Diagnostics and personalized medicine

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Lecture given for the biotechnology program at the Kellogg Graduate School of Business (NWU)

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  • 1.Diagnos(csandPersonalized Medicine DynamicsintheBiotechnologyand LifeScienceIndustry Tuesday,February6,2007

2. Objec(ves Challengecommonwisdom:helpyouthink Prepareyouforpitches Providebasicbackground 2013WintonGibbons 2 3. TopicstoCover Overviewofdiagnos(cmarket Nomenclature Markerminingandvalida(on Personalizedmedicine MiscellaneousandQ&A Recent,majoracquisi(ons Point-of-care 2013WintonGibbons 3 4. OverallMarketSizeandStructure Source:BBC,AmershamandWGanalysis In-vitro 81% In-vivo 19% 100%=$41.6billion 2013WintonGibbons 4 5. IVDMarketSizeandStructure $7,997 $6,582 $6,034 $1,861 $1,827 $1,740 $1,295 $1,217 $1,228 $4,088 Diabetes Infectious Disease Clinical Chemistry Hematology Immunology Endocrinology Coagulation Cancer Cardiac Other Source:BBCandWGanalysis 2013WintonGibbons 5 6. IVDMarketSizeandStructure Source:BBCandWGanalysis US 37% Europe 35% Japan 10% ROW 18% 2013WintonGibbons 6 7. IVDMarketSizeandStructure Source:BBCandWGanalysis Lab 75% PST 18% Ambulatory 7% 2013WintonGibbons 7 8. RocheDominatestheIVDs,Especially A`erGEsMove Roche 21% Abbott (pre GE) 12% J&J 10% Bayer (Siemens) 9% Beckman 7% Dade 6% Other 35% Source:BBCandWGanalysis 2013WintonGibbons 8 9. OtherThoughtsonIndustryStructure Top4Diagnos(csplayerspartofLargerMedicalProductFirm(Roche,GE,J&Jand Siemens) Compe((veInforma(onSpoey OverlapwithLifeSciencerms Diagnos(csusesmuchofthesametechnologyasLifeSciences,soanumberof companiesstraddleboth(Beckman,BioRad,Cepheid,CeleraandevenRoche). However,Diagnos(csisdierentduetoregulatory,medicalprac(ce,reimbursement, razor/razorbladeandlarger,diversiedplayers. In-vitroDiagnos(csisalarge($34billion),butgenerallygrowsaboutthesame rateasnominalGDP;however,thereareafewfast-growingsub-sectorsandsome nicheopportuni(es Moleculardiagnos(cs(e.g.,DNA) BloodGlucose Novelproteinmarkers(e.g.,BNPandothers) 2013WintonGibbons 9 10. M.D.s Rx firms Device firms Dx Hospitals Pharmacies Distribution Stronger Poli(calPowerforIVDFirmsTypically isnotStrong 2013WintonGibbons 10 11. Dimension RxL Max Chemistry/Immunochemistry Analyzer GeneXpert Triage Diagnos(cInstrumentsVaryinSize andComplexity 2013WintonGibbons 11 12. LargeSystemPurchasesTypically DontDependonSingleMarkers 5- to 6-year repurchase cycle Labor savings (2/3 of cost) Laboratory automation 12- to 24-month selling cycle Ease of use Easy maintenance / reliability Important analytes on the menu: Troponin I, HbA1c, BNP/NT-proBNP Menu should cover 90%+ of volume high-sensitivity TSH and HCG Source: William Blair & Company, L.L.C. analysis Purchasing Behavior for Mainframe Immunodiagnostic Analyzers 2013WintonGibbons 12 13. SomeMythsinDiagnos(cs Besttest Standardiza(on/installedbasedVHSversusBetamax(e.g.,TroponinIversusT;BNPversusNT-proBNP?) Plaoormmigra(on(NAtoIAtoCC) Trialanderror(e.g.,sta(ns) POC Costcenterversustotalcost LabDirectorpower MDoce Workow Prot(StarkIIJuly26) Pharmacogenomics Metabolizingenzymes(CYP450s) Yes Drug-druginterac(ons Individualizedmedicine Notalways Exceptcertaincancersororphans Drugstotargetbigmarkets,justusingnewbiology 2013WintonGibbons 13 14. Nomenclature Sensi(vity Percentwithdiseasewhotestposi(ve Specicity Percentofwithoutdiseasewhotestnega(ve Posi(vePredic(veValue Prevalence*Sensi(vity/(Prevalence*Sensi(vity+(1-Prevalence)*(1-Specicity)) Nega(vePredic(veValue (1-Prevalence)*Specicity/((1-Prevalence)*Specicity+Prevalence*(1-Sensi(vity) OddsRa(o Odds/Odds Odds=p/(1-p) ROCCurve TruePosi(veFrac(onversusFalsePosi(ve Disease Present Disease Absent Positive Test A B A+B Negative Test C D C+D A+C B+D Sensitivity A/A+C Specificity D/B+D 2013WintonGibbons 14 15. ReadingList Believabilityofrela(verisksandoddsra(osinabstracts:crosssec(onalstudy. BMJ,Jul2006;333:231-234 Evidenceofbiasandvaria(onindiagnos(caccuracystudies Can.Med.Assoc.J.,Feb2006;174:469-476. Tipsforlearnersofevidence-basedmedicine:5.Theeectofspectrumofdiseaseontheperformanceofdiagnos(ctests Can.Med.Assoc.J.,Aug2005;173:385-390 Predic(onofcanceroutcomewithmicroarrays:amul(plerandomvalida(onstrategy. Lancet.2005;365:488-92. CanGenentechDoubleItsNHLFranchise?FocusonFcReceptors WilliamBlair&CompanyResearchNote.December2,2004 Limita(onsoftheOddsRa(oinGaugingthePerformanceofaDiagnos(c,Prognos(c,orScreeningMarker Am.J.Epidemiol.,May2004;159:882-890. Whencanariskfactorbeusedasaworthwhilescreeningtest? BMJ,Dec1999;319:1562. DrugMetabolismandVariabilityamongPa(entsinDrugResponse N.Engl.J.Med.,May2005;352:2211-2221. CodeineIntoxica(onAssociatedwithUltrarapidCYP2D6Metabolism N.Engl.J.Med.,Dec2004;351:2827-2831. DevelopmentalPharmacologyDrugDisposi(on,Ac(on,andTherapyinInfantsandChildren N.Engl.J.Med.,Sep2003;349:1157-1167. 2013WintonGibbons 15 16. OneWeeksWorthofGene(c BiomarkerDiscovery Gene(cngerprintsiden(fybraintumors'origins(Feb1) MayoClinicResearchShows35PercentOf49YoungPeopleWhoDiedSuddenlyAndInexplicablyHad Gene(cHeartDefects(Jan31) UCLAResearchersDiscoverGenesLinkedToLymphoma,OpeningWayForNewTargetedDrugs(Jan31) Studyndsgenesthatpredicttransplantrejec(on(Jan30) AFormOfTheAlcoholDehydrogenaseGeneMayProtectAfro-TrinidadiansFromDeveloping Alcoholism(Jan30) AutoimmuneDiseaseBreakthroughGainedByIden(ca(onOf30ErrantGenes(Jan29) Gene'couldpredictADHDdrugreac(on'(Jan29) 50%ofAmericanshavegenethataectshowbodyburnssugar(Jan28) Scien(stslinkpaternalgene,au(sm(Jan26) Gene(cRiskFactorForParkinson'sFound(Jan25) CalculatedRisk:Scien(stsDiscoverGene(cRiskFactorForSmoking-linkedHeadAndNeckCancer(Jan 25) Source: National Office of Public Health Genomics (NOPHG) 2013WintonGibbons 16 17. SenatorBarackObamaIntroducestheGenomicsandPersonalized MedicineAct ThePersonalizedMedicineCoali(onwelcomestheintroduc(onof S.3822,theGenomicsandPersonalizedMedicineAct,andlooks forwardtoworkingwithSenatorBarackObama,thebill'sauthor, andhiscolleaguesinCongress,tohastentheintroduc(onof personalizedmedicine.Thelegisla(on,amongotherthings,aimsto improvethecoordina(onofpublicandprivateeortstofacilitate thedevelopmentofsaferandmoreeec(vedrugs,createa biobankingini(a(ve,expandthegenomicsworkforce,andimprove thequalityofclinicalgene(ctes(ng. 2013WintonGibbons 17 18. TheGenomicsandPersonalized MedicineActof2006 SponsoringResearch.Thebillsetsaside$150milliontosponsorresearchongenomics.Itenables ana(onalbiobankingini(a(veandsetsupasystemtopoolandsynthesizegenomicdatafrom localsources.Thisactestablishesaninteragencytaskforcetoacceleratethetransla(onof researchintomedicalprac(ce.Finally,thelegisla(oninvestsinthenextgenera(ongenomics workforcebyencouragingtherecruitmentandreten(onofgenomicprofessionals,andpromotes theintegra(onofgenomicsacrossallclinicalandpublichealthdisciplines. EncouragingInnovaAon.Thelegisla(onprovidesa100percenttaxcreditforthedevelopmentof companiondiagnos(cteststhatcanimprovetheeec(venessorsafetyofcertaindrugs.In addi(on,theNa(onalAcademieswillconductastudytodeterminewhataddi(onalincen(vesare needed,andhowtheyshouldbestructured. ModernizingtheFDAandCMS.ThebillrequiresthatFDAandCMSstudyandupdateregulatory processestoassurethequalityofgenomicteststhroughimprovedoversightandregula(on. ProtecAngConsumers.Thelegisla(onprotectsconsumersbyrearmingCongresscommitmentto stoppinggene(cdiscrimina(onandprotec(nggene(cprivacy.Inaddi(on,direct-to-consumer marke(ngofgene(ctestswouldreceivegreaterscru(nyandregula(on. 2013WintonGibbons 18 19. Cytochromep450Enzymes Thesuperfamilyhasundergonedivergentevolu(on,and theancestralgeneislikely2to31/2billionyearsold. Therecent'burst'innewP450genes,par(cularlyintheII familyduringthepast800millionyears,appearstobethe resultof'animal-plantwarfare'. Duetothepresenceorabsenceofapar(cularP450genein onespeciesbutnottheother,itmaynotbecorrectto extrapolatetoxicityorcancerdatafromrodenttohuman. IncreasesintheP450geneproduct(enzymeinduc(on) almostalwaysreectanelevatedrateingene transcrip(on,althoughthereareseveralexcep(ons. 2013WintonGibbons 19 20. Postedon:Monday,22January2007,21:00CST GENETICMEDICINE;SomeHeartPaAentsGetDNATeststoDetermineCorrectDrugDose ByLindaA.Johnson Personalizedmedicine,thetailoredtreatmentsthatafewpa(entsnowgetbasedontheirown DNA,isnallyheadedforthemasses:themanyheartpa(entsatriskofdeadlybloodclots. Atleast2millionAmericanswithanabnormal,clot-triggeringheartrhythmtakethepillwarfarin, alsosoldasCoumadin. Gewngtoolielecanleadtoastroke,andtoomuchcancauselife-threateningbleeding.Tond therightdoseforeachpa(ent,doctorsusetrialanderror--andtheerrorsleadtotensof thousandsofhospitaliza(onsanddeathseveryyear. Star(ngthismonth,about1,000pa(entswhohaveacondi(onknownasatrialbrilla(onwill takepartinaprojectthatwillmatchtheirCoumadindosetotheirspecicgene(cneeds. Thisgene(cngerprin(ngshouldsingleoutthemanypeoplewhosebodiesbreakdownwarfarin fasterorslowerthannormal,andtheirdoctorscanimmediatelyadjusttheirdosagetoprevent dangerouscomplica8ons. "Twentypercentto30percentofpeopleareeitherveryfastorveryslow"tometabolizemany drugsbutdon'tknowit,saidDr.RobertEpstein,chiefmedicaloceratprescrip(onbenet managerMedcoHealthSolu(onsofFranklinLakes,N.J.,whichiscollabora(ngintheeortwith theMayoClinic,basedinRochester,Minn. 2013WintonGibbons 20 21. EectofCYP450Muta(ons Rapidmetabolizers Carrymul(plecopies(3-13)of func(onalallelesandproduceexcess enzyma(cac(vity Normalmetabolizers Possessnormalfunc(onalalleles Intermediatemetabolizers Possessonereducedac(vityalleleor onenullallele Poormetabolizers Carrytwomutantalleleswhichresult incompletelossofenzymeac(vity 2D6geneduplica(ons Ethiopians16.0% SaudiArabians10.4% Spaniards10% Italians8.3% Zimbabweans2% Germans1.8% Chinese1.3% 2D6Intermediateandpoormetabolizers Caucasians7-8% Japanese~1% Chinese~1% AfricanAmericans~6% Source:Roche2013WintonGibbons 21 22. CYP450Substrates(drugs) 1A2 2B6 2C8 2C19 2C9 amitriptyline bupropion paclitaxel Proton Pump Inhibitors: NSAIDs: caffeine cyclophosphamide torsemide lansoprazole diclofenac clomipramine efavirenz amodiaquine omeprazole ibuprofen c