Drug discovery and development

1. 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.

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 >£13m • Total GP drugs for Leeds >£67m

4. 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

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 Discovery=find new active structure : Development=convert 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); 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

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, 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

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 >>> antianginal >>> antihypertensive >>> relieve hyperthyroid symptoms >>> antihypertensive with diuretic >>> prolonged release formulation precipitate asthma attack > 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; Alzheimer’s; CJ disease;human 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