SELECTED IMPORTANT SAFETY INFORMATION: KOVALTRY®
is contraindicated in patients who have a history of hypersensitivity reactions to the active substance, to any of the excipients, or to mouse or hamster proteins.
The science of KOVALTRY®
KOVALTRY® is an unmodified, full length rFVIII1
KOVALTRY® has a primary protein structure that has been in use for over 20 years
Posttranslational modifications of KOVALTRY® are similar to those of endogenous FVIII
1Protein composition and posttranslational modifications
The structure of natural FVIII
Endogenous FVIII is a heterodimeric protein consisting of a heavy chain with the domains A1, A2, and B, and a light chain with the domains A3, C1, and C2.2-4
During biosynthesis, endogenous FVIII undergoes complex posttranslational modifications including glycosylation, sialylation, and tyrosine sulfation.2,5
Glycosylation is the attachment of glycans to a protein; in FVIII, most attach to the B domain2,5
KOVALTRY®: A molecule designed to be
similar to endogenous FVIII
similar to endogenous FVIII
KOVALTRY® is an unmodified, full length rFVIII, containing all 6 FVIII domains.1,2
Posttranslational modifications of KOVALTRY® are similar to those of endogenous FVIII.1
As in endogenous FVIII, the KOVALTRY® molecule demonstrates consistent glycosylation, predominantly on the B domain. Multiple
N-linked and O-linked glycans are present on the B domain of the KOVALTRY® molecule1,9
2The role of sialylation
At least 80% of glycans on endogenous FVIII are capped with sialic acid, which helps prevent FVIII from being recognized by carbohydrate-binding clearance proteins.5
This helps to ensure that FVIII is not prematurely cleared by the liver, and instead can be released into circulation5,6
KOVALTRY® demonstrates consistent glycosylation and a high level of sialylation.9,10
96% of the terminal galactose residues on a KOVALTRY® molecule are sialylated9
3The role of tyrosine sulfation
Additionally, the tyrosine residues in the acidic regions between the major A domains undergo sulfation.7,8
Tyrosine sulfation is needed for the binding of FVIII to the carrier protein, von Willebrand factor (vWF)7,8
The KOVALTRY® molecule is sulfated on 6 tyrosine sites.9
The sulfation of tyrosine sites on the KOVALTRY® molecule is similar
to that of endogenous FVIII1,7,8
Tyrosine sulfation is needed for binding to the carrier protein, von Willebrand factor1,7,8
KOVALTRY® is an unmodified, full length rFVIII1
KOVALTRY® has a primary protein structure that has been in use for over 20 years
Posttranslational modifications of KOVALTRY® are similar to those of endogenous FVIII
1Protein composition and
posttranslational modifications
posttranslational modifications
The structure of natural FVIII
Endogenous FVIII is a heterodimeric protein consisting of a heavy chain with the domains A1, A2, and B, and a light chain with the domains A3, C1, and C2.2-4
During biosynthesis, endogenous FVIII undergoes complex posttranslational modifications including glycosylation, sialylation, and tyrosine sulfation.2,5
Glycosylation is the attachment of glycans to a protein; in FVIII, most attach to the B domain2,5
KOVALTRY®: A molecule designed to be
similar to endogenous FVIII
similar to endogenous FVIII
KOVALTRY® is an unmodified, full length rFVIII, containing all 6 FVIII domains.1,2
Posttranslational modifications of KOVALTRY® are similar to those of endogenous FVIII.1
As in endogenous FVIII, the KOVALTRY® molecule demonstrates consistent glycosylation, predominantly on the B domain. Multiple N-linked and O-linked glycans are present on the B domain of the KOVALTRY® molecule1,9
2The role of sialylation
At least 80% of glycans on endogenous FVIII are capped with sialic acid, which helps prevent FVIII from being recognized by carbohydrate-binding clearance proteins.5
This helps to ensure that FVIII is not prematurely cleared by the liver, and instead can be released into circulation5,6
KOVALTRY® demonstrates consistent glycosylation and a high level of sialylation.9,10
96% of the terminal galactose residues on a KOVALTRY® molecule are sialylated9
3The role of tyrosine sulfation
Additionally, the tyrosine residues in the acidic regions between the major A domains undergo sulfation.7,8
Tyrosine sulfation is needed for the binding of FVIII to the carrier protein, von Willebrand factor (vWF)7,8
The KOVALTRY® molecule is sulfated on 6 tyrosine sites.9
The sulfation of tyrosine sites on the KOVALTRY® molecule is similar to that of endogenous FVIII1,7,8
Tyrosine sulfation is needed for binding to the carrier protein, von Willebrand factor1,7,8
INDICATION FOR KOVALTRY®
KOVALTRY® Antihemophilic Factor (Recombinant) is a recombinant human DNA sequence derived, full length Factor VIII concentrate indicated for use in adults and children with hemophilia A for:
On-demand treatment and control of bleeding episodes
Perioperative management of bleeding
Routine prophylaxis to reduce the frequency of bleeding episodes
KOVALTRY is not indicated for the treatment of von Willebrand disease.
IMPORTANT SAFETY INFORMATION
KOVALTRY is contraindicated in patients who have a history of hypersensitivity reactions to the active substance, to any of the excipients, or to mouse or hamster proteins.
Hypersensitivity reactions, including anaphylaxis, are possible with KOVALTRY. Early signs of hypersensitivity reactions, which can progress to anaphylaxis, may include chest or throat tightness, dizziness, mild hypotension and nausea. Discontinue KOVALTRY if symptoms occur and seek immediate emergency treatment.
KOVALTRY may contain trace amounts of mouse and hamster proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.
Neutralizing antibody (inhibitor) formation has occurred following administration of KOVALTRY. Previously untreated patients (PUPs) are at greatest risk for inhibitor development with all Factor VIII products. Carefully monitor patients for the development of Factor VIII inhibitors, using appropriate clinical observations and laboratory tests. If expected plasma Factor VIII activity levels are not attained or if bleeding is not controlled as expected with administered dose, suspect the presence of an inhibitor.
Hemophilic patients with cardiovascular risk factors or diseases may be at the same risk to develop cardiovascular events as non-hemophilic patients when clotting has been normalized by treatment with Factor VIII.
Catheter-related infections may occur when KOVALTRY is administered via central venous access devices (CVADs). These infections have not been associated with the product itself.
The most frequently reported adverse reactions in clinical trials (≥5%) were inhibitors in previously untreated patients (PUPs)/minimally treated patients (MTPs), and pyrexia, headache, and rash.
For additional important risk and use information, please see full Prescribing Information.
References: 1. KOVALTRY® [prescribing information]. Whippany, NJ: Bayer HealthCare LLC; 2021. 2. Pipe SW. Functional foles of the factor VIII B domain. Haemophilia. 2009;15(6):1187-1196. 3. Saenko EL, Shima M, Sarafanov AG. Role of activation of coagulation factor VIII in interaction with vWF, phospholipid, and functioning within the factor Xase complex. Trends Cardiovasc Med. 1999;9(7):185-192. 4. Santagostino E. A new recombinant factor VIII: from genetics to clinical use. Drug Design Dev Ther. 2014;8:2507-2515. 5. Lenting PJ, Pegon JN, Christophe OD, Denis CV. Factor VIII and von Willebrand factor—too sweet for their own good. Haemophilia. 2010;16(suppl 5):194-199. 6. Bovenschen N, Rijken DC, Havakes LM, van Vlijmen BMJ, Mertens K. The B domain of coagulation factor VIII interactcs with the asialoglycoprotein receptor. J Thromb Haemost. 2005;3(6):1257-1265. 7. Lenting PJ, van Mourik JA, Mertens K. The life cycle of coagulation factor VIII in view of its structure and function. Blood. 1998;92(11):3983-3996. 8. Leyte A, van Schijndel HB, Niehrs C, et al. Sulfation of Tyr1680 of human blood coagulation factor VIII is essential for the interaction of factor VIII with von Willebrand factor. J Biol Chem. 1991;266(2):740-746. 9. Garger S, Severs J, Regan L, et al. BAY 81-8973, a full-length recombinant factor VIII: manufacturing processes and product characteristics. Haemophilia. 2017;23(2):e67-e78. 10. Teare J, Sim D, Shah A, et al. Increased branching and sialylation of N-linked glycans of recombinant factor VIII leads to an improved pharmacokinetic profile for BAY 81-8973. Poster presented at the European Association for Haemophilia and Allied Disorders. 10th Annual Congress. February 1-3, 2017. Paris, France.
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