10.4081/btvb.2022.32
The phase 3 clinical study of gene transfer in hemophilia A using the BioMarin vector AAV5-hFVIII-SQ (also identified as valoctocogene roxaparvovec) recently reported the results obtained in as many as 134 adult men with severe hemophilia A, so that it is at the moment the largest gene transfer study ever conducted in a rare monogenic disorder [...].
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Pier Mannuccio Mannucci
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Bleeding, Thrombosis and Vascular Biology
Editorial
Gene transfer in hemophilia A: not cogent yet
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2022-04-20
2022-04-01
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Bleed Thromb Vascul Biol
Pier Mannuccio Mannucci
2022/04/20
10.4081/btvb.2022.32
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan
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Peyvandi F, Garagiola I, Mannucci PM. Post-authorization pharmacovigilance for hemophilia in Europe and the USA: independence and transparency are keys. Blood Rev 2021;49:100828.
Gene transfer in hemophilia A: not cogent yet
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                                                                                                                       EDITORIAL

Gene transfer in hemophilia A: not cogent yet
Pier Mannuccio Mannucci

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




    The phase 3 clinical study of gene transfer in hemo-                    this approach in the context of the currently blooming sce-
philia A using the BioMarin vector AAV5-hFVIII-SQ                           nario of the care of persons with hemophilia (PWH). My
(also identified as valoctocogene roxaparvovec) recently                    personal views are those of a senior insider who is also
reported the results obtained in as many as 134 adult men                   an innocent bystander, because I am not personally in-
with severe hemophilia A, so that it is at the moment the                   volved in any of the many ongoing trials of gene transfer
largest gene transfer study ever conducted in a rare mono-                  in hemophilia A and B.
genic disorder.1 The relevance of the study is witnessed                         I shall also try to first convey the opinions of a few
by its publication in a leading medical journal such as the                 PWH. When at joint meetings and/or in the frame of my




                                                                                             ly
New England Journal of Medicine,1 with an accompany-                        clinical practice I meet them and I happen to explain to




                                                                                      on
ing editorial.2 The article and related editorial provide in-               them and their next-of-kin the outstanding progresses wit-
formation on the many positive results obtained but also                    nessed in the management of this disease, particularly in
on the limitations and still unanswered questions. Among                    the last 10 miraculous years,3 their comment is almost al-



                                                                                e
them, the pre-existing antibodies against the viral vector,                 ways the same “OK, doc, fantastic!, but when are we
the high between-patients variability of the factor VIII re-
                                                                           us
                                                                            going to be ultimately cured from this scourge?” This
sponse and its downward trend during the limited follow-                    eager question is made in the context of a scenario char-
up period. Yet, it is expected that this publication will                   acterized by a life expectancy of PWH that is practically
                                                                           al
accelerate the regulatory approval within 2022 of this                      identical to that of their male peers without the disease
                                                        ci

gene transfer products for clinical use, at least by the Food               and by a quality of life that, notwithstanding a lifelong
and Drug Administration in the USA.                                         chronic ailment, is made good by the fact that currently
                                                      er



    With this preamble on the monument of ingenuity rep-                    available intravenous and subcutaneous therapeutic prod-
resented by this hallmark study that demonstrates the fea-                  ucts succeed to avoid almost completely spontaneous
                                                     m




sibility of transfer to patients of such a huge gene as F8,                 bleeding episodes (the so called zero bleeding rate).
                                          om




I shall try to convey my views on the real-life impact of                        In this frame, which expectations but also uncertain-
                                                                            ties on gene therapy do I gather from PWH? Their moti-
                                                                            vations and exigencies for this novel therapeutic approach
                                   -c




                                                                            are to skip forever the need of repeated intravenous infu-
                                                                            sions or subcutaneous punctures, the desire to live a new
                          on




  Correspondence: Pier Mannuccio Mannucci, Fondazione IRCCS
  Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi                  a life without hemophilia with the related mental freedom,
  Bonomi Hemophilia and Thrombosis Center, Milan, Italy.
                                                                            as well as the ability to freely travel to countries or regions
                    N




  Tel.: +39.02. 55035421.
  E-mail: piermannuccio.mannucci@unimi.it                                   where treatment is not available or less than optimal. By
                                                                            the same token, patients are cognizant of barriers that still
  Key words: Gene transfer, hemophilia A, editorial.
                                                                            make them hesitant. Beside concerns about potential, very
  Conflict of interest: The author declares no potential conflict of in-    rare and thus still unknown long-term side effects that
  terest.                                                                   may emerge only post marketing in real life use, as well
                                                                            as the limited evidence that the attained factor VIII plasma
  Funding: None.
                                                                            levels will be sufficient to obtain and maintain the goal of
  Received for publication: 1 April 2022.                                   zero bleeding, PWH mention the burden of gene therapy
  Accepted for publication: 1 April 2022.                                   in terms of costs for them and the community, as well as
                                                                            the uncertainty regarding the need and feasibility of re-
  This work is licensed under a Creative Commons Attribution Non-
  Commercial 4.0 License (CC BY-NC 4.0).
                                                                            peating the first gene transfer. On the whole, my impres-
                                                                            sion is that, notwithstanding the positive current scenario
  ©
   Copyright: the Author(s), 2022                                           of their care they are happy about the forthcoming avail-
  Licensee PAGEPress, Italy                                                 ability of this new weapon, but also fully aware of existing
  Bleeding, Thrombosis and Vascular Biology 2022; 1:32
  doi:10.4081/btvb.2022.32                                                  and potential limitations.
                                                                                 With this preamble on the opinions recorded from

                                              Bleeding, Thrombosis and Vascular Biology 2022; 1:32
34                                                       P.M. Mannucci




PWH, in the second part of this commentary I shall share          sence of approval. My hope of an uncurable optimist is
with you my own concerns and hesitancies, notwithstand-           that in Italy and perhaps other countries the national drug
ing my enthusiasm for this milestone that will hopefully          agencies will be able to negotiate a reasonable price with
come soon to a climax with the regulatory approval.1 In           the manufactures, taking as example the antiviral drugs
addition to the unanswered question on whether or not a           for hepatitis C that are much less costly than in other
single intravenous injection of the vector carrying the           countries such as the USA.
transgene will be able to offer life-long bleeding preven-            All in all, my comments on the article Ozelo et al.1 are
tion, it is a fact and deed that at the time being and also       that the reported findings are still unsettled in terms of the
when approved gene therapy will be applicable only to             broad application of this therapy in real life, at a time
adults but not to children with hemophilia, obviously and         when drugs such as emicizumab and FVIII products with
definitely the main and ideal target of any curative strategy     a truly extended plasma half-life are offering further
in any inherited disease. Furthermore, I am concerned not         promising weapons to the already rich array.4,5 My perusal
only by the potential of DNA integration of the transgene         of the article and accompanying editorial tells me that
but much more so by the observed high rate of serum               both authors and editorialist are aware of the preliminary
transaminases increase, that means unequivocally that             value to their findings, because there is clear emphasis on
some degree of hepatocyte necrosis occurred after the             the need of a more prolonged patient follow-up. More-
transgene reached the liver. This frequent adverse effect         over, I strongly hope that strict post-marketing surveil-




                                                                                            ly
                                                                  lance will be implemented transparently and
did need for its control high doses of corticosteroids for at




                                                                                   on
                                                                  independently from manufacturers.6
least two months, but even longer for many cases.1,2 Inci-
dentally, the term transaminitis, frequently used to describe
this biochemical abnormality, is not only inaccurate but


                                                                              e
                                                                  REFERENCES
also misleading, because it gives the undue impression of                us
a benign phenomenon, which remains to be demonstrated              1. Ozelo MC, Mahlangu J, Pasi KJ, et al. Valoctocogene roxa-
in the absence of liver biopsies and a long follow-up.                parvovec gene therapy for hemophilia A. N Engl J Med
                                                                      2022;386:1013-25.
                                                                 al
    An obvious and additional snag is that there is still
                                                                   2. Thornburg CD. Prepare the way for hemophilia A gene ther-
no information of the costs and models of payment for
                                                      ci

                                                                      apy. N Engl J Med 2022;386:1081-2.
gene therapy in hemophilia. The early voices and hints             3. Mannucci PM. Miracle of haemophilia drugs: personal views
                                                    er



are worrisome. BioMarin, the Californian-based com-                   about a few main players. Haemophilia 2018;24:557-52.
pany that developed valoctocogene roxaparvovec and                 4. Mannucci PM. Treatment of hemophilia - more amazing
                                                   m




conducted so far all the experimental and pivotal clinical            progress. N Engl J Med 2020;383:1068-70.
studies, did declare to the Wall Street Journal that after         5. Konkle BA, Shapiro AD, Quon DV, et al. BIVV001 fusion
                                          om




                                                                      protein as factor VIII replacement therapy for hemophilia
approval for clinical use they planned to look for a price
                                                                      A. N Engl J Med 2020;383:1018-27.
between 2 and 3 million dollars per dose and patient.              6. Peyvandi F, Garagiola I, Mannucci PM. Post-authorization
                                    -c




This would make this pharmaceutical product the most                  pharmacovigilance for hemophilia in Europe and the USA:
expensive in the history of medicine! A comprehensive                 independence and transparency are keys. Blood Rev
                             on




cost-effectiveness analysis is still not available in the ab-         2021;49:100828.
                         N




                                     Bleeding, Thrombosis and Vascular Biology 2022; 1:32
