ApoC-III inhibition reduces triglycerides in patients at high risk for or with established ASCVD
Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk
Introduction and methods
Apolipoprotein C-III (apoC-III) is an important regulator of plasma triglyceride levels [1,2]. A study suggested that ApoC-III may exert proatherogenic effects, both directly by enhancing inflammation in the vessel wall or indirectly by fostering hypertriglyceridemia . In addition, epidemiological studies have shown that apoC-III levels are associated with ASCVD risk and CV mortality [4-6].
Olezarsen is an N-acetyl-galactosamine (GalNAc)-conjugated, antisense oligonucleotide targeted to hepatic APOC3 mRNA. Olezarsen can thereby inhibit apoC-III production.
Aim of the study
This study evaluated the effect of apoC-III inhibition by olezarsen on triglyceride levels and triglyceride-rich lipoprotein (TRL) levels in patients with elevated fasting triglyceride levels (200-500 mg/dl or 2.26-5.65 mmol/L) who are at high risk for ASCVD or with established ASCVD.
This phase 2, dose-ranging, multi-center, randomized, double-blind, placebo-controlled trial randomized 141 patients to one of four treatment groups (olezarsen 10 mg or placebo subcutaneously every 4 weeks; olezarsen 15mg or placebo subcutaneously every 2 weeks, olezarsen 10mg or placebo subcutaneously every week, and olezarsen 50mg or placebo subcutaneously every 4 weeks). In each treatment group, patients were randomized in a 4:1 ratio to receive olezarsen or placebo. Patients received treatment for at least 6 months and up to 12 months. Post-treatment follow-up period was 13 weeks.
The primary efficacy endpoint was the percent change in fasting triglyceride levels from baseline to 6 months of treatment. Secondary endpoints included the percent change from baseline to 6 months of treatment in apoC-III, total cholesterol, LDL-c, HDL-c, non-HDL-c, VLDL-c, apoB, and apoA-I, and the proportion of patients who achieved serum triglyceride levels < 150 mg/dL (<1.7mmol/L) or triglyceride levels <100 mg/dL (<1.13 mmol/L).
Changes in triglyceride levels
- Olezarsen reduced fasting triglyceride levels from baseline to 6 months of treatment in all treatment groups, with least-squares mean (LSM) changes of: -23% (95% CI -34 to -10) in those receiving a dose of 10 mg every 4 weeks, -56% (95% CI -62 to -49) at 15 mg every 2 weeks, -60% (95% CI -66 to -54) at 10 mg every week, and -60% (95% CI -65 to -53) at 50 mg every 4 weeks. In comparison, fasting triglyceride levels increased by 6% ( 95% CI -9 to 23) in the pooled placebo group (P-value for the comparison of olezarsen with placebo ranged from 0.0042 to <0.0001).
- The corresponding absolute mean change in triglyceride levels from baseline to 6 months in olezarsen-treated individuals ranged from -58.8 (SD 102.4) mg/dL [-0.66 (SD 1.16) mmol/L] in those who received 10 mg every 4 weeks to -184.3 (SD 94.1) mg/dL [-2.08 (SD 1.06) mmol/L] in those who received 10 mg every week. Triglyceride levels increased in the pooled placebo group by 42.8 (SD 206.6) mg/dL [SD 0.48 (2.33) mmol/L].
Changes in atherogenic lipids and apolipoproteins levels
- Changes in atherogenic lipids with the highest dose of 50 mg every 4 weeks compared with placebo at 6 months of treatment were -74% (95% CI -80 to -66) for apoC-III (P < 0.0001), -58% (95% CI -63 to -52) for VLDL-c (P< 0.0001), -20% (95% CI -29 to -9) for non-HDL-c (P= 0.009), -10% (-19 to -1) for apoB (P=0.024), 30% (95% CI 18 to 44) for HDL-c (P <0.0001), and 14% (95% CI 7 to 20) for apolipoprotein A-I (P <0.0001). There were no significant changes in LDL-c and total cholesterol.
Proportion of patients achieving triglyceride levels <150 mg/dL or <100 mg/dL
- The percentage of olezarsen-treated patients achieving fasting triglyceride levels <150 mg/dL (<1.7 mmol/L) was 14% in the group that received 10 mg every 4 week, 65% in the group that received 15 mg every 4 weeks, 74% in the group that received 10 mg every week, and 91% in the group that received 50 mg every 4 weeks. Corresponding percentages for patients achieving fasting triglyceride levels <100 mg/dL (<1.13 mmol/L) were 0%, 26%, 22% and 45%. In the pooled placebo group, 4% of patients reached triglyceride levels <150 mg/dL and 0% reached <100 mg/dL.
- Adverse event rates were similar between groups. There were no drug-related serious adverse events and there was no significant difference in flu-like symptoms compared with placebo. The most frequent adverse events in olezarsen-treated patients compared to placebo-treated patients were injection site erythema (15.6% vs. 0%), arthralgia (12.2% vs. 0%), nasopharyngitis (12.2% vs. 8.3%), and upper respiratory tract infection (11.1% vs. 8.3%).
This phase 2 study shows that targeting hepatic APOC3 mRNA with olezarsen in patients at risk of or with established ASCVD results in substantial reductions in fasting triglyceride levels, compared with placebo.