Lerodalcibep, a novel, third-generation proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, reduced low-density lipoprotein cholesterol (LDL-C) by more than 50% after 1 year in patients with or at a high risk for cardiovascular disease (CVD), new phase 3 results showed.
Newer, more stringent LDL targets in 90% of patients receiving lerodalcibep vs only 16% of those on placebo, despite concurrent treatment with a statin or statin plus ezetimibe.
"This hopefully gives doctors a more practical PCSK9 antagonist that's small volume, can be administered monthly, and is an alternative to the every 2 week injection of monoclonal antibodies and probably more effective in LDL cholesterol–lowering compared to the small interfering RNA" medicines, study author Eric Klug, MBBCh, MMed, associate professor, Division of Cardiology, University of the Witwatersrand, Johannesburg, South Africa, told theheart.org | Medscape Cardiology.
The findings from the LIBerate-HR trial were presented at the American College of Cardiology (ACC) Scientific Session 2024.
Additional Therapy Needed
The first goal is to get at least a 50% reduction in LDL-C, said Klug. The ACC, the American Heart Association, and the European Society of Cardiology recommended LDL-C of no more than 55 mg/dL as a goal for patients with CVD or who are at a very high risk for myocardial infarction or stroke and no more than 70 mg/dL for high-risk patients.
Most patients don't get to that combined goal with statins and ezetimibe and need additional therapy, "and it appears the earlier you give the therapy the better," said Klug.
Lerodalcibep is given as a low-dose (1.2-mL) monthly injection and is more convenient than other LDL-C–lowering options, said Klug. "This is a small-volume molecule that can be delivered subcutaneously once a month and can be kept on the shelf so it doesn't need to be kept in the fridge, and you can travel with it."
LIBerate-HR included 922 patients with CVD or at a high or very high risk for myocardial infarction or stroke at 66 centers in 11 countries. Over half (52%) fell into the at-risk category.
The mean age of participants was 64.5 years, 77% were White, and, notably, about 45% were women. Some 84% were taking a statin, 16.6% ezetimibe, a quarter had diabetes, and 10% had the more severe inherited familial hypercholesterolemia (FH).
Patients were randomly assigned to receive monthly 300-mg (1.2-mL) subcutaneous injections of lerodalcibep (n = 615) or placebo (n = 307) for 52 weeks.
The mean LDL-C at baseline was 116.9 mg/dL in the placebo group and 116.3 mg/dL in the treatment group.
The co-primary efficacy endpoints were the percent change from baseline in LDL-C at week 52 and the mean of weeks 50 and 52 (average of the peak and trough dose).
Compared with placebo, lerodalcibep reduced LDL-C by 56.19% at week 52 (P < .0001) and by 62.69% at mean week 50/52 (P < .0001). The absolute decreases were 60.6 mg/dL at week 52 and 74.5 mg/dL for mean week 50/52.
Rule of Thumb
"There's a sort of rule of thumb that for every 40 mg/dL that LDL-C is reduced, you reduce major adverse cardiovascular events (MACE) by 20%-23%," said Klug. "So, by reducing LDL-C by 60 mg/dL at week 52, you're reducing your risk of MACE maybe by 30% or 35%."
All subgroups reaped the same benefit from the intervention, noted Klug. "Whether you were male or female, under age 65, over age 65, baseline BMI less than median or more than median, White, Black or other, baseline statin intensity, diabetic or not diabetic, diagnosis of FH or not, it made no difference."
As for secondary outcomes, most patients attained the newer, more stringent guideline-recommended LDL targets. About 94% of all patients achieved a 50% or greater reduction in LDL-C compared to 19% on placebo. These percentages were 90% vs 12% for those at a high risk for CVD and 96% vs 21% for those with CVD or very high risk for CVD.
The treatment also reduced non–high-density lipoprotein cholesterol by 47%, apolipoprotein B by 43%, and Lp(a) by 33%.
Lerodalcibep was well-tolerated, with the number of patients with at least one adverse event similar to placebo (71.6% vs 68.1%) as was the case for the number with at least one serious adverse event (12.4% vs 13.4%).
Injection site reactions were mild to moderate. There was no difference in discontinuation rates due to these reactions (4.2% for the treatment and 4.6% for placebo).
A larger and longer trial to begin later this year should determine if the amount of LDL-C–lowering seen with lerodalcibep translates to greater reductions in cardiovascular events.
The company plans to file an application for approval to the US Food and Drug Administration in the next 2-4 months, said Klug.
Still Work to Do
During a press briefing, Dave L, Dixon, PharmD, professor and chair, Virginia Commonwealth University School of Pharmacy, and member of the ACC Prevention of Cardiovascular Disease Council, congratulated the investigators "on moving this product forward and demonstrating the LDL-lowering efficacy, as well as providing some additional safety and tolerability data."
He added it's "clear" from the baseline LDL characteristics that "we have a lot of work to do in terms of helping patients achieve their lipid goals."
Dixon noted up to about 30% of patients have some form of statin intolerance. "So, we really have to utilize our non-statin therapies, and unfortunately, we're not doing a great job of that."
That the trial enrolled so many women is "fantastic," said Dixon, adding the investigators also "did a great job" of enrolling underrepresented minorities.
Having a once-a-month self-injection option "is great" and "fills a nice niche" for patients, said Dixon.
The study was funded by LIB Therapeutics, which manufactures lerodalcibep. Klug had no conflicts relevant to this study (he received honoraria from Novartis, Amgen, and Sanofi-Aventis).