Abstract Body (Do not enter title and authors here):
Hypothesis and Purpose
Severe hypertriglyceridemia (HTG), characterized by fasting serum triglyceride (TG) levels of 500 mg/dl or higher, can lead to serious health issues such as acute pancreatitis. Olezarsen is an antisense oligonucleotide that targets the mRNA of apolipoprotein C-III (apoC-III), a protein that slows TG clearance by inhibiting lipoprotein lipase activity and the liver's uptake of triglyceride-rich particles. The efficacy and safety of olezarsen in severe HTG has not been established. CORE-TIMI 72a and CORE2-TIMI 72b are pivotal phase 3 trials studying olezarsen in severe HTG.

Study Design and Methods
Patients were randomly assigned in a 1:1 ratio to Cohort A (50 mg) or Cohort B (80 mg), followed by 2:1 randomization within each cohort to either olezarsen or matching placebo administered subcutaneously every four weeks (Figures 1 and 2). Subjects were treated for 12 months. Each trial also includes an MRI substudy to assess changes in hepatic fat at one year.

Sample Size
A total of 1063 patients were randomized, 617 patients in CORE-TIMI 72a and 446 in CORE2-TIMI 72b.

Population Studied
Individuals with severe hypertriglyceridemia (TGs of 500 mg/dl or higher).

Intervention(s)
Olezarsen 50 mg and 80 mg doses given subcutaneously every 4 weeks.

Power Calculations
This sample size will provide greater than 90% power to demonstrate a 60% reduction in TG levels with each dose of olezarsen compared with placebo using a 2-sided alpha level of 0.05 and assuming a standard deviation of 73% and a discontinuation rate of 20%.

Primary End Points
The primary endpoint is the placebo-adjusted percent change in triglyceride levels from baseline to six months.

Secondary End Points
Secondary endpoints include percent change in TG levels at 12 months and percent changes in ApoC-III, remnant cholesterol, and non-HDL-C at 6 and 12 months. Combined secondary endpoints of CORE and CORE2 will also examine the proportion of participants achieving TG levels less than 880 and 500 mg/dl, as well as olezarsen’s impact on incident acute pancreatitis events.

Preliminary Baseline Data
Across both trials, the median age was 54 years and 24% were women. The median baseline triglyceride level was 794 mg/dl. Overall, 455 patients (43%) had triglycerides of 880 mg/dl or greater, and 195 (18%) had a history of pancreatitis. Additionally, a combined total of 333 subjects participated in the hepatic MRI substudy. Primary and secondary results are pending trial completion.