Alzheimer Clinical Trials: History and Lessons

Jeffrey Cummings, MD, ScD Center for Neurodegeneration and Translational

Neuroscience Cleveland Clinic Lou Ruvo Center for Brain Health

Disclosures Dr. Cummings has provided consultation to Acadia, Avanir,

Axsome, BiOasis, Biogen, Boehinger-Ingelheim, Bracket, Eisai, Genentech, Lilly, Lundbeck, Medavante, QR, Resverlogix, Roche, and Samus pharmaceutical and assessment companies.

Dr. Cummings has stock options in Prana, Neurokos, ADAMAS, MedAvante, QR pharma.

Dr. Cummings owns the copyright of the Neuropsychiatric Inventory.

This lecture will include reference to unapproved medications

AD Clinical Trials: History and Lessons •  Idiosyncra+chistoryofinfluen+alagents•  Cholinesteraseinhibitorsandmeman+ne•  Monoclonalan+bodies•  Smallmolecules•  Progressiverefinementoftrials•  Lessons

AD Clinical Trials: History and Lessons

1993

Tacrine: The Breakthrough Agent NEJM1986;315:1241-1245

•  Markedimprovementreported•  Unknowninstruments•  Poortrialmethods•  “Lost”records•  Pa+entadvocacyledtofollow-ontrials

Tacrine: The Breakthrough Agent

NEJM1992;327:1253-1259

JAMA1992;268:2523-2529

Tacrine: The Breakthrough Agent •  Definedmanyoftheassessmentsanddesigns+llusednow•  Cogni+veoutcome

–  ADAssessmentScale–cogni+vesubscale(ADAS-cog1)•  Globaloutcome

–  ClinicalGlobalImpressionofChange(CGIC)•  Behavioraloutcome

–  ADAS-noncog1•  Studyentry

–  MMSE10-26

1RosenW;MohsR,DavisK.Anewra+ngscaleforAlzheimer’sdisease.AmJPsychiatry1984;141:1356-1364

Tacrine: The Breakthrough Agent •  ApprovedbytheFDA,1993•  PaulLeber,headofNeurologyDivisionofFDA•  Dracguidelines(1990)

–  Symptoma+cand“defini+ve”treatments–  Dualoutcomes:

•  Core:cogni+onplus•  Measuresofclinicalmeaningfulness:globalorfunc+onal

–  Placebocomparison(“internalcontrol”vshistoricalcontrols)

LeberP.GuidelinesfortheClinicalEvalua+onofan+Demen+aDrugs(1990drac).

Tacrine: The Breakthrough Agent

Alzheimer’sdiseaseistreatable!

AD Clinical Trials: History and Lessons

1993

AD Clinical Trials: History and Lessons

1993 1996 2000 2004

Cholinesterase Inhibitors •  Donepezil(Aricept)1

–  5,10mg(1996)–  Highdose(23mg);2010

•  Rivas+gmine(Exelon)2

–  Oralform;3mg,4.5mg,6mg(2000)–  Patch(transdermalformula+on)(2007)–  Highdose(13.3mg)patch(2012)

•  Galantamine(Reminyl[2004]àRazadyne[2005])3

•  Mild,moderateandsevere(donepezil,rivas+gmine)ADdemen+a1RogersS,etal.Neurol1998;50:1360145;2RoslerM,etal.BMJ1999;318:633-638;3WilcockG,etal.BMJ2000;321:1445-1449

Cholinergic Casualties and Catastrophes •  Cholinesteraseinhibitors

–  Physos+gmine;shorthalflife1

–  Metrifonate;respiratoryparalysis2,3

•  Muscarinicagonists–  Syncope(xanomeline4)

•  Nico+nicagonists–  Promisinginsometrials–  Outcomesinconsistent5

•  Notallcholinergicapproachessucceeded

1BellerS,etal.Psychopharm1985;87:147-151;2Lopez-ArrietaJ,SchneiderL.CochraneDatabaseSystRev2006;19:CD003155;3CummingsJ,etal.Neurology1998;50:1214-1221;4BodickNetal.ArchNeurol1997;54:465-4735FlorianH,etal.JAlzDis2016;51:1237-1247

AD Clinical Trials: History and Lessons 1993-2004

AD Clinical Trials: History and Lessons 1993-2004 2003

Memantine •  N-methyl-d-aspartateinhibitor•  Monotherapy1andadd-ontherapy2

•  ModeratetosevereAD•  Usedinconjunc+onwithcholinesteraseinhibitors•  Add-ontreatmenttostandard-of-careisthetrialnorm

establishedbymeman8ne

1ReisbergBetal.NewEnglJMed2003;348:1333-1341;2TariotPetal.JAMA2004;291:317-324

AD Clinical Trials: History and Lessons 1993-2004 2003

AD Clinical Trials: History and Lessons 1993-2004 2003 2005

AN 1792 •  Amyloidbetaprotein(Aℬ)vaccine•  BasedonAPPanimalmodelofAD1

•  Clinicaltrial2–  Firstmajordisease-modifica+ontrial–  Firstimmunotherapytrial–  An+bodiesgenerated–  6%developedmeningoencephali+s–  Noconsistentclinicalbenefit

1SchenkD,etal.Nature1999;400:173-177;2GilmanS,etal.Neurology2005;64:1553-1562

DaleSchenk,PhD

AD Clinical Trials: History and Lessons 1993-2004 2003 2005

AD Clinical Trials: History and Lessons 1993-2004 2003 2005 2009

Tarenflurbil (R-flurbuprofen)1

•  Renan+omerofibuprofen(reducedan+-inflammatoryeffectsandNSAIDs-relatedsideeffects)

•  Gamma-secretasemodulator;reducedbrainamyloidinanimalmodels

1GreenR,etal,JAMA2009;302:2557-2564

Tarenflurbil (R-flurbuprofen)1

•  Targetengagementnotshowninhumans•  Brainpenetra8onpoorinhumans•  Dose-responsenotexploredinhumans•  Phase2trialnega8ve;subgroupanalysisguidedPhase3

–  Mildpa8ents–  Highserumlevels

1GreenR,etal,JAMA2009;302:2557-2564

AD Clinical Trials: History and Lessons 1993-2004 2003 2005 2009

AD Clinical Trials: History and Lessons 1993-2004 2003 2005 2009 2013

Semagecestat

DoodyR,etal.NEJM2013;369:341-350

•  Gamma-secretaseinhibitor•  Mild-moderateAD•  Nobiologicalconfirma+onofdx•  Worsenedcogni+on•  Worsenedfunc+on•  Skincancerintreatmentgroup

Semagecestat

GrillJ,etal.AlzRes&Therapy2015:7:39

Timetodiscon+nua+on(reten+on)•  Differsbyglobalregion•  Japan–highlylikelytostayinstudy•  EasternEurope–high

discon+nua+onrate•  Createsheterogeneityindata•  Heterogeneityinrateofdecline,

adverseevents,etc

AD Clinical Trials: History and Lessons 1993-2004 2003 2005 2009 2013

AD Clinical Trials: History and Lessons 1993-2004 2003 2005 2009 2013 2014

Bapineuzumab

•  Vaccine(AN1792)causedencephali+s•  Monoclonalan+bodiesrepresentedamorefocusedtypeof

immunotherapy•  Bapineuzumabrepresentedthenextstepinimmunotherapy

–  Phase2showednoeffectonADAS-cog1–  PosthocanalysissuggestedbenefitinApoE-4noncarriers–  P3showednobenefitincarriersornon-carriers2–  Mild-to-moderateAD;dxnotconfirmedbiologically

1SallowayS,etal.Neurology2009;73:2061-2070;2SallowayS,etal.2914;370:322-333

Bapineuzumab

Phase2:Nonsignificant1 Phase3:Nonsignificant2

1SallowayS,etal.Neurology2009;73:2061-2070;2SallowayS,etal.2914;370:322-333

AD Clinical Trials: History and Lessons 1993-2004 2003 2005 2009 2013 2014

AD Clinical Trials: History and Lessons 1993-2004 2003 2005 2009 2013 2014 2016

Aducanumab

SevignyJetal.Nature2016;537:50-58

Aducanumab •  Removedamyloidplaque•  Reducedcogni+vedeclineon

CDR,MMSE(notNTB)•  ProdromalADandmildAD

demen+a•  Biologicallyconfirmed(PET)•  Phase2(165pa+ents)•  HighrateofARIA

SevignyJetal.Nature2016;537:50-58

Aducanumab: Phase I/ Phase III Differences

Feature PRIME ENGAGE EMERGE

N 197(planned) 1350(+255) 1350(+255)

Countries USonly US+13countries US+12countries

ProdromalAD MMSE24-30CDR0.5FCSRT<27

MMSE24-30CDR0.5

MMSE24-30CDR0.5

MildADdemen+a MMSE20-26CDR0.5or1

Notincluded Notincluded

Cohorts 9(drugwpbo) 3(2doses,pbo) 3(2doses,pbo)

Dura+on 52weeks 78weeks 78weeks

Primaryoutcome Safety CDR-sb CDR-sb

Secondaryoutcome

Amyloidimaging MMSEADAS-cogADCS-ADL(MCI)

MMSEADAS-cogADCS-ADL(MCI)

AD Clinical Trials: History and Lessons 1993-2004 2003 2005 2009 2013 2014 2016

AD Clinical Trials: History and Lessons 1993-2004 2003 2005 2009 2013 2014 2016 2018

Verubecestat •  Betaamyloidprecursorproteincleavageenzyme(BACE)

inhibitor•  1958pa+entsintrial•  Mild-moderateAD•  Dxnotbiologicallyconfirmed•  ReducedCSFAℬ65-90%

–  Effec+vepharmacology•  Nocogni+vebenefit(terminatedforfu+lity)

EganM,etal.NEJM2018;378;1691-1703

AD Clinical Trials: History and Lessons 1993-2004 2003 2005 2009 2013 2014 2016 2018

AD Clinical Trials: History and Lessons 1993-2004 2003 2005 2009 2013 2014 2016 2018 2018

Solanezumab

DoodyR,etal.NEJM2014;370:311-321

•  Posthoc•  Improved

inmildAD

RachelleDoody

Solanezumab

HonigL,etal.NEJM2018;378:321-330.

•  MildADonly•  Dxbiologically

confirmed(CSForPET)•  Nobenefit

AD Clinical Trials: History and Lessons 1993-2004 2003 2005 2009 2013 2014 2016 2018 2018

AD Clinical Trials: History and Lessons 1993-2004 2003 2005 2009 2013 2014 2016 2018 2018 2018

BAN-24011

•  Monoclonalan+body•  Prefibrillaramyloidtargetepitope•  ProdromalADandmildADdemen+a•  Dxbiologicallyconfirmed•  Phase2•  856randomized•  Adap+vedesign•  ADCOMS2;novelprimaryoutcome•  Irregularrandomiza+onofApoE-4carriers

1KramerL,etal.AAIC,2018;2WangJ,etal.JNNP2016;87:993-999

BAN-2401

KramerL,etal.AAIC,2018

•  AmyloidPETSUVR•  81%convertedfromvisual+

tovisual(-)onamyloidPET•  LowrateofARIA

BAN-2401

KramerL,etal.AAIC,2018

ADCOMS1 ADAS-cog

1WangJ,etal.JNNP2016;87:993-999

Monoclonal Antibodies •  Solanezumabinpreven+ontrialofcogni+velynormalamyloidposi+veindividuals(A4)

•  Gantanerumab1

•  Crenezumab2

1OstrowitzkiS,etal.AlzResTherapy2017;9:95;2CummingsJ,etal.Neurology2018;90:e1889-1897

Amyloidreduc+onwithgantenerumab

AD Clinical Trials: History and Lessons •  Thisishardwork!•  Progressiveimprovementinunderstandingbiology,

developingtherapies,conduc+ngtrials•  Animalsmaynotpredictefficacyorsafety(AN1792;

tarenflurbil)•  Brainpenetra+on,dose,andtargetengagementmust

solvedinPhase2(tarenflurbil)•  Posthocsub-groupfindingsareapoorbasisforPhase3

(bapineuzumab,solanezumab)

CummingsJ.ClinTranslSci2018;11:147-152

AD Clinical Trials: History and Lessons •  Biologicalconfirma+onofdiagnosistoinsurethepresenceofthetargetpathology

•  Globaltrialsintroduceheterogeneityofdata•  Drugsmaymakepa+entsworse(semagecestat)•  Trea+ngearlierindiseasemayhavebenefit(aducanumab,BAN-2401;notsolanezumab)

•  Newtrialtoolsareemerging(BAN-2401)

CummingsJ.ClinTranslSci2018;11:147-152

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