Guest Blog: Genetic Alliance UK on personalised medicines
HER2 is a protein which promotes growth and it plays an important role in the progression of certain types of aggressive breast cancer. It is essential that only sub-groups of patients who are HER2-receptor positive take trastuzumab as the risks would clearly outweigh the benefits; cardiac toxicity is the most serious known side-effect associated with trastuzumab. Therefore tests need to be undertaken to ensure that this drug is only administered to those who are not at risk (who do not have pre-existing heart problems or high blood pressure) and those who are likely to benefit (those who are HER2-receptor positive). Tests are usually performed on biopsy samples and immunohistochemistry is used to measure the amount of HER2 protein present in the sample. Alternatively, fluorescence in situ hybridisation (FISH) can be used to measure the number of copies of the gene which are present.
One of the major benefits of testing for a patient sub-population is the reduction in adverse side effects. Given the risk of cardiac damage from taking Herceptin (approx. 2 – 7%) it clearly wouldn’t make sense for a patient without elevated HER2 levels to ‘take a punt’ on the drug working for them. Prescribing drugs to the correct patient sub-group reduces the risk of disappointing failures whereby the drug doesn’t work but the patient suffers the side-effects. This kind of testing also reduces ‘trial and error’ prescribing which can be extremely expensive for the NHS and frustrating for the patient – it tells the doctor whether a drug is likely to work before the patient starts to take it. The benefits to be found in identifying appropriate patient sub-groups are pretty clear, both to the patient and in terms of cost.
Now there are many other examples of treatments which require a companion diagnostic to reveal the true picture of a drug’s effectiveness. As you can read in our response to the Ensuring equitable access to complex molecular diagnostic testing for cancer patients consultation, the most high-profile of these tend to be cancer treatments. For example, Roche/Genentech’s Zelboraf, which is linked to the BRAFV600E gene mutation for melanoma and Pfizer’s Xalkori linked to structural variants of anaplastic lymphoma kinase were the next drugs with companion diagnostic tests to receive FDA approval in the states after Herceptin (in 1998).
This is very exciting and BIVDA is working hard to ensure that diagnostic companies build relationships with pharmaceutical companies so that personalised medicines and companion diagnostics are the technologies of today and not just the dreams of tomorrow. Cancer Research UK also does some amazing work. However for this week’s Testing Tuesday Genetic Alliance UK has kindly offered to guest blog for us, in order to highlight the breadth of personalised medicines. For they are much broader than just cancer and patients suffering from all kinds of conditions look set to benefit from this new approach to treating diseases.
Over to Genetic Alliance UK...
Cancer treatments have been the main focus of developments in personalised medicine so far, but the principle does not only apply to cancer. Many conditions appear to be a single condition when considering symptoms, but at a molecular level are actually a group of conditions, each with different treatment options. Here, we have two examples of treatments for genetic conditions which are showing a great deal of promise.
Exon skipping for Duchenne muscular dystrophy
Duchenne muscular dystrophy (DMD) is a severe progressive condition which affects boys born with the condition. Boys with DMD get gradually weaker as their muscles waste away. They are likely to need a wheelchair by the age of 13 and life expectancy is greatly reduced (more info here). DMD is rare, affecting 1 in 3,600 boys.
DMD is the result of a faulty dystrophin protein. The manufacture of the protein is halted because of a flaw in the genetic code for the protein. The exon skipping technique is a promising therapy which allows the error in the code to be skipped, in turn allowing the production of a more complete dystrophin protein. (More info here here)
The gene for dystrophin is the longest gene we have. There are many different mutations in it that can cause DMD, and these require a range of different exon skipping techniques. The particular mutation affecting a boy is recorded when they are diagnosed with DMD. Thankfully the exon skipping approach seems to be applicable to all forms of the condition, so in the long term we can expect the research to deliver treatments for all boys affected. The treatment will be developed for exon 51 first, skipping this exon will help the largest group of boys with DMD (13%), and techniques to skip other exons are under investigation.
Exon skipping is currently at the clinical trial stage for exon 51. For personalised medicines applied to rare diseases, like DMD, the populations available for clinical trials are very small, given that the treatments are only applicable to a subset of a small population. When it comes to the regulatory phase, we hope that principles established in the licensing of the first treatment, skipping exon 51, will be applicable to the treatments that follow, skipping other exons. As the target group drops in size, the ease by which evidence for the regulatory process can be gathered drops too. There will be different molecules used for treatments to skip different exons, which would theoretically require a whole new set of licensing procedures, but if the same exon skipping principle is applied, we hope the burden of evidence can be reduced.
Ivacaftor for cystic fibrosis
Cystic fibrosis (CF) is also a severe progressive condition. It affects the cell secretions in the lungs, and the glands in the gut and pancreas. Patients have problems with repetitive infections in their lungs and with the absorption of nutrients. CF is also a life limiting condition (more info here).
Mutations in a single gene, the cystic fibrosis conductance regulator (CFTR) gene cause cystic fibrosis. Patients in the UK have their mutation recorded when they are diagnosed with CF. In this case, it is the understanding of a particular mutation, G551D, which affects 4% of people affected by CF in the UK that has allowed researchers to develop a treatment ivacaftor. This group of patients is larger in the UK than in other populations in Europe, because it is a mutation associated with the Celtic population.
Unlike exon skipping the principle behind this treatment is specific to the G551D mutation, and it will not be applicable to other affected patients.
Ivacaftor has a marketing authorisation in Europe now, and work is ongoing to make this drug available to patients in the UK (more info here).
Both of these examples show that personalised medicine is being applied more broadly than ever. The problems associated with rare diseases, such as low patient populations for research, can be amplified when a personalised medicine is a possible treatment. In both these cases an accurate genetic diagnosis is essential to understand the next steps for treatment of affected individuals.
Genetic Alliance UK is the national charity, with a membership of 155 patient organisations, supporting all those affected by genetic disorders. Their aim is to improve the lives of people affected by genetic conditions by ensuring that high quality services and information are available to all who need them. They provide an over-arching strategic view on the needs and priorities of patients and families living with and at risk of genetic disorders; they have a powerful voice, influencing and shaping policy and practice. They work in partnership with key stakeholders such as government, the NHS, academia, industry and other patient groups on areas of shared interest.
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