Download PDF
CC BY 4.0 · Hamostaseologie 2023; 43(03): 196-207
DOI: 10.1055/a-1957-4477
Original Article

Gene therapy of Hemophilia: Recommendations from the German, Austrian, and Swiss Society for Thrombosis and Haemostasis Research (GTH)

Article in several languages: deutsch | English
Wolfgang Miesbach
1   Medizinische Klinik 2, Institut für Transfusionsmedizin, Universitätsklinikum Frankfurt, Frankfurt, Deutschland
,
Johannes Oldenburg
2   Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Medical Faculty, University of Bonn, Bonn, Deutschland
,
Robert Klamroth
3   Klinik für Innere Medizin – Angiologie und Hämostaseologie, Zentrum für Gefäßmedizin, Vivantes Klinikum im Friedrichshain, Berlin, Deutschland
,
Hermann Eichler
4   Institut für Klinische Hämostaseologie und Transfusionsmedizin, Universität und Universitätsklinikum des Saarlandes, Homburg/Saar, Deutschland
,
Jürgen Koscielny
5   Gerinnungsambulanz mit Hämophiliezentrum, Charité, Berlin, Deutschland
,
Susanne Holzhauer
6   Klinik für Pädiatrie m. S. Onkologie und Hämatologie, Charité, Universitätsmedizin, Berlin, Deutschland
,
Katharina Holstein
7   II. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland
,
Johanna A. Kremer Hovinga
8   Universitätsklinik für Hämatologie und Hämatologische Zentrallabor, Universitätsspital Bern, Universität Bern, Bern, Schweiz
,
Lorenzo Alberio
9   Division of Haematology and Haematology Central Laboratory, University Hospital of Lausanne (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
,
Martin Olivieri
10   Hämophiliezentrum LMU Klinikum - Bereich Pädiatrie, Dr. von Haunerschen Kinderspital, LMU München, München, Deutschland
,
Ralf Knöfler
11   Universitätsklinikum Dresden Klinik/Poliklinik für Kinder- und Jugendmedizin Bereich Hämatologie, Dresden, Deutschland
,
Christoph Male
12   Abteilung für Kinder- und Jugendheilkunde, Medizinische Universität Wien, Österreich
,
Andreas Tiede
13   Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation, Medizinische Hochschule Hannover, Hannover, Deutschland
› Author Affiliations
› Further Information
Also available at
   Permissions and Reprints

Corrected by:

Erratum: Gentherapie der Hämophilie: Empfehlung der Gesellschaft für Thrombose- und Hämostaseforschung (GTH)Hamostaseologie 2023; 43(03): e1-e1
DOI: 10.1055/s-0042-1760262

Abstract

Gene therapy has recently become a realistic treatment perspective for patients with hemophilia. Reviewing the literature and our personal experience from clinical trials, we discuss key aspects of hemophilia A and B gene therapy with vectors derived from adeno-associated virus, including predictable results, risks, adverse events, and patient-reported outcomes. Patient selection, informed consent, administration, and monitoring of gene therapy as well as data collection are explained. We also discuss the need for interdisciplinary cooperation with hepatology and other specialties. We emphasize structural and organizational requirements for treatment centers according to the hub-and-spoke model and recommend the use of electronic diaries to ensure safe and timely collection and exchange of data. Electronic diaries will play a key role as a primary source of data for pharmacovigilance, postmarketing clinical studies, national and international registries, as well as health technology and benefit assessment. Reimbursement aspects and the future of gene therapy in adolescents and children are also considered. In a rapidly evolving scientific environment, these recommendations aim to support treatment providers and payers to prepare for the implementation of gene therapy following marketing authorization.

Keywords

practice guideline - haemophilia - gene therapy - recommendations - factor VIII - factor IX

Disclosure of potential conflicts of interest

Wolfgang Miesbach reports support for clinical trials and scientific projects from Bayer, BioMarin, Biotest, CSL Behring, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, sobi, Takeda/Shire, uniQure as well as fees for lectures or consulting from Bayer, BioMarin, Biotest, CSL Behring, Chugai, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, Regeneron, Roche, Sanofi, sobi, Takeda/Shire, and uniQure.

Johannes Oldenburg reports support for clinical trials from Bayer, Biotest, CSL Behring, Pfizer, sobi, and Takeda, as well as fees for lectures or consulting from Bayer, Biogen, BioMarin, Biotest, CSL Behring, Chugai, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Spark Therapeutics, sobi, and Takeda.

Robert Klamroth reports support for clinical trials and fees for lectures or consulting from Bayer, BioMarin, Biotest, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, Sobi, Takeda/Shire, and uniQure.

Hermann Eichler reports support for lectures or consulting from Bayer Vital, Biotest, CSL Behring, Novo Nordisk, Pfizer, Roche, and sobi.

Jürgen Koscielny reports support for lectures and fees from Alexion, Aspen, Bayer, Biotest, BMS, CSL Behring, Chugai, Daiichi-Sankyo, Ferring, Leo Pharma, LFB, Medpoint, Mitsubishi, MSD, Novo Nordisk, Pfizer, Roche, Siemens, Takeda, Vivantes, Berliner Ärztekammer, and BEST.

Susanne Holzhauer reports support for scientific projects from Pfizer and SOBI as well as fees for lectures or consulting from BioMarin, Chugai, and SOBI.

Katharina Holstein reports support for lectures and consulting from Bayer, Biotest, Chugai, CSL Behring, Novo Nordisk, Pfizer, Roche, sobi, and Takeda.

Johanna A. Kremer Hovinga reports support for clinical trials, scientific projects, and fees for lectures or consulting from Bayer, CSL Behring, Novo Nordisk, Roche, Sanofi, Sobi, and Takeda/Shire. All fees go to her employer, Insel Gruppe AG Bern.

Lorenzo Alberio reports support for clinical trials and scientific projects from Bayer, CSL Behring, Novartis, Novo Nordisk, Octapharma, Roche, Sobi, Takeda/Shire, and Werfen, as well as fees for lectures or consulting from Bayer, Biotest, Boehringer-Ingelheim, CSL Behring, Daiichi Sankyo, Novo Nordisk, OrPha Swiss, Roche, Sanofi-Aventis, Sanofi-Genzyme, Siemens, Sobi, Takeda/Shire, and Werfen.

Martin Olivieri reports support for lectures and fees from Bayer, BioMarin, Biotest, Chugai, CSL Behring, Grifols, NovoNordisk, Octapharma, Pfizer, Roche, SOBI, and Takeda.

Ralf Knöfler reports support for lectures and fees from BioMarin.

Christoph Male reports support for clinical trials and scientific projects from Bayer, Biotest, CSL Behring, Novo Nordisk, SOBI, and Takeda, as well as fees for lectures or consulting from Bayer, Biotest, CSL Behring, Grifols, Novo Nordisk, Pfizer, Roche, and Takeda.

Andreas Tiede reports support for clinical trials and scientific projects from Bayer, BioMarin, Biotest, Chugai, Novo Nordisk, Octapharma, Pfizer, Roche, SOBI, and Takeda, as well as fees for lectures or consulting from Bayer, BioMarin, Biotest, Chugai, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, SOBI, and Takeda.




Publication History

Received: 02 August 2022

Accepted: 06 October 2022

Article published online:
14 December 2022

© 2022. 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/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Duda H, Hesse J, Haschberger B, Hilger A, Keipert C. The German Hemophilia Registry: Growing with Its Tasks. J Clin Med 2020; 9 (11) E3408
    Search in Google Scholar
  • 2 Iorio A, Stonebraker JS, Chambost H. et al; Data and Demographics Committee of the World Federation of Hemophilia. Establishing the Prevalence and Prevalence at Birth of Hemophilia in Males: A Meta-analytic Approach Using National Registries. Ann Intern Med 2019; 171 (08) 540-546
    Search in Google Scholar
  • 3 Stonebraker JS, Bolton-Maggs PHB, Brooker M. et al. The World Federation of Hemophilia Annual Global Survey 1999-2018. Haemophilia 2020; 26 (04) 591-600
    Search in Google Scholar
  • 4 Srivastava A. et al. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia; 2020. 26 Suppl 6: p. 1-158.
    Search in Google Scholar
  • 5 Oldenburg J, Kurnik K, Tiede A. Arzneimittel zur Therapie der angeborenen und erworbenen Hämophilie und der von-Willebrand-Erkrankung, in Querschnitts-Leitlinien zur Therapie mit Blutkomponenten und Plasmaderivaten 2020. Bundesärztekammer Berlin; Berlin: p. 118-146.
  • 6 Peyvandi F, Garagiola I, Boscarino M, Ryan A, Hermans C, Makris M. Real-life experience in switching to new extended half-life products at European haemophilia centres. Haemophilia 2019; 25 (06) 946-952
    Search in Google Scholar
  • 7 Callaghan MU, Negrier C, Paz-Priel I. et al. Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies. Blood 2021; 137 (16) 2231-2242
    Search in Google Scholar
  • 8 Nuss R, Soucie JM, Evatt B. Hemophilia Surveillance System Project Investigators. Changes in the occurrence of and risk factors for hemophilia-associated intracranial hemorrhage. Am J Hematol 2001; 68 (01) 37-42
    Search in Google Scholar
  • 9 Oldenburg J. Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens. Blood 2015; 125 (13) 2038-2044
    Search in Google Scholar
  • 10 Gualtierotti R, Solimeno LP, Peyvandi F. Hemophilic arthropathy: Current knowledge and future perspectives. J Thromb Haemost 2021; 19 (09) 2112-2121
    Search in Google Scholar
  • 11 Ucero-Lozano R, López-Pina JA, Ortiz-Pérez A, Cuesta-Barriuso R. Quality of life and its predictors among adult patients with haemophilic arthropathy. An observational study. BMC Musculoskelet Disord 2021; 22 (01) 448
    Search in Google Scholar
  • 12 Skinner MW, Nugent D, Wilton P. et al. Achieving the unimaginable: Health equity in haemophilia. Haemophilia 2020; 26 (01) 17-24
    Search in Google Scholar
  • 13 Nguyen NAT, Auquier P, Beltran Anzola A. et al; INTHEMO Study Group. Occupational integration of adults with severe haemophilia (INTHEMO): A study based on the FranceCoag registry. Haemophilia 2022
  • 14 Chuah MK, Evens H, VandenDriessche T. Gene therapy for hemophilia. J Thromb Haemost 2013; 11 (Suppl. 01) 99-110
    Search in Google Scholar
  • 15 Nathwani AC. Gene therapy for hemophilia. Hematology (Am Soc Hematol Educ Program) 2019; 2019 (01) 1-8
    Search in Google Scholar
  • 16 Nguyen GN, Everett JK, Kafle S. et al. A long-term study of AAV gene therapy in dogs with hemophilia A identifies clonal expansions of transduced liver cells. Nat Biotechnol 2021; 39 (01) 47-55
    Search in Google Scholar
  • 17 Samelson-Jones BJ, Finn JD, Raffini LJ. et al. Evolutionary insights into coagulation factor IX Padua and other high-specific-activity variants. Blood Adv 2021; 5 (05) 1324-1332
    Search in Google Scholar
  • 18 Lisowski L, Staber JM, Wright JF, Valentino LA. The intersection of vector biology, gene therapy, and hemophilia. Res Pract Thromb Haemost 2021; 5 (06) e12586
    Search in Google Scholar
  • 19 Klamroth R, Hayes G, Andreeva T. et al. Global Seroprevalence of Pre-existing Immunity Against AAV5 and Other AAV Serotypes in People with Hemophilia A. Hum Gene Ther 2022; 33 (7-8): 432-441
    Search in Google Scholar
  • 20 Leebeek FWG, Miesbach W. Gene therapy for hemophilia: a review on clinical benefit, limitations, and remaining issues. Blood 2021; 138 (11) 923-931
    Search in Google Scholar
  • 21 Konkle BA, Walsh CE, Escobar MA. et al. BAX 335 hemophilia B gene therapy clinical trial results: potential impact of CpG sequences on gene expression. Blood 2021; 137 (06) 763-774
    Search in Google Scholar
  • 22 Pasi KJ, Laffan M, Rangarajan S. et al. Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A. Haemophilia 2021; 27 (06) 947-956
    Search in Google Scholar
  • 23 Ozelo MC, Mahlangu J, Pasi KJ. et al; GENEr8-1 Trial Group. Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A. N Engl J Med 2022; 386 (11) 1013-1025
    Search in Google Scholar
  • 24 Leavitt AD. et al. Updated follow-up of the Alta study, a phase 1/2 study of giroctocogene fitelparvovec (SB-525) gene therapy in adults with severe hemophilia A. [abstract, Am. Soc. Hematol 2020] Blood 2020; 136: 12
    Search in Google Scholar
  • 25 Miesbach W, Meijer K, Coppens M. et al. Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B. Blood 2018; 131 (09) 1022-1031
    Search in Google Scholar
  • 26 George LA, Sullivan SK, Giermasz A. et al. Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant. N Engl J Med 2017; 377 (23) 2215-2227
    Search in Google Scholar
  • 27 Miesbach W. Final analysis from the pivotal phase 3 HOPE-B Gene Therapy trial: Stable steady-state efficacy and Safety of etranacogene dezaparvovec in adults with severe or moderately severe haemophilia B [abstract EAHAD 2022 and CSL Behring Press Release 4th Feb 2022]. 22.07.2022]; Available from: https://eahad.org/eahad-2022-latest-clinical-trial-results-session-press-release/ https://www.cslbehring.com/newsroom/2022/hope-b-data-presented-at-eahad2022
  • 28 Laffan M. et al. Hemostatic results for up to 6 years following treatment with valoctocogene roxaparvovec, an AAV5-hFVIII-SQ gene therapy for severe hemophilia A [abstract, ISTH 2022]. 2022 19.07.2022]; Available from: https://abstracts.isth.org/abstract/hemostatic-results-for-up-to-6-years-following-treatment-with-valoctocogene-roxaparvovec-an-aav5-hfviii-sq-gene-therapy-for-severe-hemophilia-a/
  • 29 Bryson S. FDA Lifts Hold on Phase 3 Trial of Gene Therapy SB-525 for Hem A. 2022 22.07.2022]; Available from: https://hemophilianewstoday.com/news/fda-lifts-hold-phase-3-trial-gene-therapy-sb-525-hemophilia-a/
  • 30 Chowdary P, Shapiro S, Makris M. et al. Phase 1-2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B. N Engl J Med 2022; 387 (03) 237-247
    Search in Google Scholar
  • 31 Miesbach W, O'Mahony B, Key NS, Makris M. How to discuss gene therapy for haemophilia? A patient and physician perspective. Haemophilia 2019; 25 (04) 545-557
    Search in Google Scholar
  • 32 Wang M, Negrier C, Driessler F, Goodman C, Skinner MW. The Hemophilia Gene Therapy Patient Journey: Questions and Answers for Shared Decision-Making. Patient Prefer Adherence 2022; 16: 1439-1447
    Search in Google Scholar
  • 33 Eichler H, Pedroni MA, Halimeh S. et al. [Leitlinie der Gesellschaft für Thrombose- und Hämostaseforschung (GTH) zur Struktur- und Prozessqualität von Hämophilie-Zentren]. Hamostaseologie 2019; 39 (04) 311-321
    Search in Google Scholar
  • 34 Miesbach W, Chowdary P, Coppens M. et al. Delivery of AAV-based gene therapy through haemophilia centres-A need for re-evaluation of infrastructure and comprehensive care: A Joint publication of EAHAD and EHC. Haemophilia 2021; 27 (06) 967-973
    Search in Google Scholar
  • 35 Miesbach W, Baghaei F, Boban A. et al. Gene therapy of hemophilia: Hub centres should be haemophilia centres: A joint publication of EAHAD and EHC. Haemophilia 2022; 28 (03) e86-e88
    Search in Google Scholar
  • 36 Sawyer EK. et al. Clearance of vector DNA following systemic administration of AAV5-hFIX or AAV5-hFIX Padua in patients with severe or moderate-severe hemophilia B. [abstract; Am Soc Hematol 2019] Blood 2019; 134: 2062
    Search in Google Scholar
  • 37 Schmidt MR. et al. Liver Safety Case Report from the Phase 3 HOPE-B Gene Therapy Trial in Adults with Hemophilia B [abstract, ISTH 2021]. 2021 22.07.2022]; Available from: https://abstracts.isth.org/abstract/liver-safety-case-report-from-the-phase-3-hope-b-gene-therapy-trial-in-adults-with-hemophilia-b/
  • 38 BioMarin follows up on previously-reported serious adverse event in its phase I/II gene therapy clinical trial for haemophilia A. 2022 22.07.2022]; Available from: https://wfh.org/biomarin-follows-up-on-previously-reported-serious-adverse-event-in-its-phase-i-ii-gene-therapy-clinical-trial-for-haemophilia-a/
  • 39 https://www.ehc.eu/biomarin-announced-an-additional-serious-adverse-event-in-its-gene-therapy-clinical-trial-for-haemophilia-a/?pk_campaign=feed&pk_kwd=biomarin-announced-an-additional-serious-adverse-event-in-its-gene-therapy-clinical-trial-for-haemophilia-a
  • 40 Miesbach W, Eichler H, Holstein K. et al. Electronic diaries in the management of haemophilia gene therapy: Perspective of an expert group from the German, Austrian and Swiss Society on Thrombosis and Haemostasis (GTH). Haemophilia 2022; 28 (02) 264-269
    Search in Google Scholar
  • 41 Tiede A, Bonanad S, Santamaria A. et al. Quality of electronic treatment records and adherence to prophylaxis in haemophilia and von Willebrand disease: Systematic assessments from an electronic diary. Haemophilia 2020; 26 (06) 999-1008
    Search in Google Scholar
  • 42 Banchev A, Goldmann G, Marquardt N. et al. Impact of telemedicine tools on record keeping and compliance in haemophilia care. Hamostaseologie 2019; 39 (04) 347-354
    Search in Google Scholar
  • 43 Mondorf W, Eichler H, Fischer R. et al. Smart Medication, an electronic diary for surveillance of hemophilia home care and optimization of resource distribution. Hamostaseologie 2019; 39 (04) 339-346
    Search in Google Scholar
  • 44 Konkle BA, Coffin D, Pierce GF. et al; Members of the WFH Gene Therapy Registery Steering Committee. World Federation of Hemophilia Gene Therapy Registry. Haemophilia 2020; 26 (04) 563-564
    Search in Google Scholar
  • 45 Henriksen E, Burkow TM, Johnsen E, Vognild LK. Privacy and information security risks in a technology platform for home-based chronic disease rehabilitation and education. BMC Med Inform Decis Mak 2013; 13: 85
    Search in Google Scholar