Global Clinical Head, NASH BioPharmaceuticals R&D
Director/Senior Principal Scientist Bioscience Metabolism, BioPharmaceuticals R&D
The liver can be seen as the conductor of the metabolic orchestra – so how can we unlock the science to change the tune for patients?
International NASH Day on 10th June highlights the growing global unmet need of non-alcoholic steatohepatitis (NASH). Where virally-driven liver disease used to be predominant, NASH is now the growing cause of liver disease around the world. This is in part due to the development of highly-effective treatments for viral liver disease, but more importantly a direct result of the rising levels of obesity and diabetes worldwide.
The NASH story so far
NASH is a relatively ‘new’ disease and has existed as a concept only since the 1990s. While it is now known that there are both genetic and environmental components to NASH, we are still building a picture of what NASH entails and the mechanisms at play. Diagnosis often comes late as it is a clinically silent disease and patients seldom have symptoms until the disease is in its advanced stages. The rate of disease progression may be slow and asymptomatic, but NASH can lead to severe illness including hepatocellular carcinoma and abrupt decompensation – almost always requiring a liver transplant to prevent death. There are currently no approved therapies for NASH and the disease is managed largely by diet and lifestyle changes.
The next chapter for NASH: how AstraZeneca is thinking differently to give patients new possibilities
First and foremost, we believe it is essential to uncover key drivers of disease to create the first generation of therapeutics. This is followed by further elucidation of additional novel pathways enabling the development of next generation of therapeutics. Our approach in NASH is no different. We recognise that NASH is a pathophysiologically evolving, multi-modal disease with a major metabolic component. As such, it is becoming evident that by targeting the different disease drivers, such as reversal of steatosis, fibrosis and inflammation, we can reasonably expect to reduce the totality of disease burden, which in turn would ultimately improve overall clinical outcomes for patients with NASH.
The second important endeavour is our investment in the development of new diagnostic tools, both to aid clinical trials and to improve the patient experience. Currently, diagnosis is invasive and requires a liver biopsy. As part of our current studies, we are looking at a systematic comparison of non-invasive versus invasive diagnostic procedures. Our data set continues to grow gradually, and with continued investment we hope this will lead to a reduction in the number of invasive procedures for patients as well as driving earlier NASH diagnosis.
The third key element comes from our ability to develop innovative therapeutic modalities for targets that were previously considered undruggable. The task at hand is to isolate the best therapeutic targets for NASH and to identify which modality will bring about the desired effect. Coupled with precision medicine, we are able to segment the broad NASH patient population, either via a specific genetic component or prevalence of specific markers of disease, will enable us to optimise the response of tailored treatment interventions. Not only does this mean we can run smaller, more efficient clinical trials, but we can also increase our confidence in the molecules we progress in our pipeline.
And finally, we recognise that all this progress cannot happen in isolation. We value our involvement in pre-competitive, public-private partnerships and collaborations, – such as the EU/UK-based Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) Consortium and the United States-based Non-Invasive Biomarkers of Metabolic Liver Disease (NIMBLE) Consortium – to better define patient populations and find potential non-invasive biomarkers to aid and accelerate the development of novel therapeutics. Support from global relationships allows us access to different cohorts, data and samples – all of which help us define the natural history of disease, characterise disease progression, determine those patients at risk for progression and identify critical points of opportunity for intervention. Quite simply, the more we understand the science, the closer we get to developing an effective treatment.
Precise pharmacological solutions for the liver and the broader metabolic system
The liver can be seen as the conductor of the metabolic orchestra and our focus, therefore, starts at the liver. Given its pivotal influence over other organs and processes, we need to be cognisant of the broader impact of drugging liver targets. At the same time, this is an opportunity to consider potential extra-hepatic benefits that can be brought to the table.
We are well placed to explore this arm of thinking with extensive experience in cardiovascular, renal and metabolic disease, and as such, our current NASH programmes are uncovering connected cardiovascular and renal benefits. Potential combination treatment approaches that address complementary biologies may see broader benefits for these patients who often have a number of co-morbidities.
Leveraging our expertise in genetic medicine, we are leading the way with precision medicine approaches. This includes treating NASH patients carrying a variant in the PNPLA3 gene which leads to a dysfunctional liver enzyme that is not only unable to digest fat itself, but impedes another type of enzyme from doing it too.
Our vision for NASH patients
We believe a truly improved disease experience for patients comes through a combination of improved disease recognition, simple non-invasive diagnostic, and effective multi-modal holistic therapeutic options. We are striving to arrest disease progression, reverse existing disease, improve co-morbidities and reduce the overall morbidity burden to enable patients with NASH to live life without limits.