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Clinical Trials – Interstitial Lung Disease

Breathing Matters was established 6 years ago with the aim of finding better treatments for interstitial lung diseases (ILD) and lung infections. Since that time we have raised money and awareness into these often neglected conditions. Looking back over the 6 years we have come much further than any of us would have anticipated in the beginning. We have established new theories on the development of ILD or lung fibrosis and the role of the immune system in particular the clotting cascade and neutrophils. We have also better ways of monitoring and diagnosing these conditions and our novel nuclear medicine imaging programme and relatively non-invasive lung biopsy service are the first in the UK. We could not have achieved any of this without the support of our funders and our patients, so thank you all. This review highlights our achievements to date and our future directions in ILD.

 

Relatively Non-Invasive Lung Cryobiopsy (2014-2019):

Objective: To find a less invasive and better diagnostic tool for every patient with ILD

Main benefactor:  Teresa Timberlake and family

Breathing Matters investment: £52,000 salary; £36,000 (total £88,000)

Leveraged funding: £347,000

Outcomes: Novel cryobiopsy service, first in the UK including training other centres; presentations at European Respiratory Society (2015), British Thoracic Society (2014-6); publications: review 2016; papers in preparation:

Next steps: Lung-COOL and Lung-INHALE

This project was developed in discussion with a family whose mother had had a surgical lung biopsy towards the end of her life. Her experience was such that her family felt that a less invasive alternative must be available. Dr Theresia Mikolasch took this on for Breathing Matters to find out and about and train in new techniques. Dr Mikolasch then returned to UCLH and established the first and only UK cryoscopic lung biopsy (CLB) service. CLB is a new way of obtaining larger lung biopsies using a flexible bronchoscope passed into the lungs through the mouth. The patient is sedated and surgery is avoided. This is not only better for the patient than a surgical lung biopsy but also provides a solution to the lack of biopsy samples available for scientific research.  GSK were so excited by the technique that they awarded Dr Mikolasch and Dr Porter a grant of over £300,000 to carry on the service for an additional 3 years. Current studies planned are

  • The COOL-LUNG trial (CryOextractiOn of Lung tissue for diagnosis of interstitial LUNG diseases) to compare the outcome of patients who have CLB compared to current pathways.
  • INHALE: Study to assess inhaled drug deposition using CLB from subjects with suspected ILD undergoing cryobiopsy for clinical reasons.

 

Novel FDG-PET Imaging to Predict Prognosis and Response to Treatment in ILD (2014-2019):

Objective: To find a new test (biomarker) that will enable us to predict prognosis and response to treatment in each individual patient.

Breathing Matters investment: £34,766

Leveraged funding: £173,850

Funding from BLF for clinical trial of FDG-PET in post transplant bronchiolitis £40,000

Outcomes: Novel FDG-PET imaging programme in ILD- first in the UK; presentations at American Nuclear Medicine Society (2015), British Thoracic Society (2015-6); publications: papers in preparation:

Next steps: FDG-PET will be used as a response biomarker in our Losmapimod in RA-ILD study; and for the anticoagulation in IPF study.

Interstitial lung disease (ILD) consists of a heterogeneous group of diseases with varying amounts of interstitial inflammation and fibrosis. Survival in the most severe form of lung fibrosis, idiopathic pulmonary fibrosis or IPF, is particularly poor, however there is heterogeneity in outcome. Some patients gradually deteriorate; some undergo stepwise progression, whilst others decline rapidly. Moreover, much of the prognostic data heralds from an era when the criteria for diagnosing IPF were less well and differently defined than at present.  There is a definite need to find prognostic biomarkers to predict outcome in IPF patients

Positron emission tomography (PET) offers the ability to non-invasively investigate cellular metabolism in vivo. PET studies in animals have yielded valuable insights into the biology of IPF and ILD and there is potentially encouraging evidence that PET may aid the development of therapeutic interventions to treat these debilitating conditions. It has been recently demonstrated that18F-Fluorodeoxyglucose (18F-FDG) PET signal is consistently raised and can be objectively measured in patients with IPF. Moreover, these PET signals are shown to be stable and reproducible. We have shown over several years and imaging hundreds of patients with ILD that the baseline measures of pulmonary18F-FDG PET signal to predict survival in patients with IPF compared to other more established prognostic data

Future studies are to investigate the role of FDG-PET scanning in other ILDs such as Rheumatoid arthritis (see below) and systemic sclerosis.

 

Rheumatoid Arthritis (RA) Associated ILD (2012-2017):

Objective: To discover why 1:5 patients with RA will develop lung fibrosis and what novel treatment can prevent disease progression

Breathing Matters investment: £34,766

Leveraged funding:  £102,766

Outcomes: Novel biomarker test for Neutrophils extracellular traps (NETS) in ILD in discussion with UCL business for further development; presentations at American College of Rheumatology (2014-6); British Thoracic Society (2016); British Rheumatology Society (2014-6); publications: 2  papers in preparation:

Next steps: A trial of the p38 MAPKinase inhibitor Losmapimod in RA-ILD using FDG-PET as a response biomarker

RA is a chronic debilitating disease estimated to afflict 13% of the world population. Around 10% of patients with RA will develop an ILD that is very similar to the lung fibrosis that we see with IPF. Dr Akif Khawaja was funded by Rosetrees and UCL to carry out a PhD into the aetiology of RA-ILD. His work proposed that RA is a disease that starts in the lung. That chronic lung damage caused by smoking, infection and other insults causes the immune response to recognize the lungs and joints as “foreign” and attack them causing chronic damage. His work implicated neutrophils in this process and in particular the p38 MAPkinase pathway.  Breathing Matters and Rosetrees are now funding Akif to carry out further work to investigate the role of the p38 MAPKinase inhibitor Losmapimod  in patients with RA-ILD and this will combined with our novel PET imaging work.  We are also hoping to develop a new test using blood or sputum to detect early activation of neutrophils in the lungs of patients at risk of ILD.  This same test may act as a biomarker for prognosis and to detect early response to novel therapies.

This work had led onto the first clinical trial of a treatment in RA-ILD: in particular we will use an established pharmacological inhibitor of p38 MAPkinase to investigate the role of this pathway in the FDG PET signal seen in the lungs of patients with RA-ILD; in particular, to demonstrate a change in FDG avidity following p38MAPkinase inhibition.

 

A Trial of Anticoagulation in IPF (2016-2017):

Objective: To assess the potential of anticoagulation as a treatment for IPF

Breathing Matters investment: TBA, but approximately £40,000

Leveraged funding:  TBA

Next steps: A trial of anticoagulation with heparin in IPF using FDG-PET as a response biomarker

At present, we do not know the exact cause of idiopathic pulmonary fibrosis (IPF), although research has identified lots of processes that are likely to be involved. Currently, we believe that microscopic injury occurs in patients with IPF and then the body responds to repair this, but does so in a way that leads to more damage and scarring. One of the processes involved in repair pathway is coagulation, which minimises blood loss when tissues are damaged.  Patients with IPF are at increased risk of blood clots and this can reduce their already low life expectancy. We also think that these blood clots drive the worsening of their lung disease. Researchers have shown that clotting is over-activated in the lungs of IPF patients and we want to investigate how reducing this might improve the disease.  Based on work carried out at UCL we believe that anticoagulation with heparin is safe and may even prevent disease progression in IPF. Patients will be asked if they would be willing to take heparin for 3 to 4 weeks, to reduce clotting. We will perform blood tests and FDG-PET scans before and after taking the drug to judge response.  If we find that the heparin is safe and the patients report some improvement, that we can confirm with questionnaires, lung function and FDG-PET scans, then we will progress to leverage funding for a much bigger trial.

If you are a UCLH patient and want to get involved in any of the above studies, please discuss this with your consultant.