Evolution of haemophilia integrated care in the era of gene therapy: Treatment centre’s readiness in United States and EU

Miesbach, Wolfgang; Pasi, K. J.; Pipe, Steven W.; Hermans, Cédric; O’Mahony, Brian; Guelcher, Christine; Steiner, Bruno; Skinner, Mark W

doi:10.1111/hae.14309

Cited by 16 publications

(38 citation statements)

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“…The joint publication from the European Association for Haemophilia and Allied Disorders (EAHAD) and the European Haemophilia Consortium has outlined a proposed “hub and spoke” model of integrated care that could be implemented with modifications within any country with the expectation that the care models would be dynamic and adaptable as more is learned regarding safety and efficacy of this treatment modality and with better understanding of the hurdles that must be overcome at individual sites 22 . Potential division of responsibilities among one or more centres within this hub and spoke model include a Supervisory/Coordinating Centre with responsibility for all aspects of gene therapy care (consenting, dosing, follow up and data reporting), Dosing Centre responsible for the receipt, preparation and administration of the gene therapy product and a Referral/Follow Up Centre , responsible for identification and screening of eligible patients and involved in specific aspects of follow up care under guidance of the Coordinating Center 23 …”

Section: Infrastructure Required For Gene Therapy Implementationmentioning

confidence: 99%

“…22 Potential division of responsibilities among one or more centres within this hub and spoke model include a Supervisory/Coordinating Centre with responsibility for all aspects of gene therapy care (consenting, dosing, follow up and data reporting), Dosing Centre responsible for the receipt, preparation and administration of the gene therapy product and a Referral/Follow Up Centre, responsible for identification and screening of eligible patients and involved in specific aspects of follow up care under guidance of the Coordinating Center. 23 Both the "hub and spoke" and division of responsibility models have developed organically among the HTCs within the clinical trial programs to date. Practical implementation of gene therapy within the HTCs will involve expanding these models of care and transitioning from the clinical trial infrastructure to the clinical care infrastructure.…”

Section: Infrastructure Required For Gene Therapy Implementationmentioning

confidence: 99%

“…Multidisciplinary haemophilia experts have established four universal principles for the introduction of gene therapy: (1) The Person with haemophilia (PWH) should be at the centre of decision-making, (2) All PWH should have equal opportunity to access gene therapy, (3) Safe introduction of commercial gene therapy with lifelong follow-up is paramount to ensuring long-term success, and (4) The integrated comprehensive care model currently employed for the treatment of haemophilia improves outcomes and is best placed to support the introduction and long-term follow up of gene therapy. 23 Accordingly, the haemophilia treatment centres (HTCs) will need to be involved throughout the patient's journey, leveraging the existing expertise and relationship with PWH under their care.…”

Section: Infrastructure Required For Gene Therapy Implementationmentioning

confidence: 99%

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Gene therapy: Practical aspects of implementation

2022

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The first wave of gene therapies for haemophilia submitted for regulatory review utilize a liver-directed approach in which a functional gene copy of factor VIII (FVIII) or factor IX (FIX) is packaged inside a recombinant adeno-associated viral vector (rAAV).Following a single treatment event, these particles are taken up into liver cells, where the rAAV uncoats and delivers the DNA to the nucleus of the cell, where genetic elements that accompany the gene allow for efficient expression and secretion of FVIII or FIX protein into the plasma. An immune response to the vector capsid has been manifest by elevations in common liver enzymes that must be diligently followed postinfusion for weeks and months afterward and if signs of toxicity appear, will trigger a course of immunosuppression. Despite this, the studies have shown that this works in the great majority of individuals and the immunosuppression course is either avoided or short-lived for many. Optimal outcomes in the haemophilia population will be dependent on proper screening assessment and maintenance of liver health prior to consideration of gene therapy, close short-term follow up and implementation of immunomodulatory strategies to identify and manage liver toxicity and preserve durable transgene expression. This review proposes best practices to assist clinical teams with overcoming the challenges this platform of therapy poses to the traditional clinical care models and infrastructure within the haemophilia treatment centres (HTCs) who will be coordinating the patient's journey through this potentially transformative therapy. K E Y W O R D Sgene therapy, haemophilia treatment centre, immunosuppression, infrastructure, liver health LIVER HEALTH, SCREENING AND SHORT-TERM FOLLOW-UPSeveral hepatic considerations are relevant in the context of gene therapy as not uncommonly, such patients may have underlying liver disease at baseline or have hepatic abnormalities while undergoing therapy with the attendant long-term risk of hepatocellular carcinoma (HCC), a potential concern in patients undergoing gene therapy. The common hepatic conditions that are encountered in the general pop-This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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Section: Infrastructure Required For Gene Therapy Implementationmentioning

confidence: 99%

Section: Infrastructure Required For Gene Therapy Implementationmentioning

confidence: 99%

Section: Infrastructure Required For Gene Therapy Implementationmentioning

confidence: 99%

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Gene therapy: Practical aspects of implementation

2022

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“…As a new technology, gene therapy presents unique challenges for healthcare providers who will be introducing and delivering it to the patients. Initiatives toward formulating principles and providing guidance are afoot 136–139 . AAV gene therapy has proven itself as a powerful platform for therapeutic gene transfer, as evidenced by almost 150 clinical trials registered to date and several regulatory approvals, but it has room for improvement and will continue to evolve 140–142 .…”

Section: Chasing the Dream Of Gene Therapymentioning

confidence: 99%

“…Initiatives toward formulating principles and providing guidance are afoot. [136][137][138][139] AAV gene therapy has proven itself as a powerful platform for therapeutic gene transfer, as evidenced by almost 150 clinical trials registered to date and several regulatory approvals, but it has room for improvement and will continue to evolve. [140][141][142] Due diligence in addressing uncertainties will be paramount for the haemophilia community, who have endured a difficult safety legacy and failed hopes.…”

Section: Reducing Uncertaintymentioning

confidence: 99%

Gene therapy – are we ready now?

Kaczmarek

2022

Haemophilia

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Introduction:Haemophilia therapy has evolved from rudimentary transfusion-based approaches to an unprecedented level of innovation with glimmers of functional cure brought by gene therapy. After decades of misfires, gene therapy has normalized factor (F)VIII and factor (F)IX levels in some individuals in the long term. Several clinical programmes testing adeno-associated viral (AAV) vector gene therapy are approaching completion with imminent regulatory approvals.Discussion: Phase 3 studies along with multiyear follow-up in earlier phase investigations raised questions about efficacy as well as short-and long-term safety, prompting a reappraisal of AAV vector gene therapy. Liver toxicities, albeit mostly low-grade, occur in the first year in at least some individuals in all haemophilia A and B trials and are poorly understood. Extreme variability and unpredictability of outcome, as well as a slow decline in factor expression (seemingly unique to FVIII gene therapy), are vexing because immune responses to AAV vectors preclude repeat dosing, which could increase suboptimal or restore declining expression, while overexpression may result in phenotoxicity. The long-term safety will need lifelong monitoring because AAV vectors, contrary to conventional wisdom, integrate into chromosomes at the rate that calls for vigilance.Conclusions: AAV transduction and transgene expression engage the host immune system, cellular DNA processing, transcription and translation machineries in ways that have been only cursorily studied in the clinic. Delineating those mechanisms will be key to finding mitigants and solutions to the remaining problems, and including individuals who cannot avail of gene therapy at this time.

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Data sharing to advance gene‐targeted therapies in rare diseases

Lekstrom-Himes

Augustine

Brower

et al. 2023

American J of Med Genetics Pt C

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Recent advancements in gene‐targeted therapies have highlighted the critical role data sharing plays in successful translational drug development for people with rare diseases. To scale these efforts, we need to systematize these sharing principles, creating opportunities for more rapid, efficient, and scalable drug discovery/testing including long‐term and transparent assessment of clinical safety and efficacy. A number of challenges will need to be addressed, including the logistical difficulties of studying rare diseases affecting individuals who may be scattered across the globe, scientific, technical, regulatory, and ethical complexities of data collection, and harmonization and integration across multiple platforms and contexts. The NCATS/NIH Gene‐Targeted Therapies: Early Diagnosis and Equitable Delivery meeting series held during June 2021 included data sharing models that address these issues and framed discussions of areas that require improvement. This article describes these discussions and provides a series of considerations for future data sharing.

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Evolution of haemophilia integrated care in the era of gene therapy: Treatment centre’s readiness in United States and EU

Abstract: How to cite this article: Miesbach W, Pasi KJ, Pipe SW, et al. Evolution of haemophilia integrated care in the era of gene therapy: Treatment centre's readiness in United States and EU.

Cited by 16 publications

References 12 publications

Gene therapy: Practical aspects of implementation

Gene therapy: Practical aspects of implementation

Gene therapy – are we ready now?

Data sharing to advance gene‐targeted therapies in rare diseases

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