{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T15:32:47Z","timestamp":1788535967697,"version":"build-2803163510"},"reference-count":31,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T00:00:00Z","timestamp":1779667200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T00:00:00Z","timestamp":1779667200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:p>\n                    Bemnifosbuvir (BEM) is a potent, pan\u2010genotypic inhibitor targeting the hepatitis C virus (HCV) NS5B polymerase. Its antiviral activity was evaluated in an ascending dose phase I clinical trial involving 30 patients treated once a day for 7\u2009days. After treatment initiation, plasma HCV RNA declined in a biphasic manner with a mean reduction of 2.3 log\n                    <jats:sub>10<\/jats:sub>\n                    IU\/mL after 24\u2009hours and 4.4 log\n                    <jats:sub>10<\/jats:sub>\n                    IU\/mL by day 7 for the highest dose. Alanine aminotransferase (ALT) also normalized in most patients. We employed a multiscale mathematical model fitted to the HCV RNA and ALT dynamics to quantify the antiviral activity and evaluate the modes of action of BEM. We found that models in which BEM only acted as a typical HCV RNA polymerase inhibitor and reduced the intracellular production of HCV RNA did not fit the data as well as models in which BEM had multiple modes of action, including suppressing viral assembly and secretion and enhancing intracellular HCV RNA degradation. BEM's effectiveness in inhibiting intracellular HCV RNA production increased with dose (150\u2009mg\/day: 88.2%, 300\u2009mg\/day: 98.8%, 600\u2009mg\/day: 99.5%), while inhibition of viral assembly and release was ~95% effective regardless of dose. We observed a dose\u2010dependent enhancement in the degradation of intracellular HCV RNA, with degradation rates 1.5\u2010fold higher in patients receiving 300\u2009mg\/day and 2.7\u2010fold higher in those receiving 600\u2009mg\/day than in patients receiving 150\u2009mg\/day. No significant differences in antiviral activity were detected between HCV genotypes 1b and 3 or between patients with and without compensated cirrhosis.\n                  <\/jats:p>","DOI":"10.1002\/cpt.70342","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T12:09:42Z","timestamp":1779710982000},"page":"552-562","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Bemnifosbuvir: An\n                    <scp>HCV NS5B<\/scp>\n                    Inhibitor With Multiple Modes of Action"],"prefix":"10.1002","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5188-0042","authenticated-orcid":false,"given":"Carolin","family":"Zitzmann","sequence":"first","affiliation":[{"name":"Theoretical Biology and Biophysics Los Alamos National Laboratory  Los Alamos New Mexico USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3988-8241","authenticated-orcid":false,"given":"Ruy M.","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Theoretical Biology and Biophysics Los Alamos National Laboratory  Los Alamos New Mexico USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6936-5388","authenticated-orcid":false,"given":"Aur\u00e9lien","family":"Marc","sequence":"additional","affiliation":[{"name":"Theoretical Biology and Biophysics Los Alamos National Laboratory  Los Alamos New Mexico USA"},{"name":"CEA, INSERM, UMR1184 Immunology of Viral, Auto\u2010Immune, Hematological and Bacterial Diseases (IMVA\u2010HB\/IDMIT Department)  Fontenay\u2010aux\u2010Roses\/Le Kremlin\u2010Bic\u00eatre France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7662-1616","authenticated-orcid":false,"given":"Xiao\u2010Jian","family":"Zhou","sequence":"additional","affiliation":[{"name":"Atea Pharmaceuticals, Inc.  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2455-0002","authenticated-orcid":false,"given":"Alan S.","family":"Perelson","sequence":"additional","affiliation":[{"name":"Theoretical Biology and Biophysics Los Alamos National Laboratory  Los Alamos New Mexico USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,25]]},"reference":[{"key":"e_1_2_10_1_1","unstructured":"World Health Organization.Hepatitis C<https:\/\/www.who.int\/news\u2010room\/fact\u2010sheets\/detail\/hepatitis\u2010c>."},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/v17020163"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2022.114595"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2016.60"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s15010-018-1188-3"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2021.03.004"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jfma.2020.08.010"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-016-0685-x"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/phar.1933"},{"key":"e_1_2_10_10_1","unstructured":"World Health Organization.Accelerating access to hepatitis C diagnostics and treatment: overcoming barriers in low\u2010 and middle\u2010income countries. Global progress report 2020(2021)."},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciae431"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(25)00068-8"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1080\/13543784.2024.2305137"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01201-19"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0227104"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1203110110"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mbs.2013.04.012"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1002959"},{"key":"e_1_2_10_19_1","doi-asserted-by":"crossref","unstructured":"Perelson A.S. Neumann A.U. Markowitz M. Leonard J.M.&Ho D.D.HIV\u20101 dynamics in\u00a0vivo: Virion clearance rate infected cell life\u2010span and viral generation time. Science.271 1582\u20131586(1996).","DOI":"10.1126\/science.271.5255.1582"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/jvh.13229"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(16)30015-2"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1177\/0049124104268644"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(24)02257-8"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(25)02179-8"},{"issue":"1","key":"e_1_2_10_25_1","first-page":"S85","article-title":"Abst. 0089 multiscale modeling of results from a phase 2 study of an 8\u2010week combination regimen of Bemnifosbuvir and ruzasvir in patients with chronic hepatitis C virus infection. The liver meeting: 2025 abstracts","volume":"82","author":"Zitzmann C.","year":"2025","journal-title":"Hepatology"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2160"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofac157"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2020.104862"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.282.5386.103"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-014-9363-3"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2015.97"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70342","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.70342","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70342","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T03:15:33Z","timestamp":1783912533000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.70342"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,25]]},"references-count":31,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1002\/cpt.70342"],"URL":"https:\/\/doi.org\/10.1002\/cpt.70342","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,25]]},"assertion":[{"value":"2026-02-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}