The purpose of this study is to evaluate the dose/response pharmacodynamic effects of ISIS ApoC-III Rx vs. Placebo on fasting total apoC-III levels.

Inclusion Criteria:

• Severe hypertriglyceridemia

Exclusion Criteria:

• HbA1c >/=9.0%, type 1 diabetes, or history of outpatient insulin use for more than 2 weeks in the last year
• Body mass index (BMI) >40 kg/m2
• History of bariatric surgery or currently on weight loss drugs
• Use of oral contraceptives or hormone replacement therapy or statins unless stable for 3 months prior to dosing
• Group 1 and 2 patients: Use of systemic corticosteroids, fibrates, niacin, fish oil or other products containing omega-3 fatty acids within 6 weeks of dosing. Group 3 patients: unable to discontinue use of systemic corticosteroids at least 6 weeks prior to dosing ; use of niacin, fish oil, or other products containing omega-3 fatty acids unless on a stable well controlled dose for at least 30 days prior to screening that is not anticipated to change during the study period. Group 4 patients: unable to discontinue use of systemic corticosteroids at least 6 weeks prior to dosing; use of fibrates niacin, fish oil, or other products containing omega-3 fatty acids unless on a stable well controlled dose for at least 30 days prior to screening that is not anticipated to change during the study period.
• Use of topical corticosteroids, anticoagulants, or drugs or dietary supplements with potential lipid-altering effects unless dose is stable and well controlled for 30 days prior to dosing
• Any Screening laboratory values that are out of allowed reference ranges
• Inability to comply with protocol or study procedures
• Any other significant illness or condition that may adversely affect the subjects participation in the study