Continuing with our series of blogs on ‘biological pathways’, AstraZeneca’s new framework strategy for respiratory research and development, we take a look at epithelial-driven pathology and how it is opening up avenues for early intervention to prevent lung damage in conditions such as chronic obstructive pulmonary disease.
While the first two fields of interest in AstraZeneca’s new ‘biological pathways’ framework for respiratory research and development – eosinophilic and T2 disease respectively – focused on relatively well-defined processes involved in airway inflammation, the company is also delving into much broader, currently uncharted territory.
The third biological pathway, epithelial-driven pathology, typifies this more expansive approach to the fundamental drivers of conditions such as asthma and chronic obstructive pulmonary disease (COPD).
Principally, it is to do with problems caused by the breakdown of mucosal immunity, leading to bacterial or viral infections and exacerbation of existing disease.
For example, the company is running a Phase II clinical trial in severe-asthma patients with AZD9412, an inhaled interferon-beta compound licensed from Synairgen.1 The licensing agreement includes the option to expand this clinical programme into other pulmonary diseases, including COPD.
In the longer term, AstraZeneca aims to dig deeper by exploring subdivisions of epithelial pathology, as well as truly disruptive strategies such as restoring damaged epithelial tissue in COPD.
These latter strategies would involve reversing the cell-differentiation processes that lead to tissue damage and bacterial or viral colonisation of the lungs - for example, by examining the collateral cells around the epithelium (such as macrophages) that instruct it to adopt a particular phenotype.
It is known, for example, that the epithelium shows marked abnormalities in both asthma and COPD. In the case of asthma, changes in the gene-expression profile have even been found in infants predisposed to asthma. In COPD, the main cause of epithelial change is usually inhaled smoke, further compounded by acquired mutations.
In both diseases there is emerging evidence of altered micro-RNA and non-coding regulatory RNA, pointing to potentially reversible epigenetic causes.
Moreover, changes in the extracellular matrix, and the interaction between the epithelium and inflammatory cells that may themselves have undergone epigenetic reprogramming, could reveal entirely new targets for therapeutic intervention.
These insights open up opportunities to treat respiratory disease at a much earlier stage, before the lung structure incurs serious damage. COPD is often diagnosed very late in life. For example in Sweden, the median age of diagnosis is 74.2 Because of this the majority of patients entering clincal trials are often elderly with very advanced disease.2
Earlier intervention will, however, necessitate changing regulatory mindsets around clinical trials and associated endpoints in respiratory disease, as well as the treatment paradigms that result from those efforts – in the same way, for example, as prophylactic use of statins is now widely accepted as a strategy in ‘healthy’ people at risk of heart disease.
AstraZeneca is well equipped to explore these emerging pathways. Our colleagues at MedImmune, for example, are world leaders in research into the epithelial alarmin IL-33 and the cytokine thymic stromal lymphopoietin (TSLP), both of which are implicated as major disease drivers and positioned upstream of T2 and T1 immune responses.
MEDI9929/AMG157 is a potent, fully human monoclonal antibody that targets TSLP, and is being developed in collaboration with Amgen. AstraZeneca is exploring the role of TSLP blockade in the epithelium-driven T2 and T1 immune responses in severe asthmatics (Ph2b ‘PATHWAY’ study) as well as patients with moderate-to-severe atopic dermatitis (Ph2a).
The overarching approach is to move beyond the current era of research, dominated by agents that block pro-inflammatory mediators or signalling pathways but do not fundamentally modify tissue. AstraZeneca is instead pursuing strategies that might enable reversion of tissue from a diseased to a healthy phenotype.
hBD-2 and COPD exacerbations
One paper presented at the American Thoracic Society Meeting in San Francisco, US, looks at the relationship between COPD exacerbations and human beta defensin 2 (hBD-2), an antimicrobial peptide produced by the lung epithelium.
The hBD-2 peptide exhibits broad antimicrobial activity as well as promoting host immune responses to infection.
The relationship between COPD status and this key mediator of lung epithelial defences was explored by measuring sputum and serum levels of hBD-2 in a cohort of COPD patients recruited in Guangzhou, China.
This was for a two-year observational study assessing the occurrence and frequency of COPD exacerbations, as well as their association with environmental factors such as air pollution and viral or bacterial infections.
Christopher McRae and colleagues found that reduced levels of hBD-2 in COPD patients experiencing exacerbations were linked to compromised antimicrobial defences in the airways. They suggested that these, in turn, might lead to a higher burden of colonising pathogenic bacteria and an aggravated risk of exacerbations.
Based on these findings, the researchers concluded that therapeutic strategies aimed at boosting antimicrobial defences warranted further investigation as a potential novel treatment approach to COPD.
This is the third in a series of blogs exploring the scientific rationale behind AstraZeneca’s biological pathway framework for respiratory disease.
Gary Anderson, a pharmacologist, immunologist and founding Director of the Lung Health Research Centre, has authored around 180 highly cited papers. His translational research is at the interface of genetic disease models and clinical cohorts focused on understanding molecular mechanisms in asthma, COPD, lung cancer and interstitial lung disease. In 2008, he proposed the widely adopted “Endotype” concept of asthma, and his work has contributed to the development of several lung medicines used worldwide. He was awarded the Research Medal of the Thoracic Society of Australia and New Zealand in 2006, and was elected a Fellow in 2014. He has served on the NHMRC Research Committee, the Board of Directors of TSANZ where he chaired the Research Committee, and on the Council of the Australian Lung Foundation. In 2015, he was elected a Fellow of the European Respiratory Society.
View Gary Anderson’s published research
1. Consilium News. AstraZeneca commences AZD9412 Phase II trial in severe asthma. Available at: http://www.consilium-comms.com/news-detail.aspx?news=95 Last accessed August 2016
Sundblad BM, Jansson SA, Nystrom L et al. Chronic Obstructive Pulmonary Disease (COPD) during the two last years of life – a retrospective study of decedents. PLOS One. 2013: 8(12): 1-8