drug development
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◆ Selection of therapeutic targetsSelection of therapeutic targets
◆ Stages of developmentStages of development
◆ Clinical developmentClinical development
◆ Major challengesMajor challenges
DRUG DEVELOPMENTDRUG DEVELOPMENT
Determined by:Determined by:
◆ Existing therapiesExisting therapies
◆ Commercial potentialCommercial potential
◆ ‘‘Individualisation’ of treatment (genomics)Individualisation’ of treatment (genomics)
◆ Patient/Public demandsPatient/Public demands
THERAPEUTIC NEED - 1THERAPEUTIC NEED - 1
Existing Therapies:Existing Therapies:
◆ Well served diseases (but room for improvement)Well served diseases (but room for improvement)• heart failureheart failure• hypertensionhypertension• asthmaasthma
◆ Poorly served diseasesPoorly served diseases• chronic neurological diseaseschronic neurological diseases• Alzheimer’sAlzheimer’s• Motor Neurone DiseaseMotor Neurone Disease
THERAPEUTIC NEED - 2THERAPEUTIC NEED - 2
Existing Therapies:Existing Therapies:
◆ Major OpportunitiesMajor Opportunities• VaccinesVaccines
• AIDSAIDS• Type I diabetes mellitusType I diabetes mellitus
◆ Emerging resistances to antibioticsEmerging resistances to antibiotics
THERAPEUTIC NEED 3THERAPEUTIC NEED 3
A possible scenario:A possible scenario:
◆ Minor, self-limiting ‘conditions’Minor, self-limiting ‘conditions’• generic companiesgeneric companies• healthcare departments of major companieshealthcare departments of major companies
◆ Novel, chemically based small moleculesNovel, chemically based small molecules• surface and intracellular receptorssurface and intracellular receptors• enzymesenzymes• ion channelsion channels
◆ Individualised therapies for diseases with specific and Individualised therapies for diseases with specific and selective deficienciesselective deficiencies
THERAPEUTIC NEED 4THERAPEUTIC NEED 4
◆ Therapeutic NeedTherapeutic Need
◆ Feasible hypothesisFeasible hypothesis
SELECTION OF SELECTION OF THERAPEUTIC TARGETSTHERAPEUTIC TARGETS
◆ TraditionalTraditional
◆ EmpiricalEmpirical
◆ MolecularMolecular
APPROACHES TO APPROACHES TO NEW MEDICINES DISCOVERYNEW MEDICINES DISCOVERY
TraditionalTraditional
APPROACHES TO APPROACHES TO NEW MEDICINES DISCOVERYNEW MEDICINES DISCOVERY
◆ Trial and errorTrial and error
◆ Diverse cultures and systems of medicines e.g. Diverse cultures and systems of medicines e.g. morphine, quinine, ephedrine and artemisinin (anti-morphine, quinine, ephedrine and artemisinin (anti-malarial)malarial)
EmpiricalEmpirical
APPROACHES TO APPROACHES TO NEW MEDICINES DISCOVERYNEW MEDICINES DISCOVERY
◆ Builds on understanding of relevant physiological Builds on understanding of relevant physiological processprocess
◆ Use of naturally occurring lead molecule e.g. Use of naturally occurring lead molecule e.g. tubocurarine, propranolol and other tubocurarine, propranolol and other ß-adrenoceptor antagonists, Hß-adrenoceptor antagonists, H22-antagonists-antagonists
Molecular (1)Molecular (1)
APPROACHES TO APPROACHES TO NEW MEDICINES DISCOVERYNEW MEDICINES DISCOVERY
Most drug discovery is based on this approachMost drug discovery is based on this approach
◆ Molecular biological techniquesMolecular biological techniques
◆ Advances in genomicsAdvances in genomics
Molecular (2)Molecular (2)
APPROACHES TO APPROACHES TO NEW MEDICINES DISCOVERYNEW MEDICINES DISCOVERY
Categories:Categories:
◆ Rational drug designRational drug design
◆ Computer-assisted techniquesComputer-assisted techniques
◆ Anti-sense approachAnti-sense approach
◆ Manipulation of genetic targetsManipulation of genetic targets
◆ Random screeningRandom screening
◆ Pragmatic and dominant at presentPragmatic and dominant at present
Molecular (3)Molecular (3)
APPROACHES TO NEW MEDICINES APPROACHES TO NEW MEDICINES DISCOVERYDISCOVERY
Technological Developments:Technological Developments:
◆ High throughputs of potential compoundsHigh throughputs of potential compounds
◆ Molecular biological knowledgeMolecular biological knowledge
◆ InstrumentationInstrumentation
◆ Information TechnologyInformation Technology
◆ ScreeningScreening
Molecular (3) contMolecular (3) cont
APPROACHES TO NEW MEDICINES APPROACHES TO NEW MEDICINES DISCOVERYDISCOVERY
◆ Availability of molecular targetsAvailability of molecular targets
◆ Engineering of targets in simple Engineering of targets in simple reporter systems e.g. yeastreporter systems e.g. yeast
◆ Use of robotics to handle samples Use of robotics to handle samples and conduct assaysand conduct assays
Random Random screening of screening of
chemical chemical diversitydiversity
STEPS INVOLVED IN THE GENETICSTEPS INVOLVED IN THE GENETICREVOLUTION IN MEDICINEREVOLUTION IN MEDICINE
Disease with genetic Disease with genetic componentcomponent
MapMap
Clone geneClone gene
Gene therapyGene therapy
TimeTime
Accelerated by Accelerated by Human Genome Human Genome
ProjectProjectDiagnosticsDiagnostics
Preventive Preventive MedicineMedicine
PharmacogenomicsPharmacogenomics
Understand Understand basic biologic basic biologic
defectdefect
Drug therapyDrug therapy
STEPS INVOLVED IN THE GENETICSTEPS INVOLVED IN THE GENETICREVOLUTION IN MEDICINEREVOLUTION IN MEDICINE
Uncovering the genetic contributions to an illness is accomplished by Uncovering the genetic contributions to an illness is accomplished by cloning the gene for the disease, with the use of the tools of the cloning the gene for the disease, with the use of the tools of the Human Genome Project. Once the contributing genes and their Human Genome Project. Once the contributing genes and their disease - predisposing variants have been identified, diagnostic tests disease - predisposing variants have been identified, diagnostic tests can be developed to predict future risk - but these tests are most can be developed to predict future risk - but these tests are most effective when a preventative strategy is available to reduce the risk in effective when a preventative strategy is available to reduce the risk in persons found to be predisposed to a particular disease. Another persons found to be predisposed to a particular disease. Another rapidly developing application of diagnostics is pharmacogenomics, rapidly developing application of diagnostics is pharmacogenomics, the prediction of responsiveness to drugs. Ultimately, the real payoff the prediction of responsiveness to drugs. Ultimately, the real payoff of genetic research will be the development of new gene therapies of genetic research will be the development of new gene therapies and drug therapies, but they will generally require more years of and drug therapies, but they will generally require more years of intensive research.intensive research.
Traditional medical uses of natural products
DRUG DISCOVERY SOURCES IN CONTEXTDRUG DISCOVERY SOURCES IN CONTEXT
Sources of compoundsSources of compounds
Chemical librariesHistorical compound collectionsNatural product librariesCombinatorial libraries
Therapeutic TargetsTherapeutic Targets
Rational synthesis
Antisense oligonucleotides
Drug discovery screening assays
Lead optimisation and candidate selection
Empirical understanding of physiology and pathology
Molecular cloining of receptors and signalling molecules
Genomics
Drug developmentDrug development
DRUG DISCOVERY SOURCES IN CONTEXTDRUG DISCOVERY SOURCES IN CONTEXT
Different types of chemical compounds (top left hand side of diagram) Different types of chemical compounds (top left hand side of diagram) are tested against bioassays that are relevant to therapeutic targets, are tested against bioassays that are relevant to therapeutic targets, which are derived from several possible sources of information (right which are derived from several possible sources of information (right hand side). The initial lead compounds discovered by the screening hand side). The initial lead compounds discovered by the screening process are optimised by analogue synthesis and tested for process are optimised by analogue synthesis and tested for appropriate pharmacokinetic properties. The candidate compounds appropriate pharmacokinetic properties. The candidate compounds then enter the development process, involving regulatory toxicology then enter the development process, involving regulatory toxicology studies and clinical trials.studies and clinical trials.
Molecular Approach for Potential Drug TargetsMolecular Approach for Potential Drug Targets
APPROACHES TO NEW MEDICINES APPROACHES TO NEW MEDICINES DISCOVERYDISCOVERY
◆ High throughputs of potential compoundsHigh throughputs of potential compounds
◆ Understanding of physiological processes at molecular level Understanding of physiological processes at molecular level is possible e.g. -is possible e.g. -
-- (in 1999 May) > 250 gene products relating to (in 1999 May) > 250 gene products relating to neurotransmittersneurotransmitters
-- Several hundreds of subtypes of ion channels Several hundreds of subtypes of ion channels characterisedcharacterised
-- Understanding of intracellular signalling pathwaysUnderstanding of intracellular signalling pathways
Molecular:Issues/ChallengesMolecular:Issues/Challenges
APPROACHES TO APPROACHES TO NEW MEDICINES DISCOVERYNEW MEDICINES DISCOVERY
Dissection of a disease processDissection of a disease process
◆ Reductionism loses systems integration and potential Reductionism loses systems integration and potential loss of understanding of pathophysiological processloss of understanding of pathophysiological process
◆ Provision of too many potential targets to be validated in Provision of too many potential targets to be validated in vitro, in animals or manvitro, in animals or man
◆ Number and which compounds to test by random Number and which compounds to test by random screening, e.g. structural diversity, natural productsscreening, e.g. structural diversity, natural products
FEASIBLE HYPOTHESISFEASIBLE HYPOTHESIS
◆ In animals (in vitro/in vivo)In animals (in vitro/in vivo)
◆ Greater potency or selectivityGreater potency or selectivity
◆ Validated animal model of diseaseValidated animal model of disease
◆ Surrogate markersSurrogate markers
FEASIBLE HYPOTHESISFEASIBLE HYPOTHESIS
◆ In ManIn Man
◆ Back ups and follow-ups:Back ups and follow-ups:
Improvements on existing molecules (kinetics, Improvements on existing molecules (kinetics, metabolism pharmaceutical)metabolism pharmaceutical)
◆ Novel mechanism:Novel mechanism:
Improvements in biological understandingImprovements in biological understanding
◆ Potential breakthroughPotential breakthrough
SURROGATE MARKERSSURROGATE MARKERS
◆ A biological measurement which substitutes for A biological measurement which substitutes for the therapeutic end-pointthe therapeutic end-point
SURROGATE MARKERSSURROGATE MARKERS
◆ Characteristics of a “good” surrogate:Characteristics of a “good” surrogate:
-- Biological feasibilityBiological feasibility
-- Dose-related response to interventionDose-related response to intervention
-- Easy to measureEasy to measure
-- Reproducible, specific and sensitive with high Reproducible, specific and sensitive with high predictive valuepredictive value
-- Acceptable by expertsAcceptable by experts
-- Acceptable by Regulatory AuthoritiesAcceptable by Regulatory Authorities
◆ Therapeutic NeedTherapeutic Need
◆ Feasibility hypothesisFeasibility hypothesis
◆ Commercial considerationsCommercial considerations
SELECTION OF SELECTION OF THERAPEUTIC TARGETSTHERAPEUTIC TARGETS
◆ New Product Launches - 36 (2001)New Product Launches - 36 (2001)
Slow down due to:Slow down due to:• merger distractionsmerger distractions• focus on early-stage ‘genomics’ related focus on early-stage ‘genomics’ related
researchresearch• increasing costs ($800M per drug)increasing costs ($800M per drug)• tougher regulatory standardstougher regulatory standards
◆ Time of developmentTime of development
◆ Chances of successChances of success
◆ CompetitionCompetition
COMMERCIAL CONSIDERATIONSCOMMERCIAL CONSIDERATIONS
Unmet Unmet Medical Medical NeedNeed
COMMERCIAL COMMERCIAL CONSIDERATIONSCONSIDERATIONS
Examples:Examples:
1. Cystic fibrosis1. Cystic fibrosis
2.2.
3. Heart failure 3. Heart failure many cancers many cancers
4. Allergic Rhinitis4. Allergic Rhinitis
➀➀
➁➁
➂➂
➃➃
IMPACTIMPACT
◆ Therapeutic NeedTherapeutic Need
◆ Feasibility hypothesisFeasibility hypothesis
◆ Commercial considerationsCommercial considerations
◆ Regulatory issuesRegulatory issues
SELECTION OF SELECTION OF THERAPEUTIC TARGETSTHERAPEUTIC TARGETS
◆ Highly regulated activityHighly regulated activity
◆ Application for Phase I in USA (IND) and most Application for Phase I in USA (IND) and most countriescountries
◆ No Governmental approval required for Phase I in No Governmental approval required for Phase I in the UK, Holland or Switzerlandthe UK, Holland or Switzerland
◆ Approval to register a drug does not guarantee Approval to register a drug does not guarantee successful marketingsuccessful marketing
REGULATORY ISSUESREGULATORY ISSUES
◆ Approval to register may take 3 years or more (NDA) Approval to register may take 3 years or more (NDA) in USAin USA
◆ Impact of European Union (E.M.E.A)Impact of European Union (E.M.E.A)
◆ International Harmonisation ConferencesInternational Harmonisation Conferences
◆ (I.C.H.) on the uniformity of regulatory requirements (I.C.H.) on the uniformity of regulatory requirements (USA, Europe, Japan)(USA, Europe, Japan)
REGULATORY ISSUES (cont)REGULATORY ISSUES (cont)
◆ Pharmaco-economic assessmentPharmaco-economic assessment
◆ NICENICE
◆ guidelinesguidelines
◆ cost-effectivenesscost-effectiveness
THE FOURTH HURDLETHE FOURTH HURDLE
◆ Why non-patient volunteers?Why non-patient volunteers?◆ Ease of organisationEase of organisation◆ no problems with placebos or active drugsno problems with placebos or active drugs◆ security of data interpretationsecurity of data interpretation◆ no regulatory approval required in UKno regulatory approval required in UK
◆ Use of target patient population at exploratory Use of target patient population at exploratory phase because of benefit received, does not stand phase because of benefit received, does not stand scrutinyscrutiny
◆ ““risk to the few for the good of the many”risk to the few for the good of the many”
ETHICAL CONSIDERATIONSETHICAL CONSIDERATIONS(For Phase I Studies)(For Phase I Studies)
STAGES OF DEVELOPMENTSTAGES OF DEVELOPMENTClinical DevelopmentClinical Development
Nos. ofNos. of subjectsubject
PhasePhase ActivitiesActivities
10’s-100’s10’s-100’s
10’s10’s 11
22
aa
Safety & tolerability kinetics H.N.V & Safety & tolerability kinetics H.N.V & DynamicsDynamicsDose responseDose responseProof of conceptProof of concept
Early patient studies:Early patient studies:Proof of conceptProof of concept“Powered” studies for efficacy“Powered” studies for efficacybb
SILDENAFIL (Viagra)SILDENAFIL (Viagra)
PDE5PDE5
GTPGTPGDPGDP
Nitric OxideNitric Oxide
SildenafilSildenafil
GuanylateGuanylateCyclaseCyclase
CavernosalCavernosalsmooth musclesmooth muscle
RelaxationRelaxation
Penile ErectionPenile Erection
GMPGMP
++
--
DNA CHIP AND MICRO-ARRAY DNA CHIP AND MICRO-ARRAY TECHNOLOGY (1)TECHNOLOGY (1)
◆ Human genetic variations to subclassify diseasesHuman genetic variations to subclassify diseases
◆ Individualisation of therapiesIndividualisation of therapies
◆ Identification of toxic reactionsIdentification of toxic reactions Pharmaco-Pharmaco-
genomicsgenomics
Enzyme InhibitorsEnzyme Inhibitors
◆ Intracellular/extracellularIntracellular/extracellular
◆ SpecificitySpecificity
◆ AccessAccess
◆ Competitive/non competitive Competitive/non competitive bindingbinding
STAGES OF DEVELOPMENTSTAGES OF DEVELOPMENTResearchResearch
ExamplesExamples
◆ HMG Co AHMG Co A
◆ ReductaseReductaseinhibitorsinhibitors
◆ ACE inhibitorsACE inhibitors
Cell Surface ReceptorsCell Surface Receptors
◆ DistributionDistribution
◆ ClassificationClassification
◆ SelectivitySelectivity
◆ AvailabilityAvailability
STAGES OF DEVELOPMENTSTAGES OF DEVELOPMENTResearchResearch
ExamplesExamples
◆ HH22 antagonists antagonists
◆ BB11 & B & B1/21/2 Blockers Blockers
◆ 5HT5HTIAIA agonists agonists
◆ Getting the dose range rightGetting the dose range right
◆ Gene therapyGene therapy
◆ Value of animal toxicity testing for recombitiant - Value of animal toxicity testing for recombitiant - derived productsderived products
◆ Pharmaco-economics, disease management, Pharmaco-economics, disease management, protocol-driven prescribing strategiesprotocol-driven prescribing strategies
DRUG DEVELOPMENTDRUG DEVELOPMENTMajor Challenges for the FutureMajor Challenges for the Future
◆ PharmacogenomicsPharmacogenomics
-- Individualisation on response to drugsIndividualisation on response to drugs
-- Identification of toxic reactionsIdentification of toxic reactions
-- Gene based drugs for treatments,Gene based drugs for treatments,e.g. recombitientse.g. recombitients
GENETIC TESTINGGENETIC TESTING
DNA tests to:-DNA tests to:-
◆ diagnose genetic diseasediagnose genetic disease
◆ predict disease in later lifepredict disease in later life
◆ identify heterozygote carriers of recessive identify heterozygote carriers of recessive diseasesdiseases
DIAGNOSTIC APPLICATIONSDIAGNOSTIC APPLICATIONSFROM GENETICSFROM GENETICS
Examples:Examples:
(1)(1) High penetrant changes in single genesHigh penetrant changes in single genes
-- Haemochromatosis Haemochromatosis- Phenylketonuria- Phenylketonuria-- Familial hypercholesterolaemia Familial hypercholesterolaemia
(2)(2) Environmental interplay and multiple genesEnvironmental interplay and multiple genes
- Highly heritable subgroups- Highly heritable subgroupse.g. e.g. (1) B RCA 1 & 2 in breast cancer(1) B RCA 1 & 2 in breast cancer
(2) HNF - 4(2) HNF - 4∝∝ in MODY type I in MODY type I(3) GCK in MODY type II(3) GCK in MODY type II
DIAGNOSTIC APPLICATIONSDIAGNOSTIC APPLICATIONSFROM GENETICSFROM GENETICS
APPROACHESAPPROACHES TO TO NEW MEDICINES DISCOVERY (3)NEW MEDICINES DISCOVERY (3)
◆ Availability and understanding of molecular target Availability and understanding of molecular target for proposed drugfor proposed drug
e.g.e.g. Anti-sense oligonuleotidesAnti-sense oligonuleotides
Gene therapyGene therapy
-- Cystic FibrosisCystic Fibrosis
-- VEGFVEGF
DNA TECHNOLOGY AND DNA TECHNOLOGY AND MICRO-ARRAY SYSTEMS (2)MICRO-ARRAY SYSTEMS (2)
Examples:Examples:
(1)(1) Alzheimer patients with E4 subtype of gene for Alzheimer patients with E4 subtype of gene for apolipoprotein E (APOapolipoprotein E (APOEE4) affecting cholinergic brain 4) affecting cholinergic brain
function less likely to respond to tacrinefunction less likely to respond to tacrine
(2)(2) CETP (cholesteryl ester transfer protein) important in CETP (cholesteryl ester transfer protein) important in control of HDL metabolismcontrol of HDL metabolism
DNA CHIP AND MICRO-ARRAY DNA CHIP AND MICRO-ARRAY TECHNOLOGY (2)TECHNOLOGY (2)
StageStage TimeTime (Years) (Years) Major ActivityMajor Activity
ResearchResearch
Clinical Clinical ResearchResearch
RegistrationRegistration
MarketingMarketing
2-72-7
2-42-4
1-21-2
Candidate Compound Candidate Compound Plausible - HypothesiaPlausible - Hypothesia
Confirmation of dose range. Confirmation of dose range. Explorative - treatment. Explorative - treatment. Safety databaseSafety database
Preparation of DossierPreparation of Dossier
New Product Launches - 36New Product Launches - 36
Slow down due to:Slow down due to:
◆ merger distractionsmerger distractions
◆ focus on early-stage ‘genomics’ related researchfocus on early-stage ‘genomics’ related research
◆ increasing costs ($800M per drug)increasing costs ($800M per drug)
◆ tougher regulatory standardstougher regulatory standards
PRODUCT BREAKTHROUGHSPRODUCT BREAKTHROUGHS(2001)(2001)
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