Lepodisiran Reduced Lower Serum Lp(a) by More than 90% in Phase 2 Trial

Steve Nissen, MD
Credit: Cleveland Clinic

Lepodisiran, a long-duration small interfering RNA therapy targeting lipoprotein(a) [Lp(a)], achieves profound and sustained reductions in Lp(a) levels, with effects persisting for up to 18 months.

Presented at the American College of Cardiology (ACC) 2025 Annual Scientific Sessions, results of the ALPACA trial offer new insight into the effects of lepodisiran, which Eli Lilly and Company announced is being examined in the ACCLAIM-Lp(a) Phase 3 clinical development program that is currently enrolling.1,2

“We've got a long-acting drug. It's designed differently from other nucleic acid-based therapies for lipoprotein(a) and its design differences confer a particularly long duration of action,” said Steve Nissen, MD, chief academic officer of the Heart Vascular & Thoracic Institute at Cleveland Clinic, in an interview with HCPLive.

Launched in 2022, the ALPACA trial was conducted at 66 sites across 5 continents and designed as a randomized, placebo-controlled trial with the intent of assessing the safety and efficacy of lepodisiran in patients with elevated Lp(a) for up to 540 days. The trial randomized 320 patients in a 1:2:2:2:2 ratio to receive lepodisiran at a dose of 16 mg, 96 mg, or 400 mg at baseline and again at day 180, lepodisiran at a dose of 400 mg at baseline and placebo at day 180, or placebo at baseline and day 180. Per trial protocol, lepodisiran was administered twice at each dose, once at baseline and day 180, with a separate group receiving 400 mg at baseline and placebo at day 180.1,2

The primary outcome of interest for the study was the time-averaged percent change from baseline in the serum Lp(a) concentration during the period from day 60 to day 180.1

Results of the trial suggested the placebo-adjusted time-averaged percent change from baseline in the serum Lp(a) concentration from day 60 to day 180 was −40.8 percentage points (95% confidence interval [CI], −55.8 to −20.6) in the 16 mg lepodisiran group, −75.2 percentage points (95% CI, −80.4 to −68.5) in the 96 mg lepodisiran group, and −93.9 percentage points (95% CI, −95.1 to −92.5) in the pooled 400 mg groups. Further analysis revealed the change from day 30 to day 360 was −41.2 percentage points (95% CI, −55.4 to −22.4), −77.2 percentage points (95% CI, −81.8 to −71.5), −88.5 percentage points (95% CI, −90.8 to −85.6), and −94.8 percentage points (95% CI, −95.9 to −93.4) in the 16 mg, 96 mg, 400 mg-placebo, and 400 mg-400 mg dose groups, respectively.1

Secondary endpoint analysis indicated those who received 400 mg of lepodisiran at baseline and day 180 experienced a 94.8% reduction in Lp(a) levels, which remained 91.0% lower at 1 year and 74.2% lower at 1.5 years. Additionally, this same group experienced reduced apoB level reductions of 14.1% at day 60 and 13.7% at day 180, with sustained effects through day 540.1

"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," Nissen said.2 “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."

Safety data from the trial suggested treatment-emergent adverse events related to the study drug occurred in 1% of the placebo group, 3% of the 16 mg lepodisiran group, 12% of the 96 mg lepodisiran group, and 14% of the pooled 400 mg group. Investigators pointed out there were no serious adverse events related to lepodisiran treatment. Of note, a single death occurred in the 16 mg lepodisiran group due to complications of chronic coronary disease, but no participants receiving lepodisiran experienced a treatment-emergent adverse event that led to withdrawal from treatment or the study.1

References:

1. Nissen SE, Ni W, Shen X, et al. Lepodisiran — A Long-Duration Small Interfering RNA Targeting Lipoprotein(a). New England Journal of Medicine. Published online March 30, 2025. doi: 10.1056/nejmoa2415818

2. Eli Lilly and Company. 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 | Eli Lilly and Company. Eli Lilly and Company. Published March 30, 2025. Accessed March 30, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-lepodisiran-reduced-levels-genetically-inherited-heart