LIBerate-HeFH – Randomized, Double-Blind, Placebo-Controlled, Phase 3, Study to Evaluate the Long-Term Efficacy and Safety of Leroalcibep in Heterozygous Familial Hypercholesterolaemia Patients (LIBerate-HeFH)

Presented at the ESC congress 2023 by: Frederick Raal, MD - Johannesburg, South Africa

Introduction and methods

Lerodalcibep (LIB-003) is a small binding protein that binds to PCSK9. Binding to PCSK9 leads to blockage of the interaction between PCSK9 and the LDL receptor (LDLR), prevention of LDLR degradation, increased LDLR recycling, enhanced LDL-c clearance, and eventually lowered LDL-c levels. Lerodalcibep is an alternative to monoclonal antibodies against PCSK9. It consist of adnectin -a PCSK9-binding domain- fused with albumin to extend the plasma half-life to 12-15 days.

Smaller injection volumes are possible for lerodalcibep than for mAbs due to prolonged stability at ambient temperature, small size of the protein (77 kDa) and high solubility.

In the phase 3 LIBerate-HeFH trial, the safety and efficacy of lerodalcibep was evaluated in heterozygous FH (HeFH) patients on stable statin and/or ezetimibe therapy who required additional LDL-c lowering. 478 Patients with HeFH were randomized in a 2:1 ratio to monthly 1.2 ml SC injections of lerodalcibep 300 mg (n=319) or placebo (n=159) for 24 weeks.

The primary efficacy endpoints were the percent change from baseline in LDL-c at week 24 and then mean percent change of week 22 and week 24.

Main results

• The placebo-adjusted change in LDL-c at week 24 was -58.6% for the lerodalcibep group (P<0.0001) and the mean percent placebo-adjusted change in LDL-c at 22 and 24 weeks was -65.0% (P<0.0001).
• In the lerodalcibep group, 86.2% of patients achieved ≥50% reduction in LDL-c vs. 3.8% in the placebo group. Moreover, 69.6% of patients were at their LDL-c target with lerodalcibep vs. 4.4% in the placebo group.
• In the lerodalcibep group, the placebo-adjusted changes at 24 weeks for LDL-c (measured by ultracentrifugation), apoB and Lp(a) were -56.0%, -45.6% and 23.9% respectively (all P<0.0001). The change in free PCSK9 at week 24 was -94.3% in the lerodalcibep group (P<0.0001).
• Subgroup analysis showed no heterogeneity for the effect of lerodalcibep.
• There were no differences in adverse events between the lerodalcibep and placebo groups.
• Injection site reactions were however more seen in the lerodalcibep group vs. the placebo group (10.1% vs. 1.3% respectively). Low levels of transient and sporadic anti-drug antibodies were detected and 3.4% of patients had in-vitro neutralising Abs (NAbs), but none of these NAbs were associated with in-vivo effects.

Conclusion

Addition of lerodalcibep 300 mg monthly to maximally tolerated lipid-lowering therapy reduced LDL-c further by 60% in patients with HeFH. Lerodalcibep was well tolerated and had a safety profile similar to placebo. Prof. Raal concluded: “These results support the use of lerodalcibep for the management of HeFH.”

- Our reporting is based on the information provided at the ESC Congress -

The results of the LIBerate-HeFH trial were simultaneously published in the Eur Heart J