Eli Lilly and Company recently unveiled breakthrough Phase 2 results for lepodisiran, an investigational siRNA therapy targeting lipoprotein(a) [Lp(a)], a key genetic risk factor for heart disease. The ALPACA study showed the highest tested dose of lepodisiran (400 mg) reduced Lp(a) levels by an impressive 94% over a period of up to 18 months.

The findings, presented at the American College of Cardiology 2025 Scientific Sessions and published in the New England Journal of Medicine, highlight the potential of siRNA therapies to address the unmet need for effective treatments for elevated Lp(a), a risk factor affecting 20% of Americans and contributing to heart attacks, strokes, and other cardiovascular complications.

Lepodisiran’s impact on Lp(a)

In the ALPACA Phase 2 trial, participants receiving 400 mg of lepodisiran saw their Lp(a) levels drop by 93.9% on average between days 60 and 180. Notably, reductions remained sustained, with levels 91% below baseline at 360 days and 74% below baseline at 540 days. Participants in the 96 mg and 16 mg groups also experienced significant reductions in Lp(a) by 75.2% and 40.8%, respectively.

“These results are truly groundbreaking,” said Steven Nissen, MD, chief academic officer of the Cleveland Clinic’s Heart, Vascular & Thoracic Institute.

“Elevated Lp(a) is a genetically inherited condition with no approved therapies, and lifestyle interventions like diet and exercise aren’t effective. Lepodisiran’s ability to reduce Lp(a) by such a significant margin opens up the possibility for long-term, meaningful cardiovascular risk reduction.”

Sustained benefits and safety profile

The trial’s secondary endpoints revealed that lepodisiran also reduced apolipoprotein B (ApoB), a separate cholesterol biomarker linked to cardiovascular disease, by 14.1% at day 60 and 13.7% at day 180 in the 400 mg group. Additionally, participants who received two doses of 400 mg lepodisiran showed sustained reductions in ApoB levels through day 540.

While treatment-emergent adverse events (TEAEs) were reported in a small number of participants, the safety profile of lepodisiran was largely favorable, with no serious adverse events related to the treatment. A single death, unrelated to the study drug, occurred in the 16 mg group due to complications of chronic coronary disease.

A future in cardiovascular care

Lilly’s commitment to advancing genetic therapies was underscored by Ruth Gimeno, Group Vice President of Diabetes, Obesity, and Cardiometabolic Research. “This is a critical unmet need for patients with high Lp(a). These findings suggest that siRNA therapies like lepodisiran could potentially offer durable, long-term benefits. We remain committed to evaluating its effects in our ongoing Phase 3 cardiovascular outcomes trial,” she said.

The ongoing ACCLAIM-Lp(a) Phase 3 trial is currently enrolling patients and aims to further assess lepodisiran’s impact on reducing cardiovascular events in patients with elevated Lp(a).

About ALPACA

The ALPACA trial was a randomized, double-blind, placebo-controlled Phase 2 study conducted to evaluate lepodisiran’s efficacy and safety in adults with elevated Lp(a). A total of 320 participants were enrolled, receiving either placebo or one of three doses of lepodisiran. The primary endpoint was the placebo-adjusted, time-averaged percent change in Lp(a) serum concentration from day 60 to 180. The results from the 400 mg doses were pooled for analysis.