antisense oligonucleotides to regulate triglycerides

antisense oligonucleotides to regulate triglycerides
antisense oligonucleotides to regulate triglycerides

Olezarsen, an antisense oligonucleotide that regulates triglyceride levels, shows efficacy in reducing triglyceride levels in patients with hypertriglyceridemia or familial chylomicronemia syndrome in two clinical trials published in the New England Journal of Medicine.

Antisense oligonucleotides make it possible to regulate the expression of specific genes. Image: Rosario García.

He increased blood triglyceride levels It is an important risk factor for the development of cardiovascular diseases. High levels of these types of lipids can contribute to hardening of the arteries and arteriosclerosis, which in turn increases the risk of a heart attack or stroke. Furthermore, when they are very high, as occurs in patients with rare genetic disorders such as familial chylomicronemia syndromecan cause inflammation of the pancreas or pancreatitis.

Until now, therapeutic options to reduce very high triglyceride levels (hypertriglyceridemia) were not completely effective, which has led to the search for new approaches. One of them is the use of antisense oligonucleotides to regulate the expression of genes related to the transport or metabolism of triglycerides.

Recently, two clinical trials have shown that Olezarsen, an antisense oligonucleotide therapy to regulate gene expression APOC3, allows reducing triglyceride levels with a favorable safety profile. The results have been published in parallel in the journal New England Journal of Medicine.

APOC3 as a target of antisense oligonucleotides

The apolipoprotein C-III (APOC3), a key protein in triglyceride metabolism, is a very interesting target to regulate triglyceride levels. APOC3 increases triglyceride levels by inhibiting lipoprotein lipase (enzyme responsible for removing triglyceride-rich lipoproteins from the circulation). In addition, it stimulates inflammatory processes in the pancreas and vascular system.

In a setting of hypertriglyceridemia, therefore, reducing the expression or activity of APOC3 is a desirable objective to reduce triglyceride levels. In fact genetic studies have shown that loss of APOC3 function is associated with lower triglyceride levels and a lower risk of cardiovascular disease. In this direction, different oligonucleotide-based strategies have emerged to block APOC3 expression. An example is volanesorsen (marketed as Waylivra) indicated as “addition to the diet in adult patients with genetically confirmed familial chylomicronemia syndrome and at high risk of pancreatitis, in whom the response to diet and triglyceride-lowering treatment has not been enough”.

What does Olezarsen consist of?

Developed by the company Ionis Pharmaceuticals, Olezarsen is a antisense oligonucleotidea small single-stranded nucleic acid fragment designed to bind to the gene’s messenger RNA APOC3 and inhibit the synthesis of this protein.

A characteristic of Olezarsen is that it is conjugated with N-acetylgalactosamine, a molecule that provides great affinity for a molecule on the surface of liver cells. This modification favors the specificity of the therapy, avoiding unwanted effects on other cell types. It also allows lower and less frequent doses to be used than the aforementioned volanesorsen.

The way Olezarsen, which is administered by subcutaneous injection every 4 weeks, works is simple. First, the conjugated oligonucleotide binds to the surface molecules of liver cells and enters them by endocytosis. Once it reaches the nucleus, the drug binds to the APOC3 messenger RNA and induces its degradation. As a result, liver cells decrease their production and secretion of APOC3 protein.

What are the results of clinical trials with Olezarsen?

Olezarsen has shown positive results in two clinical trials, one with patients with high cardiovascular risk due to high or moderate levels of triglycerides and another with patients with chylomicronemia syndromea genetic disorder that causes severe hypertriglyceridemia and acute pancreatitis.

In the first trial, 154 patients participated, who received placebo or olezarsen at doses of 50 milligrams or 80 milligrams, monthly for 12 months. In this study, patients receiving olezarsen showed a significant reduction in triglycerides compared to placebo. Reductions in levels of APOC3, apolipoprotein B, and non-HDL cholesterol were also observed. These last two are especially interesting since they represent risk markers for atherosclerosis, which do not experience significant reductions with many therapies targeting triglyceride-rich lipoproteins.

In the second trial, Phase 3, 66 patients with chylomicronemia syndrome participated, who also received placebo or olezarsen in doses of 50 milligrams or 80 milligrams. In those patients who received the highest dose, the researchers detected a rsignificant reduction in triglyceride levels, compared to placebo. Reduction was also observed with the lowest dose, but in this case it was not statistically significant. Furthermore, it was observed a notable reduction in episodes of acute pancreatitis in the groups treated with the antisense oligonucleotide, with one episode in each group, compared to the placebo group where 11 episodes occurred. Other adverse effects were also less common in the olezarsen treatment groups.

In both studies, an adequate tolerance and safety profile for the treatment was observed.

Toward a therapy for severe hypertriglyceridemia and chylomicronemia syndrome

The clinical trials carried out indicate that Olezarsen represents a Promising triglyceride-lowering therapy in severe hypertriglyceridemia and chylomicronemia syndrome. In this latter condition, treatment could be especially beneficial for patients, since standard therapies to reduce triglyceride levels are not very effective and nutrition-based management is very restrictive.

“As a physician who has seen firsthand the struggles of people living with chylomicronemia syndrome and its serious complications, there is a significant need for an effective therapy to lower triglycerides and reduce acute pancreatitis events,” said Erik Stroes. , professor of Medicine at the University of Amsterdam and one of the principal investigators of the study. “Olezarsen represents a new medicine that can change the lives of these patients who suffer from chronic debilitating symptoms, such as abdominal pain and cognitive symptoms, as well as hospitalizations associated with life-threatening episodes of acute pancreatitis.”

Tests underway to solve some limitations

Some limitations of the studies, recognized by the authors, are the small number of participants, as well as the low population diversity and the relatively short duration of the trials. In this direction, larger studies will be necessary to confirm the results and answer some of the remaining questions.

At the moment, Olezarsen remains an investigational drug for moderate hypertriglyceridemia with cardiovascular risk or severe hypertriglyceridemia. However, the US Food and Drug Administration has granted Olezarsen “Fast Track” and “Orphan Drug” designation and “Breakthrough Therapy designation” for the treatment of familial chylomicronemia syndrome.

Scientific articles:

Stroes ESG, et al. Olezarsen, Acute Pancreatitis, and Familial Chylomicronemia Syndrome. N Engl J Med. 2024 May 16;390(19):1781-1792. doi:

Bergmark BA, et al. Olezarsen for Hypertriglyceridemia in Patients at High Cardiovascular Risk. N Engl J Med. 2024 May 16;390(19):1770-1780. doi:

Other sources:

Watts GF. Shooting the Messenger to Treat Hypertriglyceridemia. N Engl J Med. 2024 May 16;390(19):1818-1823. doi: presents positive results from Phase 3 Balance study of olezarsen for familial chylomicronemia syndrome.

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