Evaluation of ISIS 678354 Sodium Salt in Patients with Severe Hypertriglyceridemia: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial

The primary objective of this study is to evaluate the efficacy of **olezarsen** compared to placebo in terms of the percent change in fasting triglycerides (TG) from baseline in patients with severe hypertriglyceridemia. This is clinically relevant as elevated TG levels are associated with an increased risk of cardiovascular events and pancreatitis, and effective management of TG levels can significantly reduce these risks.

Secondary objectives include evaluating the efficacy of olezarsen compared to placebo on several parameters:

• Proportion of patients achieving fasting TG levels below 500 mg/dL (5.65 mmol/L).
• Proportion of patients achieving fasting TG levels below 880 mg/dL (10 mmol/L).
• Proportion of patients achieving fasting TG levels below 1000 mg/dL (11.29 mmol/L).
• Percent change from baseline in fasting apolipoprotein C-III (apoC-III), very-low-density lipoprotein cholesterol (VLDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and high-density lipoprotein cholesterol (HDL-C).
• Adjudicated acute pancreatitis event rate in patients with two or more events of adjudicated acute pancreatitis in the five years prior to enrollment.
• Overall adjudicated acute pancreatitis event rate.

The clinical trial involves a total of **251 participants** diagnosed with **severe hypertriglyceridemia**. The study population includes both male and female subjects, aged 18 years and older, encompassing adults and older adults. Participants were selected based on specific criteria, including a fasting triglyceride level of 500 mg/dL (5.65 mmol/L) or higher at screening and qualification. All participants are required to be on lipid-lowering therapy that aligns with the standard of care per local guidelines, with medications optimized and stabilized for at least four weeks prior to screening. The trial population includes individuals from vulnerable populations, ensuring a comprehensive evaluation of the treatment's efficacy across diverse demographic groups. Lifestyle factors such as diet and physical activity were not specified in the available data.

The clinical trial is a **randomized, double-blind, placebo-controlled, Phase 3 study** designed to evaluate the efficacy of **olezarsen** in patients with severe **hypertriglyceridemia**. The primary objective is to assess the percent change in fasting triglycerides (TG) from baseline compared to placebo. The trial involves the administration of **ISIS 678354**, an antisense oligonucleotide, via subcutaneous injection, with a maximum daily dose of 80 mg and a total treatment period of 53 weeks. The study is expected to conclude by January 31, 2025, with recruitment having commenced on August 1, 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as fasting TG levels of ≥ 500 mg/dL and stable lipid-lowering therapy. Following the screening, participants will be randomized to receive either the active treatment or placebo. The trial includes multiple follow-up visits to monitor safety and efficacy, with primary endpoints assessed at 6 months and secondary endpoints at 12 months. The end-of-study visit will occur at the conclusion of the treatment period to evaluate long-term outcomes and any adverse events.

Participant involvement is expected to last approximately 53 weeks, with conditions for early termination including significant adverse events or non-compliance with study protocols. The study aims to provide comprehensive data on the impact of olezarsen on fasting TG levels and other lipid parameters, contributing to the understanding of its therapeutic potential in managing severe hypertriglyceridemia.

The clinical trial involves the administration of **ISIS 678354**, also known as **AKCEA-APOCIII-LRx**, which is an experimental medication developed by Ionis Pharmaceuticals, Inc. This medication is formulated as an **injection** and is classified as an **antisense oligonucleotide**. The active substance in this medication is **ISIS 678354 sodium salt**, which originates from nucleic acid. The medication is administered via the **subcutaneous** route. The dosing regimen for ISIS 678354 involves a maximum daily dose of 80 mg, with a total maximum dose of 1.04 g over a treatment period of 53 weeks. The study protocol ensures that the administration of the drug is monitored for compliance, and the dosing schedule is strictly adhered to throughout the trial duration.

The trial also includes a **placebo** control, which is a sterile, preservative-free, parenteral solution composed of sodium chloride and riboflavin in water for injection. This placebo is intended for **subcutaneous** injection and is provided in a volume of 0.8 ml. The placebo serves as a comparator treatment to evaluate the efficacy of ISIS 678354 in patients with severe hypertriglyceridemia. The administration of the placebo follows the same route and frequency as the experimental medication to maintain the double-blind nature of the study. Compliance with the placebo administration is monitored to ensure the integrity of the trial results.

The efficacy of the investigational product, **olezarsen**, will be assessed in a randomized, double-blind, placebo-controlled, Phase 3 clinical trial involving patients with severe hypertriglyceridemia. The primary endpoint for evaluating efficacy is the percent change from baseline in fasting triglycerides (TG) at 6 months, specifically the average of weeks 25 and 27, compared to placebo. Secondary endpoints include the percent change from baseline in fasting TG at 12 months, the proportion of participants achieving fasting TG levels below 500 mg/dL at 6 and 12 months, and other lipid parameters such as fasting apolipoprotein C-III (ApoC-III), very low-density lipoprotein cholesterol (VLDL-C), non-high-density lipoprotein cholesterol (Non-HDL-C), and high-density lipoprotein cholesterol (HDL-C) at 6 and 12 months. Additionally, the trial will assess the adjudicated acute pancreatitis event rate during the treatment period and from week 13 to week 53.

Measurements will be collected at specified time points throughout the study, with fasting TG levels being a critical parameter. The trial will utilize validated laboratory tests to ensure accurate and reliable data collection. The study is designed to compare the efficacy of olezarsen with placebo, with the primary focus on lipid-lowering effects and the potential reduction in acute pancreatitis events. The trial is expected to conclude by January 31, 2025, with recruitment having started on August 1, 2021.