Endothelial Cell Activation and Total Pulmonary Resistance in PAH

Prior treatment

• Hospital admission related to PAH or change in PAH therapy within 3 months prior to screening
• 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

Other illness

• Hypersensitivity to XBD173 or to any of the excipients
• Individuals known to have haemoglobinopathy sickle cell disease, thalassaemia
• 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
• Patients with a history of uncontrolled systemic hypertension
• Acute infection (including eye, dental, and skin infections)
• Chronic inflammatory disease including HIV, and Hepatitis B

Lab values

• Clinically-significant renal disease (confirmed by creatinine clearance \<30 ml/min per 1.73m2)
• Clinically-significant liver disease (confirmed by serum transaminases \>2 times than upper normal limit)
• Anaemia confirmed by haemoglobin concentration \<10 g/dl
• 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

Other

• Unable to provide informed consent and/or are non-fluent speakers of the English language
• Women of childbearing potential who are pregnant or breastfeeding (if applicable)

• 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