# US 2014/0193441 A1 · Method of Administering Porcine B-domainless fVIII

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- Number: US 2014/0193441 A1
- Document ID: US20140193441A1
- Status: Published application
- Kind: A1
- Application number: 13/959,523
- Filed: 2013-08-05
- Published: 2014-07-10
- Earliest claimed: 2004-05-03
- Inventors: John S. Lollar; Garrett E. Bergman
- Web page: https://patentgrep.com/patent/US20140193441A1

## CPC

- A61K 38/37: Factors VIII
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61K 39/0005: {Vertebrate antigens (from snakes A61K39/38)}
- A61K 47/02: Inorganic compounds
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61K 47/18: Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides a method of administering porcine B-domainless factor VIII (OBI-1) to a patient having factor VIII deficiency to provide more rapid and effective protection against bleeding episodes, compared to formerly available methods, or to provide more effective protection to such patients during non-bleeding periods. This invention is based on the discovery that the recombinant B-domainless porcine fVIII, termed OBI-1, has greater bioavailability compared to the natural porcine fVIII partially purified from porcine plasma, termed HYATE:C. Therefore, the inventive method employs lower unit doses of OBI-1, including, alternatively, omission of antibody-neutralizing dosage, or has longer intervals between the administration, compared to HYATE:C, to provide equivalent protection in patients having fVIII deficiency. The invention further provides pharmaceutical compositions and kits containing OBI-1 in combination with a pharmaceutically acceptable carrier, that are useful for treating patients in need of fVIII more effectively.

## Claims

### Claim 1

A solid pharmaceutical composition obtainable by lyophilization of a solution comprising OBI-1, wherein the OBI-1 is a product of expression of a nucleic acid molecule encoding SEQ ID NO:2, a surfactant, calcium chloride, sucrose, sodium chloride and trisodium citrate, wherein the solution is maintained at a pH of 6-8 using a buffering agent prior to lyophilization and after reconstitution in water for injection, and wherein the solution is devoid of amino acids.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the surfactant is a polysorbate or wherein the surfactant is polysorbate 80.

### Claim 3 (depends on 1)

The composition of claim 1, wherein the buffer is tris(hydroxymethyl)methylamine.

### Claim 4 (depends on 2)

The composition of claim 2, wherein the buffer is tris(hydroxymethyl)methylamine.

### Claim 5 (depends on 1)

The composition of claim 1, wherein the pH range is 6.5 to 7.5.

### Claim 6 (depends on 1)

A kit comprising the solid pharmaceutical composition of claim 1 and sterile water optionally containing sodium chloride, said solid pharmaceutical composition and said sterile water being disposed in separate containers.

### Claim 7 (depends on 6)

The kit of claim 6, wherein the pharmaceutical composition comprises polysorbate or polysorbate 80 as a surfactant.

### Claim 8 (depends on 6)

The kit of claim 6, wherein the pharmaceutical composition comprises tris(hydroxymethyl)methylamine as a buffer.

### Claim 9

A pharmaceutical composition for administration to a patient having factor VIII deficiency to achieve and maintain a therapeutically effective level of factor VIII in said patient, wherein the composition comprises OBI-1 at a concentration from 50 to 10,000 Units/mL and a physiologically acceptable carrier, wherein the OBI-1 is a product of expression of a nucleic acid molecule encoding SEQ ID NO:2.

### Claim 10

A method of reducing blood clotting time in a patient having factor VIII deficiency, comprising administering a composition comprising a porcine partially B-domainless factor VIII (OBI-1) and a physiologically acceptable carrier to the patient in need thereof in an amount sufficient to reduce the patient's blood clotting time to a desired value wherein the amount of OBI-1 sufficient to reduce the patient's blood clotting time is ½ to 1/10 of the amount of plasma-derived porcine factor VIII sufficient to achieve the same reduction of blood clotting time obtained upon administering the partially B-domainless porcine fVIII (OBI-1), and wherein said OBI-1 is the expression product of SEQ ID NO:1, and wherein the OBI-1 is administered at a rate of 1000-10,000 Units/minute.

### Claim 11 (depends on 10)

The method of claim 10, wherein the plasma-derived porcine fVIII is HYATE:C.

### Claim 12 (depends on 10)

The method of claim 10, wherein the patient is a congenital hemophilia patient.

### Claim 13 (depends on 12)

The method of claim 12, wherein the patient is a congenital hemophilia A patient.

### Claim 14 (depends on 10)

The method of claim 10, wherein the patient is an acquired hemophilia patient.

### Claim 15 (depends on 10)

The method of claim 10, wherein a first administration of an amount of porcine partially B-domainless fVIII (OBI-1) that reduces the patient's blood clotting time to a desired value is followed by a second administration of an amount of porcine partially B-domainless fVIII (OBI-1) that reduces the patient blood clotting time to the desired value, the patient's blood clotting time remaining reduced at or near said desired value during such time interval, and said time interval being at least 2-fold greater than the corresponding time interval within which said desired value can be maintained by administration of the same dose of porcine plasma-derived fVIII, and wherein said OBI-1 is the expression product of SEQ ID NO:1, and wherein the OBI-1 is administered at a rate of 1000-10,000 Units/minute.

### Claim 16 (depends on 15)

The method of claim 15, wherein the porcine plasma-derived fVIII is HYATE:C.

### Claim 17

A method of administering a porcine partially B-domainless factor VIII (OBI-1) to a patient having factor VIII deficiency, said patient having factor VIII-inhibiting antibodies, wherein the porcine B-domainless factor VIII is administered intravenously to said patient in combination with a physiologically acceptable carrier at a dose about 10-150 Units/kg of body weight and at a rate of 1000-10,000 Units/minute, and wherein said OBI-1 is the expression product of DNA encoding SEQ ID NO:2.

### Claim 18 (depends on 17)

The method of claim 17, wherein the dose of OBI-1 is at about 15 Units/kg of body weight of said patient.

### Claim 19 (depends on 17)

The method of claim 17, wherein the patient is in the bleeding state.

### Claim 20 (depends on 17)

The method of claim 17, wherein the patient is in the non-bleeding state, and OBI-1 is administered at a frequency of not more than once per day.

### Claim 21 (depends on 17)

The method of claim 17, wherein the patient is a congenital hemophilia A patient.

### Claim 22

A method of reducing blood clotting time in a patient having factor VIII deficiency, comprising administering a composition comprising a porcine partially B-domainless factor VIII (OBI-1) and a physiologically acceptable carrier to the patient in an amount sufficient to reduce the patient's blood clotting time wherein the amount of OBI-1 sufficient to reduce the patient's blood clotting time is ½ to 1/10 of the amount of plasma-derived porcine factor VIII sufficient to achieve the same reduction of blood clotting time obtained upon administering a B-domainless porcine fVIII (OBI-1), wherein said OBI-1 is administered at a rate of 1000-10,000 Units/minute and wherein said OBI-1 is the expression product of SEQ ID NO:1.

### Claim 23 (depends on 22)

The method of claim 22, wherein the plasma-derived porcine fVIII is HYATE:C.

### Claim 24 (depends on 22)

The method of claim 22, wherein a first administration of an amount of porcine partially B-domainless fVIII (OBI-1) that reduces the patient's blood clotting time to a desired value is followed by a second administration of an amount of porcine B-domainless fVIII (OBI-1) that reduces the patient blood clotting time to the desired value, the patient's blood clotting time remaining reduced at or near said desired value during such time interval, and said time interval being at least 2-fold greater than the corresponding time interval within which said desired value can be maintained by administration of the same dose of porcine plasma-derived fVIII, and wherein said OBI-1 is the expression product of SEQ ID NO:1.

### Claim 25 (depends on 21)

The method of claim 21, wherein the porcine plasma-derived fVIII is HYATE:C.

### Claim 26 (depends on 22)

The method of claim 22, wherein the dose of OBI-1 is at about 10-50 Units/kg of body weight of said patient.

### Claim 27 (depends on 26)

The method claim 26, wherein the dose of OBI-1 is about 15 Units/kg of body weight of said patient.

### Claim 28

A method of administering a porcine B-domainless fVIII (OBI-1) to control a bleeding episode in a hemophilia A patient in need of such control comprising the steps of
a) administering to the patient an intravenous dose of from 10-150 U/kg patient weight of OBI-1 without administration of an antibody-neutralizing dose of OBI-1 whereby bleeding is controlled, wherein said OBI-1 is the expression product of SEQ ID NO:1, wherein said OBI-1 is administered at a rate of 1000-10,000 Units/minute, or
b) if bleeding is not controlled, giving subsequent doses as in step (a), at 4-12 hour intervals until bleeding is controlled.

### Claim 29 (depends on 28)

The method of claim 28, wherein the patient is a congenital hemophilia A patient.