A Study of Olezarsen (Formerly Known as AKCEA-APOCIII-LRx) in Adults With Hypertriglyceridemia and Atherosclerotic Cardiovascular Disease (Established or at Increased Risk for), and/or With Severe Hypertriglyceridemia

A Randomized, Double-blind, Placebo-Controlled, Phase 2b Study of ISIS 678354 in Patients With Hypertriglyceridemia and Atherosclerotic Cardiovascular Disease (Established or at Increased Risk for), and/or With Severe Hypertriglyceridemia

The purpose of the study was to evaluate the effect of olezarsen on percent change in fasting triglyceride (TG) levels compared to placebo at Months 6 and 12 and the proportion of participants who achieve different thresholds in fasting TG. Other objectives were to evaluate the effect of olezarsen on percent change in fasting apolipoprotein C-III (apoC-III), very low-density lipoprotein cholesterol (VLDL-C), remnant cholesterol, non-high-density lipoprotein cholesterol (non-HDL-C), HDL-C, total cholesterol (TC), apolipoprotein B (apoB), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein A-1 (apoA-1).

This was a multi-center, randomized, double-blind, placebo-controlled study in participants with hypertriglyceridemia (triglycerides > 150 milligrams per deciliter [mg/dL]) and established or at increased risk for atherosclerotic cardiovascular disease, and/or with severe hypertriglyceridemia. The study had an up to 8-week screening period, a 53-week treatment period, and a 13-week post-treatment follow-up period.

Inclusion Criteria:

1. Aged ≥ 18 years at the time of informed consent

2. Fall into at least 1 of the following groups (a or b):

   1. Hypertriglyceridemia with fasting TG ≥ 150 mg/dL (1.69 millimoles per liter [mmol/L]) and < 500 mg/dL (5.65 mmol/L) with either clinical diagnosis of atherosclerotic cardiovascular disease (ASCVD) or at increased risk for ASCVD
   2. Severe hypertriglyceridemia with fasting TG ≥ 500 mg/dL (5.65 mmol/L).

3. Participants must be on standard-of-care (SOC), lipid-lowering medications per local guidelines.

4. Participants must be willing to comply with diet and lifestyle recommendations as able.

Exclusion Criteria:

1. Diabetes with any of the following:

   1. Newly diagnosed within 12 weeks of screening
   2. Hemoglobin A1C (HbA1c) ≥ 9.5% at Screening
   3. Change in basal insulin regimen > 20% within 3 months prior to Screening
   4. For participants with type 1 diabetes: episode of diabetic ketoacidosis, or ≥ 3 episodes of severe hypoglycemia within 6 months prior to Screening

2. Acute coronary syndrome or stroke/transient ischemic attack (TIA) within 6 months prior to Screening

3. Major surgery, peripheral revascularization, or non-urgent percutaneous coronary intervention (PCI) within 3 months prior to Screening, or upcoming planned major surgery or major procedure (e.g., arterial revascularization) during the course of the study

4. Active pancreatitis within 4 weeks prior to Screening