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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: An assessment of LVEF in the prior 12 months is not required in situations where LVEF has been persistently \<50% on prior assessments obtained at least 3 months apart (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, PK Cohort \[Cohort B\]).
* 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 \[Cohort B\]).
* Evidence of cachexia or fatigue or functional impairment, as demonstrated by at least one of the following at screening (Note: Does not apply to open-label, PK Cohort \[Cohort B\]):

  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 in the 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 administered at screening.

Exclusion Criteria:

* Acute decompensated HF within 1 month prior to Screening Visit 1 or during the screening period.
* Implantation of a cardiac resynchronization therapy device or valve repair or replacement within 3 months prior to randomization or intent to do so during the trial.

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 of intravenous inotropes (eg, dobutamine, milrinone).
* Acute coronary syndrome within 1 month prior to randomization.
* Coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting) within 3 months prior to randomization or intent to undergo coronary 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 treat a cardiac rhythm abnormality (ie, tachyarrhythmia or bradyarrhythmia).
* Previous administration with an investigational product (drug or vaccine) within 30 days (or as determined by the local requirement) or 5 half lives (whichever is longer) preceding the first dose of study intervention used in this study. Treatment with an investigational biologic agent within 6 months or 5 half-lives (whichever is longer) 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 LFT abnormalities at the time of screening, confirmed by a repeat test if deemed necessary: AST or ALT level ≥ 3 x ULN, or total bilirubin level ≥ 2 x ULN (unless history of Gilbert's syndrome).

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