Phase II ALPACA Trial Shows Lepodisiran Produces Significant, Sustained Lipoprotein(a) Reductions

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Results from the Phase II ALPACA trial (NCT05565742) published by The New England Journal of Medicine show that lepodisiran (Eli Lilly) produced significant and sustained reductions in lipoprotein(a) levels, demonstrating its potential to address this major genetic risk factor for cardiovascular disease.^1,2 Lepodisiran, an investigational, noncanonical, tetraloop, Dicer-substrate small interfering RNA (siRNA) therapy, has been found to limit hepatic production of apolipoprotein(a) in early phase clinical trials.

"Nearly a quarter of the world's population has elevated levels of [lipoprotein(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 a press release. "These significant and sustained [lipoprotein(a)] reductions are encouraging and suggest that siRNA approaches like lepodisiran could potentially offer durable benefits with long-term dosing."³

The study authors noted that serum concentrations of lipoprotein(a) above 125 nmol per liter affect up to approximately 25% of the global population, representing between 1.4 billion and 2 billion people. They added that prior research shows a strong correlation between elevated lipoprotein(a) levels and atherosclerotic cardiovascular disease, aortic stenosis, and death from any cause.

“Traditional approaches to reduction in the risk of cardiovascular disease, including lifestyle alterations and statin therapy, have minimal effects on serum lipoprotein(a) concentrations,” the study authors wrote. “Proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors slightly reduce lipoprotein(a) concentrations but have not been studied in dedicated prospective, randomized trials assessing cardiovascular outcomes among persons with elevated lipoprotein(a) concentrations. No pharmacologic therapies have been approved by regulatory authorities, although plasma apheresis is approved in some countries.”¹

Trial Design

The randomized, placebo-controlled ALPACA trial enrolled 320 participants aged 40 years and above from 66 centers in Argentina, China, Denmark, Germany, Japan, Mexico, the Netherlands, Romania, Spain, and the United States from November 11, 2022, to April 17, 2023. The median baseline lipoprotein(a) concentration among participants was 253.9 nmol per liter.

Patients were randomly assigned in a 1:2:2:2:2 ratio to receive subcutaneous (SC) lepodisiran at dose ranges of 16 mg, 96 mg, or 400 mg at baseline and again at day 180; SC lepodisiran at a dose of 400 mg at baseline and SC placebo at day 180; or SC placebo at baseline and at day 180.

Investigators pooled the data for the primary analysis from the cohorts administered the 400 mg lepodisiran doses at baseline. The trial’s primary endpoint was time-averaged percent change from baseline in serum lipoprotein(a) concentration from day 60 to 180.

The results achieved the trial’s primary endpoint with a placebo-adjusted time-averaged percent change from baseline in serum lipoprotein(a) concentration from day 60 to day 180 of -40.8 percentage points (95% confidence interval [CI], -55.8 to -20.6) in the 16-mg lepodisiran cohort, -75.2 percentage points (95% CI, -80.4 to -68.5) in the 96-mg cohort, and -93.9 percentage points (95% CI, -95.1 to -92.5) in the pooled 400-mg cohorts.

Corresponding changes from day 30 to day 360 were -41.2 percentage points in the 16-mg cohort (95% CI, -55.4 to -22.4), -77.2 percentage points in the 96-mg cohort (95% CI, -81.8 to -71.5), -88.5 percentage points 400-mg plus placebo cohort (95% CI, -90.8 to -85.6), and -94.8 percentage points in the 400-mg–400-mg cohort (95% CI, -95.9 to -93.4).

In terms of safety, a total of 12% of participants in the 400-mg–400-mg cohort reported generally mild injection-site reactions. Serious adverse events (SAEs) occurred in 35 participants; however, investigators determined these SAEs were not related to lepodisiran or placebo.

"Reducing the inherited cardiovascular risk for patients with high [lipoprotein(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 release. "These data underscore Lilly's commitment to advancing genetic medicine to address one of the world's most pressing healthcare challenges. We will continue to evaluate the potential benefits of lepodisiran in the ongoing Phase 3 cardiovascular outcomes trial."³

References

1. Nissen S., et al. Lepodisiran — A Long-Duration Small Interfering RNA Targeting Lipoprotein(a). N Engl J Med 2025. DOI: 10.1056/NEJMoa2415818. Published March 30, 2025. Accessed March 31, 2025.

2. A Study of LY3819469 in Participants With Elevated Lipoprotein(a) [Lp(a)]. ClinicalTrials.gov. Updated March 25, 2025. Accessed March 31, 2025. https://clinicaltrials.gov/study/NCT05565742

3. 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. Published March 30, 2025. Accessed March 31, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-lepodisiran-reduced-levels-genetically-inherited-heart