Eli Lilly’s Phase 2 ALPACA study demonstrated that lepodisiran, an investigational siRNA therapy, significantly reduced lipoprotein(a) [Lp(a)] levels—a key genetic risk factor for cardiovascular disease.

The trial enrolled 320 participants with elevated Lp(a) and randomized them to receive placebo or lepodisiran at doses of 16 mg, 96 mg, or 400 mg, administered at baseline and again at day 180. An additional group received a single 400 mg dose at baseline followed by a placebo at day 180.

The primary endpoint—placebo-adjusted, time-averaged percent change in Lp(a) from days 60 to 180—was met, with the highest tested dose (400 mg) achieving a 93.9% reduction.

Lower doses of 16 mg and 96 mg also produced meaningful reductions of 40.8% and 75.2%, respectively. 

Importantly, the Lp(a)-lowering effects were sustained over the 18-month trial period. Among participants who received two 400 mg doses, Lp(a) levels remained 91% below baseline at one year and 74.2% lower at 1.5 years, highlighting the durability of lepodisiran’s effects.

Secondary endpoints also showed that lepodisiran reduced apolipoprotein B (apoB), another marker of cardiovascular risk. The 400 mg dose resulted in a 14.1% apoB reduction at day 60, sustained through day 540 after the second dose.

Safety data showed that lepodisiran was well-tolerated. Treatment-related adverse events occurred in 14% of participants at the highest dose. No serious adverse events were linked to the drug, and no participants withdrew due to side effects.

The Phase 3 ACCLAIM-Lp(a) trial is now enrolling to assess lepodisiran’s impact on reducing cardiovascular events. Given Lp(a)’s role in heart attack, stroke, and aortic valve disease, this therapy could address a critical unmet need in cardiovascular medicine.