Title: Developing a biomarker guided strategy to treat patients with pulmonary fibrosis
Funder: Department of Health and Social Care

Abstract: Background Idiopathic Pulmonary Fibrosis (IPF) is a devastating, progressive fibrotic lung disease with a median survival of 3 years and a 25% 5-year survival rate. The incidence continues to rise throughout the world, with >6000 deaths/year in the UK alone. Development of anti-fibrotic' drugs has lead to improved outcomes for patients with IPF, although patients continue to progress despite therapy. However, disease progression is highly variable and recognition of two related conditions has added further complexity disease management. Patients with progressive fibrotic lung disease of known aetiology, or not sharing classical radiological or pathological characteristics of IPF, are not eligible for anti-fibrotic therapy even though disease trajectory and molecular pathogenesis may be shared. Furthermore, recent data suggests Interstitial Lung Abnormalities (ILAs) on CT scanning may represent early progressive fibrotic lung disease, which could affect over half a million people in the UK, who have no clear management pathway. Research Question The overarching hypothesis underpinning this application is that genetic and serum biomarkers can identify a subgroup of patients with pulmonary fibrosis who will benefit most from anti-fibrotic therapy'. Methods This proposal will use information gained from the PROFILE study to guide analysis from two cohort studies, one observing progressive pulmonary fibrosis (INJUSTIS study) and one observing early ILAs (SUMMIT study), and an on-going interventional clinical trial (INMARK trial), to identify molecular endotypes of patients with rapidly progressive pulmonary fibrosis. The information gained will be used to develop a feasibility study of anti-fibrotic therapy in patients with early progressive fibrotic lung disease. Specific Aims Aim 1) Identify endotypic biomarkers reflecting progressive pulmonary fibrosis. I will further analyse data from the PROFILE cohort as well as analysing data from the Its Not Just IPF Study (INJUSTIS) cohort to determine whether endotypes of progressive pulmonary fibrosis are conserved regardless of disease aetiology or clinical phenotype. Results will be validated in cohorts obtained from US collaborators. Aim 2) Identify biomarkers that predict progressive fibrosis in people with ILAs. I will undertake a discovery analysis in ILAs identified in patients participating in a CT Screening study for lung cancer (The SUMMIT study). Results from the UK screening study will be validated in US cohorts of ILA in collaboration with US investigators. Aim 3) Develop a prediction model to determine which patients with pulmonary fibrosis are likely to progress. I will assess the interaction between markers of genetic risk of disease susceptibility, progression and mortality with serum biomarkers of disease progression and outcome to develop a computational model for prediction of disease progression. Aim 4) Validate biomarkers of response to therapy. I will assess the response of known, and novel, biomarkers in samples from patients treated with anti-fibrotic drugs (INMARK trial), and develop a health economic model for the use of biomarker driven therapeutic decision-making. Aim 5) Determine the feasibility of using biomarker-guided strategy for managing patients with ILAs. Impact These studies will define endotypes of progressive fibrotic lung disease that will clarify management and improve outcomes for patients with these complex conditions.

Lay abstract: Lung scarring of unknown cause is called Idiopathic Pulmonary Fibrosis (IPF). It is a progressive lung disease with a worse outcome than most cancers. The build-up of excess fibrous tissue in the lung starts gradually and most patients don't realise that their symptoms of breathlessness on exertion are anything serious. As the disease progresses patients are often treated for other conditions such as chest infections or heart failure before being diagnosed with IPF. Anti-fibrotic drugs are available that slow down loss of lung function as IPF progresses. Anti-fibrotic drugs are expensive (26,000/patient/year) and have numerous side effects. NICE has approved anti-fibrotic drugs for patients with advanced IPF based on lung function criteria (Forced Vital Capacity between 50 and 80% predicted), but the best time to start therapy is not known. Despite medication, the progression of IPF is remorseless leading to considerable suffering, disability and ultimately death. The speed of scarring varies considerably between patients with rapid progression often occurring after a period of relatively stable symptoms. There are also other types of progressive lung fibrosis, although less common and less well defined than IPF. These conditions have a similar biology and devastating disease course, however they are ineligible for anti-fibrotic therapy. Ideally, given the cost and side effects of anti-fibrotic drugs, only patients likely to benefit should start them, and only patients gaining health benefits should continue taking them. Unfortunately it is difficult to predict the speed of disease progression at the time of diagnosis in any given patient. Furthermore, there is no way of telling which patient is going to benefit from anti-fibrotic treatment, worse still it isn't possible to say whether a patient's health is benefitting from anti-fibrotic drugs. This is because the lung function tests usually get worse regardless of whether or not the patient is treated, and it is not possible to determine in an individual patient whether the reduction in lung function would, or would not, have been different with, or without, treatment. My hypothesis is that genetic and chemical signals from the blood can identify patients with pulmonary fibrosis who will benefit from anti-fibrotic therapy. The goal of my project is to identify these genetic and chemical signals, which will help decide when to start, stop or change anti-fibrotic drugs regardless of the type of lung scarring. I will achieve this by identifying chemical signals from a range of cohort studies and clinical trials to define the likely benefit from treatment with anti-fibrotic drugs. I will do this by building on my recent work that has identified genetic risk factors for the development of IPF and distinct blood tests that reflect different biological patterns of fibrosis. I will see if there are other chemical signals in IPF and then I will see if these signals are found in patients with other types of progressive fibrotic lung disease. I will then measure these chemical and genetic signals in the blood of people who have been identified as having early lung fibrosis whilst undergoing screening studies for lung cancer or screening studies for relatives of patients with familial lung scarring. I will extend my collaboration with industrial partners to investigate the effect of anti-fibrotic therapy on these chemical signals, to determine whether they can be used to define treatment response before finally undertaking a feasibility study to identify whether it will be possible to use these blood tests to treat people with fibrosis who otherwise have no symptoms of disease. The results of these studies will improve patient care by ensuring that we prescribe the right drug, to the right patient at the right time.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RESPIRATORY