Recombinant Leptin Therapy for Treatment of Nonalcoholic Steatohepatitis (NASH)
Condition: Fatty Liver Disease, Nonalcoholic
MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
Intervention: metreleptin
Intervention description: 0.1 mg/kg/day once a day via subcutaneous injections
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 9.0
Sex: Male
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Nonalcoholic fatty liver disease; Insulin resistance; Obesity; Leptin therapy; NASH

Summary:

      Nonalcoholic steatohepatitis (or NASH) is known to be caused by deposition of fat in the
      liver and development of scarring. This condition occurs more frequently in overweight and
      obese persons. It is often associated with resistance to the actions of insulin hormone. Fat
      cells secrete a hormone called leptin. Recently, we have learned that obese or overweight
      persons make too much leptin, which may contribute to insulin resistance. Paradoxically,
      patients who do not have any fat cells, also have insulin resistance. In these patients,
      insulin resistance is caused by the absence of leptin and leptin replacement significantly
      improves insulin resistance and fat deposition in the liver. In an earlier study, we
      determined the leptin levels in patients with NASH and how these levels are related to body
      fat levels as well as responsiveness to insulin. We saw that a subgroup of patients with NASH
      have relatively low levels of leptin in contrast to the amount of body fat they had. We now
      would like to see if restoring leptin levels to normal will improve the disease process in
      these patients. Our study patients will be male patients, aged between 18 and 65 (inclusive),
      who do not have any other cause for their liver disease. We have put some restrictions in
      body size such that a spectrum of patients from normal weight to obese range would be
      included. They will also demonstrate low leptin levels (levels similar to only 25% of normal
      population). We will use a genetically engineered form of leptin manufactured by Amylin Inc.
      given via injections under the skin. We plan to continue therapy for a period of one year and
      evaluate the change in liver disease by a liver biopsy. We will also follow the metabolic
      parameters and body composition characteristics that we examined in our earlier study. We
      expect that patients with low blood leptin levels will show improvement in their liver
      disease and insulin resistance when their blood leptin levels are restored to normal.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Biopsy proven NASH

          -  Circulating fasting leptin <9 ng/mL (staggered criteria for different BMI levels)

        Exclusion Criteria:

          -  Presence of advanced liver disease (as evidenced by abnormal synthetic function,
             abnormal prothrombin time or albumin)

          -  Presence of clinical lipodystrophy

          -  Presence of other liver disease

          -  Presence of clinical diabetes (fasting >126 mg/dL or 2 hour post 75 g-glucose >200
             mg/dL or random glucose >200 mg/dL with presence of diabetes symptoms or known history
             of diabetes)

          -  Any medication for treatment of NASH or obesity

          -  Presence of HIV

          -  Inability to give informed consent

          -  Presence of end-stage renal disease, any type of active cancer, or >class 2 congestive
             heart failure ((New York Heart Association Functional Classification System), based on
             medical history and physical examination

          -  Presence of any other condition that limits life expectancy to <2 years

          -  Active infection (may be transient)

          -  Any other condition in the opinion of the investigators that may impede successful
             data collection