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CC BY 4.0 · Thromb Haemost 2021; 121(11): 1400-1408
DOI: 10.1055/s-0040-1722623
Coagulation and Fibrinolysis

Simoctocog Alfa (Nuwiq) in Previously Untreated Patients with Severe Haemophilia A: Final Results of the NuProtect Study

Ri J. Liesner
1   Great Ormond Street Hospital for Children NHS Trust Haemophilia Centre, NIHR GOSH BRC, London, United Kingdom
,
Aby Abraham
2   Department of Hematology, Christian Medical College, Vellore, India
,
Carmen Altisent
3   Unitat d'Hemofilia, Hospital Vall D'Hebron, Barcelona, Spain
,
Mark J. Belletrutti
4   Pediatric Hematology, Department of Pediatrics, University of Alberta, Edmonton, Canada
,
Manuel Carcao
5   Division of Haematology/Oncology and Child Health Evaluative Sciences, Department of Paediatrics, Research Institute, Hospital for Sick Children, Toronto, Canada
,
Manuela Carvalho
6   Congenital Coagulopathies Reference Centre, São João University Hospital Centre, Porto, Portugal
,
Hervé Chambost
7   AP-HM, Department of Pediatric Hematology Oncology, Children Hospital La Timone, Aix Marseille Univ, INSERM, INRA, C2VN, Marseille, France
,
Anthony K. C. Chan
8   Division of Pediatric Hematology/Oncology, McMaster University, Hamilton, Canada
,
Leonid Dubey
9   Department of Pediatrics, Western Ukrainian Specialized Children's Medical Centre, Lviv, Ukraine
,
Jonathan Ducore
10   Department of Pediatrics, University of California Davis Medical Center, Sacramento, United States
,
Michael Gattens
11   Department of Paediatric Haematology and Oncology, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust, Cambridge, United Kingdom
,
Paolo Gresele
12   Department of Medicine and Surgery, University of Perugia, Perugia, Italy
,
Yves Gruel
13   Centre Régional de Traitement de l'Hémophilie, Hôpital Trousseau, Tours, France
,
Benoit Guillet
14   Haemophilia Treatment Centre, Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France
,
Victor Jimenez-Yuste
15   Servicio de Hematología, Hospital Univeristario La Paz, Autónoma University, Madrid, Spain
,
Lidija Kitanovski
16   Department of Haemato-Oncology, University Medical Center Ljubljana, Ljubljana, Slovenia
,
Anna Klukowska
17   Department of Pediatrics, Haematology and Oncology, Warsaw Medical University, Warsaw, Poland
,
Sunil Lohade
18   Department of Hematology, Sahyadri Speciality Hospital, Pune, India
,
Maria Elisa Mancuso
19   Center for Thrombosis and Hemorrhagic Diseases, Humanitas Clinical and Research Center - IRCCS, Rozzano, Milan, Italy
,
Johannes Oldenburg
20   Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
,
Anna Pavlova
20   Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
,
Berardino Pollio
21   Department of Transfusion Medicine, Regina Margherita Children Hospital of Turin, Turin, Italy
,
Marianne Sigaud
22   Centre Régional de Traitement de I'Hémophilie, University Hospital of Nantes, Nantes, France
,
Vladimir Vdovin
23   Department of Hematology, Morozovskaya Children's Hospital, Moscow, Russian Federation
,
Kateryna Vilchevska
24   Department of Hematology, State Institution “Institute of Urgent and Reconstructive Surgery named after V.K. Gusak of National Academy of Medical Sciences of Ukraine,” Donetsk, Ukraine
,
John K. M. Wu
25   British Columbia Children's Hospital, Vancouver, Canada
,
Martina Jansen
26   Octapharma Pharmazeutika Produktionsges.mbH, Vienna, Austria
,
Larisa Belyanskaya
27   Octapharma AG, Lachen, Switzerland
,
Olaf Walter
27   Octapharma AG, Lachen, Switzerland
,
Sigurd Knaub
27   Octapharma AG, Lachen, Switzerland
,
Ellis J. Neufeld
28   St. Jude Children's Research Hospital, Memphis, Tennessee, United States
› Author Affiliations Funding This trial was sponsored by Octapharma AG (Lachen, Switzerland) with medical writing assistance provided by nspm ltd, Meggen, Switzerland, and funded by Octapharma AG.
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Abstract

Introduction FVIII 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.

Methods The 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 <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−1 (≥0.6 to <5 low-titre, ≥5 high titre).

Results A total of 108 PUPs with a median age at first treatment of 12.0 months (interquartile range: 8.0–23.5) 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.

Conclusion In 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.

Keywords

coagulation - FVIII inhibitors - haemophilia

Author Contribbutions

R. J. Liesner designed the research, analysed the data and wrote the first draft of the manuscript. All authors provided input, reviewed and approved the manuscript.




Publication History

Received: 14 October 2020

Accepted: 04 December 2020

Article published online:
13 February 2021

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Konkle BA, Huston H, Fletcher SN. Hemophilia A. In: Adam MP, Ardinger HH, Pagon RA. et al., eds. GeneReviews® [Internet]. Seattle, WA: University of Washington; , Last updated 2017. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1404/
  • 2 Srivastava A, Santagostino E, Dougall A. et al. WFH guidelines for the management of hemophilia, 3rd edition. Haemophilia 2020; 26: 1-158
    CrossrefPubMedSearch in Google Scholar
  • 3 Makris M. Prophylaxis in haemophilia should be life-long. Blood Transfus 2012; 10 (02) 165-168
    PubMedSearch in Google Scholar
  • 4 Goudemand J, Peyvandi F, Lacroix-Desmazes S. Key insights to understand the immunogenicity of FVIII products. Thromb Haemost 2016; 116 (Suppl. 01) S2-S9
    Thieme ConnectPubMedSearch in Google Scholar
  • 5 van den Berg HM, Fischer K, Carcao M. et al; PedNet Study Group. Timing of inhibitor development in more than 1000 previously untreated patients with severe hemophilia A. Blood 2019; 134 (03) 317-320
    CrossrefPubMedSearch in Google Scholar
  • 6 Carcao M, Escuriola-Ettingshausen C, Santagostino E. et al; Future of Immunotolerance Treatment Group. The changing face of immune tolerance induction in haemophilia A with the advent of emicizumab. Haemophilia 2019; 25 (04) 676-684
    CrossrefPubMedSearch in Google Scholar
  • 7 Morfini M, Haya S, Tagariello G. et al. European study on orthopaedic status of haemophilia patients with inhibitors. Haemophilia 2007; 13 (05) 606-612
    CrossrefPubMedSearch in Google Scholar
  • 8 Mahlangu J, Oldenburg J, Callaghan MU. et al. Health-related quality of life and health status in persons with haemophilia A with inhibitors: a prospective, multicentre, non-interventional study (NIS). Haemophilia 2019; 25 (03) 382-391
    CrossrefPubMedSearch in Google Scholar
  • 9 Di Minno MN, Di Minno G, Di Capua M, Cerbone AM, Coppola A. Cost of care of haemophilia with inhibitors. Haemophilia 2010; 16 (01) e190-e201
    CrossrefPubMedSearch in Google Scholar
  • 10 Walsh CE, Jiménez-Yuste V, Auerswald G, Grancha S. The burden of inhibitors in haemophilia patients. Thromb Haemost 2016; 116 (Suppl. 01) S10-S17
    Thieme ConnectPubMedSearch in Google Scholar
  • 11 Santagostino E, Young G, Escuriola Ettingshausen C, Jimenez-Yuste V, Carcao M. Inhibitors: a need for eradication?. Acta Haematol 2019; 141 (03) 151-155
    CrossrefPubMedSearch in Google Scholar
  • 12 Oldenburg J, Lacroix-Desmazes S, Lillicrap D. Alloantibodies to therapeutic factor VIII in hemophilia A: the role of von Willebrand factor in regulating factor VIII immunogenicity. Haematologica 2015; 100 (02) 149-156
    CrossrefPubMedSearch in Google Scholar
  • 13 Gouw SC, van den Berg HM, Oldenburg J. et al. F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis. Blood 2012; 119 (12) 2922-2934
    CrossrefPubMedSearch in Google Scholar
  • 14 Peyvandi F, Garagiola I. Product type and other environmental risk factors for inhibitor development in severe hemophilia A. Res Pract Thromb Haemost 2018; 2 (02) 220-227
    CrossrefPubMedSearch in Google Scholar
  • 15 Goudemand J, Laurian Y, Calvez T. Risk of inhibitors in haemophilia and the type of factor replacement. Curr Opin Hematol 2006; 13 (05) 316-322
    CrossrefPubMedSearch in Google Scholar
  • 16 Chalmers EA, Brown SA, Keeling D. et al; Paediatric Working Party of UKHCDO. Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A. Haemophilia 2007; 13 (02) 149-155
    CrossrefPubMedSearch in Google Scholar
  • 17 Mancuso ME, Mannucci PM, Rocino A, Garagiola I, Tagliaferri A, Santagostino E. Source and purity of factor VIII products as risk factors for inhibitor development in patients with hemophilia A. J Thromb Haemost 2012; 10 (05) 781-790
    CrossrefPubMedSearch in Google Scholar
  • 18 Gouw SC, van der Bom JG, Auerswald G, Ettinghausen CE, Tedgård U, van den Berg HM. Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study. Blood 2007; 109 (11) 4693-4697
    CrossrefPubMedSearch in Google Scholar
  • 19 Gouw SC, van der Bom JG, Ljung R. et al; PedNet and RODIN Study Group. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med 2013; 368 (03) 231-239
    CrossrefPubMedSearch in Google Scholar
  • 20 Fischer K, Lassila R, Peyvandi F. et al; EUHASS participants. Inhibitor development in haemophilia according to concentrate. Four-year results from the European HAemophilia Safety Surveillance (EUHASS) project. Thromb Haemost 2015; 113 (05) 968-975
    Thieme ConnectPubMedSearch in Google Scholar
  • 21 Peyvandi F, Mannucci PM, Garagiola I. et al. A randomized trial of factor VIII and neutralizing antibodies in hemophilia A. N Engl J Med 2016; 374 (21) 2054-2064
    CrossrefPubMedSearch in Google Scholar
  • 22 Lieuw K. Many factor VIII products available in the treatment of hemophilia A: an embarrassment of riches?. J Blood Med 2017; 8: 67-73
    CrossrefPubMedSearch in Google Scholar
  • 23 Casademunt E, Martinelle K, Jernberg M. et al. The first recombinant human coagulation factor VIII of human origin: human cell line and manufacturing characteristics. Eur J Haematol 2012; 89 (02) 165-176
    CrossrefPubMedSearch in Google Scholar
  • 24 Kannicht C, Ramström M, Kohla G. et al. Characterisation of the post-translational modifications of a novel, human cell line-derived recombinant human factor VIII. Thromb Res 2013; 131 (01) 78-88
    CrossrefPubMedSearch in Google Scholar
  • 25 Sandberg H, Kannicht C, Stenlund P. et al. Functional characteristics of the novel, human-derived recombinant FVIII protein product, human-cl rhFVIII. Thromb Res 2012; 130 (05) 808-817
    CrossrefPubMedSearch in Google Scholar
  • 26 Winge S, Yderland L, Kannicht C. et al. Development, upscaling and validation of the purification process for human-cl rhFVIII (Nuwiq®), a new generation recombinant factor VIII produced in a human cell-line. Protein Expr Purif 2015; 115: 165-175
    CrossrefPubMedSearch in Google Scholar
  • 27 Brooks SA. Appropriate glycosylation of recombinant proteins for human use: implications of choice of expression system. Mol Biotechnol 2004; 28 (03) 241-255
    CrossrefPubMedSearch in Google Scholar
  • 28 Walsh G, Jefferis R. Post-translational modifications in the context of therapeutic proteins. Nat Biotechnol 2006; 24 (10) 1241-1252
    CrossrefPubMedSearch in Google Scholar
  • 29 Lissitchkov T, Klukowska A, Pasi J. et al. Efficacy and safety of simoctocog alfa (Nuwiq®) in patients with severe hemophilia A: a review of clinical trial data from the GENA program. Ther Adv Hematol 2019; 10: 2040620719858471
    CrossrefPubMedSearch in Google Scholar
  • 30 Liesner RJ, Abashidze M, Aleinikova O. et al. Immunogenicity, efficacy and safety of Nuwiq® (human-cl rhFVIII) in previously untreated patients with severe haemophilia A - Interim results from the NuProtect Study. Haemophilia 2018; 24 (02) 211-220
    CrossrefPubMedSearch in Google Scholar
  • 31 Verbruggen B, Novakova I, Wessels H, Boezeman J, van den Berg M, Mauser-Bunschoten E. The Nijmegen modification of the Bethesda assay for factor VIII:C inhibitors: improved specificity and reliability. Thromb Haemost 1995; 73 (02) 247-251
    Thieme ConnectPubMedSearch in Google Scholar
  • 32 Yaish H, Matsushita T, Belhani M. et al. Safety and efficacy of turoctocog alfa in the prevention and treatment of bleeds in previously untreated paediatric patients with severe haemophilia A: Results from the guardian 4 multinational clinical trial. Haemophilia 2020; 26 (01) 64-72
    CrossrefPubMedSearch in Google Scholar
  • 33 Santagostino E, Koenigs C, Djambas Khayat C. et al. Interim analysis of the extension study with rVIII-SingleChain in previously untreated patients (PUPs) with severe hemophilia A (CSL627–3001). Blood 2019; 134 (Suppl. 01) 162
    CrossrefPubMedSearch in Google Scholar
  • 34 Rosendaal FR, Palla R, Garagiola I, Mannucci PM, Peyvandi F. SIPPET Study Group. Genetic risk stratification to reduce inhibitor development in the early treatment of hemophilia A: a SIPPET analysis. Blood 2017; 130 (15) 1757-1759
    CrossrefPubMedSearch in Google Scholar
  • 35 Bachelet D, Albert T, Mbogning C. et al; ABIRISK consortium. Risk stratification integrating genetic data for factor VIII inhibitor development in patients with severe hemophilia A. PLoS One 2019; 14 (06) e0218258
    CrossrefPubMedSearch in Google Scholar
  • 36 Lorenzo JI, López A, Altisent C, Aznar JA. Incidence of factor VIII inhibitors in severe haemophilia: the importance of patient age. Br J Haematol 2001; 113 (03) 600-603
    CrossrefPubMedSearch in Google Scholar
  • 37 van der Bom JG, Mauser-Bunschoten EP, Fischer K, van den Berg HM. Age at first treatment and immune tolerance to factor VIII in severe hemophilia. Thromb Haemost 2003; 89 (03) 475-479
    Thieme ConnectPubMedSearch in Google Scholar
  • 38 Santagostino E, Mancuso ME, Rocino A. et al. Environmental risk factors for inhibitor development in children with haemophilia A: a case-control study. Br J Haematol 2005; 130 (03) 422-427
    CrossrefPubMedSearch in Google Scholar
  • 39 Garagiola I, Palla R, Peyvandi F. Risk factors for inhibitor development in severe hemophilia A. Thromb Res 2018; 168: 20-27
    CrossrefPubMedSearch in Google Scholar
  • 40 Miller CH, Benson J, Ellingsen D. et al; Hemophilia Inhibitor Research Study Investigators. F8 and F9 mutations in US haemophilia patients: correlation with history of inhibitor and race/ethnicity. Haemophilia 2012; 18 (03) 375-382
    CrossrefPubMedSearch in Google Scholar
  • 41 Miller CH. Game, set, match for factor VIII mismatch?. Blood 2015; 126 (07) 829-830
    CrossrefPubMedSearch in Google Scholar