WO2017017677A1 - Polythérapie pour maladies du foie - Google Patents

Polythérapie pour maladies du foie Download PDF

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Publication number
WO2017017677A1
WO2017017677A1 PCT/IL2016/050816 IL2016050816W WO2017017677A1 WO 2017017677 A1 WO2017017677 A1 WO 2017017677A1 IL 2016050816 W IL2016050816 W IL 2016050816W WO 2017017677 A1 WO2017017677 A1 WO 2017017677A1
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Prior art keywords
aramchol
vitamin
vdr agonist
salt
combination
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PCT/IL2016/050816
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English (en)
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Allen BAHARAFF
Maya HALPERN
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Galmed Research And Development Ltd.
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Publication of WO2017017677A1 publication Critical patent/WO2017017677A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
    • 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

Definitions

  • Embodiments of the invention relate to compositions and methods for treatment of liver disease, in particular non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).
  • liver disease in particular non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • NAFLD is a liver disease in which excessive fat accumulates in the liver. It may be demonstrated histologically by presence of vesicular fat droplets in the liver tissue. NAFLD may be detected by blood tests indicating abnormal liver function.
  • NASH is a severe form of NAFLD, in which the fat accumulation in the liver is accompanied by inflammation, necrosis and eventually fibrosis of the liver. Both NASH and NAFLD are commonly associated with excessive dietary intake, obesity and a variety of other causes other than excess alcohol consumption. The excess fibrosis which is the result of inflammation and liver cell necrosis in NASH may lead to cirrhosis, potentially leading to liver dysfunction, hepatocarcinoma and/or death. Patients with NASH may also be prone to develop other complications such as myocardial infarction or stroke. NASH is a multi-factorial disease whose pathophysiology not completely understood. It is therefore difficult to predict which classes of drugs, through which mechanism of action, will improve the hepatic features and prevent complications associated with the disease.
  • Vitamin D is a secosteroid hormone regulating mineral metabolism.
  • the two major forms of vitamin D are Vitamin D2 (ergocalciferol), produced by certain phytoplankton, invertebrates and yeast, and vitamin D3 (cholecalciferol), produced in the skin of most vertebrates following to ultraviolet (UV) irradiation.
  • Vitamin D receptor also known as the calcitriol receptor and NR1I1 (nuclear receptor subfamily 1, group I, member 1), is a member of the nuclear receptor family of transcription factors.
  • VDR has four major domains that interact to confer ligand-activated transcription factor activity: a ligand-binding domain, a retinoid X receptor (RXR) heterodimerization domain, a DNA binding domain to vitamin D response elements, and a recruitment domain of VDR coregulators.
  • RXR retinoid X receptor
  • the VDR Upon activation by vitamin D, the VDR forms a heterodimer with the retinoid-X receptor and binds to hormone response elements on DNA resulting in expression or trans-repression of specific gene products (Kwok ei at, Hepatology, Vol. 58, No. 3, 2013).
  • vitamin D Although the leading physiological function of vitamin D is to regulate mineral and skeletal homeostasis, putative properties of this vitamin, in regulating cell proliferation, differentiation and apoptosis as well as immune-cells regulation, have been suggested. VDR has also been suggested as a negative regulator of the transforming growth factor beta (TGF- ySmad signaling and fibroblast activation in models of systemic sclerosis (Zerr et al. , Ann Rheum Dis 2014; 0:1-8) and in hepatic stellate cells (HSC) of certain genotypes.
  • TGF- ySmad signaling and fibroblast activation in models of systemic sclerosis (Zerr et al. , Ann Rheum Dis 2014; 0:1-88) and in hepatic stellate cells (HSC) of certain genotypes.
  • Various vitamin D analogs, acting as VDR agonists have been developed and are available commercially. Some of these analogs have been suggested to suppress HSC proliferation in culture
  • Fatty acid bile salt conjugates referred to also as Fatty Acid Bile Acid Conjugates
  • FABACs are a family of synthetic molecules that may be used to improve conditions related to bile acids or cholesterol metabolism. FABACs are believed to lower blood cholesterol concentration, reduce liver fat levels and dissolve gallstones (Gilat et al., Hepatology 2003; 38 : 436-442; and Gilat et al, Hepatology 2002; 35: 597-600). FABAC include inter alia 3 ⁇ - arachidylamido-7a,12a-dihydroxy-5 -cholan-24-oic acid, also known as Aramchol.
  • FABACs were disclosed in US Patents 7,501 ,403, 8,975,246 and 8,110,564 for use in treating fatty liver, in reducing blood cholesterol levels and in treating hyperglycemia, diabetes, insulin resistance and obesity. Further therapeutic uses of FABACs are disclosed in Safadi et al. ⁇ Clin Gastroenterol Hepatol. 2014 Dec;12(12):2085-91) and in WO 2015/019358 and WO 2015/019359, and amine salts of certain FABACs are disclosed in WO 2015/083164.
  • U.S. Pat. No. 8,865,641 discloses a method of treating a fatty liver disease in a subject, comprising administering to the subject an effective amount of a cholinergic pathway stimulating agent, such as a nicotinic receptor agonist, a muscarinic receptor agonist, a cholinesterase inhibitor and an antagonist of presynaptic acetylcholine autoreceptors.
  • a cholinergic pathway stimulating agent such as a nicotinic receptor agonist, a muscarinic receptor agonist, a cholinesterase inhibitor and an antagonist of presynaptic acetylcholine autoreceptors.
  • 9,012,509 discloses methods of treating NAFLD and/or NASH, and/or negative effects of each thereof by administering phenoxyalkylcarboxylic acids such as MN-001 and MN-002.
  • WO 2015/053379 discloses methods for treating a fatty liver disease or disorder in a subject in need thereof, particularly in pre -menopausal women, comprising administering to the subject omega 3 fatty acids or derivatives thereof such as ethyl eicosapentanoate, eicosapentaenoic acid, or pharmaceutically acceptable amides, salts, ester or phospholipids thereof.
  • This publication further suggests administering these agents in combination with various additional drugs, vitamins and antioxidants.
  • Embodiments of the invention relate to compositions, methods, pharmaceutical packages and combined preparations for treatment of liver disease, in particular non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).
  • the compositions, methods, pharmaceutical packages and combined preparations according to these embodiments employ the use of a combination of a Fatty Acid Bile Acid Conjugate (FABAC) with a vitamin D receptor (VDR) agonist, or salts thereof.
  • Fatty Acid Bile Acid Conjugate FABAC
  • VDR vitamin D receptor
  • Aramchol in combination with a VDR agonist such as vitamin D3 or a precursor, analog or active metabolite thereof is contemplated.
  • the invention relates to a therapeutic combination of Aramchol or a pharmaceutically acceptable salt thereof and a VDR agonist (e.g. in the form of a pharmaceutically acceptable salt thereof), for use in the treatment of a liver disease selected from the group consisting of NASH and NAFLD in a patient in need thereof.
  • Aramchol (3 -arachidylamido-7a,12a-dihydroxy-5 -cholan-24-oic acid) is a bile acid/ fatty acid conjugate comprising an arachidic acid moiety and a cholic acid moiety.
  • Aramchol is described in United States Patent Numbers 6,384,024, 6,395,722, 6,589,946, 7,501,403, 8,110,564 and 8,975,246, incorporated herein by reference.
  • VDR vitamin D receptor
  • calcitriol receptor is a nuclear receptor known to be involved in, inter alia, mineral (such as calcium) metabolism, the neuromuscular system and the immune response.
  • VDR agonists include, but are not limited to an agent or agents selected from the group consisting of: calciferol, alfacalcidol (la(OH)D 3 , 1- hydroxycholecalciferol), 1,25-dihydroxyvitamin D 3 , ergocalciferol (Vitamin D2), cholecalciferol (Vitamin D 3 ), calcitriol (1 ,25-dihydroxycholecalciferol), 22- dihydroergocalciferol (Vitamin D 4 ), sitocalciferol (Vitamin D5), dihydrotachysterol, calcipotriol, tacalcitol 1 ,24-dihydroxyvitamin D 3 and paricalcitol.
  • Aramchol as a monotherapy, may reduce liver fat infiltration in animals fed a high fat diet, through reduction of fatty acid synthesis and inhibition of stearoyl CoA desaturase activity.
  • VDR agonists as a monotherapy, may exert anti-fibrotic properties.
  • combination therapy comprising Aramchol with a VDR agonist according to the invention may provide an improved and preferably greater than additive effect in NAFLD and/or NASH patients, e.g. in treating and/or preventing development of hepatic fibrosis.
  • the invention provides a method for treatment of disease, selected from the group consisting of NAFLD and NASH, in a patient in need thereof, comprising administering to the patient an amount of Aramchol or a pharmaceutically acceptable salt thereof in combination with an amount of a VDR agonist or a pharmaceutically acceptable salt thereof to treat the disease.
  • the invention relates to the use of Aramchol or a pharmaceutically acceptable salt thereof in combination with a VDR agonist, for the preparation of a medicament for the treatment of a liver disease selected from the group consisting of NASH and NAFLD in a patient in need thereof.
  • composition comprising Aramchol or a pharmaceutically acceptable salt thereof in combination with a VDR agonist as the active ingredients, and optionally pharmaceutically acceptable carriers, excipients and/or diluents.
  • the invention provides a package comprising a) a first pharmaceutical composition comprising Aramchol or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; b) a second pharmaceutical composition comprising a VDR agonist and a pharmaceutically acceptable carrier; and c) instructions for use of the first and second pharmaceutical compositions in combination to treat a subject afflicted with a liver disease, preferably NAFLD or NASH.
  • the liver disease treated by the compositions, methods and combinations of the invention is NAFLD.
  • the liver disease is NASH.
  • the medicament or combination consists of Aramchol and the VDR agonist as active ingredients.
  • the combination may be for simultaneous, separate or sequential use in the treatment of the liver disease.
  • Aramchol and the VDR agonist are provided in a single dosage form.
  • Aramchol and the VDR agonist are provided in an oral dosage form.
  • Aramchol and the VDR agonist are administered in the form of a single oral dosage form.
  • the medicament or combination comprises between about 100 and 600 miligrams (mg) of Aramchol free acid or equivalent amount of salt thereof.
  • the method comprises administering a daily dose of 100-600 mg of Aramchol free acid or equivalent amount of salt thereof.
  • the medicament or combination comprises between about 50-15,000 International Units (IU) of the VDR agonist.
  • the method, medicament or combination is adapted for providing a daily dosage of between about 400 mg and 600 mg of Aramchol or equivalent amount of a salt thereof and a daily dose of between about 400-10,000 IU of the VDR agonist.
  • the composition, medicament or combination is formulated for oral administration.
  • Aramchol is in the form of Aramchol free acid.
  • Aramchol is in the form of an amine-based salt, including, but not limited to, meglumine, lysine and tromethamine Aramchol salt.
  • meglumine e.g., meglumine
  • lysine e.g., meglumine
  • tromethamine Aramchol salt e.g., meglumine, lysine and tromethamine Aramchol salt.
  • the VDR agonist may be selected from the group consisting of calciferol, alfacalcidol, 1,25-dihydroxyvitamin D 3 , Vitamin D 2 , Vitamin D 3 , calcitriol, Vitamin D4, Vitamin D5 , dihydrotachysterol, calcipotriol, tacalcitol 1 ,24- dihydroxyvitamin D3 and paricalcitol.
  • the VDR agonist is vitamin D3 or a precursor, analog or active metabolite thereof.
  • said VDR agonist is selected from the group consisting of: vitamin D3, a vitamin D metabolite, and a vitamin D3 precursor.
  • the VDR agonist comprises cholecalciferol, e.g. at an amount of between about 400 and 5,000 IU.
  • the method comprises (or the combination is adapted for) administering a daily dose of 400-5,000 IU of cholecalciferol (e.g. 500-4500, 1000-4000 or 1500-4000).
  • the VDR agonist comprises alfacalcidol, e.g. at an amount of between about 0.25 and 1 microgram.
  • the method comprises (or the combination is adapted for) administering a daily dose 0.25 and 1 microgram of alfacalcidol.
  • the combinations of the invention may be administered in concurrent or sequential combination with calcium supplementation (e.g. in the form of a pharmacologically acceptable salt thereof such as calcium citrate).
  • the calcium supplementation may be adapted for providing a daily dose of 100-1000 mg.
  • the calcium supplementation comprises 150-750 mg, e.g. 500 mg of elemental calcium in the form of calcium citrate.
  • the methods of the invention further comprise administering calcium to said patient.
  • the methods comprise, or the combinations, compositions and packages are adapted for administering a daily dose of 100-1000 mg of elemental calcium in the form of a carbonate, citrate, gluconate, succinate or citrate maleate.
  • the methods comprise (or the combinations, compositions and packages are adapted for) administering a daily dose of 150-750 mg of elemental calcium in the form of calcium citrate.
  • the methods comprise (or the combinations, compositions and packages are adapted for) administering a daily dose of 300-500 mg of Aramchol or an equivalent amount of a salt thereof, a daily dose of 400-5,000 IU of cholecalciferol and a daily dose of 150-750 mg of elemental calcium in the form of calcium citrate.
  • the combination, medicament, composition or method may be used for the treatment of liver fibrosis in the patient.
  • the fibrosis is in a patient suffering from NASH.
  • the invention relates to compositions, methods, pharmaceutical packages, therapeutic combinations and combined preparations useful for treatment of liver disease, in particular nonalcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).
  • Embodiments of the invention include or employ the use of a combination of a Fatty Acid Bile Acid Conjugate (FABAC) such as Aramchol with a vitamin D receptor (VDR) agonist, or salts thereof.
  • Fatty Acid Bile Acid Conjugate such as Aramchol with a vitamin D receptor (VDR) agonist
  • VDR vitamin D receptor
  • the use of Aramchol or a pharmaceutically acceptable salt thereof in combination with vitamin D3 or a precursor, analog or active metabolite thereof is contemplated.
  • Embodiments of the invention relate to treatments of disease using Aramchol or a pharmaceutically acceptable salt thereof in combination with a VDR agonist.
  • Other embodiments of the invention relate to compositions and pharmaceutical packages comprising Aramchol or a pharmaceutically acceptable salt thereof in combination with a VDR agonist.
  • “In combination” or “combination” refer to both drugs being substantially effective in the body at a same time. Both drugs can be administered substantially at the same time, or both drugs can be administered at different times but have effect on the body at the same time.
  • “in combination” includes administering Aramchol before the administration of the VDR agonist, and subsequently administering the VDR agonist while functioning of Aramchol in the body is substantially extant.
  • combination includes administering the VDR agonist before the administration of Aramchol, and subsequently administering the Aramchol while functioning of the VDR agonist in the body is substantially extant.
  • a pharmaceutical composition is described as containing Aramchol and a VDR agonist in combination, this term refers to both agents being concurrently present in the composition.
  • compositions and methods of the invention may optionally be under treatment with other therapeutic agents (e.g. for ameliorating other unrelated conditions)
  • the invention surprisingly demonstrates that Aramchol, in combination with a VDR agonist, provides a surprisingly beneficial treatment for NAFLD/NASH patients in the absence of adjunct therapy.
  • the terms "in combination” and “combination” may further relate to the advantageous use of Aramchol and a VDR agonist in the absence of concomitant treatment for liver diseases such as NAFLD or NASH.
  • concomitant treatment with fatty acids such as ethyl eicosapentanoate, eicosapentaenoic acid, and their amides, salts and phospholipids is explicitly excluded.
  • the combinations of the invention consist essentially of Aramchol and VDR agonists as active ingredients.
  • the composition may further contain calcium or other additives for enhancing the absorption of the VDR agonist and/or Aramchol.
  • the combinations of the invention consist of Aramchol and VDR agonists as sole active ingredients.
  • VDR agonists referred to herein include vitamin D compounds (forms) as described herein and vitamin D analogs and active metabolites thereof that induce ligand-mediated VDR activation in vivo.
  • the term further includes vitamin D precursors (prodrugs), capable of being converted to an agonist of the VDR by one or more enzymes.
  • that enzyme is CYP27B1.
  • precursors include vitamin D3 (cholecalciferol), 25-hydroxy- vitamin D3 (25-OH-D3) (calcidiol), as well as vitamin D2 (ergocalciferol) and its precursors.
  • Vitamin D active metabolites include VDR ligands (that activate the receptor directly upon binding) such as calcitriol, and other compounds formed by vitamin D metabolism that retain the ability to induce ligand-mediated VDR activation (either directly or upon further enzymatic processing).
  • Vitamin D analogs referred to herein are synthetic compounds comprising a vitamin D scaffold with side chain modifications and/or modifications of the scaffold itself, that exhibit a biological activity on the vitamin D receptor comparable to that of naturally occurring vitamin D compounds. This term may further refer specifically to a molecule having a 9,10-seco-steroidal structure, and similar chemical or biological activity to vitamin D3. Certain vitamin D analogs having improved properties, such as reduced risk for hypercalcemia, have been reported, non- limitative examples of which include alfacalcidol, calcipotriol (Dovonex), 19-nor-l,25(OH)(2)D(2) (Zemplar), doxercalciferol (Hectorol), and 22-oxacalcitriol (Maxacalcitol).
  • VDR agonist is a vitamin D3 analog that is a non-endogenous product of a chemical synthetic reaction which uses a substrate other than any of the naturally occurring following group: vitamin D3, a vitamin D metabolite, a vitamin D3 precursor.
  • a non-limiting example of a vitamin D3 analog is calcipotriol.
  • vitamin D compounds e.g. vitamin D3
  • vitamin D analogs may be considered in other embodiments, for example in patients with renal dysfunction that may impair vitamin D metabolism.
  • the VDR agonist is an agent or agents selected from the group consisting of: calciferol, alfacalcidol (la(OH)D3, 1-hydroxycholecalciferol), 1 ,25- dihydroxyvitamin D 3 , ergocalciferol (Vitamin D 2 ), cholecalciferol (Vitamin D 3 ), calcitriol (1,25-dihydroxycholecalciferol), 22-dihydroergocalciferol (Vitamin D 4 ), sitocalciferol (Vitamin D 5 ), dihydrotachysterol, calcipotriol, tacalcitol 1 ,24-dihydroxyvitamin D 3 and paricalcitol.
  • said VDR agonist is vitamin D3 or a precursor, analog or active metabolite thereof (e.g. calcitriol).
  • said VDR agonist is selected from the group consisting of: vitamin D3, a vitamin D metabolite, and a vitamin D3 precursor.
  • said VDR agonist is cholecalciferol (vitamin D3).
  • VDR agonists may be synthesized by readily available methods.
  • cholecalciferol may be synthesized by the ultraviolet irradiation of 7- dehydrocholesterol extracted from lanolin found in sheep's wool.
  • Various VDR agonists are commercially available.
  • calcitriol is marketed under various trade names including Rocaltrol (Roche), Calcijex (Abbott), Decostriol (Mibe, Jesalis), Biowoz (Solmarc) and Vectical (Galderma), Rolsical (Sun Pharma).
  • Ergocalciferol is manufactured and marketed under various names, including Deltalin (Eli Lilly and Company), Drisdol (Sanofi-Synthelabo) and Calcidol (Patrin Pharma).
  • vitamin D formulations further comprising calcium supplements are commercially available.
  • Aramchol is chemically named 3 -arachidylamido-7a,12a-dihydroxy-5 -cholan-24-oic acid, and is represented by the following chemical structure:
  • the combinations, compositions, methods and packages of the invention may comprise Aramchol in its free acid form.
  • Aramchol is in its salt form.
  • the salt may be an amine-based salt.
  • the amine-based salt may be selected from the group consisting of meglumine, lysine and tromethamine salts.
  • an amount of Aramchol or a pharmaceutically acceptable salt thereof is provided in combination with an amount of VDR agonist in a single dosage form. According to an embodiment of the invention, an amount of Aramchol or a pharmaceutically acceptable salt thereof is provided in combination with an amount of VDR agonist in separate dosage forms.
  • compositions, methods and packages for treatment of liver disease in particular NAFLD and NASH, employing the use of a combination of a Fatty Acid Bile Acid Conjugate (FABAC) with a VDR agonist, or salts thereof.
  • Fatty Acid Bile Acid Conjugate FABAC
  • the compositions, methods and packages may comprise Aramchol and at least one additional FABAC in combination with one or more VDR agonists.
  • the FABAC is of Formula I:
  • the bonding member is NH.
  • each of said one or two fatty acid radicals is a radical of a fatty acid selected from the group consisting of: arachidylic acid, stearic acid, behenic acid, palmitic acid, arachidonic acid, eicosapentaenoic acid and oleic acid.
  • arachidylic acid selected from the group consisting of: arachidylic acid, stearic acid, behenic acid, palmitic acid, arachidonic acid, eicosapentaenoic acid and oleic acid.
  • said one or two fatty acid radicals are radicals of arachidylic acid. Each possibility represents a separate embodiment of the present invention.
  • W represents a single fatty acid radical.
  • the bile acid is selected from the group consisting of: cholic acid, ursodeoxycholic acid, chenodeoxycholic acid, deoxycholic acid, lithocholic acid and derivatives thereof. Each possibility represents a separate embodiment of the present invention.
  • the bile acid is cholic acid, chenodeoxycholic acid, or deoxycholic acid.
  • the bile acid is other than ursodeoxycholic acid and lithocholic acid.
  • the bile acid is cholic acid.
  • the FABAC is 3 -arachidylamido-7a, 12a-dihydroxy- 5 -cholan-24-oic acid.
  • the combinations of the invention may be provided or administered in concurrent or sequential combination with calcium.
  • the calcium in the form of a pharmacologically acceptable salt thereof, including, but not limited to a carbonate, citrate, gluconate, succinate or citrate maleate.
  • the use of calcium citrate may be advantageous in providing enhanced absorption and/or improved safety, e.g. with respect to renal toxicity and kidney stone formation.
  • the calcium is amorphous, e.g. amorphous calcium carbonate.
  • the calcium is at an amount (e.g. daily dose) of 100-1000 mg, e.g.
  • compositions comprising Aramchol or a pharmaceutically acceptable salt thereof and a VDR agonist.
  • Such pharmaceutical compositions may be administered to patients suffering from NAFLD and/or NASH according to embodiments of the invention.
  • a package comprising a pharmaceutical dosage form comprising Aramchol or a pharmaceutically acceptable salt thereof and a pharmaceutical dosage form comprising VDR agonist is provided.
  • the package may further comprise instructions to administer the pharmaceutically dosage forms to a patient in need thereof.
  • Aramchol or a pharmaceutically acceptable salt thereof in combination with an amount of VDR agonist may be provided in a pharmaceutical composition or separate pharmaceutical compositions via oral administration.
  • the pharmaceutical compositions according to an embodiment of the invention may be conveniently presented in unit dosage form and may be prepared by any of methods well known in the art of pharmacy.
  • the unit dosage form is in the form of a tablet, capsule, lozenge, wafer, powder or liquid form.
  • the compositions of the present invention are generally administered in the form of a pharmaceutical composition comprising at least one active component together with a pharmaceutically acceptable carrier or diluent.
  • a pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like. Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate are employed along with various disintegrants.
  • compositions for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries as desired, to obtain tablets or dragee cores.
  • suitable excipients include fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol, cellulose preparations such as, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, and sodium carbomethylcellulose, and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • disintegrating agents such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate, may be added.
  • disintegrating agents such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Capsules and cartridges of, for example, gelatin for use in a dispenser may be formulated containing a powder mix of the compound and a suitable powder base, such as lactose or starch.
  • Solid dosage forms for oral administration include without limitation capsules, tablets, pills, powders, and granules.
  • the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch.
  • Such dosage forms can also comprise, as it normal practice, additional substances other than inert diluents, e.g., lubricating, agents.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • enteric coating refers to a coating which controls the location of composition absorption within the digestive system.
  • Non-limiting examples for materials used for enteric coating are fatty acids, waxes, plant fibers or plastics.
  • Liquid dosage forms for oral administration may further contain adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
  • the compositions according to embodiments of this invention may also be administered in a controlled release formulation such as a slow release or a fast release formulation.
  • a controlled release dosage composition may be prepared using methods known to those skilled in the art.
  • compositions according to embodiments of the invention may contain an active amount of 0.1 -95 (by weight basis relative to total composition) of the Aramchol and VDR agonist, preferably l %-70%.
  • composition comprising Aramchol or a pharmaceutically acceptable salt thereof in combination with a VDR agonist as the active ingredients, and optionally pharmaceutically acceptable carriers, excipients and/or diluents.
  • composition is formulated as an oral (e.g. solid) dosage form.
  • the VDR agonist is selected from the group consisting of calciferol, alfacalcidol, 1 ,25-dihydroxyvitamin D3, Vitamin D2, Vitamin D3, calcitriol, Vitamin D4, Vitamin D5, dihydrotachysterol, calcipotriol, tacalcitol 1 ,24-dihydroxyvitamin D3 and paricalcitol.
  • the VDR agonist is vitamin D3 or a precursor, analog or active metabolite thereof.
  • said VDR agonist is selected from the group consisting of: vitamin D3, a vitamin D metabolite, and a vitamin D3 precursor.
  • the VDR agonist comprises cholecalciferol (vitamin D3).
  • composition comprises 400-5,000 IU of cholecalciferol in unit dosage form. In another embodiment the composition comprises 500-4,000, 750-4500, 1000-4000 or 2000-5000 IU of cholecalciferol in unit dosage form.
  • VDR agonist comprises alfacalcidol. In another embodiment the composition comprises alfacalcidol at an amount of between about 0.25 and 1 microgram.
  • Aramchol is in the form of Aramchol free acid.
  • Aramchol is in the form of a meglumine, lysine or tromethamine Aramchol salt.
  • the composition comprises 100-600 mg of Aramchol free acid or equivalent amount of salt thereof in unit dosage form.
  • composition consists essentially of Aramchol and the VDR agonist.
  • composition further comprises calcium.
  • said composition comprises 100-1000 mg, 150-750 or 250-500 mg of elemental calcium in the form of a carbonate, citrate, gluconate, succinate or citrate maleate.
  • said composition comprises 150-750 mg of elemental calcium in the form of calcium citrate.
  • said composition does not comprise calcium.
  • said composition consists of Aramchol and the VDR agonist (e.g. vitamin D3 or a precursor, analog or active metabolite thereof) as sole active ingredients.
  • said composition is adapted for providing a daily dosage of between about 400 mg and 600 mg of Aramchol or equivalent amount of a salt thereof and a daily dose of between about 400-10,000 IU of the VDR agonist.
  • the term "about,” when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations, as such variations are appropriate to perform the disclosed method or embodiment as determined by the skilled artisan.
  • the term encompasses variations of up to ⁇ 20% and typically no more than ⁇ 10%.
  • the variations may be of ⁇ 5%, ⁇ 1 %, ⁇ 0.5%, or ⁇ 0.1 % from the specified amount, as such variations are appropriate to perform the disclosed method.
  • said composition may comprise 300-500 mg of Aramchol or an equivalent amount of a salt thereof, 400-5,000 IU of cholecalciferol or a precursor, analog or active metabolite thereof. In another embodiment said composition may comprise 300-500 mg of Aramchol or an equivalent amount of a salt thereof, 400-5,000 IU of cholecalciferol or a precursor, analog or active metabolite thereof and 100-1000 mg of elemental calcium in the form of a carbonate, citrate, gluconate, succinate or citrate maleate. In another embodiment said composition may comprise 300-500 mg of Aramchol or an equivalent amount of a salt thereof, 400-5,000 IU of cholecalciferol and 150-750 mg of elemental calcium in the form of calcium citrate.
  • the composition may be used in the treatment of liver disease.
  • the composition may be used in the treatment of NAFLD.
  • the composition may be used in the treatment of NASH.
  • said pharmaceutical composition is used in the preparation of a medicament for the treatment of liver disease, preferably NAFLD and NASH.
  • the liver disease is NAFLD.
  • the liver disease is NASH.
  • said medicament is for the treatment of liver fibrosis in a patient in need thereof.
  • the invention provides a package comprising a) a first pharmaceutical composition comprising Aramchol or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; b) a second pharmaceutical composition comprising a VDR agonist and a pharmaceutically acceptable carrier; and c) instructions for use of the first and second pharmaceutical compositions in combination to treat a subject afflicted with a liver disease.
  • the disease is selected from the group consisting of NAFLD and NASH.
  • the instructions are for use of the first and second pharmaceutical compositions in combination to treat a subject afflicted with NAFLD.
  • the instructions are for use of the first and second pharmaceutical compositions in combination to treat a subject afflicted with NASH.
  • the VDR agonist is selected from the group consisting of calciferol, alfacalcidol, 1 ,25-dihydroxyvitamin D3, Vitamin D2, Vitamin D3, calcitriol, Vitamin D4, Vitamin D5, dihydrotachysterol, calcipotriol, tacalcitol 1 ,24-dihydroxyvitamin D3 and paricalcitol.
  • the VDR agonist is vitamin D3 or a precursor, analog or active metabolite thereof.
  • said VDR agonist is selected from the group consisting of: vitamin D3, a vitamin D metabolite, and a vitamin D3 precursor.
  • the VDR agonist comprises cholecalciferol (vitamin D3).
  • the package comprises 400-5,000 IU of cholecalciferol in unit dosage form. In another embodiment the package comprises 500-4,000, 750-4500, 1000-4000 or 2000-5000 IU of cholecalciferol in unit dosage form.
  • the VDR agonist comprises alfacalcidol. In another embodiment the package comprises alfacalcidol at an amount of between about 0.25 and 1 microgram.
  • Aramchol is in the form of Aramchol free acid.
  • Aramchol is in the form of a meglumine, lysine or tromethamine Aramchol salt.
  • the composition comprises 100-600 mg of Aramchol free acid or equivalent amount of salt thereof in unit dosage form.
  • the package consists essentially of Aramchol and the VDR agonist.
  • the package further comprises calcium.
  • said package comprises 100-1000 mg, 150-750 or 250-500 mg of elemental calcium in the form of a carbonate, citrate, gluconate, succinate or citrate maleate.
  • said package comprises 150-750 mg of elemental calcium in the form of calcium citrate.
  • said package does not comprise calcium.
  • said package consists of Aramchol and the VDR agonist (e.g. vitamin D3 or a precursor, analog or active metabolite thereof) as sole active ingredients.
  • said package is adapted for providing a daily dosage of between about 400 mg and 600 mg of Aramchol or equivalent amount of a salt thereof and a daily dose of between about 400-10,000 IU of the VDR agonist.
  • said package may comprise 300-500 mg of Aramchol or an equivalent amount of a salt thereof, and 400-5,000 IU of cholecalciferol or a precursor, analog or active metabolite thereof.
  • said package may comprise 300-500 mg of Aramchol or an equivalent amount of a salt thereof, 400-5,000 IU of cholecalciferol or a precursor, analog or active metabolite thereof and 100- 1000 mg of elemental calcium in the form of a carbonate, citrate, gluconate, succinate or citrate maleate.
  • said package may comprise 300-500 mg of Aramchol or an equivalent amount of a salt thereof, 400-5,000 IU of cholecalciferol and 150-750 mg of elemental calcium in the form of calcium citrate.
  • the package is used in the treatment of a liver disease selected from the group consisting of NASH and NAFLD.
  • the package consists of Aramchol and the VDR agonist as the active ingredients.
  • said package is for use in the treatment of liver disease, preferably NAFLD and NASH.
  • the liver disease is NAFLD.
  • the liver disease is NASH.
  • said medicament is for the treatment of liver fibrosis in a patient in need thereof.
  • the subject to be treated by the compositions and methods of the invention also referred to herein as a patient in need thereof, is a mammalian and preferably a human subject.
  • the subject has been diagnosed as suffering from NAFLD or NASH.
  • the invention relates to treatments of liver disease with Aramchol or a pharmaceutically acceptable salt thereof in combination with VDR agonist.
  • the liver disease is NAFLD.
  • the liver disease is NASH. Determining the presence of liver diseases such as NAFLD and NASH is readily performed by well known diagnostic methods. For example, without limitation, the liver disease may be confirmed by one or more than one of: liver enzyme level in serum, ultrasound, liver biopsy, magnetic resonance imaging (MRI), and by known genetic and metabolic markers.
  • the liver disease is associated with fibrosis.
  • the subject is diagnosed with proton density fat fraction (PDFF) > 5.5% as measured by magnetic resonance imaging (MRI) using multiecho Dixon methods.
  • PDFF proton density fat fraction
  • said subject is afflicted with liver fibrosis exhibiting liver stiffness (e.g. at least 3.9 kPa) measured by magnetic resonance elastography (MRE).
  • 25-hydroxyvitamin D (25(OH)D), also known as calcifediol, is a metabolite of vitamin D, produced by hydroxylation of cholecalciferol (Vitamin D 3 ).
  • a 25-hydroxyvitamin D serum level below a threshold of 12 nanograms/milliliter (ng/ml) in a subject indicates that the subject is vitamin D deficient.
  • the threshold is 20 ng/ml of 25-hydroxyvitamin D in serum.
  • the compositions and methods of the invention may be particularly advantageous in vitamin D deficient patients. Thus, e.g.
  • the methods of the invention may include a step of determining whether the patient is vitamin D deficient, as described herein.
  • the compositions and methods of the invention may be surprisingly effective even in vitamin D non-deficient patients, not hitherto considered to be amenable for vitamin D supplement treatment.
  • the patient has not been diagnosed with vitamin D deficiency.
  • the patient is vitamin D non-deficient.
  • the additional condition is selected from the group consisting of: insulin resistance, diabetes, arteriosclerosis, metabolic syndrome, elevated triglycerides, low high density lipoprotein (HDL) levels, elevated fasting glucose levels, hypertension, acquired lipodystrophy, human immunodeficiency virus (HlV)-associated lipodystrophy and obesity.
  • the patient is not concomitantly afflicted with another condition, e.g. the conditions as detailed above. Each possibility represents a separate embodiment of the invention.
  • the subject is not afflicted with impaired renal function or kidney stones.
  • said subject is not afflicted with primary hypercalcemia or another condition that carries a risk of hypercalcemia (e.g. sarcoid, tuberculosis).
  • said subject is not afflicted with inflammatory bowel disease (IDB), chronic pancreatic disease, or celiac disease.
  • said patient is not afflicted with an additional liver disease, such as autoimmune hepatitis, hepatitis B, hepatitis C, alcoholic liver disease, or hepatocellular carcinoma (HCC).
  • said patient is not afflicted with HIV.
  • said subject is not under concomitant treatment for an additional liver disease, e.g. interferon-gamma or other immunomodulating or antiviral treatments.
  • said subject is characterized by the bAt (CCA) VDR haplotype.
  • said subject is characterized by the bat (CAA) and/or BaT (TAG) VDR haplotype.
  • a method for treatment of disease selected from the group consisting of NAFLD and NASH, in a patient in need thereof comprising administering to the patient, an amount of Aramchol or a pharmaceutically acceptable salt thereof in combination with an amount of a VDR agonist or a pharmaceutically acceptable salt thereof to treat the disease.
  • the liver disease is fibrotic NASH.
  • the invention relates to a therapeutic combination of Aramchol or a pharmaceutically acceptable salt thereof and a VDR agonist, for use in the treatment of a liver disease selected from the group consisting of NASH and NAFLD in a patient in need thereof.
  • Embodiments of the invention comprise administering Aramchol or a pharmaceutically acceptable salt thereof in combination with a VDR agonist (which combination may be referred to hereinafter as "the active pharmaceutical agents") in amounts (e.g. daily doses) in which there is a synergistic effect on treatment of liver disease.
  • the active pharmaceutical agents comprise administering the active pharmaceutical agents in amounts in which there is a complementary effect on treatment of NAFLD and/or NASH.
  • the method comprises administering Aramchol or a pharmaceutically acceptable salt thereof in combination with a VDR agonist in amounts in which there is a greater than additive effect relative to treatment with one of the active pharmaceutical agents individually. It is suggested that embodiments of the invention using VDR agonists in combination with Aramchol, may show at least an additive or greater than additive effect on non-alcoholic liver disease (NAFLD and/or NASH) in treatment of fibrosis of the liver in the patient. It is suggested that embodiments of the invention using VDR agonists in combination with Aramchol, may show at least an additive or greater than additive effect on non-alcoholic liver disease (NAFLD and/or NASH) in treatment of inflammation of the liver in the patient.
  • NAFLD and/or NASH non-alcoholic liver disease
  • VDR agonists in combination with Aramchol or a pharmaceutically acceptable salt thereof may provide improved therapy of NAFLD and/or NASH patients with respect to therapeutic potency and/or safety.
  • use of VDR agonists in combination with Aramchol or a pharmaceutically acceptable salt thereof as described herein may provide reduced risk for hypercalcemia.
  • the treatment is provided in a chronic manner, as needed e.g. once, twice, three times or four times daily or weekly.
  • the methods and therapeutic uses are effective in improving one or more symptoms of fatty liver disease, such as reducing liver fat content and/or liver stiffness.
  • the methods and therapeutic uses are effective in reducing PDFF to a level lower than 5.5% as measured by MRI using a multiecho Dixon method.
  • the methods and therapeutic uses are effective in reducing liver stiffness to a level lower than 3.9 kPa measured by MRE.
  • the method is effective to reduce one, or more than one of the following histological features: steatosis, lobular inflammation, hepatocellular ballooning and liver fibrosis.
  • the method is effective in lowering alanine aminotransferase (ALT) levels.
  • the methods of the invention may be effective in improving one or more additional parameters in a patient afflicted with fatty liver disease, e.g. parameters associated with co-morbidities of the disease.
  • the method is effective in improving insulin resistance.
  • the insulin resistance is optionally determined by HOMA score.
  • the method is effective in reducing glycated haemoglobin (HbAlc) levels.
  • the method is effective in reducing leptin adiponectin ratio.
  • the method is effective in reducing inflammation or fibrosis in a patient.
  • the inflammation or fibrosis is reduced as evident from a reduction of a biomarker selected from the group consisting of: Fibrinogen, CK-18, C-reactive protein (CRP), TNFa and IL-6.
  • the method is effective in reducing body weight in a patient.
  • the method is effective in reducing waist circumference in a patient.
  • the combination is effective in reducing the incidence of myocardial infarction or stroke
  • the method or treatment comprises administering 400 mg daily of Aramchol or an equivalent amount of a pharmaceutically acceptable salt thereof.
  • the method or treatment comprises administering at least
  • the method or treatment comprises administering less than 400 mg daily of Aramchol or an equivalent amount of a pharmaceutically acceptable salt thereof.
  • Aramchol is administered once daily.
  • VDR agonist is administered to a patient in need thereof in an amount of between 50-15,000 International Units (IU) per day.
  • the VDR agonist is Vitamin D 3 , and the amount administered per day is between 400 IU and 5,000 IU per day.
  • Vitamin D 3 is administered in an amount of 500-4,000, 750-4500, 1000-4000, 1000-3000, 2000-5000 or 3000-5000 IU, e.g. 400, 600, 800, 1000, 2,000, 4,000 or 5,000 IU per day.
  • 50,000 IU of Vitamin D3 is administered once every 14 days.
  • An international unit of VDR agonist is equivalent to 0.025 micrograms of cholecalciferol.
  • the VDR agonist is alfacalcidol and the amount administered is between 0.25 and 1 microgram per day.
  • the dose of the VDR agonist to be administered may be adjusted by the treating physician according to the change in serum 25(OH)D levels.
  • a daily dose of 3000-5000 IU of Vitamin D 3 may be administered to a patient having a serum 25(OH)D level lower than 20 ng/ml
  • a daily dose of 1000-3000 IU of Vitamin D 3 may be administered to a patient having a serum 25(OH)D level of 20 ng/ml or more.
  • the aforementioned daily doses may be administered at intervals less regular than once daily.
  • the daily dosage should be multiplied by the number of days between administrations.
  • Aramchol or pharmaceutically acceptable salt thereof and the VDR agonist are provided in a single dosage form.
  • Aramchol or pharmaceutically acceptable salt thereof and the VDR agonist are provided in separate dosage forms.
  • the preparation comprises between about 400 mg and 600 mg of Aramchol or equivalent amount of a salt thereof and between about 400-10,000 IU of the VDR agonist.
  • the invention provides a method for treatment of disease, selected from the group consisting of non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), in a patient in need thereof, comprising administering to the patient an amount of Aramchol or a pharmaceutically acceptable salt thereof in combination with an amount of a VDR agonist or a pharmaceutically acceptable salt thereof to treat the disease.
  • the method is for use in the treatment of liver fibrosis in said patient.
  • Aramchol and the VDR agonist are administered in the form of a single oral dosage form.
  • the VDR agonist is selected from the group consisting of calciferol, alfacalcidol, 1 ,25-dihydroxyvitamin D3, Vitamin D2, Vitamin D3, calcitriol, Vitamin D4, Vitamin D5, dihydrotachysterol, calcipotriol, tacalcitol 1 ,24-dihydroxyvitamin D3 and paricalcitol.
  • the VDR agonist is vitamin D3 or a precursor, analog or active metabolite thereof.
  • said VDR agonist is selected from the group consisting of: vitamin D3, a vitamin D metabolite, and a vitamin D3 precursor.
  • the VDR agonist comprises cholecalciferol (vitamin D3).
  • the method comprises administering a daily dose of 400-5,000 IU of cholecalciferol (e.g. 500- 4,000, 750-4500, 1000-4000 or 2000-5000 IU).
  • Aramchol is in the form of Aramchol free acid.
  • Aramchol is in the form of a meglumine, lysine or tromethamine Aramchol salt.
  • the method comprises administering a daily dose of 100-600 mg of Aramchol free acid or equivalent amount of salt thereof.
  • the method is adapted for providing a daily dosage of between about 400 mg and 600 mg of Aramchol or equivalent amount of a salt thereof and a daily dose of between about 400-10,000 IU of the VDR agonist.
  • the method further comprises administering calcium to said patient.
  • said method comprises administering a daily dose of 100-1000 mg of elemental calcium in the form of a carbonate, citrate, gluconate, succinate or citrate maleate.
  • said method comprises administering a daily dose of 150-750 mg of elemental calcium in the form of calcium citrate.
  • the method comprises administering a daily dose of 300-500 mg of Aramchol or an equivalent amount of a salt thereof, a daily dose of 400-5,000 IU of cholecalciferol and a daily dose of 150-750 mg of elemental calcium in the form of calcium citrate.
  • a therapeutic combination of Aramchol or a pharmaceutically acceptable salt thereof and a VDR agonist for use in the treatment of a liver disease selected from the group consisting of NASH and NAFLD in a patient in need thereof.
  • a liver disease selected from the group consisting of NASH and NAFLD in a patient in need thereof.
  • the liver disease is NAFLD.
  • the liver disease is NASH.
  • the combination is for use in the treatment of liver fibrosis in the patient.
  • the fibrosis is in a patient suffering from NASH.
  • the combination consists of Aramchol and the VDR agonist as active ingredients. In another embodiment the combination is for simultaneous, separate or sequential use in the treatment of the liver disease. In another embodiment Aramchol and the VDR agonist are provided in a single dosage form. In a particular embodiment Aramchol and the VDR agonist are provided in an oral dosage form.
  • the VDR agonist is selected from the group consisting of calciferol, alfacalcidol, 1 ,25-dihydroxyvitamin D3, Vitamin D2, Vitamin D3, calcitriol, Vitamin D4, Vitamin D5, dihydrotachysterol, calcipotriol, tacalcitol 1 ,24-dihydroxyvitamin D3 and paricalcitol.
  • said VDR agonist is selected from the group consisting of: vitamin D3, a vitamin D metabolite, and a vitamin D3 precursor.
  • the combination comprises between about 100 and 600 mg of Aramchol free acid or equivalent amount of salt thereof. In another embodiment the combination comprises between 100 and 600 mg of Aramchol free acid or equivalent amount of salt thereof. In another embodiment the combination comprises between about 50-15,000 International Units (IU) of the VDR agonist. In another embodiment the combination is adapted for providing a daily dosage of between about 400 mg and 600 mg of Aramchol or equivalent amount of a salt thereof and a daily dose of between about 400-10,000 IU of the VDR agonist.
  • Aramchol is in the form of Aramchol free acid.
  • Aramchol is in the form of an amine-based salt.
  • the salt is a meglumine, lysine or tromethamine Aramchol salt.
  • the VDR agonist comprises cholecalciferol (vitamin D3). In another embodiment the combination comprises cholecalciferol at an amount of between about 400 and 5,000 IU. In another embodiment the VDR agonist comprises alfacalcidol. In another embodiment the combination comprises alfacalcidol at an amount of between about 0.25 and 1 microgram.
  • the combination further comprises calcium.
  • the combination comprises a daily dose of 100-1000 mg of elemental calcium in the form of a carbonate, citrate, gluconate, succinate or citrate maleate.
  • the combination comprises a daily dose of 150-750 mg of elemental calcium in the form of calcium citrate.
  • the combination comprises a daily dose of 300-500 mg of Aramchol or an equivalent amount of a salt thereof, a daily dose of 400-5,000 IU of cholecalciferol and a daily dose of 150-750 mg of elemental calcium in the form of calcium citrate.
  • Example 1 Mouse model of Methionine-choline deficient (MCD) diet.
  • the MCD diet is a diet deficient in methionine/choline in which test animals such as mice develop serologic and histological features of NASH including fat deposition, inflammation, necrosis and fibrosis.
  • mice Male mice (C57BL/6J, 8 wks) are housed in a pathogen-free barrier facility. All mice are fed MCD diet for 21 days.
  • mice are weighed and separated into 7comparable groups (1 control group and 6 test compound groups) upon starting the testing.
  • the study is composed of two phases, a dose selection phase and a combination phase. At the first phase a dose of each treatment is been selected for the combination treatment phase.
  • Test compounds are administered for 2 weeks, daily, via oral gavage. After the treatment periods, mice are sacrificed. Serum and liver samples are processed for alanine aminotransferase (ALT) and Hematoxylin and eosin (H&E) staining. Inflammatory cell infiltration is examined by myeloperoxidase staining, and Sirius red staining is used to monitor fibrosis. researchers blinded as to the grouping of the mice assess tissue samples.
  • ALT alanine aminotransferase
  • H&E Hematoxylin and eosin
  • Treated mice are examined for additive or greater than additive effects in at least one of the parameters of fat deposition, inflammation, necrosis, fibrosis, weight, blood cholesterol and glucose levels relative to the control group.
  • a double-blinded study is performed using about 200 patients diagnosed with NAFLD or NASH. Patients are weighed and tested for diabetes and metabolic syndrome, and a liver biopsy is performed before the treatment is initiated. Patients' disease severity is determined and patients are randomly designated to one of three groups:
  • Groups 1 and 2 are also administered one placebo tablet once daily. Administration is continued for 52 weeks. Administration is terminated if adverse reactions occur.
  • All patients are tested for a variety of parameters at baseline, week 24 and week 52, including a liver biopsy to determine the presence of NASH and the degree of steatosis, lobular inflammation, liver fat concentration and hepatocellular ballooning, ALT levels, insulin resistance, HOMA score, glycated haemoglobin (HbAlc) levels, leptin adiponectin ratio, liver inflammation, liver fibrosis, fibrinogen, CK-18, CRP, TNFa and IL-6. Patient body weight and waist circumference are also measured. Patients are examined for the presence of additive or greater than additive effects with respect to NASH presence, NAFLD activity score in a repeated biopsy after 52 weeks of treatment and/or one or more of the aforementioned parameters.
  • a liver biopsy to determine the presence of NASH and the degree of steatosis, lobular inflammation, liver fat concentration and hepatocellular ballooning, ALT levels, insulin resistance, HOMA score, glycated haemoglobin
  • This study is a single-blind, placebo-controlled randomized trial of Aramchol ⁇ cholan- 24-oic acid, 7, 12-dihydroxy-3-[(l-oxoeicosyl) amino]-, (3 ⁇ , 5 ⁇ , 7 ⁇ , 12 a, tested alone and in combination with vitamin D 3 and calcium in patients with vitamin D deficiency and nonalcoholic fatty liver disease (NAFLD) and liver stiffness. Study drugs are given for 24 weeks. The main comparison is between baseline and end of treatment measurements of liver stiffness and liver fat.
  • This study has four arms: Aramchol at 400 mg/day combined with vitamin D- placebo (Aramchol/ placebo), Aramchol at 400 mg/day combined with 4000 IU/day of vitamin D 3 (Aramchol/ vitamin D), Aramchol-placebo combined with 4000 IU/day of vitamin D 3 (placebo/ vitamin D), and Aramchol-placebo combined with vitamin D-placebo (placebo/ placebo).
  • the trial includes 80 adult patients (18 years of age or older) diagnosed with NAFLD (fatty liver) and increased liver stiffness (correlated with liver fibrosis).
  • Parameters confirmed prior to treatment include, inter alia:
  • liver stiffness measured with MRE indicating > stage 2 fibrosis (> 3.9 kPa);
  • liver disease such as autoimmune hepatitis, hepatitis B, hepatitis C, alcoholic liver disease, hepatocellular carcinoma (HCC) or HIV, as indicated by negative serum tests for markers of viral hepatitis and HIV; patients taking medications for diabetes must be on a stable regimen for at least 6 months prior to randomization;
  • patients taking dietary supplements containing > 400 IU/day vitamin E and/or > 2 g/day polyunsaturated fatty acid or ursodeoxycholic acid are on a stable regimen for at least 6 months prior to randomization;
  • patients with a history of hypertension are on a stable dose of anti-hypertensive medication for at least 2 months prior to screening.
  • a history of primary hypercalcemia or another condition that carries a risk of hypercalcemia if the patient is prescribed vitamin D (e.g. sarcoid, tuberculosis), inflammatory bowel disease (IDB), previous intestinal (ileal or colonic) operation, chronic pancreatic, celiac disease or previous vagotomy, and previous bariatric surgery are excluded.
  • Aramchol/vitamin D, Aramchol/placebo (vitamin D), placebo (Aramchol)/vitamin D, placebo (Aramchol)/placebo (vitamin D) are taken by mouth once daily for 24 weeks.
  • Calcium (500 mg) in the form of calcium citrate (two tablets of 250 mg, Douglas Laboratories) is taken by mouth once daily for 24 weeks. Height, weight and waist/hip ratio are measured.
  • blood/plasma is collected for analysis of CK 18, metabolomics, genomic DNA, and other factors (e.g., miRNA).
  • HCG in women of child bearing potential
  • fasting insulin hemoglobin Ale
  • CBC with platelets hsCRP
  • Transplant Monitoring Panel fasting glucose, sodium, potassium, chloride, CO 2 , urea nitrogen, creatinine, phosphorus, protein total, albumin, calcium, alkaline phosphatase, ALT, AST, gamma GT, bilirubin total, bilirubin direct, LDH, amylase, magnesium
  • Lipid Panel cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, cholesterol/HDL ratio, LDL/HDL ratio).
  • Liver fat content and liver stiffness are measured using MRI/MRE (magnetic resonance imaging/magnetic resonance elastography) and FibroScan (Echosens, France)/FibroScan with the Controlled Attenuation Parameter (CAP).
  • CAP reports the degree of ultrasound attenuation, which correlates with hepatic fat content.
  • FibroScan and FibroScan CAP tests measuring liver stiffness and PDFF, respectively, are performed five times: twice prior to the start of treatment, twice near and at the end of treatment (at weeks 20 and 24), and at the 4 week follow up visit.
  • MRI/MRE and ultrasound (US) are performed at the second screening visit and at the end of treatment (at week 24).
  • the primary outcome is the difference in the change in liver stiffness (baseline to end of treatment), measured by MRE comparing placebo/ placebo to Aramchol placebo and comparing placebo/ placebo to Aramchol/ vitamin D, analyzed by t-tests, or Mann- Whitney U tests, without correction for multiple testing.
  • Secondary endpoints include (1) changes in PDFF (measured by MRI and FibroScan/CAP), (2) changes in liver stiffness measured by FibroScan, (3) comparison placebo/ vitamin D to placebo/ placebo, (4) changes levels of factors in blood, including, but not limited to the AST/ ALT ratio and total bilirubin, (5) changes in serum levels of 25(OH)D and calcium, (6) the difference in the change in liver stiffness (baseline to end of treatment) Aramchol/placebo versus Aramchol/ vitamin D, (7) safety/adverse events.
  • each of the verbs, "comprise”, “include” and “have”, and conjugates thereof, are used to indicate that the object or objects of the verb are not necessarily a complete listing of components, elements or parts of the subject or subjects of the verb.

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Abstract

Des modes de réalisation de la présente invention se rapportent à une polythérapie pour une maladie du foie comprenant une quantité d'aramchol ou un sel pharmaceutiquement acceptable de celui-ci en combinaison avec une quantité d'agoniste de récepteur de la vitamine D (VDR) pour traiter la maladie. La maladie du foie peut être la maladie du foie gras non alcoolique (NAFLD) ou une stéato-hépatite non alcoolique (NASH). L'invention concerne également des compositions comprenant de l'aramchol et un agoniste du VDR.
PCT/IL2016/050816 2015-07-27 2016-07-26 Polythérapie pour maladies du foie WO2017017677A1 (fr)

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