A Study of Lepodisiran in Participants With Elevated Lipoprotein(a) - ALPACA

Mar 30, 2025
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Author/Summarized by Author:
Carlos A Vergara Sanchez, MD
Summary Reviewer:
Fred M. Kusumoto, MD, FACC; R. Scott Wright, MD, FACC
Trial Sponsor:
Eli Lilly
Date Presented:
03/30/2025
Date Published:
03/30/2025
Date Updated:
03/30/2025
Original Posted Date:
03/30/2025
References

Contribution To Literature:

The ALPACA trial showed that among patients with elevated lipoprotein(a), lepodisiran reduces mean serum concentrations of lipoprotein(a) from 60 to 180 days after administration.

Description:

The goal of the ALPACA phase 2 trial was to assess the safety of lepodisiran in patients with higher lipoprotein(a) concentrations, determine the magnitude and duration of the reduction in lipoprotein(a) concentrations, and help inform the dose and dosing interval for a long-term phase 3 trial assessing cardiovascular outcomes, which is currently under way.

Study Design

Participants were randomly assigned in a 1:2:2:2:2 ratio to receive lepodisiran 16 mg, 96 mg, or 400 mg at baseline and again at day 180; lepodisiran 400 mg at baseline and placebo (0.9% sodium chloride) at day 180; or placebo at baseline and at day 180, all administered subcutaneously.

  • Total number of enrollees: 320
  • Duration of follow-up: 540 days
  • Mean patient age: 62.7 years
  • Percentage female: 43%

Inclusion criteria:

  • Adults aged ≥40 years
  • Serum lipoprotein(a) concentration ≥175 nmol/L
  • Participants receiving lipid-modifying drugs (e.g., statins, PCSK9 inhibitors, other drugs known to influence lipoprotein[a] concentrations) must have received stable doses for ≥4 weeks before screening

Exclusion criteria:

  • Had cardiovascular event within 3 months before screening
  • Moderate or severe heart failure
  • Estimated GFR <30 mL/min/1.73 m2
  • Hepatic enzyme levels >3 times the upper limit of normal
  • Women of child-bearing potential

Other salient features/characteristics:

  • Median baseline lipoprotein(a) concentration: 253.9 nmol/L
  • Median LDL cholesterol: 79.3 mg/dL
  • Median apolipoprotein B concentration: 79.0 mg/dL

Principal Findings:

The main outcomes evaluated placebo-adjusted time-averaged-reductions in lipoprotein(a) over time intervals:

Primary outcome:

  • Timed-averaged-reductions at days 60 to 180
    • 16 mg: -40.8 percentage points (95% CI, -55.8 to -20.6)
    • 96 mg: -75.2 percentage points (95% CI, -80.4 to -68.5)
    • 400 mg (pooled): -93.9 percentage points (95% CI, -95.1 to -92.5)

Secondary outcomes:

  • Placebo-adjusted time-averaged-reductions at days:
    • 30 to 360 days:
      • 16 mg: -41.2 percentage points (95% CI, -55.4 to -22.4)
      • 96 mg: -77.2 percentage points (95% CI, -81.8 to -71.5)
      • 400 mg-400 mg: -94.8 percentage points (95% CI, -95.9 to -93.4)
      • 400 mg-placebo: -88.5 percentage points (95% CI, -90.8 to -85.6)
    • 30 to 180 days:
      • 16 mg: -41.6 (95% CI, -55.6 to -23.2)
      • 96 mg: -75.6 (95% CI, -80.5 to -69.5)
      • 400 mg-400 mg: N/A
      • 400 mg-placebo: -95.5 (95% CI, -96.3 to -94.5)
    • 240 to 360 days:
      • 16 mg: -38.9 percentage points (95% CI, -54.9 to -17.2)
      • 96 mg: -77.4 percentage points (95% CI, -82.4 to -71.1)
      • 400 mg-400 mg: -95 percentage points (95% CI, -96.1 to -93.6)
      • 400 mg-placebo: -76.8 percentage points (95% CI, -81.9 to -70.2)

Safety:

Adverse events and lab evaluations: 35 participants with serious adverse events (11%), none of them related to placebo or lepodisiran. Other relevant adverse events were:

  • Injection site reaction: placebo 1% vs. lepodisiran (8.1-11.6%)
  • Liver function enzyme elevation (>3 times the upper limit of normal): 2.7-5.8% in the intervention arm 

Interpretation:

In this phase 2b study in patients with elevated lipoprotein(a), lepodisiran potently reduces lipoprotein(a) by up to 95%, with no signal of serious adverse events, but was associated with injection site reactions in up to 11.6% of patients and clinically meaningful elevations of ALT and AST in up to 5.8% of patients. Ongoing studies will determine the clinical and safety profile of this promising therapy. This is yet another exciting potential tool, which may be part of our arsenal to combat elevated lipoprotein(a) and help reduce cardiovascular disease burden globally.

References:

Nissen SE, Ni W, Shen X, et al. Lepodisiran — A Long-Duration Small Interfering RNA Targeting Lipoprotein(a). N Engl J Med 2025;Mar 30:[Epub ahead of print].

Presented by Dr. Steven E. Nissen at the American College of Cardiology Annual Scientific Session (ACC.25), Chicago, IL, March 30, 2025.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Advanced Lipid Testing, Lipid Metabolism

Keywords: ACC25, ACC Annual Scientific Session, Dyslipidemias, Lipoprotein(a), Primary Prevention


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