{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T20:13:09Z","timestamp":1790367189193,"version":"4.1.0"},"reference-count":16,"publisher":"American Medical Association (AMA)","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Cardiol"],"published-print":{"date-parts":[[2026,6,1]]},"abstract":"<jats:sec>\n                    <jats:title>Importance<\/jats:title>\n                    <jats:p>\n                      In individuals with heterozygous familial hypercholesterolemia (HeFH), it is uncertain whether and to what extent the reduction in low-density lipoprotein cholesterol (LDL-C) with proprotein convertase subtilisin\/kexin type 9 (PCSK9) inhibitor therapy is dependent on the residual functional activity of the\n                      <jats:italic>LDLR<\/jats:italic>\n                      gene carrying the pathogenic variant.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To evaluate the reduction in LDL-C achieved with PCSK9 inhibition according to FH genotype in a large cohort of patients with HeFH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design, Setting, and Participants<\/jats:title>\n                    <jats:p>This nonrandomized clinical trial reports on a predefined, pooled subanalysis of participants with HeFH requiring additional lipid-lowering therapy in the open-label worldwide phase 3 study of the PSCK9 inhibitor lerodalcibep. This study included participants randomized to 5 phase 3 studies with the plasma PSCK9 inhibitor lerodalcibep and who participated in the open-label extension study from December 2020 to May 2025. Data were analyzed from March 2025 to February 2026.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Intervention<\/jats:title>\n                    <jats:p>All participants received lerodalcibep 300 mg subcutaneously monthly for 72 weeks.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main Outcome and Measures<\/jats:title>\n                    <jats:p>The co\u2013primary efficacy end points were LDL-C reduction at weeks 48 and 72. Secondary and exploratory end points included LDL-C response according to FH genotype and the achievement of currently recommended LDL-C goals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Among 703 included participants (mean [range] age, 53.8 [18-80] years; 372 male [52.9%]), 86 (12.2%) were Black, South Asian, or multiracial and 617 (87.8%) were White; 217 participants (72.3%) had atherosclerotic cardiovascular disease (ASCVD) or were at very high risk for ASCVD and 195 participants (27.7%) were at high risk for ASCVD. Despite most participants receiving treatment with statins or ezetimibe, the mean (SD) baseline LDL-C was 144.9 (61.9) mg\/dL. Mean (SD) reductions in LDL-C associated with lerodalcibep were 50.3% (28.9%) and 50.3% (28.7%) (mean [SD] absolute change, \u221272.6 [50.5] mg\/dL and \u221271.8 [48.0] mg\/dL) at weeks 48 and 72, respectively. Of 740 participants (92.5%) who underwent genetic testing, monogenic FH-causing variants were found in 455 participants (61.5%), including 432 participants (95.7%) with the\n                      <jats:italic>LDLR<\/jats:italic>\n                      pathogenic variant. LDL-C reduction with lerodalcibep was independent of\n                      <jats:italic>LDLR<\/jats:italic>\n                      variant functional activity. More than 70% of participants achieved both a reduction in LDL-C of at least 50% and their ASCVD risk-based LDL-C goal.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Relevance<\/jats:title>\n                    <jats:p>\n                      These findings suggest that lerodalcibep was associated with significantly and consistently reduced LDL-C in patients with HeFH, with response found to be independent of\n                      <jats:italic>LDLR<\/jats:italic>\n                      function of the pathogenic variant. These findings support that LDL-C reductions in patients with HeFH with PCSK9 inhibition are predominantly mediated by upregulation of the unaffected wild-type\n                      <jats:italic>LDLR<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial Registration<\/jats:title>\n                    <jats:p>\n                      ClinicalTrials.gov Identifier:\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT04798430\">NCT04798430<\/jats:ext-link>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1001\/jamacardio.2026.0879","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T15:30:53Z","timestamp":1777476653000},"page":"593","source":"Crossref","is-referenced-by-count":1,"title":["Response to PCSK9 Inhibition Based on LDL Receptor Function in Familial Hypercholesterolemia"],"prefix":"10.1001","volume":"11","author":[{"given":"Frederick J.","family":"Raal","sequence":"first","affiliation":[{"name":"Carbohydrate and Lipid Metabolism Research Unit, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nyda","family":"Fourie","sequence":"additional","affiliation":[{"name":"Iatros International, Bloemfontein, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell","family":"Scott","sequence":"additional","affiliation":[{"name":"New Zealand Clinical Research, Christchurch, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk J.","family":"Blom","sequence":"additional","affiliation":[{"name":"Division of Lipidology, Department of Medicine, University of Cape Town, Cape Town, South Africa"},{"name":"Cape Heart Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthys M. 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