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Long-term efficacy and safety of lerodalcibep in heterozygous familial hypercholesterolaemia: the LIBerate-HeFH trial
Frederick J. RaalNyda FourieRussell ScottDirk BlomMatthys De Vries BassonMeral KayıkçıoğluKate CaldwellDavid KallendEvan A. SteinTraci TurnerJean BergeronArtuela ÇakuAvishay ElisRonen DurstZafer YalımMeral KayıkçıoğluBahadır KırılmazAtaç ÇelikIrfan DuzenAbdurraham Oguzhanİbrahim BaşarıcıFrederick J. RaalDirk BlomM AbelsonMatthys M de V BassonLesley BurgessNyda FourieEli HeggenEmil Andreas AsprustenVimal MehtaRaman PuriAshwani MehtaPreeti GuptaMilan ChagAkshyaya PradhanFernando Civeira MurilloRussell Scott
Key result
Lerodalcibep reduces LDL-C by ~59% vs placebo in heterozygous familial hypercholesterolaemia.
- placebo-adjusted difference of -58.61%
- P<0.0001
- n=478
Figures
Why the study?
The safety and efficacy of lerodalcibep for additional LDL-C lowering in heterozygous familial hypercholesterolaemia patients required evaluation in a global Phase 3 trial.
Does lerodalcibep reduce LDL-C in patients with heterozygous familial hypercholesterolaemia on maximally tolerated lipid-lowering therapy?
Key Points
- Evaluate the efficacy and safety of lerodalcibep, a novel PCSK9-binding recombinant fusion protein, in patients with heterozygous familial hypercholesterolaemia requiring additional LDL-C lowering.
- Phase 3 global trial randomizing 478 patients 2:1 to monthly subcutaneous injections of lerodalcibep 300 mg (n=319) or placebo (n=159) for 24 weeks.
- The primary efficacy endpoints in the intention-to-treat population were the per cent change from baseline in LDL-C at Week 24 and the mean of Weeks 22 and 24.
- Lerodalcibep reduced LDL-C compared with placebo by an absolute 2.08 (0.11) mmol/L (95% CI -2.30 to -1.87) with a percentage difference of -58.61 (3.25)% at Week 24, and by 2.28 (0.10) mmol/L (95% CI -2.47 to -2.09) with a percentage difference of -65.0 (2.87)% at the mean of Weeks 22 and 24 (P < .0001 for all).
- Both an LDL-C reduction ≥ 50% and recommended European Society of Cardiology LDL-C targets were achieved by 68% of subjects receiving lerodalcibep compared with 1.9% on placebo (odds ratio 220.23, 95% CI 65.77–737.45; P < .0001).
- Treatment-emergent adverse events occurred in 72.3% on lerodalcibep and 68.6% on placebo, with mild or moderate injection site reactions reported in 10.1% vs. 1.3%, respectively.
Study Design
Type
RCT (n=478)
Blinding
Double-blind
Randomization
2:1
Multicenter
Yes
Structured PICO
Does lerodalcibep reduce LDL-C in patients with heterozygous familial hypercholesterolaemia on maximally tolerated lipid-lowering therapy?
P
Population
478 adults (mean age 53, 51.7% female) with heterozygous familial hypercholesterolaemia on maximally tolerated lipid-lowering therapy were randomized to lerodalcibep or placebo for 24 weeks.
I
Intervention
Lerodalcibep 300 mg subcutaneous injection once monthly for 24 weeks
C
Comparator
Matching placebo subcutaneous injection once monthly for 24 weeks
O
Outcome
Per cent change from baseline in LDL-C at Week 24 and the mean of Weeks 22 and 24surrogate
Main Result
Mean Difference: -58.61
Absolute Event Rate: -50.5% vs 8.1%
p-value: p=<0.0001
Lerodalcibep provides a highly effective, once-monthly subcutaneous alternative to monoclonal antibodies for LDL-C reduction in patients with HeFH.
Limitations
- Relatively short 24-week duration
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
LLLisa LiuVP and Head of Medical, Hasten Biopharma
“Data from Phase III clinical trials abroad have demonstrated that Lerodalcibep, a novel third-generation PCSK9 inhibitor, can sustainably reduce LDL-C when administered as a monthly subcutaneous one-shot dose. Meanwhile, the results of existing stability experiments show that it possesses superior stability at room temperature. We will actively cooperate with the regulatory authorities in the review of Lerodalcibep to advance the clinical trial process, so that it can provide more treatment options for patients with atherosclerotic cardiovascular disease (ASCVD) and/or those at very high or high risk of ASCVD as soon as possible.”
“We founded LIB Therapeutics with a mission to bring an effective and more patient-friendly treatment option to the millions of patients who still need additional LDL-C reduction in order to achieve the lower targets recommended in recent guidelines. Today's FDA approval validates that mission and the focus of my medical career.”
Implication
Offers a convenient monthly alternative for further LDL-C lowering in HeFH; extends Phase 2 efficacy data with Phase 3 confirmation.
Abstract
BACKGROUND AND AIMS: Lerodalcibep, a novel small recombinant fusion protein of a proprotein convertase subtilisin/kexin type 9 gene-binding domain (adnectin) and human serum albumin, demonstrated highly effective low-density lipoprotein cholesterol (LDL-C) reduction with monthly 300 mg in 1.2 mL subcutaneous dosing in Phase 2. In this global Phase 3 trial, the safety and efficacy of lerodalcibep were evaluated in heterozygous familial hypercholesterolaemia patients requiring additional LDL-C lowering. METHODS: Patients were randomized 2:1 to monthly subcutaneous injections of either lerodalcibep 300 mg or placebo for 24 weeks. The primary efficacy endpoints were the per cent change from baseline in LDL-C at Week 24 and the mean of Weeks 22 and 24. RESULTS: In 478 randomized subjects [mean age (range); 53 (18-80) years, 51.7% female, mean (SD) baseline LDL-C 3.88 (1.66) mmol/L], lerodalcibep reduced LDL-C, compared with placebo by an absolute amount of 2.08 (0.11) mmol/L [LS mean (SE); 95% confidence interval -2.30 to -1.87] with a percentage difference of -58.61 (3.25)% at Week 24 and by 2.28 (0.10) mmol/L (95% confidence interval -2.47 to -2.09) with a percentage difference of -65.0 (2.87)% at the mean of Weeks 22 and 24 (P < .0001 for all). With lerodalcibep, 68% of subjects achieved both a reduction in LDL-C ≥ 50% and the recommended European Society of Cardiology LDL-C targets during the study. Except for mild injection site reactions, treatment-emergent adverse events were similar between lerodalcibep and placebo. CONCLUSIONS: Lerodalcibep, a novel anti-proprotein convertase subtilisin/kexin type 9 gene small binding protein dosed monthly as an alternative to monoclonal antibodies, significantly reduced LDL-C in subjects with heterozygous familial hypercholesterolaemia with a safety profile similar to placebo.
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Cite This Study
Raal et al. (2023) conducted an RCT in Heterozygous familial hypercholesterolaemia (HeFH) (n=478). Lerodalcibep vs. Placebo was evaluated on Per cent change from baseline in LDL-C at Week 24 (placebo-adjusted difference of -58.61%, p=<0.0001). Lerodalcibep significantly reduced LDL-C by a placebo-adjusted 58.61% at 24 weeks in patients with heterozygous familial hypercholesterolaemia.