{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T22:23:57Z","timestamp":1790634237935,"version":"4.1.0"},"reference-count":41,"publisher":"Georg Thieme Verlag KG","issue":"11","license":[{"start":{"date-parts":[[2021,2,13]],"date-time":"2021-02-13T00:00:00Z","timestamp":1613174400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100016300","name":"Octapharma AG","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100016300","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Thromb Haemost"],"published-print":{"date-parts":[[2021,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>\n          Introduction\u2003FVIII inhibitor development is the most serious contemporary treatment complication in haemophilia A, particularly in previously untreated patients (PUPs). No inhibitors developed in clinical trials in previously treated patients treated with simoctocog alfa (Nuwiq), a fourth-generation recombinant FVIII produced in a human cell line.<\/jats:p><jats:p>\n          Methods\u2003The NuProtect study investigated the immunogenicity of simoctocog alfa in PUPs. NuProtect was a prospective, multinational, open-label, non-controlled, phase III study. PUPs with severe haemophilia A (FVIII:C &lt;1%) of any age and ethnicity were treated with simoctocog alfa for 100 exposure days or a maximum of 5 years. Patients were true PUPs without prior exposure to FVIII concentrates or blood components. Inhibitor titres were measured with the Nijmegen-modified Bethesda assay; cut-off for positivity was 0.6 BU mL\u22121 (\u22650.6 to &lt;5 low-titre, \u22655 high titre).<\/jats:p><jats:p>\n          Results\u2003A total of 108 PUPs with a median age at first treatment of 12.0 months (interquartile range: 8.0\u201323.5) were treated with simoctocog alfa. F8 mutation type was known for 102 patients (94.4%) of whom 90 (88.2%) had null F8 mutations and 12 (11.8%) had non-null mutations. Of 105 PUPs evaluable for inhibitor development, 28 (26.7%) developed inhibitors; 17 high titre (16.2%) and 11 low titre (10.5%). No PUPs with non-null F8 mutations developed inhibitors.<\/jats:p><jats:p>\n          Conclusion\u2003In the NuProtect study, the rate of inhibitor development in PUPs with severe haemophilia A treated with simoctocog alfa was lower than the rate reported for hamster-cell-derived recombinant factor VIII products in other recent clinical trials. No inhibitors were reported in PUPs with non-null F8 mutations.<\/jats:p>","DOI":"10.1055\/s-0040-1722623","type":"journal-article","created":{"date-parts":[[2021,2,14]],"date-time":"2021-02-14T05:30:52Z","timestamp":1613280652000},"page":"1400-1408","source":"Crossref","is-referenced-by-count":22,"title":["Simoctocog Alfa (Nuwiq) in Previously Untreated Patients with Severe Haemophilia A: Final Results of the NuProtect Study"],"prefix":"10.1055","volume":"121","author":[{"given":"Ri J.","family":"Liesner","sequence":"additional","affiliation":[{"name":"Great Ormond Street Hospital for Children NHS Trust Haemophilia Centre, NIHR GOSH BRC, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aby","family":"Abraham","sequence":"additional","affiliation":[{"name":"Department of Hematology, Christian Medical College, Vellore, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Altisent","sequence":"additional","affiliation":[{"name":"Unitat d'Hemofilia, Hospital Vall D'Hebron, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark J.","family":"Belletrutti","sequence":"additional","affiliation":[{"name":"Pediatric Hematology, Department of Pediatrics, University of Alberta, Edmonton, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Carcao","sequence":"additional","affiliation":[{"name":"Division of Haematology\/Oncology and Child Health Evaluative Sciences, Department of Paediatrics, Research Institute, Hospital for Sick Children, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Congenital Coagulopathies Reference Centre, S\u00e3o Jo\u00e3o University Hospital Centre, Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herv\u00e9","family":"Chambost","sequence":"additional","affiliation":[{"name":"AP-HM, Department of Pediatric Hematology Oncology, Children Hospital La Timone, Aix Marseille Univ, INSERM, INRA, C2VN, Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony K. C.","family":"Chan","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology\/Oncology, McMaster University, Hamilton, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonid","family":"Dubey","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Western Ukrainian Specialized Children's Medical Centre, Lviv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Ducore","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California Davis Medical Center, Sacramento, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Gattens","sequence":"additional","affiliation":[{"name":"Department of Paediatric Haematology and Oncology, Addenbrooke\u2019s Hospital, Cambridge University Hospital NHS Foundation Trust, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Gresele","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yves","family":"Gruel","sequence":"additional","affiliation":[{"name":"Centre R\u00e9gional de Traitement de l'H\u00e9mophilie, H\u00f4pital Trousseau, Tours, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benoit","family":"Guillet","sequence":"additional","affiliation":[{"name":"Haemophilia Treatment Centre, Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail) - UMR_S 1085, Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Jimenez-Yuste","sequence":"additional","affiliation":[{"name":"Servicio de Hematolog\u00eda, Hospital Univeristario La Paz, Aut\u00f3noma University, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lidija","family":"Kitanovski","sequence":"additional","affiliation":[{"name":"Department of Haemato-Oncology, University Medical Center Ljubljana, Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Klukowska","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Haematology and Oncology, Warsaw Medical University, Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunil","family":"Lohade","sequence":"additional","affiliation":[{"name":"Department of Hematology, Sahyadri Speciality Hospital, Pune, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Elisa","family":"Mancuso","sequence":"additional","affiliation":[{"name":"Center for Thrombosis and Hemorrhagic Diseases, Humanitas Clinical and Research Center - IRCCS, Rozzano, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Oldenburg","sequence":"additional","affiliation":[{"name":"Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Pavlova","sequence":"additional","affiliation":[{"name":"Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berardino","family":"Pollio","sequence":"additional","affiliation":[{"name":"Department of Transfusion Medicine, Regina Margherita Children Hospital of Turin, Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne","family":"Sigaud","sequence":"additional","affiliation":[{"name":"Centre R\u00e9gional de Traitement de I'H\u00e9mophilie, University Hospital of Nantes, Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir","family":"Vdovin","sequence":"additional","affiliation":[{"name":"Department of Hematology, Morozovskaya Children's Hospital, Moscow, Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kateryna","family":"Vilchevska","sequence":"additional","affiliation":[{"name":"Department of Hematology, State Institution \u201cInstitute of Urgent and Reconstructive Surgery named after V.K. 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Four-year results from the European HAemophilia Safety Surveillance (EUHASS) project","volume":"113","author":"K Fischer","year":"2015","journal-title":"Thromb Haemost"},{"issue":"21","key":"ref21","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.1056\/NEJMoa1516437","article-title":"A randomized trial of factor VIII and neutralizing antibodies in hemophilia A","volume":"374","author":"F Peyvandi","year":"2016","journal-title":"N Engl J Med"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"67","DOI":"10.2147\/JBM.S103796","article-title":"Many factor VIII products available in the treatment of hemophilia A: an embarrassment of riches?","volume":"8","author":"K Lieuw","year":"2017","journal-title":"J Blood Med"},{"issue":"02","key":"ref23","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1111\/j.1600-0609.2012.01804.x","article-title":"The first recombinant human coagulation factor VIII of human origin: human cell line and manufacturing characteristics","volume":"89","author":"E Casademunt","year":"2012","journal-title":"Eur J Haematol"},{"issue":"01","key":"ref24","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.thromres.2012.09.011","article-title":"Characterisation of the post-translational modifications of a novel, human cell line-derived recombinant human factor VIII","volume":"131","author":"C Kannicht","year":"2013","journal-title":"Thromb Res"},{"issue":"05","key":"ref25","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1016\/j.thromres.2012.08.311","article-title":"Functional characteristics of the novel, human-derived recombinant FVIII protein product, human-cl rhFVIII","volume":"130","author":"H Sandberg","year":"2012","journal-title":"Thromb Res"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.pep.2015.08.023","article-title":"Development, upscaling and validation of the purification process for human-cl rhFVIII (Nuwiq\u00ae), a new generation recombinant factor VIII produced in a human cell-line","volume":"115","author":"S Winge","year":"2015","journal-title":"Protein Expr Purif"},{"issue":"03","key":"ref27","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1385\/MB:28:3:241","article-title":"Appropriate glycosylation of recombinant proteins for human use: implications of choice of expression system","volume":"28","author":"S A Brooks","year":"2004","journal-title":"Mol Biotechnol"},{"issue":"10","key":"ref28","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1038\/nbt1252","article-title":"Post-translational modifications in the context of therapeutic proteins","volume":"24","author":"G Walsh","year":"2006","journal-title":"Nat Biotechnol"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"2040620719858471","DOI":"10.1177\/2040620719858471","article-title":"Efficacy and safety of simoctocog alfa (Nuwiq\u00ae) in patients with severe hemophilia A: a review of clinical trial data from the GENA program","volume":"10","author":"T Lissitchkov","year":"2019","journal-title":"Ther Adv Hematol"},{"issue":"02","key":"ref30","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1111\/hae.13320","article-title":"Immunogenicity, efficacy and safety of Nuwiq\u00ae (human-cl rhFVIII) in previously untreated patients with severe haemophilia A - 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