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“Rewriting the Textbook” for Precision Medicine

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Precision medicine places the patient at the center of healthcare, using a variety of tools to develop tailored and targeted therapeutics and diagnostics.

Promised to “revolutionize” the landscape of modern medicine, precision medicine requires an in-depth knowledge of the molecular underpinnings of healthy and diseased states. Advances in molecular biology techniques and bioinformatic platforms are helping to provide such knowledge, equipping researchers and physicians with the tools to implement precision medicine approaches across different disease areas.

Thus far, oncology – the field of cancer research and treatment – has arguably seen the most benefit from precision medicine. However, the pharmaceutical and biotechnology company AstraZeneca believes that precision medicine will “rewrite the textbook” for the diagnosis and treatment of chronic diseases. Technology Networks recently had the pleasure of speaking with Mark Fidock, vice president for Diagnostic Development, Precision Medicine at AstraZeneca, to find out how the company is “rising to the challenge” of delivering precision medicines for chronic diseases.

Molly Campbell (MC): Can you talk about some of the ways in which AstraZeneca is actively pursuing precision medicine?

Mark Fidock (MF): I think an interesting metric is that, when we look at our portfolio, over 90% of it has a precision medicine strategy. Precision medicine as a strategy and as a discipline really does encompass the full spectrum of drug research and development. That includes finding new targets – which requires the use of cutting-edge methods that are available – advancing and pioneering new technologies and of course, driving for better patient outcomes and a more sustainable healthcare system.

One of the areas in which we've made major advances is oncology. AstraZeneca has already achieved over 50 regulatory-approved companion diagnostics across a variety of indications and across a variety of different sample types. This has enabled innovative targeted therapies to be developed and benefit millions of cancer patients worldwide.

The work and success we have achieved in oncology has almost produced a “framework” for which we can develop precision medicine approaches for chronic diseases. However, we need to recognize that chronic disease is biologically complex and very heterogenous in origin, so a key priority in this space is to investigate the ways in which precision medicine can be deployed and used that increases our disease understanding and leads to better patient outcomes.

The opportunity in the precision medicine space is huge, especially for chronic diseases. We’re now in an era where, through precision medicine, we are rewriting the textbook for many indications, and changing the way in which we ultimately treat patients.


MC: Let’s talk more about the tools and technologies used. What are the key technological developments that are helping us to understand the biology behind diseases, and harness that information to tailor treatments?


MF: One of the key technology areas (in which AstraZeneca is a leader) is genomics research. Our in-house Centre for Genomics Research intends to sequence 2 million genomes by 2026 – which of course, isn’t all that far away now. Using very innovative bioinformatics analysis methods, the groups behind this project are looking for rare variants associated with diseases. Through doing so, they are uncovering new biological insights into disease, discovering new therapeutic targets and describing the diseases at a much more granular – almost molecular – or genetic, way. This creates opportunities for the development of targeted therapies for different segments of a particular disease.


Key examples include the discovery of novel targets in respiratory and immunology diseases, cardiovascular research and renal and metabolic diseases. One of AstraZeneca’s areas of interest is pulmonary fibrosis, and the group has previously published the discovery of a gene called SPDL1 identified in idiopathic pulmonary fibrosis.


The SPDL1 gene encodes a protein known as “Spindly” which is responsible for signaling during cell division. Previously, this gene had not been described in relation to idiopathic pulmonary fibrosis. The identification of a novel mechanism underpinning the disease opens the door for novel therapeutic discoveries.


In cardiomyopathy, the group also published a finding relating to the TTN gene. Both examples are key illustrations of how genomic techniques can be used to inform our understanding of a disease. These publications have been shared widely amongst the scientific community.


The TTN gene encodes a protein called “titin”. Truncated variants of the gene contribute to approximately 15–25% cases of nonischemic dilated cardiomyopathy, a condition where the left ventricle becomes enlarged.


MC: Can you talk about the importance of biomarkers in precision medicine? How are they used to identify patients and develop targeted therapies?


MF: I think the opportunity space for precision medicine across all disease indications that AstraZeneca is exploring is huge. It will enhance our ability to rewrite the medical textbooks that physicians are using to understand, diagnose and treat disease.


How do we do this? A core aspect of precision medicine is identifying predictive biomarkers, which is achieved through the insights gathered using genomic studies and other means. Predictive biomarkers provide the opportunity to include the right patients in our clinical trials and to develop targeted companion diagnostics and treatment approaches most appropriately.


In those disease areas where we already have multiple targeted treatment options available, we also have identified biomarkers for selecting patients. One example is in non-alcoholic steatohepatitis (NASH) where published literature has shown that mutations in the PNPLA3 gene are associated with impaired normal fat breakdown in liver cells. Through a collaboration with the biotech company Ionis Pharmaceuticals, we are investigating advanced ligand conjugated antisense oligonucleotides (ASOs) to downregulate PNPLA3 with the aim of restoring fat break down in the liver. A second example is IL33 – a cytokine that is seen and raised in many different indications, from asthma to diabetic kidney disease and even in COVID-19.

These are areas whereby the biomarker – and the scientific research surrounding the biomarker – is helping us to identify the right patients, which allows us to direct where our targeted therapeutics will have the most beneficial clinical outcomes.


MC: Can you talk about the importance of collaboration in the precision medicine space? How is AstraZeneca pursuing collaborative projects?


MF: AstraZeneca works in a very collaborative way, with many collaborations established across each of the different research spaces in which we choose to operate.


We must develop companion diagnostics that are scalable and have global reach, so they're aligned not only to our targeted treatments, but they're also analytically and clinically validated and demonstrate patient benefit. We've built global partnerships to deliver these tests that can be commercialized, which really does enable maximal access to patients. It also ensures these diagnostics are used consistently within the regulatory requirements across whichever part of the world that they will be used.


Through one of our collaborations with Almac, we are developing and validating companion diagnostic tests for patient selection across a variety of different clinical trials for a range of therapeutic areas, such as chronic kidney disease, NASH and respiratory diseases. This is a robust framework that we can adapt for use with other ongoing collaborations, such as our work with Roche diagnostics, among others.


In terms of challenges, when you're innovative, leading in a space and you are creating information that is “rewriting rulebooks” and “rewriting” the ways in which treatments are being derived, of course there are going to be some challenges. I think we can all agree that health is a fundamental right that we should all have access to, and that it should be inclusive and tailored to the individual. We think that precision medicine will be a vital part of this offering, it will improve health and it will improve health equality. We need to have discussions to ensure that all healthcare systems can fully adopt this approach into clinical practice, which is achieved through interactions, partnerships and engaging in symposiums and summits. We recently spoke at the World Health Summit, and AstraZeneca aims to bring together panels of external leaders across different diagnostic organizations, to talk through policy and to look at ways in which we can help to bring novel approaches to the clinical community and healthcare structures.


MC: Looking to the future of precision medicine, what are the key priorities in precision medicine for AstraZeneca? What do you envision that this space is going to look like in, say, 10–15 years?


MF: The more that we use precision medicine within the chronic disease space, and the more that science really begins to uncover how these complex chronic diseases are derived and their etiology, the more we can look to develop new therapeutic modalities. We can identify the right patient populations for diagnostics to target treatments and ultimately, this will deliver much better outcomes for patients in the long term.


What will it look like in the future? I think that a key focus is asking: how do we bring in novel diagnostics into clinical practice? How do we bring precision medicine to the patient? The future is about patient convenience. One day, it would be fantastic to be able to introduce molecular diagnostic devices to the home, so that patients can monitor their diseases as they are happening. This will involve bringing digital advancements – such as progress in artificial intelligence (AI) – into the different areas of precision medicine. How do we do this? How do we use digital mediums to derive actionable diagnostic data, where patients can take a diagnostic test in their own environment, that data is then shared with their treating physician enabling decisions and discussions to be held for the patients’ benefit? These will be important considerations.


A big part of the future is looking to further develop the scientific understanding of chronic disease and bringing together all the learnings that we've had in precision medicine and maximizing the outcome for patients. The future of precision medicine is about having a deep understanding of chronic disease at a molecular, genetic or metabolic level, in such a way that we're able to really make sure that the patient is at the heart of everything, and that they can have the benefit and the convenience of precision medicine in the future.

Mark Fidock, VP for Diagnostic Development, Precision Medicine at AstraZeneca was speaking to Molly Campbell, Senior Science Writer for Technology Networks.