Assessment of Lipoprotein(a) Lowering in Cardiovascular Disease With SLN360 - ALPACAR

Nov 18, 2024
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Author/Summarized by Author:
Anthony A. Bavry, MD,MPH,FACC
Summary Reviewer:
Kim A. Eagle, MD, MACC
Trial Sponsor:
Silence Therapeutics
Date Presented:
11/18/2024
Date Published:
11/18/2024
Original Posted Date:
11/18/2024
References

Contribution To Literature:

The ALPACAR trial showed that among patients with ASCVD and elevated lipoprotein(a), zerlasiran reduces lipoprotein(a) by >80%.

Description:

The goal of this phase 2 trial was to evaluate zerlasiran compared with placebo among patients with atherosclerotic cardiovascular disease (ASCVD) and elevated lipoprotein(a). Zerlasiran is a small-interfering RNA that targets hepatic synthesis of apolipoprotein(a) and subsequent lipoprotein(a) production.

Study Design

  • Randomized
  • Parallel
  • Blinded
  • Placebo

Patients with ASCVD and elevated lipoprotein(a) were randomized to zerlasiran 450 mg every 24 weeks (n = 45) vs. zerlasiran 300 mg every 16 weeks (n = 44), vs. zerlasiran 300 mg every 24 weeks (n = 44), vs. placebo (n = 47).

  • Total number of enrollees: 180
  • Duration of follow-up: 60 weeks
  • Mean patient age: 64 years
  • Percentage female: 26%
  • Percentage with diabetes: 16%

Inclusion criteria:

  • Patients 18-80 years of age with ASCVD
  • Elevated lipoprotein(a) (≥125 nmol/L)

Exclusion criteria:

  • Acute CV event within previous 12 weeks
  • Estimated glomerular filtration rate <30 mL/min/1.73 m2
  • History of liver disease
  • Moderate to severe heart failure

Principal Findings:

The primary outcome, time-averaged percent change in lipoprotein(a) concentration from baseline to 36 weeks vs. placebo, was: -85.6 in the 450 mg every 24-week group vs. -82.8 in the 300 mg every 16-week group vs. -81.3 in the 300 mg every 24-week group.

Secondary outcomes:

  • Time-averaged percent change in low-density lipoprotein cholesterol from baseline to 36 weeks vs. placebo: -25.1 in the 450 mg every 24-week group vs. -31.9 in the 300 mg every 16-week group vs. -29.7 in the 300 mg every 24-week group
  • Time-averaged percent change in lipoprotein(a) concentration from baseline to 48 weeks vs. placebo: -83.0 in the 450 mg every 24-week group vs. -83.1 in the 300 mg every 16-week group vs. -78.7 in the 300 mg every 24-week group
  • Time-averaged percent change in lipoprotein(a) concentration from baseline to 60 weeks vs. placebo: -77.1 in the 450 mg every 24-week group vs. -79.2 in the 300 mg every 16-week group vs. -71.8 in the 300 mg every 24-week group

There were no serious adverse events related to the study drug.

Interpretation:

Among patients with ASCVD and elevated lipoprotein(a), zerlasiran reduces lipoprotein(a) by >80%. Persistent reductions in lipoprotein(a) were observed at 48 and 60 weeks after initial study drug administration. There were no serious adverse events related to the study drug. These findings support further evaluation of zerlasiran in phase 3 clinical trials.

References:

Nissen SE, Wang Q, Nicholls SJ, et al. Zerlasiran—A Small-Interfering RNA Targeting Lipoprotein(a): A Phase 2 Randomized Clinical Trial. JAMA 2024;Nov 18:[Epub ahead of print.

Presented by Dr. Steven E. Nissen at the American Heart Association Scientific Sessions, Chicago, IL, November 18, 2024.

Clinical Topics: Dyslipidemia, Advanced Lipid Testing, Lipid Metabolism, Prevention

Keywords: AHA Annual Scientific Sessions, AHA24, Atherosclerosis, Dyslipidemia, Lipoprotein(a)


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