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

5. Good and Bad Drugs? Safe Drugs? What is a drug? “ A Chemical Substance that Interacts with a Living System and Produces a Biological Response” 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 Lock Key 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 Lock Key BindingBiological 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. Binding of Drug is preferred vs. Biological response is altered OR shut down But when an effective drug is present  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 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

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?

21. The Companies in 2010

22. Major Therapeutic Targets

23. Top 10 Therapies - sales in 2008 (US$Bn) 2008 sales% share Oncology agents45.86.4 Lipid regulators34.24.8 Respiratory agents30.74.3 Acid pump inhibitors26.73.8 Antidiabetics26.03.7 Antipsychotics22.43.1 Angiotensin antagonists21.63.0 Antidepressants20.42.9 US$227.8Bn32.1%

24. 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

25. Case Study Cimetidine (Tagamet) 1964 1966 1968 1970 1972 1974 1976 1979 First lead Burimamide Cimetidine Into volunteers UK US Programme starts H 2 blocker; anti-ulcer/heartburn 1983 First drug to reach $1Bn Cleared for OTC in 1995

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