Eli Lilly shared new Phase II trial data showing that its experimental siRNA therapy, lepodisiran, leads to reductions in levels of lipoprotein(a) (Lp(a)) — a genetically inherited risk factor for heart disease — in adults with elevated levels of the marker.
In the Phase II ALPACA trial, a single 400 mg dose of lepodisiran led to an average decrease of 93.9% in Lp(a) levels over the 60- to 180-day period after treatment compared to placebo, meeting the trial’s primary endpoint.
The 400 mg dose was the highest lepodisiran dose in the trial. Individuals who received the 16 mg and 96 mg doses achieved reductions of 40.8% and 75.2% in Lp(a) levels over the same time period, respectively.
The liver produces Lp(a), a lipoprotein particle similar to low-density lipoprotein (LDL). Lp(a) contributes to plaque buildup in arteries, thereby increasing the risk of heart attacks, strokes and other cardiovascular conditions.
Genetics primarily determine elevated Lp(a) levels, and lifestyle changes or current lipid-lowering therapies do not significantly affect them.
Experts view high Lp(a) levels as a genetic risk factor that markedly increases the likelihood of cardiovascular disease.
High Lp(a) levels can double or even triple the risk of a heart attack. They are also associated with other serious conditions, including stroke and aortic valve stenosis (narrowing of the heart valve).
Approximately 20% of Americans have elevated levels of Lp(a), and an estimated 2 billion people globally.
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More on the Lepodisiran Phase II Trial
Lepodisiran is an investigational siRNA therapy that targets the production of apolipoprotein(a) (apo(a)) — a key building block of Lp(a) — to help reduce its levels in the body.
The Phase II trial enrolled 320 adults aged 40 or older with Lp(a) serum concentrations of 175 nmol/L or higher. Researchers randomized participants to receive varying doses of lepodisiran or a placebo.
Additionally, Lp(a) levels remained 91.0% and 74.2% below baseline at 360 days (one year) and 540 days (18 months), respectively, after the single 400 mg dose.
Safety assessments also indicated that lepodisiran was well-tolerated, with no serious adverse events related to the drug reported.
Transient and generally mild injection-site reactions occurred in up to 11.6% of participants, following a dose-dependent pattern.
The findings suggest that lepodisiran could offer a durable treatment option for individuals with elevated Lp(a) levels.
The Phase II results were presented at the American College of Cardiology 2025 Scientific Sessions.
Ruth Gimeno, Eli Lilly’s vice president of Diabetes, Obesity and Cardiometabolic Research, emphasized the potential of lepodisiran to provide long-term benefits with infrequent dosing.
“Reducing the inherited cardiovascular risk for patients with high Lp(a) has long been a critically unmet need. These results offer hope for a long-term, durable treatment option,” she said
She shared that the company “will continue to evaluate the potential benefits of lepodisiran in the ongoing Phase III cardiovascular outcomes trial.”
Lilly shared that the ACCLAIM-Lp(a) Phase III clinical development program is currently enrolling. The program will evaluate lepodisiran’s effectiveness in reducing cardiovascular events associated with high Lp(a) levels.
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Competitors of Lilly’s Lepodisiran
Lilly is about three years behind competitors Novartis and Amgen in its Phase III work for lepodisiran.
Novartis is testing pelacarsen in Phase III trials, and Amgen is testing olpasiran in Phase III trials. Both are on track for completion next year, while Lilly’s Phase III lepodisiran trial has an end date of 2029.
Amgen’s olpasiran (previously known as AMG 890) is licensed from Arrowhead Pharmaceuticals. Its Phase II readout was encouraging, showing placebo-adjusted reductions in Lp(a) of 95%. The data indicated an advantage over pelacarsen.
Almost one year after stopping therapy, Lp(a) levels in individuals who took olpasiran remained 40% to 50% lower than those on placebo.
However, according to reporting by Fierce Pharma, on an earnings call last year, Lilly’s chief scientific officer Daniel Skovronsky, MD, PhD, said lepodisiran may have advantages over its competitors.
“First is the depth of clearance of Lp(a),” he said. “We don’t know how much you have to reduce Lp(a) to lead to benefits in cardiovascular outcomes and whether there’s a threshold effect or a floor to this,” Skovronsky said.
He also said frequency of administration or durability of action, which could be closely linked, may also be in lepodisiran’s favor.
In the Phase III studies, participants receive pelacarsen monthly and olpasiran every three months.
In comparison, at a dosing frequency of once every six months, lepodisiran led to over 90% reductions in Lp(a). It maintained a 74% reduction in levels even with dosing intervals of nearly one year.
Meanwhile, oral drugs for lowering Lp(a) are also in the works, including from Lilly.
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