Clinical trial NCT02948569: Evaluation of 3-V Bioscience-2640 to Reduce de Novo Lipogenesis in Subjects With Characteristics of Metabolic Syndrome
Official title: Evaluation of 3-V Bioscience-2640, a FASN Inhibitor, to Reduce de Novo Lipogenesis in Subjects With Characteristics of the Metabolic Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Metabolic Syndrome
Keywords: Obesity
Hyperlipidemia
Impaired fasting glucose
Insulin resistance
Hypertension
Lead sponsor: University of Missouri-Columbia
Sponsor class: OTHER
Collaborators: name: Sagimet Biosciences Inc.
First posted: 2016-10-28
Enrollment: 12
Sex: MALE
Minimum age (years): 35
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Men with characteristics of metabolic syndrome

   1. Waist circumference greater than 40 in (102 cm)
   2. Plasma TG greater than 150 mg/dL
   3. HDL cholesterol less than 40 mg/dL
   4. Blood pressure greater than or equal to 130/85 mmHg
   5. Fasting plasma glucose greater than 100 mg/dL but less than 126 mg/dL
   6. Fasting insulin great than 10 microunits/mL
2. 35-60 years of age
3. Overweight/obese subjects with BMI 27.1 - 35.0 kg/m2
4. Family history of cardiovascular disease or diabetes
5. Habitual diets containing ≥ 5.0% of energy from added sugars
6. Creatinine clearance of ≥80 mL/min

Exclusion Criteria:

1. 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)
2. Chronic skin disorder or treatment for acne
3. History of clinically significant dry eye or eye diseases such as glaucoma
4. Diabetes defined as fasting glucose ≥ 125 mg/dL or HbA1c ≥ 6.5%
5. Habitual diets with low content of added sugars (\<5% of total energy)
6. Any tobacco use
7. 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)
8. Contraindications of MRI
9. Alcohol intake weekly greater than 56 g/week (4 standard drinks/wk).
10. Major surgery or donation of blood of \>500 mL within the past 8 wks.
11. Patients with uncontrolled hypertension, i.e. ≥160/95 mmHg.
12. Patients with known cardiac abnormalities.

Primary outcomes:
measure: Change in Hepatic Lipogenesis
timeFrame: Baseline and after 10 days of treatment
Secondary outcomes:
measure: Change in Liver Fat Measured by MRI
timeFrame: Baseline and 10 days of treatment
measure: Change in Skin Sebum Production
timeFrame: Baseline and 10 days of treatment
Other outcomes:
Locations:
city: Columbia
country: United States
facility: University of Missouri
state: Missouri
Study officials:
affiliation: University of Missouri-Columbia
name: Elizabeth J Parks, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Syed-Abdul MM, Parks EJ, Gaballah AH, Bingham K, Hammoud GM, Kemble G, Buckley D, McCulloch W, Manrique-Acevedo C. Fatty Acid Synthase Inhibitor TVB-2640 Reduces Hepatic de Novo Lipogenesis in Males With Metabolic Abnormalities. Hepatology. 2020 Jul;72(1):103-118. doi: 10.1002/hep.31000. Epub 2020 May 7.