WO2018118941A1 - Amino acid compositions and methods for the treatment of liver diseases - Google Patents

Amino acid compositions and methods for the treatment of liver diseases Download PDF

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Publication number
WO2018118941A1
WO2018118941A1 PCT/US2017/067345 US2017067345W WO2018118941A1 WO 2018118941 A1 WO2018118941 A1 WO 2018118941A1 US 2017067345 W US2017067345 W US 2017067345W WO 2018118941 A1 WO2018118941 A1 WO 2018118941A1
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WO
WIPO (PCT)
Prior art keywords
amino acid
composition
acid entity
entity
nac
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2017/067345
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English (en)
French (fr)
Inventor
Michael HAMILL
Raffi AFEYAN
Chung-Wei Lee
Harry LUITHARDT
David Berry
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Axcella Health Inc
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Axcella Health Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to CA3046551A priority Critical patent/CA3046551A1/en
Priority to AU2017382170A priority patent/AU2017382170B2/en
Priority to JP2019533079A priority patent/JP2020504108A/ja
Priority to KR1020197020657A priority patent/KR20190099242A/ko
Priority to MX2019007351A priority patent/MX2019007351A/es
Priority to EP17829105.0A priority patent/EP3554492A1/en
Priority to CN202211400026.6A priority patent/CN115814053A/zh
Priority to IL296614A priority patent/IL296614A/en
Priority to EA201991502A priority patent/EA201991502A1/ru
Priority to CN201780078656.7A priority patent/CN110087647B/zh
Priority to BR112019012529-9A priority patent/BR112019012529A2/pt
Application filed by Axcella Health Inc filed Critical Axcella Health Inc
Priority to CU2019000058A priority patent/CU20190058A7/es
Publication of WO2018118941A1 publication Critical patent/WO2018118941A1/en
Priority to ZA2019/03580A priority patent/ZA201903580B/en
Priority to CONC2019/0006291A priority patent/CO2019006291A2/es
Priority to IL267480A priority patent/IL267480B/en
Priority to PH12019501414A priority patent/PH12019501414A1/en
Anticipated expiration legal-status Critical
Priority to IL284371A priority patent/IL284371B2/en
Priority to JP2022193127A priority patent/JP2023029946A/ja
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/175—Amino acids
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/18—Peptides; Protein hydrolysates
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/30—Dietetic or nutritional methods, e.g. for losing weight
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2250/00—Food ingredients
    • A23V2250/02—Acid
    • A23V2250/06—Amino acid
    • A23V2250/0634—N-Acetyl-Cysteine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the wt. ratio of the L-amino acid entity, the R-amino acid entity, the L-glutamine or a salt thereof, and the NAC or salt thereof is about 0.5 to 3 : 0.5 to 4 : 1 to 4 : 0.1 to 2.5, e.g., the wt. ratio of the L-amino acid entity, the R- amino acid entity, the L-glutamine or a salt thereof, and the NAC or salt thereof is about 1 : 1.5 : 2 : 0.15 or about 1 : 1.5 : 2 : 0.3. In certain embodiments, the wt.
  • the branched-chain amino acid is leucine, isoleucine, and valine.
  • Another aspect of the invention features a dietary composition including the composition of any one of the foregoing aspects or embodiments, e.g., wherein the dietary composition is chosen from a medical food, a functional food, or a supplement.
  • the subject has pediatric NAFLD. In some embodiments, the patient has steatosis.
  • the subject has non-alcoholic steatohepatitis (NASH).
  • NASH non-alcoholic steatohepatitis
  • the subject has cirrhosis.
  • the subject has type 2 diabetes.
  • the subject has hepatocarcinoma, an increased risk of liver failure, or an increased risk of death.
  • administering the composition results in an improvement in one or more metabolic symptoms in the subject.
  • the improvement in one or more metabolic symptoms is selected from the following: increased free fatty acid and lipid metabolism, improved mitochondrial function, white adipose tissue (WAT) browning, decreased reactive oxygen species (ROS), increased levels of glutathione (GSH), decreased hepatic inflammation, decreased hepatocyte ballooning, improved gut barrier function, increased insulin secretion, or improved glucose tolerance.
  • (a) is a L- amino acid entity dipeptide or a salt thereof (e.g., a L-leucine dipeptide or a salt thereof).
  • (a) is a homodipeptide.
  • (a) is a heterodipeptide, e.g., Ala-Leu.
  • composition satisfies the properties of (gg)-(ii) defined above.
  • nn a combination of two or three of (kk)-(mm).
  • the composition satisfies the properties of (kk)-(mm) defined above. In certain embodiments, the composition satisfies the properties of at least 2, 3, or 4 of any of properties (kk)-(nn) defined above.
  • ratio of the R-amino acid entity to the S-amino acid entity or a salt thereof is greater than 1:4, greater than 1:3, about 1:2, or about 9:20, and not more than 1.5:2 or 1: 1, e.g., the ratio of the R-amino acid entity to the S-amino acid entity is about 1:2, or the ratio of the R-amino acid entity to the S-amino acid entity is about 9:20; or 22) a combination of two or three of (19)-(21).
  • the composition further comprises one or both of L-glycine and L-serine.
  • the composition comprises an L- amino acid entity, an I-amino acid entity, an V-amino acid entity, an R-amino acid entity, an L-glutamine or a salt thereof, an NAC or a salt thereof, and an L-glycine.
  • the composition comprises an L-amino acid entity, an I- amino acid entity, an V-amino acid entity, an R-amino acid entity, an L-glutamine or a salt thereof, an NAC or a salt thereof, and an L-serine.
  • the wt. ratio of the L-amino acid entity, the I-amino acid entity, the V-amino acid entity, the R-amino acid entity, the L-glutamine or salt thereof, and the NAC or salt thereof is about 1 : 0.5: 0.5: 1.5 : 2 : 0.15, about 1 : 0.5: 0.5: 1.5 : 2 : 0.225, about 1 : 0.5: 0.5: 1.5 : 2 : 0.3, or about 1 : 0.5: 0.5: 1.5 : 2 : 0.5.
  • the composition comprises about 4 g of the L-amino acid entity, about 2 g of the I- amino acid entity, about 1 g of V-amino acid entity, about 3 g of R-amino acid entity, about 4 g of L-glutamine or a salt thereof, about 0.9 g of NAC or a salt thereof, about 3 g of L-serine or a salt thereof, and about 3 g of L-glycine or a salt thereof.
  • L-Valine is provided as part of a dipeptide comprising L- Valine, or a salt thereof, or a tripeptide comprising L- Valine, or a salt thereof.
  • NAC is provided as a part of a dipeptide comprising NAC, or a salt thereof, or a tripeptide comprising NAC, or a salt thereof.
  • Another aspect of the invention features a method for treating fatty liver disease, wherein the method comprises administering to a subject in need thereof an effective amount of a composition comprising:
  • the subject has a disease or disorder selected from the group consisting of non-alcoholic fatty liver (NAFL), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic fatty liver disease (AFLD), and alcoholic steatohepatitis (ASH).
  • NAFL non-alcoholic fatty liver
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • AFLD alcoholic fatty liver disease
  • ASH alcoholic steatohepatitis
  • the subject has pediatric NAFLD.
  • the subject exhibits muscle atrophy or has a decreased ratio of muscle tissue to adipose tissue relative to a normal subject, e.g., without the one or more symptoms or without a fatty liver disease, e.g., the subject exhibits muscle atrophy without one or both of fibrosis or cirrhosis.
  • FIGS. 1A-1B are graphs showing the effect of treatment with an amino acid composition (Amino Acid Composition A-l) on the NAFLD activity score, ballooning, and fibrosis in the STAM mouse model (FIG. 1A) and in the FATZO mouse model (FIG. IB).
  • FIG. 2 is a schematic showing the metabolic symptoms of patients with non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and cirrhosis prior to administration of a composition comprising amino acid entities described herein (top) and the improvement in patients with NAFLD, NASH, and cirrhosis after administration of the composition (bottom).
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • FIGS. 1A-1B are graphs showing the effect of treatment with an amino acid composition (Amino Acid Composition A-l) on the NAFLD activity score, ballooning, and fibrosis in the STAM mouse model (FIG
  • the amino acid entity composition may be administered to the subject for a treatment period of, e.g., two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, or longer at a dose of about 15 total grams per day to about 90 total grams per day (e.g., a total of about 48 g or a total of about 72 g per day).
  • NAFL NAFL
  • AFLD e.g., ASH
  • “About” and “approximately” shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values.
  • a "pharmaceutical composition” described herein comprises at least one amino acid and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition is used as a therapeutic, a nutraceutical, a medical food, or as a supplement.
  • compositions, formulation or product refers to amino acids, materials, excipients, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • a composition, formulation or product is "therapeutic” if it provides a beneficial clinical effect. A beneficial clinical effect can be shown by lessening the progression of a disease and/or alleviating one or more symptoms of the disease.
  • Amino acid entities include amino acids, precursors, metabolites, and derivatives of the compositions described herein.
  • the composition further comprises one or two additional branched-chain amino acid (BCAA)-entities, e.g., one or both of an isoleucine (I)-amino acid- entity and a valine (V)-amino acid-entity.
  • BCAA branched-chain amino acid
  • I isoleucine
  • V valine
  • both the I-amino acid-entity and the V-amino acid-entity are present.
  • the L-entity is present at a higher amount (% by weight) than one or both of the I-amino acid-entity and the V-amino acid- entity (e.g., the L-entity is present at an amount of at least 10 wt. %, at least 15 wt. %, at least 20 wt.
  • the composition comprises a combination of 2 to
  • the BCAA is leucine.
  • the BCAA is leucine, isoleucine, and valine.
  • the amino acids leucine, isoleucine, valine, arginine HCl, glutamine and N-acetylcysteine are present in a weight ratio of about 1 : 0.5 : 0.5 : 1.5 : 2 : 0.1 to 0.3. In some embodiments, the amino acids leucine, isoleucine, valine, arginine HCl, glutamine and N-acetylcysteine are present in a weight ratio of about 1 : 0.5 : 0.5 : 1.5 : 2 : 0.25.
  • a total weight (wt) of the amino acids is about 2 g to about 60 g.
  • the composition includes about 1 g of leucine, about 0.5 g of isoleucine, about 0.5 g of valine, about 1.5 g of arginine (or 1.81 g of arginine HCl), about 2 g of glutamine, and about 0.15 g of N-acetylcysteine.
  • Table 4 Exemplary amino acid components of the composition including Arginine.
  • An exemplary Amino Acid Composition includes leucine, isoleucine, valine, arginine, glutamine, and N-acetylcysteine as its amino acid entities in a wt. ratio of 1 : 0.5 : 0.5 : 0.75 : 2 : 0.15 (Table 6). Table 5. Exemplary amino acid components of the composition including Arginine HCl.
  • An exemplary Amino Acid Composition includes leucine, isoleucine, valine, arginine HCl, glutamine, N-acetylcysteine, and serine as its amino acid entities in a wt. ratio of 1 : 0.5 : 0.25 : 0.905 : 1 : 0.225 : 0.667 (Table 11).
  • An exemplary Amino Acid Composition includes leucine, isoleucine, valine, arginine, glutamine, N-acetylcysteine, and serine as its amino acid entities in a wt. ratio of 1 : 0.5 : 0.25 : 0.75 : 1 : 0.225 : 1.667 (Table 12).
  • the composition that decreases and/or prevents steatosis comprises one or more BCAAs, one or more CEAAs, and an antioxidant or ROS scavenger.
  • the composition comprises a coloring agent.
  • suitable color agents include food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), and external drug and cosmetic colors (Ext. D&C).
  • the coloring agents can be used as dyes or their corresponding lakes.
  • the composition reduces or inhibits liver fibrosis in a subject with NAFLD (e.g., a subject with pediatric NAFLD). In some embodiments, the composition reduces or inhibits liver fibrosis in a subject with NAFLD (e.g., a subject with pediatric NAFLD).
  • administration of the composition results in increased free fatty acid and lipid metabolism in a subject with NASH (e.g., a subject with NAFLD, fibrosis, and type 2 diabetes). In some embodiments, administration of the composition results in improved mitochondrial function in a subject with NASH. In some embodiments, administration of the composition results in white adipose tissue (WAT) browning in a subject with NASH (e.g., a subject with NAFLD, fibrosis, and type 2 diabetes).
  • WAT white adipose tissue
  • administration of the composition results in increased insulin secretion in a subject with cirrhosis (e.g., a subject with hepatocarcinoma, increased risk of liver failure, and increased risk of death). In some embodiments, administration of the composition results in improved glucose tolerance in a subject with cirrhosis (e.g., a subject with
  • the composition is administered at a dose of about 20 g to about 40 g total amino acids, e.g., once per day, twice per day, three times per day, four times per day, five times per day, or six times per day (e.g., three times per day).
  • the composition is administered at a dose of about 24 g total amino acids, e.g., once per day, twice per day, three times per day, four times per day, five times per day, or six times per day (e.g., three times per day).
  • the composition is administered at a dose of about 24 g total amino acids three times per day.
  • the composition includes at least 1 g of leucine, at least 0.5 g of isoleucine, at least 0.5 g of valine, at least 0.75 g of arginine (or 0.905 g of arginine HCl), at least 2 g of glutamine, and at least 0.15 g of N-acetylcysteine for administration three times per day (e.g., for a total of at least 18 g per day).
  • the composition includes about 1 g of leucine, about 0.5 g of isoleucine, about 0.25 g of valine, about 0.75 g of arginine (or 0.905 g of arginine HCl), about 1 g of glutamine, and about 0.225 g of N-acetylcysteine for administration three times per day (e.g., for a total of about 18 g per day).
  • administration of the dietary composition results in an
  • TIMP1 tissue inhibitor of metalloproteinase
  • TIMP2 tissue inhibitor of metalloproteinase
  • MMP matrix metalloproteinase
  • composition comprises L-leucine, a R-amino acid entity, a Q-amino acid entity, and homocysteine.
  • composition of embodiment 1-lD, 4, or 136, wherein the composition comprises HMB, a R-amino acid entity, a Q-amino acid entity, and serine.
  • composition of embodiment 1-lD, 4, or 136, wherein the composition comprises HMB, a R-amino acid entity, a Q-amino acid entity, and L-cysteine.
  • composition of embodiment 1-lD, 4, or 136 wherein the composition comprises HMB, a R-amino acid entity, glutamate, and serine.
  • composition of embodiment 1- lD, 4, or 136 wherein the composition comprises HMB, a R-amino acid entity, carbamoyl-P, and acetylserine.
  • composition of embodiment 1-lD, 4, or 136 wherein the composition comprises HMB, D-arginine, a Q-amino acid entity, and L-cysteine.
  • composition of embodiment 1-lD, 4, or 136 wherein the composition comprises HMB, N-acetyl-arginine, argininosuccinate, and cystine.
  • composition of embodiment 1-lD, 4, or 197 wherein the composition comprises isovaleryl-CoA, glutamate, a Q-amino acid entity, and an antioxidant or ROS scavenger, e.g., a NAC entity.
  • composition of embodiment 1-lD, 4, or 197, wherein the composition comprises isovaleryl-CoA, citrulline, D-glutamine, and an antioxidant or ROS scavenger, e.g., a NAC entity.
  • composition of embodiment 1-lD, 4, or 197, wherein the composition comprises isovaleryl-CoA, aspartate, N-acetyl-glutamine, and an antioxidant or ROS scavenger, e.g., a NAC entity.
  • composition of embodiment 1-lD, 4, or 197, wherein the composition comprises isovaleryl-CoA, creatine, D-glutamine and D-cysteine.
  • composition of embodiment 1-lD, 5, or 258, wherein the composition comprises D-leucine, a R-amino acid entity, L-glutamine, and L-cysteine. 308.
  • composition of embodiment 1-lD, 5, or 258, wherein the composition comprises D-leucine, a R-amino acid entity, a glutamate, and cystine.

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PCT/US2017/067345 2016-12-19 2017-12-19 Amino acid compositions and methods for the treatment of liver diseases Ceased WO2018118941A1 (en)

Priority Applications (18)

Application Number Priority Date Filing Date Title
BR112019012529-9A BR112019012529A2 (pt) 2016-12-19 2017-12-19 composições de aminoácido e métodos para o tratamento de doenças hepáticas
JP2019533079A JP2020504108A (ja) 2016-12-19 2017-12-19 アミノ酸組成物および肝疾患の治療方法
KR1020197020657A KR20190099242A (ko) 2016-12-19 2017-12-19 아미노산 조성물 및 간 질환의 치료 방법
MX2019007351A MX2019007351A (es) 2016-12-19 2017-12-19 Composiciones de aminoacidos y metodos de tratamiento de enfermedades hepaticas.
EP17829105.0A EP3554492A1 (en) 2016-12-19 2017-12-19 Amino acid compositions and methods for the treatment of liver diseases
CN202211400026.6A CN115814053A (zh) 2016-12-19 2017-12-19 氨基酸组合物及肝疾病的治疗方法
IL296614A IL296614A (en) 2016-12-19 2017-12-19 Amino acid compounds and methods for treating liver diseases
EA201991502A EA201991502A1 (ru) 2017-10-24 2017-12-19 Композиции на основе аминокислот и способы лечения заболеваний печени
CU2019000058A CU20190058A7 (es) 2016-12-19 2017-12-19 Composiciones de aminoácidos relacionadas con mejoras de la función hepática
CA3046551A CA3046551A1 (en) 2016-12-19 2017-12-19 Amino acid compositions and methods for the treatment of liver diseases
AU2017382170A AU2017382170B2 (en) 2016-12-19 2017-12-19 Amino acid compositions and methods for the treatment of liver diseases
CN201780078656.7A CN110087647B (zh) 2016-12-19 2017-12-19 氨基酸组合物及肝疾病的治疗方法
ZA2019/03580A ZA201903580B (en) 2016-12-19 2019-06-04 Amino acid compositions and methods for the treatment of liver diseases
CONC2019/0006291A CO2019006291A2 (es) 2016-12-19 2019-06-17 Composiciones de aminoácidos y métodos de tratamiento de enfermedades hepáticas
IL267480A IL267480B (en) 2016-12-19 2019-06-18 Amino acid compounds and methods for treating liver diseases
PH12019501414A PH12019501414A1 (en) 2016-12-19 2019-06-19 Amino acid compositions and methods for the treatment of liver diseases
IL284371A IL284371B2 (en) 2016-12-19 2021-06-24 Amino acid compounds and methods for treating liver diseases
JP2022193127A JP2023029946A (ja) 2016-12-19 2022-12-01 アミノ酸組成物および肝疾患の治療方法

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
US201662436073P 2016-12-19 2016-12-19
US62/436,073 2016-12-19
US201762443205P 2017-01-06 2017-01-06
US62/443,205 2017-01-06
US201762491773P 2017-04-28 2017-04-28
US62/491,773 2017-04-28
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