Volanesorsen Shows Promise in Multifactorial Chylomicronemia

By Reuters Staff

April 08, 2021

NEW YORK (Reuters Health) - Treatment with volanesorsen significantly reduces triglyceride levels in patients with multifactorial chylomicronemia syndrome and may reduce acute pancreatitis events in these patients, according to results of the industry-funded COMPASS trial.

In an earlier study, the researchers found that lowering hepatic apolipoprotein C-III (APOC3) synthesis with the antisense oligonucleotide volanesorsen effectively lowered triglycerides in patients with familial chylomicronemia syndrome.

But familial chylomicronaemia syndrome accounts for only a small subset of patients with severe hypertriglyceridemia and chylomicronemia. The COMPASS phase-3 study explored the safety and efficacy of volanesorsen in patients with multifactorial chylomicronemia syndrome, also known as multifactorial severe hypertriglyceridemia.

Volanesorsen, sold by Akcea Therapeutics as Waylivra, was conditionally approved by the European Medicines Agency in 2019 for treatment of familial chylomicronemia syndrome. It has not been approved in the U.S.

COMPASS included 113 patients with multifactorial severe hypertriglyceridemia or familial chylomicronemia syndrome, who had a BMI of 45 kg/m2 or less and fasting plasma triglyceride of 500 mg/dL or higher.

By random assignment, 76 patients received subcutaneous volanesorsen (300 mg) once a week for 26 weeks and 38 received a matched volume of placebo. After 13 weeks of treatment, dosing was changed to 300 mg of volanesorsen or placebo every two weeks, except in patients who had completed at least five months of treatment.

According to the Lancet Diabetes and Endocrinology report, volanesorsen significantly lowered mean plasma APOC3 (by 76.1%) and mean plasma triglyceride levels (by 71.2%) from baseline to three months, significantly more than the 3.3% and 0.9% decreases, respectively, with placebo. These reductions were sustained at six months.

During the treatment period, five acute pancreatitis events occurred in three of 38 patients in the placebo group compared with none in the volanesorsen group.

"The most common adverse events were related to tolerability and included injection-site reactions (average of 24% of all volanesorsen injections vs 0.2% of placebo injections), which were all mild or moderate," Dr. Joseph Witztum of University of California San Diego and colleagues report.

"One participant in the volanesorsen group had a platelet count reduction to less than 50,000 per uL and one patient had serum sickness, both of which were regarded as serious adverse events," they note.

Limitations of the trial include the short treatment period, the small number of patients, the enrollment of a predominantly white population, and the fact that the decrease in incidence of acute pancreatitis was an exploratory outcome.

However, the investigators "speculate that if the study was larger and longer, the protection of pancreatitis would be more robust and this hypothesis should be explored in future studies."

In a linked comment, Dr. Gerald Watts and Dr. Natalie Ward with the University of Western Australia in Perth note that the COMPASS trial "augments other volanesorsen studies by showing that this intervention is efficacious across a wide range of plasma triglyceride concentrations and particularly in patients with multifactorial chylomicronemia syndrome. The efficacy of treatment was independent of the type of genetic variants impairing lipoprotein lipase activity, which is a new finding that reinforces the notion that volanesorsen operates via lipoprotein lipase-independent mechanisms - eg, by inhibiting the production of triglyceride-rich lipoproteins."

"Beyond the prevention of acute pancreatitis in patients with chylomicronemia syndrome, RNA based therapies targeted at APOC3 and ANGPTL3 gene transcripts have the potential to lower the risk of atherosclerotic cardiovascular disease against best standard of care. Large clinical trials in relevant populations are required to confirm the long-term efficacy, safety, and cost-effectiveness of these potent and selective new treatments in mitigating multiple health risks of hypertriglyceridemia," they conclude.

The study was funded by Ionis Pharmaceuticals and Akcea Therapeutics. Several authors have financial relationships with the companies.

SOURCE: https://bit.ly/39KTbNG and https://bit.ly/31SG8Fm Lancet Diabetes and Endocrinology, online March 30, 2021.

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