Inclusion Criteria:

• Adult male or female, ≥ 30 years of age.
• Competent to understand the information given in the Institutional Review Board (IRB) or Independent Ethics Committee (IEC)-approved Informed Consent Form (ICF) and must sign the form prior to the initiation of any study procedures.
• Body mass index (BMI) ≥ 30 kg/m^2.
• Signs and symptoms of HF in the judgement of the Investigator, and meets the following disease severity criteria:
  • KCCQ OSS ≤ 80 (by exception, Investigator judgment in consult with the Medical Monitor, subjects may be enrolled who meet all eligibility criteria but have a KCCQ OSS ≤ 82);
  • NYHA Classification Class II-III;
  • Baseline peak VO2 ≤ 20 mL/kg/min for females or ≤ 22 mL/kg/min for males;
  • Peak respiratory exchange ratio (respiratory quotient) (RER [RQ]) at baseline of >1.0;
  • Left ventricular ejection fraction (EF) ≥ 50%;
  • The Investigator has determined that the subject has the established diagnosis of chronic HFpEF based on medical history and supported by one of the following criteria (Lang 2014, Arques 2018, Ibrahim 2020, Nassif 2021):
  • Documented hospitalization with HF as primary cause, or emergency room or other urgent outpatient visit for acute HFpEF (as primary cause) at which administration of IV loop diuretic was provided as treatment (≥ 1 month prior to screening);
  • Increased left atrial size (LA): confirmed by the echo core lab and defined as: AP dimension (cm): ≥ 4.0 in men, > 3.8 in women; or LA length ≥ 5.0 cm or LA volume ≥ 55 mL or LA volume index ≥ 29 mL/m^2;
  • Pulmonary capillary wedge pressure (PCWP) at rest > 1 5 mmHg (or left ventricular end-diastolic pressure [LVEDP] ≥18 mmHg) or ≥ 25 mmHg (or ≥ 2.0 mmHg/L/min) with exercise;
  • Either of the following at rest by Doppler and Tissue Doppler: a) for patients in sinus rhythm: E/e’ ratio ≥ 15 at septal annulus, or E/e’ ratio 13 at lateral annulus, or average E/e’ ratio 14; for patients in atrial fibrillation E/e’ ≥ 11 at the septal annulus. v. Currently: • Local lab: BNP ≥ 35 pg/mL (≥ 75 pg/mL with chronic atrial fibrillation) or • Central lab: elevated NT-proBNP ≥125 pg/mL (≥ 250 with chronic atrial fibrillation) vi. History of BNP ≥ 75 pg/mL (≥ 100 pg/mL with chronic fibrillation) or NTproBNP ≥ 225 pg/mL (≥375 pg/mL with chronic atrial fibrillation).
• Participants should maintain their stable level of physical activity throughout the duration of the study and must agree to not enroll in an exercise training program during the study.
• Participants should maintain their stable diet and no plan to enter into a weight loss program prior to or during the course of the study.
• Clinically euthyroid as assessed by a thyroid profile utilizing thyroid stimulating hormone (TSH) and free thyroxine (T4) testing at screening as assessed by the Investigator based on the medical history of the subject. Subjects with a stable history of thyroid disease and who have been on stable doses of thyroid medications for a minimum of 4 months can be enrolled. (Guidance to Investigator: Generally, TSH values greater than 1.5x upper limit of normal (ULN) or less than 1.5x lower limit of normal (LLN) would be exclusionary, but it needs interpretation in the context of T4. In subjects with TSH values within these ranges, there should be no evidence of clinically significant, insufficiently treated hyper- or hypothyroidism that could be contributing to symptoms of dyspnea, exercise intolerance, or weight changes in the opinion of the site Investigator).
• Ambulatory (not wheelchair- or scooter-dependent) and able to perform upright exercise testing including a 6 MWT.
• Stable doses of medications (defined as no new medication or change in existing dose of medication >50%) for approximately 30 days prior to screening, with additional specific criteria for the diuretics: a. If treated with a loop or thiazide diuretic, must be on stable regimen for approximately 3 weeks prior to enrollment.
• The following applies for male and female subjects: a. Male subject whose sexual partner is of childbearing potential and agrees to use of reliable method of contraception as defined in Section 8.2.2); b. Female subject is of childbearing potential and agrees to use a reliable method of contraception (as defined in Section 8.2.2); c. Female subject is of non-childbearing potential, defined as surgically sterile (hysterectomy or bilateral tubal ligation) or post-menopausal (having amenorrhea for a minimum of 12 consecutive months with follicle stimulating hormone [FSH] >40 U/L).

Exclusion Criteria:

• Life expectancy <1 year due to non-cardiovascular reasons, in the judgement of the Investigator.
• History of malignancy within 5 years (except non-high-grade skin cancers, carcinoma-in-situ, or low-grade prostate cancer).
• Weight change (gain or loss) of ≥ 10 pounds either by self-reporting or documented weight loss within the past 30 days.
• Bariatric surgery prior to screening or planned bariatric surgery during the course of the study.
• Treatment with GLP-1 receptor agonist begun within approximately 1 year of screening.
• Treatment with SGLT2 inhibitors begun within approximately 3 months of screening.
• Intolerance to MRI or with conditions contraindicated for MRI procedures including but not limited to: a. Having surgical clips/metallic implants/shrapnel/MRI-incompatible internal electric implants (e.g. pacemaker); b. Inability to fit into MRI scanner due to subject habitus or exceeding weight tolerance limit of the scanner (generally, 350 or 400 lbs, dependent on manufacturer); or c. Claustrophobia: history of severe claustrophobia that would lead to inability to conduct MRI. (Subjects may receive medication (for example, oral benzodiazepine) for anxiety one hour prior to the conduct of the MRI at the discretion of the Investigator as per facility’s guidelines).
• Current acute decompensated HFpEF requiring intravenous (IV) diuretics or recent (<1 month before screening) hospitalization for HFpEF.
• Any condition (e.g., ongoing substance, drug, or alcohol abuse) that may interfere with participation or safety of investigations, in the opinion of the Investigator.
• Uncontrolled diabetes (HBA1c >10%) or history of recurrent ketoacidosis.
• Wilson’s disease.
• History of malignant hyperthermia.
• Uncontrolled psychiatric disorder. 35. Contraindication for CPET: a. Severe hypertension or hypotension; b. Recent or untreated acute coronary syndrome; c. Heart rate < 40 bpm; d. Systolic blood pressure < 90 mmHg; e. Instability on the treadmill.
• Laboratory Values at Screening: a. Serum ferritin, < 30 ng/mL for males and < 13 ng/mL for females; b. Anemia (hemoglobin < 9.5 g/dL); c. Serum copper or ceruloplasmin below the normal reference range; d. Serologic evidence of Hepatitis B based on hepatitis B surface antigen (HBsAG); e. Serologic evidence of Hepatitis C antibody (HCV Ab) and HCV RNA; f. Serologic evidence of human immunodeficiency virus (HIV); g. Absolute blood neutrophil count below 1500/µL; h. Female subjects with a positive urine β-human chorionic gonadotropin (β-hCG) test at screening or prior to dosing or who are breastfeeding.
• Treatment with any investigational drug or device within 30 days or 5 half-lives (whichever is longer) prior to the beginning of screening (this includes investigational formulations of marketed products, inhaled and topical drugs), or plans to participate in an investigational drug or device study at any time during this study.
• Known hypersensitivity to HU6, the metabolite, or formulations excipients.
• Currently taking prohibited medications: a. Herbal preparations (except where allowed after discussion with Sponsor to avoid potential interaction with HU6 based on emerging data); b. Any over the counter drug, mail order or prescription drug for weight loss; c. Oral, intranasal or inhaled products with cannabidiol; d. Prescription or over the counter stimulants including: dextroamphetamine/Dexedrine®, dextroamphetamine/amphetamine combination product/Adderall®, or methylphenidate (Ritalin®, Concerta®); e. Systemic corticosteroids, methotrexate, tamoxifen, amiodarone, chronic use of tetracycline; 40. Planning to receive volatile anesthetics (for elective surgery) at any time from randomization until the end of study follow-up visit.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 8/22/23. Questions regarding updates should be directed to the study team contact.