Gene therapy of hemophilia: Hub centres should be haemophilia centres: A joint publication of EAHAD and EHC

Abstract

Gene therapy has become an increasingly promising, and rapidly developing field, using various innovative techniques to treat, in particular, very rare diseases for which there are no or inadequate treatments. A small number of gene therapies based on adeno-associated viruses (AAV) and lentiviruses have already been approved in the EU and the USA for various hereditary diseases, and several gene therapies are in the late phase of clinical testing. In addition, gene therapies and cell-based therapies are also being used to treat various types of cancer. Accordingly, many types of diseases are now being studied and treated in clinical trials with different gene transfer vectors.1 With this progress, academic hospitals have started to establish general gene therapy centres to pool knowledge and experience with different gene therapy approaches. One advantage could be broader collaboration with other disciplines that use AAV-based gene therapy for monogenic disorders. Outside these centres, knowledge about the different gene therapy approaches, the preparation of genetically modified material with regard to biosafety aspects and the special precautions that become necessary after administration is not well known. While these general approaches may work in other areas, these gene therapy approaches for haemophilia should be done within haemophilia centres. The treatment of haemophilia has been optimised in recent decades through the development of specialised haemophilia centres and improved treatment options. The introduction of long-acting factor concentrates and non-factor therapy, as well as individualised prophylactic approaches, has made treatment more convenient and effective in preventing and treating bleeding.2 The structure of haemophilia treatment centres (HTC) includes multidisciplinary team members to ensure optimal treatment and follow-up of haemophilia as well as possible haemophilia-related comorbidities. The experience of haemophilia doctors therefore, included the treatment of patients infected with various hepatitis B and C viruses as well as HIV, and the long-term treatment of patients who developed severe complications from these infections.3 HTCs have been established to provide a multidisciplinary model of care with access to clinical specialities, emergency departments and appropriate laboratory facilities. The EUHANET project identified 409 haemophilia centres in Europe,4 of which 117 were certified as European Haemophilia Comprehensive Care Centres (EHCCCs), providing specialised and multidisciplinary care at the highest level. Gene therapy for haemophilia presents the potential for further improvement in haemophilia care by enabling long-term expression of the missing factor at therapeutic levels following a single intravenous infusion of the gene therapy construct. Various gene therapies have been studied for both haemophilia A and haemophilia B, and the first products are expected to be approved and available to haemophilia patients in Europe, the Middle East and the United States in 2022. Although trials with AAV predominate, lentiviral vectors for systemic infusion or ex vivo transduction are also being tested preclinically or in phase I clinical trials5; however, no results are published yet. Logistical considerations may be different using the lentivirus approach. Patient information and informed consent is only possible if the aspects of eligibility criteria, implementation and follow-up, as well as the uncertainties associated with gene therapy, can be discussed with the patient. In order to better prepare haemophilia centres, we previously described various aspects of gene therapy in general and safety issues related to gene therapy in haemophilia.6 Gene therapy has some requirements that go beyond the existing diagnostic and treatment capabilities of the haemophilia centres. During the clinical trials, gene therapy was carried out by a few carefully selected haemophilia centres, with the possibility that patients from other centres could also be treated. Therapy and follow-up within the framework of the clinical trials were carried out according to previously defined strict and regularly monitored criteria. For monitoring of safety and efficacy a hub-and-spoke model has recently been proposed.7 Although different models will evolve in different countries, we believe that in haemophilia this is optimally delivered by a hub which is also a haemophilia centre. This model addresses the logistics of patients moving between centres when necessary and the many aspects specific to haemophilia gene therapy, including preparation and administration of the gene therapy product, determination of coagulation and immunological parameters, joint score and function, liver, bone health and long term quality of life of patients. This approach will be progressively developed with the aim of better qualifying more haemophilia centres to deliver gene therapy, ultimately making gene therapy available to all haemophilia patients, regardless of their country or centre of origin. From experience with haemophilia gene therapy trials, several criteria have emerged that a haemophilia gene therapy treatment centre (hub centre) should fulfil in addition to the criteria for the treatment of haemophilia in general. These criteria include knowledge of the preparation, storage and administration of the gene therapy product, but also the management of safety issues. While safety issues during or shortly after administration of the gene therapy product are rare and usually involve allergic reactions that are easily managed, laboratory values (e.g., liver function tests) need to be monitored very closely in the first weeks and months after treatment. Since about 80% of patients in haemophilia A trials and about 30% in haemophilia B trials have had an increased level of ALT,5 the management of such side effect-with immunosuppressive therapy is crucial. Such therapy has both the intended beneficial role of abrogating risk of acutely losing factor expression with potential of unintended, harmful side effects depending on agent and duration of use. Thus, immunosuppressive intervention and oversight requires very close and careful management. The hub-and-spoke centres’ roles in this intensive post gene therapy surveillance period need to be clearly defined and their interactions very carefully coordinated to ensure the optimal management and timely immunosuppressive intervention when indicated. Centres will also need to guide the PwH how to reduce exogenous prophylaxis (either factor or non-factor based) as gene therapy expression emerges post gene therapy infusion, as well as guidance about if and when trauma or procedure based exogenous factor treatment might be required depending on the individual's endogenous factor expression levels. There may be different treatment thresholds for additional treatment between F8 or F9 gene therapy given the former is an acute phase protein for which FVIII levels > 100 IU/dl will be required for serious injury or major trauma, whilst levels of > 50 IU/dl FIX expression would suffice for the equivalent scenario. Our proposed hub-and-spoke model allows patients to be treated in centres with the most experience in gene therapy for haemophilia and to receive their follow-up care in their own spoke centre, which works closely with the hub centre. In contrast to the approach of general gene therapy centres, haemophilia gene therapy has so far been prepared and administered in haemophilia centres that have been appropriately developed for the requirements of gene therapy administration. In addition to the more technical aspect of preparing and administering the gene therapy product, the haemophilia centres specialised for this purpose therefore guarantee many years of expertise in haemophilia treatment as well as contacts with other haemophilia centres, despite regionally different standards. Through long-standing cooperation with other disciplines, haemophilia treatment centres treat acute and long-term complications of haemophilia including treatment-related events such as infectious diseases (e.g., hepatitis C, HIV). Through these pre-existing inter-speciality relationships, haemophilia centres are well positioned to meet the special characteristics of gene therapy for haemophilia in which cooperation with other disciplines, such as hepatologists and immunologists, will play a greater role in both pre and post infusional stages of the gene therapy pathway. In addition, HTCs offer knowledge about the breadth of approved haemophilia treatment options, other emerging therapeutics in clinical trials as well as the nuances of protocol and inclusion criteria differences between gene therapy platforms, to ensure fully supported counselling and truly informed consent before gene therapy is undertaken (Table 1). Compared to other gene therapies, the psychological element of informed consent is different, as the decision is made by the patient and not the parents. Therefore, informed consent needs to be assessed by haemophilia physicians with the involvement of specialist psychologists. Gene therapies have excellent clinical potential, but their success depends critically on adherence to inclusion and exclusion criteria, informed and prepared patient, safe administration of the gene therapy product and close follow-up and support for patients. The various tasks described are to be included in the calculation of reimbursement for gene therapy for haemophilia. A network of centres structured according to the hub-and-spoke model, with both centres acting as haemophilia centres, will optimise patient access to gene therapy and ensure that patients with haemophilia can be adequately informed about haemophilia gene therapy within the standards of care. Hub HTCs will work as a coordinated network, sharing technical skills and resources to deliver safe and effective gene therapy. In the future, the certification process for HTCs will include hub centres and their technical and collaborative capabilities. Wolfgang Miesbach: Bayer, Biomarin, Biotest, CSL Behring, Chugai, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Takeda/Shire, uniQure. Ana Boban: Bayer, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, Sobi, Takeda. Fariba Baghaei: Bayer, Octapharma, Pfizer, Novo Nordisk, Shire/Takeda, Roche, BioMarin, uniQure, Sobi. Pratima Chowdary: advisory boards for Bayer, Boehringer Ingelheim, CSL Behring, Chugai, Freeline, NovoNordisk, Pfizer, Roche, Sanofi, Spark, Sobi and Takeda; and has received research funding from Bayer, CSL Behring, Freeline, Novo Nordisk, Pfizer, SOBI and Takeda. Michiel Coppens: Research support: Bayer, CSL Behring, Roche, Sanquin Blood Supply, UniQure; Consultancy or lecturing fees: Bayer, CSL Behring, Medcon International, MEDtalks, NovoNordisk, Pfizer, Sobi. Daniel P. Hart: Bayer, Biomarin, Biotest, CSL Behring, Grifols, NovoNordisk, Octapharma, Pfizer, Roche, Sanofi, Sobi, Spark, Takeda, UniQure. Victor Jimenez-Yuste: Bayer, Biomarin, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Takeda/Shire. Robert Klamroth: Research Funding and Consultancy: Bayer, Biomarin, Biotest, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, SOBI, Takeda/Shire, uniQure. Mike Makris participated in advisory boards run by Freeline, Spark Therapeutics and NovoNordisk. Flora Peyvandi: speaker at educational symposia organized by Roche, Sanofi, Sobi, Takeda. Member of Advisory Board of Roche, Sanofi, Sobi, Takeda. Wolfgang Miesbach, Fariba Baghaei, Ana Boban, Pratima Chowdary, Michiel Coppens, Daniel P. Hart, Victor Jimenez-Yuste, Robert Klamroth, Mike Makris, Declan Noone, Flora Peyvandi are members of the gene therapy working group or the certification working group of the EAHAD. Wolfgang Miesbach and Flora Peyvandi produced the first draft of this manuscript, which was subsequently revised and finalized with all authors. All authors approved the final manuscript.

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