A Study of Sotatercept in Participants With PAH WHO FC III or FC IV at High Risk of Mortality

Open to people ages 18-75

Eligible participants must meet all of the following inclusion criteria to be enrolled in the study:

1. Age 18 to 75 years, inclusive
2. Documented diagnostic right heart catheterization prior to screening confirming the diagnosis of WHO PAH Group 1 in any of the following subtypes:
3. Idiopathic PAH
4. Heritable PAH
5. Drug/toxin-induced PAH
6. PAH associated with CTD
7. PAH associated with simple, congenital systemic to pulmonary shunts at least 1 year following repair
8. Symptomatic PAH classified as WHO FC III or IV
9. REVEAL Lite 2 risk score of ≥ 10
10. Right heart catheterization performed during screening (or within 2 weeks prior to screening, if done at the clinical study site) documenting a minimum PVR of ≥ 5 Wood units and a pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure (LVEDP) of ≤ 15 mmHg
11. Clinically stable and on stable doses of maximum tolerated (per investigator's judgment) double or triple background PAH therapies for at least 30 days prior to screening
12. Females of childbearing potential must:
13. Have 2 negative urine or serum pregnancy tests as verified by the investigator prior to starting study therapy; must agree to ongoing urine or serum pregnancy testing during the course of the study and until 8 weeks after the last dose of the study drug
14. If sexually active, have used, and agree to use highly effective contraception without interruption; for at least 28 days prior to starting the investigational product, during the study (including dose interruptions), and for 16 weeks (112 days) after discontinuation of study treatment
15. Refrain from breastfeeding a child or donating blood, eggs, or ovum for the duration of the study and for at least 16 weeks (112 days) after the last dose of study treatment
16. Male participants must:
17. Agree to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (e.g., polyurethane), during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions, and for at least 16 weeks (112 days) following investigational product discontinuation, even if he has undergone a successful vasectomy
18. Refrain from donating blood or sperm for the duration of the study and for 16 weeks (112 days) after the last dose of study treatment
19. Ability to adhere to study visit schedule and understand and comply with all protocol requirements
20. . Ability to understand and provide written informed consent

1. Diagnosis of PAH WHO Groups 2, 3, 4, or 5
2. Diagnosis of the following PAH Group 1 subtypes: human immunodeficiency virus-associated PAH and PAH associated with portal hypertension
3. Diagnosis of pulmonary veno-occlusive diseases or pulmonary capillary hemangiomatosis or overt signs of capillary and/or venous involvement
4. Hemoglobin at screening above gender-specific upper limit of normal (ULN), per local laboratory test
5. Baseline platelet count < 50,000/mm3 (< 50.0 x 109/L) at screening
6. Baseline systolic blood pressure < 85 mmHg at screening
7. Pregnant or breastfeeding women
8. Any of the following clinical laboratory values at the Screening Visit:
9. Estimated glomerular filtration rate < 30 mL/min/m2 (as defined by the Modification of Diet in Renal Disease Study equation)
10. Serum alanine aminotransferase or aspartate aminotransferase levels > 3 × ULN or total bilirubin > 2.0 × ULN
11. Currently enrolled in or have completed any other investigational product study within 30 days for small molecule drugs or within 5 half-lives for biologics prior to the date of signed informed consent
12. . Prior exposure to or known allergic reaction to sotatercept (ACE 011) or luspatercept (ACE-536)
13. . History of pneumonectomy
14. . Pulmonary function test values of forced vital capacity < 60% predicted within 1 year prior to the Screening Visit
15. . Untreated obstructive sleep apnea
16. . History of known pericardial constriction
17. . History of restrictive or congestive cardiomyopathy
18. . Electrocardiogram (ECG) with Fridericia's corrected QT interval (QTcF) > 450 ms (or > 500 ms if right bundle branch block is present) during the Screening Period
19. . Personal or family history of long QT syndrome or sudden cardiac death
20. . Left ventricular ejection fraction < 50% on historical echocardiogram within 1 year prior to the Screening Visit
21. . Any current or prior history of symptomatic coronary disease (prior myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or cardiac anginal chest pain) in the past 6 months prior to the Screening Visit
22. . Cerebrovascular accident within 3 months prior to the Screening Visit
23. . Significant (≥ 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular disease