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, Alzheimer’s; obesity); low efficacy (dementia, cancer); side effects (antidepressants, antipsychotics)

• downstream health costs; (Alzheimer’s; 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 regulatory process

marketingpost registrationmonitoring

lessons&development

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

Approaches to drug discovery• Historical; cinchona (quinine) & willow barks (aspirin); chinese medicine

currently.

• Study disease process; breast cancer (tamoxifen); Parkinson’s 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

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 + receptorBINDING

+ transductionsystem (secondmessenger; enzyme)

BIOCHEMICAL TESTING

functionalwhole orpart organs

ISOLATED TISSUE EXPERIMENTS

Anaesthetised or conscious animals

WHOLE ANIMAL EXPERIMENTS

• 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 of efficacy

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

R R R

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, don’t replicate work unnecessarily, don’t 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.

• 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.

Safety & toxicity in animals

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

cross-over

others:-- matched pairs; combinations; ++

AB

A

A

B

BBA

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

0

Unit sales

Time

serious side effectsadverse reactions

wonder drugno side effects

not alwayseffective

appreciate where bestused and risks

balanced view ofadvantages &problems

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; Alzheimer’s; 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