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

A Phase 2, Double-Blind, Placebo-Controlled, Randomized Study to Compare the Efficacy and Safety of Sotatercept (ACE-011) Versus Placebo When Added to Standard of Care for the Treatment of Pulmonary Arterial Hypertension (PAH)

Study A011-09 is designed to assesses the efficacy and safety of sotatercept (ACE-011) relative to placebo in adults with pulmonary arterial hypertension (PAH). Eligible participants will receive study treatment for 24 weeks during the placebo-controlled treatment period, and then will be eligible to enroll into a 30-month extension period during which all participants will receive sotatercept. All treated patients will also undergo a follow-up period after last study drug treatment.

This is a Phase 2, double-blind, randomized, placebo-controlled, parallel-group study of sotatercept plus standard of care (SOC) versus placebo plus SOC in participants with PAH of World Health Organization (WHO) Group 1, functional class II-III. Participants will be randomly assigned in a 3:3:4 ratio to receive placebo, sotatercept 0.3 mg/kg, or sotatercept 0.7 mg/kg by subcutaneous (SC) injection every 21 days for a period of 24 weeks in the placebo-controlled treatment period of the study while on SOC therapy. Evaluations will include changes in pulmonary vascular resistance (PVR), 6-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 30-month extension period in which sotatercept-treated participants will receive their latest dose level of sotatercept SC every 21 days and placebo-treated participants will be re-randomized 1:1 to receive sotatercept 0.3 mg/kg SC or sotatercept 0.7 mg/kg SC every 21 days while on SOC 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:

   i. Idiopathic ii. Heritable PAH iii. Drug- or toxin-induced PAH iv. PAH associated with connective tissue disease v. 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 to 70% 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 Cycle 1 Day 1 (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. Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days prior to C1D1 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).

9. 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

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

11. History of known pericardial constriction

12. Electrocardiogram (ECG) with Fridericia's corrected QT interval (QTcF) >480 msec during Screening Period or C1D1

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

14. Cerebrovascular accident within 3 months of C1D1

15. History of restrictive or congestive cardiomyopathy

16. 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.

17. 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)

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

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

20. Any of the following clinical laboratory values during the Screening Period prior to C1D1:

    1. Baseline Hgb >16.0 g/dL
    2. Serum alanine aminotransferase or aspartate aminotransferase levels >3X upper limit of normal (ULN) or total bilirubin >1.5X ULN within 28 days of C1D1
    3. Estimated glomerular filtration rate <30 ml/min/1.73m2 (4-variable Modification of Diet in Renal Disease equation) within 28 days of C1D1 or required renal replacement therapy within 90 days
    4. WBC count <4000/mm3
    5. Platelets <100,000/μL
    6. Absolute neutrophil count <1500/mm3

21. History of opportunistic infection (e.g., invasive candidiasis or pneumocystis pneumonia) within 6 months prior to Screening; serious local infection (e.g., cellulitis, abscess) or systemic infection (e.g., septicemia) within 3 months prior to Screening

22. History of severe allergic or anaphylactic reaction or hypersensitivity to recombinant proteins or excipients in the investigational product

23. Major surgery within 8 weeks prior to C1D1. Participants must have completely recovered from any previous surgery prior to C1D1.

24. Prior heart or heart-lung transplants or life expectancy of <12 month

25. Pregnant or breastfeeding females

26. If on corticosteroids, and at any time in the last 30 days prior to the Screening Period: have been receiving doses of >20 mg/day of prednisone (or equivalent) or on a new or changing dose of ≤20 mg/day; only participants receiving stable doses of ≤20 mg prednisone (or equivalent) in last 30 days prior to the Screening Period permitted in the study

27. History of active malignancy, with the exception of fully excised or treated basal cell carcinoma, cervical carcinoma in-situ, or ≤2 squamous cell carcinomas of the skin

28. History of clinically significant (as determined by the investigator) non-PAH related cardiac, endocrine, hematologic, hepatic, (auto)immune, metabolic, urologic, pulmonary, neurologic, neuromuscular, dermatologic, psychiatric, renal, and/or another disease that may limit participation in the study. Autoimmune diseases are excluded with the exception of those related to PAH etiologies included in this study.

29. Participation in another clinical trial involving intervention with another investigational drug, approved therapy for investigational use, or investigational device within 4 weeks prior to C1D1, or if the half-life of the previous product is known, within 5 times the half-life prior to C1D1, whichever is longer

30. Weight >140 kg at Screening