Appraisal of Olezarsen for Treatment of Hypertriglyceridemia

Abstract

Olezarsen is antisense antinucleotide under investigation that inhibits synthesis of apolipoprotein C3 (ApoC3) resulting in reduction of plasma triglycerides levels. In a phase 3 clinical trial of patients having familial chylomicronemia syndrome (FCS) with extreme hypertriglyceridemia at baseline (mean plasma triglycerides 2,630 mg/dl), olezarsen 80 mg administered subcutaneously every 4 weeks decreased triglycerides by 43.5 percentage points (95% CI, 69.1 to 17.9; P<0.001) after 6 months compared with placebo. By 53 weeks, 1 episode of acute pancreatitis occurred in olezarsen group versus 11 episodes in the placebo group, rate ratio (RR) 0.12 (95% CI, 0.02 TO 0.66). Two phase 2 trials evaluated olezarsen in patients with moderately elevated triglycerides (<500 mg/dl) and high cardiovascular (CV) risk recorded similar magnitude of reduction of triglycerides. Olezarsen reduced levels of atherogenic lipoproteins such as ApoC3 by 73%, non-high-density lipoprotein cholesterol (non-HDL-C) by 17-23% and increased high-density lipoprotein cholesterol (HDL-C) levels by 30-40%. Meanwhile, olezarsen increased mean values of low-density lipoprotein (LDL-C) from 22.8 to 37.6 mg/dl in patients with FCS but had no significant effects in patients with high CV risk having higher baseline LDL-C levels. Discontinuation rates due to adverse effects of olezarsen were 9-12% versus 0% with placebo. The most common adverse effects of olezarsen were elevation of liver enzymes, mostly below 3 times the upper limit of normal, and injection-site reactions. Platelet count < 140,000/µl occurred in 18% in patients receiving olezarsen versus 3% with placebo (risk ratio 6.8; 95% CI, 0.91 to 51.3; P=0.03). No patient had severe thrombocytopenia with platelet number < 75,000/µl. Overall, olezarsen is a promising new therapy for hypertriglyceridemia and for prevention of hypertriglyceridemia-induced pancreatitis. Long-term randomized trials are urgently needed to examine the effects of olezarsen on CV events and mortality and establish its long-term safety.