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Drug development


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Drug development

  1. 1. <ul><li>Selection of therapeutic targets </li></ul><ul><li>Stages of development </li></ul><ul><li>Clinical development </li></ul><ul><li>Major challenges </li></ul>DRUG DEVELOPMENT
  2. 2. <ul><li>Therapeutic Need </li></ul>SELECTION OF THERAPEUTIC TARGETS
  3. 3. <ul><li>Determined by: </li></ul><ul><li>Existing therapies </li></ul><ul><li>Commercial potential </li></ul><ul><li>‘ Individualisation’ of treatment (genomics) </li></ul><ul><li>Patient/Public demands </li></ul>THERAPEUTIC NEED - 1
  4. 4. <ul><li>Existing Therapies: </li></ul><ul><li>Well served diseases (but room for improvement) </li></ul><ul><ul><li>heart failure </li></ul></ul><ul><ul><li>hypertension </li></ul></ul><ul><ul><li>asthma </li></ul></ul><ul><li>Poorly served diseases </li></ul><ul><ul><li>chronic neurological diseases </li></ul></ul><ul><ul><li>Alzheimer’s </li></ul></ul><ul><ul><li>Motor Neurone Disease </li></ul></ul>THERAPEUTIC NEED - 2
  5. 5. <ul><li>Existing Therapies: </li></ul><ul><li>Major Opportunities </li></ul><ul><ul><li>Vaccines </li></ul></ul><ul><ul><ul><li>AIDS </li></ul></ul></ul><ul><ul><ul><li>Type I diabetes mellitus </li></ul></ul></ul><ul><li>Emerging resistances to antibiotics </li></ul>THERAPEUTIC NEED 3
  6. 6. <ul><li>A possible scenario: </li></ul><ul><li>Minor, self-limiting ‘conditions’ </li></ul><ul><ul><li>generic companies </li></ul></ul><ul><ul><li>healthcare departments of major companies </li></ul></ul><ul><li>Novel, chemically based small molecules </li></ul><ul><ul><li>surface and intracellular receptors </li></ul></ul><ul><ul><li>enzymes </li></ul></ul><ul><ul><li>ion channels </li></ul></ul><ul><li>Individualised therapies for diseases with specific and selective deficiencies </li></ul>THERAPEUTIC NEED 4
  7. 7. <ul><li>Therapeutic Need </li></ul><ul><li>Feasible hypothesis </li></ul>SELECTION OF THERAPEUTIC TARGETS
  8. 8. <ul><li>Traditional </li></ul><ul><li>Empirical </li></ul><ul><li>Molecular </li></ul>APPROACHES TO NEW MEDICINES DISCOVERY
  9. 9. Traditional APPROACHES TO NEW MEDICINES DISCOVERY <ul><li>Trial and error </li></ul><ul><li>Diverse cultures and systems of medicines e.g. morphine, quinine, ephedrine and artemisinin (anti-malarial) </li></ul>
  10. 10. Empirical APPROACHES TO NEW MEDICINES DISCOVERY <ul><li>Builds on understanding of relevant physiological process </li></ul><ul><li>Use of naturally occurring lead molecule e.g. tubocurarine, propranolol and other ß-adrenoceptor antagonists, H 2 -antagonists </li></ul>
  11. 11. Molecular (1) APPROACHES TO NEW MEDICINES DISCOVERY <ul><li>Most drug discovery is based on this approach </li></ul><ul><li>Molecular biological techniques </li></ul><ul><li>Advances in genomics </li></ul>
  12. 12. Molecular (2) APPROACHES TO NEW MEDICINES DISCOVERY <ul><li>Categories: </li></ul><ul><li>Rational drug design </li></ul><ul><ul><li>Computer-assisted techniques </li></ul></ul><ul><li>Anti-sense approach </li></ul><ul><ul><li>Manipulation of genetic targets </li></ul></ul><ul><li>Random screening </li></ul><ul><ul><li>Pragmatic and dominant at present </li></ul></ul>
  13. 13. Molecular (3) APPROACHES TO NEW MEDICINES DISCOVERY <ul><li>Technological Developments: </li></ul><ul><li>High throughputs of potential compounds </li></ul><ul><ul><li>Molecular biological knowledge </li></ul></ul><ul><ul><li>Instrumentation </li></ul></ul><ul><ul><li>Information Technology </li></ul></ul><ul><ul><li>Screening </li></ul></ul>
  14. 14. Molecular (3) cont APPROACHES TO NEW MEDICINES DISCOVERY <ul><li>Availability of molecular targets </li></ul><ul><li>Engineering of targets in simple reporter systems e.g. yeast </li></ul><ul><li>Use of robotics to handle samples and conduct assays </li></ul>Random screening of chemical diversity
  15. 15. 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
  16. 16. 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.
  17. 17. 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
  18. 18. 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.
  19. 19. Molecular Approach for Potential Drug Targets APPROACHES TO NEW MEDICINES DISCOVERY <ul><li>High throughputs of potential compounds </li></ul><ul><ul><li>Understanding of physiological processes at molecular level is possible e.g. - </li></ul></ul>- (in 1999 May) > 250 gene products relating to neurotransmitters - Several hundreds of subtypes of ion channels characterised - Understanding of intracellular signalling pathways
  20. 20. Molecular:Issues/Challenges APPROACHES TO NEW MEDICINES DISCOVERY <ul><li>Dissection of a disease process </li></ul><ul><li>Reductionism loses systems integration and potential loss of understanding of pathophysiological process </li></ul><ul><li>Provision of too many potential targets to be validated in vitro, in animals or man </li></ul><ul><li>Number and which compounds to test by random screening, e.g. structural diversity, natural products </li></ul>
  21. 21. FEASIBLE HYPOTHESIS <ul><li>In animals (in vitro/in vivo) </li></ul><ul><ul><li>Greater potency or selectivity </li></ul></ul><ul><ul><li>Validated animal model of disease </li></ul></ul><ul><ul><li>Surrogate markers </li></ul></ul>
  22. 22. FEASIBLE HYPOTHESIS <ul><li>In Man </li></ul><ul><ul><li>Back ups and follow-ups: </li></ul></ul><ul><ul><li>Improvements on existing molecules (kinetics, metabolism pharmaceutical) </li></ul></ul><ul><ul><li>Novel mechanism: </li></ul></ul><ul><ul><li>Improvements in biological understanding </li></ul></ul><ul><ul><li>Potential breakthrough </li></ul></ul>
  23. 23. SURROGATE MARKERS <ul><li>A biological measurement which substitutes for the therapeutic end-point </li></ul>
  24. 24. SURROGATE MARKERS <ul><li>Characteristics of a “good” surrogate: </li></ul><ul><li>- Biological feasibility </li></ul><ul><li>- Dose-related response to intervention </li></ul><ul><li>- Easy to measure </li></ul><ul><li>- Reproducible, specific and sensitive with high predictive value </li></ul><ul><li>- Acceptable by experts </li></ul><ul><li>- Acceptable by Regulatory Authorities </li></ul>
  25. 25. <ul><li>Therapeutic Need </li></ul><ul><li>Feasibility hypothesis </li></ul><ul><li>Commercial considerations </li></ul>SELECTION OF THERAPEUTIC TARGETS
  26. 26. <ul><li>New Product Launches - 36 (2001) </li></ul><ul><li>Slow down due to: </li></ul><ul><ul><li>merger distractions </li></ul></ul><ul><ul><li>focus on early-stage ‘genomics’ related research </li></ul></ul><ul><ul><li>increasing costs ($800M per drug) </li></ul></ul><ul><ul><li>tougher regulatory standards </li></ul></ul><ul><li>Time of development </li></ul><ul><li>Chances of success </li></ul><ul><li>Competition </li></ul>COMMERCIAL CONSIDERATIONS
  27. 27. Unmet Medical Need COMMERCIAL CONSIDERATIONS Examples: 1. Cystic fibrosis 2. 3. Heart failure many cancers 4. Allergic Rhinitis     IMPACT
  28. 28. <ul><li>Therapeutic Need </li></ul><ul><li>Feasibility hypothesis </li></ul><ul><li>Commercial considerations </li></ul><ul><li>Regulatory issues </li></ul>SELECTION OF THERAPEUTIC TARGETS
  29. 29. <ul><li>Highly regulated activity </li></ul><ul><li>Application for Phase I in USA (IND) and most countries </li></ul><ul><li>No Governmental approval required for Phase I in the UK, Holland or Switzerland </li></ul><ul><li>Approval to register a drug does not guarantee successful marketing </li></ul>REGULATORY ISSUES
  30. 30. <ul><li>Approval to register may take 3 years or more (NDA) in USA </li></ul><ul><li>Impact of European Union (E.M.E.A) </li></ul><ul><li>International Harmonisation Conferences </li></ul><ul><li>(I.C.H.) on the uniformity of regulatory requirements (USA, Europe, Japan) </li></ul>REGULATORY ISSUES (cont)
  31. 31. <ul><li>Pharmaco-economic assessment </li></ul><ul><li>NICE </li></ul><ul><ul><li>guidelines </li></ul></ul><ul><ul><li>cost-effectiveness </li></ul></ul>THE FOURTH HURDLE
  32. 32. <ul><li>Why non-patient volunteers? </li></ul><ul><ul><li>Ease of organisation </li></ul></ul><ul><ul><li>no problems with placebos or active drugs </li></ul></ul><ul><ul><li>security of data interpretation </li></ul></ul><ul><ul><li>no regulatory approval required in UK </li></ul></ul><ul><li>Use of target patient population at exploratory phase because of benefit received, does not stand scrutiny </li></ul><ul><li>“ risk to the few for the good of the many” </li></ul>ETHICAL CONSIDERATIONS (For Phase I Studies)
  33. 33. 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
  34. 34. SILDENAFIL (Viagra) PDE5 GTP GDP Nitric Oxide Sildenafil Guanylate Cyclase Cavernosal smooth muscle Relaxation Penile Erection GMP + -
  35. 35. DNA CHIP AND MICRO-ARRAY TECHNOLOGY (1) <ul><li>Human genetic variations to subclassify diseases </li></ul><ul><li>Individualisation of therapies </li></ul><ul><li>Identification of toxic reactions </li></ul>Pharmaco- genomics
  36. 36. <ul><li>Enzyme Inhibitors </li></ul><ul><ul><li>Intracellular/extracellular </li></ul></ul><ul><ul><li>Specificity </li></ul></ul><ul><ul><li>Access </li></ul></ul><ul><ul><li>Competitive/non competitive binding </li></ul></ul>STAGES OF DEVELOPMENT Research <ul><li>Examples </li></ul><ul><ul><li>HMG Co A </li></ul></ul><ul><ul><li>Reductase inhibitors </li></ul></ul><ul><ul><li>ACE inhibitors </li></ul></ul>
  37. 37. <ul><li>Cell Surface Receptors </li></ul><ul><ul><li>Distribution </li></ul></ul><ul><ul><li>Classification </li></ul></ul><ul><ul><li>Selectivity </li></ul></ul><ul><ul><li>Availability </li></ul></ul>STAGES OF DEVELOPMENT Research <ul><li>Examples </li></ul><ul><ul><li>H 2 antagonists </li></ul></ul><ul><ul><li>B 1 & B 1/2 Blockers </li></ul></ul><ul><ul><li>5HT IA agonists </li></ul></ul>
  38. 38. <ul><li>Getting the dose range right </li></ul><ul><li>Gene therapy </li></ul><ul><li>Value of animal toxicity testing for recombitiant - derived products </li></ul><ul><li>Pharmaco-economics, disease management, protocol-driven prescribing strategies </li></ul>DRUG DEVELOPMENT Major Challenges for the Future
  39. 39. <ul><li>Pharmacogenomics </li></ul><ul><ul><li>- Individualisation on response to drugs </li></ul></ul><ul><ul><li>- Identification of toxic reactions </li></ul></ul><ul><ul><li>- Gene based drugs for treatments, e.g. recombitients </li></ul></ul>GENETIC TESTING
  40. 40. <ul><li>DNA tests to:- </li></ul><ul><ul><li>diagnose genetic disease </li></ul></ul><ul><ul><li>predict disease in later life </li></ul></ul><ul><ul><li>identify heterozygote carriers of recessive diseases </li></ul></ul>DIAGNOSTIC APPLICATIONS FROM GENETICS
  41. 41. 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
  42. 42. APPROACHES TO NEW MEDICINES DISCOVERY (3) <ul><li>Availability and understanding of molecular target for proposed drug </li></ul><ul><li>e.g. Anti-sense oligonuleotides </li></ul><ul><li>Gene therapy </li></ul><ul><li>- Cystic Fibrosis </li></ul><ul><li>- VEGF </li></ul>
  43. 43. 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
  44. 44. 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
  45. 45. <ul><li>New Product Launches - 36 </li></ul><ul><li>Slow down due to: </li></ul><ul><ul><li>merger distractions </li></ul></ul><ul><ul><li>focus on early-stage ‘genomics’ related research </li></ul></ul><ul><ul><li>increasing costs ($800M per drug) </li></ul></ul><ul><ul><li>tougher regulatory standards </li></ul></ul>PRODUCT BREAKTHROUGHS (2001)