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The Pharmaceutical Industry and The Process of Drug Discovery

The Pharmaceutical Industry and The Process of Drug Discovery. What is a Drug? Types of Pharmaceutical Products What are the Important Disease Targets? How the Industry Has Evolved Drug Discovery and The Process of Getting a Drug to Market - an overview. What is a drug?.

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The Pharmaceutical Industry and The Process of Drug Discovery

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  1. The Pharmaceutical Industry and The Process of Drug Discovery • What is a Drug? • Types of Pharmaceutical Products • What are the Important Disease Targets? • How the Industry Has Evolved • Drug Discovery and The Process of Getting a Drug to Market - an overview

  2. What is a drug? “A Chemical Substance that Interacts with a Living System and Produces a Biological Response”

  3. What is a drug? “A Chemical Substance that Interacts with a Living System and Produces a Biological Response”

  4. What is a drug? “A Chemical Substance that Interacts with a Living System and Produces a Biological Response” • Good and Bad Drugs? • Safe Drugs?

  5. What is a drug? “A Chemical Substance that Interacts with a Living System and Produces a Biological Response” • Good and Bad Drugs? • Safe Drugs? Morphine (bad?)vs.penicillin (good?) Curare vs. paracetamol

  6. Classification of Drug Types • Ethical drugs • Generic drugs (no longer under patent) • “Prescription Only” vs “Over the Counter” • “Off Label” applications • Orphan drugs • Biotechnology products • Counterfeit drugs • Street drugs!

  7. What criteria MUST new drugs meet? • Drugs must address a new need or provide a significant “added benefit” over an existing medicine • Drugs must also meet five criteria: • Must be safe, effective, of high quality • …cost effective (1980s) • ……….affordable (1990s) • ……………REALLY affordable (2000+)

  8. Major Therapeutic Targets • Infectious disease – anti-infectives • Anti-bacterial, anti-viral, anti-parasitic drugs • Metabolic disease • cancer, cardiovascular, diabetes,inflammation, high blood pressure, neurological disease, pain • Other aspects of health care • Hormonal treatments, contraception, vaccines, immunosuppresents, anaesthetics, nutraceuticals, “life style” drugs

  9. A History of the Pharmaceutical Industry • The early days - Egyptians, Greeks, Arabs, China, India • Plant-derived medicines • morphine (1805), quinine (1819), colchicine (1820), pilocarpine (1875) • Hormones • insulin (1921), estradiol (1929), testosterone (1931), “the pill” (1960) • Antibiotics, Psychoactive drugs (post-1945 to 1960’s) • penicillin (1944), streptomycin (1944), valium (1963) • Treatment of metabolic disorders (1960’s to current day) • Ventolin (1969), Lipitor (1997), Viagra (1998), Avandia (1999), Vioxx (1999), Gleevec (2001) • Search for gene therapies (1990), stem cell-based therapies • Stem-cell replacement of a trachea (2008)

  10. Some Important Events • American Civil War • Legislation – UK Cruelty to Animals Act (1876); US Federal Food and Drug Act (1906) • World War 1 - Development of UK regulatory rules • World War 2 – antibiotics • Vaccines – Smallpox: Jenner (1796) – eradicated in 1977 • Thalidomide (1960) – report adverse drug reactions • AIDS (1980s) – fast track approval, “buyer power” • Viagra (1998) • Tamiflu – H1N1 (swine flu) pandemic (2009) • NICE (1999) – the affordability factor • Vioxx – anti-inflammatory – 1999-2004 due to litigation • Avandia – Type 2 (non-insulin dependent) diabetes - 1999-2010 also due to litigation

  11. How do drugs work? • The Biological Target - enzyme or receptor • Where is the target - part of “us” or elsewhere • Paul Ehrlich, Nobel Prize 1908, salvarsan; • blood-brain barrier; “Lock and Key” hypothesis; chemotherapy and “magic bullet” The Lock - Active Site of Enzyme/Receptor The Key - the Drug

  12. The “Lock and Key” analogy Key Lock Binding • Here the KEY is the natural substrate • Binding of the KEY to the LOCK (an enzyme or a receptor) then causes a response – a shape change in the protein/receptor

  13. The “Lock and Key” analogy Key Lock Binding Biological Response • Here the KEY is the natural substrate • Binding of the KEY to the LOCK (an enzyme or a receptor) then causes a response – a shape change in the protein/receptor

  14. Biological response is altered OR shut down But when an effective drug is present vs. Binding of Drug is preferred • Drug may bind preferentially to the “active site” • Antagonist – binds and BLOCKS • Agonist – binds and ACTIVATES • Partial agonist – induces a partial response

  15. Who discovers drugs? Doctors? • Identify biological target - biology • Prioritise/ validate target – pharmacology and chemistry • Identify and optimise lead molecules – chemistry/pharmacology • Preclinical studies – chemistry/pharmacology/ toxicology • Formulation - pharmaceutical sciences • Clinical evaluation – medicine • Manufacture - chemical engineering

  16. Getting a drug to market • Disease target - possible drug candidates • Pre-clinical testing; R&D (1-3 yrs) • Toxicology, “ADME” • Clinical R&D (2-10 yrs; Av. 5yrs) • Phase 1 – healthy volunteers • Phase 2 – small patient group • Phase 3 – larger patient group • Regulatory approval (2-10(!) yrs) • Market • Phase 4 – long term monitoring

  17. The Gamble - wastage and timescale • For EACHDRUGapproved, an average of 7500 compounds will have been made • Of this 7500, anaverage of 21 will be tested for subacute toxicology, 6.5 will be tested in humans and 2.5 will reach Phase 3 – 1 then gets to market……… • Entire process takes onaverage 12 years • Costs $138M (1975); $800M (2000); $1.6Bn (2008) • Development costs do NOT include pre-launch marketing which can DOUBLE costs

  18. The “Pay Off”……to the companies • Typical R&D budget: 33% R and 67%D • R&D = 15 to 25 % of sales turnover • Patent protection – 20 years from filing • On average, 11yrs. of productive market life • Losec – $2.7Bn in 1998; Nexium (single enantiomer) $7.7Bn in 2008 • Lipitor - $1Bn in 1998; $13.8Bn in 2008

  19. The “Pay Off”…….to us • Massive contributions to health, quality of life, reduced child mortality, life expectancy • Vaccines have eradicated major disease – smallpox; vaccines for malaria and pneumonia soon……..? • But costs and accessibility to healthcare are becoming major social and geopolitical issues • And, is there something seedy about making money out of illness? • What will happen into the future?

  20. The Companies in 2010

  21. Major Therapeutic Targets

  22. Top 10 Therapies - sales in 2008 (US$Bn)

  23. What makes a good drug? Lipinski's rules (Chris Lipinski – 1997) In general, an orally active drug will meet most of the following: • Not more than 5 hydrogen bond donors (nitrogen or oxygen atoms with one or more hydrogen atoms) • Not more than 10 hydrogen bond acceptors (nitrogen or oxygen atoms) • A molecular weight under 500 daltons • An octanol-water partition coefficient log P of less than 5 • http://www.molinspiration.com/cgi-bin/properties

  24. US UK Into volunteers Cimetidine Burimamide First lead Programme starts Case Study Cimetidine (Tagamet) 1979 • H2 blocker; anti-ulcer/heartburn • 1983 First drug to reach $1Bn • Cleared for OTC in 1995 1976 1974 1972 1970 1968 1966 1964

  25. What is a drug? “A Chemical Substance that Interacts with a Living System and Produces a Biological Response”

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