B&W - American College of Medical Toxicology


B&W - American College of Medical Toxicology

3/11/12Looking for Drug Induced Liver Injuryin Clinical TrialsSam Jackson, M.D., M.B.A.Disclosures• I am an employee of Genentech.• The opinions and recommendationsdiscussed today are my own (although they may be shared by others).• No proprietary materials or data were usedin the preparation of this presentation.Acknowledgments• John Senior, FDA• Paul Watkins, Hamner-UNC Institute forDrug Safety Sciences• Former colleagues at Amgen GlobalSafety and at the Banner Good SamMedical Toxicology Program1

3/11/12One more caveat• “Power corrupts. Powerpoint corruptsabsolutely.” – Edward Tufte (2003)Objectives for today• To develop a basic understanding of thechallenge of identifying drug-induced liverinjury (DILI) in clinical trials• To briefly discuss the content of the FDAguidance on DILI and its implications forsponsors of clinical trialsIdentifying DILI in Clinical TrialsAmanita bisporigeraAmerican Death Angel“Death Angel”2

3/11/12• Principal organ in themaintenance ofphysiologic homeostasis• Primary site ofbiotransformation ofxenobiotics― First pass for drugsabsorbed from the GI tract– Receives 75% of its bloodsupply from the portal veinThe liver• Large functional reservein healthy patientsPosition and function of the livermake it uniquely vulnerable todrug-induced injuryThe liver is central to drug metabolismSmallMoleculeDrugPhase 1 ReactionsOxidationReductionHydrolysis(e.g. CYP450,Epoxide Hydrolase)Phase 2 ConjugationReactionsAddition of a moietycatalyzed by various“transferase” enzymes(e.g. N-acetyltransferase,UDPglucuronosyltransferase)ExcretionHydrophobic Addition of groups: Conjugation with: Hydrophilicdrugs -OH, -SH, -O sulfate, glucuronic acid, bileotherxenobiotics-COOH, -NH 2glutathione, acetyl ormethyl groupurineDrug-induced liver injury• Many mechanisms– Intrinsic hepatotoxins – produce injury in apredictable, dose-dependent manner (e.g.,acetaminophen, carbon tetrachloride)– Idiosyncratic – almost all of the rest!– Others: immune-mediated, mitochondrial,xenobiotic-related autoimmune• Timing: immediate and delayed• Interaction with host factors – the mostpromising research frontier– CYP2D6 deficiency and perhexiline3

3/11/12Drug-host interactions underlieidiosyncratic DILIDRUGEliminationToxificatione.g. CYP450sTransporterse.g. MDR, BSEPDetoxificatione.g. GST, EHStressed HepatocyteAcquired ImmuneResponseInnate ImmuneResponseHepatocyteDeathEH=epoxide hydrolaseGST=glutathione-s-transferaseFigure: After Paul Watkins, M.D., Hamner InstituteA few hepatotoxins and their associated injuriesToxin Morphology Clinical featuresAcetaminophenAcute HepatocellularNecrosisN-acetyl cysteine antidotelimits mortalityIsoniazidAcute HepatocellularNecrosisAsymptomatic elevation oftransaminases is commonValproic acidMicrovesicularSteatosis(mitochondrial defect)Hyperammonemia; L-carnitine “antidote” hastheoretical benefitPyrrolizidine alkaloids(e.g., comfrey tea)Venoocclusive Disease“Nutmeg liver”; rapidlyfatal in 15-20% of cases;mediated by CYP450Identifying DILI is an importantproblem . . .• Most frequent cause of safety-related “nonapproval”and withdrawals for marketed drugs(Temple, 2006)– Troglitazone (Parke-Davis, 2000, withdrawn from US market)– Ximelagatran (Astra-Zeneca, 2006, development halted prior toUS approval)• Also limits use of many marketed drugs (e.g.,nevirapine, isoniazid, valproic acid)• Likely under-reported and underestimated ingeneral population (Sgro, 2002)– “Most dangerous disease” that the FDA sees in clinical trials(John Senior, personal communication)– Mortality is >70% without transplant (Ostapowicz, 2002)• Very, very costly . . .4

3/11/12Identifying DILI is also adifficult problem . . .xenobiotics that causeabnormalities in hepaticlaboratory values• Limited mechanisticunderstanding of DILI• Animal models have apoor negative predictivevalue for DILI• Wide range of hostsusceptibility• Drugs that cause severeDILI often do so at a lowrate– Many subtypesxenobiotics that causesevere DILImitochondrial injuryBiologics can also cause hepatotoxicity• Gemtuzumab (Mylotarg) – showed postmarketingevidence of hepatic veno-occlusivedisease; withdrawn for safety and efficacyconcerns• Infliximab (Remicade) – autoimmune hepatitis• Natalizumab (Tysabri) – hypersensitivity as wellas autoimmune hepatititis• Tocilizumab (Actemra) – elevatedaminotransferase levels (common); correlatedwith histological changes in the liver in one casereport• Visilizumab – anti CD3 mAb which causesaminotransferase elevations as part of thecytokine release syndrome (development recentlyterminated)The clinical trials conundrum• Only the most overt hepatotoxins can be expected to resultin cases of severe DILI in the clinical trials setting– Toxins that cause predictable & dose-related injury are usuallyeliminated in pre-clinical or very early development phases• Much more worrisome: toxicity that is not clearly doserelated– Xenobiotics that are tolerated by vast majority of patients– Toxicity depends on individual, idiosyncratic susceptibilities– True rate of severe DILI

3/11/12San Francisco Bay Bridge 1989Clinical trials are underpowered todetect rare eventsTrue incidence of adverse eventApprox # of patients in each arm for95% confidence~1/10,000 30,000~1/20,000 60,000……Even one or two casesof severe DILI in a clinical trial canlead to non-approvalDiagnosis of DILI is difficult• Laboratory tests indicate cellular injury butare not predictive of clinical course– Aminotransferases – AST & ALT (not very specific, althoughALT is more so than AST)– Synthetic & excretory function: bilirubin, prothrombin time(INR) & albumin• DILI can mimic all of thehistological patternsfound in primary liverdisease– Most common pattern is acutehepatitis with or withoutcholestasis6

3/11/12Analytical solution: Hy’s LawHyman Zimmerman, M.D.1914-1999• 1968: made the observation thatdrug-induced hepatocellularinjury accompanied by jaundicehad a poor prognosis (mortality:10-50%)• The Term “Hy’s Law”actually coined by BobTemple, FDA, in the1980s• Hepatocellular injurysevere enough toimpair conjugation ofbilirubin• Expected minimumincidence in practice:~1/10 th rate of Hy’s Lawcases in clinical trials• Per FDA: “≥ 2 Hy’s Lawcases per 1000:unacceptable in nononcologicdrugs”Operationalizing Hy’s Law• Hy’s Law cases must have the followingfeatures:1. Evidence of hepatocellular injury: either AST orALT >3x ULN2. AND: A functional deficit, manifest by an elevation oftotal bilirubin >2x ULN (or an INR >1.5)3. AND: No other reason which can be found to explainthe combination of increased aminotransferase andtotal bilirubin values4. AND: Without initial findings of cholestasis (i.e. analkaline phosphatase

3/11/12How accurate is Hy’s Law in predictingDILI?– Not sensitive enough for some drugs(e.g., troglitazone); too sensitive for others(e.g., tacrine)– The FDA is “not aware of the occurrenceof false positive Hy’s Law findings for adrug that was subsequently found not tocause severe DILI in a larger treatmentpopulation.”Detecting DILI: Theory Into PracticePiper methysticum“Kava”FDA DILI Guidance: Highlights• History and scope: finalized in 2009– Intended to assist in the assessment of “the potential for a drug tocause severe liver injury” defined as “irreversible liver failure that isfatal or requires transplantation”• Definition of serious DILI: uses Hy’s Law• Reporting of events: explicitly states that all eventsof hepatotoxicity need to be explained in an NDAor BLA application• Assessment and analysis: the potential for DILIshould always be evaluated as part of thesponsor’s application• “Contains Nonbinding Recommendations”8

3/11/12For illustrative purposes onlyTime course of “typical” serious DILIALT & ASTBilirubinAlk. Phos.• Initial hepatocellular injury (aminotransferase elevations) followed bya TBL peak weeks later (often manifest in the patient as jaundice)Source: Senior, JR, Drug Hepatotoxicity from the Regulatory Perspective, Clinics in Liver Disease, 2007For illustrative purposes onlyPotential DILI cases in an NDA: medicalreview (I)• Hypothetical dataset of 8000 patients• Using the most liberal interpretation of Hy’s Law –i.e., lab abnormalities at any visit)Confounded/UnlikelyPossibleLikely154• After discarding confounded cases, as many as 8cases (0.1%) in the dataset could be adjudicatedas DILI by the FDA4For illustrative purposes onlyPotential DILI cases in a filing:medical review (II)• Medical review limited by– Incomplete and non-standardized data acrossmultiple ongoing and completed trials• In clinical practice, serious DILI is estimatedto be at least 10% of the rate of Hy’s Lawcases seen in clinical trials (Temple, 2001)– Implied rate of serious DILI in “real world”setting: at least 0.01%, or ~ 1/10,000 patients9

3/11/12Getting it wrong: The trabectedin Oncology DrugAdvisory Committee (ODAC), 7/15/2009Hy’s Law cases in trabectedin combination armSubjectIDALT orASTGreaterthan3xULNCycle #(StudyDays)TBLGreaterthan orequal to2xULNCycle #(StudyDays)ALPLessthanorequalto2xULNLiverMets?Identified bySponsor orFDAMeet All LabTest CriteriaConcomitantly240016 Yes 3 Yes 3 Yes No Both Yes250005* Yes 2 Yes 2 Yes No Both Yes280005 Yes 1 Yes 1 Yes No Both Yes200033 Yes 2 (~35) Yes 2 (~44) Yes No FDA NoOne cycle = 3 weeks*This patient got an overdose220089 Yes 1 (~15) Yes 1 (~8) Yes No FDA NoGetting it right: The pazopanib ODAC(10/5/2009)Hy’sLawCaseRecoveryOccurence of SevereLiver InjurySponsor’sAssessmentFDA’sAssessment1 No Death with hepatic injury Included Probablyrelated2 No Death Not excluded Possiblyrelated3 Yes No (discontinued) Included Probably• Analysis was performed in consultation with FDArelated• Sponsor and FDA agreed upon the number of4 Yes No (adapted) Included ProbablyHy’s Law casesrelatedConclusionsAmanita phalloidesDeath cap3010

3/11/12Uncertainty and risk are not the sameRiskUncertaintyQuantification Measurable Not measurableEpistemology Knowable Not knowableMitigationPossible withappropriate planningDifficultDonald Rumsfeld“Known unknowns”“Unknown unknowns”:things we don’t know wedon’t knowTaxonomy of risk in drug development• Scientific risk – addressed by our most rational, datadrivenunderstanding of a phenomenon– Pan-α4 integrin inhibition (natalizumab) & Progressive MultifocalLeukoencephalopathy (PML)– vs. specific inhibition of α4β7 integrin (e.g., vedolizumab(Soler, et al, 2009)) & PML• Medical risk – addressed by our confidence in ourscientific understanding as we apply it to human disease& therapeutics– Is the sponsor comfortable studying an α4β7 integrin inhibitor inhealthy volunteers who receive no benefit from the trial?• Regulatory risk – difficult for us to address: FDA’s (oranother regulator’s) understanding of the data– FDA may be not be convinced by our scientific arguments andrequire monitoring for PML in our clinical trialSummary• Hepatotoxicity remains the most important safetyrelatedreason for drug development failure– Clinical trials are designed to demonstrate efficacy;they are not powered to detect rare events– The study of DILI is an evolving science that isconsensus-based• In order to avoid the trabectedin ODAC scenario,sponsors will need to adopt a strategy ofaggressive proactive surveillance in the search fordrug-induced liver injury in clinical trials11

3/11/12Questions and comments3412

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