Eli Lilly has linked lepodisiran to sustained reductions in a cardiovascular disease risk factor for nearly 1.5 years, bolstering the company’s argument that the siRNA candidate has an edge over rivals from Amgen and Novartis.
The phase 2 trial tested the effect of lepodisiran on lipoprotein(a) (Lp(a)). Studies suggest up to 2 billion people globally have elevated Lp(a), which is associated with cardiovascular disease, and none of the established approaches for improving heart health lower the lipoprotein. Companies are racing to fill the gap in the treatment toolkit, with several phase 3 trials scheduled to read out in the coming years.
Lilly, which is about three years behind the front-runners, shared phase 2 data on its candidate Sunday, March 30, at the American College of Cardiology 2025 Scientific Sessions. The study randomized 320 people to take placebo or one of three doses at baseline and Day 180.
Lp(a) levels fell by an average of 93.9% over the 60- to 180-day period after treatment with the highest tested dose, 400 mg, meeting the primary endpoint. Levels declined by 40.8% and 75.2% at the low and middle doses, respectively.
Amgen set the bar in the space in 2022, reporting placebo-adjusted Lp(a) reductions of 95% in its phase 2 trial to suggest its olpasiran has an advantage over Novartis’ pelacarsen. Nearly one year after stopping therapy, Lp(a) levels in people who took olpasiran remained 40% to 50% lower than in their peers on placebo.
The waning of efficacy in the off-treatment extension period offered Lilly an opportunity. After giving the second and final dose of lepodisiran on Day 180, Lilly continued to track patients through Day 360 and 540. Lp(a) levels were 91% below baseline at Day 360 and 74.2% below baseline at Day 540.
Novartis’ pelacarsen and Amgen’s olpasiran, which the companies licensed from Ionis and Arrowhead, respectively, are in phase 3 trials that are scheduled to wrap up next year. Lilly’s phase 3 lepodisiran trial has a completion date in 2029. However, as Lilly Chief Scientific Officer Daniel Skovronsky, M.D., Ph.D., said on an earnings call last year, lepodisiran may have advantages over its rivals.
“First is the depth of clearance of Lp(a)," he said on the call. "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. “The second ... could be frequency of administration or durability of action, those two being closely linked.”
In phase 3, patients are receiving pelacarsen every month and olpasiran every three months. Lilly’s phase 2 trial suggests lepodisiran can drive 90%-plus reductions in Lp(a) when given every six months and keep levels suppressed by 74% when patients go almost one year between doses. Other companies, including Lilly, are developing oral drugs for reducing Lp(a).