Lepodisiran Reduces Lipoprotein(a) By Nearly 94% in Adults With Elevated Levels of Lp(a)

Lepodisiran (Eli Lilly), an investigational small interfering RNA (siRNA) therapy designed to reduce the production of lipoprotein(a) [Lp(a)], meaningfully reduced Lp(a) levels by an average of 93.9% over a 60-to-180-day period in adults with high Lp(a) levels following treatment at the highest tested dose of 400 mg, according to results from the phase 2 ALPACA (NCT05565742) trial that were presented at the American College of Cardiology 2025 Scientific Sessions.^1-3

Lipoprotein(a) is a variant of low-density lipoprotein. | Image Credit: © Rameeza - stock.adobe.com

The ALPACA study, a randomized, double-blind, placebo-controlled trial, was designed to investigate the safety and efficacy of lepodisiran in adults with elevated Lp(a). Different doses of lepodisiran were investigated, including 16-mg and 96-mg doses; for patients receiving each of those doses, 40.8% and 75.2% reductions in Lp(a) levels were reported, respectively, according to the news release. Additional secondary end points were met, demonstrating Lp(a) reductions following 1 or 2 administrations of any dose across all timepoints throughout the trial.^1,2

Steven Nissen, MD, chief academic officer of the Heart, Vascular, and Thoracic Institute at the Cleveland Clinic and lead author of ALPACA, discussed the necessity for novel treatments to reduce elevated Lp(a) levels, given the significantly higher risk of cardiovascular events like strokes and heart attacks associated with such levels. In the US, 20% of Americans have high Lp(a) levels, which can double or perhaps triple the risk of a heart attack. With its siRNA-based mechanism of action, lepodisiran is poised to transform the space of Lp(a) management.¹

“Unfortunately, there are no approved cholesterol-lowering therapies specifically for this genetic risk factor, and lifestyle changes like diet and exercise do not provide meaningful reductions," Nissen explained in the news release. "These significant and sustained Lp(a) reductions are encouraging and suggest that siRNA approaches like lepodisiran could potentially offer durable benefits with long-term dosing."¹

Indicators of cholesterol lowering were positive across a series of critical end points in ALPACA. In the trial, lepodisiran reduced levels of apolipoprotein B (apoB), which is a separate biomarker of cholesterol, by 14.1% and 13.7% at days 60 and 180, respectively, at a 400-mg dose. Additionally, these apoB reductions were sustained through day 540 following a second 400-mg lepodisiran dose at day 180, according to the investigators.^1,2

Regarding safety, treatment-emergent adverse events (TEAEs) related to lepodisiran were found in 3% of the 16 mg group, 12% of the 96 mg group, and 14% of the pooled 400 mg group. In an important development, there were no serious AEs that were related to lepodisiran treatment; only a single death, which occurred in the 16 mg dose group due to complications of chronic coronary disease, was repeated.^1,2

"Reducing the inherited cardiovascular risk for patients with high Lp(a) has long been a critically unmet need,” Ruth Gimeno, group vice president, diabetes, obesity, and cardiometabolic research at Lilly, said in the news release. “These results offer hope for a long-term, durable treatment option.”¹

Lepodisiran is set to be studied further in the ACCLAIM-Lp(a) phase 3 clinical development program, which is designed to evaluate the effect of lepodisiran on the reduction of cardiovascular events in adults with elevated Lp(a). According the investigators, it will be pertinent to clarify the effect of additional doses of lepodisiran beyond the 3 studied in this trial, given that these effects remain undetermined.¹

REFERENCES

1. Lilly. Lilly's lepodisiran reduced levels of genetically inherited heart disease risk factor, lipoprotein(a), by nearly 94% from baseline at the highest tested dose in adults with elevated levels. News Release. Released March 30, 2025. Accessed April 17, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-lepodisiran-reduced-levels-genetically-inherited-heart

2. Nissen S, Ni W, Shen X, et al. Lepodisiran—A long-duration small interfering RNA targeting lipoprotein(a). N Engl J Med. 2025. doi:10.1056/NEJMoa2415818

3. ClinicalTrials.gov. A study of LY3819469 in participants with elevated lipoprotein(a) [Lp(a)]. National Library of Medicine. Last Updated January 6, 2025. Accessed April 17, 2025. https://clinicaltrials.gov/study/NCT05565742