Recombinant factor VIII products and inhibitor development in previously untreated patients with severe haemophilia A: Combined analysis of three studies

Volkers, Peter; Hanschmann, K.-M.; Calvez, Thierry; Chambost, Hérvè; Collins, Peter William; Demiguel, Virginie; Hart, Daniel P.; Hay, C. R. M.; Goudemand, Jenny; Ljung, Rolf; Palmer, Ben; Santagostino, Elena; Hardeveld, Ella M. van; Berg, Marijke van den; Keller‐Stanislawski, Brigitte

doi:10.1111/hae.13747

Cited by 24 publications

(29 citation statements)

References 25 publications

(25 reference statements)

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“…Another topic addressed by the revised guideline is the harmonization of existing national and international hemophilia registries. While hemophilia registries can and do collaborate in regulatory and scientific projects (e.g., [14]), the opportunities for collaboration are limited to registries with compatible datasets. By providing a core dataset for well-defined hemophilia registries in the revised guideline [11], EMA seeks to spur harmonization and facilitate future collaborations between European hemophilia registries.…”

Section: Introductionmentioning

confidence: 99%

The German Hemophilia Registry: Growing with Its Tasks

Duda

Hesse

Haschberger

et al. 2020

JCM

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Hemophilia is a rare heredity bleeding disorder that requires treatment for life. While few therapeutic options were available in the past, multiple recent breakthroughs have fundamentally altered and diversified hemophilia therapy, with even more new therapeutic options forthcoming. These changes are mirrored by significant regulatory and legal changes, which have redefined the role of hemophilia registries in the European Union (EU). This dual paradigm shift poses new regulatory, scientific but also structural requirements for hemophilia registries. The aim of this manuscript is to enumerate these significant challenges and to demonstrate their incorporation into the redesign of the German Hemophilia Registry (Deutsches Hämophilieregister, dhr). To identify the spectrum of hemophilia therapies and the degree of regulatory changes, a horizon screening was performed. Consequently, a core dataset for the dhr was defined by harmonization with regulatory guidelines as well as other hemophilia registries and by heeding the needs of different stakeholders (patients, clinicians, regulators, and scientists). Based on this information, a new registry structure was established, which is optimized for capturing data on new and established hemophilia therapies in a changing therapeutic and regulatory landscape

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Section: Introductionmentioning

confidence: 99%

The German Hemophilia Registry: Growing with Its Tasks

Duda

Hesse

Haschberger

et al. 2020

JCM

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“…Interpretation of its relevance within clinical studies is complex, in that one analysis has demonstrated increased inhibitor risk relating to B‐domain‐deleted rFVIII (Aledort et al , ). However, these findings have not been reproduced in subsequent studies (Volkers et al , ).…”

Section: Factor VIII Proteinmentioning

confidence: 78%

“…Increased inhibitor incidence has recently been confirmed for rFVIII (44·5%) in comparison to pdFVIII (26·8%) in a prospective randomised controlled study in previously untreated severe HA patients (PUPs) (SIPPET, Survey of Inhibitors in Plasma‐Product Exposed Toddlers) (Peyvandi et al , ). Differences in inhibitor incidence have also been described for different individual products and generations of rFVIII concentrates (Volkers et al , ). Potential explanations for these observations might include the FVIII haplotype of the recombinant protein, post‐translational modifications which vary with different cell lines used in preparation or the presence of protein aggregates.…”

Section: Factor VIII Proteinmentioning

confidence: 96%

Advances in knowledge of inhibitor formation in severe haemophilia A

et al. 2020

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Summary Anti‐drug antibody formation following factor VIII (FVIII) replacement therapy is the most important treatment‐related complication in patients with severe haemophilia A. A significant number of these antibodies show neutralising activity against FVIII and are referred to as FVIII inhibitors. Alloimmunity to FVIII, given the absence of endogenous circulating FVIII protein, may be predictable to some extent; however, only 30% of patients develop inhibitors. Genetic and environmental risk factors have been identified, contributing to the likelihood of inhibitor development. Multiple immunological theories have been proposed which in part explain the outcomes of many epidemiological studies. Significant differences exist among replacement therapies, including the source, FVIII sequence, glycosylation, formulation components, impurities and aggregation potential, which significantly complicate interpretation of the results from these studies. In this review, we present recent advances in the understanding of the cellular mechanisms of inhibitor formation and highlight some areas of uncertainty requiring further investigation.

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“…Since the publication of the prospective randomized SIPPET study data, demonstrating a 1.87-fold increase in FVIII inhibitor incidence in previously untreated patients (PUPs) with the use of recombinant as opposed to plasma-derived FVIII, there has been a further search for factors that might provide a biological explanation for this difference (123). Furthermore, four independent cohort studies evaluating FVIII inhibitor incidence in PUPs have documented significant differences between a 2nd generation full-length rFVIII product and 3rd generation rFVIII concentrates, with the 2nd generation concentrate demonstrating a 1.6 to 2.8-fold increase in inhibitor incidence (124)(125)(126)(127)(128). Notably, the full-length 2nd generation product is expressed in baby hamster kidney (BHK) cells and the 3rd generation concentrates in Chinese hamster ovary (CHO) cells.…”

Section: Glycan Influences On Fviii Immunogenicitymentioning

confidence: 99%

Tolerating Factor VIII: Recent Progress

et al. 2020

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Development of neutralizing antibodies against biotherapeutic agents administered to prevent or treat various clinical conditions is a longstanding and growing problem faced by patients, medical providers and pharmaceutical companies. The hemophilia A community has deep experience with attempting to manage such deleterious immune responses, as the lifesaving protein drug factor VIII (FVIII) has been in use for decades. Hemophilia A is a bleeding disorder caused by genetic mutations that result in absent or dysfunctional FVIII. Prophylactic treatment consists of regular intravenous FVIII infusions. Unfortunately, 1/4 to 1/3 of patients develop neutralizing anti-FVIII antibodies, referred to clinically as "inhibitors," which result in a serious bleeding diathesis. Until recently, the only therapeutic option for these patients was "Immune Tolerance Induction," consisting of intensive FVIII administration, which is extraordinarily expensive and fails in ∼30% of cases. There has been tremendous recent progress in developing novel potential clinical alternatives for the treatment of hemophilia A, ranging from encouraging results of gene therapy trials, to use of other hemostatic agents (either promoting coagulation or slowing down anti-coagulant or fibrinolytic pathways) to "bypass" the need for FVIII or supplement FVIII replacement therapy. Although these approaches are promising, there is widespread agreement that preventing or reversing inhibitors remains a high priority. Risk profiles of novel therapies are still unknown or incomplete, and FVIII will likely continue to be considered the optimal hemostatic agent to support surgery and manage trauma, or to combine with other therapies. We describe here recent exciting studies, most still pre-clinical, that address FVIII immunogenicity and suggest novel interventions to prevent or reverse inhibitor development. Studies of FVIII uptake, processing and presentation on antigen-presenting cells, epitope mapping, and the roles of complement, heme, von Willebrand factor, glycans, and the microbiome in FVIII immunogenicity are elucidating mechanisms of primary and secondary immune responses and suggesting additional novel targets. Promising tolerogenic therapies include development of FVIII-Fc fusion proteins, nanoparticle-based therapies, oral tolerance, and engineering of regulatory or cytotoxic T cells to render them FVIII-specific. Importantly, these studies are highly applicable to other scenarios where establishing immune tolerance to a defined antigen is a clinical priority.

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Recombinant factor VIII products and inhibitor development in previously untreated patients with severe haemophilia A: Combined analysis of three studies

Cited by 24 publications

References 25 publications

The German Hemophilia Registry: Growing with Its Tasks

The German Hemophilia Registry: Growing with Its Tasks

Advances in knowledge of inhibitor formation in severe haemophilia A

Tolerating Factor VIII: Recent Progress

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