At AstraZeneca, personalised healthcare is about matching medicines to the patients most likely to benefit from them.
The approach involves a detailed understanding of the biology of a disease, identifying biomarkers and developing tests, known as companion diagnostics, which doctors can use to identify who is most likely to respond to treatment with a targeted therapy.
The greatest leap forward for personalised healthcare has been in treatment for cancer. One example of this approach is the discovery in lung cancer that patients who have activated epidermal growth factor receptor genes are more likely to respond to drugs that inhibit this pathway1.
Next-generation sequencing (NGS) is a new technology that is bringing us to the brink of a new leap forward. The quest to sequence the first human genome involved an international consortium of 200 scientists, took 10 years and cost just under $3 billion. With NGS, whole genome sequencing can now be performed for under $1,000 in a few days2.
Such advances, however, bring new complexities – the biggest challenge is no longer a lack of genetic data. The challenge now is how to handle this big data – the sheer volume of it, and how to interpret it and turn it into knowledge.
AstraZeneca’s ambitions for personalised healthcare go far beyond treating cancer. It aims to apply the team’s expertise to a range of diseases across all its focus areas. Common conditions, like cardiovascular and metabolic disease, may be caused by a mix of environmental and genetic factors. Cardiovascular disease is the leading cause of death worldwide3 yet only a small percentage of genes have been discovered that contribute to its disease risk4.
Ever wondered what causes some people to develop certain medical conditions? Or why some patients experience side effects or respond to medication differently when prescribed exactly the same treatment? For Ruth March, Vice-President and Head of Personalised Healthcare and Biomarkers, IMED Biotech Unit, and her team, these are two questions that constantly drive them in their pursuit of bringing new treatments to patients.
The field of personalised healthcare is exciting with advances in technology opening up a world of possibilities. Not just confined to developing new medicines, it is changing approaches to research and the underlying causes of diseases, through to how patients are treated in the clinic.
At AstraZeneca, personalised healthcare is about matching medicines to the patients most likely to benefit from them. In practice, it’s not as simple as it sounds. The approach involves a detailed understanding of the biology of a disease, identifying biomarkers and developing tests, known as companion diagnostics, which doctors can use to identify who is most likely to respond to treatment with a targeted therapy.
“The most significant advances of the last five to 10 years in oncology stem from the discovery that tumours are driven by individual genes,” says Dr March. “If you can find out which genes are important and inhibit them, you can develop a targeted medicine that is best for that tumour, and select the right patients to be treated.”
“In the last decade we have gained so much more information about the biology of diseases,” adds Dr March. “We can use this information to be much more precise in targeting specific patients with our medicines and in the development of these medicines.”
The first so-called 'personalised medicines' were approved over a decade ago, and relied on the genetic technology of the time to select patients for treatment5. As both the time and the cost of DNA sequencing has fallen exponentially in the last 10 years, scientists and clinicians are uncovering more of the differences that matter when it comes to preventing or treating disease.
"Our belief is that personalised healthcare will be transformational in the way that we use medicine if we apply science in the best possible way," explains Dr March. “The way we do this is by developing new medicines linked to companion diagnostics that select patients for whom treatment will be most effective. This supports doctors in making treatment decisions and alleviates some of the guesswork – the current trial and error approach to prescribing many medicines.”
Personalised healthcare has helped tailor drugs that are already developed. But it can also lead to the identification of brand new drugs. AstraZeneca’s personalised healthcare team works to identify biomarkers early on in the drug development process as this has been shown to actually shorten the development time needed to bring new medicines on to the market6.
“The way we are designing these drugs allows us to very quickly go from first test in patients to registering the drug. Selecting the correct patient population gives a much greater chance of developing a successful treatment,” says Thorsten Gutjahr, Global Head of Companion Diagnostics and Head of the Companion Diagnostics Oncology Unit at AstraZeneca. “It is hugely exciting if you think about how personalised healthcare can change clinical practice across all therapeutic areas and make a massive difference to patients.”
We will use the most up to date way to examine all the variations. This would have been impossible a few years back.
Progress in the understanding and treatment of cancer has been boosted by genomics, however this research has been slower for other complex diseases like asthma, heart disease and diabetes. In these conditions the genetic influence is much more subtle; genes interact with the environment making it more challenging for AstraZeneca’s personalised healthcare team to find biomarkers that can be used to select patients or monitor disease.
“I fly the flag for complex diseases,” says Adam Platt, Executive Director and Head of the Respiratory, Inflammation and Autoimmune (RIA) companion diagnostic unit at AstraZeneca. “The causes of common disease are unlikely to be simple genetics," he explains, highlighting that although genetics can provide a molecular insight into disease, complex diseases require a more holistic view of the complex interactions between organ systems of the body and the environment.
“What next-generation sequencing (NGS) can do in common conditions is help you understand the pathophysiology of the disease, which will bring new targets and lead you to biomarkers.”
AstraZeneca is also looking at targeted treatments in its RIA focus area, where simple tests may aid the diagnosis and monitoring of disease. Diagnostics and biomarkers are being explored to develop innovative new personalised therapies for asthma, rheumatoid arthritis and lupus.
The quest to sequence the first human genome took 10 years and cost nearly $3 billion. With NGS, whole genomes can now be sequenced for under $1,000 and in a few days.
AstraZeneca and The Montreal Heart Institute (MHI) will use NGS technology to interrogate the genomes of up to 80,000 patients using DNA samples from the AstraZeneca Biobank. The samples were collected over 12 years of clinical trials for diabetes or cardiovascular disease.
The interrogation of genomes is a search for patterns related to variations in DNA samples. MHI and AstraZeneca will use the latest techniques to scan the samples for any genes that may be associated with a predisposition to either disease. “Patterns related to variations in DNA samples are more obvious using a greater number of people and NGS gives the potential for wide monitoring,” explains Benoit Destenaves, Director, Molecular Diagnostics Labs and Pharmacogenomics, IMED Biotech Unit.
“The large sample size used in the collaboration with MHI will help to detect even small genetic variations, distinguishing between subsets of patients and revealing new insights into debilitating diseases like coronary heart disease and dyslipidemia,” he adds.
According to Dr March, MHI’s experience in running clinical trials means it is uniquely positioned to interpret the discoveries that come out of the archive. “It’s a wonderful opportunity to honour the commitment of these patients who have donated tissue and blood and have signed an additional consent to progress research.”
Information collected with each sample relating to disease complications and treatment outcomes will also help to define subgroups of patients. "Some patients respond to treatment and their disease is controlled, whereas others progress quickly and may develop serious complications,” adds Dr March. “Examining the genomics of these patients in detail will help us understand new pathways that can be targeted in novel treatments, and how to select them for treatment using new biomarkers."
Patterns related to variations in DNA samples are more obvious using a greater number of people and NGS gives the potential for wide monitoring.
"We see patients treated with medicines that may not have made it to the market without the biomarker contribution." Dr March is referring to the first of a new drug class approved by the FDA called a PARP (poly ADP ribose polymerase) inhibitor – designed to derail a cancerous cell's ability to repair its DNA. The therapy is approved with a companion diagnostic for treating ovarian cancer patients with the BRCA mutation7.
The BRCA diagnostic is the first approved test to use a central laboratory to analyse blood samples where, previously, FDA guidelines in the US assumed all tests would be contained in a kit supplied to multiple laboratories. The team at AstraZeneca and its diagnostic partner, Myriad, pioneered this approach by demonstrating to the FDA that the same principles for approval could be applied to a central laboratory-based test.
“We introduced one of the first targeted cancer therapies to oncologists, and the first companion diagnostic to use circulating tumour DNA in a patient’s blood sample,” says Dr Gutjahr. "Our team is familiar with a lot of research groups – academics, partners in the diagnostic section of a young start-up or seasoned company, whoever has the best tool. A constant dialogue is embedded to help us get under the skin of the biology and stay on top of the science."
“Five of the six oncology drug projects in our late-stage pipeline have a diagnostic," adds Dr Gutjahr. A partnership with Illumina may yield another first for AstraZeneca as it develops a novel, NGS-based companion diagnostic test in pivotal studies for one of its investigational oncology compounds. It is expected to be among the first NGS-based tests to undergo regulatory review for an oncology indication.
Once again AstraZeneca is working with diagnostic companies, the FDA and other regulators as they define how a cutting-edge diagnostic will gain approval. The personalised healthcare team is pushing forward to deliver scientifically-leading technology to benefit patients.
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2. Sequencing technologies - the next generation. Nat Rev Genet. 2010 Jan;11(1):31-46. doi: 10.1038/nrg2626. Epub 2009 Dec 8. Metzker ML.
3. WHO fact sheet
4. Finding the missing heritability of complex diseases - Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, Slatkin M, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TF, McCarroll SA, Visscher PM. Nature. 2009 Oct 8;461(7265):747-53. doi: 10.1038/nature08494.
5. March, R. Delivering on the promise of personalized healthcare. Personalized Medicine 2010 7: 327
6. Stratified medicine: strategic and economic implications of combining drugs and clinical biomarkers. Mark R. Trusheim, Ernst R. Berndt & Frank L. Douglas Nature Reviews Drug Discovery 6, 287-293 (April 2007) | doi:10.1038/nrd2251
7. PARP Inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies. Ann Oncol. 2014 Jan;25(1):32-40. doi: 10.1093/annonc/mdt384. Epub 2013 Nov 12. Lee JM, Ledermann JA, Kohn EC.
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