Changes in the amino acid sequence of the recombinant human factor VIIa analog, vatreptacog alfa, are associated with clinical immunogenicity

Abstract

Summary. 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 TM 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 TM 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.

Safety, Stability and Pharmacokinetic Properties of superFactor Va, a Novel Engineered Coagulation Factor V for Treatment of Severe Bleeding

“…There, formation of inhibitory antibodies to exogenous FVIII or FIX preparations is observed at a median of 10 exposure days in ~30% of patients with FVIII-deficiency and ~5% of patients with FIX-deficiency (37,38). Inhibitor formation with rh FVIIa is rare, but has been observed with a modified, higher potency FVIIa product following repeated exposure over many months (39). For single short-term use such as for traumatic bleeding or DOAC-associated bleeding the risk of inhibitor formation appears therefore negligible and less relevant.…”

The evolution of factor VIIa in the treatment of bleeding in haemophilia with inhibitors

“…51,52 The clinical development of a glycopegylated variant with an extended half-life (N7-GP) was similarly halted due to the lack of a dose-response and inferior activity compared with eptacog alfa. Two early investigational variants, vatreptacog alfa and BAY 86-6150, had increased biological activity from specific amino acid mutations; however, both failed in clinical trials due to the observation of antidrug antibodies.…”

Development of a strategy and computational application to select candidate protein analogues with reduced HLA binding and immunogenicity

“…This immunogenicity, in turn, may be associated with decreased efficacy and/or potential safety issues. Accordingly, developing the capacity to predict potential immunogenicity, affording strategies to decrease the potential immunogenicity of protein drugs, has been the subject of intense investigation . Several groups, including De Groot and co‐workers, have worked on this subject and produced valuable contributions …”