The purpose is to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of IONIS ANGPTL3-LRx (ISIS 703802) given to healthy volunteer subjects with elevated triglycerides and subjects with familial hypercholesterolemia.

Inclusion Criteria for All Cohorts:

• Must have given written informed consent and be able to comply with all study requirements
• Males or females 18 to 65 years, inclusive, at the time of informed consent
• Body Mass Index (BMI) ≤ 35.0 kg/m2
• Females must be non-pregnant and non-lactating, and either surgically sterile or postmenopausal.
• Males must be surgically sterile, abstinent or using an acceptable contraceptive method

Inclusion criteria for Cohorts, A, D, and AA to DD only:

• Fasting triglycerides (TG) ≥ 150 mg/dL at Screening
• Fasting low density lipoprotein cholesterol (LDL-C) > 70 mg/dL at Screening

Inclusion criteria for Cohorts B and C only:

• Fasting TG 90 - 150 mg/dL at Screening
• Fasting LDL-C > 70 mg/dL at Screening

Inclusion Criteria for Cohort EE Only:

• Homozygous FH diagnosis and fasting LDL-C ≥ 190 mg/dL (4.9 mmol/L)

Inclusion Criteria for Cohort FF Only:

• Heterozygous FH diagnosis and fasting LDL-C ≥ 160 mg/dL (4.1 mmol/L)

Inclusion Criteria for Cohorts EE and FF Only:

• Maximally tolerated stable LDL-C lowering agents (stable for at least 12 weeks)
• On stable low-fat diet
• Stable weight (± 4 kg) for ≥ 6 weeks prior to screening

Exclusion Criteria for All Cohorts:

• Known history or positive test for Human Immunodeficiency Virus (HIV), Hepatitis C (HCV), or Hepatitis B (HBV)
• Treatment with another Study Drug, biological agent, or device within one-month or 5-half-lives of screening
• Regular use of alcohol within 6 months of screening
• Use of concomitant drugs unless authorized by the Sponsor Medical Monitor
• Known contraindication and/or allergy to heparin
• Smoking > 10 cigarettes a day
• Considered unsuitable for inclusion by the Principal Investigator

Exclusion Criteria for Cohorts EE and FF:

• Myocardial infarction, percutaneous transluminal coronary intervention, or coronary artery bypass graft surgery within 12 weeks prior to screening, or cerebrovascular accident within 24 weeks prior to screening. Participants with adequately treated stable angina, per Investigator assessment, may be included
• Congestive heart failure defined by NYHA Classes III or IV
• Type 2 diabetes mellitus (T2DM) with HbA1c > 8.0%
• Prior treatment with gene therapy
• Currently receiving apheresis treatments or last apheresis treatment was within 8 weeks of screening