Compositions and methods for treating liver disease

Abstract

The present invention provides compositions and methods for treating, reducing, or preventing liver disease, particularly alcoholic liver disease (e.g., alcoholic hepatitis, alcoholic liver failure) and drug-induced liver disease, or related diseases and disorders.

Description

[Technical Field]

[0001] Priority claims and related patent applications This application claims the benefit of priority to U.S. Provisional Application No. 63 / 446,087, filed February 16, 2023, and Chinese Patent Application No. 2024101689759, filed February 6, 2024, all of which are incorporated herein by reference in their entireties.

[0002] Technical field of the invention The present invention generally relates to pharmaceuticals and their therapeutic uses.In particular, the present invention provides compositions and methods for treating liver disease, particularly alcoholic liver disease (e.g., alcoholic hepatitis, alcoholic liver failure) and drug-induced liver disease, and related diseases and disorders. [Background technology]

[0003] Liver disease, or liver disease, refers to any of a number of liver disorders. Some liver disorders can be long-term or chronic, while others can develop rapidly or become acute and require emergency treatment. Generally, liver disorders are classified into those caused by viral infections, such as hepatitis A, hepatitis B, and hepatitis C; those caused by excessive consumption of chemicals, drugs, poisons, or alcohol; and those caused by heredity or genetic factors, such as hemochromatosis and Wilson's disease. Many of these disorders can lead to hepatitis, cirrhosis, cancer, and / or liver failure. ("Liver Diseases," MedlinePlus. https: / / medlineplus.gov / liverdiseases.html; Williams, 2006. "Global challenges in liver disease," Hepatology 522; Blachier et al., 2013. "The burden of liver disease in Europe: A review of available epidemiological data," J Hepatology 58:593-608.)

[0004] Drug-induced liver injury or disease is common because nearly every class of drug can cause liver injury or disease. Drug-induced hepatotoxicity is the most frequent cause of acute liver failure in the United States and can be classified as acute or chronic, and as hepatitic, cholestatic, or mixed patterns of liver injury. (David et al., 2011, "Drug-induced Liver Injury," US Gastroenterol Hepatol Rev. 6:73-80; Ostapowicz et al., 2002, "Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States," Ann Intern Med. 137:947-54.)

[0005] Alcoholic liver disease (ALD), also known as alcohol-related liver disease, is a common condition caused by heavy alcohol consumption. ALD involves three general stages: alcoholic fatty liver, alcoholic hepatitis, and alcoholic cirrhosis. Heavy alcoholics progress through these three stages over time. Excessive alcohol consumption causes the development of large fat globules (microvacuolar degeneration) throughout the liver. Alcoholic fatty liver is the accumulation of fat inside liver cells, which leads to liver enlargement. Alcoholic hepatitis refers to inflammation of liver cells. Over time, liver cell death can lead to the progression of fibrosis and cirrhosis, which is caused by permanent scarring and destruction of normal liver tissue. Cirrhosis is a serious, late-stage liver disease characterized by inflammation, fibrosis, and damaged membranes that prevent the body from detoxifying chemicals, resulting in scarring and necrosis. (O'Shea et al., 2010, "Alcoholic liver disease: AASLD Practice Guideline," Hepatology 51(1):307-28; Basra, 2011, "Definition, epidemiology and magnitude of alcoholic hepatitis," World Journal of Hepatology 3(5):108-113; Seitz et al., 2018, "Alcoholic liver disease," Nat. Rev. Disease Primers 4,16.)

[0006] ALD can progress from alcoholic fatty liver (AFL) to alcoholic steatohepatitis (ASH), which is characterized by liver inflammation. Chronic ASH can eventually lead to fibrosis and cirrhosis, and potentially hepatocellular carcinoma (HCC). In addition, severe ASH (with or without cirrhosis) can lead to alcoholic hepatitis, an acute clinical manifestation of ALD associated with liver failure and high mortality (Seitz et al., 2018, "Alcoholic liver disease." Nat. Rev. Disease Primers 4, 16).

[0007] ALD is the leading cause of liver disease worldwide. The prognosis of ALD depends on liver histology and cofactors, such as concomitant chronic viral hepatitis. ALD tends to be diagnosed at a later stage than other liver diseases. Approximately 25% to one-third of chronic heavy drinkers develop alcoholic hepatitis. Among patients with alcoholic hepatitis, progression to cirrhosis occurs in 10-20% within one year, and approximately 70% eventually develop cirrhosis. Despite cessation of alcohol use, only 10% achieve normalization of histology and serum liver enzyme levels. In most cases, cirrhosis eventually leads to liver failure. In the United States, the ALD mortality rate is 7.3 per 100,000.(Shah et al., 2019, "Alcohol-Related Liver Disease Is Rarely Detected at Early Stages Compared with Liver Diseases of Other Etiologies Worldwide," Clin Gastroenterol Hepatol 17:2320; Barrio et al., 2004, "Liver Disease in Heavy Drinkers with and Without Alcohol Withdrawal Syndrome," Alcoholism: Clinical & Experimental Research 28(1):131-136; Menon et al., 2001, "Pathogenesis, diagnosis, and treatment of alcoholic liver disease," Mayo Clin. Proc. 76(10): pp. 1021-1029; Dunn et al., 2005, "MELD accurately predicts mortality in patients with alcoholic hepatitis," Hepatology 41(2): pp. 353-358; Signal et al., 2018, "ACG Clinical Guideline: Alcoholic Liver Disease," Am. J. Gastroenterol. 113(2): pp. 175-194; Peery et al., 2022, "Burden and Cost of Gastrointestinal, Liver, and Pancreatic Diseases in the United States: Update 2021," Gastroenterol. 162, 2: pp. 621-644.

[0008] Currently, pharmacological treatment options for ALD in general and alcoholic hepatitis in particular are very limited. Despite conflicting research results regarding their efficacy and the risk of side effects with long-term use, corticosteroids remain the current standard of care for patients with severe alcoholic hepatitis in the United States and Europe. (Saberi et al., 2016, "Current Management of Alcoholic Hepatitis and Future Therapies," J Clin Transl Hepatol. 4(2):113–122.) Other noncorticosteroid medications (e.g., magnesium isoglycyrrhizinate injection, metadoxine) have been approved in China, albeit with limited efficacy. Difficulties in patient recruitment and retention, along with challenges posed by high mortality, heterogeneity, and pathophysiology, all contribute to the current lack of safe and effective treatment options for ALD in general and alcoholic hepatitis in particular.

[0009] There is clearly an unmet medical need for new pharmacological treatments for ALD and alcoholic hepatitis. Summary of the Invention

[0010] The present invention relates to analogs disclosed herein of the active center of Reg3α (e.g., Ac-IGLHDPSHGTLPAGS) for use in the effective treatment or reduction of ALD-related diseases or conditions (e.g., alcoholic hepatitis, and acute liver failure).

[0011] In one aspect, the present invention generally relates to a method for treating, reducing, or preventing liver disease or a related disease or condition, comprising administering to a subject in need of treatment, reduction, or prevention of liver disease or a related disease or condition a pharmaceutical composition comprising a compound that is an analog of the active center of Reg3α.

[0012] In another aspect, the present invention generally relates to a method for treating, reducing, or preventing drug-induced liver disease or a related disease or condition, comprising administering a pharmaceutical composition comprising a compound that is an analog of the active center of Reg3α to a subject in need of treatment, reduction, or prevention of drug-induced liver disease or a related disease or condition.

[0013] In yet another aspect, the present invention generally relates to a method for treating, reducing, or preventing alcoholic liver disease or a related disease or condition, comprising administering to a subject in need of treatment, reduction, or prevention of alcoholic liver disease or a related disease or condition a pharmaceutical composition comprising a compound that is an analog of the active center of Reg3α.

[0014] In another aspect, the present invention generally relates to a pharmaceutical composition comprising Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable excipient, carrier, or diluent, suitable for treating alcoholic liver disease or a related disease or condition.

[0015] In yet another aspect, the invention generally relates to a unit dosage form comprising the pharmaceutical composition described above.

[0016] In yet another aspect, the invention generally relates to the use of Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, to treat liver disease or a related disease or condition.

[0017] In yet another aspect, the invention generally relates to the use of Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, to treat alcoholic liver disease or a related disease or condition.

[0018] In yet another aspect, the invention generally relates to the use of Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, to treat alcoholic fatty liver disease or a related disease or condition.

[0019] In yet another aspect, the invention generally relates to the use of Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, to treat alcoholic steatohepatitis or a related disease or condition.

[0020] In yet another aspect, the invention generally relates to the use of Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, to treat alcoholic hepatitis.

[0021] In yet another aspect, the invention generally relates to the use of Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, to treat moderate alcoholic hepatitis.

[0022] In yet another aspect, the invention generally relates to the use of Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, to treat severe alcoholic hepatitis.

[0023] In yet another aspect, the invention generally relates to the use of Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, to treat alcoholic cirrhosis.

[0024] In yet another aspect, the invention generally relates to the use of Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, to treat acute liver failure associated with alcoholic hepatitis.

[0025] In yet another aspect, the invention generally relates to a method for reducing the severity of acute liver disease, comprising administering a pharmaceutical composition comprising Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, to a subject in need thereof.

[0026] In yet another aspect, the invention generally relates to a method for reducing mortality from alcoholic hepatitis, comprising administering a pharmaceutical composition comprising Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, to a subject in need thereof.

[0027] In yet another aspect, the invention generally relates to a method for reducing mortality from acute liver failure (e.g., associated with alcoholic liver disease or alcohol use), comprising administering a pharmaceutical composition comprising Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, to a subject in need thereof. [Brief explanation of the drawings]

[0028] [Figure 1] FIG. 1 shows an exemplary experimental timeline. [Figure 2] FIG. 1 shows exemplary data on survival rates. [Figure 3] FIG. 1 shows an exemplary experimental timeline. [Figure 4] FIG. 1 shows exemplary data on survival rates. [Figure 5] FIG. 1 shows exemplary data on survival rates. DETAILED DESCRIPTION OF THE INVENTION

[0029] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Abbreviations used herein have their conventional meaning in the chemical and biological arts. The chemical structures and formulas described herein are to be interpreted in accordance with the standard rules of chemical valence known in the chemical arts.

[0030] As used in this disclosure, the following words and phrases are generally intended to have the meanings set forth below, unless a different meaning is expressly stated or indicated otherwise by the context in which they are used.

[0031] In this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0032] The term "and / or" is used in this disclosure to mean either "and" or "or," unless the context clearly dictates otherwise.

[0033] As used herein, "at least" a particular value is understood to be that value and all values ​​greater than that value.

[0034] Applicant's disclosure is described herein in preferred embodiments with reference to the Figures, in which like numerals represent the same or similar components. Throughout this specification, reference to "one embodiment," "an embodiment," or similar language means that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the invention. Thus, throughout this specification, the phrases "in one embodiment," "in an embodiment," and similar language references may, but do not necessarily, all refer to the same embodiment.

[0035] When used in defining compositions and methods, the term "comprising" is intended to mean that the compositions and methods include the recited components, but do not exclude other components. When used in defining compositions and methods, the term "consisting essentially of" is intended to mean that the compositions and methods include the recited components and exclude other components of any essential importance to the compositions and methods. For example, "consisting essentially of" refers to the administration of pharmacologically active agents expressly recited and excludes pharmacologically active agents not expressly recited. The term "consisting essentially of" does not exclude pharmacologically inactive or non-active agents, such as pharmaceutically acceptable excipients, carriers, or diluents. When used in defining compositions and methods, the term "consisting of" is intended to mean excluding trace elements of other components and substantial method steps. Embodiments defined by each of these transition terms are within the scope of the present invention.

[0036] Throughout this description, where compositions and kits are described as having, including, or comprising particular components, or where processes and methods are described as having, including, or comprising particular steps, it is contemplated that there are additionally compositions and kits of the invention that consist essentially of or consist of the recited components, and that there are processes and methods of the invention that consist essentially of or consist of the recited process steps.

[0037] Whenever a component or ingredient is referred to herein as being included in and / or selected from a list of recited components or ingredients, it is understood that the component or ingredient can be any one of the recited components or ingredients, or the component or ingredient can be selected from a group consisting of two or more of the recited components or ingredients.

[0038] Unless specifically stated or otherwise clear from the context, as used herein, the term "about" is understood to mean within the normal tolerance of error in the art, e.g., within 2 standard deviations of the mean. About may be understood to mean within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values ​​provided herein may be modified by the term about.

[0039] At various places herein, variables or parameters are disclosed in groups or ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, a range of 1 to 16 is understood to include any number, combination of numbers, or subrange from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0040] As used herein, "pharmaceutical composition" refers to a combination of a therapeutically active agent with one or more pharmaceutically acceptable excipients, carriers, or diluents, making the composition particularly suitable for in vivo or ex vivo diagnostic or therapeutic use.

[0041] As used herein, the term "pharmaceutically acceptable excipient, carrier, or diluent" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that accompanies the delivery or transport of a subject pharmaceutical agent from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose, starches such as corn starch and potato starch, cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate, excipients such as powdered tragacanth, malt, gelatin, talc, cocoa butter, and suppository wax, oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil, glycols such as propylene glycol, polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol, esters such as ethyl oleate and ethyl laurate, agar, buffers such as magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solution, and other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents, emulsifying agents, and lubricants such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymers, as well as coloring agents, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants may also be present in the composition.

[0042] As used herein, the term "subject" refers to any animal (e.g., mammal), including, but not limited to, humans, non-human primates, rodents, etc., that will be the recipient of a particular treatment. Typically, the terms "subject" and "patient" are used interchangeably herein with reference to a human subject. "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)), and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[0043] As used herein, "administering" refers to oral administration, pulmonary administration, suppository administration, intramuscular administration, intrathecal administration, intranasal administration, or subcutaneous administration to a subject, or implantation of a sustained-release device, such as a mini-osmotic pump. Administration is by any route, including transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or intravenous). Parenteral administration includes, for example, intramuscular and subcutaneous administration. Other delivery modes include, but are not limited to, the use of liposomal formulations, and the like. "Co-administering" means that a composition described herein is administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapies (e.g., therapeutic agents, chemotherapeutic agents, or treatments for neurodegenerative diseases). The compound of Formula (I) can be administered alone or simultaneously to a patient. Co-administration is intended to include simultaneous or sequential administration of compounds individually or in combination (two or more compounds or agents). Thus, the formulations may be combined with other active agents, if desired (eg, to reduce metabolic degradation).

[0044] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0045] As used herein, the terms "treating," "reducing," or "preventing" a disease or disorder refer to ameliorating such pathology before or after it occurs. The degree of such reduction or prevention, as measured by any standard technique, is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100%, as compared to an equivalent untreated control. The terms "treat," "treating," and "treatment" contemplate actions that occur while a subject is suffering from a particular disease, disorder, or condition and that reduce the severity of the disease, disorder, or condition or slow or slow the progression of the disease, disorder, or condition ("therapeutic treatment"), and actions that occur before a subject begins to suffer from a particular disease, disorder, or condition ("prophylactic treatment"). In one embodiment, the compounds provided herein are contemplated for use in methods of therapeutic treatment where the actions occur while a patient is suffering from a particular disease, disorder, or condition and result in a reduction in the severity of the disease, disorder, or condition, or a slow or slow progression of the disease, disorder, or condition. In alternative embodiments, the compounds provided herein are contemplated for use in methods of prophylactic treatment where the action occurs before a patient begins to suffer from a particular disease, disorder, or condition and results in the prevention of the disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, or the prevention of the recurrence of the disease, disorder, or condition.

[0046] As used herein, the term "effective amount" of an active agent refers to an amount sufficient to elicit a desired biological response. As will be understood by those skilled in the art, the effective amount of a compound of the present invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the patient.

[0047] Following their preparation, the compounds of the invention are preferably isolated and purified to yield compounds containing 95% or more by weight ("substantially pure"), which are then used or formulated as described herein. In certain embodiments, the compounds of the invention are greater than 99% pure.

[0048] Detailed Description of the Invention The present invention is based in part on the surprising discovery that the analogs disclosed herein of the active center of Reg3α (e.g., Ac-IGLHDPSHGTLPAGS) can be effectively used to reduce or treat ALD-related diseases or conditions, particularly alcoholic hepatitis and acute liver failure.

[0049] In one aspect, the present invention generally relates to a method for treating, reducing, or preventing liver disease or a related disease or condition, comprising administering to a subject in need of treatment, reduction, or prevention of liver disease or a related disease or condition a pharmaceutical composition comprising a compound that is an analog of the active center of Reg3α.

[0050] In a specific embodiment, the amino acid sequence of the active center of Reg3α is H-IGLHDPSHGTLPNGS-OH.

[0051] In certain embodiments, the compound is Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof.

[0052] In certain embodiments, the subject suffers from at least a chemically caused or induced liver disease or related disease or condition.

[0053] In certain embodiments, the subject suffers from chronic liver disease or a related disease or condition.

[0054] In certain embodiments, the subject is suffering from acute liver disease or a related disease or condition.

[0055] In certain embodiments, the subject suffers from steatohepatitis or a related disease or condition.

[0056] In certain embodiments, the subject suffers from cirrhosis of the liver or a related disease or condition.

[0057] In certain embodiments, the subject is suffering from acute liver injury.

[0058] In certain embodiments, the subject is suffering from acute liver failure.

[0059] In certain embodiments, the chemical is an industrial chemical or a drug.

[0060] In certain embodiments, the industrial chemical is selected from alcohols, CCl4, CHCl3, nitrites, pesticides, poisons, and food additives.

[0061] In certain embodiments, the subject suffers from alcoholic liver disease.

[0062] In certain embodiments, the subject has alcoholic hepatitis.

[0063] In another aspect, the present invention generally relates to a method for treating, reducing, or preventing drug-induced liver disease or a related disease or condition, comprising administering a pharmaceutical composition comprising a compound that is an analog of the active center of Reg3α to a subject in need of treatment, reduction, or prevention of drug-induced liver disease or a related disease or condition.

[0064] In certain embodiments, the compound is Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof.

[0065] In certain embodiments, the subject suffers from drug-induced chronic liver disease or a related disease or condition.

[0066] In certain embodiments, the subject is suffering from drug-induced acute liver disease or a related disease or condition.

[0067] In certain embodiments, the subject suffers from drug-induced fatty liver or a related disease or condition.

[0068] In certain embodiments, the subject is suffering from drug-induced steatohepatitis or a related disease or condition.

[0069] In certain embodiments, the subject has moderate drug-induced steatohepatitis.

[0070] In certain embodiments, the subject has drug-induced severe steatohepatitis.

[0071] In certain embodiments, the subject suffers from cirrhosis of the liver.

[0072] In certain embodiments, the subject is suffering from drug-associated acute liver injury.

[0073] In certain embodiments, the subject is suffering from drug-associated acute liver failure.

[0074] In certain embodiments, the subject survives drug-induced acute liver failure after treatment.

[0075] Drugs that may cause liver disease (e.g., liver injury, liver failure, hepatitis) include, but are not limited to, antibiotics, anticancer drugs, analgesics, antipyretics, antituberculosis drugs, antiepileptic drugs, antidepressants, lipid-lowering drugs, traditional Chinese medicines, or dietary supplements.

[0076] In certain embodiments, the subject is suffering from acetaminophen (N-acetyl-p-aminophenol, APAP or Tylenol®)-induced liver injury.

[0077] In yet another aspect, the present invention generally relates to a method for treating, reducing, or preventing alcoholic liver disease or a related disease or condition, comprising administering to a subject in need of treatment, reduction, or prevention of alcoholic liver disease or a related disease or condition a pharmaceutical composition comprising a compound that is an analog of the active center of Reg3α.

[0078] In certain embodiments, the compound is Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof.

[0079] In certain embodiments, the subject suffers from alcoholic fatty liver or a related disease or condition.

[0080] In certain embodiments, the subject suffers from alcoholic steatohepatitis or a related disease or condition.

[0081] In certain embodiments, the subject has severe alcoholic steatohepatitis.

[0082] In certain embodiments, the subject has alcoholic hepatitis.

[0083] In certain embodiments, the subject has moderate alcoholic hepatitis.

[0084] In certain embodiments, the subject suffers from severe alcoholic hepatitis.

[0085] In certain embodiments, the subject survives acute liver failure after treatment.

[0086] In certain embodiments, the subject has moderate alcoholic steatohepatitis.

[0087] In certain embodiments, the subject suffers from alcoholic cirrhosis.

[0088] In certain embodiments, the subject is suffering from acute liver failure associated with alcoholic hepatitis.

[0089] Any suitable route of administration may be utilized in the methods of the present invention. In certain embodiments, the administering is subcutaneous, intravenous, intramuscular, or by inhalation.

[0090] In certain embodiments, the administering is a subcutaneous injection.

[0091] In certain embodiments, the compound is administered in a daily dosage ranging from about 10 mg to about 2,000 mg.

[0092] In certain embodiments, the compound is administered in a daily dosage ranging from about 10 mg to about 1,000 mg.

[0093] In certain embodiments, the compound is administered for a period of about 1 day to about 6 months.

[0094] In certain embodiments, the compound is administered for a period of about 1 day to about 30 days.

[0095] In certain embodiments, the compound is administered at a daily dosage ranging from about 10 mg to about 2,000 mg for a period of about 1 day to about 30 days.

[0096] In certain embodiments, the compound is administered at a daily dosage ranging from about 10 mg to about 1,000 mg for a period of about 1 day to about 30 days.

[0097] In certain embodiments, the first administration of the compound is administered within 48 hours of the onset or diagnosis of alcoholic hepatitis.

[0098] In certain embodiments, the first administration of the compound is administered within 24 hours of the onset or diagnosis of alcoholic hepatitis.

[0099] In certain embodiments, the first administration of the compound is administered within 12, 6, 4, 3, 2, or 1 hour of the onset or diagnosis of alcoholic hepatitis.

[0100] In certain embodiments, the first administration of the compound is administered within 24 hours of the onset or diagnosis of acute liver failure.

[0101] In certain embodiments, the first administration of the compound is administered within 12, 6, 2, or 1 hour of the onset or diagnosis of alcoholic liver disease or acute liver failure associated with alcohol consumption.

[0102] In certain embodiments, the methods of the invention further comprise administering to said subject a second therapeutic agent.

[0103] In certain embodiments, the second therapeutic agent is a corticosteroid.

[0104] In certain embodiments, the subject has been previously treated with a corticosteroid.

[0105] In another aspect, the present invention generally relates to a pharmaceutical composition comprising Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable excipient, carrier, or diluent, suitable for treating alcoholic liver disease or a related disease or condition.

[0106] In yet another aspect, the invention generally relates to a unit dosage form comprising the pharmaceutical composition described above.

[0107] In certain embodiments, the pharmaceutical composition is an aqueous formulation suitable for subcutaneous injection.

[0108] In certain embodiments, the aqueous formulation is stable at a temperature between about 2°C and about 8°C for at least 48 months.

[0109] In yet another aspect, the invention generally relates to the use of Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, to treat liver disease or a related disease or condition.

[0110] In yet another aspect, the invention generally relates to the use of Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, to treat alcoholic liver disease or a related disease or condition.

[0111] In yet another aspect, the invention generally relates to the use of Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, to treat alcoholic fatty liver disease or a related disease or condition.

[0112] In yet another aspect, the invention generally relates to the use of Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, to treat alcoholic steatohepatitis or a related disease or condition.

[0113] In yet another aspect, the invention generally relates to the use of Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, to treat alcoholic hepatitis.

[0114] In yet another aspect, the invention generally relates to the use of Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, to treat moderate alcoholic hepatitis.

[0115] In yet another aspect, the invention generally relates to the use of Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, to treat severe alcoholic hepatitis.

[0116] In yet another aspect, the invention generally relates to the use of Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, to treat alcoholic cirrhosis.

[0117] In yet another aspect, the invention generally relates to the use of Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, to treat acute liver failure associated with alcoholic hepatitis.

[0118] In yet another aspect, the invention generally relates to a method for reducing the severity of acute liver disease, comprising administering a pharmaceutical composition comprising Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, to a subject in need thereof.

[0119] In certain embodiments, the subject suffers from alcoholic liver disease, alcoholic hepatitis or acute liver injury associated with alcohol consumption or industrial chemicals or drugs.

[0120] In yet another aspect, the invention generally relates to a method for reducing mortality from alcoholic hepatitis, comprising administering a pharmaceutical composition comprising Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, to a subject in need thereof.

[0121] In yet another aspect, the invention generally relates to a method for reducing mortality from acute liver failure (e.g., associated with alcoholic liver disease or alcohol use), comprising administering a pharmaceutical composition comprising Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, to a subject in need thereof. [Example]

[0122] The following examples are illustrative of the practice of the present invention and are not intended to be limiting in any way. Materials, equipment, and methods

[0123] Carbon tetrachloride (CCl4) (Sigma)

[0124] Test compound: Ac-IGLHDPSHGTLPAGS (Shenzhen Hightide Biopharmaceutical Co., Ltd.)

[0125] DUR-928: (Shenzhen Hightide Biopharmaceutical)

[0126] Vehicle control: 0.9% NaCl injection (Guizhou Kelun Pharmaceutical Co., Ltd.)

[0127] [ka]

[0128] DUR-928 (ralscosterol) is an endogenous sulfated oxysterol and epigenetic regulator. DUR-928 primarily targets DNA methyltransferases (DNMTs) and epigenetically regulates the expression of multiple clusters of master genes involved in many important cell signaling pathways, stabilizing mitochondria, reducing lipotoxicity, controlling inflammation or stress responses, and promoting cell survival. DUR-928 is currently being investigated by DURECT for the treatment of alcoholic hepatitis and nonalcoholic steatohepatitis. (https: / / classic.clinicaltrials.gov / ct2 / show / NCT04563026; Hassanein et al. 2024, Am J Gastroenterol. 119(1):107-115.)

[0129] Example 1 Efficacy study in a CCl4-induced acute liver injury model in rats. Animal models Sprague-Dawley rats (6-10 weeks old, weighing approximately 220-350 g, SPF grade) were used. The SPF grade animal room was maintained at a target temperature of 20-26°C and a relative humidity of 40-70% throughout the study. The actual room temperature was 20.1-26.8°C, and the actual relative humidity was 36-78.55%. Fluorescent lighting was used for 12 hours per day. Certified rodent chow and filtered water were provided ad libitum throughout the quarantine and study periods, unless otherwise required by the research procedure. After 7 days of acclimation, acute liver failure was induced by intraperitoneal injection of 50% (v / v) CCl4 in olive oil at a dose of 4 mL / kg.

[0130] Group design and treatment The model rats were randomly divided into two groups: a vehicle control group (G1, n=22) and a test substance treatment group (G2, n=21). One hour after model induction, animals from G1 and G2 received a single subcutaneous injection of saline (4 mL / kg) as a vehicle control or a test compound (1.25 mg / kg), respectively. All animals were continuously observed throughout the study period for, but not limited to, mortality, morbidity, mental status, behavior, respiration, secretions, excretory signs, and food and water availability. The detailed study design is summarized in Table 1 below.

[0131] [Table 1]

[0132] Figures 1-2 show specific exemplary data regarding experimental timelines and survival rates.

[0133] The results are shown in Figure 2. Animals began to die by 3 hours after ALF induction. The results showed that mortality was delayed in the test compound-treated group compared to the vehicle control. At the end of the study, the survival rate of the test substance group was 38.1%, while the survival rate of the model group was 27.3%.

[0134] After the model induction, cage-side observation revealed a decrease in spontaneous motor activity, shortness of breath, and pain-induced wriggling responses in the animals. In addition to an increase in survival rate in the test substance-treated group, the activity status of the animals also improved significantly. All of these results indicated that the test substance had a beneficial effect on liver injury.

[0135] Example 2 Efficacy study in a CCl4-induced rat acute liver injury model with characteristics of alcoholic hepatitis. Animal models Sprague-Dawley rats (6-10 weeks old, weighing approximately 220-350 g, SPF grade) were housed in SPF-grade animal rooms maintained at a target temperature of 20-26°C and a relative humidity of 40-70% throughout the study. The actual room temperature was 20.1-26.8°C. The actual relative humidity was 36-78.55%. Fluorescent lighting was used for 12 hours per day. Certified rodent chow and filtered water were provided ad libitum throughout the quarantine and study periods, except when required by the study. After 7 days of acclimation, acute liver failure was induced by intraperitoneal injection of 50% (v / v) CCl4 in olive oil at a dose of 4 mL / kg.

[0136] Grouping and treatment Model rats were randomly divided into three groups, each consisting of 18 rats: a vehicle control group (G1) and test substance-treated groups (G2 and G3). One hour after model induction, animals from G1 to G3 received a single subcutaneous injection of saline (4 mL / kg) as a vehicle control or a single dose of the test compound (1.25 mg / kg). All animals were continuously observed throughout the study period for, but not limited to, mortality, morbidity, mental status, behavior, signs of respiration, secretions, and excretions, as well as food and water availability. The detailed study design is summarized in Table 2 below.

[0137] [Table 2]

[0138] Figures 3-4 show specific exemplary data regarding experimental timelines and survival rates.

[0139] The results are shown in Figure 4. Animals began to die by 3.9 hours after ALF induction. Death was delayed in the test compound treated group compared to the vehicle control. Better efficacy was observed in the test compound 1 hour group than in the test compound 2 hour group.

[0140] Example 3 Efficacy Study in an APAP-Induced C57 Mouse Model of Alcoholic Hepatitis Characterized by Acute Liver Injury C57 mice (12-week-old, male, SPF-grade) were used. The SPF-grade animal room was maintained at a target temperature of 20°C to 26°C and a relative humidity of 40% to 70% throughout the study. The actual room temperature was 20.1°C to 26.8°C. The actual relative humidity was 36% to 78.55%. Fluorescent lighting was used for 12 hours per day. Certified rodent chow and filtered water were provided ad libitum throughout the quarantine and study periods, except when required by the study. After 7 days of acclimation, mice were pair-assigned by weight into several groups, including vehicle, control, and test groups. Acute liver failure was induced in the control and all test groups by a single intraperitoneal injection of acetaminophen (APAP) in PBS solution, while the vehicle group received PBS in the same manner. Two hours before, during, or after challenge with APAP or PBS solution, each group was assigned to receive the test substance or vehicle as designed. The frequency, interval, dose level, and duration of administration for each group can be designed adaptively. All animals were continuously observed throughout the study period for, but not limited to, mortality, morbidity, mental status, behavior, respiration, secretions, excretory signs, and food and water availability. (General methods for establishing acute liver injury models and related efficacy studies may also be found in Steinebrunner et al., 2014, "Pharmacologic cholinesterase inhibition improves survival in acetaminophen-induced acute liver failure in the mouse." BMC Gastroenterol. 14:148.)

[0141] Example 4 Protective effects of Ac-IGLHDPSHGTLPAGS (HTD4010) and DUR-928 in a lipopolysaccharide (LPS)-induced acute liver failure (ALF) mouse model. Male C57BL / 6 mice (8-9 weeks old, SPF grade) were acclimated for at least one week and then randomized into four groups (15 mice per group), including a model control group G0 and test groups G1-G3, as shown in the table below. The ALF model was induced by intravenously challenging all mice with 40 mg / kg LPS. Day 1 was defined as the day of LPS injection.

[0142] For the G0 group on day 1, the mice were subcutaneously injected with the vehicle once 1 hour after LPS stimulation and once 8 hours after LPS injection, and from day 2 onwards, the mice were subcutaneously injected with the vehicle twice a day.

[0143] For the G1 group on day 1, mice were subcutaneously injected with HTD4010 (5 mg / kg) once 1 hour after LPS stimulation and once 8 hours after LPS injection. From day 2 onwards, mice were subcutaneously injected with HTD4010 (5 mg / kg) twice daily.

[0144] For group G2, mice were pretreated by intravenous injection of DUR-928 (50 mg / kg) 2 hours before LPS injection on day 1.

[0145] For group G3, on day 1, mice were treated by intravenous injection of DUR-928 (50 mg / kg) 1 hour after LPS injection.

[0146] The animals were closely monitored throughout the study, including for mental status, activity, excretion, and mortality. The study was terminated approximately on day 7 until no deaths were observed within 12 hours for each group.

[0147] [Table 3]

[0148] Notes: 1. In the G1-HTD4010 group, the dose level of 10 mg / kg / day and the administration method (subcutaneous, 1 hour after LPS injection, twice daily) used in this study were selected based on the results of previous studies. 2. In the G2-DUR-928(pre) group, the dose level of 50 mg / kg and the administration method (intravenous injection, 2 hours before LPS injection) were selected based on literature (Ning et al., 2017, Metabolism 71:83-93; Wang et al., 2021, Cells 10(11):3027) and clinical route of drug delivery (Am J Gastroenterol. May 8, 2023). 3. In the G3-DUR-928 group, the administration method of DUR-928 1 hour after LPS injection was the same as that including HTD4010.

[0149] result FIG. 5 shows exemplary data regarding the survival rate of each group in the LPS-induced ALF mouse model (compared to the G0 model control in the Log-rank (Mantel-Cox) test). * P<0.05. #P<0.05 compared with G3 in the DUR-928 group.

[0150] DUR-928, when administered as a preventative treatment (50 mg / kg, 2 h before LPS injection), showed a significant protective effect in this mouse model of ALF (P<0.05), which was consistent with data reported in the literature (Ning et al., 2017, Metabolism 71:83-93) and was more potent than that obtained 1 h after LPS injection (80% vs. 53%).

[0151] HTD4010 at a dose level of 10 mg / kg / day showed significant protective effects when given after LPS injection (P<0.01). When given after LPS injection, the treatment effect of HTD4010 was slightly stronger than that of DUR-928 when given as a preventive treatment before LPS injection (87% vs. 80%). The protective effect of the HTD4010 group was significantly stronger than that of DUR-928 (87% vs. 53%) when both were given after LPS injection, achieving statistical significance (P<0.05).

[0152] The described features, structures, or characteristics of Applicant's disclosure may be combined in any suitable manner in one or more embodiments. In the description herein, numerous specific details are set forth for a thorough understanding of the embodiments of the present invention. However, one skilled in the relevant art will recognize that Applicant's compositions and / or methods may be practiced without one or more of the specific details, or with other methods, components, materials, etc. In other instances, well-known structures, materials, or operations have not been shown or described in detail to avoid obscuring aspects of the present disclosure.

[0153] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of this disclosure, the preferred methods and materials are now described. The methods described herein may be carried out in any order that is logically possible, in addition to the specific order disclosed.

[0154] Incorporation by Reference References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web content, etc., are made in this disclosure. All such documents are incorporated herein by reference in their entirety for all purposes. Any material or portion thereof that is incorporated herein by reference that conflicts with existing definitions, statements, or other disclosure material expressly set forth herein, shall be incorporated only to the extent that no conflict arises between the incorporated material and the material of this disclosure. In the event of a conflict, the conflict shall be resolved in favor of the present disclosure as the preferred disclosure.

[0155] equivalent The representative examples are intended to serve to illustrate the invention and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention, and numerous further embodiments of the invention, in addition to those shown and described herein, will be apparent to those skilled in the art from the entire contents of this document, including the examples contained herein and references to the scientific patent literature. The examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

Claims

1. A method for treating, reducing, or preventing liver disease or a related disease or condition, comprising administering a pharmaceutical composition containing a compound that is an analog of the active center of Reg3α to a subject in need of treatment, reduction, or prevention of liver disease or a related disease or condition.

2. 2. The method of claim 1, wherein the compound is Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof.

3. 3. The method of claim 1 or 2, wherein the subject is suffering from at least a chemically caused or induced liver disease or related disease or condition.

4. The method of any one of claims 1 to 3, wherein the subject suffers from chronic liver disease or a related disease or condition.

5. The method of any one of claims 1 to 3, wherein the subject is suffering from acute liver disease or a related disease or condition.

6. The method of any one of claims 1 to 3, wherein the subject is suffering from steatohepatitis or a related disease or condition.

7. The method of any one of claims 1 to 3, wherein the subject is suffering from cirrhosis or a related disease or condition.

8. The method of any one of claims 1 to 3, wherein the subject is suffering from acute liver injury.

9. The method of any one of claims 1 to 3, wherein the subject is suffering from acute liver failure.

10. The method of any one of claims 3 to 9, wherein the chemical is an industrial chemical or a drug.

11. 3. The method of claim 1 or 2, wherein the subject suffers from alcoholic liver disease.

12. The method of claim 1 or 2, wherein the subject is suffering from alcoholic hepatitis.

13. A method for treating, reducing, or preventing drug-induced liver disease or a related disease or condition, comprising administering a pharmaceutical composition containing a compound that is an analog of the active center of Reg3α to a subject in need of treatment, reduction, or prevention of drug-induced liver disease or a related disease or condition.

14. 14. The method of claim 13, wherein the compound is Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof.

15. 14. The method of claim 13, wherein the subject is suffering from drug-induced acute liver disease or a related disease or condition.

16. 14. The method of claim 13, wherein the subject is suffering from drug-induced fatty liver or a related disease or condition.

17. 14. The method of claim 13, wherein the subject is suffering from drug-induced steatohepatitis or a related disease or condition.

18. 14. The method of claim 13, wherein the subject has drug-induced moderate steatohepatitis.

19. 14. The method of claim 13, wherein the subject is suffering from drug-induced severe steatohepatitis.

20. 14. The method of claim 13, wherein the subject is suffering from cirrhosis.

21. 14. The method of claim 13, wherein the subject is suffering from acute liver injury.

22. 14. The method of claim 13, wherein the subject is suffering from acute liver failure.

23. 23. The method of claim 22, wherein the subject survives drug-induced acute liver failure after treatment.

24. 24. The method of any one of claims 13 to 23, wherein the drug is selected from antibiotics, anticancer drugs, analgesics, antipyretics, antituberculosis drugs, antiepileptic drugs, antidepressants, lipid-lowering drugs, traditional Chinese medicines, and dietary supplements.

25. A method for treating, reducing, or preventing alcoholic liver disease or a related disease or condition, comprising administering a pharmaceutical composition containing a compound that is an analog of the active center of Reg3α to a subject in need of treatment, reduction, or prevention of alcoholic liver disease or a related disease or condition.

26. 26. The method of claim 25, wherein the compound is Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof.

27. 27. The method of claim 25 or 26, wherein the subject is suffering from alcoholic fatty liver or a related disease or condition.

28. 27. The method of claim 25 or 26, wherein the subject is suffering from alcoholic steatohepatitis or a related disease or condition.

29. 27. The method of claim 25 or 26, wherein the subject is suffering from alcoholic hepatitis.

30. 27. The method of claim 25 or 26, wherein the subject suffers from moderate alcoholic hepatitis.

31. 27. The method of claim 25 or 26, wherein the subject is suffering from severe alcoholic hepatitis.

32. 27. The method of claim 25 or 26, wherein the subject is suffering from alcoholic cirrhosis.

33. 27. The method of claim 25 or 26, wherein the associated disease or condition is acute liver failure associated with alcoholic hepatitis.

34. 34. The method of any one of claims 1 to 33, wherein the administering is subcutaneous, intravenous, intramuscular, or inhalation administration.

35. 35. The method of claim 34, wherein the administering is a subcutaneous injection.

36. 36. The method of claim 34 or 35, wherein the compound is administered at a daily dosage ranging from about 10 mg to about 2,000 mg for a period of from about 1 day to about 6 months.

37. 37. The method of claim 36, wherein the compound is administered at a daily dosage ranging from about 10 mg to about 1,000 mg for a period of about 1 day to about 1 month.

38. 36. The method of claim 34 or 35, wherein the compound is first administered within 12 hours of the onset of alcoholic hepatitis or alcoholic liver failure.

39. 39. The method of any one of claims 1 to 38, further comprising administering to the subject a second therapeutic agent.

40. 40. The method of claim 39, wherein the second therapeutic agent is selected from a corticosteroid agent.

41. 39. The method of any one of claims 1 to 38, wherein the subject has been previously treated with a corticosteroid.

42. 1. A method for reducing the mortality rate of alcoholic hepatitis, comprising administering a pharmaceutical composition comprising Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, to a subject in need thereof.

43. 1. A method for reducing mortality from acute liver failure, comprising administering a pharmaceutical composition comprising Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, to a subject in need thereof.

44. A pharmaceutical composition comprising Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable excipient, carrier, or diluent, suitable for the treatment of alcoholic liver disease or a related disease or condition.

45. 45. A unit dosage form comprising the pharmaceutical composition of claim 44.

46. 46. ​​The unit dosage form of claim 45, wherein the pharmaceutical composition is an aqueous formulation suitable for subcutaneous injection.

47. 47. The unit dosage form of claim 46, wherein the aqueous formulation is stable at a temperature between about 2°C and about 8°C for at least 48 months.

48. Use of Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, for treating liver disease or a related disease or condition.

49. Use of Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, for treating alcoholic liver disease or a related disease or condition.

50. Use of Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, for treating alcoholic fatty liver or a related disease or condition.

51. Use of Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, for treating alcoholic steatohepatitis or a related disease or condition.

52. Use of Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, for treating alcoholic hepatitis.

53. Use of Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, for treating moderate alcoholic hepatitis.

54. Use of Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, for treating severe alcoholic hepatitis.

55. Use of Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, for treating cirrhosis of the liver.

56. Use of Ac-IGLHDPSHGTLPAGS, or a pharmaceutically acceptable form thereof, for treating acute liver failure.

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