Evaluation of 3-V Bioscience-2640 to Reduce de Novo Lipogenesis in Subjects With Characteristics of Metabolic Syndrome

Study Overview
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Brief Summary
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Metabolic syndrome increases the risk for development of heart disease. Another condition associated with metabolic syndrome is fatty liver disease which is also referred to as nonalcoholic fatty liver disease (NAFLD). Recently, drugs that block fatty acid synthesis have been developed to treat cancer. These drugs are now being considered for the treatment of NAFLD. A research test designed to measure liver fatty acid synthesis involves consumption of a sugary solution and measurement of blood fats over a six-hour period. The present study will test the drug 3-V Bioscience-2640 in healthy subjects with characteristics of the metabolic syndrome before and after 10 days of treatment to determine if 50 mg/d significantly reduces liver fat synthesis and lowers liver fat storage.

Detailed Description
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The drug 3-V Bioscience-2640 has been tested previously in subjects with cancer because the lipogenesis pathway is important to the control of some cancer progression. Palmitate (C16:0), a saturated, 16-carbon fatty acid is a biomarker of lipogenesis present in blood triglyceride (TG), was found to be reduced significantly. A second biomarker of lipogenesis, malonyl carnitine, was significantly increased in patients as expected. The present study will test a lower dose (50 mg/d) than the maximum dose previously administered. Here, the subjects will be men with characteristics of the metabolic syndrome, who are otherwise healthy. The focus on subjects with metabolic syndrome is based on the fact that the future use of the drug will be in patients with NAFLD who will likely have metabolic syndrome characteristics. In humans, the primary organ that synthesizes fatty acids is the liver, and this process occurs when simple sugars are consumed in the diet. The carbons in the sugars clear to the liver and become the molecule acetyl-Coenzyme A, which is the building block of fatty acids. The Laboratory of Elizabeth Parks, co-investigator, has developed an oral sugars tolerance test (OSTT) to determine the magnitude of liver stimulation of fatty acid synthesis when an individual consumes an oral bolus of sugars. This test involves the subject undergoing IV infusion with the stable (non-radioactive) isotope (13C1-acetate). The isotope gets incorporated into fatty acids that are being synthesized during the course of the infusion and when sugars stimulate lipogenesis, the label is more abundance. Those labeled fatty acids are detected as present in the blood very low-density lipoprotein (VLDL) component. In the present study, the investigators will use this protocol to determine whether 10 days of drug treatment (one dose per day) will significantly reduce fasting and fructose-stimulated lipogenesis. The study is divided into 3 parts which will support the plan for minor adjustments in the dose of drug after the results from the first two research subjects are available in order to optimize the suppression of lipogenesis, while also minimizing any side effects the drug might have. The study is a repeated-measures design, with each subject serving as his own control. The study will be unblinded with respect to the research staff working directly with the subjects. However, laboratory personnel who will be running the biochemical analyses will be blinded as to whether they are analyzing baseline or post-treatment samples.

Official Title
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Evaluation of 3-V Bioscience-2640, a FASN Inhibitor, to Reduce de Novo Lipogenesis in Subjects With Characteristics of the Metabolic Syndrome

Conditions
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Metabolic Syndrome

Intervention / Treatment
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* Drug: 3-V Bioscience-2640


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men with characteristics of metabolic syndrome Waist circumference greater than 40 in (102 cm) Plasma TG greater than 150 mg/dL HDL cholesterol less than 40 mg/dL Blood pressure greater than or equal to 130/85 mmHg Fasting plasma glucose greater than 100 mg/dL but less than 126 mg/dL Fasting insulin great than 10 microunits/mL 35-60 years of age Overweight/obese subjects with BMI 27.1 - 35.0 kg/m2 Family history of cardiovascular disease or diabetes Habitual diets containing ≥ 5.0% of energy from added sugars Creatinine clearance of ≥80 mL/min Exclusion Criteria: Diagnosed cardiovascular disease (unstable angina, New York Heart Association angina > Grade 2), abnormal thyroid function or liver/kidney disease, renal dysfunction (defined by a glomerular filtration rate <80 mL/min) Chronic skin disorder or treatment for acne History of clinically significant dry eye or eye diseases such as glaucoma Diabetes defined as fasting glucose ≥ 125 mg/dL or HbA1c ≥ 6.5% Habitual diets with low content of added sugars (<5% of total energy) Any tobacco use Elevated liver enzymes ≥ 3x normal (regional norms Alanine transaminase <42 U/L, aspartate aminotransferase <40 U/L, and gamma-glutamyl transferase 8-61 U/L) Contraindications of MRI Alcohol intake weekly greater than 56 g/week (4 standard drinks/wk). Major surgery or donation of blood of >500 mL within the past 8 wks. Patients with uncontrolled hypertension, i.e. ≥160/95 mmHg. Patients with known cardiac abnormalities.

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 3-V Bioscience-2640<br>Subjects will take a singly daily dose of 3-V Bioscience-2640 before bedtime or 22:30, whichever comes first, for 10 days. | Drug: 3-V Bioscience-2640<br>* Subjects will take a singly daily dose of 3-V Bioscience-26400 before bedtime or 22:30, whichever comes first, for 10 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Hepatic Lipogenesis | Subject undergoes a stable isotope infusion followed by blood draws. Plasma lipid samples are measured by gas chromatography/mass spectrophotometry. | Baseline and after 10 days of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Liver Fat Measured by MRI | Subject undergoes MRI of abdomen to quantify liver fat. | Baseline and 10 days of treatment | 
| Change in Skin Sebum Production | Subjects will undergo a skin test in which 4 pieces of clear Sebutape will be placed on the forehead for 30 minutes. The tape is then removed with a sample of sebum (skin oils). The tape is shipped to a lab for processing where lipid content will be analyzed. | Baseline and 10 days of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Obesity, Hyperlipidemia, Impaired fasting glucose, Insulin resistance, Hypertension