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Publication Number
US-10273466-B2
Publication Date
2019-04-30
Expiration Date
Abstract
Short-acting Factor VII peptides are disclosed. A shortened half-life is desirable for treatment of acute bleeding and similar disorders. Modification of the sialylation and/or glycosylation of Factor VII and variants thereof produced peptides useful in treating conditions of acute bleeding.
Core Innovation
The patent discloses human Factor VIIa therapeutics designed to be short-acting for acute bleeding by modifying glycosylation and sialylation to shorten in vivo half-life and clearance while retaining or increasing coagulation activity. The disclosed polypeptides are human Factor VIIa comprising the amino acid sequence of SEQ ID NO: 16 with glycans covalently attached at amino acid residues 145 and 322. A central feature is a reduced ratio of moles of conjugated sialic acid to moles of N-linked glycan, including embodiments with very low or undetectable conjugated sialic acid levels.
The patent further describes variant designs relative to SEQ ID NO: 16, including P10Q and K32E, and additional substitutions such as T106N and V253N in V1/V2. Glycosylation and sialylation are addressed through N-glycan site disruption or desialylation strategies, including deglycosylation via N→Q substitutions such as N145 and N322 site disruption. The document also describes producing compositions with specific conjugated sialic acid:N-linked glycan ratios, including very low or undetectable values and reduced ranges.
The disclosed short-acting Factor VIIa variants are positioned for treating acute bleeding and bleeding-related conditions, including reversal of anticoagulants and antithrombotics, while aiming to reduce thromboembolic risk. The experimental support summarized in the provided content includes rapid clearance for desialylated or hypoglycosylated variants and maintained or increased in vitro activity, including phospholipid FX activation and phospholipid-dependent thrombin generation. The patent also reports in vivo efficacy in Hemophilia A mouse models and an improved thrombus-risk profile versus wild-type in coagulation-competent and thrombosis models, including reduced thrombin generation marker TAT and reduced thrombus formation.
Claims Coverage
Two independent claims are identified. Across them, the core inventive elements focus on administering SEQ ID NO: 16 human Factor VIIa with glycans covalently attached at amino acid residues 145 and 322, while reducing conjugated sialic acid content to achieve short-acting therapeutic behavior.
Administering a Factor VIIa with reduced sialic acid to N-linked glycan ratio
A method for treating a patient wherein blood clot formation is desirable, comprising administering an effective amount of a human Factor VIIa polypeptide comprising the amino acid sequence of SEQ ID NO: 16, having glycans covalently attached at amino acid residues 145 and 322, wherein the ratio of moles of conjugated sialic acid to moles of N-linked glycan is less than 1.0.
Administering a desialylated Factor VIIa pharmaceutical formulation with defined glycan attachments
A method of treating a patient having a blood clotting disorder that benefits from blood coagulation comprising administering a therapeutically effective amount of a pharmaceutical formulation comprising a desialylated human Factor VIIa polypeptide comprising the amino acid sequence of SEQ ID NO: 16 and having glycans covalently attached at amino acid residues 145 and 322, and a pharmaceutically acceptable excipient or carrier.
The claim coverage centers on administering SEQ ID NO: 16 human Factor VIIa with covalently attached glycans at amino acid residues 145 and 322, while enforcing a reduced conjugated sialic acid to N-linked glycan ratio or administering a desialylated formulation.
Stated Advantages
Short-acting behavior is achieved by shortening in vivo half-life and clearance while retaining or increasing coagulation activity.
Reduced thromboembolic risk is described as a rationale for the reduced sialic acid/glycosylation design.
In vivo efficacy is reported in Hemophilia A mouse models, including faster efficacy and reduced thrombin generation marker TAT.
An improved thrombus-risk profile is described versus wild-type in coagulation-competent and thrombosis models, including reduced thrombus formation.
Documented Applications
Treating acute bleeding and hemorrhage disease or disorder by administering the disclosed human Factor VIIa therapeutics.
Reversal of anticoagulants and antithrombotics is described as a use case within bleeding-related conditions.
Treatment indications include gastrointestinal bleeding, uncontrolled bleeding, bleeding while undergoing transplantation or resection or surgery, variceal bleeding, thrombocytopenia, hemophilia, intracranial hemorrhage, aortic aneurysm, and Factor VII deficiency, among others.
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