A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Compare the Efficacy and Safety of Sotatercept Versus Placebo When Added to Background Pulmonary Arterial Hypertension (PAH) Therapy for the Treatment of PAH

1. Age >= 18 years
2. Documented diagnostic right heart catheterization (RHC) at any time prior to
screening confirming the diagnosis of WHO PAH Group 1 in any of the following
subtypes:
• Idiopathic PAH
• Heritable PAH
• Drug/toxin-induced PAH
• PAH associated with CTD
• PAH associated with simple, congenital systemic-to-pulmonary shunts at least
1 year following repair
3. Symptomatic pulmonary hypertension classified as WHO FC II or III
4. Baseline RHC performed during the Screening Period documenting a minimum PVR
of >= 5 Wood units (WU) and a pulmonary capillary wedge pressure (PCWP) or left
ventricular end-diastolic pressure of <= 15 mmHg.
5. At stable doses of background PAH therapy and diuretics (i.e.,
patientspecific dose goal for each therapy already achieved) for at least 90
days prior to screening; for infusion prostacyclins, dose adjustment within 10%
of optimal dose is allowed per medical practice.
6. 6MWD >= 150 and <= 500 m repeated twice at screening (measured at least 4
hours apart, but no longer than 1 week), and both values are within 15% of each
other (calculated from the highest value)
7. Females of childbearing potential must:
• Have 2 negative urine or serum pregnancy tests as verified by the
investigator prior to starting study drug administration; she must agree to
ongoing pregnancy testing during the course of the study and until 8 weeks
after the last dose of the study drug
• 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
• 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
8. Male participants must:
• Agree to use a condom, defined as a male latex condom or non-latex 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
• Refrain from donating blood or sperm for the duration of the study and for
112 days (112 days) after the last dose of study treatment
9. Ability to adhere to study visit schedule and understand and comply with all
protocol requirements
10. Ability to understand and provide written informed consent

1. Diagnosis of pulmonary hypertension WHO Groups 2, 3, 4, or 5
2. Diagnosis of the following PAH Group 1 subtypes: human immunodeficiency
virus (HIV)-associated PAH and PAH associated with portal hypertension.
Exclusions in PAH Group I should also include schistosomiasis associated PAH
and pulmonary veno-occlusive disease
3. Hemoglobin (Hgb) at screening above gender-specific upper limit of normal,
per local laboratory test
4. Baseline platelet count < 50,000/mm3 (< 50.0 × 109/L) at screening
5. Uncontrolled systemic hypertension as evidenced by sitting systolic blood
pressure (BP) > 160 mmHg or sitting diastolic blood pressure > 100 mmHg
during screening visit after a period of rest
6. Baseline systolic blood pressure < 90 mmHg at screening
7. Pregnant or breastfeeding women
8. Any of the following clinical laboratory values at the screening visit:
• eGFR < 30 mL/min/m2 (as defined by the Modification of Diet in Renal Disease
[MDRD] equation)
• Serum alanine aminotransferase, aspartate aminotransferase levels or total
bilirubin > 3 × ULN (bilirubin criterion waived if there is a documented
history of Gilbert*s syndrome)
9. Currently enrolled in or have completed any other investigational product
study within 30 days for small-molecule drugs or within 5 halflives for
biologics prior to the date of signed informed consent
10. Prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536) or known
allergic reaction to either one
11. History of full pneumonectomy
12. Pulmonary function test (PFT) values of forced vital capacity (FVC) <
60% predicted at the screening visit or within 6 months prior to the screening
visit. If PFT is not available, a chest CT scan showing more than mild
interstitial lung disease at the screening visit or 1 years prior to it
13. Initiation of an exercise program for cardiopulmonary rehabilitation within
90 days prior to the screening visit or planned initiation during the study
(participants who are stable in the maintenance phase of a program and who will
continue for the duration of the study are eligible)
14. History of more than mild obstructive sleep apnea that is untreated
15. Known history of portal hypertension or chronic liver disease, including
hepatitis B and/or hepatitis C (with evidence of recent
infection and/or active virus replication), defined as mild to severe hepatic
impairment (Child-Pugh Class A-C).
16. History of restrictive, constrictive or congestive cardiomyopathy
17. History of atrial septostomy within 180 days prior to the screening visit
18 Electrocardiogram (ECG) with Fridericia's corrected QT interval (QTcF) >500
ms during Screening Period.
19 Personal or family history of long QT syndrome (LQTS) or sudden cardiac death
20Left ventricular ejection fraction (LVEF) < 45% on historical ECHO
within 6 months 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. Note: Anginal pain can be ignored as an exclusion
criterion if coronary angiography shows no obstructions
22 Cerebrovascular accident within 3 months prior to the screening visit
23 Acutely decompensated heart failure within 30 days prior to the screening
visit, as per investigator assessment
24 Significant (>= 2+ regurgitation) mitral regurgitation or aortic
regurgitation valvular disease.
25 Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine,
vasopressin) within 30 days prior to the screening visit.