Clinical Protocol to Investigate the Efficacy of Recombinant Human Leptin (Metreleptin) in Nonalcoholic Steatohepatitis (NASH) or Nonalcoholic Fatty Liver Disease (NAFLD) Associated With Lipodystrophy

The goal is to test the efficacy of restorative leptin therapy on the degree of hepatic
steatosis and on amelioration of pathological features of NASH/NAFLD. In addition, the study
will evaluate the impact of leptin therapy on total body insulin sensitivity and lipid
levels as well as energy expenditure. In order to accomplish this aim, we now propose an
efficacy study with recombinant human leptin therapy in patients with all forms of
lipodystrophy who also have NASH/NAFLD.

1. AIM 1: To determine the efficacy of leptin in promoting amelioration of body
composition, hepatic steatosis and histopathological scores in patients with all forms
of lipodystrophy and NAFLD/NASH. We will conduct a 1 year, open-label study, to assess
the metabolic effects of recombinant human leptin (METRELEPTIN, AztraZeneca,
Wilmington, DE). The primary outcome measure will be NASH scores. We will also explore
body weight, insulin sensitivity, glucose and lipid control, body composition, and free
fatty acid levels.

2. AIM 2: To Investigate molecular effects of leptin therapy. In parallel to our
preliminary studies, gene expression will be performed on individuals participating in
Aim 1 at baseline and following 1 year of leptin. We will combine this with measures of
liver metabolite levels to provide novel insights into alterations in metabolism that
occur secondary to leptin therapy. We will also measure plasma metabolites at baseline
and after 2 (optional), 24 and 48 weeks of therapy to assess the dynamic changes
induced by leptin and correlate these changes with phenotypic measures.

Inclusion Criteria:

- Is male or female ≥ 5 years old at baseline.

- Is male, female not of childbearing potential, or meets all the following criteria if
female of childbearing potential (including perimenopausal women who have had a
menstrual period within one year):

- Not breastfeeding

- Negative pregnancy test result (human chorionic gonadotropin, beta subunit
[βhCG]) at baseline (not applicable to hysterectomized females).

- Must practice and be willing to continue to practice appropriate birth control
(defined as a method which results in a low failure rate when use consistently
and correctly, such as implants, injectables, oral contraceptives, some
intrauterine contraceptive devices, sexual abstinence, tubal ligation, or a
vasectomized partner) during the entire duration of metreleptin treatment.

- Has physician-confirmed lipodystrophy as defined by evidence of generalized (whole
body) or partial (limbs) loss of body fat outside the range of normal variation.

- Alcohol consumption of less than 40 grams/week.

- A liver ultrasound confirming non-alcoholic fatty liver disease, or previous liver
biopsy confirming NASH status.

- If ≥ 18 years of age, is able to read, understand and sign the U of M IRBMED approved
informed consent form (ICF), communicate with study physician and study team,
understand and comply with protocol requirements.

- If < 18 and ≥ 7 years of age, is able to read, understand and sign the appropriate U
of M IRBMED approved assent form and has a parent or legal guardian that is able to
read, understand and sign the ICF.

- If < 7 and ≥ 5 years of age or unable to read, the appropriate assent form must be
explained to the child.

- If previously treated with thiazolidinediones or Vitamin E, stable dose of these
medications for at least 3 months.

Exclusion Criteria:

- Presence of advanced liver disease (as evidenced by abnormal synthetic function,
abnormal PT or albumin).

- Evidence of other etiologies of viral hepatitis.

- Presence of clinically significant hematologic abnormalities (such as neutropenia
and/or lymphadenopathy).

- Presence of HIV infection.

- Very poorly controlled diabetes; HbA1c >10%

- Inability to give informed consent.

- Presence of ESRD, 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.

- Active infection (may be transient).

- Has known allergies to E. coli-derived proteins or hypersensitivity to any component
of metreleptin treatment.

- Any other condition in the opinion of the investigators that may impede successful
data collection.