Recombinant factor VIII products and inhibitor development in previously untreated boys with severe hemophilia A

Abstract

Key Points• A currently marketed rFVIII product is associated with a higher risk of inhibitor development in boys with severe hemophilia A.• This result, validated by extensive sensitivity analyses, confirms a recently published study and cannot be explained by identified biases.Six recombinant factor VIII (rFVIII) products have been marketed worldwide. In 2013, the Research of Determinants of Inhibitor Development (RODIN) study group reported an unexpectedly high risk of inhibitor development with a second-generation full-length rFVIII (Product D) in previously untreated patients (PUPs) with severe hemophilia A (HA). In 1994, French public health authorities established a prospective cohort to monitor hemophilia treatment safety. A PUP subgroup was designed to investigate inhibitor risk factors. We analyzed this subcohort in view of the RODIN findings. After excluding 50 patients who participated in the RODIN study, the primary analysis focused on 303 boys with severe HA first treated with a rFVIII product. A clinically significant inhibitor was detected in 114 boys (37.6%). The inhibitor incidence was higher with Product D vs the most widely used rFVIII product (adjusted hazard ratio [aHR], 1.55; 95% confidence interval [CI], 0.97-2.49). Similar results were found for high-titer inhibitors and in 10 sensitivity analyses. No heterogeneity was observed between RODIN and our results. Combined aHRs were 1.58 (95% CI, 1.17-2.14) for all inhibitors and 1.70 (95% CI, 1.15-2.52) for high-titer inhibitors. Our results confirm the higher immunogenicity of Product D vs other rFVIII products in PUPs with severe HA. (Blood. 2014;124(23):3398-3408)

Factor VIII brand and the incidence of factor VIII inhibitors in previously untreated UK children with severe hemophilia A, 2000-2011

“…Data on ReFacto AF were not reported. 18 A biologically plausible explanation for the observation of the different incidence of inhibitors is lacking, although the RODIN group argues that this does not undermine the validity their finding.…”

Production of recombinant coagulation factors: Are humans the best host cells?

“…However, it is possible that changes in the manufacturing process can lead to changes in the immunogenicity of the product. 10 Despite this supposed lower risk of inhibitor development, some of the third-generation products use murine derived-mAbs during downstream processing (affinity chromatography). Although efficient, the use of murine mAb-derived affinity purification in the manufacturing process can raise the possibility of antigenicity when the product is infused into patients since residual mAb can be present in the effluent due to leaching from the support matrix used during chromatography.…”

“…Some studies have shown that patients treated with second-generation rFVIII products presented a higher risk of inhibitor development when compared with third-generation products. [9][10][11] FVIII inhibitor is an immunoglobulin G (IgG) produced by patient that has high polyclonal affinity directed against the FVIII protein. 12 Inhibitory antibodies are directed usually against the A2, A3 and C2 FVIII domains.…”

Can a “center effect” explain the higher frequency of inhibitors for a second-generation recombinant factor VIII product?

“…1 Recently, a novel mechanism was described for VWF release in which an actomyosin ring forms around the WPB several seconds after its fusion with the plasma membrane to squeeze VWF from the WPB. 2 This new mechanism was described in experiments using the potent secretagogue phorbol 12-myristate 13-acetate (PMA), and has received considerable attention. [3][4][5] However, the mechanism of action of PMA differs in several key respects from that of physiological secretagogues, such as histamine, that elevate intracellular free calcium ion concentrations ([Ca 21 ] i ).…”

“…PMA action is characterized by a slow onset (tens of seconds to minutes) but a protracted (hours) period of WPB fusion that occurs without an increase in [Ca 21 ] i . VWF is released slowly from the WPB after fusion with the plasma membrane (tens of seconds), and secretion is prevented by inhibition of protein kinase C, 6 myosin IIB (MyoIIB), 2 or actin disruption or stabilization. 7 In contrast, histamine (or ionomycin) triggers a rapid (,1 second) but transient (10-30 seconds) burst in WPB exocytosis.…”