10.4081/btvb.2023.64
Very few rare diseases have witnessed the gigantic progress in patient care that took place for the hemophilias in the last 20 years. The first landmark was in the 1990s, when recombinant DNA technology afforded the industrial production, regulatory approval and commercialization of an array of factor VIII (FVIII) and factor IX (FIX) products, potentially available in unlimited quantity, efficacious and free from the risk of transmission of such bloodborne infections as HIV and the hepatitis virus B and C [...].
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Pier Mannuccio Mannucci
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Bleeding, Thrombosis and Vascular Biology
efanesoctocog
Growing weapons to fight hemophilia
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Invited Editorials
2023-02-23
2023-02-16
2023-01-27
2023-04-04
Bleed Thromb Vascul Biol
Pier Mannuccio Mannucci
2023/02/23
10.4081/btvb.2023.64
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan
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efanesoctocog
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Shapiro AD, Angchaisuksiri P, Astermark J, et al. Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: phase 2 trial results. Blood 2019;134:1973-82.
Growing weapons to fight hemophilia
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                                                                                                          INVITED EDITORIAL

Growing weapons to fight hemophilia
Pier Mannuccio Mannucci

Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan,
Italy




    Very few rare diseases have witnessed the gigantic                       episodes for the prevention of arthropathy, the main chronic
progress in patient care that took place for the hemophilias                 consequence of hemophilia. Following this trial and the
in the last 20 years. The first landmark was in the 1990s,                   availability of recombinant products prophylaxis, pioneered
when recombinant DNA technology afforded the industrial                      in Sweden,3 but not implemented on a large scale else-
production, regulatory approval and commercialization of                     where, became truly feasible.
an array of factor VIII (FVIII) and factor IX (FIX)                              The snag of prophylaxis was the need to administer re-
products,1 potentially available in unlimited quantity, effi-                combinant FVIII by intravenous injections that, owing to




                                                                                               ly
cacious and free from the risk of transmission of such                       the short plasma half-life of this protein, had to be generally




                                                                                       on
bloodborne infections as HIV and the hepatitis virus B and                   carried out at alternate days in order to transform severe he-
C (Figure 1). Recombinant FVIII made feasible one of the                     mophilia A (plasma levels FVIII less than 1%) into a mod-
few randomized clinical trials ever done in such a rare dis-                 erately severe disease (factor levels of at least 2-3%) and,




                                                                                 e
ease as hemophilia.2 Its results provided for the first-time                 thereby, minimize the rate of bleeding episodes.4 To give
unequivocal evidence that prophylactic replacement ther-
apy was superior to the episodic management of bleeding
                                                                            us
                                                                             an idea of the burden of prophylaxis, the average patient
                                                                             with severe FVIII deficiency had to undergo as many as
                                                                             160-180 yearly venipunctures, with inevitable adherence
                                                                            al
                                                                             issues particularly for children and patients with an active
                                                         ci

                                                                             lifestyle. As much as recombinant DNA technology was
  Correspondence: Pier Mannuccio Mannucci, Fondazione IRCCS                  the turning point in the 1990s to start effective patient care,
                                                       er


  Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi                   this technology was again employed in the 2010-2020
  Bonomi Hemophilia and Thrombosis Center, Milan, Italy.
                                                                             decade in the attempt to extend the relatively short plasma
                                                      m



  Tel.: +39.02. 55035421.
  E-mail: piermannuccio.mannucci@unimi.it                                    half-life of coagulation factors, increase the time interval
                                          om




                                                                             between the doses and ultimately reduce the number of
  Citation: Mannucci PM. Growing weapons to fight hemophilia.                venipunctures. Two main protein modification techniques
  Bleeding, Thrombosis, and Vascular Biology 2023;2:64.
                                                                             have been employed to obtain therapeutic factor products
                                    -c




  Key words: hemophilia, recombinant prophylactic therapy, rFVIII            with a more extended half-life: recombinant fusion with
                                                                             plasma proteins endowed with a long half-life such as al-
                           on




  plasma half-life, efanesoctocog
                                                                             bumin and the Fc component of IgG1 immunoglobin or
  Conflict of interest: The Author declares no potential conflict of
                                                                             conjugation with a chemical such as polyethylene glycol
                     N




  interest.
                                                                             (PEG). Both these techniques have been implemented by
  Funding: None.                                                             industrial manufactures of recombinant FVIII and FIX
                                                                             products, so that at the time being 7 different brands are ap-
  Received for publication: 16 February 2023.
  Accepted for publication: 17 February 2023.                                proved by the regulatory agencies Food and Drug Admin-
                                                                             istration in the USA and European Medicines Agency in
  Publisher’s note: All claims expressed in this article are solely those    Europe (Table 1).5,6 The pivotal clinical trials that led to the
  of the authors and do not necessarily represent those of their affili-     approval and commercial availability of these products
  ated organizations, or those of the publisher, the editors and the re-
  viewers. Any product that may be evaluated in this article or claim
                                                                             showed that both the protein modification techniques were
  that may be made by its manufacturer is not guaranteed or endorsed         able to extend the plasma half-life of the coagulation factors
  by the publisher.                                                          deficient in the hemophilias: in average from 12-14 hours
                                                                             to 16-18 for FVIII, more so for FIX (from 18-22 to 90-100
  ©
   Copyright: the Author(s), 2023
                                                                             hours) (Table 1).5,6
  Licensee PAGEPress, Italy
  Bleeding, Thrombosis and Vascular Biology 2023; 2:64                           The clinical advantages in terms of reduction of the
  doi:10.4081/btvb.2023.64                                                   yearly number of intravenous injections are unequivocal:
                                                                             from 180 to 120 injections for hemophilia A, from 100 to
  This work is licensed under a Creative Commons Attribution-
  NonCommercial 4.0 International License (CC BY-NC 4.0).
                                                                             50 for hemophilia B. The definite but only partially satis-
                                                                             factory extension of the half-life of FVIII products led to

                                              Bleeding, Thrombosis and Vascular Biology 2023; 2:64
20                                                               P.M. Mannucci




further research efforts and to the novel medicine efanesoc-                  creates a ceiling to the efforts to prolong FVIII half-life, be-
tocog alfa.7 However, a preamble is needed to explain why                     cause the FVIII products modified by protein fusion or
the extension of FVIII plasma half-life was less than satis-                  PEG conjugation bind to VWF in plasma and thus depend
factory at variance with that of FIX. The point of the matter                 on the half-life of the latter protein. Efanesoctocog alfa is a
is that whereas FIX circulates free in blood, FVIII binds to                  monument of ingenuity in terms of molecular engineering.7
another plasma protein, von Willebrand factor (VWF), and                      To each FVIII molecule the manufactures were able to at-
thus acquires the half-life of its chaperon, only slight longer               tach by fusion 1 Fc molecule and 2 synthetic polypeptides
than that of FVIII (16-18 hours). Hence, binding of VWF                       XTEN.7 However, the truly crucial step was the addition to



Table 1. Factor VIII and IX recombinant products with extended plasma half-life.
Protein name and approval year                 Brand name and manufacturer           Protein modification                  Plasma       Time
                                                                                     technology                            half-life   longer
                                                                                                                           (hours)     half-life




                                                                                                          ly
Efmoroctocog alfa, rFVIII (2014)               Elocta/Eloctate, Sobi                 Fc-fusion                                19       1.5-1.7
Eftrenonacog alfa, rFIX (2014)                 Alprolix, Sobi                        Fc-fusion                                82         4.3




                                                                                                  on
Rurioctocog alfa pegol, rFVIII (2015)          Adynovi/Adynovate, Baxalta/Takeda PEGylatedb (2x20 kDa)                       14.3      1.3-1.5
Albutrepenanocog alfa, rFIX (2016)             Idelvion, CSL Behring                 Albumin-fusion                          101         5.3




                                                                                            e
Nanocog beta pegol, rFIX (2017)                Refixia, Novo Nordisk                 GlycoPEGylatedb (40 kDa)                 93         5.8
Damoctocog alfa pegol, rFVIII (2018)
Turoctocog alfa pegol, rFVIII (2018)
                                               Jivi, Bayer
                                               Esperoct, Novo Nordisk
Efanesoctocog alfa, rFVIII, not yet approved Sanofi/Sobi
                                                                                    us
                                                                                     PEGylatedb (60 kDa)
                                                                                     GlycoPEGylatedb (40 kDa)
                                                                                     FC fusion, XTEN polypeptide fusion,
                                                                                                                              19
                                                                                                                             18.4
                                                                                                                             43.3
                                                                                                                                         1.6
                                                                                                                                         1.6
                                                                                                                                         3-4
                                                                            al
                                                                                     VWF D’D3 fusion
rFVIII, recombinant factor VIII; rFIX, recombinant factor IX; FC, fragment crystallizable; PEG, polyethylene glycol.
                                                                ci
                                                              er
                                                             m
                                                om
                                          -c
                                   on
                            N




Figure 1. Therapeutic advances in hemophilia.


                                           Bleeding, Thrombosis and Vascular Biology 2023; 2:64
                                              Growing weapons to fight hemophilia                                                21



FVIII by molecular engineering of the D’D3 domain of re-           yearly needed infusions will be further reduced in number
combinant VWF, the site where FVIII binds to its                   to at least 50 as it happens already in hemophilia B. Other
chaperon.7 This intriguing and seemingly paradoxical step          competitors will be the bispecific monoclonal antibody
succeeded in disconnecting the half-life of FVIII from that        emicizumab, that mimics the coagulant activity of FVIII
of VWF and thus to counter the half-life ceiling due to the        with the advantage of being administered subcutaneously
binding of FVIII to VWF.                                           at weekly or even more spaced intervals (Figure 1).12 An-
    Spectacular clinical results were obtained when this           other option for adult patients with severe hemophilia A is
product, designed to emancipate FVIII from the slaving             the launch and regulatory approval, at least in Europe, of
exerted by VWF, started clinical development in the frame          the gene therapy product valoctogene roxaparvovec,13 that,
of a phase 1-2 study, that I commented with an editorial           however, can only be used in adults but not in children and
in 2020.8 Konkle et al.9 evaluated two different dosages           has a number of drawbacks discussed elsewhere.14 Other
of the new FVIII (25 IU/Kg and 65 IU/Kg) in 16 adults              products are in the development pipeline. Fitusiran in-
with severe hemophilia A in order to explore not only the          creases thrombin formation by quenching the naturally oc-
degree of FVIII plasma increase and pace of its post-in-           curring anticoagulant antithrombin and can be injected
fusion plasma clearance, but also the safety of this highly        subcutaneously at intervals as spaced as monthly.14 Con-
engineered molecule. The main findings were that both              cizumab is a monoclonal antibody that is designed to re-




                                                                                     ly
doses increased FVIII in plasma as predicted and, most             balance the defective coagulation of hemophilia patients by




                                                                             on
importantly, that FVIII remained in plasma with a half-            inhibiting another naturally occurring anticoagulant, the tis-
life that was up to four times longer than that observed           sue factor pathway inhibitor.16
when the same patients were infused a standard FVIII                   All in all, striking progress is taking place and more is




                                                                       e
product (Table 1). In addition, this early study assured that      coming in the treatment of patients with hemophilia, who
the infusion patients of this highly manipulated molecule
did not disrupt immune tolerance to FVIII, so that none
                                                                us have now acquired a life expectancy very close to that of
                                                                   male peers without hemophilia.
of them developed anti-FVIII inhibitory alloantibodies.
                                                           al
More recently, a phase 3 study of once weekly efanesoc-
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                                              ci

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in hemophilia B. Indeed, it will be feasible to administer             2011;17:41-4.
                                                                    5. Aledort L, Mannucci PM, Schramm W, Tarantino M. Factor
efanesoctocog alfa at weekly or longer intervals in the ma-
                                                                       VIII replacement is still the standard of care in haemophilia
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ongoing pivotal phase 3 study in children was delayed by            7. Chhabra ES, Liu T, Kulman J, et al. BIVV001, a new class of
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                                     Bleeding, Thrombosis and Vascular Biology 2023; 2:64
22                                                           P.M. Mannucci




    tocog alfa prophylaxis for patients with severe hemophilia A.     14. Mannucci PM. Gene transfer in hemophilia A: not cogent yet.
    N Engl J Med 2023;388:310-8.                                          Bleeding, Thrombosis and Vascular Biology 2022; 1:32.
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13. Ozelo MC, Mahlangu J, Pasi KJ, et al. Valoctocogene roxa-             neous concizumab prophylaxis in hemophilia A and hemo-
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