DEPARTMENT OF CLINICAM PHARMACOLOGY DEPARTMENT OF CLINICAM PHARMACOLOGY YAROSLAVL STATE MEDICAL ACADEMYYAROSLAVL STATE MEDICAL ACADEMY
Dr. Mohamed Bawoh
DRUG DEVELOPMENTDRUG DEVELOPMENT
Selection of therapeutic targetsSelection of therapeutic targets
Stages of developmentStages of development
Clinical developmentClinical development
Major challengesMajor challenges
Therapeutic NeedTherapeutic Need
SELECTION OF SELECTION OF THERAPEUTIC TARGETSTHERAPEUTIC TARGETS
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
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
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 Individualised therapies for diseases with specific and selective deficienciesand selective 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 morphine, quinine, ephedrine and artemisinin (anti-malarial)(anti-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 Use of robotics to handle samples and conduct assayssamples and conduct assays
Random Random screening screening
of chemical of 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 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.
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 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.
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
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
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 Improvements on existing molecules (kinetics, metabolism pharmaceutical)(kinetics, metabolism pharmaceutical)
Novel mechanism:Novel mechanism:
Improvements in biological understandingImprovements in biological understanding
Potential breakthroughPotential breakthrough
SURROGATE MARKERSSURROGATE MARKERS
A biological measurement which A biological measurement which substitutes for the therapeutic end-pointsubstitutes for the 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’ 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
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
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 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
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)
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 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)
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 Human genetic variations to subclassify diseasesdiseases
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 identify heterozygote carriers of recessive diseasesrecessive diseases
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 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
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
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
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)