CLINICAL PROTOCOL to Investigate the Long-term Safety and Efficacy of Metreleptin in Various Forms of Partial Lipodystrophy

Leptin is now an approved therapeutic in the form of Myalept in patients with generalized
forms of lipodystrophy. However, it is still under investigation for patients with partial
forms of the disease based on FDA decision on February 24, 2014. The study investigators have
been carrying out a protocol in patients with partial lipodystrophy, specifically familial
partial lipodystrophy. There have been a number of patients who have been treated under this
protocol who are not covered by the currently approved label, but who have experienced
significant clinical benefit.

This study would allow continued treatment of patients with partial forms of lipodystrophy
who volunteered and completed treatment under the investigators' ongoing protocol (MB002-014)
and who have derived significant clinical benefit as judged by an amelioration of their
HbA1c, triglyceride levels, and/or reduction in their baseline diabetes or lipid therapies
that affect quality of life.

Inclusion Criteria:

- Previously completed study protocol:

o CLINICAL PROTOCOL to investigate the efficacy of recombinant human leptin
(METRELEPTIN) in nonalcoholic steatohepatitis (NASH) or nonalcoholic fatty liver
disease (NAFLD) associated with lipodystrophy, MB002-014 (IRMBED: HUM00058708)

- Demonstrates clinical benefit as defined by meeting at least one of the following
criteria upon completion of the above stated protocols:

- Reduction of HbA1c ≥ 1.0% or,

- Reduction of triglycerides ≥ 30% of baseline or,

- Decrease in insulin requirements ≥ 40% or,

- Reduction in total NASH score by ≥ 2 points,

- Significant worsening of metabolic parameters after discontinuation of
Metreleptin if discontinuation has been undertaken.

- A health condition that appears to have significantly improved by metreleptin for
which two independent health care providers make a request to prevent drug
discontinuation. In addition, the PI has to document absence of contraindications
for drug continuation (such as bone marrow suppression).

- 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) 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 partial (limbs) loss
of body fat outside the range of normal variation.

- If ≥ 18 years of age, is able to read, understand and sign the University of Michigan
institutional review board (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
University of Michigan 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 partial thromboplastin time 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.

- 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.

- 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.