Evaluation of the safety and pharmacokinetics of a fast‐acting recombinant FVIIa analogue, NN1731, in healthy male subjects

Abstract

To cite this article: Møss J, Scharling B, Ezban M, Møller Sørensen T. Evaluation of the safety and pharmacokinetics of a fast-acting recombinant FVIIa analogue, NN1731, in healthy male subjects. J Thromb Haemost 2009; 7: 299-305.Summary. Background: NN1731 is a recombinant activated factor VII (rFVIIa) analog with enhanced activity. Objectives: This clinical trial aimed to assess the safety and pharmacokinetics of single doses of NN1731 in healthy male subjects. Methods: This was a randomized, placebo-controlled doseescalation trial with four dose tiers (NN1731 5-30 lg kg). Eight subjects were randomized to either NN1731 (n = 6) or placebo (n = 2) in each tier. Results: No thromboembolic or serious adverse events were reported and no antibody formation towards NN1731 was detected. NN1731 was demonstrated to be pharmacologically active based on coagulation-related parameters (prothrombin fragment 1+2, activated partial thromboplastin time and prothrombin time). There were five mild/moderate adverse events in three subjects. The FVIIa activity of NN1731 after ascending single-dose administration of NN1731 fits well with a two-compartment model, indicating a bi-exponential decline with a rapid initial distribution of approximately 73% FVIIa activity (half-life = 20 min), followed by a less rapid terminal elimination phase eliminating the remaining 27% (half-life = 3 h). Dose proportionality in healthy male subjects at the dose levels investigated (5-30 lg kg . No immunogenic or thromboembolic events were reported. The pharmacokinetic profile of NN1731 as measured by FVIIa activity appears to follow two-compartment pharmacokinetics characterized by an initial rapid distribution phase followed by a less rapid elimination phase.

Factor VIIa analog has marked effects on platelet function and clot kinetics in blood from patients with hemophilia A

“…NN1731 (Novo Nordisk A/S, Bagsvaerd, Denmark) is one such rFVIIa variant analog under development that has three amino acid substitutions [6,7]. The human pharmacokinetics of NN1731 has been described [8], and preliminary data have characterized its in vitro and ex vivo hemostatic effects [9][10][11]. The mechanism of action of rFVIIa and NN1731 is based upon the enhancement of thrombin generation on the activated platelets at the site of injury.…”

Back to the future: a recent history of haemophilia treatment

“…Newer preparations of rFVIIa endowed with higher haemostatic potency or more-prolonged half-life are currently undergoing clinical trials [60][61][62][63][64][65][66]. Porcine FVIII, originally derived from animal plasma and endowed with low cross-reactivity to human FVIII inhibitors, was recently produced by recombinant DNA technology as a B-domainless molecule and tested in a phase 2 trial in haemophilia A patients with inhibitors [67].…”

Catalytic domain modification and viral gene delivery of activated factor VII confers hemostasis at reduced expression levels and vector doses in vivo

“…This has been achieved by enhancing the phospholipid binding or increasing the catalytic activity of rhFVIIa. [5][6][7][8] Although data from human subjects suggest that a single-dose of a rhFVIIa variant (rhFVIIa-DVQ, also known as NN1731) with enhanced, TF-independent activity is safe, 9 efficacy and long-term safety data in hemophilic patients are limited. Moreover, the majority of its in vivo efficacy data have been derived using nonhomologous animal models in short-term studies, where potential species incompatibilities between human FVIIa and endogenous (animal) TF 10 may affect the hemostatic outcomes.…”