A Randomized, Double-Blind, Placebo-Controlled, with an Open Label Extension, Phase 2/3 Study of volanesorsen Administered Subcutaneously to Patients with Familial Partial Lipodystrophy

1. Must give written informed consent to participate in the study (signed and dated) and any authorizations required by law
2. Age * 18years at the time of informed consent
3. Clinical diagnosis of familial partial lipodystrophy plus diagnosis of type 2 diabetes mellitus and hypertriglyceridemia.
4. A diagnosis of type 2 diabetes mellitus as defined by the International Diabetes Federation guidelines of 2012, made at least 6 months prior to the Screening, and
* A HbA1c * 7% to * 12% at Screening,
* On anti-diabetic therapy consisting of:
a. Metformin * 1500 mg/day, or
b. If the dose of metformin is < 1500 mg/day, or metformin is not tolerated, then the patient should be on other oral anti-diabetic drugs (OAD) or an injectable glucagon-like peptide-1 (GLP-1) receptor agonist, or
c. Insulin therapy alone or in combination with other anti-diabetic drugs;5.Hypertriglyceridemia is defined as Fasting TG levels * 500mg/dL (*5.7mmol/L) at Screening and Qualification Visit.
Patients with the clinical diagnosis of FPL and with Fasting TG levels * 200 (* 2.26 mmol/L) to < 500 mg/dL (* 5.7 mmol/L) at both Screening and Qualification Visits who meet the genetic or family history criteria for study inclusion may be further screened and enrolled in the study.
6. Presence of hepatosteatosis (fatty liver), as evidenced by a Screening MRI indicating a hepatic fat fraction (HFF) * 6.4%
7. 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 replacing saturated for unsaturated fats.
8. Satisfy one (1) of the following:
a. Females: Non-pregnant and non-lactating; surgically sterile (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy), post-menopaudal (defined as 12 months of spontaneous amenorrhea in females > 55 years of age or, in females * 55years, 12 months of spontaneous amenorrhea without an alternative medical cause and follicle-stimulating hormone (FSH) levels in the postmenopausal range for the laboratory involved), abstinent, or if engaged in sexual relations of child-bearing potential, patient is using an acceptable contraceptive method from time of signing the informed consent form until at least 13 weeks after the last dose of Study Drug administration
b. Males: Surgically sterile, abstinent, or if engaged in sexual relations with a female of child-bearing potential, patient is utilizing an acceptable contraceptive method from the time of signing the informed consent form until at least 13 weeks after the last dose of Study Drug administration

1. A diagnosis of generalized lipodystrophy
2. A diagnosis of acquired partial lipodystrophy (APL)
3. Acute pancreatitis within 4 weeks of Screening
4. History within 6 months of Screening of acute or unstable cardiac ischemia (myocardial infarction, acute coronary syndrome, new onset angina), stroke, transient ischemic attack or unstable congestive heart failure requiring a change in medication
5. Major surgery within 3 months of Screening
6. history of heart failure with New York Heart Association functional classification (NYHA) greater than Class II or unstable congestive cardiac failure requiring a change in medication
7. Uncontrolled hypertension (blood pressure [BP] >160 mm Hg systolic and/or 100 mm Hg diastolic)
8. Any of the following laboratory values at Screening:
a. Cardiac troponin I > upper limit of normal (ULN)
b. LDL-C > 130mg/dL on maximal tolerated statin therapy
c. Hepatic: Total bilirubin >ULN; Alanine aminotransferase (ALT) > 3.0xULN; Aspartate aminotransferase (AST) > 3.0xULN
d. Renal: Persistently positive (2 out of 3 tests * trace positive) for blood on urine dipstick. In the event of a positive test eligibility may be confirmed with urine microscopy showing * 5 red blood cells per high power field; Two (2) out of three (3) consecutive tests * 1+ for protein on urine dipstick. In the event of a positive test eligibility may be confirmed by a quantitative total urine protein measurement of < 1.0g/24hrs; Estimated creatinine clearance calculated according to the formula of Cockcroft and Gault < 60mL/min
e.Platelet count < lower limit of normal (LLN)
f. Clinically significant (as determined by the Investigator or Sponsor) abnormalities on laboratory examination that will increase risk to the patient or interfere with data integrity
9. Uncontrolled hypothyroidism (abnormal thyroid function tests should be approved by Study Medical Monitor)
10. History within 6 months of Screening of drug or alcohol abuse
11. History of bleeding diathesis or coagulopathy or clinically significant abnormality in coagulation parameters at Screening
12. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1
13. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C or chronic hepatitis B
14. 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
15. Treatment with another investigational durg, biological agent, or device within one (1) month of Screening, or 5 half-lives of investigational agent, whichever is longer
16. Unwilling to comply with lifestyle requirements
17. Use of any of the following:
a. Metreleptin within the last 3 months prior to Screening
b. Antidiabetic, lipid lowering, or atypical antipsychotic medication, unless on a stable dose for at least 3 months prior to Screening
c. insulin unless on a stable daily insuling dose regime (±20%) for at least 4 weeks prior to dosing
d. GLP-1 agonists within 4 weeks prior to dosing, if patient has a history of pancreatitis
e. Nicotinic acid or derivates of nicotinic acid within 4 weeks prior to screening
f. Systemic corticosteroids or anabolic steroids within 6 weeks prior to Screening unless approved by the Sponsor Medical Monitor
g. Antihypertensive medication unless on a stable dose for at least 4 weeks prior to dosing
h. Tamoxifen, estrogens or progestins unless on a stable dose for at least 4 months prior to Screening and dose and regimen expected to remain constant throughout the study
i. oral anticoagulants unless on a stable dose for at least 4 weeks prior to dosing and regular clinical monitoring is performed
j. Anti-obesity drugs within 12 weeks prior to screening
k. Prior exposure to volanesorsen
l. Any other medication unless stable at least 4 weeks prior to dosing (occasional or intermittent use of over-the-counter medications will be allowed at Investigator's discretion)
18. Blood donation of 50 to 499mL within 30 days of Screening or of >499mL within 60 days of Screening
19. Have any other conditions, which, in the opinion of the Investigator or the Sponsor would make the patient unsuitable for inclusion, or could interfere with the patient participating in or completing the study