drug devel ment

46
DEPARTMENT OF CLINICAM PHARMACOLOGY DEPARTMENT OF CLINICAM PHARMACOLOGY YAROSLAVL STATE MEDICAL ACADEMY YAROSLAVL STATE MEDICAL ACADEMY Dr. Mohamed Bawoh

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Dr. Mohamed Bawoh Department of Clinical Pharmacology Yaroslavl State Medical Academy

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Page 1: Drug Devel Ment

DEPARTMENT OF CLINICAM PHARMACOLOGY DEPARTMENT OF CLINICAM PHARMACOLOGY YAROSLAVL STATE MEDICAL ACADEMYYAROSLAVL STATE MEDICAL ACADEMY

Dr. Mohamed Bawoh

Page 2: Drug Devel Ment

DRUG DEVELOPMENTDRUG DEVELOPMENT

Selection of therapeutic targetsSelection of therapeutic targets

Stages of developmentStages of development

Clinical developmentClinical development

Major challengesMajor challenges

Page 3: Drug Devel Ment

Therapeutic NeedTherapeutic Need

SELECTION OF SELECTION OF THERAPEUTIC TARGETSTHERAPEUTIC TARGETS

Page 4: Drug Devel Ment

Determined by:Determined by:

Existing therapiesExisting therapies

Commercial potentialCommercial potential

‘‘Individualisation’ of treatment Individualisation’ of treatment (genomics)(genomics)

Patient/Public demandsPatient/Public demands

THERAPEUTIC NEED - 1THERAPEUTIC NEED - 1

Page 5: Drug Devel Ment

Existing Therapies:Existing Therapies:

Well served diseases (but room for Well served diseases (but room for improvement)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

Page 6: Drug Devel Ment

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

Page 7: Drug Devel Ment

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 Individualised therapies for diseases with specific and selective deficienciesand selective deficiencies

THERAPEUTIC NEED 4THERAPEUTIC NEED 4

Page 8: Drug Devel Ment

Therapeutic NeedTherapeutic Need

Feasible hypothesisFeasible hypothesis

SELECTION OF SELECTION OF THERAPEUTIC TARGETSTHERAPEUTIC TARGETS

Page 9: Drug Devel Ment

TraditionalTraditional

EmpiricalEmpirical

MolecularMolecular

APPROACHES TO APPROACHES TO NEW MEDICINES DISCOVERYNEW MEDICINES DISCOVERY

Page 10: Drug Devel Ment

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 morphine, quinine, ephedrine and artemisinin (anti-malarial)(anti-malarial)

Page 11: Drug Devel Ment

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

Page 12: Drug Devel Ment

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

Page 13: Drug Devel Ment

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

Page 14: Drug Devel Ment

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

Page 15: Drug Devel Ment

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 Use of robotics to handle samples and conduct assayssamples and conduct assays

Random Random screening screening

of chemical of chemical diversitydiversity

Page 16: Drug Devel Ment

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

Page 17: Drug Devel Ment

STEPS INVOLVED IN THE GENETICSTEPS INVOLVED IN THE GENETICREVOLUTION IN MEDICINEREVOLUTION IN MEDICINE

Uncovering the genetic contributions to an illness is Uncovering the genetic contributions to an illness is accomplished by cloning the gene for the disease, with the use of accomplished by cloning the gene for the disease, with the use of the tools of the Human Genome Project. Once the contributing the tools of the Human Genome Project. Once the contributing genes and their disease - predisposing variants have been genes and their disease - predisposing variants have been identified, diagnostic tests can be developed to predict future identified, diagnostic tests can be developed to predict future risk - but these tests are most effective when a preventative risk - but these tests are most effective when a preventative strategy is available to reduce the risk in persons found to be strategy is available to reduce the risk in persons found to be predisposed to a particular disease. Another rapidly developing predisposed to a particular disease. Another rapidly developing application of diagnostics is pharmacogenomics, the prediction application of diagnostics is pharmacogenomics, the prediction of responsiveness to drugs. Ultimately, the real payoff of genetic of responsiveness to drugs. Ultimately, the real payoff of genetic research will be the development of new gene therapies and drug research will be the development of new gene therapies and drug therapies, but they will generally require more years of intensive therapies, but they will generally require more years of intensive research.research.

Page 18: Drug Devel Ment

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

Page 19: Drug Devel Ment

DRUG DISCOVERY SOURCES IN CONTEXTDRUG DISCOVERY SOURCES IN CONTEXT

Different types of chemical compounds (top left hand side of Different types of chemical compounds (top left hand side of diagram) are tested against bioassays that are relevant to diagram) are tested against bioassays that are relevant to therapeutic targets, which are derived from several possible therapeutic targets, which are derived from several possible sources of information (right hand side). The initial lead sources of information (right hand side). The initial lead compounds discovered by the screening process are optimised compounds discovered by the screening process are optimised by analogue synthesis and tested for appropriate by analogue synthesis and tested for appropriate pharmacokinetic properties. The candidate compounds then pharmacokinetic properties. The candidate compounds then enter the development process, involving regulatory toxicology enter the development process, involving regulatory toxicology studies and clinical trials.studies and clinical trials.

Page 20: Drug Devel Ment

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 Understanding of physiological processes at molecular

level is possible e.g. -level 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 Understanding of intracellular signalling pathwayspathways

Page 21: Drug Devel Ment

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 Reductionism loses systems integration and potential loss of understanding of pathophysiological potential loss of understanding of pathophysiological processprocess

Provision of too many potential targets to be Provision of too many potential targets to be validated in vitro, in animals or manvalidated in vitro, 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

Page 22: Drug Devel Ment

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

Page 23: Drug Devel Ment

FEASIBLE HYPOTHESISFEASIBLE HYPOTHESIS

In ManIn Man

Back ups and follow-ups:Back ups and follow-ups:

Improvements on existing molecules Improvements on existing molecules (kinetics, metabolism pharmaceutical)(kinetics, metabolism pharmaceutical)

Novel mechanism:Novel mechanism:

Improvements in biological understandingImprovements in biological understanding

Potential breakthroughPotential breakthrough

Page 24: Drug Devel Ment

SURROGATE MARKERSSURROGATE MARKERS

A biological measurement which A biological measurement which substitutes for the therapeutic end-pointsubstitutes for the therapeutic end-point

Page 25: Drug Devel Ment

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

Page 26: Drug Devel Ment

Therapeutic NeedTherapeutic Need

Feasibility hypothesisFeasibility hypothesis

Commercial considerationsCommercial considerations

SELECTION OF SELECTION OF THERAPEUTIC TARGETSTHERAPEUTIC TARGETS

Page 27: Drug Devel Ment

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’ focus on early-stage ‘genomics’

related researchrelated research• 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

Page 28: Drug Devel Ment

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

IMPACTIMPACT

Page 29: Drug Devel Ment

Therapeutic NeedTherapeutic Need

Feasibility hypothesisFeasibility hypothesis

Commercial considerationsCommercial considerations

Regulatory issuesRegulatory issues

SELECTION OF SELECTION OF THERAPEUTIC TARGETSTHERAPEUTIC TARGETS

Page 30: Drug Devel Ment

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 No Governmental approval required for Phase I in the UK, Holland or Switzerlandin the 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

Page 31: Drug Devel Ment

Approval to register may take 3 years or more Approval to register may take 3 years or more (NDA) in USA(NDA) in 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 (I.C.H.) on the uniformity of regulatory requirements (USA, Europe, Japan)requirements (USA, Europe, Japan)

REGULATORY ISSUES (cont)REGULATORY ISSUES (cont)

Page 32: Drug Devel Ment

Pharmaco-economic assessmentPharmaco-economic assessment

NICENICE guidelinesguidelines

cost-effectivenesscost-effectiveness

THE FOURTH HURDLETHE FOURTH HURDLE

Page 33: Drug Devel Ment

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 phase because of benefit received, does not stand scrutinystand scrutiny

““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)

Page 34: Drug Devel Ment

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

Page 35: Drug Devel Ment

SILDENAFIL (Viagra)SILDENAFIL (Viagra)

PDE5PDE5

GTPGTPGDPGDP

Nitric OxideNitric Oxide

SildenafilSildenafil

GuanylateGuanylateCyclaseCyclase

CavernosalCavernosalsmooth musclesmooth muscle

RelaxationRelaxation

Penile ErectionPenile Erection

GMPGMP

++

--

Page 36: Drug Devel Ment

DNA CHIP AND MICRO-ARRAY DNA CHIP AND MICRO-ARRAY TECHNOLOGY (1)TECHNOLOGY (1)

Human genetic variations to subclassify Human genetic variations to subclassify diseasesdiseases

Individualisation of therapiesIndividualisation of therapies

Identification of toxic reactionsIdentification of toxic reactions

Pharmaco-Pharmaco-

genomicsgenomics

Page 37: Drug Devel Ment

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

Page 38: Drug Devel Ment

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

Page 39: Drug Devel Ment

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

Page 40: Drug Devel Ment

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

Page 41: Drug Devel Ment

DNA tests to:-DNA tests to:-

diagnose genetic diseasediagnose genetic disease

predict disease in later lifepredict disease in later life

identify heterozygote carriers of identify heterozygote carriers of recessive diseasesrecessive diseases

DIAGNOSTIC APPLICATIONSDIAGNOSTIC APPLICATIONSFROM GENETICSFROM GENETICS

Page 42: Drug Devel Ment

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

Page 43: Drug Devel Ment

APPROACHESAPPROACHES TO TO NEW MEDICINES DISCOVERY (3)NEW MEDICINES DISCOVERY (3)

Availability and understanding of molecular Availability and understanding of molecular target for proposed drugtarget for proposed drug

e.g.e.g. Anti-sense oligonuleotidesAnti-sense oligonuleotides

Gene therapyGene therapy

-- Cystic FibrosisCystic Fibrosis

-- VEGFVEGF

Page 44: Drug Devel Ment

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 4) affecting cholinergic

brain function less likely to respond to tacrinebrain function less likely to respond to tacrine

(2)(2) CETP (cholesteryl ester transfer protein) CETP (cholesteryl ester transfer protein) important in control of HDL metabolismimportant in control of HDL metabolism

Page 45: Drug Devel Ment

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 Confirmation of dose range. Explorative - range. Explorative - treatment. treatment. Safety databaseSafety database

Preparation of DossierPreparation of Dossier

Page 46: Drug Devel Ment

New Product Launches - 36New Product Launches - 36

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

PRODUCT BREAKTHROUGHSPRODUCT BREAKTHROUGHS(2001)(2001)