{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T05:45:33Z","timestamp":1793339133742,"version":"4.5.0"},"reference-count":25,"publisher":"American Medical Association (AMA)","issue":"18","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA"],"published-print":{"date-parts":[[2024,5,14]]},"abstract":"<jats:sec><jats:title>Importance<\/jats:title><jats:p>Lipoprotein(a) is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic stenosis, with no pharmacological treatments approved by regulatory authorities.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>To assess the safety and tolerability of zerlasiran, a short interfering RNA targeting hepatic synthesis of apolipoprotein(a), and effects on serum concentrations of lipoprotein(a).<\/jats:p><\/jats:sec><jats:sec><jats:title>Design, Setting, and Participants<\/jats:title><jats:p>Single- and multiple-dose study in healthy participants and patients with stable ASCVD, respectively, with lipoprotein(a) serum concentrations greater than 150 nmol\/L, conducted at 7 research sites in the US, the Netherlands, UK, and Australia between November 18, 2020, and February 8, 2023, with last follow-up on August 23, 2023.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interventions<\/jats:title><jats:p>Participants were randomized to receive (1) a single subcutaneous dose of placebo (n\u2009=\u20098), zerlasiran 300 mg (n\u2009=\u20096) or 600 mg (n\u2009=\u20096); or (2) 2 doses of placebo (n\u2009=\u20099), zerlasiran 200 mg (n\u2009=\u20099) at a 4-week interval or 300 mg (n\u2009=\u20099) or 450 mg (n\u2009=\u20099) at an 8-week interval.<\/jats:p><\/jats:sec><jats:sec><jats:title>Main Outcomes Measures<\/jats:title><jats:p>The primary outcome was safety and tolerability. Secondary outcomes included serum levels of zerlasiran and effects on lipoprotein(a) serum concentrations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Among 37 patients in the multiple-dose group (mean age, 56 [SD, 10.4] years; 15 [42%] women), 36 completed the trial. Among 14 participants with extended follow-up after single doses, 13 completed the trial. There were no serious adverse events. Median baseline lipoprotein(a) concentrations in the multiple-dose group were 288 (IQR, 199-352) nmol\/L. Median changes in lipoprotein(a) concentration at 365 days after single doses were 14% (IQR, 13% to 15%) for the placebo group, \u221230% (IQR, \u221251% to \u221218%) for the 300 mg of zerlasiran group, and \u221229% (IQR, \u221239% to \u22127%) for the 600-mg dose group. After 2 doses, maximal median changes in lipoprotein(a) concentration were 19 (IQR, \u221217 to 28) nmol\/L for the placebo group, \u2212258 (IQR, \u2212289 to \u2212188) nmol\/L for the 200 mg of zerlasiran group, \u2212310 (IQR, \u2212368 to \u2212274) nmol\/L for the 300-mg dose group, and \u2212242 (IQR, \u2212343 to \u2212182) nmol\/L for the 450-mg dose group, with maximal median percent change of 7% (IQR, \u22124% to 21%), \u221297% (IQR, \u221298% to \u221295%), \u221298% (IQR, \u221299% to \u221297%), and \u221299% (IQR, \u221299% to \u221298%), respectively, attenuating to 0.3% (IQR, \u22122% to 21%), \u221260% (IQR, \u221271% to \u221240%), \u221290% (IQR, \u221291% to \u221274%), and \u221289% (IQR, \u221291% to \u221276%) 201 days after administration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Zerlasiran was well tolerated and reduced lipoprotein(a) concentrations with infrequent administration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial Registration<\/jats:title><jats:p>ClinicalTrials.gov Identifier: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT04606602\">NCT04606602<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1001\/jama.2024.4504","type":"journal-article","created":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T15:01:06Z","timestamp":1712588466000},"page":"1534","source":"Crossref","is-referenced-by-count":94,"title":["Single Ascending and Multiple-Dose Trial of Zerlasiran, a Short Interfering RNA Targeting Lipoprotein(a)"],"prefix":"10.1001","volume":"331","author":[{"given":"Steven E.","family":"Nissen","sequence":"first","affiliation":[{"name":"Cleveland Clinic Center for Clinical Research, Cleveland, 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