Breakthrough in Lipoprotein(a) Reduction
Lepodisiran, a long-acting small interfering RNA (siRNA) therapy, has demonstrated significant and sustained reductions in lipoprotein Lowering Lp(a) levels in a Phase 2 clinical trial, with effects lasting up to 18 months. The findings were presented at the American College of Cardiology (ACC) 2025 Annual Scientific Sessions, where researchers highlighted the potential of this innovative therapy. Eli Lilly and Company, which is developing the drug, confirmed that lepodisiran is currently being evaluated in the ACCLAIM-Lp(a) Phase 3 trial.
Dr. Steve Nissen, chief academic officer of the Heart, Vascular & Thoracic Institute at Cleveland Clinic, emphasized the unique design of lepodisiran, which allows for its extended duration of action compared to other nucleic acid-based treatments. “We’ve got a long-acting drug, designed differently from other therapies, and this design enables a particularly prolonged effect,” Nissen stated.
ALPACA Trial Demonstrates Strong Efficacy on Lowering Lp(a)
The ALPACA trial, launched in 2022, was a randomized, placebo-controlled study conducted at 66 sites across five continents. It aimed to evaluate the safety and efficacy of lepodisiran in patients with elevated Lp(a) over a period of 540 days. A total of 320 participants were randomly assigned to receive different doses of lepodisiran (16 mg, 96 mg, or 400 mg) or a placebo at designated intervals.
The primary outcome measured was the average percentage reduction in Lp(a) concentration from baseline between days 60 and 180. Results showed that Lp(a) levels were reduced by 40.8% in the 16 mg group, 75.2% in the 96 mg group, and an impressive 93.9% in the 400 mg group compared to placebo. Further analysis indicated that the 400 mg dose group maintained a 94.8% reduction at one year and a 74.2% reduction at 1.5 years. Additionally, apoB levels, another key biomarker associated with cardiovascular risk, showed modest but sustained reductions.
“Nearly a quarter of the world’s population has elevated Lp(a) levels, which significantly increases their risk for cardiovascular events such as heart attacks and strokes. Currently, there are no approved treatments specifically targeting this genetic risk factor,” Nissen explained. “The significant and lasting reductions in Lowering Lp(a) observed in this study suggest that siRNA-based therapies like lepodisiran could provide long-term benefits with ongoing treatment.”
Safety and Future Implications
The trial also provided encouraging safety data, with no serious adverse events attributed to lepodisiran treatment. Reported treatment-related side effects were minimal, occurring in 3% of patients in the 16 mg group, 12% in the 96 mg group, and 14% in the 400 mg group. Importantly, no participants discontinued the trial due to adverse effects. The only fatality recorded was in the 16 mg group, where a patient with chronic coronary disease passed away, though it was unrelated to the treatment.
With these promising results, lepodisiran is now progressing into Phase 3 trials, where researchers hope to further validate its effectiveness and safety in a larger patient population. If successful, this groundbreaking therapy could become the first approved treatment to specifically target elevated Lp(a), offering new hope for millions at risk of cardiovascular disease.
