Identification
- Generic Name
- Turoctocog alfa pegol
- DrugBank Accession Number
- DB14738
- Background
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 12. Turoctocog alfa is produced in Chinese hamster ovary (CHO) cells without addition of any human or animal-derived materials 12. 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 11. 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.
- Type
- Biotech
- Groups
- Approved
- Biologic Classification
- Protein Based Therapies
Blood factors - Protein Chemical Formula
- Not Available
- Protein Average Weight
- Not Available
- Sequences
- Not Available
- Synonyms
- Antihemophilic factor (recombinant), glycopegylated-exei
- N8-GP
- Turoctocog alfa pegol
- Turoctocog alfa pegol, N8-GP
Pharmacology
- Indication
Turoctocog alfa pegol is indicated for use in adults and children with hemophilia A for on-demand treatment and control of bleeding episodes, perioperative management of bleeding, and routine prophylaxis to reduce the frequency of bleeding episodes. It is not indicated for the treatment of von Willebrand disease.10
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Prophylaxis of Bleeding caused by hemophilia a •••••••••••• ••••••••••• •••••• ••••••••• Management of Bleeding caused by hemophilia a •••••••••••• ••••••••••• •••••• ••••••••• Management of Bleeding caused by hemophilia a •••••••••••• ••••••••••• •••••• ••••••••• - Associated Therapies
- Contraindications & Blackbox Warnings
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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 11. 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 11. Additionally, N8-GP was also found to be efficacious in the treatment and control of bleeding episodes and the perioperative management of bleeding 11. Across the clinical trials and age groups, N8-GP was shown to be well tolerated and no safety concerns were identified 11. The overall safety profile of N8-GP is similar to what has been reported for other long-action FVIII products 11. 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 13. 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 13.
Target Actions Organism ACoagulation factor IX activatorHumans ACoagulation factor X activatorHumans AProthrombin binderHumans Avon Willebrand factor binderHumans - 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 11.
- Clearance
The mean clearance recorded for turoctocog alfa pegol (N8-GP) is 1.79 +/- 0/92 (mL^-1 h^-1 kg^-1) 2.
- Adverse Effects
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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 11. 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 11.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbciximab The therapeutic efficacy of Turoctocog alfa pegol can be decreased when used in combination with Abciximab. Acenocoumarol The therapeutic efficacy of Turoctocog alfa pegol can be decreased when used in combination with Acenocoumarol. Alpha-1-proteinase inhibitor Alpha-1-proteinase inhibitor may increase the thrombogenic activities of Turoctocog alfa pegol. Alteplase The therapeutic efficacy of Turoctocog alfa pegol can be decreased when used in combination with Alteplase. Aminocaproic acid The risk or severity of adverse effects can be increased when Aminocaproic acid is combined with Turoctocog alfa pegol. - Food Interactions
- Not Available
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Esperoct Injection, powder, for solution 5000 IU Intravenous Novo Nordisk 2023-11-28 Not applicable EU 
Esperoct Injection, powder, for solution 2000 IU Intravenous Novo Nordisk 2021-01-12 Not applicable EU Esperoct Injection, powder, for solution 500 IU Intravenous Novo Nordisk 2021-01-12 Not applicable EU Esperoct Powder, for solution 1500 unit / vial Intravenous Novo Nordisk Not applicable Not applicable Canada 
Esperoct 3000 [iU]/1mL Intravenous Novo Nordisk 2019-02-19 Not applicable US 
Categories
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- 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
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 9Y9727LS4D
- CAS number
- 1309086-46-1
References
- General References
- 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. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- Salen P, Babiker HM: Hemophilia A . [Article]
- 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. [Article]
- 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. [Article]
- 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]
- FiercePharma [Link]
- FDA Approved Drug Products: ESPEROCT [antihemophilic factor (recombinant), glycopegylated-exei] lyophilized powder for solution, for intravenous use [Link]
- Novo Nordisk receives US FDA approval of ESPEROCT® (turoctocog alfa pegol, N8-GP) Press Release [File]
- Turoctocog alfa EMA Label [File]
- 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
Phase Status Purpose Conditions Count 3 Completed Treatment Congenital Hematological Disorder / Hemophilia A 5 3 Completed Treatment Hemophilia A 1 1 Completed Treatment Congenital Hematological Disorder / Hemophilia A 3 Not Available Enrolling by Invitation Not Available Hemophilia A 3 Not Available Recruiting Not Available Hemophilia A 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, powder, for solution Intravenous 2000 IU Injection, powder, for solution Intravenous 3000 IU Injection, powder, for solution Intravenous 4000 IU Injection, powder, for solution Intravenous 500 IU Injection, powder, for solution Intravenous 5000 IU Powder, for solution Intravenous 1000 unit / vial Powder, for solution Intravenous 1500 unit / vial Powder, for solution Intravenous 2000 unit / vial Powder, for solution Intravenous 3000 unit / vial Powder, for solution Intravenous 500 unit / vial Injection, powder, for solution Parenteral 1000 iu Injection, powder, for solution Parenteral 1500 iu Injection, powder, for solution Parenteral 2000 iu Injection, powder, for solution Parenteral 3000 iu Injection, powder, for solution Parenteral 500 iu Injection, powder, for solution Intravenous 1000 IU Injection, powder, for solution Intravenous 1500 IU Injection, powder, lyophilized, for solution Intravenous 2000 IU Injection, powder, lyophilized, for solution Intravenous 30000 IU - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Not Available
- Experimental Properties
- 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
- 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
- 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
- Australian report [Link]
- 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
- 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. [Article]
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
- 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. [Article]
- 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
- 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. [Article]
Drug created at February 20, 2019 05:23 / Updated at March 24, 2022 01:23