Phase 2a Study of HU6 in Subjects With Elevated Liver Fat and High BMI Volunteers

Exclusion Criteria

• •Subjects will be excluded from the study if any of the following criteria are met:
• •1. Insulin-controlled diabetes.
• •2. Pregnant or breastfeeding or plans to become pregnant.
• •3. Intolerance to Magnetic Resonance Imaging (MRI) or with conditions contraindicated for MRI procedures including but not limited to inability to fit into MRI scanner or surgical clips/metallic implants/shrapnel. Subjects must not be claustrophobic, have a history of claustrophobia, or intolerance of closed or small spaces.
• •4. Weight gain or loss \>5% in 3 months prior to study or \>10% in 6 months prior to screening.
• •5. History of lap banding, intragastric balloon, duodenal-jejunal sleeve, or bariatric surgery within 5 years of screening, plans for bariatric surgery prior to conclusion of study participation, or plans to lose weight during this study either through a special diet, exercise program or both.
• •6. History of malignant hyperthermia.
• •7. History of chronic serious recurrent skin rashes of unknown cause.
• •8. History of or current clinically significant cardiovascular disease including but not limited to transient ischemic attack, stroke, cardiac arrhythmias, syncope, unstable angina, myocardial infarction in the 6 months prior to screening, congestive heart failure, or uncontrolled hypertension. (Uncontrolled hypertension is defined as a systolic blood pressure ≥160 mmHg or a diastolic blood pressure ≥100 mmHg based on an average of three resting determinations in the sitting position with an appropriately sized cuff).
• •9. Resting heart rate \<45 or \>110 bpm.
• •10. On screening ECG or by history:
• •1. A marked baseline prolongation of QT/QTcF interval (e.g., repeated demonstration of a QTcF interval \> 450 msec for males and \>470 msec for females).
• •2. A history of additional risk factors for Torsades de Pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome) or a family history of sudden cardiac death of unknown origin.
• •11. Kidney disease, kidney transplant, or estimated glomerular filtration rate (eGFR) \<50 mL/min/1.73 m2 based on the CKD-EPI Creatinine Equation (NKF 2009; https://www.kidney.org/content/ckd-epi-creatinine-equation-2009).
• •12. Significant lung disease requiring chronic daily medication including chronic obstructive pulmonary disease (COPD), emphysema, pulmonary fibrosis, or asthma.
• •13. Untreated obesity hypoventilation syndrome (OHS) or obstructive sleep apnea (OSA).
• •14. History of or active (acute or chronic) liver disease other than nonalcoholic fatty liver disease (NAFLD)/ nonalcoholic steatohepatitis (NASH), such as but not limited to autoimmune liver disease, viral hepatitis, genetic hemochromatosis, primary biliary cirrhosis, Wilson disease, alpha-1-antitrypsin deficiency, alcohol liver disease, acute fatty liver of pregnancy or drug induced (including acetaminophen) liver disease.
• •15. History of or treatment for clinically significant gastroparesis, inflammatory bowel disease, or any surgery of the upper gastrointestinal tract with the exception of cholecystectomy, or minor gastric procedures that are approved by the medical monitor.
• •16. History of cirrhosis and/or hepatic decompensation, including ascites, hepatic encephalopathy, or variceal bleeding.
• •17. History of acute pancreatitis within one year of screening or chronic pancreatitis of any cause.
• •18. Serum triglyceride concentrations exceeding 500 mg/dL.
• •19. HbA1c \>9.0%.
• •20. Familial (mother/father/sibling) and/or personal history of retinal detachment any time in the past.
• •21. Any history of or current diagnosis of Glaucoma.
• •22. Evidence of the following on screening ophthalmologic examination:
• •1. Peripheral retinal pathology requiring treatment, retinal tears, or lattice that require treatment.
• •2. Diabetic retinopathy with macula exudates or macula edema as shown by optical coherence tomography (OCT) and examination.
• •3. Any active macular disease that affects the vision, including macula pucker (epiretinal membrane) and macular degeneration.
• •4. Visually significant cataract as determined by ophthalmologist.
• •5. Any previous intravitreal injection of anti-VEGF agents for macular degeneration.
• •6. History of prior vitrectomy.
• •23. History of malignant neoplasms within 5 years of screening, except for basal cell or squamous cell skin cancer, cervical carcinoma in situ, or prostate cancer that is not currently or expected to require radiation therapy, chemotherapy and/or surgical interventions or to initiate hormonal treatment.
• •24. History of organ transplantation.
• •25. Received a COVID-19 vaccine less than 1 week prior to dosing (Visit 2 / Day 1) and/or plans to receive a COVID-19 vaccine during the study period.
• •26. History of significant drug abuse within one year prior to Screening or frequent use of soft drugs (such as marijuana) within 3 months prior to the Screening visit, or hard drugs (such as cocaine, phencyclidine \[PCP\], opioid derivatives including heroin, and amphetamine derivatives) within 1 year prior to screening.
• •27. History of alcoholism in the last 2 years or current evidence of excessive alcohol consumption as assessed by screening evaluation using the Alcohol Use Disorders Identification Test (AUDIT, Thompson 2018 \[Appendix A\]), and history of regular alcohol consumption exceeding approximately 14 drinks/week for men and 7 drinks/week for women \[1 drink = 4 ounces (120 mL) of wine or 12 ounces (360 mL) of beer or 1 ounce (30 mL) of hard liquor\] within 6 months of Screening, as determined by the Investigator.
• •28. Positive urine drug screen for drugs of abuse or positive phosphatidylethanol (PEth) blood test result \>25 ng/mL at Screening.
• •29. Current regular vaping or more than 5 cigarettes or the equivalent per week. Use of nicotine patches for smoking cessation is permitted.
• •30. Positive test results of hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab), or human immunodeficiency virus (HIV1/2) antibody.
• •31. Neutropenia, defined as absolute neutrophil count ≤1000/μL.
• •32. Serum AST or ALT \>5 x upper limit of normal (ULN) at screening. (One repeat test may be allowed within 7 days at the discretion of the Investigator).
• •33. Total bilirubin \> ULN, unless due to Gilbert's syndrome or if considered normal variability in the absence of other clinically relevant liver impairment as approved by Medical Monitor.
• •34. International normalized ratio (INR) ≥1.3 at screening if there is other evidence of potential significant liver impairment.
• •35. Participation in another clinical trial at the time of screening or exposure to any investigational agent, including topical, within 30 days of screening or 5 half-lives, if half-life known.
• •36. No tattoo or body piercings during the course of the study. Any underlying physical or psychological medical condition that, in the opinion of the Investigator or sponsor, would make it unlikely that the subject is able comply with the study requirements or would be unable to complete the study.
• •37. Any condition that the investigator believes would interfere with his/her ability to provide written informed consent, comply with study instructions, or which might confound the interpretation of the study results or put the subject at undue risk.
• •38. Known or potential hypersensitivity to HU6 or its excipients.
• •Prohibited Medications (Current Use):
• •39. Any herbal supplement, over the counter drug, mail order or prescription drug for weight loss.
• •40. Prescription or over the counter stimulants including: dextroamphetamine/Dexedrine, dextroamphetamine/amphetamine combination product/Adderall, or methylphenidate (Ritalin®, Concerta®).
• •41. Thiazolidinediones (TZD): pioglitazone/Actos, rosiglitazone/Avandia.
• •42. Glucagon-like peptide 1 (GLP1) agonists: exenatide/Byetta/Bydureon, lixisenatide/Adlyxin, liraglutide/Victoza, dulaglutide/Trulicity, semaglutide/Ozempic.
• •43. Sodium-glucose cotransporter-2 (SGLT2) inhibitors: canagliflozin/Invokana, dapagliflozin/Farxiga, empagliflozin/Jardiance, ertugliflozin/Steglatro.
• •44. Vitamin E: use of ursodiol or high dose vitamin E \>400 IU/day for at least one month within in the last 6 months or started high dose vitamin E within last 3 months of screening.
• •45. Recent (within 3 months of screening) or current use of obeticholic acid/Ocaliva, systemic corticosteroids, methotrexate, tamoxifen, amiodarone, or long-term use of tetracyclines.
• •46. Warfarin, heparin, factor Xa inhibitors (dabigatran betrixaban edoxaban, apixaban, and rivaroxaban).
• •47. Concomitant medications that prolong the QT/QTc interval and are known to be associated with increased risk of Torsade des pointes as identified in the https://crediblemeds.org/ website list category of 'Known Risk' (Appendix B).
• •48. Products with cannabidiol (CBD).