Lecture 13: Use of genomic information for targeted drug discovery -Prof Hingorani

Question 1

What percentage of drug development programmes fail?

Answer 1

96%

Question 2

What consequences does drug failure lead to for healthcare systems and patients?

Answer 2

New drugs are priced to recoup cost of prior failure

This leads to financial pressure on healthcare systems

This raises taxation, diverts funds from other sectors and limits access to less cost effective drugs

Question 3

What consequences does drug failure lead to for the pharmaceutical industry?

Answer 3

Job losses and risk averse research and development

Risk averse research and development lead to being ’Me-too’ drugs whereby drugs developed adopt same mechanism of action as previous validated and successful drugs. Also lead to Evergreening, whereby a pharmaceutical company seeks to extend an existent drug by inducing small change in its formulation, rather than creating an entirely new drug. E.g. an effective drug may be reformulated as a long acting preparation. because this is a new chemical entity, it can garner patent extension and revenue stream to the pharmaceutical company can be sustained for a longer period.

Question 4

Both healthcare systems and patient consequences and pharmaceutical industry consequences of failed drug development programmes result in what?

Answer 4

Patchy therapeutic armamentarium

Question 5

Why do drug development programmes fail?

What does this suggest?

Answer 5

Main reason is failure due to lack of efficacy (drug developed to treat a particular condition failed to work for that condition).

This suggests the whole process of preclinical drug development that led to drug identification, target etc is false.

Question 6

What are the four stages of drug development?

Which of these is the crucial step?

Answer 6

1. Target-disease matching
2. Compound-target matching
3. Prove target engagement
4. Prove safety and efficacy

Target-disease matching

Question 7

What are two flaws in the Target-disease matching stage of drug development?

Answer 7

1. Pre clinical discovery:

Unreliable predictor of treatment efficacy
in humans as cell/ non human animal models used

2. Capacity to test only a few targets at a time

High false discovery rate

Consequence of this being that many spurious treatment targets are then pursued based on preclinical development findings and are taken forward into clinical phase testing, evaluated in randomised controlled trials which are the final step in drug development and result in failure for lack of efficacy

Question 8

What are the issues of experimental preclinical studies?

Answer 8

External validity

Reproducibility

Question 9

What are the issues of observational preclinical studies?

Answer 9

Confounding
Reverse causation
Reproducibility

Question 10

There may be few true protein-disease relationships to discover since not all proteins are encoded by genes.

How many proteins are considered as more readily targeted by small molecule drugs?

Answer 10

4000

Question 11

What is the false discovery rate in biomedical science?

Answer 11

92.6%

Question 12

What is the purpose of Human genomics for drug target-disease indication matching
(target identification)?

Answer 12

1. Human genomic work is addressing illness and disease in correct organism
2. As one can undertake evaluations of sequence variations throughout genome, variants that affect expression and function in every protein, there is potential to test all proteins, not needed to select targets as done in preclinical experiments
3. Low FDR- Human genetic studies are now conducted on a large scale with vision of minimising false discoveries
4. Variants in a gene are allocated at random at conception according to mendals second law, and this emulates random allocation of a drug in a clinical trial, in effect human genetic studies are natural randomised control trials

Question 13

What are the principles underlying human genomics use for drug target-disease indication matching
(target identification)?

Answer 13

Drug

Protein: Natural genetic variations (common or rare) - influence the level expression of protein or function, variants can be used as instruments to understand effects of targeted same encoding protein on a disease outcome and on physiological, metabolic and other functional changes that may arise from targeting that protein.

Disease

Question 14

How can a GWAS be used for drug target identification?

Answer 14

When GWAS implemented, interrogate the association of natural variation in genes throughout genome for their association with a particular disease of interest

Question 15

What is phenome-wide association study and how can it aid target validation?

Answer 15

A study design in which the association between single-nucleotide polymorphisms or other types of DNA variants is tested across a large number of different phenotypes.

This elucidates mechanisms of action, identifying alternative indications, or predicting adverse drug events (ADEs).

Question 16

What has a study investigating genetic variation in IL6R and human disease found?

Answer 16

Gene IL6R encodes protein interleukin 6 receptor, identified in GWAS of rheumatoid arthritis

Variants of gene encoding interleukin receptor are associated with protection against rheumatoid arthritis

Present rheumatoid arthritis drug, developed to block IL6R, not created on basis of GWAS

IL6R is implicated in other disorders such as coronary heart disease- raises question as to whether thus drug may be used in these conditions

Drug repurposing

Effect of IL6R gene variation in asthma, suggesting this gene may trigger or exacerbate asthma

Genetic investigation upon a range of conditions is valuable to validate drug targets

Question 17

What is Open targets?

Answer 17

Open database, collaboration between several pharmaceutical companies

Question 18

How can convergence of the effect of natural genetic variation and drug action on proteins to validate target be computed?

Answer 18

1. Drug
2. Altered expression or activity of protein- Natural genetic variation (common or rare) identified by genotyping or sequencing and using variants in or around a gene encoding a protein that affects its expression or activity.

Where protein is a drug target, testing association of those genetic variants that influence protein expression activity and associations with disease endpoints e.g. metabolism, altered physiology or function.

In doing so anticipating possible effect of drug that targets same protein

Question 19

What is the HMGCR gene?

Answer 19

target for well known statin drugs to low cholesterol to prevent coronary heart disease

Question 20

What did a Mendelian randomisation study for target validation of STATINS do and find?

Answer 20

Participants genotyped for a common SNP in gene encoded target for HMGCR and a blood sample drawn to measure metabolic markers circulating in plasma using nuclear magnetic resonance metabolomics.

Among the 28000 individuals, just over 5 and half thousand commenced treatment for statin – had blood sample obtained before and after treatment and the same metabolic markers were measured,

Using dataset it was possible to compare association of SNP in HMGCR gene with each of these metabolic biomarkers, with the effect of statin before vs after change in same markers- those metabolic markers that were most different between those who did or did not carry the gene, were most altered by taking statin. Can use this to predict new HMGCR drug effect.

Question 21

There is now a compelling case for using human genomics and linked biomedical data to aid target identification and validation, however what is required?

Answer 21

Mapping genotype to phenotype with even greater scale, breadth and resolution than hitherto.

Achieving scale, breadth and resolution is likely to require wider societal engagement – citizens, healthcare systems, academia, industry, charities – and could provide a lever for a more needs-led than profit-led approach to drug development.