drug discovery process
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
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