Patients with severe hypertriglyceridemia (>500 mg/dL, >5.645 mmol/L) have an increased risk of pancreatitis. Severe hypertriglyceridemia is responsible for approximately 10% of pancreatitis cases. Olezarsen is an antisense oligonucleotide that targets the messenger RNA of apolipoprotein C-III. Two randomized, double-blind studies were conducted.¹ Patients with severe hypertriglyceridemia were assigned in a 1:1:1 ratio to olezarsen 50 mg, olezarsen 80 mg, or placebo for twelve months. The primary endpoint was the change in triglycerides after six months. Secondary endpoints were changes in triglycerides after twelve months and changes in apolipoprotein C-III, cholesterol, and non-HDL cholesterol after six and twelve months. Compared with placebo, olezarsen reduced triglycerides by 49.2% and 54.2%, respectively. Non-HDL cholesterol was reduced to a greater extent with olezarsen. The number of pancreatitis events was significantly reduced in both olezarsen groups. Adverse events occurred at similar rates across all groups. At the 80-mg dose, elevations in liver enzymes and thrombocytopenia occurred more frequently.
To understand the mechanism of action of olezarsen, one must first understand the role of apolipoprotein C-III (ApoC-III). ApoC-III is a small protein produced in the liver and intestine that plays a key role in lipid metabolism. ApoC-III inhibits the breakdown of triglyceride-rich lipoproteins (VLDL, chylomicrons) by inhibiting lipoprotein lipase (an enzyme that degrades triglycerides in the blood). When less ApoC-III is produced, lipoprotein lipase is more active and more triglyceride-rich lipoproteins are degraded. In addition, ApoC-III blocks hepatic uptake of VLDL and chylomicron remnants. The higher the ApoC-III level, the slower the elimination of triglycerides from the blood.
Olezarsen lowers ApoC-III. In the liver, ApoC-III is encoded by a gene on chromosome 19. The mRNA remains in the cytoplasm of the hepatocyte and is translated at ribosomes into functional ApoC-III protein. Olezarsen binds to the mRNA, resulting in less protein being produced at the ribosomes of the endoplasmic reticulum in hepatocytes. With less ApoC-III, lipoprotein lipase becomes more active and degrades more triglycerides.
Antisense oligonucleotide against APOC3
• Olezarsen is a GalNAc-conjugated antisense oligonucleotide
• It binds to APOC3 mRNA in hepatocytes
• → Translation of ApoC-III is inhibited
• → Plasma ApoC-III levels decrease markedly
ApoC-III:
• inhibits lipoprotein lipase (LPL)
• blocks hepatic uptake of VLDL and chylomicron remnants (LDLR, LRP1, HSPGs)
• indirectly promotes persistence of triglyceride-rich particles
High ApoC-III = slower breakdown of VLDL
What happens when ApoC-III is reduced (with olezarsen):
A) LPL activity increases
• VLDL triglycerides are hydrolyzed more rapidly
→ The overall VLDL pool shrinks
Typical lipid effects
Parameter |
Effect |
Triglycerides |
↓↓↓ ~60–80% |
VLDL |
↓↓↓ |
Remnant cholesterol |
↓↓ |
ApoB |
↓ (moderate) |
LDL-C |
↔ / slight ↑ or ↓ (variable) |
(LDL-C is not a primary target of olezarsen) |
Summary
Olezarsen ↓ ApoC-III → ↑ lipoprotein lipase + ↑ hepatic remnant clearance → ↓ VLDL → ↓ triglycerides (often 60–80%).
