An Open-Label Extension Study of Olezarsen (ISIS 678354) Administered Subcutaneously to Patients with Severe Hypertriglyceridemia (SHTG)

The primary objective of this study is to evaluate the **safety** and tolerability of olezarsen in patients with Severe Hypertriglyceridemia (SHTG). This is clinically relevant as ensuring the safety and tolerability of a treatment is crucial for its potential use in managing SHTG, a condition associated with increased risk of cardiovascular events and pancreatitis.

Secondary objectives include:

• To evaluate the effect of treatment with olezarsen on reduction in fasting triglycerides (TG).
• To assess the effect of olezarsen on 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).
• To evaluate the effect of olezarsen on reduction in event rate of acute pancreatitis.

These secondary objectives aim to provide insights into the broader metabolic effects of olezarsen, which could inform its therapeutic potential in reducing cardiovascular risk factors and preventing acute pancreatitis in patients with SHTG.

The clinical trial involves a total of **348 participants** diagnosed with **Severe Hypertriglyceridemia (SHTG)**. 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 satisfactory completion of either ISIS 678354-CS5 or ISIS 678354-CS6, with an acceptable safety profile as judged by the investigator. Additionally, participants are required to be on a stable regimen of lipid-lowering therapy that aligns with the standard of care per local guidelines. The trial includes a vulnerable population, indicating that special considerations are in place to ensure their safety and well-being throughout the study. The selection criteria ensure that the participants are representative of the target population for evaluating the safety and tolerability of olezarsen.

The clinical trial is designed to evaluate the safety and tolerability of **olezarsen** in patients with **severe hypertriglyceridemia**. This study is an open-label extension of previous trials, specifically targeting individuals who have satisfactorily completed either ISIS 678354-CS5 or ISIS 678354-CS6, with the last dose administered at Week 49 and an acceptable safety profile as judged by the investigator. The trial employs a randomized, controlled design, with participants receiving subcutaneous injections of the investigational product, **ISIS 678354 sodium salt**, an antisense oligonucleotide. The trial is expected to last until April 2026, with participant recruitment having commenced in May 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on the principal inclusion criteria, which include being on a stable regimen of lipid-lowering therapy adhering to the standard of care per local guidelines. The trial will consist of regular follow-up visits to monitor safety and efficacy, with the primary endpoints focusing on changes in clinical laboratory values from baseline to Week 53, including platelet count, major bleeding events, and changes in renal function markers. The proportion of participants experiencing adverse events and those using concomitant medications will also be assessed over a time frame of up to 66 weeks.

The expected length of participant involvement is approximately 66 weeks, with the trial's maximum treatment period set at 53 weeks. Conditions that may lead to early termination from the study include significant adverse events or deviations from the protocol that compromise participant safety or data integrity. The end-of-study visit will conclude the trial, during which final assessments will be conducted to evaluate the overall safety and tolerability of the treatment. Participants will be closely monitored throughout the trial to ensure adherence to the protocol and to address any safety concerns promptly.

The clinical trial involves the administration of the experimental medication **ISIS 678354**, also known as AKCEA-APOCIII-LRx, which is an **antisense oligonucleotide**. The active substance in this medication is **ISIS 678354 sodium salt**, originating from nucleic acid. The pharmaceutical form of the medication is an **injection**, and it is administered subcutaneously. The maximum daily dose is 80 mg, with a total maximum dose of 1.04 g over a treatment period of 53 weeks. The medication is provided by Ionis Pharmaceuticals, Inc.

Another formulation of **ISIS 678354** is also used in the trial, with a maximum daily dose of 50 mg and a total maximum dose of 650 mg over the same treatment period of 53 weeks. This formulation is similarly administered via subcutaneous injection. The administration device for this formulation is the YpsoMate™ 1.0 mL, a single-use disposable needle-based injection system with automated functions. This device is designed to deliver a single fixed dose of the drug into the subcutaneous tissue from a prefilled 1 mL syringe, ensuring that all contents are expelled.

There are no non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, specified in this study. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial's main objective is to evaluate the safety and tolerability of olezarsen in patients with severe hypertriglyceridemia.

Efficacy in the clinical trial will be assessed through several primary endpoints. These include the proportion of participants with changes in clinical laboratory values from baseline to Week 53. Specific laboratory values to be monitored include platelet count values below 50,000 mm³, major bleeding events, clinically relevant non-major bleeding events, a decrease in estimated glomerular filtration rate (eGFR) by more than 30% or 50%, urine protein/creatinine ratio (UPCR) of 1000 mg/g or higher, urine/albumin creatinine ratio (UACR) of 500 mg/g or higher, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than five times the upper limit of normal (ULN), total bilirubin levels exceeding 2.0 mg/dL, and ALT or AST levels greater than three times ULN with total bilirubin levels more than twice ULN.

Additionally, the trial will evaluate the proportion of participants who experience adverse events (AEs) and those who use concomitant medications over a time frame of up to 66 weeks. These efficacy parameters will be collected and analyzed at specified time points, with the primary focus on changes observed by Week 53. The trial involves the administration of **olezarsen** (ISIS 678354) via subcutaneous injection, utilizing the YpsoMate™ 1.0 mL device, a single-use disposable needle-based injection system. This system is designed to deliver a fixed dose of the drug into the subcutaneous tissue from a prefilled syringe, ensuring complete expulsion of the syringe contents.