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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”
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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?
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
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
LockKey
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
LockKey
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
Binding of Drugis preferred
vs.
Biological responseis 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
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
Total Sales $billions 1 Johnson & Johnson 61.9 2 Pfizer 50.0 3 Roche 47.4 4 GSK 45.8 5 Novartis 44.3 6 Sanofi-Aventis 42.0 7 AstraZeneca 32.8 8 Abbott 30.8 9 Merck 27.4 10 Bayer 22.3
Major Therapeutic Targets
CNS
Metabolic
Cardiovascular
Anti-infectives
Respiratory
Gentio-urinary
Musculoskeletal
Oncology
Top 10 Therapies - sales in 2008 (US$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)
1964
1966
1968
1970
1972
1974
1976
1979
First lead
Burimamide
Cimetidine
Into volunteers
UK US
Programme starts
H2 blocker; anti-ulcer/heartburn
1983 First drug to reach $1Bn Cleared for OTC in 1995
What is a drug?
“A Chemical Substance that Interacts with a Living System and Produces a Biological Response”
O
CO2H
Me
O
NH
NN
N
OEt
SN
O O
MeO
MeN
Asprin Sildenafil
