Muvalaplin Significantly Lowers Lipoprotein(a) in Adults With High Risk for Cardiovascular Events

Muvalaplin (Lilly), an oral, once-daily treatment, was found to significantly lower lipoprotein(a) [Lp(a)] by up to 85% in adults at high risk for cardiovascular events, according to results from a 12-week phase 2 study.¹

Muvalaplin inhibits the formation of Lp(a) by blocking the initial interaction between apolipoprotein(a) [apo(a)] and apo(b). According to a news release, about 20% of individuals in the US have high levels of Lp(a), which can double or even triple the risk of heart attack as well as other cardiovascular issues.¹

Patient taking a pill | Image credit: © Africa Studio | stock.adobe.com

The study’s primary end point was percent change in Lp(a) from baseline to week 12. Muvalaplin 10 mg, 60 mg, and 240 mg showed significant reductions in Lp(a) levels compared with placebo, up to 85.8% using an intact Lp(a) assay and up to 70% using an apo(a) assay. Investigators noted that reductions were more significant with larger doses. Specifically, reductions were 47.6% (10 mg), 80.7% (60 mg), and 85.8% (240 mg) using the intact Lp(a) assay, and 40.4% (10 mg), 70% (60 mg), and 68.9% (240 mg) with the apo(a) assay.¹

Lp(a) is a genetic independent risk factor for heart disease, and levels can be high regardless of healthy lifestyle factors and controlled heart disease risk factors. About 1 in 5 individuals has high Lp(a), defined as 50 mg/dL or higher. Many of these individuals do not have symptoms.²

“High levels of Lp(a) have been shown to be a significant risk factor for atherosclerotic cardiovascular disease, affecting over 1 billion adults globally,” Stephen J. Nicholls, MBBS, PhD, director of the Victorian Heart Hospital and Institute in Australia, said in a news release. “Current cholesterol-lowering therapies are not approved to lower Lp(a) levels, highlighting an unmet need for people living with cardiovascular disease. These data represent a needed scientific advancement with the potential to reduce the risk of cardiovascular events such as heart attacks or strokes with a once-daily pill.”¹

Researchers have also been investigating injectable options for lowering Lp(a), as seen in the clinical program for lepodisiran (Lilly), a small interfering RNA that blocks the production of a key protein component of Lp(a) in the kidney. According to trial results presented at the American Heart Association Scientific Sessions 2023, a single injection of lepodisiran reduced Lp(a) by up to 94%, and reductions lasted for nearly 1 year.³

With the highest dose of lepodisiran (608 mg), levels of Lp(a) in the blood declined rapidly and were undetectable by day 29, remaining unmeasurable until day 281 before rising slightly. With smaller doses, reduced levels of Lp(a) did not last as long, although it remained reduced by 75% at 48 weeks among those who received the 304 mg dose.³

Muvalaplin could offer an oral option. In addition to the primary end points, it met secondary end points for all 3 tested doses, achieving statistical significance for Lp(a) thresholds. Using the intact Lp(a) assay, 64.2% of patients achieved Lp(a) levels below 125 nmol/L using the 10 mg dose; 95.9% achieved this threshold with the 60 mg dose; and 96.7% achieved this threshold with the 240 mg dose. Using the apo(a) assay, these percentages were 38.9%, 81.9%, and 77.4%, respectively, compared with 3.6% in the placebo group.¹

Furthermore, the 60 mg and 240 mg doses also achieved statistical significance for apo(b) reductions. Apo(b) levels were reduced at all doses, with placebo-adjusted reductions of 8.9% with 10 mg, 13.1% with 60 mg, and 16.1% with 240 mg.¹

Adverse events were similar in the muvalaplin and placebo groups, with treatment-emergent adverse events related to the study drug occurring in 14.9% with placebo, 5.9% with 10 mg muvalaplin, 14.3% with 60 mg muvalaplin, and 14.7% with 240 mg muvalaplin. The incidence of adverse events leading to discontinuation of the study drug ranged from 0% to 8.8% across treatment groups and were single events spread across system organ classes.¹

“While injectable approaches for Lp(a) are currently in phase 3 development, including Lilly’s own lepodisiran program, these are the first positive phase 2 data for an oral approach,” Ruth Gimeno, PhD, group vice president of Diabetes and Metabolic Research at Lilly Research Laboratories, said in the news release. “We are very pleased to see these promising results and look forward to further exploring next steps to muvalaplin.”

REFERENCES

1. Lilly’s muvalaplin lowered lipoprotein(a) levels in adults with high risk for cardiovascular events by up to 85% at highest tested dose. News release. Lilly. November 18, 2024. Accessed December 5, 2024. https://investor.lilly.com/news-releases/news-release-details/lillys-muvalaplin-lowered-lipoproteina-levels-adults-high-risk

2. Lipoprotein(a). American Heart Association. Accessed December 5, 2024. https://www.heart.org/en/health-topics/cholesterol/genetic-conditions/lipoprotein-a

3. One dose of experimental therapy reduced lipoprotein(a) more than 94% for nearly a year. News release. American Heart Association. November 12, 2023. Accessed December 5, 2024. https://newsroom.heart.org/news/one-dose-of-experimental-therapy-reduced-lipoprotein-a-more-than-94-for-nearly-a-year