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ClosinginonAlzheimersdisease|Feature|PharmaceuticalJournal

Dementia

ClosinginonAlzheimersdisease
ThePharmaceuticalJournal,14AUG2015 ByDawnConnelly

KnowledgeabouttheneuropathologyofAlzheimersdiseasehas
blossomedoverthepastfewdecades,leadingtoabetterunderstandingof
theconditionandnewwaystoattackit.
Alzheimersdiseaseisaprogressivedisorder.Aftersymptomsfirstappear,lifeexpectancyisaround810
years.Memoryistypicallythefirstproblem,thendifficultieswithcognitionandplanningbecomemarked,
speechandlanguageareaffected,andpatientsmayexperiencealteredpersonalityandbehaviour.Eventually,
individualsareunabletocareforthemselves(seePDFofgraphic).
Twomainprocessesarethoughttodrivedegeneration:intracellularaccumulationofaproteincalledtauand
extracellulardepositionofaproteincalledbetaamyloid(A),leadingtoformationofneurofibrillatorytangles
andamyloidplaques.Althoughmostpeopledevelopsometanglesandplaquesastheyage,thosewith
symptomsofAlzheimersdiseasetendtodevelopfarmore.

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Pathology
Oligomersarethoughttobemoredamagingthanplaquesbecausetheyblockcelltocellsignallingat
synapsesandmayalsoactivateimmunesystemcellstriggeringanattack

Tauandtangles
(1)Insidethehealthyneuron,parallelmicrotubulesprovidethecellstransportsystemfornutritionandkey
materialstobedelivered.Tauproteinactasscaffoldingforthemicrotubules,keepingtheminplace.
(2)Hyperphosphorylationoftauleadstoformationoftauoligomers.Theseoligomersclumptogetherwith
othermoleculesandformtangles.
(3)Bydistortingthespacingofmicrotubules,tanglesimpairaxonaltransportthusaffectingthenutritionof
axonterminalsanddendrites,eventuallyleadingtocelldeath.

BetaAmyloid
(1)APPisatransmembraneprotein,madebyneuronsandotherbraincells.(2)AiscutfromAPPbythe
enzymessecretase(alsocalledBACE1)andsecretasereleasingAmonomersintotheextracellular
environment.(3)Onceclipped,Amonomerscanassembleinatleasttwoways:onepathwayleadsto
solubleoligomersofA42,whicharesmallenoughtoentersynapses.(4)AnotherpathwayforA
monomersistoassembleintoinsolublefibrilsandlargerplaques,whichcanprovokeharmful
inflammation.

Biologicaltargets
Licenseddrugstreatsymptomsbyregulatinglevelsoftheneurotransmittersacetylcholineandglutamate,which
areimportantforneuronalcommunication.Incontrast,drugsindevelopmentaimtoinhibitthemechanismsthat
leadtothebuildupofplaquesandtanglescharacteristicoftheconditionbytargetingA,tauorthe
inflammationcausedbyplaquesandtangles.

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Licensedtreatments
ThreecholinesteraseinhibitorsarecurrentlylicensedtotreatAlzheimersdiseasesymptoms,aswellas
oneNmethylDaspartate(NMDA)blocker.

Pipelinedrugs
Monoclonalantibodies(blue)aimtocleartoxicAeitherdirectlyorthroughmicrogliaorastrocyte
activation.However,antibodieshavelimitedbioavailabilityinthebrainandcaninduceimmunogenicity.
Smallmolecules(yellow)aimtoreduceAproduction,preventtauaggregationortarget
neuroinflammation.Theyhavebetterbioavailabilityinthebrainthantheantibodies.Seetablebelowfor
breakdownofdrugs

Monoclonalantibodies
1

ChugaiPharmaceutical/HoffmannLaRochesgantenerumabisafullyhumanIgG1monoclonalantibodythatrecognises
primarilyfibrilsofA.Itstimulatesmicrogliatoclearamyloidplaques.

Biogensaducanumabisahighaffinity,fullyhumanIgG1monoclonalantibodythatbindsaggregatedformsofA,not
monomers.Itstimulatesmicrogliatoclearamyloidplaques.

EliLillyssolanezumabisahumanisedmonoclonalIgG1antibody,whichrecognisessolublemonomersof
3 A,notfibrils.Itstimulatesmicrogliatocleartoxicamyloidmonomers.
GenentechscrenezumabisafullyhumanIgG4monoclonalantibody,whichrecognisesmultipleformsofaggregatedA,

4 includingoligomersandfibrilsandamyloidplaqueswithhighaffinity,andmonomerswithlowaffinity.Itstimulatesmicroglia
enoughtoclearA,butnotenoughtoinduceaninflammatoryresponse.

Biogen/EisaisBAN2401isahumanisedIgG1monoclonalantibodythatselectivelybindstolarge,solubleAprotofibrilsand
stimulatestheirclearancebymicroglialcells.

Smallmolecules
6

Gammasecretasemodulators,suchasMercksGSM1andEisaisE2012,reducethecleavageofAPPthatproducesthemost
toxicpeptide,A42,whilestillallowingtheenzymetocleaveitsothersubstrates.

MercksMK8931andAstraZenecasAZD3293bothinhibitBACE1,sointerferewithproductionofA.

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TauRxTherapeuticssLTMXisatauaggregationinhibitorthatreduceslevelsofaggregatedormisfoldedtauproteins.

Twolicenseddrugs(namesnotreleased)havebeenfoundtoinhibittheenzymePERK,whichisthoughttoswitchoff
productionofallnewproteinsinthebraininresponsetoaccumulationofamyloidplaques.Newproteinsarenecessaryfor
neuronalplasticityandmemoryconsolidation.

10

T3DTherapeuticssT3D959isadualnuclearreceptoragonist,whichhasthepotentialtoinhibitboththeAandtau
pathways.

11

Pfizer/TransTechsazeliragonisanantagonistofthecellsurfacereceptorRAGE,whichcanleadtoinflammationand
oxidativedamagewhenoccupied.RAGEmayalsomediatethetoxiceffectsofAoligomers.

Drugdevelopment
Azheimersdisease(AD)wasfirstidentifiedbyGermandoctorAloisAlzheimerin1906butitwasnotuntil
1993thatthefirstdrugtotargetthesymptomsofAlzheimerswasapprovedbytheUSFoodandDrug
Administration(FDA).Despitea99.6%attritionrateforADdrugsbetween2002and2012,thereishopefor
currentpipelinedrugsbeingtestedinprodromalandmildAD,withtheaimofstoppingdiseasedevelopment
ratherthantreatingsymptoms.
1993:WarnerLambertstacrine(Cognex)receivesFDAapprovalformildtomoderateADbutislater
discontinued.
1996:Eisaisdonepezil(Aricept)receivesFDAapprovalformildtomoderateAD.Thiswasextendedto
includesevereADin2006.
2000:Novartissrivastigmine(Exelon)receivesFDAapprovalformildtomoderateAD.
2000:Shiresgalantamine(Reminyl)receivesEuropeanMedicinesAgency(EMA)approvalformildto
moderateAD.
2002:ForestLaboratoriessmemantine(Ebixa)receivesEMAapprovalformoderatetosevereAD.
2012:TwophaseIIItrialsofEliLillysmonoclonalantibodysolanezumabinpatientswithmildto
moderateADdonotreachtheirendpoints.
2012:PhaseIItrialofBiogen/EisaismonoclonalantibodyBAN2401beginsrecruiting800peoplewith
earlystageAD.EstimatedcompletiondateisJuly2018.
2012:TwophaseIIItrialsofTauRxTherapeuticssLMTX,asecondgenerationtauaggregationinhibitor,
begininpatientswithmildandmildtomoderateAD.Studyresultsareexpectedin2016.
2013:PhaseIItrialofGenentechsmonoclonalantibodycrenezumabstartsinpatientswithpreclinicalAD,
withresultsduein2020.Twoadditionalphase2trialsinmildtomoderateADareongoing.
2013:PhaseIIItrialbeginstoassesssafetyandefficacyofMSDsBACEinhibitorMK8931compared
withplaceboinpatientswithprodromalAD.Thetrialissettorununtil2018.
2014:Actavis/Adamassdonepezil/memantinecombinationproduct(Namzaric)receivesFDAapprovalfor
moderatetosevereAD.
2015:Biogenreportsadosedependentreductioninamyloidplaqueandslowingofcognitivedeclinefor
monoclonalantibodyaducanumabinaninterimanalysisofphase1bdataforprodromalormildAD
patients.
2015:NewdelayedstartanalysisofnegativephaseIIIsolanezumabtrialssuggestsitmayslow
progressionofmildAD.

Citation:ThePharmaceuticalJournal,22/29August2015,Vol295,No7876/7,online|URI:20069081

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