Long-acting coagulation factors and methods of producing same
Inventors
Assignees
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Publication Number
US-9249407-B2
Publication Date
2016-02-02
Expiration Date
Abstract
Polypeptides comprising at least one carboxy-terminal peptide (CTP) of chorionic gonadotrophin attached to the carboxy terminus but not to the amino terminus of a coagulation factor and polynucleotides encoding the same are disclosed. Pharmaceutical compositions comprising the polypeptides and polynucleotides of the invention and methods of using and producing same are also disclosed.
Core Innovation
The patent describes long-acting, CTP-modified coagulation factor polypeptides intended to reduce excessive bleeding in a subject. In particular, it focuses on CTP-modified activated Factor VII (FVIIa) and CTP-modified Factor IX (FIX) polypeptides in which three to five chorionic gonadotropin carboxy terminal peptides (CTPs) are attached to the carboxy terminus of the factor polypeptide.
The disclosed work characterizes CTP-modified coagulation factor polypeptides using antigen and protein characterization assays and clotting activity assays. It reports ELISA, SDS-PAGE and Western, chromogenic and PT/aPTT clotting assays, and comparative analysis among constructs with differing CTP copy number, including evaluation of comparative pharmacokinetics and pharmacodynamics.
The patent further documents that CTP fusion extends half-life and increases AUC with maintained or comparable hemostatic potency. It states that this enables reduced dosing frequency by improving long-acting exposure, and reports animal efficacy and bleeding challenge outcomes using intravenous and subcutaneous administration, including comparison to NovoSeven® and related reference materials.
Claims Coverage
The provided material includes two independent claims, each directed to reducing excessive bleeding by administering a CTP-modified coagulation factor polypeptide. Each claim centers on attaching three to five chorionic gonadotropin carboxy terminal peptides (CTPs) to the carboxy terminus of a specific coagulation factor polypeptide.
CTP-modified activated Factor VIIa with three to five CTPs at the carboxy terminus
Administering a pharmaceutical composition comprising a CTP-modified activated Factor VII (FVIIa) polypeptide comprising an FVII polypeptide with three to five chorionic gonadotropin carboxy terminal peptides (CTPs) attached to the carboxy terminus, thereby reducing excessive bleeding in the subject.
CTP-modified Factor IX with three to five CTPs at the carboxy terminus
Administering to the subject a pharmaceutical composition comprising a CTP-modified Factor IX (FIX) polypeptide comprising a FIX polypeptide with three to five chorionic gonadotropin carboxy terminal peptides (CTPs) attached to the carboxy terminus, thereby reducing excessive bleeding in the subject.
Across the independent claims, the coverage is directed to reducing excessive bleeding through administration of pharmaceutical compositions containing coagulation factor polypeptides modified by attaching three to five CTP repeats at the carboxy terminus, specifically CTP-modified activated Factor VII (FVIIa) and CTP-modified Factor IX (FIX).
Stated Advantages
Reduces excessive bleeding in the subject.
CTP modification protects the coagulation factors from degradation and clearance.
Extends half-life and pharmacokinetic exposure (including Cmax, Tmax, T1/2, and AUC).
Maintains or improves biological activity.
CTP fusion extends half-life and increases AUC with maintained or comparable hemostatic potency.
This enables reduced dosing frequency.
Improved stability/long-acting effect.
Improved absorption after subcutaneous administration.
Enhanced compliance.
Documented Applications
Therapeutic or prophylactic use for hemophilia A.
Therapeutic or prophylactic use for hemophilia B.
Use for acquired hemophilia.
Reducing bleeding in connection with surgery or invasive procedures.
Broader use for clotting and bleeding disorders.
In vivo functional outcomes in hemophilia and warfarin-treated models, including tail vein transection bleeding and survival/bleeding time comparisons.
Reducing excessive bleeding in a subject by administering a pharmaceutical composition comprising a CTP-modified activated Factor VII (FVIIa) polypeptide, including evaluation in animal pharmacokinetics/pharmacodynamics and bleeding challenge studies after intravenous and subcutaneous administration.
Reducing excessive bleeding in a subject by administering a pharmaceutical composition comprising a CTP-modified Factor IX (FIX) polypeptide.
Hemophilia B as an indication for administering a CTP-modified Factor IX (FIX) polypeptide to a subject.
Subcutaneous administration and intravenous administration are described as administration modalities for the pharmaceutical compositions.
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