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? “A Chemical Substance that Interacts with a Living System and Produces a Biological Response” What is a drug? “A Chemical Substance that Interacts with a Living System and Produces a Biological Response” What is a drug? “A Chemical Substance that Interacts with a Living System and Produces a Biological Response”  Good and Bad Drugs?  Safe Drugs? 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 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! 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+) 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 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) 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 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 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 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 But when an effective drug is present Biological response is altered OR shut down 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 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 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 The Gamble - wastage and timescale  For EACH DRUG approved, an average of 7500 compounds will have been made  Of this 7500, an average 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 on average 12 years  Costs $138M (1975); $800M (2000); $1.6Bn (2008)  Development costs do NOT include pre-launch marketing which can DOUBLE costs 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 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? The Companies in 2010 1 2 3 4 5 6 7 8 9 10 Johnson & Johnson Pfizer Roche GSK Novartis Sanofi-Aventis AstraZeneca Abbott Merck Bayer Total Sales $billions 61.9 50.0 47.4 45.8 44.3 42.0 32.8 30.8 27.4 22.3 Major Therapeutic Targets CNS Metabolic Cardiovascular Anti-infectives Respiratory Gentio-urinary Musculoskeletal Oncology Top 10 Therapies - sales in 2008 (US$Bn) 2008 sales % share Oncology agents 45.8 6.4 Lipid regulators 34.2 4.8 Respiratory agents 30.7 4.3 Acid pump inhibitors 26.7 3.8 Antidiabetics 26.0 3.7 Antipsychotics 22.4 3.1 Angiotensin antagonists 21.6 3.0 Antidepressants 20.4 2.9 US$227.8Bn 32.1% 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 Case Study Cimetidine (Tagamet) 1979  H2 blocker; anti-ulcer/heartburn US 1976 UK  1983 First drug to reach $1Bn 1974  Cleared for OTC in 1995 1972 1970 1968 1966 1964 Programme starts Into volunteers Cimetidine Burimamide First lead What is a drug? “A Chemical Substance that Interacts with a Living System and Produces a Biological Response”