American Heart Association Scientific Sessions 2024, Abstract 4171286

Research Highlights:

• The oral medication muvalaplin may safely lower high levels of lipoprotein(a), also known as Lp(a), an independent, inherited risk factor for cardiovascular disease.
• Muvalaplin is a small molecule inhibitor that prevents the bonding of the two protein components that combine to make Lp(a). There are no currently FDA-approved medications to lower Lp(a) levels, though other medications are currently being evaluated in clinical trials. Muvalaplin is the first oral medication developed to lower Lp(a) levels.
• Results from the KRAKEN clinical trial find that muvalaplin was well-tolerated and decreased Lp(a) levels within 24 hours of the first dose, with the majority of the effect seen by 4 weeks and persisting through the study, the researchers noted.
• Note: The study featured in this news release is a research abstract. Abstracts presented at American Heart Association's scientific meetings are not peer-reviewed, and the findings are considered preliminary until published as full manuscripts in a peer-reviewed scientific journal.

Embargoed until 1:52 p.m. CT/2:52 p.m. ET, Monday, Nov. 18, 2024

This news release contains updated information from the researcher that was not in the abstract.

CHICAGO, Nov. 18, 2024 - A clinical trial testing muvalaplin, a novel oral medication, was able to safely and effectively lower high levels of lipoprotein (a), according to late-breaking science presented today at the American Heart Association's Scientific Sessions 2024. The meeting, Nov. 16-18, 2024, in Chicago, is a premier global exchange of the latest scientific advancements, research and evidence-based clinical practice updates in cardiovascular science. The study is simultaneously published 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 individuals of African descent and South Asian populations often have the highest Lp(a) levels, 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 is different 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 cardiovascular disease or familial hypercholesterolemia.

There are several injectable medications undergoing clinical evaluation as treatments to lower Lp(a) levels. However, none have yet been approved by the U.S. Food and Drug Administration.

"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," said study author Stephen Nicholls, MBBS, Ph.D., director of the Victorian Heart Institute at Monash University in Melbourne, Australia.

The KRAKEN clinical trial included 233 adults around the world who were identified at high risk of having a cardiovascular event due to very high Lp(a) levels (greater than 175 nmol/L). Researchers evaluated the effects of muvalaplin at different doses-10 mg, 60 mg or 240 mg, taken daily-compared with a daily placebo for 12 weeks. The researchers tested Lp(a) levels using both the traditional Lp(a) blood test and a new test that more specifically measures the levels of intact Lp(a) particles in the blood.

At week 12, the study found:

• Compared to 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 Lp(a) particle 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.
• Muvalaplin treatment resulted in approximately 97% of participants achieving Lp(a) lower than 125 nmol/L, as measured by the intact Lp(a) particle test, or approximately 82% of participants as measured with the traditional blood test.
• Compared to placebo, muvalaplin lowered apoB, one of two major proteins that make up Lp(a), by as much as 16%, with no notable 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 Lp(a)-lowering in these 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 Lp(a) lowering will result in fewer heart attacks and strokes."

The study had limitations, including that it was relatively small and trial participants were treated for only 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 women and 67% were men. 66% self-identified 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 U.S., from December 2022 to June 2024.
• Participants had clinical visits at study enrollment (baseline) and weeks 1, 2, 4, 8 and 12 during the treatment period. The clinic visits consisted of blood tests for Lp(a) analysis, measurement of a standard lipid profile, and recording of safety and tolerability.

Co-authors and disclosures are listed in the manuscript. The trial was funded by Eli Lilly and Company.

Statements and conclusions of studies that are presented at the American Heart Association's scientific meetings are solely those of the study authors and do not necessarily reflect the Association's policy or position. The Association makes no representation or guarantee as to their accuracy or reliability. Abstracts presented at the Association's scientific meetings are not peer-reviewed, rather, they are curated by independent review panels and are considered based on the potential to add to the diversity of scientific issues and views discussed at the meeting. The findings are considered preliminary until published as a full manuscript in a peer-reviewed scientific journal.

The Association receives funding primarily from individuals; foundations and corporations (including pharmaceutical, device manufacturers and other companies) also make donations and fund specific Association programs and events. The Association has strict policies to prevent these relationships from influencing the science content. Revenues from pharmaceutical and biotech companies, device manufacturers and health insurance providers and the Association's overall financial information are available here.

Additional Resources:

• Multimedia is available on the right column of the release link.
• Link to abstract; and AHA Scientific Sessions 2024 Online Program Planner
• AHA news release: One dose of experimental therapy reduced lipoprotein(a) more than 94% for nearly a year (Nov. 2023)
• AHA news release: New research project aims to set standardized approach to lipoprotein(a) management (March 2023)
• AHA health information: Lipoprotein (a) Meaning and How Does it Impact My Heart Health?
• For more news at AHA Scientific Sessions 2024, follow us on X @HeartNews,#AHA24

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