solving the world’s hardest problems · 2017-11-10 · • drugs for life-threatening illnesses...
TRANSCRIPT
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SolvingTheWorld’sHardestProblems
February23st,2017
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TheRoleofToxicologyinDrugDevelopment
soladosis facit venenum
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Toxicology• Toxicologyisthestudyoftheadverse
effectsofchemical,physical,orbiologicalagentsonpeople,animals,andtheenvironment.
• Toxicologistsarescientiststrainedtoinvestigate,interpretandcommunicatethenatureofthoseeffects.
• Factorsthatinfluencechemicaltoxicityincludethedosage(andwhetheritisacuteorchronic);therouteofexposure,thespecies,age,sexandenvironment.
• Therelationshipbetweendoseanditseffectsontheexposedorganismisofhighsignificanceintoxicology.
“Solelythedosedeterminesthatathingisnotapoison.”Paracelsus(German-Swissphysician),1493-1541.
Water,inexcess,istoxic.
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• Needtoprovenewdrugsaresafe:– Beforefirstadministrationtohumans– Beforelaterclinicaltrials
• Is“safe”arealisticgoal?• WhatdoesNonclinicaltoxicologyreallydo?– Hazardidentification– Riskassessment
WhyDoToxicologyTesting?
5/10/17
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HazardIdentificationvsRiskAssessment
HAZARD RISK
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IfToxicologyTestingisneededtoprovedrugs“safe”forhumanuse,wheredoesToxicologyfitinDrugDevelopment?
5/10/17
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Mile-HighViewofDrugDevelopment
Discovery• TargetValidation
• LeadDiscovery&Optimization
Pre-ClinicalEvaluations• Safety• Efficacy
ClinicalTrials• PhaseI• PhaseII
GettingtotheMarket• PhaseIII
Pre-clinical Clinical
ToxicologyineveryPhase=Nonclinical
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ToxicologySupportofDrugDevelopment
Discovery
• LimitedToxicologysupport;primarilyintheformofintellectualinput(consultation)andlimitedscreening
LeadDiscovery
• Non-GLPinvitroscreens;limitedinvivoscreening
Pre-clinicalEval
• GLPGeneralToxicology,GeneticToxicologyandSafetyPharmacology
Clinical
• GLPReproductiveToxicology,subchronic GeneralToxicology;Pre-Oncogenicity dose-ranging;InvestigativeToxicology
Market
• GLPChronicGeneralToxicology,ReproductiveToxicology,Immunotoxicology,Oncogenicity
PostMarketing
• InvestigativeToxicology;Pharmacovigilance (consultation)
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NonclinicalDeliverablesDiscoveryPhase
LeadCompound
Intellectualinput:Earlyleadsandtargetliabilityassessment
CandidateSelection-18months -12months -6months
“PHARMACY”Prelimform.ForSAandFTIHstudies
Assistancewithformulationsforanimalmodels
BIOANALYSISAssaydevelopment,preliminarymetabolismstudiessupportforSAandPharmacy
TASUPPLY Synth~300g,doserangingstudies
Supplyof~50gcompoundfromMedChem
Startsynth28daytoxandFTIHsupplies
SAFETYASSESSMENTGenotox(insilico SAR)
Adhocscreens (teratogenicity,cytotoxicity,mutagenicity,HERG,ratCVetc)orbiomarkersBasedonpriorknowledge
Formulation,speciesselectionforGLP
Bacterialmutagenicityscreen
Non-GLPRatToxscreens
Mammaliangenotoxicity(invitro)
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• Thecrossoverpointbetweendrugdiscoveryanddrugdevelopment.– Provideinformationonmechanism(s)ofactionofadrug– Providesanearlyindicationofthepotentialforsomekindsoftoxiceffects,allowingadecisiontoterminateadevelopmentprogrambeforespendingtoomuchmoney.
• Invitromethodsarewidelyusedfor:– Screeningandrankingchemicals– Studyingcell,tissue,ortargetspecificeffects– Improvesubsequentstudydesign
InVitroToxicology
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• Invitromethodsareusually– Lessexpensivetorunthaninvivostudies– Fasterthaninvivostudies– Compliantwiththe3Rsinitiative
• Replacement• Reduction• Refinement
– Somewhatlesspredictiveoftoxicityinintactorganisms
InVitroToxicology
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TargetValidation
LeadDiscovery
LeadOptimization
Pre-ClinicalEvaluation
PhaseI
PhaseII
PhaseIII
Registration&LaunchPhaseIV
WhereDoInVitroModelsFitinDrugDevelopment?
Disease/EfficacyModels
• Highbiologicalrelevance
• Understandingofanimal– versushuman–relevantModeofAction
•Medium/Lowthroughputacceptable
Predictivetests:earlyprioritizationofdrugcandidates
• Fastturnaroundtime• High/mediumthroughput
• Lowcompoundrequirement
• Qualitativeassessmenttoguidemedicinalchemistry
InvestigativePlatforms
• Highbiologicalrelevance
• UnderstandingofhumanModeofAction
• Lowthroughputacceptable
Traditionally,thisiswhere90%ofinvitrotestingtookplace.
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PredictiveToxicologyCompoundRelated
Toxicity
•Insilico flags
•Similaritytopreviouscompounds
•Predictivetox signaturese.g.BioMAP*,connectivitymapping
• Selectivity(offtargetevaluation)
TargetRelatedToxicity
EarlySafetyPrediction(ESP)
TailoredSafetyEvaluation
Supplement invivoefficacystudies(ifapplicable)withtoxicologyendpoints
Includenon-standardelementsinearlytoxicologystudies
Includeadditionalinvitro/invivoassaysinscreeningcascadee.g.Mitoactivity,myocyte,podocytes
• SecondaryPharmacology
• Genotoxicity
• Cardiotoxicity
• Hepatotoxicity
• Physicochemicalproperties
CoreStrategies
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• CrossPharmareviewofrationale,strategiesandmethodologiesforinvitropharmacologicalprofilingat4majorPharmacompanies(AZ,GSK,Novartis&Pfizer)– NineteenmoleculartargetswereidenticalinallfourPharmacompanies– Another25targetsweretestedin3outof4ofthecompanies– Recommendedminimalpaneloftargets(44targets)
SecondaryPharmacologyTargets
GPCRsAdenosine(A2a)
Adrenergic(a1a,a2a,b1,b2)Cannabanoid (CB1,CB2)
Peptidergic (CCK-A,ET-A,V1a)Dopamine(D1,D2)Histamine(H1,H2)Opioid (d,k,µ)
Muscarinic (M1,M2,M3)Serotonin(5HT1a,5HT1b,5HT2a,5HT2b)
Ionchannels
Voltagegated(Cav1.2,hERG,KCNQ1/KCNE1,Nav1.5)
Ligand gated(nACHR a1ora4,GABA-a,NR1,5HT3)
Enzymes
AchECOX1COX2MAOaPDE3APDE4DLCK
TransportersDAT,NET,SERT
NuclearHormoneReceptorsAR,GR
Bowesetal.NatureReviewsDrugDiscovery11,909(2012)
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• Thegoalistoincreasebetterdrugqualityselectionthroughtheuseofphysiologicallyrelevantinvitroculturesfortarget/diseaseinvestigation,drugdispositionandmetabolism,andtoxicityprofilingBEFORE yougointoanyanimal
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• Resultsfromnonclinicaltoxicologystudiesshould,ataminimum:– Establishasafestartingdoseforclinicalstudies– Provideinformationonadrug-treatmentregimenthatwouldproducetheleasttoxicity
– Assesstargetorgantoxicityanditsreversibility– Provideinsightintobiomarkersforclinicalmonitoring
InVivoToxicology- Purpose
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NonclinicalDeliverablesCandidatetoFirstTimeinHumans
TOXICOLOGY
Output:SummariesforIND/CIB
FinalReportsforIND
-3months -6monthsCandidateSelection FTIH
GLPGeneticToxAmesTestMouseLymphomaMicronucleus
Doserangingnon-rodent
Doseranginginrats(ifrequired) RepeatdoseTox
28Dayrodent28Daynon-rodent
SafetyPharmacologyRatIrwinstudyRatRespiratoryNon-rodentCVinvitroHerg assay
Deliver28DayToxdrug
Definelongtermrouteandfinalisolation
Startprepof6monthtoxsupplies
InitialOccupationalHazardEval.forAPI
Toxicokinetics &MajorMetaboliteID
5/10/17
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NonclinicalDeliverablesFTIHto‘ProofofConcept’(PoC)
5/10/17
+6months EndPhase(+9months)
InitiateProgramofInvestigativestudiesasrequired.
SubChronic Toxicity3/6monthrepeatdosetox studies(rodent&non-rodent)possibleenabler
Pre-Onco Studies[4yrs.before NDA/MAA]
SupplyDS3/6monthtox &preOnco
Preparedrugsupply9/12monthTox.&Carc studies
ReproductiveToxicology
RodentEFDStudy
Rabbitdoserange
Rodentfemalefertilitystudy
RabbitEFD
Supplydrugsubstanceforreprotox
BioA supportforhumanbioavailabilitystudy
AdditionalOcc.&Enviro.Safetystudies(withCHESGroup)
JapanDevelopment:Ratacute,clinicalroute
FTIH PoC (~18M)
Teratology
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NonclinicalDeliverablesPoC toMarket
5/10/17
Phase2B MarketCommitPhase3 Filing(L-12)
Rat&MouseOncostudies(3yrspre-file)
Non-rodent9/12Month
Rat6month(ifnotdoneprev.)
Ratmalefertility
RatPre/PostnatalTox
CompilationofNDA/MAA
RespondtoReg.Questions
Othersupportingstudies - bridging,combo,newroutes,regionalrequirements,investigativetox.JapanDevelopment - ‘recovery’animaldataforJNDA
+continuingactivitiesinChemistry/PharmaceuticaldepartmentsandBioAnalysis.
ImmunoToxstudiesifreq.
JuvenileTox studies(timingdependentonclinicalplan)
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NonclinicalActivitiesandDeliverablesPost-MarkettoEndofTALifeCycle
5/10/17
BIOANALYSIS
TOXICOLOGY
CHEMISTRY
ALLDEPARTMENTS
LineExtensionsIntellectualPropertydefence
RegulatoryUpdatesNewsubmissionsEmergingissuesOTCproducts
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• The numberandtypesofstudiesrequireddependonthetherapeuticindication.
• Drugsforlife-threateningillnessesrequirefewerstudiestoreachtheclinic.
• Ingeneral,animalstudiesareconductedintwospecies,onerodent(e.g.,rat,mouse)andonenon-rodent(e.g.,dog,nonhumanprimate).Biologicsmayrequireonlyonespecies.– Why2species?
• Otherspecies(e.g.,rabbits,ferrets,hamsters,mini-pigs)maybeusedforspecialstudies(e.g.,vaccinestudies).
CommentsonNonclinicalSafetyStudies
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• KeyAssumptions– Otherorganismscanserveasaccuratepredictivemodelsoftoxicityinhumans.
– Selectionofanappropriatemodeltouseiskeytoaccuratepredictioninhumans.
– Understandingthestrengthsandweaknessesofanyparticularmodelisessentialtounderstandingtherelevanceofspecificfindingstohumans.
• Caveat– Drugsshowingsafetyandefficacyinpreclinicalanimalmodelsmayshowverydifferentpharmacologicalproperties whenadministeredtohumans
AnimalModelsinToxicologyTesting
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• Developmentofproperpreclinicalmodelswhichcanefficientlypredictdrugbehaviorinhumansisessentialpriortotestingadruginahumansubject.
• TheFDAandotherregulatoryagenciesaremoreandmorerequiringSponsorstoprovidedatatosupportselectionofthespecificspecies(andevenstrains)usedtosupporttestingofnewdrugs.
AnimalModelsinToxicologyTesting
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WhatisthefutureofToxicologyinDrugDevelopment?
5/10/17
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CurrentSituation• Currently,drugdevelopmentisalong
andcostlyprocessinlargepartduetothefailureofdrugcandidatesidentifiedininitialinvitroscreenstoperformasintendedinhumans.
• Betweentheinitialtargetidentification/validationandhumanclinicaltrials,liesalargegulfthatisbridgedthroughtheuseofinvivoanimalmodelswhichareusedtopredictthepotentialefficacyandsafetyinhumans.
• Thistraditionalpathofdrugdiscoveryisinefficient atbest,withonly~9%ofcompoundsachievingMarketApproval.
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• Naturereviewsdrugdiscovery– Toxicityisleadingcauseofattritionatallstagesofdrugdevelopmentprocess– Majorityofsafety-relatedattritionoccursinpreclinicalstudies– Earlypredictionpreclinicalsafetyliabilities:design/selectionofbetterdrug
candidates– Betterdrugcandidatespossessincreasedprobabilityofmarketing/approval
Safety-RelatedAttrition:GeneralConsensus
NatureReviewsDrugDiscovery6,636-649(2007);NatureReviewsDrugDiscovery3,711-715(2004)
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Safety-RelatedAttrition:OneCompany
7.9
21
2.1 2.6
22
5
0.23
21
18
0.00
5.00
10.00
15.00
20.00
25.00
Term
inationfore
achcrite
rion(%
)
Majorreasonsforprojectterminationswithin1Company(2004-2013)
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Safety-RelatedAttrition:OneCompany
0
5
10
15
20
25
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Cardiovascular
Liver
CNS
Gastrointestinal
2007-2012
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• Twomaincontributorstothisinefficiencylieintheinvitroandinvivomodelsusedtocharacterizethecandidatemolecules.
• Thetranslatabilityofin-vitrotoin-vivotoclinicaloutcomeischallenging.– Akeyproblemisthatleadcompoundsaretypicallyvalidatedandoptimizedin
oversimplifiedculturemodelswhichlackintegrativephysiology.– Pre-clinicalinvivocharacterizationiscurrentlydependentonanimalmodels
whenthefinalcustomer(thepatient)ishuman.– However,canageneticallystablebreedofrodentsinacontrolled
environmentrepresentageneticallydiversepopulationofhumanpatientslivingindiverseenvironments?• Forexample,humansoftenmetabolizechemicalcompoundsverydifferentlyfromthe
testanimalspecies.
• Analternatepathfordrugdiscoverymaybenefitfromtheuseofmorehumanrelevant,complexinvitromodelsthatintegratetheinvivophysiology.Efficacy,ADME,drugdispositionintissueandToxicityarecriticalbreakpointsindrugdevelopmentandcouldgivethegreatestreturnonutilizationoftheseimprovedmodelsystems.
RootCauseofthisInefficiency
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PrimaryScreeningandAnimalandHumanTrials
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BACK-UPSLIDES
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• Regulationstoensuretheintegrityofdatafromnonclinicalstudies.
• IntheUSA,theGLPsareadministeredbytheFDA,andarelaidoutin21CFRPart58
• Otherregulatoryagencies(OECD,EPA)havetheirownsetsofGLPregulationsthataresimilartobutnotidenticaltothoseoftheFDA.
• DefinitivepreclinicalstudiesmustbeGLPcompliant
GoodLaboratoryPractices
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SalientPointsaddressedbyinvitroModelsforDrugSafety
RequirementsforaninvitromodelinthisSituation OrganRelevantPhysiology– Low
ThroughputSpecificeffect– HighThroughput§ Predictivetests:earlyprioritization
ofdrugcandidates- Fastturnaroundtime- High/mediumthroughput- Lowcompoundrequirement- Qualitativeassessmentto
guidemedicinalchemistry
§ Highlystandardized,thoroughlycharacterizedinvitromodelwithlowtechnical&biologicalvariability
§ Easeofuse,simplehandling§ Amenabletoautomation§ Readoutallowsquickevaluation
anddecisionmaking
§ Mechanistictests:de–riskingofinvivofindingsindevelopmentstages- Highbiologicalrelevance- Understandingofanimal–
versushuman–relevantModeofAction
- Quantitativeassessmenttomake«GO/NOGO»decision
§ ModeofActionunknown:Ascloseaspossiblerecapitulationofinvivosituation– invivophenotypedisplayedininvitrosystem
§ Humanrelevantphysiology§ Abilitytocompareanimalversus
humanataninvitrolevel§ Quantitativemeasurements
possible
OrganRelevantP
hysio
logy–
LowThrou
ghpu
t
Specificeffect–High
Throughput
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PotentialUsesofComplexInVitroCulturesinDrugDevelopment
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Adipose
Heart
FemaleReproduction
Liver
BloodVessel
Muscle
Kidney
Gut
Lung
Brain
Skin
NIHFundedandIndustrySupportedSingleand
Multi-OrganChipProjects
ParticipatingInstitutionsCharlesStartDraperLabGladstoneInstituteClevelandClinicClevelandClinic;FlocellUniversityofCalifornia,SanFranciscoUniversityofIllinoisCharlesStarkDraperLabUniversityofWashingtonUniversityofCalifornia,SanDiegoYaleUniversityVanderbiltUniversityWyssInstitute,HarvardMedicalSchoolUniversityofCalifornia,BerkeleyJohnsHopkinsUniversityColumbiaUniversityMorgridge InstituteforResearch,Inc.MassachusettsInstituteofTechnologyBaylorCollegeofMedicineWashingtonUniversityGlaxoSmithKline
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BloodBrainBarrier
• MIMETAS• Blood:Brain BarrierConsortium
– TheaimoftheprojectistodevelopamorepredictiveinvitroBBBmodelbytheintegrationofphysiologicallyrelevantfactorsintheOrganoPlateTM.
– Basedoncriteriasetbytheconsortium,theprojectwillstartwithanon-competitivephasefocusingentirelyonthedevelopmentoftheBBBmodel.
– Themodelwillbevalidatedwithaselectedcompoundlibraryandcomparedwithexistingdatatosetthebasisforinvitrotoinvivoextrapolation.
https://www.youtube.com/watch?v=L_VEJAZ5J6U
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SynovialJointModel
A)Schematicrepresentationofthesynovialjoint,adaptedfromStrandV.etal.NatureReviewsDrugDiscovery6,75-92(January2007).B)SynovialmodelintheOrganoPlateTM
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LiverOrganoid Model
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WhatIsTheBestModelofEfficacy?
ClinicalTrial(<80% attrition?)
Relevantcellandtissue
MolecularFingerprintsBiomarkers
Genetics
Emergingpath
Traditionalpath
MolecularTarget
RecombinantCellularAssay
Animalmodels
ClinicalTrial(95%attrition)