Measuring Lp(a) particles with a novel isoform-insensitive immunoassay illustrates efficacy of muvalaplin
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) concentrati...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-01-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227524002281 |
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| author | Craig A. Swearingen John H. Sloan Grace M. Rhodes Robert W. Siegel Nico Bivi Yuewei Qian Robert J. Konrad Michael Boffa Marlys Koschinsky John Krege Giacomo Ruotolo Stephen J. Nicholls Laura F. Michael Yi Wen |
| author_facet | Craig A. Swearingen John H. Sloan Grace M. Rhodes Robert W. Siegel Nico Bivi Yuewei Qian Robert J. Konrad Michael Boffa Marlys Koschinsky John Krege Giacomo Ruotolo Stephen J. Nicholls Laura F. Michael Yi Wen |
| author_sort | Craig A. Swearingen |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-565368a91b8d4980abc1cf50a5c342ad |
| institution | Kabale University |
| issn | 0022-2275 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj-art-565368a91b8d4980abc1cf50a5c342ad2025-01-30T05:12:40ZengElsevierJournal of Lipid Research0022-22752025-01-01661100723Measuring Lp(a) particles with a novel isoform-insensitive immunoassay illustrates efficacy of muvalaplinCraig A. Swearingen0John H. Sloan1Grace M. Rhodes2Robert W. Siegel3Nico Bivi4Yuewei Qian5Robert J. Konrad6Michael Boffa7Marlys Koschinsky8John Krege9Giacomo Ruotolo10Stephen J. Nicholls11Laura F. Michael12Yi Wen13Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USALilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USALilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USALilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USALilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USALilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USALilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USARobarts Research Institute, University of Western Ontario, London, ON, CanadaRobarts Research Institute, University of Western Ontario, London, ON, CanadaLilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USALilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USAVictorian Heart Institute, Monash University, Clayton, VIC, AustraliaLilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA; For correspondence: Laura F. Michael; Yi WenLilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA; For correspondence: Laura F. Michael; Yi WenLipoprotein(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.http://www.sciencedirect.com/science/article/pii/S0022227524002281Lipoprotein (a)antibodieslipoprotein (a) metabolismclinical trialsdrug therapycardiovascular disease |
| spellingShingle | Craig A. Swearingen John H. Sloan Grace M. Rhodes Robert W. Siegel Nico Bivi Yuewei Qian Robert J. Konrad Michael Boffa Marlys Koschinsky John Krege Giacomo Ruotolo Stephen J. Nicholls Laura F. Michael Yi Wen Measuring Lp(a) particles with a novel isoform-insensitive immunoassay illustrates efficacy of muvalaplin Journal of Lipid Research Lipoprotein (a) antibodies lipoprotein (a) metabolism clinical trials drug therapy cardiovascular disease |
| title | Measuring Lp(a) particles with a novel isoform-insensitive immunoassay illustrates efficacy of muvalaplin |
| title_full | Measuring Lp(a) particles with a novel isoform-insensitive immunoassay illustrates efficacy of muvalaplin |
| title_fullStr | Measuring Lp(a) particles with a novel isoform-insensitive immunoassay illustrates efficacy of muvalaplin |
| title_full_unstemmed | Measuring Lp(a) particles with a novel isoform-insensitive immunoassay illustrates efficacy of muvalaplin |
| title_short | Measuring Lp(a) particles with a novel isoform-insensitive immunoassay illustrates efficacy of muvalaplin |
| title_sort | measuring lp a particles with a novel isoform insensitive immunoassay illustrates efficacy of muvalaplin |
| topic | Lipoprotein (a) antibodies lipoprotein (a) metabolism clinical trials drug therapy cardiovascular disease |
| url | http://www.sciencedirect.com/science/article/pii/S0022227524002281 |
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