WO2018183940A1

WO2018183940A1 - Methods and compositions for treating niemann-pick disease

Info

Publication number: WO2018183940A1
Application number: PCT/US2018/025539
Authority: WO
Inventors: IV George Mitchell GRASS
Original assignee: Neurovia Inc
Current assignee: Neurovia Inc
Priority date: 2017-03-31
Filing date: 2018-03-30
Publication date: 2018-10-04
Anticipated expiration: 2019-09-30

Abstract

Disclosed are methods for treating Niemann-Pick disease (e.g., Niemann-Pick disease type C (e.g., type C1)) by administering an effective amount of sobetirome or a sobetirome prodrug to a patient having the Niemann-Pick disease (e.g., Niemann-Pick disease type C (e.g., type C1)). Also disclosed are compositions containing sobetirome or a sobetirome prodrug for use in treating Niemann-Pick disease (e.g., Niemann-Pick disease type C (e.g., type C1)).

Description

METHODS AND COMPOSITIONS FOR TREATING NIEMANN-PICK DISEASE

Related Applications

This application claims the benefit of U.S. Provisional Application No. 62/480,198, filed on March 31 , 2017. The entire teachings of the above applications are incorporated herein by reference.

Field of the Invention

In general, the present invention relates to methods and compositions for treating Niemann- Pick disease (e.g., Niemann-Pick disease Type C).

Background

Niemann-Pick disease is a fatal sterol homeostasis disease for which no effective treatments exist. The disease is inherited and autosomally recessive. Common symptoms include enlargement of the liver and spleen, low platelet count, and persistent lung infection. Furthermore, disruption of normal sterol homeostasis can result in accumulation of sphingomyelin in the central nervous system (CNS), thereby resulting in seizures, ataxia, dysarathria, dysphagia, and a number of other cognitive and physical impairments. Niemann-Pick disease is divided into three subtypes: Niemann-Pick disease type A (NPA), Niemann-Pick disease type B (NPB), and Niemann-Pick disease type C (NPC). The latter is often further divided into Niemann-Pick disease type C1 and Niemann-Pick disease type C2 (NPC1 and NPC2, respectively). This classification of the Niemann-Pick disease types is based on mutations within different genes. NPA is usually childhood lethal by 18 months, NPB presents itself in mid-childhood with survival into adulthood, and NPC1 and NPC2 typically presents later with some patients surviving into adulthood. Current standard of treatment for Niemann-Pick disease focuses on symptomatic relief. New treatments for Niemann-Pick disease are needed.

Summary of the Invention

In general, the invention provides methods for treating a subject having or at risk of developing Niemann-Pick disease. The methods of the invention include administering to the subject an effective amount of sobetirome or a sobetirome prodrug.

In some embodiments, the Niemann-Pick disease is Niemann-Pick disease type A. In certain embodiments, the Niemann-Pick disease is Niemann-Pick disease type B. In further embodiments, the Niemann-Pick disease is Niemann-Pick disease type C. In yet further embodiments, the

Niemann-Pick disease is Niemann-Pick disease type C1. In still further embodiments, the Niemann- Pick disease is Niemann-Pick disease type C2.

In particular embodiments, sobetirome or the sobetirome prodrug is administered orally, parenterally, or topically. In certain embodiments, sobetirome or the sobetirome prodrug is administered orally. In some embodiments, sobetirome or the sobetirome prodrug is administered parenterally. In further embodiments, sobetirome or the sobetirome prodrug is administered buccally, sublingually, sublabially, or by inhalation. In yet further embodiments, sobetirome or the sobetirome prodrug is administered sublingually. In still further embodiments, sobetirome or the sobetirome prodrug is administered intramuscularly, intravenously, or subcutaneously. In other embodiments, sobetirome or the sobetirome prodrug is administered intra-arterially, intravenously, intraventricularly, intramuscularly, subcutaneously, intraspinally, intraorbitally, or intracranially.

In certain embodiments, sobetirome or the sobetirome prodrug is administered at a dose of about 1 μς to about 1 mg. In particular embodiments, at least 10 μς (e.g., at least 30 μς, at least 50 Mg, at least 70 μς, at least 100 μς, or at least 200 μς) of sobetirome or the sobetirome prodrug are administered. In some embodiments, 500 μς or less (e.g., 400 μς or less, 200 μς or less, 100 μς or less, or 70 μg or less) of sobetirome or the sobetirome prodrug are administered.

In further embodiments, the administration of sobetirome or the sobetirome prodrug ameliorates one or more symptoms selected from the group consisting of seizures, ataxia, dysarthria, and dysphagia.

In particular embodiments, sobetirome is administered.

In certain embodiments, the sobetirome prodrug is administered.

In another aspect, the invention provides a method of treating a subject having Niemann-Pick disease. The method includes contacting a cell in the subject with sobetirome or a sobetirome prodrug.

In certain embodiments, the cell is contacted with sobetirome. In other embodiments, the cell is contacted with the sobetirome prodrug. In particular embodiments, the cell is a neuronal cell, fibroblast, neuron, macrophage, glial cell, astroglia, microglia, astrocyte, myelin producing cell, oligodendrocyte, Purkinje cell, or hepatocyte.

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 sobetirome or a sobetirome prodrug by an effective route. Exemplary routes of administration are described herein below.

"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 (C_2-6alkenyl). 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 (C-|. 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 (C_2-

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. "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.

"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.

"Effective amount" is a quantity of a therapeutic agent (e.g., sobetirome or sobetirome prodrug) 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 sobetirome or a sobetirome prodrug is the amount sufficient to ameliorate at least one symptom of a Niemann-Pick disease (e.g., Niemann-Pick disease type C (e.g., type C1 )).

"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.

A "pharmaceutically acceptable salt" refers to a salt of a therapeutic agent (e.g., sobetirome or a sobetirome prodrug) 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 sobetirome or a sobetirome prodrug (e.g., a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient at a dosage used. 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, micro-crystalline 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 sobetirome or a sobetirome prodrug 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:

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 a-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 as having or at risk of developing a Niemann-Pick disease (e.g., Niemann-Pick disease type C (e.g., type C1 )). 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. For example, such a risk factor can be family history of Niemann-Pick disease.

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.

Detailed Description

The invention provides methods and compositions for treating Niemann-Pick disease using sobetirome or a 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.

In some embodiments, sobetirome is administered at a dose of about 1 μς to about 1 mg (e.g., to about 500 μς). In certain embodiments, sobetirome is administered at a dose of about 10 μς to about 100 μς.

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 μς (e.g., at least 50 μς, such as at least 100 μς). In some embodiments, the effective amount is at least 30 μς (e.g., at least 50 μς, such as at least 100 μς) daily. In certain embodiments, the effective amount is at least 30 μς (e.g., at least 50 μς, such as at least 100 μς) twice daily. In particular embodiments, the effective amount is at least 30 μς (e.g., at least 50 μς, such as at least 100 μς) once weekly. In other embodiments, the effective amount is at least 30 μς (e.g., at least 50 μς, such as at least 100 μς) twice weekly. In certain embodiments, the effective amount is at least 30 μς (e.g., at least 50 μς, such as at least 100 μg) three times weekly. In some embodiments, the effective amount is 1 mg or less (e.g., 500 μg or less, e.g., 200 μς or less).

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

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).

In some embodiments, a sobetirome prodrug is administered at a dose of about 1 μς to about 1 mg (e.g., to about 500 μς). In certain embodiments, a sobetirome prodrug is administered at a dose of about 10 μς to about 100 μς.

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, 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 μς (e.g., at least 50 μς, e.g., at least 100 μς). In some embodiments, the effective amount is at least 30 μg (e.g., at least 50 μς, e.g., at least 100 μς) daily. In certain embodiments, the effective amount is at least 30 μg (e.g., at least 50 μς, e.g., at least 100 μς) twice daily. In particular embodiments, the effective amount is at least 30 μς (e.g., at least 50 μς, e.g., at least 100 μς) once weekly. In other embodiments, the effective amount is at least 30 μς (e.g., at least 50 μς, e.g., at least 100 μς) twice weekly. In certain embodiments, the effective amount is at least 30 μς (e.g., at least 50 μς, e.g., at least 100 μg) three times weekly. In some embodiments, the effective amount is 1 mg or less (e.g., 500 μg or less, e.g., 200 μg or less).

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

Methods of the invention may be used in the treatment of Niemann-Pick disease. In some embodiments, methods of the invention may be used in the treatment of one or more symptoms of the Niemann-Pick disease (e.g., Niemann-Pick disease type C (e.g., type C1 )). The symptoms of Niemann-Pick disease may include seizures, ataxia, dysarthria, and/or dysphagia.

Niemann-Pick disease is a metabolic disorder in which sphingolipids accumulate in cell lysosomes. Lysosomes are responsible for transportation of material in and out of cells, while mutations that disrupt this process can cause the disease. Niemann-Pick disease is commonly divided into three subtypes, type A (NPA), B (NPB), and C (NPC). The latter is often further divided into types C1 (NPC1 ) and C2 (NPC2). NPA and NPB are associated with mutations in the SMPD1 gene, a sphingomyelin phosphodisesterase, and mutations in the NPC1 and NPC2 genes are associated with NPC1 and NPC2, respectively. Niemann-Pick disease is associated with

accumulation of cholesterol and other lipids, including sphingomyelin, sphingosine, and gangliosides (GM2 and GM3), within the late endosomes/lysosomes (LE/L). In mice and humans, this impairment leads to progressive neurodegeneration, hepatosplenomegaly, and, ultimately, premature death. Typically, clinical manifestations become evident in early childhood, although age of onset can range from the perinatal period to adulthood. Disease progression is often more rapid when onset of symptoms occurs in early life.

Niemann-Pick disease is inherited and autosomally recessive. Common symptoms include enlargement of the liver and spleen due to accumulation of sphingomyelin, low platelet count, and persistent lung infection. Further, accumulation of sphingomyelin in the central nervous system (CNS) can result in seizures, ataxia, dysarthria, and dysphagia. NPA is often childhood lethal by 18 months, NPB presents itself in mid-childhood with survival into adulthood, while NPC1 and NPC2 present later with some subjects having NPC1 or NPC2 surviving into adulthood. Therapeutic Methods

Sobetirome or a sobetirome prodrug can be administered orally, parenterally, and/or topically. In some embodiments, sobetirome or a sobetirome prodrug is administered at a dose of about 1 μς to about 1 mg (e.g., about 1 μς to about 500 μς). In some examples, sobetirome or a sobetirome prodrug is administered at a dose of about 10 μς to about 100 μς.

In some embodiments, sobetirome or a sobetirome prodrug is administered daily.

In some embodiments, sobetirome or a sobetirome prodrug is administered at a dose of about 1 μg to about 500 μς. In further embodiments, sobetirome or a sobetirome prodrug is administered at a dose of about 10 μς to about 100 μς. In yet further embodiments, sobetirome or a sobetirome prodrug is administered at a dose of about 10 μς to about 30 μς. In still further embodiments, sobetirome or a sobetirome prodrug is administered at a dose of about 30 μς to about 50 μς. In certain embodiments, sobetirome or a sobetirome prodrug is administered at a dose of about 50 μς to about 70 Mg. In particular embodiments, sobetirome or a sobetirome prodrug is administered at a dose of about 70 Mg to about 100 Mg. In other embodiments, sobetirome or a sobetirome prodrug is administered at a dose of about 100 Mg to about 200 Mg- In yet other embodiments, sobetirome or a sobetirome prodrug is administered at a dose of about 200 Mg to about 400 Mg- In still other embodiments, sobetirome or a sobetirome prodrug is administered at a dose of about 400 Mg to about 1 mg.

In some embodiments, sobetirome or a sobetirome prodrug is administered daily. In particular embodiments, 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, sobetirome or a sobetirome prodrug is administered to the subject once daily. In other embodiments, the effective amount is at least 30 Mg (e.g., at least 50 Mg, such as at least 100 Mg)- In some embodiments, the effective amount is at least 30 Mg (e.g., at least 50 Mg, such as at least 100 Mg) daily. In certain embodiments, the effective amount is at least 30 Mg (e.g., at least 50 Mg, such as at least 100 Mg) twice daily. In particular embodiments, the effective amount is at least 30 Mg (e.g., at least 50 Mg, such as at least 100 Mg) once weekly. In other embodiments, the effective amount is at least 30 Mg (e.g., at least 50 Mg, such as at least 100 Mg) twice weekly. In certain embodiments, the effective amount is at least 30 Mg (e.g., at least 50 Mg, such as at least 100 Mg) three times weekly. In some embodiments, the effective amount is 1 mg or less (e.g., 500 μg or less, e.g., 200 μg or less).

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

Sobetirome or a sobetirome prodrug can be administered using a suitable route of administration for the treatment of Niemann-Pick disease (e.g., Niemann-Pick disease type C (e.g., type C1 )). For example, standard routes of administration include oral, parenteral, or topical routes of administration. In particular, the route of administration of sobetirome or a sobetirome prodrug may be oral. Parenteral routes of administration of sobetirome or a sobetirome prodrug may be, e.g., buccal, sublingual, sublabial, by inhalation, intra-arterial, intravenous, intraventricular, intramuscular, subcutaneous, intraspinal, intraorbital, or intracranial. Topical routes of administration may be, e.g., cutaneous, intranasal, or ophthalmic. Methods of the invention also include methods of treating Niemann-Pick disease by contacting a cell in a subject with sobetirome or a sobetirome prodrug. In some embodiments, the cell is a neuronal cell, fibroblast, neuron, macrophage, glial cell, astroglia, microglia, astrocyte, myelin producing cell, oligodendrocyte, Purkinje cell, or hepatocyte.

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 patient 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, intrathecal, 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 comprising 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, using any of the methods described herein, may be administered to patients or animals 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 patients suffering from a disease in which demyelination occurs. Administration may begin before the patient 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-m ethyl 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 patient, and the dosage varies with the age, weight, and response of the particular patient. 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 patient 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 comprises 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., sobetirome or a

sobetirome prodrug), or a solution thereof; (2) "Drug for Injection": the drug substance (e.g., sobetirome or a sobetirome prodrug) 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., sobetirome or a sobetirome prodrug) that is dissolved or dispersed in a suitable emulsion medium;

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

(5) "Drug for Injectable Suspension": the drug substance (e.g., sobetirome or a sobetirome prodrug) 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. In Vitro Test of Sobetirome or a Sobetirome Prodrug

Sobetirome or a sobetirome prodrug may be tested in an in vitro model of Niemann-Pick disease. In vitro models of Niemann-Pick disease are known in the art. For an in vitro model of Niemann-Pick disease type C, see, e.g., Efthymiou et al., Stem Cells Trans Med. 4:230-238, 2015; Bergamin et al., Orphanet Journal of Rare Diseases, 8:34, 2013. For a review of in vitro models of diseases including Niemann-Pick types A, B, and C, see, e.g., Xu et al., Ann. N. Y. Acad. Sci.,

1371 : 15-29, 2016.

Example 2. In Vivo Test of Sobetirome or a Sobetirome Prodrug

Sobetirome or a sobetirome prodrug may be tested in an animal model of Niemann-Pick disease. Animal models of Niemann-Pick disease are known in the art. For a review of animal disease models, including animal models for Niemann-Pick disease, see, e.g., Vaquer et al. Nat. Rev., 12:287-305, 2013. For an exemplary animal model of Niemann-Pick disease types A and B, see, e.g., Horinouchi et al., Nat. Genet, 10:288-293, 1995. For an exemplary animal model of Niemann-Pick disease type C, see, e.g., Maue et al., Hum. Mol. Genet, 21 :730-750, 2012.

Example 3. Assay of Sobetirome or a Sobetirome Prodrug

Sobetirome or a sobetirome prodrug may be assessed in a cell-based assay of Niemann-Pick disease. The use of cell-based assay will enable the inventor to assess the function of sobetirome or a sobetirome prodrug as effective therapeutic agents that regulate cholesterol transport and alter cholesterol metabolism. Methods used for imaging and analysis of cholesterol accumulation in lysosomal storage organelles (LSOs) for assessing Niemann-Pick disease are known in the art, see, e.g., Pipalia et al. J Lipid Res., 47:284-301 , 2006; Pipalia et al. PNAS, 108:5620-5625, 201 1 ; Pipalia et al. J Lipid Res., 58:695-708, 2017.

A general procedure for assay of sobetirome or a sobetirome prodrug in human fibroblasts is described herein. Human fibroblasts homozygous for the NPC1 -I 1061T mutation are plated in a 384 well plate. Sobetirome or a sobetirome prodrug is added at varying doses, generally 8-16 wells per dose and increasing concentration by successive factors of three to get a range of doses for the assay. A solvent, such as DMSO, is used as a negative control and vorinostat (see Pipalia et al. J Lipid Res., 58:695-708, 2017) is used as a standard positive control. The concentration range of sobetirome or a sobetirome prodrug used in the assay may range from 10 μΜ to 1000 μΜ. Cells are incubated for 3 days in a suitable growth medium such as MEM growth medium. Cells are then fixed with formaldelyde and stained with a fluorescent dye, usually filipin and a nuclear stain, for example Draq5. Finally, fluorescence images are acquired using an ImageXpress micro imaging system (Molecular Devices LLC, San Jose, CA). The cell count is obtained from the nuclear stain.

The NPC1 mutant cells have a bright cluster of filipin labeled LSOs. Free (i.e. unesterified) cholesterol levels in LSOs are determined quantitatively by automated image processing based on the binding of filipin to cholesterol. The LSO fluorescence per cell is determined. This is averaged for all the microscope fields at a certain concentration or dose of sobetirome or a sobetirome prodrug. From this measurement, a dose response curve can be prepared. The above procedure is repeated at least three times on separate days. 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 Niemann-Pick disease, comprising administering to the subject an effective amount of sobetirome or a sobetirome prodrug.

2. The method of claim 1 , wherein the Niemann-Pick disease is Niemann-Pick disease type A.

3. The method of claim 1 , wherein the Niemann-Pick disease is Niemann-Pick disease type B.

4. The method of claim 1 , wherein the Niemann-Pick disease is Niemann-Pick disease type C.

5. The method of claim 4, wherein the Niemann-Pick disease is Niemann-Pick disease type C1.

6. The method of claim 4, wherein the Niemann-Pick disease is Niemann-Pick disease type C2.

7. The method of any one of claims 1-6, wherein sobetirome or the sobetirome prodrug is administered orally, parenterally, or topically.

8. The method of claim 7, wherein sobetirome or the sobetirome prodrug is administered orally.

9. The method of claim 7, wherein sobetirome or the sobetirome prodrug is administered parenterally.

10. The method of claim 9, wherein sobetirome or the sobetirome prodrug is administered buccally, sublingually, sublabially, or by inhalation.

11. The method of claim 10, wherein sobetirome or the sobetirome prodrug is administered sublingually.

12. The method of claim 9, wherein sobetirome or the sobetirome prodrug is administered intramuscularly, intravenously, or subcutaneously.

13. The method of claim 9, wherein sobetirome or the sobetirome prodrug is

administered intra-arterially, intravenously, intraventricularly, intramuscularly, subcutaneously, intraspinally, intraorbitally, or intracranially.

14. The method of any one of claims 1 -13, wherein sobetirome or the sobetirome prodrug is administered at a dose of about 1 μς to about 1 mg.

15. The method of any one of claims 1 -14, wherein at least 10 μg of sobetirome or the sobetirome prodrug are administered.

16. The method of claim 15, wherein at least 30 μg of sobetirome or the sobetirome prodrug is administered.

17. The method of claim 16, wherein at least 50 μg of sobetirome or the sobetirome prodrug are administered.

18. The method of claim 17, wherein at least 70 μg of sobetirome or the sobetirome prodrug are administered.

19. The method of claim 18, wherein at least 100 μg of sobetirome or the sobetirome prodrug are administered.

20. The method of claim 19, wherein at least 200 μg of sobetirome or the sobetirome prodrug are administered.

21. The method of any one of claims 1 -20, wherein 500 μg or less of sobetirome or the sobetirome prodrug are administered.

22. The method of any one of claims 1 -20, wherein 400 μg or less of sobetirome or the sobetirome prodrug are administered.

23. The method of any one of claims 1 -20, wherein 200 μg or less of sobetirome or the sobetirome prodrug are administered.

24. The method of any one of claims 1 -20, wherein 100 μg or less of sobetirome or the sobetirome prodrug are administered.

25. The method of any one of claims 1 -17, wherein 70 μg or less of sobetirome or the sobetirome prodrug are administered.

26. The method of any one of claims 1 -25, wherein the administration of sobetirome or the sobetirome prodrug ameliorates one or more symptoms selected from the group consisting of seizures, ataxia, dysarthria, and dysphagia.

27. The method of any one of claims 1 -25, wherein sobetirome is administered.

28. The method of any one of claims 1 -25, wherein the sobetirome prodrug is administered.

29. A method of treating a subject having Niemann-Pick disease, comprising contacting a cell in the subject with sobetirome or a sobetirome prodrug.

30. The method of claim 29, wherein the Niemann-Pick disease is Niemann-Pick disease type A.

31. The method of claim 29, wherein the Niemann-Pick disease is Niemann-Pick disease type B.

32. The method of claim 29, wherein the Niemann-Pick disease is Niemann-Pick disease type C.

33. The method of claim 32, wherein the Niemann-Pick disease is Niemann-Pick disease type C1.

34. The method of claim 32, wherein the Niemann-Pick disease is Niemann-Pick disease type C2.

35. The method of any one of claims 29-34, wherein the cell is contacted with sobetirome.

36. The method of any one of claims 29-34, wherein the cell is contacted with the sobetirome prodrug.