The role of previously untreated patient studies in understanding the development of FVIII inhibitors

Abstract

Development of inhibitors against factor VIII (FVIII), the major complication of haemophilia A treatment today, is influenced by multiple factors. Genetic (F8 mutation, family history, ethnicity, polymorphisms in immune modulating genes) and non‐genetic (intensive exposure to FVIII, presence of pro‐inflammatory signals as might occur with large bleeds, infections, surgery, or other immune stimulants [e.g. vaccines]) risk factors as well as their complex inter‐relationships contribute to the inhibitor risk profile of haemophilia patients, particularly in the previously untreated patient (PUP) population. Studies in PUPs have been fundamental to furthering the understanding of FVIII inhibitor development, as well as discovering previously unappreciated risk factors. The multi‐factorial nature of inhibitor development makes it difficult to ascertain the contribution of FVIII products in inhibitor development through individual PUP studies. Sufficiently powered studies of large cohorts may overcome these limitations but interpretations should be conducted cautiously. Proper design and implementation of PUP safety studies will become even more important with the introduction of new molecules, such as extended half‐life or human cell‐line derived FVIII that propose reduced immunogenicity. Despite these difficulties, carefully performed clinical studies in PUPs may provide important insights into the natural history of the immune response to FVIII and may suggest targets for intervention to reduce immunogenicity.

Prediction of factor VIII inhibitor development in the SIPPET cohort by mutational analysis and factor VIII antigen measurement

“…The residual amount of endogenous FVIII offers a likely explanation for this difference, through the induction of natural immune tolerance . Furthermore, established determinants of inhibitor formation are the patient's genetic background, and environmental factors . Among them, the type of mutation in F8 is the strongest risk factor for inhibitor development .…”

Clinical trials and registries in haemophilia: Opponents or collaborators? Comparison of PUP data derived from different data sources

“…Data collection in registries reflects real‐life use of factor concentrates, which may allow comparison between products. Further harmonization of data collected in CTs and registries is needed to avoid methodological constraints and differences in design and realization . Clarification of the legal ownership of registry data (or patient data in general) and access to these data must be addressed to improve clinical insights and support regulatory decisions .…”

“…Further harmonization of data collected in CTs and registries is needed to avoid methodological constraints and differences in design and realization. 38 Clarification of the legal ownership of registry data (or patient data in general) and access to these data must be addressed to improve clinical insights and support regulatory decisions. 29 Data derived from registries should not be regarded as opponents to CTs but as important complementary data sources after MA.…”

Gene therapy for hemophilia

“…Over the past 20 years of clinical trial and worldwide experience, recombinant clotting factors have not had any PIPE infectious pathogen transmission, no safety signals on adverse event reporting and no evidence of increased rate of inhibitors in previously treated patients. 9,10 Further, recombinant DNA technology has facilitated efforts that are exploiting insights on the structure and function of FVIII and FIX to introduce targeted modifications that enhance their functional properties. This has best been exemplified in a recent wave of bioengineered molecules that have more efficient production and purification, optimized posttranslational modifications, and enhanced pharmacokinetics.…”

“…The rationale for recombinant clotting factors included (1) that they would be safer than their plasma‐derived counterparts, especially as they were being developed on the backdrop of the catastrophic viral contamination of plasma‐derived clotting factors, (2) the development of consistent manufacturing and processing that was liberated from the uncertainties of securing source plasma, (3) a potentially unlimited supply that could drive down costs of replacement therapy, (4) that this would facilitate an increase in the utilization of prophylaxis, and (5) wider availability of replacement products for patients in developing countries. Over the past 20 years of clinical trial and worldwide experience, recombinant clotting factors have not had any infectious pathogen transmission, no safety signals on adverse event reporting and no evidence of increased rate of inhibitors in previously treated patients . Further, recombinant DNA technology has facilitated efforts that are exploiting insights on the structure and function of FVIII and FIX to introduce targeted modifications that enhance their functional properties.…”