{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T06:32:48Z","timestamp":1792132368178,"version":"4.4.0"},"reference-count":27,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2024,1,30]],"date-time":"2024-01-30T00:00:00Z","timestamp":1706572800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2024,1,30]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>Homozygous familial hypercholesterolemia is a genetic disease characterized by extremely high levels of low-density lipoprotein cholesterol (LDL-C) and a high risk of premature cardiovascular events. The proof-of-concept study ORION-2 (A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia) showed that inclisiran, a small interfering RNA that prevents production of the hepatic PCSK9 protein (proprotein convertase subtilisin\/kexin type 9), could lead to durable reductions in LDL-C levels when added to statins and ezetimibe in patients with homozygous familial hypercholesterolemia.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>ORION-5 was a phase 3, 2-part, multicenter study in 56 patients with homozygous familial hypercholesterolemia and elevated LDL-C levels despite maximum tolerated doses of LDL-C\u2013lowering therapies with or without lipoprotein apheresis. Patients eligible for part 1 (double-blind, 6 months) were randomized 2:1 to receive either 300 mg of inclisiran sodium (equivalent to 284 mg of inclisiran) or placebo. Placebo-treated patients from part 1 were transitioned to inclisiran in part 2 (open-label, 18 months). The primary end point was the percentage change in LDL-C levels from baseline to day 150.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              The mean age of the patients was 42.7 years, and 60.7% were women. The mean baseline LDL-C levels were 294.0 mg\/dL and 356.7 mg\/dL in the inclisiran and placebo groups, respectively. The placebo-corrected percentage change in LDL-C level from baseline to day 150 was \u22121.68% (95% CI, \u221229.19% to 25.83%;\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =0.90), and the difference was not statistically significant between the inclisiran and placebo groups. The placebo-corrected percentage change in PCSK9 levels from baseline to day 150 was \u221260.6% with inclisiran treatment (\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              &lt;0.0001); this was sustained throughout the study, confirming the effect of inclisiran on its biological target of PCSK9. No statistically significant differences between the inclisiran and placebo groups were observed in the levels of other lipids and lipoproteins (apolipoprotein B, total cholesterol, and non\u2212high-density lipoprotein cholesterol). Adverse events and serious adverse events did not differ between the inclisiran and placebo groups throughout the study.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>Inclisiran treatment did not reduce LDL-C levels in patients with homozygous familial hypercholesterolemia despite substantial lowering of PCSK9 levels. Inclisiran was well-tolerated, and the safety findings were consistent with previously reported studies and the overall safety profile.<\/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: NCT03851705.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.122.063460","type":"journal-article","created":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T09:00:16Z","timestamp":1697619616000},"page":"354-362","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":91,"title":["Efficacy, Safety, and Tolerability of Inclisiran in Patients With Homozygous Familial Hypercholesterolemia: Results From the ORION-5 Randomized Clinical Trial"],"prefix":"10.1161","volume":"149","clinical-trial-number":[{"clinical-trial-number":"nct03851705","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9170-7938","authenticated-orcid":true,"given":"Frederick","family":"Raal","sequence":"first","affiliation":[{"name":"Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa (F.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3559-1050","authenticated-orcid":true,"given":"Ronen","family":"Durst","sequence":"additional","affiliation":[{"name":"Cardiology Department, Hadassah-Hebrew University Medical Centre, Jerusalem, Israel (R.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7977-1427","authenticated-orcid":true,"given":"Ran","family":"Bi","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation, East Hannover, NJ (R.B., Z.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsolt","family":"Talloczy","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation, East Hannover, NJ (R.B., Z.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Maheux","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation, Basel, Switzerland (P.M., A.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Lesogor","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation, Basel, Switzerland (P.M., A.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2018-4532","authenticated-orcid":true,"given":"John J.P.","family":"Kastelein","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Netherlands (J.J.P.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"on behalf of the ORION-5 Study Investigators","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","unstructured":"Family Heart Foundation. Homozygous FH. Accessed June 15 2023. https:\/\/familyheart.org\/familial-hypercholesterolemia\/homozygous-familial-hypercholesterolemia"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1097\/MOL.0000000000000677"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehu274"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2017.04.002"},{"key":"e_1_3_3_6_2","unstructured":"Warden BA Fazio S Shapiro MD Feingold KR Anawalt B Boyce A Chrousos G de Herder WW Dhatariya K Dungan K et al. Familial hypercholesterolemia: genes and beyond [posted online October 23 2021]. 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