Bridge–TIMI (Thrombolysis in Myocardial Infarction) 73a - Bridge–TIMI 73a

Apr 07, 2024
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Author/Summarized by Author:
Amit Saha, MD
Summary Reviewer:
Dharam J. Kumbhani, MD, SM, FACC
Trial Sponsor:
Ionis Pharmaceuticals
Date Presented:
04/07/2024
Date Published:
04/07/2024
Original Posted Date:
04/07/2024
References

Contribution To Literature:

The Bridge–TIMI 73a trial showed that in patients with moderate to severe hypertriglyceridemia, the investigational drug olezarsen achieved significantly greater reductions in both TG and other atherogenic lipoprotein levels compared with placebo.

Description:

The goal of the trial was to determine the triglyceride (TG)-lowering effect and safety of olezarsen, an antisense oligonucleotide targeting apolipoprotein C-III (APOC3), compared with placebo in patients with hypertriglyceridemia and at risk of or with established atherosclerotic cardiovascular disease (ASCVD).

Study Design

  • Phase 2b
  • Multicenter (USA/Canada)
  • Randomized
  • Double-blind

Patients with moderate to severe hypertriglyceridemia were randomized to receive olezarsen 50 mg (n = 58) or 80 mg (n = 57) subcutaneous injection administered once every 4 weeks or matching placebo (n = 39).

  • Total number of enrollees: 154
  • Duration of follow-up: 12 months
  • Median patient age: 62 years
  • Percentage female: 42%

Inclusion criteria:

  • Age ≥18 years
  • Eligible hypertriglyceridemia, defined as either: 1) moderate (fasting TG 150-499 mg/dL) AND established ASCVD, type 2 diabetes mellitus (DM), or ≥2 ASCVD risk factors; OR 2) severe (fasting TG ≥500 mg/dL)
  • Stable doses of lipid-lowering therapy per local standard of care

Exclusion criteria:

  • DM newly diagnosed <12 weeks prior
  • Hemoglobin A1c ≥9.5%
  • >20% change in basal insulin regimen <3 months prior
  • Type 1 DM with ≥1 episode of diabetic ketoacidosis or ≥3 episodes of severe hypoglycemia <6 months prior
  • Acute coronary syndrome, stroke, or transient ischemic attack <6 months prior
  • Coronary or peripheral revascularization <3 months prior
  • Active pancreatitis <4 weeks prior

Other salient features/characteristics:

  • Median body mass index: 33 kg/m2
  • Percentage with DM: 68%
  • Median baseline TG: 242 mg/dL
  • Baseline TG ≥500 mg/dL: 10%
  • ≥2 lipid-lowering therapies: 31%

Principal Findings:

Primary outcome, percent change from baseline TG compared with placebo at 6 months:

  • Olezarsen 50 mg: -49.3% (95% confidence interval [CI] -39.5% to -59.9%), p < 0.001
  • Olezarsen 80 mg: -53.1% (95% CI -43.4% to -62.9%), p < 0.001

Secondary outcomes at 6 months vs. placebo:

  • Percent change from baseline APOC3:
  • Olezarsen 50 mg: -64.2% (95% CI -53.6% to -74.7%), p < 0.001
  • Olezarsen 80 mg: -73.2% (95% CI -62.5% to -83.9%), p < 0.001
  • Moderate hypertriglyceridemia achieving TG <150 mg/dL:
  • Olezarsen 50 mg: 86%, p <0.001
  • Olezarsen 80 mg: 93%, p <0.001
  • Placebo: 12%
  • Acute pancreatitis: 0% (all groups)

Safety outcomes through 28 days following last dose vs. placebo:

  • Any adverse event resulting in study drug discontinuation:
  • Olezarsen 50 mg: 12%, p = 0.04
  • Olezarsen 80 mg: 5%, p = 0.27
  • Placebo: 0%
  • Aminotransferase elevation >3 times upper limit of normal:
  • Olezarsen 50 mg: 7%, p = 0.15
  • Olezarsen 80 mg: 2%, p = 1.00
  • Placebo: 0%
  • Decrease in estimated glomerular filtration rate ≥30%:
  • Olezarsen 50 mg: 10%, p = 0.16
  • Olezarsen 80 mg: 7%, p = 0.06
  • Placebo: 21%
  • Thrombocytopenia <100,000/µL:
  • Olezarsen 50 mg: 0%, p = 0.40
  • Olezarsen 80 mg: 5%, p = 0.64
  • Placebo: 3%
  • Dose reduction (from 80 to 50 mg): n = 1
  • Death: n = 1 (olezarsen 50 mg)

Interpretation:

Olezarsen is a conjugated antisense oligonucleotide directed against APOC3, which increases circulating TG and whose absence is associated with decreased ASCVD risk in human loss-of-function mutations. In Bridge–TIMI 73a, olezarsen resulted in at least 50% reduction in TG in patients with clinically relevant hypertriglyceridemia and/or established ASCVD, exceeding the treatment effect of currently available lipid-lowering therapies. Olezarsen apparently achieves this through dose-dependent inhibition of APOC3 but was also associated with decreases in other atherogenic lipoproteins including apolipoprotein B and both very low and non–high-density lipoprotein cholesterol (non–HDL-C). Significant increases were also observed in HDL-C compared with placebo.

The study drug was generally well tolerated compared with placebo and did not carry the same risk of thrombocytopenia as its unconjugated predecessor volanesorsen. Phase 3 trials will shed light on whether olezarsen’s significant effects on atherogenic lipoproteins actually correlate with reduced risk of ASCVD, which as yet remains an elusive goal for contemporary TG-lowering therapies.

References:

Bergmark BA, Marston NA, Prohaska TA, et al., on behalf of the Bridge–TIMI 73a Investigators. Olezarsen for Hypertriglyceridemia in Patients at High Cardiovascular Risk. N Engl J Med 2024;Apr 7:[Epub ahead of print].

Presented by Dr. Brian A. Bergmark at the American College of Cardiology Annual Scientific Session (ACC.24), Atlanta, GA, April 7, 2024.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Hypertriglyceridemia, Prevention, Vascular Medicine

Keywords: ACC24, ACC Annual Scientific Session, Atherosclerosis, Hypertriglyceridemia, Novel Agents


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