Key Points
– Newer cholesterol guidelines advise lower target values for LDL-C for high-risk patients, yet many patients do not reach this goal on statin therapy alone
– Lerodalcibep is a small binding protein that blocks binding of PCS9 inhibitor to the LDL-R, promoting increased uptake of LDL-C
– LIBerate-HR trial assessed the efficacy and safety of lerodalcibep in patients at very-high and high risk for CVD compared to placebo
– Lerodalcibep, injected once monthly, was found to significantly lower LDL-C as well as ApoB and Lp(a), compared to placebo
Newer cholesterol guidelines advise lower target values for LDL-C in patients with or at high-risk of cardiovascular disease (CVD). PCSK9 Inhibitors are useful for adequately lowering LDL-C in patients already on statin therapy and not at LDL-C goal.
Current injectable PCSK9 inhibitors rely on monoclonal antibodies to block PCSK9 from binding to the LDL-Receptor and are usually injected twice a month. However, Lerodalcibep, a small binding protein with a high degree of stability, permits once a month injection.
Dr. Eric Klug from the University of Witwatersrand, South Africa, presented the findings of the LIBerate-HR trial at ACC 2024, which investigated the effect on Lerodalcibep in those with CVD or at high risk who are already on statin therapy
A total of 922 participants with CVD or high risk for CVD were randomized in this double-blind, placebo-controlled, multi-national trial to receive monthly 1.2 ml subcutaneous Lerodalcibep (300 mg) or placebo for 52 weeks. The co-primary endpoints were a percent change in LDL-C at 52 weeks and the average of week 50 and 52, compared to baseline. Secondary outcomes included measurements of other lipids and apolipoproteins.
The median age of the participant was 64 years, 45% were female, 78% were white, the average LDL-C was 116mg/dL, and 48% had clinical ASCVD. In the treatment group, 82% of participants were on a stable dose of a statin and 16% taking ezetimibe.
At 52 weeks, Lerodalcibep decreased LDL-C by 56% (60.6mg/dl) and by 62% when using the mean LDL-C at week 50 and 52 (74.5 mg/dL). Over 90% of participants receiving Lerodalcibep achieved a target LDL-C of less than 55mg/dl.Significant improvements were also noted in other lipid parameters. ApoB and Lp(a) levels decreased 43% and 33% respectively in the intention-to-treatment analysis at 52 weeks.
There were no significant differences in discontinuation of Lerodalcibep or placebo. Injection site reactions were more common with Lerodalcibep (6.9% vs 0.3%) but graded as mild to moderate. Lastly, Lerodalcibep, in-vivo, did not demonstrate significant anti-drug antibodies that would diminish the effect of the drug.
“These are the first long-term data for lerodalcibep, which showed it to be both highly effective and safe after one year of follow-up,” said Eric Klug, MBBCh, MMed, of the University of Witwatersrand in Johannesburg, South Africa, and the study’s lead author. “We have demonstrated persistent LDL- cholesterol-lowering efficacy over 52 weeks, with over 90% of patients achieving both a reduction greater than 50% and the new much lower LDL targets. In addition, lerodalcibep was well-tolerated, with minimal adverse effects.”