FVIIa analogue

Category

FVIIa

ID

NNC0078-0007

Amount per vial

2.2 mg

Vatreptacog alfa (see the Persson E et al. reference listed in the reference section below) is a variant of human coagulation factor VIIa (hFVIIa), also known as “rFVIIa analog NN1731” or “FVIIaDVQ”. It is a two-chain recombinant protein produced in mammalian cells. The heavy and light chains are connected via a disulfide bond. The LC features an N-terminal Gla-domain containing multiple gamma-carboxy glutaminyl residues as well as two EGF-like domains. The catalytic domain is part of the HC. Compared to hFVIIa, vatreptacog alfa contains three amino acid changes, V158D, E296V, and M298Q. These substitutions result in considerable enhancement of the intrinsic (tissue factor-independent) activity. The enhanced activity of vatreptacog alfa has been demonstrated in numerous in vitro systems and in vivo model mimicking hemophilia. Vatreptacog alfa has been investigated in phase 1, 2, and 3 clinical trials. Vatreptacog alfa was discontinued after phase 3 clinical trial due to anti-drug antibodies (Mahlangu J N et al. et al. - reference section) in a few patients. A post hoc assessment of the immunogenicity of vatreptacog alfa was subsequently performed in collaboration with FDA (see the Lamberth K et al. reference listed in the reference section below).

Category

FVIIa

ID

NNC0078-0007

Amount per vial

2.2 mg

ParameterNNC0078-0007
pI5.6
MW average50 kDa
MW LC20 kDa
MW HC30 kDa
A280 (1 mg/ml)1.37
GlycosylationsAsn145 and Asn322 (complex biatennary)
Max thrombin generation rate3-10 times higher than rhFVIIa (see fourth reference below)

Figure 1

2D structure of vatreptacoq alfa with domains, post-translational modifications, and special residues indicated.
PropertiesNNC0078-0007
Content 2.2 mg/vial
HMWP2.4%
Total impurities9.7%
Oxidized forms2.7%
Heavy chain degradation4.3%
Gamma-carboxylationComplies
N-terminal sequenceComplies
Specific activity1085 U/ug
Bacterial Endotoxin<0.10 U/mg
Aspects of preclinical and clinical pharmacology, pharmacokinetics, and safety is described in the Persson E et al. reference listed in the reference section below.
No reference compound available
The freeze dried material can be stored at +5C or below. Reconstitute one vial of Vatreptacoq alfa in 2.1 ml 10 mM histidine, pH 6.0. The reconstituted protein contains various salts and additives.

Persson E et al.

Vatreptacog alfa from conception to clinical proof of concept.

Seminars in Thrombosis and Hemostasis 2012,38(3):274-281

DOI PubMed

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 2015,13(11): 1989-1998

DOI PubMed

Lamberth K et al.

Post hoc assessment of the immunogenicity of bioengineered factor VIIa demonstrates the use of preclinical tools

Science Translational Medicine 2017, 9(372): eaag1286

DOI PubMed

Allen G A et al.

A Variant of Recombinant Factor VIIa With Enhanced Procoagulant and Antifibrinolytic Activities in an In Vitro Model of Hemophilia

Arteriosclerosis, Thrombosis, and Vascular Biology 2007, 27(3): 683-689

DOI PubMed