Nonacog beta pegol

Identification

Logo pink
Are you a
new drug developer?
Contact us to learn more about our customized products and solutions.
Name
Nonacog beta pegol
Accession Number
DB13933
Type
Biotech
Groups
Approved, Investigational
Description

Nonacog beta pegol is a recombinant coagulation factor IX derivative. It is produced without animal-derived materials and with an attached 40kDa polyethylene glycol (PEG) molecule for peptide activation by a site-directed glycoPEGylation. Once activated, the activation molecule with PEG are cleaved to leave the activated factor IX (Factor IXa).1 Nonacog beta pegol was developed by Novo Nordisk, obtained EMA marketing authorisation in June 6, 2017.9

Synonyms
  • Coagulation Factor IX (Recombinant), GlycoPEGylated
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
RebinynPowder, for solution2000 unitIntravenousNovo Nordisk2018-03-23Not applicableCanada
RebinynPowder, for solution1000 unitIntravenousNovo Nordisk2018-03-23Not applicableCanada
RebinynPowder, for solution500 unitIntravenousNovo Nordisk2018-03-23Not applicableCanada
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

    Learn more
  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

    Learn more
Categories
UNII
27Y83O992Q
CAS number
1175512-71-6

Pharmacology

Indication

Nonacog beta pegol is indicated for the use in adults and children with hemophilia B for control and prevention of bleeding episodes, routine prophylaxis and perioperative management.10 In the EMA approval, it is also indicated for on-demand treatment of bleeding episodes.9 Hemophilia B is characterized by a deficiency in the coagulation factor IX which results in prolonged oozing after injuries and delayed or recurring bleeding prior wound healing. Hemophilia B patients present more frequent bleeding episodes during childhood and adolescence than in adulthood.7

Associated Conditions
Pharmacodynamics

After nonacog beta pegol is activated by the coagulation factor IXa and tissue-coagulation factor VIIa, the peptide is cleaved off.10 In preclinical studies, once the peptide is free, there was a restoration of whole blood clotting time activity and the activated-partial thromboplastin time was returned to normal limits. In clinical trials, the administration of nonacog beta pegol significantly increased the levels of factor IX in plasma and temporarily correct the level of activated partial thromboplastin time.11 The effect of nonacog beta pegol translated into good hemostasis when used to treat bleeds on-demand and in a reduction of annualized bleeding rates when used as prophylaxis without formation of factor IX inhibitors, allergic reactions or thromboembolic complications.2 The reports in clinical trials have also shown a significant prolongation in the duration of the hemostatic effect.12

Mechanism of action

Nonacog beta pegol is activated by the factor IXa and the tissue complex factor VII. When activated, the peptide including the 40kDa PEG moiety is cleaved off leaving an activated recombinant factor IX ready to be part of the coagulation cascade replacing the missing clotting factor IX.9 Thus, after activation, nonacog beta pegol will present the same mechanism of action than the endogenous coagulation factor IXa.10 The activated coagulation factor IX function is, in combination with the factor VIIIa, to activate the coagulation factor X to trigger the coagulation cascade that finalizes in the conversion of prothrombin into thrombin and the thrombin-driven conversion of fibrinogen into fibrin for the formation of a clot.3

TargetActionsOrganism
ACoagulation factor VII
cofactor
Humans
ACoagulation factor VIII
cofactor
Humans
ACoagulation factor X
agonist
Humans
Additional Data Available
Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

Learn more
Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

Learn more
Additional Data Available
Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

Learn more
Absorption

In preclinical overdose studies, there was reported an AUC of 1200 IU/kg in rats and 3750 IU/kg in monkeys.11 In clinical studies, the absorption properties of nonacog beta pegol were AUC of 92 IU h/ml at steady state.9 In precliniacl studies, there was a reduced accumulation of systemic drug after multiple dosing.12

Volume of distribution

The reported volume of distribution for nonacog beta pegol is variable depending on the patient's age. After single administration, the volume of distribution goes from 72 ml/kg when the patient is less than 6 years old, 68 ml/kg between 7-12 years old, 59 ml/kg between 13-17 years old and 47 ml/kg when the patient is over 18 years old.9 At steady state, the volume of distribution of nonacog beta pegol is 64 ml/kg.9

Protein binding

Nonavog brta pegol is not expected to bind to plasma proteins.12

Metabolism

Nonacog beta pegol is rapidly distributed with the highest distribution in the well-perfused tissues. The proteinic part of nonacog beta pegol is degraded over time leaving just the 40 kDa PEG in circulation for 7.5-9 times longer than the original compound.10 As previously reported, the nonacog beta pegol will undergo uptake into cells and the protein part will be degraded in the lysosomes/endosomes leaving the PEG part to return to the plasma.5

Route of elimination

Nonacog beta pegol is eliminated from all tissues indicating that it will reach steady state in plasma and tissue but it will not accumulate. The 40 kDa PEG is eliminated by urine and feces taking approximately 49 and 40% of the administered dose respectively.6 The PEG part of the drug seems to be eliminated with a bi-phasic profile that was registered at 2-3 days and at 15-18 days.12

Half life

The terminal half life of nonacog beta pegol is in the range of 96-110 hours which is 5 times longer than an unmodified coagulation factor IX.4

Clearance

The registered clearance rate of nonacog beta pegol at steady state is of 0.4 ml h/kg.9

Toxicity

There are reports indicating that long-term administration of nonacog beta pegol results in the development of cross-reacting neutralizing antibodies.11 Studies regarding carcinogenicity, genotoxicity and reproductive toxicity have not been made.9

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

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe therapeutic efficacy of Nonacog beta pegol can be decreased when used in combination with (R)-warfarin.
(S)-WarfarinThe therapeutic efficacy of Nonacog beta pegol can be decreased when used in combination with (S)-Warfarin.
4-hydroxycoumarinThe therapeutic efficacy of Nonacog beta pegol can be decreased when used in combination with 4-hydroxycoumarin.
AbciximabThe therapeutic efficacy of Nonacog beta pegol can be decreased when used in combination with Abciximab.
Abicipar PegolThe therapeutic efficacy of Nonacog beta pegol can be decreased when used in combination with Abicipar Pegol.
AcenocoumarolThe therapeutic efficacy of Nonacog beta pegol can be decreased when used in combination with Acenocoumarol.
Acetylsalicylic acidThe therapeutic efficacy of Nonacog beta pegol can be decreased when used in combination with Acetylsalicylic acid.
Alpha-1-proteinase inhibitorAlpha-1-proteinase inhibitor may increase the thrombogenic activities of Nonacog beta pegol.
AlteplaseThe therapeutic efficacy of Nonacog beta pegol can be decreased when used in combination with Alteplase.
AmediplaseThe therapeutic efficacy of Nonacog beta pegol can be decreased when used in combination with Amediplase.
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. Collins PW, Moss J, Knobe K, Groth A, Colberg T, Watson E: Population pharmacokinetic modeling for dose setting of nonacog beta pegol (N9-GP), a glycoPEGylated recombinant factor IX. J Thromb Haemost. 2012 Nov;10(11):2305-12. doi: 10.1111/jth.12000. [PubMed:22998153]
  2. Syed YY: Nonacog Beta Pegol: A Review in Haemophilia B. Drugs. 2017 Dec;77(18):2003-2012. doi: 10.1007/s40265-017-0836-8. [PubMed:29124682]
  3. Palta S, Saroa R, Palta A: Overview of the coagulation system. Indian J Anaesth. 2014 Sep;58(5):515-23. doi: 10.4103/0019-5049.144643. [PubMed:25535411]
  4. Mancuso ME: GlycoPEGylated factor IX: a new step forward. Blood. 2014 Dec 18;124(26):3836-7. doi: 10.1182/blood-2014-10-604983. [PubMed:25525079]
  5. Baumann A, Tuerck D, Prabhu S, Dickmann L, Sims J: Pharmacokinetics, metabolism and distribution of PEGs and PEGylated proteins: quo vadis? Drug Discov Today. 2014 Oct;19(10):1623-31. doi: 10.1016/j.drudis.2014.06.002. Epub 2014 Jun 11. [PubMed:24929223]
  6. Sternebring O, Christensen JK, Bjornsdottir I: Pharmacokinetics, tissue distribution, excretion, and metabolite profiling of PEGylated rFIX (nonacog beta pegol, N9-GP) in rats. Eur J Pharm Sci. 2016 Sep 20;92:163-72. doi: 10.1016/j.ejps.2016.06.025. Epub 2016 Jul 1. [PubMed:27378188]
  7. Konkle B., Huston H. and Fletcher S. (2017). Gene Reviews. University of Washington..
  8. Globe Newswire [Link]
  9. Novo Nordisk News [Link]
  10. FDA Advisory committees [Link]
  11. FDA Advisory committees [Link]
  12. EMA Reports [Link]
External Links
Not Available
AHFS Codes
  • 20:28.16 — Hemostatics

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentCongenital Hematological Disorder / Haemophilia B1
3Active Not RecruitingTreatmentCongenital Hematological Disorder / Haemophilia B1
3CompletedTreatmentCongenital Hematological Disorder / Haemophilia B3
3RecruitingTreatmentCongenital Hematological Disorder / Haemophilia B1
Not AvailableEnrolling by InvitationNot AvailableHaemophilia B2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Powder, for solutionIntravenous1000 unit
Powder, for solutionIntravenous2000 unit
Powder, for solutionIntravenous500 unit
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilitySolubleBolourchian N., et al. 12(Suppl): 11-20. (2013)

Taxonomy

Classification
Not classified

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Cofactor
General Function
Serine-type peptidase activity
Specific Function
Initiates the extrinsic pathway of blood coagulation. Serine protease that circulates in the blood in a zymogen form. Factor VII is converted to factor VIIa by factor Xa, factor XIIa, factor IXa, o...
Gene Name
F7
Uniprot ID
P08709
Uniprot Name
Coagulation factor VII
Molecular Weight
51593.465 Da
References
  1. Novo Nordisk News [Link]
  2. FDA Advisory committees [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Cofactor
General Function
Oxidoreductase activity
Specific Function
Factor VIII, along with calcium and phospholipid, acts as a cofactor for factor IXa when it converts factor X to the activated form, factor Xa.
Gene Name
F8
Uniprot ID
P00451
Uniprot Name
Coagulation factor VIII
Molecular Weight
267007.42 Da
References
  1. Novo Nordisk News [Link]
  2. FDA Advisory committees [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
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. Novo Nordisk News [Link]
  2. FDA Advisory committees [Link]

Drug created on December 22, 2017 07:27 / Updated on July 18, 2019 19:07