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March 30, 2025
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Key takeaways:Lepodisiran greatly lowered lipoprotein(a) at 6 months and 1 year compared with placebo. A cardiovascular outcomes trial of lepodisiran is underway. CHICAGO — Lepodisiran, a small interfering RNA agent, lowered lipoprotein(a) levels at 180 days, with a reduction of more than 90 percentage points with a single 400-mg dose compared with placebo, according to results from the ALPACA trial. The phase 2 ALPACA trial of lepodisiran (Eli Lilly), presented at the American College of Cardiology Scientific Session and simultaneously published in The New England Journal of Medicine, enrolled 320 patients with elevated Lp(a) (mean, 253.9 nmol/L).
“Lepodisiran is attached to a compound known as N-acetylgalactosamine, or GalNAc, that is picked up by the hepatocytes and then delivers lepodisiran into the cell, where it forms an RNA-induced silencing complex and degrades messenger RNA for apolipoprotein A, an essential component of lipoprotein(a),” Steven E. Nissen, MD, MACC, chief academic officer of the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute and the Lewis and Patricia Dickey Chair in Cardiovascular Medicine at Cleveland Clinic and a member of the Healio | Cardiology Today Editorial Board, told Healio. “If you stop the production of apolipoprotein A, you don’t make lipoprotein(a). [Small interfering] RNAs represent a new approach to developing medication that can the concentrate drug the liver using GalNAc, allowing it to work very efficiently.” Nissen noted that lepodisiran is “designed differently from other small interfering RNAs or DNA-based therapies for lipoprotein(a). It is a double-stranded RNA with a tetraloop of four nucleotides that join the two strands along with other features that give the drug a long duration of action.” Patients were randomly assigned 1:2:2:2:2 to one of five groups, with treatment administered by subcutaneous injection: lepodisiran 16 mg at baseline and 180 days; lepodisiran 96 mg at baseline and 180 days; lepodisiran 400 mg at baseline and 180 days; lepodisiran 400 mg at baseline and placebo at 180 days; or placebo at baseline and 180 days. The primary endpoint was placebo-adjusted difference in time-averaged percent change from baseline in serum Lp(a) concentration from day 60 to day 180. Significant drop in Lp(a)The primary endpoint showed 40.8 percentage points (95% CI, 55.8 to 20.6) reduction in the 16-mg lepodisiran group, 75.2 percentage points (95% CI, 80.4 to 68.5) in the 96-mg lepodisiran group and 93.9 percentage points (95% CI, 95.1 to 92.5) in the pooled 400-mg groups, the researchers reported.The placebo-adjusted change in serum Lp(a) concentration from day 30 to day 360 was 41.2 percentage points (95% CI, 55.4 to 22.4) in the 16-mg lepodisiran group, 77.2 percentage points (95% CI, 81.8 to 71.5) in the 96-mg lepodisiran group, 88.5 percentage points (95% CI, 90.8 to 85.6) in the group assigned lepodisiran 400 mg at baseline and placebo at 180 days and 94.8 percentage points (95% CI, 95.9 to 93.4) in the group assigned lepodisiran 400 mg at baseline and 180 days, according to the researchers.“Virtually everybody responds” to lepodisiran 400 mg, Nissen told Healio. “What we learned is that this drug has a long duration of action which will allow very infrequent administration to lower lipoprotein(a) by more than 90%.”There were no serious adverse events deemed to be related to lepodisiran or placebo. Injection-site reactions occurred in up to 12% of the group assigned lepodisiran 400 mg at baseline and 180 days, “which were transient, mild and generally not of concern,” Nissen said. “A very small number had transient elevations of liver enzymes, as is seen with drugs in this class. This drug was very safe and extraordinarily effective, with a very long duration of action.” A phase 3 trial of lepodisiran is underway, Nissen said. “If we can successfully demonstrate a reduction in morbidity and mortality, drugs in this class, including lepodisiran, will have an enormous impact” on patients with elevated Lp(a), Nissen told Healio. “In many ways, this is one of the last frontiers. We can control LDL cholesterol in almost everyone. We have a variety of therapies for hypertension. But lipoprotein(a) has eluded treatment. We are now entering an era where, I am optimistic, we are going to be able to help these patients avoid morbidity and mortality from cardiovascular disease.” ‘We need to know who to treat’A challenge will be getting doctors to order Lp(a) tests for their patients to be able to identify who may need treatment for high Lp(a), as this is not routinely done in clinical practice today, Nissen told Healio. “When we develop these drugs and they get approved, we need to know who to treat,” he said. “The only way we know who to treat is if we obtain levels of lipoprotein(a) more routinely in cardiovascular practice and primary care.” Other Lp(a) treatments are further along in development, but have to be given more frequently than lepodisiran, he said. Reference:For more information: Steven E. Nissen, MD, MACC, can be reached at nissens@ccf.org.
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Source:
Nissen SE, et al. Featured clinical research I. Presented at: American College of Cardiology Scientific Session; March 29-31, 2025; Chicago (hybrid meeting).
Disclosures:
The study was funded by Eli Lilly. Nissen reports his institution received research grants from Eli Lilly, but that he receives no personal compensation from industry. Please see the study for all other authors’ relevant financial disclosures.
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