Lilly's RNA Silencer Lepodisiran Shows Promising Results in Lowering Cardiovascular Risk Marker

Eli Lilly's investigational siRNA therapeutic lepodisiran has demonstrated significant potential in reducing lipoprotein(a) [Lp(a)] levels, a key biomarker for cardiovascular risk. Data from the Phase II ALPACA study, presented at the American College of Cardiology 2025 Scientific Sessions, revealed that lepodisiran can elicit up to a 93.9% reduction in Lp(a) levels.

ALPACA Study Details and Results

The ALPACA trial, a randomized, double-blinded, and placebo-controlled study, enrolled 320 patients with elevated Lp(a) levels. Participants received one of three doses of lepodisiran—16 mg, 96 mg, or 400 mg—at baseline and after 180 days. The primary endpoint measured the change in serum Lp(a) levels from day 60 to 180.

Results, simultaneously published in The New England Journal of Medicine, showed dose-dependent reductions in Lp(a):

• 400 mg dose: 93.9% reduction
• 96 mg dose: 75.2% reduction
• 16 mg dose: 40.8% reduction

Importantly, the 400 mg dose also achieved a key secondary endpoint, producing a 94.8% decrease in average Lp(a) levels from day 30 to 360. The durability of the treatment effect was further demonstrated by Lp(a) concentrations remaining 91% below baseline at 360 days and 74.2% below baseline at 540 days.

Competitive Landscape and Market Implications

BMO Capital Markets analysts view these results positively, potentially positioning lepodisiran as "one of the most durable assets in development to date" in the competitive Lp(a) space. The drug's dosing regimen—once every six months—could be a clear differentiator compared to competitors:

• Ionis and Novartis's pelacarsen (antisense oligonucleotide): given monthly
• Amgen's olpasiran (siRNA silencer): injected subcutaneously once every 12 weeks

Despite the promising efficacy data, BMO analysts note that the Lp(a) market still needs further development. They emphasize the need for significant improvements in Lp(a) diagnostic testing to shape a commercial market for the drug.

Future Developments and Lilly's Cardiovascular Portfolio

Lilly is currently running the Phase III ACCLAIM-Lp(a) program to test lepodisiran's effect on cardiovascular events in adults with elevated Lp(a) levels. This trial is actively enrolling participants and will provide crucial data on the drug's clinical efficacy.

In addition to lepodisiran, Lilly's cardiovascular portfolio includes muvalaplin, an oral pill that demonstrated a nearly 86% reduction in Lp(a) at 12 weeks for a 240 mg dose in November 2024. Lilly plans to discuss the next steps for muvalaplin with the FDA, potentially paving the way for the first oral Lp(a)-lowering therapy.

As the pharmaceutical industry continues to focus on addressing cardiovascular risk factors, Lilly's advancements in Lp(a)-lowering therapies position the company as a significant player in this growing market segment.