FVIIa Therapy GEN-0828 Shows Efficacy in Hem B Mouse Study

Experimental treatment may be as effective as NovoSeven but at lower doses

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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An illustration of mice in a lab.

An investigational factor VIIa (FVIIa) therapy called GEN-0828 may be able to minimize blood loss and accelerate blood clotting at lower doses than NovoSeven, an approved medication used to control bleeding in hemophilia patients, according to a study in a mouse model of hemophilia B.

Still, both treatments had a similar overall hemostatic efficacy, or the ability to control bleeding, and demonstrated similar affinity for the protein that FVIIa normally interacts with to initiate blood clotting.

GEN-0828 did show other promising features, including greater exposure in the bloodstream compared with the same dose of NovoSeven.

The study, “The pharmacokinetics and pharmacodynamics of a novel recombinant activated human factor VII, GEN-0828, in hemophilia B mice,” was published in the Journal of Pharmaceutical Sciences

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Hemophilia is usually caused by genetic mutations that lead to a missing or defective clotting protein in the bloodstream. For hemophilia A, it is the factor VIII protein that is lacking, whereas factor IX is the clotting factor missing in hemophilia B.

Replacement therapy — which aims to provide the missing clotting protein — is considered a mainstay for both types of hemophilia. Still, some patients develop antibodies against the delivered clotting factors, called inhibitors, that minimize the therapy’s effectiveness.

For these patients, a bypassing agent, like Novo Nordisk’s NovoSeven, can be used. NovoSeven is a lab-made (recombinant) version of a different clotting protein, called FVIIa. This protein kicks off a chain of reactions that facilitate blood clotting in hemophilia patients, circumventing the need for conventional replacement therapy.

In this study, researchers compared the effects of a new FVIIa treatment, called GEN-0828, with NovoSeven in a mouse model of hemophilia B. The investigational treatment was specifically designed to result in higher protein levels and have better safety than NovoSeven.

Specifically, the Chinese research team was interested in comparing the pharmacokinetics and pharmacodynamics of the two treatments. Pharmacokinetics refers to a treatment’s movement into, through, and out of the body. Pharmacodynamics refers to its effects on the body, particularly on FVIIa activity and blood clotting in this case.

First, the researchers performed an in vitro, or in the lab, study to determine how well each treatment bound to a lab-made version of tissue factor — the protein FVIIa normally binds with to initiate blood clotting cascades.

Results showed the two treatments had comparable affinity for this protein.

For the pharmacodynamic analysis, hemophilia B mice were divided into 12 different groups and received either GEN-0828 or NovoSeven at doses of 5–120 kilo international units per kilogram of body weight (KIU/kg). Additional control groups of hemophilia B mice and healthy mice were left untreated.

Mice were anesthetized and the tips of their tails cut off. Bleeding times and total blood loss were then measured for a period of 30 minutes.

As expected, hemophilia B mice showed significantly increased bleeding times and blood loss compared with healthy mice.

With GEN-0828 or NovoSeven, blood loss and clotting time tended to decrease with increasing treatment doses, reflecting that both therapies could effectively reduce bleeding.

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Both treatments showed similar efficacy in controlling bleeds

Overall, the two treatments showed similar hemostatic efficacy.

Still, the lowest dose of GEN-0828 that could normalize blood loss to similar levels as healthy mice was 15 KIU/kg — a significantly lower dose than the 60 KIU/kg of NovoSeven that was needed.

Likewise, the lowest GEN-0828 dose needed to normalize clotting time was 5 KIU/kg compared with the 15 KIU/kg of NovoSeven.

These findings suggest that GEN-0828 has a “[relatively] more [powerful] potency of hemostatic activities at low dosage and provided wider potential dosage range,” the researchers wrote.

FVIIa activity levels were not statistically different between the two treatments.

Pharmacokinetic results in hemophilia B mice indicated that GEN-0828 “had better pharmacokinetic characteristics than NovoSeven,” the researchers wrote, including greater overall treatment exposure in the bloodstream.

“GEN-0828 has some promise as an independently developed protein medicine with a long half-life [time active in the bloodstream], high exposure, and wide therapeutic window, all of which are advantageous to its manufacture and commercialization in China,” the team wrote.