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Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide,1 affecting one in ten people over 40 years old.2 While there has been considerable progress in our understanding of COPD biology, advances in COPD care for this progressive disease have been slow over recent decades.
As a long-standing leader in respiratory medicine, we are bringing inhaled therapy to COPD and leading the science to deliver next generation treatments with the potential to reduce exacerbations, hospitalisations and mortality. We are committed to developing new therapies that target the underlying drivers of COPD to move beyond exacerbation prevention and symptom control to slow and reverse disease progression by enhancing lung regeneration.
Beyond treatment, we are working with governments and policy makers around the world to address systemic challenges and make COPD a public health priority – including Act on COPD, a programme designed to educate and provide resources to change the mindset of COPD care and to reduce hospitalisations and mortality. In a separate initiative, we are collaborating in a first-of-its-kind COPD quality improvement program, Collaboration on Quality improvement initiative for achieving Excellence in Standards of COPD care (CONQUEST), that aims to improve outcomes for patients at greater risk of future COPD exacerbations by developing and implementing quality standards into routine care and measuring implementation success.
By tackling COPD across all fronts, we hope to achieve our bold ambition of cutting the COPD exacerbation rate in half by 2030 and reduce the associated cardiovascular mortality risk.
We have an investigational treatment in Phase 1 clinical trials which may provide a new approach to target fibrotic pathways earlier versus other mechanisms in development for IPF. Our porcupine inhibitor has been shown to suppress Wnt signalling (an important pathway in cell maintenance, differentiation and renewal), which is known to be highly active in diseases like IPF. By suppressing targeted signalling pathways, we hope that the novel treatment may be able to slow or prevent fibrosis in IPF and potentially other types of fibrotic diseases.
Working to slow or reverse disease progression
Slowing and ultimately reversing the progression of COPD is critical to improving the devasting outlook for patients today. We are committed to our work in this area and are investing in treatments and trials that will enable us to demonstrate true disease modification – stopping lung function decline over time and reversing the structural damage caused by the disease.
COPD is biologically complex with multiple disease drivers and our scientific strategy is built on our deep understanding of these pathways and the identification of novel drug targets that we can address with our array of new modalities. Using a precision medicine approach from the onset will mean that patients can be matched with the treatments they are most likely to benefit from, right from the start.
Following the science in novel disease pathways
Current therapies treat symptoms but do not address the underlying causes of cell damage in COPD. We are exploring approaches demonstrating disease modification through lung tissue regeneration in a number of novel inflammatory pathways:
Interleukin 33 (IL-33)
IL-33 is a broad-acting cytokine at the top of the inflammatory cascade that is released by the cells lining the lung following cell damage or stress.
IL-33 is an attractive target in multiple diseases, including COPD, where it is hoped that inhibition of this inflammatory pathway could have the potential to deliver disease modification by addressing the IL-33-driven inflammation associated with tissue remodelling in the lung.3,4 Increased IL-33 is seen in moderate-to-severe COPD patients and is correlated with increased exacerbations.
Our pre-clinical research has shown that blocking the IL-33 pathway can reduce the build-up of goblet cells and mucus production back to levels seen in healthy cells. Furthermore, IL-33 is a clinically validated target in COPD3,4 with emerging clinical data suggesting that IL-33 blockade can improve lung function and reduce exacerbation risk in COPD.
Through our Centre for Genomics Research (CGR) initiative, we are gaining a better understanding of the potential of IL-33 as a biomarker in COPD and other chronic diseases.
Myeloperoxidase (MPO)
MPO is an enzyme known to be involved in the root causes of inflammation in COPD. Increased levels of MPO have been detected in the airways of patients with COPD, driving both the triggering of exacerbations, as well as continued and accelerated damage of the lung in the stable disease state.5
It is hoped that inhibition of this inflammatory pathway could deliver disease modification in COPD. In addition, higher circulating MPO levels are associated with an increased risk of adverse cardiovascular (CV) outcomes and excess death from CV-related causes,6 which is important to address since CV diseases are some of the most clinically important comorbidities in COPD.
Forkhead box O4 (FOXO4)
FOXO4 is a transcription factor involved in cell cycle control, cell death and metabolism, as part of the p53 signalling pathway.7 Cells exposed to chronic stress, such as with smoking, can become damaged yet resistant to cell death and clearance from the lung – a state known as senescence.8 As these cells continue to survive, they release signalling molecules to surrounding cells which promotes further damage, as well as inflammation and fibrosis, leading to chronic disease.9
We have identified a role for the FOXO4-p53 interaction in promoting cellular senescence in the lung and are exploring approaches to disrupt this pathway that would initiate cell death and removal of damaged cells from the lung. In our early research, we have found that targeting this interaction creates an environment favourable to lung regeneration, leading to improved lung function, and a decrease in the damage caused by emphysema.
Transforming COPD care
As we pursue our ambition to slow or reverse disease progression in COPD, we are pushing the boundaries of science to tackle the toughest and most complex unsolved problems by targeting the underlying disease drivers and achieving greater efficacy through new modalities and novel combinations. Applying a precision medicine approach from the start, while leveraging new tools and technologies to accelerate progress, means we are moving towards a world where disease modification in COPD could become a reality, so these patients can start to live better, healthier lives. - and without this debilitating and life-threating condition.
