N8-GP, also known as turoctocog alfa pegol, is developed by Novo Nordisk. It is a glyco-PEGylated factor VIII (FVIII) in which the B-domain (a region within the factor) is deleted. N8-GP is manufactured in Chinese hamster ovary (CHO) cells (a type of cell line) by site-specific addition of polyethylene glycol (PEG), whose molecular weight is 40 kDa-
Activation of the blood-clotting pathway results in the removal of the PEG molecule, generating recombinant FVIII similar in structure to native FVIII.
Clinical studies with N8-GP
N8-GP was evaluated in a Phase 1 dose escalation trial (NCT01205724 Pathfinder1) in 26 people with severe hemophilia A. Participants received one of three doses (25, 50 or 75 IU/kg) of N8-GP evaluated by means of pharmacokinetic assessment. The drug was well-tolerated at either dose and none of the participants developed inhibitors against it. The mean terminal half-life of the factor concentrate was 19 hours, representing a 1.6-fold prolongation in comparison to the FVIII products previously used.
A Phase 3 multinational, open-label, non-randomized trial (NCT01480180 Pathfinder2) evaluated the safety, pharmacokinetics, and effectiveness of N8-GP used on prophylaxis and for episodic treatment of bleeds in 186 previously treated patients with severe hemophilia A, ages 12 years and above. The results of this trial were published in the Journal of Thrombosis and Haemostasis.
Of the 186 patients, 175 received regular prophylaxis with 50 IU/kg of N8-GP every fourth day with a median annual bleed rate (the number of bleeds a person experiences over the course of one year) of 1.33. Seventy patients (40% of all patients) had no bleeds during the trial and overall, 84% of bleeding episodes resolved after a single infusion.
N8-GP was in generally well-tolerated. One patient tested positive for anti-FVIII inhibitors after 93 exposure days to N8-GP; initially, the patient had no signs of clinical impact of the antibody and continued to be treated with N8-GP. However, three months after his rolling over in the extension phase of the trial, a high-titer (i.e., 13.5 BU/mL) was detected and the patient was withdrawn from the study.
A Phase 3 trial (NCT01731600 Pathfinder5) evaluating the safety, pharmacokinetics, and effectiveness of N8-GP used in prophylaxis in previously treated children with severe hemophilia A, younger than 12 years, is underway, although no longer actively recruiting new participants.
Another Phase 3 trial (NCT01489111 Pathfinder3), aiming to evaluate the effectiveness of N8-GP during surgical procedures in people with hemophilia A, is currently recruiting participants.
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