Drug development

◆ Selection of therapeutic targetsSelection of therapeutic targets

◆ Stages of developmentStages of development

◆ Clinical developmentClinical development

◆ Major challengesMajor challenges

DRUG DEVELOPMENTDRUG DEVELOPMENT

◆ Therapeutic NeedTherapeutic Need

SELECTION OF SELECTION OF THERAPEUTIC TARGETSTHERAPEUTIC TARGETS

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


◆ Feasible hypothesisFeasible hypothesis


◆ TraditionalTraditional

◆ EmpiricalEmpirical

◆ MolecularMolecular

APPROACHES TO APPROACHES TO NEW MEDICINES DISCOVERYNEW MEDICINES DISCOVERY

TraditionalTraditional


◆ 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


◆ 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)


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



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


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


◆ 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


◆ 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


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


◆ Feasibility hypothesisFeasibility hypothesis

◆ Commercial considerationsCommercial considerations


◆ 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


◆ Feasibility hypothesisFeasibility hypothesis

◆ Commercial considerationsCommercial considerations

◆ Regulatory issuesRegulatory issues


◆ 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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Drug development

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