Oral Muvalaplin for Lowering of Lipoprotein(a): A Randomized Clinical Trial

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.

Figure 1.. Participant Flow in the KRAKEN Trial

^aOther ineligible participants included single cases of judged unreliable, uncontrolled hypertension, not at high risk of cardiovascular event, malignancy within prior 5 years, and younger than 40 years.

Figure 2.. Percentage Change in Lipoprotein(a) Concentration Measured by Intact Lipoprotein(a) Assay and Apolipoprotein(a)-Based Assay

Data are presented as least-squares means (solid dots), medians (lines), IQRs (boxes), 2.5th and 97.5th percentiles (whiskers), and outliers (open circles). Intact lipoprotein(a) was not measured at weeks 1, 2, or 8. Intact lipoprotein(a) was not measured in 30 patients in China, as storage of samples was not permitted.

Figure 3.. Absolute Change in Lipoprotein(a) Concentration Among Individual Participants at Week 12 Measured by Intact Lipoprotein(a) Assay and Apolipoprotein(a)-Based Assay

Waterfall plots demonstrate individual absolute changes from baseline in lipoprotein(a) concentration at week 12 with placebo and different doses of muvalaplin. Intact lipoprotein(a) was not measured in 30 patients in China, as storage of samples was not permitted.