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WO2018183940A1 - Méthodes et compositions destinées au traitement de la maladie de niemann-pick - Google Patents

Méthodes et compositions destinées au traitement de la maladie de niemann-pick Download PDF

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WO2018183940A1
WO2018183940A1 PCT/US2018/025539 US2018025539W WO2018183940A1 WO 2018183940 A1 WO2018183940 A1 WO 2018183940A1 US 2018025539 W US2018025539 W US 2018025539W WO 2018183940 A1 WO2018183940 A1 WO 2018183940A1
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sobetirome
prodrug
niemann
pick disease
administered
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IV George Mitchell GRASS
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Neurovia Inc
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Neurovia Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 

Definitions

  • the present invention relates to methods and compositions for treating Niemann- Pick disease (e.g., Niemann-Pick disease Type C).
  • Niemann- Pick disease e.g., Niemann-Pick disease Type C.
  • 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.
  • CNS central nervous system
  • 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).
  • Niemann-Pick disease type C1 and Niemann-Pick disease type C2 are 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.
  • 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.
  • 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.
  • the Niemann- Pick disease is Niemann-Pick disease type C2.
  • 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.
  • sobetirome or the sobetirome prodrug is administered at a dose of about 1 ⁇ to about 1 mg.
  • at least 10 ⁇ e.g., at least 30 ⁇ , at least 50 Mg, at least 70 ⁇ , at least 100 ⁇ , or at least 200 ⁇
  • 500 ⁇ or less e.g., 400 ⁇ or less, 200 ⁇ or less, 100 ⁇ or less, or 70 ⁇ g or less
  • sobetirome or the sobetirome prodrug are administered.
  • the administration of sobetirome or the sobetirome prodrug ameliorates one or more symptoms selected from the group consisting of seizures, ataxia, dysarthria, and dysphagia.
  • sobetirome is administered.
  • the sobetirome prodrug is administered.
  • 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.
  • 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.
  • the Niemann- Pick disease is Niemann-Pick disease type C2.
  • the cell is contacted with sobetirome. In other embodiments, the cell is contacted with the sobetirome prodrug.
  • the cell is a neuronal cell, fibroblast, neuron, macrophage, glial cell, astroglia, microglia, astrocyte, myelin producing cell, oligodendrocyte, Purkinje cell, or hepatocyte.
  • administering 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 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 2-6 alkenyl). Preferably, alkenyl is acyclic alkenyl (e.g., acyclic lower alkenyl). Alkenyl may be optionally substituted as described herein.
  • Alkyl refers to a branched or unbranched, cyclic or acyclic saturated hydrocarbon group containing from 1 to 24 carbon atoms.
  • 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.
  • alkyl is lower alkyl.
  • a lower alkyl group is a saturated branched or unbranched hydrocarbon having from 1 to 6 carbon atoms (C-
  • alkyl is acyclic alkyl (e.g., acyclic lower alkyl).
  • Alkyl may be optionally substituted as described herein.
  • Alkylamino 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— NX 1 X 2 or— (NX 1 X 2 X 3 ) + in which X 1 , X 2 , and X 3 are each independently H, a substituted alkyl, or an unsubstituted alkyl, provided that the group does not have the structure— NH 2 or— NH 3 + and the total number of non-hydrogen atoms does not exceed 24.
  • alkylamino groups include the following structures:— NHCH 3 ,— N(CH 3 ) 2 ,— NH(CH 3 ) 2 + ,— N(CH3) 3 + ,—
  • Alkylamino encompasses heteroalkyls containing one or two nitrogen atoms and one or more heteroatoms independently selected from the group consisting of oxygen and sulfur.
  • alkylamino also contemplates heterocycloalkyl groups containing one or two nitrogen atoms, for example, a group NX 1 X 2 X 3 , in which X 1 is H or a valency (e.g., X 1 is H), and X 2 and X 3 , together with the atom to which they are attached, are a 4- to 8- member ring that may contain valency, provided that NX 1 X 2 X 3 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., NX 1 X 2 X 3 , where X 1 is alkyl, and X 2 and X 3 , 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 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.
  • alkynyl is lower alkynyl.
  • a lower alkynyl group contains from 2 to 6 carbon atoms (C 2-
  • alkynyl is acyclic alkynyl (e.g., acyclic lower alkynyl).
  • Alkynyl may be optionally substituted as described herein.
  • Amide refers to a group with the structure— CONX 1 X 2 , where X 1 and X 2 are independently H or an organic group such as an alkyl or aryl group.
  • amino acid refers to a compound of formula NH(R 1 )-CH(R 2 )-COOH or to a group -NR 1 -CH(R 2 )-COOH, where R 1 is H and R 2 is optionally substituted alkyl, or R 1 and R 2 , together with the atom to which each is attached, combine to form an optionally substituted heterocyclyl.
  • amino acid is a proteinogenic amino acid. Proteinogenic amino acids are known in the art.
  • 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(R 1 )-CH(R 2 )-COOR 3 or to a group -NR 1 -CH(R 2 )-COOR 3 , where each or R 1 and R 2 are as defined above, and R 3 is optionally substituted alkyl.
  • Cycloalkenyl 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 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 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.
  • 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 refers to a group with the structure— COOX where X is a substituent described herein.
  • X is a substituent described herein.
  • an ethyl ester has the structure— COOCH 2 CH 3 .
  • Halogen or "halide,” as used interchangeably herein, refer to F, CI, Br, or I.
  • Heteroalkyl 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 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.
  • 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.”
  • 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, thiadiazoly
  • 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.
  • methylammonium 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 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
  • BHT butylated hydroxytoluene
  • calcium carbonate calcium phosphate (dibasic)
  • calcium stearate calcium stearate
  • croscarmellose crosslinked polyvinyl pyrrolidone
  • citric acid crospovidone
  • cysteine ethylcellulose
  • gelatin hydroxypropyl cellulose
  • hydroxypropyl cellulose hydroxypropyl
  • the pharmaceutically acceptable excipients or carriers useful for each specific mode of administration are described herein below.
  • sobetirome prodrug refers a sobetirome ester prodrug or sobetirome amide prodrug.
  • Sobetirome ester prodr is a compound of formula:
  • R 1 can be ethyl, 2- trimethylaminoethyl, (N-morpholinyl)ethyl, 2-(lysinoyl)aminoethyl, 2-(valinoyl)aminoethyl, 2- (phenylalaninoyl)aminoethyl, or glucosyl.
  • R 1 can be alkylamino, such as substituted alkylamino, cycloalkylamino or substituted cycloalkylamino.
  • R 1 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.
  • R 1 is:
  • R 2 is optionally substituted alkyl or optionally substituted aryl.
  • R 2 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.
  • R 2 is:
  • Subject 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.
  • 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.
  • a risk factor can be family history of Niemann-Pick disease.
  • a substituted group may have, valency permitting, for example, 1 , 2, 3, 4, 5, 6, 7, 8, or 9 substituents.
  • each hydrogen in a group may be replaced by a substituent group (e.g., perhaloalkyl groups such as -CF 3 or -CF 2 CF 3 or perhaloaryls such as -C 6 F 5 ).
  • a substituent may itself be further substituted, valency permitting, with unsubstituted substituents defined herein.
  • a substituent may be substituted with 1 , 2, 3, 4, 5, or 6 unsubstituted substituents as defined herein.
  • a lower C1-C6 alkyl or an aryl substituent group e.g., heteroaryl, phenyl, or naphthyl
  • aryl substituent group e.g., heteroaryl, phenyl, or naphthyl
  • 1 , 2, 3, 4, 5, or 6 substituents as described herein, if valency permits.
  • the invention provides methods and compositions for treating Niemann-Pick disease using sobetirome or a sobetirome prodrug.
  • Sobetirome a sobetirome prodrug.
  • Sobetirome is a compound of formula:
  • compositions that include an effective amount of sobetirome.
  • sobetirome is administered at a dose of about 1 ⁇ to about 1 mg (e.g., to about 500 ⁇ ). In certain embodiments, sobetirome is administered at a dose of about 10 ⁇ to about 100 ⁇ .
  • 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.
  • sobetirome is administered daily (e.g., once daily or twice daily).
  • sobetirome is administered to the subject once daily.
  • the effective amount is at least 30 ⁇ (e.g., at least 50 ⁇ , such as at least 100 ⁇ ). In some embodiments, the effective amount is at least 30 ⁇ (e.g., at least 50 ⁇ , such as at least 100 ⁇ ) daily.
  • the effective amount is at least 30 ⁇ (e.g., at least 50 ⁇ , such as at least 100 ⁇ ) twice daily. In particular embodiments, the effective amount is at least 30 ⁇ (e.g., at least 50 ⁇ , such as at least 100 ⁇ ) once weekly. In other embodiments, the effective amount is at least 30 ⁇ (e.g., at least 50 ⁇ , such as at least 100 ⁇ ) twice weekly. In certain embodiments, the effective amount is at least 30 ⁇ (e.g., at least 50 ⁇ , such as at least 100 ⁇ g) three times weekly. In some embodiments, the effective amount is 1 mg or less (e.g., 500 ⁇ g or less, e.g., 200 ⁇ or less).
  • a unit dosage form containing from 10 ⁇ g to 100 ⁇ g of sobetirome is administered once, twice, or three times per day. In some embodiments, a unit dosage form containing from 10 ⁇ g to 75 ⁇ g of sobetirome is administered once, twice, or three times per day. In other embodiments, a unit dosage form containing from 30 ⁇ g to 75 ⁇ g of sobetirome is administered once, twice, or three times per day. In particular embodiments, a unit dosage form containing from 10 ⁇ g to 50 ⁇ g of sobetirome is administered once, twice, or three times per day.
  • a unit dosage form containing from 30 ⁇ to 50 ⁇ of sobetirome is administered once, twice, or three times per day. In still other embodiments, a unit dosage form containing from 50 ⁇ g to 75 ⁇ g 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:
  • R 1 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.
  • R 1 is alkyl or aryl.
  • sobetirome prodrug is of the following formula:
  • R 2 is amino or alkylamino.
  • Another particular example is a compound of the following structure:
  • a sobetirome amide prodrug is a compound of formula:
  • R 2 is optionally substituted alkyl or optionally substituted aryl.
  • R 2 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.
  • R 2 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
  • 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.
  • 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).
  • a sobetirome prodrug is administered at a dose of about 1 ⁇ to about 1 mg (e.g., to about 500 ⁇ ). In certain embodiments, a sobetirome prodrug is administered at a dose of about 10 ⁇ to about 100 ⁇ .
  • 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.
  • a sobetirome prodrug is administered daily (e.g., once daily or twice daily).
  • a sobetirome prodrug is administered to the subject once daily.
  • the effective amount is at least 30 ⁇ (e.g., at least 50 ⁇ , e.g., at least 100 ⁇ ). In some embodiments, the effective amount is at least 30 ⁇ g (e.g., at least 50 ⁇ , e.g., at least 100 ⁇ ) daily.
  • the effective amount is at least 30 ⁇ g (e.g., at least 50 ⁇ , e.g., at least 100 ⁇ ) twice daily. In particular embodiments, the effective amount is at least 30 ⁇ (e.g., at least 50 ⁇ , e.g., at least 100 ⁇ ) once weekly. In other embodiments, the effective amount is at least 30 ⁇ (e.g., at least 50 ⁇ , e.g., at least 100 ⁇ ) twice weekly. In certain embodiments, the effective amount is at least 30 ⁇ (e.g., at least 50 ⁇ , e.g., at least 100 ⁇ g) three times weekly. In some embodiments, the effective amount is 1 mg or less (e.g., 500 ⁇ g or less, e.g., 200 ⁇ g or less).
  • a unit dosage form containing from 10 ⁇ g to 100 ⁇ g of a sobetirome prodrug is administered once, twice, or three times per day.
  • a unit dosage form containing from 10 ⁇ g to 75 ⁇ g of a sobetirome prodrug is administered once, twice, or three times per day.
  • a unit dosage form containing from 30 ⁇ g to 75 ⁇ g of a sobetirome prodrug is administered once, twice, or three times per day.
  • a unit dosage form containing from 10 ⁇ to 50 ⁇ of a sobetirome prodrug is administered once, twice, or three times per day.
  • a unit dosage form containing from 30 ⁇ g to 50 ⁇ g of a sobetirome prodrug is administered once, twice, or three times per day.
  • a unit dosage form containing from 50 ⁇ g to 75 ⁇ g of a sobetirome prodrug is administered once, twice, or three times per day.
  • Methods of the invention may be used in the treatment of Niemann-Pick disease.
  • 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
  • GM2 and GM3 sphingomyelin, sphingosine, and gangliosides
  • L/L late endosomes/lysosomes
  • 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 is administered daily.
  • sobetirome or a sobetirome prodrug is administered at a dose of about 50 ⁇ 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.
  • sobetirome or a sobetirome prodrug is administered daily.
  • 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.
  • sobetirome or a sobetirome prodrug is administered to the subject once daily.
  • 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.
  • 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 ⁇ g or less, e.g., 200 ⁇ g or less).
  • a unit dosage form containing from 10 ⁇ g to 100 ⁇ g of sobetirome or a sobetirome prodrug is administered once, twice, or three times per day.
  • a unit dosage form containing from 10 ⁇ g to 75 ⁇ g of sobetirome or a sobetirome prodrug is administered once, twice, or three times per day.
  • a unit dosage form containing from 30 ⁇ g to 75 ⁇ g of sobetirome or a sobetirome prodrug is administered once, twice, or three times per day.
  • 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.
  • a unit dosage form containing from 30 ⁇ g to 50 ⁇ g of sobetirome or a sobetirome prodrug is administered once, twice, or three times per day.
  • a unit dosage form containing from 50 ⁇ g to 75 ⁇ g of sobetirome or a sobetirome prodrug is administered once, twice, or three times per day.
  • 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.
  • 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.
  • 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).
  • excipients examples include 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.
  • 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.
  • 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.
  • 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 ⁇ to 1000 ⁇ .
  • 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.
  • 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.

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Abstract

L'invention concerne des méthodes de traitement d'une maladie de Niemann-Pick (par exemple, une maladie de Niemann-Pick de type C (par exemple, de type C1)) par administration d'une quantité efficace de sobetirome ou d'un promédicament de sobetirome à un patient atteint de la maladie de Niemann-Pick (par exemple, une maladie de Niemann-Pick de type C (par exemple, de type C1)). L'invention concerne également des compositions contenant du sobetirome ou un promédicament de sobetirome destinées à être utilisées dans le traitement de la maladie de Niemann-Pick (par exemple, une maladie de Niemann-Pick de type C (par exemple, de type C1)).
PCT/US2018/025539 2017-03-31 2018-03-30 Méthodes et compositions destinées au traitement de la maladie de niemann-pick Ceased WO2018183940A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120004165A1 (en) * 2010-06-21 2012-01-05 Sanofi Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments
US20160081955A1 (en) * 2013-05-03 2016-03-24 Oregon Health & Science University Sobetirome in the treatment of myelination diseases
US20160244418A1 (en) * 2015-02-20 2016-08-25 Oregon Health & Science University Derivatives of sobetirome

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120004165A1 (en) * 2010-06-21 2012-01-05 Sanofi Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments
US20160081955A1 (en) * 2013-05-03 2016-03-24 Oregon Health & Science University Sobetirome in the treatment of myelination diseases
US20160244418A1 (en) * 2015-02-20 2016-08-25 Oregon Health & Science University Derivatives of sobetirome

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "Niemann-PICK disease", WIKIPEDIA, THE FREE ENCYCLOPEDIA, 18 March 2017 (2017-03-18), pages 1 - 7, XP055542868, Retrieved from the Internet <URL:https://en.wikipedia.org/w/index.php?title=Niemann–Pick_disease&oldid=770972749> *
HAJHOSSEINY ET AL.: "The Ebbs and Flows in the Development of Cholesterol-Lowering Drugs: Prospects for the Future", CLINICAL PHARMACOLOGY AND THERAPEUTICS, vol. 96, no. 1, July 2014 (2014-07-01), pages 64 - 73, XP055542867 *
HOCHHOLZER ET AL.: "Does it Make Sense to Combine Statins with Other Lipid-Altering Agents Following AIM-HIGH, SHARP and ACCORD", CURR ATHEROSCLER REP, vol. 15, no. 1, 16 December 2012 (2012-12-16), pages 1 - 10, XP035165161 *

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