Identification

Logo pink
Are you a
new drug developer?
Contact us to learn more about our customized products and solutions.
Name
Turoctocog alfa pegol
Accession Number
DB14738
Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Blood factors
Description

Turoctocog alfa pegol is a pegylated version of turoctocog alfa. Novo Nordisk's brand name Esperoct (turoctocog alfa pegol, N8-GP) was approved by the US FDA on February 19, 2019.

Fundamentally, the N8-GP moiety is identical to turoctocog alfa, a recombinant human clotting factor VIII (rFVIII) with a truncated B-domain made from the sequence coding for 10 amino acids from the N-terminus and 11 amino acids from the C-terminus of the naturally occurring B-domain 11. Turoctocog alfa is produced in Chinese hamster ovary (CHO) cells without addition of any human or animal-derived materials 11. During secretion, some rFVIII molecules are cleaved at the C-terminal of the heavy chain (HC) at amino acid 720, and a monoclonal antibody binding C-terminal to this position is used in the purification process allowing isolation of the intact rFVIII 7. It was developed by Novo Nordisk and approved by the US FDA on October 16, 2013 9.

The essential difference between turoctocog alfa and N8-GP, however, is the specific attachment of a 40-kDa polyethylene glycol (PEG) group to a specific O-glycan in the truncated B-domain of the general turoctocog alfa rFVIII structure 1,2. This modification to the general turoctocog alfa rFVIII structure makes N8-GP an extended half-life factor VIII molecule for factor VIII replacement therapy in patients with factor VIII deficiency, or hemophilia A 10. As such, turoctocog alfa pegol is a valuable expansion to the drug therapies available for treating hemophilia A as it ultimately provides a less burdensome and more convenient dosing regimen for patients that is less frequent than that for turoctocog alfa.

Protein chemical formula
Not Available
Protein average weight
Not Available
Sequences
Not Available
Synonyms
  • N8-GP
  • Turoctocog alfa pegol
  • Turoctocog alfa pegol, N8-GP
Categories
UNII
9Y9727LS4D
CAS number
1309086-46-1

Pharmacology

Indication

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 10.

Associated Conditions
Pharmacodynamics

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 10. 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 10. Additionally, N8-GP was also found to be efficacious in the treatment and control of bleeding episodes and the perioperative management of bleeding 10. Across the clinical trials and age groups, N8-GP was shown to be well tolerated and no safety concerns were identified 10. The overall safety profile of N8-GP is similar to what has been reported for other long-action FVIII products 10. Moreover, in general, no FVIII inhibitor antibodies have been detected, and no thromboembolic events have occurred with the use of N8-GP 4.

Mechanism of action

The principal characteristic that defines hemophilia A is the limited presence or complete deficiency of human clotting factor VIII in the body 5. 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 5. 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 5. Furthermore, excessive bleeds that bleed into muscles, organs, and joints are also associated with dangerous complications and regular pain 5.

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 1,2. In particular, the general rFVIII component of N8-GP is turoctocog alfa, a human coagulation factor VIII (rDNA), with a truncated B-domain 1,2. 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 1,2.

In blood, factor VIII predominantly circulates in a stable non-covalent complex with von Willebrand factor (vWF) 3,6. 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 1,2. Subsequently, when infused into a hemophilia patient, this rFVIII binds to endogenous vWF in the patient’s circulation 1,2. The resultant factor VIII/vWF complex consists of two molecules (factor VIII and vWF) with different physiological functions 1,2,3,6. Factor VIII is activated by thrombin (factor IIa) 1,2,5. Activated factor VIII acts as a co-factor for activated factor IX, accelerating the conversion of factor X to activated factor X 5. Activated factor X converts prothrombin into thrombin 5. Thrombin then converts fibrinogen into fibrin and a clot can be formed 5. 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 1,2. 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 1,2. 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 12. 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 12.

TargetActionsOrganism
ACoagulation factor IX
activator
Humans
ACoagulation factor X
activator
Humans
AProthrombin
binder
Humans
Absorption

Studies have determined that the pharmacokinetics of turoctocog alfa pegol (N8-GP) are dose linear 2. In particular, the area under the plasma activity curve from administration to infinity was a mean 14.74 +/- 5.35 (U h mL^-1), 38.85 +/- 11.41 (U h mL^-1), and 46.76 +/- 20.56 (U h mL^-1) at dosages of 25 U/kg, 50 U/kg, and 75 U/kg, respectively 2. Moreover, the C(30 min) factor VIII plasma activity 30 minutes after administration for the same three dosage categories was documented as being 0.65 +/- 0.12 U/mL, 1.24 +/- 0.28 U/mL, and 1.93 +/- 0.58 U/mL, respectively 2.

Volume of distribution

The mean volume of distribution recorded for turoctocog alfa pegol (N8-GP) is 45.27 +/- 17.78 mL/kg 2.

Protein binding

Data regarding the protein binding of turoctocog alfa pegol (N8-GP) is not readily available or accessible.

Metabolism

Once activated by thrombin (clotting factor IIa), factor VIII dissociates from the stable non-covalent complex with von Willebrand Factor (vWF) that it generally circulates about in the blood with 3,6. Separated from the protection of its complexation with vWF, it is believed that factor VIII undergoes proteolysis into its component amino acids by phospholipid binding proteases like protein C and activated factor Xa before being cleared from the bloodstream 3,6.

Route of elimination

Studies regarding the elimination and clearance of factor VIII propose that the clotting factor likely experiences clearance by way of tissue mechanisms such as receptor-mediated endocytosis followed by catabolism rather than hepatic metabolism and renal excretion 3,6. In particular, it is believed that receptor-mediated clearance of free factor VIII molecules is associated with structures like low-density lipoprotein (LDL) receptor-related protein (LRP1), LDL-receptors (LDLRs), heparan-sulfate proteoglycans (HSPG), megalin receptors, asialoglycoprotein receptors (ASGPRs), and various as of yet unidentified carbohydrate receptors 3. Some of these receptors may operate in association with each other, some may be able to internalize factor VIII by themselves, and some may be expressed on hepatocytes while still others may be expressed on macrophages 3.

Half life

The mean plasma half-life recorded for turoctocog alfa pegol (N8-GP) is 19.04 +/- 5.53 hours 2. Regardless, N8-GP is ultimately considered an extended half-life factor VIII molecule which offers a 1.6 fold half-life extension in adults and adolescents and a 1.9 fold half-life extension in children when compared the half-life of standard factor VIII medications 10.

Clearance

The mean clearance recorded for turoctocog alfa pegol (N8-GP) is 1.79 +/- 0/92 (mL^-1 h^-1 kg^-1) 2.

Toxicity

At the moment, due to third-party IP agreements, Novo Nordisk will not be able to launch the retail ESPEROCT® (turoctocog alfa pegol) product before 2020 in the USA 10. Subsequently, despite a relative lack of toxicity data - from clinical studies, post-marketing surveillance, or otherwise - general experience with the medication has suggested that it is well tolerated across all age groups and indications, and no safety concerns were identified after more than 5 years of clinical exposure 10.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe therapeutic efficacy of Turoctocog alfa pegol can be decreased when used in combination with (R)-warfarin.
(S)-WarfarinThe therapeutic efficacy of Turoctocog alfa pegol can be decreased when used in combination with (S)-Warfarin.
4-hydroxycoumarinThe therapeutic efficacy of Turoctocog alfa pegol can be decreased when used in combination with 4-hydroxycoumarin.
AbciximabThe therapeutic efficacy of Turoctocog alfa pegol can be decreased when used in combination with Abciximab.
AcenocoumarolThe therapeutic efficacy of Turoctocog alfa pegol can be decreased when used in combination with Acenocoumarol.
Acetylsalicylic acidThe therapeutic efficacy of Turoctocog alfa pegol can be decreased when used in combination with Acetylsalicylic acid.
Alpha-1-proteinase inhibitorAlpha-1-proteinase inhibitor may increase the thrombogenic activities of Turoctocog alfa pegol.
AlteplaseThe therapeutic efficacy of Turoctocog alfa pegol can be decreased when used in combination with Alteplase.
AmediplaseThe therapeutic efficacy of Turoctocog alfa pegol can be decreased when used in combination with Amediplase.
Aminocaproic AcidThe risk or severity of adverse effects can be increased when Aminocaproic Acid is combined with Turoctocog alfa pegol.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

    Learn more
  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

    Learn more
  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

    Learn more
  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

    Learn more
Food Interactions
Not Available

References

General References
  1. Agerso H, Stennicke HR, Pelzer H, Olsen EN, Merricks EP, Defriess NA, Nichols TC, Ezban M: Pharmacokinetics and pharmacodynamics of turoctocog alfa and N8-GP in haemophilia A dogs. Haemophilia. 2012 Nov;18(6):941-7. doi: 10.1111/j.1365-2516.2012.02896.x. Epub 2012 Jul 20. [PubMed:22812621]
  2. Tiede A, Brand B, Fischer R, Kavakli K, Lentz SR, Matsushita T, Rea C, Knobe K, Viuff D: Enhancing the pharmacokinetic properties of recombinant factor VIII: first-in-human trial of glycoPEGylated recombinant factor VIII in patients with hemophilia A. J Thromb Haemost. 2013 Apr;11(4):670-8. doi: 10.1111/jth.12161. [PubMed:23398640]
  3. Lenting PJ, VAN Schooten CJ, Denis CV: Clearance mechanisms of von Willebrand factor and factor VIII. J Thromb Haemost. 2007 Jul;5(7):1353-60. doi: 10.1111/j.1538-7836.2007.02572.x. Epub 2007 Apr 7. [PubMed:17425686]
  4. Hampton K, Chowdary P, Dunkley S, Ehrenforth S, Jacobsen L, Neff A, Santagostino E, Sathar J, Takedani H, Takemoto CM, Negrier C: First report on the safety and efficacy of an extended half-life glycoPEGylated recombinant FVIII for major surgery in severe haemophilia A. Haemophilia. 2017 Sep;23(5):689-696. doi: 10.1111/hae.13246. Epub 2017 May 4. [PubMed:28470862]
  5. Salen P, Babiker HM: Hemophilia A . [PubMed:29261993]
  6. Lenting PJ, van Mourik JA, Mertens K: The life cycle of coagulation factor VIII in view of its structure and function. Blood. 1998 Dec 1;92(11):3983-96. [PubMed:9834200]
  7. Ezban M, Vad K, Kjalke M: Turoctocog alfa (NovoEight(R))--from design to clinical proof of concept. Eur J Haematol. 2014 Nov;93(5):369-76. doi: 10.1111/ejh.12366. Epub 2014 May 28. [PubMed:24797664]
  8. American Society of Hematology Blood: Efficacy of an Extended Half-Life GlycoPEGylated rFVIII (N8-GP): Pooled Analysis of ABR (Results from Two Clinical Trials) [Link]
  9. FiercePharma [Link]
  10. Novo Nordisk receives US FDA approval of ESPEROCT® (turoctocog alfa pegol, N8-GP) Press Release [File]
  11. Turoctocog alfa EMA Label [File]
  12. PeerView CME: Illuminating the Role of Shared Decision-Making as the Hemophilia A Management Landscape Continues to Evolve: Progress in Practice [File]
External Links
Wikipedia
Turoctocog_alfa

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentCongenital Hematological Disorder / Hemophilia A3
3Active Not RecruitingTreatmentCongenital Hematological Disorder / Hemophilia A1
3CompletedTreatmentCongenital Hematological Disorder / Hemophilia A3
3Enrolling by InvitationTreatmentCongenital Hematological Disorder / Hemophilia A1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available

Taxonomy

Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Activator
General Function
Serine-type endopeptidase activity
Specific Function
Factor IX is a vitamin K-dependent plasma protein that participates in the intrinsic pathway of blood coagulation by converting factor X to its active form in the presence of Ca(2+) ions, phospholi...
Gene Name
F9
Uniprot ID
P00740
Uniprot Name
Coagulation factor IX
Molecular Weight
51778.11 Da
References
  1. Turoctocog alfa EMA Label [File]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Activator
General Function
Serine-type endopeptidase activity
Specific Function
Factor Xa is a vitamin K-dependent glycoprotein that converts prothrombin to thrombin in the presence of factor Va, calcium and phospholipid during blood clotting.
Gene Name
F10
Uniprot ID
P00742
Uniprot Name
Coagulation factor X
Molecular Weight
54731.255 Da
References
  1. Turoctocog alfa EMA Label [File]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Binder
General Function
Thrombospondin receptor activity
Specific Function
Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostas...
Gene Name
F2
Uniprot ID
P00734
Uniprot Name
Prothrombin
Molecular Weight
70036.295 Da
References
  1. Australian report [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Serine-type endopeptidase activity
Specific Function
Protein C is a vitamin K-dependent serine protease that regulates blood coagulation by inactivating factors Va and VIIIa in the presence of calcium ions and phospholipids (PubMed:25618265). Exerts ...
Gene Name
PROC
Uniprot ID
P04070
Uniprot Name
Vitamin K-dependent protein C
Molecular Weight
52070.82 Da
References
  1. Lenting PJ, VAN Schooten CJ, Denis CV: Clearance mechanisms of von Willebrand factor and factor VIII. J Thromb Haemost. 2007 Jul;5(7):1353-60. doi: 10.1111/j.1538-7836.2007.02572.x. Epub 2007 Apr 7. [PubMed:17425686]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Serine-type endopeptidase activity
Specific Function
Factor Xa is a vitamin K-dependent glycoprotein that converts prothrombin to thrombin in the presence of factor Va, calcium and phospholipid during blood clotting.
Gene Name
F10
Uniprot ID
P00742
Uniprot Name
Coagulation factor X
Molecular Weight
54731.255 Da
References
  1. Lenting PJ, VAN Schooten CJ, Denis CV: Clearance mechanisms of von Willebrand factor and factor VIII. J Thromb Haemost. 2007 Jul;5(7):1353-60. doi: 10.1111/j.1538-7836.2007.02572.x. Epub 2007 Apr 7. [PubMed:17425686]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Binder
General Function
Protein n-terminus binding
Specific Function
Important in the maintenance of hemostasis, it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surf...
Gene Name
VWF
Uniprot ID
P04275
Uniprot Name
von Willebrand factor
Molecular Weight
309261.83 Da
References
  1. Lenting PJ, VAN Schooten CJ, Denis CV: Clearance mechanisms of von Willebrand factor and factor VIII. J Thromb Haemost. 2007 Jul;5(7):1353-60. doi: 10.1111/j.1538-7836.2007.02572.x. Epub 2007 Apr 7. [PubMed:17425686]

Drug created on February 19, 2019 22:23 / Updated on May 01, 2019 12:03