Pharma goes FAIR · Open PHACTS data sources DTL meeng Utrecht 23/11/2017 10 Phenotypic Drug Discovery Workflows Digles et al, MedChemComm, 7: 1237 (2016) “Knowing the knowns”

PharmagoesFAIR

HermanvanVlijmenJanssenPharmaceu9ca

Beerse,Belgium

WhatisFAIR?

23/11/2017 2DTLmee9ngUtrecht

hIps://www.dtls.nl/fair-data/fair-data/

SciData.2016,3:160018


WhyisFAIRimportant?

•  Manydatasetsanddatabasesares9llsiWnginsiloswith–  Pooraccessibilityand/orfindabilityofdata– Absentorincompleteuseofnomenclaturestandards

•  Theamountanddiversityofscien9ficdataisgrowingfast

•  Mostvaluableanalysisinvolvesdatafromdifferentdomains/technologies

•  Machinelearninganddataminingrequireunambiguouscomputer-readabledata


23/11/2017 5

Frommoleculetomedicine

5 FROMDISCOVERYOFADRUGTOSUBMISSIONOFREGISTRATIONFILE FROMREGISTRATIONTOLAUNCH FROMLAUNCHTOLOSSOFPATENT

0YEAR 20y4 6 12,5y

BASICRESEARCH DEVELOPMENT CLINICALTRIALS REGISTRATION COMMERCIALIZATION

5

è è

BasicResearch/Discovery-  SelectDisease-  SelectDrugTarget-  IdenCfyBioassay-  Findcompoundhits-  Findleadcompound(s)-  Selectclinicalcandidate

Development-  Drugmetabolismand

PharmacokineCcs-  SafetyevaluaCon-  ChemicalproducCon-  PharmaceuCcalformulaCon

ClinicalTrials-  Safety(PhaseI)-  Efficacy&Dose(PhaseII)-  Efficacy(PhaseIII)-  PostmarkeCng(PhaseIV)

5DTLmee9ngUtrecht

WhyisFAIRimportanttoJanssen?•  Ifthedataistherebutnobody(re)usesit…•  Scien9stsatJanssenrarelyusealldatatheyhaveaccessto–  Difficulttoaccessmul9pledatabases–  Lackofawarenessofdatabases–  LiIleexperiencewithdefini9onofcross-domainanalysis

•  Datafrommul9pledomainsandsources(private,public,commercial)isneededforbestpossibleanalysis–  Targetiden9fica9onandvalida9on–  Hitfinding,H2L,LeadOp9miza9on–  Phenotypicscreens,Omicsexperiments– Mechanis9canalysistox,sideeffects,drugrepurposing–  Transla9onalanalysis(cellphenotype<->animal->human)–  ClinicalandRealWorldEvidenceanalysis


23/11/2017 7

Answeringmorecomplexques9ons

DTLmee9ngUtrecht


23/11/2017 9

OpenPHACTSdatasources

DTLmee9ngUtrecht

23/11/2017 10

Phenotypic Drug Discovery Workflows

Diglesetal,MedChemComm,7:1237(2016)

“Knowingtheknowns”

DTLmee9ngUtrecht

23/11/2017 11

OpenPHACTSdevelopments:PatentInfo

•  Hugeamountofknowledgeinpatentcorpus,mostofwhichwillneverbepublishedelsewhere,butpoten9allygreatvaluetodrugdiscovery

•  SureChEMBLsystem(EBI)alreadyautoma9callyextractscompoundsfromthesedocuments

•  OpenPHACTSconsor9umfundedprojecttoalsoextractgene/diseaseinforma9on(EMBL-EBIandSciBite)

•  ~4millionpatentsintotal,260millionannota9ons(patent-compound,patent-geneorpatent-diseaseassocia9ons)

•  Exampleusecases:–  Foragiventargetordisease,givemeallthecompoundsthatarelinkedtothisthroughpatents

•  Importanttofindnewextrac9ontoolstocon9nuethisannota9onandmakeavailableatEBI

DTLmee9ngUtrecht

23/11/2017 12

Abroadsetofusecasescanbeaddressedusingalinkeddatasystem

Someexamples:TargetidenCficaConandvalidaCon•  Givemealldirectandindirectsuppor9ngevidencelinkingageneanddisease•  Arethereexamplesofcompoundstarge9nganymemberofthistargetfamily?•  Whataretherelevantindirectlinksbetweenageneandaphenotypicassay?LeadidenCficaConandopCmizaCon•  Whatcompoundsbindtothistargetorrelatedtargets(family,3Dsimilarity)?•  Whatbioac9vi9esandpathwaysareassociatedtoacompound?•  Showtheac9vityofthesecompoundsonallkinasesinvolvedinthispathway•  Whatarepoten9alside-effectsofhiWngsimilarbindingsitestoourtarget?•  Whatsideeffectshavesimilarcompounds?Biomarkerdiscovery•  Whatsecretedproteinsinapar9cular9ssueareassociatedwiththiscellularpathwayandmightbe

biomarkers?•  Newbiomarkers:forwhichindirectbiomarker-diseaselinksthereisnodirectreportedassocia9on,

andwhichoneshavethestrongestlevelofdatasupport?

DTLmee9ngUtrecht

23/11/2017 13

Queryinghigherlevelresearchques9ons

WhataretheJanssencompoundsac9veinthisJanssenassay?

Givemeallinternal/commercial/publicdataoncompoundsthatareac9veonmytargetandothercloselyrelatedtargets.

Whatisthedifferenceingeneexpressionprofilebetweentumorandnormal9ssue?

Giventhedifferencesinexpressionprofilesbetweenthese9ssues,givemethecompoundswithbiochemicalacCvityprofilesthatresemblethedifferenceprofilemost

SearchPubMedforpoten9altarget-diseaseassocia9on:“bcl2schizophrenia”

Showmeallpossibledirectandindirectlinksbetweenbcl2andschizophrenia,rankedbylevelofscienCficdatasupport

IhaveaCDK7leadcompound.IsthereanythingknowninPubMedontoxicityofCDK7inhibitors?

GivenmyCDK7leadcompound,whatarethemostlikelymechanismsbywhichthiscompoundclasscouldcausetoxicity

Acomparisonofthequeriesthataredonetodayversuswhatwillbepossible

TODAY FUTURE

DTLmee9ngUtrecht

InternaleffortsinDiscovery:Chem3

23/11/2017 14

•  SemanCcgraphdatabaseofinternalandexternaldatalinkedtochemistry– CompoundAc9vity:

•  ABCD,Athena,PIRlab,CAPE(allinternalJanssen)•  ChEMBL,PubChem,GOSTAR,Clarivate•  Pending:

–  SureChEMBL–  Etc.basedonuserneeds

–  Plasorm:Virtuoso–  Fastchemicalcartridge(internal)

•  Interfacein3DX,PipelinePilot,RDTLmee9ngUtrecht

23/11/2017 15

ExamplesofLinkedDatachallengesinPharma

Datatypesandunitsforpharmacologicalac9vityinChEMBL

LeeandGobbi.J.Chem.Inf.Model.2012,52,285−292

Stereochemistry Tautomerism

DTLmee9ngUtrecht

InternaleffortsinDiscovery:ExploringuseofEuretosKnowledgePlasormforTI/TV

23/11/2017 16

Step1 Step2

www.euretos.comDTLmee9ngUtrecht

InternaleffortsinDiscovery:ExploringuseofEuretosKnowledgePlasormforTI/TV

23/11/2017 17

Step3 Step4

www.euretos.comDTLmee9ngUtrecht

23/11/2017 18

-  CalllaunchedinJuly2017-  Candidateconsor9aarecurrentlybeingevaluated

-  LikelystartprojectQ32018,dura9on3years-  Budget:Thefinancialcontribu9onfromIMI2isamaximumofEUR4M

-  Pharmapartners:Janssen,AZ,Bayer,BoehringerIngelheim,EliLilly,GSK,Novar9s

DTLmee9ngUtrecht

SummaryofFAIRifica9onProposal•  Selectdatasetsanddatabasesfromfinishedandongoing

IMIprojects,basedon:–  Scien9ficvalueofmakingthisdataaccessibleandinteroperable–  Complexityofmakingthedataavailable

•  SelectdatabasesatindividualEFPIAcompanies–  Selec9onbasedonvalueforcompanies–  Consolida9ontolimitedsetofdatadomains

•  FAIRifythesedatasetstoenablethesustainableuseofthedatainansweringresearchques9ons–  WorksessionswithdataownersandFAIRifica9onexperts,including

datadomainexperts(vocabularies,ontologies,usecases)andITexperts(conversionofdata,databaseimplementa9on)

–  Implementa9onofsustainablesolu9onforstorageandmaintenanceofFAIRifiedIMIdatabases

–  Iden9fica9onofsustainablesolu9onforstorageandmaintenanceofFAIRifiedEFPIAdatabases

23/11/2017 DTLmee9ngUtrecht 19

-ELFEuropeanLeadFactory-EMIFEuropeanMedicalInforma9onFramework-EMTRAINEuropeanMedicinesResearchTrainingNetwork-ENABLEEuropeanGram-nega9veAn9bacterialEngine-EPADEuropeanpreven9onofAlzheimer’sdemen9aconsor9um-eTOXIntegra9ngbioinforma9csandchemoinforma9csapproachesforthedevelopmentofExpertsystemsallowingtheinsilicopredic9onoftoxici9es-eTRIKSDeliveringEuropeanTransla9onalInforma9on&KnowledgeManagementServices-EU-AIMSEuropeanAu9smInterven9ons-aMul9centreStudyforDevelopingNewMedica9ons-Eu2PEuropeanprogrammeinPharmacovigilanceandPharmacoepidemiology-EUPATIEuropeanPa9ents'AcademyonTherapeu9cInnova9on-EUROPAINUnderstandingchronicpainandimprovingitstreatment-FLUCOPStandardiza9onanddevelopmentofassaysforassessmentofinfluenzavaccinescorrelatesofprotec9on-GETREALIncorpora9ngreal-lifeclinicaldataintodrugdevelopment-iABCInhaledan9bio9csinbronchiectasisandcys9cfibrosis-IMIDIAImprovingbeta-cellfunc9onandiden9fica9onofdiagnos9cbiomarkersFortreatmentmonitoringindiabetes

-iPiEIntelligentAssessmentofPharmaceu9calsintheEnvironment-K4DDKine9csforDrugDiscovery-MARCARBiomarkersandmoleculartumourclassifica9onfornon-genotoxiccarcinogenesis-MIP-DILIMechanism-BasedIntegratedSystemsforthePredic9onofDrug-InducedLiverInjury-ND4BBNewDrugsforBadBugs-NEWMEDSNovelmethodsleadingtonewmedica9onsindepressionandschizophrenia-OncoTrackMethodsforsystema9cnextgenera9ononcologybiomarkerdevelopment-OpenPHACTSTheOpenPharmacologicalConceptsTripleStore-ORBITOOralbiopharmaceu9cstools-Pharma-CogPredic9onofcogni9veproper9esofnewdrugcandidatesforneurodegenera9vediseasesinearlyclinicaldevelopment-PharmatrainPharmaceu9calMedicineTrainingProgramme-PRECISESADSMolecularreclassifica9ontofindclinicallyusefulbiomarkersforsystemicautoimmunediseases-PredectNewmodelsforpreclinicalevalua9onofdrugefficacyincommonsolidtumours-PreDiCT-TBModel-basedpreclinicaldevelopmentofan9-tuberculosisdrugcombina9ons-PRO-acCvePhysicalAc9vityasaCrucialPa9entReportedOutcomeinCOPD

-ABIRISKAn9-Biopharmaceu9calImmuniza9on:Predic9onandAnalysisofClinicalRelevancetoMinimizetheRisk-ADVANCEAccelerateddevelopmentofvaccinebenefit-riskcollabora9oninEurope-AETIONOMYOrganisingmechanis9cknowledgeaboutneurodegenera9vediseasesfortheimprovementofdrugdevelopmentandtherapy-BioVacSafeBiomarkersforEnhancedVaccineImmunosafety-BTCureBeTheCure-CHEM21Chemicalmanufacturingmethodsforthe21stcenturypharmaceu9calindustries-COMBACTECombaWngBacterialResistanceinEurope-COMBACTE-CARECombaWngBacterialResistanceinEurope-CarbapenemResistance-COMBACTE-MAGNETCombaWngbacterialresistanceinEurope-moleculesagainstGramnega9veinfec9ons-COMPACTCollabora9onontheop9misa9onofmacromolecularpharmaceu9calaccesstocellulartargets-DDMoReDrugDiseaseModelResources-DIRECTDiabetesresearchonpa9entstra9fica9on-DRIVE-ABDrivingre-investmentinR&Dandresponsiblean9bio9cuse-EBiSCEuropeanBankforinducedpluripotentStemCells-Ebola+Ebolaandotherfiloviralhaemorrhagicfevers-EHR4CRElectronicHealthRecordsSystemsforClinicalResearch

-PROTECTPharmacoepidemiologicalresearchonoutcomesoftherapeu9csbyaEuropeanconsor9um-Quic-ConceptQuanta9veimagingincancer:connec9ngcellularprocesswiththerapy-RAPP-IDDevelopmentofrapidpoint-of-caretestplasormsforinfec9ousdiseases-SAFE-TSaferandFasterEvidence-basedTransla9on-SafeSciMETEuropeanModularEduca9onandTrainingProgrammeinSafetySciencesforMedicines-SPRINTTSarcopeniaandphysicalfrailtyinolderpeople:mul9-componenttreatmentstrategies-STEMBANCCStemcellsforbiologicalassaysofnoveldrugsandpredic9vetoxicology-SUMMITSurrogatemarkersformicro-andmacro-vascularhardendpointsforinnova9vediabetestools-TRANSLOCATIONMolecularbasisofthebacterialcellwallpermeability-U-BIOPREDUnbiasedbiomarkersforthepredic9onofrespiratorydiseaseoutcomes-WEB-RADRRecognisingAdverseDrugReac9ons

IMIProjects


ProgrammeCall Project No Project Acronym Project Title Start Date End Date FAIRification legal Coordinator Short Name (A2.1)IMI1 1 115001 MARCAR bioMARkers and molecular tumor classification for non-genotoxic CARcinogenesis1/01/2010 30/06/2015 Yes NovartisIMI1 1 115002 eTOX Integrating bioinformatics and chemoinformatics approaches for the development of expert systems allowing the in silico prediction of toxicities1/01/2010 31/12/2016 Yes NovartisIMI1 1 115003 SAFE-T SAFER AND FASTER EVIDENCE-BASED TRANSLATION15/06/2009 14/06/2015 Yes NovartisIMI1 1 115004 PROTECT Pharmacoepidemiolocal Research on Outcomes of Therapeutics by a European ConsorTium1/09/2009 30/04/2015 Yes EMAIMI1 1 115005 IMIDIA Improving beta-cell function and identification of diagnostic biomarkers for treatment monitoring in diabetes1/02/2010 30/09/2015 Yes SADIMI1 1 115006 SUMMIT SUrrogate markers for vascular Micro- and Macrovascular hard endpoints for Innovative diabetes Tools1/11/2009 31/10/2015 Yes Boehringer IngelheimIMI1 1 115007 EUROPAIN Understanding chronic pain and improving its treatment1/10/2009 30/09/2015 Yes HLUIMI1 1 115008 NEWMEDS Novel Methods leading to New Medications in Depression and Schizophrenia1/09/2009 28/02/2015 Yes HLUIMI1 1 115009 PHARMA-COG Prediction of cognitive properties of new drug candidates for neurodegenerative diseases in the early clinical development1/01/2010 31/12/2015 Yes GSKIMI1 1 115010 U-BIOPRED Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes1/10/2009 30/09/2015 Yes NOVIMI1 1 115011 PRO- Active Physical Activity as a Crucial Patient Reported Outcome in COPD1/09/2009 31/05/2016 Yes ChiesiIMI1 1 115012 SafeSciMET European Modular Education and Training Programme in Safety Sciences for Medicines1/01/2010 31/08/2016 No ROCHEIMI1 1 115013 PharmaTrain Pharmaceutical Medicine Training Programme1/05/2009 30/04/2014 No PharmaTrain FederationIMI1 1 115014 EU2P European programme in Pharmacovigilance and Pharmacoepidemiology1/09/2009 30/06/2016 Yes ROCHEIMI1 1 115015 EMTRAIN European Medicines Research Training Network1/10/2009 30/09/2016 No AstraZenecaIMI1 2 115142 BTCURE BeTheCuRE 1/04/2011 31/03/2017 Yes UCBIMI1 2 115151 QUIC-CONCEPT QUantitative Imaging in Cancer: CONnecting CEllular Processes with Therapy1/09/2011 31/08/2016 Yes EORTCIMI1 2 115153 RAPP-ID Development of RApid Point-of-Care test Platforms for Infectious Diseases1/04/2011 30/09/2016 Yes JNJIMI1 2 115156 DDMoRe Drug Disease Model Resources 1/03/2011 31/08/2016 ? PfizerIMI1 2 115188 PREDECT New Models for Preclinical Evaluation of Drug Efficacy in Common Solid Tumours1/02/2011 30/04/2016 Yes ServierIMI1 2 115189 EHR4CR Electronic Health Record systems for Clinical Research1/03/2011 29/02/2016 Blank AZIMI1 2 115191 Open PHACTS The Open Pharmacological Concepts Triple Store1/03/2011 29/02/2016 Yes GSKIMI1 2 115234 OncoTrack OncoTrack - Methods for systematic next generation oncology biomarker development1/01/2011 31/12/2016 Yes BHPIMI1 3 115300 EU-AIMS European Autism Interventions - A Multicentre Study for Developing New Medications1/04/2012 31/03/2017 Yes ROCHEIMI1 3 115303 ABIRISK Anti-Biopharmaceutical Immunization:Prediction and analysis of clinical relevance to minimize the risk1/03/2012 28/02/2017 Yes GSKIMI1 3 115308 BioVacSafe Biomarkers For Enhanced Vaccine Safety1/03/2012 28/02/2017 Yes GSK Vaccines SrlIMI1 3 115317 DIRECT DIabetes REsearCh on patient sTratification1/02/2012 31/01/2017 Yes SADIMI1 3 115334 EUPATI European Patients' Academy on Therapeutic Innovation1/02/2012 31/01/2017 No VFAIMI1 3 115336 MIP-DILI Mechanism-Based Integrated Systems for the Prediction of Drug-Induced Liver Injury1/02/2012 31/01/2017 Yes AstraZenecaIMI1 3 115337 PreDiCT-TB Model-based preclinical development of anti-tuberculosis drug combinations1/05/2012 30/10/2017 Yes GSKIMI1 4 115360 CHEM21 Chemical Manufacturing Methods for the 21st Century Pharmaceutical Industries 1/10/2012 30/09/2016 ? GSKIMI1 4 115363 Compact Collaboration on the Optimisation of Macromolecular Pharmaceutical Access to Cellular Targets1/11/2012 31/10/2017 ? SADIMI1 4 115366 K4DD Kinetics for Drug Discovery (K4DD) 1/11/2012 31/10/2017 Yes Bayer IMI1 4 115369 OrBiTo Oral biopharmaceutics tools 1/10/2012 30/09/2017 Yes AstraZenecaIMI1 4 115372 EMIF European Medical Information Framework1/01/2013 31/12/2017 Yes JanssenIMI1 4 115439 StemBANCC Stem cells for Biological Assays of Novel drugs and prediCtive toxiCology (StemBANCC)1/10/2012 30/09/2017 Yes ROCHEIMI1 4 115446 eTRIKS Delivering European Translational Information & Knowledge Management Services 1/10/2012 30/09/2017 Yes AstraZenecaIMI1 5 115489 EUC²LID European Lead Factory 1/01/2013 31/12/2017 ? Bayer IMI1 6 115523 COMBACTE Combatting Bacterial Resistance in Europe1/01/2013 31/12/2019 ? AstraZenecaIMI1 6 115525 Translocation Molecular basis of the outer membrane permeability1/01/2013 31/12/2017 Yes GSKIMI1 7 115546 GetReal Incorporating real-life clinical data into drug development1/10/2013 31/12/2016 Yes GSKIMI1 7 115557 ADVANCE Accelerated Development of Vaccine benefit-risk Collaboration in Europe1/10/2013 30/09/2018 Yes EMCIMI1 8 115565 PRECISESADS Molecular Reclassification to Find Clinically Useful Biomarkers for Systemic Autoimmune Diseases1/02/2014 31/01/2019 Yes UCBIMI1 8 115568 AETIONOMY Aetionomy – Organising Mechanistic Knowledge about Neurodegenerative Diseases for the Improvement of Drug Development and Therapy1/01/2014 31/12/2018 Yes UCBIMI1 8 115582 EBiSC European Bank for induced pluripotent Stem Cells1/01/2014 31/12/2016 Yes Pfizer

PreliminaryanalysisofIMIprojectsforavailabilityofFAIRifiabledatasets(par9allist)AnalysisdonebyAnthonyRowe(Janssen)andColmCarroll(IMI)


ExpectedImpact•  Thescien9ficcommunitycanmaximallyleveragedatafromlegacyandcurrentIMIprojects

•  Strengtheningthecapacityofcrea9on,cura9on,andstewardshipofFAIRdatabaseswithinITcommuni9esofacademia,SME,andpharma

•  BeIerunderstandingofthecomplexity,structure,andbreadthofpharmaceu9caldata:AllowtheSMEcommunitytomaketheirdata,analysistoolsandservicesbeIerconnectedandalignedtopharma

•  Along-las9ngvalue-addingimpactoneffec9vescien9ficdatausage


23/11/2017 23

BuildingonIMI1programmes,e.g.EHR4CR(ElectronicHealthRecordsforClinicalResearch)EMIF(EuropeanMedicalInforma9onFramework)ADVANCE(Dataframeworkforvaccinerisk/benefitanalysis)GetReal(RWEcollec9onandsynthesis)andotherFP7programmes,wewillbeu9lisingtheoutputsofthosePPPs,therela9onshipsandtheircontribu9ons(BigDataforBeIerOutcomesBD4BO)

•  WorkPackage1:MethodologicalResearch•  Federatednetworkcrea9on•  Dataharmonisa9on,evalua9onandqualitybenchmark•  Eviden9allinkagewithRegulators,HTAs•  FromtechnologytoRWE

DTLmee9ngUtrecht

Conclusions

•  Pharmahasstronginterestandneedforimplemen9ngFAIRdataprinciples

•  Exper9seisusuallylaggingduetocomplexlegacydatasystemsandlimitedITresources

•  Scien9ficacceptanceofFAIRifica9oninPharmarequiresstrongusecaseexamples

•  Collabora9onwithacademiaandSMEcommunitycatalyzesexper9seandacceptanceofFAIRdata


Documents

Pharma goes FAIR · Open PHACTS data sources DTL meeng Utrecht 23/11/2017 10 Phenotypic Drug Discovery Workflows Digles et al, MedChemComm, 7: 1237 (2016) “Knowing the knowns”