The Pharmaceutical Industry and The Process of Drug Discovery What is a Drug? Types of Pharmaceutical Products What are the Important Disease Targets?

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”

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CO2H

Me

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NH

NN

N

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SN

O O

MeO

MeN

Asprin Sildenafil