Muvalaplin, an Oral Lp(a)-Lowering Agent, Shows Promise in Phase 2 KRAKEN Trial

Stephen Nicholls, MBBS, PhD
Credit: Monash University

New research from the American Heart Association (AHA) Annual Scientific Sessions 2024 demonstrates muvalaplin, a once-daily, oral treatment, reduced lipoprotein (a) [Lp(a)] by up to 85% at the highest tested dose in adults with elevated Lp(a) and high risk for cardiovascular events.¹

A 12-week, phase 2 trial conducted among 233 adults with elevated Lp(a), results of the study offer evidence of the potential for an oral agent to be used in management, as most agents being examined in phase 2 or 3 trials, including Eli Lilly and Company’s lepodisiran, are injectables.^1,2,3

“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 lead investigator Stephen Nicholls, MBBS, PhD, director of the Victorian Heart Institute at Monash University in Melbourne, Australia.²

In recent years, the evidence base linking elevated Lp(a) to elevated risk of cardiovascular events and recent pipeline advances aimed at addressing Lp(a) have become a focal point of discussions at major scientific congresses and meetings, including AHA 2024. A phase 2 trial, named KRAKEN, the study enrolled 233 patients across 43 sites in 5 countries.^1,2

For inclusion in the trial, patients were required to have Lp(a) concentrations of 175 nmol/L or greater with atherosclerotic cardiovascular disease, diabetes, or familial hypercholesterolemia. Patients were randomized in a 1:2:2:2 ratio to receive muvalaplin at dosages of 10 mg/d, 60 mg/d, or 240 mg/d or placebo therapy for 12 weeks, with 34, 64, 68, and 67 patients randomized to each group, respectively.¹

The 233-patient cohort had a median age of 66 years, 33% were female, 66% identified as White, 27% identified as Asian, and 4% identified as Black. The cohort had a median baseline Lp(a) of 216.8nmol/L using the intact Lp(a) assay and 246.5 nmol/L using the apolipoprotein(a) assay.¹

The primary outcome of interest for the trial was the placebo-adjusted percentage change from baseline in Lp(a) molar concentration at 12 weeks. For the purpose of analysis’ investigators used 2 different assays to assess changes in Lp(a) levels: the intact Lp(a) assay and the apo(a) assay. Secondary endpoints of note for the trial included the percentage change in apolipoproteinB and high-sensitivity C-reactive protein (hsCRP).¹

Results demonstrated use of muvalaplin was associated with placebo-adjusted reductions in Lp(a) of 47.6% (95% CI, 35.1% to 57.7%), 81.7% (95% CI, 78.1%-84.6%), and 85.8% (95% CI, 83.1% to 88.0%) for the 10 mg/d, 60 mg/d, and 240 mg/d dosages, respectively, using the intact Lp(a) assay. When using apolipoprotein(a)-based assay, the observed placebo-adjusted reductions in Lp(a) were 40.4% (95% CI, 28.3% to 50.5%), 70.0% (95% CI, 65.0% to 74.2%), and 68.9% (95% CI, 63.8% to 73.3%), with the 10 mg/d, 60 mg/d, and 240 mg/d dosages, respectively.¹

Analysis of secondary endpoints of interest revealed use of 8.9% (95% CI,−2.2% to 18.8%), 13.1% (95% CI, 4.4% to 20.9%), and 16.1% (95% CI, 7.8% to 23.7%) with the 10mg/d, 60mg/d, and 240mg/d, respectively. Investigators highlighted there was no change in hsCRP and there were no safety or tolerability concerns observed at any dosage.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," said Ruth Gimeno, PhD, group vice president, Diabetes and Metabolic Research, Lilly Research Laboratories.² "We are very pleased to see these promising results and look forward to further exploring next steps for muvalaplin."

References:

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