A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension

A Phase 2a Single-Arm, Open-Label, Multicenter Exploratory Study to Assess the Effects of Sotatercept (ACE-011) for the Treatment of Pulmonary Arterial Hypertension

This study evaluates the effect of sotatercept (ACE-011) in adults with pulmonary arterial hypertension (PAH). Each eligible participant will receive standard of care (SOC) plus sotatercept (ACE-011) for a 24-week treatment period, followed by an 18-month extension period, and an 8-week follow-up period.

This is a Phase 2a, single-arm, open-label, multicenter exploratory study to determine the effects of sotatercept plus SOC in adults with WHO functional class III PAH.

All eligible participants will receive SOC plus sotatercept at a starting dose level of 0.3 mg/kg by subcutaneous (SC) injection 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 the 24-week treatment period and once every three weeks for the 18-month extension period 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.

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
   3. 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.

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. Electrocardiogram (ECG) with QTcF > 480 msec during Screening or C1D1
12. History of personal or family history of long QTc syndrome or sudden cardiac death
13. History of restrictive or constrictive cardiomyopathy
14. Left ventricular ejection fraction < 45% on echocardiogram performed within 6 months of Screening OR pulmonary capillary wedge pressure (PCWP) > 15 mm Hg on RHC during baseline evaluation
15. 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)
16. Acutely decompensated heart failure within 30 days prior to C1D1, as per investigator assessment
17. Significant (≥ 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular disease