Transcription
Drug Discovery & DevelopmentNeal G. Simon, Ph.D.ProfessorDepartment of Biological Sciences
Drug Discovery & Development: Bench, Bedside, &BeyondI. BackgroundII. The R&D LandscapeIII. Innovation and TransformationIV. The Preclinical Development ProcessV. Case Study: A Novel AntidepressantVI. Ethical Issues: Money, Data, & Politics
Disclaimer“Those who have knowledge, don’t predict.Those who predict, don’t have knowledge.”Lao Tzu, 6th Century BC Chinese Poet
Serendipity or Good Science: Building OpportunityHoffmanOsterloh
I. Background
Drug Development Process: StagesUS FDA
Drug Development Process: Phases
Biopharmaceutical Drug Development: Attrition250 CompoundsPhase I20-100VolunteersPhase III1000-5000Volunteers5 CompoundsNDA Submitted10,000CompoundsFDAReviewClinical TrialsPre-ClinicalIND SubmittedDrugDiscoveryLarge ScaleManufacturing/ Phase IV1 FDAApprovedDrugPhase II100-500Volunteers5 years1.5 yearsQuelle: Burrell Report Biotechnology Industry 20066 years2 years2 years
II. The Research & Development Landscape
New Chemical Entities: R&D Cost ModelDiscovery: 263/ 824 millionDevelopment: 632/1054 millionPaul et al (2010). Nature Rev Drug Discovery
Annual Private & Public R&D Spending
Research & Development Spending: Return on InvestmentSaltzmann (2009). Feeding the Pipeline
III. Innovation & Transformation
Innovation Models and TransformationHu et al (2007)
Antidepressants: Me Too Drugs1986Fluvoxamine(Luvox; Solvay) SSRI1987Fluoxetine(Prozac; Lilly)1992Sertraline(Zoloft; Pfizer) SSRI/NRI1993Venlafaxine(Effexor; Wyeth) SSRI/NRI1996Buproprion(Wellbutrin; Wyeth) SNRI/DRI2002Escitalopram(Lexapro; Forrest) SSRI2004Duloxetine(Cymbalta; Lilly) SSRI/NRI2008Desvenlafaxine(Pristiq; Wyeth/Pfizer) SNRI2011Vilazidone(Vybrid; Forest Labs) SSRI/5HT1aSSRI
Personalized Medicine (sort of)
Discovery & Preclinical DevelopmentIV. Discovery & Development
Preclinical DevelopmentDrug CandidateConfirmationPreclinical DrugCharacterizationEfficacy Assessment: Does it work?ADME Profiling: How can it be delivered and what does the body do?Toxicology/Safety Pharmacology Assessment: Is it safe?Pharmaceutics: Is the manufacture viable and controllable?Adapted from TetraQRegulatory Submission to FDALead Selection andOptimization (iterative)
Stage 1: Lead Selection and OptimizationEssential Pharmaceutics Screening Efficacy In vitro models In vivo models OtherAdapted from TetraQStructural CharacterizationImpurity IdentificationSolubility assessmentPrototype formulationStability testingEarly ADME In silico profiling Develop simpleanalytical method Measure membranepermeability Plasma StabilityEarly Toxicology Off target screen In vitro cytotoxicity Preliminary AMES hERG binding
Stage 2: Drug Candidate ConfirmationData from Lead Optimization StagePreliminary CMC(Chemistry,Manufacture andControl) Formulation forGLP Toxicology Stability testingof activeingredient Detailedphysicochemicalcharacterization ImpurityanalysisAdapted from TetraQ“Benchmark” invivo Models In vivo models Validatedmodels Models in otherdisease areasADME ProfilingPreliminaryToxicology Optimizedanalyticalmethoddevelopment Basic pharmacokinetics (PK)& OralBioavailability Determinemetabolism ofdrug Maximumtolerated dose(MTD) Repeat Dose(non-GLP) PreliminaryCardiovascularSafetyPharmacology
Stage 3: Preclinical Drug CharacteristicsData from Prior StagesDetailed PreclinicalCMC ICH StabilityTesting ICH impurityanalysis Develop prototypeclinical formulationComprehensiveADMEGLP ToxicologyPackage analytical methoddevelopment ComprehensivePharmacokinetics GLP TK Comprehensiveidentification ofmetabolites acute study subchronic repeatdose study GenotoxicityBattery SafetyPharmacologyRegulatory Submission to FDA or Presentation to Pharmaceutical CompanyAdapted from TetraQ
V. Case Study: Agomelatine
Major Depression: Symptoms Anhedonia Blunted Affect Disturbed Sleep Weight Gain/Weight Loss Compromised Social Interactions
The ScreamFear Circuits: Core ComponentsHippocampusand AmygdalaAnterior &RostralCingulateCortexInsular CortexEdvard Munch, 1893Shin & Liberzon (2010)
Hypothalamic-Pituitary-Adrenal AxisBiological Sciences
Hypothalamic-Pituitary-Adrenal AxisKey Considerations Regulatory Peptides CRF AVP Feedback Regulation Glucocorticoids Biorhythm Disturbance Sleep Temperature Cardiac HPA axisBiological Sciences
Major Depression & Biorhythms Alterations in circadian rhythms of behavior, sleep, core temperature and thesecretion of cortisol and other hormones Blunted amplitude of daily rhythms and poor responsiveness to environmentalentraining stimuli. Circadian desynchronization may also be triggered by disorganization of thesuprachiasmatic nucleus Circadian disturbances may be provoked by an abnormal pineal output ofmelatonin, a key synchronizer of biological rhythms and sleep Depression is associated with an altered diurnal rhythm of melatonin output,including a blunted night time surge Administration of melatonin itself is ineffective in major depression Re-coordination of biological rhythms by recruitment of melatonergicmechanisms may be a therapeutically relevant strategy for improving depressedstates.
Melatonin, Circadian Rhythms, & Agomelatine
Agomelatine: Mechanism of Action
Discovery, Development, Characterization, &Approval of AgomelatineKey Pharmacological Observations
V. Ethics
NeurontinPFIZER LOSES A ROUND OVER MARKETING OF NEURONTINBy BLOOMBERG NEWSA judge in Boston upheld a jury decision that Pfizer illegally promoted Neurontin forunapproved uses. Pfizer said it would appeal. January 29, 2011EXPERTS CONCLUDE PFIZER MANIPULATED STUDIESBy STEPHANIE SAULThe drug maker manipulated the publication of studies to bolster use of its epilepsy drugNeurontin, according to expert witnesses in a lawsuit against the company. Oct 8, 2008PFIZER TO PAY 430 MILLION OVER PROMOTING DRUG TO DOCTORSBy GARDINER HARRISPfizer pleads guilty and agrees to pay 430 million to resolve criminal and civil chargesthat it paid doctors to prescribe epilepsy drug Neurontin to patients with ailments thatdrug was not federally approved to treat. May 14, 2004
Politics, Medicine, & Responsibilityhttp://www.youtube.com/watch?v pPZn9mRQlq4
Serendipity or Good Science: Building OpportunityHoffmanOsterhloh
Thank you for your time and attention
The drug maker manipulated the publication of studies to bolster use of its epilepsy drug Neurontin, according to expert witnesses in a lawsuit against the company. Oct 8, 2008 PFIZER TO PAY 430 MILLION OVER PROMOTING DRUG TO DOCTORS By GARDINER HARRIS Pfizer pleads guilty and agrees to pay 430 million to resolve criminal and civil charges
