Formulations and methods for treating amyloidosis   

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

This application is a continuation of U.S. application Ser. No. 11/405,348 filed Apr. 17, 2006, which claims the benefit Under 35 U.S.C. §119(e) of U.S. Provisional Application No. 60/671,866, filed Apr. 15, 2005, which are incorporated herein by reference in their entireties and for all purposes.

BACKGROUND OF THE INVENTION

Amyloidosis is the generic term for a number of diseases related by extracellular deposition of insoluble fibrillar proteins (amyloid) in specific organs, which eventually leads to the failure of the involved organs. R. H. Falk et al, The Systemic Amyloidosis, 337 N ENGL J MED 898-909 (1997), P. N. Hawkins, Amyloidosis, 9 BLOOD REV 135-42 (1995), J. D. Sipe, Amyloidosis, 31 CR REV CE1N LAB SC 1325-54 (1994); A. S. Cohen, Amyloidosis, 40(2) BULL RHEUM DISEASES 1-12 (1991). Amyloid deposits can remain limited to one organ (localized amyloidosis) or may be more broadly distributed (systemic amyloidosis). Systemic amyloidoses are generally classified into four types based on the nature of the fibrillar deposits: (i.) idiopathic or primary amyloidosis (AL amyloidosis); (ii.) reactive, secondary or amyloid A (AA) amyloidosis; (iii.) familial amyloidotic polyneuropathy; and (iv.) dialysis-associated amyloidosis. Though diverse in their occurrence, all amyloid deposits have common morphologic properties, stain with specific dyes (e.g., Congo red), and have a characteristic birefringent appearance in polarized light after staining. They also share common ultrastructural features and common X-ray diffraction and infrared spectra.

AA amyloidosis is thought to be related to amyloid A (AA) protein formed from the precursor serum amyloid A (SAA), an acute phase protein produced and secreted by hepatocytes in response to inflammation. AA amyloidosis is associated with chronic inflammatory conditions (e.g. rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, etc.), chronic infections (e.g., tuberculosis, osteomyelitis etc.), and hereditary fevers, e.g., Familial Mediterranean Fever (R. H. Falk et al., 337 N ENGL J MED 898-909 (1997), A. S. Cohen, 40(2) BULL RHEUM DISEASES 1-12 (1991), G. Grateau, 12 CURRENT OPINION IN RHEUMATOL 61-64 (2000)). Rheumatoid arthritis is the major cause of AA amyloidosis in Western Europe and North America (M. Skinner Amyloidosts, CURRENT THERAPY IN ALLERGY, IMMUNOLOGY, AND RHEUMATOLOGY 235-40 (Mosby-Year Book Inc., 1996), M. A. Gertz, Secondary amyloidosis, 232 J INT MED 517-18 (1992)).

AA amyloidosis mainly affects parenchymatous organs, such as, kidneys, spleen, liver, and adrenals. The most common clinical feature of AA amyloidosis is renal dysfunction manifested as nephrotic-range proteinuria or renal insufficiency at the time of diagnosis. End-stage renal failure is the cause of death in 40-60% of cases (M. Skinner Amyloidosis, CURRENT THERAPY IN ALLERGY, IMMUNOLOGY, AND RHEUMATOLOGY 235-40 (Mosby-Year Book Inc., 1996), M. A. Gertz, 232 J INT MED 517-18 (1992), M. A. Gertz and R. A. Kyle, 70 MEDICINE 246-256 (1991)). Gastrointestinal involvement is also frequent and is usually manifested as chronic diarrhea, body weight loss and malabsorption. Enlargement of the liver and spleen may also occur in some subjects. Cardiac involvement is rare and occurs late in the disease. The median survival time from diagnosis varies from 2 to 8 years depending on the stage of the disease at time of diagnosis (M. A. Gertz and R. A. Kyle, 70 MEDICINE 246-256 (1991)).

AA amyloidosis is usually seen associated with chronic infection (such as tuberculosis) or chronic inflammation (such as rheumatoid arthritis or hereditary fevers). A familial form of AA amyloidosis is seen Familial Mediterranean Fever (FMF). This familial type of amyloidosis is genetically inherited and is found in specific population groups. In both AL and AA amyloidosis, deposits are found in several organs and are thus considered systemic amyloid diseases.

“Localized amyloidoses” are those that tend to involve a single organ system. Different amyloids are also characterized by the type of protein present in the deposit. For example, neurodegenerative diseases such as scrapie, bovine spongiform encephalitis, Creutzfeldt-Jakob disease, and the like are characterized by the appearance and accumulation of a protease-resistant form of a prion protein (referred to as AScr or PrP-27) in the central nervous system. Similarly, Alzheimer\'s disease, another neurodegenerative disorder, is characterized by neuritic plaques and neurofibrillary tangles. In this case, the amyloid plaques found in the parenchyma and the blood vessel is formed by the deposition of fibrillar Aβ amyloid protein. Other diseases such as adult-onset diabetes (type II diabetes) are characterized by the localized accumulation of amyloid fibrils in the pancreas.

Once these amyloids have formed, there is no known, widely accepted therapy or treatment which significantly dissolves amyloid deposits in situ, prevents further amyloid deposition or prevents the initiation of amyloid deposition.

Each amyloidogenic protein has the ability to undergo a conformational change and to organize into β-sheets and form insoluble fibrils which may be deposited extracellularly or intracellularly. Each amyloidogenic protein, although different in amino acid sequence, has the same property of forming fibrils and binding to other elements such as proteoglycan, amyloid P and complement component. Moreover, each amyloidogenic protein has amino acid sequences which, although different, show similarities such as regions with the ability to bind to the glycosaminoglycan (GAG) portion of proteoglycan (referred to as the GAG binding site) as well as other regions which promote β-sheet formation. Proteoglycans are macromolecules of various sizes and structures that are distributed almost everywhere in the body. They can be found in the intracellular compartment, on the surface of cells, and as part of the extracellular matrix. The basic structure of all proteoglycans is comprised of a core protein and at least one, but frequently more, polysaccharide chains (GAGs) attached to the core protein. Many different GAGs have been discovered including chondroitin sulfate, dermatan sulfate, keratan sulfate, heparin, and hyaluronan.

Some GAG mimetics are known to be useful for inhibiting amyloid deposition and/or treating some forms of amyloidosis. See WO 94/22437, WO 96/28187, and WO 00/64420.

SUMMARY

In one embodiment, the invention pertains to a method of treating or preventing AA amyloidosis in a target subject, by administering to the target subject a therapeutically effective amount of a compound of 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 renal impairment (PRI). Furthermore, in this embodiment, the target subject is being treated for AA amyloidosis and has or is susceptible to a parameter associated with renal impairment. In a further embodiment the compound of formula (I) is 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt.

In another embodiment, the invention includes a method of treating or preventing AA amyloidosis in a target subject, by administering to the target subject a therapeutically effective amount of a compound of formula (I), e.g., 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt, such that the AA amyloidosis is treated or prevented while maintaining an acceptable tolerance index (ATI) for a parameter associated with gastrointestinal impairment (PGI). Furthermore, in this embodiment, the target subject is being treated for AA amyloidosis and has or is susceptible to a parameter associated with gastrointestinal impairment.

In another further embodiment, the invention also pertains to a method of treating or preventing an amyloid related disease in a subject by administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I), e.g., 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt, at a dosage selected based upon creatinine clearance rate, such that the amyloid related disease is treated or prevented.

The invention also pertains, at least in part, to a method for treating or preventing AA amyloidosis in a subject, by administering to the subject in need thereof, a therapeutically effective amount of a compound of formula (I), e.g., 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt, which is administered in a dosage, such that an effective exposure is provided in a subject, for example, as measured by, e.g., AUC, Cmax, AUCss, Css, Tmax, etc.

In addition, the invention also pertains to a method of stabilizing or improving renal and/or gastrointestinal function in a subject. The method includes administering to a subject a therapeutically effective amount of a compound of formula (I), e.g., 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt.

In another embodiment, the invention pertains to a method of treating or preventing AA amyloidosis in a subject. The method includes administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I), e.g., 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt, in combination with a second agent such that AA amyloidosis is treated or prevented.

In yet another embodiment, the invention pertains, at least in part, to a method of increasing the oral bioavailability of a compound in a subject, by administering to a subject a therapeutically effective amount of the compound of formula (I), e.g., 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt, in a pharmaceutical composition without food such that the oral bioavailability of the compound in the subject is increased.

The invention also pertains, at least in part, to a method of treating an inflammatory disease in a subject, by administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I), e.g., 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt, in combination with a second agent such that said inflammatory disease is treated in the subject.

The invention also pertains, at least in part, to a method of treating a hereditary fever in a subject, by administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I), e.g., 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt, in combination with a second agent such that said hereditary fever is treated in the subject.

The invention also pertains, at least in part, to a method for treating rheumatoid arthritis in a subject. The method includes administering to a subject a therapeutically effective amount of a compound of formula (I), e.g., 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt, in combination with a second agent.

In addition, the invention also includes a method of treating a malignant neoplasm in a subject. The method includes administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I), e.g., 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt, in combination with a second agent such that the malignant neoplasm is treated in the subject.

In a further embodiment, the invention pertains, at least in part, to a method of treating a chronic infection, e.g., microbial or viral, in a subject. The method includes administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I), e.g., 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt, in combination with a second agent such that the chronic infection is treated in the subject.

In another further embodiment, the invention pertains at least in part to method of stabilizing or improving renal function or delaying progression of renal disease in a subject having an inflammatory disorder, a malignant neoplasm, a chronic infection or a hereditary fever. The method includes administering to the subject a therapeutically effective amount of 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, such that renal function is stabilized or improved or progression of renal disease is delayed.

In another embodiment, the invention pertains, at least in part, to a method for preventing or delaying progression to ESRD/dialysis in a subject having AA amyloidosis. The method includes administering to the subject, e.g., a subject having AA amyloidosis, a therapeutically effective amount of a compound of formula (I), e.g., 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt, such that progression to ESRD/dialysis is delayed or prevented.

In another embodiment, the invention pertains, at least in part, to a method for preventing or delaying the time to the doubling of serum creatinine in a subject having AA amyloidosis. The method includes administering to the subject a therapeutically effective amount of a compound, of formula (I), e.g., 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt, such that the time to the doubling of serum creatinine is delayed or prevented.

In yet another embodiment, the invention pertains, at least in part, to a method for preventing or delaying the time to at least a 50% decrease in creatinine clearance in a subject having AA amyloidosis. The method includes administering to a subject a therapeutically effective amount of a compound of formula (I), e.g., 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt, such that the time to the at least a 50% decrease in creatinine clearance is delayed or prevented.

In another embodiment, the invention pertains, at least in part, to a method for decreasing the time to at least a 50% increase in creatinine clearance in a subject having AA amyloidosis. The method includes administering to the subject a therapeutically effective amount of a compound of formula (I), e.g., 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt, such that the time to the at least 50% increase in creatinine clearance is decreased.

In yet another embodiment, the invention includes a method for reducing the rate of progression of renal disease as measured by the slope of creatinine clearance in a subject having AA amyloidosis. The method includes administering to the subject a therapeutically effective amount of a compound of formula (I), e.g., 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt, such that the rate of progression of renal disease is reduced.

In another embodiment, the invention pertains, at least in part, to a method for stabilizing or reducing proteinuria in a subject having AA amyloidosis. The method includes administering to the subject a therapeutically effective amount of a compound of formula (I), e.g., 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt, such that the proteinuria in said subject is stabilized or reduced.

In yet another embodiment, the invention includes a method for stabilizing renal function or delaying progression of renal disease in a subject having AA amyloidosis. The method includes administering to the subject a therapeutically effective amount of a compound of formula (I), e.g., 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt, such that renal function is stabilized or progression of renal disease is delayed. In one aspect, progression of renal disease may be measured by a 50% decrease in creatinine clearance (CrCI), doubling of serum creatinine (SCr), and/or progression to ESRD.

In yet another further embodiment, the invention pertains, at least in part, to a method for treating renal impairment in a subject having AA amyloidosis. The method includes administering to the subject a therapeutically effective amount of a compound of formula (I), e.g., 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt, such that the renal impairment is treated.

The invention also pertains, at least in part, to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), e.g., 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt, and a second agent.

In a further embodiment, the invention pertains to a packaged pharmaceutical composition. The packaged pharmaceutical composition includes a therapeutically effective amount of a compound of formula (I), e.g., 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt, packaged in combination with a label or insert advising that the composition be administered in combination with a second agent.

In yet another further embodiment, the invention pertains to a packaged pharmaceutical composition, which includes a therapeutically effective amount of a second agent packaged in combination with a label or insert advising that the composition be administered in combination with a compound of formula (I), e.g., 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt.

In yet another embodiment, the invention pertains to a packaged pharmaceutical composition, which includes a container holding a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), e.g., 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt, in combination with a label or insert advising that the composition be administered without food.

In yet another embodiment, the invention pertains to a pharmaceutical formulation for treating AA amyloidosis. The formulation comprising a therapeutically effective amount of a compound of formula (I), e.g., 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt, in a formulation, wherein the formulation has at least one favorable biological property (FBP) upon administration to the subject.

The invention also pertains, at least in part, to an anti-amyloidogenic agent in a formulation, wherein the anti-amyloidogenic agent-containing formulation is equivalent to a standard formulation predetermined to have at least one favorable biological property upon administration to a subject such that it is a biologically favorable formulation.

In another embodiment, the invention also includes a pharmaceutical formulation, which comprising a compound of formula (I), and one or more pharmaceutically acceptable carriers. In this embodiment, the pharmaceutical formulation, when administered once to a subject in need thereof, provides a Cmax of about 200 to about 2000 ng/mL.

In yet another embodiment, the invention also pertains to a pharmaceutical formulation, comprising a compound of formula (I), and one or more pharmaceutically acceptable carriers. In this embodiment, the pharmaceutical formulation, when administered to a subject in need thereof, provides an AUC∞ about 2,000 to about 44,000 ng/mL.

The invention also pertains, at least in part, to a method of administering a compound to a subject in need thereof. The method includes administering a compound of formula (I) to the subject in an amount sufficient to achieve a Cmax of about 200 to about 3,400 ng/mL. The Cmax may occur about 0.25 to about 9.00 hours after administration.

In another embodiment, the invention also pertains, at least in part, to a method of administering a compound of formula (I) to a subject in need thereof. The method includes administering a compound of formula (I) to the subject in an amount sufficient to achieve an AUC∞ of about 2,000 to about 44,000 ng/mL.

In yet another embodiment, the invention pertains to a pharmaceutical formulation, which comprises a 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers. The pharmaceutical formulation provides a Cmax of about 200 to about 2000 ng/mL, when administered once to a subject in need thereof.

In yet another embodiment, the invention also includes a pharmaceutical formulation, which comprises 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers. The pharmaceutical formulation provides a AUC∞ of about 2,000 to about 44,000 ng/mL, when administered to a subject in need thereof.

In yet another embodiment, the invention also pertains to a method of administering 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof. The method includes administering 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof to a subject in an amount sufficient to achieve a Cmax of about 200 to about 3,400 ng/mL about 0.25 to about 9.00 hours after administration.

In another embodiment, the invention also pertains to a method of administering 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof, by administering 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof to the subject in an amount sufficient to achieve an AUC∞ of about 2,000 to about 44,000 ng/mL.

In yet another embodiment, the invention pertains, at least in part, to a pharmaceutical formulation. The pharmaceutical formulation comprises an active agent (e.g., 1,3-propanedisulfonic acid, disodium salt (also referred to as PDS) in an amount effective to treat or prevent AA amyloidosis, and a pharmaceutically acceptable carrier, wherein, when the formulation is orally administered to a healthy subject, a mean plasma concentration profile of the active agent having a mean AUC∞ of about from 2900 to about 9000 ng·h/mL±20% and a mean Cmax of about from 450 to about 2150 ng/mL±20% is achieved.

In yet another further embodiment, the invention also pertains, at least in part, to a pharmaceutical formulation, which comprises an active agent (e.g., PDS) in an amount effective to treat or prevent AA amyloidosis, and a pharmaceutically acceptable carrier, wherein, when the formulation is orally administered to a healthy subject, a mean plasma concentration profile of the active agent having a mean AUC∞ of from about 2,900 to about 9,000 ng·h/mL±20% is achieved.

In yet another further embodiment, the invention pertains to a pharmaceutical formulation, which comprises an active agent (e.g., PDS) in an amount effective to treat or prevent AA amyloidosis, and a pharmaceutically acceptable carrier, wherein, when the formulation is orally administered to a healthy subject, a mean plasma concentration profile of the active agent having a mean Cmax of about from 450 to about 2150 ng/mL±20% is achieved.

In yet another further embodiment, the invention pertains, at least in part, to a pharmaceutical formulation, comprising an active agent (e.g., PDS), 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 Cmax 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 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 Cma, 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 Cmax of about 800-925 ng/mL±20% is achieved.

In yet another further embodiment, the invention also pertains to a pharmaceutical formulation, comprising 800 mgs of an active agent (e.g., PDS), and a pharmaceutically acceptable carrier, wherein, when the formulation is orally administered to a subject: when said subject is healthy, a mean plasma concentration profile of the active agent having a mean AUC∞ of about 4,000-6,000 ng·h/mL±20%, and a mean Cmax of about 1,200-1,300 ng/mL±20% is achieved; or when the subject has mild renal impairment, a mean plasma concentration profile of the active agent having a mean AUC∞ of about 12,000-14,000 ng·h/mL±20%, and a mean Cmax of about 2,500-3,500 ng/mL±20% is achieved; or when the subject has moderate renal impairment, a mean plasma concentration profile of the active agent having a mean AUC∞ of about 9,000-11,000 ng·h/mL±20%, and a mean Cmax of about 2,000-2,200 ng/mL±20% is achieved; or when the subject has severe renal impairment, a mean plasma concentration profile of the active agent having a mean AUC∞ of about 40,000-46,000 ng·h/mL±20%, and a mean Cmax of about 2,100-2,300 ng/mL±20% is achieved.

In yet another further embodiment, the invention also pertains, at least in part, to a pharmaceutical formulation, which comprises an active agent (e.g., PDS), and a pharmaceutically acceptable carrier, wherein, when the formulation is orally administered to a subject having AA amyloidosis for twenty-four months: in a dose of 400 mg of the active agent, a mean plasma concentration profile of the active agent having a mean AUC∞ of about 25,000-26,000 ng·h/mL±20%, and a mean Cmax of about 2,000-2,300 ng/mL±20% is achieved; or in a dose of 800 mg of the active agent, a mean plasma concentration profile of the active agent having a mean AUC∞ of about 20,000-22,000 ng·h/mL±20%, and a mean Cmax of about 1,600-2,000 ng/mL±20% is achieved; or in a dose of 1200 mg of the active agent, a mean plasma concentration profile of the active agent having a mean AUC∞ of about 8,000-10,000 ng·h/mL±20%, and a mean Cmax of about 800-1,000 ng/mL±20% is achieved.

In yet another further embodiment, the invention also pertains, at least in part, to a pharmaceutical formulation, comprising an active agent (e.g., PDS), and a pharmaceutically acceptable carrier, wherein, when the formulation is orally administered to healthy male subjects for seven days: in a dose of 400 mg QID of the active agent, a mean plasma concentration profile of the active agent having a mean AUC∞ of about 10,000-11,500 ng·h/mL±20%, and a mean Cmax of about 900-1100 ng/mL±20% is achieved; or in a dose of 800 mg QID of the active agent, a mean plasma concentration profile of the active agent having a mean AUC∞ of about 19,000-21,000 ng·h/mL±20%, and a mean Cmax of about 1,600-1,800 ng/mL±20% is achieved; or in a dose of 1600 mg TID of the active agent, a mean plasma concentration profile of the active agent having a mean AUC∞ of about 25,000-27,000 ng·h/mL±20%, and a mean Cmax of about 4,000-6,000 ng/mL±20% is achieved; or in a dose of 1600 mg QID of the active agent, a mean plasma concentration profile of the active agent having a mean AUC∞ of about 23,000-25,500 ng·h/mL±20%, and a mean Cmax of about 4,500-6,500 ng/mL±20% is achieved.

In yet another embodiment, the invention also pertains to a method of stabilizing or improving renal function or delaying progression of renal disease in a subject having AA amyloidosis. The method includes orally administering a formulation comprising 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, in an amount determined in accordance with the subject\'s rate of creatinine clearance. For example, when the formulation is administered in a dose of 400 mg, a mean plasma concentration profile of 1,3-propanedisulfonic acid having a mean AUC∞ of about 10,000-12,000 ng·h/mL±20%, and a mean Cmax of about 800-900 ng/mL±20% is achieved; or when the formulation is administered in a dose of 800 mg, 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 Cmax about 750-875 ng/mL±20% is achieved; or when the formulation is administered in a dose of 1200 mg, 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 Cmax of about 800-925 ng/mL±20% is achieved.

In yet another further embodiment, the invention also pertains, at least in part, to a pharmaceutical formulation, which comprises an active agent which is 1,3-propane disulfonic acid or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Furthermore, when this 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 6,000-17,000 ng·h/mL±20%, and a mean Cmax of about 500-1200 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 3000-20000 ng·h/mL±20%, and a mean Cmax of about 300-1200 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 2,000-11,000 ng·h/mL±20%, and a mean Cmax of about 400-1500 ng/mL±20% is achieved.

In yet another embodiment, the invention also pertains, at least in part, to a method of stabilizing or improving renal function or delaying progression of renal disease in a subject having AA amyloidosis, comprising orally administering a formulation comprising 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, in an amount determined in accordance with the subject\'s rate of creatinine clearance. Furthermore, when the formulation is administered in a dose of 400 mg, a mean plasma concentration profile of 1,3-propanedisulfonic acid having a mean AUC∞ of about 6,000-17,000 ng·h/mL 20%, and a mean Cmax of about 500-1200 ng/mL±20% is achieved; or when the formulation is administered in a dose of 800 mg, a mean plasma concentration profile of the active agent having a mean AUC∞ of about 3000-20000 ng·h/mL±20%, and a mean Cmax of about 300-1200 ng/mL±20% is achieved; or when the formulation is administered in a dose of 1200 mg, a mean plasma concentration profile of the active agent having a mean AUC∞ of about 2,000-11,000 ng·h/mL±20%, and a mean Cmax of about 400-1500 ng/mL±20% is achieved.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph depicting a Kaplan-Meier curve for the time to the first “worse” event for subjects administered PDS versus a placebo.

FIG. 2 is a line graph showing the slope of creatinine clearance for subjects administered PDS versus a placebo.

FIG. 3 is a graph depicting a Kaplan-Meier curve for the time to a 50% decrease in creatinine clearance for subjects administered PDS versus a placebo.

FIG. 4 is a graph depicting a Kaplan-Meier curve for the time to ESRD/Dialysis for subjects administered PDS versus a placebo.

DETAILED DESCRIPTION

In one embodiment, the invention pertains, at least in part, to a method of treating or preventing AA amyloidosis in a target subject who is being treated for AA amyloidosis and has or is susceptible to a parameter associated with renal impairment. The method includes administering to the target subject a therapeutically effective amount of a compound of 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).

In another embodiment, the invention includes a method of treating or preventing AA amyloidosis in a target subject, who is being treated for AA amyloidosis and has or is susceptible to a secondary disorder or state associated with gastrointestinal impairment. The method includes administering to the target subject a therapeutically effective amount of a compound of formula (I), while maintaining an acceptable tolerance index (All) for a parameter associated with gastrointestinal impairment (PGI).

Generally, AA amyloidosis is a manifestation of a number of diseases that provoke a sustained acute phase response. Such diseases include chronic inflammatory disorders, chronic local or systemic microbial infections, and malignant neoplasms. The most common form of reactive or secondary (AA) amyloidosis is seen as the result of long-standing inflammatory conditions. For example, subjects with Rheumatoid Arthritis or Familial Mediterranean Fever (which is a genetic disease) can develop AA amyloidosis. The terms “AA amyloidosis,” “secondary amyloidosis” and “secondary (AA) amyloidosis” are used interchangeably.

AA fibrils are generally composed of 8,000 Dalton fragments (AA peptide or protein) formed by proteolytic cleavage of serum amyloid A protein (ApoSAA), a circulating apolipoprotein which is mainly synthesized in hepatocytes in response to such cytokines as IL-1, IL-6 and TNF. Once secreted, ApoSAA is complexed with HDL. Deposition of AA fibrils can be widespread in the body, with a preference for parenchymal organs. The kidneys are usually a deposition site, and the liver and the spleen may also be affected. Deposition is also seen in the heart, gastrointestinal tract, and the skin.

Underlying diseases which can lead to the development of AA amyloidosis include, but are not limited to, inflammatory diseases, such as chronic inflammatory disease, rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthropathy, Reiter\'s syndrome, Adult Still\'s disease, Behcet\'s syndrome, familial Mediterranean fever, inflammatory bowel disease, hereditary periodic fevers, juvenile chronic arthritis, juvenile rheumatoid arthritis, ulcerative colitis, chronic fevers, bronchiostasis, malaria, vasculitis, IV drug use, psoriatic arthritis, lupus erythematosus arthritis, periarthritis nodosa, Wegner\'s granulomatosis, Muckle-Wells syndrome and Crohn\'s disease. AA deposits are also produced as a result of chronic infections, e.g., AIDS, HIV, hepatitis B, hepatitis C, chronic microbial infections, e.g., leprosy, tuberculosis, bronchiectasis, decubitus ulcers, pyelonephritis, osteomyelitis, acne conglobata, common variable immunodeficiency, hypolagammaglobulinemia, cystic fibrosis, pulmonary tuberculosis, pulmonary infection(s), recurrent abscesses, Behcet\'s disease, and Whipple\'s disease. Certain malignant neoplasms can also result in AA fibril amyloid deposits. These include such conditions as Hodgkin\'s lymphoma, renal carcinoma, carcinomas of gut, lung and urogenital tract, basal cell carcinoma, hepatoma, Castleman\'s disease, Schnitzler\'s syndrome, Waldenstrom\'s disease, and hairy cell leukemia.

The term “subject” includes living organisms in which AA amyloidosis or an amyloid related disease can occur, or which are susceptible to AA amyloidosis or amyloid related diseases. The term “subject” includes animals (e.g., mammals, e.g., cats, dogs, horses, pigs, cows, goats, sheep, rodents, e.g., mice or rats, rabbits, squirrels, bears, primates (e.g., chimpanzees, monkeys, gorillas, and humans)), as well as chickens, ducks, peking ducks, geese, and transgenic species thereof.

The term “target subject,” refers to a subject, e.g., a human, specifically chosen to receive the compositions or compounds of formula (I). Accordingly, in some embodiments, target subjects include subjects who are at risk of or have been diagnosed with an AA amyloid related disease, e.g., AA amyloidosis. Subjects at risk of developing AA amyloidosis include those with an underlying disease, such as an inflammatory disease, infection, hereditary fever or neoplasm. In other embodiments, target subjects include subjects that have or are susceptible to a parameter associated with renal impairment and/or gastrointestinal impairment. Target subjects also may include subjects who have been diagnosed with both an AA amyloid related disease and are known to have a parameter associated with renal impairment and/or gastrointestinal impairment. The preferred target subject is a human.

The terms “Acceptable Tolerance Index” and “ATI” are used interchangeably to refer to a level of illness in a subject that is considered satisfactory at a given time point in the disease or disorder afflicting the subject. In some embodiments, an ATI is an improvement or stabilization of the illness in a subject, as described herein. In other embodiments, an ATI is less worsening of an illness in a subject, as compared to a previous time point, e.g., when a subject is experiencing a rapid increase in serum creatinine levels, an ATI may be a slower increase in serum creatinine levels. Accordingly, in one embodiment, an ATI is less worsening in a subject of at least one of the parameters associated with renal impairment or gastrointestinal impairment. In another embodiment, an ATI is less worsening in a subject of at least two of the parameters associated with renal impairment and/or gastrointestinal impairment. In still another embodiment, an ATI is less worsening in a subject of at least three, four or five of the parameters associated with renal impairment and/or gastrointestinal impairment.

The terms “parameter associated with renal impairment,” and “PRI” are used interchangeably to include parameters generally associated with abnormal kidney function, such as, but not limited to decreased creatinine clearance, increased levels of serum creatinine, proteinuria, progression to dialysis/End Stage Renal Disease (ESRD), hypoalbuminemia, and/or edema. In some embodiments, the parameter associated with renal impairment is caused, at least in part, by AA amyloidosis or the presence of amyloid A protein in the body.

The terms “parameter associated with gastrointestinal impairment,” and “PGI” include parameters generally associated with abnormal gastrointestinal function, such as, but not limited to, chronic diarrhea and/or loss of body weight. In some embodiments, the parameter associated with gastrointestinal impairment is caused, at least in part, by AA amyloidosis or the presence of amyloid A protein in the body.

The terms “treatment” or “treating” of a subject includes the application or administration of a compound of the invention to a subject (or application or administration of a compound of the invention to a cell or tissue from a subject) with the purpose of stabilizing, curing, healing, alleviating, relieving, altering, remedying, less worsening, ameliorating, improving, or affecting the disease or condition, the symptom of the disease or condition, or the risk of (or susceptibility to) the disease or condition. The term “treating” refers to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; lessening of the rate of worsening; stabilization, diminishing of symptoms or making the injury, pathology or condition more tolerable to the subject; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; or improving a subject\'s physical or mental well-being. In an embodiment, the term “treating” can include increasing a subject\'s life expectancy.

The term “remission of chronic diarrhea” refers to no episodes of chronic diarrhea and no chronic use of antidiarrheal agents for at least four consecutive months.

In one embodiment, the progression to dialysis is delayed or prevented in a subject, e.g., a subject having AA amyloidosis. For example, a subject\'s progression to dialysis may be delayed by 1 month or longer, 2 months or longer, 3 months or longer, 4 months or longer, 5 months or longer, 6 months or longer, 7 months or longer, 8 months or longer, 10 months or longer, 11 months or longer, 1 year or longer, 1.5 years or longer, 2 years or longer, 3 years or longer, 4 years or longer, 5 years or longer, 7.5 years or longer, 10 years or longer, 15 years or longer, or 20 years or longer. In a particular embodiment, it is delayed by about 6 months.

In another embodiment, the term “treating” includes decreasing the risk of any “worse” event of renal decline (see Example 3) or all-cause mortality by at least 5% or greater, at least 10% or greater, at least 15% or greater, at least 20% or greater, at least 30% or greater, at least 40% or greater, at least 50% or greater, at least 60% or greater, or at least 63% or greater. In another embodiment, the risk of any “worse” event of renal decline or all-cause mortality is decreased 7%-63%.

In another embodiment, the term “treating” also includes increasing the mean time to the first “worse” event. The increase may be about 0.5 months or longer, about 1 month or longer, about 2 months or longer, about 3 months or longer, about 4 months or longer, about 5 months or longer, about 6 months or longer, about 7 months or longer, about 8 months or longer, about 9 months or longer, about 10 months or longer, or about 11 months or longer. In another embodiment, the time is increased by about: 2.8 months±7.5 months longer in PDS treated subjects.

In another embodiment, the subject\'s creatinine clearance rate is stabilized or improved. For example, a subject\'s creatinine clearance rate may be increased by about 10% or greater, by about 20% or greater, by about 30% or greater, by about 40% or greater, by about 50% or greater, by about 60% or greater, by about 70% or greater, by about 80% or greater, by about 90% or greater, or by about 100% or greater as compared to the subject\'s level prior to treatment with the compounds of the invention.

In another embodiment, the risk of a 50% or greater decrease in creatinine clearance is reduced at least about 5% or more, at least about 10% or more, at least about 15% or more, or at least about 18% or more. In a further embodiment, the risk of a 50% or greater decrease in creatinine clearance is reduced about 18% to 72%.

In another embodiment, a subject\'s serum creatinine, serum albumin levels, and/or serum alkaline phosphatase levels are stabilized or improved. For example, a subject\'s serum creatinine, serum albumin levels, and/or serum alkaline phosphatase levels may be increased by about 10% or greater, by about 20% or greater, by about 30% or greater, by about 40% or greater, by about 50% or greater, by about 60% or greater, by about 70% or greater, by about 80% or greater, by about 90% or greater, or by about 100% or greater as compared to the subject\'s level prior to treatment with the compounds of the invention.

In a further embodiment, the risk of the doubling of serum creatinine is reduced by at least 5% or greater, at least 10% or greater, at least 11% or greater, at least 12% or greater, at least 13% or greater, or at least 14% or greater. In a further embodiment, a subject\'s risk of having their serum creatinine is double is reduced from about 14% to about 81%.

In another embodiment, the term “treating” also includes increasing the mean time to the doubling of serum creatinine. The increase may be about 0.5 months or longer, about 1 month or longer, about 2 months or longer, about 3 months or longer, about 4 months or longer, about 5 months or longer, about 6 months or longer, about 7 months or longer, about 8 months or longer, about 9 months or longer, about 10 months or longer, about 11 months or longer, or about a year or longer.

In another embodiment, a subject\'s proteinuria levels, visceral amyloid burden, and/or amyloid content in aspirated fat tissue are stabilized or improved. For example, a subject\'s proteinuria levels, visceral amyloid burden, and/or amyloid content in aspirated fat tissue may be reduced by about 10% or greater, by about 20% or greater, by about 30% or greater, by about 40% or greater, by about 50% or greater, by about 60% or greater, by about 70% or greater, by about 80% or greater, by about 90% or greater, or by about 100% or greater as compared to the subject\'s level prior to treatment with the compounds of the invention.

In another embodiment, a subject\'s visceral amyloid burden is reduced or stabilized. A subject\'s visceral amyloid burden can be assessed by, for example, using 123I-radiolabeled serum amyloid P component (SAP) scintigraphy. SAP binds specifically to amyloid fibrils and is retained in tissue amyloid deposits for prolonged periods, apparently protected from the normal rapid catabolism to which it is subject in the circulation. Scintigraphic imaging with radiolabeled SAP has been developed as a specific noninvasive method for assessing visceral amyloid burden (Hawkins P N et al. N Engl J Med, 1990; 323:508-13). Visceral amyloid burden can be quantified, for example, by visual assessment of whole body scintigraphs obtained 24 hours after the injection of the radionuclide.

In another embodiment, a subject\'s amyloid content in aspirated fat tissue is reduced or stabilized. The term “amyloid content in aspirated fat tissue” refers to the content of amyloid A in aspirated fat tissue. Changes in amyloid A content in aspirated fat tissue can be measured semi-quantitatively by Congo red staining. Amyloid A content in fat tissue can be measured quantitatively, for example, by using a monoclonal antibody-based sandwich ELISA using fat tissue collected from a subject. (Hazenberg B et al. Ann Rheum Dis, 1999; 58: 96-102).

The term “orthostatic hypotension” refers to a sudden fall in blood pressure that occurs when a person assumes a standing position. Symptoms, which generally occur after sudden standing, include dizziness, lightheadedness, blurred vision, and syncope (temporary loss of consciousness). The autonomic nervous system (ANS) is sometimes affected in AA amyloidosis. A postural decrease in blood pressure (e.g. a drop from the supine to standing position of 20 mmHg in systolic blood pressure or 10 mmHg in diastolic blood pressure sustained for at least 3 min) is a sign of ANS dysfunction.

In another embodiment, a subject\'s body weight loss is improved or stabilized, or the subject gains weight. For example, a subject might gain 5% or more, about 10% or more, about 20% or more, about 30% or more, about 40% or more, about 50% or more, or about 60% or more of their body weight prior to treatment with the compounds of the invention.

In another embodiment a subject\'s nephrotic syndrome may be stabilized or go into remission. In another embodiment, a subject\'s edema may be resolved or alleviated. In another embodiment, the stabilization, improvement, cure, or remission of diarrhea in a subject may occur. In yet another embodiment, there may be stabilization or reduction of orthostatic hypotension, splenomegaly, and/or hepatomegaly in a subject.

In one embodiment, remission of nephrotic syndrome includes a decrease in proteinuria to ≦1 g/24 h and either an increase in serum albumin to greater than 3.4 g/dL or resolution of an edema and/or discontinuation of diuretics in response to improvement in edema.

The term “therapeutically effective amount” refers to the amount of a compound which is effective to treat a subject, e.g., treat a subject for AA amyloidosis or an amyloid related disease or treat a subject having an underlying disease, such as, but not limited to, an inflammatory disorder, a malignant neoplasm, or chronic microbial infection. The therapeutically effective amount may vary based on the particular disorder(s) the subject is suffering from, the age, weight, and lifestyle of a particular subject. In addition, the therapeutically effective amount may depend on the seventy of the disease state, organ function, kidney function, or underlying disease (e.g., the subject may be suffering from an inflammatory disease, a malignant neoplasm, a chronic infection). In an embodiment, the subject is nephrotic. In another embodiment, the subject is non-nephrotic.

The term “nephrotic” refers to a subject suffering from nephrotic syndrome. Nephrotic syndrome is generally defined as heavy proteinuria (e.g., urinary protein >3 g/24 h) in combination with the two following extrarenal features 1) hypoalbuminemia (e.g., serum albumin <3.4 g/dL); and 2) a peripheral edema by physical examination and/or use of diuretics to treat edema.

The term “non-nephrotic” refers to a subject who has not yet progressed to nephrotic syndrome or who is in remission of nephrotic syndrome. Remission of nephrotic syndrome is a decrease in proteinuria to ≦1 g/24 h and an improvement in one of the two following extrarenal features: 1) increase in serum albumin to 3.4 g/dL or 2) resolution of edema and/or discontinuation of diuretics in response to improvement in edema. Progression to nephrotic syndrome is an increase in proteinuria to >3 g/24 h and occurrence of the two following extrarenal features: 1) hypoalbuminemia (serum albumin <3.4 g/dL) and 2) edema and/or use of diuretics to treat edema.

In another further embodiment, the invention also pertains to a method of treating or preventing amyloid related disease in a subject by administering to the subject a therapeutically effective amount of a compound of formula (I) at a dosage selected based upon the subject\'s creatinine clearance rate, proteinuria level, and/or serum albumin levels.

The term “creatinine clearance” is art recognized and refers to the rate at which the kidneys clear creatinine from the blood. Creatinine is a substance that is easily excreted by the kidney in healthy subjects. Creatinine clearance generally compares the level of creatinine in urine with the creatinine level in the blood. Clearance is often measured as milliliters/minute (ml/min).

The dosage administered in the methods of the present invention may be selected based upon creatinine clearance rate. For example, the dosage of the compound of formula (I) may be selected to be about 1200 mg twice daily for a creatinine clearance rate of >80 mL/min. For a creatinine clearance rate of between about 30 and 80 mL/min, the dosage of the compound of formula (I) may be selected to be about 800 mg twice daily. For a creatinine clearance rate of between about 20 and 30 mL/min, the dosage of the compound of formula (I) may be selected to be about 400 mg twice daily. In addition, the dosage also may be adjusted based on the changing creatinine clearance rates in the subject.

In one embodiment, the dosage may be selected such that desired pharmacokinetic parameters and/or biologically favorable parameters are obtained after administration of the compound of the invention to the subject. In one embodiment, the dosage is selected such that once administered to the subject, the mean AUCss in the subject is about 7,000 to about 26,000 ng·h/mL and the mean steady state concentration is about 500 to about 1200 ng/mL. In another embodiment, the dosage is selected such that once administered to the subject, the Cmax in the subject is about 1,200 to about 3,100 ng/mL and the AUC∞ is about 5,000 to about 43,000 ng·h/mL. In subjects with impaired renal function, the dosages needed to achieve a particular AUCss, AUC∞, Cmax, and steady state mean concentration may need to be adjusted.

In a further embodiment, the Cmax, AUC0-tlast, and/or AUC∞ may vary for a particular subject by about ±10%, by about ±20%, by about ±30%, or by about ±40% as compared to the values shown in Table 1.

The language “amyloid-related disease” refers to a pathological condition characterized by the presence of amyloid fibers. “Amyloid” is a generic term referring to a group of diverse but specific protein deposits (intracellular or extracellular) which are seen in a number of different diseases. Though diverse in their occurrence, all amyloid deposits have common morphologic properties, stain with specific dyes (e.g., Congo red), and have a characteristic red-green birefringent appearance in polarized light after staining. They also share common ultrastructural features and common X-ray diffraction and infrared spectra.

The invention also pertains, at least in part, to another method for treating or preventing AA amyloidosis in a subject. This method includes administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I), which is administered in a dosage such that an effective systemic exposure is provided in a subject, for example, as measured by, e.g., AUC, Cmax, AUCss, Css, Tmax, etc.

The term “target plasma concentration” refers to a range of concentrations in the subject of the compound of the invention which result in treatment of the subject for AA amyloidosis. In one embodiment, the subject maintains a steady state concentration (Css) of about 500 to about 1200 ng/mL. In another embodiment, the subject maintains an AUCss from about 7000 to about 26,000 ng·h/mL. For example, the subject may maintain a steady state concentration of about 600 to about 700 ng/mL, or about 900 to about 1100 ng/mL and/or an AUC∞ of about 8000 to about 9000 ng·h/mL, or about 11,000 to about 13,000 ng·h/mL, or about 23,000 to about 26,000 ng·h/mL, or about 15,500 to about 16,500 ng·h/mL. In a further embodiment the AUCss or the steady state concentration are within ±20% of these values.

In addition, the invention pertains, at least in part, to a method of stabilizing or improving renal and/or gastrointestinal function in a subject. The method includes administering to a subject a therapeutically effective amount of a compound of formula (I).

In a further embodiment, the invention also pertains, at least in part, to a pharmaceutical formulation. The formulation comprises an active agent which is 1,3-propane disulfonic acid or a pharmaceutically acceptable salt thereof in an amount effective to treat or prevent AA amyloidosis, and a pharmaceutically acceptable carrier. Furthermore, when the formulation is orally administered to a healthy subject, a mean plasma concentration profile of the active agent having a mean AUC∞ of about from 2900 to about 9000 ng·h/mL±20% and a mean Cmax of about from 450 to about 2150 ng/mL±20% is achieved. In alternate embodiment, when the formulation is orally administered to a healthy subject, a mean plasma concentration profile of the active agent having a mean AUC∞ of from about 2,900 to about 9,000 ng·h/mL±20% is achieved. In another alternate embodiment, when the formulation is orally administered to a healthy subject, a mean plasma concentration profile of the active agent having a mean Cmax of about from 450 to about 2150 ng/mL±20% is achieved.

In another embodiment, the invention also pertains to a pharmaceutical formulation, which comprises an active agent which is 1,3-propane disulfonic acid or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In this embodiment, 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 Cmax 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 Cmax 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 Cmax of about 800-925 ng/mL±20% is achieved.

In another embodiment, this invention also pertains to a pharmaceutical formulation, comprising 800 mgs of an active agent, which is 1,3-propane disulfonic acid or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Furthermore, when this formulation is orally administered to a subject: when the subject is healthy, a mean plasma concentration profile of the active agent having a mean AUC∞ of about 4,000-6,000 ng·h/mL±20%, and a mean Cmax of about 1,200-1,300 ng/mL±20% is achieved; or when the subject has mild renal impairment, a mean plasma concentration profile of the active agent having a mean AUC∞ of about 12,000-14,000 ng·h/mL±20%, and a mean Cmax of about 2,500-3,500 ng/mL±20% is achieved; or when the subject has moderate renal impairment, a mean plasma concentration profile of the active agent having a mean AUC∞ of about 9,000-11,000 ng·h/mL±20%, and a mean Cmax of about 2,000-2,200 ng/mL±20% is achieved; or when the subject has severe renal impairment, a mean plasma concentration profile of the active agent having a mean AUC∞ of about 40,000-46,000 ng·h/mL±20%, and a mean Cmax of about 2,100-2,300 ng/mL±20% is achieved.

In another further embodiment, the invention pertains to 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. Furthermore, when this formulation is orally administered to a subject having AA amyloidosis for twenty-four months: in a dose of 400 mg of the active agent, a mean plasma concentration profile of the active agent having a mean AUC∞ of about 25,000-26,000 ng·h/mL±20%, and a mean Cmax of about 2,000-2,300 ng/mL±20% is achieved; or in a dose of 800 mg of the active agent, a mean plasma concentration profile of the active agent having a mean AUC∞ of about 20,000-22,000 ng·h/mL±20%, and a mean Cmax of about 1,600-2,000 ng/mL±20% is achieved; or in a dose of 1200 mg of the active agent, a mean plasma concentration profile of the active agent having a mean AUC∞ of about 8,000-10,000 ng·h/mL±20%, and a mean Cmax of about 800-1,000 ng/mL±20% is achieved.

In another embodiment, the invention also pertains to 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. Furthermore, wherein, when this formulation is orally administered to healthy male subjects for seven days: in a dose of 400 mg QID of the active agent, a mean plasma concentration profile of the active agent having a mean AUC∞ of about 10,000-11,500 ng·h/mL±20%, and a mean Cmax of about 900-1100 ng/mL±20% is achieved; or in a dose of 800 mg QID of the active agent, a mean plasma concentration profile of the active agent having a mean AUC∞ of about 19,000-21,000 ng·h/mL±20%, and a mean Cmax of about 1,600-1,800 ng/mL±20% is achieved; or in a dose of 1600 mg TID of the active agent, a mean plasma concentration profile of the active agent having a mean AUC∞ of about 25,000-27,000 ng·h/mL±20%, and a mean Cmax of about 4,000-6,000 ng/mL±20% is achieved; or in a dose of 1600 mg QID of the active agent, a mean plasma concentration profile of the active agent having a mean AUC∞ of about 23,000-25,500 ng·h/mL±20%, and a mean Cmax of about 4,500-6,500 ng/mL±20% is achieved.

In another further embodiment, the invention also pertains to a method of stabilizing or improving renal function or delaying progression of renal disease in a subject having AA amyloidosis. The method includes orally administering a formulation comprising 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, in an amount determined in accordance with the subject\'s rate of creatinine clearance. Furthermore, when the formulation is administered in a dose of 400 mg, a mean plasma concentration profile of 1,3-propanedisulfonic acid having a mean AUC∞ of about 10,000-12,000 ng·h/mL 20%, and a mean Cmax of about 800-900 ng/mL±20% is achieved; or when the formulation is administered in a dose of 800 mg, 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 Cmax of about 750-875 ng/mL±20% is achieved; or when the formulation is administered in a dose of 1200 mg, 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 Cmax of about 800-925 ng/mL±20% is achieved.

In a further embodiment, the dose is 400 mg when the subject\'s rate of creatinine clearance is less than about 30 mL/min, the dose is 800 mg when the subject\'s rate of creatinine clearance is from about 30 to about 80 ml/min, and the dose is 1200 mg when the subject\'s rate of creatinine clearance is greater than about 80 mL/min. In another further embodiment, the subject\'s rate of creatinine clearance is about 60 to about 90 mL/min and a dose of 1200 mg is administered.

In another embodiment, the invention pertains to a method of treating or preventing AA amyloidosis in a subject. The method includes administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I) in combination with a second agent, such that AA amyloidosis is treated or prevented.

The term “in combination with” refers to the concurrent administration of a compound of formula (I) and a second agent; the administration of the compound of formula (I) prior to the administration of the second agent; or administration of the second agent prior to administration of the compound of formula (I).

The term “second agent” includes drugs known to treat underlying diseases, e.g., inflammatory diseases (e.g., chronic inflammatory disease, rheumatoid arthritis, juvenile chronic arthritis, ankylosing spondylitis, psoriasis, psoriatic arthropathy, Reiter\'s syndrome, psoriatic arthritis, lupus erythematosus arthritis, periarthritis nodosa, Wegner\'s granulomatosis, Muckle-Wells syndrome, Adult Still\'s disease, Behcet\'s syndrome, familial Mediterranean fever, inflammatory bowel disease, hereditary periodic fevers, and Crohn\'s disease, etc.), diseases associated with chronic infections (e.g., AIDS, HIV, hepatitis B, hepatitis C, etc.), diseases associated with chronic microbial infections (e.g., leprosy, tuberculosis, bronchiectasis, decubitus ulcers, pyelonephritis, osteomyelitis, Whipple\'s disease, acne conglobata, common variable immunodeficiency, pulmonary tuberculosis, pulmonary infection(s), recurrent abscesses, Behcet\'s Disease, hypolagammaglobulinemia, cystic fibrosis, etc.), or certain malignant neoplasms (e.g., Hodgkin\'s lymphoma, renal carcinoma, carcinomas of gut, lung and urogenital tract, basal cell carcinoma, Castleman\'s disease, Schnitzler\'s syndrome, hepatoma, Waldenstrom\'s disease, and hairy cell leukemia). The term “second agent” also includes rescue agents, chemotherapeutic agents, anti-inflammatory agents, e.g., non-steroidal anti-inflammatory agents, etc., and antibiotics. Examples of second agents include methotrexate, colchicine, anti-TNF antibodies and anti-interleukin 1 or 6 antibodies.

Examples of nonsteroidal anti-inflammatory agents (“NSAIDs”) include ibuprofen, naproxen, sulindac, and indomethacin. Other anti-inflammatory agents include COX-2 inhibitors (such as Vioxx™ and Celebrex™), cytokine inhibitors (such as thalidomide disclosed in WO 95/04533 and dexanabinol) complement inhibitors, leukotriene receptor antagonists and combinations thereof. Examples include acetic acid derivatives sulindac (Clinoril™, Merck & Co., Inc., Rahway, N.J.), indomethacin (Indocin™, Merck & Co., Inc., Rahway, N.J.); etodolac (Lodine™, Wyeth, Madison, N.J.), nabumetone (Relafen™, GlaxoSmithKline, Middlesex, England), tolmetin sodium (Tolectin™, McNeil Pharmaceuticals, Spring House, Pa.); anthranilic acid derivatives: meclofenamate sodium (Meclomen™, Pfizer, New York, N.Y.), mefenamic acid (Ponstel™, Pfizer, New York, N.Y.); enolic acid derivatives: piroxicam (Feldene™, Pfizer, New York, N.Y.), Mobic™ (meloxicam); phenylacetic acid derivatives: arthrotec (diclofenac/misoprostol), Voltaren™ (diclofenac); propionic acid derivatives: naproxen sodium (Anaprox™, Naprosyn™, Hoffmann-La Roche Inc. (Roche), Nutley, N.J.), flurbiprofen (Ansaid™, Upjohn, now Pfizer, New York, N.Y.), oxaprozin (Daypro™, G.D Searle, now Pfizer, New York, N.Y.); ibuprofen (Motrin™, Upjohn, now Pfizer, New York, N.Y.), fenoprofen calcium (Nalfon™, Dista, Ranbaxy, Princeton, N.J.), ketoprofen (Oruvail™ or Orudis™, Wyeth, Madison, N.J.), ketorolac tromethamine (Toradol™, Syntex Laboratories, Hoffmann-La Roche Inc. (Roche), Nutley, N.J.); salicylic acid derivative: diflunisal (Dolobid™, Merck & Co., Inc., Rahway, N.J.); and COX-2 selective inhibitors: Bextra™ (valdecoxib), Celebrex™ (celecoxib, Pfizer, New York, N.Y.), and Vioxx™ (rofecoxib, Merck & Co., Inc., Rahway, N.J.), and cyclosporin (Maas BiolAB, Albuquerque, N. Mex.).

The language “chemotherapeutic agent” includes agents which inhibit the growth of proliferating cells or tissues wherein the growth of such cells or tissues is undesirable or otherwise treat at least one resulting symptom of such a growth. Examples of chemotherapeutic agents include: bleomycin, docetaxel (Taxotere), doxorubicin, edatrexate, etoposide, finasteride (Proscar), flutamide (Eulexin), gemcitabine (Gemzar), goserelin acetate (Zoladex), granisetron (Kytril), irinotecan (Campto/Camptosar), ondansetron (Zofran), paclitaxel (Taxol), pegaspargase (Oncaspar), pilocarpine hydrochloride (Salagen), porfimer sodium (Photofrin), interleukin-2 (Proleukin), rituximab (Rituxan), topotecan (Hycamtin), trastuzumab (Herceptin), tretinoin (Retin-A), Triapine, vincristine, and vinorelbine tartrate (Navelbine).

Other examples of chemotherapeutic agents include alkylating drugs such as nitrogen mustards (e.g., mechlorethamine (HN2), cyclophosphamide, ifosfamide, Melphalan (L-sarcolysin), Chlorambucil, etc.); ethylenimines, methylmelamines (e.g., hexamethylmelamine, thiotepa, etc.), alkyl sulfonates (e.g., busulfan, etc.), nitrosoureas (e.g., carmustine (BCNU), lomustine (CCNU), semustine (methyl-CCNU), streptozocin (streptozotocin), etc.), triazenes (e.g., decarbazine (DTIC; dimethyltriazenoimidazolecarboxamide)), alkylators (e.g., cis-diamminedichloroplatinum II (CDDP)), etc.

Other examples of chemotherapeutic agents include antimetabolites such as folic acid analogs (e.g., methotrexate (amethopterin)); pyrimidine analogs (e.g., fluorouracil (′5-fluorouracil; 5-FU); floxuridine (fluorode-oxyuridine); FUdr; Cytarabine (cyosine arabinoside), etc.); purine analogs (e.g., Mercaptopurine (6-mercaptopurine; 6-MP); Thioguanine (6-thioguanine; TG); and Pentostatin (2′-deoxycoformycin)), etc.

Other examples of chemotherapeutic agents also include vinca alkaloids (e.g., vinblastin (VLB) and vincristine); topoisomerase inhibitors (e.g., etoposide, teniposide, camptothecin, topotecan, 9-amino-campotothecin CPT-11, etc.); antibiotics (e.g., dactinomycin (actinomycin D), adriamycin, daunorubicin, doxorubicin, bleomycin, plicamycin (mithramycin), mitomycin (mitomycin C), taxol, taxotere, etc.); enzymes (e.g., L-asparaginase); and biological response modifiers (e.g., interferon-α; interleukin 2, etc.). Other chemotherapeutic agents include cis-diaminedichloroplatinum II (CDDP); crboplatin; anthracendione (e.g, mitoxantrone); hydroxyurea; procarbazine (N-methylhydrazine); and adrenocortical suppressants (e.g., mitotane, aminoglutethimide, etc.).

Other chemotherapeutic agents include adrenocorticosteroids (e.g., prednisone); progestins (e.g., hydroxyprogesterone caproate; medroxyprogesterone acetate, megestrol acetate, etc.); estrogens (e.g., diethylstilbestrol; ethenyl estradiol, etc.); antiestrogens (e.g tamoxifen, etc.); androgens (e.g., testosterone propionate, fluoxymesterone, etc.); antiandrogens (e.g., flutamide); and gonadotropin-releasing hormone analogs (e.g., leuprolide).

The term “antibiotic agents” include antibiotics known in the art to treat microbial infections. Examples of anti-biotic agents include, but are not limited to, amoxicillin, aminoglycoside, aminoglycoside analogs, beta-lactam, beta-lactamase, beta-lactamase analogs, clindamycin, chloramphenicol, cephalosporin, cephalosporin analogs, ciprofloxacin, ciprofloxacin analogs, erythromycin, fluoroquinolone, fluoroquinolone analogs, macrolide, macrolide analogs, metronidazole, penicillin, penicillin analogs, quinolone, quinolone analogs, rifampin, streptomycin, sulfonamide, tetracycline, tetracycline analogs, trimethoprim, trimethoprim-sulfamthoxazole, and vancomycin.

The term “rescue medication” refers to any medication commenced during treatment which has the potential to suppress the underlying disease, but which is introduced with the primary indication of ameliorating features of progressive AA amyloidosis. Such medications may include, but are not limited to, colchicine, cytotoxic agents, and anti-TNF agents.

Examples of anti-TNF agents include agents which inhibit TNF, e.g., anti-TNFα antibodies. Examples of anti-TNF agents include etanercept (Enbrel™, Amgen), infliximab (Remicade™, Johnson and Johnson, see, for example U.S. Pat. No. 6,790,444), human anti-TNF monoclonal antibody (D2E7/HUMIRA™, Abbott Laboratories), CDP 571 (Celltech), and CDP 870 (Celltech).

Examples of other second agents include immunosuppressants, corticosteroids (including systemically administered corticosteroids), sulfasalazine, renin-angiotensin system blockers or antagonists, diuretics (e.g., furosemide), calcium channel blockers, beta blocking agents, antirheumatic products, Angiotensin converting enzyme inhibitors (ACEi), Angiotensin II receptor blockers (ARBs), acetylsalicylic acid, amoxicillin, calcium, calcium carbonate, chlorambucil, colchicine, cyclophosphamide, diclofenac, enalapril, folic acid, methotrexate, methylprednisolone, omeprazole, paracetamol, prednisolone, and prednisone.

In another embodiment, the invention pertains, at least in part, to a method of treating an inflammatory disease in a subject. The method includes administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I) in combination with a second agent such that the inflammatory disease is treated in the subject. In a further embodiment, the second agent is an anti-inflammatory agent.

The term “inflammatory disease” include diseases or disorders which are associated with inflammation and can be treated using the compounds of the invention. The inflammatory disease may include diseases which are associated with, cause, caused by, result from, or otherwise related to amyloidosis, e.g., AA amyloidosis. Examples of such inflammatory diseases include, but are not limited to chronic inflammatory disease, rheumatoid arthritis, juvenile chronic arthritis, ankylosing spondylitis, psoriasis, psoriatic arthropathy, Reiter\'s syndrome, Adult Still\'s disease, Behcet\'s syndrome, familial Mediterranean fever, inflammatory bowel disease, hereditary periodic fevers, psoriatic arthritis, lupus erythematosus arthritis, periarthritis nodosa, Wegner\'s granulomatosis, Muckle-Wells syndrome and Crohn\'s disease.

In a further embodiment, the therapeutically effective amount of the compound of the invention is effective to treat, prevent or delay the onset of AA amyloidosis and the second agent is administered in an effective amount to treat the underlying disorder, e.g., an underlying inflammatory disorder.

In yet another embodiment, the invention includes a method of treating rheumatoid arthritis in a subject. The method includes administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I) in combination with a second agent such that rheumatoid arthritis is treated in the subject. In a further embodiment, the second agent is an anti-inflammatory agent. In a further embodiment, the second agent is infliximab, which may be administered, for example by the procedure described in U.S. Pat. No. 6,790,444, incorporated herein by reference.

In a further embodiment, the second agent is an agent which is known to treat inflammatory diseases such as chronic inflammatory disease, rheumatoid arthritis, juvenile chronic arthritis, ankylosing spondylitis, psoriasis, psoriatic arthropathy, Reiter\'s syndrome, familial Mediterranean fever, Adult Still\'s disease, Behcet\'s syndrome, inflammatory bowel disease, psoriatic arthritis, lupus erythematosus arthritis, periarthritis nodosa, Wegner\'s granulomatosis, Muckle-Wells syndrome, hereditary periodic fevers, or Crohn\'s disease. Examples of agents which may be administered to the subject include, for example, anti-TNF agents, methotrexate, anti-inflammatory agents, and combinations thereof.

In a further embodiment, the therapeutically effective amount of the compound of the invention is effective to treat, prevent or delay the onset of AA amyloidosis and the second agent is administered in an effective amount to treat rheumatoid arthritis.

In a further embodiment, the invention pertains, at least in part, to a method of treating a malignant neoplasm in a subject. The method includes administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I) in combination with a second agent such that the malignant neoplasm is treated in the subject.

The term “malignant neoplasm” includes neoplasms which can be treated using the compounds of the invention. The malignant neoplasms may include neoplasms which are associated with, caused by, cause, result from, or otherwise related to amyloidosis, e.g., AA amyloidosis. Examples of such malignant neoplasms include, but are not limited to, Hodgkin\'s lymphoma, renal carcinoma, gut carcinoma, lung carcinoma, urogenital tract carcinoma, basal cell carcinoma, hepatoma, Castleman\'s disease, Schnitzler\'s syndrome, Waldenstrom\'s disease, or hairy cell leukemia.

Examples of second agents which may be useful for the treatment of malignant neoplasms include agents which are known to treat Hodgkin\'s lymphoma, renal carcinoma, gut carcinoma, lung carcinoma, urogenital tract carcinoma, basal cell carcinoma, or hairy cell leukemia. Further examples of second agents which may be used include chemotherapeutic or cytotoxic agents.

In a further embodiment, the therapeutically effective amount of the compound of the invention is effective to treat, prevent or delay the onset of AA amyloidosis and the second agent is administered in an effective amount to treat malignant neoplasm.

In yet another embodiment, the invention pertains to methods of treating chronic infections. The methods include administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I) in combination with a second agent such that the chronic infection is treated.

The term “chronic infections” includes chronic viral, bacterial, fungal, and microbial infections which can be treated using the compounds of the invention. The infections may include infections which are associated with, cause, caused by, result from, or otherwise related to amyloidosis, e.g., AA amyloidosis. The microbial infections may be local or systemic. Examples of such microbial infections include, but are not limited to, acne conglobata, common variable immunodeficiency, hypolagammaglobulinemia, cystic fibrosis, leprosy, tuberculosis, bronchiectasis, decubitus ulcers, pyelonephritis, osteomyelitis, pulmonary tuberculosis, pulmonary infection(s), recurrent abscesses, Behcet\'s disease, and Whipple\'s disease. Other chronic infections include AIDS, HIV, hepatitis B, and hepatitis C.

Examples of second agents which may be useful for the treatment of infections include agents which are known to treat AIDS, HIV, hepatitis B, hepatitis C, leprosy, tuberculosis, bronchiectasis, decubitus ulcers, pyelonephritis, osteomyelitis, acne conglobata, common variable immunodeficiency, hypolagammaglobulinemia, cystic fibrosis, pulmonary tuberculosis, pulmonary infection(s), recurrent abscesses, Behcet\'s disease, or Whipple\'s disease. Examples of agents which may be administered to the subject include, for example, anti-inflammatory agents and antibiotic agents.

In a further embodiment, the therapeutically effective amount of the compound of the invention is effective to treat, prevent or delay the onset of AA amyloidosis and the second agent is administered in an effective amount to treat the chronic infection.

In yet another embodiment, the invention pertains, at least in part, to a method of increasing the oral bioavailability of a compound in a subject, by administering to a subject a therapeutically effective amount of the compound of formula (I) in a pharmaceutical composition without food such that the oral bioavailability of the compound in the subject is increased.

The term “oral bioavailability” refers to the quantity of drug reaching the bloodstream after oral administration. The term “increased oral bioavailability” refers to an increase in the bioavailability of about 5% or greater, about 10% or greater, about 15% or greater, about 20% or greater, about 25% or greater, about 30% or greater, about 35% or greater, about 40% or greater, about 50% or greater, about 55% or greater, about 60% or greater, about 65% or greater, about 70% or greater, about 75% or greater, about 80% or greater, about 85% or greater, about 90% or greater, about 95% or greater, or about 100% or greater.

In a further embodiment, the administration of the compound of the invention without food results in an increase in the maximal plasma concentration (Cmax) and extent of absorption (AUC) of the compound as compared to administration with food. The increase of the Cmax and/or the AUC may be about 5% or greater, about 10% or greater, about 15% or greater, about 20% or greater, about 25% or greater, about 30% or greater, about 35% or greater, about 40% or greater, about 50% or greater, about 55% or greater, about 60% or greater, about 65% or greater, about 70% or greater, about 75% or greater, about 80% or greater, about 85% or greater, about 90% or greater, about 95% or greater, or about 100% or greater as compared to administration of the compound with food. In a further embodiment, the subject is informed (e.g., by instructions by a physician or pharmacist, or by a label or insert accompanying the compound of the invention) that the administration results in an increase in the maximal plasma concentration (Cmax) and extent of absorption (AUC) of the compound as compared to administration with food.

The term “without food” refers to the administration of a medication or a composition of the present invention on a substantially empty stomach. Accordingly, in some embodiments, administration without food includes administration more than 15 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours or 8 hours after the most recent consumption of food. In other embodiments, administration without food includes administration at least 15 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours or 8 hours before the next consumption of food. In one embodiment, the term “without food” is administration of the compound of the invention at least one hour before a meal or at least two hours after a meal. In this embodiment, the term “about” includes values±10-20% of the indicated period.

In another embodiment, the invention pertains to a method of reducing the rate of progression of nephropathy in a subject in need thereof, as measured by, e.g., the occurrence of a doubling of serum creatinine, greater than or equal to a 50% decrease in creatinine clearance, dialysis/end-stage renal disease, and/or all-cause mortality. The may, for example, have AA amyloidosis, rheumatoid arthritis, chronic inflammation, chronic infection, hereditary fever, etc.

In another embodiment, the invention pertains to a method for preventing or delaying progression to End Stage Renal Disease (ESRD) and/or dialysis in a subject having AA amyloidosis. The method includes administering to the subject a therapeutically effective amount of a compound of formula (I), such that progression to ESRD and/or dialysis is delayed or prevented.

In a further embodiment, the progression to ESRD and/or dialysis is delayed by 1 month or longer, 2 months or longer, 3 months or longer, 4 months or longer, 5 months or longer, 6 months or longer, 7 months or longer, 8 months or longer, 9 months or longer, 10 months or longer, or 12 months or longer. In yet a further embodiment, dialysis and/or ESRD is delayed six months as compared to a standard subject with a similar disorder who has not been treated with the compound of the invention.

In another embodiment, the risk of progressing to ESRD is reduced by about 0-78%. In another embodiment, the risk is decreased by about 5%, by about 10%, by about 15%, by about 20%, by about 25%, by about 30%, by about 35%, by about 40%, by about 45%, by about 50%, by about 55%, by about 60%, by about 65%, by about 70%, by about 75%, or by about 78%. In this embodiment, the term “about” includes values±5%.

In a further embodiment, the median time to dialysis is delayed by at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, or about 9 months. In this embodiment, the term “about” includes the range of ±0.5 months of the indicated period. In a further embodiment, the median time to dialysis is 3.5 months±5.5, or up to 9 months longer in subjects with a compound of formula (I), e.g., PDS.

In a further embodiment, the invention pertains, at least in part, to a method for preventing or delaying the time to the doubling of serum creatinine in a subject having AA amyloidosis. The method includes administering to the subject a therapeutically effective amount of a compound of formula (I), such that the time to the doubling of serum creatinine is delayed or prevented.

In a further embodiment, the invention includes a method for preventing or delaying the time to at least 50% decrease in creatinine clearance in a subject having AA amyloidosis. The method includes administering to the subject a therapeutically effective amount of a compound, such that the time to the at least 50% decrease in creatinine clearance is delayed or prevented. In a further embodiment, the median time to at least a 50% decrease in creatinine clearance is about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months or about 12 months in subjects treated with compounds of formula (I), such as PDS. In this embodiment, the term “about” includes the range of ±0.5 months of the indicated period. In a further embodiment, the median time to at least a 50% decrease in creatinine clearance is up to 12 months longer in PDS treated patients.

In a further embodiment, the time to doubling of serum creatinine and/or the at least 50% decrease in creatinine clearance is delayed by 1 month or longer, 2 months or longer, 3 months or longer, 4 months or longer, 5 months or longer, 6 months or longer, 7 months or longer, 8 months or longer, 9 months or longer, 10 months or longer, or 12 months or longer. In another embodiment, the 50% decrease in creatinine clearance is delayed about 3 to about 5 months, or about 4 months. In yet a further embodiment, the doubling of serum creatinine and/or the at least 50% decrease in creatinine clearance is delayed at least about six months as compared to standard subject with a similar disorder who has not been treated with the compound of the invention. In a further embodiment, the time to the doubling of serum creatinine is delayed by about 3 months to about 5 months, or about 4 months.

In yet another embodiment, the invention includes a method for decreasing the time to at least 50% increase in creatinine clearance in a subject having AA amyloidosis. The method includes administering to the subject a therapeutically effective amount of a compound of formula (I), such that the time to the at least 50% increase in creatinine clearance is decreased.

In a further embodiment, the time to an at least 50% increase in creatinine clearance is decreased by 1 month or longer, 2 months or longer, 3 months or longer, 4 months or longer, 5 months or longer, 6 months or longer, 7 months or longer, 8 months or longer, 9 months or longer, 10 months or longer, or 12 months or longer. In yet a further embodiment, the at least 50% increase in creatinine clearance is decreased six months as compared to standard subject with a similar disorder who has not been treated with the compound of the invention.

In another further embodiment, the invention includes a method for reducing the rate of progression of renal disease as measured by the slope of creatinine clearance in a subject having AA amyloidosis. The method includes administering to the subject a therapeutically effective amount of a compound of formula (I), such that the rate of progression of renal disease is reduced, as measured, e.g., by a decline in the rate of decrease of creatinine clearance.

In a further embodiment, the slope of creatinine clearance is reduced by about 0-10 mL/min/1.73 m2/year. In another further embodiment, the slope of creatine clearance is reduced by about 1 mL/min/1.73 m2/year, by about 2 mL/min/1.73 m2/year, by about 3 mL/min/1.73 m2/year, by about 4 mL/min/1.73 m2/year, by about 5 mL/min/1.73 m2/year, by about 6 mL/min/1.73 m2/year, by about 7 mL/min/1.73 m2/year, by about 8 mL/min/1.73 m2/year, by about 9 mL/min/1.73 m2/year, or by about 10 mL/min/1.73 m2/year. In a further embodiment, the slope of creatinine clearance is reduced by about 4.7±5 mL/min/1.73 m2/year. In this embodiment, the term “about” includes values±0.5 mL/min/1.73 m2/year.

In a further embodiment, the rate of progression of renal disease is reduced by about 10% or greater, about 20% or greater, about 30% or greater, about 40% or greater, about 50% or greater, or about 60% or greater. In a particular embodiment, the rate of progression of renal disease is reduced by about 30% to about 40%.

The language “rate of change of creatinine clearance” refers to the rate of change in creatinine clearance normalized for a subject\'s body surface area over time. For example, a subject\'s creatinine clearance can be measured through, for example, a 24 hr urine collection at designated time points. This creatinine clearance is normalized for body surface area and the least-squares estimate of the within-subject slope may be calculated using available creatinine clearance measurements for that subject. Generally, the slope of creatinine clearance is expressed as an annual rate of change. A suitable transformation (i.e. log transformation) may be applied, if necessary, prior to the slope calculation.

In a further embodiment, the rate of change of a subject\'s creatinine clearance is improved by about 1 mL/min/year or more; about 2 mL/min/year or more; about 3 mL/min/year or more; about 4 mL/min/year or more; about 5 mL/min/year or more; about 6 mL/min/year or more; about 7 mL/min/year or more; about 8 mL/min/year or more; about 9 mL/min/year or more; or about 10 mL/min/year or more. In a further embodiment, the decrease in the rate of the creatinine clearance is lessened by about 2 to about 5 mL/min/year.

In a further embodiment, the invention pertains, at least in part, to a method for stabilizing or reducing proteinuria in a subject having AA amyloidosis. The method includes administering to the subject a therapeutically effective amount of a compound of formula (I), such that the proteinuria in the subject is stabilized or reduced. In one embodiment, the proteinuria is reduced by about 0.5 g/24 hours or more; about 1 g/24 hours; about 1.5 g/24 hours; or by about 2 g/24 hours. In one embodiment, the proteinuria is stabilized at below or equal to 1 g/24 hours.

In another embodiment, the invention pertains, at least in part, to a method for stabilizing renal function or delaying progression of renal disease in a subject having AA amyloidosis. The method includes administering to the subject a therapeutically effective amount of a compound of formula (I), such that the subject\'s renal function is stabilized or the progression of renal disease is delayed.

In a further embodiment, the progression of renal disease is delayed by 1 month or longer, 2 months or longer, 3 months or longer, 4 months or longer, 5 months or longer, 6 months or longer, 7 months or longer, 8 months or longer, 9 months or longer, 10 months or longer, or 12 months or longer.

In yet another embodiment, the invention pertains to a method for treating renal impairment in a subject having AA amyloidosis. The method includes administering to the subject a therapeutically effective amount of a compound of formula (I), such that the renal impairment is treated

In another embodiment, the invention pertains, at least in part, to a method for preventing or delaying progression to nephrotic syndrome in a subject having AA amyloidosis. The method includes administering to the subject a therapeutically effective amount of a compound of Formula (I), e.g. 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt, such that progression to nephrotic syndrome is prevented or delayed.

In another embodiment, the invention pertains, at least in part, to a method for treating nephrotic syndrome in a subject having AA amyloidosis. The method includes administering to the subject a therapeutically effective amount of a compound of Formula (I), e.g. 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt, such that the parameters associated with nephrotic syndrome are improved or nephrotic syndrome is remitted.

In another embodiment, the invention pertains, at least in part, to a method for sustaining remission of nephrotic syndrome in a subject having AA amyloidosis. The method includes administering to the subject a therapeutically effective amount of a compound of Formula (I), e.g. 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt, such that remission of nephrotic syndrome is sustained over a period of, e.g., about 4, 6, 8, 10 or 12 months. In a particular embodiment, remission of nephrotic syndrome is sustained in a patient over a period of about 6 to about 8 months.

In another embodiment, the invention pertains, at least in part, to a method for stabilizing or increasing GFR in a subject having AA amyloidosis. The method includes administering to the subject a therapeutically effective amount of a compound of Formula (I), e.g. 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, e.g. a disodium salt, such that GFR is stabilized or increased.

The terms “glomerular filtration rate” and “GFR” are used interchangeably herein and are an indicator of kidney function. One measure of a subject\'s GFR, for example, is the rate of creatinine clearance. Renal function and/or GFR can be assessed using a number of criteria, such as, for example: serum creatinine levels, urinary creatinine levels, urinary albumin levels, urinary microproteins levels (e.g. retinol binding protein, N-acetyl-β-D-glucosaminidase, microalbumin, etc.), plasma clearance of inulin, creatinine clearance, proteinurea, etc.

Furthermore, a subject may have mild, moderate or severe renal impairment. For example, a healthy subject typically has a GFR of greater than about 100 mL/min. A subject with “mild” renal impairment may, for example, have a GFR of about 50 to about 80 mL/min or a GFR of less than 100, or a creatinine clearance rate of about 60 to about 90 mL/min. A subject with “moderate” renal impairment may, for example, have a GFR of about 30 to about 50 mL/min, or a creatinine clearance rate of about 30 to about 60 mL/min. A subject with “severe” renal impairment may, for example, have a GFR of less than about 30 mL/min, or a creatinine clearance rate of about 15 to about 30 mL/min. Subjects may also be classified as mild, moderate or severe as described in the examples herein, or using criteria known in the art (see, e.g., McCullough, P. A., Rev. Cardiovasc. Med. 2003; 4(suppl. 1): S2-S6; K/DOQI guidelines at www.kidney.org/professionals).

In other embodiments, a subject may have a creatine clearance rate, before treatment (e.g., at baseline) of about 50 to about 120 mL/min, about 60 to about 100 mL/min, about 70 to about 110 ml/min, or about 70 to about 100 ml/min.

In a further embodiment, the subject is nephrotic. In another further embodiment, the subject is non-nephrotic. The subject may be suffering from a disorder such as, for example, an inflammatory disorder, a malignant neoplasm, or a chronic infection.

In an embodiment, the invention pertains to compounds of formula (I):

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; m is 1 or 2, provided that when m is 2, one hydrogen of the —(CH2)n— group is absent.

The term “cationic group” includes groups with a positive charge and hydrogen atoms. Examples of cations include pharmaceutically acceptable salts of the SO3− or OSO3−. Examples of cationic groups include ions of alkali or alkaline earth metals, such as lithium, sodium, potassium, calcium, magnesium, and aluminum and the like. In a further embodiment, the cationic groups are H+ or Na+.

Examples of compounds of the invention include the compounds below and pharmaceutically acceptable salts thereof.

1,2-Ethanedisulfonic acid HO3SCH2CH2SO3H Sodium 1,2-ethanedisulfonate NaO3SCH2CH2SO3NA 1,3-propanedisulfonic acid HO3SCH2CH2CH2SO3H Sodium 1,3-propanedisulfonate (1,3- NaO3SCH2CH2CH2SO3Na propanedisulfonic acid, disodium salt) 1,2-Ethanediol bis(hydrogen sulfate) HO3SOCH2CH2OSO3H 1,2-Ethanediol disulfate, disodium NaO3SOCH2CH2OSO3Na salt 1,3-Propanediol bis(hydrogen sulfate) HO3SOCH2CH2CH2OSO3H 1,3-Propanediol disulfate, disodium NaO3SOCH2CH2CH2OSO3Na

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