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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 LU ; Tiede, Andreas; Iorio, Alfonso; Mancuso, Maria Elisa; Zhivkov, Tihomir and Lissitchkov, Toshko (2019) In Annals of Hematology
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... (More)

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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author
organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
Extended half-life, Head-to-head study, Hemophilia A, PEGylated, Pharmacokinetics, Population pharmacokinetics
in
Annals of Hematology
publisher
Springer Verlag
external identifiers
  • scopus:85068186510
ISSN
0939-5555
DOI
10.1007/s00277-019-03747-2
language
English
LU publication?
yes
id
ccd3cf09-9348-4f06-b35b-667b452dd99d
date added to LUP
2019-07-10 11:14:43
date last changed
2019-08-06 03:24:04
@article{ccd3cf09-9348-4f06-b35b-667b452dd99d,
  abstract     = {<p>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 &lt; 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 (AUC<sub>last</sub>, 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}]) AUC<sub>last</sub> 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.</p>},
  author       = {Shah, Anita and Solms, Alexander and Wiegmann, Sara and Ahsman, Maurice and Berntorp, Erik and Tiede, Andreas and Iorio, Alfonso and Mancuso, Maria Elisa and Zhivkov, Tihomir and Lissitchkov, Toshko},
  issn         = {0939-5555},
  keyword      = {Extended half-life,Head-to-head study,Hemophilia A,PEGylated,Pharmacokinetics,Population pharmacokinetics},
  language     = {eng},
  month        = {06},
  publisher    = {Springer Verlag},
  series       = {Annals of Hematology},
  title        = {Direct comparison of two extended-half-life recombinant FVIII products : a randomized, crossover pharmacokinetic study in patients with severe hemophilia A},
  url          = {http://dx.doi.org/10.1007/s00277-019-03747-2},
  year         = {2019},
}