10.4081/btvb.2023.70
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2785-5309
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Giancarlo Castaman
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Bleeding, Thrombosis and Vascular Biology
hemophilia
Gene transfer in hemophilia B: a big step forward
Text.Serial.Journal
https://www.btvb.org/btvb
2
Invited Editorials
2023-05-17
2023-03-17
2023-04-30
2023-06-27
Bleed Thromb Vascul Biol
Giancarlo Castaman
2023/05/17
10.4081/btvb.2023.70
Center for Bleeding Disorders and Coagulation, Department of Oncology, Careggi University Hospital, Florence
2785-5309
2
hemophilia
en
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: joint publication of EAHAD and EHC. Haemophilia 2021;27:967-73.
Gene transfer in hemophilia B: a big step forward
https://www.btvb.org/btvb/article/download/70/66
2
                                                                                                           INVITED EDITORIAL

Gene transfer in hemophilia B: a big step forward
Giancarlo Castaman

Center for Bleeding Disorders and Coagulation, Department of Oncology, Careggi University Hospital, Florence, Italy




     The phase 3 open-label study of gene transfer in hemophilia            very high levels of FIX and inherited thrombophilia.4 The FIX-
B using the vector AAV5-etranacogene dezaparvovec (HOPE-B                   Padua protein demonstrates a 6- to 8-fold increase in FIX activity
trial) has recently reported the results in 54 men affected by he-          compared to wild type FIX4 and a preliminary clinical trial
mophilia B (factor IX activity ≤2 IU/dL).1 Etranacogene deza-               showed FIX levels achieved post-gene transfer in the range of
parvovec (previously identified as AMT-061) is derived from a               mild hemophilia or at near-lower normal level after one year of
previous AMT-060 vector that consists of an adeno-associated                follow-up.5
virus 5 vector incorporating a small gene cassette containing                    After a lead-in period (≥6 months) of usual FIX prophylaxis,
codon-optimized wild-type human FIX coding sequence under                   participants in the HOPE-B study were treated with a single infu-




                                                                                                        ly
the control of a liver-specific promoter (LP1).2 AMT-060 induced            sion of etranacogene dezaparvovec (2×1013 gc/kg) and followed-
sustained FIX levels in the range of 5-10 IU/dL up to 5 years in            up for 18 months. In total, 53 participants completed the follow-up




                                                                                               on
9/10 patients with severe or moderately severe hemophilia B.3               period. One participant discontinued treatment after receiving a
Etranacogene dezaparvopvec has the identical AMT-060 design                 partial dose of ~10% following an event of hypersensitivity.
except for a two- nucleotide substitution in the FIX coding se-             Etranacogene dezaparvovec significantly increased FIX activity,




                                                                                         e
quence resulting in a single amino acid change (R338L) in the               with a mean of 36.2 IU/dL, 38.8 IU/dL and 34.3 IU/dL at 6-, 12-
catalytic domain. This change reproduces the highly active FIX-
Padua variant, a natural occurring FIX variant associated with                    us
                                                                            and 18-months post- treatment, respectively.1 Mean annualized
                                                                            bleeding rate (ABR) decreased from 4.19 (95%CI: 3.22, 5.45)
                                                                            during the lead-in period to 1.51 (95%CI: 0.81, 2.82) during
                                                                            al
                                                                            months 7-18 post-treatment. The mean ABR decreased from 1.52
                                                                            (95%CI: 1.01, 2.30) during the lead-in period to 0.44 (95%CI:
                                                                  ci

  Correspondence: Giancarlo Castaman, Center for Bleeding Disor-            0.17, 1.12) during months 7-18. Overall, 63% of participants had
  ders and Coagulation, Department of Oncology, Careggi Univer-
                                                                            zero bleeding episodes post-treatment, compared with 26% of par-
                                                                er


  sity Hospital, 50134 Florence, Italy.
  E-mail: giancarlo.castaman@unifi.it;                                      ticipants during lead-in. Following treatment with etranacogene
                                                               m



  castaman@aou-careggi.toscana.it                                           dezaparvovec, FIX concentrate prophylaxis was discontinued in
                                                                            96% (52/54) of participants from day 21 through to month 18.
                                                    om




  Citation: Castaman G. Gene transfer in hemophilia B: a big step                Notably, transaminitis requiring corticosteroid treatment was
  forward. Bleeding, Thrombosis, and Vascular Biology 2023;2:70.            observed in about 20% of patients only, a figure by far lower than
                                                                            that observed in a recent gene therapy trial for hemophilia A.6 Fur-
  Key words: gene transfer; hemophilia.
                                             -c




                                                                            thermore, successful transgene expression was achieved despite
                                                                            the presence of anti-AAV5 antibodies (up to a titer of 1:700); one
  Conflict of interest: GC is in the steering Committee of HOPE-B
                                    on




  study (CSL Behring).                                                      participant with a very high AAV5 NAbs titer (1:3212) did not
                                                                            express FIX Padua and remained on FIX prophylaxis.1
  Funding: GC received speaker fees or for participation into Advi-              These results represent an outstanding, big step forward for
                              N




  sory Boards from Bayer, Biomarin, CSL Behring, Takeda, SOBI,              effective gene transfer in hemophilia B. Early AAV-mediated gene
  Novo Nordisk, Pfizer, Roche, LFB, Grifols, Kedrion.                       therapy trials focused on hemophilia B in part because the FIX
                                                                            cDNA is relatively small (1.5 kb), its expression pathway is sig-
  Received: 17 March 2023.                                                  nificantly less complex than that of FVIII and hepatocytes are the
  Accepted: 21 April 2023.
                                                                            natural site of FIX synthesis. The history of gene therapy for he-
  Publisher’s note: all claims expressed in this article are solely those   mophilia began indeed with the first trial published in 2011 in 10
  of the authors and do not necessarily represent those of their affili-    hemophilia B subjects who received a single intravenous infusion
  ated organizations, or those of the publisher, the editors and the re-    of self-complementary AAV2/8-LP1-hFIXco at a dose of 2𝗑1011
  viewers. Any product that may be evaluated in this article or claim       vg/kg, 6𝗑1011 vg/kg, or 2𝗑1011 vg/kg.7 Long-term FIX expression
  that may be made by its manufacturer is not guaranteed or endorsed        at 1 IU/dL to 8 IU/dL of normal FIX activity was established in
  by the publisher.                                                         all 10 subjects and levels have remained stable over 10 years of
                                                                            follow-up, with a significant reduction in the annual FIX concen-
  ©
   Copyright: the Author(s), 2023                                           trate usage and frequency of spontaneous bleeding.8
  Licensee PAGEPress, Italy
                                                                                 An important aspect of gene therapy, together with long-term
  Bleeding, Thrombosis and Vascular Biology 2023; 2:70
  doi:10.4081/btvb.2023.70                                                  safety, is represented by the durability of transgene expression in
                                                                            individual patients. In clinical trials, no decline of FIX expression
  This work is licensed under a Creative Commons Attribution-               has been observed in adult patients with hemophilia B up to 8-
  NonCommercial 4.0 International License (CC BY-NC 4.0).                   years post-administration.8 AMT-060 has demonstrated stability
                                                                            and durability for up to 5-years post-administration and etranaco-


                                              Bleeding, Thrombosis and Vascular Biology 2023; 2:70
                                              Gene transfer in hemophilia B: a big step forward                                              9



gene dezaparvovec has demonstrated stability and durability for           given to the patient. Patient association groups can play an im-
up to 3-years post-administration.9 This pattern contrasts with the       portant role in this aspect. An adequate laboratory surveillance
decline of FVIII over the first 2-5 years post-administration after       needs to be available at all stages pre- and post-procedure and a
gene therapy with valoctocogene roxaparvovec.10 Whatever the              structured follow-up must be provided to all patients, particularly
reason for this discrepancy, it should be kept in mind the possi-         in the first year after gene therapy. All in all, however, gene ther-
bility of a harmful endoplasmic reticulum stress response caused          apy for hemophilia appears to have taken a path of no return.
by overexpression of FVIII transgene which, at variance with FIX,
is not naturally synthesized in hepatocytes, but rather in endothe-
lial cells.11                                                             References
     The safety profile of etranacogene dezaparvovec was compa-
rable in patients with and without pre-existing AAV5 Nabs.1 A se-          1. Pipe SW, Leebeek FWG, Recht M, et al. gene therapy with
rious adverse event of hepatocellular carcinoma (HCC) occurred                etranacogene dezaparvovec for hemophilia B. N Engl J Med
in a participant in HOPE-B trial with multiple independent risk               2023;388:706-18.
factors. An independent molecular tumor characterization and               2. Miesbach W, Meijer K, Coppens M, et al. Gene therapy with
vector integration analysis established that the HCC event was                adeno-associated virus vector 5-human factor IX in adults
unrelated to treatment.12 Integration analysis measured a low level           with hemophilia B. Blood 2018;131:1022-31.
of integration (0.027%) in both tumor and control liver tissue sam-        3. Batty P, Lillicrap D. Hemophilia gene therapy: approaching
ple.12 The data from the original study by Nathwani et al. and                the first licensed product. Hemasphere 2021;5:e540.




                                                                                             ly
those from AMT- 060 study however did not report long-term                 4. Simioni P, Tormene D, Tognin G, et al. X-linked thrombo-




                                                                                     on
safety issues,2,7 but clearly accurate long-term follow-up is manda-          philia with a mutant factor IX (factor IX Padua). N Engl J
tory to record any safety issue potentially related to gene therapy.          Med 2009;361:1671-5.
     So, what will the role of gene therapy in hemophilia B be with        5. George LA, Sullivan SK, Giermasz A, et al. Hemophilia B




                                                                               e
the present therapeutic options? Traditional treatment options for            gene therapy with a high- specific-activity factor IX variant.
                                                                              N Engl J Med 2017;377:2215-27.
hemophilia B take now huge advantage of the significant prolon-
gation of FIX half-life achieved with extended half-life concen-
trates which allow for infusion administered every 7-14 days or
                                                                        us 6. Ozelo MC, Mahlangu J, Pasi KJ, et al. Valoctocogene
                                                                              roxaparvovec gene therapy for hemophilia A. N Engl J Med
                                                                   al
even 21 days.13 Thus, the option of gene transfer must be weighted            2022; 386:1013-25.
considering the efficacy and safety of the traditional therapy, the        7. Nathwani AC, Tuddenham EG, Rangarajan S et al.
                                                    ci

fact that gene therapy is available for persons aged ≥18 years only           Adenovirus-associated virus vector- mediated gene transfer
and patient’s expectations.                                                   in hemophilia B. N Engl J Med 2011;365:2357-65.
                                                  er


     With the recent approval of etranacogene dezaparvovec                 8. Nathwani AC, Reiss U, Tuddenham E, et al. Adeno-associated
(Hemgenix®) in US in November 2022 and in EU in February                      mediated gene transfer for hemophilia B: 8 year follow up
                                                 m




2023,14,15 the affordability of AAV gene therapy becomes an urgent            and impact of removing "empty viral particles" on safety and
                                                                              efficacy of gene transfer. Blood 2018;132:491.
                                       om




issue that should be managed accurately by the regulatory author-
ities together with the pharmaceutical companies. Payment mod-             9. von Drygalski A, Gomez E, Giermasz A, et al. Stable and
els for this high-cost one-time therapy should be developed with              durable factor IX levels in hemophilia B patients over 3 years
possible repayment schemes, which should also include the costs               post etranacogene dezaparvovec gene therapy. Blood Adv
                                 -c




of intense follow-up.16 Hemgenix® has been priced with the high-              2022 [Online ahead of print].
                         on




est, unprecedented cost for a drug which could result in impeding         10. Mahlangu J, Kaczmarek R, von Drygalski A et al. Two-year
patient access and strain health care budget. However, successful             outcomes of valoctocogene roxaparvovec therapy for
gene therapy for hemophilia B could offer the potential advantage             hemophilia A. N Engl J Med 2023;388:694-705.
                   N




of continuous endogenous expression of clotting factor, therefore         11. Fahs SA, Hille MT, Shi Q, et al. A conditional knockout
eliminating breakthrough and sub-clinical bleeding, thus reducing             mouse model reveals endothelial cells as the principal and
the need for frequent medical interventions, improving quality of             possibly exclusive source of plasma factor VIII. Blood
life and preventing long-term disability. Thus, gene therapy has              2014;123:3706-13.
the potential to yield significant savings for the health care system     12. Schmidt M, Foster G, Coppens M, et al. Liver safety case
and society in general but may still prove to be unaffordable for             report from the phase 3 HOPE- B gene therapy trial in adults
patients living in developing or emerging economies.                          with hemophilia B. Res Pract Thromb Haemost 2021;5.
     Gene therapy is a complex and costly treatment process, and          13. Mancuso ME, Lubetsky A, Pan-Petesch B, et al. Long-term
it will likely first be offered at comprehensive care centers with            safety and efficacy of rIX-FP prophylaxis with extended
facilities available and significant expertise in the management              dosing intervals up to 21 days in adults/adolescents with
of patients with hemophilia. A recent joint publication from the              hemophilia B. J Thromb Haemost 2020;18:1065-74.
European Association for Haemophilia and Allied Disorders and             14. CSL Behring. Prescribing Information - HEMGENIX 2022.
the European Haemophilia Consortium suggested that a modi-                    Available from: https://www.fda.gov/media/163467/ down-
fied hub-and- spoke model, incorporating a long-term safety and               load. [Accessed on January 2023].
efficacy surveillance system, should be introduced to ensure ap-          15. CSL Behring. HEMGENIX - Summary of Product
propriate prescription, administration and monitoring of gene                 Characteristics 2023. Available from: https://www.ema.
therapy results.17,18                                                         europa.eu/en/documents/product-information/hemgenix-epar-
     An active engagement of patients will be very important and              product-information_en.pdf [Accessed on March 2023].
can be obtained through an adequate explanation and support               16. Vokinger KN, Avorn J, Kesselheim AS. Sources of innovation


                                          Bleeding, Thrombosis and Vascular Biology 2023; 2:70
10                                                            G. Castaman




    in gene therapies- Approaches to achieving affordable prices.         eahad.org/wp-content/uploads/2020/05/Hub-and-Spoke.pdf
    N Engl J Med 2023;388:292-5.                                          [Accessed on May 2022].
17. European Association for Haemophilia and Allied Disorders.        18. Miesbach W, Chowdary P, Coppens M, et al. Delivery of AAV-
    EAHAD-EHC joint statement on: promoting hub-and-spoke                 based gene therapy through haemophilia centres: a need for re-
    model for the treatment of haemophilia and rare bleeding              evaluation of infrastructure and comprehensive care: joint pu-
    disorders using gene therapies. Available online: http://             blication of EAHAD and EHC. Haemophilia 2021;27:967-73.




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