Exploratory Ph 2A, Double-Blind, Placebo-Controlled Dose Escalation Study of Safety, Tolerability, PD, & PK of HU6 for Subjects With Obese HFpEF

Inclusion Criteria

• •1. Adult male or female, ≥40 years of age.
• •2. 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.
• •3. Body mass index (BMI) ≥30 kg/m2;
• •4. Signs and symptoms of HF in the judgement of the Investigator, and meets the following disease severity criteria:
• •a. KCCQ OSS ≤80; b. NYHA Classification Class II-III; c. Baseline peak VO2 ≤18 mL/kg/min for females or ≤20 mL/kg/min for males; d. Respiratory exchange ratio (respiratory quotient) (RER \[RQ\]) at baseline of \>1.0; e. Left ventricular ejection fraction (EF) ≥50%; f. At least 1 of the following objective criteria for HF: i. Documented hospitalization with HF as primary cause within in last year, or if greater than the past year, then with addition of structural heart disease on echocardiography (increased left atrial volume size or left ventricular hypertrophy, with sex-specific cut-points as per Lang, 2015) as follows:
• •* Left ventricular hypertrophy (LVH):
• •1. Men: Either septal wall thickness (cm) either ≥1.1 or posterior wall thickness ≥1.1;
• •2. Women: Either septal wall thickness (cm) either ≥ 1.0 or posterior wall thickness ≥1.0;
• •* Left atrial dilation (LAD): AP dimension (cm): ≥4.0 in men; \>3.8 in women; ii. Pulmonary capillary wedge pressure (PCWP) at rest \>15 mmHg (or left ventricular end-diastolic pressure \[LVEDP\] ≥18 mmHg) or \>25 mmHg (or 2.0 mmHg/L/min) with exercise in the last year; iii. E/e' ratio ≥14 at septal annulus at rest on Doppler and tissue Doppler imaging in the last year; or iv. Currently elevated NT-proBNP defined as \>125 pg/mL without atrial fibrillation and \>350 pg/mL for subjects with chronic controlled atrial fibrillation.
• •5. 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.
• •6. 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.
• •7. Euthyroid as assessed by a thyroid profile utilizing thyroid stimulating hormone (TSH) and free thyroxine (T4) testing at screening. 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.
• •8. Ambulatory (not wheelchair- or scooter-dependent) and able to perform upright exercise testing including a 6 MWT.
• •9. Stable doses of medications (defined as no new medication or change in existing dose of medication ≥50%) for 30 days prior to screening, with additional specific criteria for the diuretics:
• •1. If treated with a loop or thiazide diuretic, must be on stable regimen, which dose permits a flexible diuretic dosing schedule.