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) andmust 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 thefollowing disease severity criteria: a. KCCQ OSS ≤80; b. NYHA Classification Class II-III; c. Baseline peak VO2 ≤18mL/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 ejectionfraction (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 ifgreater than the past year, then with addition of structural heart disease onechocardiography (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 wallthickness ≥1.1;
2. Women: Either septal wall thickness (cm) either ≥ 1.0 or posterior wallthickness ≥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 ventricularend-diastolic pressure [LVEDP] ≥18 mmHg) or >25 mmHg (or 2.0 mmHg/L/min) withexercise in the last year; iii. E/e' ratio ≥14 at septal annulus at rest onDoppler and tissue Doppler imaging in the last year; or iv. Currently elevatedNT-proBNP defined as >125 pg/mL without atrial fibrillation and >350 pg/mL forsubjects with chronic controlled atrial fibrillation.

5. Participants should maintain their stable level of physical activity throughout theduration of the study and must agree to not enroll in an exercise training programduring the study.

6. Participants should maintain their stable diet and no plan to enter into a weightloss 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 historyof thyroid disease and who have been on stable doses of thyroid medications for aminimum of 4 months can be enrolled.

8. Ambulatory (not wheelchair- or scooter-dependent) and able to perform uprightexercise testing including a 6 MWT.

9. Stable doses of medications (defined as no new medication or change in existing doseof medication ≥50%) for 30 days prior to screening, with additional specificcriteria for the diuretics:

10. If treated with a loop or thiazide diuretic, must be on stable regimen, whichdose permits a flexible diuretic dosing schedule.

Exclusion Criteria:

1. Life expectancy <1 year due to non-cardiovascular reasons, in the judgement of theInvestigator.

2. History of malignancy within 5 years (except non-high-grade skin cancers,carcinoma-in-situ, or low-grade prostate cancer).

3. Weight change (gain or loss) of ≥10 pounds either by self-reporting or documentedweight loss within the past 90 days.

4. Bariatric surgery prior to screening or planned bariatric surgery during the courseof the study.

5. Treatment with GLP-1 receptor antagonist begun within 1 year of screening.

6. Treatment with SGLT2 inhibitors begun within 6 months of screening.

7. Intolerance to MRI or with conditions contraindicated for MRI procedures includingbut not limited to:

8. Having surgical clips/metallic implants/shrapnel/internal electric implants; or

9. Inability to fit into MRI scanner due to subject habitus or exceeding weighttolerance limit of the scanner (generally, 350 or 400 lbs, dependent onmanufacturer); or

10. Claustrophobia: history of severe claustrophobia that would lead to inabilityto conduct MRI.

11. Current acute decompensated HF requiring intravenous (IV) diuretics or recent (<1month before screening) hospitalization for HF.

12. Primary cardiomyopathy (e.g., constrictive, restrictive, infiltrative, toxic,hypertrophic [congenital], congenital, or any other primary cardiomyopathy, in thejudgement of the Investigator.

13. Active myocarditis (COVID-induced or otherwise).

14. Active collagen vascular disease.

15. Current greater than moderate left- or right sided valve disease, in the opinion ofthe Investigator.

16. Planned cardiac surgery or catheter intervention during the time of trialparticipation.

17. Prior documented EF <40% within the last 3 years.

18. Tachycardia (>110 beats/minute) at screening.

19. Atrial fibrillation or atrial flutter with an uncontrolled heart rate response orwith a resting heart rate greater than 110 bpm by ECG at screening. Subjects mayrescreen after appropriate adjustment of medication to manage the atrialfibrillation. A maximum of 16 subjects with this condition can be enrolled in thisstudy.

20. Untreated, life-threatening dysrhythmia.