A Study of Olezarsen (ISIS 678354) in Participants With Hypertriglyceridemia and Atherosclerotic Cardiovascular Disease, or With Severe Hypertriglyceridemia

Phase 3

Completed

• Conditions: Cardiovascular Diseases; Hypertriglyceridemia; Atherosclerosis
• Interventions: Drug: Placebo; Drug: Olezarsen

• Registration Number: NCT05610280
• Lead Sponsor: Ionis Pharmaceuticals, Inc.

Brief Summary

The purpose of the study is to evaluate the effect of olezarsen on percent change in fasting triglyceride (TG) levels compared to placebo in participants with hypertriglyceridemia and atherosclerotic cardiovascular disease, or with severe hypertriglyceridemia.

Detailed Description

This is a Phase 3, multi-center, placebo-controlled study in approximately 1475 participants with hypertriglyceridemia and atherosclerotic cardiovascular disease. The study consists of 3 periods: 1) Screening Period: Week -12 to Week -1 (up to 12 weeks); 2) Treatment Period up to Week 53; and 3) Post-Treatment Follow-up Period: Week 54 to Week 66 (13 weeks). Participants enrolled will receive olezarsen or placebo once every 4 weeks during the 53-week Treatment Period.

The Screening Period was extended with no impact to overall study timelines.

A coronary computed tomographic angiography (CTA) sub study will be performed to assess whether triglyceride lowering through inhibition of apoC-III protein synthesis may reduce coronary plaque progression.

Study Timeline

• Study First Submitted: 2022-11-02
• Study First Submitted QC: 2022-11-02
• Study First Posted: 2022-11-09
• Study Start: 2022-11-21
• Primary Completion: 2024-08-08
• Study Completion: 2025-06-09
• Status Verified: 2025-07
• Disposition First Submitted: 2025-07-09
• Last Update Submitted: 2025-07-09
• Disposition First Posted: 2025-07-11
• Last Update Posted: 2025-07-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 1478

Inclusion Criteria

• Participants must fall into 1 of the following groups (a or b):

  a. Hypertriglyceridemia with fasting TG ≥200 mg/dL (2.26 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

  b. Severe hypertriglyceridemia with fasting TG ≥500 mg/dL (5.65 mmol/L)

• Participants should be on standard of care (SOC) lipid-lowering medications per local guidelines. Lipid-lowering medications should be optimized and stabilized for at least 4 weeks prior to Screening to minimize changes in these medications during the study.

Exclusion Criteria

• Hemoglobin A1c (HbA1c) ≥ 9.5% at Screening
• Alanine aminotransferase or aspartate aminotransferase > 3.0 × upper limit of normal
• Total bilirubin > 1.5 upper limit of normal unless due to Gilbert's syndrome
• Estimated GFR < 30 mL/min/1.73 m^2

NOTE: Other Inclusion/Exclusion criteria may apply.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Participants will be randomized to receive olezarsen-matching placebo, once every 4 weeks by SC injection up to Week 49.
Olezarsen	Olezarsen	Participants will be randomized to receive multiple doses of olezarsen, once every 4 weeks by subcutaneous (SC) injection up to Week 49.

Primary Outcome Measures

Name	Time	Method
Percent Change From Baseline to Week 25 in Fasting Triglycerides (TG) Compared to Placebo	Baseline to Week 25

Secondary Outcome Measures

Name	Time	Method
Percent Change From Baseline to Weeks 25 and 53 in Fasting Apolipoprotein B (apoB) Compared to Placebo	Baseline to Weeks 25 and 53
Percent Change From Baseline to Weeks 25 and 53 in Fasting Very Low-Density Lipoprotein-Cholesterol (VLDL)-C Compared to Placebo	Baseline to Weeks 25 and 53
Percent Change From Baseline to Weeks 25 and 53 in Fasting Apolipoprotein C-III (apoC-III) Compared to Placebo	Baseline to Weeks 25 and 53
Proportion of Participants who Achieve Fasting TG <150 Milligrams per Deciliter (mg/dL) at Weeks 25 and 53 Compared to Placebo	Baseline, Weeks 25 and 53
Percent Change From Baseline to Weeks 25 and 53 in Fasting non-High Density Lipoprotein-Cholesterol (HDL)-C Compared to Placebo	Baseline to Weeks 25 and 53
Percent Change From Baseline to Weeks 25 and 53 in Fasting High-Density Lipoprotein-Cholesterol (HDL)-C Compared to Placebo	Baseline to Weeks 25 and 53
Percent Change From Baseline to Weeks 25 and 53 in Fasting Remnant Cholesterol Compared to Placebo	Baseline to Weeks 25 and 53
Percent Change From Baseline to Weeks 25 and 53 in Fasting Low-Density Lipoprotein-Cholesterol (LDL)-C Compared to Placebo	Baseline to Weeks 25 and 53
Percent Change From Baseline to Week 53 in Fasting TG Compared to Placebo	Baseline to Week 53

Trial Locations

Locations (166)

Alabama Clinical Therapeutics, LLC Alabaster; 🇺🇸 Birmingham, Alabama, United States

Heart Center Research PC; 🇺🇸 Huntsville, Alabama, United States

Cardiovascular Research Foundation of Southern California; 🇺🇸 Beverly Hills, California, United States

Westside Medical Associates of Los Angeles; 🇺🇸 Beverly Hills, California, United States

Diabetes/Lipid Management & Research Center; 🇺🇸 Huntington Beach, California, United States

University of California, San Diego (UCSD); 🇺🇸 La Jolla, California, United States

Clinical Trials Research; 🇺🇸 Lincoln, California, United States

Amicis Research; 🇺🇸 Northridge, California, United States

Valley Clinical Trials, Inc.; 🇺🇸 Northridge, California, United States

Northern California Research; 🇺🇸 Sacramento, California, United States

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