A Dose-escalation Study in Subjects With Pulmonary Arterial Hypertension (PAH)

GSK2586881, a purified intravenous (IV) formulation of soluble recombinant human Angiotensin Converting Enzyme (rhACE2) is being investigated as a treatment for PAH. This GlaxoSmithKline (GSK) study will evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of GSK2586881 in subjects with PAH. This open-label, dose-escalation study will comprise of 4 separate groups based on the planned dose range, and subjects in each group will be administered a single dose of GSK2586881 ranging between 0.1, 0.2, 0.4 and 0.8 milligram per kilogram (mg/kg) via IV route. Dose escalation will occur after 4 subjects have been dosed per cohort and review of safety, tolerability, PK and hemodynamic data up to 24 hours post dose has taken place. A maximum of 27 subjects will be included in the study and the total duration of the study will be up to a maximum of 59 days.


Eligibility Criteria:
Inclusion Criteria

* Subjects must be between 18-75 years of age (inclusive), at the time of signing the informed consent.
* Documented diagnosis of PAH, defined as mPAP \> 25 millimeter of mercury (mmHg) and pulmonary wedge pressure (PWP) \<= 15.
* Idiopathic PAH (IPAH), Hereditary PAH (HPAH), or PAH associated with collagen vascular disease, or appetite suppressant use.
* World Health Organization (WHO) functional class I, II, or III, stable for at least 8 weeks prior to enrollment.
* Hemodynamically stable on background therapy with no evidence of uncontrolled right heart failure (historic data), as determined by the investigator.
* Six minute walk (6MW) distance, as performed at screening or within 6 months prior to screening, of \>= 100 meters (m) and \<= 500 m.
* Mean BP of \>60 mmHg.
* Receiving stable doses of one or more medications that are approved for treatment of PAH, including endothelin receptor antagonists, phosphodiesterase 5 inhibitors, and/or prostanoids/prostacyclin receptor agonists, for a minimum of 12 consecutive weeks before enrollment.
* Diuretic dose stable for 8 weeks.
* Body weight \<= 100 kg and body mass index (BMI) within the range 18-35 kg per m square (kg/m\^2) (inclusive).
* Male and/or female (following confirmation of negative pregnancy test for Women of Childbearing Potential \[WOCBP\]). Women who are pregnant or breastfeeding are excluded.
* Capable of giving signed informed consent.

Exclusion Criteria

* History of systemic hypotension, defined as systolic BP \<90 mmHg and/or diastolic BP \<50 mmHg.
* Hospitalization for PAH associated deterioration in the previous 6 months.
* Any additional medical condition, serious intercurrent illness, or other extenuating circumstance that, in the opinion of the Investigator, may significantly interfere with study compliance, including all prescribed evaluations and follow-up activities. Concurrent disease or condition that may interfere with study participation or safety include bleeding disorders, arrhythmia, organ transplant, organ failure, current neoplasm, poorly controlled diabetes mellitus, and serious neurological disorders.
* Complex repaired and unrepaired congenital heart disease.
* Subjects with Eisenmenger physiology.
* Alanine transferase (ALT) \>2x upper limit of normal (ULN).
* Bilirubin \>1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35 percent).
* Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
* Estimated glomerular-filtration-rate (eGFR) \<45 milliliter per minute per 1.73 meter square (mL/min/1.73m\^2).
* QTc \>480 millisecond (msec) or QTc \> 500 msec in subjects with bundle branch block.
* Any bleeding concerns as evidenced by International normalized ratio (INR) \>1.5 (in subjects not receiving anticoagulation therapy) or platelet count \<80,000.
* Hemoglobin (Hb) \<10 gram per deciliter (g/dL).
* Sensitivity to any of the study treatments, or components thereof, or drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates participation in the study.
* Any use of an Angiotensin-converting enzyme (ACE) inhibitor or Angiotensin receptor blocker or renin inhibitors within 14 days prior to dosing. Therapy can be stopped to enable inclusion if deemed safe by the subject's treating physician.
* Use of any investigational product (IP) or device within 30 days prior to dosing, or known requirement for any investigational agent prior to completion of all scheduled study assessments.
* Positive human immunodeficiency virus (HIV) antibody test.
* Presence of Hepatitis B surface antigen (HBsAg) at screening.
* Positive Hepatitis C antibody test result at screening or within 3 months prior to starting study treatment.
* Positive Hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose of study treatment.
* Participation in the study would result in loss of blood or blood products in excess of 300mL within 65 days.
* Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
* A known or suspected history of alcohol or drug abuse within the 2 years prior to screening.
* Unable to refrain from smoking during the in-house treatment period.