Administration of recombinant FVIIa (rFVIIa) to concizumab‐dosed monkeys is safe, and concizumab does not affect the potency of rFVIIa in hemophilic rabbits
Author(s): ,
Brian Lauritzen
Affiliations:
Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark
Correspondence: Brian Lauritzen, Global Drug Discovery, Novo Nordisk A/S, Novo Nordisk Park, H6.01.019, DK‐2760 Måløv, Denmark|Tel.: +45 30 797 0682|E‐mail: blz@novonordisk.com
,
Janne Olling
Affiliations:
Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark
,
Kristin L. Abel
Affiliations:
Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark
,
Cecilia Augustsson
Affiliations:
Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark
,
Kristoffer Balling
Affiliations:
Clinical Operations, Novo Nordisk A/S, Søborg, Denmark
,
Mads Bjelke
Affiliations:
Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark
,
Anne Charlotte Hegelund
Affiliations:
Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark
Ida Hilden
Affiliations:
Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark
ISTH Academy. Lauritzen B. Mar 1, 2019; 273393
Brian Lauritzen
Brian Lauritzen
Login now to access Regular content available to all registered users.

Access to Premium content is currently a membership benefit.

Click here to join ISTH or renew your membership.

You may also access ISTH content "anytime, anywhere" with the FREE ISTH Academy App for iOS and Android.
Journal Abstract
Discussion Forum (0)
Rate & Comment (0)


Background
Concizumab is a monoclonal antibody (mAb) against tissue factor pathway inhibitor (TFPI), currently in clinical development as a subcutaneous prophylactic therapy for hemophilia A/B with and without inhibitors. In patients with inhibitors, the treatment choice for breakthrough bleeding will comprise bypassing agents, e.g. activated recombinant FVIIa (rFVIIa) or activated prothrombin complex concentrates.
Objectives
To explore the effect and safety of concizumab and rFVIIa when they are simultaneously present.
Methods
Human blood made hemophilic with a FVIII antibody was spiked with increasing concentrations of concizumab, rFVIIa, or concizumab and rFVIIa in combination, and this was followed by thrombin generation test or thromboelastography. Blood loss in hemophilic rabbits was measured when concizumab, rFVIIa or concizumab + rFVIIa was administered either before or during cuticle bleeding. In a safety study, cynomolgus monkeys were exposed to high steady‐state concizumab concentrations and given three doses of rFVIIa, and then subjected to full necropsy and histopathological examination.
Results
In human blood, concizumab + rFVIIa had more pronounced procoagulant effects under hemophilic conditions than the sum of individual responses. In contrast, concizumab + rFVIIa had no additional effects on blood loss in hemophilic rabbits as compared with rFVIIa or concizumab alone. In cynomolgus monkeys, the macroscopic and microscopic pathological examinations revealed no thrombi or other signs of excessive coagulation activation. Both rFVIIa and concizumab caused increases in thrombin–antithrombin and D‐dimer concentrations; this effect tended to be additive with concomitant administration.
Conclusions
Concizumab did not affect the potency or safety of rFVIIa in vivo. These results support a clinical evaluation of rFVIIa at standard dose (90 μg kg) to treat breakthrough bleeds in concizumab clinical trials.
Keyword(s)
factor VII, hemophilia A, hemophilia B, mAb 2021, recombinant FVIIa
Code of conduct/disclaimer available in General Terms & Conditions

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies