MICA: The Role of GABAB Receptor Mechanisms in Chronic Cough
Lead Research Organisation:
University of Manchester
Department Name: School of Medical Sciences
Abstract
Coughing is the most common reason for which people visit their GP, but currently we know very little about why people cough and the current medications for treating cough are not helpful. Some people suffer from severe coughing which can last from eight weeks to many years, and yet they seem to have no obvious cause for their cough. This is known as a Chronic Cough. One theory is that chronic cough might be a response to a condition known as gastro-oesophageal reflux, where food and acid in the stomach flow back into the oesophagus (food pipe). Gastro-oesophageal reflux usually causes heartburn and indigestion which can get better with acid blocking medicines, but in people who develop cough, rather than heartburn, acid does not seem to be the problem and these treatments do not work. Previous research has suggested that in up to 50% of patients with chronic cough, the coughing may be triggered by gastro-oesophageal reflux.
This project will study a new medicine, known as a GABA-B receptor agonist, developed to reduce the amount of gastro-oesophageal reflux. Although this medicine was not found to be helpful in patients with heartburn who were already taking acid blocking treatments, but we will test whether it improves chronic cough which has been triggered by reflux. This new medicine may also reduce the sensitivity of the nerves that make people cough and could also be helpful in chronic cough patients where reflux is not a problem for them.
We plan two studies using this medicine. Firstly we will test this treatment in healthy people to see whether it reduces the sensitivity of the nerves responsible for coughing. Secondly we will test the treatment in patients with chronic cough and measure any reduction in the number of times people cough compared to a placebo (dummy) treatment. In this study we will also measure gastro-oesophageal reflux and the sensitivity of the cough reflex to work out which patients might find this medication helpful in the future.
If these studies show this GABA-B receptor agonist improves chronic cough, then this could lead to the development of more effective treatments for coughing, which in turn may help more patients that just those with chronic cough.
This project will study a new medicine, known as a GABA-B receptor agonist, developed to reduce the amount of gastro-oesophageal reflux. Although this medicine was not found to be helpful in patients with heartburn who were already taking acid blocking treatments, but we will test whether it improves chronic cough which has been triggered by reflux. This new medicine may also reduce the sensitivity of the nerves that make people cough and could also be helpful in chronic cough patients where reflux is not a problem for them.
We plan two studies using this medicine. Firstly we will test this treatment in healthy people to see whether it reduces the sensitivity of the nerves responsible for coughing. Secondly we will test the treatment in patients with chronic cough and measure any reduction in the number of times people cough compared to a placebo (dummy) treatment. In this study we will also measure gastro-oesophageal reflux and the sensitivity of the cough reflex to work out which patients might find this medication helpful in the future.
If these studies show this GABA-B receptor agonist improves chronic cough, then this could lead to the development of more effective treatments for coughing, which in turn may help more patients that just those with chronic cough.
Technical Summary
Cough is the most common symptom for which patients seek medical care. Chronic cough (>8weeks) is reported by 14-23% of the population and has a substantial impact on quality of life. Remarkably little is understood about the mechanisms involved in the human cough reflex. Gastro-oesophageal reflux disease is thought to be a major cause of chronic cough but evidence suggests acid suppressing therapies such as proton pump inhibitors are ineffective. We have developed a validated, semi-automated ambulatory monitoring system, which objectively identifies the precise timing and frequency of coughing episodes. Combining this method with oesophageal pH/impedance monitoring, we have shown that in almost 50% of chronic cough patients, cough follows reflux events more often than expected by chance alone, and irrespective of the acidity of the refluxate.
The main mechanism underlying gastro-oesophageal reflux events is transient lower oesophageal sphincter relaxation (tLOSR). Gamma-aminobutyric acid type B (GABAB) receptor agonists such as Baclofen inhibit tLOSRs and consequently reflux events by up to 40%. Baclofen also inhibits cough responses to inhaled capsaicin in healthy controls and subjectively improves treatment resistant chronic cough, but longterm therapy is poorly tolerated due to CNS side effects and acute withdrawal can result in seizures.
We hypothesise that Lesogaberan, a novel mainly peripherally acting GABAB receptor agonist will inhibit human cough (without CNS side effects) via two mechanisms i) a direct inhibitory effect on afferent pathways responsible for evoking cough and ii) an indirect effect via reduction in tLOSRs and reflux events in patients where reflux is temporally linked to cough. We therefore propose two studies to investigate the effect of Lesogaberan i) on cough reflex sensitivity in healthy controls and ii) on objective cough frequency in chronic cough patients with and without cough triggered by reflux events.
The main mechanism underlying gastro-oesophageal reflux events is transient lower oesophageal sphincter relaxation (tLOSR). Gamma-aminobutyric acid type B (GABAB) receptor agonists such as Baclofen inhibit tLOSRs and consequently reflux events by up to 40%. Baclofen also inhibits cough responses to inhaled capsaicin in healthy controls and subjectively improves treatment resistant chronic cough, but longterm therapy is poorly tolerated due to CNS side effects and acute withdrawal can result in seizures.
We hypothesise that Lesogaberan, a novel mainly peripherally acting GABAB receptor agonist will inhibit human cough (without CNS side effects) via two mechanisms i) a direct inhibitory effect on afferent pathways responsible for evoking cough and ii) an indirect effect via reduction in tLOSRs and reflux events in patients where reflux is temporally linked to cough. We therefore propose two studies to investigate the effect of Lesogaberan i) on cough reflex sensitivity in healthy controls and ii) on objective cough frequency in chronic cough patients with and without cough triggered by reflux events.
Planned Impact
The main beneficiaries of this proposal are patients suffering from chronic cough, as the medication to be investigated has the potential to be an effective anti-tussive treatment. This project may find that GABAB agonism has an inhibitory effect on the cough reflex in all patients with chronic cough, therefore all patients may benefit. It is also possible that GABAB agonsim will only be effective in patients in whom significant reflux-cough associations are present, which according to our previous data represents approximately 50% of those presenting to specialist cough clinics. Should this be the case, this study will identify those patients who will benefit the most. As there are currently no licensed treatments for chronic cough, and established anti-tussive agents seem to be ineffective in these patients, the identification of an effective novel therapy would be an important development. Furthermore as a peripherally acting therapy, this treatment has been found to be associated with few side effects, this is in contrast to many treatments used in chronic cough such as opioids and baclofen. Further clinical clinical trials will be required, following these proof of principle studies, to progress this treatment to be available to patients, however a substantial body of work on safety, tolerability and dosing has already been completed by Astrazeneca for the original indication of treatment of typical reflux symptoms, shortening the time to availability for patients.
Publications
Houghton LA
(2016)
Respiratory disease and the oesophagus: reflux, reflexes and microaspiration.
in Nature reviews. Gastroenterology & hepatology
Houghton LA
(2017)
Gastro-oesophageal reflux events: just another trigger in chronic cough?
in Gut
Kahrilas PJ
(2016)
Chronic Cough Due to Gastroesophageal Reflux in Adults: CHEST Guideline and Expert Panel Report.
in Chest
Morice AH
(2020)
ERS guidelines on the diagnosis and treatment of chronic cough in adults and children.
in The European respiratory journal
Morice AH
(2015)
Cough hypersensitivity syndrome: clinical measurement is the key to progress.
in The European respiratory journal
Satia I
(2019)
Allergen challenge increases capsaicin-evoked cough responses in patients with allergic asthma
in Journal of Allergy and Clinical Immunology
Smith J
(2020)
"Truth is ever to be found in simplicity, and not in the multiplicity and confusion of things" - Sir Isaac Newton
in European Respiratory Journal
Smith JA
(2016)
Chronic Cough.
in The New England journal of medicine
Smith JA
(2019)
Cough: New Pharmacology.
in The journal of allergy and clinical immunology. In practice
Description | American College of Chest Physicians Cough Expert Panel |
Geographic Reach | North America |
Policy Influence Type | Influenced training of practitioners or researchers |
Description | Chair of BTS Cough SAG |
Geographic Reach | National |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | Membership of ERS taskforce for update of Cough Guidelines |
Geographic Reach | Europe |
Policy Influence Type | Membership of a guideline committee |
URL | https://erj.ersjournals.com/content/early/2019/09/02/13993003.01136-2019 |
Description | NIHR Clinical Research Facility |
Amount | £15,500,000 (GBP) |
Organisation | National Institute for Health Research |
Sector | Public |
Country | United Kingdom |
Start | 09/2022 |
End | 08/2027 |
Description | NIHR Clinical Research Facility Funding |
Amount | £12,500,000 (GBP) |
Organisation | Sheffield Teaching Hospitals NHS Foundation Trust |
Department | NIHR Clinical Research Facility |
Sector | Hospitals |
Country | United Kingdom |
Start | 04/2017 |
End | 03/2022 |
Description | NIHR Manchester Biomedical Research Centre Award. |
Amount | £28,500,000 (GBP) |
Organisation | National Institute for Health Research |
Department | NIHR Biomedical Research Centre |
Sector | Public |
Country | United Kingdom |
Start | 04/2017 |
End | 03/2022 |
Description | NIHR Senior Investigator |
Amount | £45,000 (GBP) |
Organisation | National Institute for Health Research |
Sector | Public |
Country | United Kingdom |
Start | 04/2019 |
End | 03/2023 |
Description | Treating idiopathic pulmonary fibrosis with the addition of lansoprazole |
Amount | £1,621,846 (GBP) |
Funding ID | NIHR127479 |
Organisation | National Institute for Health Research |
Sector | Public |
Country | United Kingdom |
Start | 09/2019 |
End | 08/2025 |
Description | Wellcome Institutional Strategic Support Fund/University of Manchester Equality Diversity Inclusion "Perera" Fellowship |
Amount | £50,000 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2022 |
End | 02/2023 |
Title | RADAR cough recording database |
Description | Ethically approved database of cough recordings (anonymised) for the development of cough detection and analysis algorithms. Allows sharing of data with academic and commercial researchers in the field. |
Type Of Material | Database/Collection of data |
Year Produced | 2016 |
Provided To Others? | Yes |
Impact | Collaboration and Funding from a phamaceutical company to further develop fully automated cough monitoring. |
URL | https://www.research.manchester.ac.uk/portal/en/datasets/radar-database-of-anonymised-acoustic-cough... |
Description | AstraZeneca Collaboration |
Organisation | AstraZeneca |
Department | Respiratory, Inflammation and Autoimmunity |
Country | Sweden |
Sector | Private |
PI Contribution | Provision of expertise and intellectual input into targets for novel cough therapies, clinical trial design and endpoints. Completion of two RCTs of AZ drug (lesogaberan) as part of AZ/MRC funded mechanisms of disease project grant. Planned provision of clinical samples from chronic cough patients for biomarker analysis. |
Collaborator Contribution | Match drug (lesogaberan) and placebo and knowledge of drug safety/tolerability. Expertise and cutting edge technology for biomarker measurement and expertise in the development of devices for close-to-patient biomarker measurement. |
Impact | Completion of two randomised controlled trials, manuscripts in progress. |
Start Year | 2017 |
Description | Johns Hopkins Collaboration |
Organisation | Johns Hopkins Medicine |
Department | Johns Hopkins Asthma and Allergy Center |
Country | United States |
Sector | Hospitals |
PI Contribution | One year attachment in laboratory Intellectual Contribution Expertise in clinical trials |
Collaborator Contribution | Training in animal models of cough Intellectual contribution to research training in immunohistochemical nerve staining |
Impact | Multi-disciplinary collaboration between basic science (neurophysiology) and clinician (respiratory medicine) Awarded MRC project grant MR/K015141/1 (studies completed and manuscripts in preparation). Peer reviewed publications: (1) Peter W. West, Brendan J Canning, Emilio Merlo-Pich, Ashley A. Woodcock, Jaclyn A. Smith. Morphological Characterisation of Nerves in Whole Mount Airway Biopsies. Am J Respir Crit Care Med 2015 Jul 1;192(1):30-39 PMID: 25906337 (2) Brendan J Canning, Anne B. Chang, Jaclyn A. Smith, Stuart B. Mazzone, Lorcan McGarvey. Anatomy and Neurophysiology of Cough. Chest Guideline and Expert Panel Report Chest 2014 Dec 1;146(6):1633-48. PMID 25188530 (3) Alyn H. Morice, Adam D. Jakes, Shoaib Faruqi, Surinder S. Birring, Lorcan McGarvey, Brendan Canning, Jaclyn A. Smith, Sean M. Parker, Kian Fan Chung, Kefang Lai, Stuart Mazzone, Ian D. Pavord, Peter Dicpinigaitis. A worldwide survey of chronic cough: A manifestation of enhanced somatosensory response? Eur Respir J. 2014 Nov;44(5):1149-55. PMID 25186267 (4) 50. J.A. Smith, E. Young, L. Saulsberry, B.J. Canning. The anti-tussive effects of memantine in guinea pigs. Chest. 2012 Apr;141(4):996-1002. PMID 22016492 (5) P. Dicpinigaitis, A.H. Morice, S. Birring, L. McGarvey, J.A. Smith, B.J. Canning, C.P. Page. Anti-tussive drugs - past, present and future. Pharmacol Rev. 2014 Mar 26;66(2):468-512. PMID 24671376 |
Start Year | 2009 |
Description | Mathematically modelling of cough clustering |
Organisation | Manchester University |
Country | United States |
Sector | Academic/University |
PI Contribution | Sharing of cough event data from our research database (containing recordings funded by previous grants) |
Collaborator Contribution | Collaborators in mathematics department are modelling of the distribution of coughs in time in different respiratory diseases to look at simialrities and differences between these. |
Impact | Multidisciplinary collaboration between mathematics and medicine. Outputs to dat, one abstract and one paper written and submitted. |
Start Year | 2020 |
Title | Lesogaberan |
Description | Lesogaberan is a GABAb agonist developed for the treatment of gastro-oesophageal reflux disease. In a proof of concept clinical trial we found a 26% reduction in cough frequency over placebo (P=0.1) and a 31% reduction in cough epochs (p<0.05). |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Early clinical assessment |
Year Development Stage Completed | 2018 |
Development Status | Actively seeking support |
Clinical Trial? | Yes |
Impact | The finding that the effect of this therapy has a greater impact on cough epochs compared with individual cough events has caused me to re-evaluate how cough is quantified in clinical studies. We have developed a new collaboration with the school of mathematics to explore novel means to quantify clustering of cough events. |
URL | http://www.isrctn.com/ISRCTN77000698 |
Company Name | MI-TRIAL LIMITED |
Description | Clinical trial companion system and app for scheduling of trial visits and study information. |
Year Established | 2021 |
Impact | None as yet |
Website | https://www.mi-trial.com/ |
Description | 'Body Experience' organised by Manchester Museum |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | We performed lung function testing and played cough sounds to children and their parents attending this event. This provoked discussion about lung symptoms, health and research. Have been invited to participate again next year. |
Year(s) Of Engagement Activity | 2014 |
Description | Annual Public Engagement Event: Combat my Cough |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | 35 patients and the public attend an event consisting of displays, talks and interviews about my research |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.combatmycough.com/events |
Description | Annual public engagement Event 'Combat my Cough' |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | A day event consisting of talks about clinical research, basic research (with collaborators attending from Imperial College London) and also talk by a patient with chronic cough. Also included workshops about clinical and research procedures to exchange knowledge and opinions with patients and a question and answer session. |
Year(s) Of Engagement Activity | 2013,2014,2015,2016,2017,2018 |
URL | https://www.combatmycough.com/events |
Description | Combat my Cough |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Participants in your research and patient groups |
Results and Impact | My team and I gave a series of presentations about our research. A specific question and answer session was held and much discussion with patients about their condition was provoked. Increased patient interest and recruitment to studies. Requests for further similar events. |
Year(s) Of Engagement Activity | 2014 |
URL | http://www.combatmycough.com |
Description | Combat my cough website |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Website describes our clinical service for patients with chronic cough and the research studies we perform. |
Year(s) Of Engagement Activity | 2015,2016,2017 |
URL | https://www.combatmycough.com/ |
Description | Community Science Showcase |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Event for the general public in Manchester based on the university campus. Showcased respiratory research through displays and discussion. |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.manchestersciencefestival.com/event/community-science-showcase/ |
Description | Press release about P2X3 study |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | A press release via NOCRI describing a phase two clinical trial of a novel cough therapy, on which I was chief investigator. Led to further press coverage, a TV interview and numerous enquiries through our website and email about clinical trial participation. |
Year(s) Of Engagement Activity | 2016 |
Description | Tackling Chronic Coughing |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | Regional |
Primary Audience | Participants in your research and patient groups |
Results and Impact | 20 patients attended an talk about the causes of coughing in respiratory disease followed by a 30 minute question and answer session Further engagement event planned for next year |
Year(s) Of Engagement Activity | 2012 |
Description | press release about lancet paper on gefapixant |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Press release descibing the results of two posiive phase 3 trials of the first new therapy for chronic cough, ublished in the Lancet. Story was picked up by several nationl newspapers and resulted in email enquiries about trials from patients and the pharmaceutical industry. |
Year(s) Of Engagement Activity | 2022 |
Description | press release about refunding of CRF |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Press release about £15.5M 5 year funding for NIHR Mancheser CRF, resulted in BBC radio interview |
Year(s) Of Engagement Activity | 2022 |