Dose-Escalating Safety Study in Subjects on Stable Statin Therapy

• Percent reduction in apoB-100 [ Time Frame: From baseline measurement ] [ Designated as safety issue: No ]
• Percent change in HDL-cholesterol, triglycerides, total cholesterol, non-HDL cholesterol, VLDL plus LDL-cholesterol and LDL-cholesterol particle size and concentration [ Time Frame: From baseline measurement ] [ Designated as safety issue: No ]
• Percent change from baseline in LDL/HDL and apoB-100/apo-A1 ratios [ Time Frame: From baseline measurement ] [ Designated as safety issue: No ]
• AEs, SAEs, physical examination data, vital signs, and laboratory analyzes [ Time Frame: Duration of study ] [ Designated as safety issue: Yes ]

• Percent reduction in apoB-100 from baseline
• Percent change from baseline in HDL-cholesterol, triglycerides, total cholesterol, non-HDL cholesterol, VLDL plus LDL-cholesterol and LDL-cholesterol particle size and concentration
• Percent change from baseline in LDL/HDL and apoB-100/apo-A1 ratios

The aim of this study is to assess the safety of varying doses of ISIS 301012 in subjects on Stable statin therapy.

• Drug: ISIS 301012 or Placebo
  30 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29
• Drug: ISIS 301012 or Placebo
  100 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29
• Drug: ISIS 301012 or Placebo
  200 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29
• Drug: ISIS 301012 or Placebo
  300 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29
• Drug: ISIS 301012 or Placebo
  400 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29
• Drug: ISIS 301012 or Placebo
  200 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, and 85
• Drug: ISIS 301012 or Placebo
  300 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, and 85

• Experimental: Cohort A
  Loading doses followed by weekly maintenance doses
  Intervention: Drug: ISIS 301012 or Placebo
• Experimental: Cohort B
  Loading doses followed by weekly maintenance doses
  Intervention: Drug: ISIS 301012 or Placebo
• Experimental: Cohort C
  Loading doses followed by weekly maintenance doses
  Intervention: Drug: ISIS 301012 or Placebo
• Experimental: Cohort D
  Loading doses followed by weekly maintenance doses
  Intervention: Drug: ISIS 301012 or Placebo
• Experimental: Cohort E
  Loading doses followed by weekly maintenance doses
  Intervention: Drug: ISIS 301012 or Placebo
• Experimental: Cohort F
  Loading doses followed by extended weekly maintenance doses
  Intervention: Drug: ISIS 301012 or Placebo
• Experimental: Cohort G
  Loading doses followed by extended weekly maintenance doses
  Intervention: Drug: ISIS 301012 or Placebo

Inclusion Criteria:

• On a stable dose of >/= 40 mg Simvastatin or atorvastatin daily for >/= 3 months prior to baseline and expected to remain on this dose for the remainder of the study
• LDL-cholesterol between 2.60 and 5.70 mmol/L (100 and 220 mg/dL), inclusive at screening
• Females not of childbearing potential.

Exclusion Criteria:

• History of CHD or CHD-equivalent (such as diabetes mellitus, or another clinical form of atherosclerotic disease, e.g., peripheral arterial disease, abdominal aortic aneurysm, or symptomatic carotid artery disease)
• Fasting triglyceride >2.26 mmol/L (200 mg/dL) at screening
• Any uncontrolled medical/surgical/psychiatric condition, including conditions that may predispose to secondary hypercholesterolemia
• Current diagnosis or known history of complement deficiency or abnormality
• A positive hepatitis B surface antigen or hepatitis C antibody, or a known positive HIV status
• Current diagnosis or known history of liver disease, or has an ALT >ULN at screening
• Known history of fibromyalgia, myopathy, myositis, rhabdomyolysis, any unexplained muscle pain, or has a CPK >ULN at screening
• Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin that has been adequately treated
• The advisability of a subject taking any prescription medication (apart from simvastatin or atorvastatin) within 6 weeks prior to screening should be discussed with the Isis Medical Monitor
• Subject unwilling to discontinue taking alternative/herbal medication for the duration of the study
• History of drug abuse within 2 years of screening
• Subject unwilling to limit alcohol consumption for the duration of the study: male subjects to a maximum of 3 drinks (30 g) per day, and <12 drinks (120 g) per week; female subjects to a maximum of 2 drinks (20 g) per day, and <8 drinks (80 g) per week
• Known allergy or hypersensitivity to simvastatin
• Undergoing or has undergone treatment with another investigational drug, biologic agent, or device within 3 months, or 3 half lives, prior to screening, whichever is longer