A clinical trial testing muvalaplin, a new oral drug, was able to safely and effectively lower high levels of lipoprotein (a), according to the latest science presented today at the American Heart Association’s 2024 Scientific Meetings. The meeting, November 16, 18, 2024, in Chicago, is a leading global exchange of the latest scientific advances, of research and evidence-based clinical practice updates in cardiovascular science. The study is published simultaneously today in JAMA, the Journal of the American Medical Association.
Lipoprotein (a), or Lp(a), is a type of inherited cholesterol level that is a common, independent risk factor for cardiovascular disease, affecting about 1 in 5 people worldwide. Black people of African descent and South Asian populations often have the highest levels of Lp(a), according to the American Heart Association’s 2021 scientific statement Lipoprotein(a): A Genetically Determined, Causal and Prevalent Risk Factor for Atherosclerotic Cardiovascular Disease ». It differs from low-density lipoprotein (LDL) or “bad” cholesterol. Lp(a) numbers of 50 mg/dL (125 nmol/L) or higher promote clotting and inflammation, significantly increasing the risk of heart attack, stroke, aortic stenosis, and peripheral artery disease, especially for people who also have CVD disease or familial hypercholesterolemia.
There are several injectable drugs undergoing clinical evaluation as treatments to lower Lp(a) levels. However, none have yet been approved by the US Food and Drug Administration.
Most drugs being developed to lower Lp(a) are injectable. Muvalaplin is the first oral agent developed to lower Lp(a) levels and works by disrupting the formation of the Lp(a) particle.
Stephen Nicholls, MBBS, Ph.D., study author, director of the Victorian Heart Institute at Monash University in Melbourne, Australia
The KRAKEN clinical trial included 233 adults worldwide who were identified as being at high risk of having a cardiovascular event due to very high Lp(a) levels (above 175 nmol/L). The researchers evaluated the effects of muvalaplin at different doses – 10 mg, 60 mg or 240 mg, taken daily – compared to a daily placebo for 12 weeks. The researchers looked at Lp(a) levels using both the traditional Lp(a) blood test and a new test that more specifically measures levels of intact Lp(a) particles in the blood.
At week 12, the study found:
- Compared with placebo, muvalaplin treatment reduced Lp(a) by up to 70% as measured by the traditional blood test and by up to 85.5% as measured by the new intact particle Lp(a) test. Participants who received either 60 or 240 mg of muvalaplin had similar reductions in Lp(a) levels, both of which were greater than the reductions in Lp(a) levels of participants who received 10 mg of muvalaplin.
- Treatment with muvalaplin resulted in approximately 97% of participants achieving an Lp(a) lower than 125 nmol/L as measured by the whole particle Lp(a) assay, or approximately 82% of participants as measured by the traditional blood test.
- Compared to placebo, muvalaplin reduced apoB, one of the two major proteins that make up Lp(a), by up to 16%, without appreciable change in levels of high-sensitivity C-reactive protein (hsCRP), which is a way to measure heart attack and stroke risk.
“We were encouraged by the degree of reduction in Lp(a) in those patients who are most likely to benefit from its use and by the safety and tolerability,” Nicholls said. “While muvalaplin appears to be an effective approach to lowering Lp(a) levels, we still need to study whether lowering Lp(a) will lead to fewer heart attacks and strokes.”
The study had limitations, including that it was relatively small and that trial participants were only treated for 12 weeks. “Larger, more diverse and longer-term studies are needed,” Nicholls noted.
Study details, background and design:
- The study included 233 adults with high Lp(a) levels, defined as greater than 175 nmol/L, and either atherosclerotic cardiovascular disease, type 2 diabetes, or familial hypercholesterolemia. 33% of participants were female and 67% were male. 66% identify as white adults. 27% as Asian adults. 4% as black adults. and 3% identified as adults of “other” race.
- The KRAKEN phase II clinical trial was conducted at 43 sites in Asia, Europe, Australia, Brazil and the US from December 2022 to June 2024.
- Participants had clinic visits at study enrollment (baseline) and at weeks 1, 2, 4, 8, and 12 during the treatment period. Clinic visits included blood tests for Lp(a) analysis, measurement of a standard lipid profile, and recording of safety and tolerability.
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