Evaluation of Subcutaneous ISIS 678354 Sodium Salt in Patients with Familial Chylomicronemia Syndrome: An Open-Label Extension Study

The primary objective of this study is to evaluate the effect of **olezarsen** on the percent change in fasting triglycerides (TG) from baseline in patients with Familial Chylomicronemia Syndrome (FCS). This is clinically relevant as elevated TG levels are a hallmark of FCS, leading to increased risk of pancreatitis and other complications. Reducing TG levels can significantly improve patient outcomes and quality of life.

Secondary objectives include: - Evaluating the effect of olezarsen on the percent change in fasting TG upon extended treatment, assessing the durability of the effect. - Determining the proportion of patients achieving ≥ 40% and ≥ 70% reduction in fasting TG from baseline. - Assessing the percent change in fasting apolipoprotein C-III (apoC-III), apolipoprotein B (apoB), apolipoprotein 48 (apoB48), and non-High Density Lipoprotein Cholesterol (non-HDL-C) from baseline. - Evaluating the proportion of patients achieving fasting TG levels ≤ 880 mg/dL and ≤ 500 mg/dL. - Assessing the effect on adjudicated acute pancreatitis event rate during the treatment period, including in patients with a history of pancreatitis within 10 years prior to screening or with ≥ 2 events of adjudicated acute pancreatitis in the 5 years prior to treatment.

The clinical trial involves a total of **30 participants** diagnosed with **Familial Chylomicronemia Syndrome (FCS)**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults. Participants were selected based on their satisfactory completion of the ISIS 678354 CS3 index study, with an acceptable safety profile as judged by the investigator. Additionally, participants are required to adhere to a diet comprising no more than 20 grams of fat per day throughout the study. The trial includes a vulnerable population, indicating that special considerations are in place to ensure the safety and ethical treatment of all participants.

The clinical trial is designed as an **open-label extension study** to evaluate the safety and tolerability of **olezarsen** in patients with **Familial Chylomicronemia Syndrome (FCS)**. The primary objective is to assess the effect of olezarsen on the percent change in fasting triglycerides (TG) from baseline. The trial will involve subcutaneous administration of the investigational product, **ISIS 678354**, also known as AKCEA-APOCIII-LRx, which is an antisense oligonucleotide. The study is expected to run from July 2022 to August 2026, with a maximum treatment period of up to 157 weeks for participants.

Participants will be required to have satisfactorily completed the ISIS 678354 CS3 index study with an acceptable safety profile and must adhere to a diet comprising ≤ 20 g of fat per day during the study. The trial will include several key visits: an inclusion (screening) visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess final outcomes. The follow-up visits will occur at specified intervals, with primary endpoints evaluated at Month 6, and secondary endpoints assessed at Months 6, 12, 24, 36, and 48.

The expected length of participant involvement is up to 209 weeks, depending on individual response and safety assessments. Conditions that may lead to early termination from the study include non-compliance with the dietary requirements, adverse events, or withdrawal of consent. The study will utilize a single-use disposable needle-based injection system, YpsoMate, for the administration of the drug. The trial aims to provide comprehensive data on the long-term effects of olezarsen in managing FCS, with a focus on reducing fasting TG levels and monitoring the incidence of acute pancreatitis events.

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 intended for **subcutaneous use**. The active substance in the medication is **ISIS 678354 sodium salt**, originating from **nucleic acid**. The pharmaceutical form is a prefilled syringe, and the medication is administered using the YpsoMate™ 1.0 ml, a single-use disposable needle-based injection system. This device is designed to deliver a single fixed dose of the drug into the subcutaneous tissue, ensuring that all contents of the container are expelled. The maximum daily dose is 80 mg, with a total maximum dose of 1040 mg over a treatment period of up to 147 days.

Another formulation of **ISIS 678354** is also used in the trial, with similar characteristics. This version is also an **injection** for **subcutaneous use**, containing the same active substance, **ISIS 678354 sodium salt**. The maximum daily dose for this formulation is 80 mg, with a total maximum dose of 1040 mg over a treatment period of up to 157 days. This formulation does not utilize the YpsoMate™ device for administration.

A third formulation of **ISIS 678354** is included in the study, also administered as an **injection** for **subcutaneous use**. It contains the same active substance, **ISIS 678354 sodium salt**, and is delivered using the YpsoMate™ device. The maximum daily dose for this formulation is 50 mg, with a total maximum dose of 650 mg over a treatment period of up to 147 days. This formulation, like the first, utilizes the YpsoMate™ device to ensure precise delivery of the medication.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial documentation. Participant compliance with the dosing schedule is monitored through the use of the YpsoMate™ device, which ensures accurate administration of the medication. The trial aims to evaluate the effect of the medication on the percent change in fasting triglycerides from baseline in patients with **Familial Chylomicronemia Syndrome**.

The efficacy of the clinical trial will be assessed by evaluating the effect of **olezarsen** on the percent change in fasting triglycerides (TG) from baseline. The primary endpoint focuses on safety and tolerability, while secondary endpoints include several efficacy parameters. These parameters involve the percent change in fasting TG from baseline at various timepoints: Month 6 (average of Weeks 23, 25, and 27), Month 12 (average of Weeks 51 and 53), Month 24 (average of Weeks 103 and 105), Month 36 (average of Weeks 155 and 157), and Month 48 (average of Weeks 205 and 209). Additionally, the proportion of patients achieving a ≥40% reduction in fasting TG from baseline at these timepoints will be measured.

Other secondary endpoints include the percent change in fasting apoB48, apoC-III, and non-HDL from baseline at the same timepoints. The trial will also assess the proportion of patients achieving fasting TG levels of ≤500 mg/dL and ≤880 mg/dL at the specified months. Furthermore, the adjudicated acute pancreatitis event rate will be monitored during the treatment period, which spans from Week 1 through Weeks 53, 105, 157, or 209, depending on the patient's history of pancreatitis. The efficacy assessments will be conducted using validated laboratory tests and patient-reported outcomes at the designated timepoints throughout the trial duration.