A Study of Ponsegromab in People With Heart Failure

Inclusion Criteria:

• Male and female participants aged 18 years or older

-. Clinical evidence of HF with each of the following criteria:

1. LVEF <50% on most recent measurement, within 12 months of screening. Note: Anassessment of LVEF in the prior 12 months is not required in situations whereLVEF has been persistently <50% on prior assessments obtained at least 3 monthsapart (including the most recent measurement).

2. NYHA class II-IV at screening.

3. NT-proBNP ≥400 pg/mL at screening (Note: Does not apply to open-label, PKCohort [Cohort B]).

• Serum GDF-15 concentration ≥2000 pg/mL at screening.

• Cohort D only: Serum GDF-15 concentration <2000 pg/mL at screening.

• KCCQ-23 CSS <75 at screening (Note: Does not apply to open-label, PK Cohort [CohortB]).

• Evidence of cachexia or fatigue or functional impairment, as demonstrated by atleast one of the following at screening (Note: Does not apply to open-label, PKCohort [Cohort B]):

1. Non-edematous unintentional weight loss ≥5% in the last 6 months or current BMI <20 kg/m2, associated with subjective fatigue or anorexia; or

2. Fatigue at least 3 times per week AND at least moderately bothersome fatigue inthe past 2 weeks based on the KCCQ-23 administered at screening; or

3. A score of <60 on the Physical Limitations Domain of the KCCQ 23 administeredat screening.

Exclusion Criteria:

• Acute decompensated HF within 1 month prior to Screening Visit 1 or during thescreening period.

• Implantation of a cardiac resynchronization therapy device or valve repair orreplacement within 3 months prior to randomization or intent to do so during thetrial.

For the open-label, PK cohort (Cohort B) only: implantation of a cardiac resynchronization therapy device more than 1 month prior to randomization is permitted.

• History of heart transplantation, currently listed for heart transplant,current/planned mechanical circulatory support, or current/planned use ofintravenous inotropes (eg, dobutamine, milrinone).

• Acute coronary syndrome within 1 month prior to randomization.

• Coronary revascularization (percutaneous coronary intervention or coronary arterybypass grafting) within 3 months prior to randomization or intent to undergocoronary revascularization during the trial.

For the open-label, PK cohort (Cohort B) only: coronary revascularization more than 1 month prior to randomization is permitted.

• Untreated indication for an implantable cardiac defibrillator or pacemaker to treata cardiac rhythm abnormality (ie, tachyarrhythmia or bradyarrhythmia).

• Previous administration with an investigational product (drug or vaccine) within 30days (or as determined by the local requirement) or 5 half lives (whichever islonger) preceding the first dose of study intervention used in this study. Treatmentwith an investigational biologic agent within 6 months or 5 half-lives (whichever islonger) of Day 1.

• Previous exposure to ponsegromab in a prior clinical study.

• Renal disease requiring ongoing dialysis.

• Cirrhosis with evidence of portal hypertension not due to HF, or the following LFTabnormalities at the time of screening, confirmed by a repeat test if deemednecessary: AST or ALT level ≥ 3 x ULN, or total bilirubin level ≥ 2 x ULN (unlesshistory of Gilbert's syndrome).