{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T18:14:18Z","timestamp":1793297658106,"version":"4.5.0"},"reference-count":24,"publisher":"American Medical Association (AMA)","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Cardiol"],"published-print":{"date-parts":[[2024,9,1]]},"abstract":"Importance<\/jats:title>Recent changes in national and international lipid guidelines for reducing cardiovascular events recommend additional drugs, greater reductions, and lower targets for low-density lipoprotein cholesterol (LDL-C) if not attained with statins. The achievement of these targets with proprotein convertase subtilisin\/kexin type 9 (PCSK9) inhibitors has not yet been evaluated in a randomized clinical trial.<\/jats:p><\/jats:sec>Objective<\/jats:title>To evaluate the 52-week safety and efficacy of lerodalcibep, a small anti\u2013PCSK9-binding protein, in patients with cardiovascular disease (CVD) or who are at very high or high risk of CVD and requiring addition LDL-C\u2013lowering treatment.<\/jats:p><\/jats:sec>Design, Setting, and Participants<\/jats:title>This was a randomized, double-blind, placebo-controlled phase 3 trial. The trial was conducted at 66 clinics in 11 countries between April 23, 2021, and November 15, 2023. Individuals 18 years and older taking maximally tolerated statin therapy with LDL-C of 70 mg\/dL or greater with CVD or 100 mg\/dL or greater if at high risk of CVD were included.<\/jats:p><\/jats:sec>Interventions<\/jats:title>Patients were randomized 2:1 to monthly 1.2-mL subcutaneous lerodalcibep, 300 mg, or placebo for 52 weeks.<\/jats:p><\/jats:sec>Main Outcomes and Measures<\/jats:title>The safety analysis included all randomized patients. The co-primary efficacy end points were percent change from baseline in LDL-C at week 52 and the mean of weeks 50 and 52. Secondary efficacy outcomes included additional lipid apolipoprotein measures and achievement of guideline-recommended LDL-C targets.<\/jats:p><\/jats:sec>Results<\/jats:title>Of 922 randomized participants (mean [range] age, 64.5 [27-87] years; 414 [44.9%] female; mean [SD] baseline LDL-C, 116.2 [43.5] mg\/dL), 811 (88%) completed the trial. The mean (SE) placebo-adjusted reduction in LDL-C with lerodalcibep by modified intention-to-treat (mITT) analysis was 56.2% (2.2%) at week 52 and 62.7% (1.9%) for the mean of weeks 50 and 52; 49.7% (2.4%) and 55.3% (2.2%) by ITT with imputation using a washout model, and 60.3% (2.3%) and 65.9% (1.9%) by per-protocol analysis at week 52 and the mean of weeks 50 and 52, respectively (P<\/jats:italic>\u2009&amp;lt;\u2009.001 for all). With lerodalcibep, 555 of 615 participants (90%) achieved both a reduction in LDL-C of 50% or greater and recommended LDL-C targets during the study. Treatment-emergent adverse events were similar between lerodalcibep and placebo, except for injection site reactions. These occurred in 42 of 613 participants receiving lerodalcibep (6.9%) compared to 1 of 307 receiving placebo (0.3%), were graded mild or moderate, and did not result in higher discontinuation of treatment, at 26 of 613 (4.2%) and 14 of 307 (4.6%), respectively. Sporadic in vitro antidrug antibodies were detected, which had no impact on free PCSK9 or LDL-C\u2013lowering efficacy.<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>In this trial, lerodalcibep, a novel anti-PCSK9 small binding protein, dosed monthly and stable at ambient temperatures significantly reduced LDL-C in patients with CVD or at high risk of atherosclerotic cardiovascular disease with a safety profile similar to placebo. These results support long-term use of lerodalcibep in patients with CVD or at high risk of CVD who are unable to achieve adequate LDL-C reduction while receiving maximal tolerated statins alone.<\/jats:p><\/jats:sec>Trial Registration<\/jats:title>ClinicalTrials.gov Identifier: NCT04806893<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1001\/jamacardio.2024.1659","type":"journal-article","created":{"date-parts":[[2024,7,3]],"date-time":"2024-07-03T15:10:00Z","timestamp":1720019400000},"page":"800","source":"Crossref","is-referenced-by-count":62,"title":["Efficacy and Safety of Lerodalcibep in Patients With or at High Risk of Cardiovascular Disease"],"prefix":"10.1001","volume":"9","author":[{"given":"Eric Q.","family":"Klug","sequence":"first","affiliation":[{"name":"Tickerdoc Research, Netcare Sunninghill Hospital, Sandton, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Llerena","sequence":"additional","affiliation":[{"name":"Columbus 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