Gemcabene for the Treatment of Pediatric NAFLD

This is a multicenter, prospective, open-label, Phase 2, proof of concept study to test preliminary efficacy and safety of gemcabene in children with established nonalcoholic fatty liver disease (NAFLD) incompletely treated by lifestyle changes. The hypothesis of the study is that 300 mg of gemcabene once a day for 12 weeks will reduce alanine aminotransferase (ALT), hepatic steatosis, dyslipidemia and down regulate de novo lipogenesis in children with NAFLD.

Nonalcoholic fatty liver disease (NAFLD) has quickly become the most common liver disease in children in the US and is rising worldwide. While the true prevalence and incidence are not known, estimates have placed prevalence in the US as high as 7 million children. The prevalence varies greatly across race and ethnic groups with Hispanic, Asian and White children having increased rates compared to African American children. Lifestyle changes are the first line treatment, but many children fail to respond to these. Pharmaceutical treatments are needed for children that cure NAFLD and ideally also benefit the systemic features (dyslipidemia, insulin sensitivity, BMI). Gemcabene calcium (Gemcabene) is a promising therapeutic that may benefit pediatric NAFLD and early phase trials are needed to support further development for this indication. It has several mechanisms of action including enhancing the clearance of very-low-density lipoprotein (VLDL) and blocking the production of hepatic triglyceride and cholesterol synthesis. Gemcabene was previously tested in adults for treatment of dyslipidemia and has extensive safety data.

In this study, 40 children ages 12-17 years with histologically confirmed NAFLD or MRI based diagnosis and elevated ALT will receive 300 mg of gemcabene per day for 12 weeks. Study visits will occur at screening, baseline, week 2, week 6 and week 12. A follow up phone call will occur one month after the child stops taking the study medication.

Eligibility Criteria:
Inclusion Criteria:

1. Provision of signed and dated informed consent form
2. Provision of signed and dated assent, if indicated
3. Stated willingness to comply with all study procedures and availability for the duration of the study
4. Children aged 12-17 years at the time of informed consent
5. History of clinical diagnosis of NAFLD including a, b and c below:

   1. Medical history eliminating, other chronic liver diseases (for example mitochondrial diseases, hepatotoxic drugs, anorexia nervosa)
   2. Laboratory studies: negative testing for hepatitis C and normal ceruloplasmin
   3. Either liver biopsy confirming NAFLD or MRI \> 10% steatosis within the past three years
6. ALT ≥ 54 U/L for boys or ≥ 46 U/L for girls and ≤ 250 U/L at screening visit and within past three months (prior to screening). If ALT at screening is more than two times the historic value (or a historic value is not available), the subject will be asked to repeat the ALT after four weeks. If the repeat ALT is more than 50% increased or decreased over the screening ALT a third ALT may be obtained. If a third ALT is not within 50% of the previous value then the subject is ineligible, but may be rescreened at a later date.
7. Body weight ≥ 60 kg at the time of screening
8. Able to take oral medication and be willing to adhere to the study drug regimen
9. Minimum of three months of attempted lifestyle modification to treat the NAFLD and agreement to adhere to Lifestyle Considerations (dietary improvement and physical activity) throughout study duration

Exclusion Criteria:

1. Heart disease (e.g., myocardial infarction, heart failure, unstable arrhythmias)
2. Seizure disorder
3. Active coagulopathy (international normalized ratio (INR) \> 1.4)
4. Renal dysfunction with an estimated glomerular filtration rate (eGFR) \<60ml/min/1.73 calculated using Schwartz Bedside GFR calculator for children
5. History of active malignant disease requiring chemotherapy or radiation
6. History of significant alcohol intake (AUDIT questionnaire) or inability to quantify alcohol consumption
7. Use of new medications or supplements with the intent to treat NAFLD/nonalcoholic steatohepatitis (NASH) during the 30 days prior to screening, including statin therapy. Medications or supplements (including metformin and vitamin E) that they have been on and are on a stable dose are acceptable
8. History of bariatric surgery or planning to undergo bariatric surgery during study duration
9. Clinically significant depression
10. Any girl nursing, planning a pregnancy, known or suspected to be pregnant, or who has a positive pregnancy screen
11. Non-compensated liver disease defined as cirrhosis and any one of the following hematologic, biochemical, and serological criteria on entry into protocol:

    * Hemoglobin \< 10 g/dL;
    * White blood cell (WBC) \< 3,500 cells/mm3;
    * Neutrophil count \< 1,500 cells/mm3;
    * Platelets \< 150,000 cells/mm3;
    * Total bilirubin \> 1.3 mg/dL unless due to Gilbert's syndrome (subjects with a history of Gilbert's syndrome may be included if both direct bilirubin and the reticulocyte count do no exceed the upper limit of normal (ULN) \[reflexive direct bilirubin testing will be used to confirm Gilbert's syndrome\])
    * Albumin \< 3.2 g/dL
    * INR \> 1.3
    * Abnormal alkaline phosphatase
    * Any history of ascites, variceal bleeding, hepatic encephalopathy, or hepatocellular carcinoma (HCC)
12. Poorly controlled diabetes mellitus (hemoglobin A1c (HbA1c) \> 8%) or requiring insulin
13. Patients with type I diabetes mellitus
14. Chronic liver disease other than NAFLD
15. Patients on Cytochrome P450 3A4 (CYP3A4) inhibitors such as itraconazole or macrolide antibiotics are excluded
16. Patients who are on thiazolidinediones, fibrates or fish oils are excluded
17. Patients who are on daily prescription medications are excluded except for allergy medications, Attention Deficit Hyperactivity Disorder (ADHD) medications, asthma medications, or any other acceptable medication in the opinion of the investigator
18. Abnormal creatinine kinase levels at screening (may be repeated if the elevation is thought to be exercise related)
19. Sexually active female participants of childbearing potential and Tanner stage ≥ 4 or menstruating unwilling to utilize two acceptable forms of contraception from screening through completion of the study or unwilling to complete pregnancy tests throughout the study
20. Currently enrolled in a clinical trial or who received an investigational study drug within 90 days of screening
21. Participants who are not able or willing to comply with the protocol or have any other condition that would impede compliance or hinder completion of the study, in the opinion of the investigator