A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension

Inclusion Criteria

• Age ≥ 18 years
• Documented findings on RHC at any time prior to Screening consistent with a diagnosis of World Health Organization (WHO) pulmonary hypertension Group 1: PAH of any of the following subtypes:
• Idiopathic PAH
• Heritable PAH
• Drug- or toxin-induced PAH
• PAH associated with connective tissue disease
• PAH associated with simple, congenital systemic-to-pulmonary shunts at least 1 year following shunt repair
• Symptomatic pulmonary hypertension classified as WHO functional class III
• Screening RHC documenting a minimum PVR of ≥ 4 Wood units
• Pulmonary function tests within 6 months prior to Screening as follows:
• Total lung capacity > 70% predicted; or if between 60% to 70% predicted, or not possible to be determined, confirmatory high-resolution computed tomography (CT) indicating no more than mild interstitial lung disease per investigator interpretation or
• Forced expiratory volume (first second) (FEV1)/forced vital capacity (FVC) > 70% predicted
• For subjects with a history of lobectomy or pneumonectomy, and for whom there are no population-based normalization methods, assessment based on residual lung volume will be permitted to assess eligibility.
• Ventilation-perfusion (VQ) scan (or, if unavailable, a negative CT pulmonary angiogram [CTPA] or pulmonary angiography result), any time prior to Screening or conducted during Screening Period with normal or low probability result
• 6MWD ≥ 100 and ≤ 550 meters repeated twice during Screening Period and both values within 15% of each other, calculated from the highest value
• Combination PAH therapy at stable (per investigator) dose levels for at least 90 days prior to Cycle 1 Day 1 (C1D1)

Exclusion Criteria

Participants will be excluded from the study if they meet any of the following criteria:

• Started or stopped receiving any general supportive therapy for pulmonary hypertension (e.g., diuretics, oxygen, anticoagulants, digoxin) within 60 days prior to C1D1 (Cycle 1 Day 1)
• Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, vasopressin) within 30 days prior to C1D1
• History of atrial septostomy within 180 days prior to Screening
• History of more than mild obstructive sleep apnea that is untreated
• History of portal hypertension or chronic liver disease, defined as mild to severe hepatic impairment (Child-Pugh Classes A to C)
• History of human immunodeficiency virus infection-associated PAH
• Prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536)
• Uncontrolled systemic hypertension as evidenced by sitting systolic BP > 160 mm Hg or sitting diastolic BP > 100 mm Hg during Screening after a period of rest
• Systolic BP 480 msec during Screening or C1D1
• History of personal or family history of long QTc syndrome or sudden cardiac death
• History of restrictive or constrictive cardiomyopathy
• Left ventricular ejection fraction 15 mm Hg on RHC during baseline evaluation
• Any current symptomatic coronary disease (myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or cardiac anginal chest pain in the past 6 months prior to Screening)
• Acutely decompensated heart failure within 30 days prior to C1D1, as per investigator assessment
• Significant (≥ 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular disease