Muvalaplin Found to Significantly Lower Lipoprotein(a) Levels, Offering Hope for Cardiovascular Disease Patients
The Phase II KRAKEN trial demonstrated that muvalaplin, Eli Lilly's first-in-class oral small molecule inhibitor, significantly reduces lipoprotein(a) levels with minimal adverse effects, offering a promising new approach to addressing a major cardiovascular risk factor.
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Results of the Phase II KRAKEN trial (NCT05563246) show that muvalaplin (Eli Lilly) produced a significant reduction in lipoprotein(a) levels with minimal adverse effects (AEs) in adults with an elevated risk of atherosclerotic cardiovascular disease (ASCVD).1,2
These data, presented at the American Heart Association Scientific Sessions 2024 and published in the Journal of the American Medical Association, indicate that the investigational once-daily therapy is the first oral small molecule inhibitor that reduces lipoprotein(a) levels.3
"High levels of Lp(a) have been shown to be a significant risk factor for atherosclerotic cardiovascular disease, affecting over one billion adults globally," Stephen J. Nicholls, MBBS, PhD, director of the Victorian Heart Hospital and Institute, and professor of cardiology at Monash University, Australia, said in a press 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
In a previously conducted 14-day Phase I trial, muvalaplin was found to be well tolerated while lowering lipoprotein(a) levels up to 65%. Investigators stated that it remains to be determined whether lipoprotein(a) is a modifiable risk factor, which patients could benefit from reduced lipoprotein(a), and the degree to which lipoprotein(a) needs to be reduced to lower the risk of cardiovascular events.
“Therapeutic options for patients with elevated lipoprotein(a) levels are currently limited,” the study authors wrote. “Genetic epidemiology studies suggest that large reductions of 85 to 250 nmol/L may be needed to lower cardiovascular risk, and there is currently no pharmacotherapy approved for lowering lipoprotein(a) levels. Apheresis has been used to lower lipoprotein(a) but it is invasive, time-consuming, and costly.”3
The placebo-controlled, randomized, double-blind trial enrolled 233 patients with lipoprotein(a) concentrations of 175 nmol/L or greater with ASCVD, diabetes, or familial hypercholesterolemia. The trial was conducted at 43 sites in Asia, Europe, Australia, Brazil, and the United States between December 10, 2022, and November 22, 2023.
The trial’s primary endpoint was the placebo-adjusted percentage change from baseline in lipoprotein(a) molar concentration after 12 weeks, with secondary endpoints that included percentage change in apolipoprotein B and high-sensitivity C-reactive protein. Investigators randomly assigned patients to receive oral muvalaplin at dosages of 10 mg/d (n = 34), 60 mg/d (n = 64), or 240 mg/d (n = 68), or placebo (n = 67) for 12 weeks.
Using an intact lipoprotein(a) assay, investigators found that muvalaplin produced placebo-adjusted lowering of lipoprotein(a) of 47.6% in the 10 mg/d dosage cohort (95% CI, 35.1%-57.7%), 81.7% in the 60 mg/d cohort (95% CI, 78.1%-84.6%), and 85.8% in the 240 mg/d cohort (95% CI, 83.1%-88.0%). Using an apolipoprotein(a)-based assay, lipoprotein(a) reductions were 40.4% in the 10 mg/d dosage cohort (95% CI, 28.3%-50.5%), 70.0% in the 60 mg/d cohort (95% CI, 65.0%-74.2%), and 68.9% in the 240 mg/d cohort (95% CI, 63.8%-73.3%).
Dose-dependent reductions in apolipoprotein B were found to be 8.9% in the 10 mg/d dosage cohort (95% CI, −2.2% to 18.8%), 13.1% in the 60 mg/d cohort (95% CI, 4.4%-20.9%), and 16.1% in the 240 mg/d cohort (95% CI, 7.8%-23.7%).
In terms of safety, AEs were similar across the muvalaplin and placebo cohorts. Treatment-emergent AEs were in reported by 14.9% of patients the placebo cohort, 5.9% in the 10 mg cohort, 14.3% in the 60 mg cohort, and 14.7% in the 240 mg cohort.
“While most therapies in clinical development have used injectable agents that target apolipoprotein(a) messenger RNA, muvalaplin inhibits lipoprotein(a) assembly with oral delivery, with evidence of effective lipoprotein(a) lowering and a favorable safety and tolerability profile,” the study authors concluded. “Future studies are needed to determine whether muvalaplin reduces clinical events and plays a role in the prevention of cardiovascular disease.”3
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. Eli Lilly. November 18, 2024. Accessed November 21, 2024. https://investor.lilly.com/news-releases/news-release-details/lillys-muvalaplin-lowered-lipoproteina-levels-adults-high-risk
2. A Study of LY3473329 in Adult Participants With Elevated Lipoprotein(a) at High Risk for Cardiovascular Events (KRAKEN). ClinicalTrials.gov. Updated March 28, 2024. Accessed November 21, 2024. https://www.clinicaltrials.gov/study/NCT05563246
3. Nicholls SJ, Ni W, Rhodes GM, et al. Oral Muvalaplin for Lowering of Lipoprotein(a): A Randomized Clinical Trial. JAMA. Published online November 18, 2024. doi:10.1001/jama.2024.24017
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