Emapunil for pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH), a rare condition in which the blood vessels of the lungs become narrowed, remains an unmet clinical need. UK national audit data show that patients still die prematurely of right heart failure (40% mortality at 5 years). The currently available treatments help relieve some of the symptoms but none as yet have been shown to change the underlying disease process. The introduction of sotatercept into the UK later next year may improve patient options but it is an injectable with ongoing questions about safety. Neither doctors nor patients consider it to be the final solution for PAH. Many researchers think that a major feature of PAH is mitochondrial dysfunction. Mitochondria are often referred to as the 'powerhouse' of the cell because they provide the cell with energy. The function of mitochondria in cells from PAH patients is impaired. We have identified a drug (emapunil) that binds a protein on mitochondria called The Translocator Protein (TSPO) and improves mitochondrial function in cell and animal models of pulmonary hypertension. TSPO levels are increased in the lungs of patients with PAH. Emapunil has been given to humans but not to patients with PAH. Here we propose using it as a tool compound to provide proof-of-concept that targeting TSPO in PAH reduces pulmonary artery pressure and measures of pulmonary vascular health and right heart workload and may offer a novel approach to treating the condition. There are two main parts to the study. Part 1: We have used positron emission tomography (PET) scanning to demonstrate that emapunil binds to TSPO in the lungs of healthy volunteers when given at a dose we know to be well tolerated. In Part 1 of the study we will use PET scanning to determine the optimal dose regimen (how much and how often emapunil needs to be given) to ensure that it binds to lung TSPO over a 24 hour period. Part 2: Once we have established the dose and dose frequency in Part 1, we will treat a small group of PAH patients with this dose regimen. We will recruit patients from a cohort in the UK with implanted devices (CardioMEMS, to measure pulmonary artery pressure, and LINQ, a heart rate-activity recorder) that report daily physiological measurements remotely. We will treat the patients with emapunil for 6 weeks, and then continue to monitor them for a period after we stop the drug. A beneficial effect that persists after the drug is washed out from the body will provide evidence that the it is modifying the disease. We will also measure glucose uptake by the heart at the end of treatment with emapunil to evaluate how hard the heart is having to work. The study is expected to provide data to encourage follow on investment to take emapunil forward into a larger phase 2 study, with the prospect of developing an orally administered drug with a novel mechanism of action that alters the course of PAH. External capital investment and further development of emapunil as a treatment could be triggered by any one of the following: (i) A dose regimen of emapunil that produced sustained binding of TSPO in the lung; (ii) A clinically significant reduction in resistance to blood flow through the lung; (iii) the demonstration that emapunil reduces right heart workload.