{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T03:32:42Z","timestamp":1791948762439,"version":"4.3.4"},"reference-count":33,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Haemophilia"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Emicizumab has revolutionized hemophilia A care, yet limitations regarding the \u201cceiling\u201d of hemostatic efficacy (equivalent to mild hemophilia) and global access persist. This review critically examines two distinct paradigms shaping the future of care: Innovation and Access. Regarding innovation, we synthesize the latest clinical data on next\u2010generation FVIIIa mimetics. Mim8 (denecimig) demonstrated superiority over prior prophylaxis in the FRONTIER 2 phase 3 study, offering flexible weekly to monthly dosing options. NXT007, engineered with FAST\u2010Ig technology to incorporate dual light chains, has shown potential to achieve non\u2010hemophilic coagulation ranges in recent Phase 1\/2 studies. Regarding access, we evaluate low\u2010dose emicizumab regimens as a strategy for resource\u2010constrained settings. While acknowledging their potential to reduce treated bleeds, we provide a critical appraisal of their limitations, particularly regarding the lack of sensitive joint health monitoring and the risk of subclinical breakthrough bleeding. This review provides a comprehensive roadmap for advancing the standard of care while addressing global equity.<\/jats:p>","DOI":"10.1111\/hae.70231","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T11:05:26Z","timestamp":1776337526000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["FVIIIa Mimetics: New Approaches and Next\u2010Generation Initiatives"],"prefix":"10.1111","author":[{"given":"Tadashi","family":"Matsushita","sequence":"first","affiliation":[{"name":"Depatment of Transfusion Medicine Nagoya University Hospital  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiji","family":"Nogami","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Nara Medical University  Kashihara Nara Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandrakala","family":"Shanmukhaiah","sequence":"additional","affiliation":[{"name":"Department of Clinical Hematology Seth GS Medical College and KEM Hospital  Mumbai India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,16]]},"reference":[{"issue":"6","key":"e_1_2_12_2_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/hae.14046","article-title":"WFH Guidelines for the Management of Hemophilia","volume":"26","author":"Srivastava A.","year":"2020","journal-title":"Haemophilia"},{"issue":"11","key":"e_1_2_12_3_1","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1182\/bloodadvances.2019001311","article-title":"Young Adult Outcomes of Childhood Prophylaxis for Severe Hemophilia A: Results of the Joint Outcome Continuation Study","volume":"4","author":"Warren B. B.","year":"2020","journal-title":"Blood Advances"},{"issue":"17","key":"e_1_2_12_4_1","doi-asserted-by":"crossref","first-page":"2368","DOI":"10.1182\/blood-2016-02-683169","article-title":"Prophylaxis Usage, Bleeding Rates, and Joint Outcomes of Hemophilia, 1999 to 2010: A Surveillance Project","volume":"129","author":"Manco\u2010Johnson M. J.","year":"2017","journal-title":"Blood"},{"issue":"11","key":"e_1_2_12_5_1","doi-asserted-by":"crossref","first-page":"2901","DOI":"10.1182\/bloodadvances.2023012285","article-title":"Predictive Parameters for Spontaneous Joint Bleeding During Emicizumab Prophylaxis","volume":"8","author":"Arcudi S.","year":"2024","journal-title":"Blood Advances"},{"issue":"10","key":"e_1_2_12_6_1","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1038\/nm.2942","article-title":"A Bispecific Antibody to Factors IXa and X Restores Factor VIII Hemostatic Activity in a Hemophilia A Model","volume":"18","author":"Kitazawa T.","year":"2012","journal-title":"Nature Medicine"},{"issue":"2","key":"e_1_2_12_7_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0057479","article-title":"Identification and Multidimensional Optimization of an Asymmetric Bispecific IgG Antibody Mimicking the Function of Factor VIII Cofactor Activity","volume":"8","author":"Sampei Z.","year":"2013","journal-title":"PLoS ONE"},{"issue":"21","key":"e_1_2_12_8_1","doi-asserted-by":"crossref","first-page":"2044","DOI":"10.1056\/NEJMoa1511769","article-title":"Factor VIII\u2010Mimetic Function of Humanized Bispecific Antibody in Hemophilia A","volume":"374","author":"Shima M.","year":"2016","journal-title":"New England Journal of Medicine"},{"issue":"9","key":"e_1_2_12_9_1","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1056\/NEJMoa1703068","article-title":"Emicizumab Prophylaxis in Hemophilia A With Inhibitors","volume":"377","author":"Oldenburg J.","year":"2017","journal-title":"New England Journal of Medicine"},{"issue":"9","key":"e_1_2_12_10_1","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1056\/NEJMoa1803550","article-title":"Emicizumab Prophylaxis in Patients who Have Hemophilia A Without Inhibitors","volume":"379","author":"Mahlangu J.","year":"2018","journal-title":"New England Journal of Medicine"},{"issue":"16","key":"e_1_2_12_11_1","doi-asserted-by":"crossref","first-page":"2231","DOI":"10.1182\/blood.2020009217","article-title":"Long\u2010Term Outcomes With Emicizumab Prophylaxis for Hemophilia A With or Without FVIII Inhibitors From the HAVEN 1\u20134 Studies","volume":"137","author":"Callaghan M. U.","year":"2021","journal-title":"Blood"},{"key":"e_1_2_12_12_1","first-page":"369","article-title":"Investigation Into the Acceptability of Moderate\u2010to\u2010Large Volume Subcutaneous Injections in Healthy Volunteers: Results From a Single\u2010Center Randomized Controlled Study","volume":"17","author":"Akinseye C.","year":"2024","journal-title":"Medical Devices (Auckland, N Z)"},{"key":"e_1_2_12_13_1","unstructured":"World Federation of Hemophilia.Report on the annual global survey 2015.2016 https:\/\/www1.wfh.org\/publication\/files\/pdf\u20101669.pdf;2016."},{"issue":"1","key":"e_1_2_12_14_1","first-page":"19","article-title":"Epidemiology & Social Costs of Haemophilia in India","volume":"140","author":"Kar A.","year":"2014","journal-title":"Indian Journal of Medical Research"},{"key":"e_1_2_12_15_1","unstructured":"World Federation of Hemophilia.Report on the annual global survey 2023.2023 https:\/\/www1.wfh.org\/publication\/files\/pdf\u20101669.pdf."},{"issue":"14","key":"e_1_2_12_16_1","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1182\/blood.2020010331","article-title":"A Factor VIIIa\u2010Mimetic Bispecific Antibody, Mim8, Ameliorates Bleeding Upon Severe Vascular Challenge in Hemophilia A Mice","volume":"138","author":"Ostergaard H.","year":"2021","journal-title":"Blood"},{"issue":"8","key":"e_1_2_12_17_1","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1111\/jth.12634","article-title":"Recombinant Factor VIIa Analog in the Management of Hemophilia With Inhibitors: Results From a Multicenter, Randomized, Controlled Trial of Vatreptacog Alfa","volume":"12","author":"Lentz S. R.","year":"2014","journal-title":"Journal of Thrombosis and Haemostasis"},{"issue":"6","key":"e_1_2_12_18_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.rpth.2023.102181","article-title":"Mim8, a Novel Factor VIIIa Mimetic Bispecific Antibody, Shows Favorable Safety and Pharmacokinetics in Healthy Adults","volume":"7","author":"Persson P.","year":"2023","journal-title":"Research and Practice in Thrombosis and Haemostasis"},{"key":"e_1_2_12_19_1","unstructured":"M. E.Mancuso C. J.Lyu T.Matsushita et\u00a0al. Efficacy and safety of Mim8 prophylaxis in adults and adolescents with hemophilia A with or without inhibitors: Phase 3 open\u2010label randomized controlled FRONTIER2 study Paper presented at: International Society on Thrombosis and Haemostasis (ISTH) Congress 2024; Bangkok Thailand."},{"issue":"1","key":"e_1_2_12_20_1","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1182\/blood-2024-198617","article-title":"Safety and Efficacy of Mim8 Prophylaxis Administered Once Every Two Weeks for Patients With Hemophilia A With or Without Inhibitors: Interim Analysis of the FRONTIER4 Open\u2010Label Extension Study","volume":"144","author":"Matsushita T.","year":"2024","journal-title":"Blood"},{"issue":"1","key":"e_1_2_12_21_1","article-title":"Efficient Production of Bispecific Antibody by FAST\u2010Ig(TM) and Its Application to NXT007 for the Treatment of Hemophilia A","volume":"15","author":"Koga H.","year":"2023","journal-title":"Monoclonal Antibodies"},{"issue":"7","key":"e_1_2_12_22_1","doi-asserted-by":"crossref","first-page":"2164","DOI":"10.1016\/j.jtha.2025.03.034","article-title":"Insights From in Vitro Global Assays on Possible Doses of Concomitant Hemostatic Agents in the Presence of NXT007 in Hemophilia A","volume":"23","author":"Ogiwara K.","year":"2025","journal-title":"Journal of Thrombosis and Haemostasis"},{"issue":"2","key":"e_1_2_12_23_1","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/j.jtha.2023.09.034","article-title":"A Bispecific Antibody NXT007 Exerts a Hemostatic Activity in Hemophilia A Monkeys Enough to Keep a Nonhemophilic State","volume":"22","author":"Teranishi\u2010Ikawa Y.","year":"2024","journal-title":"Journal of Thrombosis and Haemostasis"},{"issue":"10","key":"e_1_2_12_24_1","doi-asserted-by":"crossref","first-page":"3098","DOI":"10.1016\/j.jtha.2025.06.013","article-title":"A First\u2010in\u2010Human Study of NXT007, a Next\u2010Generation, Activated Factor VIII\u2010Mimetic Bispecific Antibody, in Healthy Participants","volume":"23","author":"Sambe T.","year":"2025","journal-title":"Journal of Thrombosis and Haemostasis"},{"key":"e_1_2_12_25_1","doi-asserted-by":"crossref","unstructured":"K.Nogami C. W.You Y. S.Park et\u00a0al. \u201cNXTAGE: A Phase 1\/2 Study of NXT007 to Assess Safety Pharmacokinetics and Efficacy in Hemophilia A Without Inhibitors \u201dBlood(2026): blood.2025031894 https:\/\/ashpublications.org\/blood\/article\/doi\/10.1182\/blood.2025031894\/566441\/NXTAGE-a-phase-1-2-studyof-NXT007-to-assess.","DOI":"10.1182\/blood.2025031894"},{"issue":"1","key":"e_1_2_12_26_1","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1182\/blood-2025-302","article-title":"NXT007 Prophylaxis in People With Hemophilia A With or Without FVIII Inhibitors: A Global Phase I\/II Multiple\u2010Ascending\u2010Dose Study","volume":"146","author":"Mancuso M. E.","year":"2025","journal-title":"Blood"},{"issue":"3","key":"e_1_2_12_27_1","doi-asserted-by":"crossref","DOI":"10.1097\/01.HS9.0000977256.26946.4e","article-title":"PB2643: Efficacy of Reduced\u2010Dose Emicizumab in Hemophilia A With Inhibitors: Real World Experience in Malaysia","volume":"7","author":"Tang A. S. O.","year":"2023","journal-title":"HemaSphere"},{"issue":"4","key":"e_1_2_12_28_1","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1016\/j.phoj.2022.03.022","article-title":"Response to Standard vs Low Dose Emicizumab in Inhibitor Positive Hemophilia A","volume":"6","author":"Radhakrishnan N.","year":"2021","journal-title":"Pediatric Hematology Oncology Journal"},{"issue":"2","key":"e_1_2_12_29_1","first-page":"e53","article-title":"Do We Need all that Emicizumab?","volume":"28","author":"Lehtinen A.\u2010E.","year":"2022","journal-title":"Haemophilia"},{"issue":"1","key":"e_1_2_12_30_1","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1111\/hae.14707","article-title":"Effectiveness of Monthly Low Dose Emicizumab Prophylaxis Without 4\u2010Week Loading Doses Among Patients With Haemophilia A With and Without Inhibitors: A Case Series Report","volume":"29","author":"Chuansumrit A.","year":"2023","journal-title":"Haemophilia"},{"issue":"3","key":"e_1_2_12_31_1","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1111\/hae.14785","article-title":"Low Dose Emicizumab Prophylaxis in Haemophilia a Patients: A Pilot Study From India","volume":"29","author":"Bansal S.","year":"2023","journal-title":"Haemophilia"},{"issue":"2","key":"e_1_2_12_32_1","article-title":"Non\u2010Clotting Factor Therapies for Preventing Bleeds in People With Congenital Hemophilia A or B","volume":"2","author":"Olasupo O. O.","year":"2024","journal-title":"Cochrane Database of Systematic Reviews (Online)"},{"key":"e_1_2_12_33_1","unstructured":"J.Lund J. R.Bjelke T.Egebjerg et\u00a0al. Novel FVIIIa\u2010mimetic molecule with the potential to be the first oral treatment for severe hemophilia A Paper presented at: International Society on Thrombosis and Haemostasis (ISTH) Congress 2024; Bangkok Thailand."},{"issue":"11","key":"e_1_2_12_34_1","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1007\/s40262-021-01042-w","article-title":"Pharmacokinetics and Associated Efficacy of Emicizumab in Humans: A Systematic Review","volume":"60","author":"Donners A.","year":"2021","journal-title":"Clinical Pharmacokinetics"}],"container-title":["Haemophilia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/hae.70231","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/hae.70231","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/hae.70231","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T11:05:35Z","timestamp":1776337535000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/hae.70231"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,16]]},"references-count":33,"alternative-id":["10.1111\/hae.70231"],"URL":"https:\/\/doi.org\/10.1111\/hae.70231","archive":["Portico"],"relation":{},"ISSN":["1351-8216","1365-2516"],"issn-type":[{"value":"1351-8216","type":"print"},{"value":"1365-2516","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,16]]},"assertion":[{"value":"2025-11-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-12","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"hae.70231"}}