This proof-of-concept study is designed as a Phase 2, multicenter, randomized, double-blind, placebo controlled study comparing ubenimex with placebo in patients with pulmonary arterial hypertension (PAH) (World Health Organization [WHO] Group 1) and have a WHO/New York Heart Association (NYHA) Functional Classification (WHO/NYHA-FC) of II or III.

Ubenimex is being developed for the treatment of PAH (WHO Group 1) to improve exercise capacity and delay clinical worsening. This proof-of-concept study is designed as a Phase 2, multicenter, randomized, double-blind, placebo controlled study comparing ubenimex with placebo in patients with PAH (WHO Group 1) and have a WHO/NYHA Functional Classification (WHO/NYHA-FC) of II or III. The Primary Objectives for the study are:

• To evaluate the efficacy of ubenimex in patients with PAH (WHO Group 1).
• To evaluate the safety and tolerability of ubenimex in patients with WHO Group 1 PAH.

Inclusion Criteria:

1. Male or female, 18-75 years old.

2. Has a diagnosis of WHO Group 1 PAH.

3. Right heart catheterization performed at Screening with results that are:

   1. Mean pulmonary arterial pressure ≥25 mmHg (at rest) and
   2. Pulmonary venous hypertension (measured as pulmonary capillary wedge pressure (PCWP) ≤15 mmHg. If PCWP is not available, then mean left atrial pressure or left ventricular end-diastolic pressure ≤15 mmHg in the absence of left atrial obstruction. and
   3. Pulmonary vascular resistance (PVR) ≥300 dyn•s/cm5 (3.75 Wood units)

4. Has WHO/NYHA-FC of II or III.

5. Be on stable dose of at least one of the following PAH-specific therapies: endothelin receptor antagonist, an agent acting on the nitric oxide pathway (phosphodiesterase type 5 inhibitor or soluble guanylate cyclase stimulator), and/or a prostacyclin or prostacyclin analog.

6. Has a 6-minute walk distance that is ≥150 and ≤500 meters.

7. Have a ventilation-perfusion scan that rules out thromboembolic disease.

Exclusion Criteria:

Exclusions Related to Cardiovascular Disease

1. History of uncontrolled hypertension

2. Persistent hypotension at Screening.

3. Evidence or history of left-sided heart disease and/or clinically significant cardiac disease in which pulmonary hypertension is more likely WHO Group 2.

4. Acute decompensated heart failure within 1 month of Screening.

5. Recent initiation (<8 weeks from Screening) or planned initiation of cardiopulmonary rehabilitation exercise program.

   Exclusions Related to Pulmonary Disease

6. Newly diagnosed with PAH and not on PAH-specific therapy.

7. Pulmonary hypertension due to:

   1. Uncorrected congenital systemic-to-pulmonary shunt.
   2. Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis
   3. Persistent pulmonary hypertension of the newborn
   4. WHO clinical classification Groups 2-5

8. Evidence of significant airway and/or parenchymal lung disease.

9. Chronic infection related to tuberculosis or fungal or mycobacterial disease.

   Exclusions Based on Other Medical Conditions

10. Chronic infections including, but not limited to tuberculosis (TB), hepatitis B virus (HBV) or hepatitis C virus (HCV).

11. History of portal hypertension or chronic liver disease, including positive serology for infection with HCV and/or HBV.

12. Evidence of active infection requiring intravenous or oral antibiotics within 4 weeks of Screening.

13. Body mass index ≥35.0 at Screening.

14. History of obstructive sleep apnea.

15. History of malignancy within the last 5 years, except nonmelanoma skin cancer and cervical carcinoma in situ treated with curative intent.

16. Neuropsychiatric disorders/symptoms or psychological conditions.

17. Pregnancy or breast-feeding

18. Prior treatment with B cell or lymphocyte-depleting agents (eg, rituximab, Campath)

    Exclusions Based on Concomitant Medication Use

19. Concurrent regular use of another leukotriene pathway inhibitor, including over-the-counter medications or herbal remedies.

    Exclusions Based on Laboratory Values

20. Significant/chronic renal insufficiency.

21. Transaminases (alanine transaminase, aspartate transaminase) levels >3 × upper limit of normal (ULN) and/or bilirubin level >2 × ULN.

22. Absolute neutrophil count <1500 mm3.

23. Hemoglobin concentration <9 g/dL at Screening.

24. Hepatic dysfunction as defined by Child-Pugh Class B or C