Turoctocog alfa pegol is a pegylated version of [turoctocog alfa]. Novo Nordisk's emblem name Esperoct (turoctocog alfa pegol, N8-GP) became permitted by way of america FDA on February 19, 2019. essentially, the N8-GP moiety is equal to [turoctocog alfa], a recombinant human clotting issue VIII (rFVIII) with a truncated B-domain made from the collection coding for 10 amino acids from the N-terminus and 11 amino acids from the C-terminus of the clearly taking place B-domain [F3685]. Turoctocog alfa is produced in chinese hamster ovary (CHO) cells with out addition of any human or animal-derived materials [F3685]. at some point of secretion, some rFVIII molecules are cleaved on the C-terminal of the heavy chain (HC) at amino acid 720, and a monoclonal antibody binding C-terminal to this function is used in the purification process allowing isolation of the intact rFVIII [A31504]. It become developed with the aid of Novo Nordisk and authorized by america FDA on October 16, 2013 [L1104]. The essential distinction between turoctocog alfa and N8-GP, but, is the unique attachment of a 40-kDa polyethylene glycol (PEG) institution to a selected _O_-glycan inside the truncated B-domain of the overall turoctocog alfa rFVIII structure [A31506, A32069]. this alteration to the overall turoctocog alfa rFVIII shape makes N8-GP an extended half of-existence factor VIII molecule for thing VIII substitute therapy in patients with issue VIII deficiency, or hemophilia A [F3649]. As such, turoctocog alfa pegol is a treasured expansion to the drug remedies available for treating hemophilia A as it ultimately presents a less burdensome and greater handy dosing routine for patients that is much less common than that for turoctocog alfa.
Based on results obtained from the Pathfinder clinical studies, turoctocog alfa pegol (N8-GP) was shown to provide effective routine prophylaxis in people with severe haemophilia A through a fixed dosing regimen of one injection every 4 days in adults and adolescents, or every 3-4 days (twice-weekly) in children [F3649]. Furthermore, N8-GP provided effective prophylaxis and maintained a low median annualized bleeding rate (ABR) of 1.18 when administered at doses of 50 IU/kg every 4 days in adults and adolescents [F3649]. Additionally, N8-GP was also found to be efficacious in the treatment and control of bleeding episodes and the perioperative management of bleeding [F3649]. Across the clinical trials and age groups, N8-GP was shown to be well tolerated and no safety concerns were identified [F3649]. The overall safety profile of N8-GP is similar to what has been reported for other long-action FVIII products [F3649]. Moreover, in general, no FVIII inhibitor antibodies have been detected, and no thromboembolic events have occurred with the use of N8-GP [A175081].
Turoctocog alfa pegol (N8-GP) is indicated for use in adults and children of all ages with hemophilia A (congenital factor VIII deficiency) for routine prophylaxis in reducing the frequency of bleeding episodes, on-demand treatment and control of bleeding episodes, and the perioperative management of bleeding [F3649].
The principal characteristic that defines hemophilia A is the limited presence or complete deficiency of human clotting factor VIII in the body [A31505]. Subsequently, because factor VIII is a critical component that is essential for the extrinsic tissue factor pathway of the blood coagulation cascade process to proceed, individuals with hemophilia A ultimately experience increased bleeding - in comparison to individuals without a factor VIII deficiency - after injury or any kind of medical procedure [A31505]. Such increased bleeding can be heavy and/or fatal and may occur due to minimal injury or even when there is no injury whatsoever - in which case the bleeding is spontaneous [A31505]. Furthermore, excessive bleeds that bleed into muscles, organs, and joints are also associated with dangerous complications and regular pain [A31505]. The turoctocog alfa pegol (N8-GP) drug is consequently recombinant factor VIII (rFVIII) in which specific site-directed glycoPEGylation has been performed in an effort to increase the half-life of the rFVIII moiety without altering its hemostatic activity [A31506, A32069]. In particular, the general rFVIII component of N8-GP is turoctocog alfa, a human coagulation factor VIII (rDNA), with a truncated B-domain [A31506, A32069]. This glycoprotein has the same structure as human clotting factor VIII when activated, and also possesses post-translational modifications that are similar to those of the plasma-derived molecule [A31506, A32069]. In blood, factor VIII predominantly circulates in a stable non-covalent complex with von Willebrand factor (vWF) [A175078, A175093]. Concurrently, the tyrosine sulfation site present at the Tyr1680 (native full length) position, which is important for binding to vWF, has been found to be fully sulfated in the turoctocog alfa molecule [A31506, A32069]. Subsequently, when infused into a hemophilia patient, this rFVIII binds to endogenous vWF in the patientâ€™s circulation [A31506, A32069]. The resultant factor VIII/vWF complex consists of two molecules (factor VIII and vWF) with different physiological functions [A31506, A32069, A175078, A175093]. Factor VIII is activated by thrombin (factor IIa) [A31506, A32069, A31505]. Activated factor VIII acts as a co-factor for activated factor IX, accelerating the conversion of factor X to activated factor X [A31505]. Activated factor X converts prothrombin into thrombin [A31505]. Thrombin then converts fibrinogen into fibrin and a clot can be formed [A31505]. Turoctocog alfa pegol consequently functions predominantly as factor VIII replacement therapy for patients with factor VIII deficient hemophilia A. Finally, the particular N8-GP molecule has a 40-kDa polyethylene glycol (PEG) attached to a specific _O_-glycan in the truncated B-domain of the general turoctocog alfa rFVIII structure [A31506, A32069]. Upon activation by thrombin, this B-domain possessing the pegylation is cleaved away, leaving active rFVIIIa - which as discussed above, is highly similar to and elicits the same blood clotting activities as native factor VIII [A31506, A32069]. Subsequently, the PEG group of N8-GP ultimately serves to extend the half-life of the overall drug molecule in the body. As an inert chemical, the PEG group prolongs N8-GP's half-life by acting like an obstructive 'cloud' around the rFVIII molecule to which it is attached [F3703]. Since the PEG group is generally too large to be cleared by the kidneys and does not bind particularly well with the clearance receptors that typically eliminate endogenous factor VIII, N8-GP demonstrates a longer half-life than the general turoctocog alfa rFVIII structure [F3703].