Direct comparison of two extended-half-life recombinant FVIII products

a randomized, crossover pharmacokinetic study in patients with severe hemophilia A

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)2035-2044
JournalAnnals of Hematology
Volume98
Issue number9
DOIs
Publication statusPublished - Jan 1 2019

Fingerprint

Hemophilia A
Cross-Over Studies
Half-Life
Pharmacokinetics
Proteins
Factor VIII
Area Under Curve
BAY 94-9027
Confidence Intervals
Population

Keywords

  • Extended half-life
  • Head-to-head study
  • Hemophilia A
  • PEGylated
  • Pharmacokinetics
  • Population pharmacokinetics

ASJC Scopus subject areas

  • Hematology

Cite this

Direct comparison of two extended-half-life recombinant FVIII products : a randomized, crossover pharmacokinetic study in patients with severe hemophilia A. / Shah, Anita; Solms, Alexander; Wiegmann, Sara; Ahsman, Maurice; Berntorp, Erik; Tiede, Andreas; Iorio, Alfonso; Mancuso, Maria Elisa; Zhivkov, Tihomir; Lissitchkov, Toshko.

In: Annals of Hematology, Vol. 98, No. 9, 01.01.2019, p. 2035-2044.

Research output: Contribution to journalArticle

Shah, Anita ; Solms, Alexander ; Wiegmann, Sara ; Ahsman, Maurice ; Berntorp, Erik ; Tiede, Andreas ; Iorio, Alfonso ; Mancuso, Maria Elisa ; Zhivkov, Tihomir ; Lissitchkov, Toshko. / Direct comparison of two extended-half-life recombinant FVIII products : a randomized, crossover pharmacokinetic study in patients with severe hemophilia A. In: Annals of Hematology. 2019 ; Vol. 98, No. 9. pp. 2035-2044.
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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.",
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