Oral inhibition
A new isoform-insensitive Lp(a) particle assay reveals commercial assays underestimated muvalaplin's efficacy (J Lipid Res 2025)
Original title: Measuring Lp(a) particles with a novel isoform-insensitive immunoassay illustrates efficacy of muvalaplin
Because current commercial Lp(a) assays measure total apolipoprotein(a) [apo(a)] rather than intact Lp(a) particles, they may inaccurately assess Lp(a) lowering by a new class of small-molecule Lp(a) formation inhibitors like muvalaplin. The authors developed a novel immunoassay measuring only intact Lp(a) particles, which showed robust analytical performance, was insensitive to apo(a) isoform size, and correlated with a liquid chromatography-tandem mass spectrometry reference method. Applying both the new intact Lp(a) assay and commercial assays to samples from a muvalaplin phase I multiple ascending dose study and a lepodisiran (a small interfering RNA Lp(a)-lowering agent) phase I single ascending dose study, the commercial total apo(a) assay underestimated muvalaplin's Lp(a)-lowering efficacy relative to the intact Lp(a) assay, while lepodisiran's effect was comparable between assay types. The findings show that assay choice can meaningfully distort how effective a novel Lp(a)-lowering mechanism appears to be, particularly for agents like muvalaplin that act on Lp(a) particle assembly.
Original abstract
Lipoprotein(a) [Lp(a)] is a cardiovascular risk factor, and there is considerable interest in developing Lp(a)-lowering therapeutics for cardiovascular prevention. Current commercial Lp(a) assays measure total apolipoprotein(a) [apo(a)] and may be insufficient to accurately measure Lp(a) concentrations and determine Lp(a) lowering by a new class of small-molecule Lp(a) formation inhibitors such as muvalaplin. We developed a novel immunoassay that measures only Lp(a) particles. This intact Lp(a) assay demonstrated robust analytical performance, was insensitive to apo(a) isoform size, and correlated with a liquid chromatography-tandem mass spectrometry method. Muvalaplin phase I multiple ascending dose study samples and lepodisiran, a small-interfering RNA that lowers Lp(a), phase I single ascending dose study samples were analyzed using the intact Lp(a) assay and commercial assays. The Lp(a)-lowering efficacy of muvalaplin was underestimated by the commercial assay measuring total apo(a) compared with the intact Lp(a) assay specifically measuring Lp(a) particles. In contrast, the Lp(a)-lowering effect of lepodisiran was clinically comparable between the intact Lp(a) assay and commercial assay. This novel intact Lp(a) assay provides a more accurate approach for the assessment of Lp(a)-lowering agents and the study of Lp(a)-associated risk compared with currently available assays.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.