Table 1 Inclusion and exclusion criteria

Age ≥ 18 years at the time of informed consent

Diagnosis of generalized lipodystrophy or acquired partial lipodystrophy (APL)

Clinical diagnosis of familial partial lipodystrophy plus diagnosis of type 2 diabetes mellitus and hypertriglyceridemia.

Diagnosis of lipodystrophy is based on deficiency of subcutaneous body fat in a partial fashion assessed by physical examination and low skinfold thickness in the anterior thigh by caliper measurement: men (≤ 10 mm) and women (≤ 22 mm), and at least 1 of the following:

• Genetic diagnosis of familial PL (e.g., mutations in LMNA, PPAR-γ, AKT2, CIDEC, PLIN1 genes)

OR

• Family history of FPLD or family history of abnormal and similar fat distribution plus 1 Minor Criteria

OR

2 Minor Criteria (In the absence of FPLD-associated genetic variant or family history) and BMI< 35 kg/m2 MINOR Criteria

a. Requirement for high doses of insulin, e.g., requiring ≥ 200 U/day, ≥ 2 U/kg/day, or currently taking U-500 insulin

b. Presence of acanthosis nigricans on physical examination

c. Evidence/history of polycystic ovary syndrome (PCOS) or PCOS-like symptoms (hirsutism, oligomenorrhea, and/or polycystic ovaries)

d. History of pancreatitis associated with hypertriglyceridemia

e. Evidence of non-alcoholic fatty liver disease

• Hepatomegaly and/or elevated transaminases in the absence of a known cause of liver disease or radiographic evidence of hepatic steatosis (e.g., on ultrasound or CT)

Medical history of:

• Recently diagnosed with acute pancreatitis (4 weeks from Screening)

• acute or unstable cardiac ischemia (myocardial infarction, acute coronary syndrome, new-onset angina), stroke, transient ischemic attack (6 months from screening)

• major surgery within 3 months of Screening

• History of heart failure with New York Heart Association functional classification (NYHA) greater than Class II

• Uncontrolled hypertension (blood pressure [BP] > 160 mm Hg systolic and/or 100 mm Hg diastolic)

• History of bleeding diathesis or coagulopathy or clinically significant abnormality in coagulation parameters at Screening

• Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed before Study Day 1

• Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C or chronic hepatitis B

• Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated

Presence of diabetes mellitus associated with lipodystrophy [Hemoglobin (Hb) A1c ≥ 7 % and ≤ 12 %]

Clinically significant abnormalities in screening laboratory values that would render a subject unsuitable for inclusion, including the following:

• Urine protein/creatinine ratio (UPCR) ≥ 0.25 mg/mg.

• Estimated GFR ˂ 60 mL/min/1.73 m2

• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2x ULN

• Bilirubin > ULN

• Alkaline phosphatase (ALP) > 1.5 X ULN

• Platelet count ˂ LLN

Elevated fasting plasma triglycerides (≥ 500 mg/dL or ≥ 5.7 mmol/L)

Use of metreleptin or anti-obesity drugs within 3 months before screening, GLP-1 agonists or systemic corticosteroids or anabolic steroids within 4 weeks before screening

Presence of hepatosteatosis (fatty liver), as evidenced by a Screening MRI indicating a hepatic fat fraction (HFF) ≥ 6.4 %

History within 6 months of Screening of drug or alcohol abuse

Willing to maintain their customary physical activity level and to follow a diet moderate in carbohydrates and fats with a focus on complex carbohydrates and to replace saturated for unsaturated fats

Unwilling to comply with lifestyle requirements

Provided written informed consent