Study Highlights Long-Term Potential of Lerodalcibep in LDL-C Treatment for High-Risk CVD Patients

In the randomized clinical trial, monthly subcutaneous administration of lerodalcibep, 300 mg (1.2 mL) significantly reduced LDL-C. Most participants achieved a ≥50% reduction in LDL-C and met guideline-recommended targets, with a safety profile comparable to placebo. The findings were published online in JAMA Cardiology on July 3, 2024.

Recent modifications in international and national lipid guidelines for lowering cardiovascular (CV) events recommend additional drugs, greater reductions, and lower targets for LDL-C if not attained with statins. Achieving these targets with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has yet to be evaluated in a randomized clinical trial. Considering this, Eric Q. Klug, Tickerdoc Research, Netcare Sunninghill Hospital, Sandton, South Africa, and colleagues aimed to evaluate the 52-week efficacy and safety of lerodalcibep, a small anti–PCSK9-binding protein, in patients with CVD or who are at very high or high risk of CVD and requiring addition LDL-C–lowering treatment.

For this purpose, the researchers conducted a randomized, double-blind, placebo-controlled phase 3 trial at 66 clinics in 11 countries between 2021 and 2023.

Adults aged 18 years and above, receiving the highest tolerated statin therapy, with LDL-C levels of 70 mg/dL or higher in the presence of CVD, or 100 mg/dL or higher if deemed at high risk of CVD, were enrolled. Patients were randomized 2:1 to monthly for 52 weeks to 1.2-mL subcutaneous lerodalcibep, 300 mg, or placebo.

The safety analysis encompassed all patients who were randomly assigned. The co-primary efficacy endpoints were the percentage change from baseline in LDL-C at week 52 and the average for weeks 50 and 52. Secondary efficacy measures included other lipid apolipoprotein assessments and meeting LDL-C targets recommended by guidelines.

The study led to the following findings:

• Of 922 randomized participants (mean age, 64.5 years; 44.9% female; mean baseline LDL-C, 116.2 mg/dL), 88% completed the trial.
• The mean placebo-adjusted reduction in LDL-C with lerodalcibep by modified intention-to-treat (mITT) analysis was 56.2% at week 52 and 62.7% for the mean of weeks 50 and 52; 49.7% and 55.3% by ITT with imputation using a washout model, and 60.3% and 65.9% by per-protocol analysis at week 52 and the mean of weeks 50 and 52, respectively.
• With lerodalcibep, 90% of participants achieved an LDL-C reduction of 50% or greater and recommended LDL-C targets during the study.
• Treatment-emergent adverse events were similar between lerodalcibep and placebo, except for injection site reactions. These occurred in 6.9% receiving lerodalcibep compared to 0.3% receiving placebo, were graded mild or moderate, and did not result in higher treatment discontinuation, at 4.2% and 4.6%, respectively.
• Sporadic in vitro antidrug antibodies were detected, which did not impact free PCSK9 or LDL-C–-lowering efficacy.

In conclusion, lerodalcibep, a novel anti-PCSK9 small binding protein, dosed monthly and stable at ambient temperatures significantly decreased LDL-C in patients with CVD or at high risk of CVD with a safety profile similar to placebo.

These results support extended lerodalcibep use in patients with CVD or at high risk of CVD who are unable to achieve adequate LDL-C reduction while receiving maximal tolerated statins alone, the study stated.

Reference:

Klug EQ, Llerena S, Burgess LJ, et al. Efficacy and Safety of Lerodalcibep in Patients With or at High Risk of Cardiovascular Disease: A Randomized Clinical Trial. JAMA Cardiol. Published online July 03, 2024. doi:10.1001/jamacardio.2024.1659