The aim of the study is to investigate whether the cells which line the blood vessels (called "endothelial cells") are involved in the processes which contribute to Pulmonary Arterial Hypertension (PAH). PAH is a rare condition in which a narrowing of blood vessels carrying blood through the lungs puts an increased workload on the heart; it has to work harder to pump blood through the lungs. Previous studies have shown that these "endothelial cells" may be involved in causing this narrowing. We have shown that a particular protein (called TSPO) which is present on these cells, might be involved in this process. The purpose of the study is to use a drug (called XBD173) which targets TSPO, in order to learn how it affects endothelial cells and the blood vessels.

Patients will be invited to participate by their local pulmonary hypertension hospital. Participants will be treated with XBD173 (180mg daily, in three divided doses of 60mg). The total period of treatment for each patient is 6 weeks, followed by 4 weeks follow up off XBD173. If a patient does not tolerate the XBD173 the local PI will determine whether to stop XBD173, reduce the dose to 60mg OD or BD, or pause dosing and restart at 60mg OD or BD. Participants will undergo an echocardiogram and an 18-FDG PET scan of the heart and lung before and after the intervention period.

Doses of 180mg per day (in two doses of 90mg) have been well tolerated in patients with cerebral small vessel disease in another ongoing study (IRAS 339664).

The proposed study will recruit patients with PAH attending specialist clinics that have an approved implanted cardiopulmonary monitor (CardioMEMSTM Heart Failure system) that permits remote sensing. The monitor will have been implanted on clinical grounds. Patients with stable readings for at least a month will be considered for recruitment. These stable readings provide a good baseline from which to measure the effect of the study drug and relate to changes in blood biomarkers.

Remote sensing offers greater oversight of the patient and closer safety monitoring. Remotely acquired patient data are reviewed twice a week via a central clinical team based in Sheffield. Relevant data will be shared as de-identifiable information, and sent to Imperial College London (upon request) as pseudonymised (coded) data if there are any concerns regarding patients' safety. Follow-up would be scheduled by telephone or video conferencing with hospital visits being optional.

The most common side effects reported with XBD173 include nervous system and gastrointestinal symptoms, but the frequencies of these side effects are no higher than placebo.

The end of the study will be the last visit of the last subject.

Inclusion Criteria:

1. Subjects aged between 18-75 years old
2. PAH which is: idiopathic; PAH heritable; PAH associated with connective tissue disease; PAH after ≥ 1 year repair of congenital systemic to pulmonary shunt; or PAH associated with anorexignes or other drugs.
3. Resting mean pulmonary artery pressure ≥25 mmHg, pulmonary capillary wedge pressure ≤15 mmHg, PVR >5 wood units, and normal or reduced cardiac output, as measured by a previous right heart catheterisation (RHC).
4. Have an insertable FDA/CE cardiac rhythm monitor and pulmonary artery pressure monitor that captures cardiopulmonary haemodynamics and daily activity.
5. Six-minute walking distance >50m at entry
6. Stable on an unchanged PAH therapeutic regime comprising at least 2 therapies licensed for PAH (any combination of endothelin receptor antagonist, phosphodiesterase inhibitor or prostacyclin analogue) for at least 1 month prior to screening
7. Subjects willing to be genotyped for genes that influence XBD173 activity
8. Able to provide written informed consent prior to any study mandated procedures
9. Contraception: Fertile females (women of childbearing potential) are eligible to participate after a negative highly sensitive pregnancy test, if they are taking a highly effective method of contraception other than the oral contraceptive pill during treatment and until the end of relevant systemic exposure

Exclusion Criteria:

• 1. Unable to provide informed consent and/or are non-fluent speakers of the English language 2. Hypersensitivity to XBD173 or to any of the excipients 3. Clinically-significant renal disease (confirmed by creatinine clearance <30 ml/min per 1.73m2) 4. Clinically-significant liver disease (confirmed by serum transaminases >2 times than upper normal limit) 5. Anaemia confirmed by haemoglobin concentration <10 g/dl 6. Individuals known to have haemoglobinopathy sickle cell disease, thalassaemia 7. Hospital admission related to PAH or change in PAH therapy within 3 months prior to screening 8. History of left-sided heart disease and/or clinically significant cardiac disease, including but not limited to any of the following:

  1. Aortic or mitral valve disease (stenosis or regurgitation) defined as greater than mild aortic insufficiency, mild aortic stenosis, mild mitral stenosis, moderate mitral regurgitation

  2. Mechanical or bioprosthetic cardiac valve

  3. Pericardial constriction, effusion with tamponade physiology, or abnormal left atrial size.

  4. Restrictive or congestive cardiomyopathy

  5. Left ventricular ejection fraction ≤50% (measured in echocardiogram at screening)

  6. Symptomatic coronary disease

  7. Significant (2+ for regurgitation) valvular disease other than tricuspid or pulmonary regurgitation

  8. Acutely decompensated left heart failure within 1 month of screening

  9. History of untreated obstructive sleep apnoea 9. Evidence of significant lung disease on high-resolution CT (if available) or recent (performed within 12 months) lung function, where FEV1 < 50% predicted and FVC < 70% predicted, and DLCO (or TLCO) < 50% predicted if any CT abnormalities; judged by the Site Physician 10. Patients with a history of uncontrolled systemic hypertension 11. Acute infection (including eye, dental, and skin infections) 12. Chronic inflammatory disease including HIV, and Hepatitis B 13. Women of childbearing potential who are pregnant or breastfeeding (if applicable) 14. Patients who have received an Investigational Medicinal Product (IMP) within 5 half-lives of the last dose of the IMP or 1 month (which ever is greater) before the baseline visit 15. Use of the following medications or therapies:

     • Severe and moderate P450 CY3A4 inhibitors: Boceprevir, Clarithromycin, Cobicistat, Idelalisib, Itraconazole, Ketoconazole, Nelfinavir, Ritonavir, Saquinavir, Telaprevir, Telithromycin, Voriconazoleb, Aprepitant, Conivaptan, Crizotinib, Diltiazem, Dronedarone, Erythromycin, Fluconazole, Imatinib, Isavuconazole, Nefazodone, Netupitant, Nilotinib, Posaconazolee, Tofisopam, Verapamil, Delavirdine.
     • Severe and moderate P450 CY3A4 inducers: Carbamazepine, Enzalutamide, Fosphenytoin, Mitotane, Phenytoin, Rifampicin, Bosentan, Efavirenz, St John's wort, Barbiturates, Nevirapine, Primidone, Rifabutin, Rifapentine.
     • Oral contraceptives
     • Oral anticoagulants or antiplatelet agents other than low dose aspirin