Selection of therapeutic targets

1
DRUG DEVELOPMENT

• Selection of therapeutic targets
• Stages of development
• Clinical development
• Major challenges

2
SELECTION OF THERAPEUTIC TARGETS

• Therapeutic Need

3
THERAPEUTIC NEED - 1

• Determined by
• Existing therapies
• Commercial potential
• Individualisation of treatment (genomics)
• Patient/Public demands

4
THERAPEUTIC NEED - 2

• Existing Therapies
• Well served diseases (but room for improvement)
• heart failure
• hypertension
• asthma
• Poorly served diseases
• chronic neurological diseases
• Alzheimers
• Motor Neurone Disease

5
THERAPEUTIC NEED 3

• Existing Therapies
• Major Opportunities
• Vaccines
• AIDS
• Type I diabetes mellitus
• Emerging resistances to antibiotics

6
THERAPEUTIC NEED 4

• A possible scenario
• Minor, self-limiting conditions
• generic companies
• healthcare departments of major companies
• Novel, chemically based small molecules
• surface and intracellular receptors
• enzymes
• ion channels
• Individualised therapies for diseases with
  specific and selective deficiencies

7
SELECTION OF THERAPEUTIC TARGETS

• Therapeutic Need
• Feasible hypothesis

8
APPROACHES TO NEW MEDICINES DISCOVERY

• Traditional
• Empirical
• Molecular

9
APPROACHES TO NEW MEDICINES DISCOVERY
Traditional

• Trial and error
• Diverse cultures and systems of medicines e.g.
  morphine, quinine, ephedrine and artemisinin
  (anti-malarial)

10
APPROACHES TO NEW MEDICINES DISCOVERY
Empirical

• Builds on understanding of relevant physiological
  process
• Use of naturally occurring lead molecule e.g.
  tubocurarine, propranolol and other
  ß-adrenoceptor antagonists, H2-antagonists

11
APPROACHES TO NEW MEDICINES DISCOVERY
Molecular (1)

• Most drug discovery is based on this approach
• Molecular biological techniques
• Advances in genomics

12
APPROACHES TO NEW MEDICINES DISCOVERY
Molecular (2)

• Categories
• Rational drug design
• Computer-assisted techniques
• Anti-sense approach
• Manipulation of genetic targets
• Random screening
• Pragmatic and dominant at present

13
APPROACHES TO NEW MEDICINES DISCOVERY
Molecular (3)

• Technological Developments
• High throughputs of potential compounds
• Molecular biological knowledge
• Instrumentation
• Information Technology
• Screening

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APPROACHES TO NEW MEDICINES DISCOVERY
Molecular (3) cont

• Availability of molecular targets
• Engineering of targets in simple reporter systems
  e.g. yeast
• Use of robotics to handle samples and conduct
  assays

Random screening of chemical diversity
15
STEPS INVOLVED IN THE GENETIC REVOLUTION IN
MEDICINE
Disease with genetic component
Map
Accelerated by Human Genome Project
Clone gene
Time
Diagnostics
Understand basic biologic defect
Preventive Medicine
Pharmacogenomics
Drug therapy
Gene therapy
16
STEPS INVOLVED IN THE GENETIC REVOLUTION IN
MEDICINE
Uncovering the genetic contributions to an
illness is accomplished by cloning the gene for
the disease, with the use of the tools of the
Human Genome Project. Once the contributing
genes and their disease - predisposing variants
have been identified, diagnostic tests can be
developed to predict future risk - but these
tests are most effective when a preventative
strategy is available to reduce the risk in
persons found to be predisposed to a particular
disease. Another rapidly developing application
of diagnostics is pharmacogenomics, the
prediction of responsiveness to drugs.
Ultimately, the real payoff of genetic research
will be the development of new gene therapies and
drug therapies, but they will generally require
more years of intensive research.
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DRUG DISCOVERY SOURCES IN CONTEXT
Sources of compounds
Therapeutic Targets
Traditional medical uses of natural products
Chemical librariesHistorical compound
collectionsNatural product librariesCombinatoria
l libraries
Empirical understanding of physiology and
pathology
Rational synthesis
Molecular cloining of receptors and signalling
molecules
Antisense oligonucleotides
Genomics
Drug discovery screening assays
Lead optimisation and candidate selection
Drug development
18
DRUG DISCOVERY SOURCES IN CONTEXT
Different types of chemical compounds (top left
hand side of diagram) are tested against
bioassays that are relevant to therapeutic
targets, which are derived from several possible
sources of information (right hand side). The
initial lead compounds discovered by the
screening process are optimised by analogue
synthesis and tested for appropriate
pharmacokinetic properties. The candidate
compounds then enter the development process,
involving regulatory toxicology studies and
clinical trials.
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APPROACHES TO NEW MEDICINES DISCOVERY
Molecular Approach for Potential Drug Targets

• High throughputs of potential compounds
• Understanding of physiological processes at
  molecular level is possible e.g. -

- (in 1999 May) gt 250 gene products relating to
neurotransmitters - Several hundreds of subtypes
of ion channels characterised - Understanding of
intracellular signalling pathways
20
APPROACHES TO NEW MEDICINES DISCOVERY
MolecularIssues/Challenges

• Dissection of a disease process
• Reductionism loses systems integration and
  potential loss of understanding of
  pathophysiological process
• Provision of too many potential targets to be
  validated in vitro, in animals or man
• Number and which compounds to test by random
  screening, e.g. structural diversity, natural
  products

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FEASIBLE HYPOTHESIS

• In animals (in vitro/in vivo)
• Greater potency or selectivity
• Validated animal model of disease
• Surrogate markers

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FEASIBLE HYPOTHESIS

• In Man
• Back ups and follow-ups
• Improvements on existing molecules (kinetics,
  metabolism pharmaceutical)
• Novel mechanism
• Improvements in biological understanding
• Potential breakthrough

23
SURROGATE MARKERS

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

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SURROGATE MARKERS

• Characteristics of a good surrogate
• - Biological feasibility
• - Dose-related response to intervention
• - Easy to measure
• - Reproducible, specific and sensitive with high
  predictive value
• - Acceptable by experts
• - Acceptable by Regulatory Authorities

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SELECTION OF THERAPEUTIC TARGETS

• Therapeutic Need
• Feasibility hypothesis
• Commercial considerations

26
COMMERCIAL CONSIDERATIONS

• New Product Launches - 36 (2001)
• Slow down due to
• merger distractions
• focus on early-stage genomics related research
• increasing costs (800M per drug)
• tougher regulatory standards
• Time of development
• Chances of success
• Competition

27
COMMERCIAL CONSIDERATIONS
Examples 1. Cystic fibrosis 2. 3. Heart failure
many cancers 4. Allergic Rhinitis
?
?
Unmet Medical Need
?
?
IMPACT
28
SELECTION OF THERAPEUTIC TARGETS

• Therapeutic Need
• Feasibility hypothesis
• Commercial considerations
• Regulatory issues

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REGULATORY ISSUES

• Highly regulated activity
• Application for Phase I in USA (IND) and most
  countries
• No Governmental approval required for Phase I in
  the UK, Holland or Switzerland
• Approval to register a drug does not guarantee
  successful marketing

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REGULATORY ISSUES (cont)

• Approval to register may take 3 years or more
  (NDA) in USA
• Impact of European Union (E.M.E.A)
• International Harmonisation Conferences
• (I.C.H.) on the uniformity of regulatory
  requirements (USA, Europe, Japan)

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THE FOURTH HURDLE

• Pharmaco-economic assessment
• NICE
• guidelines
• cost-effectiveness

32
ETHICAL CONSIDERATIONS (For Phase I Studies)

• Why non-patient volunteers?
• Ease of organisation
• no problems with placebos or active drugs
• security of data interpretation
• no regulatory approval required in UK
• Use of target patient population at exploratory
  phase because of benefit received, does not stand
  scrutiny
• risk to the few for the good of the many

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STAGES OF DEVELOPMENT Clinical Development
Nos. of subject
Phase
Activities
Safety tolerability kinetics H.N.V
DynamicsDose responseProof of concept
10s
1
10s-100s
2
Early patient studiesProof of conceptPowered
studies for efficacy
a
b
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SILDENAFIL (Viagra)
Nitric Oxide
GuanylateCyclase

Cavernosalsmooth muscle
GTPGDP
GMP
Relaxation
-
PDE5
Penile Erection
Sildenafil
35
DNA CHIP AND MICRO-ARRAY TECHNOLOGY (1)

• Human genetic variations to subclassify diseases
• Individualisation of therapies
• Identification of toxic reactions

Pharmaco- genomics
36
STAGES OF DEVELOPMENT Research

• Enzyme Inhibitors
• Intracellular/extracellular
• Specificity
• Access
• Competitive/non competitive binding

• Examples
• HMG Co A
• Reductaseinhibitors
• ACE inhibitors

37
STAGES OF DEVELOPMENT Research

• Cell Surface Receptors
• Distribution
• Classification
• Selectivity
• Availability

• Examples
• H2 antagonists
• B1 B1/2 Blockers
• 5HTIA agonists

38
DRUG DEVELOPMENT Major Challenges for the Future

• Getting the dose range right
• Gene therapy
• Value of animal toxicity testing for recombitiant
  - derived products
• Pharmaco-economics, disease management,
  protocol-driven prescribing strategies

39
GENETIC TESTING

• Pharmacogenomics
• - Individualisation on response to drugs
• - Identification of toxic reactions
• - Gene based drugs for treatments,e.g.
  recombitients

40
DIAGNOSTIC APPLICATIONS FROM GENETICS

• DNA tests to-
• diagnose genetic disease
• predict disease in later life
• identify heterozygote carriers of recessive
  diseases

41
DIAGNOSTIC APPLICATIONS FROM GENETICS
Examples (1) High penetrant changes in single
genes - Haemochromatosis- Phenylketonuria-
Familial hypercholesterolaemia (2) Environmental
interplay and multiple genes - Highly heritable
subgroups e.g. (1) B RCA 1 2 in breast
cancer (2) HNF - 4? in MODY type I (3)
GCK in MODY type II
42
APPROACHES TO NEW MEDICINES DISCOVERY (3)

• Availability and understanding of molecular
  target for proposed drug
• e.g. Anti-sense oligonuleotides
• Gene therapy
• - Cystic Fibrosis
• - VEGF

43
DNA TECHNOLOGY AND MICRO-ARRAY SYSTEMS (2)
Examples (1) Alzheimer patients with E4 subtype
of gene for apolipoprotein E (APOE4) affecting
cholinergic brain function less likely to respond
to tacrine (2) CETP (cholesteryl ester transfer
protein) important in control of HDL metabolism
44
DNA CHIP AND MICRO-ARRAY TECHNOLOGY (2)
Stage
Time (Years)
Major Activity
Candidate Compound Plausible - Hypothesia
Research
2-7
Clinical Research
2-4
Confirmation of dose range. Explorative -
treatment. Safety database
Registration
1-2
Preparation of Dossier
Marketing
45
PRODUCT BREAKTHROUGHS(2001)

• New Product Launches - 36
• Slow down due to
• merger distractions
• focus on early-stage genomics related research
• increasing costs (800M per drug)
• tougher regulatory standards