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UnmetNeedsforParkinsonsDiseaseTherapeutics

CarolineMTannerMD,PhDDirector,Parkinson'sDiseaseResearchEducationandClinicalCenter

SanFranciscoVeteran'sAffairsMedicalCenter&

ProfessorinResidence,Dept.ofNeurologyUniversityofCalifornia SanFrancisco

CoalitionAgainstMajorDiseases&FDAWorkshopOctober20,2014

Disclosures:ConsultantforAdamas &PfizerPharmaceuticals

Topics

WhyParkinsonsDiseasetherapeuticsmatters

TherapeuticGaps BridgingtheGaps

Newapproaches Continuingchallenges

GlobalBurdenofParkinsonsDiseaseIsExpectedtoIncreaseAsLifeExpectancyIncreasesWorldWide

AGE60+

2015

4

Consequently, the global burden of Parkinsons disease is expected to increase

Change in number of people with Parkinsons disease in the worlds most populous nations from 2005 to 2030*

Source: Dorsey et al, Neurology 2007;68:384-6

*Amongindividualsover50intheworldstenmostandWesternEuropesfivemostpopulousnations

ConsequencesforSociety

Costs:DirectcostsofhealthcareIndirectcosts:

Lossofyearsworked,lostsocietalcontributions

Mental&physicalcostsAffectspersonwithPD&familymembers,colleagues,friends

Mov Disord 2013

CanWeReducetheBurden?Advocacy

HealthServicesEducationResearch

BetterTreatment

HistoryofPDTherapyintheUS1817: ParkinsondescribedParalysisagitansLate1800s: BelladonnaalkaloidsasRx1950s: Syntheticanticholinergics asRXLate1960s: Ldopa1970s:

Ldopa+decarboxylase inhibitor(dci)AmantadineBromocriptine asadjuncttoldopa

1980s:Pergolide asadjuncttoldopaWithdrawn2007Sustainedreleaseldopa/dciSelegilineasadjuncttoldopa

1990s:1997Pramixpexole (mono,adjunct)1997Ropinirole (mono,adjunct)1998 Tolcapone (withldopa/dci)Blackboxhepaticfailure1999Entacapone (withldopa/dci)

2000s:2004Apomorphine s.c.(Intermittenthypomobility)2006Rasagaline (mono,adjunct)2007Rotigotine patchRecall20082006/7Rivastigmine oral&patchDementia

2010 :2012Rotigotine patchReintroduced?

ALLBUT1DRUG:SYMPTOMATICTREATMENTFORMOTORSYNDROME

ClinicalKnowledgeGapsinParkinsonsDisease

CLINICALCOURSE: Nodiagnostictest Nopredictorofrisk(formost) Noreliablemarkerofprogression NoreliablepredictorofprognosisTREATMENT: Nowaytopreventdisease Nocure Nowaytoslowdiseaseprogression InadequateSymptomaticTreatment:

Motor imperfectcontrolofsymptoms,andwithsideeffects Nonmotor manyanddiverseproblems,fewtreatments

BridgingtheGap

THEFIRSTCHALLENGE:DefiningParkinsonsDisease

LangstonAnnNeurol2006Langston,2008

Stri

atal

dop

amin

e

0%

80%

100%

20

60%

40%

PARKINSONSDISEASEPRODROMAL

At diagnosis of Motor PD:

50% neuron loss in the substantia nigra

80% striatal dopamine deficit

PRECLINICAL

TheSecondChallengeMeasuringDiseaseProgression

PreventSymptomOnset

SloworStopProgressionofmotorsyndrome

Pathogenesis&clinicalcourseofPDonlypartiallyunderstood

Preventdiseasefeatures:dyskinesias,dementia

HEALTH DISEASE DISEASE OUTCOMES

Markers of risk Prodromal Diagnosis Progression

Genes Exposure group?

HyposmiaANS RBD Tissue*? Imaging?

Clinical Post-mortem Imaging(adjunct)

Tissue*?

Clinical exam Tissue*? Imaging?

The3rd Challenge:DefineMeasuresofRisk,Onset&ProgressioninParkinsonsDisease

*Blood,CSF,skin,GI(ENS),salivarygland,other?

RELIABLEBIOMARKERSNEEDED!

PPMIThe Parkinsons Progression Markers Initiative: A Prospective Biomarkers Study

OBJECTIVES

PPMI

Dataset/sample

collection

Standardizedprotocols

Biomarkerverificationstudies

Identifyprogressionmarkers

Imaging & Biologic markers may increase efficiency of clinical trials

Frasier et al, 2010; Marek et al 2011

EarlyUntreatedPD

POPULATIONS

MatchedControls

RBD

LRRK2,SNCAPD&Families

Hyposmics

RealTimeDataSharing

OvercomingBarrierstoSuccessinStudiesofParkinsonsDisease

Slowenrollmentisamajorcauseofdelayandexpense

Onlyabout10%ofpersonseligibletoparticipateinstudiesenroll

Canchangesinoutcomes&studyconductspeedthingsup?

ImproveOutcomeMeasuresDevelopMeasuresNotDependentonMotorDisease: Imaging:brain(DaTScan ),otherorgans Physiologicalmeasures:Tremorrecording,tappingtime,EEGspectralanalysis

Globalclinicalmeasures:selfreportedorexamination&interviewbased(UPDRS,QOL)

Otherbiomarkers:laboratorymeasurementsofbodytissues(blood,urine,CSF,saliva,biopsiedtissue)

FUTURE:Combinationsofmeasures

IncreaseEnrollment&RetentionInClinicalTrials

RemoteAssessment

Telemedicine

BIGDATA Informationfromcontinuousmonitoring Largenumbersofpeople Universalplatform Cancombinew/otherinfo(imaging,genes)PotentialBenefits: Identifypatternsofdiseaseprogression Reducetheburdenofclinicaltrialparticipation Identifysubgroupsmorelikelytobenefitfromcertaininterventions

Providenewoutcomemeasures?

LinkedClinicalTrials:Repurposing

The map

Revise the map of LCT

Brundinetal,JPD2014

THANKYOU!

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