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 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

• Age ≥18 years
• 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

• Symptomatic pulmonary hypertension classified as WHO functional class II or III
• Screening RHC documenting a minimum PVR of ≥400 dyn·sec/cm5 (5 Wood units)
• Pulmonary function tests (PFTs) within 6 months prior to Screening as follows:

• 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
• Forced expiratory volume (first second) (FEV1)/ forced vital capacity (FVC) >70% predicted
• 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),
• No contraindication per investigator for RHC during the study
• 6MWD ≥150 and ≤550 meters repeated twice at Screening and both values within 15% of each other, calculated from the highest value
• PAH therapy at stable (per investigator) dose levels of SOC therapies

Exclusion criteria

• 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)
• Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, vasopressin) within 30 days prior to study visit C1D1
• History of atrial septostomy within 180 days prior to Screening
• History of more than mild obstructive sleep apnea that is untreated
• 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)
• History of human immunodeficiency virus infection-associated PAH
• Prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536)
• 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).
• 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
• Systolic BP <90 mmHg during Screening or at baseline
• History of known pericardial constriction
• Electrocardiogram (ECG) with Fridericia's corrected QT interval (QTcF) >480 msec during Screening Period or C1D1
• Personal or family history of long QTc syndrome or sudden cardiac death
• Cerebrovascular accident within 3 months of C1D1
• History of restrictive or congestive cardiomyopathy
• 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.
• 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)
• Acutely decompensated heart failure within 30 days prior to study visit C1D1, as per investigator assessment
• Significant (≥2+ regurgitation) mitral regurgitation (MR) or aortic regurgitation (AR) valvular disease
• Any of the following clinical laboratory values during the Screening Period prior to C1D1:

• Baseline Hgb >16.0 g/dL
• Serum alanine aminotransferase or aspartate aminotransferase levels >3X upper limit of normal (ULN) or total bilirubin >1.5X ULN within 28 days of C1D1
• 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
• WBC count <4000/mm3
• Platelets <100,000/μL
• Absolute neutrophil count <1500/mm3
• 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
• History of severe allergic or anaphylactic reaction or hypersensitivity to recombinant proteins or excipients in the investigational product
• Major surgery within 8 weeks prior to C1D1. Participants must have completely recovered from any previous surgery prior to C1D1.
• Prior heart or heart-lung transplants or life expectancy of <12 month
• Pregnant or breastfeeding females
• 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
• 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
• 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.
• 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
• Weight >140 kg at Screening