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 1960s)

penicillin (1944), streptomycin (1944), valium (1963)

Treatment of metabolic disorders (1960s 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

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

The Lock and Key analogy

Lock

Key
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 Offto 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

Major Therapeutic Targets

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