Lec 14- personalised medicine

Question 1

One size doesn’t fit all

Answer 1

• Every year 2 million people in the US die due to adverse drug effects
• Drug efficacy is only in 60% of the population
• The other 40% have poor drug effects or no effects at all
• Major issue: Biological heterogenicity plus co-morbidities
  
  • Changes to the biology of a person (e.g. kidney and diabetes will change how a drug acts in the body)
• In humans, 99.9% bases are the same
• Remaining 0.1% (about 3 million bases) makes a person unique

Question 2

One size doesn’t fit all

Answer 2

• Remaining 0.1% makes a person unique
  
  • Different attributes/ characteristics/ traits
    
    • How a person looks
    • Diseases the person develops
• These variations may be:
  
  • Harmless (change in a phenotype)
  • Harmful (diabetes, cancer, heart disease, Huntington’s disease and haemophilia)
  • Latent (variations found in coding and regulatory regions, are not harmful on their own, and the change in each gene only becomes apparent under certain conditions eg. susceptibility to lung cancer)

Question 3

SNPs- a major source of variation

Answer 3

• Single Nucleotide Polymorphisms (SNPs)
  
  • Single base change in DNA
    
    • AAGCCTA
    • AAGCTTA
  • SNPs arise as a consequence of mistakes during normal DNA replication
  • Average frequency is 1/1000bp
• Other sources of variation
  
  • Insertions, deletions, translocation, duplications, repeats
  • Copy number variation is a major element

Question 4

Human variation

Answer 4

• Changes the expected PD and PCK characteristics of the drug: efficacy
  
  • PD- how a drug interacts with receptors in the body
  • PK- (ADME)- What the body does to the drug

Question 5

Drug metabolism enzymes

Answer 5

• Lots of clinical relevant polymorphisms in CYP enzymes

Question 6

CYP enzymes are involved in the metabolism of clinically important drugs

Answer 6

• 1A1- caffeine, testosterone, R-warfarin
• 1A2- Acetaminophen, Caffeine, R-warfarin
• 2A6- b-estradiol, testosterone
• 2B6- Cyclophosphamide, Erythromycin
• 2C- Acetaminophen, Testosterone, R + S-warfarin, Phenytoin
• 2E1- Acetaminophen, Caffeine, Halothane
• 2D6- Acetaminophen, Codeine
• 3A4- Acetaminophen, Caffeine, CBZ, Cortisol, Erythromycin, S+R- warfarin, Phenytoin, Codeine
• If there is a drug that is metabolised by just one enzyme and there is a polymorphism there will be a profound clinical effect

Question 7

Factors influencing activity and level of CYP enzymes

Answer 7

Question 8

Add in genetics/genomics

Answer 8

• Pharmacogenetics
  
  • The effect of (a single gene) genetic variation on drug response
• Pharmacogenomics
  
  • The application of genomics to the study of human variability in drug response
  • Far wider than pharmacogenetics
• Pharmacogenetics and pharmacogenomics are expected to play an important role in the development of better medicines for populations and targeted therapies will improve benefit/risk ratios for individuals

Question 9

Human drug variation

Answer 9

*

Question 10

What is personalised medicine

Answer 10

• Personalised medicine “is the tailoring of medical treatment to the individual characteristics of each patient”
  
  • The Age of Personalised medicine
• “The science of individualised prevention and therapy”
  
  • National Institute of Health
• Personalized medicine is a clinical practice model that uses an armamentarium of molecular (genetic) data, non-genetic data, demographic information, and clinical observations to define the best treatment and health outcome for patients.

Question 11

Personalised medicine

Answer 11

• Personalised medicine: a move away from a ‘one size fits all’ approach to the treatment and care of patients with a particular condition, to one which uses new approaches to better manage patients’ health and target therapies to achieve the best outcomes in the management of a patient’s disease or predisposition to disease

Question 12

Personalised medicine

Has the ability to offer

Answer 12

• The right drug
• To the right patient
• For the right disease
• At the right time
• With the right dosage
• Providing the right outcomes
• Genetic and metabolic data will allow drugs to be tailored to patient sub-groups
• We can predict good response to tested drugs
• Predict poor or non-response (use a different drug)
• Predict toxicity

Question 13

Mercaptopurine case study

Answer 13

Question 14

The futures

Answer 14

Question 15

Components of personalised medicine

Answer 15

• PM addresses two pragmatic questions:
  
  • Who should be treated with which drug?
  • How should treatment be administered?
• Targeted therapies (who?)
  
  • E.g. Trastuzumab(Herceptin) targeted to cancers with overexpression of HER2 cells (HER2+ metastatic cancers)
• Targeted dosing (how much?)
  
  • E.g. Warfarin dosing should be guided by CYP2C9 and VKORC1 genotypes (determine slow and fast metabolisers) used to adjust doses
• Warfarin is a major culprit showing minor and major adverse events, of all the commonly prescribed drugs for outpatients, because of its narrow therapeutic index

Question 16

Driving force of PM

Answer 16

• Improving drug safety
• Drug recalls are surprisingly common

Question 17

Many reasons for drug recalls

Answer 17

• Large proportion of recall due to adverse

Question 18

Driving force of PM

Answer 18

• Rocecoxib- 2.5bn/year blockbuster drug from Merck
• Approved in 1999 by the FDA, withdrawn in 2004 –why?
• Increasing evidence of greater risk of suffering a heart attack after therapy
• More pharmacogenomics tests would have discovered patients with the likelihood of suffering adverse effect and eliminated these
• 2006, Pfizer terminated the development of Torcetrapib, a cholesterol ester transfer protein (CETP) inhibitor
• Drug to reduce plaque on blood vessels and increase ‘good’ high-density lipoproteins
• Out of 15,000 patients tested (atorvastatin alone or artovastatin+torcetrapid), 81 deaths occurred in the dual therapy group than 51 in the single therapy group
• What if there was a genomic biomarker that could have predicted which patients were at risk

Question 19

Technologies that advance PM

Answer 19

• Pharmacogenetics and pharmacogenomics could assist by using biomarkers to populate clinical trials with subjects who will respond while excluding those at risk of side effects
• 2006, FDA approved first molecular diagnostic test MammaPrintsTest –profiles genes from cancer patients to determine the likelihood of remission within 5-10 years
• SNP array chip launched by Affymetrixin 2007
• Can reportedly measure >500,000 SNP and copy number variations across the genome
• Can discover new genetic biomarkers or high volume/ cost-effective whole-genome studies
• Prototype instrument being produced in Japan, to allow fast (90min) determination of patients metabolising enzymes to specific drugs
• Leads to targeted therapies and targeted doses
• 3D printing of medicines

Question 20

Roadblocks

Answer 20

• A lot of data gathering is required -genetic, biological and clinical but also lifestyle information—about a lot of individuals from diverse backgrounds
• Big Pharma companies must accept and change their business model to one that develops diagnostics and therapies targeted to a patient’s own genetic mutations –increasing the cost
• Who will bear the cost of personalising medicine?
• Economic barriers –socioeconomic disparities between the wealthy and the ‘masses’ -the data providers

Question 21

Bioethics/issues

Answer 21

• Unequal distribution of resources
• Who contributes to the data gathering process and who reaps the benefits? Cost discrimination?
• Invasion of medical privacy + confidentiality, security
• Discrimination due to involvement of genetic tests
• Access to information technologies
• Increasing electronic health records (EHRs) and EHR networks
  
  • Patients may withhold information for fear of loss of privacy –insufficient therapy;
  • Public health risk –infectious or sexually transmitted diseases, substance abuse etc
  • Fear of stigmatisation and discrimination if the disclosure is made public

Question 22

BiDil

Answer 22

• Combination pill containing two drugs (isosorbide dinitrate/ hydralazine) for heart failure, CVD and/or diabetes
• Clinical trials did not show overall benefit across the entire population
• Subgroups of patients showed the best overall benefit
  
  • BiDilapproved solely for use in African-descent patients

Question 23

Benefits of Personalised Medicine

Answer 23

• Better matching of patients to drugs instead of “trial and error”
• Customised pharmaceuticals may eliminate life-threatening adverse reactions
• Reduced costs of clinical trials by:
  
  • Quickly identifying total failures
  • Favourable responses for particular backgrounds
• Improved efficacy of drugs

Question 24

Future infrastructure of PM

Answer 24

• Increased awareness amongst prescribers of available kits/ diagnostic genomic tests
• Access to complete medical records of patients -medical history, physician and staff notes, automated checks for drug allergies and interactions, prescription drug history, and laboratory test results
• Push towards concierge medicine –fewer patients, longer time spent with patients, more individualised therapies?
• Pharma companies to change the business model

Question 25

Bottom Line

Answer 25

• The field of PG is rapidly evolving and it shows how drugs work in different patients
• PG approaches have the potential to provide clinical benefits
• It will help the pharmaceutical industry /health services in the future