Adverse side-effects associated with administration of an anti-hyaluronan agent and methods for ameliorating or preventing the side-effects

• US 10,265,410 B2
• Filed: 04/15/2016
• Issued: 04/23/2019
• Est. Priority Date: 07/20/2010
• Status: Active Grant

• Current Assignee: Halozyme, Inc. (Halozyme Therapeutics, Inc.)
• Original Assignee: Halozyme, Inc. (Halozyme Therapeutics, Inc.)
• Inventors: Shepard, Harold Michael, Thompson, Curtis, Li, Xiaoming, Frost, Gregory I.
• Primary Examiner(s): Claytor, Renee
• Assistant Examiner(s): Clarke, Trent R
• Application Number:
  US15/130,860
• Publication Number:
  US 20160220690A1
• Time in Patent Office: 1,103 Days
• Field of Search: None
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/37 Coumarins, e.g. psoralen
• CPC Class Codes: A61K 31/42 Oxazoles
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 38/47 acting on glycosyl compounds (3.2), e.g. cellulases, lactases
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: 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
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 : for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 : Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/10 : Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C12Y 302/01035 : Hyaluronoglucosaminidase (3.2.1.35), i.e. hyaluronidase

Abstract

Provided herein are methods for ameliorating an adverse effect of systemic administration of a PEG hyaluronan degrading enzyme to a subject. The methods involve systemically administering a PEGylated hyaluronan degrading enzyme, particularly a PEGylated hyaluronidase, such as any of the animal or bacterial hyaluronidases, to the subject and administering an amount of a corticosteroid sufficient to ameliorate the adverse effect. Also provided are method of treating a hyaluronan-associated disease or condition for single-agent therapy or combination therapy.

Claims

1. A method for ameliorating in a human subject an adverse musculoskeletal effect from an administered hyaluronidase, comprising:

a) systemically administering a hyaluronidase to the subject, wherein;

the hyaluronidase is a PEGylated soluble human PH20 hyaluronidase; and

the adverse musculoskeletal effect is more severe than Grade 1, and is up to and including Grade 4;

the grade of the adverse musculoskeletal effect is defined by Common Terminology Criteria for Adverse Events (CTCAE) scale; and

b) administering a sufficient amount of a glucocorticoid to the subject to ameliorate the adverse musculoskeletal effect.

3. The method of claim 1, wherein the glucocorticoid is selected from among a cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone and a prednisone.

4. The method of claim 1, wherein the glucocorticoid is a dexamethasone.

5. The method of claim 1, wherein the glucocorticoid is administered orally.

6. The method of claim 1, wherein the adverse musculoskeletal effect is selected from among one or more of muscle and joint pain and stiffness, stiffness of upper extremities, stiffness of lower extremities, cramping, muscle soreness and tenderness over the entire body, weakness, fatigue and a decrease in range of motion at knee and elbow joints.

8. The method of claim 1, wherein the glucocorticoid is co-administered with the hyaluronidase.

10. The method of claim 1, wherein the glucocorticoid is administered subsequent to administration of the hyaluronidase.

11. The method of claim 1, wherein administration of the glucocorticoid is at least 8 hours to 12 hours after administration of the hyaluronidase.

12. The method of claim 1, wherein the amount of glucocorticoid administered is between at or about 0.1 to 20 mgs.

13. The method of claim 1, wherein the amount of glucocorticoid administered is between at or about 0.4 to 20 mgs.

15. The method of claim 1, wherein the hyaluronidase is administered by intratumoral administration, arterial injection, intravenous administration, intraperitoneal administration, or intravesical administration.

16. The method of claim 1, wherein the hyaluronidase is administered several times a week, twice a week, once a week, every 21 days or once monthly.

17. The method of claim 1, wherein the hyaluronidase is administered to treat a hyaluronan associated disease or condition.

18. The method of claim 17, wherein the hyaluronan associated disease or condition is selected from among one that is associated with high interstitial fluid pressure, a cancer, edema, disc pressure and an inflammatory disease.

20. The method of claim 18, wherein the cancer is selected from among any one or more of a late-stage cancer, a metastatic cancer and an undifferentiated cancer.

23. The method of claim 1, wherein;

the subject has cancer.

24. The method of claim 1, wherein the human PH20 hyaluronidase lacks the C-terminal glycosylphosphatidyl-inositol (GPI) attachment site or a portion of the GPI attachment site.

25. The method of claim 1, wherein the soluble human PH20 hyaluronidase comprises a polypeptide having the sequence of amino acids set forth in any of SEQ ID NOS:

4-9.

27. The method of claim 24, wherein the soluble human PH20 hyaluronidase is selected from:

(a) a polypeptide that consists of the sequence of amino acids 36-467, 36-468, 36-469, 36-470, 36-471, 36-472, 36-473, 36-474, 36-475, 36-476, 36-477, 36-478, 36-479, 36-480, 36-481, 36-482, 36-483, 36-484, 36-485, 36-486, 36-487, 36-488, 36-489, 36-490, 36-491, 36-492, 36-493, 36-494, 36-495, 36-496, 36-497, 36-498, 36-499 or 36-500 of SEQ ID NO;

1;

or

(b) a polypeptide consisting of a sequence of amino acids that exhibits at least 95% sequence identity to a polypeptide of a).

28. The method of claim 1, wherein the soluble human PH20 hyaluronidase polypeptide consists of a sequence of amino acid residues having at least 98% sequence identity to residues 36-483 of SEQ ID NO:

1.

30. The method of claim 1, wherein the glucocorticoid is administered to the human subject before the hyaluronidase.

31. The method of claim 30, wherein the glucocorticoid is dexamethasone.

32. The method of claim 1, wherein the hyaluronidase is administered intravenously.

2. A method for ameliorating an adverse musculoskeletal effect in a human subject from an administered hyaluronidase, comprising:

a) prior to administering the hyaluronidase, administering a sufficient amount of a glucocorticoid to the subject to ameliorate an adverse musculoskeletal effect of the hyaluronidase when it is administered, wherein;

the adverse musculoskeletal effect is more severe than Grade 1, and is up to and including Grade 4; and

the grade of the adverse musculoskeletal effect is defined by Common Terminology Criteria for Adverse Events (CTCAE) scale; and

then

b) systemically administering the hyaluronidase, wherein;

the hyaluronidase is a PEGylated soluble human PH20 hyaluronidase.

7. The method of claim 2, further comprising administering a sufficient amount of a glucocorticoid concurrent with or subsequent to administration of the hyaluronidase.

9. The method of claim 2, wherein administration of the glucocorticoid is at least at or about 1 or more hours prior to administration of the hyaluronidase.

29. The method of claim 2, wherein:

the adverse musculoskeletal effect results from administering the hyaluronidase in an amount that is between or about between 0.1 μ

g/kg to 1 mg/kg of the mass of the subject to whom it is administered; and

the amount of hyaluronidase administered is between or about between 0.1 μ

g/kg to 1 mg/kg of the mass of the subject to whom it is administered.

33. The method of claim 2, wherein the hyaluronidase is administered intravenously.

14. A method of ameliorating in a human subject an adverse musculoskeletal effect from a systemically administered hyaluronidase,

wherein:

the hyaluronidase that had been administered is a PEGylated soluble human PH20 hyaluronidase;

the adverse musculoskeletal effect is more severe than Grade 1, and is up to and including Grade 4;

the grade of the adverse musculoskeletal effect is defined by Common Terminology Criteria for Adverse Events (CTCAE) scale; and

the method comprises administering a sufficient amount of a glucocorticoid to the subject to ameliorate the adverse musculoskeletal effect.

34. The method of claim 14, wherein the hyaluronidase was administered intravenously.

19. A method of ameliorating an adverse musculoskeletal effect in a subject treated for cancer with a treatment comprising administration of a hyaluronidase,

wherein:

the hyaluronidase is a PEGylated soluble human PH20 hyaluronidase that was systemically administered for treatment of cancer;

the subject is human;

the adverse musculoskeletal effect is more severe than Grade 1, and is up to and including Grade 4;

the grade of the adverse musculoskeletal effect is defined by Common Terminology Criteria for Adverse Events (CTCAE) scale; and

the method comprises administering a sufficient amount of a glucocorticoid to the subject to ameliorate the adverse musculoskeletal effect.

21. The method of claim 19, wherein the cancer is selected from among any one or more of ovarian cancer, in situ carcinoma (ISC), squamous cell carcinoma (SCC), prostate cancer, pancreatic cancer, non-small cell lung cancer, breast cancer, brain cancer and colon cancer.

22. The method of claim 19, wherein administration of the hyaluronidase is effected intravenously (IV), subcutaneously, intramuscularly, intradermally, transdermally or sub-epidermally.

26. The method of claim 19, wherein the glucocorticoid is dexamethasone.

35. The method of claim 19, wherein the hyaluronidase was administered intravenously.