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Formulations and methods for treating amyloidosis

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Formulations and methods for treating amyloidosis


Methods, formulations, and compositions for the treatment of amyloidosis are described.
Related Terms: Amyloidosis

Browse recent Kiacta Sarl patents - ,
Inventors: Denis Garceau, Wendy Hauck, Richard Briand
USPTO Applicaton #: #20120270939 - Class: 514517 (USPTO) - 10/25/12 - Class 514 
Drug, Bio-affecting And Body Treating Compositions > Designated Organic Active Ingredient Containing (doai) >(o=)n(=o)-o-c Containing (e.g., Nitrate Ester, Etc.) >Carbon Bonded To -ncx Or -xcn (e.g., Cyanate, Thiocyanate Or Isothiocyanate, Etc.) (x Is Chalcogen) >S-x-c Containing (e.g., Sulfates, Etc.) (x Is Chalcogen)



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The Patent Description & Claims data below is from USPTO Patent Application 20120270939, Formulations and methods for treating amyloidosis.

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RELATED APPLICATIONS

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

OF THE INVENTION

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

OF THE INVENTION A. Methods of Treating a Target Subject Using Compounds of the Invention

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.



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stats Patent Info
Application #
US 20120270939 A1
Publish Date
10/25/2012
Document #
File Date
12/19/2014
USPTO Class
Other USPTO Classes
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