{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T18:40:15Z","timestamp":1791830415387,"version":"4.3.4"},"reference-count":33,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T00:00:00Z","timestamp":1738108800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Pharm in Drug Dev"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Rusfertide, a peptide hepcidin mimetic, has shown efficacy in polycythemia vera. This trial investigated the multiple\u2010dose pharmacokinetics, pharmacodynamics, and safety of once\u2010weekly rusfertide 60\u00a0mg for 5 weeks in healthy subjects. Subjects were randomized to subcutaneous injection in the abdomen, upper arm, or thigh. Eighteen subjects were enrolled, and 15 completed the study. Geometric mean peak rusfertide plasma concentrations (C<jats:sub>max<\/jats:sub>) following the first dose were 547, 387, and 560\u00a0ng\/mL following injection in the abdomen, thigh, and arm, respectively (<jats:italic>P<\/jats:italic>\u00a0=\u00a0.0054). There was no difference between injection sites in the rusfertide area under the plasma concentration\u2010time curve (AUC) following the first dose (<jats:italic>P<\/jats:italic> \u2265\u00a0.179) or in the C<jats:sub>max<\/jats:sub> or AUC during the dosing interval following the last dose (<jats:italic>P<\/jats:italic>\u00a0\u2265\u00a0.238). Geometric mean accumulation (Dose 5\/Dose 1) for AUC and C<jats:sub>max<\/jats:sub> was 1.5 and 1.2, respectively, and similar across injection sites. Mechanism\u2010based decreases in serum iron, transferrin\u2010iron saturation, hemoglobin, and hematocrit were noted following multiple doses. There were no differences between injection sites in the pharmacodynamic effect as measured by change from baseline in hematocrit values. There were no serious adverse events. Treatment\u2010emergent adverse events in 2 or more subjects were injection\u2010site reactions (erythema, induration, pruritus), fatigue, and headache. There were no clinically relevant findings in the safety laboratory parameters, vital signs, electrocardiograms, or physical examination. While a higher incidence of treatment\u2010emergent adverse events was noted in these healthy participants following multiple doses of 60\u00a0mg, rusfertide was generally well tolerated. There were no clinically meaningful differences in rusfertide pharmacokinetics or pharmacodynamics between injection sites.<\/jats:p>","DOI":"10.1002\/cpdd.1514","type":"journal-article","created":{"date-parts":[[2025,1,30]],"date-time":"2025-01-30T07:52:38Z","timestamp":1738223558000},"page":"311-323","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Multiple\u2010Dose Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Subcutaneous Rusfertide, a Hepcidin Mimetic, in Healthy Subjects"],"prefix":"10.1002","volume":"14","author":[{"given":"Nishit B.","family":"Modi","sequence":"first","affiliation":[{"name":"Protagonist Therapeutics, Inc.  Newark CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip","family":"Dinh","sequence":"additional","affiliation":[{"name":"Protagonist Therapeutics, Inc.  Newark CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ifode","family":"Ajari","sequence":"additional","affiliation":[{"name":"Protagonist Therapeutics, Inc.  Newark CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,1,29]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2006-939430"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.3109\/10428194.2013.813500"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.23690"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/ejh.12256"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03546"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa051113"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2005.03.023"},{"key":"e_1_2_9_9_1","first-page":"31","article-title":"Risk factors for disease progression and treatment goals in polycythemia vera","volume":"22","author":"Waksal JA","year":"2024","journal-title":"Clin Adv Hematol Oncol"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.27002"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2017.01.032"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-018-0207-9"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M008922200"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.3945\/an.116.013961"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-043021-032816"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2013.084624"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-010-9222-0"},{"key":"e_1_2_9_18_1","first-page":"E223","article-title":"Hepcidin mimetic PTG\u2010300 for treatment of ineffective erythropoiesis and iron overload","volume":"92","author":"Bourne G","year":"2017","journal-title":"Am J Hematol"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2308809"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2021-149205"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(23)00250-9"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2021.06.038"},{"key":"e_1_2_9_23_1","first-page":"461","article-title":"Subcutaneous administration of biotherapeutics: current experience in animal models","volume":"12","author":"McDonald TA,","year":"2010","journal-title":"Curr Opin Mol Ther"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-012-9367-0"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.114.059238"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/ejh.14243"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40268-024-00497-z"},{"issue":"3","key":"e_1_2_9_28_1","first-page":"2007","article-title":"Pharmacokinetic and pharmacodynamic effects of rusfertide in polycythemia vera: results from an ongoing phase 2 study in patients with elevated hematocrit values","volume":"7","author":"Kremyanskaya M","year":"2023","journal-title":"HemaSphere"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/dth.12817"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1177\/12034754231188444"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12961"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.2337\/ds20-0033"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/dom.14718"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.2165\/00128071-200304100-00001"}],"container-title":["Clinical Pharmacology in Drug Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpdd.1514","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T21:51:44Z","timestamp":1744062704000},"score":1,"resource":{"primary":{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/10.1002\/cpdd.1514"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,29]]},"references-count":33,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,4]]}},"alternative-id":["10.1002\/cpdd.1514"],"URL":"https:\/\/doi.org\/10.1002\/cpdd.1514","archive":["Portico"],"relation":{},"ISSN":["2160-763X","2160-7648"],"issn-type":[{"value":"2160-763X","type":"print"},{"value":"2160-7648","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,29]]},"assertion":[{"value":"2024-10-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}