BMO Capital Markets analysts said the results potentially position lepodisiran as “one of the most durable assets in development to date” in the competitive Lp(a) space, where drugs are designed to lower the risk of cardiovascular events such as heart attack and stroke.
Eli Lilly’s investigational siRNA therapeutic lepodisiran can elicit up to a nearly 94% reduction in lipoprotein(a) levels, according to data from the Phase II ALPACA study presented over the weekend at the American College of Cardiology 2025 Scientific Sessions.
“We view these results positively amongst the competitive Lp(a) space, potentially positioning lepodisiran as one of the most durable assets in development to date,” analysts at BMO Capital Markets said in an investor note on Sunday.
ALPACA is a randomized, double-blinded and placebo-controlled trial that enrolled 320 patients with elevated Lp(a) levels, which can increase risk of cardiovascular events such as heart attack or stroke. Patients in the treatment group were given one of three doses—16 mg, 96 mg or 400 mg—at baseline and after 180 days. Change in serum Lp(a) levels were measured from day 60 to 180.
The results, which were simultaneously published in The New England Journal of Medicine, showed that the 400-mg dose cut Lp(a) levels by 93.9%. Meanwhile, the 96-mg and 16-mg doses led to a 75.2% and 40.8% reduction in Lp(a), respectively.
Lepodisiran also hit a key secondary endpoint, producing a 94.8% decrease in average Lp(a) levels from day 30 to 360 for its 400-mg dose. Lp(a) concentrations remained 91% below baseline at 360 days and 74.2% below baseline at 540 days. The BMO analysts were particularly encouraged by these data, which they believe are suggestive of a durable treatment effect.
Lilly’s ALPACA data also “show the feasibility of [once every six months] dosing” for lepodisiran, which could be “a clear differentiator” in the Lp(a) space. For instance, Ionis and Novartis’s pelacarsen, an antisense oligonucleotide, is given monthly. Meanwhile, Amgen’s siRNA silencer olpasiran is injected subcutaneously once every 12 weeks.
Despite the potential step forward in dosing regimen, BMO believes that Lilly, and pharma at large, still needs to develop the market further for lepodisiran. “While efficacy is obvious, we believe Lp(a) diagnostic testing needs to improve significantly to start to shape a commercial market for the drug.”
Lepodisiran is an siRNA molecule that targets the mRNA that encodes for apolipoprotein(a), an important structural component of Lp(a). In November 2023, Phase I data supported this mechanism of action, showing that a 608-mg dose could elicit a 94% Lp(a) reduction at 48 weeks. Lilly is running the Phase III ACCLAIM-Lp(a) program to test the effect of lepodisiran on cardiovascular events in adults with heightened Lp(a). The trial is currently enrolling.
Aside from lepodisiran, Lilly’s cardiovascular portfolio also includes the oral pill muvalaplin, which in November 2024 reduced Lp(a) by nearly 86% at 12 weeks for a 240-mg dose. At the time, Lilly said that it would discuss the next steps for muvalaplin with the FDA, building toward the potential first oral Lp(a)-lowering therapy.
