Efficacy, Safety and Tolerability of ISIS 304801 in People With Partial Lipodystrophy With an Open-Label Extension

* INCLUSION CRITERIA: * Age greater than or equal to 18 years at enrollment (the time of informed consent, week -1) * Fasting triglyceride (TG) levels greater than or equal to 500 mg/dL (greater than or equal to 5.7 mmol/L) at enrollment. If the fasting TG value is \<500 mg/dL (\<5.7 mmol/L) but greater than or equal to 350 mg/dL (greater than or equal to 4.0 mmol/L) up to two additional tests may be performed in order to qualify, and a single level greater than or equal to 500 mg/dL will permit enrollment. OR * Fasting TG levels greater than or equal to 200 mg/DL (2.6 mmol/L) with a hemoglobin A1C over 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 * Clinical diagnosis of lipodystrophy based on deficiency of subcutaneous body fat in a partial fashion assessed by physical examination, and low skinfold thickness in anterior thigh by caliper measurement: men (less than or equal to 10mm) and women (less than or equal to 22mm), plus one of the following: * Genetic diagnosis of familial PL (e.g., mutations in LMNA, PPARG, AKT2, or PLIN1 genes) OR * Family history of familial PL or abnormal and similar fat distribution plus 1 minor criterion (below), OR * 2 minor criteria (below) in the absence of genetic diagnosis of family history * MINOR Criteria * Diabetes mellitus with requirement for high doses of insulin, eg, requiring greater than or equal to 200 U/day,greater than or equal to 2 U/kg/day, or currently taking U-500 insulin * Presence of acanthosis nigricans on physical examination * History of polycystic ovary syndrome (PCOS) or PCOS-like symptoms (hirsutism, oligomenorrhea, and/or polycystic ovaries) * History of pancreatitis associated with hypertriglyceridemia * 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) * Satisfy one of the following: * Females: Non-pregnant and non-lactating; surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy), post-menopausal (defined as 12 months of spontaneous amenorrhea in females \>55 years of age or, in females less than or equal to 55 years, 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. * 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. Note: Abstinence is only an effective method of birth control when this is the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial and withdrawal are not acceptable methods of contraception. EXCLUSION CRITERIA: * A diagnosis of generalized lipodystrophy * Current or history of autoimmune diseases (even with a diagnosis of PL) unless approved by the Investigator and Sponsor Medical Monitor * Acute pancreatitis within 4 weeks of enrollment * History within 6 months of enrollment 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 * Major surgery within 3 months of enrollment * History of heart failure with New York Heart Association functional classification (NYHA) greater than Class II * Uncontrolled hypertension (blood pressure \[BP\] \>160/100 mm Hg) * Any of the following laboratory values at enrollment: * Cardiac troponin T \> upper limit of normal (ULN) * Measured or estimated (in case of triglycerides \> 400 mg/dL) LDL-C \>130 mg/dL on maximal tolerated statin therapy * Hemoglobin HbA1c greater than or equal to 9.5% * Hepatic: * Total bilirubin \>ULN * Alanine transaminase (ALT) \>3.0 x ULN. Higher levels will be permitted after a safety review by a hepatologist, that includes no evidence of cirrhosis. * Aspartate aminotransferase ( (AST) \>3.0 x ULN. Higher levels will be permitted after a safety review by a hepatologist, that includes no evidence of cirrhosis. * Renal: * Persistently positive (2 out of 3 tests greater than or equal to trace positive) for blood on urine dipstick. In the event of a positive test eligibility may be confirmed with urine microscopy showing less than or equal to 5 red blood cells per high power field (urine will be screened at admission and repeated if abnormal). If red blood cell counts (RBC) are high every effort will be made to determine if the source is renal or benign, such as from menstrual bleeding. If the presence of RBC is determined to be from a non-renal source, the PI will make the decision to proceed with protocol testing and/or randomization. * Two out of three consecutive tests greater than or equal to 1+ for protein on urine dipstick. In the event of a positive test eligibility may be confirmed by either a spot urine albumin to creatinine ratio \<1000mg/g or a quantitative total urine albumin measurement of \< 1g/24 hrs (urine will be screened at admission and repeated if abnormal) * Estimated creatinine clearance calculated according to the formula of Cockcroft and Gault \<60 mL/min * Platelet count below 140,000 K/uL * 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 * Uncontrolled hypothyroidism (abnormal thyroid function tests should be approved by the Investigator) * History within 6 months of enrollment of screening of drug or alcohol abuse * History of bleeding diathesis or coagulopathy or clinically significant abnormality in coagulation parameters at enrollment * Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to enrollment * 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 * Treatment with another investigational drug, biological agent, or device within one month of enrollment, or 5 half-lives of investigational agent, whichever is longer * Unwilling to comply with contraceptive and lifestyle (diet/exercise) requirements * Use of any of the following: * Use of metreleptin within the last 3 months prior to enrollment * Antidiabetic, lipid lowering, or atypical antipsychotic medication, unless on a stable dose for at least 3 months prior to enrollment * Insulin unless on a stable daily insulin dose regimen (+/- 20 %) for at least 4 weeks prior to enrollment * Use of nicotinic acid or derivatives within the last 4 weeks prior to enrollment * Systemic corticosteroids or anabolic steroids within 6 weeks prior to enrollment unless approved by the Investigator * Antihypertensive medication unless on a stable dose for at least 4 weeks prior to enrollment * Tamoxifen, estrogens or progestins unless on a stable dose for at least 4 months prior to enrollment and dose and regimen expected to remain constant throughout the study * Oral anticoagulants unless on a stable dose for at least 4 weeks prior to enrollment and regular clinical monitoring is performed * Prior exposure to ISIS 304801 * Anti-obesity drugs \[e.g., the combination of phentermine and extended-release topiramate (Osymia, orlistat (Xenical), liraglutide \[rDNA origin\] injection (Saxenda) and lorcaserin (Belvig), phentermine, amphetamines, herbal preparations\] within 12 weeks prior to screening * Any other medication unless stable at least 4 weeks prior to enrollment (occasional or intermittent use of over-the-counter medications will be allowed at Investigator s discretion) * Blood donation of 50 to 499 mL within 30 days or of \>499 mL within 60 days * 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