{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T04:17:50Z","timestamp":1792642670671,"version":"4.5.0"},"reference-count":46,"publisher":"American Society for Microbiology","issue":"12","license":[{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100007013","name":"F. Hoffmann-La Roche","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007013","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2025,12,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Poly(A) RNA polymerases D5 and D7 (PAPD5, PAPD7) are host factors that stabilize hepatitis B virus (HBV) RNA transcripts. RO7239958, a liver-targeted locked nucleic acid (LNA) antisense oligonucleotide (ASO), induces intracellular degradation of PAPD5- and PAPD7-encoding messenger RNAs (mRNAs). This first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of RO7239958 in healthy volunteers and adults with chronic hepatitis B (CHB) receiving standard-of-care antiviral therapy. Forty healthy volunteers were randomized (4:1) to single ascending subcutaneous doses of RO7239958 (0.1, 0.3, 1.0, or 1.5 mg\/kg) or placebo. Based on a population PK model built to predict liver exposure, two parallel CHB cohorts (\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      = 8 and\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      = 7 per cohort) were randomized to two 4-weekly doses of RO7239958 (0.2 or 0.4 mg\/kg) or placebo. RO7239958 plasma exposure increased more than dose-proportionally at dose levels of 1.0 and 1.5 mg\/kg, suggesting saturation of liver uptake. RO7239958 was generally well tolerated in healthy volunteers; transaminase elevations occurred at the highest doses, including one reversible Grade 3 elevation. The PK model indicated that doses of 0.2 and 0.4 mg\/kg would reduce PAPD5 and PAPD7 mRNA by 50% and 62%, respectively, with minimal liver toxicity. Consistent with predictions, RO7239958 was well-tolerated and safe in patients. At 0.4 mg\/kg, the maximum reduction from baseline in serum hepatitis B surface antigen was observed on Day 43 (mean decline 0.2 log\n                      <jats:sub>10<\/jats:sub>\n                      IU\/mL; range 0.0\u20130.5 log\n                      <jats:sub>10<\/jats:sub>\n                      IU\/mL). While RO7239958 showed a potentially narrow therapeutic window, PAPD5 and PAPD7 remain potential therapeutic targets in HBV curative strategies.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>CLINICAL TRIALS<\/jats:title>\n                      <jats:p>\n                        This study was registered at\n                        <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT03762681\" xlink:type=\"simple\">NCT03762681<\/jats:ext-link>\n                        .\n                      <\/jats:p>\n                    <\/jats:sec>\n                  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