Formulations and methods for treating amyloidosis

• US 20060252829A1
• Filed: 04/17/2006
• Published: 11/09/2006
• Est. Priority Date: 04/15/2005
• Status: Active Grant

• Current Assignee: Kiacta Sarl
• Original Assignee: Kiacta Sarl
• Inventors: Hauck, Wendy, Briand, Richard, Garceau, Denis
• Granted Patent: US 8,178,580 B2
• Time in Patent Office: Days
• US Class Current: 514/517
• CPC Class Codes: A61K 31/16 Amides, e.g. hydroxamic acids
• CPC Class Codes: A61K 31/185 Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids hydroxamic acids A61K31/16; peroxy acids A61K31/327
• CPC Class Codes: A61K 31/255 of sulfoxy acids or sulfur analogues thereof
• CPC Class Codes: A61K 31/525 Isoalloxazines, e.g. riboflavins, vitamin B2
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• 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

Abstract

Methods, formulations, and compositions for the treatment of amyloidosis are described.

Claims

1. A method of treating or preventing AA amyloidosis in a target subject comprising,

administering to the target subject a therapeutically effective amount of a compound having the formula:

Y—

(CH₂)_n—

[CH₂Y]_m  

 

(I)

wherein Y is SO₃X or OSO₃X independently chosen for each occurrence;

X is cationic group independently chosen for each occurrence;

n is 1, 2, 3 or 4; and

m is 1 or 2, such that AA amyloidosis is treated or prevented while maintaining an acceptable tolerance index (ATI) for a parameter associated with renal impairment (PRI),

wherein the target subject is being treated for AA amyloidosis and has or is susceptible to a parameter associated with renal impairment.

2. A method of treating or preventing AA amyloidosis in a target subject, comprising

administering to the target subject a therapeutically effective amount of a compound having the formula:

Y—

(CH₂)_n—

[CH₂Y]_m  

 

(I)

wherein Y is SO₃X or OSO₃X independently chosen for each occurrence;

X is cationic group independently chosen for each occurrence;

n is 1, 2, 3 or 4; and

m is 1 or 2, such that the AA amyloidosis is treated or prevented while maintaining an acceptable tolerance index (ATI) for a parameter associated with gastrointestinal impairment (PGI), wherein the target subject is being treated for AA amyloidosis and has or is susceptible to a parameter associated with gastrointestinal impairment.

3-4. -4. (canceled)

5. A method of treating or preventing AA amyloidosis in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the formula:

Y—

(CH₂)_n—

[CH₂Y]_m  

 

(I)

wherein Y is SO₃X or OSO₃X independently chosen for each occurrence;

X is cationic group independently chosen for each occurrence;

n is 1, 2, 3 or 4; and

m is 1 or 2, such that AA amyloidosis is treated or prevented, wherein the compound is administered in a dosage such that the subject maintains a target plasma concentration.

6-7. -7. (canceled)

8. A method of stabilizing or improving renal function or delaying progression of renal disease in a subject, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound having the formula:

Y—

(CH₂)_n—

[CH₂Y]_m  

 

(I)

wherein Y is SO₃X or OSO₃X independently chosen for each occurrence;

X is cationic group independently chosen for each occurrence;

n is 1, 2, 3 or 4; and

m is 1 or 2, such that the renal function in the subject is stabilized or improved or the progression of renal disease in the subject is delayed.

10. The method of claim 8, wherein the therapeutically effective amount of the compound of formula (I) is between about 100 and 2500 mg daily.

19. The method of claim 8, wherein creatinine clearance rate is stabilized or improved in the subject.

28. The method of claim 8, wherein the compound of formula (I) is administered in combination with a second agent.

33. The method of claim 8, wherein said compound of formula (I) is 1,2-ethanedisulfonic acid, sodium 1,2-ethanedisulfonate, 1,3-propanedisulfonic acid, 1,3-propanedisulfonic acid disodium salt, 1,2-ethanediol bis(hydrogen sulfate), 1,2-ethanediol disulfate disodium salt, 1,3-propanediol bis(hydrogen sulfate), 1,3-propanediol disulfate disodium salt, 2-sulfomethyl-1,4-butanedisulfonic acid, or 2-sulfomethylbutane-1,4-disulfonic acid trisodium salt.

34. The method of claim 33, wherein the compound of formula (I) is 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof.

36. The method of claim 8, wherein said compound of formula (I) is administered in an amount sufficient to result in an AUC_ss in said subject of about 7000 to about 26,000 ng·

h/mL.

37. The method of claim 8, wherein said compound of formula (I) is administered in an amount sufficient to result in a C_max in said subject of about 500 to about 1200 ng/mL.

9. A method of treating or preventing AA amyloidosis in a subject comprising administering to a subject in need thereof, a therapeutically effective amount of a compound in combination with a second agent such that AA amyloidosis is treated or prevented in the subject, wherein the compound has the formula:

Y—

(CH₂)_n—

[CH₂Y]_m  

 

(I)

wherein Y is SO₃X or OSO₃X independently chosen for each occurrence;

X is cationic group independently chosen for each occurrence;

n is 1, 2, 3 or 4; and

m is 1 or 2.

11-18. -18. (canceled)

20-27. -27. (canceled)

29-32. -32. (canceled)

35. (canceled)

38. A pharmaceutical composition comprising a therapeutically effective amount of a compound having the formula:

Y—

(CH₂)_n—

[CH₂Y]_m  

 

(I)

wherein Y is SO₃X or OSO₃X independently chosen for each occurrence;

X is cationic group independently chosen for each occurrence;

n is 1, 2, 3 or 4; and

m is 1 or 2, and a second agent.

40. The pharmaceutical composition of claim 38, wherein the second agent is selected from the group consisting of anti-inflammatory agents, colchicine, cytotoxic agents, chemotherapeutic agents, anti-TNF agents, antibiotics, and combinations thereof.

41. The pharmaceutical composition of claim 38, wherein said compound of formula (I) is 1,2-ethanedisulfonic acid, sodium 1,2-ethanedisulfonate, 1,3-propanedisulfonic acid, 1,3-propanedisulfonic acid disodium salt, 1,2-ethanediol bis(hydrogen sulfate), 1,2-ethanediol disulfate disodium salt, 1,3-propanediol bis(hydrogen sulfate), 1,3-propanediol disulfate disodium salt, 2-sulfomethyl-1,4-butanedisulfonic acid, or 2-sulfomethylbutane-1,4-disulfonic acid trisodium salt, or pharmaceutically acceptable salts thereof.

42. The pharmaceutical composition of claim 38, wherein the compound of formula (I) is 1,3-propanedisulfonic acid disodium salt.

43. The pharmaceutical composition of claim 38, wherein the therapeutically effective amount administered to a subject results in the subject having a mean AUC_∞

of about 7000 to about 26000 ng.h/ml, and a mean C_max about 500 to about 1200 ng/ml.

44. The pharmaceutical composition of claim 38, wherein the therapeutically effective amount administered to a subject results in the subject having a C_max of about 300 to about 3500 ng/ml, and an AUC_∞

of about 2500 to about 46,000 ng.h/ml.

39. (canceled)

45. A pharmaceutical formulation for treating or preventing AA amyloidosis, comprising a therapeutically effective amount of a compound in a formulation such that the formulation has at least one favorable biological property (FBP) upon administration to a subject,

wherein the compound has the formula:

Y—

(CH₂)_n—

[CH₂Y]_m  

 

(I)

wherein Y is SO₃X or OSO₃X independently chosen for each occurrence;

X is cationic group independently chosen for each occurrence;

n is 1, 2, 3 or 4; and

m is 1 or 2, and the at least one FBP is selected from the group consisting of C_max, T_max, AUC_ss, and T_1/2.

46-57. -57. (canceled)

58. A method of treating an inflammatory disorder in a subject comprising administering to a subject in need thereof, a therapeutically effective amount of a compound in combination with a second agent such that said inflammatory disease is treated in the subject, wherein the compound has the formula:

Y—

(CH₂)_n—

[CH₂Y]_m  

 

(I)

wherein Y is SO₃X or OSO₃X independently chosen for each occurrence;

X is cationic group independently chosen for each occurrence;

n is 1, 2, 3 or 4; and

m is 1 or 2.

59-88. -88. (canceled)

89. A method of administering 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof, comprising administering said 1,3-propanedisulfonic acid or pharmaceutically acceptable salt thereof to said subject in an amount sufficient to achieve a C_max of about 200 to about 3,400 ng/mL in about 0.25 to about 9.00 hours after administration.

90. A method of administering 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof, comprising administering said 1,3-propanedisulfonic acid or pharmaceutically acceptable salt thereof to said subject in an amount sufficient to achieve an AUC_∞

of about 2,000 to about 44,000 ng/mL.

91-95. -95. (canceled)

96. A pharmaceutical formulation, comprising an active agent which is 1,3-propane disulfonic acid or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,

wherein, when the formulation is orally administered to a subject having AA amyloidosis:

in a dose of 400 mg of the active agent to a subject having a creatinine clearance rate of less than about 30 mL/min, a mean plasma concentration profile of the active agent having a mean AUC_∞

of about 10,000-12,000 ng·

h/mL±

20%, and a mean C_max of about 800-900 ng/mL±

20% is achieved;

or

in a dose of 800 mg of the active agent to a subject having a creatinine clearance rate of from about 30 to about 80 mL/min, a mean plasma concentration profile of the active agent having a mean AUC_∞

of about 9,000-10,500 ng·

h/mL±

20%, and a mean C_max of about 750-875 ng/mL±

20% is achieved;

or

in a dose of 1200 mg of the active agent to a subject having a creatinine clearance rate of greater than about 80 mL/min, a mean plasma concentration profile of the active agent having a mean AUC_∞

of about 5,000-6,000 ng·

h/mL±

20%, and a mean C_max of about 800-925 ng/mL±

20% is achieved.

97-115. -115. (canceled)