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

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

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.

Keywords: Extended half-life; Factor VIII; Head-to-head study; Hemophilia A; PEGylated; Population pharmacokinetics.

Conflict of interest statement

Alexander Solms is a Bayer employee and shareholder; Anita Shah is a Bayer employee and shareholder. Erik Berntorp has received grants/research support from Bayer, CSL Behring, Shire, and Sobi/Bioverativ; honoraria/consultation fee from Bayer, Octapharma, and Shire/Takeda; and speaker fees from Bayer. Andreas Tiede has received grants/research support from Biotest, Novo Nordisk, Octapharma, Roche, and Takeda and honoraria/consultation fee from Bayer, Biotest, Chugai, CSL Behring, Novo Nordisk, Octapharma, Roche, and Takeda. Alfonso Iorio has received grants/research support through from Bayer, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, and Shire; Camila Linardi is a Bayer employee; Maurice Ahsman is a consultant for Bayer; Maria Elisa Mancuso has received honoraria/consultation fee from Bayer, Bioverativ, Catalyst, CSL Behring, Grifols, Kedrion, Novo Nordisk, Octapharma, Pfizer, Roche, Shire, and Sobi and received speaker fees from Bayer, Biotest, CSL Behring, Grifols, Kedrion, Novo Nordisk, Octapharma, Pfizer, Roche, Shire, and Sobi; Tihomir Zhivkov has received grants/research support from Bayer and is a subinvestigator of clinical trials for Apellis, Bayer, Catalyst, Octapharma, and Sanofi. Toshko Lissitchkov has received honoraria/consultation fee for advisory boards from Bayer, Roche, and Sobi; received speaker fees from Bayer, Novo Nordisk, Roche, and Sobi; and is a principal investigator of clinical trials sponsored by Bayer, CSL Behring, Biotest, Novo Nordisk, Octapharma, Pfizer, Rigel, Sanofi-Alnylam, and Sanofi-Bioverativ.

Figures

Fig. 1
Fig. 1
Study design. BMI, body mass index; EHL, extended half-life; FVIII, factor VIII; SHL, standard half-life
Fig. 2
Fig. 2
Dose-normalized AUC, clearance, and half-life after a single infusion of damoctocog alfa pegol or rurioctocog alfa pegol. Blue and gray lines indicate those patients who are in favor of damoctocog alfa pegol and rurioctocog alfa pegol, respectively. AUCnorm, area under the curve normalized for dose per body weight; CL, clearance; t1/2, half-life
Fig. 3
Fig. 3
Median modeled time to FVIII threshold level after a single infusion of 50 IU/kg damoctocog alfa pegol or rurioctocog alfa pegol. FVIII, factor VIII; h, hours

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