Effect of APOC3 Inhibition With Olezarsen on Coronary Atherosclerosis: Essence-TIMI 73b Imaging Study

Clinical Snapshot

Key Findings

• P Value: p = 0.36

• Effect Size: 2.98% difference favouring placebo (non-significant)

• Primary Outcome: No significant difference in noncalcified coronary plaque volume change at 12 months

• Nnt Or Sensitivity: Not applicable - no significant benefit demonstrated

• Confidence Interval: 95% CI: -3.4% to 9.3%

Clinical Application

Limited by high cost of antisense oligonucleotide therapy and requirement for subcutaneous injection Unlikely to receive PBS listing given lack of demonstrated clinical benefit. Current Australian guidelines emphasise statins and lifestyle for triglyceride management. TGA approval would require demonstration of clinical cardiovascular benefit Patients with moderate hypertriglyceridemia and established or high-risk cardiovascular disease already on optimal lipid-lowering therapy

Abstract

BACKGROUND: Whether lowering triglyceride-rich lipoproteins and remnant cholesterol favorably modifies coronary atherosclerosis is unclear. Olezarsen, an antisense oligonucleotide that targets apolipoprotein C-III, reduces triglycerides by ~60% and remnant cholesterol by ~70%, has a neutral effect on LDL (low-density lipoprotein) cholesterol (LDL-C), and reduces apoB (apolipoprotein B) by ~15% in moderate hypertriglyceridemia. We investigated the effect of olezarsen on coronary plaque in adults with largely moderate hypertriglyceridemia. METHODS: We conducted a coronary computed tomography angiography study within Essence-TIMI 73b, a randomized, placebo-controlled trial of olezarsen versus placebo that enrolled patients between November 2022 and February 2024. Inclusion criteria were triglycerides ≥150 mg/dL (2.26 mmol/L), presence of or high risk for cardiovascular disease, and, for this imaging study, noncalcified plaque on baseline coronary computed tomography angiography. The primary end point was percent change from baseline to 12 months in noncalcified plaque volume. RESULTS: Of 468 participants (349 olezarsen, 119 placebo), the median age was 63 years (interquartile range, 56-70); 31% were women, and 97% received lipid-lowering therapy. Median baseline triglycerides were 249 mg/dL (interquartile range, 197-331), and remnant cholesterol was 53 mg/dL (interquartile range, 38-76). Median baseline noncalcified plaque volume was 125.3 mm³ (interquartile range, 63.2-213.3). At 6 months, olezarsen reduced triglycerides by 63.9%, remnant cholesterol by 71.9%, and apoB by 16.0% over placebo, with no difference in LDL-C. The percent change in noncalcified plaque volume from baseline to month 12 did not differ between olezarsen and placebo (placebo-adjusted least-squares mean difference, 2.98% [95% CI, -3.4 to 9.3]; p=0.36). No significant differences between olezarsen and placebo were observed for changes in low-attenuation, calcified, or total plaque volumes at 12 months. CONCLUSIONS: Despite substantial triglyceride and remnant cholesterol lowering, treatment with olezarsen for 12 months on top of standard-of-care lipid-lowering therapy in patients with largely moderate hypertriglyceridemia did not affect noncalcified coronary plaque volume. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05610280.

References

1. 1.Marston, N. A., Bergmark, B. A., Prohaska, T. A., Moura, F. A., Zimerman, A., Alexander, V. J., Kang, Y. M., Weinland, J., Ran, X., Murphy, S. A., Zhang, S., Li, D., Banach, M., Stroes, E. S. G., Kiss, R., Gaudet, D., Vrablik, M., Goudev, A., Bax, J. J., Budoff, M. J., Foldyna, B., Lu, M. T., Tsimikas, S., Giugliano, R. P., & Sabatine, M. S. (2026). Effect of APOC3 inhibition with olezarsen on coronary atherosclerosis: Essence-TIMI 73b imaging study. Circulation. https://doi.org/10.1161/CIRCULATIONAHA.126.080012