A Phase 2 Study of the Effects of Ponsegromab on Health-Related Quality of Life and Safety in Patients With Heart Failure (GARDEN-TIMI 74)

Prior treatment

• Acute decompensated HF within 1 month prior to SV1 or during the screening period.
• 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.
• 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 only: implantation of a cardiac resynchronization therapy device more than 1 month prior to randomization is permitted.
• 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 only: coronary revascularization more than 1 month prior to randomization is permitted.
• Current use of any prohibited concomitant medication(s). Refer to Section 6.9 Prior and Concomitant Therapy.

Other illness

• Renal disease requiring ongoing dialysis.
• History of heart transplantation, currently listed for heart transplant, current/planned mechanical circulatory support, or current/planned use of intravenous inotropes (eg, dobutamine, milrinone).
• Untreated indication for an implantable cardiac defibrillator or pacemaker to treat a cardiac rhythm abnormality (ie, tachyarrhythmia or bradyarrhythmia).
• History of allergic or anaphylactic reaction to any therapeutic or diagnostic monoclonal antibody (IgG protein) or molecules made of components of monoclonal antibody.

Lab values

• 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).
• Other medical (eg, severe, uncorrected aortic stenosis; active malignancy) or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, may limit life expectancy to less than 1 year and/or make the participant inappropriate for the study.

Other

• Investigator site staff directly involved in the conduct of the study and their family members, site staff otherwise supervised by the investigator, and sponsor and sponsor delegate employees directly involved in the conduct of the study and their family members.

• Participants aged 18 years or older (or the minimum age of consent in accordance with local regulations) at screening. a. A female participant is eligible to participate if she is not pregnant or breastfeeding. b. Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female (Section 10.4.2) participants.
• Clinical evidence of HF with each of the following criteria: a. 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). b. NYHA class II-IV at screening. c. Main cohort only: NT-proBNP ≥400 pg/mL at screening.
• Serum GDF-15 concentration ≥2000 pg/mL at screening.
• Main cohort only: KCCQ-23 CSS <75 at screening.
• Main cohort only: Evidence of cachexia or fatigue or functional impairment, as demonstrated by at least one of the following at screening: a. Non-edematous unintentional weight loss ≥5% in the last 6 months or current BMI <20 kg/m2, associated with subjective fatigue or anorexia; or b. 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 c. A score of <60 on the Physical Limitations Domain of the KCCQ-23 administered at screening.
• Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures (including but not limited to subcutaneous injection of study intervention).