Olezarsen Earns First-Ever FDA Approval for Familial Chylomicronemia Syndrome

The US Food and Drug Administration (FDA) has approved olezarsen (TRYNGOLZA), an investigational RNA-targeted medicine, as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome (FCS).1

Announced by Ionis Pharmaceuticals, on December 19, 2024, olezarsen marks the first-ever FDA-approved therapy to significantly reduce triglyceride levels and acute pancreatitis events in adults with FCS when used in conjunction with an appropriate diet (≤20 grams of daily fat.

“With no treatment options previously available, we were limited to relying only on extremely strict diet and lifestyle changes as the sole preventative treatment option,” said investigator Alan Brown, MD, clinical professor of medicine at Rosalind Franklin University of Medicine and Science. "The FDA approval of [olezarsen] is an important moment for people living with FCS, their families and physicians who now, for the first time, have a treatment that significantly lowers triglycerides and decreases the risk of potentially life-threatening acute pancreatitis events, as an adjunct to a low-fat diet."

A rare, genetic disease defined by severely elevated triglycerides, FCS impacts an estimated 1 to 13 people per million in the US.2 Without an FDA-approved therapy, people with FCS are typically nonresponsive to triglyceride-lowering treatment and remain at high risk of acute pancreatitis and other chronic health issues. Instead, these individuals rely on highlight-restrictive nutrition management to manage the disease’s risks.

Olezarsen is designed to lower the body's production of apoC-III, a protein produced in the liver that regulates triglyceride metabolism in the blood.3 The FDA accepted the NDA for olezarsen in June 2024 and granted the medicine Priority Review, setting a December PDUFA date without requiring an advisory committee meeting.

Its application in FCS was centered on data from the randomized, double-blind, placebo-controlled Phase 3 BALANCE trial, demonstrating a significant reduction in fasting triglyceride levels with olezarsen treatment.

The BALANCE trial measured the safety and efficacy of olezarsen 80 mg and 50 mg versus placebo over 53 weeks.4 The trial involved 66 patients with genetically identified FCS, with 21, 22, and 23 individuals randomized to olezarsen 80 mg, olezarsen 50 mg, and placebo once monthly, respectively.

This patient population had a mean triglyceride level of 2630 mg/dL, with the majority female, White, and had a normal body mass index (BMI). BALANCE’s dual primary endpoints were the difference between olezarsen 80 mg and placebo, and olezarsen 50 mg and placebo, in the percent change in fasting triglyceride levels from baseline to 6 months.

Upon analysis, triglyceride levels at 6 months were significantly reduced with the 80 mg dose of olezarsen compared with placebo (–42.5%; P = .0084), while the 50 mg dose did not achieve statistical significance (−22.4%; 95% CI, −47.2 to 2.5; P = .08).

These BALANCE data showed reductions from baseline to 12 months were further improved, with olezarsen showing a placebo-adjusted 57% mean reduction in triglycerides.

Secondary endpoint analysis linked the use of olezarsen 80 mg to a 73.7% reduction in mean apolipoprotein C-III (APOC3) level from baseline to month 6, while olezarsen 50 mg achieved a 65.5% reduction, compared with placebo. Safety analyses at 53 weeks showed that 7 patients experienced 11 episodes of acute pancreatitis in the placebo group, compared with a single episode in the pooled olezarsen group (rate ratio [RR], 0.12; 95% CI, 0.02 to 0.66).

At the time of NDA acceptance, Ionis also announced the completion of enrollment for the Phase 3 CORE, CORE2, and ESSENCE trials for severe hypertriglyceridemia, with expected results in the second half of 2025.3

"Today's FDA approval of [olezarsen] heralds the arrival of the first-ever FCS treatment in the U.S. – a transformational moment for patients and their families," Brett P. Monia, PhD, chief executive officer of Ionis, added in a statement. "For the first time, adults with FCS can now access a treatment that substantially reduces triglycerides and the risk of debilitating and potentially life-threatening acute pancreatitis."

References

1. TryngolzaTM (Olezarsen) approved in U.S. as first-ever treatment for adults living with familial chylomicronemia syndrome as an adjunct to Diet. Ionis Pharmaceuticals, Inc. December 19, 2024. Accessed December 19, 2024. https://ir.ionis.com/news-releases/news-release-details/tryngolzatm-olezarsen-approved-us-first-ever-treatment-adults.
2. Vaezi Z, Amini A. Familial Hypercholesterolemia. [Updated 2022 Sep 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK556009/
3. Campbell P. FDA grants priority review for Olezarsen in familial chylomicronemia syndrome. HCP Live. June 25, 2024. Accessed December 17, 2024. https://www.hcplive.com/view/fda-grants-priority-review-for-olezarsen-in-familial-chylomicronemia-syndrome.
4. Campbell P. Olezarsen shows ability to reduce triglycerides for patients with FCS in balance trial. HCP Live. September 29, 2024. Accessed December 17, 2024. https://www.hcplive.com/view/olezarsen-shows-ability-to-reduce-triglycerides-for-patients-with-fcs-in-balance-trial.