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`13372426
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`5998
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`Title of Invention:
`
`Treatment for Multiple Sclerosis
`
`First Named Inventor/Applicant Name:
`
`Matvey E. LU KASHEV
`
`Customer Number:
`
`53644
`
`Filer:
`
`Marsha A. Rose/Erin Miller
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`Marsha A. Rose
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`13-FEB-2012
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`Page 1 of 49
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`Biogen Exhibit 2383
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`Coalition v. Biogen
`IPR2015-01993
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`Page 1 of 49
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`Biogen Exhibit 2383
`Coalition v. Biogen
`IPR2015-01993
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`\\Nu.vu:uA\»A
`3 Express Mai] Labey Na \
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`Treatment for Multig
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`I
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`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
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`International Bureau
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`IlllllllllllllIllllilllll||l||||||l||llIll|||E|||l|||||I||l||l||lI
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`llllllllllllllllllllll
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`(43) International Publication Date
`14 August 2008 (14.08.2008)
`
`(51) International Patent Classification:
`G01N 33/50 (2006.01)
`
`(21) International Application Number:
`PCT/US2008/001602
`
`(22) International Filing Date: 7 February 2008 (07.02.2008)
`
`(25) Filing Language:
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`(26) Publication Langnage:
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`English
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`English
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`(30) Priority Data:
`60/888,921
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`8 Fcbruaiy 2007 (03.02.2007)
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`US
`
`(71) Applicant (for all designated States except US): BIOGEN
`[DEC MA INC. [US/US]; 14 Cambridge Center, Cam-
`bridge, MA (Y2142 (US).
`
`(72) Inventor; and
`LUKASHEV,
`(for US only):
`(75) I11ventorlApp]icant
`Matvey, E. [US/US]; 3 Louis Road, Tewksbury, MA
`01876 (US).
`
`(10) International Publication Number
`
`WO 2008/097596 A2
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA,
`CEI, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE,
`EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID,
`IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC,
`LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN,
`MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH,
`PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV,
`SY, TJ, TM, TN, TR,
`TZ, UA, UG, US, UZ, VC, VN,
`ZA, ZM, ZW.
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, ICE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HR, HU, IE, IS,
`LT, LU, LV, MC, MT, NL,
`NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG,
`CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`(74) Agent; GARRETT, Artlgur, 8.; Finnegan, Henderson,
`Farabow, Gairett & Dunner L.i,.¥'., 90‘: New York .: venue,
`NW, Washington, DC 0001441} (US).
`
`,
`.
`i
`I‘ abiishe-ti‘
`without international search report and to be repaclvlisired
`upon receipt (;f'.*!':zz:‘ report
`
`(54) Title: NRF2 SCREENING ASSAYS AND RELATED METHODS AND COL/[POSITIONS
`
`N % s
`
`o
`ax
`In
`l\
`:7:
`9&
`as
`
`e:
`
`(‘I (57) Abstract: Provided are certain methods of screening, identifying, and evaluating neuroprotective compounds useful for t:eat—
`?‘ ment of neurological diseases, such as, e.g., multiple sclerosis (MS). The compounds described upregulate the cellular cytoprotective
`pathway regulated by Nrl2. Also provided are certain methods of utilizing such compounds in therapy for neurological disease, par—
`ticularly, for slowing or reducing demyelination, axonal loss, or neuronal and oligodendrocyte death.
`
`W(
`
`Page 8 of 49
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`

`

`WO 2008/097596
`
`PCT/US2008/001602
`
`Nrf2 SCREENING ASSAYS
`
`AND RELATED METHODS AND COEV‘i?OS|T|ONS
`
`[0001]
`
`Provided are certain compounds for treating neurological diseases,
`
`including dernyelinating neurological diseases, such as, e.g., multiple sclerosis.
`
`[0002]
`
`Multiple sclerosis (MS) is an autoimmune disease with the autoimmune
`
`activity directed against central nervous system (CNS) antigens. The disease is
`
`characterized by inflammation in parts of the CNS, leading to the loss of the myelin
`
`sheathing around neuronal axons (demyelination), loss of axons, and the eventual
`
`death of neurons, oligodenrocytes and glial cells.
`
`[0003] An estimated 2,500,000 people in the world suffer from MS.
`
`It is one of
`
`the most common diseases of the CNS in young adults. MS is a chronic, progressing,
`
`disabling disease, which generally strikes its victims some time after adolescence, with
`
`diagnosis generally made between 20 and 40 years of age, although onset may occur
`
`earlier. The disease is not directly hereditary, although genetic susceptibility plays a
`
`part in its development. Relapsing-remitting MS presents in the form of recurrent
`
`attacks of focal or multifocal neurologic dysfunction. Attacks may occur, remit, and
`
`recur, seemingly randomly over many years. Remission is often incomplete and as
`
`one attack follows another, a stepwise downward progression ensues with increasing
`
`permanent neurological deficit.
`
`[0004] Although various immunotherapeutic drugs can provide relief in
`
`patients with MS, none is capable of reversing disease progression, and some can
`
`cause serious adverse effects. Most current therapies for MS are aimed at the
`
`reduction of inflammation and suppression or modulation of the immune system. As of
`
`2006, the available treatments for MS reduce inflammation and the number of new
`
`episodes but not all have an effect on disease progression. A number of clinical trials
`
`have shown that the suppression of inflammation in chronic MS rarely significantly
`
`iimits the accumuiatien of disability through sustained disease progression, suggesting
`
`that neurnnat damage and inflammation are independent pathologies. Promoting CNS
`
`rernyeiination as a repair mechanism and otherwise preventing axonal loss and
`
`Page 9 of 49
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`

`

`‘§VC§ 2t)t}$§4/ti§}7S‘;}ti
`
`§’CT.fUS2tiii8:’{it}16E}2
`
`neuronal death are some of the important goals for the treatment of MS. For a
`
`comprehensive review of MS and its current therapies, see, e.g., McA|pine's Multiple
`
`Sclerosis. by Alastair Compston et al., 4th edition, Churchill Livingstone Elsevier,
`
`2006.
`
`[0005]
`
`“Phase 2 enzymes" serve as a protection mechanism in mammalian
`
`cells against oxygen/nitrogen species (ROS/RNS), electrophiles and xenobiotics.
`
`These enzymes are not normally expressed at their maximal levels and, their
`
`expression can be induced by a variety of natural and synthetic agents. Nuclear factor
`
`E2-related factor 2 (Nrf2) is a transcription factor responsible for the induction of a
`
`variety of important antioxidant and detoxification enzymes that coordinate a protective
`
`cellular response to metabolic and toxic stress.
`
`[0006] ROS/RNS are most damaging in the brain and neuronal tissue, where
`
`they attack post-mitotic (i.e., non-dividing) cells such as glial cells, oligodendocytes,
`
`and neurons, which are particularly sensitive to free radicals. This process leads to
`
`neuronal damage. Oxidative stress has been implicated in the pathogenesis of a
`
`variety of neurodegenerative diseases, including ALS, Alzheimer's disease (AD), and
`
`Parkinson's disease (PD). For review, see, e.g., van Muiswinkel et al., Curr. Drug
`
`Targets CNS--Neurol. Disord., 2005, 4:267-281. An anti-oxidative enzyme under
`
`control of Nrf2, NQO1 (NAD(P)H dehydrogenase, quinone (1). was recently reported
`
`to be substantially upregulated in the brain tissues of AD and PD subjects (Muiswinkel
`
`et al., Neurobiol. Aging. 2004, 25: 1253). Similarly. increased expression of NQO1
`
`was reported in the ALS subjects’ spinal cord (Muiswinkel et al., Curr. Drug
`
`Targets-CNS. Neurol. Disord., 2005, 4:267-281) and in active and chronic lesions in
`
`the brains of patients suffering from MS (van Horssen et al., Free Radical Biol. & Med.,
`
`2038, $1 31 i«3‘i 1}. These ebservatierss indicate that the Ne? pathway may be
`
`activateti in neeredegeneretive and neiireintiammetery diseases as an ericiegeneus
`
`protective mechanism.
`
`indeed, meet —reee:'itiy, it has been reported that induced
`
`activation of Nrf2-dependent genes by certain eyciepenanene-«based eemeoiinds
`
`(NEPF) counters the texts effeets ef metaieeiie irahibitien and ROS./RNS preductien is":
`
`Page 10 of 49
`
`

`

`‘W0 2t?}i)8/‘MP’.-’59(s
`
`PKTT/EJSQGG8/001602
`
`the brain and protects neurons from death in vitro and in vivo (see Satoh et al., PNAS,
`
`2006, 103(3):768-773).
`
`[0007] Additionally, many publications have reported neuroprotective effects of
`
`compounds in natural plant-derived compounds (“phytochemicals"), including
`
`or-tocopherol (vitamin E), lycopene (tomatoes), resveratrol (red grapes), sulforaphane
`
`(broccoli), EGCG (green tea), etc. For review, see Mattson and Cheng, Trends in
`
`Neurosci, 2006, 29(11):632-639. Originally, the action of these compounds was
`
`attributed to their anti-oxidant properties. However, while most anti-oxidants are
`
`effective only at high concentrations, at least some of these compounds appear to
`
`exert neuroprotective effects at much lower doses. Emerging evidence suggests that
`
`these compounds may exert their neuroprotective effects by activating cellular
`
`stress-response pathways, including the Nrf2 pathway, resulting in the upregulation of
`
`neuroprotective genes. However, the exact mechanism of action of these compounds
`
`remains poorly understood.
`
`[0008] To date, more than 10 different chemical classes of inducers of Nrf2
`
`pathway have been identified including isothiocyanates and their thiol addition
`
`products, dithiocarbamates, as well as 1,2-dithiole-3-thiones, trivalent arsenic
`
`derivatives (e.g., phenyl arsenoxide), heavy metals, certain conjugated cyclic and
`
`acyclic polyenes (including porphyrins, chlorophyllins, and chlorophyll), and viclnal
`
`dimercaptans. These inducers have few structural similarities. They are mostly
`
`electrophiles, and all can react chemically with thiol groups by alkylation, oxidation, or
`
`reduction, suggesting that the intracellular sensor for inducers is likely to contain very
`
`highly reactive (cysteine) thiols. The inducers can naodify thiol groups by a variety of
`
`mechanisms including: alkylation (Michael addition acceptors, isothiocyanates,
`
`quinones); oxidation (e.g., peroxides and hydroperoxides); and direct reaction with
`
`thiol/disulfide linkages (e.g., vicinal dithiols such as 1,2-dimercaptopropanol, Iipoic
`
`acid). These diverse response mechanisms provide plasticity for cellular responses to
`
`a variety of electrophilic and oxidant stressors.
`
`[0009] Provided are methods that comprise at least one of the following
`
`methods:
`
`Page 11 of 49
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`

`

`‘W9 2€}t}8/'tP9”.75§.36
`
`PCTIUSEQGS/$9} W2
`
`1} methestte ef screening fer at teeet (me new candidate eempeunct for
`
`treating a heumtegieet tttsease;
`
`2) methede et evetuatihg neutepretecttve preperttes et‘ at teeet one drug
`
`candidate fer treating a steureiogicat eiseaee;
`
`3} methees of comparing (e‘g., ter hieequtveiense} at Eeeet twe
`
`phermaceuticet $C3§3‘E§3G$§t§Gtt$ which comprise tumartc: acid derivatives;
`
`4) methods at treating a neuretegteat eteeese by administering te the subject
`
`in need thereef at teaet ene (3Ct§Tt§30t,if‘tEZ§ that is pastéetty strueturatty eimtier te
`
`DEVEF er h/th/it‘; and
`
`methods ef treating a zteumtegécet disease hy e cemhihatieh therapy that
`
`cemprtsee edmtntstratieh at at feast ehe hret sempetmd that tspregutates
`
`the we pathway and at teeet ehe eecend cempeuhct that ctees not
`
`upregutete the Ntt2 pathway.
`
`iflfitttt
`
`in same erhhedtmehte, the heuretegtcat disease is 3 heurectegeherative
`
`disease $tJC§"‘i ee, fer exempts, ALS, Perkiheehh dieeeee, Atzhetmefe disease, and
`
`Ht.tt"tt§t“t§?€3tt”t“s dieeeee.
`
`in same emhecttmehte the neuretegteat disease is MS er
`
`ehether demyetihetthg heuretegieet disease.
`
`{G61 t}
`
`in same embediments, the methods “t-3 further cemprtee:
`
`e} ccmtecttng a set? with the test eempotme, and
`
`h) ctetermthtng whether the htrfz pathway is upregtztetee th the cett.
`
`tn same emhetttmehte, the metheds may ‘turther cemhrtee:
`
`<3} determining whether the test cehapeund stews er §I}t"S\’8§‘t§:‘$ ttemyetinatien,
`
`exehat tees, endier heurehat death, and/er
`
`d} eetecttng the test <3€3tt’1§’.‘§Gt.§t'tC§ es e candidate fer treating heurectegeneretican
`
`it‘: a neuretegtcet dtseaee it 1} the hErt2 pathway is upregutated and :2)
`
`demyetihettohg exehet tees, ehttior heurehat eeath erelie prevented or
`
`stewed.
`
`{@9123
`
`in eeme emhhdimehte, the methecte ‘HS cemprtse mntaettng 23 cett with
`
`at Feast me test eompeund and determining whether the htrt2 pathway fie upreguteted
`
`in the cett.
`
`in such methede, eh upregutetéen at the Nrtié pathway above e thresheid
`
`Page 12 of 49
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`‘W3 2€)t§8it)975§3t§
`
`.‘99CT/'U§2{t08lt§t}1{i02
`
`(e.g., by at teast 30% aver a mntmt) indicates; that the at teast {me competmd has at
`
`teas’: {me bietcgtcai preperty benetictat tn treating a rteumtagtcat ctisease ($9.,
`
`neurcpretecttve pmtzsetfttes}.
`
`in same emtmdtments, the upregutattcm at that ttztz
`
`pathway is assessed {in viva andlar in vitro) by at Beast we at the tctttcawingz
`
`E}
`
`£'~.‘X§Z3t'E‘3$SiG§‘t Eevets at endageneusty pmfiucect anditsr axegemusiy
`
`intrtsduced Nrtz;
`
`ii) subcettutar tcacaitzatécm andim" nuctear transtocation Qt Nrfzg
`
`tit) ax;:sr'esst<m Sevets antfiim’ astivity at (me Qt" mare genes under cantrtzt at
`
`Nt‘f2 {e.g., endagencsus RG01} Cit” an Nrt2-mguiateé reparter gene in an
`
`atttftciat reparter tzezmstmct;
`
`ieaveis at Ns'f2 binding to the §‘\trt2—bEm:tEng EDNA etement ARE;
`
`stabtttty of Nrt2fKea;::t camptexes; and
`
`mzzscttficatien {e.g.. atkytatttm) Eeveis at Keapt andier at Beast we Ctihet’
`
`t\trt2it<eap’§ -asscciated pmteins.
`
`{@913}
`
`in Same emtmdiments at methacts 1»-3,, the e:s::mpt3unti3 that are being
`
`screamed, evattsatact, Gt’ mmpared cemprise at Eeast we memtaar at at teast me at the
`
`tottawing ciassss at campcunds: miid attiyiattng agents, tvttchaat addttttm. at:t;eptt>rs,,
`
`and cflmgmunds that are metabaitzed upan atimtnistratinn ta ttiticttafit additicn
`
`accegtttrs.
`
`{rt SGM8 amtzafiiments, the tvtitthaet adctétttsn accegtor has the structure at
`
`Furmuta t, it, ESE, at av set tmttt betcw.
`
`{@014}
`
`in same etttbcaditttettts mettted t tztrsmprtsas:
`
`at ctmtacting a wit with 3 pturatéty at tettt mmpaunds,
`
`£3}
`
`ttetertnintng wttettter the Nrtfi patttway is umegutated in the seat, and
`
`:2) setectifig tram the pturaiity at comptsunds at teas: arse ccmtgound that
`
`upreguiates ttta Nrtii pathway,
`
`wtteretn an umegutatian at the Nrfz gatttway hy the $%§SC€&{.'§ at Beast {me ccsmpaund
`
`indicates that the setecsteé at teast {me €3€)t‘t‘t;:>t)t£E°td may be: usefut tar treating a
`
`neumtsagicat fitseam, The piurattty at cttsmpmmds may be represented, e,g., by a
`
`cembértatottat chemicat tibrary, and the metheci may be pertmmed, e.g., by
`
`htgt:—tt‘amu§hg3ut screwing.
`
`Page 13 of 49
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`KVO 2088/{E97596
`
`PCT/'15S2t)ti8."0(t‘tt‘E€§2
`
`[0015]
`
`in some embodiments method 2 comprises:
`
`a) contacting a cell with the at least one drug or drug candidate. and
`
`b) determining whether the Nrf2 pathway is upregulated in the cell.
`
`wherein an upregulation of the Nrf2 pathway by the at feast one drug or drug
`
`candidate indicates that the at least one drug or drug candidate is useful for
`
`neuroprotection in treating a human having a neurological disease.
`
`[0016]
`
`In some embodiments method 3 comprises:
`
`a) contacting a cell with a first composition comprising at least one test
`
`cempottncl, and
`
`h) comparing the tevei of Nrf2 pathway upreguiatioh in the ceti by the at teast
`
`one test compound to the corresponding tevel of the Nrf2 pathway
`
`hpregulatien in a cohtret cell treated with a secend compositich cemprisihg
`
`at least one of DMF and MMF.
`
`[0017]
`
`In some embodiments of method 3, the test compound is fumaric acid,
`
`a salt thereof, or a fumaric acid derivative.
`
`In some embodiments, the first
`
`composition comprises DMF, MMF, or both.
`
`In some embodiments, the dose and/or
`
`the formulation of the first composition differs from the dose and/or the formulation of
`
`the second composition.
`
`[0018]
`
`In some embodiments. method 3 further comprises:
`
`c) comparing at least one pharmacokinetic parameter (e.g., serum-half-life) of
`
`the first and the second compositions.
`
`[0019]
`
`In some embodiments method 4 comprises administering to the
`
`mammal a therapeutically effective amount of at least one neuroprotective compound
`
`having Formula I, ll. ill, or IV, e.g., a fumaric acid derivative (e.g., DMF or MMF).
`
`[0020]
`
`In some embodiments method 4 provides a method of slowing or
`
`preventing neurodegeneration in a patient in need thereof, by administering the
`
`compound in an amount and for a period of time sufficient to slow or prevent
`
`demyelination, axonal loss, and/or neuronal death, e.g., by at least 30% relative to a
`
`control.
`
`[0021]
`
`in some embodiments methect 5 comprises:
`
`Page 14 of 49
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`W9 2€){§3,/t}§37S§6
`
`E’CT/§JS2{}538!'{){ii6i}?;
`
`a) administering is the manamai a therapeuticaiiy effective amsunt at at least
`
`she first eempeund that upreguiates the Nit? pathway, and
`
`b) administering a therapeutically effective amount of at least one second
`
`compound that does not upregulate the Nrf2 pathway.
`
`[0022]
`
`In some embodiments of method 5, the at least one first compound,
`
`used in step (a), is a compound of Formula I, II, III, or IV, e.g., a fumaric acid derivative
`
`(e.g., DMF or MMF); and the at least one second compound, which is used in step (b),
`
`is an immunosuppressive or an immunomodulatory compound that does not
`
`upregulate the Nrf2 pathway (e.g., by more than 30% over a control).
`
`[0023]
`
`In some embodiments method 5 comprises administering to the
`
`mammal a therapeutically effective amount of a compound of Formula I, ll, lll, or IV.
`
`[0024]
`
`in some embodiments of methods 1-5, the at least onecompound being
`
`screened, identified, evaluated, or used for treating a neurological disorder is not
`
`fumaric acid or its salt, or a fumaric acid derivative (e.g., DMF or MMF).
`
`[0025] Other features and embodiments of the invention will be apparent from
`
`the following description and the claims.
`
`x «.m.....---.
`“«u«. v4-uuuzu
`.
`K-A-A-'1\'€.’(V1\\f_h-ex‘-H.-s-.it...e\-_w\--,-.
`i‘3:RiEFi._.i@;§..$._§§.i£f?;Z!1".i$i‘i. 3E..°i'.i:iE $iG’5—5‘RE£$.
`
`{(3026} Figure 1 demenstrates that DMF’ and Mitzi? are activaters et Nit? at
`
`cehcentratiens within ciinicai exposure range (ceiis in culture).
`
`{002?} Figure 2 shews resuits of RNAi experiments.
`
`{(3028} Figure 3 shows evidence at Nrf2 activation by DMF and MMF in viva.
`
`{@020} Figure 4 shews evittence Qt‘ Nrf2 activaiien by DMF and MMF in viva.
`
`{G030} Fumaric acid esters, such as EMF, have been §)i’G§.'ti§S$t’i fer treatment
`
`at MS (see, e.g., Sehimrigit et ai., Eur. J. Neurei., 2008, ’i3(6):804~‘t0; Brugs RM},
`
`2005, 6(4};229~30).
`
`{G031}
`
`Prctsvidee are, among ether things, means for identifying ccmpsunds
`
`with a new therapeutic modality useful in at least one of multiple neurological
`
`indications and, optionally, complementary to other drugs for the treatment of a
`
`neurological disease, including a number of currently used immunomodulators.
`
`Page 15 of 49
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`WO 2008/097596
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`PCT/US2008/001602
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`[0032] DMF is a member of a large group of anti-oxidant molecules known for
`
`their cytoprotective and anti—inflammatory properties. These molecules also share the
`
`property of the Nrf2 pathway activation. Thus, the finding that DMF activates the Nrf2
`
`pathway in conjunction with the neuroprotective effects of DMF further offers a
`
`rationale for identification of structurally and/or mechanistically related molecules that
`
`would be expected to be therapeutically effective for the treatment of neurological
`
`disorders, such as, e.g., MS.
`
`[0033] Certain terms are defined in this section; additional definitions are
`
`provided throughout the description.
`
`[0034] The terms “activation" and “upregulation,” when used in reference to
`
`the Nrf2 pathway, are used interchangeably herein.
`
`{D035} The terms “disease” and "disorder” are used interchangeably herein.
`
`[0036] The term "a drug for treating a neurological disease” refers to a
`
`compound that has a therapeutic benefit in a specified neurological disease as shown
`
`in at least one animal model of a neurological disease or in human clinical trials for the
`
`treatment of a neurological disease.
`
`[0037] The term “neuroprotection" and its cognates refer to prevention or a
`
`slowing in neuronal degeneration, including, for example, demyelination and/or axonal
`
`loss, and/or, neuronal and/or oligodendrocyte death. Neuroprotection may occur
`
`through several mechanisms, e.g., through reducing inflammation, providing
`
`neurotrophic factors, scavenging free radicals, etc. As used herein, a compound is
`
`considered neuroprotective if it (1) upregulates the Nrf2 pathway above a certain
`
`threshold and (2) provides neuroprotection, regardless of possible other mechanisms
`
`of action.
`
`{E3038} The terms “treatment," ‘fiterepeutéc mettted," “therapeutic benefits,“ end
`
`the like refer to therapeutic as well as ereehyieeticipreventetive measures. Thus,
`
`these in need of treatment may include iradividuets etreedy having a specified disease
`
`and these whe are at risk for acquiring that disease.
`
`[0039] The terms "therapeutically effective dose" and “therapeutically effective
`
`amount" refer to that amount of a compound which results in at least one of prevention
`
`Page 16 of 49
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`W0 2008/09 7596
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`PCT/US20CE8/001602
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`or delay of onset or amelioration of symptoms of a neurological disorder in a subject or
`
`an attainment of a desired biological outcome, such as reduced neurodegeneration
`
`(e.g., demyelination, axonal loss, and neuronal death) or reduced inflammation of the
`
`cells of the CNS.
`
`[0040]
`
`In one aspect, provided are methods of evaluating neuroprotective
`
`properties of test compounds, including the following methods:
`
`1) methods of screening for new candidate compounds that may be
`
`useful for treating a neurological disease;
`
`2) methods of evaluating neuroprotective properties of drugs and
`
`candidates that are used or proposed for treating a neurological
`
`disease;
`
`3) methods of comparing (e.g., for bioequivalence) two or more
`
`pharmaceutical compositions which contain fumaric acid
`
`derivatives;
`
`[0041]
`
`In some embodiments, methods 1-3 may coneprise:
`
`a) contacting a cell with the test compound.
`
`b) deterreining whether the Nrf2 pathway is upregulated in the cell,
`
`and, in some embodiments, additionally performing the following step(s):
`
`c) detennining whether the test compound slows or prevents demyelination,
`
`axonal loss, and/or neuronal death, and/or
`
`d) selecting the test compound as a candidate for treating neurodegeneration
`
`in a neurological disease if 1) the Nrf2 pathway is upregulated and 2)
`
`demyelination, axonal loss, and/or neuronal death are/is prevented or
`
`stowed,
`
`Method 1
`
`[0042]
`
`in some embodiments the methods of screening for a candidate
`
`compound for treating a neurological disease comprise:
`
`a) contacting a cell with a plurality of test compounds.
`
`b) detennining whether the Nrf2 pathway is upregulated in the cell, and
`
`c) selecting from the plurality of compounds at least one compound that
`
`upreguéates the Nrf2 pathway,
`
`Page 17 of 49
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`Vi/K) 2{}i_‘i8fii97596
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`PCT/US2008/001602
`
`wherein an upregulation of the Nrf2 pathway by the selected at least one compound
`
`indicates that the selected at least one compound may be useful for treating a
`
`neurological disease. For example, the plurality of compounds may be represented by
`
`a combinatorial chemical library, and the screening method may be performed by a
`
`high-throughput screening as described in, e.g., High-Throughput Screening in Drug
`
`Discovery (Methods and Principles in Medicinal Chemistry), by Jorg Htiser (ed.), John
`
`Wiley 8: Sons (2006).
`
`[0043] Combinatorial libraries of compounds are also described in, e.g.,
`
`Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight
`
`Compound Libraries (Tetrahedron Organic Chemistry) lan Salusbury (ed.), Elsevier
`
`(1998); Combinatorial Libraries: Synthesis, Screening and Application Potential
`
`(Library Binding), by