Immunogenicity Lessons Learned from the Clinical Development of Vatreptacog Alfa, A Recombinant Activated Factor VII Analog, in Hemophilia with Inhibitors

  • Kasper LamberthEmail author
  • Karin Nana Weldingh
  • Silke Ehrenforth
  • Mette Ribel Chéhadé
  • Henrik Østergaard
Part of the Topics in Medicinal Chemistry book series (TMC, volume 21)


Hemophilia A is a rare bleeding disorder characterized by defective blood clotting due to diminished levels or absence of coagulation Factor VIII (FVIII). The preferred treatment option is FVIII replacement therapy. However, in 20–30% of the patients neutralizing (inhibitory) anti-FVIII antibodies develop rendering patients dependent on other treatment modalities such as the bypassing agent recombinant factor VIIa (rFVIIa). rFVIIa has a 20-year safety track record with no reports of immunogenicity in congenital hemophilia patients with inhibitors. To improve treatment efficacy of rFVIIa, the recombinant analog vatreptacog alpha was developed by Novo Nordisk A/S and taken into clinical development in 2006. Despite differing from rFVIIa by only three amino acid substitutions, results from the phase III trial demonstrated that some patients developed anti-drug antibodies. In this chapter, we give an introduction to hemophilia with focus on rFVIIa and the development of vatreptacog alfa. In addition, we summarize the findings from the clinical trials and characterization of the identified anti-drug antibodies. Finally, we show how various immunogenicity prediction tools have been used to investigate the immunogenicity risk of vatreptacog alfa leading to the identification of a potential new T-cell epitope that could contribute to the observed immunogenicity of the compound in humans.


Antidrug antibodies FVIIa Hemophilia Immunogenicity Inhibitors Prediction T-cell epitope Vatreptacog alfa 


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© Springer International Publishing AG 2017

Authors and Affiliations

  • Kasper Lamberth
    • 1
    Email author
  • Karin Nana Weldingh
    • 1
  • Silke Ehrenforth
    • 2
  • Mette Ribel Chéhadé
    • 1
  • Henrik Østergaard
    • 1
  1. 1.Novo NordiskCopenhagenDenmark
  2. 2.Novo NordiskZurichSwitzerland

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