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NIH Clinical Pharmacology 3-25-10Nonclinical Drug DevelopmentChris H. Takimoto, MD, PhD, FACPTranslational Medicine Early DevelopmentOncology Therapeutic AreaJanssen R&DMarch 20121

NIH Clinical Pharmacology 3-25-10Disclosure InformationChris H. Takimoto, MD, PhD• Employment: Janssen R&D/Johnson & Johnson• Stock: Johnson & Johnson• Off Label Use: I will not discuss off label use of anyproducts2

NIH Clinical Pharmacology 3-25-10Lecture Outline• Nonclinical Drug Development Definitions & Scope• Components of Nonclinical Drug Development– Pharmacology Studies– Safety Pharmacology– PK/ADME Studies– Toxicology– Starting Dose Selection and Study Desgin Issues for FIH• Nonclinical Translational Research Strategies– Targeted therapies/Biomarkers– Pharmacological Audit Trail/Model-based drug development– Translational clinical development plans3

NIH Clinical Pharmacology 3-25-10Nonclinical Drug DevelopmentAn Industrial PerspectiveTarget ID/ValidationDiscoveryNMEDeclarationEarlyDevelopment-- Kramer et al Nat Rev Drug Disc 20075

NIH Clinical Pharmacology 3-25-106

NIH Clinical Pharmacology 3-25-10Components of Nonclinical DrugDevelopment• Pharmacology Studies/Model Selection• Safety Pharmacology• PK/ADME Studies• Toxicology• Starting Dose Selection and study designissues for FIH7

NIH Clinical Pharmacology 3-25-10S9 Oncology Specific Guidance• Applies to targeted small molecules andbiopharmaceuticals used for treating “patients withadvanced disease and limited therapeutic options”– Advanced cancer is a progressive, fatal disease– Existing therapies have limited effectiveness– Treatment at or close to adverse effect dose levels• Type, timing, and flexibility of oncology studies maydiffer from other therapeutic areas• Does NOT apply to cancer prevention, supportivecare, healthy volunteers, radiopharmaceuticals,vaccines, cellular or gene therapies-- S9 Guidance for Industry, 20108

NIH Clinical Pharmacology 3-25-10S9 Oncology Specific GuidanceGoals of Nonclinical Testing1. Identify the pharmacologic properties of apharmaceutical2. Understand the toxicological profile of apharmaceutical3. Establish a safe initial dose level of the firsthuman exposure-- S9 Guidance for Industry, 20109

NIH Clinical Pharmacology 3-25-10Nonclinical Drug DevelopmentIn Vitro Pharmacology Models• In vitro studies performed in cell lines or cellfreesystems– Often form the basis for screening andoptimization during discovery• Oncology uses human tumor cell lines forevaluation of:– Mechanism of action– Evaluation of potency and selectivity– Early indication selection– Predictive biomarker discovery10

NIH Clinical Pharmacology 3-25-10In Vitro Cell Line AnalysesCisplatinCarboplatinCellLinesRelative Potency (GI 50 )11

NIH Clinical Pharmacology 3-25-10Limitations of 2D Tumor ModelsTumor Microenvironment-- Pollard, Nat Rev Cancer, 200812

NIH Clinical Pharmacology 3-25-10Humanized 3D Models(for Advanced Biomarker and Drug Discovery Applications)Abbreviations: TGA, tumor growth assay; IrBME, Irradiated basement membrane extract; hMSC, humanmesenchymal stem cells; hCAF, human cancer associated fibroblasts; TME, tumor microenviroment-- B. Hall, Janssen R&D13

NIH Clinical Pharmacology 3-25-103D-TGA: Diverse Biologic ApplicationsSasser, et al. 2007 Cancer Letts; Sasser, et al 2007 FASEB J, Studebaker, et al. 2008 Cancer Res; Spaeth, et al. 2009 PLoS One; Sullivan, et al. 2009 Oncogene-- B. Hall, Ortho Biotech Oncol R&D14

NIH Clinical Pharmacology 3-25-10In Vivo Animal Models• The ideal animal model should be:– Valid– Selective– Predictable– Reproducible“There is no perfect tumor model”“All models are wrong, some are useful”15

NIH Clinical Pharmacology 3-25-10Endostatin: An Endogenous Inhibitor ofAngiogenesis and Tumor GrowthO'Reilly et al, Cell 88:277-285 (1997)16

NIH Clinical Pharmacology 3-25-10In Vivo Efficacy Models in Cancer• Spontaneous tumors– Idiopathic– Carcinogen-induced– Transgenic/gene knockout animals: p53, RB, etc• Transplanted tumors– Syngeneic animal tumors: Lewis lung, S180sarcoma, B16 melanoma murine tumors– Human tumors growing in vivo in implantablehollow fibers17

NIH Clinical Pharmacology 3-25-10Human Tumor Xenografts Models• Most common in vivo preclinical efficacymodels in oncology– Current NCI standard in vivo efficacy testingsystem• Consist of human tumor cells implanted inimmunocompromised animals– Nude mice– SCID mice– Nude rats• Diverse human tumor cell lines propagated invitro can grow as xenograft models18

NIH Clinical Pharmacology 3-25-10Nude Mouse Hosts for XenograftStudies• Athymic “nude” mice developed in 1960’s• Mutation in nu gene on chromosome 11• Phenotype: retarded growth, low fertility, nofur, immunocompromised– Lack thymus gland, T-cell immunity• First human tumor xenograft of colonadenocarcinoma by Rygaard & Poulson,196919

NIH Clinical Pharmacology 3-25-10Differential Tumor Growth ofProstate Cancer Xenograftsn = 10NogrowthRapidgrowth(Mahajan, Cancer Res 2005;65:10514)20

NIH Clinical Pharmacology 3-25-10Xenograft Advantages• Diverse selection of different human tumor types– Molecular characterization, GEP, available in public databases• Ease and speed of start up and conduct of studies• Simultaneous evaluation of safety and efficacy (therapeuticindex)• Some correlation with clinical activity lung, colon, breast, andmelanoma cancers• Although subcutaneous implantation is most common,orthotopic injections are possible– Mammary fat pad, CNS, intraperitoneal, etc• Wide accessibility• Many decades of experience21

NIH Clinical Pharmacology 3-25-10Xenograft Disadvantages• Atypical biological behavior– Metastases are rare– Survival not an ideal endpoint, with historical deaths from tumorbulk, not invasion– Short doubling times– Less necrosis, better blood supply• Positive predictive value is poor• Poorly mimics the tumor microenvironment– Human tumor cells with murine stroma– Host directed therapies (immunomodulation, stromal tissuetargets) may not be applicable• Species specific differences between humans and mice– Examples: Antibody biopharmaceutics that only recognizehuman targets22

NIH Clinical Pharmacology 3-25-10Low Passage Patient TumorgraftsPrimary human tumors•Primary--R. A. Weinberg, in The Biology of Cancer, 2007(Courtesy of W. Hait)23

NIH Clinical Pharmacology 3-25-10Patient Tumorgraft ClinicalCorrelationsColorectal Tumorgraft(Estrada et al, EORTC-NCI-AACR, 2010)Myoepithelial Salivary GlandTumorgraftSubcutaneous ImplantSalivary Metastases(Courtesy of M. Wick, START Laboratories)24

NIH Clinical Pharmacology 3-25-10Transgenic Animal Models of Cancer• p53 or other tumor suppressor gene knockout animalshave high incidence of endogenous tumor development• Theoretically more directly analogous to human situation• Advantages– Intact immune system– Murine tumor and stroma– Better for cancer prevention– May be engineered for specific purposes• Disadvantages– Long experimental start up times– Variable penetrance– Monitoring tumor growth in individual animals is challenging25

NIH Clinical Pharmacology 3-25-10Components of Nonclinical DrugDevelopment• Pharmacology Studies/Model Selection• Safety Pharmacology• PK/ADME Studies• Toxicology• Starting Dose Selection and study designissues for FIH26

NIH Clinical Pharmacology 3-25-10Safety Pharmacology Studies• For non-oncology agents, a core battery of safety pharmacologytests is required (ICH S7A, Section 2.7)– Central Nervous System– Cardiovascular System– Respiratory System• Additional supplemental studies must be individualized for eachdrug– May incorporate into general toxicology studies• Oncology recommendations (S9 Guidance)– Vital organ assessment still required, but may not need stand alonesafety studies in the absence of specific risk– Incorporate core vital organ evaluations into cGLP toxicology studies• References– S9 Guidance 2010– S7A Safety Pharmacology Studies for Human Pharmaceuticals, 200027

NIH Clinical Pharmacology 3-25-10Safety Pharmacology StudiesQTc Prolongation Risk AssessmentSiu et al, JCO 2007• Prolonged QTc caused by delayed ventricular repolarization– Increased risk of ventricular arrhythmias, especial Torsade de Pointes– Increased risk with hypokalemia, structural heart disease, or bradycardia• Late repolarization of cardiac action potential– Mediated by efflux of K+ (I Kr and I Ks ) through delayed rectifier K+ channels• Human ether-a-go-go-related gene (hERG)– Encodes the alpha subunit of the human K+ channel proteins responsible for IKr– Basis for preclinical in vitro testing for QTc prolongation risk• Pharmaceuticals that prolong QTc can have proarrhythmic effects• References– S7B, Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization,200528

NIH Clinical Pharmacology 3-25-10Nonclinical QTc Testing Strategy(ICH S7B, 2005)• Routine Nonclinical Tests– In Vitro I Kr (hERG) assay, and– In vivo QT assay in nonrodent species• May incorporate CV core battery study– Assess chemical/pharmacological class for choice ofreference compounds• Integrated Risk Assessment– Consider all relevant nonclinical information– Consider follow up studies• Action potential, Rabbit wedge, etc• Determine Evidence of Risk29

NIH Clinical Pharmacology 3-25-10Components of Nonclinical DrugDevelopment• Pharmacology Studies/Model Selection• Safety Pharmacology• PK/ADME Studies• Toxicology• Starting Dose Selection and study designissues for FIH30

NIH Clinical Pharmacology 3-25-10Nonclinical PK/ADME Studies forOncology Studies• Limited pharmacokinetic parameter estimation innonclinical animal species– Cmax, AUC, and half-life• Use to facilitate dose selection, schedule, andescalation in Phase 1• Additional nonclinical ADME studies should begenerated in parallel with clinical development (!)• Reference– S9 FDA Guidance 201031

NIH Clinical Pharmacology 3-25-10Nonclinical PK/ADME Studies• Cellular uptake and membrane transport– MDR (P-glycoprotein), MRP, etc.– Predictions of bioavailability and distribution• In vitro drug metabolism– P450 isoenzyme metabolism, inhibition orinduction• Plasma protein binding studies32

NIH Clinical Pharmacology 3-25-10Components of Nonclinical DrugDevelopment• Pharmacology Studies/Model Selection• Safety Pharmacology• PK/ADME Studies• Toxicology• Starting Dose Selection and study designissues for FIH33

NIH Clinical Pharmacology 3-25-10Nonclinical Toxicology Studies inOncology• IND-enabling general toxicology studies– Use the same route and formulation as clinical trial– Approximate the clinical schedule• Small molecule toxicology testing usually includesrodents and non-rodents (i.e., dogs)– Non-human primates for biologicals• Assess the potential to recover from toxicity– Terminal non-dosing period recommended– Complete recovery demonstration is not essential• Toxicokinetics evaluations as appropriate-- S9 Guidance for Industry, 201034

NIH Clinical Pharmacology 3-25-10Good Laboratory Practice (GLP)• Most safety pharmacology and toxicology studiesshould be conducted with GLP– Full GLP may not be feasible in some safetypharmacology studies• All core battery safety pharmacology studiesshould be GLP• Primary pharmacodynamic (generalpharmacology) studies do not need to beconducted in compliance with GLP-- S7A Guidance Section 2.1135

NIH Clinical Pharmacology 3-25-10Reproduction Toxicology(S9 Guidance)• Embryonic and fetal toxicology studies required atthe time of marketing application– In rare cases may not need at all for genotoxic agents thattarget rapidly dividing cells or known developmental toxins• Typically conducted in two different species– Biologicals may use one relevant species• Fertility and early embryonic development studiesare not required for use in advanced cancer patients• Pre- and post-natal toxicology studies not warrantedfor oncology-- S9 Guidance for Industry, 201036

NIH Clinical Pharmacology 3-25-10Other Toxicology Studies(S9 Guidance)• Genotoxicity– Not essential for oncology clinical trials– Should be performed to support marketing application• Carcinogenicity– Not warranted for marketing in oncology patients• Immunotoxicity– May evaluate in general toxicology studies for oncology– May require more extensive study for knownimmunomodulators• Photosafety testing– Initial phototoxic potential assessment prior to Phase 1based upon known photochemical properties-- S9 Guidance for Industry, 201037

NIH Clinical Pharmacology 3-25-10Components of Nonclinical DrugDevelopment• Pharmacology Studies/Model Selection• Safety Pharmacology• PK/ADME Studies• Toxicology• Starting Dose Selection and Study DesignIssues for FIH38

NIH Clinical Pharmacology 3-25-10Starting Dose for First in HumanStudies in Oncology• Goal:– Select a start dose that is expected to havepharmacological effects and is reasonably safe touse• Based on all available nonclinical data• Scale up from animal studies– For small molecules, normalize to body surfacearea– For biologicals, scale to body weight, AUC orother exposure parameters-- S9 Guidance for Industry, 201039

NIH Clinical Pharmacology 3-25-10Duration of Nonclinical ToxicologyStudies• Treatment duration in Phase 1 oncology may continueaccording to patients response– New toxicology studies not required• Phase 2 studies may be supported by existing nonclinicaland clinical Phase 1 data– Additional toxicology not required• Phase 3 studies may require repeat dose studies of 3months duration– Sufficient to support marketing• New drug combination regimens do not requirespecialized toxicology studies– In vivo pharmacology studies of the combination may suffice-- S9 Guidance for Industry, 201040

NIH Clinical Pharmacology 3-25-10Treatment Schedules to Support InitialOncology Trials(S9 Guidance for Industry, March 2010)Clinical Schedule Nonclinical Treatment Schedule *Once every 3-4 wksDaily for 5 days every 3 wksDaily for 5-7 days, alternatingwksOnce a week for 3 wks, 1 wkoffTwo or three times a weekDailyWeeklySingle doseDaily for 5 dayDaily for 5-7 days, alternating wks(2-dose cycles)Once a week for 3 weeksTwo or three times a week for 4 wksDaily for 4 wksOnce a week for 4-5 doses41

NIH Clinical Pharmacology 3-25-10Oncology Small Molecule DoseSelection• In oncology, the start dose at 1/10 theseverely toxic dose in 10% of animals(STD 10 ) in rodents• If non-rodent is most appropriate species,then 1/6 the highest non-severely toxic dose(HNSTD)– HNSTD is the highest dose level that does notproduce evidence of life-threatening toxicities orirreversible findings-- S9 Guidance for Industry, 201042

NIH Clinical Pharmacology 3-25-10Biologicals: MABEL Instead ofNOAEL, MAYBE ?• New European recommendations basedupon Tegenero FIH disaster,– EMEA Guidelines, 2007• MABEL: minimal anticipated biological effectlevel– Consider differences in sensitivity for the mode ofaction across species• Consider selection of starting doses basedupon reduction from the MABEL43

NIH Clinical Pharmacology 3-25-10Calculation of MABEL(EMEA Guidelines, 2007)• MABEL calculations should utilize nonclinicaldata available, including…– Target binding and receptor occupancy data in targetcells in vitro in human and animals– Concentration-response curves in vitro– Dose/exposure-response in vivo in relevant animals• Wherever possible an integrated PK/PDmodeling approach should be used• Apply a safety factor to the MABEL for therecommended starting dose (i.e., 1/10 MABEL)44

NIH Clinical Pharmacology 3-25-10Nonclinical TranslationalResearch Strategies in DrugDevelopment45

NIH Clinical Pharmacology 3-25-10The Drug Discovery & DevelopmentPipelineDiscovery DevelopmentNewProjectsPer Year24 19 15 12 9 5 2 1LaunchSuccessTime (yr)Cost (USD)Total time = 13.5 yearsTotal cost = $1.778 billion*-- Modified from Paul et al, Nature Rev Drug Discov 2010* Capitalized costs46

NIH Clinical Pharmacology 3-25-10A Blueprint for a RestructuredDrug Development OrganizationDiscoveryEarlyDevelopmentLateDevelopmentEarly clinicaldevelopmentNMEPh1/2aPOCPhase2bPhase3• How to make better decisions at POC?• How to improve the probability of success(pTS) in Phase 2b and 3?PWIP x pTS x VC x CT-- Modified from Paul et al, Nature Rev Drug Discov 201047

NIH Clinical Pharmacology 3-25-10Our Translational Strategy• Focus on Molecularly Targeted Therapieswith strong Biomarker support• Pharmacological Audit Trail (PhAT)evaluation in preclinical and early clinicaltrials• Model-based Drug Development approachinitiated during preclinical stages• Novel biomarker-driven Phase I FIH studydesigns translational clinical developmentplans48

NIH Clinical Pharmacology 3-25-10Characteristics of MolecularlyTargeted Therapies (adapted from Paoletti 2005)Characteristic Cytotoxic Agents Targeted AgentsDiscoveryCell based, empiricalReceptor basedscreen, rationaleMechanism Often unknown Basis for screeningPharmacologicalEffectCytotoxicCytostaticSpecificity Non-selective SelectiveDose and scheduleDevelopmentStrategyPulsed, cyclical at MTDBiomarkers for decisionmaking is rareContinuous, attolerable doseBiomarkers forPD/MofA and patientselection49

NIH Clinical Pharmacology 3-25-10The Biomarker Hypothesis(adapted from Nic Dracopoli)The use of biomarkers will….• Improve decision making in early development– Early proof of mechanism of action– Selection of optimal dose and schedules– Better understanding of pharmacological behavior through PhATevaluation– Better Go/No Go Proof of Concept decisions• Increase probability of technical and registrational success(PTRS) in late stage development– Smaller, more focused, enriched study populations– Greater magnitude of clinical benefit• Provide greater benefits for our patients through personalizedmedicine– Enable more cost-effective delivery of healthcare– Value-based pricing– Faster uptake and higher market penetration50

NIH Clinical Pharmacology 3-25-10Translational Research TimelinesTarget ID/Valid. NME Ph I/II Ph IIIDrug Development TimelinePredictive BiomarkersPD/MofA BiomarkersCompanionDiagnostic• Pharmacodynamic/Mechanism of Action Biomarkers– Inform about a drug’s pharmacodynamic actions– What is the drug doing in the patient and/or tumor?• Predictive Biomarkers– Optimize patient selection by selecting subpopulations fortreatment– Who should or should not get this drug?– Basis for stratified/personalized medicine strategies51

NIH Clinical Pharmacology 3-25-10The Pharmacological Audit Trail-- Paul Workman, Mol Cancer Therap 2003 and Current Pharmaceut Design 200352

NIH Clinical Pharmacology 3-25-10The Pharmacological Audit Trail(from Workman et al, Mol Cancer Therap 2003)Is the targetexpressed oractivated?Modulation ofdownstreampathway?Adequate drugdose & schedule?Activeconcentrations inplasma?Activeconcentrations intumor?Active against themolecular target?Reduce UncertaintyBiological effectachieved?Clinical responseor benefit?Predictivebiomarkers ofactivity?Proof of Conceptachieved?Reduce UncertaintyUnknownWeakEstablishedStrong53

NIH Clinical Pharmacology 3-25-10Model Based Drug Development ExamplecMET InhibitionSacrifice a subset at 1,4,8, and24 h (n = 3 per time point)Plasma PK Analysis•Plasma•Dose at 3.1, 6.3, 12.5,•25, and 50 mg/kg•TumorTumor Growth InhibitionAssay Tumor PD Biomarker--Adapted from Yamazaki et al Drug Met Dispos 200854

NIH Clinical Pharmacology 3-25-10Model Based Drug DevelopmentPlasmaPKTumorPKBiomarkerChangeAntitumorActivity(Yamazaki et al Drug Met Dispos 2008)55

NIH Clinical Pharmacology 3-25-10Translational Phase I Study withBiomarker-Defined EndpointsStartingDoseLevelPD biomarker monitoringin surrogate tissue“Biological Activity”Target PD biomarkereffect in surrogate tissuesor if any clinical activityPotentialPhase 2DoseRange“MTD”MaximumToleratedDose“DLT”ExpansionCohort 3ExpansionCohort 2ExpansionCohort 1Tumor biopsies and/orPredictive biomarker selected pts56

NIH Clinical Pharmacology 3-25-10Clinical Development in 2011 andBeyondTranslationalPhase 1 TrialsPBM SelectedPhase 2 TrialsSmall EnrichedPhase 3 TrialsPhase 1MultipleTumorsAssessPK, MTD,biologicalactivity& ptselectionPhase 1ExpansionCohort APhase 1ExpansionCohort BPhase 1ExpansionCohort CPhase 1ExpansionCohort DPhase 2POCDiseasePhase 2TumorType CPhase 2TumorType DPROOFOFCONCEPTPhase 3 inPOCDiseasePhase 3TumorType BPhase 3TumorType CNo efficacyPredictive Biomarker IdentificationQualification57

NIH Clinical Pharmacology 3-25-10Summary• Nonclinical drug development involves thecollection of key pharmacology, safety,toxicology, and PK/ADME data prior to theinitiation of FIH studies• Strict regulatory requirements regarding dataneeded for IND submission• Key period for formulating TranslationalResearch plans for clinical development58

NIH Clinical Pharmacology 3-25-10And Finally….Translational MedicineNonclinicalPharmacologyEfficacy/SafetyTraditionalanimal studiesPK/PDToxicologyBiomarkers &Molecular targetsClinicalPharmacologist“Model-baseddrug development”Early ClinicalTrialsTraditional dose andtoxicity endpointsTraditional PK/PDBiomarkers &Molecular endpointsPatient selectionIt is a great time to be in drug development!59