Lepodisiran Reduced Lp(a) Levels by Nearly 94% in Phase 2 ALPACA Trial, Slated for Phase 3 Development

Lepodisiran, an investigational small interfering RNA (siRNA) therapy designed to reduce lipoprotein(a) [Lp(a)] levels, reduced Lp(A) by an average of 93.9% over 60 to 180 days following administration of the highest tested dose (400 mg), meeting the primary endpoint of the phase 2 ALPACA trial, according to an announcement today from sponsor Eli Lilly and Company. Lp(A) levels in this study subgroup remained 91.0% below baseline at approximately 1 year and 74.2% below baseline at 1.5 years.

Steven Nissen, MD

Participants who received the 16 mg and 96 mg lepodisiran doses experienced a 40.8% reduction and a 75.2% reduction in Lp(a) levels over the same time period, respectively, the company reported.

The new data highlighting the efficacy of the siRNA against the genetically inherited risk factor for cardiovascular disease were presented at the American College of Cardiology 2025 Scientific Sessions, March 29-31, and published simultaneously in the New England Journal of Medicine. Lilly will advance lepodisiran into phase 3 trials as part of the ACCLAIM-Lp(a) program to assess its potential in reducing cardiovascular events in patients with elevated Lp(a)

"Nearly a quarter of the world's population has elevated levels of Lp(a), putting them at a significantly higher risk of cardiovascular events such as heart attacks and strokes. 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," Steven Nissen, MD, chief academic officer of the Heart, Vascular & Thoracic Institute at the Cleveland Clinic, said in the press statement. "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."

The randomized, double-blind, placebo controlled ALPACA trial included 320 participants with elevated Lp(a) levels who were randomized to receive placebo or one of three lepodisiran doses (16 mg, 96 mg, or 400 mg) at baseline and again at day 180. An additional group received a single 400 mg dose at baseline followed by placebo at day 180. Participants in the 400 mg cohort sustained an average Lp(a) reduction of 91.0% at one year and 74.2% at 1.5 years. The 96 mg and 16 mg doses yielded reductions of 75.2% and 40.8%, respectively, over the same observation period.

Secondary endpoints demonstrated that lepodisiran also reduced apolipoprotein B (apoB) levels, an additional lipid biomarker. Participants receiving 400 mg of lepodisiran exhibited apoB reductions of 14.1% at day 60 and 13.7% at day 180, with sustained decreases through day 540 following a second 400 mg dose.

Treatment-emergent adverse events (TEAEs) occurred in 1% (1/69) of placebo recipients, 3% (1/36) of those in the 16 mg group, 12% (9/74) in the 96 mg group, and 14% (20/141) among those receiving 400 mg. No serious adverse events related to lepodisiran were reported. A single fatality in the 16 mg cohort resulted from complications of chronic coronary disease. No lepodisiran-treated participants withdrew from the study due to TEAEs.

Approximately 20% of Americans have elevated Lp(a) levels, which can double or triple the risk of myocardial infarction, stroke, or aortic valve stenosis.2,3 Currently, no approved therapies specifically target Lp(a) reduction, and lifestyle modifications have minimal impact.

"Reducing the inherited cardiovascular risk for patients with high Lp(a) has long been a critically unmet need. These results offer hope for a long-term, durable treatment option," Ruth Gimeno, group vice president, diabetes, obesity and cardiometabolic research at Lilly, said in the statement. "We will continue to evaluate the potential benefits of lepodisiran in the ongoing Phase 3 cardiovascular outcomes trial."

References

1. Nissen SE, Ni W, Shen X, et al. Lepodisiran — a long-duration small interfering RNA targeting lipoprotein(a). N Engl J Med. Published online March 30, 2025. doi: 10.1056/nejmoa2415818
2. 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. Eli Lilly and Company. March 30, 2025. Accessed March 31, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-lepodisiran-reduced-levels-genetically-inherited-heart