Tiprelestat Versus Placebo When Added to Standard of Care for the Treatment of Pulmonary Arterial Hypertension (PAH)

1. Adults age 18 to 75 years.
2. Willingness to give written informed consent prior to any study-related procedures being performed and to be able to adhere to the study restrictions and examination schedule.
3. Diagnosis of WHO Group I PAH.
4. WHO functional class II - IV despite optimized treatment SOC, with 1 or more modalities including phosphodiesterase 5 (PDE5) inhibitor, soluble guanylate cyclase stimulator (sGCS), endothelin receptor antagonist (ERA), and/or a prostacyclin analogue or receptor agonist (SC/inhaled/PO) (see #5), as well as Sotatercept (see #6).
5. On stable doses of PDE5 inhibitor, ERA, sGCS, or prostacyclin analogue/receptor agonist for at least 90 days prior to screening; for infusion prostacyclins, dose adjustment within 10% of baseline dose during the duration of the study is allowed per medical practice.
6. On stable doses of Sotatercept therapy for at least 6 months prior to screening, and intended to be continued during the duration of the study.
7. Screening right heart catheterization mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg at rest; pulmonary wedge pressure (PAWP) ≤ 15 mmHg or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg; AND pulmonary vascular resistance (PVR) ≥ 400 dynes•sec/cm5 (5 Wood Units).
8. If participant is of childbearing potential, willing to use adequate methods of contraception throughout the course of the study. If participant is of childbearing potential (a participant \< 55 years of age who has not been postmenopausal for ≥ 5 years or who has not had a bilateral salpingectomy, hysterectomy and/or oophorectomy), need to employ two reliable means of contraception which may include surgical sterilization, barrier methods, spermicidals, intrauterine devices, and/or hormonal contraception, unless the participant chooses abstinence (to avoid heterosexual intercourse completely). If a participant chooses abstinence, then a second reliable means of contraception is not needed.
9. 6MWD ≥100 and ≤500 meters at screening.
10. Willing to adhere to study restrictions and examination schedule.

Exclusion Criteria:

1. Diagnosis of WHO Group 2 - 5 Pulmonary Hypertension.
2. Participation in another clinical trial, or experimental use, involving a PAH investigational drug or device within the last 3 months.
3. Total lung capacity (TLC) \< 60% predicted; if TLC is ≥ 60% and \< 70% predicted, high resolution computed tomography (HRCT) must be available to exclude significant interstitial lung disease.
4. FEV1 / FVC \< 70% predicted and FEV1 \< 60% predicted.

5. Significant left-sided heart disease (based on screening Echocardiogram):

   1. Moderate or severe aortic or mitral valve disease
   2. Diastolic dysfunction ≥ Grade II
   3. LV systolic function \< 45%
   4. Pericardial constriction
   5. Restrictive cardiomyopathy
   6. Significant coronary disease with demonstrable ischemia
6. Chronic renal insufficiency defined as an estimated creatinine clearance \< 30 ml/min.
7. Current atrial arrhythmias not under optimal control.
8. Uncontrolled systemic hypertension: SBP > 160 mmHg or DBP > 100mmHg.
9. Severe hypotension: SBP \< 80 mmHg.
10. Pregnant or breast-feeding.
11. Psychiatric, addictive, or other disorders that compromise the patient's ability to provide informed consent, to follow study protocol, and adhere to treatment instructions.
12. Known allergy or hypersensitivity to tiprelestat.
13. Moderate to severe hepatic dysfunction with a Child Pugh score >10.
14. Hyperkalemia defined as Potassium > 5.1 mEq/L at screening.
15. Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days prior to screening or planned during the study. Subjects who are already stable in the maintenance phase of an exercise program which will continue for the duration of the study are eligible.
16. Known active infection requiring antibiotic, antifungal, or antiviral therapies. Patients may be rescreened at physician discretion after the resolution of infection and discontinuation of antibiotic, antifungal, or antiviral therapies.
17. Co-morbid conditions that would impair a patient's exercise performance and ability to assess WHO functional class, including but not limited to chronic low-back pain or peripheral musculoskeletal problems, other comorbidities expected to alter the patient's clinical course (i.e. active cancer; >3 comorbidities e.g., obesity, systemic HTN, diabetes).