A Study of Ponsegromab in People With Heart Failure

Overview

The primary purpose of this clinical trial is to compare the effects of study medicine (Ponsegromab/PF-06946860) with a placebo (an injection that looks like the study medicine but does not contain the active medicine) to find out if the study medicine is better than the placebo (an injection that looks like the study medicine but does not contain the active medicine) for treatment of symptoms related to heart failure. Participants will not know which treatment group they are assigned to. Most participants in this study will receive the study medicine or placebo by shots under the skin every four weeks. People may be able to participate in this study if they have heart failure. Participants will take part in this study for about 9 months. During this time participants will visit the study clinic once a month.

A separate PK cohort within this clinical trial will receive open-label study medicine (Ponsegromab/PF-06946860) only. Participants in this open-label, PK cohort will not receive placebo. These participants will receive the study medicine by shots under the skin every four weeks. People may be able to participate in this study cohort if they also have heart failure. Participants will take part in the open-label, PK cohort for about 7 months.

Description

The primary purpose of this study is to assess the effect of repeated subcutaneous administration of ponsegromab (PF-06946860) compared to placebo on frequency, severity, and burden of symptoms as well as physical limitations in participants with heart failure and elevated circulating GDF-15 concentrations. The study will also assess the safety, tolerability, PK, PD, and immunogenicity of ponsegromab.

A separate, open-label, PK cohort, with more frequent PK and GDF-15 collection after single and multiple subcutaneous administration of ponsegromab (PF-06946860), will be enrolled at certain sites in the United States and Canada to facilitate a more comprehensive assessment of PK characteristics and PK/PD relationship for GDF-15 in participants with heart failure.

Eligibility

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. 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:
  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 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 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).