Perspective – The case for zero bleeds and drug bioequivalence in the treatment of congenital hemophilia A in 2021

• Published in: Blood reviews Vol. 50; p. 100849
• Main Authors: Di Minno, Alessandro, Spadarella, Gaia, Esposito, Salvatore, Mathew, Prasad, Di Minno, Giovanni, Mannucci, Pier Mannuccio
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.11.2021
• Subjects: Bioequivalence; Cross-Over Studies; Emicizumab; Extended half-life FVIII products; Factor VIII - pharmacokinetics; HA and B; Half-Life; Hemophilia A - drug therapy; Hemorrhage - drug therapy; Hemorrhage - etiology; Hemostatics; Humans; Monogenic disorder; Newer determinants of FVIII half-life; Pharmaceutical Preparations; Phenotypic heterogeneity of patients; Standard half-life FVIII products; Tailored prophylaxis; Therapeutic Equivalency; von Willebrand Factor - metabolism; Zero bleeding; Zero bleeding; Emicizumab; Phenotypic heterogeneity of patients; Bioequivalence; Monogenic disorder; Newer determinants of FVIII half-life; Standard half-life FVIII products; HA and B; Extended half-life FVIII products; Tailored prophylaxis
• ISSN: 0268-960X; 1532-1681; 1532-1681
• DOI: 10.1016/j.blre.2021.100849

Not all patients with severe hemophilia A (HA) respond optimally to a given dose of a given product. Within-individual variance in cross-over studies makes each patient unique in the response to each standard half-life (SHL) factor VIII (FVIII) product in pharmacokinetic (PK) terms. This hampers the prediction of efficacy when a SHL FVIII product is employed. PK data showing that half-lives of SHL rFVIII are unsatisfactory to achieve zero bleeding in individual HA patients provide the rationale for switching from SHL to extended half-life (EHL) products. However, not all subjects receiving prophylaxis with EHL products achieve zero bleeding, the most cogent objective of personalized prophylaxis. Known determinants of FVIII half-life (age, von Willebrand factor [VWF] levels, blood group) cumulatively account for one third of the total inter-individual variation in FVIII clearance in subjects with severe HA. Investigations into precision, and accuracy of laboratory measurement to be employed; newer pathways for the clearance of both free-FVIII and VWF-bound FVIII, and adequately powered studies on omics and phenotypic heterogeneity, are likely to provide additional information on the remaining two thirds of inter-individual variation in FVIII clearance in HA. Variability in the clinical response has also been documented in patients when FVIII activity is mimicked by fixed subcutaneous doses of the bispecific antibody emicizumab. National registries that collect PK data of available FVIII products and ad hoc information on the individual response to emicizumab should be encouraged, to establish newer standards of care and ease personalized clinical decisions to achieve zero bleeding.