A novel oral medication, muvalaplin, has shown promise in safely and effectively lowering high levels of lipoprotein(a) (Lp(a)), a genetically determined risk factor for cardiovascular disease. The findings, from the KRAKEN clinical trial, were presented at the American Heart Association’s Scientific Sessions 2024 and simultaneously published in JAMA.
Targeting Lipoprotein(a) with Muvalaplin
Lp(a) affects approximately 1 in 5 people worldwide and is recognized as an independent risk factor for cardiovascular events. Elevated Lp(a) levels, specifically those at or above 50 mg/dL (125 nmol/L), are associated with increased risks of heart attack, stroke, aortic stenosis, and peripheral artery disease. Muvalaplin is designed to inhibit the bonding of protein components that form Lp(a).
Stephen Nicholls, MBBS, Ph.D., director of the Victorian Heart Institute at Monash University in Melbourne, Australia, noted, "Most medications being developed to lower Lp(a) are injectable. Muvalaplin is the first oral agent being developed to lower Lp(a) levels and acts by disrupting formation of the Lp(a) particle."
KRAKEN Trial Results
The KRAKEN trial enrolled 233 adults globally with high cardiovascular risk due to Lp(a) levels exceeding 175 nmol/L. Participants were administered muvalaplin at doses of 10 mg, 60 mg, or 240 mg daily, or a placebo, for 12 weeks. The study measured Lp(a) levels using both a traditional blood test and a novel test for intact Lp(a) particles.
Key findings at week 12 included:
- Lp(a) reduction by up to 70% with muvalaplin compared to placebo, as measured by the traditional blood test.
- Up to 85.5% reduction in Lp(a) as measured by the new intact Lp(a) particle test.
- Similar Lp(a) reductions with 60 mg and 240 mg doses, both greater than the 10 mg dose.
- Approximately 97% of muvalaplin-treated participants achieved Lp(a) levels below 125 nmol/L, as measured by the intact Lp(a) particle test, and approximately 82% as measured by the traditional blood test.
- ApoB, a major protein component of Lp(a), was lowered by as much as 16% with muvalaplin, with no significant change in high-sensitivity C-reactive protein (hsCRP) levels.
Clinical Implications and Future Directions
"We were encouraged by the degree of Lp(a)-lowering in these patients who are most likely to benefit from its use and by the safety and tolerability," said Nicholls. He also emphasized the need for further research to determine whether Lp(a) lowering with muvalaplin translates into fewer cardiovascular events.
The study's limitations include its relatively small size and short duration (12 weeks). Nicholls stated that "Larger, more diverse and longer-term studies are needed."
The KRAKEN trial was a phase II clinical trial conducted across 43 sites in Asia, Europe, Australia, Brazil, and the U.S. between December 2022 and June 2024. The study population included 33% women and 67% men, with 66% identifying as White, 27% as Asian, 4% as Black, and 3% as "other" race. Participants had either atherosclerotic cardiovascular disease, Type 2 diabetes, or familial hypercholesterolemia.
