Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of Olezarsen (ISIS 678354) in Hypertriglyceridemia and Atherosclerotic Cardiovascular Disease

The primary objective of this study is to evaluate the effect of **olezarsen** on the percent change in fasting triglyceride (TG) levels compared to placebo. This is clinically relevant as elevated TG levels are associated with an increased risk of cardiovascular diseases, including atherosclerosis, and managing these levels is crucial for patients with hypertriglyceridemia and atherosclerotic cardiovascular disease.

Secondary objectives include:

• Evaluating the effect of olezarsen compared to placebo on the percent change in fasting TG levels over a longer treatment duration of one year.
• Assessing the effect of olezarsen on the proportion of patients achieving different thresholds in fasting TG levels.
• Investigating the effect of olezarsen on the percent change in fasting levels of apolipoprotein C III (apoC-III), very low-density lipoprotein cholesterol (VLDL-C), remnant cholesterol, non-high-density lipoprotein cholesterol (non-HDL-C), high-density lipoprotein cholesterol (HDL-C), apoB, and low-density lipoprotein cholesterol (LDL-C).
• Evaluating the safety and tolerability of olezarsen.

The clinical trial involves a total of **913 participants** diagnosed with **hypertriglyceridemia**, **cardiovascular diseases**, or **atherosclerosis**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific inclusion criteria, such as having fasting triglyceride levels indicative of hypertriglyceridemia or severe hypertriglyceridemia, a clinical diagnosis of atherosclerotic cardiovascular disease (ASCVD), or being at increased risk for ASCVD. All participants are required to be on standard of care lipid-lowering medications, optimized and stabilized for at least four weeks prior to screening. The trial also includes a vulnerable population, ensuring a comprehensive evaluation of the treatment's effects across diverse groups. Lifestyle factors such as diet and physical activity are not explicitly detailed in the provided data.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled, Phase 3 study** to evaluate the efficacy of olezarsen (ISIS 678354) in patients with **hypertriglyceridemia** and atherosclerotic cardiovascular disease, or with severe hypertriglyceridemia. The primary objective is to assess the effect of olezarsen on the percent change in fasting triglyceride (TG) levels compared to placebo. The trial is expected to last until July 28, 2025, with recruitment having commenced on May 22, 2023. Participants will be involved in the study for a maximum treatment period of 53 weeks.

The trial will include several study visits, beginning with a screening visit to determine eligibility based on specific inclusion criteria, such as having fasting TG levels within defined ranges and a clinical diagnosis of atherosclerotic cardiovascular disease or being at increased risk for it. Participants must be on stable lipid-lowering medications for at least four weeks prior to the screening. Following the screening, participants will be randomized to receive either the investigational product, olezarsen, or a placebo via subcutaneous injection. The study will include follow-up visits at regular intervals to monitor safety and efficacy endpoints, including the primary endpoint of percent change in fasting TG from baseline at Week 25 compared to placebo.

Secondary endpoints will be evaluated at Weeks 25 and 53, including the proportion of patients achieving fasting TG levels below 150 mg/dL, and changes in other lipid parameters such as apoC-III, VLDL-C, remnant cholesterol, non-HDL-C, HDL-C, apoB, and LDL-C. Safety and tolerability will be assessed through adverse events, vital signs, physical examinations, laboratory tests, and electrocardiograms. An end-of-study visit will conclude the trial, where final assessments will be conducted. Participants may be withdrawn from the study early if they experience significant adverse events or if they do not adhere to the study protocol. The trial aims to provide comprehensive data on the efficacy and safety of olezarsen in the target patient population.

The clinical trial involves the administration of **ISIS 678354**, an experimental medication, which is an **antisense oligonucleotide**. The pharmaceutical form of ISIS 678354 is an injection, specifically designed for subcutaneous administration. The active substance in this medication is ISIS 678354 sodium salt, originating from nucleic acid. The maximum daily dose is 80 mg, with a total maximum dose of 1.04 g over the treatment period. The treatment duration is set for a maximum of 53 weeks. The medication is provided by Ionis Pharmaceuticals, Inc. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

In addition to the experimental treatment, a **placebo injection** is utilized as a comparator in this double-blind, placebo-controlled study. The placebo consists of an injection containing 1.5 µg/ml of riboflavin in a volume of 0.8 ml. The placebo is administered via the same subcutaneous route as the experimental medication to maintain blinding. The placebo serves as a control to evaluate the effect of ISIS 678354 on fasting triglyceride levels in patients with hypertriglyceridemia and atherosclerotic cardiovascular disease or severe hypertriglyceridemia. Participant compliance with the placebo administration is similarly monitored to ensure the integrity of the study results.

Efficacy in this clinical trial will be assessed by evaluating the effect of olezarsen on the percent change in fasting triglyceride (TG) levels compared to placebo. The primary endpoint is the percent change in fasting TG from baseline at Week 25. Secondary endpoints include the percent change in fasting TG from baseline at Week 53, the proportion of patients achieving fasting TG levels below 150 mg/dL at Weeks 25 and 53, and the percent change in fasting apoC-III, VLDL-C, remnant cholesterol, non-HDL-C, HDL-C, apoB, and LDL-C from baseline at Weeks 25 and 53. Safety and tolerability will also be assessed through adverse events, vital signs, weight, physical examinations, clinical laboratory tests, electrocardiograms (ECG), and the use of concomitant medications. These assessments will compare results between patients receiving olezarsen and those receiving placebo.