WO2018208707A1 - Methods and compositions for treating demyelinating diseases - Google Patents

Abstract

Disclosed are methods for treating a subject having or at risk of developing a disease or condition associated with demyelination, insufficient myelination, or underdevelopment of myelin sheath, by administering an effective amount of a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) and an effective amount of a thyroid hormone to the subject. Also disclosed are pharmaceutical compositions in unit dosage form containing an effective amount of a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug), an effective amount of a thyroid hormone, and a pharmaceutically acceptable excipient.

Description

METHODS AND COMPOSITIONS FOR TREATING DEMYELINATING DISEASES

Related Applications

This application claims the benefit of U.S. Provisional Application No. 62/503,057, filed on May 8, 2017. The entire teachings of the above applications are incorporated herein by reference.

Field of the Invention

The invention relates to methods and compositions for treating demyelinating diseases. Background

Demyelinating diseases are diseases in which myelin, the lipid substance that forms an insulating sheath around many nerve fibers, is damaged, lost, or exhibits impaired growth or development. As myelination is critical for the rapid conduction of nerve impulses throughout the nervous system, demyelination causes a breakdown in conduction and results in various functional impairments. Subjects suffering from demyelinating diseases may experience muscle weakness, loss of sensation, impaired vision, impaired cognition, ataxia, and paralysis, among other symptoms. Current standards for treating certain demyelinating diseases primarily affect the rate of disease progression. There is a need for new treatments for demyelinating diseases (e.g., for promoting myelination or demyelination).

Summary of the Invention

In general, the invention provides methods of administering a TR beta selective thyromimetic and compositions therefor.

In one aspect, the invention provides a method of administering a TR beta selective thyromimetic to a subject (e.g., a subject having a demyelinating disease) by administering an effective amount of a TR beta selective thyromimetic and an effective amount of a thyroid hormone, where administering the thyroid hormone maintains thyroid function, as measured by T4 serum levels.

In one aspect, the invention provides a method of treating a subject having or at risk of developing X-linked adrenoleukodystrophy by administering to the subject an effective amount of a TR beta selective thyromimetic and an effective amount of a thyroid hormone.

In a related aspect, the invention provides a method of treating a subject having or at risk of developing a disease or condition associated with demyelination, insufficient myelination, or underdevelopment of myelin sheath, by administering to the subject an effective amount of TR beta selective thyromimetic and an effective amount of a thyroid hormone.

In some embodiments, the disease or condition is multiple sclerosis, a leukodystrophy, a leukoencephalopathy, an idiopathic inflammatory demyelinating disease, or Alzheimer's disease. In certain embodiments, the multiple sclerosis is relapsing-remitting multiple sclerosis, primary- progressive multiple sclerosis, secondary-progressive multiple sclerosis, or progressive-relapsing multiple sclerosis. In particular embodiments, the disease or condition is central pontine myelolysis, acute disseminated encephalomyelitis, Balo concentric sclerosis, Marburg multiple sclerosis, tumefactive multiple sclerosis, diffuse myelinoclastic sclerosis, acute hemorrhagic leukoencephalitis, neuromyelitis optica, a chronic inflammatory demyelinating polyneuropathy, Leber hereditary optic neuropathy, multifocal motor neuropathy, paraproteinemic demyelinating polyneuropathy, tropical spastic paraparesis, a Guillain-Barre syndrome, infantile Refsum disease, adult Refsum disease 1 , adult Refsum disease 2, Zellweger syndrome, X-linked adrenoleukodystrophy (X-ALD),

metachromatic leukodystrophy, Krabbe disease, Pelizaeus-Merzbacher disease, Canavan disease, Alexander disease, peroneal muscular atrophy, cerebrotendineous xanthomatosis, Binswanger's disease, leukoencephalopathy with vanishing white matter, toxic leukoencephalopathy, van der Knaap disease, progressive multifocal leukoencephalopathy, Marchiafava-Bignami disease or transverse myelitis.

In other embodiments, the Guillain-Barre syndrome is acute inflammatory demyelinating polyneuropathy. In yet other embodiments, the chronic inflammatory demyelinating polyneuropathy is multifocal acquired demyelinating sensory and motor neuropathy. In still other embodiments, the chronic inflammatory demyelinating polyneuropathy is induced by H IV infection.

In particular embodiments, the X-linked adrenoleukodystrophy is adrenomyeloneuropathy. In further embodiments, the X-linked adrenoleukodystrophy is Addison's disease.

In yet further embodiments, the disease or condition is a chronic axonal neuropathy. In still further embodiments, the disease or condition results from intraventricular hemorrhage, neonatal hypoxia, or acute hypoxemic respiratory failure. In certain embodiments, the disease or condition is cerebral palsy.

In some embodiments, administration of the TR beta selective thyromimetic and the thyroid hormone prevents or mitigates at least one symptom of the disease or condition. In particular embodiments, the symptom is a lack of sphincter control, erectile dysfunction, paraparesis, ataxia, adrenocortical insufficiency, progressive neuropathy, paresthesia, dysarthria, dysphagia, clonus, or any combination thereof. In certain embodiments, administration of the TR beta selective thyromimetic and the thyroid hormone prevents or mitigates damage to central nervous system myelin, peripheral nervous system myelin, adrenal cortex, testicular Leydig cells, or any combination thereof.

In further embodiments, the thyroid hormone is levothyroxine or a pharmaceutically acceptable salt thereof. In yet further embodiments, the thyroid hormone is liothyronine or a pharmaceutically acceptable salt thereof.

In particular embodiments, the TR beta selective thyromimetic is administered orally, parenterally, or topically. In certain embodiments, the TR beta selective thyromimetic is administered orally. In further embodiments, the TR beta selective thyromimetic is administered parenterally. In yet further embodiments, the TR beta selective thyromimetic is administered buccally, sublingually, sublabially, or by inhalation. In still further embodiments, the TR beta selective thyromimetic is administered sublingually. In other embodiments, the TR beta selective thyromimetic is administered intramuscularly, intravenously, or subcutaneously. In yet other embodiments, the TR beta selective thyromimetic is administered intra-arterially, intravenously, intraventricularly, intramuscularly, subcutaneously, intraspinally, intrathecal^, intraorbitally, or intracranially. In still other embodiments, the thyroid hormone is administered orally, parenterally, or topically.

In some embodiments, the thyroid hormone is administered orally. In certain embodiments, the thyroid hormone is administered parenterally. In particular embodiments, the thyroid hormone is administered buccally, sublingually, sublabially, or by inhalation. In certain embodiments, the thyroid hormone is administered sublingually. In further embodiments, the thyroid hormone is administered intramuscularly, intravenously, or subcutaneously. In yet further embodiments, the thyroid hormone is administered intra-arterially, intravenously, intraventricularly, intramuscularly, subcutaneously, intraspinally, intraorbital^, or intracranially.

In certain embodiments, the TR beta selective thyromimetic is administered in combination with the thyroid hormone. In particular embodiments, the TR beta selective thyromimetic is administered prior to the thyroid hormone. In other embodiments, the TR beta selective thyromimetic is administered after the thyroid hormone.

In particular embodiments, administration of the TR beta selective thyromimetic and administration of the thyroid hormone occur within one hour. In further embodiments, administration of the TR beta selective thyromimetic and administration of the thyroid hormone occur within 12 hours. In yet further embodiments, administration of the TR beta selective thyromimetic and administration of the thyroid hormone occur within 24 hours. In still further embodiments, administration of the TR beta selective thyromimetic and administration of the thyroid hormone occur within one week.

In other embodiments, the subject is male. In yet other embodiments, the subject is female.

In further embodiments, the subject is 1 to 50 years old (e.g., 1 to 30 years old, 1 to 20 years old, 3 to 30 years old, 3 to 20 years old, or 3 to 18 years old).

In some embodiments, the TR beta selective thyromimetic is administered daily. In particular embodiments, about 1 μg to about 1 mg of the TR beta selective thyromimetic are administered. In certain embodiments, at least 10 μg (e.g., at least 30 μg, at least 50 μg, at least 70 μg, at least 100 μg, or at least 200 μg) of the TR beta selective thyromimetic are administered. In further embodiments, 500 μg or less (e.g., 400 μg or less, 200 μg or less, 100 μg or less, or 70 μg or less) of the TR beta selective thyromimetic are administered. In yet further embodiments, from about 5 pg to about 500 Mg of the thyroid hormone are administered. In still further embodiments, from about 10 pg to about 400 pg of the thyroid hormone are administered.

In particular embodiments, the TR beta selective thyromimetic is sobetirome. In certain embodiments, the TR beta selective thyromimetic is the sobetirome prodrug.

In another aspect, the invention provides a pharmaceutical composition in unit dosage form containing a TR beta selective thyromimetic, a thyroid hormone, and a pharmaceutically acceptable excipient.

In some embodiments, the unit dosage form is a capsule, tablet, troche, film, solution, depot, powder, lozenge, sachet, cachet, elixir, emulsion, or syrup. In particular embodiments, the pharmaceutical composition contains about 1 Mg to about 1 mg of the TR beta selective thyromimetic. In certain embodiments, the pharmaceutical composition contains at least 10 Mg of the TR beta selective thyromimetic. In further embodiments, the pharmaceutical composition contains at least 30 μg (e.g., at least 50 μg, at least 70 μg, at least 100 μg, or at least 200 μg) of the TR beta selective thyromimetic. In yet further embodiments, the pharmaceutical composition contains 500 μg or less (e.g., 400 μg or less, 200 μg or less, 100 μg or less, or 70 μg or less) of the TR beta selective thyromimetic.

In other embodiments, the TR beta selective thyromimetic is sobetirome. In yet other embodiments, the TR beta selective thyromimetic is the sobetirome prodrug.

In certain embodiments, the pharmaceutical composition contains from about 5 pg to about 500 pg of the thyroid hormone. In particular embodiments, the pharmaceutical composition contains from about 10 pg to about 400 pg of the thyroid hormone. In further embodiments, the thyroid hormone is levothyroxine or a pharmaceutically acceptable salt thereof. In yet further embodiments, the thyroid hormone is liothyronine or a pharmaceutically acceptable salt thereof.

Definitions

"About," as used herein, refers to a quantity that is ± 10% of the indicated value.

"Administration," as used herein, refers to providing or giving a subject a therapeutic agent

(e.g. a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) and/or thyroid hormone) by an effective route. Non-limiting examples of routes of administration are described herein. Therapeutic agents may be administered in combination or sequentially.

"Alkenyl," as used herein, refers to a branched or unbranched, cyclic or acyclic hydrocarbon group containing one or two carbon-carbon double bonds. Alkenyl contains from 2 to 24 carbon atoms. Preferably, alkenyl is lower alkenyl. A lower alkenyl group contains from 2 to 6 carbon atoms (C₂.₆alkenyl). Preferably, alkenyl is acyclic alkenyl (e.g., acyclic lower alkenyl). Alkenyl may be optionally substituted as described herein.

"Alkyl", as used herein, refers to a branched or unbranched, cyclic or acyclic saturated hydrocarbon group containing from 1 to 24 carbon atoms. Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like. Preferably, alkyl is lower alkyl. A lower alkyl group is a saturated branched or unbranched hydrocarbon having from 1 to 6 carbon atoms (Ci_ ₆alkyl). Preferably, alkyl is acyclic alkyl (e.g., acyclic lower alkyl). Alkyl may be optionally substituted as described herein.

"Alkylamino," as used herein, refers to a heteroalkyl containing one, two, or three nitrogen atoms. An alkylamino can be a straight chain, branched or cycloalkylamino. An alkylamino generally has the structure— NX¹X² or— (NX¹X²X³)⁺ in which X¹ , X², and X³ are each independently H, a substituted alkyl, or an unsubstituted alkyl, provided that the group does not have the structure— NH₂ or— NH₃ ⁺ and the total number of non-hydrogen atoms does not exceed 24. Examples of alkylamino groups include the following structures:— NHCH₃,— N(CH₃)₂,— NH(CH₃)₂ ⁺,— N(CH3)₃ ⁺,—

NHCH₂CH₃,— NH₂CH₂CH₃ ⁺,

— N(CH₃)CH₂CH₃,— N(CH₂CH₃)₂, and— NH(CH₃)CH₂CH₃ ⁺. Alkylamino encompasses heteroalkyls containing one or two nitrogen atoms and one or more heteroatoms independently selected from the group consisting of oxygen and sulfur. The term alkylamino also contemplates heterocycloalkyl groups containing one or two nitrogen atoms, for example, a group NX¹X²X³, in which X¹ is H or a valency (e.g. , X¹ is H), and X² and X³, together with the atom to which they are attached, are a 4- to 8- member ring that may contain valency, provided that NX¹X²X³ contains one valency. These include 4-member rings containing one nitrogen (azetidinyl), 5-member rings containing one nitrogen (e.g., pyrrolidinyl), or 6-member ring containing one nitrogen (e.g., piperidinyl). The cyclic alkylamino structures also include ring systems containing two nitrogen atoms, as well as substituted cyclic alkylamino structures, e.g., NX¹X²X³, where X¹ is alkyl, and X² and X³, together with the atom to which they are attached, are a 4- to 8-member ring that contains valency. Alkylamino is further exemplified by 3-azetidinyl that may be substituted or unsubstituted as described herein.

"Alkynyl," as used herein, refers to a branched or unbranched, acyclic hydrocarbon group containing one or two carbon-carbon triple bonds. Alkynyl contains from 2 to 24 carbon atoms.

Preferably, alkynyl is lower alkynyl. A lower alkynyl group contains from 2 to 6 carbon atoms (C₂. ₆alkynyl). Preferably, alkynyl is acyclic alkynyl (e.g., acyclic lower alkynyl). Alkynyl may be optionally substituted as described herein.

"Amide," as used herein, refers to a group with the structure— CONX¹X², where X¹ and X² are independently H or an organic group such as an alkyl or aryl group.

"Amino acid," as used herein, refers to a compound of formula NH(R¹)-CH(R²)-COOH or to a group -NR¹-CH(R²)-COOH, where R¹ is H and R² is optionally substituted alkyl, or R¹ and R², together with the atom to which each is attached, combine to form an optionally substituted heterocyclyl. In some embodiments, amino acid is a proteinogenic amino acid. Proteinogenic amino acids are known in the art. For example, proteinogenic amino acids are alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, selenocysteine, and pyrrolysine. An ester of an amino acid is a compound of formula NH(R¹)-CH(R²)-COOR³ or to a group -NR¹-CH(R²)-COOR³, where each or R¹ and R² are as defined above, and R³ is optionally substituted alkyl.

"Aryl," as used herein, refers to an aromatic carbocyclic or heterocyclic group having at least five atoms in a cyclic array. A carbocylic aryl can be a single 6- to 10-member ring (monocyclic) or a group of 2 or 3 fused rings (polycyclic), each ring independently being a 6- to 10-member ring. A heterocyclic aryl is called "heteroaryl." Heteroaryl is a single 5- or 6-member ring (monocyclic) or a group of 2 or 3 fused rings (polycyclic), each ring independently being a 5- to 8-member ring, at least one of the rings containing at least one heteroatom that is oxygen, nitrogen, sulfur, or phosphorus. The ring(s) of heteroaryl contain at least one (e.g., from 1 to 4) heteroatom that is oxygen, nitrogen, sulfur, or phosphorus. Non-limiting examples of carbocyclic aryls include naphthalenyl and phenyl. Aryl may be unsubstituted or substituted as described herein.

"Cycloalkenyl," as used herein, refers to a non-aromatic carbocyclic group having at least five atoms in a cyclic array and one or two endocyclic carbon-carbon double bonds. The cyclic array may be a 5- to 8-member ring (C5-C8 cycloalkenyl). Non-limiting examples of cycloalkyl groups include cyclopentenyl and cyclohexenyl.

"Cycloalkyl," as used herein, refers to a non-aromatic carbocyclic or heterocyclic group having at least three atoms in a cyclic array. The cyclic array may be a 3- to 8-member ring. Non- limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Heterocyclic cycloalkyl is called herein "heterocycloalkyl." A heterocycloalkyl containing at least one endocyclic nitrogen is also termed a cycloalkylamino herein.

"Effective amount" is a quantity of a therapeutic agent (e.g., a TR beta selective thyromimetic

(e.g., sobetirome or a sobetirome prodrug) or a thyroid hormone) sufficient to achieve a desired effect in a subject, or in a cell, being treated with the therapeutic agent. The effective amount of the therapeutic agent depends on several factors, including, but not limited to the subject or cells being treated, and the manner of administration of the therapeutic composition. In some embodiments, an "effective amount" of a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) or a thyroid hormone, is the amount sufficient to promote myelination in a subject. In other embodiments, a "effective amount" of a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) or a thyroid hormone, is the amount sufficient to reduce or inhibit demyelination in a subject.

"Ester," as used herein, refers to a group with the structure— COOX where X is a substituent described herein. For example an ethyl ester has the structure— COOCH₂CH₃.

"Halogen" or "halide," as used interchangeably herein, refer to F, CI, Br, or I.

"Heteroalkyl," as used herein, refers to (i) an acyclic alkyl, in which one, two, three, or four carbon atoms are replaced with heteroatom(s), each heteroatom independently selected from oxygen, nitrogen, sulfur, and phosphorus, or (ii) heterocycloalkyl. Heteroalkyl may be unsubstituted or substituted as described herein.

"Heterocyclyl," as used herein, refers to an aromatic or non-aromatic cyclic group having at least three atoms in a cyclic array, at least one of the atoms (e.g., from 1 to 4) within the cyclic array being a heteroatom that is oxygen, nitrogen, sulfur, or phosphorus. The cyclic array may be a single 3- to 8-member ring (monocyclic) or a group of 2 or 3 fused rings (polycyclic), each ring independently being a 3- to 8-member ring. An aromatic heterocyclyl group is called "heteroaryl." Heteroaryl is a single 5- or 6-member ring (monocyclic) or a group of 2 or 3 fused rings (polycyclic), each ring independently being a 5- to 8-member ring, at least one of the rings containing at least one heteroatom that is oxygen, nitrogen, sulfur, or phosphorus. The ring(s) of heteroaryl contain at least one (e.g., from 1 to 4) heteroatom that is oxygen, nitrogen, sulfur, or phosphorus. Non-aromatic heterocyclyl group is called "heterocycloalkyl." Non-limiting examples of heterocyclyls include azepinyl, aziridinyl, azetyl, azetidinyl, diazepinyl, dithiadiazinyl, dioxazepinyl, dioxolanyl, dithiazolyl, furanyl, isooxazolyl, isothiazolyl, imidazolyl, morpholinyl, oxetanyl, oxadiazolyl, oxiranyl, oxazinyl, oxazolyl, piperazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperidinyl, pyridyl, pyranyl, pyrazolyl, pyrrolyl, pyrrolidinyl, thiatriazolyl, tetrazolyl, thiadiazolyl, triazolyl, thiazolyl, thienyl, tetrazinyl, thiadiazinyl, triazinyl, thiazinyl, thiopyranyl, furoisoxazolyl, imidazothiazolyl, thienoisothiazolyl, thienothiazolyl, imidazopyrazolyl, cyclopentapyrazolyl, pyrrolopyrrolyl, thienothienyl, thiadiazolopyrimidinyl, thiazolothiazinyl, thiazolopyrimidinyl, thiazolopyridinyl, oxazolopyrimidinyl, oxazolopyridyl, benzoxazolyl, benzisothiazolyl, benzothiazolyl, imidazopyrazinyl, purinyl, pyrazolopyrimidinyl, imidazopyridinyl, benzimidazolyl, indazolyl, benzoxathiolyl, benzodioxolyl, benzodithiolyl, indolizinyl, indolinyl, isoindolinyl, furopyrimidinyl, furopyridyl, benzofuranyl, isobenzofuranyl, thienopyrimidinyl, thienopyridyl, benzothienyl, cyclopentaoxazinyl, cyclopentafuranyl, benzoxazinyl, benzothiazinyl, quinazolinyl, naphthyridinyl, quinolinyl, isoquinolinyl, benzopyranyl, pyridopyridazinyl, and pyridopyrimidinyl groups. Heterocyclyl may be unsubstituted or substituted as described herein.

"Maintains thyroid function," as used herein, refers to maintenance of T4 serum levels within 50% of the T4 serum levels prior to first administration of a TR beta selective thyromimetic.

A "pharmaceutically acceptable salt" refers to a salt of a therapeutic agent (e.g., a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) or a thyroid hormone) which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1 -19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free carboxylic acid group with a suitable base. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, primary ammonium, secondary ammonium, tertiary ammonium, or quaternary ammonium cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium,

methylammonium, dimethylammonium, trimethylammonium, triethylammonium, ethylammonium, and the like.

A "pharmaceutically acceptable excipient" is any ingredient other than a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) or a thyroid hormone. For example, a pharmaceutically acceptable excipient may be a vehicle capable of suspending or dissolving the active compound and having the properties of being substantially nontoxic and non-inflammatory in a subject. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, or waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl

methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone,

pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. The pharmaceutically acceptable excipients or carriers useful for each specific mode of administration are described herein below.

Preventing or treating a disease: "Preventing" refers to a prophylactic treatment or treatment that prevents one or more symptoms or conditions of a disease, disorder, or conditions described herein. Preventive treatment that includes administration of a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) and a thyroid hormone can be chronic. The doses administered may be varied during the course of preventative treatment. "Treating," as used herein in reference to a disease or condition, refers to an approach for obtaining beneficial or desired results, e.g., clinical results. Beneficial or desired results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; diminishment of extent of disease or condition; stabilized (i.e., not worsening) state of disease, disorder, or condition; preventing spread of disease or condition; delay or slowing the progress of the disease or condition; amelioration or palliation of the disease or condition; and remission (whether partial or total), whether detectable or undetectable. "Ameliorating" or "palliating" a disease or condition means that the extent and/or undesirable clinical manifestations of the disease, disorder, or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment.

"Sobetirome," as used herein, refers to a compound of formula:

or a pharmaceutically acceptable salt thereof.

"Sobetirome prodrug," as used herein, refers a sobetirome ester prodrug or sobetirome amide prodrug.

"Sobetirome ester prodr " is a compound of formula:

or a pharmaceutically acceptable salt thereof,

where

R¹ is unsubstituted alkyl, substituted alkyl, unsubstituted heteroalkyl, substituted heteroalkyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. In further embodiments, R¹ is alkyl or aryl. In yet further embodiments, R¹ can be ethyl, 2- trimethylaminoethyl, (N-morpholinyl)ethyl, 2-(lysinoyl)aminoethyl, 2-(valinoyl)aminoethyl, 2- (phenylalaninoyl)aminoethyl, or glucosyl. In still further embodiments, R¹ can be alkylamino, such as substituted alkylamino, cycloalkylamino or substituted cycloalkylamino. In additional examples, R¹ can be ethylamino, ethyl(N,N,N)-trimethylamino, ethylmorpholinyl, ethyl(N,N)-dimethylamino, 3-(N- methyl)azetidinyl, 4-pyrrolidinyl, 3-pyrrolidinyl, 2,2-dimethylethylamino, 3-(3-trifluoromethyl)azetidinyl, 2-pyrrolidinyl, 2-methylethylamino, 2-trifluoromethylamino, and N-methylethylamino. In some embodiments, R¹ is:

"Sobetirome amide prodrug" is a compound of formula:

or a pharmaceutically acceptable salt thereof,

where

R² is optionally substituted alkyl or optionally substituted aryl. In some embodiments, R² is together with NH, to which it is attached, forms an amino acid or an ester thereof, where the NH group is α-amino group of the amino acid. In particular embodiments, R² is:

"Subject," as used herein, refers to an animal (e.g., a mammal, such as a human). A subject to be treated according to the methods described herein may be one who has been diagnosed with a neurodegenerative disease involving demyelination, insufficient myelination, or under-development of a myelin sheath, or one at risk of developing the condition. Diagnosis may be performed by any method or technique known in the art. One skilled in the art will understand that a subject to be treated according to the present disclosure may have been subjected to standard tests or may have been identified, without examination, as one at risk due to the presence of one or more risk factors associated with the disease or condition.

"Thyroid hormone," as used herein, refers to a compound that activates thyroid receptor alpha or is converted in vivo to a compound that activates thyroid receptor alpha. Non-limiting examples of thyroid hormones are levothyroxine, liothyorinene, 3,5-diidothyropropionic acid (DITPA), and esters thereof and polymeric forms thereof. Further examples of thyroid hormones are described in WO 2006/031922.

"TR beta selective thyromimetic," as used herein, refers to an agonist or an agonist prodrug of thyroid hormone receptor β with a K_D value that is at least twice smaller than the K_D value for the same compound and thyroid hormone receptor a. Non-limiting examples of the TR beta selective thyromimetics are sobetirome and sobetirome prodrugs.

Where a group is substituted, the group may be substituted with 1 , 2, 3, 4, 5, or 6 substituents, if valency permits. Each optional substituents is independently: C1 -C6 alkyl; C2-C6 alkenyl; C2-C6 alkynyl; C3-C8 cycloalkyl; C5-C8 cycloalkenyl; three- to eight-membered heterocyclyl; C6-C10 aryl; five- to six-membered heteroaryl; halogen; azido(-N₃); nitro (-N0₂); cyano (-CN); acyloxy (-OC(=0)R') ; acyl (-C(=0)R'); alkoxy (-OR'); amido; amino (-NRR'); carboxylic acid (-C0₂H), carboxylic ester (-C0₂R'); carbamoyl (-OC(=0)NR'R" or -NRC(=0)OR'); hydroxy (-OH); oxo (=0); isocyano (-NC) ; sulfonate (-S(=0)₂OR); sulfonamide (-S(=0)₂NRR' or -NRS(=0)₂R'); or sulfonyl (-S(=0)₂R), where each R, R', and R" is selected, independently, from H or an optionally substituted group that is C1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, three- to eight-membered heterocyclyl, C6-C10 aryl, or five- to ten-membered heteroaryl. A substituted group may have, valency permitting, for example, 1 , 2, 3, 4, 5, 6, 7, 8, or 9 substituents. In some embodiments, each hydrogen in a group may be replaced by a substituent group (e.g., perhaloalkyl groups such as -CF₃ or -CF₂CF₃ or perhaloaryls such as -C₆F₅). A substituent may itself be further substituted, valency permitting, with unsubstituted substituents defined herein. For example, a substituent may be substituted with 1 , 2, 3, 4, 5, or 6 unsubstituted substituents as defined herein. For example, a lower C1 -C6 alkyl or an aryl substituent group (e.g., heteroaryl, phenyl, or naphthyl) may be further substituted with 1 , 2, 3, 4, 5, or 6 substituents as described herein, if valency permits.

Brief Description of the Drawings

FIG. 1 is a dose-response curve showing cholesterol and TSH serum levels in response to the sobetirome (GC-1 ) regimen of 62 μg/kg/day or liothyronine (T3) regimen of 6 μg/kg/day. The data are normalized to the cholesterol and TSH serum levels in rats administered vehicle alone.

Detailed Description

The invention provides methods of administering a TR beta selective thyromimetic. The inventors have observed that a TR beta selective thyromimetic-based therapy can induce a hypothyroid condition in subjects. The therapy-induced hypothyroid condition may be more pronounced in children, adolescents, and/or young adults (e.g., subjects that are 1 to 30 years old, 1 to 20 years old, 3 to 30 years old, 3 to 20 years old, or 3 to 18 years old). The hypothyroid condition (hypothyroidism) typically can produce one or more of the following symptoms: fatigue, weakness, weight gain or increased difficulty losing weight, hair loss, cold intolerance, muscle cramps, muscle aches, constipation, depression, irritability, memory loss, decreased libido, and changes in the menstrual cycle. Since treating demyelinating diseases is contemplated and can involve chronic administration of a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug), management of the hypothyroid condition is important for reducing morbidity associated with treating a demyelinating disease. Thus, the invention provides methods of treating a demyelinating disease in a subject by administering a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) and a thyroid hormone. The methods of the invention can be used for treating a demyelinating disease, while ameliorating the hypothyroid condition associated with chronic administration of a TR beta selective thyromimetic (e.g., sobetirome or the sobetirome prodrug).

Sobetirome

Sobetirome is a compound of formula:

or a pharmaceutically acceptable salt thereof.

Also disclosed are pharmaceutical compositions that include an effective amount of sobetirome and optionally one or more thyroid hormones described herein (e.g., levothyroxine or liothyronine or a pharmaceutically acceptable salt thereof).

In some embodiments, sobetirome is administered at a dose of about 1 μg to about 500 μg. In certain embodiments, sobetirome is administered at a dose of about 1 0 μg to about 1 00 μg.

In particular embodiments, the compound is administered to the subject once daily, twice daily, three times daily, once every two days, once weekly, twice weekly, three times weekly, once biweekly, once monthly, or once bimonthly. In some embodiments, sobetirome is administered daily (e.g., once daily or twice daily). In certain embodiments, sobetirome is administered to the subject once daily. In other embodiments, the effective amount is at least 30 pg (e.g., at least 50 pg, such as at least 1 00 pg). In some embodiments, the effective amount is at least 30 pg (e.g., at least 50 pg, such as at least 100 pg) daily. In certain embodiments, the effective amount is at least 30 pg (e.g., at least 50 pg, such as at least 1 00 pg) twice daily. In particular embodiments, the effective amount is at least 30 pg (e.g., at least 50 pg, such as at least 1 00 pg) once weekly. In other embodiments, the effective amount is at least 30 pg (e.g., at least 50 pg, such as at least 1 00 pg) twice weekly. In certain embodiments, the effective amount is at least 30 pg (e.g., at least 50 pg, such as at least 1 00 Mg) three times weekly. In some embodiments, the effective amount is 1 mg or less (e.g., 500 pg or less, e.g., 200 pg or less).

In some embodiments, a unit dosage form containing from 10 pg to 100 pg of sobetirome is administered once, twice, or three times per day. In some embodiments, a unit dosage form containing from 10 pg to 75 pg of sobetirome is administered once, twice, or three times per day. In other embodiments, a unit dosage form containing from 30 pg to 75 pg of sobetirome is administered once, twice, or three times per day. In particular embodiments, a unit dosage form containing from 10 Mg to 50 pg of sobetirome is administered once, twice, or three times per day. In yet other embodiments, a unit dosage form containing from 30 pg to 50 pg of sobetirome is administered once, twice, or three times per day. In still other embodiments, a unit dosage form containing from 50 pg to 75 pg of sobetirome is administered once, twice, or three times per day.

Sobetirome Prodrugs

Sobetirome prodrugs that may be used in the methods of the invention are sobetirome ester prodrugs or sobetirome amide prodrugs. The sobetirome ester prodrug is a compound of formula:

or a pharmaceutically acceptable salt thereof,

where

R¹ is unsubstituted alkyl, substituted alkyl, unsubstituted heteroalkyl, substituted heteroalkyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. In further embodiments, R¹ is alkyl or aryl. In yet further embodiments, R¹ can be ethyl, 2- trimethylaminoethyl, (N-morpholinyl)ethyl, 2-(lysinoyl)aminoethyl, 2-(valinoyl)aminoethyl, 2- (phenylalaninoyl)aminoethyl, or glucosyl. In still further embodiments, R¹ can be alkylamino, such as substituted alkylamino, cycloalkylamino or substituted cycloalkylamino. In additional examples, R¹ can be ethylamino, ethyl(N,N,N)-trimethylamino, ethylmorpholinyl, ethyl(N,N)-dimethylamino, 3-(N- methyl)azetidinyl, 4-pyrrolidinyl, 3-pyrrolidinyl, 2,2-dimethylethylamino, 3-(3-trifluoromethyl)azetidinyl, 2-pyrrolidinyl, 2-methylethylamino, 2-trifluoromethylamino, and N-methylethylamino.

In some embodiments, R¹ is:

In some instances, the sobetirome prodrug is of the following formula:

or a pharmaceutically acceptable salt thereof,

where R² is amino or alkylamino.

Examples of compounds of this structure include pharmaceutically acceptable salts (e.g. halide salts) of:

Another particular example is a compound of the following structure:

or a pharmaceutically acceptable salt thereof.

A sobetirome amide prodrug is a compound of formula:

or a pharmaceutically acceptable salt thereof,

where R² is optionally substituted alkyl or optionally substituted aryl. In some embodiments, R² is together with NH, to which it is attached, forms an amino acid or an ester thereof, where the NH group is α-amino group of the amino acid. In particular embodiments, R² is:

Sobetirome prodrugs can be prepared using methods known in the art. Non-limiting examples of sobetirome ester prodrugs and methods of their preparation are disclosed in US 2016/0244418. Sobetirome amide prodrugs may be prepared by subjecting sobetirome or an O- protected version thereof to amidation reaction with an amine source. Typical amidation conditions include the use of reagents, such as EDC/DMAP, HATU/HOAt, or HBTU/HOAt. Alternatively, amidation conditions may involve Staudinger ligation (see, e.g., Kosal et al., Chem. Eur. J., 18:14444- 14453, 2012; and Kosal et al., Angew. Chem. Int. Ed., 51 , 12036-12040, 2012).

Also disclosed are pharmaceutical compositions that include an effective amount of a sobetirome prodrug and optionally one or more thyroid hormones described herein (e.g., levothyroxine or liothyronine or a pharmaceutically acceptable salt thereof).

In some embodiments, a sobetirome prodrug is administered at a dose of about 1 μg to about 500 μg. In certain embodiments, a sobetirome prodrug is administered at a dose of about 10 μg to about 100 μg.

In particular embodiments, the sobetirome prodrug is administered to the subject once daily, twice daily, three times daily, once every two days, once weekly, twice weekly, three times weekly, once biweekly, once monthly, or once bimonthly. In some embodiments, a sobetirome prodrug is administered daily (e.g., once daily or twice daily). In certain embodiments, a sobetirome prodrug is administered to the subject once daily. In other embodiments, the effective amount is at least 30 pg (e.g., at least 50 pg, e.g. , at least 100 pg). In some embodiments, the effective amount is at least 30 Mg (e.g., at least 50 pg, e.g., at least 100 pg) daily. In certain embodiments, the effective amount is at least 30 pg (e.g., at least 50 pg, e.g., at least 100 pg) twice daily. In particular embodiments, the effective amount is at least 30 pg (e.g., at least 50 pg, e.g., at least 100 pg) once weekly. In other embodiments, the effective amount is at least 30 pg (e.g., at least 50 pg, e.g., at least 100 pg) twice weekly. In certain embodiments, the effective amount is at least 30 pg (e.g., at least 50 pg, e.g., at least 100 pg) three times weekly. In some embodiments, the effective amount is 1 mg or less (e.g., 500 Mg or less, e.g., 200 pg or less).

In some embodiments, a unit dosage form containing from 10 pg to 100 pg of a sobetirome prodrug is administered once, twice, or three times per day. In some embodiments, a unit dosage form containing from 10 pg to 75 pg of a sobetirome prodrug is administered once, twice, or three times per day. In other embodiments, a unit dosage form containing from 30 pg to 75 pg of a sobetirome prodrug is administered once, twice, or three times per day. In particular embodiments, a unit dosage form containing from 10 pg to 50 pg of a sobetirome prodrug is administered once, twice, or three times per day. In yet other embodiments, a unit dosage form containing from 30 pg to 50 pg of a sobetirome prodrug is administered once, twice, or three times per day. In still other embodiments, a unit dosage form containing from 50 pg to 75 pg of a sobetirome prodrug is administered once, twice, or three times per day.

Thyroid Hormones

Thyroid hormones useful for treating (e.g., palliating) hypothyroid conditions are known in the art. Non-limiting examples of the thyroid hormones are levothyroxine, liothyronine, and

pharmaceutically acceptable salts thereof. The thyroid hormones may be used in the methods and compositions of the invention to ameliorate a hypothyroid condition associated with chronic administration of a TR beta selective thyromimetic (e.g., sobetirome or the sobetirome prodrug).

In some embodiments, a thyroid hormone (e.g., levothyroxine or liothyronine or a pharmaceutically acceptable salt thereof) is administered at a dose of from about 5 pg to about 500 Mg (e.g., from about 10 pg to about 400 pg, from about 20 pg to about 200 pg, or from about 20 pg to about 150 pg) per day. In certain embodiments, a thyroid hormone (e.g., levothyroxine or liothyronine or a pharmaceutically acceptable salt thereof) is administered at a dose of from about 0.5 pg/kg/day to about 17.0 pg/kg/day (e.g., from about 1.0 pg/kg/day to about 15.0 pg/kg/day, from about 1.0 Mg/kg/day to about 10.0 pg/kg/day, or from about 1.0 pg/kg/day to about 6.0 pg/kg/day).

In some embodiments, a thyroid hormone is administered daily. In particular embodiments, a thyroid hormone is administered to the subject once daily, twice daily, three times daily, once every two days, once weekly, twice weekly, or three times weekly.

In some embodiments, a unit dosage form containing from about 5 pg to about 500 pg of a thyroid hormone is administered once, twice, or three times per day. In some embodiments, a unit dosage form containing from about 10 pg to about 400 pg of a thyroid hormone is administered once, twice or three times per day. In other embodiments, a unit dosage form containing from about 20 pg to about 200 pg of a thyroid hormone is administered once, twice, or three times per day. In particular embodiments, a unit dosage form containing from about 20 pg to about 150 pg of a thyroid hormone is administered once, twice or three times per day. Demyelinating Diseases

Myelin is a lipid substance that forms a sheath around the axons of many nerve fibers. The myelin sheath is formed by oligodendrocytes during a process called myelination, and the sheath provides electrical insulation and speeds the conduction of nerve impulses in nerve fibers. Rapid conduction is important for proper nervous system function, and damage to the sheath (from, e.g., injury, toxin exposure, infection, inflammation, or disease) can be devastating. There is a need for treatments to prevent or reverse demyelination and/or promote myelination or remyelination, the repair or reformation of the myelin sheath.

The invention provides methods and compositions for treating demyelinating diseases. A demyelinating disease is any disease of the nervous system in which myelin is damaged or lost, or in which the growth or development of the myelin sheath is impaired. Demyelination inhibits the conduction of signals in the affected nerves, causing impairment in sensation, movement, cognition, or other functions for which nerves are involved. Demyelinating diseases have a number of different causes and can be hereditary or acquired. In some cases, a demyelinating disease is caused by an infectious agent, an autoimmune response, a toxic agent or traumatic injury. In other cases, demyelination is caused by ischemia or occurs during a neurodegenerative disease, such as

Alzheimer's disease. In other cases, the cause of the demyelinating disease is unknown ("idiopathic") or develops from a combination of factors.

The disease or condition to be treated by the methods or compositions of the invention can be any disease or condition associated with demyelination, insufficient myelination or underdevelopment of myelin sheath. In some embodiments, the disease or condition is multiple sclerosis, a

leukodystrophy, a leukoencephalopathy, an idiopathic inflammatory demyelinating disease, or

Alzheimer's disease.

In some embodiments, the disease is a leukoencephalopathy. Leukoencephalopathies are diseases affecting the white substance of the brain, for example, leukoencephalopathy with vanishing white matter and toxic leukoencephalopathy. Leukoencephalopathies are leukodystrophy-like diseases.

In some embodiments, the demyelinating disease is a leukodystrophy. Leukodystrophies are diseases that affect the growth or development of the myelin sheath. In some embodiments, the leukodystrophy is X-linked adrenoleukodystrophy (X-ALD, ALD, or X-linked ALD, also known as Addison-Schilder disease or Siemerling-Creutzfeldt disease), Alexander disease, Pelizaeus- Merzbacher disease (PMD), Van der Knaap disease (also known as megalencephalic

leukoencephalopathy with subcortical cysts (MLC)), Zellweger syndrome, Canavan disease (also known as Canavan-Van Bogaert-Bertrand disease, aspartoacylase deficiency and aminoacylase 2 deficiency), Cerebrotendineous xanthomatosis, Metachromatic leukodystrophy (MLD), or Krabbe disease (also known as globoid cell leukodystrophy or galactosylceramide lipidosis).

In some embodiments, the phenotype of X-linked adrenoleukodystrophy is childhood cerebral, adolescent, adrenomyeloneuropathy, adult cerebral, olivo-ponto-cerebellar, Addison disease, or asymptomatic. In other embodiments, the phenotype of X-linked adrenoleukodystrophy is asymptomatic, mild myelopathy, moderate to severe myelopathy (e.g., adrenomyeloneuropathy), cerebral, and adrenal. In certain embodiments, the phenotype of X-linked adrenoleukodystrophy is cerebral. In other embodiments, the phenotype of X-linked adrenoleukodystrophy is myelopathy (e.g., moderate to severe myelopathy). In certain other embodiments, the phenotype of X-linked adrenoleukodystrophy is asymptomatic. In yet other embodiments, the phenotype of X-linked adrenoleukodystrophy is Addison disease. In certain embodiments, the phenotype of X-linked adrenoleukodystrophy is olivo-ponto-cerebellar. In some embodiments, the demyelinating disease is multiple sclerosis (MS). Multiple sclerosis is a slowly progressive CNS disease characterized by disseminated patches of demyelination in the brain and spinal cord, resulting in multiple and varied neurological symptoms and signs, usually with remissions and exacerbation. In some embodiments, the multiple sclerosis is relapsing-remitting multiple sclerosis (RRMS), secondary-progressive multiple sclerosis (SPMS), primary-progressive multiple sclerosis (PPMS), or progressive-relapsing multiple sclerosos (PRMS).

In some embodiments, the demyelinating disease is a neuropathy. A neuropathy is a functional disturbance or pathological change in the peripheral nervous system. An axonal neuropathy is a disorder that disrupts axonal function. In some embodiments, the neuropathy is paraproteinemic demyelinating polyneuropathy, chronic inflammatory demyelinating polyneuropathy (CIDP, also known as chronic relapsing polyneuropathy (CRP) or chronic inflammatory demyelinating polyradiculoneuropathy), Lewis-Sumner syndrome, Leber hereditary optic neuropathy, multifocal motor neuropathy (MMN), peroneal muscular atrophy (PMA, also known as Charcot-Marie-Tooth disease (CMT), Charcot-Marie-Tooth neuropathy and hereditary motor and sensory neuropathy (HMSN)), or Guillain-Barre syndrome. In some embodiments, the neuropathy is a subtype of Guillain- Barre syndrome, for example, acute inflammatory demyelinating polyneuropathy (AIDP), Miller Fischer syndrome, acute motor axonal neuropathy (Chinese paralytic syndrome), acute motor sensory axonal neuropathy, acute panautonomic neuropathy, or Bickerstaff's brainstem encephalitis. In some embodiments, the disease or condition is a chronic axonal neuropathy.

In some examples, the chronic inflammatory demyelinating polyneuropathy is multifocal acquired demyelinating sensory and motor neuropathy. In some examples, the chronic inflammatory demyelinating polyneuropathy is induced by HIV infection.

In some embodiments, the demyelinating disease is caused by a virus, infection, or immune deficiency, for example, progressive multifocal leukoencephalopathy (PML) or tropical spastic paraparesis (TSP, also known as HTLV-associated myelopathy or chronic progressive myelopathy)

In some embodiments, the demyelinating disorder is an idiopathic inflammatory demyelinating disease (HDD). HDDs include a broad spectrum of central nervous system disorders that can usually be differentiated on the basis of clinical, imaging, laboratory and pathological findings. Idiopathic inflammatory demyelinating diseases are sometimes known as borderline forms of multiple sclerosis. HDD generally refers to a collection of multiple sclerosis variant diseases, including but not limited to, acute disseminated encephalomyelitis (ADEM, known as recurrent disseminated encephalomyelitis or multiphasic disseminated encephalomyelitis after more than one demyelinating episode), Balo concentric sclerosis, Diffuse myelinoclastic sclerosis (also known as Schilder's disease), Marburg multiple sclerosis (also known as tumefactive multiple sclerosis or fulminant multiple sclerosis), Devic's syndrome (also known as Devic's disease or neuromyelitis optica (NMO)), acute hemorrhagic leukoencephalitis (AHL or AHLE, also known as acute necrotizing encephalopathy (AN E), acute hemorrhagic encephalomyelitis (AH EM), acute necrotizing hemorrhagic leukoencephalitis (ANHLE), Weston-Hurst syndrome, or Hurst's disease), optic-spinal MS, transverse myelitis, and solitary sclerosis.

In some embodiments, the demyelinating disease is cerebral palsy. In some embodiments, the disease or condition is central pontine myelolysis, acute disseminated encephalomyelitis, Balo concentric sclerosis, Marburg multiple sclerosis, tumefactive multiple sclerosis, diffuse myelinoclastic sclerosis, acute hemorrhagic leukoencephalitis, neuromyelitis optica, a chronic inflammatory demyelinating polyneuropathy, Leber hereditary optic neuropathy, multifocal motor neuropathy, paraproteinemic demyelinating polyneuropathy, tropical spastic paraparesis, a Guillain-Barre syndrome, infantile Refsum disease, adult Refsum disease 1 , adult Refsum disease 2, Zellweger syndrome, X-linked adrenoleukodystrophy (X-ALD), metachromatic leukodystrophy, Krabbe disease, Pelizaeus-Merzbacher disease, Canavan disease, Alexander disease, Binswanger's disease, peroneal muscular atrophy, cerebrotendineous xanthomatosis, leukoencephalopathy with vanishing white matter, toxic leukoencephalopathy, van der Knaap disease, progressive multifocal leukoencephalopathy, Marchiafava-Bignami disease or transverse myelitis.

In some embodiments, the disease or condition results from intraventricular hemorrhage, neonatal hypoxia, or acute hypoxemic respiratory failure.

In some embodiments of the disclosed method, administration of a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug), and a thyroid hormone prevents or mitigates at least one symptom of the disease or condition. In some examples, the symptom is a lack of sphincter control, erectile dysfunction, paraparesis, ataxia, adrenocortical insufficiency, progressive neuropathy, paresthesia, dysarthria, dysphagia, clonus, or any combination thereof.

In some embodiments, administration of a TR beta selective thyromimetic(e.g., sobetirome or a sobetirome prodrug), and a thyroid hormone prevents or mitigates damage to central nervous system myelin, peripheral nervous system myelin, adrenal cortex, testicular Leydig cells, or any combination thereof. Therapeutic Methods

A TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) and a thyroid hormone can be administered orally, parenterally, and/or topically. In some embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) and the thyroid hormone are administered together in the same pharmaceutical composition. In other embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) and the thyroid hormone are administered in separate unit dosage forms. In further embodiments, a TR beta selective thyromimetic (e.g. , sobetirome or a sobetirome prodrug) and the thyroid hormone are administered by the same route of administration (e.g., orally or parenterally). In yet further embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) and the thyroid hormone are administered via different routes of administration (e.g., orally and parenterally). In still further embodiments, parenteral administration can be buccal, sublingual, sublabial, or by inhalation.

In some embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered prior to a thyroid hormone. In further embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered within 1 hour of the thyroid hormone (e.g., before, e.g., 15 min, 30 min, or 1 hour before). In some embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered within 12 hours of the thyroid hormone administration (e.g., before, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , or 12 hours before). In certain embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered within 24 hours of the thyroid hormone administration (e.g., before, e.g. , 12 or 24 hours before). In particular embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered within 1 week of the thyroid hormone administration (e.g., before, e.g., 1 , 2, 3, 4, 5, or 6 days before). In some embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered within 1 month of the thyroid hormone administration (e.g., before, e.g., 1 , 2, 3, or 4 weeks before).

In some embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered prior to a thyroid hormone. In further embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered within 1 hour of the thyroid hormone (e.g., after, e.g., 15 min, 30 min, or 1 hour after). In some embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered within 12 hours of the thyroid hormone administration (e.g., after, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , or 12 hours after). In certain embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered within 24 hours of the thyroid hormone administration (e.g., after, e.g., 12 or 24 hours after). In particular embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered within 1 week of the thyroid hormone administration (e.g., after, e.g. , 1 , 2, 3, 4, 5, or 6 days after). In some embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered within 1 month of the thyroid hormone administration (e.g., after, e.g., 1 , 2, 3, or 4 weeks after).

In some embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered at a dose of about 1 μg to about 1 mg (e.g., about 1 μg to about 500 μg). In some examples, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered at a dose of about 10 μg to about 100 μg.

In some embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered daily.

In some embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered at a dose of about 1 μg to about 500 μg. In further embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered at a dose of about 10 μg to about 100 μg. In yet further embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered at a dose of about 10 μg to about 30 μg. In still further embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered at a dose of about 30 μg to about 50 μg. In certain embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered at a dose of about 50 μg to about 70 μg. In particular embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered at a dose of about 70 μg to about 100 μg. In other embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered at a dose of about 100 μg to about 200 μg. In yet other embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered at a dose of about 200 μg to about 400 μg. In still other embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered at a dose of about 400 μg to about 1 mg.

In some embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered daily. In particular embodiments, a TR beta selective thyromimetic(e.g., sobetirome or a sobetirome prodrug) is administered to the subject once daily, twice daily, three times daily, once every two days, once weekly, twice weekly, three times weekly, once biweekly, once monthly, or once bimonthly. In certain embodiments, a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered to the subject once daily. In other embodiments, the effective amount is at least 30 pg (e.g., at least 50 pg, such as at least 100 pg). In some embodiments, the effective amount is at least 30 pg (e.g., at least 50 pg, such as at least 100 Mg) daily. In certain embodiments, the effective amount is at least 30 pg (e.g., at least 50 pg, such as at least 100 Mg) twice daily. In particular embodiments, the effective amount is at least 30 pg (e.g., at least 50 pg, such as at least 100 Mg) once weekly. In other embodiments, the effective amount is at least 30 pg (e.g., at least 50 pg, such as at least 100 Mg) twice weekly. In certain embodiments, the effective amount is at least 30 pg (e.g., at least 50 pg, such as at least 100 Mg) three times weekly. In some embodiments, the effective amount is 1 mg or less (e.g., 500 pg or less, e.g., 200 pg or less).

In some embodiments, a unit dosage form containing from 10 pg to 100 pg of a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered once, twice, or three times per day. In some embodiments, a unit dosage form containing from 10 pg to 75 pg of a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered once, twice, or three times per day. In other embodiments, a unit dosage form containing from 30 pg to 75 Mg of a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered once, twice, or three times per day. In particular embodiments, a unit dosage form containing from 10 Mg to 50 Mg of a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered once, twice, or three times per day. In yet other embodiments, a unit dosage form containing from 30 Mg to 50 Mg of a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered once, twice, or three times per day. In still other embodiments, a unit dosage form containing from 50 Mg to 75 Mg of a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) is administered once, twice, or three times per day.

In some embodiments, a thyroid hormone (e.g., levothyroxine or liothyronine or a pharmaceutically acceptable salt thereof) is administered at a dose of from about 5 Mg to about 500 Mg (e.g., from about 10 Mg to about 400 Mg, from about 20 Mg to about 200 Mg, or from about 20 Mg to about 150 Mg) per day. In certain embodiments, a thyroid hormone (e.g., levothyroxine or liothyronine or a pharmaceutically acceptable salt thereof) is administered at a dose of from about 0.5 Mg/kg/day to about 17.0 Mg/kg/day (e.g., from about 1.0 Mg/kg/day to about 15.0 Mg/kg/day, from about 1 .0 Mg/kg/day to about 10.0 Mg/kg/day, or from about 1.0 Mg/kg/day to about 6.0 Mg/kg/day).

In some embodiments, a thyroid hormone is administered daily. In particular embodiments, a thyroid hormone is administered to the subject once daily, twice daily, three times daily, once every two days, once weekly, twice weekly, or three times weekly. In some embodiments, a unit dosage form containing from about 5 pg to about 500 pg of a thyroid hormone is administered once, twice, or three times per day. In some embodiments, a unit dosage form containing from about 10 pg to about 400 pg of a thyroid hormone is administered once, twice or three times per day. In other embodiments, a unit dosage form containing from about 20 pg to about 200 pg of a thyroid hormone is administered once, twice, or three times per day. In particular embodiments, a unit dosage form containing from about 20 pg to about 150 pg of a thyroid hormone is administered once, twice or three times per day.

TR beta selective thyromimetics (e.g., sobetirome or sobetirome prodrugs) and thyroid hormones can be administered according to any suitable route of administration for the treatment of a disease or condition associated with demyelination, insufficient myelination, or underdevelopment of myelin sheath. For example, standard routes of administration include oral, parenteral, or topical routes of administration. In particular, the route of administration of a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) and/or a thyroid hormone may be oral. Parenteral routes of administration of a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) and/or a thyroid hormone may be, e.g., buccal, sublingual, sublabial, by inhalation, intra-arterial, intravenous, intraventricular, intramuscular, subcutaneous, intraspinal, intrathecal, intraorbital, or intracranial. Topical routes of administration may be, e.g., cutaneous, intranasal, or ophthalmic.

Pharmaceutical Compositions

The compounds used in the methods described herein are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo. Pharmaceutical compositions typically include one or more compounds as described herein and a pharmaceutically acceptable excipient.

The compounds used in the methods described herein can also be used in the form of salts, or as prodrugs, or pharmaceutical compositions thereof. All forms are within the scope of the invention. The compounds, salts, prodrugs, or pharmaceutical compositions thereof, may be administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The compounds used in the methods described herein may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration, and the pharmaceutical compositions formulated accordingly.

Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intraspinal, intrathecal, intraorbital, intracranial, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

For human use, the compounds used in the methods described herein can be administered alone or in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions for use in accordance with the present invention thus can be formulated in a conventional manner using one or more physiologically acceptable carriers containing excipients and auxiliaries that facilitate processing of the compounds used in the methods described herein into preparations that can be used pharmaceutically.

This invention also includes pharmaceutical compositions which can contain one or more pharmaceutically acceptable carriers. In making the pharmaceutical compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semisolid, or liquid material (e.g., normal saline), which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, and soft and hard gelatin capsules. As is known in the art, the type of diluent can vary depending upon the intended route of administration. The resulting compositions can include additional agents, e.g., preservatives.

The excipient or carrier is selected on the basis of the mode and route of administration. Suitable pharmaceutical carriers, as well as pharmaceutical necessities for use in pharmaceutical formulations, are described in Remington: The Science and Practice of Pharmacy, 21 ^st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005), a well-known reference text in this field, and in the USP/NF (United States Pharmacopeia and the National Formulary). Examples of suitable excipients are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents, e.g., talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents, e.g., methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. Other exemplary excipients are described in Handbook of Pharmaceutical Excipients, 6^th Edition, Rowe et al., Eds., Pharmaceutical Press (2009).

These pharmaceutical compositions can be manufactured in a conventional manner, e.g., by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Methods well known in the art for making formulations are found, for example, in Remington: The Science and Practice of Pharmacy, 21 ^st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005), and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York. Proper formulation is dependent upon the route of administration chosen. The formulation and preparation of such compositions is well-known to those skilled in the art of pharmaceutical formulation. In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of 200 mesh or less. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.

Formulations

A compound identified as capable of treating any of the conditions described herein, usi any of the methods described herein, may be administered to subjects with a pharmaceutically- acceptable diluent, carrier, or excipient, in unit dosage form. The chemical compounds for use in such therapies may be produced and isolated by any standard technique known to those in the field of medicinal chemistry. Conventional pharmaceutical practice may be employed to provide suitable formulations or compositions to administer one or more compounds used in the methods described herein to subjects suffering from a disease in which demyelination occurs. Administration may begin before the subject is symptomatic.

Exemplary routes of administration of compounds described herein, or pharmaceutical compositions thereof, used in the present invention include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intra-arterial, intracranial, subcutaneous, intraorbital, intraventricular, intraspinal, intraperitoneal, intranasal, inhalation, and topical administration. Compounds used in the methods described herein desirably are administered with a pharmaceutically acceptable carrier. Pharmaceutical formulations of compounds formulated for treatment of the disorders described herein are also part of the present invention. Formulations for Oral Administration

The pharmaceutical compositions contemplated by the invention include those formulated for oral administration ("oral dosage forms"). Oral dosage forms can be, for example, in the form of tablets, capsules, a liquid solution or suspension, a powder, or liquid or solid crystals, which contain the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid) ; binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.

Formulations for oral administration may also be presented as chewable tablets, as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g. , a mixer, a fluid bed apparatus or a spray drying equipment.

Controlled release compositions for oral use may be constructed to release the active drug by controlling the dissolution and/or the diffusion of the active drug substance. Any of a number of strategies can be pursued in order to obtain controlled release and the targeted plasma concentration versus time profile. In one example, controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, e.g., various types of controlled release compositions and coatings. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes. In certain embodiments, compositions include biodegradable, pH, and/or temperature- sensitive polymer coatings.

Dissolution or diffusion controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of compounds, or by incorporating the compound into an appropriate matrix. A controlled release coating may include one or more of the coating substances mentioned above and/or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-hydroxymethacrylate, methacrylate hydrogels, 1 ,3 butylene glycol, ethylene glycol methacrylate, and/or polyethylene glycols. In a controlled release matrix formulation, the matrix material may also include, e.g., hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/or halogenated fluorocarbon.

The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils, e.g., cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

Formulations for Buccal Administration

Dosages for buccal or sublingual administration typically may contain up to 500 mg of an active agent per single dose as required. In practice, the physician determines the actual dosing regimen which is most suitable for an individual subject, and the dosage varies with the age, weight, and response of the particular subject. The above dosages are exemplary of the average case, but individual instances exist wherein higher or lower dosages are merited, and such are within the scope of this invention.

For buccal administration, the compositions may take the form of tablets, lozenges, etc. formulated in a conventional manner. Liquid drug formulations suitable for use with nebulizers and liquid spray devices and electrohydrodynamic (EHD) aerosol devices will typically include a compound of the invention with a pharmaceutically acceptable carrier. Preferably, the

pharmaceutically acceptable carrier is a liquid, e.g., alcohol, water, polyethylene glycol, or a perfluorocarbon. Optionally, another material may be added to alter the aerosol properties of the solution or suspension of compounds of the invention. Desirably, this material is liquid, e.g., an alcohol, glycol, polyglycol, or a fatty acid. Other methods of formulating liquid drug solutions or suspension suitable for use in aerosol devices are known to those of skill in the art (see, e.g., Biesalski, U.S. Pat. No. 5, 1 12,598 and Biesalski, U.S. Pat. No. 5,556,61 1 , each of which is herein incorporated by reference). Formulations for Nasal or Inhalation Administration

The compounds may also be formulated for nasal administration. Compositions for nasal administration also may conveniently be formulated as aerosols, drops, gels, and powders. The formulations may be provided in a single or multidose form. In the case of a dropper or pipette, dosing may be achieved by the subject administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved, for example, by means of a metering atomizing spray pump.

The compounds may further be formulated for aerosol administration, particularly to the respiratory tract by inhalation and including intranasal administration. The compound will generally have a small particle size for example on the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant, e.g., a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide, or other suitable gas. The aerosol may conveniently also contain a surfactant, e.g., lecithin. The dose of drug may be controlled by a metered valve. Alternatively, the active ingredients may be provided in a form of a dry powder, e.g., a powder mix of the compound in a suitable powder base, e.g., lactose, starch, and starch derivatives, e.g., hydroxypropylmethyl cellulose, and

polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatin or blister packs from which the powder may be administered by means of an inhaler.

Aerosol formulations typically include a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device, e.g., a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form contains an aerosol dispenser, it will contain a propellant, which can be a compressed gas, e.g., compressed air or an organic propellant, e.g. , fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomizer. Formulations for Parenteral Administration

The compounds described herein for use in the methods of the invention can be administered in a pharmaceutically acceptable parenteral (e.g., intravenous or intramuscular) formulation as described herein. The pharmaceutical formulation may also be administered parenterally

(intravenous, intramuscular, subcutaneous or the like) in dosage forms or formulations containing conventional, non-toxic pharmaceutically acceptable carriers and adjuvants. In particular, formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. For example, to prepare such a composition, the compounds of the invention may be dissolved or suspended in a parenterally acceptable liquid vehicle. Among acceptable vehicles and solvents that may be employed are water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1 ,3-butanediol, Ringer's solution and isotonic sodium chloride solution. The aqueous formulation may also contain one or more preservatives, for example, methyl, ethyl or n- propyl p-hydroxybenzoate. Additional information regarding parenteral formulations can be found, for example, in the United States Pharmacopeia-National Formulary (USP-NF), herein incorporated by reference.

The parenteral formulation can be any of the five general types of preparations identified by the USP-NF as suitable for parenteral administration:

(1 ) "Drug Injection": a liquid preparation that is a drug substance (e.g., a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) and/or a thyroid hormone), or a solution thereof;

(2) "Drug for Injection": the drug substance (e.g., a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) and/or a thyroid hormone) as a dry solid that will be combined with the appropriate sterile vehicle for parenteral administration as a drug injection;

(3) "Drug Injectable Emulsion": a liquid preparation of the drug substance (e.g., a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) and/or a thyroid hormone) that is dissolved or dispersed in a suitable emulsion medium;

(4) "Drug Injectable Suspension": a liquid preparation of the drug substance (e.g., a TR beta selective thyromimetic (e.g., sobetirome or a sobetirome prodrug) and/or a thyroid hormone) suspended in a suitable liquid medium; and

(5) "Drug for Injectable Suspension": the drug substance (e.g., a TR beta selective

thyromimetic (e.g., sobetirome or a sobetirome prodrug) and/or a thyroid hormone) as a dry solid that will be combined with the appropriate sterile vehicle for parenteral administration as a drug injectable suspension.

Exemplary formulations for parenteral administration include solutions of the compound prepared in water suitably mixed with a surfactant, e.g., hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21 ^st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005)and in The United States Pharmacopeia: The National Formulary (USP 36 NF31 ), published in 2013.

Formulations for parenteral administration may, for example, contain excipients, sterile water, or saline, polyalkylene glycols, e.g., polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes. Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds. Other potentially useful parenteral delivery systems for compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.

The parenteral formulation can be formulated for prompt release or for sustained/extended release of the compound. Exemplary formulations for parenteral release of the compound include: aqueous solutions, powders for reconstitution, cosolvent solutions, oil/water emulsions, suspensions, oil-based solutions, liposomes, microspheres, and polymeric gels.

The following examples are meant to illustrate the invention. They are not meant to limit the invention in any way.

Examples

Example 1. Thyroid Function Studies in Rats

Juvenile Sprague-Dawley rats were orally administered sobetirome daily for 13 weeks. Thyroid function of the treated rats was assessed after 13 weeks of sobetirome administration by measuring the serum levels of TSH, tT4, tT3, fT4, and ΓΓ3. The results for this study are provided in Table 1 and FIG. 1 .

Table 1

Table 1 illustrates data for male rats. The data for female rats is similar to the data for male rats. In Table 1 , "— " stands for undetectable and "nd" stands for not determined.

The data in Table 1 and FIG. 1 show sobetirome-induced dose-dependent suppression of TSH, tT4, tT3, and ΓΓ4. These data are indicative of the hypothyroid state in rats receiving sobetirome. The values for TSH, tT4, tT3, and ΓΓ4 were observed to return to normal after 4 weeks following the cessation of sobetirome administration.

In another study, adult rats were dosed orally at 1 0, 1 , 0.1 , and 0.01 Mg/kg once daily for 26 weeks. At 1 g/kg/day dose, the triiodothyronine (tT3) values were mildly lower in both male and female rats on days 84, 127 and 180. At 10 pg/kg/day dose, tT3 values were undetectable in male rats at day 28 and in female rats on day 84. tT3 values were undetectable in both male and female rats on days 127 and 180/183.

In addition to these effects on tT3, at 1 pg/kg/day dose, free thyroxine (ΓΓ4) values were mildly lower and low or no measurable thyroxine (fT4) values were observed in both male and female rats on days 180/183. At 10 pg/kg/day dose, the thyroid stimulating hormone (TSH) values were reduced and no measurable values of fT4, ΓΓ3, or ΓΓ4 were observed in both male and female rats. Evidence for changes associated with direct thyroid hormone β agonist effects and indirect changes arising from NV1205-induced hypothyroidism was apparent in all multiple-dose rat studies.

Example 2. Thyroid Function Studies in Cynomolgus Monkeys

Cynomolgus monkeys were orally dosed at 100, 30, or 3 mg/kg once daily (3 monkeys per dose group. Thyroid function of the monkeys was assessed on day 28 after the commencement of dosing. The results are illustrated in Table 2.

Table 2

The data in Table 2 show that tT4 serum levels were significantly suppressed at all doses in both genders, that tT3 was non-dose-dependently suppressed in both genders, and that TSH was not significantly affected at any dose in either gender.

In another experiment, Cynomolgus monkeys were dosed at 100, 30, or 3 mg/kg for about 6 weeks, and then each dose was reduced 100-fold to 1.0, 0.3, or 0.03 mg/kg, respectively. Thyroid function of the monkeys was assessed on days 25 and 81. The results are illustrated in Table 3.

Table 3

In yet another experiment, cynomolgus monkeys were orally administered 0, 10, 25, 50, or 150 μg/kg/day once daily for 28 days. Among the treated monkeys, the 150 μg/kg/day group was observed to have tT3 suppression of 66-82% and tT4 suppression of 67-93%, as compared to monkeys not receiving sobetirome.

In a final study of nine months dosing in cynomolgus monkeys, initial dose levels of 0, 3000, 30000, and 100000 μg/kg/day were administered through Day 42. Due to significant weight loss in NV1205-treated animals, the dose levels were decreased to 30, 300, and 1000 μg/kg/day between Day 43 and the end of the study, Day 274. Significant decreases in thyroid hormones were noted at all dose levels. Decreases were initially detected on Day 25 and persisted through necropsy. From Day 81 through to terminal necropsy, tT3, ΓΓ3, tT4 and ΓΓ4 levels remained decreased and were frequently below the linear range for all treated groups (≥ 3(^g/kg/day). Slight to mild fluctuations in thyroid stimulating hormone (TSH) were detected in all treatment groups during the course of the study; however, increased secretion of this hormone (as would be expected with decreased peripheral thyroid hormones), was not apparent.

Evidence for changes associated with direct thyroid hormone β agonist effects and indirect changes arising from NV1205-induced hypothyroidism was apparent in the nine month monkey study.

Other Embodiments

Various modifications and variations of the described invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the invention.

Other embodiments are in the claims.

Claims

Claims What is claimed is:

1. A method of treating a subject having or at risk of developing X-linked

adrenoleukodystrophy, comprising administering to the subject an effective amount of a TR beta selective thyromimetic and an effective amount of a thyroid hormone.

2. A method of treating a subject having or at risk of developing a disease or condition associated with demyelination, insufficient myelination, or underdevelopment of myelin sheath, comprising administering to the subject an effective amount of TR beta selective thyromimetic and an effective amount of a thyroid hormone.

3. The method of claim 2, wherein the disease or condition is multiple sclerosis, a leukodystrophy, a leukoencephalopathy, an idiopathic inflammatory demyelinating disease, or Alzheimer's disease.

4. The method of claim 3, wherein the multiple sclerosis is relapsing-remitting multiple sclerosis, primary-progressive multiple sclerosis, secondary-progressive multiple sclerosis, or progressive-relapsing multiple sclerosis.

5. The method of claim 2, wherein the disease or condition is central pontine myelolysis, acute disseminated encephalomyelitis, Balo concentric sclerosis, Marburg multiple sclerosis, tumefactive multiple sclerosis, diffuse myelinoclastic sclerosis, acute hemorrhagic leukoencephalitis, neuromyelitis optica, a chronic inflammatory demyelinating polyneuropathy, Leber hereditary optic neuropathy, multifocal motor neuropathy, paraproteinemic demyelinating polyneuropathy, tropical spastic paraparesis, a Guillain-Barre syndrome, infantile Refsum disease, adult Refsum disease 1 , adult Refsum disease 2, Zellweger syndrome, X-linked

adrenoleukodystrophy (X-ALD), metachromatic leukodystrophy, Krabbe disease, Pelizaeus- Merzbacher disease, Canavan disease, Alexander disease, peroneal muscular atrophy, cerebrotendineous xanthomatosis, Binswanger's disease, leukoencephalopathy with vanishing white matter, toxic leukoencephalopathy, van der Knaap disease, progressive multifocal

leukoencephalopathy, Marchiafava-Bignami disease or transverse myelitis.

6. The method of claim 5, wherein the Guillain-Barre syndrome is acute inflammatory demyelinating polyneuropathy.

7. The method of claim 5, wherein the chronic inflammatory demyelinating polyneuropathy is multifocal acquired demyelinating sensory and motor neuropathy.

8. The method of claim 5, wherein the chronic inflammatory demyelinating polyneuropathy is induced by H IV infection.

9. The method of claim 5, wherein the X-linked adrenoleukodystrophy is

adrenomyeloneuropathy or Addison's disease.

10. The method of claim 2, wherein the disease or condition is a chronic axonal neuropathy.

1 1 . The method of claim 2, wherein the disease or condition results from intraventricular hemorrhage, neonatal hypoxia, or acute hypoxemic respiratory failure.

12. The method of claim 2, wherein the disease or condition is cerebral palsy.

13. The method of any one of claims 1 -12, wherein administration of the TR beta selective thyromimetic and the thyroid hormone prevents or mitigates at least one symptom of the disease or condition.

14. The method of claim 13, wherein the symptom is a lack of sphincter control, erectile dysfunction, paraparesis, ataxia, adrenocortical insufficiency, progressive neuropathy, paresthesia, dysarthria, dysphagia, clonus, or any combination thereof.

15. The method of any one of claims 1 -14, wherein administration of the TR beta selective thyromimetic and the thyroid hormone prevents or mitigates damage to central nervous system myelin, peripheral nervous system myelin, adrenal cortex, testicular Leydig cells, or any combination thereof.

16. A method of administering a TR beta selective thyromimetic to a subject, the method comprising administering an effective amount of a TR beta selective thyromimetic and an effective amount of a thyroid hormone, wherein administering the thyroid hormone maintains thyroid function, as measured by T4 serum levels.

17. The method of any one of claims 1 -16, wherein the thyroid hormone is levothyroxine or a pharmaceutically acceptable salt thereof.

18. The method of any one of claims 1 -16, wherein the thyroid hormone is liothyronine or a pharmaceutically acceptable salt thereof.

19. The method of any one of claims 1 -18, wherein the TR beta selective thyromimetic is administered orally, parenterally, or topically.

20. The method of claim 19, wherein the TR beta selective thyromimetic is administered orally.

21 . The method of claim 19, wherein the TR beta selective thyromimetic is administered parenterally.

22. The method of claim 21 , wherein the TR beta selective thyromimetic is administered buccally, sublingually, sublabially, or by inhalation.

23. The method of claim 22, wherein the TR beta selective thyromimetic is administered sublingually.

24. The method of claim 21 , wherein the TR beta selective thyromimetic is administered intramuscularly, intravenously, or subcutaneously.

25. The method of claim 21 , wherein the TR beta selective thyromimetic is administered intra-arterially, intravenously, intraventricularly, intramuscularly, subcutaneously, intraspinally, intrathecal^, intraorbitally, or intracranially.

26. The method of any one of claims 1 -26, wherein the thyroid hormone is administered orally, parenterally, or topically.

27. The method of claim 26, wherein the thyroid hormone is administered orally.

28. The method of claim 26, wherein the thyroid hormone is administered parenterally.

29. The method of claim 28, wherein the thyroid hormone is administered buccally, sublingually, sublabially, or by inhalation.

30. The method of claim 29, wherein the thyroid hormone is administered sublingually.

31 . The method of claim 28, wherein the thyroid hormone is administered

intramuscularly, intravenously, or subcutaneously.

32. The method of claim 28, wherein the thyroid hormone is administered intra-arterially, intravenously, intraventricularly, intramuscularly, subcutaneously, intraspinally, intraorbitally, or intracranially.

33. The method of any one of claims 1 -32, wherein the TR beta selective thyromimetic is administered in combination with the thyroid hormone.

34. The method of any one of claims 1 -32, wherein the TR beta selective thyromimetic is administered prior to the thyroid hormone.

35. The method of any one of claims 1 -32, wherein the TR beta selective thyromimetic is administered after the thyroid hormone.

36. The method of claim 34 or 35, wherein administration of the TR beta selective thyromimetic and administration of the thyroid hormone occur within one hour.

37. The method of claim 34 or 35, wherein administration of the TR beta selective thyromimetic and administration of the thyroid hormone occur within 12 hours.

38. The method of claim 34 or 35, wherein administration of the TR beta selective thyromimetic and administration of the thyroid hormone occur within 24 hours.

39. The method of claim 34 or 35, wherein administration of the TR beta selective thyromimetic and administration of the thyroid hormone occur within one week.

40. The method of any one of claims 1 -39, wherein the subject is male.

41 . The method of any one of claims 1 -39, wherein the subject is female.

42. The method of any one of claims 1 -41 , wherein the subject is 1 to 50 years old.

43. The method of claim 42, wherein the subject is 1 to 30 years old.

44. The method of claim 42, wherein the subject is 1 to 20 years old.

45. The method of claim 42, wherein the subject is 3 to 30 years old.

46. The method of claim 42, wherein the subject is 3 to 20 years old.

47. The method of claim 42, wherein the subject is 3 to 18 years old.

48. The method of any one of claims 1 -47, wherein the TR beta selective thyromimetic is administered daily.

49. The method of any one of claims 1 -48, wherein about 1 μς to about 1 mg of the TR beta selective thyromimetic are administered.

50. The method of any one of claims 1 -49, wherein at least 10 μς of the TR beta selective thyromimetic are administered.

51 . The method of claim 50, wherein at least 30 μg of the TR beta selective thyromimetic is administered.

52. The method of claim 51 , wherein at least 50 μς of the TR beta selective thyromimetic are administered.

53. The method of claim 52, wherein at least 70 μς of the TR beta selective thyromimetic are administered.

54. The method of claim 53, wherein at least 100 μς of the TR beta selective thyromimetic are administered.

55. The method of claim 54, wherein at least 200 μς of the TR beta selective thyromimetic are administered.

56. The method of any one of claims 1 -55, wherein 500 μς or less of the TR beta selective thyromimetic are administered.

57. The method of any one of claims 1 -55, wherein 400 μς or less of the TR beta selective thyromimetic are administered.

58. The method of any one of claims 1 -55, wherein 200 μς or less of the TR beta selective thyromimetic are administered.

59. The method of any one of claims 1 -55, wherein 100 μς or less of the TR beta selective thyromimetic are administered.

60. The method of any one of claims 1 -51 , wherein 70 μg or less of the TR beta selective thyromimetic are administered.

61 . The method of any one of claims 1 -60, wherein from about 5 pg to about 500 pg of the thyroid hormone are administered.

62. The method of claim 61 , wherein from about 10 pg to about 400 pg of the thyroid hormone are administered.

63. The method of any one of claims 1 -62, wherein the TR beta selective thyromimetic is sobetirome.

64. The method of any one of claims 1 -62, wherein the TR beta selective thyromimetic is the sobetirome prodrug.

65. A pharmaceutical composition in unit dosage form comprising a TR beta selective thyromimetic, a thyroid hormone, and a pharmaceutically acceptable excipient.

66. The pharmaceutical composition of claim 64, wherein the unit dosage form is a capsule, tablet, troche, film, solution, depot, powder, lozenge, sachet, cachet, elixir, emulsion, or syrup.

67. The pharmaceutical composition of claim 65 or 66, wherein the pharmaceutical composition comprises about 1 μg to about 1 mg of the TR beta selective thyromimetic.

68. The pharmaceutical composition of any one of claims 65-67, wherein the pharmaceutical composition comprises at least 10 μg of the TR beta selective thyromimetic.

69. The pharmaceutical composition of claim 68, wherein the pharmaceutical composition comprises at least 30 μg of the TR beta selective thyromimetic.

70. The pharmaceutical composition of claim 69, wherein the pharmaceutical composition comprises at least 50 μg of the TR beta selective thyromimetic.

71 . The pharmaceutical composition of claim 70, wherein the pharmaceutical composition comprises at least 70 μg of the TR beta selective thyromimetic.

72. The pharmaceutical composition of claim 71 , wherein the pharmaceutical composition comprises at least 100 μg of the TR beta selective thyromimetic.

73. The pharmaceutical composition of claim 72, wherein the pharmaceutical composition comprises at least 200 μg of the TR beta selective thyromimetic.

74. The pharmaceutical composition of any one of claims 65-73, wherein the pharmaceutical composition comprises 500 μg or less of the TR beta selective thyromimetic.

75. The pharmaceutical composition of any one of claims 65-73, wherein the pharmaceutical composition comprises 400 μg or less of the TR beta selective thyromimetic.

76. The pharmaceutical composition of any one of claims 65-72, wherein the pharmaceutical composition comprises 200 μg or less of the TR beta selective thyromimetic.

77. The pharmaceutical composition of any one of claims 65-71 , wherein the pharmaceutical composition comprises 100 μg or less of the TR beta selective thyromimetic.

78. The pharmaceutical composition of any one of claims 65-70, wherein the pharmaceutical composition comprises 70 μς or less of the TR beta selective thyromimetic.

79. The pharmaceutical composition of any one of claims 65-78, wherein the TR beta selective thyromimetic is sobetirome.

80. The pharmaceutical composition of any one of claims 65-78, wherein the TR beta selective thyromimetic is the sobetirome prodrug.

81 . The pharmaceutical composition of any one of claims 65-80, wherein the pharmaceutical composition comprises from about 5 pg to about 500 pg of the thyroid hormone.

82. The pharmaceutical composition of claim 81 , wherein the pharmaceutical composition comprises from about 10 pg to about 400 pg of the thyroid hormone.

83. The pharmaceutical composition of any one of claims 65-82, wherein the thyroid hormone is levothyroxine or a pharmaceutically acceptable salt thereof.

84. The pharmaceutical composition of any one of claims 65-82, wherein the thyroid hormone is liothyronine or a pharmaceutically acceptable salt thereof.