Lerodalcibep Efficaciously Reduces LDL-C Lastingly and Long-Term, With Evan Stein, MD, PhD

Lerodalcibep, an investigative oral PCSK9 inhibitor, has demonstrated substantial long-term efficacy in reducing LDL-C in patients at high or very high risk for cardiovascular disease (CVD) on a stable diet and existing oral LDL-C-lowering drug therapy, according to data from an open-label extension of the LIBerate-VI trial.1

These data were first presented at the American Heart Association’s Scientific Sessions 2025 in New Orleans, Louisiana, by Evan Stein, MD, PhD, chief operating officer and chief scientific officer of LIB Therapeutics.1

“This is the first study to combine 2 different mechanisms for inhibiting PCSK9, and demonstrates that we gain synergy with this drug, which binds PCSK9 in the bloodstream,” Stein told HCPLive in an exclusive interview. “Only about 60 to 70% of PCSK9 in the bloodstream comes from hepatic synthesis; the rest comes from the gut, kidney, and other tissues. So this is a novel combination therapy which has never been tried before.”

LIBerate-VI was a randomized, open-label phase 3 study comparing lerodalcibep 300 mg to inclisiran 284 mg. For inclusion, patients were required to have a weight of ≥88 lbs and a body mass index (BMI) ≥16 and ≤42 kg/m2, a very high or high risk for CVD, high-intensity statin without other acceptable oral lipid lowering treatment plus diet stable for >4 weeks with LDL-C ≥85 mg/dL and triglycerides ≤400 mg/dL. Patients were excluded if they had homozygous familial hypercholesterolemia, severe renal dysfunction, NYHA class III or IV heart failure, or active liver disease, among other criteria.2

The study’s primary outcome was percent change in LDL-C from baseline at day 270. Secondary outcomes included the frequency and severity of injection site reactions, the percent change in free PCSK9, the percent change in ApoB and Lp(a), and the percent of patients reaching ESC/EAS treatment goals. A total of 166 patients were included in the trial and subsequently randomly assigned to either lerodalcibep 300 mg administered subcutaneously monthly or inclisiran 284 mg, subcutaneously administered at days 1 and 90.1

A total of 117 patients entered the open-label extension – of these, 107 completed the full 72-week extension period. These patients received lerodalcibep 300 mg subcutaneously monthly for the duration. They were dosed and monitored in clinic for 12 weeks, after which investigators aw them in clinic once monthly. Primary and secondary endpoints for the extension were LDL-C changes at week 72 and other lipids, achievement of LDL-C guidelines, and safety, respectively.1

At the 72-week primary endpoint, mean and absolute LDL-C reductions were 59.2% and 66.6 mg/dL, respectively. Time average reductions across all visits were 63.4% and 71.4 mg/d,L respectively. Mean ApoB was reduced by 45.3% and median Lp(a) was reduced by 35.5%. Ultimately, investigators found consistency between the LDL-C response over 72 weeks and that of patients previously on lerodalcibep.1

Additionally, patients who were switched from inclisiran had substantial reductions of 30-35% through week 24, which remained 22% lower through week 72. Similar additional reductions were noted across ApoB and Lp(a), and patients achieving guideline goals rose significantly. The team also found no treatment-related serious adverse events.1

“Basically, what we’re looking at is a more available drug that lasts longer, because there’s less PCSK9 in the bloodstream to bind to our drug, and therefore the effect lasts longer,” Stein said. “And now we can explore whether, in these different types of patients, we can look at less frequent dosing than once a month, maybe every two months, maybe three, depending on the hepatic suppression of synthesis.”

References

1. Asprusten EA, Licka M, Cariou B, et al. Long-term Efficacy and Safety of Lerodalcibep in the Open-label 72-week Extension Study of Subjects Previously on Inclisiran or Lerodalcibep in the LIBerate-VI Trial. Presented at the American Heart Association’s Scientific Sessions 2025. New Orleans, Louisiana. November 8-10, 2025.

2. LIB Therapeutics LLC. Trial to Evaluate Efficacy and Safety of LIB003 and Inclisiran in High-risk CVD Patients (LIBerate-VI). ClinicalTrials.gov Identifier: NCT05004675. Updated October 23, 2024. Accessed November 24, 2025. https://www.clinicaltrials.gov/study/NCT05004675