Therapeutic and routine prophylactic properties of rFactor VIII Fc (efraloctocog alfa, Eloctate®) in hemophilia A

Abstract

rFVIIIFc (efraloctocog alfa, Eloctate^®) is an extended half-life (EHL) factor VIII licensed for use in patients with hemophilia A for prophylaxis and treatment of bleeding and surgical episodes. Pharmacokinetic studies in adults have shown a mean 1.5-fold increase in half-life compared to full-length factor VIII. When compared to adults, the half-life is decreased by 8% in adolescents between 12 and 17 years, by 18% in children 6 to <12 years, and by 33% in children between the ages of 2 and <6 years. There is a considerable interindividual variation in the prolongation of the half-life particularly in children and across the age groups, the range extending from no increase to a 2.5-fold increase. In addition to age, von willebrand factor (VWF) antigen level has demonstrated a significant impact on rFVIIIFc half-life, with higher VWF levels associated with greater prolongation of half-life. The pivotal and pediatric clinical trials have demonstrated the efficacy and safety of rFVIIIFc for use in regular prophylaxis and in management of bleeds and surgery. In these studies, just under half the participants showed a zero annualized bleed rate (ABR), and the median ABR (1.6 in the pivotal study for the individualized prophylaxis arm) showed a further decrease in the extension study. On average, the patients required fewer infusions (reduced by at least a third), and the mean weekly consumption seems to be in keeping with standard recombinant factor VIII. EHL rFVIIIFc has made decreased infusion frequency a possibility. However, the interindividual variability in dose and infusion frequency highlights the need for a personalized approach based on individual patient's half-life and/or response to treatment.

Keywords: FVIII; efraloctocog alfa; extended half-life factors; hemophilia A; prophylaxis; rFVIIIFc.

Figure 1

Study flowchart for adults and adolescents enrolled into A-Long studies. Note: The disposition of patients in the trials along with details of dose adjustments that could be undertaken during the trial are shown. Abbreviation: PK, pharmacokinetic.

Figure 2

Study flowchart for children enrolled into A-Long studies. Note: The disposition of patients in the trials along with details of dose adjustments that could be undertaken during the trial are shown. Abbreviation: PK, pharmacokinetic.

Figure 3

Comparison of rFVIIIFc and prestudy rFVIII PK parameters in pediatric study. Notes: A comparison of the FVIII PK parameters for rFVIIIFc versus prestudy FVIII was performed for 46 subjects (<6 years of age, n=19; 6 to <12 years of age, n=27) with the one-stage clotting assay, and the ratio of rFVIIIFc PK to the PK of the prior FVIII for each subject was calculated. Representative summaries from subjects who received prestudy therapy with the most common prestudy treatments, Advate^® (antihemophilic factor [recombinant]) (A) or Helixate/Kogenate (B), are shown. Each box represents the median and interquartile range, the “whiskers” represent the minimum and maximum, and the reference unity line marks the point at which PK parameters for rFVIIIFc and prestudy FVIII are the same. For all subjects in the PK subgroup an intrasubject comparison of rFVIIIFc and prestudy FVIII PK was performed; data for the half-life comparison are shown by age cohort and prestudy FVIII product (C, D). Reproduced from Young G, Mahlangu J, Kulkarni R, et al. Recombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia A. J Thromb Haemost. 2015;13(6):967–977. © 2015 Young et al. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis. Abbreviations: PK, pharmacokinetic; rFVIIIFc, recombinant FVIII Fc fusion protein; CL, clearance; IR, incremental recovery; t_½, half-life; pdFVIII, plasma-derived FVIII; V_ss, volume of distribution at steady state.