Drug Repurposing

Question 1

Define Drug repurposing

Answer 1

Drug repurposing is the identification of new therapeutic uses for existing or investigational drugs outside their original indications.

Question 2

What is a drug centric approach
Give an example(s)

Answer 2

Starts with the drug
discovery of a new use for the drug
Off-label: Duloxetine (SNRI) for stress urinary incontinence
Reduce waste of investigational drug: Sildenafil
Safety issues (post-market) withdrawal: Thalidomide as an angiogenesis inhibitor in myeloma

Question 3

What is a disease centric approach
Give an example(s)

Answer 3

Starts with the disease
Investigate treatments used in ‘similar’ diseases

Anti-virals in COVID-19:
Chloroquinone (anti-malarial)
Ivermectin (anti-parasitic)

Question 4

What is a target centric approach

Answer 4

Identify specific molecular targets implicated in the disease and find existing compounds that can modify the targets

Question 5

Outline data driven approaches used in systematically identifying drugs for repurposing

Answer 5

Drug libraries e.g the drug repurposing Hub

Data about diseases and drug targets: Omics datasets, large retrospective datasets and combined datasets

Signature matching
Pathway or network mapping
Molecular docking

Question 6

Outline experimental approaches used in systematically identifying drugs for repurposing.
What type of centricity is this usually?

Answer 6

‘In vitro’ (cell culture)
‘In vivo’ (animal models)

This is usually target centric

Question 7

What are the limitations of data driven approaches

Answer 7

Only as good as the disease/target selection (generalisability)

Only as good as the data sets available: dependent on the experimental design of others

Large data sets may have poor data hygiene and multiple errors

Technically challenging:
Only identify potential candidates (need to be verified in lab experiments ands clinical trials)

Question 8

What are the benefits of data driven approaches

Answer 8

Use existing data: quicker than starting physical experiments from the beginning
Cheaper
Systematic, hypothesis free
Generate multiple potential candidate drugs
Less or no additional animal testing required

Question 9

What are the benefits of drug repurposing in the development of new medicines

Answer 9

Drug repurposing saves time and money (Average drug discovery is 10-15 years )
Repurposed drugs have a shorter turnaround (frame) of 3 – 12 years
It is particularly useful for rare diseases where de novo drug discovery may not be cost effective – or where a cure is needed urgently

Question 10

What are the limitations of drug repurposing in the development of new medicines

Answer 10

Computational methods are only as good as the study design and available datasets

There may not be a drug for every target
Repurposed drugs may have less efficacy compared with a new target/drug

Drugs may need reformulation

Question 11

Explain observational drug repurposing and give drug examples of this approach

Answer 11

Sildenafil for erectile dysfunction

Question 12

Explain the systematic approach to drug repurposing and give examples of drugs identified through this approach

Answer 12

Systematic approaches can be data driven or experimental approaches

Examples:
Covid-19

Question 13

What are the benefits of data driven approaches?

Question 14

What are the limitations of data driven approaches?

Question 15

What are some of the challenges of drug repurposing

Answer 15

Scientific: Computational methods are only as good as study design and available datasets

There may not be drug for every target

Drugs may need reformulation

Patents, regulatory and organisational hurdles:

Drug repurposing still requires significant investment

Patents may be elusive - deterring investment