Assays to monitor bleeding disorders

Patent metadata

Field	Value
Publication number	US-10656167-B2
Application number	US-201214234789-A
Country	US
Kind code	B2
Filing date	Jul 25, 2012
Priority date	Jul 25, 2011
Publication date	May 19, 2020
Grant date	May 19, 2020

Abstract

The present invention provides methods of dosing Factor VIII or Factor IX chimeric and hybrid polypeptides. The present invention further provides high-sensitivity methods of quantifying an amount of activated FIX protein in a test sample.

First claim

What is claimed is:

1. A method of treating a hemophilia A in a human subject wherein the subject is administered with a Factor VIII (FVIII) chimeric polypeptide, the method comprising
measuring the subject's thrombin generation activity using a thrombin generation assay (TGA) in a blood sample from the human subject, wherein the assay is performed in the presence of an exogenous thrombin at a concentration of about 5 nM, but in the absence of exogenous tissue factor;
comparing the subject's thrombin generation activity with a corresponding standard, wherein the standard correlates with a therapeutically efficacious treatment;
determining an optimized dose or dosing interval of the FVIII chimeric polypeptide based on the relative difference between the subject's thrombin generation activity and the corresponding standard; and
administering the FVIII chimeric polypeptide to the subject at the determined optimized dose or dosing interval during subsequent administrations,

wherein the FVIII chimeric polypeptide comprises a FVIII and an FcRn binding partner, and wherein the FcRn binding partner comprises an Fc region or albumin.

2. The method of claim 1 , wherein the determined optimized dosing interval for the FVIII chimeric polypeptide is at least about 2 days or longer than the dosing interval required for an equivalent amount of a reference FVIII polypeptide.

3. The method of claim 2 , wherein the determined optimized dosing interval for the FVIII chimeric polypeptide is at least every 3-8 days and the determined dose for the FVIII chimeric polypeptide is at least about 10-150 IU/kg.

4. The method of claim 1 , wherein the standard is constructed by
a. providing at least two reference samples, each containing a different, known concentration of activated FVIII reference protein; and
b. measuring thrombin generation activity for each reference sample in the presence of FVIII-deficient plasma or FVIII-deficient blood and in the presence of exogenous thrombin at a concentration of about 5 nM, but in the absence of exogenous tissue factor.

5. The method of claim 4 , wherein the reference samples comprise from about 0 pM to about 200 pM of activated FVIII protein.

6. The method of claim 1 , wherein the FcRn binding partner comprises an Fc.

7. The method of claim 6 , wherein the determined optimized dose of the FVIII chimeric polypeptide is 25 IU/kg to 65 IU/kg and wherein the determined optimized dosing interval is once every 3 or more days.

8. The method of claim 6 , wherein the determined optimized dose of the FVIII chimeric polypeptide is 65 IU/kg and wherein the determined dosing interval is once every 6-7 days.

9. The method of claim 6 , wherein the subject exhibits at least one of the following properties after administration of the FVIII chimeric polypeptide at the determined optimized dose or dosing interval during subsequent administrations:
a) a mean residence time (MRT) (activity) in the subject of about 14-41.3 hours;
b) a clearance (CL) (activity) in the subject of about 1.22-5.19 mL/hour/kg or less;
c) a t 1/2beta (activity) in the subject of about 11-26.4 hours;
d) an incremental recovery (K value) (activity; observed) in the subject of about 1.38-2.88 IU/dL per IU/kg;
e) a Vss (activity) in the subject of about 37.7-79.4 mL/kg; and
f) an AUC/dose in the subject of about 19.2-81.7 IU*h/dL per IU/kg.

10. The method of claim 1 , wherein after administering the FVIII chimeric polypeptide during the subsequent administrations to the subject at the determined optimized dose and dosing interval, a trough level of the plasma FVIII in the subject is maintained above 3 IU/dL.

11. The method of claim 1 , wherein the FVIII comprises a full-length FVIII, mature FVIII, or FVIII with a full or partial deletion of the B domain.

12. The method of claim 1 , wherein the determined optimized dose or determined dosing interval is for a prophylactic treatment or an on-demand treatment.

13. The method of claim 1 , wherein the FcRn binding partner comprises albumin.

Assignees

• Sommer Jurg
• Jiang Haiyan
• Zhang Xin
• Yang Buyue
• Pierce Glenn
• Bioverativ Therapeutics Inc

Inventors

• Sommer Jurg
• Jiang Haiyan
• Zhang Xin
• Yang Buyue
• Pierce Glenn

Classifications

• G01N2333/9645

  Factor IX (3.4.21.22) · CPC title

• C12N9/644

  Coagulation factor IXa (3.4.21.22) · CPC title

• G01N2333/755

  Factors VIII, e.g. factor VIII C [AHF], factor VIII Ag [VWF] · CPC title

• G01N2333/974

  Thrombin · CPC title

• G01N33/86 Primary

  involving blood coagulating time {or factors, or their receptors} · CPC title