Two novel therapies targeting lipoprotein(a) [Lp(a)], zerlasiran and muvalaplin, have shown positive results in early phase II studies, reducing Lp(a) levels by approximately 80% over extended follow-up periods. These findings, presented at the American Heart Association Scientific Sessions and published in JAMA, offer potential new avenues for managing cardiovascular risk associated with elevated Lp(a).
ALPACAR-360: Zerlasiran, an siRNA Therapeutic
The ALPACAR-360 trial, led by Steven Nissen, MD (Cleveland Clinic, OH), evaluated zerlasiran (Silence Therapeutics), a small interfering RNA (siRNA) therapy. The study enrolled 178 patients with atherosclerotic cardiovascular disease (ASCVD) and elevated Lp(a), randomizing them to different doses of zerlasiran or placebo. Results showed an 85.6% time-averaged, placebo-adjusted reduction in Lp(a) from baseline to 36 weeks with the 450 mg/24 weeks dose. Lower doses also demonstrated significant reductions, with 82.8% and 81.3% for the 300 mg/16 weeks and 300 mg/24 weeks regimens, respectively. Additionally, LDL-cholesterol levels decreased by 25% to 32%, and apoB concentrations declined by 10% to 15% across the doses.
Nissen noted a limitation of the study was the predominantly white, male participant pool, emphasizing the need to study the drug's effects in Black individuals, who are known to have higher Lp(a) levels.
KRAKEN: Muvalaplin, an Oral Agent
The KRAKEN trial, led by Stephen Nicholls, MBBS, PhD (Monash University, Australia), assessed muvalaplin (Eli Lilly), an oral agent that prevents Lp(a) formation. The trial included 233 patients with ASCVD, diabetes, or familial hypercholesterolemia. Participants were randomized to receive daily muvalaplin at doses of 10, 60, or 240 mg, or placebo. After 12 weeks, Lp(a) levels, measured using an intact assay, declined by 47.4%, 81.6%, and 85.7% with the 10, 60, and 240 mg doses, respectively, compared to placebo. Using a traditional apo(a) assay, reductions were 42.3%, 70.9%, and 69.9%, respectively, versus a 3.2% reduction in the placebo arm.
Nicholls highlighted the importance of offering patients a choice in treatment options, stating, "There are implications for some patients who don't want to take an injectable, and oral therapy is a good option for those patients." He also noted the potential cost benefits of oral therapeutics compared to injectable biologics.
The Unmet Need for Lp(a) Lowering
Erin Michos, MD (Johns Hopkins University School of Medicine), emphasized that one in five people have high Lp(a) levels, which are largely genetically determined and an independent predictor of ASCVD and calcific aortic stenosis. Traditional lipid-lowering therapies like statins and ezetimibe do not effectively lower Lp(a) levels, underscoring the urgent need for targeted therapies.
Future Directions and Clinical Implications
The ultimate question remains whether lowering Lp(a) can reduce cardiovascular events. Results from the Lp(a)HORIZON trial (pelacarsen) are expected in 2025, and the OCEAN(a)-Outcomes study (olpasiran) is anticipated in late 2026. The ACCLAIM-Lp(a) trial (lepodisiran) is also underway, with results expected in 2029.
Nicholls advocates for increased Lp(a) testing to identify at-risk individuals, even in the absence of available treatments, to better stratify patient risk and implement more aggressive management of other risk factors.
