EP3934640A1 - Zusammensetzung mit einer monoacetyldiacylglycerolverbindung zur behandlung von fettleberkrankheit - Google Patents

Zusammensetzung mit einer monoacetyldiacylglycerolverbindung zur behandlung von fettleberkrankheit

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Publication number
EP3934640A1
EP3934640A1 EP20766948.2A EP20766948A EP3934640A1 EP 3934640 A1 EP3934640 A1 EP 3934640A1 EP 20766948 A EP20766948 A EP 20766948A EP 3934640 A1 EP3934640 A1 EP 3934640A1
Authority
EP
European Patent Office
Prior art keywords
liver disease
formula
compound
fatty liver
subject
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.)
Withdrawn
Application number
EP20766948.2A
Other languages
English (en)
French (fr)
Other versions
EP3934640A4 (de
Inventor
Ki Young SOHN
Jae Wha Kim
Sun Young Yoon
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.)
Enzychem Lifesciences Corp
Original Assignee
Enzychem Lifesciences Corp
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 claimed from KR1020190086967A external-priority patent/KR102218545B1/ko
Application filed by Enzychem Lifesciences Corp filed Critical Enzychem Lifesciences Corp
Priority claimed from PCT/IB2020/051990 external-priority patent/WO2020178803A1/en
Publication of EP3934640A1 publication Critical patent/EP3934640A1/de
Publication of EP3934640A4 publication Critical patent/EP3934640A4/de
Withdrawn legal-status Critical Current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
    • 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
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • 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
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/231—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having one or two double bonds
    • 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

  • This invention relates to a composition comprising a monoacetyldiacylglycerol compound as an active ingredient for treating fatty liver disease and more particularly to a composition comprising a monoacetyldiacylglycerol compound for oral administration which prevents and/or alleviates symptoms of fatty liver disease.
  • the liver is one of the most important metabolic organs in the body's organs and performs important functions such as bile secretion, nutrient storage, detoxification and so on. If the liver is in an abnormal state, metabolic disorders such as glucose metabolism, lipid metabolism, protein and nitrogen metabolism, amino acid metabolism, protein metabolism and hepatic brain disease, vitamin metabolism, poor absorption, may occur. In addition, hepatic diseases may be exacerbated by infection, fatty liver, cirrhosis, and the like.
  • Hepatic diseases known to date are associated with acute hepatitis caused by drugs, alcoholic fatty liver, obesity, diabetes, non-alcoholic fatty liver caused by hyperlipidemia, acute hepatitis caused by virus infection, chronic hepatitis, cirrhosis, and so on.
  • the type 1 diabetes is an autoimmune disease in which the patient's own immune system attacks and destroys beta cells.
  • the pathogenesis of fatty liver in the type 1 diabetes(TlD) is not yet clear.
  • Regnell and Lemmark suggested that it may be caused by abnormalities of lipoproteins, which mainly serve to transport lipids through the bloodstream and lymphocytes and/or activation of the transcription factors, carbohydrate response element-binding protein(ChREBP) and sterol regulatory element-binding protein lc(SREBP-lC), which regulate glucose metabolism and lipid synthesis, respectively (S.E. Regnell, A. Lemmark, Hepatic steatosis in type 1 diabetes Rev Diabet Stud 8 (2011) 454-467).
  • NAFLD non-alcoholic fatty liver disease
  • triglyceride TG
  • streptozotocin STZ is a selective pancreatic b cell toxin that induces rapid and irreversible necrosis of cells and is often used to induce diabetes. It is also a suitable candidate for modeling liver steatosis. STZ-induced diabetes is characterized by hyperglycemia, dyslipidemia, weight loss, and hepatic steatosis.
  • compositions and methods comprising a monoacetyldiacylglycerol compound of Formula 1 for treating fatty liver disease.
  • the compound of Formula 2 is 1 -palmitoyl -2 -linoleoyl-3 -acetyl -rac-glycerol and corresponds to the compound of Formula 1 in which R 1 and R 2 of Formula 1 are palmitoyl and linoleoyl, respectively.
  • the compound of Formula 2 is sometimes referred as“PLAG” or“EC-18” in this disclosure.
  • a compound of Formula 1 and 2 is used to treat a subject suffering from or susceptible to non-alcoholic steatohepatitis (NASH).
  • NASH non-alcoholic steatohepatitis
  • a compound of Formula 1 and 2 is used to treat a subject suffering from or susceptible to non-alcoholic fatty acid liver disease (NAFLD).
  • NAFLD non-alcoholic fatty acid liver disease
  • a patient may be identified and selected as suffering from non- alcoholic steatohepatitis (NASH) and that patient identified as suffering from non- alcoholic steatohepatitis (NASH) may be administered a compound of Formula 1 or 2 to thereby alleviate or treat the non-alcoholic steatohepatitis (NASH).
  • a patient may be identified and selected as suffering from non-alcoholic fatty acid liver disease (NAFLD) and that patient identified as suffering from non-alcoholic fatty acid liver disease (NAFLD) may be administered a compound of Formula 1 or 2 to thereby alleviate or treat the non-alcoholic fatty acid liver disease (NAFLD).
  • a patient may be identified and selected as suffering from liver fibrosis and that patient identified as suffering from liver fibrosis may be administered a compound of Formula 1 or 2 to thereby alleviate or treat the non-alcoholic fatty acid liver disease (NAFLD).
  • one or more compounds of Formula 1 or 2, or PLAG may be administered to a subject in combination or coordination with one or more liver fibrosis treatment agents that are distinct from the one or more compounds of Formula 1 or 2, or PLAG.
  • the one or more distinct liver fibrosis treatment agents that are co-administered or administered in combination with one or more compounds of Formula 1 or 2, or PLAG may be obeticholic acid (OCA), elafibranor (GFT505), selonsertib (GS-4997), cenicriviroc (CVC), liraglutide, metadoxine, hydroxytyrosol and vitamin E, NGM282 (M70), BMS-986036, emricasan (IDN-6556), aramchol, atorvastatin and/or L carnitine, MGL-3196 (Resmetirom), volixibat (SHP626), GS-9674, semaglutide, sa
  • OCA obeticholic
  • PLAG may be co-administered with obeticholic acid (OCA) such as to treat a subject e.g. a human suffering from a fatty liver disease or disorder such as NASH or NAFLD.
  • OCA obeticholic acid
  • PLAG may be co-administered with MGL-3196 such as to treat a subject e.g. a human suffering from a fatty liver disease or disorder such as NASH or NAFLD.
  • PLAG may be co-administered with both MGL- 3196 and obeticholic acid (OCA) such as to treat a subject e.g. a human suffering from a fatty liver disease or disorder such as NASH or NAFLD.
  • a liver fibrosis treatment agent will be distinct from a compound of Formula 1 or 2, or PLAG where the liver fibrosis treatment agent differs in chemical structure from a compound of Formula 1 or 2, or PLAG.
  • a distinct liver fibrosis treatment may not comprise a monoacetyldiacylglycerol structure, or may not comprise a diacylglycerol structure compound, or may not comprise a glycerol structure.
  • An administered distinct liver fibrosis treatment agent also may differ (either higher or lower) in molecular weight from the co-administered compound of Formula 1 or 2, or PLAG by at least 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90 or 100 percent.
  • the present therapeutic methods are not associated with treatment of a subject suffering from hepatitis.
  • subjects that are suffering from hepatitis and/or are seeking treatment for hepatitis would be excluded from the present therapeutic methods.
  • subjects seeking treatment that have been identified as having hepatitis would be excluded from the present therapeutic methods.
  • the present therapeutic methods are not associated with treatment of a subject suffering from diabetes. In this aspect, subjects that are suffering from diabetes and/or are seeking treatment for diabetes would be excluded from the present therapeutic methods.
  • the present therapeutic methods are not associated with a subject suffering from a wound or injured tissue.
  • subjects that are suffering from a wound or injured tissue and/or are seeking treatment for a wound or injured tissue would be excluded from the present therapeutic methods.
  • subjects seeking treatment involving tissue repair or regeneration would be excluded from the present therapeutic methods.
  • compositions comprising a compound of Formula 1 or 2 as set forth above.
  • the compositions suitably may comprise one or more pharmaceutically acceptable carriers.
  • the compositions may be formulated or otherwise adapted for treatment of fatty liver disease as disclosed herein.
  • the composition may be adapted for oral administration as a tablet or capsule.
  • kits are provided for use to treat or prevent a fatty liver disease as disclosed herein.
  • Kits of the invention suitably may comprise 1) one or more compounds of Formulae 1 or 2; and 2) instructions for using the one or more compounds for treating or preventing fatty liver disease as disclosed herein.
  • a kit will comprise a therapeutically effective amount of one or more compounds of Formulae 1 or 2.
  • the instructions suitably may be in written form, including as a product label.
  • the present invention also provides a health functional food composition comprising a monoacetyldiacylglycerol compound of the Formula 1 for alleviating or preventing fatty liver disease.
  • composition of the present invention can reduce the expression of apo B protein including ApoB48 in the portal vein, is non-toxic and treats and/or alleviates fatty liver disease.
  • FIG. 3 shows photomicrographs of liver sections stained with H&E and ORO, when using the composition according to the present invention.
  • FIG. 4 shows an exemplary mechanism in which fat absorbed in the small intestine affects the liver.
  • FIG. 5 shows a chart (FIG. 5A) showing the TG levels and contents in the liver and plasma and a chart (FIG. 5B) showing the apoB48 protein expression in portal vein plasma, when using the composition according to the present invention.
  • FIG. 6 shows a chart (FIG. 6A) showing the TG content in muscle tissue, a chart (FIG. 6B) showing the relative mRNA expression of LPL in muscle tissue and pictures (FIG. 6C) showing the representative immunohistochemical images of LPL staining in muscle sections, when using the composition according to the present invention.
  • FIG. 7 shows a chart (FIG. 7A) showing the weight of muscle specimens and skeletal muscle from mice, and the result of the relative mRNA expression of caveolin3 in muscle tissue, including the gastrocnemius and quadriceps (FIG. 7B) and the result of the relative mRNA expression of caveolin3 and myogenin in myoblasts and myotubes (FIG. 7C).
  • FIG. 9 shows another experimental protocol of the present invention.
  • FIG. 10 is a graph showing the body weight change, when using the composition according to the present invention.
  • FIG. 11 is a graph showing the weight (FIG. 11A), the liver weight (FIG. 11B) and the ratio of liver weight to weight (FIG. 11C), when using the composition according to the present invention.
  • FIG. 12 is a graph showing the plasma ALT (FIG. 12A) and the plasma AST (FIG. 12B) and the ALT/AST ratio (FIG. 12C), when using the composition according to the present invention.
  • FIG. 13 shows photomicrographs of liver sections stained with H&E and ORO, when using the composition according to the present invention.
  • FIG. 14 shows graphs showing of liver sections stained with H&E and ORO, when using the composition according to the present invention.
  • FIG. 15 shows photomicrographs of Sirius red-stained liver sections, when using the composition according to the present invention.
  • FIG. 17 shows a graph of level of liver triglyceride in Groups 1-6 in Example 12.
  • FIG. 18 shows a graph of plasma CK-18 in Groups 1-6 in Example 1 2
  • FIG. 19 shows representative photomicrographs of F4/80-immunostained liver sections in Groups 1-6 in Example 12.
  • FIG. 20 shows a graph of inflammation area (F4/80-positive area %) in Groups 1-6 in Example 12.
  • composition for treating fatty liver disease comprises a monoacetyldiacylglycerol compound of Formula 1 as an active ingredient.
  • the term "monoacetyldiacylglycerol compound” means a glycerol derivative containing an acetyl group and two acyl groups and is also referred to as monoacetyldiacylglycerol (MADG).
  • R 1 and R 2 are independently a fatty acid residue of 14 to 22 carbon atoms, preferably a fatty acid residue of 15 to 20 carbon atoms.
  • the fatty acid residue means the remaining portion of the fatty acid in which the -OH group is excluded from its carboxyl group.
  • non-limiting examples of R 1 and R2 thus include palmitoyl, oleoyl, linoleoyl, linolenoyl, stearoyl, myristoyl, arachidonoyl, and so on.
  • R 1 and R2 Preferable combinations of R 1 and R2 include oleoyl/palmitoyl, palmitoyl/oleoyl, palmitoyl/linoleoyl, palmitoyl/linolenoyl, palmitoyl/arachidonoyl, palmitoyl/stearoyl, palmitoyl/palmitoyl, oleoyl/stearoyl, linoleoyl/palmitoyl, linoleoyl/stearoyl, stearoyl/linoleoyl, stearoyl/oleoyl, myristoyl/linoleoyl, myristoyl/oleoyl, and so on.
  • R 1 and R2 are palmitoyl/linoleoyl.
  • the monoacetyldiacylglycerol derivatives of Formula 1 can be (R)-form, (S)-form or a racemic mixture, preferably a racemic mixture, and may include their stereoisomers.
  • the monoacetyldiacylglycerol is a compound of the following Formula 2:
  • the compound of Formula 2 is 1 -palmitoyl -2 -linoleoyl-3 -acetyl -rac-glycerol and corresponds to the compound of Formula 1 in which R 1 and R 2 of Formula 1 are palmitoyl and linoleoyl, respectively.
  • the compound of Formula 2 is sometimes referred as“PLAG” or“EC-18” in this disclosure.
  • the monoacetyldiacylglycerol compounds can be separated and extracted from the natural deer antler or can be produced by known organic synthesis methods (Korean Patent No. 10-0789323).
  • a chemical synthetic method for the preparation of the monoacetyldiacylglycerol compounds is shown in Korean Patent No. 10-0789323. Specifically, the method comprises (a) a step of preparing 1-R1-3- protecting group - glycerol by introducing a protecting group in the position 3 of 1-R1-glycerol; (b) a step of preparing 1- R1 -2 -R2 -3 -protecting group-glycerol by introducing R2 in the position 2 of the 1-R1-3-protecting group-glycerol; and (c) a step of preparing the desired monoacetyldiacylglycerol compound by performing a deprotection reaction and the acetylation reaction of the 1-R1 -3 -protecting group-glycerol at the same time.
  • the monoacetyldiacylglycerol compound of the present invention can be effectively used for the treatment and/or alleviation of fatty liver disease.
  • fatty liver disease is a disease characterized by excessive fat (mainly triglycerides) accumulated in the liver.
  • fatty liver disease means a state that the amount of fat in the liver is more than 5 weight% of the total liver weight.
  • the fatty liver disease includes non-alcoholic fatty liver disease (NAFLD).
  • NAFLD non-alcoholic fatty liver disease
  • the non-alcoholic fatty liver disease (NAFLD) is excessive fat build-up in the liver due to causes other than alcohol use.
  • the non-alcoholic fatty liver disease is a chronic liver disease that is associated with overweight, obese, insulin resistance, diabetes (type 1 diabetes(TID), type 2 diabetes, etc.), dyslipidemia(hyperlipidemia), metabolic syndrome (for example, hypertension, high blood sugar, abdominal obesity, metabolic syndrome caused by low HDL cholesterol and high triglycerides), and so on.
  • the NAFLD is caused by the accumulation of excessive fat (mainly, triglycerides) in the liver due to causes other than alcohol use, and usually refers to the accumulation of more than 5 weight% of fat with respect to the total liver weight.
  • the NAFLD includes the diseases resulting from the NAFLD.
  • the non-alcoholic fatty liver disease includes not only non-alcoholic fatty liver in which fat is simply accumulated in the liver without damaging hepatocytes, but also non-alcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, and even hepatocellular carcinoma.
  • NASH non-alcoholic steatohepatitis
  • the non-alcoholic fatty liver disease can be classified into Type l to Type 4.
  • Type 1 means a simple fatty liver with only steatosis, without hepatocytes damage.
  • Type 2 means a steatohepatitis with inflammatory reactions in the lobules, due to severe and persistent steatosis and hepatocytes damage.
  • Type 3 means a state in which balloon-shaped alteration of hepatocytes and steatosis and fat necrosis appear.
  • Type 4 means a state in which mallory body or fibrosis appear with the symptoms of Type 3. Cirrhosis may occur in Type 3 and Type 4.
  • NASH non-alcoholic steatohepatitis
  • liver function may be deteriorated, and liver cirrhosis may occur through liver fibrosis.
  • the fibrosis is atype of wound healing process in liver tissue.
  • livertissue is damaged by hepatitis virus, non-alcoholic fatty liver, drugs, etc.
  • the vascular structure collapses in the hepatic lobules, as the hepatocytes are continuously damaged and regenerated.
  • regenerative nodules lost function take their place, and a fibrosis reaction occurs in the liver, and may lead to cirrhosis of the liver.
  • Hepatic stellate cells are a reservoir of vitamin A in normal condition, but are activated when liver damage occurs, and can synthesize and secrete various extracellular substrates such as collagen to cause liver fibrosis.
  • damaged hepatocytes can no longer be regenerated and gradually replaced with extracellular matrix such as collagen, which can lead to liver fibrosis and cirrhosis.
  • NAFLD non-alcoholic fatty liver disease
  • the monoacetyldiacylglycerol compound according to the present invention can be effectively used for the treatment of non-alcoholic fatty liver disease (NAFLD) including non-alcoholic fatty liver, non-alcoholic steatohepatitis (NASH) and liver fibrosis.
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • liver fibrosis liver fibrosis.
  • treatment includes delay or reduction of symptoms, as well as partial or complete elimination or prevention of symptoms, of non-alcoholic fatty liver, non-alcoholic steatohepatitis (NASH) and liver fibrosis by administering the composition of the present invention.
  • one or more compounds of Formula 1 or 2, or PLAG and the one or more liver fibrosis treatment agents can be administered in combination such as to treat a subject including a human suffering from a fatty liver disease including NASH.
  • the term“in combination” in the context of the administration of a therapy to a subject refers to the use of more than one therapy for therapeutic benefit.
  • the term“in combination” in the context of the administration can also refer to the prophylactic use of a therapy to a subject when used with at least one additional therapy.
  • the use of the term“in combination” does not restrict the order in which the therapies (e.g., a first and second therapy) are administered to a subject.
  • the therapies are administered to a subject in a sequence and within a time interval such that the therapies can act together.
  • the therapies are administered to a subject in a sequence and within a time interval such that they provide an increased benefit than if they were administered otherwise. Any additional therapy can be administered in any order with the other additional therapy.
  • the administration of the compounds (e.g., compounds of Formula 1 or 2, or PLAG) and the one or more liver fibrosis treatment agents may be by suitable means that results in a concentration of the therapeutic that, combined with other components, is effective in ameliorating, reducing, or stabilizing a fat liver disease, e.g.
  • the compound (e.g., compounds of Formula 1 or 2, or PLAG) and the one or more distinct liver fibrosis treatment agents may be administered simultaneously or sequentially.
  • the liver fibrosis treatment is an established therapy for the disease indication and by addition of compounds (e.g., compounds of Formula 1 or 2, or PLAG), such treatment improves the therapeutic benefit to the patients. Such improvement could be measured as increased responses on a per patient basis or increased responses in the patient population. Combination therapy could also provide improved responses at lower or less frequent doses of the therapeutic agents resulting in a better tolerated treatment regimen.
  • the combined therapy of the compound (e.g., compounds of Formula 1 or 2, or PLAG) and the one or more distinct liver fibrosis treatment agents could provide enhances clinical activity through various mechanisms, for example, mechanisms in which fat absorbed in the small intestine affects the liver (e.g., increased dietary fat delivery to the liver from the small intestine (gut), either due to increased intake or a dysregulated gut physiology and microbiome); 2) increased influx of free fatty acids from the non-esterified pool (e.g., from white adipose tissue); 3) increased de novo hepatic lipogenesis from excess carbohydrates (and or hyperinsulinemia from adipose tissue insulin resistance), and the like.
  • mechanisms in which fat absorbed in the small intestine affects the liver e.g., increased dietary fat delivery to the liver from the small intestine (gut), either due to increased intake or a dysregulated gut physiology and microbiome
  • the methods may include administration of second therapeutic agent (e.g., one or more liver fibrosis treatment agents that are distinct from a compound of Formulae 1 or 2 or PLAG) or treatment with a second therapy (e.g., a therapeutic agent or therapy that is standard in the art) for liver fibrosis.
  • second therapeutic agent e.g., one or more liver fibrosis treatment agents that are distinct from a compound of Formulae 1 or 2 or PLAG
  • a second therapy e.g., a therapeutic agent or therapy that is standard in the art
  • Exemplary therapeutic agents include one or more liver fibrosis treatment agents.
  • A“liver fibrosis treatment agent” is a chemical compound useful in the treatment of a fatty liver disease, for example, non-alcoholic fatty acid liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, fatty liver disease resulting from hepatitis, fatty liver disease resulting from obesity, fatty liver disease resulting from diabetes, fatty liver disease resulting from insulin resistance, fatty liver disease resulting from hypertriglyceridemia, Abetalipoproteinemia, glycogen storage diseases, Weber-Christian disease, Wolmans disease, acute fatty liver of pregnancy, and/or lipodystrophy.
  • NAFLD non-alcoholic fatty acid liver disease
  • NASH non-alcoholic steatohepatitis
  • liver fibrosis fatty liver disease resulting from hepatitis
  • fatty liver disease resulting from obesity fatty liver disease resulting from diabetes
  • kits and composition may comprise one or more liver fibrosis treatments agents that comprise MGL-3196 (Resmetirom) and/or obeticholic acid (OCA) including to treat a subject e.g. human suffering from a fatty liver disease or disorder such as NASH or NAFLD.
  • MGL-3196 Resmetirom
  • OCA obeticholic acid
  • liver fibrosis treatment agents include peroxisome proliferator-activator receptors (PPARs a, b/d, and/or g) agonists (e.g., GW501516, elafibranor, thiazolidinediones, pioglitazone, or saroglitazar), FXR-bile acid axis (e.g., obeticholic acid, FGF-19, NGM-282, agents in NCT02548351, agents in NCT02443116, or the like), lipid-altering agents (e.g., stearoyl-CoA desaturase (SCD) inhibitor, aramchol,), agents for incretin-based therapies (e.g., exenatide, liraglutide, sitagliptin, or the like), agents targeting inflammation, cell injury or death (apoptosis) and oxidative stress (e.g., vitamin E, agents in E
  • the peroxisome proliferator-activator receptors include a group of nuclear receptors that are expressed in the liver, adipose tissue, heart, skeletal muscle and kidney and transcriptionally regulate multiple metabolic processes including B-oxidation, lipid transport and gluconeogenesis.
  • liver fibrosis agents that may be used in the present methods, compositions and kits include soluble guanylate cyclase (sGC) stimulators such as disclosed in WO2017/136309; and cenicriviroc as disclosed in US2018/0360846.
  • sGC soluble guanylate cyclase
  • a compound of Formula 1 or 2, or PLAG and 2) one or more distinct liver fibrosis treatment agents may be“co-administered”, i.e, administered together in a coordinated fashion to a subject, either as separate pharmaceutical compositions or admixed in a single pharmaceutical composition.
  • co- administered the one or more additional distinct liver fibrosis treatment agents may also be administered simultaneously with a compound of Formula 1 or 2, or be administered separately with compound of Formula 1 or 2, including at different times and with different frequencies.
  • the one or more distinct liver fibrosis treatment agents may be administered by any appropriate route for the agent(s), such as orally, intravenously, subcutaneously, intramuscularly, nasally, and the like; and the therapeutic agent may also be administered by any conventional route. In at least certain embodiments, at the one or more distinct liver fibrosis agents may be administered orally.
  • the compounds (e.g., compounds of Formula 1 or 2, or PLAG) and/or the one or more distinct liver fibrosis treatment agents may be administered daily, e.g., every 24 hours, or, continuously or several times per day, e.g., every 1 hour, every 2 hours, every 3 hours, every 4 hours, every 5 hours, every 6 hours, every 7 hours, every 8 hours, every 9 hours, every 10 hours, every 11 hours, or every 12 hours.
  • Exemplary effective daily doses of the distinct liver fibrosis treatment agent(s) include between 0.1 mg/kg and 100 mg/kg body weight, e.g., 0.1, 0.3, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99 mg/kg body weight.
  • the distinct liver fibrosis treatment agent is administered about once per week, e.g., about once every 7 days.
  • the distinct liver fibrosis treatment agent is administered twice per week, three times per week, four times per week, five times per week, six times per week, or seven times per week.
  • Exemplary effective weekly doses of the liver fibrosis treatment agents include between 0.0001 mg/kg and 4 mg/kg body weight, e.g., 0.001, 0.003, 0.005, 0.01. 0.02, 0.03, 0.04, 0.05, 0.06,
  • an effective weekly dose of the distinct liver fibrosis treatment agent is between 0.1 mg/kg body weight and 400 mg/kg body weight.
  • the triglyceride (TG, neutral fat) is absorbed in the small intestine as exogenous fat and includes the apolipoprotein of ApoB48.
  • the triglyceride (TG) is recombined with chylomicron (CM) along with ApoB48.
  • CM chylomicron
  • the triglyceride -rich CM is transported into the blood through the lymphatic system, while circulating throughout the body, and triglycerides (TG) are absorbed into peripheral tissues, including muscle, adipose tissue and monocytes, for energy or storage.
  • triglycerides (TG) contained in the CM are hydrolyzed by the lipoprotein lipase (LPL) in order that it can be transported to the liver through the portal vein, resulting in smaller CM residual particles. Therefore, when the lipoprotein lipase (LPL) is reduced, unused CM in peripheral tissues, including muscle, adipose tissue and immune cells, is transported to the liver, resulting in excessive circulation of triglycerides (TG) into the liver. It can cause hypertriglyceridemia and lead to fatty liver disease.
  • LPL lipoprotein lipase
  • the ApoB48 is a lipoprotein that transports cholesterol in the blood and triglycerides.
  • triglyceride (TG) When the ApoB48 is excessive, it means that triglyceride (TG) is high, which contributes to dyslipidemia. Because of this, the uptake of triglycerides (TG) in the liver may promote fat accumulation of hepatocytes causing fatty liver (See FIG. 4).
  • the pharmaceutical composition of the present invention may further include other active ingredients having a therapeutic effect of fatty liver disease.
  • the pharmaceutical composition may be formulated into solid, liquid, gel or suspension form for oral or non-oral administration, for example, tablet, bolus, powder, granule, capsule such as hard or soft gelatin capsule, emulsion, suspension, syrup, emulsifiable concentrate, sterilized aqueous solution, non-aqueous solution, freeze-dried formulation, and so on.
  • conventional excipients or diluents such as fillers, bulking agents, binders, wetting agents, disintegrating agents, and surfactants can be used.
  • the solid formulation for oral administration includes tablet, bolus, powder, granule, capsule and so on, and the solid formulation can be prepared by mixing one or more of the active components and at least one excipient such as starch, calcium carbonate, sucrose, lactose, gelatin, and so on. Besides the excipient, a lubricant such as Magnesium stearate and talc can also be used.
  • the liquid formulation for oral administration includes emulsion, suspension, syrup, and so on, and may include conventional diluents such as water and liquid paraffin or may include various excipients such as wetting agents, sweeting agents, flavoring agents, and preserving agents.
  • the monoacetyldiacylglycerol compound can be administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount is used to refer to an amount that is sufficient to achieve a desired result in a medical treatment.
  • The“pharmaceutically effective amount” can be determined according to the subject’s category, age, sex, severity and type of disease, activity of drug, sensitivity to drug, administration time, administration route, excretion rate, and so forth.
  • the composition of the present invention can be administered alone or with other therapeutic agents sequentially or simultaneously.
  • the composition of the present invention can be administered once or multiple times.
  • the preferable amount of the composition of the present invention can be varied according to the condition and weight of patient, severity of disease, formulation type of drug, administration route and period of treatment.
  • composition of the present invention can be administered to any subject that requires the prevention or treatment of fatty liver disease.
  • composition of the present invention can be administered to not only human but also non-human animal (specifically mammals) such as monkey, dog, cat, rabbit, guinea pig, rat, mouse, cow, sheep, pig, goat, and so on.
  • the monoacetyldiacylglycerol compound according to the present invention may be included into a health functional food composition to improve fatty liver disease in a subject.
  • the monoacetyldiacylglycerol compound and fatty liver disease are as described above.
  • the amount of monoacetyldiacylglycerol in the health food composition can be determined suitably according to the intended use.
  • the amount of monoacetyldiacylglycerol is preferably from 0.01 to less than 15 weight%, with respect to the total amount of the health functional food composition when the monoacetyldiacylglycerol is included in food or beverages.
  • the amount of monoacetyldiacylglycerol may be increased or decreased. In case of long term use for the purpose of the health control and hygiene, the amount of the monoacetyldiacylglycerol can be less than the above range. Since there is no problem in terms of safety, the monoacetyldiacylglycerol may be used in an amount greater than the above range.
  • Foods to which the compound of the present invention can be added are not limited and include various foods, for example, meats, sausages, breads, chocolates, candies, snacks, pizzas, noodles, gums, daily products such as ice creams, soups, beverages, teas, drinks, alcoholic beverages, vitamin complexes and any health functional food.
  • the beverage product may include sweeting agents, flavoring agents or carbohydrates.
  • carbohydrates include monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol.
  • the amount of carbohydrate in the beverage composition can be widely varied without specific limitation, and is preferably 0.01 to 0.04 g, more preferably, 0.02 to 0.03 g per 100 ml of the beverage.
  • administration means introducing the pharmaceutical composition of the present invention to a patient in need by any suitable method.
  • the route of administration may be any or a various routes, oral or non-oral, as long as the target tissue can be reached, for example, oral administration, intraperitoneal administration, transdermal administration(topical application, etc.), intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, intranasal administration, rectal administration, intranasal administration, intraperitoneal administration and the like may be used, but is not limited thereto.
  • mice in the experimental group were further randomized into three groups: STZ alone-treated group and low- and high-dose PFAG plus STZ treated groups.
  • l-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol represented by the Formula 2(PLAG) was used as the active ingredient.
  • mice received PLAG via oral gavage for 3 days.
  • the intended oral dosage was 250 and 50 mg/kg BW, in mice respectively.
  • Control and STZ alone treated groups were administrated orally with the same PBS for 3 days, and the mice were sacrificed on the fourth day.
  • Example 1 Body and relative liver weight analysis
  • the relative liver weight (per g BW) in the STZ alone group was significantly higher than in the control group.
  • the PLAG-treated group had a lower mean liver weight than the STZ group, indicating that PLAG supplementation improved hepatic steatosis.
  • FIG. 3 is the picture of liver sections stained with H&E and ORO. Specifically, in other to measure the degree of accumulation of liver fat, the liver of control and experimental groups were observed, hematoxylin and eosin ( H&E) and Oil red O was used to image. The liver samples were immediately fixed in 10% buffered formalin at room temperature, and then the tissues were embedded in paraffin, sectioned, and stained with hematoxylin and eosin(H&E). Frozen liver sections were fixed for 20 min with 4% paraformaldehyde followed by ORO staining for 15 min at room temperature. Then, the samples were counterstained with Mayer’s hematoxylin for 10 s and mounted. The images were obtained under light microscopy (Olympus, Tokyo, Japan).
  • Example 3 Liver and plasma TG levels analysis
  • TG triglyceride
  • FIG. 4 is an example of the mechanism by which fat absorbed in the small intestine affects the liver
  • FIG. 5 is the chart (FIG. 5A) showing the TG levels and contents in the liver and plasma and the chart (FIG. 5B) showing the apoB48 protein expression in portal vein plasma, when using the composition according to the present invention.
  • TG triglyceride
  • liver tissue (20 mg) was homogenized in isopropanol with a tissue grinder. The homogenate was centrifuged at 5,000 rpm for 10 min, and the supernatant was collected.
  • TG content of the supernatant was measured with a Triglyceride H kit (Wako Diagnostics, Richmond, VA, USA).
  • ApoB48 expression in portal vein blood was measured, as a marker of TG-rich CM transport and uptake in the body.
  • Fig. 6 is the chart (FIG. 6A) showing the TG content in muscle tissue, the chart (FIG. 6B) showing the relative mRNA expression of LPL in muscle tissue and the picture (FIG. 6C) showing the representative immunohistochemical images of LPL staining in muscle sections, when using the composition according to the present invention.
  • LPL lipoprotein lipase
  • FIG. 6C shows the representative immunohistochemical images of LPL staining in muscle sections, when using the composition according to the present invention.
  • LPL lipoprotein lipase
  • CM the rate-limiting enzyme in TG clearance
  • Example 5 Western blotting
  • FIG 7 is the chart (FIG. 7A) showing the weight of muscle specimens and skeletal muscle from mice, and the result of the relative mRNA expression of caveolin3 in muscle tissue, including the gastrocnemius and quadriceps (FIG. 7B) and the result of the relative mRNA expression of caveolin3 and myogenin in myoblasts and myotubes (FIG. 7C).
  • the relative amounts of apolipoprotein B48(ApoB48) in portal vein plasma were evaluated by western blot. Constant volumes of plasma were separated with 5% sodium dodecyl sulfate -polyacrylamide gel electrophoresis.
  • the protein extracts were immunoblotted with ApoB48 antibody (1:500, Abeam, Cambridge, UK). Detection was conducted using Immobilon Western Chemiluminescent HRP Substrate (Millipore Corporation, Billerica, MA, USA).
  • muscle atrophy is defined as a loss of muscle mass and occurs in the setting of STZ-induced diabetes. Like BW, muscle weight was also significantly decreased by STZ treatment. While PLAG treatment slightly improved muscle mass, there was no significant difference between the STZ alone and PLAG groups (FIG. 7A).
  • Example 7 RNA isolation and RT-PCR analysis
  • Experimental Example 2 Preparation of experimental groups to examine effects of EC-18 in STAM model of non-alcoholic steatohepatitis
  • FIG. 10 is the graph showing the change in body weight, when using the composition according to the present invention
  • FIG. 11 is graph showing the weight (FIG. 11A), the liver weight (FIG. 11B) and the liver weight to weight (FIG. 11C), when using the composition according to the present invention.
  • the mice according to experimental Example 2 recorded the weight before treatment, measured the weight at the same time every day, and recorded the weight change. Mice were observed for significant clinical signs of toxicity, moribundity and mortality approximately 60 minutes after each administration. During the treatment period, it was dead one mouse in each of the OCA and EC-18 middle groups. The mice were sacrificed at 9 weeks. The relative liver weight and average body weight of the mice and are shown in Table 2 below
  • FIG. 12 is the graph showing the plasma ALT(A) and the plasma AST(B) and the ALT/AST ratio(C), when using the composition according to the present invention.
  • non-fasting blood was collected in polypropylene tubes with anticoagulant (Novo-Heparin) and centrifuged at l,000xg for 15 minutes at 4°C.
  • Plasma alanine aminotransferase (ALT) and plasma aspartate aminotransferase (AST) were measured by FUJI DRI-CHEM 7000.
  • the ALT/AST ratio was calculated and shown in Table 3 below.
  • FIG. 12 and Table 3 there were no significant differences in plasma ALT levels between the control group and the treatment groups. There were no significant differences in plasma AST levels between the control group and the other treatment groups (FIG. 12A). The plasma AST level in the OCA group tended to decrease compared with the control group (FIG. 12B). There were no significant differences in ALT/AST ratio between the control group and the other treatment groups. The ALT/AST ratio in the OCA group tended to increase compared with the control group (FIG. 12C).
  • FIG. 13 is the picture of liver sections stained with H&E and ORO, when using the composition according to the present invention.
  • FIG. 14 is the graph showing of liver sections stained with H&E and ORO, when using the composition according to the present invention.
  • NAFLD Activity score NAS
  • Table 4 results of statistically analyzing NAS in each treatment group are shown in Table 5.
  • the liver sections from the control group exhibited micro- and macrovesicular fat deposition, hepatocellular ballooning and inflammatory cell infiltration.
  • the OCA and EC- 18 high groups showed significant decreases in NAS compared with the control group.
  • NAS in the MGF-3196, EC- 18 low and EC- 18 middle groups tended to decrease compared with the control group.
  • Example 11 Histological Analysis to Determine Efficacy on Liver Fibrosis
  • FIG. 15 is the photomicrographs of HE-stained liver sections. Specifically, to visualize collagen deposition, Bouin’s fixed liver sections were stained using picro-Sirius red solution. For quantitative analysis of fibrosis area, bright field images of Sirius red-stained sections were randomly captured around the central vein using a digital camera at 200-fold magnification.
  • FIG. 16 is the graph showing the fibrous part of liver tissue (sirius red-positive area), when using the composition according to the present invention. Specifically, in the liver sections stained using the picro-Sirius red solution, the fibrosis site was observed, and the numerical value of the part was shown in Table 7 below.
  • the liver sections from the control group showed increased collagen deposition in the pericentral region of liver lobule.
  • the OCA and EC- 18 high groups showed significant decreases in the fibrosis area (Sirius red- positive area) compared with the control group.
  • the fibrosis area in the MGL-3196 and EC- 18 low groups tended to decrease compared with the Vehicle group. There was no significant difference in the fibrosis area between the Vehicle group and the EC- 18 middle group.
  • EC- 18 low and high showed statistical reductions in NAS and fibrosis area
  • EC- 18 middle showed statistical reductions in NAS compared with the control group.
  • EC- 18 showed the feature of anti- NASH and anti -fibrosis effects.
  • Example 12 In Vivo Efficacy Study of EC-18 in STAMTM Mice Model of Non-alcoholic Steatohepatitis
  • MCP Monocyte chemoattractant protein
  • NASH Non-alcoholic steatohepatitis
  • PBS Phosphate buffered saline
  • TGF Transforming growth factor
  • ⁇ MR Tissue inhibitor of metalloproteinase
  • TNF Tumor necrosis factor
  • mice were orally administered vehicle [PBS] in a volume of 5 mL/kg once daily from 6 to 9 weeks of age.
  • mice were orally administered [2% Klucel LF, 0.1% Tween 80 in water] supplemented with MGL-3196 at a dose of 3 mg/kg (in a volume of 5 mL/kg) once daily from 6 to 9 weeks of age.
  • mice were orally administered vehicle supplemented with EC- 18 at a dose of 30 mg/kg (in a volume of 5 mL/kg) once daily from 6 to 9 weeks of age.
  • mice Seven NASH mice were orally administered vehicle supplemented with EC- 18 at a dose of 100
  • Liver total lipid-extracts were obtained by Folch’s method (Folch J. et al, J. Biol. Chem. 1957;226: 497). Liver samples were homogenized in chloroform-methanol (2: 1, v/v) and incubated overnight at room temperature . After washing with chloroform- methanol-water (8:4:3, v/v/v), the extracts were evaporated to dryness, and dissolved in isopropanol. Liver triglyceride content was measured by Triglyceride E-test kit (FUJIFILM Wako Pure Chemical Corporation, Japan).
  • Plasma CK-18 level was quantified by Mouse Cytokeratin 18-M30 ELISA Kit (Cusabio Biotech Co., Ltd, China).
  • RNA was reverse-transcribed using a reaction mixture containing 4.4 mM MgC12 (F. Hoffmann-La Roche, Switzerland), 40 U RNase inhibitor (Toyobo, Japan), 0.5 mM dNTP (Promega, USA), 6.28 mM random hexamer (Promega), 5 x first strand buffer (Promega), 10 mM dithiothreitol (Invitrogen, USA) and 200 U MMLV-RT (Invitrogen) in a final volume of 20 mL.
  • the MGL-3196 group showed a significant decrease in liver triglyceride content compared with the Vehicle group.
  • Liver triglyceride content in the EC- 18 100 mg/kg and EC-18 250 mg/kg groups tended to decrease compared with the Vehicle group. There were no significant differences in liver triglyceride content between the Vehicle group and the other treatment groups.
  • Plasma CK-18 (Fig. 18 and Table 11)
  • the EC-18 30 mg/kg, EC-18 100 mg/kg and EC-18 250 mg/kg groups showed significant decreases in plasma CK-18 levels compared with the Vehicle group.
  • Plasma CK-18 level in the OCA group tended to decrease compared with the Vehicle group.
  • F4/80 immunostaining and the inflammation area (Figs. 19-20 and Table 12) Representative photomicrographs of the F4/80-immunostained sections are shown in Figure 2.1.
  • F4/80 immunostaining of liver sections from the Vehicle group demonstrated accumulation of F4/80+ cells in the liver lobule.
  • the OCA and EC- 18 250 mg/kg groups showed significant decreases in the inflammation area (F4/80- positive area) compared with the Vehicle group.
  • the inflammation area in the EC-18 30 mg/kg and EC- 18 100 mg/kg groups tended to decrease compared with the Vehicle group.
  • Treatment with MGL-3196 showed a significant decrease in liver triglyceride content, and decreasing trends in MCP-1 and TGF-b mRNA expression levels compared with the Vehicle group.
  • Treatment with OCA showed a significant decrease in the inflammation area, and a decreasing trend in plasma CK-18 level compared with the Vehicle group.
  • Treatment with EC- 18 at a dose of 30 mg/kg showed a significant decrease in plasma CK-18 level, and a decreasing trend in the inflammation area compared with the Vehicle group.
  • Treatment with EC-18 at a dose of 100 mg/kg showed a significant decrease in plasma CK-18 level, and decreasing trends in liver triglyceride content and the inflammation area compared with the Vehicle group.
  • Treatment with EC- 18 at a dose of 250 mg/kg showed significant decreases in plasma CK-18 level and the inflammation area, and a decreasing trend in liver triglyceride content compared with the Vehicle group.

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