A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension

This is a Phase 2a, single arm, open-label, multi center exploratory study to determine the
effects of sotatercept (ACE-011) plus standard of care (SOC) in adults with WHO functional
class III pulmonary arterial hypertension (PAH).

All eligible participants will receive standard of care (SOC) plus sotatercept (ACE-011) at a
starting dose level of 0.3 mg/kg SC for Cycle 1 and escalating to 0.7 mg/kg at cycle 2 for
the remainder of the treatment period. Participants will be required to attend clinic visits
once every three weeks for 24 weeks to perform one or more protocol specified evaluations.
Evaluations include hemodynamic measures collected during right heart catheterization (RHC)
with invasive cardiopulmonary exercise test (iCPET), and cardiac magnetic resonance imaging
(MR), 6-minute walk distance (6MWD), pharmacokinetic parameters, pharmacodynamic parameters,
anti-drug antibody testing, and adverse events. These assessments will be performed at the
Screening Period Visit (up to 28 days before Cycle 1 Day 1), the End of Treatment Visit (Day
169), and at the End of Study Visit (Day 260).

Inclusion Criteria:

1. Age ≥ 18 years

2. 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

3. Symptomatic pulmonary hypertension classified as WHO functional class III

4. Screening RHC documenting a minimum PVR of ≥ 4 Wood units

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

1. 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

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] or pulmonary angiography result), any time prior to Screening or conducted
during Screening Period with normal or low probability result

7. 6MWD ≥ 100 and ≤ 550 meters repeated twice during Screening Period and both values
within 15% of each other, calculated from the highest value

8. 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:

1. 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)

2. Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine,
vasopressin) within 30 days prior to 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. History of portal hypertension or chronic liver disease, defined as mild to severe
hepatic impairment (Child-Pugh Classes A to 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 BP > 160 mm Hg or
sitting diastolic BP > 100 mm Hg during Screening after a period of rest

9. Systolic BP < 90 mm Hg during Screening or at baseline

10. History of known pericardial constriction

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

12. History of restrictive or constrictive cardiomyopathy

13. Left ventricular ejection fraction < 45% on echocardiogram performed within 6 months
of Screening OR PCWP > 15 mm Hg on RHC during baseline evaluation

14. 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)

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

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