The present study seeks to provide pilot data on the safety and efficacy of medical therapy with sotatercept in patients with an established diagnosis of congenital heart disease and Eisenmenger syndrome.

CHASE is an interventional, single-arm, open-label study, that will enroll 40 patients with an established diagnosis of CHD and Eisenmenger syndrome. PAH background therapy may be present at the discretion of the investigators at the time of enrolment. CHASE will be performed only in countries where standard PAH therapies are available and reimbursed. At the end of the 24-week patient period, PAH treatment is left to the investigator's discretion.

Inclusion Criteria:

• Age ≥18 years
• Congenital heart disease with Eisenmenger syndrome (known unrepaired atrial septal defect, and/or ventricular septal defect, and/or patent ductus arteriosus; patients with anomalous pulmonary venous drainage will not be considered)
• Eisenmenger syndrome defined as right-to-left or bi-directional shunt with a mPAP >25 mmHg, PAWP < 15 mmHg, and PVR >5 WU
• In patients with pre-tricuspid shunt, the consideration of Eisenmenger syndrome requires one of the following: Systemic arterial O2 saturation (SaO2) at rest <88% and more than 70%, and/or SaO2 <80% during 6MWT, and secondary erythrocytosis (Hb > 15.0 g/dl for females and 16.0 g/dl for males)
• On stable doses of background PAH therapy* and diuretics (i.e., patient-individual dose goal for each therapy achieved) for ≥30 days
• 6-minute walking distance >100 m
• WHO-FC II or III
• Written informed consent

Exclusion Criteria:

• Age <18 years

  • Diagnosis of pulmonary hypertension groups 2, 3, 4, or 5

  • Hospitalization or change in PAH background therapies within 30 days prior to screening (changes in dose of diuretics or parenteral prostanoids [<10% change in infusion rate over the preceding 3 months] are allowed)

  • Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure >160 mmHg or sitting diastolic blood pressure >100 mmHg during screening visit after a period of rest

  • Baseline systolic blood pressure <90 mmHg at screening

  • Left ventricular systolic dysfunction (LVEF 40%)

  • Restrictive lung disease with a TLC < 60% AND demonstration of more than mild fibrosis on chest CT prior to enrolment (note that patients with congenital heart disease may have thoracic cage deformities [e.g. pectus] that may lead to thoracic cage restriction in the absence of parenchymal lung disease).

  • Obstructive lung disease (FEV1 < 60% pred. and FEV1/FVC <60%)

  • Chronic thromboembolic disease (intermediate or high probability) on V/Q scan and evidence of distal thromboembolism on CT angiography (note that proximal in-situ thrombosis is a known complication of Eisenmenger's and will not be considered an exclusion criterion - such patients may be reviewed centrally for inclusion)

  • Significant liver disease (Child II or III)

  • Any of the following clinical laboratory values at the screening visit:

    • Estimated glomerular filtration rate (eGFR) <30 mL/min/m2 (as defined by the Modification of Diet in Renal Disease [MDRD] equation)
    • Serum alanine aminotransferase, aspartate aminotransferase, or total bilirubin levels >3 × ULN (bilirubin criterion waived if there is a documented history of Gilbert's syndrome)

  • Baseline platelet count <50,000/µl (<50.0 x 109/L) at screening

  • Documented episodes of previous repetitive hyperviscosity syndrome

  • History of haemoptysis within 12 months prior to screening, and/or repeated severe epistaxis (≥ 1 episode per month)

  • Uncorrected iron deficiency (iron stores must be normal defined as a Ferritin > 100 and transferrin saturation [TSAT] ≥ 20%)

  • Recent (< 3 months) enrolment into a rehabilitation program

  • Untreated sleep disordered breathing with an AHI > 10. Patients with sleep apnea will need to have been on CPAP or BiPAP for 3 months prior to enrolment.

  • Prior or current exposure to sotatercept or luspatercept

  • Treatment by phlebotomy within 1 month prior to screening

  • Participation in another interventional study

  • Pregnant (serum B-HCG) or lactating women