Phase 3 results for novel PCSK9i in patients with CVD or high/very high CVD risk

ACC.24 - In patients with elevated LDL-c levels and CVD or high/very CVD risk, once-monthly lerodalcibep reduced LDL-c by ~60% at 52 weeks compared with placebo. About 90% of the patients on lerodalcibep met the new, stringent ESC goals. The drug was overall well tolerated.

This summary is based on the presentation of Eric Klug, MD (Johannesburg, South Africa) at the ACC.24 Scientific Session - Randomized, Double-blind, Placebo-controlled, Phase 3, Study to Evaluate Lerodalcibep Long-term Efficacy and Safety in Patients With, or at Very-high or High Risk, For Cardiovascular Disease on Stable Lipid-lowering Therapy.

Introduction and methods

Lerodalcibep is a small recombinant fusion protein that consists of a PCSK9-binding domain (adnectin) that is fused with human serum albumin, which increases the plasma half-life and allows for monthly injection of a small volume. In a recent phase 2 trial, this third-generation PCSK9 inhibitor was shown to reduce LDL-c levels by >70% over 12 weeks in patients with LDL-c >80 mg/dL despite maximally tolerated statin therapy, with no safety concerns.

The LIBerate-HR (Study of Long-Term Efficacy and Safety of LIB003 in CVD or High Risk for CVD Patients Needing Further LDL-C Reduction) trial was an international, multicenter, double-blind, placebo-controlled, phase 3 RCT. In this trial, 922 patients with LDL-c ≥70 mg/dL (if they had CVD or were at very high risk for CVD) or LDL-c ≥100 mg/dL (if they were at high risk for CVD) despite taking stable oral lipid-lowering therapy were randomized in a 2:1 ratio to subcutaneous lerodalcibep 300 mg (1.2 mL) once-monthly (n=615) or placebo (n=307) for 52 weeks. Approximately half of the study participants had high or very high CVD risk but no CVD.

The primary efficacy endpoints were the LDL-c percent change from baseline to 52 weeks and the mean LDL-c change at 50 and 52 weeks. Secondary endpoints included safety, immunogenicity, changes in other lipid parameters, and achievement of 2019 ESC/EAS-recommended LDL-c targets.

Main results

• The modified intention-to-treat analysis showed the LDL-c percent change from baseline to 52 weeks was –56.33% in patients treated with lerodalcibep (n=546) and –0.14% in placebo-treated patients (n=274) (placebo-adjusted change: –56.19%; P<0.0001).
• The mean LDL-c change at 50 and 52 weeks was –63.25% in the lerodalcibep group and –0.56% in the placebo group (placebo-adjusted change: –62.69%; P<0.0001).
• Of the patients receiving lerodalcibep, ≥90% achieved the 2019 ESC targets (i.e., ≥50% LDL-c reduction, and LDL-c <70 mg/dL if high CVD risk or LDL-c <55 mg/dL if CVD or very high CVD risk) compared with ≤28% of the placebo-treated patients.
• Among patients at high or very high CVD risk, ~90% of those on lerodalcibep also met one or both of these more stringent LDL-c goals, compared with ≤32% of the placebo-treated patients.
• At 52 weeks, lerodalcibep treatment resulted in placebo-corrected reductions from baseline in non–HDL-c of 47.3%, apoB of 43%, Lp(a) of 33.4%, and triglycerides of 16.5% and a placebo-corrected increase in HDL-c of 6.5%.
• The lerodalcibep and placebo groups did not differ in the frequencies of adverse events (~70%), adverse events leading to discontinuation of the study drug (~4.5%), and serious adverse events (~13%).
• The number of injection site reactions was higher in the lerodalcibep group than the placebo group (6.9% vs. 0.3%), but these were mild to moderately severe and transient and did not lead to a difference in discontinuation rate.
• Lerodalcibep treatment was not associated with the development of antidrug or neutralizing antibodies that reduced the free PCSK9 suppression or LDL-c efficacy.

Conclusion

In patients with elevated LDL-c levels who had a history of CVD or were at high or very high CVD risk, once-monthly injections with lerodalcibep, in addition to stable oral lipid-lowering therapy, resulted in an LDL-c reduction of ~60% at 52 weeks compared with placebo. Approximately 90% of the patients on lerodalcibep met the new, stringent ESC-recommended LDL-c goals, even those at high or very high CVD risk. The PCSK9 inhibitor also reduced other lipid parameters and was overall well tolerated.