{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T16:54:10Z","timestamp":1790441650534,"version":"4.1.0"},"reference-count":24,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2022,8,16]],"date-time":"2022-08-16T00:00:00Z","timestamp":1660608000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Pharm in Drug Dev"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Dose\u2010dependent reductions in hepatitis B virus (HBV) RNA, DNA, and viral proteins following bepirovirsen administration were observed in HepG2.2.15 cells. In HBV\u2010transgenic mice treated at 50 mg\/kg\/wk, hepatic HBV RNA and DNA were reduced by 90% and 99%, respectively. Subsequently, a phase 1 first\u2010in\u2010human study assessed pharmacokinetics and tolerability of single (75\u2013450 mg) and multiple (150\u2013450 mg on days 1, 4, 8, 11, 15, and 22) subcutaneous bepirovirsen doses in 96 healthy volunteers. Bepirovirsen at all dose levels was rapidly absorbed (maximum plasma concentration 3\u20138 hours after dosing), rapidly distributed to peripheral tissues, and slowly eliminated (median plasma terminal half\u2010life: 22.5\u201324.6 days across cohorts). Plasma exposure (dose\u2010proportional at 150\u2013450 mg) and concentration\u2010time profiles were similar following the first and sixth doses, suggesting little to no plasma accumulation (steady state achieved by day 22). Renal elimination of full\u2010length bepirovirsen accounted for &lt;2% of the total dose. Across the single and multiple dose cohorts, 197 treatment\u2010emergent adverse events were reported, with 99% and 65% classified as mild in severity and local injection site reactions, respectively. In conclusion, bepirovirsen showed an acceptable safety profile in humans with observed pharmacokinetics consistent with the chemical class, warranting further evaluation of bepirovirsen in chronic HBV infection.<\/jats:p>","DOI":"10.1002\/cpdd.1154","type":"journal-article","created":{"date-parts":[[2022,8,16]],"date-time":"2022-08-16T10:33:28Z","timestamp":1660646008000},"page":"1191-1202","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Preclinical and Phase 1 Assessment of Antisense Oligonucleotide Bepirovirsen in Hepatitis B Virus\u2013Transgenic Mice and Healthy Human Volunteers: Support for Clinical Dose Selection and Evaluation of Safety, Tolerability, and Pharmacokinetics of Single and Multiple Doses"],"prefix":"10.1002","volume":"11","author":[{"given":"Kelong","family":"Han","sequence":"first","affiliation":[{"name":"GSK  Collegeville Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dickens","family":"Theodore","sequence":"additional","affiliation":[{"name":"GSK  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gina","family":"McMullen","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals Inc.  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