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

Abstract

BAY 94-9027 is an extended-half-life, recombinant factor VIII (rFVIII) product conjugated with a 60-kDa branched polyethylene glycol (PEG) molecule indicated for use in previously treated patients (aged ≥ 12 years) with hemophilia A. This randomized, open-label, two-way crossover study compared the pharmacokinetics (PK) of BAY 94-9027 and rFVIII Fc fusion protein (rFVIIIFc) in patients with hemophilia A. Patients aged 18-65 years with FVIII < 1% and ≥ 150 exposure days to FVIII were randomized to receive intravenous single-dose BAY 94-9027 60 IU/kg followed by rFVIIIFc 60 IU/kg or vice versa, with ≥ 7-day wash-out between doses. FVIII activity was measured by one-stage assay. PK parameters, including area under the curve from time 0 to the last data point (AUClast, primary parameter), half-life, and clearance were calculated. Eighteen patients were randomized and treated. No adverse events were observed. In the analysis set excluding one outlier, geometric mean (coefficient of variation [%CV, 95% confidence interval {CI}]) AUClast was significantly higher for BAY 94-9027 versus rFVIIIFc (2940 [37.8, 2440-3550] IU h/dL versus 2360 [31.8, 2010-2770] IU h/dL, p = 0.0001). A population PK model was developed to simulate time to reach FVIII threshold levels; median time to 1 IU/dL was approximately 13 h longer for BAY 94-9027 versus rFVIIIFc after a single infusion of 60 IU/kg. In conclusion, BAY 94-9027 had a superior PK profile versus rFVIIIFc. ClinicalTrials.gov : NCT03364998.

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

Conflict of interest statement

Anita Shah, Alexander Solms, and Sara Wiegmann are employees of Bayer. Maurice Ahsman is an employee of LAP&P Consultants BV, working for Bayer. Anita Shah and Alexander Solms are also shareholders of Bayer. Erik Berntorp is a consultant for Bayer, LFB, Octapharma, Roche, and Shire; is a Speaker Bureau member for Bayer; and has received research support from Bayer, CSL Behring, Shire, and Sobi/Bioverativ. Andreas Tiede has received research grants and personal fees for lectures and consultancy from Alnylam, Bayer, Biogen Idec, Biotest, Boehringer Ingelheim, Chugai, CSL Behring, Daiichi Sankyo, Leo Pharma, Novo Nordisk, Octapharma, Pfizer, Portola, Roche, Shire, and Sobi. Alfonso Iorio’s institution has received grants/research support from Bayer, CSL, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, and Shire. Maria Elisa Mancuso is a consultant for Bayer, CSL Behring, Novo Nordisk, Roche, Pfizer, Baxalta/Shire, Kedrion, and Catalyst, and a Speaker Bureau member for Bayer, CSL Behring, Novo Nordisk, Roche, Baxalta/Shire, Biotest, and Octapharma. Toshko Lissitchkov is a shareholder of Bayer, Sobi, Octapharma, Roche, Sanofi, and Shire; has received grants/research support from Bayer, Octapharma, and Sanofi; is a consultant for Bayer, Sobi, Roche, and Shire; is a Speaker Bureau member for Roche and Shire; and has received from the company financial support as a principal investigator of clinical trials. Tihomir Zhivkov has nothing to declare.

Figures

Fig. 1

Study design

Fig. 2

Individual patient AUClast values after a single infusion of 60 IU/kg BAY 94-9027 or 60 IU/kg rFVIIIFc (N = 18). One patient (dashed line) had an AUClast of 470 IU h/dL for BAY 94-9027, considerably lower than the geometric mean of 2660 IU h/dL for BAY 94-9027 for all patients

Fig. 3

Visual predictive checks on FVIII level–time profiles in the integrated popPK model for BAY 94-9027 (a) and rFVIIIFc (b) BLQ, below the limit of quantification; LLOQ, lower limit of quantitation

Fig. 4

Modeled median time to FVIII threshold level after a single infusion of 60 IU/kg BAY 94-9027 or 60 IU/kg rFVIIIFc (analysis set B, excluding outlier; N = 17)