A Study of Sotatercept for the Treatment of Cpc-PH Due to HFpEF (MK-7962-007/A011-16)

Prior treatment

• Received any approved PAH-specific therapies (i.e., endothelin receptor antagonists, prostacyclin analogs, phosphodiesterase-5 inhibitors, soluble guanylate cyclase stimulators) within 30 days of Visit 1.The use of an oral phosphodiesterase type 5 inhibitor, if only indicated for erectile dysfunction, is permitted, if not administered within 48 hours of a study visit or procedure
• Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, vasopressin, or levosimendan) within 30 days of Visit 1
• Received erythropoietin within 6 months of Visit 1
• Prior exposure to sotatercept or luspatercept
• Currently enrolled in or have completed any other investigational product study within 30 days for small molecule drugs or within 5 half-lives for investigational biologics prior to the date of documented consent
• History of severe allergic or anaphylactic reaction or hypersensitivity to recombinant proteins or excipients in the investigational product
• Major surgery within 60 days of Visit 1. Participants must have completely recovered from any previous surgery prior to Visit 1
• Prior organ transplantation (e.g., heart, lung, liver, kidney), bone marrow transplantation, or life expectancy of \< 12 months

Other illness

• Clinically significant and active lung disease:
  • Chronic obstructive pulmonary disease with post-bronchodilator forced expiratory volume in the first second (FEV1) \<60% predicted
  • Restrictive lung disease with total lung capacity \<70% predicted
  • More than mild interstitial lung disease (ILD), with FVC\<70% or FEV1\<60% predicted (still appropriate if absence of more than mild ILD, fibrosis, or COPD on computed tomography \[CT\] imaging)
• Hospitalization for any worsening of medical conditions or any significant surgery per investigator within 30 days of Visit 1
• Known history of chronic liver disease, including untreated hepatitis B and/or hepatitis C (with evidence of recent infection and/or active virus replication), with severe hepatic impairment and/or cirrhosis (e.g., hepatic encephalopathy)
• 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) endocrine, hematologic, hepatic, (auto)immune, infectious (requiring chronic antibiotics), metabolic, urologic, pulmonary, neurologic, neuromuscular, dermatologic, psychiatric, renal, and/or another disease that may limit participation in the study
• Any non-cardiopulmonary condition or acute/chronic impairment(s) (other than dyspnea) that limits the ability to perform 6-minute walk test (6MWT)

Lab values

• Cardiovascular co-morbidities, which include any of the following:
  • History of more than mild mitral or aortic stenosis
  • Ongoing more than mild mitral or aortic regurgitation
  • More than one valve replacement or repair (mechanical or biomechanical) or anticipation of any valve replacement or repair
  • Severe tricuspid regurgitation due to primary valvular disease
  • Occurrence of myocardial infarction, acute coronary syndrome, coronary artery bypass graft or percutaneous coronary intervention within 180 days of Visit 1
  • History of serious life-threatening or hemodynamically significant arrhythmia
  • History of or anticipated heart transplant or ventricular assist device implantation
  • History of implantable cardioverter defibrillator placement or anticipated implantation of pacemaker, pacemaker implantation within 30 days of Screening
  • Anticipated implantation of pacemaker, pacemaker implantation within 30 days of Screening or history of implantable cardioverter defibrillator placement
  • Occurrence of myocardial infarction within 180 days of Visit 1
  • History of known pericardial constriction, hypertrophic cardiomyopathy, sarcoidosis, or amyloid cardiomyopathy
  • Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure \>160 mmHg or sitting diastolic blood pressure \>110 mmHg during Screening after a period of rest
  • Systemic hypotension as evidenced by sitting systolic blood pressure \<90 mmHg or sitting diastolic blood pressure \<50 mmHg during Screening
  • Resting heart rate of \<45 bpm or \>115 bpm
  • Stroke within 90 days of Visit 1
  • Acutely decompensated HF that required hospitalization within 30 days of Visit 1
  • Electrocardiogram during Screening Period with Fridericia's corrected QT interval (QTcF) \>470 msec for males or \>480 msec for females, or \>500 msec if a ventricular conduction defect (right bundle branch block; left bundle branch block; or interventricular conduction delay) is present
  • Personal or family history of Brugada syndrome, sudden cardiac arrest or unexplained sudden cardiac death or arrest
  • Personal or family history of long QT syndrome unless the participant's ECG shows a normal QTc
  • Arrhythmogenic right ventricular dysplasia (ARVD) unless the participant has a recent cardiac MRI that shows no evidence of this diagnosis
• Any of the following clinical laboratory values prior to Visit 1 as specified:
  • Hemoglobin (Hgb) above the gender-specific upper limit of normal (ULN) per local laboratory test within 28 days of Visit 1or \<10 g/dL per local laboratory within 28 days of Visit 1
  • Serum alanine aminotransferase or aspartate aminotransferase levels \>3× ULN or total bilirubin \>3× ULN within 28 days of Visit 1
  • Estimated glomerular filtration rate \<30 ml/min/1.73 m2 (4-variable Modification of Diet in Renal Disease equation) within 28 days of Visit 1 or required renal replacement therapy within 90 days of Visit 1
  • Glycated hemoglobin (HbA1c) \>10% within 28 days of Visit 1
  • Platelet count \< 75,000/mm3 within 28 days of Visit 1

Other

• Participants will be excluded from the study if any of the following criteria are met:
• A diagnosis of PH in WHO Group 1, WHO Group 3, WHO Group 4, or WHO Group 5
• Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days of Visit 1 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)
• Pregnancy or breastfeeding in females
• Body mass index ≥50 kg/m2
• More than mild obstructive sleep apnea (treated or untreated)

• Participants must meet the following criteria to be enrolled in this proof-of-concept study:
• Age 18 to 85 years
• Clinical diagnosis of HFpEF:
  • Left ventricular ejection fraction ≥50%, with no history of LVEF below 45% in more than two consecutive measurements under stable conditions
• Demonstrated Cpc-PH by all of the following:
  • Baseline RHC performed within 28 days of randomization documenting a minimum PVR of ≥320 dyn•sec/cm5 (4 wood units)
  • Mean pulmonary arterial pressure (mPAP) of \>20 mmHg
  • Pulmonary capillary wedge pressure (PCWP) \>15 mmHg but \< 30 mmHg
• New York Heart Association FC of II or III
• Six-minute Walk Distance ≥100 m repeated twice during Screening and both values within 15% of each other, calculated from the highest value
• Chronic medication for HF or for any underlying condition, administered at a stable (per investigator) dose for ≥30 days prior to Visit 1. Diuretics and/or anticoagulants are excepted from this rule but should not be newly started or stopped within 30 days of Visit 1, and a prescribed dose change should not occur within 7 days of Visit 1. Anticoagulation may be suspended for RHC if necessary
• Women of childbearing potential must:
  • Have 2 negative urine or serum pregnancy tests as verified by the investigator during the Screening Period; must agree to ongoing pregnancy testing during the course of the study and until 8 weeks after the last dose of the study drug
  • If sexually active with a male partner: use highly effective contraception without interruption for at least 28 days prior to starting the investigational product AND agree to use the same highly effective contraception in combination with a barrier method 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 drug
• Male participants must:
  • Agree to use a condom, defined as a male latex condom or non latex 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 drug
• Ability to adhere to the study visit schedule and understand and comply with all protocol requirements
• Agreement to not participate in any other trials of investigational drugs/devices while enrolled in the A011-16 study
• Ability to understand and provide documented consent for participation