Drug discovery and development

1
Drug discovery and development

• Ian Hughes, i.e.hughes_at_leeds.ac.uk
• Objectives of next 5 lectures you will
• be aware of why/how new drugs are discovered
• know the processes involved in drug discovery and
  development
• see where pharmacologists/bioscientists may
  contribute
• know about the difficulties and dangers inherent
  in the drug development process.

2
What is a drug?

• Any chemical compound - sugar ???
• Anything which produces a change in the body -
  an axe ???
• Define by characteristics
• 1. use or potential use in diagnosis or treatment
  of disease
• 2. selective in their actions

3
What costs what in Leeds? (GPs 98/99)

• Omeprazole (anti-gastric acid) 3.5m
• Simvastatin (cholesterol lowering) 2.4m
• Beclomethasone (asthma) 1.8m
• Fluoxetine (antidepressant) 1.5m
• Lansoprazole (anti-gastric acid) 1.4m
• Ranitidine (anti-gastric acid) 1.3m
• Paroxetine (antidepressant) 1.2m
• TOP 7 TOTAL gt13m
• Total GP drugs for Leeds gt67m

4
Why are new drugs needed?

• unmet medical need new diseases (BSE AIDS,
  Alzheimers obesity) low efficacy (dementia,
  cancer) side effects (antidepressants,
  antipsychotics)
• downstream health costs (Alzheimers spinal
  injury)
• cost of therapy (Viagra, Interleukins)
• costs to individual/country (depression)
• sustain industrial activity pharmaceutical
  industry employs thousands and makes a massive
  contribution to overseas earnings) patent expiry

5
The changed context of drug discovery and
development

• The 1800s natural sources limited
  possibilities prepared by individuals small
  scale not purified, standardised or tested
  limited administration no controls no idea of
  mechanisms.
• The 1990s synthetic source unlimited
  possibilities prepared by companies massive
  scale highly purified, standardised and tested
  world-wide administration tight legislative
  control mechanisms partly understood.

6
Sources of drugs
Animal insulin (pig, cow) growth
hormone (man) (Creutzfeldt-Jakob) Plant
digitalis (digitalis purpurea - foxglove)
morphine (papaver somniferum) Inorganic
arsenic mercury
lithium Synthetic chemical (propranolol)
biological (penicillin)
biotechnology (human insulin)
7
Drug discovery/development process

• discovery refinement chemical biological
  characterisation

safety toxicity in animals formulation
development
volunteer studies patient studies
regulatory process
lessons development
marketing
post registration monitoring
Discoveryfind new active structure
Developmentconvert it to a useful drug
8
Approaches to drug discovery

• Historical cinchona (quinine) willow barks
  (aspirin) chinese medicine currently.
• Study disease process breast cancer (tamoxifen)
  Parkinsons disease (L-dopa)
• Study biochem/physiological pathway
  renin/angiotensin
• Develop SAR to natural compound
  beta-adrenoceptors (propranolol), H2-receptors
  (cimetidine)
• Design to fit known structurally identified
  biological site angiotensin-converting enzyme
  inhibitors
• By chance (serendipidy) random screening (HTS)
  penicillin dimenhydramate pethidine
• Genomics identification of receptors gene
  therapy recombinant materials
• DRIVER IS UNMET MEDICAL NEED IN A VIABLE MARKET

9
Refinement of compounds

• Can it be improved? selectivity duration route
  of administration stability, isomers, ease of
  preparation.
• Can it be patented? costs 250m takes 8-14
  years high risk business.
• USE iterative approach

10
Levels of testing
DRUG receptor
transduction system (second messenger enzyme)
BINDING
functional whole or part organs
BIOCHEMICAL TESTING
ISOLATED TISSUE EXPERIMENTS
Anaesthetised or conscious animals
WHOLE ANIMAL EXPERIMENTS
11
Animal models of efficacy

• Existing normal behaviours/effects (anaesthesia
  contraception paralysis)
• Create behaviours (fat rats hypertensive rats
  anxious rats epileptic rats)
• Find unrelated behaviour affected by existing
  drugs (Straub tail for narcotic analgesics
  learned helplessness for antidepressants)
• How predictive is the model?
• exact replica 100 predictor
• mechanism same good predictor
• mechanisms different poor predictor

12
Animal models

• predictive for efficacy AND toxicity?
• expensive time consuming variable uncertain
  troublesome ethical questions skilled workers
• legislative control
• Animal (Scientific Procedures) Act (1986)
• PERSONAL LICENCE - competent, trained, procedures
  specified
• PROJECT LICENCE - allows a personal licence
  holder to carry out specified procedures for a
  specified project that cannot be done without
  animals and where severity justifies likely gain.
  
• GET INTO MAN EARLY

13

• R R R

14
Reducing animal usage

• About 2.6m animals/y used in procedures in UK
  (11.6m in Europe)
• Likely to increase more research, more targets,
  genetic capability
• 3Rs -- 3Rs -- 3Rs
• REPLACEMENT use non-animal tests if possible
  (cheaper, less trouble, less variable but not
  possible for everything at this time)
• REDUCTION get the statistics right, dont
  replicate work unnecessarily, dont overbreed
• REFINEMENT reduce suffering and severity of
  procedure, pay attention to housing, stress,
  husbandry and rich environments, proper analgesia
  and pre- and post- operative care

15
Chemical and biological characterisation

• CHEMICAL structure, synthesis, purity, isomers,
  pKa, stability, solubility, salts, assay
• BIOLOGICAL acute pharmacological profile - LD50,
  ED50, binding data for many receptors,
  dose-effect relationships, open field tests,
  particular tests for different activities (e.g.
  CVS, CNS, GI tract)
• Both positive and negative information is useful.

16
Safety toxicity in animals

• Acute toxicity profile
• Chronic toxicity profile
• -- 14 day toxicity test in one rodent and one
  non-rodent species before use in man.
• -- 3 month study read out at 28 days
• -- longer studies (12 24 month)
• Three dose levels (below, about, well above human
  dose).
• It is insufficient to to use doses which are not
  toxic the doses producing toxic effects and the
  nature of these effects MUST be established.

17
Formulation studies

• DRUG
• Additive filler, lubricant, coating, stabiliser,
  colour, binder, disintegrator
• Dosage form capsule, tablet, injection, other?
• Manipulate duration/profile e.g. sustained
  release
• Bioequivalence
• Bioavailability
• Ease of use

18
Clinical testing

• Phase 0 (non-clinical)
• Phase 1 (volunteers)
• Phase 2 (patients)
• Phase 3 (large scale multi-centre)
• Phase 4 (post registration monitoring)
• phases can also be defined by the information you
  are trying to get out of the testing

19
Volunteer studies (phase I trials)

• pharmacologists employees (15-30 in number)
• ethical approval
• healthy
• informed consent
• full rescussitation medical backup
• monitor
• single and repeat doses
• increase dose levels

20
Volunteer studies (phase I trials)

• OBJECTIVES
• metabolic and excretory pathways (impinges on
  toxicity testing in animals)
• variability between individuals effect of route
  bioavailability
• tolerated dose range
• indication of therapeutic effects
• indication of side effects

21
Patient studies (phase 2 trials)

• 150-350 ill people informed consent
• needs licence
• maximum monitoring full rescussitation
• often patients where other treatment failed
• OBJECTIVES
• indication for use type of patient severity of
  disease
• dose range, schedule and increment
• pharmacokinetic studies in ill people
• nature of side effects and severity
• effects in special groups.

22
Patient studies (phase 3 trials)

• 1500-3500 ill patients
• multicentre?
• more certain data for the objectives of phase 2
  studies
• interactions between drugs start to become
  measurable in the larger population
• sub-groups start to be established
• special features and problems show up

23
Clinical trials

• Drug action depends on
• pharmacodynamics
• pharmacokinetics and dose regimen
• drug interactions
• receptor sensitivity of patient
• mood/personality of patient doctor
• patients expectations and past experience
• social environment of patient
• clinical state of patient
• Clinical trial controls these variables and
  examines action of drug in defined set of
  circumstances

24
Clinical trials
controlled or uncontrolled
open or blind
parallel
A
B
sequential
A
B
A
A
cross- over
B
B
others-- matched pairs combinations
25
The Regulatory process

• differs from country to country
• demands safety and quality of product
• encourages efficacy and need for product
• grants clinical trials certificate if volunteer
  and animal data OK
• approves protocols and examines data
• 50-400 volumes (30,000-150,000 pages)
• original data available
• two way process authority and company trying to
  produce a safe effective product
• release for a specific purpose and use

26
Marketing

• getting the product right (packaging
  formulation)
• right therapeutic slot
• information on new drug
• information for honest comparison
• reporting problems
• reporting new indications
• therapeutic trends

27
Classic sales curve
Unit sales
serious side effects adverse reactions
balanced view of advantages problems
wonder drug no side effects
not always effective
appreciate where best used and risks
Time
28
Post-registration monitoring

• YELLOW CARD SYSTEM voluntary reporting of
  adverse effects by GP to Committee on Safety of
  Medicines easy effective?
• INTENSIVE MONITORING OF DEFINED GROUP first
  10,000 administrative nightmare as patients
  move/die costly time-consuming.
• RESTRICTED RELEASE only available to small group
  of GPs monitor their patients elitist
• MONITOR INCIDENCE OF DISEASE PROBLEM difficult
  to identify cause of change.

29
Lessons and development

• refine parts of treatment giving problems (dose
  interval? side effects? effective? niche market?)
• extend usage
• eg. PROPRANOLOL (beta adrenoceptor blocker)
• antidysrhythmic gtgtgt antianginal gtgtgt
  antihypertensive gtgtgt relieve hyperthyroid
  symptoms gtgtgt antihypertensive with diuretic gtgtgt
  prolonged release formulation
• precipitate asthma attack gt beta1 selective -
  ATENOLOL

30
The future?

• 3rd world diseases?
• orphan drugs with few users?
• improve safety and efficacy records
• reduce animal utilisation (cell lines early
  human volunteers, )
• new diseases (AIDS Alzheimers CJ diseasehuman
  BSE variant obesity cancer)
• new biology - (clone human receptors disease
  model by gene changes)
• patent times and increasing cost

31
Me-too drugs

• Similar to drugs already on market
• parallel co-incident development
• not identical - differences emerge with time
• allergy to one only
• unsuspected side effect causes discontinuation
• particular indication in sub-group of patients
• sometimes too many