Oral inhibitionLandmark
KRAKEN: oral muvalaplin lowers Lp(a) by 82 to 86 percent on an intact-particle assay (Nicholls et al., JAMA 2025)
Original title: Oral Muvalaplin for Lowering of Lipoprotein(a): A Randomized Clinical Trial
233 participants with Lp(a) of 175 nmol/L or more and ASCVD, diabetes or FH at 43 sites received muvalaplin 10, 60 or 240 mg daily or placebo for 12 weeks: placebo-adjusted reductions were 47.6, 81.7 and 85.8 percent on an intact Lp(a) assay and 40.4, 70.0 and 68.9 percent on a traditional apo(a)-based assay, apoB fell up to 16 percent, hs-CRP did not change and there were no safety concerns. The traditional assay under-reads because it detects apo(a) freed from the particle: a measurement lesson as much as a drug result.
Original abstract
Importance: Muvalaplin inhibits lipoprotein(a) formation. A 14-day phase 1 study demonstrated that muvalaplin was well tolerated and reduced lipoprotein(a) levels up to 65%. The effect of longer administration of muvalaplin on lipoprotein(a) levels in individuals at high cardiovascular risk remains uncertain.
Objectives: To determine the effect of muvalaplin on lipoprotein(a) levels and to assess safety and tolerability.
Design, Setting, And Participants: Phase 2, placebo-controlled, randomized, double-blind trial enrolling 233 participants with lipoprotein(a) concentrations of 175 nmol/L or greater with atherosclerotic cardiovascular disease, diabetes, or familial hypercholesterolemia at 43 sites in Asia, Europe, Australia, Brazil, and the United States between December 10, 2022, and November 22, 2023.
Interventions: Participants were randomized to receive orally administered 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.
Main Outcomes And Measures: The primary end point was the placebo-adjusted percentage change from baseline in lipoprotein(a) molar concentration at week 12, using an assay to measure intact lipoprotein(a) and a traditional apolipoprotein(a)-based assay. Secondary end points included the percentage change in apolipoprotein B and high-sensitivity C-reactive protein.
Results: The median age of study participants was 66 years; 33% were female; and 27% identified as Asian, 4% as Black, and 66% as White. Muvalaplin resulted in placebo-adjusted reductions in lipoprotein(a) of 47.6% (95% CI, 35.1%-57.7%), 81.7% (95% CI, 78.1%-84.6%), and 85.8% (95% CI, 83.1%-88.0%) for the 10-mg/d, 60-mg/d, and 240-mg/d dosages, respectively, using an intact lipoprotein(a) assay and 40.4% (95% CI, 28.3%-50.5%), 70.0% (95% CI, 65.0%-74.2%), and 68.9% (95% CI, 63.8%-73.3%) using an apolipoprotein(a)-based assay. Dose-dependent reductions in apolipoprotein B were observed at 8.9% (95% CI, -2.2% to 18.8%), 13.1% (95% CI, 4.4%-20.9%), and 16.1% (95% CI, 7.8%-23.7%) at 10 mg/d, 60 mg/d, and 240 mg/d, respectively. No change in high-sensitivity C-reactive protein was observed. No safety or tolerability concerns were observed at any dosage.
Conclusions And Relevance: Muvalaplin reduced lipoprotein(a) measured using intact lipoprotein(a) and apolipoprotein(a)-based assays and was well tolerated. The effect of muvalaplin on cardiovascular events requires further investigation.
Trial Registration: ClinicalTrials.gov Identifier: NCT05563246.
diabetesfamilial hypercholesterolaemiainflammationoral inhibitionoralphase 2testingtherapy
Summary written by lp-a.org from the published abstract; figures as published. Page updated 17 August 2026. Methods.