Drug discovery and development

Ian Hughes, i.e.hughes@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.

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

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 >13m Total GP drugs for Leeds >67m

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

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.

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)

Drug discovery/development process

discovery; refinement; chemical & biological characterisation
safety & toxicity in animals; formulation development

volunteer studies; patient studies

lessons & development

regulatory process marketing

post registration monitoring

Discovery=find new active structure : Development=convert it to a useful drug

Approaches to drug discovery

Historical; cinchona
currently. disease (L-dopa) (quinine) & willow barks (aspirin); chinese medicine

Study disease process; breast cancer (tamoxifen); Parkinsons

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

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

Levels of testing
DRUG + receptor + transduction system (second BINDING functional messenger; enzyme) whole or BIOCHEMICAL TESTING part organs

ISOLATED TISSUE EXPERIMENTS

Anaesthetised or conscious animals

WHOLE ANIMAL EXPERIMENTS

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

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

RRR

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

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.

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.

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

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

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

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

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.

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

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

Clinical trials
controlled or uncontrolled
open or blind

parallel
sequential crossover

A B A A B B A B

others:-- matched pairs; combinations; ++

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

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

Classic sales curve

Unit sales
serious side effects adverse reactions wonder drug no side effects not always effective balanced view of advantages & problems

appreciate where best used and risks

Time

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.

Lessons and development

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

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 disease;human BSE variant; obesity; cancer) new biology - (clone human receptors; disease model by gene changes) patent times and increasing cost

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