Sotatercept in Pulmonary Arterial Hypertension

Inclusion criteria

• to be enrolled in the study:
• Age ≥ 18 years.
• Documented diagnostic right heart catheterization (RHC) at any time prior to screening confirming the diagnosis of PAH Group 1 in any of the following subtypes:
• Idiopathic PAH
• Heritable PAH
• Drug/toxin-induced PAH
• PAH associated with CTD
• PAH associated with simple, congenital systemic-to-pulmonary shunts at least 1 year following repair.
• Symptomatic PAH classified as WHO FC II or III.
• On stable doses of ≥2 background PAH therapies for at least 60 days prior to screening; for infusion prostacyclins, dose adjustment within 10% of the optimal dose is allowed per medical practice. Patients on 1 background PAH therapy are eligible if there is documented intolerance or contraindication to use of the other 2 classes (e.g. liver enzyme elevation while taking an ERA).
• Females of childbearing potential must:
• Have a negative urine or serum pregnancy tests as verified by the investigator prior to starting study therapy.
• If sexually active, have used, and agree to use highly effective contraception without interruption during the study (including dose interruptions), and for 16 weeks (112 days) after discontinuation of study treatment.
• Refrain from breastfeeding a child or donating blood, eggs, or ovum for the duration of the study and for at least 16 weeks (112 days) after the last dose of study treatment.
• Male participants must:
• Agree to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (e.g., polyurethane), during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 16 weeks (112 days) following investigational product discontinuation, even if he has undergone a successful vasectomy.
• Refrain from donating blood or sperm for the duration of the study and for 16 weeks (112 days) after the last dose of study treatment
• Ability to adhere to study visit schedule and understand and comply with all protocol requirements.
• Ability to understand and provide written informed consent.

Exclusion criteria

• 1\. Diagnosis of pulmonary hypertension WHO Groups 2, 3, 4, or 5
• Musculoskeletal limitation that precludes participation in cycle ergometry
• Resting oxygen saturation \< 88%. (Note: patients on oxygen can be included in the study if they can maintain a resting saturation of ≥ 88 % after 3 minutes off oxygen).
• Diagnosis of the following PAH Group 1 subtypes: human immunodeficiency virus (HIV)-associated PAH and PAH associated with portal hypertension, schistosomiasis-associated PAH and pulmonary veno-occlusive disease.
• Hemoglobin (Hgb) at screening above the gender-specific upper limit of normal (ULN), per local laboratory test.
• Baseline platelet count \< 50,000/mm3 (\< 50.0 × 109/L) in the enrollment period.
• Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure \> 160 mmHg or sitting diastolic blood pressure \> 100 mmHg during a screening visit after a period of rest.
• Baseline systolic blood pressure \< 90 mmHg at screening.
• Pregnant or breastfeeding women.
• 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).
• Currently enrolled in or have completed any other investigational product study within 30 days for small-molecule drugs or within 5 half-lives for biologics prior to the date of signed informed consent.
• History of full pneumonectomy.
• Pulmonary function test (PFT) values of forced vital capacity (FVC) \< 60% predicted and/or FEV1/FVC \< lower limit of normal at the screening visit or within 6 months prior to the screening visit.
• Smoking history of ≥ 20 pack-years or any tobacco smoking or vaping within the previous 3 months.
• Body mass index ≥ 40 kg/m2.
• Planned initiation of an exercise program for cardiopulmonary rehabilitation 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).
• 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 restrictive, constrictive, or congestive cardiomyopathy.
• History of atrial septostomy within 180 days prior to the screening visit.
• Electrocardiogram (ECG) with Fridericia's corrected QT interval (QTcF) \> 500 ms during the Screening Period
• Personal or family history of long QT syndrome (LQTS) or sudden cardiac death.
• Left ventricular ejection fraction \< 45% on historical echocardiogram within 6 months prior to the screening visit.
• Any symptomatic coronary disease events (prior myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or cardiac anginal chest pain) within 6 months prior to the screening visit. Note: Anginal pain can be ignored as an exclusion criterion if coronary angiography shows no obstructions.
• Cerebrovascular accident within 3 months prior to the Screening Visit.
• Significant mitral or aortic valve dysfunction (greater than moderate mitral regurgitation or aortic regurgitation, or greater than mild mitral stenosis or aortic stenosis).
• Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, vasopressin) within 30 days prior to the screening visit.
• Known hypersensitivity to sotatercept or to any ingredient in the formulation or component of the container.