Methods for treating neurological disorders

Abstract

The present invention relates to methods for treating neurological disorders, and specifically discloses methods and compositions for treating, ameliorating, and / or preventing Alzheimer's disease in ApoE4-positive patients using certain compounds and compositions thereof.

Description

[0001] This application is a divisional application of Chinese invention patent application filed on March 23, 2015, with Chinese application number 201580015086.8 and invention title "Method for Treating Neurological Disorders".

[0002] Cross-reference to related applications

[0003] This application claims priority to U.S. Provisional Patent Application No. 61 / 968,595, filed March 21, 2014, which is incorporated herein by reference.

[0004] This application incorporates, for all purposes, the following disclosures: U.S. Application Publication No. 2008 / 0146642, filed October 12, 2007; U.S. Application Publication No. 2009 / 0182056, filed January 30, 2009; and U.S. Application Publication No. 2010 / 0113591, filed November 5, 2009. Technical Field

[0005] This article discloses methods and compositions for treating, improving, and / or preventing Alzheimer's disease in ApoE4-positive patients using specific compounds and their compositions. Background Technology

[0006] Alzheimer's disease (AD) is a progressive degenerative disease of the brain primarily associated with aging. In 2000, the prevalence of AD in the United States was close to 4.5 million. It is estimated that about one in ten individuals over the age of 65 and nearly half of those over the age of 85 are affected by Alzheimer's disease. Approximately 360,000 people are diagnosed with AD each year in the United States alone.

[0007] The clinical manifestations of Alzheimer's disease (AD) are characterized by loss of memory, cognition, reasoning, judgment, and orientation. As the disease progresses, motor, sensory, and language abilities are also affected until multiple cognitive functions are impaired across the board. These cognitive losses occur gradually but usually lead to severe impairment and eventual death within a four- to twelve-year timeframe.

[0008] Alzheimer's disease is characterized by two main pathological findings in the brain: neurofibrillary tangles and β-amyloid (or neuritis) plaques, which are primarily composed of aggregates of peptide fragments called β-amyloid peptide Aβ. Individuals with AD exhibit characteristic β-amyloid deposits in the brain (β-amyloid plaques) and characteristic β-amyloid deposits in cerebral blood vessels (β-amyloid angiopathy), as well as neurofibrillary tangles. Neurofibrillary tangles occur not only in Alzheimer's disease but also in other dementia-related conditions. Summary of the Invention

[0009] This disclosure generally relates to the treatment of neurological disorders, particularly Alzheimer's disease in a specific subgroup having one or more copies of the ApoE4 (or ε4) allele.

[0010] L-Valyl-3-aminopropanesulfonate (Val-APS) is an orally effective small-molecule prodrug of tramiprosate with improved pharmacodynamic properties. Tramiprosate was developed into a Phase 3 program involving approximately 2,000 patients, which was completed in 2007. However, the Val-APS prodrug exhibited significant advantages over tramiprosate, including improved GI tolerability, reduced nausea and vomiting, and decreased inter-subject pharmacokinetic variability. Furthermore, administration of this prodrug resulted in a beneficial 14.9-hour prolonged test time. 1 / 2 A once-daily dosing regimen is provided. Notably, oral administration of Val-APS resulted in approximately two-fold increases in plasma and brain exposure to tramiprosate in animals compared to administration of tramiprosate at an equimolar dose. Therefore, this disclosure provides for the administration of certain compounds comprising Val-APS to ApoE4-positive patients for the treatment of Alzheimer's disease.

[0011] Val-APS:

[0012] Attached Figure Description

[0013] Figure 1This study describes the reduction in ADAS-Cog scores following treatment with tramiprosate for Alzheimer's disease. At week 26, the score was -1.25 (82%) for 100 mg BID (P = 0.0219) and -1.03 (57%) for 150 mg BID (P = 0.118). At week 52, the score was -2.03 (35%) for 100 mg BID (P = 0.002) and -1.85 (32%) for 150 mg BID (P = 0.006). At week 65, the score was -1.52 (22%) for 100 mg BID (P = 0.024) and -1.90 (27%) for 150 mg BID (P = 0.005). At week 78, the incidence was -1.90 (27%) for 100 mg BID (P = 0.005) and -1.86 (21%) for 150 mg BID (P = 0.028). (n=599). Data are from Caltagirone et al., “The potential protective effect of tramiprosate (homotaurine) against Alzheimer's disease: a review,” Aging Clin Exp Res. Dec 2012; 24(6):580-7.

[0014] Figure 2 and Figure 3 A retrospective subgroup analysis of 599 ApoE4+ subjects using a mixed-effects repeated measures covariate model (MERM) demonstrated significant effects on both cognition and function (using ADAS-cog and CDR-SB).

[0015] Figure 4 Brain exposure to tramiprosate following oral administration of Val-APS (upper line) or tramiprosate (lower line) is shown. The AUC ratio of tramiprosate brain exposure induced by Val-APS to that induced by tramiprosate alone was approximately 2.1.

[0016] Figure 5 The results of the Phase 1 SAD trial in healthy elderly subjects are presented, demonstrating that oral Val-APS prodrug prolongs the t-reduction of tramiprosate. 1 / 2 .

[0017] Figure 6 Results of a Phase 1 SAD trial in healthy elderly subjects are presented, showing a reduction in the formation of metabolite NRM5074 after administration of Val-APS.

[0018] Figure 7 A study of SAD in normal HV was presented, demonstrating that orally administered Val-APS showed superior reduction in PK variability compared to MR tablets or LF capsules of tramiprosate. The loosely packed Val-APS capsules reduced PK variability by approximately 50%, and furthermore, the endpoint t 1 / 2 The duration of administration has been extended to 14.9 hours, allowing for once-daily dosing.

[0019] Figure 8 This study demonstrates the beneficial role of Tramiprosate, the active agent of Val-APS, in certain subgroups separated based on ApoE4 status. Data established significant improvements in ADAs-cog scores over time relative to placebo. Data are presented at weeks 13, 26, 39, 52, 65, and 78. The first column shows patients homozygous for ApoE4 (“ApoE4 + / +”), the second column shows combined data from both heterozygous and homozygous ApoE4 patients (“All ApoE4 Patients”), and the third column shows patients negative for ApoE4 (non-ApoE4). ApoE4 prevalence was associated with improved cognitive scores. Detailed Implementation

[0020] definition

[0021] The following definitions are used in conjunction with this disclosure: Unless otherwise defined, the term "subject" as used herein is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a non-human primate such as a monkey, chimpanzee, or baboon. In one embodiment, the subject is a human.

[0022] Unless otherwise defined, the term "pharmaceutically acceptable salt" as used herein refers to a salt of a basic group, such as an amino group, or an acidic group, such as a carboxyl group, on the compounds disclosed herein. Illustrative salts of basic groups include, but are not limited to: sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, hydrogen sulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannates, pantothenates, hydrogen tartrates, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glucuronides, sucrose salts, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, camphorsulfonates, and bis(hydroxynaphthyl)ates (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthyl)ates). Illustrative salts with acidic groups include, but are not limited to: lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, aluminum salts, chromium salts, iron salts, copper salts, zinc salts, cadmium salts, ammonium salts, guanidine salts, pyridinium salts, and organic ammonium salts.

[0023] As used herein and unless otherwise defined, the terms “hydrate” and “solvent” describe a compound or its salts, which further include chemically calculated or non-chemically calculated amounts of water or other solvents bound by non-covalent intermolecular forces.

[0024] "Effective amount" when used in combination with another therapeutic agent is the amount that can bind with the compound to effectively treat or prevent the condition. "In combination with" includes administration within the same composition and via different compositions; in the latter case, the other therapeutic agent is effective in treating or preventing the condition for the period during which the compound exerts its preventive or therapeutic effect, or vice versa.

[0025] The term “about” when used in conjunction with a reference number indicates that the reference number is added to or subtracted from that reference number by a maximum of 10%. For example, the language “about 50” covers the range of 45 to 55.

[0026] The term "amino acid" generally refers to an organic compound containing both a carboxylic acid group and an amine group. The term "amino acid" includes both "natural" and "non-natural" amino acids. Additionally, the term "amino acid" includes O-alkylated or N-alkylated amino acids, or S-alkylated or S-substituted or phosphorus-containing amino acids, and amino acids having nitrogen- or oxygen- or sulfur- or phosphorus-containing side chains (such as Lys, Orn, or Ser, Met), where the nitrogen- or oxygen- or sulfur- or phosphorus atom in the side chain has been acylated or alkylated. In some aspects, the nitrogen, oxygen, sulfur, and phosphorus atoms of the side chain are derivatized with groups other than acyl or alkyl groups. Amino acids can be pure L or D isomers or mixtures of L and D isomers, including racemic mixtures.

[0027] The term "natural amino acid" and its equivalent expression refer to L-amino acids commonly found in naturally occurring proteins. Examples of natural amino acids include, but are not limited to: alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asp), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), and β-alanine (β-ALA). In other respects, amino acids may not be L-amino acids. For example, γ-aminobutyric acid (GABA).

[0028] The term "non-natural amino acid" refers to any derivative of natural amino acids, including D-type, as well as α- and β-amino acid derivatives and any synthetic compounds containing amino and carboxyl groups. The terms "non-natural amino acid" and "non-existent amino acid" are used interchangeably herein and are intended to include the same part. It is noteworthy that some amino acids classified as non-natural amino acids herein, such as hydroxyproline, can be found in nature in certain organisms or specific proteins. Amino acids with many different protecting groups suitable for immediate use in the solid-phase synthesis of peptides are commercially available. In addition to the twenty most common naturally occurring amino acids, the following examples of non-natural amino acids and amino acid derivatives may be used as appropriate (common abbreviations in parentheses): 2-aminohexanoic acid (Aad), 3-aminohexanoic acid (β-Aad), 2-aminobutyric acid (2-Abu), α,β-dehydro-2-aminobutyric acid (8-AU), 1-aminocyclopropane-1-carboxylic acid (ACPC), aminoisobutyric acid (Aib), 3-aminoisobutyric acid (β-Aib), 2-amino-thiazoline-4-carboxylic acid, 5-aminovaleric acid (5-Ava), 6-aminohexanoic acid (6-Ahx), 2-aminoheptanoic acid (Ahe), 8-aminooctanoic acid (8-Aoc), 11-aminoundecanoic acid (11-Aun), 12-aminododecanoic acid (12-Ado), 2-aminobenzoic acid (2-Abz), 3-aminobenzoic acid (3-Abz), 4-aminobenzoic acid (4-Abz), 4-amino-3-hydroxy-6- Statine (Sta), methylheptanoic acid (Aoa), 2-aminotetrahydronaphthalene-2-carboxylic acid (ATC), 4-amino-5-cyclohexyl-3-hydroxyvalerate (ACHPA), p-aminophenylalanine (4-NH2-Phe), 2-aminopimelic acid (Apm), biphenylalanine (Blp), p-bromophenylalanine (4-Br-Phe), o-chlorophenylalanine (2-Cl-Phe), m-chlorophenylalanine (3-C l-Phe), p-chlorophenylalanine (4-Cl-Phe), m-chlorotyrosine (3-Cl-Tyr), p-benzoylphenylalanine (Bpa), tert-butylglycine (TLG), cyclohexylalanine (Cha), cyclohexylglycine (Chg), desmodium (Des), 2,2-diaminopimelic acid (Dpm), 2,3-diaminopropionic acid (Dpr), 2,4-diaminobutyric acid (Dbu), 3,4-dichlorophenylalanine (3,4-C 12-Phe), 3,4-difluorophenylalanine (3,4-F2-Phe), 3,5-diiodotyrosine (3,5-I2-Tyr), N-ethylglycine (EtGly), N-ethylasparagine (EtAsn), o-fluorophenylalanine (2-F-Phe), m-fluorophenylalanine (3-F-Phe), p-fluorophenylalanine (4-F-Phe), m-fluorotyrosine (3-F-Tyr), homoserine (Hse), homophenyl Alanine (Hfe), high tyrosine (Htyr), hydroxylysine (Hyl), allohydroxylysine (aHyl), 5-hydroxytryptophan (5-OH-Trp), 3- or 4-hydroxyproline (3- or 4-Hyp), p-iodophenylalanine (4-I-Phe), 3-iodotyrosine (3-I-Tyr), dihydroindole-2-carboxylic acid (Idc), isodexin (Ide), alloisoleucine (a-Ile), isoperidinic acid ( LNP), N-methyl isoleucine (MeIle), N-methyl lysine (MeLys), m-methyl tyrosine (3-Me-Tyr), N-methyl valine (MeVal), 1-naphthylalanine (1-NaI), 2-naphthylalanine (2-NaI), p-nitrophenylalanine (4-NO2-Phe), 3-nitrotyrosine (3-NO2-Tyr), ortholeucine (Nle), orthovaline (Nva), ornithine (Orn), 1-phosphotyrosine (H2PO3-Tyr), octahydroindole-2-carboxylic acid (Oic), penicillamine (Pen), pentafluorophenylalanine (F5-Phe), phenylglycine (Phg), piperidinic acid (Pip), propargyl glycine (Pra), pyroglutamic acid (PGLU), sarcosine (Sar), tetrahydroisoquinoline-3-carboxylic acid (Tic), thiophene alanine, and thiazolidin-4-carboxylic acid (thioproline, Th).

[0029] “C max "" refers to the peak plasma concentration of the drug or compound of the present invention after administration.

[0030] “T max "This refers to reaching C" max The time.

[0031] AUC 0-t "" refers to the area under the curve in a graph showing the plasma concentration of the drug or compound of the present invention relative to time. In some embodiments of the present invention, t is infinity ( And AUC 0-∞ It refers to the total drug exposure over time.

[0032] “T 1 / 2 "" refers to the biological half-life of a drug, and is the time it takes for the drug or compound of the present invention to lose half of its pharmacological, physiological or biological activity.

[0033] ApoE4 and Alzheimer's disease

[0034] The ε4 allele of the apolipoprotein E gene is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). ApoE4+ patients, possessing at least one ε4 allele, account for 50-60% of AD cases, compared to 25% in healthy individuals. ApoE4+ AD patients exhibit decreased age of onset, increased severity, and accelerated AD progression. Patients with two ε4 alleles account for 10-14% of AD cases and exhibit even more aggressive disease progression. The ε4 allele leads to increased Aβ amyloid deposition in the brain, increased CSF tau and p-tau, and faster cognitive decline. Furthermore, dementia patients carrying one or both ε4 alleles of ApoE are more likely to have AD, resulting in a significantly lower misdiagnosis rate in clinical studies (2% compared to 42% in non-ApoE4 patients).

[0035] The ApoE4 allele is strongly associated with Alzheimer's disease in patients with dementia, and therefore, its presence is used to reduce misdiagnosis in clinical studies. The misdiagnosis rate for dementia patients with AD is 2% in ApoE4-positive patients. In contrast, 42% of non-ApoE4 dementia patients have been reported to be misdiagnosed with AD.

[0036] Methods and compositions for treating ApoE4+ patients

[0037] This article discloses methods for treating and / or preventing Alzheimer's disease in patients carrying one or both copies of the ApoE4 allele. Compositions for said treatment and prevention are also disclosed. 3-Amino-1-propanesulfonic acid (3-APS, Tramiprosate, Alzheimer's) TM) is a promising investigational product candidate for the treatment of Alzheimer's disease, having undergone Phase III clinical trials in North America and Europe (Wright, TM, Drugs of Today (2006), 42(5):291-298). Developed by Neurochem Inc. (Laval, QC, Canada), this product is believed to act by binding to soluble Aβ monomers to reduce obstructive amyloid aggregation, deposition, and / or amyloid load in the brain. To enhance the therapeutic effect of 3-APS, it is desirable to increase maternal exposure after oral administration, metabolic stability, and / or increase 3-APS exposure, while minimizing pharmacokinetic variability among subjects. Prodrug compounds of 3-amino-1-propanesulfonic acid (3-APS) and pharmaceutical compositions thereof meet these and other requirements. Advantageously, these drugs have shown significant efficacy in treating specific subgroups. Specifically, this article discloses methods for the treatment and / or prevention of Alzheimer's disease in patients with homozygous or heterozygous ApoE4 alleles.

[0038] compound

[0039] In one embodiment, the applied compound is a compound of formula I:

[0040] (I)

[0041] It includes pharmaceutically acceptable salts, hydrates, and solvates, of which AA1 and AA2 are amino acids.

[0042] In some embodiments, AA1 and AA2 are independently selected from the group consisting of natural and non-natural amino acids. In further embodiments, AA1 and AA2 are independently selected from the group consisting of natural amino acids.

[0043] In the specific implementation scheme, AA1 and AA2 are independently selected from alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), β-alanine (β-ALA), and γ-aminobutyric acid (GABA). In other respects, either or both of AA1 and AA2 are O-benzylserine (O-BnSer) or O-benzylglutamine (O-BnGln).

[0044] In a further embodiment, AA1 and AA2 of Formula I are various of the following:

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056] Preferred implementation schemes are: I-11, I-199, I-208, I-214, I-221, I-231, I-236, I-240, I-419, and I-438. Additionally, OBnSer-Val, Ile-OBnSer, and OBnSer-Ile are also preferred.

[0057] In one embodiment, compounds of formula II are disclosed herein:

[0058] (II)

[0059] And pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein AA1 is an amino acid. In some embodiments, AA1 is selected from the group consisting of natural and non-natural amino acids. In further embodiments, AA1 is selected from the group consisting of natural amino acids.

[0060] In specific implementation schemes, AA1 is selected from alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), β-alanine (β-ALA), and γ-aminobutyric acid (GABA). In other aspects, AA1 is O-benzylserine (O-BnSer) or O-benzylglutamic acid (O-BnGlu).

[0061] Therefore, the implementation scheme disclosed herein includes AA1 of the following formula II:

[0062]

[0063] In specific implementation schemes, AA1 is selected from Val, Leu, Ser, Ala, OBnSer, and Ile.

[0064] Pharmaceutical Composition

[0065] For administration purposes, in some embodiments, the compounds described herein are administered as raw material chemicals or formulated into pharmaceutical compositions. The pharmaceutical compositions disclosed herein comprise compounds of formulas I and II, and one or more pharmaceutically acceptable carriers. The compounds of formulas I and II are present in the composition in an amount sufficient to effectively treat the specific disease or symptom of concern. The activity of the compounds of formulas I and II can be determined by those skilled in the art, for example, as described in the examples below. Appropriate concentrations and dosages can be readily determined by those skilled in the art.

[0066] The compounds and their compositions can be administered orally. They can also be administered via any other convenient route, such as intravenous infusion or bolus injection, absorption via epithelial or mucosal skin linings (e.g., oral mucosa, rectal and intestinal mucosa), and may be administered with another bioactive agent. Administration can be systemic or local. Various delivery systems are known, for example, encapsulation in liposomes, microparticles, microcapsules, capsules, etc., and can be used to administer the compounds. In some embodiments, more than one compound is administered to the subject. Methods of administration include, but are not limited to: intradermal, intramuscular (including reservoirs), intraperitoneal, intravenous, subcutaneous (including reservoirs), intranasal, epidural, oral, sublingual (including fast-dissolving tablets, gels, or equivalents), intranasal, intracerebral, intravaginal, percutaneous, transrectal, intrapulmonary (aerosols or equivalents, including by inhalation), or topical, particularly for use in the ear, nose, eye, or skin.

[0067] This composition comprises a therapeutically effective amount of the disclosed compound (optionally one or more compounds) and a suitable amount of a pharmaceutically acceptable carrier to provide a form for administration to a subject.

[0068] This composition may be taken in the form of a solution, suspension, emulsion, tablet, pill, granule, capsule, liquid-containing capsule, powder, sustained-release formulation, suppository, emulsion, aerosol, spray, suspension, or any other suitable form. In one embodiment, a pharmaceutically acceptable medium is a capsule (see, for example, U.S. Patent No. 5,698,155). Other examples of suitable pharmaceutical mediators are described by EWMartin in Remington's Pharmaceutical Sciences, which is incorporated herein by reference in its entirety to provide teaching on pharmaceutical compositions and methods of administration thereof.

[0069] In some embodiments of the invention, the compounds of the invention or their pharmaceutical salts may be coated onto or impregnated into a suitable implantable medical device. In a further embodiment of the invention, the coated or impregnated device will provide controlled release of the compounds of the invention or their pharmaceutical salts. In a specific embodiment of the invention, the medical device is a disc.

[0070] In some embodiments, the compounds and compositions are formulated according to conventional procedures into pharmaceutical compositions suitable for intravenous administration to humans. The compounds and compositions for intravenous administration may be solutions of sterile isotonic buffer solutions. The compositions may also include solubilizers. The components may be provided individually or in combination in unit dosage forms (e.g., as dry lyophilized powders or anhydrous concentrates) in closed containers such as ampoules or capsules.

[0071] Compounds and compositions thereof for oral delivery may be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs. Compounds and compositions thereof for oral delivery may also be formulated in foods and food mixtures. Orally administered compositions may contain one or more optional agents, such as sweeteners like fructose, aspartame, or saccharin; flavoring agents like peppermint, wintergreen oil, or cherry; coloring agents; and preservatives, to provide a pharmaceutically palatable formulation. The compositions may be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action over a prolonged period. Selective permeable membranes surrounding permeation-driven compounds are also suitable for orally administered compounds and compositions thereof. Time-delaying materials such as glyceryl monostearate or glyceryl stearate may also be used. Oral compositions may include standard mediators such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate.

[0072] In some embodiments, the compound or composition may be in the form of beads or microtablets. Microtablets (also described in the literature as tiny tablets or microcapsules) are small tablets typically having a diameter (or length) of about 0.5 mm to about 10 mm. Microtablets are typically prepared by techniques known in the art, such as pressing granules after wet or dry granulation; direct compression of blends; or any other tableting technique known in the art.

[0073] In a further embodiment, the compound and compositions thereof may be formulated into multiple dosage forms, i.e., into a multi-particulate dosage form comprising one or more groups of coated beads or microtablets for oral administration (e.g., hard gelatin capsules or conventional tablets prepared using a rotary tablet press). Conventional tablets disperse rapidly upon entering the stomach. The one or more groups of coated beads or microtablets may be compressed into tablets together with suitable excipients (e.g., binders, diluents / fillers, and disintegrants for conventional tablets).

[0074] The compounds and compositions thereof, in tablet, pill, bead, or microtablet form, may be coated or otherwise mixed to provide the advantages of controlled release, including delayed or prolonged release, or protection from the acidic conditions of the stomach. For example, tablets or pills may include an internal dose and an external dose component, the latter being a coating covering the former. These two components may be separated by a polymer layer that controls the release of the internal dose.

[0075] In some embodiments, the layer may comprise at least one enteric polymer. In a further embodiment, the layer may comprise a combination of at least one enteric polymer and at least one water-insoluble polymer. In an even further embodiment, the layer may comprise a combination of at least one enteric polymer and at least one water-soluble polymer. In yet another further embodiment, the layer may comprise a combination of at least one enteric polymer and a pore-forming agent.

[0076] In some embodiments, the layer may comprise at least one water-insoluble polymer. In a further embodiment, the layer may comprise a combination of at least one water-insoluble polymer and at least one water-soluble polymer. In yet another embodiment, the layer may comprise a combination of at least one water-insoluble polymer and a pore-forming agent.

[0077] Representative examples of water-soluble polymers include polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), and polyethylene glycol.

[0078] Representative examples of enteric polymers include cellulose esters and their derivatives (cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate), polyvinyl acetate phthalates, pH-sensitive methacrylate-methyl methacrylate copolymers, and shellac. These polymers can be used as dry powders or aqueous dispersions. Some commercially available materials are methacrylate copolymers (L100, S100, L30D) manufactured by Rohm Pharma and sold under the trademark Eudragit, Cellacefate (cellulose acetate phthalate) from Eastman Chemical Co., Aquateric (cellulose acetate phthalate aqueous dispersion) from FMC Corp., and Aqoat (hydroxypropyl methylcellulose acetate succinate aqueous dispersion) from Shin Etsu KK.

[0079] Representative examples of useful water-insoluble polymers include ethyl cellulose, polyvinyl acetate (e.g., Kollicoat SR#30D from BASF), cellulose acetate, cellulose acetate butyrate, neutral copolymers based on ethyl acrylate and methyl methacrylate, copolymers of acrylates and methacrylates with quaternary ammonium groups, such as EudragitNE, RS and RS30D, RL or RL30, etc.

[0080] Any of the above-described polymers may be further plasticized with one or more pharmaceutically acceptable plasticizers. Representative examples of plasticizers include triacetin, tributyl citrate, triethyl citrate, acetylated tri-n-butyl citrate, diethyl phthalate, castor oil, dibutyl sebate, acetylated monoglycerides, and mixtures thereof. When used, the plasticizer may comprise about 3 to 30% by weight of the polymer, and more typically about 10 to 25% by weight. The type and amount of the plasticizer depend on the properties of the one or more polymers and the coating system (e.g., aqueous or solvent-based, solution or dispersion, and total solids).

[0081] The term "carrier" refers to diluents or fillers, disintegrants, precipitation inhibitors, surfactants, flow aids, binders, lubricants, antioxidants, and other excipients and mediators used in conjunction with a compound. Carriers are generally described herein and in "Remington's Pharmaceutical Sciences" by EW Martin. Examples of carriers include, but are not limited to: aluminum monostearate, aluminum stearate, carboxymethyl cellulose, sodium carboxymethyl cellulose, crospovidone, glyceryl isostearate, glyceryl monostearate, hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxyoctadecyl stearate, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, lactose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 188, poloxamer 237, poloxamer 407, povidone, silica, colloidal silica, silicone, silicone binder 4102, and silicone emulsions. However, it should be understood that the carriers selected for use in the pharmaceutical compositions provided in this disclosure and the amounts of these carriers in the compositions can vary depending on the formulation method (e.g., dry granulation, solid dispersion).

[0082] The terms "diluent" or "filler" generally refer to substances used to dilute a compound of interest prior to delivery. Diluents can also be used to stabilize compounds. Examples of diluents may include starch, sugars, disaccharides, sucrose, lactose, polysaccharides, cellulose, cellulose ethers, hydroxypropyl cellulose, sugar alcohols, xylitol, sorbitol, maltitol, microcrystalline cellulose, calcium carbonate or sodium carbonate, lactose, lactose monohydrate, dicalcium phosphate, cellulose, compressible sugars, dehydrated dicalcium phosphate, mannitol, microcrystalline cellulose, and calcium phosphate.

[0083] The term "disintegrant" generally refers to a substance that, upon addition to a solid dosage form, promotes the disintegration or breakdown of the solid dosage form after administration and allows the active ingredient to be released as efficiently as possible to allow for rapid dissolution. Examples of disintegrants may include corn starch, sodium glycolate starch, croscarmellose sodium, crospovidone, microcrystalline cellulose, modified corn starch, sodium carboxymethyl starch, povidone, pregelatinized starch, and alginate.

[0084] The term "precipitation inhibitor" generally refers to a substance that prevents or inhibits the precipitation of an active agent. An example of a precipitation inhibitor is hydroxypropyl methylcellulose.

[0085] The term "surfactant" generally refers to a compound that reduces the surface tension between two liquids or between a liquid and a solid. Examples of surfactants include poloxamer and sodium lauryl sulfate.

[0086] The term "glide agent" generally refers to a substance used in tablet and capsule formulations to improve flowability during compression and to produce an anti-caking effect. Examples of glide agents can include colloidal silica, talc, calcined silica, starch, starch derivatives, and bentonite.

[0087] The term "adhesive" generally refers to any pharmaceutically acceptable membrane that can be used to bind inert components of an active ingredient and a carrier together to maintain adhesive and discrete parts. Examples of adhesives may include hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, copovidone, ethyl cellulose, gelatin, and polyethylene glycol.

[0088] The term "lubricant" generally refers to a substance added to powder blends to prevent compacted powder clumps from adhering to equipment during tableting or encapsulation. Lubricants can assist tablets in being ejected from a mold and can improve powder flow. Examples of lubricants can include magnesium stearate, stearic acid, silica, fats, calcium stearate, polyethylene glycol, sodium stearoyl fumarate, or talc; and solubilizers such as fatty acids, including lauric acid, oleic acid, and C8 / C... 10 fatty acid.

[0089] In some embodiments, the dosage is given based on the weight of 3-amino-1-propanesulfonic acid (3-APS or APS). In further embodiments, the dosage refers to the prodrug or compound of this disclosure and its pharmaceutically acceptable salts, hydrates, and solvates. The dosage described herein refers to the total amount administered; that is, if more than one compound is administered, the dosage may correspond to the total amount of the compound administered. The oral composition may contain 10% to 95% of the active ingredient by weight.

[0090] In some embodiments, the dosage range for oral administration is generally from about 0.001 mg to about 2000 mg of compound / kg body weight. In some embodiments, the oral dosage is 0.01 mg to 100 mg / kg body weight, 0.1 mg to 50 mg / kg body weight, 0.5 mg to 20 mg / kg body weight, or 1 mg to 10 mg / kg body weight. In some embodiments, the oral dosage is 5 mg of compound / kg body weight.

[0091] In a further embodiment, the dose is from about 10 mg to about 1000 mg, including all ranges and subranges therein.For example, about 10 mg to about 900 mg, about 10 mg to about 800 mg, about 10 mg to about 700 mg, about 10 mg to about 600 mg, about 10 mg to about 500 mg, about 10 mg to about 400 mg, about 10 mg to about 300 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 150 mg, about 10 mg to about 100 mg, about 10 mg to about 50 mg, about 50 mg to about 900 mg, about 50 mg to about 800 mg, about 50 mg to about 700 mg, about 50 mg to about 600 mg, about 50 mg to about 500 mg, about 50 mg to about 400 mg, about 50 mg to about 300 mg, about 50 mg to about 250 mg, about 50 mg to about 200 mg, about 50 mg to about 150 mg, about 50 mg to about 100 mg, about 100 mg to about 9 ... mg to about 800 mg, about 100 to about 700 mg, about 100 mg to about 600 mg, about 100 mg to about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 300 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 150 mg to about 250 mg, about 150 mg to about 300 mg, about 150 mg to about 400 mg, about 150 mg to about 500 mg, about 200 mg to about 900 mg, about 200 mg to about 800 mg, about 200 to about 700 mg, about 200 mg to about 500 mg, about 200 mg to about 400 mg, about 200 mg to about 300 mg, about 200 mg to about 250 mg, about 300 mg to about 900 mg, about 300 mg to about 800 mg. mg, about 300 to about 700 mg, about 300 to about 600 mg, about 300 mg to about 500 mg, about 300 mg to about 400 mg, about 400 mg to about 900 mg, about 400 mg to about 800 mg, about 400 to about 700 mg, about 400 to about 600 mg, about 400 mg to about 500 mg, about 500 mg to about 900 mg, about 500 mg to about 800 mg, about 500 to about 700 mg, about 500 to about 600 mg, about 100 mg to about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 300 mg, about 100 mg to about 250 mg. In a specific embodiment, the range is about 150 mg to about 400 mg.

[0092] In a further embodiment, the dosage is 10 mg, 25 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg.

[0093] Treatment

[0094] This disclosure also provides the use of the disclosed compounds in the manufacture of a medicament for treating patients with ApoE4-positive Alzheimer's disease. This disclosure also provides methods for treating or preventing the aforementioned disease, comprising administering a therapeutically effective amount of the compound or a composition comprising the compound to a subject in need, preferably a human subject. Therefore, relevant aspects of this disclosure relate to the prevention and / or treatment of Alzheimer's disease in ApoE4-positive humans by administering an effective amount of the disclosed compound or composition to a human subject in need.

[0095] This disclosure also provides a method for treating or preventing the aforementioned diseases, comprising administering a therapeutically effective amount of the compound or a composition comprising the compound to a subject in need, preferably a human subject, wherein the patient has a heterozygous or homozygous ApoE4 (or ε4) allele (i.e., an ApoE4 positive patient).

[0096] Identifying ApoE4-positive patients can be done using any specific method that can determine whether a patient has one or both copies of the ApoE4 (or ε4) allele. Specifically, sequencing technology is used to analyze a patient's genotype before administering the compound.

[0097] In some implementations, the efficacy of a compound can be determined using the ADAS-cog (Alzheimer's Disease Assessment Scale - Cognitive Subscale). ADAS is designed to measure the severity of the most important symptoms of Alzheimer's disease (AD). Its subscale, ADAS-cog, is the most commonly used cognitive test in clinical trials of nootropic drugs. It consists of 11 tasks that measure interference with memory, language, practical skills, attention, and other cognitive abilities (often referred to as core symptoms of AD). ADAS-cog helps evaluate cognition and differentiate between normal and impaired cognitive function. It is particularly useful for determining the degree of cognitive decline and can help assess an individual's stage of Alzheimer's disease based on their answers and scores. ADAS-cog can be used in clinical trials to determine incremental improvements or declines in cognitive function. An increase in ADAS-cog scores compared to placebo indicates improved cognitive function.

[0098] The compound or composition comprising the compound may be administered once, twice, three times, or four times daily in any of the suitable manner described above. Furthermore, in some embodiments, administration of a compound according to any chemical formula described herein, or treatment with such a compound, may continue for many weeks; for example, treatment will typically last for at least 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, or 104 weeks. In yet further embodiments, administration of a compound according to any chemical formula described herein, or treatment with such a compound, may continue for many months; for example, treatment will typically last for at least 2, 4, 6, 8, 10, 12, 15, 18, 20, or 24 months. In a further embodiment, the application of a compound according to any chemical formula described herein or the use of such compounds for treatment may continue indefinitely. In a further embodiment, the application of a compound according to any chemical formula described herein or the use of such compounds for treatment may continue until the ADAS-Cog score improves by approximately 1.5 to approximately 4.5 times. In some aspects, the improvement in score is approximately 1.5 times, approximately 2.0 times, approximately 3.5 times, approximately 4.0 times, approximately 4.5 times, approximately 5.0 times, approximately 7.5 times, approximately 10.0 times, or approximately 15.0 times. In a specific aspect, the improvement is approximately 1.5 times to approximately 10.0 times.

[0099] In a further embodiment, the administration of compounds of any chemical formula described herein, or the use of them for treatment, may continue until the metabolite NRM5074 is present in the plasma. The presence of the metabolite can be detected and quantified by LC / MS / MS bioanalytical methods.

[0100] In one specific implementation, Val-APS is administered orally in loosely filled capsules and provides an extended half-life. For example, Val-APS delivered in loosely filled capsules provides a half-life of approximately 10 hours to approximately 18 hours.

[0101] The content of each cited application and journal article is incorporated by reference as if it were fully explained in this article.

[0102] Example

[0103] Example 1

[0104] 3. APS treatment improved ADAS-Cog scores in all ApoE4+ subjects (heterozygous and homozygous).

[0105] Administer 150 mg BID and 100 mg BID of 3APS or placebo to the patient. Measure ADAS-Cog results. Data confirm the reduction in 3APS delay score. See also Figure 1 See the table below. A small improvement in ADAS-cog was observed at 13 weeks. The difference increased over time. From approximately week 52, placebo patients showed a significantly improved level of cognitive decline compared to the two treatment groups in this study (i.e., 100 mg BID and 150 mg BID).

[0106] Merged dataset of ADAS-Cog from the ApoE4 subgroup

[0107]

[0108] Merged dataset of ADAS-Cog changes in different APOE states (<80 years old)

[0109]

[0110] ADAS-Cog changes in different ApoE states in North American trials

[0111]

[0112] In addition to treatment with acetylcholinesterase inhibitors and / or memantine, tramiprosate also produced clinically meaningful improvements in cognition (ADAS-cog) and function (CDR-SB) over an 18-month period (tramiprosate 150 mg BID, n=183; ADAS-cog: slope p<0.01 relative to placebo, and p<0.05 at week 78; CDR-SB: slope p<0.01 relative to placebo, and p<0.05 at week 78). See also Figure 2 and Figure 3 .

[0113] Example 2

[0114] Val-APS showed improved brain accumulation and improved plasma half-life compared to 3APS.

[0115] Figure 4 This demonstrates the improved brain accumulation achieved by using the Val-APS prodrug compared to using tramiprosate. Enhanced accumulation at the site of action was achieved through the use of the prodrug. Figure 5 Further explanation of the improved pharmacological properties of Val-APS. When tramiprosate was administered as Val-APS (NRM8499), APS exhibited a prolonged t1 / 2. Figure 7 The summarized data demonstrate the improved properties of loosely filled Val-APS capsules compared to capsule and tablet forms of 3APS (tramiprosate). Data showed that when Val-APS was administered in loosely filled capsules, the t1 / 2 increased to 14.9 ± 3.9.

[0116] Example 3

[0117] 3APS showed significant efficacy in ApoE4-positive patients.

[0118] Patients were administered 3APS and ADAS-Cog results were obtained at different time points. Patient genotypes were then analyzed to detect the presence of the ApoE4 allele. Figure 8 This study demonstrates the beneficial role of tramiprosate, the active agent of Val-APS, in certain subgroups segregated based on Apo E4 status. Data established significant improvements in ADAs-cog scores over time relative to placebo. Data are presented at weeks 13, 26, 39, 52, 65, and 78. The first column shows patients homozygous for ApoE4 (“ApoE4 + / +”), the second column shows combined data from both heterozygous and homozygous ApoE4 patients (“ApoE4 all-rounders”), and the third column shows patients negative for ApoE4 (non-ApoE4). ApoE4 prevalence was associated with improved cognitive scores. Notably, patients heterozygous for the E4 allele showed particularly significant improvements. Overall, these data demonstrate a 4-point improvement in cognitive function relative to placebo in homozygous ApoE4 subjects (tramiprosate; 150 mg BID, n=34), reaching an ADAS-cog score of 4.62 after 18 months of treatment (p<0.01).

[0119] This disclosure relates to the following implementation plan.

[0120] 1. A method for treating Alzheimer's disease in ApoE4-positive patients, comprising the following steps:

[0121] (i) Testing for the ApoE4 allele in Alzheimer's disease patients,

[0122] (ii) Characterize patients with the ApoE4 allele as ApoE4 positive, and

[0123] (iii) Administering the compound of formula I to the ApoE4-positive patients for a period of time.

[0124] (I)

[0125] The time period mentioned above is at least 13 weeks;

[0126] The ADAS-cog score was tested at the end of the said time period and showed an improvement of at least approximately 1.5 times compared to administering a placebo to the ApoE4-positive patients during the same time period.

[0127] 2. The method according to embodiment 1, wherein the Alzheimer's disease patient is heterozygous for the ApoE4 allele.

[0128] 3. The method according to embodiment 1, wherein the Alzheimer's disease patient is homozygous for the ApoE4 allele.

[0129] 4. The method according to embodiment 1, wherein the time period is at least 26 weeks and the improvement is at least about 2.20 times.

[0130] 5. The method according to embodiment 1, wherein the time period is at least 39 weeks and the improvement is at least about 3.0 times.

[0131] 6. The method according to embodiment 1, wherein the time period is at least 65 weeks and the improvement is at least about 4.5 times.

[0132] 7. The method according to embodiment 1, wherein AA1 and AA2 are independently selected from alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), β-alanine (β-ALA), and γ-aminobutyric acid (GABA).

[0133] 8. A method for treating Alzheimer's disease in ApoE4-positive patients, comprising the following steps:

[0134] (i) Testing for the ApoE4 allele in Alzheimer's disease patients,

[0135] (ii) Characterize patients with the ApoE4 allele as ApoE4 positive, and

[0136] (iii) Administering the compound of formula I to the ApoE4-positive patients for a period of time.

[0137] (II);

[0138] The time period mentioned above is at least 13 weeks;

[0139] The ADAS-cog score was tested at the end of the said time period and showed an improvement of at least approximately 1.5 times compared to administering a placebo to the ApoE4-positive patients during the same time period.

[0140] 9. The method according to embodiment 8, wherein the Alzheimer's patient is heterozygous for the ApoE4 allele.

[0141] 10. The method according to embodiment 8, wherein the Alzheimer's disease patient is homozygous for the ApoE4 allele.

[0142] 11. The method according to embodiment 8, wherein the time period is at least 26 weeks and the improvement is at least about 2.20 times.

[0143] 12. The method according to embodiment 8, wherein the time period is at least 39 weeks and the improvement is at least about 3.0 times.

[0144] 13. The method according to embodiment 8, wherein the time period is at least 65 weeks and the improvement is at least about 4.5 times.

[0145] 14. The method according to embodiment 8, wherein AA1 is selected from the group consisting of: alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), β-alanine (β-ALA), and γ-aminobutyric acid (GABA).

[0146] 15. The method according to embodiment 14, wherein AA1 is selected from the group consisting of alanine (Ala), isoleucine (Ile), leucine (Leu), serine (Ser) and valine (Val).

[0147] 16. The method according to embodiment 15, wherein AA1 is valine (Val).

[0148] 17. The method according to embodiment 8, wherein the compound is applied once daily.

Claims

1. A method for treating Alzheimer's disease in ApoE4-positive patients, comprising the following steps: (i) Testing for the ApoE4 allele in Alzheimer's disease patients, (ii) Characterize patients with the ApoE4 allele as ApoE4 positive, and (iii) Administering the compound of formula I to the ApoE4-positive patients for a period of time. (I) The time period mentioned above is at least 13 weeks; The ADAS-cog score was tested at the end of the said time period and showed an improvement of at least approximately 1.5 times compared to administering a placebo to the ApoE4-positive patients during the same time period.

2. The method of claim 1, wherein the Alzheimer's patient is heterozygous for the ApoE4 allele.

3. The method of claim 1, wherein the Alzheimer's patient is homozygous for the ApoE4 allele.

4. The method of claim 1, wherein the time period is at least 26 weeks and the improvement is at least about 2.20 times.

5. The method of claim 1, wherein the time period is at least 39 weeks and the improvement is at least about 3.0 times.

6. The method of claim 1, wherein the time period is at least 65 weeks and the improvement is at least about 4.5 times.

7. The method according to claim 1, wherein AA1 and AA2 are independently selected from alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), β-alanine (β-ALA), and γ-aminobutyric acid (GABA).

8. A method for treating Alzheimer's disease in ApoE4-positive patients, comprising the following steps: (i) Testing for the ApoE4 allele in Alzheimer's disease patients, (ii) Characterize patients with the ApoE4 allele as ApoE4 positive, and (iii) Administering the compound of formula I to the ApoE4-positive patients for a period of time. (II); The time period mentioned above is at least 13 weeks; The ADAS-cog score was tested at the end of the said time period and showed an improvement of at least approximately 1.5 times compared to administering a placebo to the ApoE4-positive patients during the same time period.

9. The method according to claim 8, wherein AA1 is selected from the group consisting of: alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), β-alanine (β-ALA), and γ-aminobutyric acid (GABA).

10. The method of claim 8, wherein the compound is applied once daily.

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