{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T16:29:10Z","timestamp":1792427350140,"version":"4.5.0"},"reference-count":34,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"25","license":[{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2026,6,23]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Inhibition of proprotein convertase subtilisin\/kexin type 9 (PCSK9) is an effective therapy for reducing low-density lipoprotein (LDL) cholesterol (LDL-C) in adults with hyperlipidemia, including heterozygous familial hypercholesterolemia, thereby lowering cardiovascular risk. Current PCSK9 inhibitors are injectable therapies; no oral small-molecule PCSK9 inhibitor has yet been approved.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      Laroprovstat (AZD0780) is a novel small-molecule identified through structure-based design that binds to the PCSK9 C-terminal domain. The effects of laroprovstat on LDL receptor expression and LDL-C levels were assessed in vitro and in mice expressing human\n                      <jats:italic toggle=\"yes\">PCSK9<\/jats:italic>\n                      . Safety, tolerability, and pharmacokinetic and pharmacodynamic properties of laroprovstat were assessed in healthy participants with LDL-C \u226570 and \u2264190 mg\/dL after single ascending doses. Laroprovstat was also assessed in participants with LDL-C \u2265100 and \u2264190 mg\/dL at doses of 1 mg or 30 mg versus placebo administered once daily for 28 days after a rosuvastatin 20 mg run-in treatment period.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Laroprovstat does not inhibit the PCSK9\u2013LDL receptor interaction but stabilizes the PCSK9 C-terminal domain, preventing lysosomal trafficking and degradation of LDL receptor. Laroprovstat increased LDL receptor expression and reduced LDL-C levels in mice expressing human\n                      <jats:italic toggle=\"yes\">PCSK9<\/jats:italic>\n                      . Laroprovstat displayed dose-proportional pharmacokinetics and a half-life suitable for once-daily dosing (\u224840 hours). There was no clinically meaningful change in exposure when dosed with a high-fat meal compared with the fasted state (area under the plasma concentration-time curve\n                      <jats:sub>inf<\/jats:sub>\n                      and C\n                      <jats:sub>max<\/jats:sub>\n                      geometric mean reduction of 1.15 [90% CI, 1.11\u20131.19] and 1.06 [90% CI, 1.00\u20131.13], respectively). After a rosuvastatin 20 mg 3-week run-in treatment period, laroprovstat 1 and 30 mg reduced LDL-C by 29% (95% CI, 18%\u201338%) and 51% (95% CI, 44%\u201358%) compared with baseline. Combined rosuvastatin and laroprovstat treatment resulted in a total approximate reduction in LDL-C of 70% and 80% for laroprovstat 1 and 30 mg, respectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Laroprovstat was well tolerated with no safety findings of concern and may be dosed with or without food. In treatment-na\u00efve participants with hypercholesterolemia, combined rosuvastatin 20 mg and laroprovstat 30 mg treatment led to an 80% LDL-C reduction, supporting further development of laroprovstat as the first oral small-molecule PCSK9 inhibitor in patients with hypercholesterolemia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>REGISTRATION:<\/jats:title>\n                    <jats:p>\n                      URL:\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.gov\">https:\/\/www.clinicaltrials.gov<\/jats:ext-link>\n                      ; Unique identifier: NCT05384262.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.125.075973","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T09:00:15Z","timestamp":1778835615000},"page":"1999-2010","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["Laroprovstat, the First Oral Small-Molecule PCSK9 Inhibitor for the Treatment of Hypercholesterolemia: Results From a Randomized, Single-Blind, Placebo-Controlled Phase 1 Trial in Treatment-Na\u00efve Patients"],"prefix":"10.1161","volume":"153","clinical-trial-number":[{"clinical-trial-number":"nct05384262","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Rick B.","family":"Vega","sequence":"first","affiliation":[{"name":"Translational Science and Clinical Development, Cardiovascular, Renal and Metabolism (R.B.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5944-1271","authenticated-orcid":true,"given":"Gavin","family":"O\u2019Mahony","sequence":"additional","affiliation":[{"name":"Biopharma Chemistry, Discovery Sciences (G.O.), BioPharmaceuticals R&amp;D, AstraZeneca, Gothenburg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"April M.","family":"Barbour","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology &amp; 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