ISIS 678354-CS6 A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Olezarsen (ISIS 678354) Administered Subcutaneously to Patients with Severe Hypertriglyceridemia

The primary objective of this study is to assess 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 triglyceride levels are associated with an increased risk of cardiovascular diseases and pancreatitis, and effective management can significantly reduce these risks.

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

• Percent change from baseline in fasting apoC-III, remnant cholesterol (directly measured), and non-HDL-C.
• Proportion of patients achieving fasting TG levels below 500 mg/dL (5.65 mmol/L) and below 880 mg/dL (10 mmol/L).
• Adjudicated acute pancreatitis event rate.
• Absolute change in hepatic fat fraction (HFF).

The clinical trial involves a total of **200 participants** diagnosed with **severe hypertriglyceridemia**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including a fasting triglyceride level of at least 500 mg/dL (5.65 mmol/L) during both the Run-in and Qualification periods. 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 a minimum of four weeks prior to screening. Additionally, participants must be willing to adhere to prescribed diet and lifestyle modifications. The trial includes a vulnerable population, ensuring a comprehensive evaluation of the treatment's efficacy across diverse demographic groups.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled, Phase 3 study** 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 is expected to last approximately 53 weeks, with participant involvement beginning from the screening visit and continuing through the end-of-study visit. The study will include a run-in period, a qualification period, and a treatment period, with the primary endpoint measured at Month 6 and secondary endpoints assessed at Month 12.

Participants will undergo a series of study visits, starting 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 successful screening, participants will be randomized to receive either the active treatment, **ISIS 678354 sodium salt**, or a placebo, both administered via subcutaneous injection. The treatment period will involve regular follow-up visits to monitor safety, efficacy, and adherence to the study protocol. The end-of-study visit will conclude the participant's involvement, with final assessments conducted to evaluate the long-term effects of the treatment.

Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. These conditions may include significant adverse events, non-compliance with the study protocol, or withdrawal of consent. The trial aims to provide comprehensive data on the impact of olezarsen on triglyceride levels and related cardiovascular risk factors, contributing valuable insights into the management of severe hypertriglyceridemia.

The clinical trial involves the administration of **ISIS 678354**, also known as **AKCEA-APOCIII-LRx**, which is an **antisense oligonucleotide**. This experimental medication is provided in the form of an **injection** and is administered via **subcutaneous injection**. The active substance in this medication is **ISIS 678354 sodium salt**, which originates from **nucleic acid**. The maximum daily dose is 80 mg, with a total maximum dose of 1040 mg over a treatment period of 53 weeks. The dosing schedule and participant compliance are monitored throughout the study to ensure adherence to the protocol.

The study also includes a **placebo** treatment, which is a sterile, preservative-free, parenteral solution of sodium chloride and riboflavin in water for injection (WFI). This placebo is intended for **subcutaneous injection** and is used as a comparator to evaluate the efficacy of the experimental medication. The placebo is administered in a volume of 0.8 mL, and its administration follows the same schedule as the experimental treatment to maintain the double-blind nature of the study.

The efficacy of the investigational product, **olezarsen** (ISIS 678354), 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) levels compared to placebo, measured at baseline and at Month 6. Secondary endpoints include the percent change from baseline in fasting TG at Month 12, as well as changes in fasting Apolipoprotein C-III (ApoC-III), remnant cholesterol, and non-high-density lipoprotein-cholesterol (Non-HDL-C) at baseline, Month 6, and Month 12. Additionally, the proportion of patients achieving fasting TG levels below 500 mg/dL (5.65 mmol/L) and below 880 mg/dL (10 mmol/L) in a specific subgroup will be compared to placebo at Month 12. The adjudicated acute pancreatitis event rate during the treatment period, spanning from Week 1 through Week 53, will also be evaluated. Furthermore, the absolute change in hepatic fat fraction (HFF) between the olezarsen treatment group and placebo will be assessed.