J N Mahlangu1, K N Weldingh2, S R Lentz3, S Kaicker4, F A Karim5, T Matsushita6, M Recht7, W Tomczak8, J Windyga9, S Ehrenforth2, K Knobe2. 1. Haemophilia Comprehensive Care Centre, Faculty of Health Sciences, University of the Witwatersrand and National Health Laboratory Service, Johannesburg, South Africa. 2. Novo Nordisk A/S, Bagsvaerd, Denmark. 3. Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA. 4. Maimonides Medical Centre, New York, NY, USA. 5. Haemophilia Centre, National Blood Centre, Kuala Lumpur, Malaysia. 6. Department of Transfusion Medicine, Nagoya University Hospital, Nagoya, Japan. 7. Hemophilia Center, Oregon Health and Science University, Portland, OR, USA. 8. Department of Hematooncology and Bone Marrow Transplantation, Medical University of Lublin, Lublin, Poland. 9. Department of Disorders of Haemostasis and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
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.
RCT Entities:
BACKGROUND:Vatreptacog alfa, a recombinant human factor VIIa (rFVIIa) analog developed to improve the treatment of bleeds in hemophiliapatients 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 hemophiliapatients 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.
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