Direct comparison of two extended half-life PEGylated recombinant FVIII products: a randomized, crossover pharmacokinetic study in patients with severe hemophilia A

Alexander Solms,Tihomir Zhivkov,Andreas Tiede,Maurice Ahsman,Anita Shah,Erik Berntorp,Maria Elisa Mancuso,Toshko Lissitchkov,Camila Linardi,Alfonso Iorio

doi:10.1007/s00277-020-04280-3

Abstract

An open-label, crossover randomized study was performed to compare the pharmacokinetics (PK) of damoctocog alfa pegol and rurioctocog alfa pegol, two recombinant factor VIII (FVIII) products indicated in patients with hemophilia A, both conjugated to polyethylene glycol to reduce clearance and extend time in circulation. Adult patients (N = 18) with severe hemophilia A (FVIII < 1 IU/dL), previously treated with any FVIII product for ≥ 150 exposure days, were randomized to receive a single 50 IU/kg infusion of damoctocog alfa pegol followed by rurioctocog alfa pegol, or vice versa, with ≥ 7-day washout between doses. FVIII activity was measured using the one-stage clotting assay. PK parameters, including area under the curve from time 0 to the last data point (AUC0–tlast, primary parameter), dose-normalized AUC (AUCnorm), and time to threshold, were calculated based on 11 time points between 0.25 and 120 h post-dose and evaluated using a noncompartmental model. Due to differences in batch-specific vial content used for the study, actual administered median doses were 54.3 IU/kg for damoctocog alfa pegol and 61.4 IU/kg for rurioctocog alfa pegol. Based on actual dosing, a significantly higher geometric mean (coefficient of variation [%CV]) AUCnorm was observed for damoctocog alfa pegol (43.8 h kg/dL [44.0]) versus rurioctocog alfa pegol (36.0 h kg/dL [40.1, P < 0.001]). Based on population PK modeling, median time to reach 1 IU/dL was 16 h longer for damoctocog alfa pegol compared with rurioctocog alfa pegol. No adverse events or any immunogenicity signals were observed. Overall, damoctocog alfa pegol had a superior PK profile versus rurioctocog alfa pegol. Trial registration number: NCT04015492 (ClinicalTrials.gov identifier). Date of registration: July 9, 2019

Highlights

In patients with severe hemophilia A, prophylaxis with factor VIII (FVIII) replacement therapy remains the standard of care [1] and is associated with a reduction in bleeding, including joint bleeds, thereby protecting patients from further complications associated with recurrent bleeds such as joint disease and disability [1, 2]
The 50-IU/kg doses administered in this study were calculated based on the nominal potencies (1000 IU) as provided on the label of the vials which differed from that of the actual potencies, being 1030 IU/vial for damoctocog alfa pegol and 1141 IU/vial for rurioctocog alfa pegol
A numerically higher geometric mean AUC0–tlast was observed for damoctocog alfa pegol compared with rurioctocog alfa pegol for an approximately 10% lower actual dose of damoctocog alfa pegol compared with rurioctocog alfa pegol

Summary

Introduction

In patients with severe hemophilia A (factor VIII [FVIII] levels < 1 IU/dL), prophylaxis with FVIII replacement therapy remains the standard of care [1] and is associated with a reduction in bleeding, including joint bleeds, thereby protecting patients from further complications associated with recurrent bleeds such as joint disease and disability [1, 2]. Standard replacement recombinant FVIII (rFVIII) products have a short half-life (8–12 h) and, require frequent infusions to maintain FVIII plasma levels and provide optimal bleeding control [1, 3]. Such frequent dosing is associated with a significant treatment burden and may cause venous access issues or lead to inefficient prophylaxis due to poor patient adherence [4,5,6,7]. Rurioctocog alfa pegol was first licensed in 2015, and damoctocog alfa pegol in 2018, for the treatment of hemophilia A, based on efficacy and safety data from their respective pivotal phase 2/3 clinical trials [14,15,16,17,18,19]

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