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 clozapine ifosfamide cerivastatin pantoprazole lornoxicam cyclobenzaprine methadone repaglinide rabeprazole meloxicam estradiol E-3810 S-naproxen=>Nor fluvoxamine piroxicam haloperidol Anti-epileptics: diazepam=>Nor suprofen imipramine N-DeMe phenytoin(O) mexilletine S-mephenytoin Oral Hypoglycemic Agents: naproxen phenobarbitone tolbutamide olanzapine glipizide ondansetron amitriptyline phenacetin=> carisoprodol Angiotensin II Blockers: acetaminophen=>NAPQI citalopram losartan propranolol clomipramine irbesartan riluzole cyclophosphamide ropivacaine hexobarbital Sulfonylureas: tacrine imipramine N-DeME glyburide/ theophylline indomethacin glibenclamide tizanidine R-mephobarbital glipizide verapamil moclobemide glimepiride (R)warfarin nelfinavir tolbutamide zileuton nilutamide zolmitriptan primidone amitriptyline progesterone celecoxib proguanil fluoxetine propranolol fluvastatin glyburide teniposide nateglinide R-warfarin=>8-OH phenytoin=>4-OH rosiglitazone tamoxifen torsemide S-warfarin Source:CYTOCHROMEP450DRUG-INTERACTIONTABLE--LastUpdated:TueOct172006--Indiana University Department of Medicine, Division of Clinical Pharmacology 2013WintonGibbons 22 23. CYP450Substrates(drugs)--con(nued2E1 Beta Blockers: alprenolol Anesthetics: Macrolide antibiotics: Steroid 6beta-OH: carvedilol amphetamine enflurane clarithromycin estradiol S-metoprolol aripiprazole halothane erythromycin (not 3A5) hydrocortisone propafenone atomoxetine isoflurane NOT azithromycin progesterone timolol bufuralol methoxyflurane telithromycin testosterone chlorpheniramine sevoflurane Antidepressants: chlorpromazine Anti-arrhythmics: alfentanyl amitriptyline codeine (=>O-desMe) acetaminophen quinidine=>3-OH (not 3A5) aprepitant clomipramine debrisoquine =>NAPQI aripiprazole desipramine dexfenfluramine aniline Benzodiazepines: buspirone imipramine dextromethorphan benzene alprazolam cafergot paroxetine duloxetine chlorzoxazone diazepam=>3OH caffeine=>TMU encainide ethanol midazolam cilostazol Antipsychotics: flecainide N,N-dimethyl formamide triazolam cocaine haloperidol fluoxetine theophylline codeine- N-demethylation perphenazine fluvoxamine =>8-OH Immune Modulators: dapsone risperidone=>9OH lidocaine cyclosporine dexamethasone thioridazine metoclopramide tacrolimus (FK506) dextromethorphan zuclopenthixol methoxyamphetamine docetaxel mexilletine HIV Antivirals: domperidone minaprine indinavir eplerenone nebivolol nelfinavir fentanyl nortriptyline ritonavir finasteride ondansetron saquinavir gleevec oxycodone haloperidol perhexiline Prokinetic: irinotecan phenacetin cisapride LAAM phenformin lidocaine promethazine Antihistamines: methadone propranolol astemizole nateglinide sparteine chlorpheniramine odanestron tamoxifen terfenidine pimozide tramadol propranolol venlafaxine Calcium Channel Blockers: quetiapine amlodipine quinine diltiazem risperidone felodipine NOT rosuvastatin lercanidipine salmeterol nifedipine sildenafil nisoldipine sirolimus nitrendipine tamoxifen verapamil taxol terfenadine HMG CoA Reductase Inhibitors: trazodone atorvastatin vincristine cerivastatin zaleplon lovastatin ziprasidone NOT pravastatin zolpidem simvastatin 2D6 3A4,5,7 Source:CYTOCHROMEP450DRUG-INTERACTIONTABLE--LastUpdated:Tue Oct172006--Indiana University Department of Medicine, Division of Clinical Pharmacology 2013WintonGibbons 23 24. CYP450Inhibitors Source:CYTOCHROMEP450DRUG-INTERACTIONTABLE--Last Updated:TueOct172006--Indiana University Department of Medicine, Division of Clinical Pharmacology 1A2 2C19 2C9 2D6 3A4,5,7 amiodarone chloramphenicol amiodarone amiodarone HIV Antivirals: cimetidine cimetidine fenofibrate bupropion delaviridine ciprofloxacin felbamate fluconazole celecoxib indinavir fluoroquinolones fluoxetine fluvastatin chlorpheniramine nelfinavir fluvoxamine fluvoxamine fluvoxamine chlorpheniramine ritonavir furafylline indomethacin isoniazid chlorpromazine interferon ketoconazole lovastatin cimetidine amiodarone methoxsalen lansoprazole phenylbutazone citalopram aprepitant mibefradil modafinil omeprazole probenicid clemastine NOT azithromycin oxcarbazepine sertraline clomipramine chloramphenicol 2B6 probenicid sulfamethoxazole cocaine cimetidine thiotepa ticlopidine sulfaphenazole diphenhydramine clarithromycin ticlopidine topiramate teniposide doxepin diethyl- dithiocarbamate voriconazole doxorubicin diltiazem 2C8 2E1 zafirlukast duloxetine erythromycin trimethoprim diethyl- dithiocarbamate escitalopram fluoxetine fluconazole quercetin disulfiram halofantrine fluvoxamine glitazones histamine H1 receptor antagonists gestodene gemfibrozil hydroxyzine grapefruit juice montelukast levomepromazine imatinib trimethoprim methadone itraconazole metoclopramide ketoconazole mibefradil mifepristone midodrine nefazodone moclobemide norfloxacin paroxetine norfluoxetine perphenazine mibefradil quinidine star fruit ranitidine verapamil red-haloperidol voriconazole ritonavir sertraline terbinafine ticlopidine tripelennamine 2013WintonGibbons 24 25. CYP450Inducers Source:CYTOCHROMEP450DRUG-I...