Lerodalcibep reduces LDL in well-treated patients with HeFH vs. placebo
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Key takeaways:
- Lerodalcibep further reduced LDL vs. placebo in well-treated patients with HeFH.
- More than 85% of the intervention arm achieved a 50% or greater LDL reduction, despite many being at very high ASCVD risk.
Monthly lerodalcibep on top of maximum tolerated therapy reduced LDL an additional 60% over 24 weeks in patients with heterozygous familial hypercholesterolemia, with a safety profile similar vs. placebo, a speaker reported.
The results of the global phase 3 LIBerate-HeFH trial were presented at the European Society of Cardiology Congress and simultaneously published in the European Heart Journal.
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“Management of patients with heterozygous familial hypercholesterolemia (HeFH) is prevention of atherosclerotic cardiovascular disease through LDL-lowering therapy, and our basis therapy is high-intensity statins together with ezetimibe and or other oral lipid-lowering agents,” Frederick J. Raal, MMed, PhD, distinguished professor and director of the carbohydrate and lipid metabolism research unit at the University of the Witwatersrand in South Africa, said during a presentation. “But despite this therapy, the majority of HeFH patients fail to achieve sufficient LDL reduction, and additional therapies to either inhibit PCSK9 in the circulation or reduce its hepatic production and enhance LDL clearance are required.”
Lerodalcibep (LIB003, LIB Therapeutics) is a small binding protein that inhibits interaction between PCSK9 and LDL receptors — an alternative to monoclonal antibodies — and was designed with prolonged stability at ambient temperature and smaller injection volume compared with monoclonal antibodies, according to the presentation.
For the LIBerate-HeFH trial, Raal and colleagues randomly assigned 319 patients with HeFH to monthly subcutaneous 1.2 mL injections of lerodalcibep 300 mg for 24 weeks and 159 patients to placebo (mean age, 53 years; 52% women; more than 85% white).
The primary efficacy endpoints were percent change in LDL from baseline to week 24 and from baseline to a mean of weeks 22 and 24. The secondary efficacy endpoints included change in apolipoprotein B, lipoprotein(a) and achievement of ESC consensus target LDL.
For patients with HeFH and ASCVD or an additional risk factor for ASCVD, the ESC consensus target is an LDL level less than 1.4 mmol/L and a 50% or more reduction in LDL from baseline. For patients with HeFH without ASCVD or an additional risk factor for ASCVD, the ESC consensus target is an LDL level less than 1.8 mmol/L and a 50% or more reduction in LDL from baseline.
At baseline, the mean LDL was 3.79 mmol/L in the placebo group and 3.93 mmol/L in the lerodalcibep group, and nearly half of patients had documented ASCVD. More than two-thirds of the cohort were classified as very high risk for ASCVD.
Additionally, approximately 88% of participants were on a statin at baseline and approximately two-thirds were taking a high-intensity statin. Nearly half were also taking ezetimibe at baseline.
Compared with placebo, the mean 24-week placebo-adjusted reduction in LDL in the lerodalcibep arm was 58.6% (P < .0001), and the mean placebo-adjusted reduction during the average of weeks 22 and 24 was 65% (P < .0001).
Among patients who received every monthly lerodalcibep injection within the steady window period — 80% of the overall cohort — researchers reported a 24-week placebo-adjusted reduction in LDL of 63.6% (P < .0001) and a mean placebo-adjusted reduction during the average of weeks 22 and 24 of 70.2% (P < .0001).
Overall, 86.2% of the entire lerodalcibep arm achieved LDL reduction of 50% or more and 69.6% achieved ESC consensus target LDL level compared with 3.8% and 4.4% in the placebo arm, respectively.
The proportion of patients who received lerodalcibep and achieved an LDL reduction of 50% or more and ESC consensus target LDL level were consistent across subgroups of high and very high ASCVD risk.
Raal also reported significant reductions in key secondary efficacy endpoints in the lerodalcibep arm compared with placebo:
- a 45.6% placebo-adjusted reduction in ApoB;
- a 23.9% placebo-adjusted reduction in Lp(a); and
- a 94.3% median reduction in free PCSK9 (P for all < .0001).
Moreover, the reported reductions in LDL within the lerodalcibep arm were consistent across all subgroups, including patients classified by age, sex, baseline BMI, race, LDL at baseline, baseline statin intensity and history of diabetes.
Mild or moderate injection site reactions occurred in 10.1% of the lerodalcibep arm compared with 1.3% of the placebo arm, the majority of which were characterized by erythema and bruising. Among 1,853 lerodalcibep injections administered during the study, 3.1% conferred injection site reactions.
“Lerodalcibep 300 mg administered monthly, added to maximum tolerated oral lipid-lowering therapy, reduced LDL cholesterol a further 60%. Lerodalcibep resulted in approximately 70% of HeFH patients achieving both a reduction in LDL cholesterol of greater than 50% and the current 2019 ESC-recommended LDL targets for those with ASCVD or very high risk for ASCVD,” Raal said during the presentation. “Lerodalcibep also reduced ApoB by 46% and Lp(a) by 24%. It was well tolerated with a safety profile similar to placebo, and these results support the use of lerodalcibep for the management of HeFH.”
References:
- Mach F, et al. Eur Heart J. 2020;doi:10.1093/eurheartj/ehz455.
- Raal F, et al. Eur Heart J. 2023;doi:10.1093/eurheartj/ehad596.
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Raal FJ, et al. Late-breaking science on pharmacology. Presented at: European Society of Cardiology Congress; Aug. 25-28, 2023; Amsterdam (hybrid meeting).
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