The document discusses various topics related to drug development including: - Selection of therapeutic targets based on unmet medical needs and commercial potential. - Approaches to drug discovery including traditional empirical and modern molecular methods. - Stages of clinical development including pre-clinical and several phases of human trials. - Major challenges in drug development like high costs, complex regulation, and individualizing treatment.

1. DEPARTMENT OF CLINICAM PHARMACOLOGY YAROSLAVL STATE MEDICAL ACADEMY Dr. Mohamed Bawoh

2. DRUG DEVELOPMENT Selection of therapeutic targets Stages of development Clinical development Major challenges

3. Therapeutic Need SELECTION OF THERAPEUTIC TARGETS

4. Determined by: Existing therapies Commercial potential ‘ Individualisation’ of treatment (genomics) Patient/Public demands THERAPEUTIC NEED - 1

5. Existing Therapies: Well served diseases (but room for improvement) heart failure hypertension asthma Poorly served diseases chronic neurological diseases Alzheimer’s Motor Neurone Disease THERAPEUTIC NEED - 2

6. Existing Therapies: Major Opportunities Vaccines AIDS Type I diabetes mellitus Emerging resistances to antibiotics THERAPEUTIC NEED 3

7. 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 THERAPEUTIC NEED 4

8. Therapeutic Need Feasible hypothesis SELECTION OF THERAPEUTIC TARGETS

9. Traditional Empirical Molecular APPROACHES TO NEW MEDICINES DISCOVERY

10. Traditional APPROACHES TO NEW MEDICINES DISCOVERY Trial and error Diverse cultures and systems of medicines e.g. morphine, quinine, ephedrine and artemisinin (anti-malarial)

11. Empirical APPROACHES TO NEW MEDICINES DISCOVERY Builds on understanding of relevant physiological process Use of naturally occurring lead molecule e.g. tubocurarine, propranolol and other ß-adrenoceptor antagonists, H 2 -antagonists

12. Molecular (1) APPROACHES TO NEW MEDICINES DISCOVERY Most drug discovery is based on this approach Molecular biological techniques Advances in genomics

13. Molecular (2) APPROACHES TO NEW MEDICINES DISCOVERY Categories: Rational drug design Computer-assisted techniques Anti-sense approach Manipulation of genetic targets Random screening Pragmatic and dominant at present

14. Molecular (3) APPROACHES TO NEW MEDICINES DISCOVERY Technological Developments: High throughputs of potential compounds Molecular biological knowledge Instrumentation Information Technology Screening

15. Molecular (3) cont APPROACHES TO NEW MEDICINES DISCOVERY 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

16. STEPS INVOLVED IN THE GENETIC REVOLUTION IN MEDICINE Disease with genetic component Map Clone gene Gene therapy Time Accelerated by Human Genome Project Diagnostics Preventive Medicine Pharmacogenomics Understand basic biologic defect Drug therapy

17. 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.

18. Traditional medical uses of natural products DRUG DISCOVERY SOURCES IN CONTEXT Sources of compounds Chemical libraries Historical compound collections Natural product libraries Combinatorial libraries Therapeutic Targets Rational synthesis Antisense oligonucleotides Drug discovery screening assays Lead optimisation and candidate selection Empirical understanding of physiology and pathology Molecular cloining of receptors and signalling molecules Genomics Drug development

19. 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.

20. Molecular Approach for Potential Drug Targets APPROACHES TO NEW MEDICINES DISCOVERY High throughputs of potential compounds Understanding of physiological processes at molecular level is possible e.g. - - (in 1999 May) > 250 gene products relating to neurotransmitters - Several hundreds of subtypes of ion channels characterised - Understanding of intracellular signalling pathways

21. Molecular:Issues/Challenges APPROACHES TO NEW MEDICINES DISCOVERY 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

22. FEASIBLE HYPOTHESIS In animals (in vitro/in vivo) Greater potency or selectivity Validated animal model of disease Surrogate markers

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

24. SURROGATE MARKERS A biological measurement which substitutes for the therapeutic end-point

25. 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

26. Therapeutic Need Feasibility hypothesis Commercial considerations SELECTION OF THERAPEUTIC TARGETS

27. 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 COMMERCIAL CONSIDERATIONS

28. Unmet Medical Need COMMERCIAL CONSIDERATIONS Examples: 1. Cystic fibrosis 2. 3. Heart failure many cancers 4. Allergic Rhinitis     IMPACT

29. Therapeutic Need Feasibility hypothesis Commercial considerations Regulatory issues SELECTION OF THERAPEUTIC TARGETS

30. 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 REGULATORY ISSUES

31. 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) REGULATORY ISSUES (cont)

32. Pharmaco-economic assessment NICE guidelines cost-effectiveness THE FOURTH HURDLE

33. 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” ETHICAL CONSIDERATIONS (For Phase I Studies)

34. STAGES OF DEVELOPMENT Clinical Development Nos. of subject Phase Activities 10’s-100’s 10’s 1 2 a Safety & tolerability kinetics H.N.V & Dynamics Dose response Proof of concept Early patient studies: Proof of concept “Powered” studies for efficacy b

35. SILDENAFIL (Viagra) PDE5 GTP GDP Nitric Oxide Sildenafil Guanylate Cyclase Cavernosal smooth muscle Relaxation Penile Erection GMP + -

36. DNA CHIP AND MICRO-ARRAY TECHNOLOGY (1) Human genetic variations to subclassify diseases Individualisation of therapies Identification of toxic reactions Pharmaco- genomics

37. Enzyme Inhibitors Intracellular/extracellular Specificity Access Competitive/non competitive binding STAGES OF DEVELOPMENT Research Examples HMG Co A Reductase inhibitors ACE inhibitors

38. Cell Surface Receptors Distribution Classification Selectivity Availability STAGES OF DEVELOPMENT Research Examples H 2 antagonists B 1 & B 1/2 Blockers 5HT IA agonists

39. Getting the dose range right Gene therapy Value of animal toxicity testing for recombitiant - derived products Pharmaco-economics, disease management, protocol-driven prescribing strategies DRUG DEVELOPMENT Major Challenges for the Future

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

41. DNA tests to:- diagnose genetic disease predict disease in later life identify heterozygote carriers of recessive diseases DIAGNOSTIC APPLICATIONS FROM GENETICS

42. 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 DIAGNOSTIC APPLICATIONS FROM GENETICS

43. 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

44. DNA TECHNOLOGY AND MICRO-ARRAY SYSTEMS (2) Examples: (1) Alzheimer patients with E4 subtype of gene for apolipoprotein E (APO E 4) affecting cholinergic brain function less likely to respond to tacrine (2) CETP (cholesteryl ester transfer protein) important in control of HDL metabolism

45. DNA CHIP AND MICRO-ARRAY TECHNOLOGY (2) Stage Time (Years) Major Activity Research Clinical Research Registration Marketing 2-7 2-4 1-2 Candidate Compound Plausible - Hypothesia Confirmation of dose range. Explorative - treatment. Safety database Preparation of Dossier

46. 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 PRODUCT BREAKTHROUGHS (2001)