TSPO Endothelial - EMPATHY

Inclusion criteria

• Subjects aged between 18-75 years old
• 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.
• 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).
• Have an insertable FDA/CE cardiac rhythm monitor and pulmonary artery pressure monitor that captures cardiopulmonary haemodynamics and daily activity.
• Six-minute walking distance >50m at entry
• 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
• Subjects willing to be genotyped for genes that influence XBD173 activity
• Able to provide written informed consent prior to any study mandated procedures
• 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:

• Aortic or mitral valve disease (stenosis or regurgitation) defined as greater than mild aortic insufficiency, mild aortic stenosis, mild mitral stenosis, moderate mitral regurgitation
• Mechanical or bioprosthetic cardiac valve
• Pericardial constriction, effusion with tamponade physiology, or abnormal left atrial size.
• Restrictive or congestive cardiomyopathy
• Left ventricular ejection fraction ≤50% (measured in echocardiogram at screening)
• Symptomatic coronary disease
• Significant (2+ for regurgitation) valvular disease other than tricuspid or pulmonary regurgitation
• Acutely decompensated left heart failure within 1 month of screening
• 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