Table of Contents

• What is ISIS 678354?
• Medical Conditions Treated
• How It Works
• Administration
• Efficacy
• Safety and Tolerability
• Ongoing Research

What is ISIS 678354?

ISIS 678354 SODIUM SALT, also known as olezarsen or AKCEA-APOCIII-LRx, is an investigational drug being developed for the treatment of severe hypertriglyceridemia and related conditions^[1]. It belongs to a class of medications called antisense oligonucleotides, which are designed to target specific genetic sequences to modify the production of certain proteins in the body^[1].

Medical Conditions Treated

ISIS 678354 is being studied for the treatment of several related conditions characterized by high levels of triglycerides in the blood:

• Severe Hypertriglyceridemia (SHTG): A condition where blood triglyceride levels are extremely high (≥ 500 mg/dL or 5.65 mmol/L)^[1].
• Familial Chylomicronemia Syndrome (FCS): A rare genetic disorder that causes severe hypertriglyceridemia and can lead to recurrent episodes of pancreatitis^[2].
• Hypertriglyceridemia with Atherosclerotic Cardiovascular Disease (ASCVD): A condition where high triglyceride levels are present along with heart disease or an increased risk of heart disease^[3].

How It Works

ISIS 678354 works by targeting and reducing the production of apolipoprotein C-III (apoC-III), a protein that plays a crucial role in regulating triglyceride levels in the blood^[1]. By decreasing apoC-III levels, the drug aims to lower triglycerides and potentially reduce the risk of complications associated with severe hypertriglyceridemia, such as pancreatitis and cardiovascular events.

Administration

ISIS 678354 is administered as a subcutaneous injection, meaning it is injected under the skin^[1]. The drug is typically given using an auto-injector device called YpsoMate, which is designed for ease of use and consistent dosing^[1]. The frequency of injections and dosage may vary depending on the specific study protocol and patient needs.

Efficacy

Clinical trials are ongoing to evaluate the efficacy of ISIS 678354 in various patient populations. Some of the key measures being studied include:

• Percent reduction in fasting triglyceride levels from baseline^[1].
• Proportion of patients achieving specific triglyceride level targets (e.g., < 500 mg/dL, < 880 mg/dL, or < 1000 mg/dL)^[1].
• Changes in other lipid parameters, such as apoC-III, VLDL-C, non-HDL-C, and HDL-C levels^[1].
• Reduction in the rate of acute pancreatitis events, particularly in patients with a history of recurrent pancreatitis^[1].

Safety and Tolerability

The safety and tolerability of ISIS 678354 are being closely monitored in clinical trials. Some of the key safety assessments include:

• Monitoring of adverse events and serious adverse events^[1].
• Changes in laboratory values, including liver function tests, kidney function, and platelet counts^[1].
• Occurrence of bleeding events or changes in blood clotting parameters^[1].
• Effects on other metabolic parameters, such as blood sugar control^[1].

Ongoing Research

Several clinical trials are currently underway to further evaluate the efficacy and safety of ISIS 678354 in different patient populations:

• A phase 3 study in patients with severe hypertriglyceridemia (SHTG)^[1].
• A study in patients with hypertriglyceridemia and atherosclerotic cardiovascular disease or at increased risk for ASCVD^[3].
• An open-label extension study for patients with familial chylomicronemia syndrome (FCS) who were previously treated with volanesorsen, another medication for severe hypertriglyceridemia^[2].
• Long-term extension studies to evaluate the safety and efficacy of ISIS 678354 over extended periods of treatment^[4].

These ongoing studies aim to provide more comprehensive data on the long-term efficacy, safety, and potential benefits of ISIS 678354 in managing severe hypertriglyceridemia and related conditions.