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

Lead Research Organisation: University of Cambridge
Department Name: Medicine


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


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