CORE/CORE2: Olezarsen Reaches Primary Endpoint for Severe Hypertriglyceridemia

Olezarsen, an investigational therapy for severe hypertriglyceridemia (sHTG), has achieved positive topline results in the phase 3 CORE and CORE2 trials, as announced by parent company Ionis Pharmaceuticals, Inc. on September 2, 2025.1

During both studies, olezarsen demonstrated a statistically significant placebo-adjusted mean reduction in fasting triglycerides reaching 72%, which was the primary endpoint in both trials. Additionally, olezarsen met the secondary endpoints of a statistically significant reduction in acute pancreatitis events of 85% in both trials, demonstrating a favorable safety and tolerability profile.1

Olezarsen is an investigational RNA-targeted treatment designed to lower the body’s production of apoC-III. This protein, produced in the liver, manages triglyceride metabolism in the blood. Olezarsen was approved by the US Food and Drug Administration (FDA) in December of 2023 under the brand name Tryngolza as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia.1

“These data are groundbreaking, demonstrating that olezarsen is the first therapy for sHTG to significantly reduce acute pancreatitis events,” said Sam Tsimikas, MD, senior vice president of global cardiovascular development for Ionis. “Despite current standard of care and lifestyle changes, people with sHTG – who could have triglyceride levels reaching into the thousands – remain vulnerable to unpredictable and life-threatening acute pancreatitis attacks. These results reinforce our confidence that olezarsen has the potential to change the sHTG treatment paradigm.”1

CORE and CORE2 are phase 3 global, multicenter, double-blind, randomized, placebo-controlled trials, including patients aged ≥18 years with triglyceride levels ≥500 mg/dL. Participants were required to be on standard-of-care therapies for elevated triglycerides throughout the treatment period.1

A total of 617 patients were included in CORE, and 446 were included in CORE2. At baseline, 47% and 37% of patients had baseline fasting triglycerides ≥880 mg/dL in CORE and CORE2, respectively. Investigators then randomly assigned patients in a 1:1 ratio to either 50 mg or 80 mg of either olezarsen or placebo every 4 weeks subcutaneously for 12 months.2

During both trials, adverse events were balanced across all treatment groups, and investigators found serious adverse events occurred less frequently in the olezarsen groups compared to placebo. The most common side effects, injection site reactions, were mostly mild and occurred more frequently among olezarsen users than placebo. Of those who completed the trials, >90% chose to continue into the ongoing open-label extension study.1

Ionis has announced plans to submit a supplemental New Drug Application (sNDA) to the FDA by the end of 2025. Detailed data from the CORE and CORE2 trials will be presented at an upcoming medical conference.1

“Building on our success in familiar chylomicronemia syndrome, the exceptional CORE and CORE2 results position Ionis to set a new treatment standard for the many people with sHTG who are at risk of debilitating acute pancreatitis attacks,” said Brett P. Monia, PhD, chief executive officer of Ionis. “If approved, olezarsen for sHTG will mark our third independent launch in under 2 years and our first launch in a prevalent population, marking a major step forward in delivering transformative care for those who need it most.”1

References

1. Ionis Pharmaceuticals, Inc. Olezarsen significantly reduces triglycerides and acute pancreatitis events in landmark pivotal studies for people with severe hypertriglyceridemia (sHTG). Businesswire. September 2, 2025. Accessed September 2, 2025. https://www.businesswire.com/news/home/20250902733810/en/Olezarsen-significantly-reduces-triglycerides-and-acute-pancreatitis-events-in-landmark-pivotal-studies-for-people-with-severe-hypertriglyceridemia-sHTG

2. Marston NA, Bergmark BA, Alexander VJ, et al. Design and rationale of the CORE-TIMI 72a and CORE2-TIMI 72b trials of olezarsen in patients with severe hypertriglyceridemia. Am Heart J. 2025;286:125-135. doi:10.1016/j.ahj.2025.03.003