A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (PAH)

This is a Phase 2, double blind, randomized, placebo-controlled, parallel-group study of
sotatercept plus SOC versus placebo plus SOC in participants with PAH of WHO Group 1,
functional class II-III.

Participants will be randomly assigned in a 3:3:4 ratio to receive placebo every 21 days,
sotatercept 0.3 mg/kg subcutaneously (SC) every 21 days, or sotatercept 0.7 mg/kg SC every 21
days, for a period of 24 weeks in the Placebo-Controlled Treatment Period of the study while
on standard of care therapy. Evaluations will include changes in pulmonary vascular
resistance (PVR), six-minute-walk distance (6MWD), quality of life questionnaires,
echocardiographic parameters, and safety. Participants who have not discontinued early from
the Placebo-Controlled Treatment Period and have had their post-Treatment Period PVR
assessment will be able to continue into the 18-month Extension Period in which
sotatercept-treated participants will receive their latest dose level of sotatercept SC every
21 days and placebo-treated participants willbe re-randomized 1:1 to receive sotatercept 0.3
mg/kg SC every 21 days or sotatercept 0.7 mg/kg SC every 21 days while on standard of care
therapy.

Inclusion Criteria:

1. Age ≥ 18 years

2. Documented diagnostic right heart catheterization (RHC) at any time prior to Screening
confirming diagnosis of WHO diagnostic pulmonary hypertension Group I: PAH in any of
the following subtypes:

- Idiopathic

- 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

3. Symptomatic pulmonary hypertension classified as WHO functional class II or III

4. Screening RHC documenting a minimum PVR of ≥ 400 dyn·sec/cm5 (5 Wood units)

5. Pulmonary function tests (PFTs) within 6 months prior to Screening as follows:

1. Total lung capacity (TLC) > 70% predicted; or if between 60 to70% predicted, or
not possible to be determined, confirmatory high-resolution computed tomography
(CT) indicating no more than mild interstitial lung disease (ILD), per
investigator interpretation, or

2. Forced expiratory volume (first second) (FEV1)/ forced vital capacity (FVC) > 70%
predicted

6. Ventilation-perfusion (VQ) scan (or, if unavailable a negative CT pulmonary angiogram
[CTPA] result, or pulmonary angiography result), any time prior to Screening Visit or
conducted during the Screening Period, with normal or low probability result),

7. No contraindication per investigator for RHC during the study

8. 6MWD ≥ 150 and ≤ 550 meters repeated twice at Screening and both values within 15% of
each other, calculated from the highest value

9. PAH therapy at stable (per investigator) dose levels of SOC therapies

Exclusion Criteria:

1. Stopped receiving any pulmonary hypertension chronic general supportive therapy (e.g,
diuretics, oxygen, anticoagulants, digoxin) within 60 days prior to study visit C1D1

2. Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine,
vasopressin) within 30 days prior to study visit C1D1

3. History of atrial septostomy within 180 days prior to Screening

4. History of more than mild obstructive sleep apnea that is untreated

5. 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)

6. History of human immunodeficiency virus infection-associated PAH

7. Prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536)

8. Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure
(BP) > 160 mm Hg or sitting diastolic blood pressure > 100 mm Hg during Screening
Visit after a period of rest

9. Systolic BP < 90 mmHg during Screening or at baseline

10. History of known pericardial constriction

11. Personal or family history of long QTc syndrome or sudden cardiac death

12. History of restrictive or congestive cardiomyopathy

13. Left ventricular ejection fraction (LVEF) < 45% on historical echocardiogram (ECHO)
within 6 months prior to Screening Period (or done as a part of the Screening Period)
or pulmonary capillary wedge pressure (PCWP) > 15 mmHg as determined in the Screening
Period RHC.

14. 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)

15. Acutely decompensated heart failure within 30 days prior to study visit C1D1, as per
investigator assessment

16. Significant (≥ 2+ regurgitation) mitral regurgitation (MR) or aortic regurgitation
(AR) valvular disease