Lilly’s lepodisiran shows 94% reduction in lipoprotein(a), offering hope for cardiovascular risk management

Eli Lilly and Company has unveiled groundbreaking results from its Phase 2 ALPACA clinical trial for lepodisiran, a small interfering RNA (siRNA) therapy designed to combat elevated lipoprotein(a) levels, a known genetic risk factor for cardiovascular disease. The study demonstrated that lepodisiran treatment reduced lipoprotein(a) levels by nearly 94% at its highest dose, positioning it as a potential first-in-class therapy in a space with no currently approved treatments.

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-based therapies to revolutionize the way genetically inherited cardiovascular risks are managed. This development could be especially significant given that approximately 20% of Americans have elevated Lp(a) levels, which can increase the likelihood of heart attacks, strokes, and aortic valve stenosis.

Why Is Lipoprotein(a) a Critical Cardiovascular Risk Factor?

Lipoprotein(a), commonly abbreviated as Lp(a), is a cholesterol-rich molecule that is largely determined by genetics rather than lifestyle factors. Unlike low-density lipoprotein (LDL) cholesterol, which can be influenced by diet, exercise, and statins, Lp(a) levels remain largely unaffected by traditional cholesterol-lowering approaches.

Research has shown that elevated Lp(a) can double or even triple a person’s risk of heart disease. This is due to its pro-inflammatory and pro-thrombotic properties, which contribute to atherosclerosis, blood clot formation, and vascular inflammation. Until now, there have been no targeted therapies capable of effectively lowering Lp(a) to a clinically meaningful degree, making lepodisiran’s results especially promising.

How Did Lepodisiran Perform in the Phase 2 ALPACA Trial?

The Phase 2 ALPACA study evaluated the safety and efficacy of lepodisiran across three dosage levels: 16 mg, 96 mg, and 400 mg. The highest dose resulted in an average Lp(a) reduction of 93.9% between days 60 and 180 post-treatment. Lower doses also demonstrated effectiveness, with the 96 mg dose leading to a 75.2% reduction, while the 16 mg dose achieved a 40.8% decrease.

Notably, patients who received two doses of 400 mg, at baseline and again at 180 days, exhibited a 94.8% reduction in Lp(a) levels over a year-long period. The results suggest that lepodisiran could offer a durable treatment option requiring only infrequent dosing, a significant advantage for patients managing long-term cardiovascular risk.

What Sets Lepodisiran Apart From Existing Cardiovascular Treatments?

Unlike statins, PCSK9 inhibitors, and other lipid-lowering drugs, which primarily focus on LDL cholesterol, lepodisiran specifically targets the production of apolipoprotein(a) (apo[a]), a core component of Lp(a). By silencing the gene responsible for Lp(a) production, siRNA-based approaches like lepodisiran represent a new frontier in cardiovascular medicine.

Experts believe that siRNA therapies could be a turning point in preventive cardiology. According to Dr. Steven Nissen of the Cleveland Clinic, nearly a quarter of the global population has elevated Lp(a) levels but lacks access to an FDA-approved treatment. He noted that lepodisiran’s long-acting effect and infrequent dosing schedule could provide sustained benefits for high-risk individuals.

How Safe Is Lepodisiran?

The safety profile of lepodisiran was closely monitored throughout the ALPACA study, with findings indicating that the treatment was well tolerated across all dose groups. Treatment-emergent adverse events (TEAEs) occurred in 14% of patients receiving the highest dose, while no serious adverse effects were attributed to lepodisiran itself.

The most serious medical event in the trial was a fatality in the 16 mg group, though this was linked to pre-existing chronic coronary disease rather than the drug. Overall, the safety data support further clinical investigation in larger patient populations.

What Does This Mean for Eli Lilly’s Market Position?

Following the release of the Phase 2 results, investor sentiment surrounding Eli Lilly (NYSE: LLY) has remained strong. As of March 31, 2025, LLY stock is trading at $822.51, reflecting a 5.73% year-over-year increase.

Analyst ratings for Eli Lilly continue to be highly favorable, with a consensus 12-month price target of $1,000.53, representing a 21.64% potential upside. The majority of market analysts have issued a “Strong Buy” rating, citing Lilly’s leadership in genetic medicine, obesity treatments, and cardiovascular innovation as key growth drivers.

If lepodisiran successfully navigates Phase 3 clinical trials and regulatory approvals, Eli Lilly could establish itself as a dominant force in the emerging field of siRNA-based cardiovascular therapies. Investors see significant long-term value, given that no current FDA-approved treatment directly targets Lp(a).

What’s Next for Lepodisiran?

Eli Lilly has already launched the Phase 3 ACCLAIM-Lp(a) trial, designed to evaluate whether lepodisiran treatment can translate into real-world reductions in cardiovascular events such as heart attacks and strokes. This pivotal study will determine whether the therapy can move from the investigational stage to widespread clinical use.

Ruth Gimeno, Lilly’s Vice President of Cardiometabolic Research, emphasized that the company is committed to advancing genetic medicine solutions for cardiovascular disease. She pointed out that lepodisiran’s success in the ALPACA trial is an important milestone in addressing the long-standing challenge of inherited heart disease risks.

How Could Lepodisiran Shape the Future of Cardiovascular Medicine?

The growing emphasis on personalized medicine in cardiovascular treatment suggests that siRNA-based drugs could become a key tool for managing inherited risk factors like Lp(a). Given the large patient population with elevated Lp(a) levels, a successful Phase 3 trial could open the door for lepodisiran to become a standard therapy in cardiology.

For now, the outlook remains highly positive. If further studies confirm the clinical benefits of long-term Lp(a) suppression, lepodisiran could become the first FDA-approved treatment targeting this specific genetic risk factor, marking a major breakthrough in cardiovascular disease prevention.