Olezarsen in Patients With Hypertriglyceridemia at High Cardiovascular Risk - Essence-TIMI 73b

Sep 22, 2025
Font Size
A
A
A
Author/Summarized by Author:
Artur Schneider, DO
Summary Reviewer:
Fred M. Kusumoto, MD, FACC; Jordan Christopher Ray, MD, FACC
Original Posted Date:
09/22/2025
References

Contribution To Literature:

The Essence-TIMI 73b trial demonstrated that olezarsen, compared with placebo, significantly reduced triglyceride levels in patients with moderate hypertriglyceridemia and elevated cardiovascular risk.

Study Design

In this phase 3, international, double-blind, placebo-controlled trial, 1,349 patients with either moderate hypertriglyceridemia (triglyceride level 150-499 mg/dL) and elevated cardiovascular risk or severe hypertriglyceridemia (triglyceride level ≥500 mg/dL) were randomly assigned in a 3:1 ratio to one of two olezarsen dose cohorts, 50 mg or 80 mg. Within each cohort, the patients were then subsequently re-randomized in a 3:1 ratio to monthly subcutaneous olezarsen or placebo. This led to 254 patients in the olezarsen 50 mg group, 766 in the olezarsen 80 mg group, and 329 in the placebo group.

  • Total number of enrollees: 1,349
  • Duration of follow-up: 12 months, followed by a 13-week safety follow-up period
  • Median patient age: 64 years
  • Demographics: 40.3% were female, 92.8% were White (23.3% identified as Hispanic or Latino), 60% had diabetes mellitus

Inclusion criteria:

  • Aged ≥18 years at the time of informed consent
  • Adults with moderate hypertriglyceridemia (fasting triglyceride ≥150 mg/dL, <500 mg/dL) plus either:
    • Established atherosclerotic cardiovascular disease (ASCVD) (coronary artery disease, cerebrovascular disease or peripheral artery disease)
    • High risk for ASCVD (defined as type 2 diabetes and age ≥55 years)
  • Severe hypertriglyceridemia with fasting triglyceride ≥500 mg/dL
  • On standard-of-care lipid-lowering therapy, optimized and stable for ≥4 weeks before screening
  • Participants must be nonpregnant, nonlactating, and either surgically sterile, postmenopausal, sexually abstinent, or use a highly effective contraceptive if female, and all males must be either surgically sterile, abstinent, or, if engaged in sexual relations with a female of childbearing potential, use a highly effective contraceptive method

Exclusion criteria:

  • Recent acute coronary syndrome, cerebrovascular event, major surgery, or acute pancreatitis
  • Relevant renal or hepatic laboratory abnormalities (alanine aminotransferase or aspartate aminotransferase >3.0 × upper limit of the normal range [ULN], estimated glomerular filtration rate <30 mL/min/1.73 m2)
  • Newly diagnosed or poorly controlled diabetes mellitus (HbA1c ≥9.5%, change in basal insulin regimen >20% within 3 months) as well as diabetic ketoacidosis or ≥3 episodes of hypoglycemia within 6 months in patients with type 1 diabetes
  • Malignancy within 5 years with some exceptions for low-risk and treated malignancies
  • Recent treatment with non-oligonucleotide, oligonucleotide (including siRNA), biological agent, device or concomitant medications/procedures that could interfere with triglyceride levels
  • Uncontrolled hypertension, uncontrolled hypothyroidism, active infection requiring antimicrobial or antiviral therapy, active HIV/Hep C or Hep B, hypersensitivity to any of the excipients, recent blood or plasma donation

Principal Findings:

Primary outcome: A significant difference in the primary outcome was noted with a least-squares mean change in triglyceride levels from baseline of –55.6% in the olezarsen 50 mg group, –57.8% in the olezarsen 80 mg group, compared with 2.8% in the placebo group. This resulted in a placebo-adjusted least-squares mean change in triglyceride level from baseline to 6 months of –58.4% in the olezarsen 50 mg group and –60.6% in the olezarsen 80 mg group.

Secondary outcomes: Statistically significant changes were noted in the secondary outcomes as well. The placebo-adjusted least-squares mean change in triglyceride level at 12 months was –50.7% in each of the olezarsen groups. At both 6 and 12 months, a higher proportion of patients in the olezarsen groups achieved triglyceride levels <150 mg/dL (50 mg: 85.0% and 82.8%; 80 mg: 88.7% and 85.0%) compared with the placebo group (12.5% and 20.6%). Lipid levels (apolipoprotein [Apo] C-III, non-HDL, VLDL, remnant cholesterol, Apo B) at 6 and 12 months were significantly reduced in both olezarsen groups when compared to placebo, except LDL, which was increased in both olezarsen groups.

Injection site reactions and mild elevations in aminotransferase levels were significantly more common with olezarsen than placebo, while rates of other adverse events did not differ between groups.

Interpretation:

Essence-TIMI 73b met both its primary and key secondary endpoints. Olezarsen led to a significant reduction of triglyceride levels in patients with moderate hypertriglyceridemia and elevated cardiovascular risk who were receiving standard lipid-lowering therapy. Furthermore, significant reductions in atherogenic particles were described. It should be noted that the definition of elevated cardiovascular risk was limited to only those aged ≥55 years with type 2 diabetes and there was mild but notable increase in HbA1c and liver enzymes (<3x the ULN) in the olezarsen group compared to placebo. Finally, results were described in a predominately white population, reducing the generalizability to a diverse population.

Hypertriglyceridemia is associated with increased cardiovascular risk and existing pharmacological therapies only lead to modest reductions in triglycerides levels; however, this study was not designed or powered to evaluate major cardiovascular outcomes or all-cause mortality. With >80% of trial participants who received olezarsen reaching a normal triglyceride level and no major safety concerns observed, olezarsen represents a very promising therapeutic option beyond the current standard of care. Further studies should be considered to evaluate risk reduction for major cardiovascular events.

References:

Bergmark BA, Marston NA, Prohaska TA, et al. Targeting APOC3 with olezarsen in moderate hypertriglyceridemia. N Engl J Med. Published online Aug. 30, 2025. doi:10.1056/NEJMoa2507227.

Presented by Dr. Brian Bergmark at the European Society of Cardiology Congress, Madrid, Spain, Aug. 30, 2025.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Hypertriglyceridemia

Keywords: ESC Congress, ESC25, Hypertriglyceridemia, Risk


< Back to Listings