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

Inclusion Criteria:

Participants must meet the following criteria to be enrolled in this proof-of-concept study:

1. Age 18 to 85 years

2. Clinical diagnosis of HFpEF:

• Left ventricular ejection fraction ≥50%, with no history of LVEF below 45% in morethan two consecutive measurements under stable conditions

3. Demonstrated Cpc-PH by all of the following:

• Baseline RHC performed within 28 days of randomization documenting a minimumPVR 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

4. New York Heart Association FC of II or III

5. Six-minute Walk Distance ≥100 m repeated twice during Screening and both valueswithin 15% of each other, calculated from the highest value

6. 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/oranticoagulants are excepted from this rule but should not be newly started orstopped within 30 days of Visit 1, and a prescribed dose change should not occurwithin 7 days of Visit 1. Anticoagulation may be suspended for RHC if necessary

7. Women of childbearing potential must:

• Have 2 negative urine or serum pregnancy tests as verified by the investigatorduring the Screening Period; must agree to ongoing pregnancy testing during thecourse 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 contraceptionwithout interruption for at least 28 days prior to starting the investigationalproduct AND agree to use the same highly effective contraception in combinationwith 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 theduration of the study and for at least 16 weeks (112 days) after the last doseof study drug

8. Male participants must:

• Agree to use a condom, defined as a male latex condom or non latex condom NOTmade out of natural (animal) membrane (e.g., polyurethane), during sexualcontact with a pregnant female or a female of childbearing potential whileparticipating in the study, during dose interruptions, and for at least 16weeks (112 days) following investigational product discontinuation, even if hehas undergone a successful vasectomy

• Refrain from donating blood or sperm for the duration of the study and for 16weeks (112 days) after the last dose of study drug

9. Ability to adhere to the study visit schedule and understand and comply with allprotocol requirements

10. Agreement to not participate in any other trials of investigational drugs/deviceswhile enrolled in the A011-16 study

11. Ability to understand and provide documented consent for participation

Exclusion Criteria:

Participants will be excluded from the study if any of the following criteria are met:

1. A diagnosis of PH in WHO Group 1, WHO Group 3, WHO Group 4, or WHO Group 5

2. Clinically significant and active lung disease:

• Chronic obstructive pulmonary disease with post-bronchodilator forcedexpiratory 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, orCOPD on computed tomography [CT] imaging)

3. 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) oranticipation of any valve replacement or repair

• Severe tricuspid regurgitation due to primary valvular disease

• Occurrence of myocardial infarction, acute coronary syndrome, coronary arterybypass 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 deviceimplantation

• History of implantable cardioverter defibrillator placement or anticipatedimplantation of pacemaker, pacemaker implantation within 30 days of Screening

• Anticipated implantation of pacemaker, pacemaker implantation within 30 days ofScreening 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 bloodpressure >160 mmHg or sitting diastolic blood pressure >110 mmHg duringScreening after a period of rest

• Systemic hypotension as evidenced by sitting systolic blood pressure <90 mmHgor 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 QTinterval (QTcF) >470 msec for males or >480 msec for females, or >500 msec if aventricular conduction defect (right bundle branch block; left bundle branchblock; or interventricular conduction delay) is present

• Personal or family history of Brugada syndrome, sudden cardiac arrest orunexplained sudden cardiac death or arrest

• Personal or family history of long QT syndrome unless the participant's ECGshows a normal QTc

• Arrhythmogenic right ventricular dysplasia (ARVD) unless the participant has arecent cardiac MRI that shows no evidence of this diagnosis

4. Hospitalization for any worsening of medical conditions or any significant surgeryper investigator within 30 days of Visit 1

5. Received any approved PAH-specific therapies (i.e., endothelin receptor antagonists,prostacyclin analogs, phosphodiesterase-5 inhibitors, soluble guanylate cyclasestimulators) within 30 days of Visit 1.The use of an oral phosphodiesterase type 5inhibitor, if only indicated for erectile dysfunction, is permitted, if notadministered within 48 hours of a study visit or procedure

6. Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine,vasopressin, or levosimendan) within 30 days of Visit 1

7. Received erythropoietin within 6 months of Visit 1

8. Known history of chronic liver disease, including untreated hepatitis B and/orhepatitis C (with evidence of recent infection and/or active virus replication),with severe hepatic impairment and/or cirrhosis (e.g., hepatic encephalopathy)

9. Prior exposure to sotatercept or luspatercept

10. Currently enrolled in or have completed any other investigational product studywithin 30 days for small molecule drugs or within 5 half-lives for investigationalbiologics prior to the date of documented consent

11. Initiation of an exercise program for cardiopulmonary rehabilitation within 90 daysof Visit 1 or planned initiation during the study (participants who are stable inthe maintenance phase of a program and who will continue for the duration of thestudy are eligible)

12. Any of the following clinical laboratory values prior to Visit 1 as specified:

• Hemoglobin (Hgb) above the gender-specific upper limit of normal (ULN) perlocal laboratory test within 28 days of Visit 1or <10 g/dL per local laboratorywithin 28 days of Visit 1

• Serum alanine aminotransferase or aspartate aminotransferase levels >3× ULN ortotal bilirubin >3× ULN within 28 days of Visit 1

• Estimated glomerular filtration rate <30 ml/min/1.73 m2 (4-variableModification of Diet in Renal Disease equation) within 28 days of Visit 1 orrequired 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

13. History of severe allergic or anaphylactic reaction or hypersensitivity torecombinant proteins or excipients in the investigational product

14. Major surgery within 60 days of Visit 1. Participants must have completely recoveredfrom any previous surgery prior to Visit 1

15. Prior organ transplantation (e.g., heart, lung, liver, kidney), bone marrowtransplantation, or life expectancy of < 12 months

16. Pregnancy or breastfeeding in females

17. Active malignancy, with the exception of fully excised or treated basal cellcarcinoma, cervical carcinoma in situ, or ≤ 2 squamous cell carcinomas of the skin

18. 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

19. Body mass index ≥50 kg/m2

20. More than mild obstructive sleep apnea (treated or untreated)

21. Any non-cardiopulmonary condition or acute/chronic impairment(s) (other thandyspnea) that limits the ability to perform 6-minute walk test (6MWT)