Novel PCSK9 inhibitor helps achieve LDL-C targets in high-risk patients on statins

Monthly dosing of the anti-PCSK9 small binding protein lerodalcibep appears to significantly reduce low-density lipoprotein cholesterol (LDL-C) in patients with cardiovascular disease (CVD) or at high risk of atherosclerotic CVD who are unable to achieve target LDL-C levels while receiving maximal tolerated statins alone, according to the phase III LIBERATE-HR trial.

In a modified intention-to-treat (ITT) analysis, LDL-C decreased by 56.33 percent with lerodalcibep and by 0.14 percent with placebo at week 52 (mean difference, –56.19, 95 percent confidence interval [CI], –60.48 to –51.9; p<0.001) and by 63.25 percent and 0.56 percent, respectively, at the time-averaged mean of weeks 50 and 52 (mean difference, –62.69, 95 percent CI, –66.38 to –59.0; p<0.001). [JAMA Cardiol 2024;9:800-807]

Results were similar following ITT with washout imputation analysis (mean difference in change in LDL-C, −49.67 percent at week 52 and −55.33 percent at the mean of weeks 50 and 52; p<0.001 for both) and per-protocol analysis (mean difference in change in LDL-C, −60.27 percent at week 52 and −65.85 percent at the mean of weeks 50 and 52; p<0.001 for both).

“These large reductions with lerodalcibep resulted in more than 90 percent of patients at very high and high risk, with baseline LDL-C of 116 mg/dL despite maximally tolerated statins and other oral agents, to both achieve 50 percent or greater reduction from their current level and reach the new lower targets set in recent guidelines,” the investigators said.

“The effect of lerodalcibep on LDL-C reduction was consistent and independent of age, sex, body mass index, diabetes, CVD status, or background statin therapy,” they added.

Additionally, lerodalcibep yielded significant mean reductions relative to placebo in all other atherogenic lipoproteins, including nonhigh-density lipoprotein cholesterol (–47.3 percent), apolipoprotein B (–42.9 percent), lipoprotein(a) (–33.4 percent), triglycerides (–16.5 percent), as well as very LDL-C (–25.9 percent; p<0.001 for all) at 52 weeks.

In terms of safety, treatment-emergent adverse events were similar between lerodalcibep and placebo. However, injection site reactions occurred more frequently in the lerodalcibep arm than in the placebo arm (6.9 percent vs 0.3 percent), but all instances were graded as mild or moderate, none were considered severe or persistent, and did not result in higher treatment withdrawal or discontinuation (4.2 percent vs 4.6 percent).

Notably, while sporadic in vitro antidrug antibodies were detected, these exerted no impact on free PCSK9 or LDL-C–lowering efficacy.

“This trial substantiates that lerodalcibep, while a novel platform derived from human proteins, has minimal clinically significant immunogenicity, as long-term administration was not associated with in vivo active antidrug antibodies or neutralizing antibodies or any attenuation in either free PCSK9 suppression or LDL-C–lowering efficacy,” the investigators said.

Overall, the efficacy and safety data from LIBERTY-HR “support long-term use of lerodalcibep 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,” they added.

For LIBERTY-HR, 922 adult participants (mean age 64.5 years, 44.9 percent female, 78 percent White) were randomly assigned to receive monthly 1.2-mL subcutaneous injections of 300-mg lerodalcibep (n=615) or placebo (n=307) for 52 weeks. Of these, 541 (88 percent) in the lerodalcibep group and 270 (88 percent) in the placebo group completed the last dose of the study drug.

Of the participants, 47.7 percent had pre-existing CVD, 43.2 percent had diabetes, and 9.6 percent had familial hypercholesterolemia. Mean baseline LDL-C was 116.2 mg/dL, with 92.2 percent of participants receiving a lipid-lowering agent, 82.6 percent statins (39.4 percent of which were on high-intensity statins), and 16.6 percent ezetimibe either in combination with a statin or alone.