Stratified adaptive therapeutic studies in pulmonary arterial hypertension caused by mutations in BMPR2

Lead Research Organisation: University of Cambridge
Department Name: Medicine

Abstract

Pulmonary arterial hypertension is a devastating life-limiting disease more likely to affect young women. Patients face daily symptoms, an early death and potentially lung transplantation. 1 in 4 patients has a genetic form of the disease. Treatments do not address the underlying genetic cause of the disease yet. We propose the first ever trial of treatments aimed at the genetic form of the disease, mutations in a protein called the bone morphogenetic type 2 receptor, using 2 drugs that have shown promise in improving function in cells taken from patients and in animal models; hydroxychloroquine and phenylbutyrate. We have only been able to do this because of previous investment by the MRC and British Heart Foundation in the world's biggest genetic studies in pulmonary arterial hypertension that have identified patients in the UK who might benefit from the treatments. The trial uses a new way of assigning drugs to patients-an adaptive design. As the trial progresses if either drug is showing a bigger effect, the trial will "adapt" to this new information by increasing the proportion of patients who get the drug. This will allow the team to test more than one drug at a time but concentrate on drugs that are having bigger effects. The trial will be available all across the UK running from all 7 of the nationally accredited pulmonary hypertension centres.

Technical Summary

Pulmonary arterial hypertension (PAH) is a life-threatening disease with no current cure. Patients are classically diagnosed young, face life-long invasive and costly treatments including continuous intravenous infusions and eventually lung transplantation. In the UK, 5-year mortality is stuck at 57%. Current treatment approaches address the consequences, not the causes of disease. Transforming outcomes in PAH will require approaches that better stratify aetiology of this heterogeneous disease. The most pertinent aetiology of PAH ready for this approach is the genetic form of the disease, mutations in the bone morphogenetic protein type-2 receptor (BMPR2). Mutations in this single pathway cause 29% of all cases of idiopathic and familial PAH and have additionally been strongly implicated in other forms of PAH. There are currently no therapies developed that target the BMPR2 pathway. We propose to address this by undertaking randomised placebo-controlled trials (RCTs) in preclinically validated and repurposed therapies demonstrated in human and animal models to rescue BMPR2 function and reverse disease; hydroxychloroquine and phenylbutyrate. We will address this by means of a novel Bayesian stratified response-adaptive trial design which is aimed at providing a personalised approach to treatment. Utilising a multi-stage design, we will first define the optimum biomarkers of BMPR2 target engagement, and subsequently conduct a multiple-arm phase 2a RCT testing the hypothesis that BMPR2 dysfunction can be reversed and has potential for disease modification.

Planned Impact

This research is the first trial designed to treat the underlying cause of a rare but devastating genetic form of pulmonary arterial hypertension. Pulmonary arterial hypertension a form of high blood pressure in the lungs that leads to heart failure and early death or lung transplantation. NEEDS MORE WORK

Publications

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Description HElping Alleviate the Longer-term consequences of COVID-19 (HEAL-COVID): a national platform trial
Amount $3,583,669 (USD)
Funding ID NIHR133788 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 02/2021 
End 01/2024
 
Description Positioning Imatinib for Pulmonary Arterial Hypertension
Amount £1,232,879 (GBP)
Funding ID NIHR128465 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 02/2020 
End 01/2024
 
Title Biomarker for target engagement of BMPR pathway 
Description Stage 1 of the Stratosphere grant had an aim of defining a methodology for measuring BMPR2 pathway activation in participants from peripheral blood. We have designed a panel of 8 mRNA targets in canonical and non-canonical BMPR2 and validated their repeatability, reproducibility and longitudinal stability in 2 disease cohorts. We are now in the process of setting up an adaptive clinical trial that utilises this biomarker panel as the primary endpoint to demonstrate target engagement in a pulmonary arterial hypertension CTIMP. 
Type Of Material Technology assay or reagent 
Year Produced 2022 
Provided To Others? No  
Impact The work has informed and defined the primary endpoint for an early phase clinical trial in pulmonary arterial hypertension. 
 
Description Setting up of the world's first national pulmonary hypertension experimental medicine network- UniPHy National Clinical Trials Network 
Organisation British Transplantation Society (BTS)
Department Clinical Trials Network
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution I am the inaugural chair of the only formal experimental medicine network in the world to have direct membership from all specialist centres (and in fact the only formal national network anywhere of this kind). The Stratosphere grant helped catalyse this and has led to 2 further NIHR (PIPAH) and MRC awards (currently under embargo).
Collaborator Contribution The 7 national specialist centres have constituted and run the network (Glasgow, Newcastle, Sheffield, Cambridge and 3 centres in London).
Impact Mendelian randomisation and experimental medicine approaches to IL-6 as a drug target in PAH. Toshner M, Church C, Harbaum L, Rhodes C, Villar Moreschi SS, Liley J, Jones R, Arora A, Batai K, Desai AA, Coghlan JG, Gibbs JSR, Gor D, Gräf S, Harlow L, Hernandez-Sanchez J, Howard LS, Humbert M, Karnes J, Kiely DG, Kittles R, Knightbridge E, Lam B, Lutz KA, Nichols WC, Pauciulo MW, Pepke-Zaba J, Suntharalingam J, Soubrier F, Trembath RC, Schwantes-An TL, Wort SJ, Wilkins M, Gaine S, Morrell NW, Corris PA. Eur Respir J. 2021 Sep 29:2002463. doi: 10.1183/13993003.02463-2020. Online ahead of print. PMID: 34588193
Start Year 2021
 
Description International patient survey 
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 As the global co-chair of the Pulmonary Vascular Research Institute IDDI, I set up a working group on patient engagement that has now delivered the world's first ever global patient survey covering over 100 questions focussed on clinical care and research. To date it has over 3500 responses, in 17 languages and all continents.
Year(s) Of Engagement Activity 2024
URL https://pvrinstitute.org/en/professionals/news/2023/9/25/pulmonary-hypertension-global-patient-surve...
 
Description Patient group workshop with UK Pulmonary Hypertension Association 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact We have set up a new PPI/E initiative to understand patients views on clinical trial design and conduct and to move towards co-developed endpoints and trial designs. This is through both working groups and a more extensive set of surveys that are still in progress.
Year(s) Of Engagement Activity 2021,2022
 
Description Patient online survey in clinical trials https://www.phauk.org/clinical-trials-what-matters-to-you/ 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact In collaboration with the UKs largest patient organisation (the PHA-UK) we organised the largest UK pulmonary hypertension engagement exercise in clinical trials
Year(s) Of Engagement Activity 2022,2023
URL https://www.phauk.org/clinical-trials-what-matters-to-you/
 
Description We have established a new independent patient group focussed on PPI/E and clinic trials design. This is related to a larger body of work with the Pulmonary Hypertension Association 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Through an advertising campaign in collaboration with the PHA we set up an entirely independent new group of patients and carers to focus on engagement and involvement in clinical trial design and conduct. This fitted alongside a much wider Stratosphere-specific piece of PPI/E but also interacts with the National Experimental Clinical Trials Network (UNIPHY).
Year(s) Of Engagement Activity 2021