Long-acting coagulation factors and methods of producing same
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Publication Number
US-10960058-B2
Publication Date
2021-03-30
Expiration Date
Abstract
Polypeptides comprising at least one carboxy-terminal peptide (CTP) of chorionic gonadotropin attached to the carboxy terminus but not to the amino terminus of a coagulation factor and polynucleotides encoding the same are disclosed. Pharmaceutical compositions and pharmaceutical formulations comprising the polypeptides and polynucleotides of the disclosure and methods of using and producing same are also disclosed.
Core Innovation
The invention concerns a pharmaceutical formulation that includes a buffer, a tonicity agent, and a chorionic gonadotropin carboxy terminal peptide (CTP)-modified polypeptide consisting of a Factor VII coagulation factor or activated Factor VII coagulation factor with three chorionic gonadotropin carboxy terminal peptides attached to the carboxy terminus. The polypeptide does not include a signal peptide, and the formulation uses 150 mM sodium chloride and a pH of 6.4 to 6.5.
The described work further relates to a CTP-modified Factor VIIa product, MOD-5014, evaluated in anticoagulation and hemostatic performance contexts relative to NovoSeven®. The assessment includes heparin and anti-thrombin III inhibition effects, thrombin generation, clotting efficiency measurements in FVIII-deficient or inhibitor-rich plasma, and thromboelastography, ROTEM, and TEG assessments.
The disclosed characterization also includes translational in vivo pharmacokinetics and pharmacodynamics, including dog hemophilia A studies and thrombogenicity assessment using Wessler rabbit thrombogenicity results. The product is reported as well tolerated, with prolonged activity indicated by extended half-life and sustained WBCT, TEG, and aPTT improvement, and thrombogenic potential described as comparable to NovoSeven® at tested doses.
Claims Coverage
The consolidated claim coverage centers on a CTP-modified Factor VII or activated Factor VII formulation defined by three carboxy-terminal CTPs, absence of a signal peptide, and specific formulation conditions. Dependent refinements mention sequence and structural constraints, including SEQ ID 46 and a disulfide bond between cysteine residues 135 and 262, and one claim set states use for treating acquired hemophilia.
CTP-modified Factor VII or activated Factor VII polypeptide with three carboxy-terminal CTPs
A chorionic gonadotropin carboxy terminal peptide (CTP)-modified polypeptide consisting of a Factor VII coagulation factor or activated Factor VII coagulation factor and three chorionic gonadotropin carboxy terminal peptides attached to the carboxy terminus of said coagulation factor.
No signal peptide in the CTP-modified polypeptide
The CTP-modified polypeptide does not include a signal peptide.
Pharmaceutical formulation tonicity and pH constraints
A formulation comprising a buffer, a tonicity agent, and the CTP-modified polypeptide, wherein said tonicity agent is 150 mM sodium chloride and said formulation is at a pH of 6.4 to 6.5.
Defined polypeptide sequence and structural constraints
The CTP-modified polypeptide is specified as SEQ ID 46, and a further refinement characterizes a disulfide bond between a cysteine residue 135 and a cysteine residue 262 of SEQ ID NO: 46.
Use for treating acquired hemophilia
The pharmaceutical formulation is for treating acquired hemophilia.
Overall, the claims are directed to a CTP-modified Factor VII or Factor VIIa construct with three carboxy-terminal CTPs and no signal peptide, formulated with a buffer under defined tonicity and pH conditions, with additional sequence and structural limitations in dependent claims and a stated therapeutic use for acquired hemophilia.
Stated Advantages
Extending biological half-life
Improving exposure (AUC)
Reducing dosing frequency
Reducing clearance
Maintaining or partly preserving coagulation activity
Subcutaneous versus intravenous bioavailability is discussed.
Prolonged activity with extended half-life and sustained WBCT, TEG, and aPTT improvement in dog hemophilia A studies.
Comparable thrombogenic potential to NovoSeven® at tested doses in the Wessler rabbit thrombogenicity results.
Reported well tolerated performance in the translational in vivo dog hemophilia A PK/PD study.
Documented Applications
Treating acquired hemophilia
Treating hemophilia A or hemophilia B, including conditions with inhibitors to FVIII/FIX
Preventing clotting disorders
Hemostasis-related evaluation in FVIII-deficient or inhibitor-rich plasma and in hemophilia A studies.
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