MICA: A new paradigm for testing pathway tractability in lung disease

Lead Research Organisation: University of Edinburgh
Department Name: MRC Centre for Inflammation Research

Abstract

Despite significant advances in our core knowledge of disease mechanism, the number of drugs that reach medicinal status has actually diminished. The current route of validating drugs involves laboratory-based assays in cells, studies in animal models of the disease and lastly a series of clinical trials of increasing size and expense culminating in large studies designed to show drug efficacy. At each point in this process the development costs rise, often exponentially and there is a high attrition rate. Further, many drugs are entered and fail in the latter stages of clinical trials without 'proof' that they were ever biologically effective against their intended target in patients with the disease.

In this proposal, we describe a novel efficient pathway for testing the potential for a drug to become an effective medicine. The pathway is designed such that a drug can only progress to an 'efficacy study' if it can be proven that it inhibits its intended target in patients with the disease.
We aim to demonstrate this novel pathway in patients with IPF, a devastating disease with poor survival and no effective therapy. The pathogensis of IPF is complex, but there is evidence that an enzyme, MMP9, is elevated in the lungs of patients with the disease and may be suitable drug target. Through a separate MRC fund, we are developing a 'Smartprobe' that emits a visible signal when activated by MMP9. Our co-applicants, AstraZeneca have developed a drug, AZD1236, that is a potent inhibitor of MMP9. This drug has been studied in patients with emphysema and is safe, but the results indicated the drug was ineffective at treating the disease. However it is not known if the drug actually inhibits its intended target, MMP9, in the diseased lung.
Our first aim is to show that AZD1236 is able to switch off the MMP9 Smartprobe in cells and tissue from IPF patients. To prove 'target-engagement' definitively, we will also label the drug with a fluorescent tag and visualise, in real-time under direct microscopy, co-localisation of the drug with the MMP9 Smartprobe. If the AZD1236 fails to switch off the Smartprobe, the project will be stopped.
Our second aim is to demonstrate that AZD1236 inhibits the MMP9 Smartprobe in the lungs of patients with IPF. This is feasible through pCLE, a tool that allows direct visualisation of fluorescent signals in the lung airways and airsacs via a telescope in lightly sedated patients. A small quantity of MMP9 Smartprobe will be instilled directly into a diseased area of lung, and the signal measured in real-time. This will be followed by instillation of a small dose of AZD1236 (or placebo) into the same area and the reduction in signal quantified. This study requires only 6-10 patients, yields immediate results and is designed to prove that AZD1236 inhibits MMP9 in diseased lung. Failure to inhibit the MMP9 signal would end further human studies AZD1236 in IPF.
If inhibition is achieved however, we will proceed to our third aim; a study in 20 patients with IPF in which the MMP9 Smartprobe activity is quantified before and following 3 months of treatment with AZD1236 (or placebo) given by tablet. This study is designed to prove that AZD1236 given in tablet form, the route by which the drug would ultimately be used in patients, inhibits MMP9 in lung tissue.
These studies are not designed to show that AZD1236 is effective at treating IPF. Such a study would still need to be performed in a larger number of patients for a longer duration. However, by first proving that AZD1236 inhibits MMP9 in the lungs of IPF patients, the risk of a larger study 'failing' are substantially reduced.

Technical Summary

The archetypal pathway of drug validation utilises cell-based assays, an animal model of disease followed by phased studies in man. Pre-clinical models are of little value in predicting clinical efficacy, and many drugs are entered into clinical trial without 'proof' that they are biologically effective against their intended target in the disease itself. We describe a novel tractable strategy for optimising the pathway of drug development using specific optical Smartprobes and direct visualisation of pathway activity/inhibition in situ in real time using probe-based confocal laser endomicroscopy (pCLE). This pathway incorporates clear go/no go steps to reduce attrition rate, enrich the pool of drugs that progress to efficacy studies, and offers a mechanism-based method for stratifying patients for drug trials in diseases of the lung and indeed any organ accessible by fibreoscopy. Using idiopathic pulmonary fibrosis (IPF), a devastating disease, as the model, and the MMP9/12 inhibitor AZD1236 as the drug, we aim to quantify the real-time intrapulmonary activity of MMP9 and drug-mediated MMP9 inhibition in patients with IPF.
Methodology
1. In vitro evaluation of drug-mediated MMP9 activity inhibition utilising a MMP9-substrate Smartprobe and fluoro-labelled AZD1236 in cells and fresh tissue from patients with IPF. These studies aim to show colocalisation of the drug and Smartprobe and real-time inhibition of Smartprobe-activity.
2. Microdosing studies of AZD1236 and MMP9 Smartprobe in man. This includes a first-in-man study of dual microdosed drug and Smartprobe followed by an experimental study of intrapulmonary drug and Smartprobe in patients with IPF. The study is designed to prove, in situ real-time, drug-mediated MMP9 inhibition in fibrotic lung.
3. A phase IIa double blinded RCT study of AZD1236 given by the intended route (oral) utilising MMP9 Smartprobe and pCLE in IPF. Primary end-point is change in intrapulmonary MMP9 Smartprobe activity at 6 weeks.

Planned Impact

Beneficiaries
1. Pharmaceutical and biotech industry involved in drug discovery and pathway tractability
2. Drug regulatory bodies
3. Patients with IPF and all patients recruited to efficacy end point clinical trials
Despite the very significant advances in recent years in our core knowledge of mechanisms of disease, the number of drugs that reach medicinal status has actually diminished. The 'tried-and-tested' pathway of drug validation utilises cell-based assays, an animal model of disease followed by phased studies in humans. One clear 'bottle-neck' in the pathway is at the point of phase 2 clinical trials, designed to address optimum dose and potential efficacy. At this point, the financial costs are high, and the risk of either inappropriately discarding or inappropriately proceeding with the drug is very real. Drug 'failure' at this point may be broadly attributed to either of the following:

1. The drug failed to engage with and inhibit its target in the disease tissue because of:
i) inadequate dose,
ii) local tissue factors that disrupt drug activity,
iii) poor expression of the drug target at the time of drug introduction
iv) target only expressed in a subgroup of patients.

2. The drug-target was invalid i.e. not actually involved in the disease.

At present the tools used to distinguish between these causes of drug failure are inadequate. If the diseased tissue cannot be readily and repeatedly sampled, as is usually the case, evidence for target inhibition is based on testing potentially misleading surrogate tissues (blood, urine, sputum). Drugs that appear to be 'ineffective' may be discarded and the target deemed invalid but this would be inappropriate if it could be demonstrated that failure was due to inadequate engagement and inhibition of the target.
Our proposed strategy utilises optical 'Smartprobes' and yields direct and immediate visualisation of target activity/inhibition. This strategy can be used, in small numbers of patients, to establish 'proof of concept' that a drug is indeed capable of target engagement and inhibition in disease tissue. It encompasses clear go/no go milestones that will reduce 'failure' rate in efficacy studies by ensuring that only drugs that engage with and inhibit the target in the disease tissue be promoted to larger efficacy studies. Furthermore the strategy can be used to select appropriate drug dosage and to stratify patients such that only those in whom the target is (over) expressed are recruited.
We propose to test this strategy in IPF, a devastating disease with no effective therapy. International guidelines state that patients with IPF should be recruited to high quality clinical trials. Phase III trials in IPF are extremely costly and the outcomes have been notoriously unpredictable. Phase II trials are currently hampered by the lack of reliable surrogate measures of disease activity. By far the most reliable maker of disease progression in IPF is a decline in vital capacity. However at least 50-100 patients are needed to in each arm of a study and the study needs to continue for 6-12 months before changes in vital capacity can be meaningfully interpreted. Most phase 2 studies in IPF are 'negative'. Using our strategy, we could ensure that large IPF trials were only conducted with drugs that were first proven, in a small number of patients, to 'hit' their intended targets in the lung. Importantly, the strategy is applicable to any lung disease, and indeed any organ that is accessible by telescope or needle.

Regarding wealth formation for the public, there is a direct opportunity to take the products of this research into a new small business enterprise and create jobs to develop similar molecular optical imaging probes using the same development pathway. This technological approach to apply cutting-edge chemistry with state of the art physics to detect optical molecular signatures deep within human tissue is internationally unique.

Publications

10 25 50

publication icon
Barr LC (2013) A randomized controlled trial of peripheral blood mononuclear cell depletion in experimental human lung inflammation. in American journal of respiratory and critical care medicine

publication icon
Kurowska-Stolarska M (2017) The role of microRNA-155/liver X receptor pathway in experimental and idiopathic pulmonary fibrosis. in The Journal of allergy and clinical immunology

 
Description BLF Project Grant
Amount £150,000 (GBP)
Organisation British Lung Foundation (BLF) 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2010 
End 06/2012
 
Description Measurement of TGF-beta Related Biomarkers in Bronchial Alveolar Lavage Fluid (BALF)
Amount £23,000 (GBP)
Organisation UCB Pharma 
Sector Private
Country United Kingdom
Start 03/2016 
End 02/2017
 
Description Measurement of TGF-beta Related Biomarkers in cells from Bronchial Alveolar Lavage Fluid (BALF) part 2
Amount £88,977 (GBP)
Organisation UCB Pharma 
Sector Private
Country United Kingdom
Start 03/2018 
End 02/2019
 
Description Molecular endotyping lung fibrosis
Amount £80,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 08/2017 
End 08/2020
 
Description The role of macrophage CD71 and iron metabolism in lung fibrosis
Amount £80,000 (GBP)
Funding ID 1938966 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 08/2017 
End 08/2020
 
Title Edinburgh lung fibrosis cohort 
Description Unique cohort of incident consecutively presenting cases 
Type Of Material Database/Collection of data 
Year Produced 2013 
Provided To Others? Yes  
Impact Unique description of natural history of lung fibrosis 
 
Title molecular smart probe 
Description confocal laser endoscopy and smart probe programme of work 
Type Diagnostic Tool - Imaging
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2013
Development Status Under active development/distribution
Impact foundation for significant funding and collaboration 
 
Description school visit, edinburgh 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact around 60 school children aged 7-11. their attention was captured by video images of englufing cells

there are plans to repeat this excercise
Year(s) Of Engagement Activity 2009,2010,2014,2017