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

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the effect of olezarsen on percent change in fasting triglyceride (TG) levels compared to placebo at Months 6 and 12 and the percentage of participants who achieve different thresholds in fasting TG. Another objective is 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).

Detailed Description
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This will be a multi-center, randomized, double-blind, placebo-controlled study in approximately 152 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 will have an up to 8-week screening period, a 53-week treatment period, and a 13-week post-treatment follow-up period.

Official Title
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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

Conditions
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Hypertriglyceridemia, Atherosclerotic Cardiovascular Disease, Severe Hypertriglyceridemia

Intervention / Treatment
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* Drug: Olezarsen
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged ≥ 18 years at the time of informed consent Fall into at least 1 of the following groups (a or b): 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 Severe hypertriglyceridemia with fasting TG ≥ 500 mg/dL (5.65 mmol/L). Participants must be on standard-of-care (SOC), lipid-lowering medications per local guidelines. Participants must be willing to comply with diet and lifestyle recommendations as able. Exclusion Criteria: Diabetes with any of the following: Newly diagnosed within 12 weeks of screening Hemoglobin A1C (HbA1c) ≥ 9.5% at Screening Change in basal insulin regimen > 20% within 3 months prior to Screening For participants with type 1 diabetes: episode of diabetic ketoacidosis, or ≥ 3 episodes of severe hypoglycemia within 6 months prior to Screening Acute coronary syndrome or stroke/transient ischemic attack (TIA) within 6 months prior to Screening 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 Active pancreatitis within 4 weeks prior to Screening

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Olezarsen<br>Olezarsen will be administered once every 4 weeks by subcutaneous (SC) injection for up to 49 weeks. | Drug: Olezarsen<br>* Olezarsen will be administered by SC injection.<br>* Other names: AKCEA-APOCIII-LRx;|
| Placebo Comparator: Placebo<br>Olezarsen-matching placebo will be administered once every 4 weeks by SC injection for up to 49 weeks. | Drug: Placebo<br>* Olezarsen-matching placebo will be administered once every 4 weeks by SC injection for up to 49 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline at Month 6 (average of Weeks 25 and 27) in Fasting Triglycerides (TG) |  | Baseline and Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline at Month 12 in Fasting TG |  | Baseline and Month 12 | 
| Proportion of Participants with Baseline TG < 500 mg/dL (5.65 mmol/L) Who Achieve Fasting TG < 150 milligrams per deciliter (mg/dL) (1.69 millimoles per liter [mmol/L]) at Month 6 |  | Baseline and Month 6 | 
| Proportion of Participants with Baseline TG < 500 mg/dL (5.65 mmol/L) Who Achieve Fasting TG < 150 mg/dL (1.69 mmol/L) at Month 12 |  | Baseline and Month 12 | 
| Proportion of Participants with Baseline TG ≥ 500 mg/dL Who Achieve Fasting TG < 500 mg/dL (5.65 mmol/L) at Month 6 |  | Baseline and Month 6 | 
| Proportion of Participants with Baseline TG ≥ 500 mg/dL Who Achieve Fasting TG < 500 mg/dL at Month 12 |  | Baseline and Month 12 | 
| Percent Change From Baseline at Months 6 and 12 in Fasting apoC-III |  | Baseline, Months 6 and 12 | 
| Percent Change From Baseline at Months 6 and 12 in Fasting VLDL-C |  | Baseline, Months 6 and 12 | 
| Percent Change From Baseline at Months 6 and 12 in Fasting Remnant Cholesterol |  | Baseline, Months 6 and 12 | 
| Percent Change From Baseline at Months 6 and 12 in Fasting Non-HDL-C |  | Baseline, Months 6 and 12 | 
| Percent Change From Baseline at Months 6 and 12 in Fasting HDL-C |  | Baseline, Months 6 and 12 | 
| Percent Change From Baseline at Months 6 and 12 in Fasting TC |  | Baseline, Months 6 and 12 | 
| Percent Change From Baseline at Months 6 and 12 in Fasting apoB |  | Baseline, Months 6 and 12 | 
| Percent Change From Baseline at Months 6 and 12 in Fasting LDL-C |  | Baseline, Months 6 and 12 | 
| Percent Change From Baseline at Months 6 and 12 in apoA-1 |  | Baseline, Months 6 and 12 |