Drug Discovery Process

Massimiliano Beltramo, PhD

Drug Discovery Process

Aim of the two lessons:

To give an overview of the drug discovery process.

At the end of the lessons you will gain a general idea of the steps necessary to move a new drug from the bench to the bedside.

Lesson I outline:

• General notions about drugs and the drug discovery process

• Target selection/identification/validationLesson II outline:

• Target validation

• Assay development and screening

• Lead identification/selection

• Preclinical development

• Clinical development

What is a drug?

Risk

Benefit

“Medicines are useful poisons”- Sir J ames Black FRS Risk

Benefit

Risk

Benefit

“Medicines are useful poisons”- Sir J ames Black FRS

In pharmacology, a drug is "a chemical substance used in the treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental well-being”.

Various types of drugs

Drugs that interfere with the cause of the disease “ disease modifying agents “

– Their action is intended to remove the cause of the disease (antibacterial, antivirals, vaccines, etc)

Drugs which compensate for deficitsInsulin, vitamins therapy, etc

Drugs which alleviate the symptoms Symptomatic treatments (analgesic, antiallergic, etc)

Various classes of drugs

• Natural product• plant extracts • animal fluids (e.g., snake venoms)

• Synthetic small molecules• Medicinal chemistry derived• Combinatorial chemistry derived

• Biologicals• Natural products (isolation)• Recombinant products• Chimeric or novel recombinant products

A new drug: why?A new drug: why?

• To address unmet medical needs

• To reduce social cost of diseases

• To improve the quality of life

Unmet Medical Need

• Pathologies with poor or no treatment - Cancer, Alzheimer’s,

Stroke, etc

• New diseases - Swine flu

• Improvement of available therapy - Better efficacy - Reduced side effects

Disease associated costs• The medical care costs in USA in 2005 were around $2 trillion.

• Direct costs are those connected with the use of medical care in the prevention, diagnosis, and treatment of disease and in the continuing care, rehabilitation, or terminal care of patients. Examples include:

– expenditures for hospitalization,– drugs– outpatient clinical care, – nursing home care, – services of primary physicians and specialists, etc

• Indirect costs measure the value of time that patients lose from employment or other productive activity due to mortality or morbidity. These costs also include reduced productivity once the patient returns to work, including unwanted job changes and loss of opportunities for promotion or education

• Burden of illness exceeds economic costs. Estimates of the economic costs of illness do not capture some important aspects of the burden of illness such as reduced functioning, pain and suffering, and deterioration in other dimensions of health-related quality of life including emotional and psychological impacts on families, friends, and co-workers.

(Source: NIH)

The first pharmaceutical researcher

• First drugs were of natural origin:herbs, seeds, fruits, roots, part of animals, rites and ceremonies

The Drug Discovery Today

MULTIDISCIPLINARYEXPERTISE

MEDICINE AND PHYSIOLOGY

CELLULARBIOLOGY

IN VIVO AND IN VITROPHARMACOLOGY

AUTOMATION AND ROBOTICS

BIOINFORMATICS

MEDICINAL AND COMBINATORIAL

CHEMISTRY

COMPUTER BASEDDRUG DESIGN

MOLECULARBIOLOGY

The Drug Discovery Process

IDEA

Exploratoryresearch

Exploratoryresearch

Therapeuticresearch

Therapeuticresearch

Fulldevelopment

Fulldevelopment

ExploratorydevelopmentExploratory

development

DRUG

I t is a long process Risks are high and often unpredictable

Strong regulatory environment

I t is necessary a complexe organization with strong expertise in many different fields

I t is a long process Risks are high and often unpredictable

Strong regulatory environment

I t is necessary a complexe organization with strong expertise in many different fields

R&D timing

0 2 4 6 8 10 12 14 16Years

Initial number of projects: 55

4

1 drug

Research

Preclinical developmentLaboratory and animal testing

Phase I clinical trials

Phase II clinical trials

Phase III clinical trails

Regulatory agency review/approval

0 2 4 6 8 10 12 14 16Years

Initial number of projects: 55

4

1 drug

Research

Preclinical developmentLaboratory and animal testing

Phase I clinical trials

Phase II clinical trials

Phase III clinical trails

Regulatory agency review/approval

• The whole process takes between 10 to 15 years.

High risk activity Only 25 out of 100 new chemical entities (NCEs) Only 25 out of 100 new chemical entities (NCEs)

tested in man reach the markettested in man reach the market

Target-RelatedFailures(35%)

SuccessfulNCE

(25%)

MetabolismFailures(10%)

PharmacokineticFailures(10%)

Toxicity Failures(10%)

Other Failures(10%)

Increase of R&D costs to develop a drug

0125250375500625750875

10001125125013751500

1986 1987 1990 1998 1999 2001 2002 2003

Year

Mil

lion

s of

$

In 17 years (1986-2003) the cost to develop a drug is increased more then ten times.

Drugs withdrawn from the marketRemarksWithdrawnDrug name

Withdrawn because of increased risk of progressive multifocal leukoencephalopathy

2009Raptiva

Withdrawn around the world because of risk of severe depression and suicide2008Accomplia

Progressively withdrawn around the world because of serious side effects, mainly liver damage

2007-2008Lumiracoxib

Withdrawn because of increased risk of complications or death; permanently withdrawn in 2008 except for research use

2007Trasylol

Withdrawn because of imbalance of cardiovascular ischemic events, including heart attack and stroke.

2007Zelnorm

Voluntarily withdrawn in the U.S. because of the risk of heart valve damage.2007Permax

Withdrawn because of risk of hepatotoxicity2006Exanta

Voluntarily withdrawn from U.S. market because of risk of Progressive multifocal leukoencephalopathy. Returned to market July, 2006.

2005-2006Tysabri

Withdrawn from U.S. market because of hepatotoxicity2005Cylert

Withdrawn because of a high risk of accidental overdose when administered with alcohol

2005Palladone

Withdrawn because of risk of myocardial infarction2004Vioxx

Withdrawn in many countries because of risk of fatal bronchospasm2001Raplon

Withdrawn because of risk of rhabdomyolysis2001Baycol, Lipobay

Withdrawn because of risk of liver failure2001Trovan

Withdrawn because of risk of stroke2000Propagest

Withdrawn because of hepatotoxicity, dermatological side effects, and abusepotential.

2000Survector

Withdrawn in many countries because of risk of cardiac arrhytmias2000sPropulsid

Withdrawn because of risk of fatal complications; reintroduced 2002 on a restricted basis

2000Lotronex

RemarksWithdrawnDrug name

Withdrawn because of increased risk of progressive multifocal leukoencephalopathy

2009Raptiva

Withdrawn around the world because of risk of severe depression and suicide2008Accomplia

Progressively withdrawn around the world because of serious side effects, mainly liver damage

2007-2008Lumiracoxib

Withdrawn because of increased risk of complications or death; permanently withdrawn in 2008 except for research use

2007Trasylol

Withdrawn because of imbalance of cardiovascular ischemic events, including heart attack and stroke.

2007Zelnorm

Voluntarily withdrawn in the U.S. because of the risk of heart valve damage.2007Permax

Withdrawn because of risk of hepatotoxicity2006Exanta

Voluntarily withdrawn from U.S. market because of risk of Progressive multifocal leukoencephalopathy. Returned to market July, 2006.

2005-2006Tysabri

Withdrawn from U.S. market because of hepatotoxicity2005Cylert

Withdrawn because of a high risk of accidental overdose when administered with alcohol

2005Palladone

Withdrawn because of risk of myocardial infarction2004Vioxx

Withdrawn in many countries because of risk of fatal bronchospasm2001Raplon

Withdrawn because of risk of rhabdomyolysis2001Baycol, Lipobay

Withdrawn because of risk of liver failure2001Trovan

Withdrawn because of risk of stroke2000Propagest

Withdrawn because of hepatotoxicity, dermatological side effects, and abusepotential.

2000Survector

Withdrawn in many countries because of risk of cardiac arrhytmias2000sPropulsid

Withdrawn because of risk of fatal complications; reintroduced 2002 on a restricted basis

2000Lotronex