ESSENCE-TIMI 73b: Olezarsen Normalizes TGs in 80% of Patients With HTG

Results of ESSENCE-TIMI 73b suggest use of olezarsen (Tryngolza), an apolipoprotein C-III RNA-targeting therapy administered monthly, could help more than 80% of patients with hypertriglyceridemia achieve normal triglyceride (TG) levels at 12 months.

Presented at the European Society of Cardiology (ESC) Congress 2025, results of the phase 3 ESSENCE-TIMI 73b trial indicate use of the agent, which received approval from the US food and Drug Administration for familial chylomicronemia syndrome (FCS) in 2024, was associated with a statistically significant placebo-adjusted 61% and 58% reduction in TG levels at 6 months with the 80 mg and 50 mg monthly doses, respectively, among patients with moderate hypertriglyceridemia and elevated cardiovascular risk.

“High levels of triglycerides are an important risk factor for atherosclerotic cardiovascular disease and yet the effects of current therapies are modest,” said principal investigator Brian Bergmark, MD, an investigator in the TIMI Study Group and an Interventional Cardiologist in the Division of Cardiovascular Medicine at Brigham and Women's Hospital, in a press release. “Olezarsen targets the mRNA of apolipoprotein C-III, which inhibits triglyceride clearance.”

Launched in 2022 based on positive phase 2 findings in the Bridge-TIMI 73a and another small trial, the ESSENCE-TIMI 73b trial was a double-blind, randomized, placebo-controlled trial, to assess the safety and efficacy of olezarsen 50 mg and 80 mg doses among patients with moderate hypertriglyceridemia and elevated cardiovascular risk or with severe hypertriglyceridemia. Per trial protocol, investigators defined hypertriglyceridemia as TG levels of 150 to 499 mg/dL and severe hypertriglyceridemia as TG levels of 500 mg/dL or greater.

The International trial recruited patients from 160 sites across North America and Europe, with 1478 individuals undergoing randomization in a 1:3 ratio to a 50-mg or 80-mg cohort. They were subsequently randomized in a 3:1 ratio to receive monthly subcutaneous olezarsen or a matching placebo within each cohort.

The primary outcome of interest for the trial was the least-squares mean percent change in triglyceride level from baseline to 6 months among the patients with moderate hypertriglyceridemia, which investigators reported as placebo-adjusted change.

Overall, 1349 participants were included in the primary analysis. Of these, 254 received olezarsen 50 mg, 766 received olezarsen 80 mg, and 329 received placebo every 4 weeks via subcutaneous injection for 12 months. This study population had a median age of 64 years, 40% were women, and the median TG level at baseline was 238.5 mg/dL.

Primary results of the trial suggested the placebo-adjusted least-squares mean change in TG level was −58.4 percentage points (95% confidence interval [CI], −65.1 to −51.7; P <.001) in the olezarsen 50 mg group and −60.6 percentage points (95% CI, −67.1 to −54.0; P <.001) in the olezarsen 80 mg group. The least-squares mean change from baseline in triglyceride level was −55.6% (95% CI, −58.0 to −53.2) in the olezarsen 50 mg group, −57.8% (95% CI, −59.6 to −55.9) in the olezarsen 80 mg group, and 2.8% (95% CI, −3.5 to 9.0) in the placebo group. Investigators highlighted 85.0% of the olezarsen 50 mg group, 88.7% of the olezarsen 80 mg group, and 12.5% of the placebo group had a TG level of less than 150 mg/dL at 6 months (P <.001).

Analysis of safety data from the trial suggested serious adverse events occurred among 9% with olezarsen 50 mg, 14% with olezarsen 80 mg, and 11% with placebo. Additionally, investigators pointed out liver transaminase elevations to any degree above the upper limit of the normal range were more common with olezarsen 50 mg (34.2%) and olezarsen 80 mg (38.3%) than with placebo (17.6%) (both P <.001), but suggested clinically meaningful increases were rare and similar across groups.

“The positive results of this study are an important step in bringing forward a potential new treatment for people with severely elevated triglycerides. Following the FDA approval and encouraging launch of [olezarsen] for people living with FCS, a rare, genetic form of severely elevated TGs, these data support olezarsen’s potential to benefit the much broader population of people living with sHTG,” said Sam Tsimikas, MD, senior vice president, global cardiovascular development at Ionis, at the time the company announced topline results in May 2025.

References:

1. Bergmark BA, Marston NA, Prohaska TA, et al. Targeting APOC3 with Olezarsen in Moderate Hypertriglyceridemia. New England Journal of Medicine. Published online August 30, 2025. doi: 10.1056/nejmoa2507227

2. European Society of Cardiology. Olezarsen reduces levels of the blood fat, triglycerides, in patients at high cardiovascular risk. Escardio.org. Published August 30, 2025. Accessed August 31, 2025. https://www.escardio.org/The-ESC/Press-Office/Press-releases/Olezarsen-reduces-levels-of-the-blood-fat-triglycerides-in-patients-at-high-cardiovascular-risk

3. Ionis Pharmaceuticals, Inc. Ionis announces positive topline results from Essence study of olezarsen in people with moderately elevated triglycerides | Ionis Pharmaceuticals, Inc. Ionis Pharmaceuticals, Inc. Published May 19, 2025. Accessed August 31, 2025. https://ir.ionis.com/news-releases/news-release-details/ionis-announces-positive-topline-results-essence-study-olezarsen