Personalised Medicine ‘into the future’ Kate Andrews Marjorie Smith

Personalised Medicine ‘into the future’

The way in which people respond to medicines varies significantly and is driven by multiple factors Medicines (or pharmaceuticals) such as aspirin or those prescribed by doctors do not have the same effect on everyone. Some people do not respond at all to a medicine, while others experience severe side effects Many factors affect our response to drugs such as:- Our weight and age Our genetics Our sex The food and alcohol we have taken Other medicines we have taken

The Human Genome project has provided new insights as to why people react to medicines differently The Human Genome Project has enabled us to find out much more about the genetic variation It is suggested that genetic differences account for about 85% of our responses to medicines The genetic differences can affect drug absorption, distribution, metabolism and excretion

It is now possible to match particular genotypes to responses to particular medicines In order to ‘tailor make’ medicines to a person’s unique genetic make up, scientists are trying to identify which genotypes respond to particular medicines. This can be described as ‘personalised medicine’ We know that we all contain subtly different DNA. The human genome contains about 3 billion nucleotides and the genomes of any 2 individuals vary in about 3 million of them. It is no surprise, then, that individuals have different responses to the same medicine.

Pharmacogenetics is an emerging focus in the development of new medicines What is Pharmacogenetics? The study of how people respond differently to medicines due to their genetic inheritance. (pharmaco – from pharmacology: the study of how drugs work in the body and genetics – the study of how traits are inherited)

The goal of Pharmacogenetics is three fold To understand how someone’s genetic make-up determines how well a medicine works in their body To determine what side effects are likely to occur. Ultimately to ensure that patients get the right drugs at the right dose.

The potential benefits of Pharmacogenetics are significant Anticipated benefits: More powerful medicines Better, safer drugs first time More accurate methods of determining dosage Advanced screening for disease Better vaccines Improvements in drug discovery and the approval process Decreased health care costs Good discussion points here, this is the wish list BUT Health care cost may not be decreased! May just be pushing the problem around. Drugs may be more efficient but may now require screening to ensure correct target population, cost of drug treatment may be same or less but screening needs to be factored in. Hope to not treat non-responders so increase efficiency of finding correct medication, and reduce costs that way. Would hope number of adverse reactions is eliminated or vastly reduced so reducing that cost burden. How do you treat non-responders? Other drugs? which ones? how do you screen how many do you/can you screen for? All likely extra costs.

Pharmacogenetic testing is increasingly common How do we test? Pharmacogenetic tests identify variations (or mutations) in a person's genetic makeup in order to predict their responses to a medicine. Two common approaches The tests could be done directly by analysing a person's DNA - researchers may look for the presence, absence or change in a particular gene. Or it could be done indirectly by examining molecules that are influenced by DNA, such as RNA and proteins.

HIGHER BIOLOGY 3. Genome: Genomic sequencing — the sequence of nucleotide bases can be determined for individual genes and entire genomes. To compare sequence data, computer and statistical analyses (bioinformatics) are required Personal genomics and health - analysis of an individual’s genome may lead to personalised medicine through knowledge of the genetic component of risk of disease and likelihood of success of a particular treatment Pharmacogenetics

Higher Human Biology Human Genomics Personalised medicine is based on an individual’s genome. Analysis of an individual’s genome may lead to personalised medicine through understanding the genetic component of risk of disease. Pharmacogenetics is the name given to the study of the way people respond to the medicines

Personalised Medicine – Case Study Herceptin® Trastuzumab (Herceptin®) is a drug which is prescribed for some types of breast cancer. Some cancers have too much of a protein called human epidermal growth factor receptor 2 (HER2) on the surface of their cells. These are called HER2 positive cancers. The extra HER2 receptors stimulate the cancer cells to divide and grow. Herceptin locks on to the HER2 protein. This blocks the receptor and stops the cells from dividing and growing. Herceptin® only works in people who have cancer with high levels of the HER2 protein. Several tests are available to measure HER2 levels. Testing can be done at the same time as initial cancer surgery, or samples of cancer cells from previous biopsies or surgery may be used. Patients who test positive for this HER2 mutation are likely to respond well to Trastuzumab. The drug can shrink tumours, slow disease progression and increase survival. Unlike most chemotherapy drugs Trastuzumab kills just cancer cells leaving healthy cells intact. http://www.macmillan.org.uk/Cancerinformation/Cancertreatment/Treatmenttypes/Biologicaltherapies/Monoclonalantibodies/Trastuzumab.aspx http://www.gene.com/

Personalised Medicine – Case Study Herceptin® QUESTIONS: 1. What condition does the drug Herceptin® treat? 2. In what way can Herceptin® be described as ‘personalised medicine’? 3. HER2 positive cancers have too much HER2 on the surface of their cells. What does this excess HER2 do? 4. What effect does Herceptin® have on the HER2 protein? 5. Why do Doctors measure HER2 levels? 6. In what way is Herceptin® unlike most chemotherapy drugs. Look up one of the web-links below and describe some of the reactions of patients to Herceptin® treatment. http://www.macmillan.org.uk/Cancerinformation/Cancertreatment/Treatmenttypes/Biologicaltherapies/Monoclonalantibodies/Trastuzumab.aspx http://www.gene.com/

Pharmacogenetic testing and the development of “personalised medicines” raises some ethical concerns At first glance there may be few ethical concerns with these potential new treatments. However… Some people have an allele of a gene which leads to reduced ability to remove lipids such as cholesterol This allele is also associated with one form of Alzheimer’s disease Finding out information which might enable you to avoid heart disease might also tell you that you are likely to get Alzheimer’s In some parts of the world people can afford new drugs Drug research and development might be centred on the genotypes of people from these parts of the world People from less affluent areas might be excluded from new treatments –thereby creating a genetic underclass Case Study from Nuffield council on Bioethics Enzymes play an important role in the way that a medicine can be absorbed by the body. Our genes determine which kind of enzymes our body can produce. A large number of medicines (approx 25%) are metabolised by an enzyme called CYP2D6. This includes medicines for the treatment of psychiatric disorders as well as illnesses such as High Blood Pressure. It is difficult to predict how a particular person will respond to a given dose of these medicines due to the variation in the gene which produces CYP2D6 (over 70 alleles have been identified) 7% of the Caucasian population have a genetic variant that results in markedly reduced activity of this enzyme. As a result they may have reduced capacity to eliminate the main ingredient of appox 50 medicines and are thus at increased risk of developing adverse reactions. A further 2%-30% depending on ethnic group have multiple copies of the gene and they metabolise the medicines quickly requiring far greater doses of the drug to have the desired effect Genetic testing before prescription or enrolment for participation in clinical research could help prevent adverse reactions in these people as yet this testing is not routinely performed. BUT who gets this information – insurance companies? - relatives? What happens if the patient refuses the test – will doctors be willing to prescribe? Are there legal implications? Might the patients be classified as non-responders or difficult to treat?

Useful web links http://www.yourgenome.org/teachers/sequencing.shtml http://www.yourgenome.org/sis/pharm/ http://royalsociety.org/News.aspx?id=6059