WO2016164413A1 - Pharmaceutical compositions for combination therapy - Google Patents

Pharmaceutical compositions for combination therapy Download PDF

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Publication number
WO2016164413A1
WO2016164413A1 PCT/US2016/026146 US2016026146W WO2016164413A1 WO 2016164413 A1 WO2016164413 A1 WO 2016164413A1 US 2016026146 W US2016026146 W US 2016026146W WO 2016164413 A1 WO2016164413 A1 WO 2016164413A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
additional therapeutic
therapeutic agent
insulin
glucose
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/US2016/026146
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English (en)
French (fr)
Inventor
Mark Pruzanski
Luciano Adorini
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Intercept Pharmaceuticals Inc
Original Assignee
Intercept Pharmaceuticals 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 CN201680029144.7A priority Critical patent/CN107613986A/zh
Priority to EP16777168.2A priority patent/EP3280421B1/en
Priority to JP2017553131A priority patent/JP6879931B2/ja
Priority to KR1020177031857A priority patent/KR20170132879A/ko
Priority to MX2017012893A priority patent/MX2017012893A/es
Priority to CR20170456A priority patent/CR20170456A/es
Priority to MA41083A priority patent/MA41083A1/fr
Priority to CA2981507A priority patent/CA2981507A1/en
Priority to US15/564,799 priority patent/US10894054B2/en
Priority to SM20240104T priority patent/SMT202400104T1/it
Priority to EA201792203A priority patent/EA036757B1/ru
Application filed by Intercept Pharmaceuticals Inc filed Critical Intercept Pharmaceuticals Inc
Priority to ES16777168T priority patent/ES2974281T3/es
Priority to AU2016246524A priority patent/AU2016246524B2/en
Priority to TNP/2017/000426A priority patent/TN2017000426A1/en
Priority to BR112017021311A priority patent/BR112017021311A2/pt
Publication of WO2016164413A1 publication Critical patent/WO2016164413A1/en
Priority to IL254772A priority patent/IL254772A0/en
Anticipated expiration legal-status Critical
Priority to CONC2017/0010292A priority patent/CO2017010292A2/es
Priority to IL268316A priority patent/IL268316B/en
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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00

Definitions

  • Figure 6A is a bar graph showing the effect of a low dose of OCA and LIRA, alone and in combination, on change in fat tissue mass relative to body weight.
  • Figure 6B is a bar graph showing the effect of a high dose of OCA and LIRA, alone and in combination, on the change in the tissue mass relative to body weight.
  • the present application is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising (i) a first compound, (ii) at least one additional therapeutic agent, and (iii) optionally one or more pharmaceutically acceptable carriers, wherein the first compound is an FXR agonist and the at least one additional therapeutic agent lowers the glucose level in the blood, stimulates insulin secretion, and/or increases insulin sensitivity.
  • the at least one additional therapeutic agent is a bile acid sequestrant.
  • the bile acid sequestrant is selected from anion exchange resin, quaternary amines (e.g., cholestyramine or colestipol), and an ileal bile acid transporter inhibitor.
  • the first compound of the pharmaceutical composition is a compound of formula I:
  • R7 is hydroxyl or hydrogen.
  • the present application also provides a method for treating or preventing NAFLD or NASH.
  • the present application provides a method for treating or preventing NAFLD or NASH that is associated with an elevated level of glucose in the blood, decreased secretion of insulin, and/or decreased insulin sensitivity.
  • the present application provides a method for treating or preventing NAFLD or NASH, at least in part through reducing glucose level in the blood and/or increasing insulin secretion and/or insulin sensitivity.
  • the present application provides a method for treating or preventing NASH.
  • the present application provides a method for treating or preventing NASH that is associated with an elevated level of glucose in the blood, decreased secretion of insulin, and/or decreased insulin sensitivity.
  • the present application provides a method for treating or preventing NASH, at least in part through reducing glucose level in the blood and/or increasing insulin secretion and/or insulin sensitivity.
  • a disease selected from the group consisting of hepatitis B; hepatitis C; parasitic liver diseases; post-transplant bacterial, viral and fungal infections; alcoholic liver disease (ALD); non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH); liver diseases induced by methotrexate, isoniazid, oxypheni statin, methyl
  • the subject has renal fibrosis associated with a disease selected from the group consisting of diabetic nephropathy, hypertensive nephrosclerosis, chronic
  • the method of the present application reduces the level of LDH below 500 IU/L (international units per liter), 400 IU/L, 300 IU/L, 200 IU/L, 180 IU/L, 160 IU/L, 150 IU/L, 140 IU/L, or 130 IU/L. In a further example, the method of the present application reduces the level of LDH to from about 120 IU/L to about 220 IU/L.
  • compositions containing at least one additional therapeutic agent e.g., additional therapeutic agents described herein
  • additional therapeutic agent e.g., additional therapeutic agents described herein
  • the daily amount of the composition administered contains sufficient amount of the active substances to provide the desired daily dosage to the patient.
  • the pharmaceutical compositions of the application is a dosage form which comprises a first compound or a pharmaceutically acceptable salt or amino acid conjugate thereof in a daily total amount of from 0.1-1500 mg, 0.2-1200 mg, 0.3-1000 mg, 0.4-800 mg, 0.5-600 mg, 0.6-500 mg, 0.7-400 mg, 0.8-300 mg, 1-200 mg, 1-100 mg, 1-50 mg, 1-30 mg, 4-26 mg, or 5-25 mg.
  • VAT specimens are analyzed by hematoxylin and eosin staining to measure adipocyte diameter, as described previously (Maneschi et al. 2012).
  • the differentiation of rPADs, 2 days after confluence, is induced by exposing them to a differentiation mixture (DIM) (e.g., a mixture containing 5 mg/ml insulin, 1 mM dexamethasone, and 0.5 mM 3-isobutyl-l-methylxanthine (IBMX) in 5% stripped FBS-supplemented DMEM).
  • DIM differentiation mixture
  • IBMX 3-isobutyl-l-methylxanthine
  • FXR agonist refers to any compound which activates FXR.
  • an FXR agonist achieves at least 50% activation of FXR relative to CDC A, the appropriate positive control in the assay methods described in WO 2000/037077.
  • an FXR agonist achieves 100% activation of FXR in the scintillation proximity assay or the HTRF assay as described in WO2000/037077.
  • Examples of FXR agonists include but are not limited to those described in U.S. 7, 138,390; 7,932,244; 20120283234; 201202321 16;
  • amino acid conjugates refers to conjugates of a first compound of the present application (e.g., a compound of Formula I) with any suitable amino acid.
  • a suitable amino acid conjugate of a compound of Formula I will have the added advantage of enhanced integrity in bile or intestinal fluids.
  • suitable amino acids include but are not limited to glycine, sarcosine, and taurine.
  • the present application encompasses the glycine, sarcosine, and taurine conjugates of a first compound of the present application (e.g., Compound 1).
  • the dosage will also depend on the route of administration.
  • routes of administration A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like.
  • Dosage forms for the topical or transdermal administration of a compound of this application include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the first compound and/or the at least one additional therapeutic agent is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.
  • Group 1 Vehicle (PO) + Vehicle (SQ)
  • Example 3 Diet-Induced Obese NASH in C57BL/6j mice: Obeticholic Acid (OCA) ⁇ Metformin (MET) The protocols and analyses for this study are provided in Example 1.
  • OCA Obeticholic Acid
  • MET Metformin
  • Figures 9A depicts the effect of the high dose of combination of OCA and MET on total NAS.
  • the high dose combination of OCA and MET reduced NAS (p ⁇ 0.05 vs. OCA control) in a statistically significant manner at the study end.
  • the effect of high dose of the combination of OCA and MET on the steatosis component is displayed in Figures 9B.
  • the following genes in the collagen receptor family were uniquely regulated: collagen type 14al, collagen type 6al, and collagen type 6a2. See figures 13 A-13C, respectively.
  • Other genes of interest which were regulated are the decorin receptor, colectin subfamily member 10, transforming growth factor beta receptor III, and transforming growth factor, beta-induced. See figures I4A-14F.
  • Example 1 The protocols and analyses for this study are provided in Example 1.
  • Group 1 Vehicle (PO) + Vehicle (PO)
  • the liver is subsequently perfused with collagenase in the perfusion buffer.
  • the liver is dissected and transferred to ice-cold perfusion buffer.
  • the liver capsule is teased apart, and the resulting cell suspension is filtered.
  • the cell pellet is collected by centrifugation and resuspended.
  • Percoll is added to the suspension, and hepatocytes separated using a Percoll density centrifugation technique. The mixture is centrifuged, and the cell pellet washed twice with medium. Hepatocyte viability is determined by Trypan blue exclusion.
  • Insulin resistance is the putative key underlying mechanism linking adipose tissue (AT) dysfunction with liver inflammation and steatosis in metabolic syndrome (MetS). It has been demonstrated that OCA ameliorates insulin resistance and the metabolic profile with a marked reduction in the amount of visceral AT (VAT) in a high-fat diet (HFD)-induced rabbit model of MetS.
  • VAT visceral AT
  • HFD high-fat diet
  • RT-PCR has shown that in vivo OCA dosing normalizes adipocyte size, hypoxia, and the expression of perilipin and cytosolic insulin-regulated glucose transporter GLUT4 (SLC2A4) which are significantly increased in VAT isolated from the HFD rabbits as compared to rabbits on a control diet. In vivo OCA dosing also normalizes the expression of steatosis and inflammation markers in HFD rabbits.
  • MetS an algorithm taking into account the presence, as a dummy variable, of one or more of the following factors: hyperglycemia, high triglyceride levels, high cholesterol levels, increased blood pressure, and visceral fat accumulation, are designed. Cut-offs for each factor is derived by the mean ⁇ 2 S.D. of the analyzed parameter, as measured in the CON rabbits. Positivity for three or more factors indicates MetS.
  • VAT oxygenation are analyzed using the bio-reductive drug pimonidazole hydrochloride (hypoxyprobe-1, 60 mg/kg), injected i.p. 1 h before killing, as described previously (Maneschi et al. 2012, Morelli et al. 2012, 2013, Vignozzi et al. 2012).
  • Liver steatosis is assessed by Oil Red O staining of the liver sections.
  • Frozen sections are cut in a cryostat and fixed in 4% paraformaldehyde for 20 min at room temperature (RT). Then, the sections are treated for 2-5 min with isopropanol and stained with Oil Red O for 20 min.
  • Oil Red O are prepared by diluting a stock solution (0.3 g of Oil Red O in 100 ml of isopropanol) with water (3 :2) followed by filtration. After Oil Red O staining, the sections are washed several times in water and stained with hematoxylin and eosin to highlight the hepatocyte nuclei.
  • Lep oh /Lep oh or B6 mice either a low-fat diet (LFD), the high trans-fat, high fructose, high cholesterol (HTF) diet, or the high lard fat, high fructose, high cholesterol diet (HLF) diet are maintained for 8 or 12 weeks,

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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  • Child & Adolescent Psychology (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/US2016/026146 2015-04-07 2016-04-06 Pharmaceutical compositions for combination therapy Ceased WO2016164413A1 (en)

Priority Applications (18)

Application Number Priority Date Filing Date Title
EA201792203A EA036757B1 (ru) 2015-04-07 2016-04-06 Фармацевтические композиции для комбинированной терапии
JP2017553131A JP6879931B2 (ja) 2015-04-07 2016-04-06 併用療法用の医薬組成物
KR1020177031857A KR20170132879A (ko) 2015-04-07 2016-04-06 조합 요법을 위한 약제학적 조성물
MX2017012893A MX2017012893A (es) 2015-04-07 2016-04-06 Composiciones farmaceuticas para terapias combinadas.
CR20170456A CR20170456A (es) 2015-04-07 2016-04-06 Composiciones farmacéuticas para terapias combinadas
MA41083A MA41083A1 (fr) 2015-04-07 2016-04-06 Compositions pharmaceutiques pour thérapie combinée
CA2981507A CA2981507A1 (en) 2015-04-07 2016-04-06 Pharmaceutical compositions for combination therapy
US15/564,799 US10894054B2 (en) 2015-04-07 2016-04-06 FXR agonist compositions for combination therapy
ES16777168T ES2974281T3 (es) 2015-04-07 2016-04-06 Composiciones farmacéuticas para terapia de combinación
CN201680029144.7A CN107613986A (zh) 2015-04-07 2016-04-06 用于组合疗法的药物组合物
EP16777168.2A EP3280421B1 (en) 2015-04-07 2016-04-06 Pharmaceutical compositions for combination therapy
SM20240104T SMT202400104T1 (it) 2015-04-07 2016-04-06 Composizioni farmaceutiche per politerapia
AU2016246524A AU2016246524B2 (en) 2015-04-07 2016-04-06 Pharmaceutical compositions for combination therapy
TNP/2017/000426A TN2017000426A1 (en) 2015-04-07 2016-04-06 Pharmaceutical compositions for combination therapy
BR112017021311A BR112017021311A2 (pt) 2015-04-07 2016-04-06 composições farmacêuticas para terapia de combinação
IL254772A IL254772A0 (en) 2015-04-07 2017-09-28 Pharmaceutical preparations for combination therapy
CONC2017/0010292A CO2017010292A2 (es) 2015-04-07 2017-10-10 Composiciones farmacéuticas para terapias combinadas
IL268316A IL268316B (en) 2015-04-07 2019-07-29 Pharmaceutical preparations for combined treatment

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562144040P 2015-04-07 2015-04-07
US62/144,040 2015-04-07

Publications (1)

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WO2016164413A1 true WO2016164413A1 (en) 2016-10-13

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PCT/US2016/026146 Ceased WO2016164413A1 (en) 2015-04-07 2016-04-06 Pharmaceutical compositions for combination therapy

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US (1) US10894054B2 (https=)
EP (1) EP3280421B1 (https=)
JP (1) JP6879931B2 (https=)
KR (1) KR20170132879A (https=)
CN (1) CN107613986A (https=)
AR (1) AR104195A1 (https=)
AU (1) AU2016246524B2 (https=)
BR (1) BR112017021311A2 (https=)
CA (1) CA2981507A1 (https=)
CL (2) CL2017002538A1 (https=)
CO (1) CO2017010292A2 (https=)
CR (1) CR20170456A (https=)
EA (1) EA036757B1 (https=)
EC (1) ECSP17073004A (https=)
ES (1) ES2974281T3 (https=)
IL (2) IL254772A0 (https=)
MA (1) MA41083A1 (https=)
MX (1) MX2017012893A (https=)
NI (1) NI201700121A (https=)
PE (1) PE20180034A1 (https=)
SM (1) SMT202400104T1 (https=)
SV (1) SV2017005539A (https=)
TN (1) TN2017000426A1 (https=)
TW (1) TW201642869A (https=)
WO (1) WO2016164413A1 (https=)

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WO2018085623A1 (en) * 2016-11-04 2018-05-11 Children's Hospital Medical Center Compositions and methods of treating liver disease
US10174289B2 (en) 2014-05-28 2019-01-08 Children's Hospital Medical Center Methods and systems for converting precursor cells into gastric tissues through directed differentiation
WO2020025942A1 (en) 2018-07-30 2020-02-06 NZP UK Limited Fluorinated bile acid derivatives
WO2020108830A1 (en) * 2018-11-30 2020-06-04 Ureka Sarl Peptide-oligourea foldamer compounds and methods of their use
US10781425B2 (en) 2010-05-06 2020-09-22 Children's Hospital Medical Center Methods and systems for converting precursor cells into intestinal tissues through directed differentiation
WO2020205024A1 (en) * 2019-04-04 2020-10-08 Coherus Biosciences, Inc. Compositions and methods to treat non-alcoholic fatty liver diseases (nafld)
US11066650B2 (en) 2016-05-05 2021-07-20 Children's Hospital Medical Center Methods for the in vitro manufacture of gastric fundus tissue and compositions related to same
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US11267861B2 (en) 2016-04-19 2022-03-08 Ureka Sarl Peptide-oligourea foldamer compounds and methods of their use
US11400072B2 (en) 2015-03-09 2022-08-02 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
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US20240100125A1 (en) * 2021-01-14 2024-03-28 Enyo Pharma Synergistic effect of a fxr agonist and ifn for the treatment of hbv infection
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US12421500B2 (en) 2018-07-26 2025-09-23 Children's Hospital Medical Center Hepato-biliary-pancreatic tissues and methods of making same
US12428622B2 (en) 2018-09-12 2025-09-30 Children's Hospital Medical Center Organoid compositions for the production of hematopoietic stem cells and derivatives thereof
US12497597B2 (en) 2019-05-31 2025-12-16 Children's Hospital Medical Center Methods of generating and expanding hematopoietic stem cells
US12534709B2 (en) 2019-05-31 2026-01-27 Children's Hospital Medical Center Shaped organoid compositions and methods of making same
US12569543B2 (en) 2016-04-28 2026-03-10 Novo Nordisk A/S Semaglutide in cardiovascular conditions
US12600943B2 (en) 2019-02-01 2026-04-14 The University Of Hong Kong Innervated organoid compositions and methods of making same

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