Severe hypertriglyceridemia (HTG), defined as a serum triglyceride (TG) concentration ≥500 mg/dl, is present in approximately 1 in every 500 individuals and carries direct clinical consequences, including pancreatitis, which can be life-threatening. Olezarsen is an investigational antisense oligonucleotide targeted to the mRNA for apolipoprotein C-III (apoC-III), a protein known to impair TG clearance by inhibiting lipoprotein lipase and the hepatic uptake of triglycerides and triglyceride-rich remnants. Olezarsen has been evaluated in patients with predominantly moderate HTG (150-499 mg/dl) and a rare genetic condition known as Familial Chylomicronemia Syndrome (FCS), with TG lowering effects of 53% and 44%, respectively, and reductions in pancreatitis among the FCS population. However, no dedicated trial has tested olezarsen in patients with severe HTG. In these two pivotal phase 3 trials, CORE -TIMI 72a (NCT05079919) and CORE2 -TIMI 72b (NCT05552326), over 1,000 patients with severe HTG will be randomized in a 2:1 fashion to either olezarsen (80 mg or 50 mg dose) or matching placebo. Patients will be treated for a total of 53 weeks and evaluated for the primary endpoint of percent change in TGs from baseline to 6 months compared to placebo. Pooled analyses of CORE and CORE2 will also assess olezarsen's effect on acute pancreatitis events and change in hepatic steatosis. Together, CORE -TIMI 72a (NCT05079919) and CORE2 -TIMI 72b (NCT05552326) are designed to establish the efficacy and safety of olezarsen in patients with severe HTG.