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Changes in the amino acid sequence of the recombinant human factor VIIa analog, vatreptacog alfa, are associated with clinical immunogenicity.
J Thromb Haemost 2015; 13(11):1989-98JT

Abstract

BACKGROUND

Vatreptacog alfa, a recombinant human factor VIIa (rFVIIa) analog developed to improve the treatment of bleeds in hemophilia patients with inhibitors, differs from native FVIIa by three amino acid substitutions. In a randomized, double-blind, crossover, confirmatory phase III trial (adept(™) 2), 8/72 (11%) hemophilia A or B patients with inhibitors treated for acute bleeds developed anti-drug antibodies (ADAs) to vatreptacog alfa.

OBJECTIVES

To characterize the formation of anti-vatreptacog alfa ADAs in hemophilia patients with inhibitors.

METHODS/PATIENTS

This was a post hoc analysis of adept(™) 2. Immunoglobulin isotype determination, specificity analysis of rFVIIa cross-reactive antibodies, epitope mapping of rFVIIa single mutant analogs and pharmacokinetic (PK) profiling were performed to characterize the ADAs.

RESULTS

Immunoglobulin isotyping indicated that the ADAs were of the immunoglobulin G subtype. In epitope mapping, none of the rFVIIa single mutant analogs (V158D, E296V or M298Q) contained the complete antibody epitope, confirming that the antibodies were specific for vatreptacog alfa. In two patients, for whom PK profiling was performed both before and after the development of ADAs, vatreptacog alfa showed a prolonged elimination phase following ADA development. During the follow-up evaluation, the rFVIIa cross-reactivity disappeared after the last vatreptacog alfa exposure, despite continued exposure to rFVIIa as part of standard care.

CONCLUSIONS

Results from the vatreptacog alfa phase III trial demonstrate that the specific changes made, albeit relatively small, to the FVIIa molecule alter its clinical immunogenicity.

Authors+Show Affiliations

Haemophilia Comprehensive Care Centre, Faculty of Health Sciences, University of the Witwatersrand and National Health Laboratory Service, Johannesburg, South Africa.Novo Nordisk A/S, Bagsvaerd, Denmark.Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA.Maimonides Medical Centre, New York, NY, USA.Haemophilia Centre, National Blood Centre, Kuala Lumpur, Malaysia.Department of Transfusion Medicine, Nagoya University Hospital, Nagoya, Japan.Hemophilia Center, Oregon Health and Science University, Portland, OR, USA.Department of Hematooncology and Bone Marrow Transplantation, Medical University of Lublin, Lublin, Poland.Department of Disorders of Haemostasis and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.Novo Nordisk A/S, Bagsvaerd, Denmark.Novo Nordisk A/S, Bagsvaerd, Denmark.No affiliation info available

Pub Type(s)

Clinical Trial, Phase III
Comparative Study
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26362483

Citation

Mahlangu, J N., et al. "Changes in the Amino Acid Sequence of the Recombinant Human Factor VIIa Analog, Vatreptacog Alfa, Are Associated With Clinical Immunogenicity." Journal of Thrombosis and Haemostasis : JTH, vol. 13, no. 11, 2015, pp. 1989-98.
Mahlangu JN, Weldingh KN, Lentz SR, et al. Changes in the amino acid sequence of the recombinant human factor VIIa analog, vatreptacog alfa, are associated with clinical immunogenicity. J Thromb Haemost. 2015;13(11):1989-98.
Mahlangu, J. N., Weldingh, K. N., Lentz, S. R., Kaicker, S., Karim, F. A., Matsushita, T., ... Knobe, K. (2015). Changes in the amino acid sequence of the recombinant human factor VIIa analog, vatreptacog alfa, are associated with clinical immunogenicity. Journal of Thrombosis and Haemostasis : JTH, 13(11), pp. 1989-98. doi:10.1111/jth.13141.
Mahlangu JN, et al. Changes in the Amino Acid Sequence of the Recombinant Human Factor VIIa Analog, Vatreptacog Alfa, Are Associated With Clinical Immunogenicity. J Thromb Haemost. 2015;13(11):1989-98. PubMed PMID: 26362483.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Changes in the amino acid sequence of the recombinant human factor VIIa analog, vatreptacog alfa, are associated with clinical immunogenicity. AU - Mahlangu,J N, AU - Weldingh,K N, AU - Lentz,S R, AU - Kaicker,S, AU - Karim,F A, AU - Matsushita,T, AU - Recht,M, AU - Tomczak,W, AU - Windyga,J, AU - Ehrenforth,S, AU - Knobe,K, AU - ,, Y1 - 2015/10/13/ PY - 2015/05/11/received PY - 2015/08/10/accepted PY - 2015/9/13/entrez PY - 2015/9/13/pubmed PY - 2016/9/17/medline KW - antibodies KW - antibody formation KW - hemophilia KW - immunoglobulin isotypes KW - recombinant factor VIIa KW - vatreptacog alfa SP - 1989 EP - 98 JF - Journal of thrombosis and haemostasis : JTH JO - J. Thromb. Haemost. VL - 13 IS - 11 N2 - BACKGROUND: Vatreptacog alfa, a recombinant human factor VIIa (rFVIIa) analog developed to improve the treatment of bleeds in hemophilia patients with inhibitors, differs from native FVIIa by three amino acid substitutions. In a randomized, double-blind, crossover, confirmatory phase III trial (adept(™) 2), 8/72 (11%) hemophilia A or B patients with inhibitors treated for acute bleeds developed anti-drug antibodies (ADAs) to vatreptacog alfa. OBJECTIVES: To characterize the formation of anti-vatreptacog alfa ADAs in hemophilia patients with inhibitors. METHODS/PATIENTS: This was a post hoc analysis of adept(™) 2. Immunoglobulin isotype determination, specificity analysis of rFVIIa cross-reactive antibodies, epitope mapping of rFVIIa single mutant analogs and pharmacokinetic (PK) profiling were performed to characterize the ADAs. RESULTS: Immunoglobulin isotyping indicated that the ADAs were of the immunoglobulin G subtype. In epitope mapping, none of the rFVIIa single mutant analogs (V158D, E296V or M298Q) contained the complete antibody epitope, confirming that the antibodies were specific for vatreptacog alfa. In two patients, for whom PK profiling was performed both before and after the development of ADAs, vatreptacog alfa showed a prolonged elimination phase following ADA development. During the follow-up evaluation, the rFVIIa cross-reactivity disappeared after the last vatreptacog alfa exposure, despite continued exposure to rFVIIa as part of standard care. CONCLUSIONS: Results from the vatreptacog alfa phase III trial demonstrate that the specific changes made, albeit relatively small, to the FVIIa molecule alter its clinical immunogenicity. SN - 1538-7836 UR - https://www.unboundmedicine.com/medline/citation/26362483/Changes_in_the_amino_acid_sequence_of_the_recombinant_human_factor_VIIa_analog_vatreptacog_alfa_are_associated_with_clinical_immunogenicity_ L2 - https://doi.org/10.1111/jth.13141 DB - PRIME DP - Unbound Medicine ER -