-
`clonal antibody. Ann Neurol 2004;56{o):364—Sh7
`liiclekuva l3. Riehert N. l'loward T. et a]. I’lumauized antiv
`C025 {tiaclizmuaii} iuhiiiits disease activity in multiple
`sclerosis patients tailing to respond to interferon licta_ Prat:
`Nat? .‘-\c.td Sci USA 2004;10‘l(23):3705—3708
`ai.
`Bieleiuiva B. C‘ataltitmo M. Reiehert-Scrivner S. et
`Regulatory CDSfillirigbt) natural killer cells mediate immu-
`nomoduiatory effects of lL-ERaipha—tatgeted therapy (tiacli—
`aunt-ab) in multiple sclerosis. l’roc Natl Aead Sci USA 2006'.
`10.3{1 5}:3941~594e
`Cole:- A]. Cox A, Le Page E. et al. The window of
`therapeutic opportunity in tnuitipie sclerosis: evidence from
`monoclonal antibody therapy. J Neuroi 30(io;253(l);08—
`108
`
`40.
`
`Loh Y. Oyama Y. Statltute L, et a]. Development of a
`secondary autoimmune disorder after hematopoietic stem celi
`transplantation For autoimnntne diseases: role of conditioning
`regimen used. Blood 2.007309%}:2643648
`. Cltong BF, “long H K. immunobiologics in the treatment of
`psoriasis. Clin lmntunol 2007:123i2):129—l3fl
`. Gran B, Zhang (IX. Rostami A. Roie ol' the ll.-