WO2021150958A1

WO2021150958A1 - Treatment methods using a combination of pantethine and a vanin agonist

Info

Publication number: WO2021150958A1
Application number: PCT/US2021/014712
Authority: WO
Inventors: D. Christopher SCHELLING
Original assignee: Individual
Current assignee: Individual
Priority date: 2020-01-24
Filing date: 2021-01-22
Publication date: 2021-07-29
Anticipated expiration: 2022-07-24

Abstract

The present disclosure relates, in part, to methods for treating various disorders, including for example nephropathic cystinosis, primary biliary cirrhosis, lipid metabolism disorders (e.g., hyperlipidemia, dyslipidemia, triglyceridemia), and disorders of the central nervous system (e.g., Huntington's disease, Alzheimer's disease, pantothenate kinase-associated neurodegeneration). In certain aspects, methods provided herein for the treatment of, for example, nephropathic cystinosis, primary biliary cirrhosis, lipid metabolism disorders, disorders of the central nervous system, asthma, and hypertension include administration of a therapeutically effective amount of a combination of pantethine and a vanin agonist or activator.

Description

TREATMENT METHODS USING A COMBINATION OF PANTETHINE AND A VANIN AGONIST

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This application claims the benefit under 35 U.S.C. §119(e) of United States Provisional Application 62/965,677, filed January 24, 2020, which is hereby incorporated by reference in its entirety.

FIELD

The present disclosure relates, in part, to methods for treating various disorders, including for example nephropathic cystinosis, primary biliary cirrhosis, lipid metabolism disorders ( e.g ., hyperlipidemia, dyslipidemia, triglyceridemia), and disorders of the central nervous system (e.g., Huntington’s disease, Alzheimer’s disease, and pantothenate kinase- associated neurodegeneration). In certain aspects, methods provided herein for the treatment of, for example, nephropathic cystinosis, primary biliary cirrhosis, lipid metabolism disorders, disorders of the central nervous system, asthma, and hypertension include administration of a therapeutically effective amount of a combination of pantethine and a vanin agonist or activator.

BACKGROUND

Pantethine is the stable dimeric disulfide form of pantetheine, which is the cysteamine amide analog of pantothenic acid (i.e., vitamin B5). Pantethine is chemically named 2,4- dihydroxy-N-[2-(2-mercapto-ethylcarbamoyl)-ethyl]-3,3-dimethyl-butyramide). Pantethine is hydrolyzed to pantothenic acid and cysteamine.

Associated with the hydrolysis of pantethine to pantothenic acid and cysteamine, cysteamine has been shown to be the active agent in the treatment of various disorders. For example, it has been demonstrated that the lipo-modulating effect of pantethine is the hydrolysis product cysteamine and not the hydrolysis product pantothenate. (Wittwer et al., 1987, Atherosclerosis, 68:41-49).

In 1985, Witter et al. reported that pantethine is less effective than cysteamine in the treatment of nephropathic cystinosis, concluding that oral pantethine cannot produce leukocyte cystine depletion to the extent that cysteamine does. (Witter et al., 1985, J Clin Invest, 76: 1665- 1672.) The authors concluded that pantethine is not recommended for use in treating nephropathic cystinosis. Additionally, increased dosage of pantethine resulted in decreased leukocyte cystine depletion. SUMMARY

The present disclosure relates to methods for treating various disorders by administering to a subject in need thereof a combination of pantethine and a PPARoc agonist or activator. In some embodiments, the PPARoc agonist or activator is a fibrate. In some embodiments, the fibrate is selected from group consisting of aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, clofibride, fenofibrate, gemfibrozil, ronifibrate, and simfibrate, or a pharmaceutically acceptable salt, collate, clathrate, polymorph, prodrug, or pharmaceutically active metabolite thereof. In some embodiments, the method further comprises administering to the in need thereof subject a therapeutically effective amount of N- acetyl cysteine in combination with pantethine and fibrate. In some embodiments, the method further comprises administering to the subject in need thereof a therapeutically effective amount of an unsaturated fatty acid, for example, a fish oil or an omega 3 fatty acid. In some embodiments, the method comprises administering an unsaturated fatty acid, or a Ci-₆ alkyl ester thereof, selected from eicosapentaenoic acid, (e.g., ethyl eicosapentaenoic (icosapent ethyl)), alpha-linoleic acid, eicosatetraenoic acid, docosahexaenoic acid, and stearidonic acid, or a combination thereof (e.g., Lovaza® ethyl or a fish oil). The unsaturated fatty acid may be eicosapentaenoic acid, or a Ci-₆ alkyl ester thereof. In some embodiments, the unsaturated fatty acid does not include docosahexaenoic acid, or an ester thereof.

The present disclosure further relates to method for treating various disorders by administering to a subject in need thereof a therapeutically effective amount of a combination of pantethine and a vanin agonist or activator. In some embodiments, the vanin agonist or activator is a compound or agent that increases the activity and/or expression of vanin-1, vanin-2, or vanin-3. In some embodiments, the vanin agonist or activator is a fibrate. In some embodiments, the fibrate is selected from group consisting of aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, clofibride, fenofibrate, gemfibrozil, ronifibrate, and simfibrate, or a pharmaceutically acceptable salt, collate, clathrate, polymorph, prodrug, or pharmaceutically active metabolite thereof. In some embodiments, the method further comprises administering to the subject in need thereof a therapeutically effective amount of N-acetyl cysteine in combination with pantethine and a vanin agonist or activator. In some embodiments, the method further comprises administering to the subject in need thereof a therapeutically effective amount of an unsaturated fatty acid, for example, a fish oil or an omega 3 fatty acid. In some embodiments, the method comprises administering an unsaturated fatty acid, or a Ci-₆ alkyl ester thereof, selected from eicosapentaenoic acid, (e.g., ethyl eicosapentaenoic (icosapent ethyl)), alpha-linoleic acid, eicosatetraenoic acid, docosahexaenoic acid, and stearidonic acid, or a combination thereof (e.g., Lovaza® ethyl or a fish oil). The unsaturated fatty acid may be eicosapentaenoic acid, or a Ci-₆ alkyl ester thereof. In some embodiments, the unsaturated fatty acid does not include docosahexaenoic acid, or an ester thereof.

In some embodiments, the present disclosure provides a method for treating a hepatic disorder, a lipid metabolism disorder, or a disorder of the central nervous system in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination of pantethine and a PPARoc agonist or activator, thereby treating the hepatic disorder, the lipid metabolism disorder, or the disorder of the central nervous system. In some embodiments, the PPARoc agonist or activator is a fibrate. In some embodiments, the fibrate is selected from group consisting of aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, clofibride, fenofibrate, gemfibrozil, ronifibrate, and simfibrate, or a pharmaceutically acceptable salt, collate, clathrate, polymorph, prodrug, or pharmaceutically active metabolite thereof. In some embodiments, the hepatic disorder is selected from the group consisting of nephropathic cystinosis and primary biliary cirrhosis. In some embodiments, the lipid metabolism disorder is selected from the group consisting of hyperlipidemia, dyslipidemia, triglyceridemia, familial chylomicronemia syndrome (FCS), familial partial lipodystrophy (FPL), cardiovascular disease caused by hyperlipoproteinemia, cardiovascular disease caused by high triglycerides, non-alcoholic steatohepatitis (NASH), non alcoholic fatty liver disease (NAFLD), and other hepatotoxicity disorders, such as acute liver failure associated with acetaminophen therapy. In some embodiments, the disorder of the central nervous system is selected from the group consisting of Huntington’s disease and Alzheimer’s disease. In some embodiments, the method further comprises administering to the subject in need thereof a therapeutically effective amount of N-acetyl cysteine in combination with pantethine and fibrate. In some embodiments, the method further comprises administering to the subject in need thereof a therapeutically effective amount of an unsaturated fatty acid, for example, a fish oil or an omega 3 fatty acid. In some embodiments, the method comprises administering an unsaturated fatty acid, or a Ci-₆ alkyl ester thereof, selected from eicosapentaenoic acid, (e.g., ethyl eicosapentaenoic (icosapent ethyl)), alpha-linoleic acid, eicosatetraenoic acid, docosahexaenoic acid, and stearidonic acid, or a combination thereof (e.g., Lovaza® ethyl or a fish oil). The unsaturated fatty acid may be eicosapentaenoic acid, or a Ci-₆ alkyl ester thereof. In some embodiments, the unsaturated fatty acid does not include docosahexaenoic acid, or an ester thereof.

In some embodiments, the present disclosure provides a method for treating a hepatic disorder, a lipid metabolism disorder, or a disorder of the central nervous system in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination of pantethine and a vanin agonist or activator. In some embodiments, the vanin agonist or activator is a compound or agent that increases the activity and/or expression of vanin-1, vanin-2, or vanin-3. In some embodiments, the vanin agonist or activator is a fibrate. In some embodiments, the fibrate is selected from group consisting of aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, clofibride, fenofibrate, gemfibrozil, ronifibrate, and simfibrate, or a pharmaceutically acceptable salt, collate, clathrate, polymorph, prodrug, or pharmaceutically active metabolite thereof. In some embodiments, the hepatic disorder is selected from the group consisting of nephropathic cystinosis and primary biliary cirrhosis. In some embodiments, the lipid metabolism disorder is selected from the group consisting of hyperlipidemia, dyslipidemia, triglyceridemia, familial chylomicronemia syndrome (FCS), familial partial lipodystrophy (FPL), cardiovascular disease caused by hyperlipoproteinemia, cardiovascular disease caused by high triglycerides, non alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), and other hepatotoxicity disorders, such as acute liver failure associated with acetaminophen therapy. In some embodiments, the disorder of the central nervous system is selected from the group consisting of Huntington’s disease and Alzheimer’s disease. In some embodiments, the method further comprises administering to the subject in need thereof a therapeutically effective amount of N-acetyl cysteine in combination with pantethine and a vanin agonist or activator. In some embodiments, the method further comprises administering to the subject in need thereof a therapeutically effective amount of an unsaturated fatty acid, for example, a fish oil or an omega 3 fatty acid. In some embodiments, the method comprises administering an unsaturated fatty acid, or a Ci-₆ alkyl ester thereof, selected from eicosapentaenoic acid, (e.g., ethyl eicosapentaenoic (icosapent ethyl)), alpha-linoleic acid, eicosatetraenoic acid, docosahexaenoic acid, and stearidonic acid, or a combination thereof (e.g., Lovaza® ethyl or a fish oil). The unsaturated fatty acid may be eicosapentaenoic acid, or a Ci-₆ alkyl ester thereof. In some embodiments, the unsaturated fatty acid does not include docosahexaenoic acid, or an ester thereof.

In some embodiments, the present disclosure provides a method for treating asthma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination of pantethine and a PPARoc agonist or activator, thereby treating asthma. In some embodiments, the subject is a poor responder to steroid therapy, has shown a poor steroid treatment response, or is steroid-insensitive. In some embodiments, the PPARoc agonist or activator is a fibrate. In some embodiments, the fibrate is selected from group consisting of aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, clofibride, fenofibrate, gemfibrozil, ronifibrate, and simfibrate, or a pharmaceutically acceptable salt, collate, clathrate, polymorph, prodrug, or pharmaceutically active metabolite thereof. In some embodiments, the method further comprises administering to the subject in need thereof a therapeutically effective amount of N-acetyl cysteine in combination with pantethine and fibrate. In some embodiments, the method further comprises administering to the subject in need thereof a therapeutically effective amount of an unsaturated fatty acid, for example, a fish oil or an omega 3 fatty acid. In some embodiments, the method comprises administering an unsaturated fatty acid, or a Ci-₆ alkyl ester thereof, selected from eicosapentaenoic acid, (e.g., ethyl eicosapentaenoic (icosapent ethyl)), alpha-linoleic acid, eicosatetraenoic acid, docosahexaenoic acid, and stearidonic acid, or a combination thereof (e.g., Lovaza® ethyl or a fish oil). The unsaturated fatty acid may be eicosapentaenoic acid, or a Ci-₆ alkyl ester thereof. In some embodiments, the unsaturated fatty acid does not include docosahexaenoic acid, or an ester thereof.

In some embodiments, the present disclosure provides a method for treating asthma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination of pantethine and a vanin agonist or activator, thereby treating asthma. In some embodiments, the vanin agonist or activator is a compound or agent that increases the activity and/or expression of vanin-1, vanin-2, or vanin-3. In some embodiments, the subject is a poor responder to steroid therapy, has shown a poor steroid treatment response, or is steroid-insensitive. In some embodiments, the vanin-1 agonist or activator is a fibrate. In some embodiments, the fibrate is selected from group consisting of aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, clofibride, fenofibrate, gemfibrozil, ronifibrate, and simfibrate, or a pharmaceutically acceptable salt, collate, clathrate, polymorph, prodrug, or pharmaceutically active metabolite thereof. In some embodiments, the method further comprises administering to the subject in need thereof a therapeutically effective amount of N-acetyl cysteine in combination with pantethine and a vanin agonist or activator. In some embodiments, the method further comprises administering to the subject in need thereof a therapeutically effective amount of an unsaturated fatty acid, for example, a fish oil or an omega 3 fatty acid. In some embodiments, the method comprises administering an unsaturated fatty acid, or a Ci-₆ alkyl ester thereof, selected from eicosapentaenoic acid, (e.g., ethyl eicosapentaenoic (icosapent ethyl)), alpha-linoleic acid, eicosatetraenoic acid, docosahexaenoic acid, and stearidonic acid, or a combination thereof (e.g., Lovaza® ethyl or a fish oil). The unsaturated fatty acid may be eicosapentaenoic acid, or a Ci-₆ alkyl ester thereof. In some embodiments, the unsaturated fatty acid does not include docosahexaenoic acid, or an ester thereof. In some embodiments, the present disclosure provides a method for treating hypertension in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination of pantethine and a PPARoc agonist or activator, thereby treating hypertension. In some embodiments, the subject has been identified has having the SNP rs2272996 or has been identified as having aN131S mutation in the vanin-1 gene. In some embodiments, the PPARoc agonist or activator is a fibrate. In some embodiments, the fibrate is selected from group consisting of aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, clofibride, fenofibrate, gemfibrozil, ronifibrate, and simfibrate, or a pharmaceutically acceptable salt, collate, clathrate, polymorph, prodrug, or pharmaceutically active metabolite thereof. In some embodiments, the method further comprises administering to the subject in need thereof a therapeutically effective amount of N- acetyl cysteine in combination with pantethine and fibrate. In some embodiments, the method further comprises administering to the subject in need thereof a therapeutically effective amount of an unsaturated fatty acid, for example, a fish oil or an omega 3 fatty acid. In some embodiments, the method comprises administering an unsaturated fatty acid, or a Ci-₆ alkyl ester thereof, selected from eicosapentaenoic acid, (e.g., ethyl eicosapentaenoic (icosapent ethyl)), alpha-linoleic acid, eicosatetraenoic acid, docosahexaenoic acid, and stearidonic acid, or a combination thereof (e.g., Lovaza® ethyl or a fish oil). The unsaturated fatty acid may be eicosapentaenoic acid, or a Ci-₆ alkyl ester thereof. In some embodiments, the unsaturated fatty acid does not include docosahexaenoic acid, or an ester thereof.

In some embodiments, the present disclosure provides a method for treating hypertension in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination of pantethine and a vanin agonist or activator, thereby treating hypertension. In some embodiments, the vanin agonist or activator is a compound or agent that increases the activity and/or expression of vanin-1, vanin-2, or vanin-3. In some embodiments, the subject has been identified has having the SNP rs2272996 or has been identified as having aN131S mutation in the vanin-1 gene. In some embodiments, the vanin-1 agonist or activator is a fibrate. In some embodiments, the fibrate is selected from group consisting of aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, clofibride, fenofibrate, gemfibrozil, ronifibrate, and simfibrate, or a pharmaceutically acceptable salt, collate, clathrate, polymorph, prodrug, or pharmaceutically active metabolite thereof. In some embodiments, the method further comprises administering to the subject in need thereof a therapeutically effective amount of N-acetyl cysteine in combination with pantethine and a vanin agonist or activator. In some embodiments, the method further comprises administering to the subject in need thereof a therapeutically effective amount of an unsaturated fatty acid, for example, a fish oil or an omega 3 fatty acid. In some embodiments, the method comprises administering an unsaturated fatty acid, or a Ci-₆ alkyl ester thereof, selected from eicosapentaenoic acid, (e.g., ethyl eicosapentaenoic (icosapent ethyl)), alpha- linoleic acid, eicosatetraenoic acid, docosahexaenoic acid, and stearidonic acid, or a combination thereof (e.g., Lovaza® ethyl or a fish oil). The unsaturated fatty acid may be eicosapentaenoic acid, or a Ci-₆ alkyl ester thereof. In some embodiments, the unsaturated fatty acid does not include docosahexaenoic acid, or an ester thereof.

In some embodiments, the present disclosure provides a method for treating a pantothenate kinase-associated disorder, disease, or condition in a subject in need thereof,

In some aspects of the present disclosure, administration of a combination of pantethine and a vanin agonist or activator (e.g., a fibrate) results in treatment of various disorders, diseases, or conditions.

DETAILED DESCRIPTION

The present disclosure relates, in part, to methods for treating various disorders, such as nephropathic cystinosis, primary biliary cirrhosis, various lipid metabolism disorders (e.g., hyperlipidemia, dyslipidemia, triglyceridemia), and various disorders of the central nervous system (e.g., Huntington’s disease and Alzheimer’s disease).

In certain aspects, methods for the treatment of nephropathic cystinosis, primary biliary cirrhosis, lipid metabolism disorders, and disorders of the central nervous system as provided herein include administration of a therapeutically effective amount of a combination of pantethine and a PPARoc agonist or activator to a subject with nephropathic cystinosis, to a subject with primary biliary cirrhosis, to a subject with a lipid metabolism disorder, or to a subject with a central nervous system disorder. In some aspects, the PPARoc agonist or activator is a vanin agonist or activator. In some aspects, the PPARoc agonist or activator increases the expression or activity of vanin-1, vanin-2, and/or vanin-3. In certain aspects, the PPARoc agonist or activator is a fibrate. In some aspects, the vanin agonist or activator is a fibrate.

As used herein, the term “pantethine” has its general meaning in the art. Pantethine includes pantethine, a derivative thereof, or a pharmaceutically acceptable salt thereof. As used herein and unless otherwise indicated, the phrases “pantethine or a derivative thereof,” and “pantethine or derivatives thereof,” encompass, but are not limited to, D,D- pantethine, D,L- pantethine, L,L- pantethine, L,D- pantethine, D-pantetheine, L-pantetheine, D-phospho- pantetheine, L-phospho-pantetheine, D-pantothenic acid, L-pantothenic acid, mixtures thereof, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, prodrug, or pharmacologically active metabolite thereof. As used herein, the term “fibrate” has its general meaning in the art. Fibrates (or fibric acids) include pharmaceutically acceptable salts and derivatives thereof.

As used herein, the term “vanin” has its general meaning in the art. Human vanin gene family consists of three genes, vanin-1 (VNN1), vanin-2 (VNN2), and vanin-3 (VNN3). As used herein, the terms “vanin-agonist” and “vanin activator” refer to any compound that is able to increases the activity or expression of a vanin. As used herein, the terms “vanin-1 agonist,” “vanin-2 agonist,” and “vanin-3 agonist” refer to any compound that is able to increase the activity or expression of vanin-1, vanin-2, and vanin-3, respectively. The terms encompass any vanin-1 agonist or activator, any vanin-2 agonist or activator, or any vanin-3 agonist or activator that is currently known, and/or any vanin-1 agonist or activator, any vanin-2 agonist or activator, or any vanin-3 agonist or activator that is subsequently discovered or created. Additionally, the term “vanin-1 agonist or activator,” the term “vanin-2 agonist or activator,” and the term “vanin- 3 agonist or activator” refer to any compound that, in vitro and/or in vivo, increases the activity and/or expression of vanin-1, increases the activity and/or expression of vanin-2, or increases the activity and/or expression of vanin-3, respectively.

As used herein, a “PPARoc agonist or activator” is a compound or composition that increases the activity or expression of PPARoc. An increase in the activity or expression of PPARoc includes an increase in transcriptional activity of PPARoc, such as increased binding to and activating PPARoc transcriptional response elements in various genes regulated by the activity of PPARoc.

As used herein, a “fish oil” is a marine-animal-derived oil comprising at least one omega 3 fatty acid. Fish oil may be harvested from any suitable source. Non-limiting examples of sources include: abalone, scallops, albacore tuna, anchovies, catfish, clams, cod, fern fish, herring, trout, mackerel, menhaden, orange roughy, salmon, sardines, sea mullet, sea perch, shark, shrimp, squid, and tuna. The harvested fish oil may be concentrated or purified using any suitable method known to one of skill in the art.

As used herein, an “omega 3 fatty acid” or “co-3 fatty acid” is an unsaturated fatty acid that includes a carbon-carbon double bond at the 3 position of the fatty acid chain; that is, a double bond is present between the third and fourth carbon atoms at terminal (methyl) end of the alkyl chain. Omega 3 fatty acids include, but are not limited to alpha-linoleic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid, and stearidonic acid. In some embodiments, the omega 3 fatty acid may be an omega 3 polyunsaturated fatty acid. An “omega 3 fatty acid ester” or “co-3 fatty acid ester” is an ester of a omega 3 fatty acid, or an co-3 fatty acid, respectively. “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e. -(CEb^CEE), sec-butyl (i.e. -CH(CH3)CH2CH3), isobutyl (i.e. -CEbCEl(CH3)2) and tert-butyl (i.e. -C(CH3)3); and “propyl” includes n-propyl (i.e. -(CEb^CEE) and isopropyl (i.e. -CH(CH3)2). Unless otherwise specified, an alkyl group includes 1 to 10 carbon atoms (“Ci-io alkyl”). As a further example, a Ci-6 alkyl includes 1 to 6 carbon atoms.

“Ester” refers to a carboxylic group C(0)OR in which R is alkyl. Non-limiting examples of esters include unsaturated fatty acid esters such as eicosatetraenoic acid ethyl ester, eicosapentaenoic acid ethyl ester, docosahexaenoic acid ethyl ester, and stearidonic acid methyl ester.

“Carriers” as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers that are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed

As used herein, the term “preventing” includes providing prophylaxis with respect to occurrence or recurrence of a particular disease, disorder, or condition in an individual. An individual may be predisposed to, susceptible to a particular disease, disorder, or condition, or at risk of developing such a disease, disorder, or condition, but has not yet been diagnosed with the disease, disorder, or condition.

As used herein, an individual “at risk” of developing a particular disease, disorder, or condition may or may not have detectable disease or symptoms of disease, and may or may not have displayed detectable disease or symptoms of disease prior to the treatment methods described herein. “At risk” denotes that an individual has one or more risk factors, which are measurable parameters that correlate with development of a particular disease, disorder, or condition, as known in the art. An individual having one or more of these risk factors has a higher probability of developing a particular disease, disorder, or condition than an individual without one or more of these risk factors.

As used herein, the term “treatment” refers to clinical intervention designed to alter the natural course of the individual being treated during the course of clinical pathology. Desirable effects of treatment include decreasing the rate of progression, ameliorating or palliating the pathological state, and remission or improved prognosis of a particular disease, disorder, or condition. An individual is successfully “treated”, for example, if one or more symptoms associated with a particular disease, disorder, or condition are mitigated or eliminated.

An “effective amount” refers to at least an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. An effective amount can be provided in one or more administrations. An effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the treatment to elicit a desired response in the individual. An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results include clinical results such as decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival. An effective amount of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an “effective amount” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.

An “individual” for purposes of treatment, prevention, or reduction of risk refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sport, or pet animals, such as dogs, horses, rabbits, cattle, pigs, hamsters, gerbils, mice, ferrets, rats, cats, and the like. In some embodiments, the individual is human.

As used herein, administration “in conjunction” or “in combination” with another compound or composition includes simultaneous administration and/or administration at different times. Administration in conjunction or in combination also encompasses administration as a co-formulation or administration as separate compositions, including at different dosing frequencies or intervals, and using the same route of administration or different routes of administration. In some embodiments, administration in conjunction or in combination is administration as a part of the same treatment regimen. The term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.

As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly indicates otherwise. For example, reference to an “antibody” is a reference to from one to many antibodies, such as molar amounts, and includes equivalents thereof known to those skilled in the art, and so forth.

It is understood that aspect and embodiments of the present disclosure described herein include “comprising,” “consisting,” and “consisting essentially of’ aspects and embodiments. Cystinosis/Nephropathic Cystinosis

Cystinosis is a rare, autosomal recessive disorder caused by the inability to metabolize the amino acid cystine, leading to intra-lysosomal accumulation of cystine and crystals thereof within various tissues, such as spleen, liver, lymph nodes, kidney, bone marrow, and eyes.

These crystals cause tissue damage, particularly in the kidney. (See Elmonem et al, 2016, Orphanet Journal of Rare Disease, 11 :47.)

Cystinosis is caused by mutations in the gene that encodes cystinosin (CTNS gene), a lysosomal-specific transporter for cystine. The disorder follows an autosomal recessive inheritance pattern. Because of a defect in cystinosin, cystine cannot be exported from lysosomes and therefore accumulates there. As cystine is highly insoluble, when its concentration in tissue lysosomes increases, its solubility is exceeded and crystalline precipitates are formed in almost all organs and tissues.

Three clinical forms of cystinosis have been described. Infantile (or nephropathic) cystinosis; intermediate (or late-onset) cystinosis; and non-nephrotic cystinosis. Infantile or nephropathic cystinosis is usually diagnosed between 6 and 18 months of age with symptoms of excessive thirst and urination, failure to thrive, rickets, and episodes of dehydration. As a consequence, important nutrients and minerals are lost in the urine. Children with cystinosis can also have an ocular manifestation of this disease, and develop crystals in their eyes (usually after one year of age) which may lead to photosensitivity. Without specific treatment, children with cystinosis develop end-stage renal failure, leading to loss of kidney function, usually between 6 and 12 years of age.

The signs and symptoms of intermediate cystinosis are the same as nephropathic cystinosis, but they occur at a later age, typically around age twelve to fifteen. People with non- nephrotic cystinosis do not usually experience growth impairment or kidney malfunction; the only symptom non-nephrotic cystinosis is photophobia due to cystine crystals in the cornea. Cystinosis is the most common cause of Fanconi syndrome in the pediatric age group. Fanconi syndrome occurs when the function of cells in renal tubules is impaired, leading to abnormal amounts of carbohydrates and amino acids in the urine, excessive urination, and low blood levels of potassium and phosphates.

Cystinosis is currently treated by oral administration of cysteamine in order to reduce cystine accumulation within cells. CYSTAGON® (cysteamine bitartrate) capsules are currently approved for the treatment of cystinosis; a delayed-release capsule (PROCYSBI® (cysteamine bitartrate) delayed-release capsules) is also available. In addition to cysteamine, subjects with cystinosis are often given sodium citrate to treat the blood acidosis associated with the disease, as well as potassium and phosphorus supplements. In subject having an ocular manifestation of cystinosis, wherein the subject develops crystals in the eye, cysteamine is administered to the eye, such as by eyedrops.

Adhering to cysteamine treatment is cumbersome, particularly in view of the very young age of individuals suffering from this disorder. Individuals with cystinosis take oral cysteamine every 6 hours, day and night. When taken regularly, cysteamine can deplete intracellular cystine by up to 90% (as measured in circulating white blood cells), and this has been shown to reduce the rate of progression to kidney failure and transplantation. Because of the difficulty of adhering to the dosing regimen of cysteamine, reducing the dose burden for individuals with nephropathic cystinosis would be beneficial for these patients.

Nephropathic cystinosis is associated with kidney failure. To date, the only specific treatment for nephropathic cystinosis is the sulfhydryl agent cysteamine. Cysteamine acts by converting cystine to cysteine and cysteine-cysteamine mixed disulfide, which are then both able to leave the lysosome through cystine and lysine transporters, respectively. (Gahl et al, N Engl J Med, 2002, 347:111-121.) Cysteamine has been shown to lower intracellular cystine levels, thereby reducing the rate of progression of kidney failure in individuals with nephropathic cystinosis.

Without cysteamine treatment, individuals with nephropathic cystinosis can develop complications in organs other than the kidneys and eyes due to the continued accumulation of cystine throughout the body. These complications can include muscle wasting, difficulty swallowing, diabetes, and hypothyroidism. Some symptoms include the inability of the kidneys to concentrate urine and allow important quantities of sodium, potassium, phosphorus, bicarbonate and substances like carnitine to be excreted in the urine. In addition, the loss of urinary electrolytes (sodium, potassium, bicarbonate, phosphorus) must be compensated in these patients. One clinical read-out for determining the effectiveness and appropriate dosage of cysteamine treatment involves monitoring cystine levels in white blood cells. Normal individuals or individuals heterozygous for cystinosis have white blood cell cystine levels of less than 0.2 and usually below 1 nmol/l/2 cystine/mg protein, respectively. Individuals with nephropathic cystinosis have elevated white blood cell cystine levels above 2 nmol/l/2 cystine/mg protein. When taken regularly, cysteamine administration can deplete intracellular cystine by up to 90% (as measured in circulating white blood cells). Cystine levels in white blood cells are closely and frequently monitored in these patients to determine adequacy and effectiveness of drug dosing by measuring white blood cell cystine levels 5 to 6 hours after administering cysteamine. Generally, the goal of cysteamine therapy for nephropathic cystinosis is to keep white blood cell (e.g., leukocyte) cystine levels below 1 nmol/l/2 cystine/mg protein as measured five to six hours following administration of the drug.

The recommended maintenance dose of cysteamine for children up to 12 years of age is 1.3 grams/m²/day, given in four divided doses. New patients typically initiate treatment with one-quarter to one-sixth of the maintenance dose; the dose is then raised gradually over four to six weeks to avoid or minimize any intolerance to the drug. Patients over 12 years old or over 110 pounds may be administered 2.0 grams/m²/day, divided four times daily; however, cysteamine doses this high are often associated with adverse events, including vomiting, anorexia, fever, diarrhea, lethargy, and rash.

The requirement for administration of cysteamine 4 times a day (i.e., every 6 hours) is because cysteamine is only active within the body for a very short period of time not exceeding 5-6 hours. Additionally, cysteamine therapy is only effective for the treatment of nephropathic cystinosis if administered according to the above regimen day after day, indefinitely, in order to control the disease.

Because of the strict and cumbersome treatment regimen of cysteamine and the associated adverse gastrointestinal and central nervous system symptoms, nonadherence to cysteamine therapy remains a significant problem for patients suffering from nephropathic cystinosis, particularly among adolescent and young adult patients. By reducing the frequency of cysteamine dosing, or providing alternative treatment methods, such as those provided herein, adherence to a therapeutic regimen can therefore be easily achieved, thus resulting in better treatment efficacy and outcomes.

The present disclosure provides methods for treating nephropathic cystinosis using a combination of pantethine and a PPARoc agonist or a PPARoc activator. In one embodiment, the present disclosure provides methods for treating nephropathic cystinosis in a subject in need thereof, the method comprising administering to the subject having nephropathic cystinosis a therapeutically effective amount of a combination of pantethine and a PPARoc agonist or a PPARoc activator, thereby treating nephropathic cystinosis. In some embodiments, the PPARoc agonist or activator is a vanin agonist or activator. In some embodiments, the vanin agonist or activator is a compound or agent that increases the activity and/or expression of vanin-1, Vanin- 2, or vanin-3. In some embodiments, the PPARoc agonist or activator is a compound that increases the expression or activity of vanin-1, vanin-2, and/or vanin-3. In some embodiments, the PPARoc agonist or activator is a fibrate. In some embodiments, the compound that increases the expression or activity of vanin is a fibrate. In other embodiments, the method further comprises administering to the subject a therapeutically effective amount of N-acetyl cysteine in combination with pantethine and a PPARoc agonist or a PPARoc activator.

By administering a combination of pantethine and a fibrate to an individual with nephropathic cystinosis according to the methods of the present disclosure, intracellular cystine levels are reduced. In one embodiment, the present disclosure provides a method for reducing intracellular cystine levels in a subject with nephropathic cystinosis, the method comprising administering to the subject a therapeutically effective amount of a combination of pantethine and fibrate. In certain embodiments, the method reduces intracellular cystine levels by at least 25%, by at least 50%, or by at least 75% compared to the levels of intracellular cystine levels in the subject prior to administration of the combination of pantethine and fibrate. In one embodiment, the method reduces intracellular cystine levels in the subject by about 90% compared to the levels of intracellular cystine in the subject prior to administration of the combination of pantethine and fibrate. In some embodiments, reduction of intracellular cystine levels is a reduction in the levels of intracellular cystine levels in white blood cells. In other embodiments, the method further comprises administering a therapeutically effective amount of N-acetyl cysteine in combination with pantethine and a PPARoc agonist or a PPARoc activator.

The present disclosure provides methods for reducing intracellular cystine levels in a subject with nephropathic cystinosis by administering to the subject a therapeutically effect amount of a combination of pantethine and fibrate. In some embodiments, the methods of the present disclosure reduce intracellular levels of cystine in the subject to below 2 nmol/l/2 cystine/mg protein. In some embodiments, the methods of the present disclosure reduce intracellular cystine levels in the subject to below 1 nmol/l/2 cystine/mg protein. In some embodiments, the methods of the present disclosure reduce intracellular cystine levels to below 0.5 nmol/l/2 cystine/mg protein. In other embodiments, the method further comprises administering a therapeutically effective amount of N-acetyl cysteine in combination with pantethine and a PPARoc agonist or a PPARoc activator. Reducing intracellular cystine levels in patients with nephropathic cystinosis is associated with reducing the risk of, delaying the onset of, or preventing kidney failure. In one embodiment, the present disclosure provides a method for reducing the risk of developing kidney failure in a subject with nephropathic cystinosis, the method comprising administering to the subject a therapeutically effective amount of a combination of pantethine and fibrate, thereby reducing the risk of developing kidney failure in the subject. In one embodiment, the present disclosure provides a method for delaying the onset of kidney failure in a subject with nephropathic cystinosis, the method comprising administering to the subject a therapeutically effective amount of a combination of pantethine and fibrate, thereby delaying the onset of kidney failure in the subject. In one embodiment, the present disclosure provides a method for preventing kidney failure in a subject with nephropathic cystinosis, the method comprising administering to the subject a therapeutically effective amount of a combination of pantethine and fibrate, thereby preventing kidney failure in the subject. In other embodiments, the method further comprises administering a therapeutically effective amount of N-acetyl cysteine in combination with pantethine and a PPARoc agonist or a PPARoc activator.

Primary biliary cirrhosis

Primary biliary cirrhosis (PBC, also referred to as primary biliary cholangitis) is an autoimmune disease in which the bile ducts in the liver are slowly and progressively destroyed. This causes bile and other toxins to build up in the liver, a condition called cholestasis. Further slow damage to the liver can lead to scarring, fibrosis, and cirrhosis. Ursodeoxycholic acid (UDCA, e.g., Ursodiol) is the most frequently used treatment for primary biliary cirrhosis; UDCA has been shown to help cholestasis and improve liver function tests.

Serum bilirubin levels are an indicator of the prognosis of primary biliary cirrhosis with individuals having serum bilirubin levels of 2-6 mg/dL having a mean survival time of 4.1 years, individuals having serum bilirubin levels of 6-10 mg/dL having a mean survival time of 2.1 years, and individuals having serum bilirubin levels above 10 mg/dL having a mean survival of time of 1.4 years.

A meta-analysis aimed at evaluating the efficacy of fenofibrate for treatment of primary biliary cirrhosis using a systematic review of relevant literature and data pooled on changes in mean levels of alkaline phosphatase, gamma-glutamyl transferase (GGT), bilirubin, and IgM before and after treatment has been reported. Fenofibrate treatment was associated with decreased mean pooled alkaline phosphatase (-114 IU/L), decreased GGT (-92 IU/L), decreased bilirubin (-0.11 mg/dL), and decreased IgM (-88 mg/dL).

The present disclosure provides methods for treating primary biliary cirrhosis using a combination of pantethine and a PPARoc agonist or a PPARoc activator. In one embodiment, the present disclosure provides methods for treating primary biliary cirrhosis in a subject in need thereof, the method comprising administering to the subject having primary biliary cirrhosis a therapeutically effective amount of a combination of pantethine and a PPARoc agonist or a PPARoc activator, thereby treating primary biliary cirrhosis. In some embodiments, the PPARoc agonist or activator is a vanin agonist or activator. In some embodiments, the vanin agonist or activator is a compound or agent that increases the activity and/or expression of vanin-1, Vanin- 2, or vanin-3. In some embodiments, the PPARoc agonist or activator is a compound that increases the expression or activity of vanin-1, vanin-2, and/or vanin-3. In some embodiments, the PPARoc agonist or activator is a fibrate. In some embodiments, the compound that increases the expression or activity of vanin is a fibrate. In some embodiments, the subject is unresponsive to UDCA treatment. In other embodiments, the method further comprises administering a therapeutically effective amount of N-acetyl cysteine in combination with pantethine and a PPARoc agonist or a PPARoc activator.

In some aspects, the present disclosure provides methods for reducing alkaline phosphatase levels in a subject with primary biliary cirrhosis by administering to the subject a therapeutically effect amount of a combination of pantethine and fibrate. In some aspects, the present disclosure provides methods for reducing gamma-glutamyl transferase levels in a subject with primary biliary cirrhosis by administering to the subject a therapeutically effect amount of a combination of pantethine and fibrate. In some aspects, the present disclosure provides methods for reducing bilirubin levels in a subject with primary biliary cirrhosis by administering to the subject a therapeutically effect amount of a combination of pantethine and fibrate. In some aspects, the present disclosure provides methods for reducing IgM levels in a subject with primary biliary cirrhosis by administering to the subject a therapeutically effect amount of a combination of pantethine and fibrate. In other embodiments, the method further comprises administering a therapeutically effective amount of N-acetyl cysteine in combination with pantethine and a PPARoc agonist or a PPARoc activator.

Lipid metabolism disorders and dyslipidemia

Lipid metabolism disorders, such as, e.g., hyperlipidemia, dyslipidemia, triglyceridemia, are caused by various factors including, for example, high levels of total cholesterol, high levels of triglycerides, low levels of high-density lipoprotein cholesterol, elevated levels of low-density lipoprotein cholesterol, or small low-density lipoprotein particles. Hypertriglyceridemia refers to high blood levels of triglycerides. Elevated levels of triglycerides are associated with atherosclerosis, even in the absence of hypercholesterolemia, and predispose individuals to cardiovascular disease, including heart disease and stroke. Lipoprotein(a), also called Lp(a) or LPA, is a lipoprotein subclass. Genetic studies and numerous epidemiologic studies have identified high levels of Lp(a) as a risk factor for atherosclerotic diseases, such as coronary heart disease, cardiovascular disease, atherosclerosis, thrombosis, and stroke. High Lp(a) levels predicts risk of early atherosclerosis independently of other cardiovascular risk factors, including low-density lipoprotein (LDL).

Current treatments for elevated levels of Lp(a) include niacin, typically 1-3 grams per day in an extended release formulation. Niacin therapy can reduce Lp(a) levels by 20-40%. However, use of niacin is commonly associated with a broad range of side effects, such as flushing, pruritus, and hyperuricemia, thus requiring careful pharmacological management.

Other medications in various stages of development for lowering Lp(a) levels include thyromimetics, cholesterol-ester-transfer protein inhibitors, anti-sense oligonucleotides, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The goal of treatment is typically to reduce Lp(a) levels to below, e.g., 50 mg/dL, 25 mg/dL.

The present disclosure provides methods for treating a lipid metabolism disorder using a combination of pantethine and a PPARoc agonist or a PPARoc activator. In one embodiment, the present disclosure provides methods for treating a lipid metabolism disorder in a subject in need thereof, the method comprising administering to the subject having a lipid metabolism disorder a therapeutically effective amount of a combination of pantethine and a PPARoc agonist or a PPARoc activator, thereby treating the lipid metabolism disorder. In some embodiments, the lipid metabolism disorder is hyperlipidemia. In some embodiments, the lipid metabolism disorder is dyslipidemia. In some embodiments, the lipid metabolism disorder is triglyceridemia, In some embodiments, the PPARoc agonist or activator is a vanin agonist or activator. In some embodiments, the vanin agonist or activator is a compound or agent that increases the activity and/or expression of vanin-1, vanin-2, or vanin-3. In some embodiments, the PPARoc agonist or activator is a compound that increases the expression or activity of Vanin- 1, vanin-2, and/or vanin-3. In some embodiments, the PPARoc agonist or activator is a fibrate.

In some embodiments, the compound that increases the expression or activity of vanin is a fibrate. In other embodiments, the method further comprises administering a therapeutically effective amount of N-acetyl cysteine in combination with pantethine and a PPARoc agonist or a PPARoc activator. In some embodiments, the method further comprises administering to the subject in need thereof a therapeutically effective amount of an unsaturated fatty acid, for example, a fish oil or an omega 3 fatty acid. In some embodiments, the method comprises administering an unsaturated fatty acid, or a Ci-6 alkyl ester thereof, selected from eicosapentaenoic acid, (e.g., ethyl eicosapentaenoic (icosapent ethyl)), alpha-linoleic acid, eicosatetraenoic acid, docosahexaenoic acid, and stearidonic acid, or a combination thereof (e.g., Lovaza® ethyl or a fish oil). The unsaturated fatty acid may be eicosapentaenoic acid, or a Ci-₆ alkyl ester thereof. In some embodiments, the unsaturated fatty acid does not include docosahexaenoic acid, or an ester thereof.

In other embodiments, the methods provided by the present disclosure are effective in the treatment of other lipid metabolism disorders, such as, for example, familial chylomicronemia syndrome (FCS), familial partial lipodystrophy (FPL), cardiovascular disease caused by hyperlipoproteinemia, cardiovascular disease caused by high triglycerides, non alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), and other hepatotoxicity disorders, such as acute liver failure associated with acetaminophen therapy.

By administering a combination of pantethine and a fibrate to an individual with a lipid metabolism disorder, such as hyperlipidemia, dyslipidemia, or triglyceridemia, according to the methods of the present disclosure, triglyceride levels are reduced or lowered in the individual.

In one embodiment, the present disclosure provides a method for reducing triglyceride levels in a subject with hyperlipidemia, dyslipidemia, or triglyceridemia, the method comprising administering to the subject a therapeutically effective amount of a combination of pantethine and fibrate, thereby reducing triglyceride levels in the subject. In certain embodiments, the method reduces triglyceride levels by at least 10%, by at least 20 %, by at least 25%, by at least 30%, by at least 40%, by at least 50%, or by at least 75% compared to the triglyceride levels in the subject prior to administration of the combination of pantethine and fibrate. In some embodiments, the method further comprises administering to the subject in need thereof a therapeutically effective amount of an unsaturated fatty acid, for example, a fish oil or an omega 3 fatty acid. In some embodiments, the method comprises administering an unsaturated fatty acid, or a Ci-₆ alkyl ester thereof, selected from eicosapentaenoic acid, (e.g., ethyl eicosapentaenoic (icosapent ethyl)), alpha-linoleic acid, eicosatetraenoic acid, docosahexaenoic acid, and stearidonic acid, or a combination thereof (e.g., Lovaza® ethyl or a fish oil). The unsaturated fatty acid may be eicosapentaenoic acid, or a Ci-₆ alkyl ester thereof. In some embodiments, the unsaturated fatty acid does not include docosahexaenoic acid, or an ester thereof.

By administering a combination of pantethine and a fibrate to an individual with hyperlipidemia, dyslipidemia, or triglyceridemia according to the methods of the present disclosure, Lp(a) levels are reduced or lowered in the individual. In one embodiment, the present disclosure provides a method for reducing Lp(a) levels in a subject with hyperlipidemia, dyslipidemia, or triglyceridemia, the method comprising administering to the subject a therapeutically effective amount of a combination of pantethine and fibrate, thereby reducing Lp(a) levels in the subject. In certain embodiments, the method reduces Lp(a) levels by at least 10%, by at least 20 %, by at least 25%, by at least 30%, by at least 40%, by at least 50%, or by at least 75% compared to the Lp(a) levels in the subject prior to administration of the combination of pantethine and fibrate. In some embodiments, the method is effective at reducing Lp(a) levels to below 50 mg/dL. In some embodiments, the method further comprises administering to the subject in need thereof a therapeutically effective amount of an unsaturated fatty acid, for example, a fish oil or an omega 3 fatty acid. In some embodiments, the method comprises administering an unsaturated fatty acid, or a Ci-₆ alkyl ester thereof, selected from eicosapentaenoic acid, (e.g., ethyl eicosapentaenoic (icosapent ethyl)), alpha-linoleic acid, eicosatetraenoic acid, docosahexaenoic acid, and stearidonic acid, or a combination thereof (e.g., Lovaza® ethyl or a fish oil). The unsaturated fatty acid may be eicosapentaenoic acid, or a Ci-₆ alkyl ester thereof. In some embodiments, the unsaturated fatty acid does not include docosahexaenoic acid, or an ester thereof.

Disorders of the central nervous system

The present disclosure further provides methods for treating various disorders of the central nervous system, including, e.g., Huntington’s disease and Alzheimer’s disease. By administering a therapeutically effective combination of pantethine and a PPARoc agonist or activator (such as, for example, a fibrate) to a subject in need thereof, therapeutically effective levels of cysteamine are produced, resulting in an effective treatment for various central nervous system li disorders, including Huntington’s disease and Alzheimer’s disease.

The present disclosure provides methods for treating a disorder of the central nervous system using a combination of pantethine and a PPARoc agonist or a PPARoc activator. In one embodiment, the present disclosure provides methods for treating a disorder of the central nervous system in a subject in need thereof, the method comprising administering to the subject having a disorder of the central nervous system a therapeutically effective amount of a combination of pantethine and a PPARoc agonist or a PPARoc activator, thereby treating the disorder. In some embodiments, the disorder of the central nervous system is Huntington’s disease. In some embodiments, the disorder of the central nervous system is Alzheimer’s disease. In some embodiments, the PPARoc agonist or activator is a vanin agonist or activator.

In some embodiments, the vanin agonist or activator is a compound or agent that increases the activity and/or expression of vanin-1, vanin-2, and/or vanin-3. In some embodiments, the PPARoc agonist or activator is a compound that increases the expression or activity of vanin-1, vanin-2, and/or vanin-3. In some embodiments, the PPARoc agonist or activator is a fibrate. In some embodiments, the compound that increases the expression or activity of vanin is a fibrate. In other embodiments, the method further comprises administering a therapeutically effective amount of N-acetyl cysteine in combination with pantethine and a PPARoc agonist or a PPARoc activator.

Asthma

Asthma affects 25.7 million people in the U.S., including 7 million children. Although patients suffering from asthma share similar clinical symptoms, the disease is heterogeneous, contributing to the difficulty in both studying and treating asthma.

Currently, systemic corticosteroid treatment is considered an effective medication for control of chronic asthma and for rescue of acute exacerbation. Some individuals with asthma show poor corticosteroid treatment response. (See, e.g., Adcock and Lane, 2003, Journal Endocrinology, 178:347-355.) Specifically, a small number (<5%) of asthmatic patients do not respond well, or at all, to corticosteroid therapy and are considered steroid-insensitive (e.g., corticosteroid-insensitive). Recently, nasal VNN1 expression has been suggested as a clinically useful biomarker to identify a subset of difficult to treat asthmatic children with a biologic etiology for poor corticosteroid response. (See Xiao et al, 2015, J Allergy Clin Immunol, 136:923-931; Chan et al, Journal Allergy Clinical Immunol, 101:594-601.) In particular, this report showed that VNN1 mRNA expression is induced following systemic corticosteroid treatment in asthmatic children who respond well to this treatment, but not in children who are poor treatment responders, indicating that VNN1 Is required for optimal response to corticosteroid treatment. It has also been reported that VNN1 expression is required for inhaled corticoids to work during an asthma attack.

Accordingly, the present disclosure provides methods for treating asthma using a combination of pantethine and a PPARoc agonist or a PPARoc activator. In one embodiment, the present disclosure provides methods for treating asthma in a subject in need thereof, the method comprising administering to the subject having asthma a therapeutically effective amount of a combination of pantethine and a PPARoc agonist or a PPARoc activator, thereby treating asthma. In some embodiments, the PPARoc agonist or activator is a vanin agonist or activator. In some embodiments, the vanin agonist or activator is a compound or agent that activates the activity and/or expression of vanin-1, vanin-2, and/or vanin-3. In some embodiments, the PPARoc agonist or activator is a compound that increases the expression or activity of vanin-1, vanin-2, and/or vanin-3. In some embodiments, the PPARoc agonist or activator is a fibrate. In some embodiments, the compound that increases the expression or activity of vanin is a fibrate. In other embodiments, the method further comprises administering to the subject a therapeutically effective amount of N-acetyl cysteine in combination with pantethine and a PPARoc agonist or a PPARoc activator. In other embodiments, the method further comprises administering corticosteroid therapy to the subject.

In some embodiments, the present disclosure provides methods for treating asthma in a subject, wherein the subject is a poor responder to steroid therapy, has shown a poor steroid treatment response, or is steroid-insensitive. In one embodiment, the present disclosure provides methods for treating asthma in a subject in need thereof, wherein the subject is a poor responder to steroid treatment, wherein the subject has shown a poor steroid treatment response, or wherein the subject is steroid-insensitive, the method comprising administering to the subject having asthma a therapeutically effective amount of a combination of pantethine and a PPARoc agonist or a PPARoc activator, thereby treating asthma and/or improving or enhancing corticosteroid treatment response. In some embodiments, the PPARoc agonist or activator is a vanin-1 agonist or activator. In some embodiments, the vanin agonist or activator is a compound or agent that increases the activity and/or expression of vanin-1, vanin-2, and/or vanin-3. In some embodiments, the PPARoc agonist or activator is a compound that increases the expression or activity of vanin-1, vanin-2, and/or vaini-3. In some embodiments, the PPARoc agonist or activator is a fibrate. In some embodiments, the compound that increases the expression or activity of vanin is a fibrate. In other embodiments, the method further comprises administering a therapeutically effective amount of N-acetyl cysteine in combination with pantethine and a PPARoc agonist or a PPARoc activator. In other embodiments, the method further comprises administering corticosteroid therapy to the subject.

High Blood Pressure/Hypertension

High blood pressure/hypertension is the most common cardiovascular risk factor and a major contributor to heart disease and stroke. A blood pressure-associated missense single nucleotide polymorphism (SNP) - rs2272996 - in the gene encoding vanin-1 has been reported. (Wang et al, 2014, PLOS Genetics, 10:el004641). This SNP (N131S mutation) was found to be associated with significantly lower plasma vanin-1 protein levels. Additionally, this SNP is associated with hypertension is African Americans and Mexican Americans.

In some embodiments, the present disclosure provides methods for treating high blood pressure/hypertension in a subject. In one embodiment, the present disclosure provides methods for treating hypertension in a subject in need thereof, the method comprising administering to the subject having hypertension a therapeutically effective amount of a combination of pantethine and a PPARoc agonist or a PPARoc activator, thereby treating hypertension. In some embodiments, the PPARoc agonist or activator is a vanin agonist or activator. In some embodiments, the vanin agonist or activator is a compound or agent that increase the activity and/or expression of vanin-1, vanin-2, and/or vanin-3. In some embodiments, the PPARoc agonist or activator is a compound that increases the expression or activity of vanin-1, vanin-2, and/or vanin-3. In some embodiments, the PPARoc agonist or activator is a fibrate. In some embodiments, the compound that increases the expression or activity of vanin is a fibrate. In other embodiments, the method further comprises administering a therapeutically effective amount of N-acetyl cysteine in combination with pantethine and a PPARoc agonist or a PPARoc activator. In some embodiments, the subject is of African American descent. In some embodiments, the subject is of Mexican American descent. In yet other embodiments, the subject has been identified has having the SNP rs2272996. In yet other embodiments, the subject has been identified as having aN131S mutation in the vanin-1 gene. In some embodiments, the method further comprises administering to the subject in need thereof a therapeutically effective amount of an unsaturated fatty acid, for example, a fish oil or an omega 3 fatty acid. In some embodiments, the method comprises administering an unsaturated fatty acid, or a Ci-₆ alkyl ester thereof, selected from eicosapentaenoic acid, (e.g., ethyl eicosapentaenoic (icosapent ethyl)), alpha-linoleic acid, eicosatetraenoic acid, docosahexaenoic acid, and stearidonic acid, or a combination thereof (e.g., Lovaza® ethyl or a fish oil). The unsaturated fatty acid may be eicosapentaenoic acid, or a Ci-₆ alkyl ester thereof. In some embodiments, the unsaturated fatty acid does not include docosahexaenoic acid, or an ester thereof.

Pantothenate kinase-associated neurodegenerative disorders

Pantothenate kinase-associated neurodegeneration (PKAN; also known as neurodegeneration with brain iron accumulation 1 or Hallervorden-Spatz syndrome) is an autosomal recessive disorder characterized by dystonia, dysarthria, rigidity, pigmentary retinal degeneration, and brain iron accumulation (Kruer et al, 2012, Am J Neuroradiol, 33:407-414; Zhou et al, Nat Genet, 28:345-349). PKAN is the most common type of neurodegeneration with brain iron accumulation (NBIA), a group of clinical disorders marked by progressive abnormal involuntary movements, alterations in muscle tone, and postural disturbances (extrapyramidal). These disorders show radiographic evidence of iron accumulation in the brain. PKAN is typically diagnosed by molecular genetic testing, most often after a characteristic finding on magnetic resonance imaging (MRI), called the “eye-of-the-tiger” sign, is detected.

In most cases, progression of PKAN extends over several years, leading to death in childhood or early adulthood in classic cases. Symptoms include dystonia, (sustained muscle contractions causing repetitive movements), dysarthria (abnormal speech), muscular rigidity, poor balance, and spasticity (sudden involuntary muscle spasms), These features can result in clumsiness, gait (walking) problems, difficulty controlling movement, and speech problems. Another common feature is degeneration of the retina, resulting in progressive night blindness and loss of peripheral (side) vision.

Classical PKAN develops in the first ten years of life (average age for developing symptoms is three and a half years). These children may initially be perceived as clumsy and later develop more noticeable problems with walking. Speech delay is also common. Eventually, falling becomes a frequent feature. Because of the limited ability to protect themselves during falls, children may have repeated injury to the face and chin. Many individuals with the classic form of PKAN require a wheelchair by their mid-teens (in some cases earlier). Most lose the ability to move/walk independently between 10 and 15 years after the beginning of symptoms.

Individuals with classical PKAN are more likely to have specific eye problems. Approximately two-thirds of these patients will have retinal degeneration. This is a progressive degeneration of the nerve-rich membrane lining the eyes (retina), resulting in tunnel vision, night blindness, and loss of peripheral vision. Loss of this peripheral vision may contribute to the more frequent falls and gait disturbances in the early stages. [For more information on this retinopathy (retinitis pigmentosa), choose “retinitis pigmentosa” as your search term in the Rare Disease Database]

The atypical form of PKAN usually occurs after the age of ten years and progresses more slowly. The average age for developing symptoms is 13 years. Loss of independent ambulation (walking) often occurs 15 to 40 years after the initial development of symptoms. The initial presenting symptoms usually involve speech. Common speech problems are repetition of words or phrases (palilalia), rapid speech (tachylalia), and dysarthria. Psychiatric symptoms are more commonly observed and include impulsive behavior, violent outbursts, depression, or a tendency to rapid mood swings. While the movement disorder is a very common feature, it usually develops later. In general, atypical disease is less severe and more slowly progressive than early-onset PKAN.

PKAN is caused by mutations in the PANK2 gene, which codes for the mitochondrial enzyme pantothenate kinase 2. This enzyme is part of the co-enzyme A biosynthetic pathway, catalyzing the phosphorylation of vitamin B5 or pantothenate. (Hayflick, 2003, J Neurol Sci, 207:106-107).

Pank2 ^/_ mice feed a ketogenic diet show clinical signs similar to that observed in patients with PKAN, namely severe movement disorder and neurodegeneration. Pantethine administration to such mice appeared to rescue the clinical phenotype, such as improved movement, amelioration of mitochondrial dysfunctions, and extension of lifespan (Brunetti et al, 2013, Brain, p.1-12). The present disclosure provides methods for treating pantothenate kinase-associated neurodegeneration using a combination of pantethine and a PPARoc agonist or a PPARoc activator. In one embodiment, the present disclosure provides methods for treating pantothenate kinase-associated neurodegeneration in a subject in need thereof, the method comprising administering to the subject having pantothenate kinase-associated neurodegeneration a therapeutically effective amount of a combination of pantethine and a PPARoc agonist or a PPARoc activator, thereby treating nephropathic cystinosis. In some embodiments, the PPARoc agonist or activator is a vanin agonist or activator. In some embodiments, the vanin agonist or activator is a compound or agent that increases the activity and/or expression of vanin-1, Vanin- 2, or vanin-3. In some embodiments, the PPARoc agonist or activator is a compound that increases the expression or activity of vanin-1, vanin-2, and/or vanin-3. In some embodiments, the PPARoc agonist or activator is a fibrate. In some embodiments, the compound that increases the expression or activity of vanin is a fibrate. In other embodiments, the method further comprises administering to the subject a therapeutically effective amount of N-acetyl cysteine in combination with pantethine and a PPARoc agonist or a PPARoc activator. In some embodiments, the subject is heterozygous for one or more mutations within the pantothenate kinase 2 gene. In some embodiments, the subject is homozygous for one or more mutations within the pantothenate kinase 2 gene.

Pantethine

As stated above, pantethine is the stable disulfide form of pantetheine, which is the cysteamine amide analog of pantothenic acid (i.e., vitamin B5). Pantethine is hydrolyzed to pantothenic acid and cysteamine.

In some embodiments of the present disclosure, pantethine is provided and administered as the (R)-pantethine enantiomer. In some embodiments, the enantiomeric purity of the (R)- pantethine enantiomer in the pantethine composition is at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. Methods for purifying or enriching for (R)-pantethine in a composition comprising a mixture of D-pantethine and R- pantethine are well known and available to one of skill in the art.

Fibrates

Fibrates are a class of amphipathic carboxylic acids used for treatment of various metabolic disorders, including hypercholesterolemia. Fibrates, or fibric acid derivatives, are regarded as broad-spectrum lipid-modulating agents. In addition to decreasing serum triglycerides, fibrates have also been shown to be modestly effective at reducing LDL- cholesterol and raising HDL-cholesterol. Fibrates are often used in combination with statins for the treatment of hypercholesterolemia.

Fibrates include, but are not limited to, aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, clofibride, fenofibrate, gemfibrozil, ronifibrate, and simfibrate, pemafibrate, or a pharmaceutically acceptable salt, collate, clathrate, polymorph, prodrug, or pharmaceutically active metabolite thereof.

Fibrates activate peroxisome proliferator-activated receptors (PPAR), in particular PPARoc. PPARs are a class of nuclear hormone receptor proteins that function as transcription factors regulating the expression of various gene, including genes that modulate, inter alia, carbohydrate and fat metabolism and adipose tissue differentiation. Activating the activity of PPARs induces the transcription of a number of genes, many of which facilitate lipid metabolism.

Administration of fibrate increases PPARoc activity, thereby modulating expression of genes regulated by the activity of PPARoc..

Fibrate treatment has been associated with elevated levels of transaminases (AST and ALT) and the association appears to be dose related. (See Kobayashi et al. 2009, J Tocicol Sci, 34:377-387.) It is recommended that regular monitoring of liver function be carried out during fibrate therapy and the drug discontinued if levels persisted above three times the upper limit of the normal reference range. Due to the effects of administering a combination of pantethine and fibrate in the treatment of various disorders described herein, a lower dose of either pantethine, fibrate, or both agents are thus effective in such treatments, reducing any adverse side effects associated with administering higher doses of either or both agents.

Dosage amounts of a fibrate will depend on the form or formulation of the fibrate. Daily dosages include an amount of about 1 mg to about 2500 mg, from about 1 mg to about 2000 mg, from about 1 mg to about 1000 mg, from about 5 mg to about 500 mg, from about 10 mg to about 350 mg, from about 25 mg to about 200 mg, from about 48 mg to about 145 mg, from about 50 mg to about 100 mg, from about 50 mg to about 150 mg, from about 54 mg to about 160 mg, or from about 50 mg to about 200 mg, or as normally used in the art or as determined to be effective at reducing intracellular cystine levels when used in combination with pantethine.

For example, various brands of fenofibrate are administered as a 48 mg or 145 mg tablet once daily (TRICOR® fenofibrate tablets)), 50 mg, 100 mg, or 150 mg capsule once daily (LIPOFEN® fenofibrate capsules), or as 54 mg or 160 mg tablets once per day (LOFIBRA® fenofibrate tablets). Pemafibrate, a recently developed fibrate, is administered orally in 0.1 mg tablets, twice daily, and a maximum dosage is 0.2 mg twice daily. The specific amount of each of pantethine and of fibrate for use in combination for treating nephropathic cystinosis, primary biliary cirrhosis, various lipid metabolism disorders, or disorders of the central nervous system as provided by the methods described herein, can vary based on the route of administration, the specific formulation of the compounds, and effectiveness of the combination at reducing intracellular cystine levels to a desired level.

Vanin

The human vanin gene family consists of three genes: vanin-1 (VNN1), vanin-2 (VNN2), and vanin-3 (VNN3). Human vanin-1 and vanin-2 are membrane associated ectoenzymes while vanin-3 is a secreted enzyme. In humans, vanin-1 expression has been demonstrated in the spleen, thymus, lymph nodes, peripheral blood leukocytes, urethra, kidney, parts of the respiratory tract, liver, and intestine. Human vanin-2 mRNA expression has been demonstrated in almost all tissues, with highest expression in the spleen, kidney, and blood, particularly neutrophils. Vanin-3 mRNA has been detected in liver, peripheral blood leukocytes, placenta, urethra, and parts of the respiratory tract. Vanin-1 is the predominant isoform of vanin in humans and mice.

Unsaturated Fatty Acids and Omega 3 Fatty Acids

The compositions and methods provided herein may also be combined with an unsaturated fatty acid, for example, a fish oil or an omega 3 fatty acid. In some embodiments, the method comprises administering an unsaturated fatty acid, or a Ci-₆ alkyl ester thereof, selected from eicosapentaenoic acid, (e.g., ethyl eicosapentaenoic (icosapent ethyl)), alpha- linoleic acid, eicosatetraenoic acid, docosahexaenoic acid, and stearidonic acid, or a combination thereof (e.g., Lovaza® ethyl or a fish oil). The unsaturated fatty acid may be eicosapentaenoic acid, or a Ci-₆ alkyl ester thereof. In some embodiments, the unsaturated fatty acid does not include docosahexaenoic acid, or an ester thereof.

Thus, disclosed herein is a method of treating a hepatic disorder, a lipid metabolism disorder, or a disorder of the central nervous system in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a combination of pantethine and a PPARa agonist or activator, or a combination of pantethine and a vanin agonist or activator, along with an unsaturated fatty acid, e.g., a fish oil or an omega 3 fatty acid. The unsaturated fatty acid may be co-formulated with the pantethine, the PPARa agonist or activator, and/or the vanin agonist or activator. The unsaturated fatty acid may be co administered with the pantethine, the PPARa agonist or activator, and/or the vanin agonist or activator. The unsaturated fatty acid may be administered before, after, or simultaneously with the pantethine, the a PPARa agonist or activator, and/or the vanin agonist or activator.

The unsaturated fatty acid may be derived from a natural source or may be synthetic. The unsaturated fatty acid may be an unsaturated fatty acid ester, for example, a Ci-₆ alkyl ester. The unsaturated fatty acid may be monounsaturated fatty acid or a polyunsaturated fatty acid. The unsaturated fatty acid may be a constituent of a naturally derived oil, such as a fish oil. The unsaturated fatty acid may include an omega 3 fatty acid, an omega 6 fatty acid, an omega 6:3 fatty acid, an omega 9 fatty acid, or a combination thereof. In some embodiments, the unsaturated fatty acid may be selected from oleic acid, linoleic acid, alpha-linoleic acid, gamma- linoleic acid, arachidonic acid, arachidic acid, eicosadienoic acid, eicosatetraenoic acid, eicosapentaenoic acid, erucic acid, docosapentaenoic acid, docosahexaenoic acid, stearidonic acid, and combinations thereof.

In some embodiments, the unsaturated fatty acid comprises eicosapentaenoic acid (EPA). In some embodiments, the EPA comprises all-cis eicosa-5,8,11,14,17-pentaenoic acid. In some embodiments, the EPA comprises an eicosapentaenoic acid ester. In some embodiments, the EPA comprises a Ci-₆ alkyl ester of eicosapentaenoic acid. In some embodiments, the EPA comprises eicosapentaenoic acid ethyl ester, eicosapentaenoic acid methyl ester, eicosapentaenoic acid propyl ester, or eicosapentaenoic acid butyl ester. In some embodiments, the EPA comprises all-cis eicosa-5,8,11,14,17-pentaenoic acid ethyl ester. In some embodiments, the unsaturated fatty acid is at least 95%, 97%, 98%, 99%, 99.5%, or 99.9% pure EPA, or a Ci-₆ alkyl ester thereof.

In some embodiments, the unsaturated fatty acid does not include docosahexaenoic acid, or an ester thereof.

The dosage of an unsaturated fatty acid may differ depending on factors such as, but not limited to, the route by which it is to be administered to patients. Dosage amounts of an unsaturated fatty acid, or a pharmaceutically acceptable salt or derivative thereof, include an amount of from about 1 mg to about 5000 mg, from about 5 mg to about 1000 mg, from about 100 mg to about 1000 mg, or from about 100 mg to about 500 mg, or as normally employed in the art.

Dosages and Dosing Regimens

Therapeutically effective treatments and desirable clinical outcomes can occur with reduced dosages and dosing regimens (e.g., reduced quantities of either or both compounds, reduced frequency of administration) of either pantethine, fibrate, or pantethine and fibrate compared to the dosages of either compound as currently administered in the art. Administering a reduced dose, or administering either or both compounds with reduced frequency, can provide benefit to patients, including a reduction in adverse events (e.g., liver toxicity and associated risks, including elevated levels of transaminases) and a reduced dosing regimen or frequency burden on the patient. For example, according to some aspects of the present disclosure, administration of pantethine, fibrate, or of a combination of pantethine and fibrate occurs with reduced frequency, such as less than 4 times daily, less than 3 times daily, less than 2 times daily, or once daily. In other aspects of the present disclosure, administration of pantethine, fibrate, or of a combination of pantethine and fibrate may be once every 2 days (e.g., once every other day), once every 3 days, twice per week, once every 4 days, once every 5 days, once every 6 days, or once every 7 days (e.g., once per week).

Compositions of pantethine and of fibrate can be formulated and administered by controlled, delayed, or sustained release means or by delivery devices that are well known to those of ordinary skill in the art.

In some embodiments of the present disclosure, pantethine is provided as a sustained release formulation for administration to a subject. In some embodiments, fibrate is provided as a sustained release formulation for administration to a subject. Accordingly, in some embodiments of the present disclosure, methods are provided for the treatment of nephropathic cystinosis, primary biliary cirrhosis, various lipid metabolism disorders, and various disorders of the central nervous system as described herein, the method comprising administering a therapeutically effective amount of a combination of pantethine and fibrate, wherein the pantethine is formulated as a sustained or extended release formulation, wherein the fibrate is formulated as a sustained release or extended release formulation, or wherein the pantethine is formulated as a sustained release or extended release formulation and the fibrate is formulated as a sustained release or extended release formulation. In some embodiments, pantethine, fibrate, unsaturated fatty acid, and/or N-acetyl cysteine are formulated to comprise an enteric coating. Pharmaceutical Compositions

The amounts and specific types of active ingredients in a dosage form may differ depending on factors such as, but not limited to, the route by which it is to be administered to patients. Dosage amounts of pantethine, or a pharmaceutically acceptable salt or derivative thereof, include an amount of from about 1 mg to about 200 mg, from about 5 mg to about 100 mg, from about 10 mg to about 75 mg, or from about 20 mg to about 50 mg, or as normally employed in the art or as determined to be effective at reducing intracellular cystine levels when used in combination with a fibrate.

Dosages and desired drug concentration of pharmaceutical compositions of the present disclosure may vary depending on the particular use envisioned. The determination of the appropriate dosage or route of administration is well within the skill of an ordinary artisan. Animal experiments provide reliable guidance for the determination of effective doses for human therapy. Interspecies scaling of effective doses can be performed following the principles described in Mordenti, J. and Chappell, W. “The Use of Interspecies Scaling in Toxicokinetics,” In Toxicokinetics and New Drug Development, Yacobi et ak, Eds, Pergamon Press, New York 1989, pp.42-46.

Dosages for pantethine and fibrate may be determined empirically in individuals who have been given one or more administrations of a combination of pantethine and fibrate. In some instances, individuals are given incremental doses of pantethine and fibrate. To assess efficacy of a combination of pantethine and fibrate, a clinical symptom of the diseases, disorders, or conditions of the present disclosure can be monitored.

Administration of a combination of pantethine and fibrate according to the present disclosure can be continuous or intermittent, depending, for example, on the recipient’s physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to skilled practitioners. The administration of a combination of pantethine and fibrate may be essentially continuous over a preselected period of time or may be in a series of spaced doses.

Pantethine or fibrate compositions can be incorporated into a variety of formulations for therapeutic administration by combining each compound with appropriate pharmaceutically acceptable carriers or diluents, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms. Examples of such formulations include, without limitation, tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Pharmaceutical compositions can include, depending on the formulation desired, pharmaceutically-acceptable, non-toxic carriers of diluents, which are vehicles commonly used to formulate pharmaceutical compositions for animal or human administration. The diluent is selected so as not to affect the biological activity of the combination. Examples of such diluents include, without limitation, distilled water, buffered water, physiological saline, PBS, Ringer’s solution, dextrose solution, and Hank’s solution. A pharmaceutical composition or formulation of the present disclosure can further include other carriers, adjuvants, or non-toxic, nontherapeutic, nonimmunogenic stabilizers, excipients and the like. The compositions can also include additional substances to approximate physiological conditions, such as pH adjusting and buffering agents, toxicity adjusting agents, wetting agents and detergents.

Further examples of formulations that are suitable for various types of administration can be found in Remington’s Pharmaceutical Sciences, Mace Publishing Company, Philadelphia,

PA, 22nd ed. (2012).

For oral administration, the active ingredient can be administered in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. The active component(s) can be encapsulated in gelatin capsules together with inactive ingredients and powdered carriers, such as glucose, lactose, sucrose, mannitol, starch, cellulose or cellulose derivatives, magnesium stearate, stearic acid, sodium saccharin, talcum, magnesium carbonate. Examples of additional inactive ingredients that may be added to provide desirable color, taste, stability, buffering capacity, dispersion or other known desirable features are red iron oxide, silica gel, sodium lauryl sulfate, titanium dioxide, and edible white ink. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric-coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.

The components used to formulate the pharmaceutical compositions are preferably of high purity and are substantially free of potentially harmful contaminants (e.g., at least National Food (NF) grade, generally at least analytical grade, and more typically at least pharmaceutical grade). Moreover, compositions intended for in vivo use are usually sterile. To the extent that a given compound must be synthesized prior to use, the resulting product is typically substantially free of any potentially toxic agents, particularly any endotoxins, which may be present during the synthesis or purification process. Compositions for parental administration are also sterile, substantially isotonic and made under GMP conditions.

Pharmaceutical compositions for use in the methods of the present disclosure containing pantethine or a fibrate may be administered to an individual in need of treatment with a combination of pantethine and a fibrate, preferably a human, in accord with known methods, such as intravenous administration as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerobrospinal, intracranial, intraspinal, subcutaneous, intra- articular, intrasynovial, intrathecal, oral, topical, or inhalation routes.

It is within the scope of the present disclosure that different formulations will be effective for different treatments and different disorders, and that administration intended to treat a specific organ or tissue may necessitate delivery in a manner different from that to another organ or tissue. Moreover, dosages may be administered by one or more separate administrations, or by continuous infusion. For repeated administrations over several days or longer, depending on the condition, the treatment is sustained until a desired suppression of disease symptoms occurs. However, other dosage regimens may be useful. The progress of this therapy is easily monitored by conventional techniques and assays.

EXAMPLES

Example 1: Combination of pantethine and fibrate to treat a lipid metabolism disorder

To examine the efficacy of treating a lipid metabolism disorder by administering a combination of pantethine and fibrate, the following studies are performed. Rabbits are fed a high lipid diet in order to achieve a high serum lipid profile. The rabbits are then administered various amounts of pantethine alone, a fibrate alone, a combination of pantethine and a fibrate, a combination of pantethine and an unsaturated fatty acid, for example, a fish oil or an omega 3 fatty acid, or a combination of pantethine, a fibrate and an unsaturated fatty acid with a suitable dosing regimen. An appropriate fibrate for use in these studies is clofibrate.

Pharmacokinetic (PK) studies are performed. One objective of performing pharmacokinetic studies is to determine dose/exposure relationship for pantethine and fibrate when administered alone and in combination. For such PK studies, serum and plasma concentrations of pantethine, fibrate, cysteamine, and vitamin Bs are measured in animals administered various amounts of pantethine alone, a fibrate alone, or a combination of pantethine and a fibrate. Additionally, changes in the expression or activity of vanin-1 is determined.

Pharmacodynamic (PD) studies are also performed. For pharmacodynamic studies, changes in serum and plasma levels of low-density lipoprotein (LDL), high-density lipoprotein, and triglycerides (TG) are measured following administration of various amounts of pantethine alone, a fibrate alone, a combination of pantethine and a fibrate, a combination of pantethine and an unsaturated fatty acid, for example, a fish oil or an omega 3 fatty acid, or a combination of pantethine, a fibrate and an unsaturated fatty acid.

Additional experiments are performed to measure the efficacy of treatment of administering an optimized dose of pantethine alone, an optimized dose of clofibrate alone, an optimized dose of pantethine plus optimized dose of clofibrate, an optimized dose of pantethine plus sub-optimal dose(s) of clofibrate, and an optimized dose of pantethine plus an unsaturated fatty acid, for example, a fish oil or an omega 3 fatty acid.

Claims

CLAIMS What is claimed is:

1. A method for treating a hepatic disorder, a lipid metabolism disorder, or a disorder of the central nervous system in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination of pantethine and a PPARoc agonist or activator.

2. The method of claim 1, wherein the PPARoc agonist or activator is a fibrate.

3. The method of claim 2, wherein the fibrate is selected from group consisting of aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, clofibride, fenofibrate, gemfibrozil, ronifibrate, and simfibrate, or a pharmaceutically acceptable salt, collate, clathrate, polymorph, prodrug, or pharmaceutically active metabolite thereof.

4. The method of claim 1, claim 2, or claim 3, wherein the hepatic disorder is selected from the group consisting of nephropathic cystinosis and primary biliary cirrhosis.

5. The method of claim 1, claim 2, or claim 3, wherein the lipid metabolism disorder is selected from the group consisting of hyperlipidemia, dyslipidemia, triglyceridemia, familial chylomicronemia syndrome (FCS), familial partial lipodystrophy (FPL), cardiovascular disease caused by hyperlipoproteinemia, cardiovascular disease caused by high triglycerides, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), and other hepatotoxicity disorders, such as acute liver failure associated with acetaminophen therapy.

6. The method of claim 1, claim 2, or claim 3, wherein the disorder of the central nervous system is selected from the group consisting of Huntington’s disease, Alzheimer’s disease, and pantothenate kinase-associated neurodegeneration.

7. A method for treating a hepatic disorder, a lipid metabolism disorder, or a disorder of the central nervous system in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination of pantethine and a vanin agonist or activator.

8. The method of claim 7, wherein the vanin agonist or activator is a fibrate.

9. The method of claim 8, wherein the fibrate is selected from group consisting of aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, clofibride, fenofibrate, gemfibrozil, ronifibrate, and simfibrate, or a pharmaceutically acceptable salt, collate, clathrate, polymorph, prodrug, or pharmaceutically active metabolite thereof.

10. The method of claim 7, claim 8, or claim 9, wherein the hepatic disorder is selected from the group consisting of nephropathic cystinosis and primary biliary cirrhosis.

11. The method of claim 7, claim 8, or claim 9, wherein the lipid metabolism disorder is selected from the group consisting of hyperlipidemia, dyslipidemia, triglyceridemia, familial chylomicronemia syndrome (FCS), familial partial lipodystrophy (FPL), cardiovascular disease caused by hyperlipoproteinemia, cardiovascular disease caused by high triglycerides, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), and other hepatotoxicity disorders, such as acute liver failure associated with acetaminophen therapy.

12. The method of claim 7, claim 8, or claim 9, wherein the disorder of the central nervous system is selected from the group consisting of Huntington’s disease, Alzheimer’s disease, and pantothenate kinase-associated neurodegeneration.

13. A method for treating asthma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination of pantethine and a PPARoc agonist or activator.

14. The method of claim 13, wherein the subject is a poor responder to steroid therapy, has shown a poor steroid treatment response, or is steroid-insensitive.

15. The method of claim 13 or claim 14, wherein the PPARoc agonist or activator is a fibrate.

16. The method of claim 15, wherein the fibrate is selected from group consisting of aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, clofibride, fenofibrate, gemfibrozil, ronifibrate, and simfibrate, or a pharmaceutically acceptable salt, collate, clathrate, polymorph, prodrug, or pharmaceutically active metabolite thereof.

17. A method for treating asthma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination of pantethine and a vanin agonist or activator.

18. The method of claim 17, wherein the subject is a poor responder to steroid therapy, has shown a poor steroid treatment response, or is steroid-insensitive.

19. The method of claim 17 or claim 18, wherein the vanin agonist or activator is a fibrate.

20. The method of claim 19, wherein the fibrate is selected from group consisting of aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, clofibride, fenofibrate, gemfibrozil, ronifibrate, and simfibrate, or a pharmaceutically acceptable salt, collate, clathrate, polymorph, prodrug, or pharmaceutically active metabolite thereof.

21. A method for treating hypertension in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination of pantethine and a PPARoc agonist or activator.

22. The method of claim 21, wherein the subject has been identified has having the SNP rs2272996 or has been identified as having aN131S mutation in the vanin-1 gene.

23. The method of claim 21 or claim 22, wherein the PPARoc agonist or activator is a fibrate.

24. The method of claim 23, wherein the fibrate is selected from group consisting of aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, clofibride, fenofibrate, gemfibrozil, ronifibrate, and simfibrate, or a pharmaceutically acceptable salt, collate, clathrate, polymorph, prodrug, or pharmaceutically active metabolite thereof.

25. A method for treating hypertension in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination of pantethine and a vanin agonist or activator.

26. The method of claim 25, wherein the subject has been identified has having the SNP rs2272996 or has been identified as having aN131S mutation in the vanin-1 gene.

27. The method of claim 25 or claim 26, wherein the vanin agonist or activator is a fibrate.

28. The method of claim 27, wherein the fibrate is selected from group consisting of aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, clofibride, fenofibrate, gemfibrozil, ronifibrate, and simfibrate, or a pharmaceutically acceptable salt, collate, clathrate, polymorph, prodrug, or pharmaceutically active metabolite thereof.