De novo drug development is expensive, time consuming and has a high risk of failures (see below).
This situation hampers the pharmaceutical industry to find innovative strategies against
still not curable diseases.
The danger resulting from the limited view of the classical drug development pipeline was tragically demonstrated by
the catastrophic aftermath of the Thalidomide (Contergan) scandal leading to severe birth defects.
Allthough this tragedy took place half a century ago and the fact that Thalidomide is on the market again with changed
indications the development of this drug
led to defects the victims still are suffering from today. Many things have been learned since then but
the risk of late drug failure
or drugs showing severe side-effects though having passed clinical trials is still present .
Drug-repositioning tries to find unknown targets for drugs already established on the market or drugs in advanced develpment steps.
This approach could lower uncertainty of safety and pharmacological effects. Several examples in history showed that such a
repositioning can be performed very successfully (one of the most famous Sildenafil, now named Viagra). Nevertheless most cases were found by chance so far.
By applying systematical approaches as for example graph theoretical methods to biological networks more efficient approaches can be developed to identify new targets
for known drugs.
Much hope is set into the field of systematic drug-repositioning to lower the costs and risks of drug development.
Some examples of drug-repositioning
Generic
Original indication
New Indication
Year
Zidovudine
Cancer
HIV/AIDS
1987
Thalidomide
Sedation, nausea, insomnia
Leprosy and multiple myeloma
1998
Sildenafil
Angina
Erectile dysfunction
1998
Miltefosine
Breast cancer
Visceral Leishmaniasis
1998
Duloxetine
Depression
Stress urinary incontinence
2003
Topiramate
Epilepsy
Obesity
2003
Candesartan
Hypertension
Stroke
in trials...
De novo drug discovery vs. drug-repositioning
Adapted from: Ashburn TT, Thor KB. Drug repositioning: identifying and developing new uses for existing drugs. Nature reviews. Drug discovery. 2004;3(8):673-83. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15286734
De novo drug discovery and development: 10-17 year process; less than 10% overall probability of success;
Target Discovery
Disovery & screening
Lead optimization
ADMET
Development
Registration
Expression analysis
In vitro function
In vitro validation; for example knockouts
Bioinformatics
Discovery
Traditional
Combinatorical chemistry
Structure-based drug design
Screening
In vitro
Ex vivo and in vivo
High throughput
Traditional medicinal chemistry
Rational drug design
Bioavailability and systemic exposure (absoption, clearance and distribution)
Must start clinical testing at Phase I (Phase I/II for cancer)
US (FDA)
Europe (EMEA or country by country)
Japan (MHLW)
Rest of the world
To market
To market
Drug repositioning: 3-12 year process; Reduced safety uncertainty, reduced pharmacokinetic uncertainty
Compound identification
Compound acquisition
Development
Registration
Traditional medicinal chemistry
Rational drug design
Licensing
Novel IP
Both licensing and novel IP
Internal sources
May start at preclinical, Phase I or Phase II stages
