Lerodalcibep (LIB-003) a third-generation PCSK9 inhibitor, is a small binding protein consisting of an 11-kilodalton anti-PCSK9 domain known as Adnectin, derived from human fibronectin and fused with human serum albumin to prolong its plasma half-life for 12 to 15 days. Bound by PCSK9-like monoclonal antibodies, it prevents PCSK9 from binding to LDL receptors, boosting LDL receptor recycling and cholesterol clearance, thereby reducing LDL levels. Unlike antibodies, its high solubility enables smaller injection volumes for stable, prolonged LDL reduction.

In a phase 2 trial, it was established that a monthly 300 mg dose of Lerodalcibep in 1.2mL significantly reduced LDL cholesterol by >70%. Eligibility criteria included age over 18, background statin therapy plus other oral lipid-lowering agents (at least 4 weeks), and an entry LDL cholesterol level above 70 mg/dL. Those with cardiovascular disease or high LDL cholesterol were randomized in a 2:2:1 ratio to receive LIB-003 300mg monthly or placebo for 48 weeks. The trial was conducted in 66 clinical centers across 11 countries and had co-primary endpoints at weeks 50 and 52. The co-primary efficacy endpoints included the percentage change from baseline in LDL cholesterol at week 52 and the mean of weeks 50 and 52. The secondary outcomes encompassed achieving LDL cholesterol targets for their risk factors and other lipid and apolipoprotein changes. The safety analysis involved all patients randomized and receiving a dose of the study drug.

The trial, conducted from April 2021 to November 2023, screened 1,352 patients, with 922 randomized. With a 12% withdrawal rate in both arms, 88% reached the 52-week visit and received the last dose of the study drug. Co-primary efficacy endpoints were analyzed in three categories: normal modified ITT analysis, per protocol analysis, and ITT group with imputation, newly defined by regulators in 2021 where a multiple imputation washout model is used, assuming that the active arm group that discontinued the trial had outcomes similar to the placebo group. The baseline and clinical characteristics of the patients were a mean age of 65, 50% were female, and approximately 1 in 5 were black or multiracial. The secondary and primary prevention groups were nearly equal, with <50% of patients diabetic, and 10% of patients with familial hypercholesterolemia. Over 80% used statins, and 16.6% used ezetimibe. Despite being on maximum dose statin and other oral lipid-lowering agents, the entry LDL cholesterol level was 116 mg/dL.

The normal modified TT analysis showed a -56% reduction in LDL cholesterol, with almost -63% reduction for means of weeks 50 and 52. Per Protocol analysis revealed reductions of 60% in LDL cholesterol and almost 66% mean of weeks 50 and 52. ITT imputation analysis demonstrated reductions of nearly 50% at week 52 and 55% for a mean of weeks 50 and 52. Over 90% of Lerodalcibep recipients achieved ESC-recommended LDL cholesterol reduction. Similar results were seen in high-risk and very high-risk subgroups. Significant placebo-adjusted reductions from baseline were observed at week 52 in additional lipid parameters. Reductions in non-HDL cholesterol, ApoB, lipoprotein A, and triglycerides were highly significant, with a slight increase in HDL cholesterol.

Assessment of free unbound PCSK9 at trough showed >90% median reduction and >70% mean reduction in the Lerodalcibep arm at weeks 24 and 52. Adverse events and safety findings were similar between arms, except for mild to moderate injection site reactions in almost 7% of the Lerodalcibep arm, which didn't impact trial continuity. No higher discontinuation rates were observed. Immunogenicity testing revealed low levels of transient anti-drug antibodies, with 0.4% of patients showing in vitro neutralizing antibodies, unrelated to injection site reactions or PCSK9 inhibition and LDL lowering efficacy.

In summary, Lerodalcibep significantly reduced LDL cholesterol by 56% at week 52 (60.6 mg/dL absolute reduction) and by 62% at the mean of weeks 50 and 52 (74.5 mg/dL absolute reduction). Over 90% of high-risk cardiovascular disease patients on maximally tolerated statins achieved ESC targets with Lerodalcibep. Additionally, Lerodalcibep lowered non-HDL cholesterol by 47%, ApoB by 43%, and lipoprotein by 33%. Adverse events were comparable to placebo, including mild to moderate injection site reactions, with no increase in discontinuations. Lerodalcibep did not induce active anti-drug or neutralizing antibodies affecting PCSK9 or LDL cholesterol efficacy. In conclusion, Lerodalcibep presents a novel and effective alternative to current PCSK9 inhibitors, offering substantial LDL cholesterol reduction in addition to existing oral agents. Tolerability and safety similar to placebo was demonstrated with a monthly small 1.2 mL subcutaneous dose, allowing for patient home use due to long ambient stability.

American College of Cardiology (ACC) Congress 2024, 6th April – 8th April 2024, Atlanta, Georgia, USA