These results, presented at the 2024 American Heart Association (AHA) Scientific Sessions, mark a pivotal advancement in cardiovascular medicine, as elevated Lp(a) affects approximately 20% of the global population, particularly individuals of Black African and South Asian descent.
 

Lp(a), a variant of low-density lipoprotein (LDL) cholesterol, is genetically determined and resistant to lifestyle changes or traditional lipid-lowering therapies like statins. High levels (≥125 nmol/L) contribute to clotting, inflammation, and a higher risk of heart attack, stroke, and aortic stenosis. Muvalaplin works by disrupting the bond between two protein components of Lp(a)—apolipoprotein(a) and apolipoprotein(b)—preventing the particle's formation.
 

The KRAKEN trial enrolled 233 participants with Lp(a) levels exceeding 175 nmol/L, randomizing them to daily doses of 10, 60, or 240 mg of muvalaplin or placebo for 12 weeks.

Results showed that muvalaplin reduced Lp(a) levels by up to 70% using traditional blood tests and by up to 85.5% with a novel test designed to measure intact Lp(a) particles. Nearly 97% of participants achieved Lp(a) levels below 125 nmol/L with the novel test, and 82% did so with traditional testing.

The drug also reduced oxidized phospholipids—considered a key driver of atherosclerosis—and ApoB by up to 16%, without increasing markers of inflammation like high-sensitivity C-reactive protein.
 

Safety outcomes were favourable, with serious adverse events occurring in 6% of placebo recipients and only 2.9% to 5.9% in muvalaplin-treated groups. The oral formulation positions muvalaplin as a more accessible alternative to injectable Lp(a)-lowering therapies currently in trials, such as pelacarsen and olpasiran.
 

Experts, including lead investigator Stephen Nicholls, MBBS, PhD, emphasized the significance of these findings, stating that muvalaplin offers a promising solution for managing Lp(a), an independent cardiovascular risk factor. Erin Michos, MD, of Johns Hopkins University, highlighted the urgent need for Lp(a) testing and therapies, as high Lp(a) levels continue to confer substantial cardiovascular risk even in patients whose LDL cholesterol is well controlled.
 

While muvalaplin has shown robust efficacy in lowering Lp(a), larger, long-term studies are necessary to confirm its impact on cardiovascular outcomes such as heart attack and stroke. These results underscore the importance of targeted therapies in addressing previously untreatable risk factors.