Recombinant factor VIIa analog in the management of hemophilia with inhibitors: Results from a multicenter, randomized, controlled trial of vatreptacog alfa

S. R. Lentz, S. Ehrenforth, F. Abdul Karim, T. Matsushita, K. N. Weldingh, J. Windyga, J. N. Mahlangu, A. Weltermann, E. de Paula, M. Cerqueira, S. Zupancic-Salek, O. Katsarou, M. Economou, L. Nemes, Z. Boda, E. Santagostino, G. Tagariello, H. Hanabusa, K. Fukutake, M. TakiM. Shima, M. Gorska-Kosicka, M. Serban, T. Andreeva, A. Savic, I. Elezovic, J. Mahlangu, W. Tsay, M. Shen, A. Chuansumrit, P. Angchaisuksiri, K. Kavakli, A. Kupesiz, I. Sasmaz, B. Madan, S. Rangarajan, P. Giangrande, K. Saxena, S. Lentz, Michael Recht, C. Kempton, J. Barrett, G. Young, D. Quon, A. Stopeck, J. Lin, A. Ameri, S. Kaicker, P. Kuriakose, D. Obzut, M. Wang, I. Ortiz, A. Sori

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Background: Vatreptacog alfa, a recombinant factor VIIa (rFVIIa) analog with three amino acid substitutions and 99% identity to native FVIIa, was developed to improve the treatment of hemophilic patients with inhibitors. Objectives: To confirm the safety and assess the efficacy of vatreptacog alfa in treating bleeding episodes in hemophilic patients with inhibitors. Patients and methods: In this international, multicenter, randomized, double-blind, active-controlled, crossover, confirmatory phase III trial (adept2) in patients with hemophilia A or B and inhibitors, bleeds were randomized 3 2 to treatment with vatreptacog alfa (one to three doses at 80 μg kg-1) or rFVIIa (one to three doses at 90 μg kg-1). Treatment failures after three doses of trial product (TP) were managed according to the local standard of care. Results: In the 72 patients enrolled, 567 bleeds were treated with TP. Both vatreptacog alfa and rFVIIa gave 93% effective bleeding control at 12 h. Vatreptacog alfa was superior to rFVIIa in secondary efficacy outcomes, including the number of doses used to treat a bleed and sustained bleeding control 24-48 h after the first dose. Eight patients (11%) developed antibodies against vatreptacog alfa, including four with cross-reactivity against rFVIIa and one with an in vitro neutralizing effect to vatreptacog alfa. Conclusions: This large randomized controlled trial confirmed the well-established efficacy and safety profile of rFVIIa, and showed that vatreptacog alfa had similar or better efficacy than rFVIIa. However, because of the development of anti-drug antibodies, a positive benefit-risk profile is unlikely to be achieved with vatreptacog alfa.

Original languageEnglish (US)
Pages (from-to)1244-1253
Number of pages10
JournalJournal of Thrombosis and Haemostasis
Volume12
Issue number8
DOIs
StatePublished - 2014
Externally publishedYes

Fingerprint

Hemophilia A
Randomized Controlled Trials
Hemorrhage
Hemophilia B
Safety
vatreptacog alfa
recombinant FVIIa
Amino Acid Substitution
Standard of Care
Treatment Failure
Anti-Idiotypic Antibodies
Antibodies
Therapeutics

Keywords

  • Antibodies
  • Clinical trial, phase III
  • Hemophilia
  • Inhibitors
  • Recombinant factor VIIa

ASJC Scopus subject areas

  • Hematology
  • Medicine(all)

Cite this

Recombinant factor VIIa analog in the management of hemophilia with inhibitors : Results from a multicenter, randomized, controlled trial of vatreptacog alfa. / Lentz, S. R.; Ehrenforth, S.; Abdul Karim, F.; Matsushita, T.; Weldingh, K. N.; Windyga, J.; Mahlangu, J. N.; Weltermann, A.; de Paula, E.; Cerqueira, M.; Zupancic-Salek, S.; Katsarou, O.; Economou, M.; Nemes, L.; Boda, Z.; Santagostino, E.; Tagariello, G.; Hanabusa, H.; Fukutake, K.; Taki, M.; Shima, M.; Gorska-Kosicka, M.; Serban, M.; Andreeva, T.; Savic, A.; Elezovic, I.; Mahlangu, J.; Tsay, W.; Shen, M.; Chuansumrit, A.; Angchaisuksiri, P.; Kavakli, K.; Kupesiz, A.; Sasmaz, I.; Madan, B.; Rangarajan, S.; Giangrande, P.; Saxena, K.; Lentz, S.; Recht, Michael; Kempton, C.; Barrett, J.; Young, G.; Quon, D.; Stopeck, A.; Lin, J.; Ameri, A.; Kaicker, S.; Kuriakose, P.; Obzut, D.; Wang, M.; Ortiz, I.; Sori, A.

In: Journal of Thrombosis and Haemostasis, Vol. 12, No. 8, 2014, p. 1244-1253.

Research output: Contribution to journalArticle

Lentz, SR, Ehrenforth, S, Abdul Karim, F, Matsushita, T, Weldingh, KN, Windyga, J, Mahlangu, JN, Weltermann, A, de Paula, E, Cerqueira, M, Zupancic-Salek, S, Katsarou, O, Economou, M, Nemes, L, Boda, Z, Santagostino, E, Tagariello, G, Hanabusa, H, Fukutake, K, Taki, M, Shima, M, Gorska-Kosicka, M, Serban, M, Andreeva, T, Savic, A, Elezovic, I, Mahlangu, J, Tsay, W, Shen, M, Chuansumrit, A, Angchaisuksiri, P, Kavakli, K, Kupesiz, A, Sasmaz, I, Madan, B, Rangarajan, S, Giangrande, P, Saxena, K, Lentz, S, Recht, M, Kempton, C, Barrett, J, Young, G, Quon, D, Stopeck, A, Lin, J, Ameri, A, Kaicker, S, Kuriakose, P, Obzut, D, Wang, M, Ortiz, I & Sori, A 2014, 'Recombinant factor VIIa analog in the management of hemophilia with inhibitors: Results from a multicenter, randomized, controlled trial of vatreptacog alfa', Journal of Thrombosis and Haemostasis, vol. 12, no. 8, pp. 1244-1253. https://doi.org/10.1111/jth.12634
Lentz, S. R. ; Ehrenforth, S. ; Abdul Karim, F. ; Matsushita, T. ; Weldingh, K. N. ; Windyga, J. ; Mahlangu, J. N. ; Weltermann, A. ; de Paula, E. ; Cerqueira, M. ; Zupancic-Salek, S. ; Katsarou, O. ; Economou, M. ; Nemes, L. ; Boda, Z. ; Santagostino, E. ; Tagariello, G. ; Hanabusa, H. ; Fukutake, K. ; Taki, M. ; Shima, M. ; Gorska-Kosicka, M. ; Serban, M. ; Andreeva, T. ; Savic, A. ; Elezovic, I. ; Mahlangu, J. ; Tsay, W. ; Shen, M. ; Chuansumrit, A. ; Angchaisuksiri, P. ; Kavakli, K. ; Kupesiz, A. ; Sasmaz, I. ; Madan, B. ; Rangarajan, S. ; Giangrande, P. ; Saxena, K. ; Lentz, S. ; Recht, Michael ; Kempton, C. ; Barrett, J. ; Young, G. ; Quon, D. ; Stopeck, A. ; Lin, J. ; Ameri, A. ; Kaicker, S. ; Kuriakose, P. ; Obzut, D. ; Wang, M. ; Ortiz, I. ; Sori, A. / Recombinant factor VIIa analog in the management of hemophilia with inhibitors : Results from a multicenter, randomized, controlled trial of vatreptacog alfa. In: Journal of Thrombosis and Haemostasis. 2014 ; Vol. 12, No. 8. pp. 1244-1253.
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title = "Recombinant factor VIIa analog in the management of hemophilia with inhibitors: Results from a multicenter, randomized, controlled trial of vatreptacog alfa",
abstract = "Background: Vatreptacog alfa, a recombinant factor VIIa (rFVIIa) analog with three amino acid substitutions and 99{\%} identity to native FVIIa, was developed to improve the treatment of hemophilic patients with inhibitors. Objectives: To confirm the safety and assess the efficacy of vatreptacog alfa in treating bleeding episodes in hemophilic patients with inhibitors. Patients and methods: In this international, multicenter, randomized, double-blind, active-controlled, crossover, confirmatory phase III trial (adept™2) in patients with hemophilia A or B and inhibitors, bleeds were randomized 3 2 to treatment with vatreptacog alfa (one to three doses at 80 μg kg-1) or rFVIIa (one to three doses at 90 μg kg-1). Treatment failures after three doses of trial product (TP) were managed according to the local standard of care. Results: In the 72 patients enrolled, 567 bleeds were treated with TP. Both vatreptacog alfa and rFVIIa gave 93{\%} effective bleeding control at 12 h. Vatreptacog alfa was superior to rFVIIa in secondary efficacy outcomes, including the number of doses used to treat a bleed and sustained bleeding control 24-48 h after the first dose. Eight patients (11{\%}) developed antibodies against vatreptacog alfa, including four with cross-reactivity against rFVIIa and one with an in vitro neutralizing effect to vatreptacog alfa. Conclusions: This large randomized controlled trial confirmed the well-established efficacy and safety profile of rFVIIa, and showed that vatreptacog alfa had similar or better efficacy than rFVIIa. However, because of the development of anti-drug antibodies, a positive benefit-risk profile is unlikely to be achieved with vatreptacog alfa.",
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author = "Lentz, {S. R.} and S. Ehrenforth and {Abdul Karim}, F. and T. Matsushita and Weldingh, {K. N.} and J. Windyga and Mahlangu, {J. N.} and A. Weltermann and {de Paula}, E. and M. Cerqueira and S. Zupancic-Salek and O. Katsarou and M. Economou and L. Nemes and Z. Boda and E. Santagostino and G. Tagariello and H. Hanabusa and K. Fukutake and M. Taki and M. Shima and M. Gorska-Kosicka and M. Serban and T. Andreeva and A. Savic and I. Elezovic and J. Mahlangu and W. Tsay and M. Shen and A. Chuansumrit and P. Angchaisuksiri and K. Kavakli and A. Kupesiz and I. Sasmaz and B. Madan and S. Rangarajan and P. Giangrande and K. Saxena and S. Lentz and Michael Recht and C. Kempton and J. Barrett and G. Young and D. Quon and A. Stopeck and J. Lin and A. Ameri and S. Kaicker and P. Kuriakose and D. Obzut and M. Wang and I. Ortiz and A. Sori",
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TY - JOUR

T1 - Recombinant factor VIIa analog in the management of hemophilia with inhibitors

T2 - Results from a multicenter, randomized, controlled trial of vatreptacog alfa

AU - Lentz, S. R.

AU - Ehrenforth, S.

AU - Abdul Karim, F.

AU - Matsushita, T.

AU - Weldingh, K. N.

AU - Windyga, J.

AU - Mahlangu, J. N.

AU - Weltermann, A.

AU - de Paula, E.

AU - Cerqueira, M.

AU - Zupancic-Salek, S.

AU - Katsarou, O.

AU - Economou, M.

AU - Nemes, L.

AU - Boda, Z.

AU - Santagostino, E.

AU - Tagariello, G.

AU - Hanabusa, H.

AU - Fukutake, K.

AU - Taki, M.

AU - Shima, M.

AU - Gorska-Kosicka, M.

AU - Serban, M.

AU - Andreeva, T.

AU - Savic, A.

AU - Elezovic, I.

AU - Mahlangu, J.

AU - Tsay, W.

AU - Shen, M.

AU - Chuansumrit, A.

AU - Angchaisuksiri, P.

AU - Kavakli, K.

AU - Kupesiz, A.

AU - Sasmaz, I.

AU - Madan, B.

AU - Rangarajan, S.

AU - Giangrande, P.

AU - Saxena, K.

AU - Lentz, S.

AU - Recht, Michael

AU - Kempton, C.

AU - Barrett, J.

AU - Young, G.

AU - Quon, D.

AU - Stopeck, A.

AU - Lin, J.

AU - Ameri, A.

AU - Kaicker, S.

AU - Kuriakose, P.

AU - Obzut, D.

AU - Wang, M.

AU - Ortiz, I.

AU - Sori, A.

PY - 2014

Y1 - 2014

N2 - Background: Vatreptacog alfa, a recombinant factor VIIa (rFVIIa) analog with three amino acid substitutions and 99% identity to native FVIIa, was developed to improve the treatment of hemophilic patients with inhibitors. Objectives: To confirm the safety and assess the efficacy of vatreptacog alfa in treating bleeding episodes in hemophilic patients with inhibitors. Patients and methods: In this international, multicenter, randomized, double-blind, active-controlled, crossover, confirmatory phase III trial (adept™2) in patients with hemophilia A or B and inhibitors, bleeds were randomized 3 2 to treatment with vatreptacog alfa (one to three doses at 80 μg kg-1) or rFVIIa (one to three doses at 90 μg kg-1). Treatment failures after three doses of trial product (TP) were managed according to the local standard of care. Results: In the 72 patients enrolled, 567 bleeds were treated with TP. Both vatreptacog alfa and rFVIIa gave 93% effective bleeding control at 12 h. Vatreptacog alfa was superior to rFVIIa in secondary efficacy outcomes, including the number of doses used to treat a bleed and sustained bleeding control 24-48 h after the first dose. Eight patients (11%) developed antibodies against vatreptacog alfa, including four with cross-reactivity against rFVIIa and one with an in vitro neutralizing effect to vatreptacog alfa. Conclusions: This large randomized controlled trial confirmed the well-established efficacy and safety profile of rFVIIa, and showed that vatreptacog alfa had similar or better efficacy than rFVIIa. However, because of the development of anti-drug antibodies, a positive benefit-risk profile is unlikely to be achieved with vatreptacog alfa.

AB - Background: Vatreptacog alfa, a recombinant factor VIIa (rFVIIa) analog with three amino acid substitutions and 99% identity to native FVIIa, was developed to improve the treatment of hemophilic patients with inhibitors. Objectives: To confirm the safety and assess the efficacy of vatreptacog alfa in treating bleeding episodes in hemophilic patients with inhibitors. Patients and methods: In this international, multicenter, randomized, double-blind, active-controlled, crossover, confirmatory phase III trial (adept™2) in patients with hemophilia A or B and inhibitors, bleeds were randomized 3 2 to treatment with vatreptacog alfa (one to three doses at 80 μg kg-1) or rFVIIa (one to three doses at 90 μg kg-1). Treatment failures after three doses of trial product (TP) were managed according to the local standard of care. Results: In the 72 patients enrolled, 567 bleeds were treated with TP. Both vatreptacog alfa and rFVIIa gave 93% effective bleeding control at 12 h. Vatreptacog alfa was superior to rFVIIa in secondary efficacy outcomes, including the number of doses used to treat a bleed and sustained bleeding control 24-48 h after the first dose. Eight patients (11%) developed antibodies against vatreptacog alfa, including four with cross-reactivity against rFVIIa and one with an in vitro neutralizing effect to vatreptacog alfa. Conclusions: This large randomized controlled trial confirmed the well-established efficacy and safety profile of rFVIIa, and showed that vatreptacog alfa had similar or better efficacy than rFVIIa. However, because of the development of anti-drug antibodies, a positive benefit-risk profile is unlikely to be achieved with vatreptacog alfa.

KW - Antibodies

KW - Clinical trial, phase III

KW - Hemophilia

KW - Inhibitors

KW - Recombinant factor VIIa

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