By Tristan Manalac

Data from an early-stage study showed that Eli Lilly’s investigational RNA silencing therapeutic lepodisiran can induce sharp and durable reductions in serum lipoprotein(a) levels, the company revealed in a read-out presented over the weekend at the 2023 Scientific Sessions of the American Heart Association.
These findings come nearly three months after the Indianapolis-based pharma notched another Phase I victory, this time for its oral drug candidate muvalaplin, which strongly decreased lipoprotein(a) levels in healthy participants within 24 hours.
Lipoprotein(a), also known as Lp(a), is a form of cholesterol that can cause plaques to form in arteries and block blood flow and is often tied to the risk of developing cardiovascular diseases.
The first-in-human trial of lepodisiran enrolled 48 patients who were given ascending doses of the investigational therapy—from 4 mg up to 608 mg—or a placebo. At the highest dose level, lepodisiran was able to elicit a rapid decline in blood Lp(a), which dropped to undetectable levels after 29 days of treatment. This strong suppressive effect persisted through day 281.
Overall, the 608-mg dose of lepodisiran led to a median 94% Lp(a) reduction below baseline levels after 48 weeks.
Lower lepodisiran doses likewise reduced Lp(a) levels, though this effect was relatively weaker and didn’t last as long. Patients who received the 304-mg dose, for instance, saw a 75% drop in Lp(a) after 48 weeks.
Steve Nissen, lead author of the study and chief academic officer at the Heart, Vascular & Thoracic Institute at the Cleveland Clinic in Ohio, called lepodisiran’s Lp(a)-lowering effects “profound” in a statement, adding that the therapy achieved the “near-total elimination of Lp(a) that lasted for a long time.”
“This medication could be a once-a-year injection similar to a vaccine for people with high Lp(a) levels,” Nissen said.
Alongside the AHA presentation, Lilly also published these data Sunday in the Journal of the American Medical Association. A Phase II study is underway.
Lepodisiran is a small interfering RNA (siRNA) therapeutic that works by targeting and disabling the mRNA molecule that encodes for apolipoprotein(a), which is a crucial component of Lp(a). The candidate is designed to work in the liver and is attached to a sugar called GalNAc, which binds to its corresponding receptors found on hepatic cells.
Amgen is also advancing a siRNA therapeutic for Lp(a). The candidate, dubbed olpasiran, is being studied in the OCEAN(a) clinical program, focusing on patients with atherosclerotic cardiovascular disease and elevated Lp(a) levels. Amgen kicked off its Phase III cardiovascular outcomes study of olpasiran in December 2022.