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This study aimed to investigate safety, tolerability, antibody development, and reduction of low-density lipoprotein cholesterol (LDLc) following four subcutaneous immunizations.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>This phase I, single-blind, randomized, placebo-controlled study was conducted in a total of 72 healthy subjects with a mean fasting LDLc level at baseline of 117.1\u00a0mg\/dL (range 77\u2013196\u00a0mg\/dL). Each cohort enrolled 24 subjects to receive three priming immunizations at weeks 0, 4, and 8 and to receive a single booster immunization at week 60 of either AT04A, AT06A, or placebo. In addition to safety (primary objective), the antigenic peptide- and PCSK9-specific antibody response and the impact on LDLc were evaluated over a period of 90\u00a0weeks.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>The most common systemic treatment-related adverse events (AEs) reported were fatigue, headache, and myalgia in 75% of subjects in the AT06A group and 58% and 46% of subjects in the placebo and AT04A groups, respectively. Injection site reactions (ISR) representing 63% of all treatment-emergent adverse events (TEAEs), were transient and mostly of mild or moderate intensity and rarely severe (3%). Both active treatments triggered a robust, long-lasting antibody response towards the antigenic peptides used for immunization that optimally cross-reacted with the target epitope on PCSK9. In the AT04A group, a reduction in serum LDLc was observed with a mean peak reduction of 11.2% and 13.3% from baseline compared to placebo at week 20 and 70 respectively, and over the whole study period, the mean LDLc reduction for the AT04A group vs. placebo was \u22127.2% (95% CI [\u221210.4 to \u22123.9], <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.0001). In this group, PCSK9 target epitope titers above 50 were associated with clinically relevant LDLc reductions with an individual maximal decrease of 39%.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Although both AT04A and AT06 were safe and immunogenic, only AT04A demonstrated significant LDLc-lowering activity, justifying further development.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registration<\/jats:title>\n                <jats:p>EudraCT: 2015-001719-11. ClinicalTrials.gov\nIdentifier: NCT02508896.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00228-021-03149-2","type":"journal-article","created":{"date-parts":[[2021,5,10]],"date-time":"2021-05-10T01:02:19Z","timestamp":1620608539000},"page":"1473-1484","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["A phase I study assessing the safety, tolerability, immunogenicity, and low-density lipoprotein cholesterol-lowering activity of immunotherapeutics targeting PCSK9"],"prefix":"10.1007","volume":"77","author":[{"given":"Markus","family":"Zeitlinger","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Bauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"Reindl-Schwaighofer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert M.","family":"Stoekenbroek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilles","family":"Lambert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelyn","family":"Berger-Sieczkowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heimo","family":"Lagler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoe","family":"Oesterreicher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrix","family":"Wulkersdorfer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"L\u00fchrs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gergana","family":"Galabova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"Schwenke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert M.","family":"Mader","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossella","family":"Medori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Landlinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Kutzelnigg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0025-5081","authenticated-orcid":false,"given":"G\u00fcnther","family":"Staffler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,10]]},"reference":[{"key":"3149_CR1","unstructured":"Organization WH (2018) Fact sheets cardiovascular diseases"},{"key":"3149_CR2","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1016\/j.jcmg.2016.04.013","volume":"10","author":"S Shin","year":"2017","unstructured":"Shin S, Park HB, Chang HJ, Arsanjani R, Min JK, Kim YJ, Lee BK, Choi JH, Hong GR, Chung N (2017) Impact of intensive LDL cholesterol lowering on coronary artery atherosclerosis progression: a serial CT angiography study. 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The study protocol was approved by the ethics committee of the Medical University of Vienna, Austria (EudraCT: 2015-001719-11; Clinical-Trial-Identifier: NCT02508896) and the Austrian competent authority. The study was performed in accordance with Good Clinical Practice and the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Informed consent was obtained from all individual participants included in the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}},{"value":"All authors have completed and submitted the \u201cICMJE Form for Disclosure of Potential Conflicts of Interest.\u201d Conflicts of interests have been declared by the following authors: PL, CL, GS AK and GG are or were employees of AFFiRiS AG at the time of the study. RM, CS, and RMM receive honoraria from AFFiRiS AG. RMS is an employee and shareholder of The Medicines Company and Novartis AG, after completion of the study. GL received research funding from AFFiRiS AG. The Medical University of Vienna received financial support for conducting the study. No direct honoraria were obtained by MZ, MB, RRS, EBS, HL, ZO, and BW.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}