Volanesorsen (Waylivra) for Hypertriglyceridemia-Induced Acute Pancreatitis

Volanesorsen is a new second-generation antisense oligonucleotide. It lowers triglyceride levels and Apolipoprotein C3 via a mechanism different from conventional medications.

Severe Hypertriglyceridemia is seen in family members who have a genetic mutation of lipoprotein lipase, an enzyme involved in the metabolism of triglycerides.

Volanesorsen has been approved by the European Medicine Agency (EMA), under the brand name Waylivra,  for treating hypertriglyceridemia in addition to diet, especially in those patients who have failed other therapies.

However, its approval from the FDA is pending because of safety issues including low platelets and bleeding.

Newer studies are adding to the efficacy of Volanesorsen in preventing acute pancreatitis caused by severe hypertriglyceridemia.

A recently published study demonstrated the effectiveness of preventing acute pancreatitis in patients with severe hypertriglyceridemia.

Key points of the “Volanesorsen for Preventing Pancreatitis” study:

• Severe hypertriglyceridemia, defined as triglyceride level >500 mg/dL (>5.645 mmol/L), is a risk factor for acute pancreatitis, accounting for around 10% of pancreatitis cases.
• The risk of acute pancreatitis is proportional to increased plasma triglyceride levels and thus increased production of free fatty acids.
• Fibrates, n-3 fatty acids, and niacin are FDA-approved treatments for severe hypertriglyceridemia, but evidence of reduced acute pancreatitis incidence with these interventions is lacking.
• Volanesorsen, an antisense oligonucleotide targeting APOC3 mRNA, reduces APOC3 levels, triglycerides, and chylomicrons.
• The study shows the treatment with Volanesorsen, reduces the incidence of acute pancreatitis among severe hypertriglyceridemia patients.

Hypertriglyceridemia refers to a fasting plasma triglycerides measurement that is raised, typically above the 95th percentile for age and sex.

Elevated plasma triglyceride levels contribute to many factors like cardiovascular diseases and associated risk factors such as

• Obesity,
• Metabolic syndrome,
• Proinflammatory and prothrombotic biomarkers,
• Type 2 diabetes mellitus, and
• Acute pancreatitis when a patient’s triglyceride level is very high (typically > 10 mmol/L).

In the human body, triglycerides convert into simpler particles which are further hydrolyzed into free fatty acids by the action of certain enzymes responsible for hydrolysation. Thus, plasma fatty acid levels are raised due to the addition of a fatty diet and hydrolysis of triglycerides in the liver.

In hypertriglyceridemic pancreatitis, having high levels of triglycerides can harm the pancreas, leading to inflammation and acute pancreatitis.

This happens because the pancreas gets overloaded with triglycerides, which can damage its cells.

There are a few reasons this happens, including having too many triglyceride-rich fats in the blood, insufficient pancreatic enzymes to break down these fats, and the harmful effects of certain fatty acids.

A recent study focuses on treating hypertriglyceridemia using “Volanesorsen” to prevent acute pancreatitis in hyperglyceridemia.

Findings of the “Volanesorsen for Preventing Pancreatitis” study:

Treating with Volanesorsen, a triglyceride-lowering agent, inhibiting the translation of APOC3 and mRNA led to the reduction of acute pancreatitis among patients with severe hypertriglyceridemia [ref]

Methodology and Analysis:

In three studies with 207 patients who had really high triglyceride levels, some had conditions like familial chylomicronemia syndrome and familial partial lipodystrophy.

They were split into two groups by chance: one got Volanesorsen, and the other got a fake treatment for 6 to 12 months. Then, they were watched for 3 more months.

What they found was that fewer people who got volanesorsen had pancreatitis compared to those who got the fake treatment.

The results showed that fewer people who took volanesorsen got pancreatitis compared to those who took the placebo.

Only 2% of the volanesorsen group had pancreatitis during treatment, while 10% of the placebo group did.

Interestingly, no one in the Volanesorsen group got pancreatitis more than 4 months into treatment when their triglyceride levels were lowest. However, in the placebo group, cases happened at different times during treatment.

This suggests that volanesorsen, which lowers triglyceride levels, is linked to a reduced risk of pancreatitis in patients with severe hypertriglyceridemia.

It’s worth noting, though, that Volanesorsen may lead to reversible thrombocytopenia, particularly in patients with familial chylomicronemia syndrome.

If further research confirms these findings, blocking apolipoprotein C3 expression with volanesorsen could be a helpful treatment strategy for people with complications from severe hypertriglyceridemia.

What is Volanesorsen and How is it administered?

Volanesorsen is a medication used to lower triglyceride levels in individuals with certain conditions associated with severe hypertriglyceridemia.

It belongs to a class of drugs known as antisense oligonucleotides. It works by inhibiting the production of apolipoprotein C3, which plays a role in regulating triglyceride levels in the bloodstream; thus, by reducing apoC3, volanesorsen reduce triglycerides, thereby lowering the risk of complications such as pancreatitis.

It is typically administered as a subcutaneous injection, often every week. It’s important to note that volanesorsen may be associated with side effects, including reversible thrombocytopenia (a decrease in platelet count).[ref]

The EMA (European Medical Agency) has approved Volanesorsen under the brand name, Waylivra for treating severe hypertriglyceridemia as an adjunct to diet, medications, and other non-pharmacological interventions.

Non-Medical Interventions to Reduce Triglyceride Levels:

• Glycemic control:

Use foods that have a low glycemic index, especially among patients having diabetes or impaired glucose metabolism. Weight Loss is also recommended for those who are obese or overweight.

• Use of MCT (Medium Chain Triglycerides):

Medium-chain triglycerides are recommended as an alternative source to standard dietary fats for patients with high uncontrolled triglyceride levels.

The use of medium-chain triglyceride oil is helpful as it is directly absorbed into the circulation. [ref]

• Omega-3 fatty acids:

For moderate to high triglyceride levels, omega-3 fatty acids are also recommended. Omega-3 fatty acids are present in good amounts in fish oils.

• Use of indigestible carbohydrates:

The use of indigestible carbohydrates like oats, wheat, bran, and husk has a positive effect on plasma triglyceride levels.

• Lean protein:

Adding lean protein, soy protein, whey, and casein protein to meals can help reduce plasma triglyceride levels.

• Limit alcohol:

Limiting alcohol consumption is beneficial if plasma triglyceride levels are high.

• Lifestyle modification:

Reduce the intake of rapidly metabolized carbohydrates and incorporate moderate-intensity aerobic exercise.

Novel Medical Therapies to Manage Triglyceride Levels:

• LPL gene therapy:

In severe hypertriglyceridemia, there is a deficiency of an enzyme responsible for triglyceride breakdown.

The first approved gene therapy for humans, called LPL gene therapy, involves the intramuscular injection of LPL gene expression, which lowers triglyceride levels. [ref]

• Lomitapide:

This is a selective inhibitor of triglyceride transfer protein. It is approved for the treatment of patients with high cholesterol levels that contribute to hypertriglyceridemia. [ref]

• Mipomersen:

It is an oligonucleotide that interferes with the translation process of RNA when triglyceride-rich fats are formed, indirectly reducing the production of additional triglycerides. [ref]

• Monoclonal antibodies:

This therapy functions as a blocking agent in the degradation of triglyceride-rich fats in plasma, thereby reducing triglyceride levels.[ref]