Compositions and methods for treating liver disease

Abstract

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

Description

Priority claims and related patent applications

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

[0002] The present invention generally relates to medicaments and their therapeutic uses. More specifically, 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 conditions. Background Art

[0003] Liver disease or liver disease refers to any of a number of liver diseases. Some liver diseases can be long-term or chronic, while others can be rapid-onset or acute and require emergency care. Liver diseases are generally categorized as those caused by viral infections, such as hepatitis A, B, and C; those caused by chemicals, drugs, toxins, or excessive alcohol consumption; and those caused by genes or hereditary factors, such as hemochromatosis and Wilson's disease. Many of these diseases 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, as almost all classes of drugs can cause liver injury or disease. Drug-induced hepatotoxicity is the most common cause of acute liver failure in the United States and can be classified as acute or chronic and as cholestatic or mixed. (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 drinking. ALD consists of three general stages: alcoholic fatty liver disease, alcoholic hepatitis, and alcoholic cirrhosis. Heavy drinkers can progress through all three types over time. Excessive drinking causes the development of large fat globules throughout the liver (macrovesicular steatosis). Alcoholic fatty liver disease is a buildup of fat within liver cells, which causes the liver to enlarge. Alcoholic hepatitis refers to inflammation of liver cells. Over time, the death of liver cells can lead to the progression of fibrosis and cirrhosis due to 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 detoxification of chemicals in the body, ultimately leading to scarring and necrosis. (O'Shea, et al. 2010"Alcoholic liver disease: AASLDPractice Guidelines" Hepatology 51(1):307–28; Basra 2011. "Definition, epidemiology and magnitude of alcoholic hepatitis" World Journal ofHepatology3(5):108–113; Seitz, et al. 2018"Alcoholic liver disease"Nat.Rev.DiseasePrimers4,16.)

[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 in some cases, hepatocellular carcinoma (HCC). In addition, severe ASH (with or without cirrhosis) can lead to alcoholic hepatitis, which is an acute clinical manifestation of ALD and is 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 will develop alcoholic hepatitis. Among patients with alcoholic hepatitis, 10%-20% progress to cirrhosis each year, and approximately 70% will ultimately develop cirrhosis. Despite stopping drinking, only 10% of patients will have normal histology and serum liver enzyme levels. In most cases, cirrhosis will eventually lead to liver failure. In the United States, the mortality rate from ALD is 7.3 per 100,000 people.(Shah,et al.2019"Alcohol-Related Liver Disease Is Rarely Detectedat Early Stages Compared with Liver Diseases of Other Etiologies Worldwide"Clin Gastroenterol Hepatol 17:2320;Barrio,et al.2004"Liver Disease in HeavyDrinkers with and Without Alcohol Withdrawal Syndrome"Alcoholism:Clinical&Experimental Research28(1):131–136;Menon,et al.2001"Pathogenesis,diagnosis,and treatment of alcoholic liver disease"Mayo Clin.Proc.76(10):1021–9;Dunn,etal.2005"MELD accurately predicts mortality in patients with alcoholichepatitis"Hepatology 41(2):353–8;Signal,et al.2018"ACG Clinical Guideline:Alcoholic Liver Disease"Am.J.Gastroenterol.113(2):175-194;Peery,et al.2022"Burden and Cost of Gastrointestinal,Liver,and Pancreatic Diseases in theUnited States:Update 2021"Gastroenterol.162,2:621-644.)。

[0008] Currently, pharmacological treatment options for ALD in general and alcoholic hepatitis in particular are very limited. Despite conflicting research results regarding the effectiveness of corticosteroids 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 medications besides corticosteroids (e.g., magnesium isoglycyrrhizinate injection, metadoxine) are also approved for use in China, but their effectiveness is insufficient. Challenges posed by high mortality, heterogeneity, pathophysiology, and difficulties in recruiting and retaining patients have contributed to the current lack of safe and effective treatment options for ALD in general and alcoholic hepatitis in particular.

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

[0010] The present invention relates to the use of the Reg3α active center analogs disclosed herein (eg, Ac-IGLHDPSHGTLPAGS) in effectively treating or alleviating ALD-related diseases or conditions (eg, alcoholic hepatitis and acute liver failure).

[0011] In one aspect, the present invention generally relates to a method for treating, alleviating or preventing liver disease or a related disease or condition, comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound that is a Reg3α active site analog.

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

[0013] In another aspect, the present invention generally relates to a method for treating, alleviating or preventing alcoholic liver disease or a related disease or condition, comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound that is a Reg3α active site analog.

[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 present invention generally relates to unit dosage forms comprising pharmaceutical compositions.

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

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

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

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

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

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

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

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

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

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

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

[0027] In yet another aspect, the present invention generally relates to a method for reducing mortality from acute liver failure (e.g., associated with alcoholic liver disease or alcohol consumption), comprising administering to a subject in need thereof a pharmaceutical composition comprising Ac-IGLHDPSHGTLPAGS or a pharmaceutically acceptable form thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 An exemplary experimental timeline is shown.

[0029] Figure 2 Exemplary data on survival rates are shown.

[0030] Figure 3 An exemplary experimental timeline is shown.

[0031] Figure 4 Exemplary data on survival rates are shown.

[0032] Figure 5 Exemplary data on survival rates are shown. definition

[0033] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Abbreviations used herein have their conventional meanings in the fields of chemistry and biology. The chemical structures and formulae set forth herein are constructed according to standard rules of chemical valence known in the chemical art.

[0034] As used in this disclosure, the following words and phrases are generally intended to have the meanings set forth below unless expressly indicated otherwise or the context in which the following words and phrases are used indicates otherwise.

[0035] In this specification and the appended claims, the singular forms "a," "an," and "the," include plural referents unless the context clearly dictates otherwise.

[0036] Unless the context clearly indicates otherwise, the term "and / or" is used in the present invention to mean "and" or "or".

[0037] As used herein, "at least" of a particular value is understood to mean that value and all values ​​greater than that value.

[0038] Applicants' disclosure is herein described in terms of preferred embodiments with reference to the accompanying drawings, wherein like numerals represent identical or similar elements. Reference throughout this specification to "one embodiment" or "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 present invention. Thus, appearances of the phrases "in one embodiment," "in an embodiment," and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.

[0039] The term "comprising," when used to define compositions and methods, is intended to mean that the compositions and methods include the listed elements, but not to exclude other elements. The term "consisting essentially of," when used to define compositions and methods, shall mean that the compositions and methods include the listed elements, and exclude other elements that are of any substantial significance to the compositions and methods. For example, "consisting essentially of" refers to the administration of the pharmacologically active agents that are explicitly listed, and excludes pharmacologically active agents that are not explicitly listed. The term "consisting essentially of" does not exclude pharmacologically inactive or inert agents, such as pharmaceutically acceptable excipients, carriers, or diluents. The term "consisting of," when used to define compositions and methods, shall mean excluding trace elements and substantial method steps of other ingredients. Embodiments defined by each of these transition terms are within the scope of the present invention.

[0040] Throughout this specification, when compositions and kits are described as having, including, or comprising particular components, or when 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 components, and that there are processes and methods according to the invention that consist essentially of, or consist of, the processing steps.

[0041] In this application, when an element or component is considered to be included in and / or selected from a list of elements or components, it should be understood that the element or component can be any one of the elements or components, or the element or component can be selected from two or more of the elements or components.

[0042] Unless otherwise specified or obvious from the context, as used herein, the term "about" should be understood as within the normal tolerance range in the art, for example, within 2 standard deviations of the mean. About can be understood as 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 the context clearly dictates otherwise, all numerical values ​​provided herein are modified by the term "about".

[0043] In this specification, variables or parameters are disclosed in groups or ranges. Specifically, the description should include every subcombination of the members of these groups and ranges. For example, a range of 1 to 16 is understood to include any number, combination of numbers, or subrange within the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0044] As used herein, a "pharmaceutical composition" refers to a therapeutically active agent in combination 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.

[0045] 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, vehicle, solvent, or encapsulating material, that is involved in carrying or transporting a subject's drug from one organ or part of the body to another. 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, ethylcellulose, and cellulose acetate; tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; 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 glycerol, 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; ethanol; phosphate buffered saline; and other nontoxic, compatible substances used in pharmaceutical formulations. Wetting agents, emulsifiers 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 can also be present in the compositions.

[0046] As used herein, the term "subject " refers to any animal (for example, mammal), including but not limited to people, non-human primates, rodents, etc., which will become the recipient of specific treatment. Generally, the terms "subject" and "patient" are used interchangeably herein, referring to human subjects. Considering "subject" applied to include but not limited to people (i.e., male or female of any age group, such as children's subjects (for example, infants, children, teenagers) or adult subjects (for example, young people, middle-aged people or the elderly)) and / or non-human animals, for example, mammals such as primates (for example, cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats and / or dogs. In certain embodiments, the subject is a person. In certain embodiments, the subject is a non-human animal.

[0047] As used herein, "administering" means oral administration, pulmonary administration, intramuscular administration, intrathecal administration, intranasal administration or subcutaneous administration, or implanting a sustained-release device, for example, a mini-osmotic pump, to a subject. Administration can be by any route, including transmucosal (e.g., oral, sublingual, palate, gum, nose, vagina, rectum or) administration. Parenteral administration includes, for example, intramuscular and subcutaneous administration. Other modes of delivery include, but are not limited to, the use of liposome formulations, etc. "Co-administering" means that the compositions described herein are administered while, just before, or just after administering one or more other therapies (e.g., therapeutic agents, chemotherapeutic agents, or treatment of neurodegenerative diseases). The compound of formula (I) can be administered alone or can be co-administered to a patient. Co-administration is intended to include administering a compound (one or more compounds or agents) alone or in combination, simultaneously or sequentially. Therefore, when desired, the preparation can also be combined with other active substances (e.g., to reduce metabolic degradation).

[0048] As used herein, the terms "disease," "disorder," and "condition" are used interchangeably herein.

[0049] As used herein, the term "treatment", "alleviation" or "prevention" disease or condition refers to improving such disease before or after it occurs. Compared to equivalent untreated controls, measured by any standard technique, such alleviation or prevention degree is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95% or 100%. The term "treatment (treat, treating and treatment)" contemplates the action that occurs when a subject suffers from a specific disease, disease or the patient's condition, which reduces the severity of the disease, disease or the patient's condition, or slows down or slows down the progress of the disease, disease or the patient's condition ("therapeutic treatment"), and also contemplates the action that occurs before the subject starts to suffer from a specific disease, disease or the patient's condition ("prophylactic treatment"). In one embodiment, provided herein is a compound contemplated for use in a therapeutic treatment method, wherein action occurs when a subject suffers from a specific disease, disease or the patient's condition, and causes the severity of the disease, disease or the patient's condition to decrease, or the progress of the disease, disease or the patient's condition to slow down or slow down. In an alternative embodiment, the compounds provided herein are contemplated for use in methods of prophylactic treatment, wherein actions occur before a subject becomes afflicted with a particular disease, disorder, or condition, and result in preventing the disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, or preventing recurrence of the disease, disorder, or condition.

[0050] 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 appreciated by those of ordinary skill in the art, the effective amount of a compound of the 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.

[0051] After preparation, the compounds of the present invention are preferably isolated and purified to obtain compositions containing an amount equal to or greater than 95% by weight ("substantially pure") and then used or formulated as described herein. In certain embodiments, the purity of the compounds of the present invention exceeds 99%. DETAILED DESCRIPTION

[0052] The present invention is based, in part, on the surprising discovery that the Reg3α active site analogs disclosed herein (eg, Ac-IGLHDPSHGTLPAGS) can be effectively used to alleviate or treat ALD-related diseases or conditions, particularly alcoholic hepatitis and acute liver failure.

[0053] In one aspect, the present invention generally relates to a method for treating, alleviating or preventing liver disease or a related disease or condition, comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound that is a Reg3α active site analog.

[0054] In certain embodiments, the amino acid sequence of the Reg3α active center is H-IGLHDPSHGTLPNGS-OH.

[0055] In certain embodiments, the compound is Ac-IGLHDPSHGTLPAGS or a pharmaceutically acceptable form thereof.

[0056] In certain embodiments, the subject suffers from a liver disease, or a related disease or condition, caused or induced by at least one chemical substance.

[0057] In certain embodiments, the subject has chronic liver disease or a related disease or condition.

[0058] In certain embodiments, the subject has acute liver disease or a related disease or condition.

[0059] In certain embodiments, the subject has steatohepatitis or a related disease or condition.

[0060] In certain embodiments, the subject has cirrhosis or a related disease or condition.

[0061] In certain embodiments, the subject has acute liver injury.

[0062] In certain embodiments, the subject suffers from acute liver failure.

[0063] In certain embodiments, the chemical substance is an industrial chemical or a pharmaceutical.

[0064] In certain embodiments, the industrial chemical is selected from alcohols, CCl4, CHCl3, nitrites, pesticides, poisons, and food additives.

[0065] In certain embodiments, the subject has alcoholic liver disease.

[0066] In certain embodiments, the subject has alcoholic hepatitis.

[0067] In another aspect, the present invention generally relates to a method for treating, alleviating or preventing drug-induced liver disease or related diseases or conditions, comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound that is a Reg3α active site analog.

[0068] In certain embodiments, the compound is Ac-IGLHDPSHGTLPAGS or a pharmaceutically acceptable form thereof.

[0069] In certain embodiments, the subject has a drug-induced chronic liver disease or a related disease or condition.

[0070] In certain embodiments, the subject has a drug-induced acute liver disease or a related disease or condition.

[0071] In certain embodiments, the subject has drug-induced fatty liver or a related disease or condition.

[0072] In certain embodiments, the subject has drug-induced steatohepatitis or a related disease or condition.

[0073] In certain embodiments, the subject has drug-induced moderate steatohepatitis.

[0074] In certain embodiments, the subject has drug-induced severe steatohepatitis.

[0075] In certain embodiments, the subject has cirrhosis.

[0076] In certain embodiments, the subject suffers from drug-related acute liver injury.

[0077] In certain embodiments, the subject suffers from drug-related acute liver failure.

[0078] In certain embodiments, the subject survives treatment for drug-induced acute liver failure.

[0079] Drugs that can cause liver disease (e.g., liver damage, liver failure, hepatitis) include, but are not limited to, antibiotics, anticancer drugs, analgesics, antipyretics, anti-tuberculosis drugs, anti-epileptic drugs, antidepressants, lipid-lowering drugs, traditional Chinese medicines, or dietary supplements.

[0080] In certain embodiments, the subject has acetaminophen (N-acetyl-p-aminophenol, APAP or )-induced liver damage.

[0081] In another aspect, the present invention generally relates to a method for treating, alleviating or preventing alcoholic liver disease or a related disease or condition, comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound that is a Reg3α active site analog.

[0082] In certain embodiments, the compound is Ac-IGLHDPSHGTLPAGS or a pharmaceutically acceptable form thereof.

[0083] In certain embodiments, the subject has alcoholic fatty liver disease or a related disease or condition.

[0084] In certain embodiments, the subject has alcoholic steatohepatitis or a related disease or condition.

[0085] In certain embodiments, the subject has severe alcoholic steatohepatitis.

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

[0087] In certain embodiments, the subject has moderate alcoholic hepatitis.

[0088] In certain embodiments, the subject has severe alcoholic hepatitis.

[0089] In certain embodiments, the subject survives treatment for acute liver failure.

[0090] In certain embodiments, the subject has moderate alcoholic steatohepatitis.

[0091] In certain embodiments, the subject has alcoholic cirrhosis.

[0092] In certain embodiments, the subject has acute liver failure associated with alcoholic hepatitis.

[0093] Any suitable route of administration can be used in the methods of the present invention.In certain embodiments, administration is subcutaneous, intravenous, intramuscular or by inhalation.

[0094] In certain embodiments, administration is subcutaneous injection.

[0095] In certain embodiments, the compound is administered in a daily dose range of about 10 mg to about 2,000 mg.

[0096] In certain embodiments, the compound is administered in a daily dose range of about 10 mg to about 1,000 mg.

[0097] In certain embodiments, the compound is administered for a period of about 1 day to about 6 months.

[0098] In certain embodiments, the compound is administered for a period of about 1 day to about 30 days.

[0099] In certain embodiments, the compound is administered at a daily dosage range of about 10 mg to about 2,000 mg for a period of about 1 day to about 30 days.

[0100] In certain embodiments, the compound is administered at a daily dose ranging from about 10 mg to about 1,000 mg for a period of about 1 day to about 30 days.

[0101] In certain embodiments, the first dose of the compound is administered within 48 hours of the onset or diagnosis of alcoholic hepatitis.

[0102] In certain embodiments, the first dose of the compound is administered within 24 hours of the onset or diagnosis of alcoholic hepatitis.

[0103] In certain embodiments, the first dose of the compound is administered within 12 hours, 6 hours, 4 hours, 3 hours, 2 hours, or 1 hour after the onset or diagnosis of alcoholic hepatitis.

[0104] In certain embodiments, the first dose of the compound is administered within 24 hours of the onset or diagnosis of acute liver failure.

[0105] In certain embodiments, the first dose of the compound is administered within 12 hours, 6 hours, 2 hours, or 1 hour after the onset or diagnosis of acute liver failure associated with alcoholic liver disease or alcohol consumption.

[0106] In certain embodiments, the methods of the invention further comprise administering to the subject a second therapeutic agent.

[0107] In certain embodiments, the second therapeutic agent is a corticosteroid.

[0108] In certain embodiments, the subject has been previously treated with corticosteroids.

[0109] 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.

[0110] In yet another aspect, the present invention generally relates to unit dosage forms comprising pharmaceutical compositions.

[0111] In certain embodiments, the pharmaceutical composition is an aqueous formulation suitable for subcutaneous injection.

[0112] In certain embodiments, the aqueous formulation is stable at a temperature of about 2°C to about 8°C for at least 48 months.

[0113] In yet another aspect, the present invention generally relates to the use of Ac-IGLHDPSHGTLPAGS or a pharmaceutically acceptable form thereof for treating liver disease or a related disease or condition.

[0114] In yet another aspect, the present invention generally relates to the use of Ac-IGLHDPSHGTLPAGS or a pharmaceutically acceptable form thereof for treating alcoholic liver disease or a related disease or condition.

[0115] In yet another aspect, the present invention generally relates to the use of Ac-IGLHDPSHGTLPAGS or a pharmaceutically acceptable form thereof for treating alcoholic fatty liver disease or a related disease or condition.

[0116] In yet another aspect, the present invention generally relates to the use of Ac-IGLHDPSHGTLPAGS or a pharmaceutically acceptable form thereof for treating alcoholic steatohepatitis or a related disease or condition.

[0117] In yet another aspect, the present invention generally relates to the use of Ac-IGLHDPSHGTLPAGS or a pharmaceutically acceptable form thereof for treating alcoholic hepatitis.

[0118] In yet another aspect, the present invention generally relates to the use of Ac-IGLHDPSHGTLPAGS or a pharmaceutically acceptable form thereof for treating moderate alcoholic hepatitis.

[0119] In yet another aspect, the present invention generally relates to the use of Ac-IGLHDPSHGTLPAGS or a pharmaceutically acceptable form thereof for treating severe alcoholic hepatitis.

[0120] In yet another aspect, the present invention generally relates to the use of Ac-IGLHDPSHGTLPAGS or a pharmaceutically acceptable form thereof for treating alcoholic cirrhosis.

[0121] In yet another aspect, the present invention generally relates to the use of Ac-IGLHDPSHGTLPAGS or a pharmaceutically acceptable form thereof for treating acute liver failure associated with alcoholic hepatitis.

[0122] In yet another aspect, the present invention generally relates to a method for reducing the severity of acute liver disease, comprising administering to a subject in need thereof a pharmaceutical composition comprising Ac-IGLHDPSHGTLPAGS or a pharmaceutically acceptable form thereof.

[0123] In certain embodiments, the subject has alcoholic hepatitis or acute liver injury associated with alcoholic liver disease, alcohol consumption, or industrial chemicals or drugs.

[0124] In yet another aspect, the present invention generally relates to a method for reducing mortality from alcoholic hepatitis, comprising administering to a subject in need thereof a pharmaceutical composition comprising Ac-IGLHDPSHGTLPAGS or a pharmaceutically acceptable form thereof.

[0125] In yet another aspect, the present invention generally relates to a method for reducing mortality from acute liver failure (e.g., associated with alcoholic liver disease or alcohol consumption), comprising administering to a subject in need thereof a pharmaceutical composition comprising Ac-IGLHDPSHGTLPAGS or a pharmaceutically acceptable form thereof. Example

[0126] The following examples are intended to illustrate the practice of the present invention and are not intended to limit it in any way. Materials, instruments, and methods

[0127] Carbon tetrachloride (CCl4) (Sigma)

[0128] Test compound: Ac-IGLHDPSHGTLPAGS (Shenzhen Hightide Biopharmaceutical Ltd.)

[0129] DUR-928: (Shenzhen Hightide Biopharmaceutical Ltd.)

[0130] Vehicle control: 0.9% NaCl injection (Guizhou Kelun Pharmaceutical Co., Ltd.)

[0131] DUR-928 (Larsucosterol) is an endogenous sulfated oxysterol and epigenetic modulator. It primarily targets DNA methyltransferases (DNMTs) and epigenetically regulates the expression of multiple clusters of dominant genes involved in many important cell signaling pathways, through which it stabilizes mitochondria, reduces lipotoxicity, modulates inflammatory or stress responses, and promotes cell survival. DUR-928 is currently being studied 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.) Example 1. Efficacy study in CCl4-induced acute liver injury model in rats. Animal models

[0132] Sprague-Dawley rats (6 to 10 weeks old, weighing approximately 220 g to 350 g, SPF grade). The SPF 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 lamps provided 12 hours of lighting per day. During the quarantine and study period, qualified rodent chow and filtered water were provided ad libitum, except for any requirements for study operations. After 7 days of acclimatization, acute liver failure was induced by intraperitoneal injection of 4 mL / kg of 50% (vol / vol) CCl4 in olive oil. Group design and treatment

[0133] Model rats were randomly divided into two groups: a vehicle control group (G1, n = 22) and a test article treatment group (G2, n = 21). One hour after model induction, animals from G1 and G2 received a dose of normal saline (4 mL / kg) or test compound (1.25 mg / kg) as a vehicle control by subcutaneous injection. During the study period, all animals were continuously observed for signs, including but not limited to mortality, morbidity, mental state, behavior, respiration, secretion, feces, and food and water intake. The detailed study design is summarized in Table 1 below. Table 1. Group experimental animals drug dose Route of administration Dosing frequency Dosage time G1 22 Normal saline 5 mL / kg Subcutaneous injection Single 1 hour after ALF induction G2 21 Test compound 1.25 mg / kg Subcutaneous injection Single 1 hour after ALF induction

[0134] Figure 1-Figure 2 Some exemplary data regarding experimental timelines and survival rates are shown.

[0135] The results are shown in Figure 2 Animals began to die approximately 3 hours after ALF induction. The results clearly show that initial mortality was delayed in the test compound-treated group compared to the vehicle control. At the end of the study, the survival rate in the test compound group was 38.1%, while the survival rate in the model group was 27.3%.

[0136] Cage-side observations revealed decreased spontaneous motor activity, shortness of breath, and pain-induced writhing responses in the animals following the model induction. In addition to increased survival, the test article-treated group also showed significant improvement in activity compared to the model group. These results suggest that the test article has a beneficial effect on liver damage. Example 2. Efficacy study in a CCl4-induced rat acute liver injury model with features of alcoholic hepatitis. Animal models

[0137] Sprague-Dawley rats (6-10 weeks old, weighing approximately 220-350 g, SPF grade). The SPF 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 lamps provided 12 hours of illumination per day. During the quarantine and study periods, qualified rodent chow and filtered water were provided ad libitum except when required by the study. After acclimation for 7 days, acute liver failure was induced by intraperitoneal injection of 4 mL / kg of 50% (volume / volume) CCl4 in olive oil. Grouping and treatment

[0138] Model rats were randomly divided into three groups: a vehicle control group (G1) and a test article-treated group (G2 and G3), with 18 rats in each group. One hour after model induction, animals from G1 to G3 received a single dose of saline (4 mL / kg) as a vehicle control or the test compound (1.25 mg / kg) via subcutaneous injection. All animals were continuously observed for signs during the study period, including but not limited to mortality, morbidity, mental state, behavior, respiration, secretions, feces, and food and water intake. The detailed study design is summarized in Table 2 below. Table 2

[0139] Figure 3-Figure 4 Some exemplary data regarding experimental timelines and survival rates are shown.

[0140] The results are shown in Figure 4 Animals began to die approximately 3.9 hours after ALF induction. Death was delayed in the test compound-treated group compared to the vehicle control. Furthermore, greater efficacy was observed in the test compound-treated group (1 hour) compared to the test compound-treated group (2 hours). Example 3. Efficacy Study in the C57 Mouse Model of APAP-Induced Alcoholic Hepatitis Characterized by Acute Liver Injury

[0141] C57 mice (12-week-old male, SPF grade). The SPF 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 lamps provided 12 hours of lighting per day. During the quarantine and study period, qualified rodent chow and filtered water were provided ad libitum except when required by the study. After acclimation for 7 days, the mice were matched and assigned to several groups based on body weight, including a vehicle group, a control group, and a test group. For the control group and all test groups, acute liver failure was induced by a single intraperitoneal injection of acetaminophen (APAP) in PBS, while the vehicle group was designed to be injected with PBS solution in the same manner. Each group received the test article or vehicle according to the experimental design before, during, or two hours after APAP or PBS solution stimulation. The dosing frequency, dosing interval, dosing dose, and dosing time of each group can be adaptively designed. All animals were continuously observed for signs during the study period, including but not limited to mortality, morbidity, mental state, behavior, respiration, secretions, feces, and food and water intake. (General methods for establishing acute liver injury model and the associate effect study can also be referenced to Steinebrunner, et al. 2014 “Pharmacologic cholinesterase inhibition improves survival in acetaminophen-induced acute liver failure in the mouse.” BMC Gastroenterol. 14: 148.) Example 4. Study on the protective effect of Ac-IGLHDPSHGTLPAGS (HTD4010) and DUR-928 in the lipopolysaccharide (LPS)-induced acute liver failure (ALF) mouse model.

[0142] Male C57BL / 6 mice (8-9 weeks old, SPF) were acclimated for at least 1 week and then randomly divided into four groups: a model control group (G0) and test groups (G1-G3), with 15 mice per group. The experimental design is shown in the table below. All mice were injected intravenously with 40 mg / kg LPS to induce the ALF model. The day of LPS injection was defined as day 1.

[0143] On day 1, for the G0 group, the mice were subcutaneously injected with vehicle once at 1 hour after LPS injection and at 8 hours after LPS injection, respectively; and on day 2 and thereafter, the mice were subcutaneously injected with vehicle twice a day.

[0144] On day 1, for the G1 group, mice were subcutaneously injected with HTD4010 (5 mg / kg) once at 1 hour and 8 hours after LPS injection, respectively; and on day 2 and thereafter, mice were subcutaneously injected with HTD4010 (5 mg / kg) twice a day.

[0145] On day 1, for the G2 group, DUR-928 (50 mg / kg) was injected once intravenously 2 hours before LPS injection.

[0146] On day 1, for the G3 group, DUR-928 (50 mg / kg) was injected once intravenously 1 hour after LPS injection.

[0147] Animal status was closely monitored, including monitoring of mental state, activity, excretion, and mortality throughout the study period. The study was terminated on approximately day 7 until no mortality was observed within 12 hours in each group. Table 3. Grouping and treatment

[0148] Notes: 1. For the G1-HTD4010 group, the dose level of 10 mg / kg / day and the administration method (sc, 1 hour after LPS injection, BID) used in this study were selected based on the results of previous studies; 2. For the G2-DUR-928 (pretreatment) group, the dose level of 50 mg / kg and the administration method (iv injection, two hours before LPS injection) were selected based on the literature (Ning et al., 2017, Metabolism, Vol. 71: pp. 83-93; Wang et al., 2021, Cells, Vol. 10, No. 11: p. 3027) and clinical drug delivery routes (Am J Gastroenterol., May 8, 2023); 3. For the G3-DUR-928 group, the administration method of DUR-928 1 hour after LPS injection was the same as that of HTD4010. result

[0149] Figure 5 Exemplary data on the survival rate of each group in the LPS-induced ALF mouse model (*P<0.05 compared with the G0 model control using the log-rank test (Mantel-Cox method. #P<0.05 compared with G3 of the DUR-928 group).

[0150] DUR-928 showed a significant protective effect in this ALF mouse model when treated prophylactically (50 mg / kg, 2 hours before LPS injection) (P < 0.05), which is consistent with the data reported in the literature (Ning et al., 2017, Metabolism, Vol. 71: pp. 83-93) and has a stronger protective effect than when administered 1 hour after LPS injection (80% vs. 53%).

[0151] When HTD4010 was administered at a dose level of 10 mg / kg / day after LPS injection, it had a significant protective effect (P < 0.01). The therapeutic effect of HTD4010 when administered after LPS injection was slightly stronger than the prophylactic effect of DUR-928 when administered 2 hours before LPS injection (87% vs. 80%). When HTD4010 or DUR-918 was administered 1 hour after LPS injection, the protective effect of the HTD4010 group was significantly better than that of DUR-928 (87% vs. 53%), and the difference was statistically significant (P < 0.05).

[0152] The features, structures or characteristics of the applicant's disclosure may be combined in any suitable manner in one or more embodiments. In the description herein, many specific details are described to provide a thorough understanding of the embodiments of the present invention. However, those skilled in the relevant art will recognize that the applicant's compositions and / or methods may be practiced without one or more specific details, or practiced with other methods, components, materials, etc. In other cases, well-known structures, materials or operations are not 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 meanings 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 the present disclosure, the preferred methods and materials are now described. The methods described herein can be performed in any order that is logically possible, except for the specific order disclosed. References

[0154] References and citations to other documents, such as patents, patent applications, patent publications, periodicals, books, papers, and web content are incorporated throughout this disclosure. All of these documents are hereby incorporated by reference in their entirety for all purposes. Any material or portion thereof that is considered to be incorporated by reference herein but conflicts with existing definitions, statements, or other public materials clearly set forth herein is incorporated only to the extent that no conflict occurs between the incorporated material and the present disclosure. In the event of a conflict, the conflict will be resolved in a manner that is beneficial to the present disclosure as a preferred disclosure. equivalent

[0155] The representative examples are intended to help illustrate the present invention and are not intended to, and should not be construed as, limiting the scope of the present invention. Indeed, various modifications of the present invention and many other embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art in light of the entire disclosure herein, including the present examples and the references to the scientific and patent literature contained herein. These examples contain important additional information, illustrations, and guidance that may be suitable for the practice of the present invention in its various embodiments and their equivalents.

Claims

1. A method for treating, alleviating or preventing liver disease or related diseases or conditions, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound that is an analog of the Reg3α active site.

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

3. The method of claim 1 or 2, wherein the subject suffers from a liver disease, or a related disease or condition, caused or induced by at least one chemical substance.

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

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

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

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

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

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

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

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

12. The method of claim 1 or 2, wherein the subject has alcoholic hepatitis.

13. A method for treating, alleviating or preventing drug-induced liver disease or related diseases or conditions, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound that is a Reg3α active site analog.

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

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

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

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

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

19. The method of claim 13, wherein the subject has drug-induced severe steatohepatitis.

20. The method of claim 13, wherein the subject has cirrhosis of the liver.

21. The method of claim 13, wherein the subject suffers from acute liver injury.

22. The method of claim 13, wherein the subject suffers from acute liver failure.

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

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

25. A method for treating, alleviating or preventing alcoholic liver disease or related diseases or conditions, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound that is a Reg3α active site analog.

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

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

28. The method of claim 25 or 26, wherein the subject has alcoholic steatohepatitis or a related disease or condition.

29. The method of claim 25 or 26, wherein the subject has alcoholic hepatitis.

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

31. The method of claim 25 or 26, wherein the subject has severe alcoholic hepatitis.

32. The method of claim 25 or 26, wherein the subject has alcoholic cirrhosis.

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

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

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

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

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

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

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

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

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

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

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

44. 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.

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

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

47. The unit dosage form according to claim 46, wherein the aqueous formulation is stable at a temperature of about 2°C to 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 disease 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 liver cirrhosis.

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

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