CONFERENCE UPDATE: ACC 2024

LDL-C reduction with lerodalcibep in patients at very high or high risk for CVD: The phase 3 LIBerate-HR study

CARDIOLOGY
15 Jul 2024

STUDY DESIGN

Lerodalcibep is a third-generation proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor that prevents PCSK9 from binding to low-density lipoprotein receptors (LDLRs).1 Low-density lipoprotein-cholesterol (LDL-C) clearance from the bloodstream is enhanced as a result of LDLR degradation being blocked.1 Compared to monoclonal antibodies (mAbs), lerodalcibep is smaller in size and has a higher solubility, enabling prolonged and stable LDL-C reductions.1 In a prior phase 2 trial, lerodalcibep at a dose of 300mg monthly was shown to be effective in lowering LDL-C by >70%.1

The LIBerate-HR is a phase 3 study conducted to assess the efficacy and safety of lerodalcibep in patients at very high or high risk for CVD.1 The study included 922 adult patients with cardiovascular disease (CVD) or at high risk for CVD, who were receiving stable doses of statin with or without ezetimibe and have LDL-C levels ≥70mg/dL and CVD or LDL-C levels ≥100mg/dL and a high risk of CVD.1 Patients with very high risk, including those with clinical CVD or CVD risk equivalents were also included.1 They were randomized (2:1) to receive monthly subcutaneous (SC) injections of lerodalcibep 300mg (n=615) or a matching placebo (n=307) for 52 weeks.1

The coprimary endpoints were the percent change in LDL-C levels from baseline to week 52 and the mean change in LDL-C levels of weeks 50 and 52.1 Key secondary outcomes included the percentage of patients achieving ≥50% LDL-C reduction and LDL-C targets as well as the changes in other lipid and apolipoproteins.1

Co-primary efficacy endpoints Secondary outcomes
Percentage change from baseline in LDL-C at week 52 and the mean change of weeks 50 and 52 Achievement of LDL-C targets,
other lipid and apolipoprotein changes


FINDINGS

Primary endpoints: 
  • The coprimary endpoints were the percent change in LDL-C levels from baseline to week 52 and the mean change in LDL-C levels of weeks 50 and 521
  • In the modified intention to treat (mITT) analysis
    • At week 52, the lerodalcibep and placebo group had a 56.33% and 0.14% reduction in LDL-C levels from baseline, respectively (placebo-adjusted change: -56.19%; p<0.0001)1
    • At mean weeks 50 and 52, the lerodalcibep and placebo group had a 63.25% and 0.56% reduction in LDL-C levels, respectively (placebo-adjusted change: -62.69%; p<0.0001)1

Secondary endpoints:
  • The secondary outcomes were the proportion of patients achieving ≥50% LDL-C reduction and LDL-C targets, and the change in other lipids and apolipoproteins1
  • Compared with the placebo group, more patients in the lerodalcibep group achieved both a ≥50% reduction in LDL-C and their LDL-C goals (90% vs. 16%)1
  • More patients on lerodalcibep achieved a ≥50% reduction in LDL-C (94% vs. 19%) or their LDL-C goal (91% vs. 28%) compared with placebo1
  • Similar results were observed regardless of the presence of CVD or CVD risk1
  • Compared to placebo, lerodalcibep was associated with an increase in HDL-C and reductions in non-HDL-C, apolipoprotein B, lipoprotein a, and triglycerides, (p<0.001)1

Safety:

  • The rates of adverse events were similar across the groups1
  • A higher rate of injection site reactions experienced in the lerodalcibep arm (6.9% vs. 0.3%)1
  • Low levels of immunogenicity were reported with transient and sporadic anti-drug antibodies not associated with injection-site reactions and any attenuation in PCSK9 and LDL-C-lower efficacy or in-vitro1

 

“Lerodalcibep offers a novel, effective alternative to existing PCSK9 inhibitors with substantial LDL-C reductions on top of existing oral agents”

Dr. Eric Klug
Division of Cardiology,
Faculty of Health Sciences,
University of the Witwatersrand,
Johannesburg, South Africa

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