Treatment of alcoholic hepatitis

Abstract

Methods for treating alcoholic hepatitis (AH) are provided. For example, such methods may involve administering 5-cholestyr-3,25-diol, 3-sulfate (25HC3S) or a salt thereof.

Description

[Technical Field]

[0001] This invention relates to the treatment of alcoholic hepatitis. [Previous Technology]

[0002] Alcoholic hepatitis (AH) is an alcoholic liver disease caused by long-term alcohol (ethanol) intake. Signs and symptoms of AH include acute jaundice, fever, and weight loss, as well as several complications such as ascites and hepatic encephalopathy, leading to cirrhosis. AH is associated with a high mortality burden of 30 days to up to 15%, depending on the severity of the disease. The one-month mortality rate for severe AH is as high as 30% to 50%.

[0003] Corticosteroids are commonly used to treat severe cases of acute hemorrhage (AH). However, corticosteroid treatment has shown conflicting results, is associated with an increased risk of infection, and is unsuitable for patients with gastrointestinal bleeding or those allergic to steroids. Corticosteroids are typically administered daily in doses ranging from 30 mg to 40 mg, depending on the specific corticosteroid used. Patient compliance is often low due to frequent missed doses.

[0004] Liver transplantation is a radical treatment option for AH, but patients must abstain from alcohol for 6 months to be eligible. However, the 6-month mortality rate for severe AH is high (approximately 40%). Although liver transplantation is a treatment option, patients with severe AH often die before meeting the transplant criteria.

[0005] U.S. Patent No. 8,399,441, which is incorporated herein by reference, discloses the use of 5-cholestyrene-3,25-diol,3-sulfate (25HC3S) and its salts to treat conditions associated with high cholesterol and / or high triglycerides and / or inflammation (e.g., hypercholesterolemia, hypertriglyceridemia, non-alcoholic fatty liver disease, atherosclerosis, etc.).

[0006] U.S. Patent No. 9,034,859, which is incorporated herein by reference, discloses the use of 25HC3S and its salts for the prevention and treatment of liver damage or disease.

[0007] U.S. Patent No. 10,272,097, which is incorporated herein by reference, discloses oxidized cholesterol sulfates, such as 25HC3S and its salts, for the prevention and / or treatment of local ischemia, organ dysfunction and / or organ failure, including multiple organ dysfunction syndrome (MODS), and necrosis and apoptosis associated with organ dysfunction / failure.

[0008] ClinicalTrials.gov contains disclosures of studies evaluating the safety, pharmacokinetics, and pharmacodynamics of 25HC3S in patients with acute hemorrhage (AH) at dose escalation of 30 mg, 90 mg, and 150 mg. See ClinicalTrials.gov Identifier: NCT03432260.

[0009] There is an urgent need for improved methods to treat AH. [Summary of the Invention]

[0011] This disclosure proposes various methods for treating alcoholic hepatitis (AH). These methods involve administering an effective amount of 5-cholestyr-3,25-diol, 3-sulfate (25HC3S) and its salts. In some instances, these methods involve administering an effective amount of 5-cholestyr-3,25-diol, 3β-sulfate or its salts.

[0012] The results of this disclosure are surprising for several reasons. For example, the low dosage of this disclosure is surprising in some embodiments. Furthermore, the low dosing frequency is surprising in some embodiments. Additionally, the low number of doses required to achieve therapeutic efficacy in some embodiments is surprising. The results of this disclosure are also surprising in that low doses, low dosing frequency, and low total doses provide similar or better results than corticosteroids requiring larger doses, more frequent dosing, and / or higher total doses. Furthermore, this disclosure also yields effective results in AH patients characterized by specific diagnostic criteria such as the Model for End-stage Liver Disease (MELD) score and / or other criteria discussed elsewhere herein.

[0013] Other embodiments of this disclosure include: 1. A method for treating alcoholic hepatitis in a human individual in need, the method comprising administering to the individual an amount sufficient to treat the alcoholic hepatitis of 5-cholestyrene-3,25-diol,3-sulfate (25HC3S) or a salt thereof. 2. The method of embodiment 1, wherein the administration comprises administering a total amount of 25HC3S or a salt thereof in the range of about 1 mg to about 1000 mg. 3. The method of embodiment 1 or 2, wherein the administration comprises administering a total amount of 25HC3S or a salt thereof in the range of: (a) about 10 mg / month to about 500 mg / month; or (b) about 10 mg / month to about 400 mg / month. 4. The method of any one of examples 1 to 3, comprising administering to the human individual a total amount of: (a) about 10 mg / month to about 400 mg / month; or (b) about 10 mg to about 400 mg of 25HC3S or its salts over a one-month period; wherein: - the total amount is sufficient to treat the alcoholic hepatitis; - the total amount is administered in separate doses comprising at least one first dose or more; and - the one-month period is measured from the start of administration of the first dose. 5. The method of any one of examples 2 to 4, wherein the total amount is administered in one to fifteen separate doses. 6. The method of any one of examples 2 to 4, wherein the total amount is administered in one to five separate doses. 7. The method of any one of examples 2 to 4, wherein the total amount is administered in one dose or in two separate doses, preferably as a single dose. 8. The method of any one of examples 2 to 7, wherein the total amount is at least about 20 mg. 9. The method of any one of samples 2 to 8, wherein the total amount is not more than about 300 mg. 10. The method of any one of samples 2 to 8, wherein the total amount is not more than about 200 mg. 11. The method of any one of samples 2 to 8, wherein the total amount is not more than about 140 mg. 12. The method of any one of samples 4 to 11, wherein at least one of the one or more separate doses, and preferably each dose, contains about 10 mg to about 200 mg of 25HC3S or a salt thereof. 13. The method of any one of samples 4 to 12, wherein at least one of the one or more separate doses, and preferably each dose, contains about 10 mg to about 120 mg of 25HC3S or a salt thereof. 14. The method of any one of embodiments 4 to 13, wherein at least one of the one or more separate doses, and preferably each dose, comprises about 20 mg to about 100 mg of 25HC3S or a salt thereof. 15. The method of any one of embodiments 2 to 14, wherein the total amount is administered in two or more separate doses, the two or more separate doses being administered at a frequency ranging from once daily to once weekly.16. The method of sample 15, wherein the dosing frequency is in the range of once every two days to once a week. 17. The method of sample 15, wherein the dosing frequency is in the range of once every two days to once every five days. 18. The method of sample 15, wherein the dosing frequency is in the range of once every two days to once every four days. 19. The method of sample 4, wherein: - the total dose is administered in one dose or in two separate doses; - the one dose contains about 10 mg to about 200 mg of 25HC3S or a salt thereof; - each of the two separate doses contains about 10 mg to about 200 mg of 25HC3S or a salt thereof; and - the two separate doses are administered at a dosing frequency in the range of once every two days to once every four days. 20. The method of form 19, wherein the total amount is administered in a single dose, and wherein the single dose comprises: (a) about 20 mg to about 40 mg of 25HC3S or a salt thereof; or (b) about 80 mg to about 100 mg of 25HC3S or a salt thereof; or (c) about 140 mg to about 160 mg of 25HC3S or a salt thereof. 21. The method of form 19, wherein the total amount is administered in two separate doses, and wherein each of the two separate doses comprises: (a) about 20 mg to about 40 mg of 25HC3S or a salt thereof; or (b) about 80 mg to about 100 mg of 25HC3S or a salt thereof; or (c) about 140 mg to about 160 mg of 25HC3S or a salt thereof. 22. The method of any one of samples 4 to 21, wherein the total amount of 25HC3S or its salt administered per kg during the period ranges from about 0.05 mg / kg to about 20 mg / kg. 23. The method of sample 22, wherein the total amount per kg ranges from about 0.1 mg / kg to about 10 mg / kg. 24. The method of sample 22, wherein the total amount per kg ranges from about 0.2 mg / kg to about 6 mg / kg. 25. The method of sample 22, wherein the total amount per kg ranges from about 0.3 mg / kg to about 1.5 mg / kg. 26. The method of any one of samples 1 to 25, wherein the administration is not via the gastrointestinal, intravenous, intramuscular, or subcutaneous route. 27. The method of any one of samples 1 to 26, wherein the administration is by injection. 28. The method of any one of embodiments 1 to 27, wherein the 25HC3S or its salt is administered as a formulation comprising the 25HC3S or its salt and a pharmaceutically acceptable carrier. 29. The method of any one of embodiments 1 to 28, wherein the 25HC3S or its salt comprises a salt of 25HC3S, wherein the salt of 25HC3S is preferably a sodium salt. 30. The method of any one of embodiments 4 to 29, wherein the one or more separate doses are administered over a period not exceeding 14 days.31. The method of any one of samples 1 to 30, wherein the human individual has a Model for End-Stage Liver Disease (MELD) score of at least 11. 32. The method of any one of samples 1 to 31, wherein the human individual has a MELD score in the range of 11 to 45. 33. The method of any one of samples 1 to 32, wherein the human individual has a MELD score in the range of 15 to 40. 34. The method of any one of samples 1 to 33, wherein the human individual has a MELD score of at least 20. 35. The method of any one of samples 1 to 34, wherein the human individual has a MELD score of at least 30. 36. The method of any one of samples 1 to 35, wherein the human individual has a Maddrey's discriminant function (MDF) score of at least 32. 37. The method of any one of examples 1 to 36, wherein the alcoholic hepatitis is characterized by a decrease in liver function within 13 weeks of onset. 38. The method of any one of examples 1 to 36, wherein the alcoholic hepatitis is characterized by a decrease in liver function within 10 weeks of onset. 39. The method of any one of examples 1 to 38, wherein the alcoholic hepatitis is characterized by a decrease in liver function resulting in a lower 25HC3S clearance rate in the individual compared to an individual without alcoholic hepatitis. 40. The method of example 39, wherein the alcoholic hepatitis is characterized by a decrease in liver function resulting in a 25HC3S clearance rate in the individual that is 50% or less, 40% or less, 30% or less, or 25% or less of the 25HC3S clearance rate from the plasma of an individual without alcoholic hepatitis. 41. The method of any one of samples 1 to 40, wherein the alcoholic hepatitis is characterized by decreased liver function, resulting in the individual exhibiting a plasma half-life (T1 / 2) of 25HC3S after administration that is 1.5 times or longer, or 2 times or longer, than that of an individual without alcoholic hepatitis. 42. The method of any one of samples 1 to 41, wherein the individual exhibits a plasma half-life (T1 / 2) of 25HC3S after administration that is in the range of about 1.5 hours to about 6 hours or about 2 hours to about 5 hours. 43. The method of any one of samples 1 to 42, wherein the individual exhibits a Cmax of 25HC3S in the range of about 500 ng / mL to about 10,000 ng / mL, about 600 ng / mL to about 7,000 ng / mL, or about 700 ng / mL to about 5,000 ng / mL.44. The method of any one of samples 1 to 43, wherein the individual presents a Cmax of 25HC3S of about 500 ng / mL to about 10,000 ng / mL, about 600 ng / mL to about 7,000 ng / mL, or about 700 ng / mL to about 5,000 ng / mL for each 100 mg intravenously administered 25HC3S. 45. The method of any one of samples 1 to 44, wherein the individual presents an AUCinf of 25HC3S of about 3,000 ng*h / mL to about 50,000 ng*h / mL, about 4,000 ng*h / mL to about 40,000 ng*h / mL, or about 5,000 ng*h / mL to about 30,000 ng*h / mL. 46. ​​The method of any one of samples 1 to 45, wherein each 100 mg of 25HC3S or its salt administered intravenously results in an AUCinf of 25HC3S in the individual ranging from about 3000 ng*h / mL to about 50,000 ng*h / mL, about 4000 ng*h / mL to about 40,000 ng*h / mL, or about 5000 ng*h / mL to about 30,000 ng*h / mL. 47. The method of any one of samples 1 to 46, wherein the individual exhibits a distribution volume of 25HC3S ranging from about 10 L to about 50 L, about 15 L to about 45 L, or about 20 L to about 40 L. 48. The method of any one of embodiments 1 to 47, wherein the individual exhibits 25HC3S clearance in the range of about 2 L to about 8 L / h, about 2.5 L / h to about 7.5 L / h, or about 3 L / h to about 7 L / h. 49. The method of any one of embodiments 1 to 48, wherein the alcoholic hepatitis is characterized by loss of liver function within 13 weeks of onset. 50. The method of any one of embodiments 1 to 48, wherein the alcoholic hepatitis is characterized by loss of liver function within 10 weeks of onset. 51. A 5-cholestyren-3,25-diol,3-sulfate (25HC3S) or a salt thereof, used for treating alcoholic hepatitis in a human individual in need, wherein the method is as defined in any one of embodiments 1 to 50. 52. Use of a 5-cholestene-3,25-diol,3-sulfate (25HC3S) or a salt thereof in a method of manufacturing a pharmaceutical agent for treating alcoholic hepatitis in a human individual in need, wherein the method is as defined in any one of samples 1 to 50.

Implementation Method

[0015] This article describes methods for treating alcoholic hepatitis (AH). These methods involve contacting the liver with 25HC3S or a salt thereof. This contact typically involves administering to a human patient an amount of 25HC3S or a salt thereof that is effective or sufficient to treat AH.

[0016] As discussed above, the results of this disclosure are surprising for several reasons. For example, the low dosage disclosed in some embodiments is surprising. Furthermore, the low dosing frequency is surprising in some embodiments. Additionally, the low number of doses required to achieve therapeutic efficacy in some embodiments is surprising. The results of this disclosure are also surprising in that low doses, low dosing frequency, and / or low total doses provide similar or better results than corticosteroids requiring larger doses, more frequent dosing, and higher total doses. Furthermore, this disclosure also yields effective results in AH patients characterized by specific diagnostic criteria such as the MELD score and / or other criteria discussed elsewhere herein. Definitions

[0017] The following definitions are used throughout the text:

[0018] As used herein, “treatment” (treatment, treating, etc.) means administering 25HC3S or a salt thereof to a human individual who: (1) exhibits at least one symptom of AH; and / or (2) is diagnosed with AH by a trained clinical professional; and / or (3) is diagnosed with AH based on laboratory (e.g., molecular indicators) or clinical trials of one or more bodily fluids such as blood. In some embodiments, an individual is diagnosed with AH by examination of a liver tissue section. In other words, at least one parameter known to be associated with AH has been measured, detected, or observed in the individual. “Treatment” of AH involves reducing or attenuating, or in some instances, completely eradicating, at least one symptom of AH present before or at the time of administration of 25HC3S or a salt thereof. In some embodiments, as described in more detail below, treatment of AH according to the present invention is sufficient to improve the laboratory or clinical indicators of AH in an individual. In some cases, the improvement in the laboratory or clinical indicators of AH in an individual makes the individual no longer considered to have AH. In one instance, the topic approach was sufficient to reduce the scores of individuals with a Maddrey Discriminant Function (MDF) score ≥32 to an MDF score <32.

[0019] "Abnormal liver function" refers to a condition or healthy state in which the liver fails to perform its expected functions, such as when certain biological or molecular indicators are measured outside the normal physiological range. Liver function represents the expected function of the liver within its physiological range. Those skilled in the art understand the individual function of the liver during a health check. Abnormal liver function typically involves a clinical syndrome of progressive and potentially reversible physiological dysfunction in the liver, depending on the circumstances, without anatomical damage.

[0020] "Liver failure" means that the liver function is so abnormal that it cannot maintain the stability of the normal internal environment without external clinical intervention.

[0021] "Acute liver dysfunction" refers to a rapid decrease in liver function that occurs within days or weeks (e.g., within 26 weeks, within 13 weeks, within 10 weeks, within 5 weeks, within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, within 5 days, within 4 days, within 3 days, or within 2 days), and usually occurs in people without pre-existing diseases.

[0022] "Acute liver failure" refers to a rapid loss of liver function that occurs within days or weeks (e.g., within 26 weeks, within 13 weeks, within 10 weeks, within 5 weeks, within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, within 5 days, within 4 days, within 3 days, or within 2 days), and usually occurs in people without pre-existing conditions. Acute liver failure will be discussed in more detail below.

[0023] "Pharmaceutically acceptable" refers to a medium that does not interfere with the bioactivity of the active ingredient and is non-toxic to the host to which it is administered. Overview of patient populations with alcoholic hepatitis.

[0024] Alcoholic hepatitis (AH) can range from mild hepatitis where abnormal laboratory tests are the only indication of the disease, to severe liver dysfunction with complications such as jaundice (yellowing of the skin due to bilirubin retention), hepatic encephalopathy (neurological dysfunction due to liver failure), ascites (fluid accumulation in the abdomen), hemorrhagic esophageal varices (varicose veins in the esophagus), abnormal thrombosis, and coma. In some cases, patients develop jaundice within the previous 8 weeks, such as within the previous 7 weeks, 6 weeks, 5 weeks, 4 weeks, 3 weeks, or 2 weeks, including those who develop jaundice within the previous week. AH is usually reversible if the patient stops drinking alcohol, but hepatitis often takes months to resolve. AH causes liver scarring and cirrhosis. Typical histological findings in the liver include hepatocellular necrosis and swelling, as well as alcoholic Mallory hyaline bodies (abnormal aggregation of intermediate filament proteins in fibrotic cells). Cholestasis is usually prominent. The severity of the disease can be classified according to the Maddrey discriminant function (MDF) (based on bilirubin and prothrombin time), the Glasgow Alcoholic Hepatitis score (based on age, white blood cell count, urea, prothrombin time, and bilirubin), or the Model for End-Stage Liver Disease (MELD) score (based on the international normalized ratio (INR) of creatinine, bilirubin, and prothrombin time) (Lucey et al., N. Engl. J. Med., 360(26), 2758-2769 (2009); Vergis et al., Gastroenterology, 152(5):1068-1077 (2017)). When the MDF is >32, the AH grade is severe. Alcohol consumption

[0025] In some cases, patients have a history of severe alcohol abuse for at least 6 months, with women consuming >40 g / day or men >60 g / day, and abstaining from alcohol for, for example, <60 days (e.g., <8 weeks) before the onset of jaundice. Excessive alcohol consumption over many years can lead to alcoholic liver disease and AH. In some cases, excessive alcohol consumption involves alcohol intake of >80 g / day for men or >60 g / day for women. Therefore, one embodiment is the use of 25HC3S or a salt thereof to treat AH in male or female individuals consuming excessive alcohol, where the male individual consumes >80 g of alcohol per day or the female individual consumes >60 g of alcohol per day. In other embodiments, this disclosure relates to the use of 25HC3S or a salt thereof to treat or alleviate AH in male or female individuals with a history of excessive alcohol consumption (such as those who have experienced one or more episodes of average alcohol consumption of 40 g / day or more for 6 months or longer). In some implementation scenarios, the individual had experienced one or more instances of consuming an average of 60 g / day or more for up to 6 months or longer. (bilirubin)

[0026] A characteristic feature of acute hepatitis (AH) is elevated bilirubin, indicating impaired hepatic metabolic function in the absence of biliary obstruction. In some cases, patients have serum bilirubin >3 mg / dL. Therefore, an implementation approach is to treat or alleviate AH symptoms in individuals with serum bilirubin levels >50 μmol / L, such as >60 μmol / L or >80 μmol / L, prior to administration of 25HC3S or its salts. In some cases, patients to be treated have bilirubin levels in the range of about 2 mg / dL to 50 mg / dL, such as about 3 mg / dL to about 40 mg / dL or about 4 mg / dL to about 30 mg / dL. In some cases, the bilirubin level of the patient to be treated is measured to be >8 mg / dL.

[0027] In some embodiments, the method includes measuring serum bilirubin in a patient to be treated. The patient's serum bilirubin can be measured using any convenient protocol, such as colorimetric or fluorescence assay. In these embodiments, the patient's serum bilirubin can be measured 10 minutes or longer before treatment according to the method described herein, such as 15 minutes or longer, 30 minutes or longer, 60 minutes or longer, 2 hours or longer, 6 hours or longer, and including 12 hours or longer. In some embodiments, the patient's serum bilirubin is measured the day before treatment according to the method described herein.

[0028] In some embodiments, the method includes measuring the patient's serum bilirubin after one or more rounds of treatment according to the subject method, such as two or more rounds, three or more rounds, four or more rounds, and including five or more rounds. In these embodiments, serum bilirubin may be measured immediately after the last dose of 25HC3S or a salt thereof or at a predetermined time thereafter, such as 5 minutes or longer after the last dose of 25HC3S or a salt thereof, such as 10 minutes or longer, such as 15 minutes or longer, such as 30 minutes or longer, such as 60 minutes or longer, such as 2 hours or longer, such as 6 hours or longer, and including 12 hours or longer. In some embodiments, the patient's serum bilirubin is measured at a time on the same day as the last dose of 25HC3S or a salt thereof. In some cases, the patient's bilirubin rises sharply, for example, by ≥3 mg / dL within 8 weeks. In some cases, this method is sufficient to reduce an individual's serum bilirubin, such as by 1 mg / dL or more, such as by 2 mg / dL or more, and including by 3 mg / dL or more. In some cases where an individual exhibits a sharp increase in bilirubin, this method is sufficient to increase the amount of reduction in bilirubin, such as by 1 mg / dL or more, such as by 2 mg / dL or more, and including by 3 mg / dL or more. In some embodiments, the subject method is sufficient to reduce a patient's serum bilirubin (e.g., 7 or 28 days after the start of treatment) by 10% or more, such as by 15% or more, such as by 20% or more, such as by 25% or more, such as by 30% or more, such as by 35% or more, such as by 40% or more, such as by 45% or more, and including by 50% or more. MELD

[0029] The Model for End-Stage Liver Disease (MELD) is a scoring system used to assess the severity of liver disease. An elevated MELD score indicates a greater risk of death, while a decreased MELD score indicates a reduced risk. MELD uses the international normalized ratio (INR) of serum bilirubin, serum creatinine, and prothrombin time to predict survival and is calculated using the following formula: MELD = 3.78xln[serum bilirubin (mg / dL)] + 11.2xln[INR] + 9.57xln[serum creatinine (mg / dL)] + 6.43

[0030] In some cases, patients have MELD scores ranging from about 11 to about 40, such as about 11 to about 35, about 11 to about 33, or about 21 to about 30. In some cases, patients have MELD scores ≥11, such as ≥15 or ≥21. In some cases, patients have MELD scores <35, such as <30, <25, <20, or <15. Therefore, an embodiment is to treat or alleviate the symptoms of AH in an individual using 25HC3S or a salt thereof, wherein the individual is characterized by a MELD score ranging from about 11 to about 30 or from about 21 to about 30 prior to administration of 25HC3S or a salt thereof.

[0031] In some embodiments, the method includes determining the MELD score of the patient to be treated. In these embodiments, the patient's MELD score may be determined 10 minutes or longer, such as 15 minutes or longer, such as 30 minutes or longer, such as 60 minutes or longer, such as 2 hours or longer, such as 6 hours or longer, and including 12 hours or longer, before the patient is to be treated according to the method described herein. In some embodiments, the patient's MELD score is determined the day before the patient is to be treated according to the method described herein.

[0032] In some embodiments, the method includes determining the patient's MELD score after one or more rounds of treatment according to the subject method, such as two or more rounds, three or more rounds, four or more rounds, and including five or more rounds. In these embodiments, the MELD score may be determined immediately after the last dose of 25HC3S or a salt thereof or at a predetermined time thereafter, such as 5 minutes or more after the last dose of 25HC3S or a salt thereof, such as 10 minutes or more, such as 15 minutes or more, such as 30 minutes or more, such as 60 minutes or more, such as 2 hours or more, such as 6 hours or more, and including 12 hours or more. In some embodiments, the patient's MELD score is determined at a time on the same day as the last dose of 25HC3S or a salt thereof.

[0033] In some implementations, the subject method is sufficient to reduce the MELD score exhibited by the patient (e.g., 7 or 28 days after the start of treatment) by 5% or more, such as 10% or more, such as 15% or more, and including 20% ​​or more, the MELD score measured prior to treatment with 25HC3S or its salts as described herein. MDF

[0034] The Maddrey discriminant function (MDF) is a model for assessing the severity and prognosis of AH. The MDF score is a statistical model that can be used to predict an individual's short-term prognosis, particularly 30- or 90-day mortality. A score of 32 or higher (severe alcoholic hepatitis (SAH)) suggests an unfavorable outcome with a 30-day mortality rate in the range of 35% to 45%. Conversely, an MDF < 32 identifies patients with mild / moderate AH, with a low but not zero risk of death under supportive care.

[0035] MDF is calculated according to the following formula: MDF = 4.6 x (prothrombin formation time (PT patients - PT control group) + serum bilirubin μmol / L) / 17.1

[0036] Therefore, an implementation example is the use of 25HC3S or a salt thereof to treat or alleviate the symptoms of AH in an individual, wherein the individual is characterized by an MDF score ≥32 prior to administration of 25HC3S or a salt thereof. Thus, in some cases, the patient has an MDF score ≥32. In other cases, the patient has an MDF score <32.

[0037] In some embodiments, the method includes determining the MDF score of the patient to be treated. In these embodiments, the patient's MDF score may be determined 10 minutes or longer before treatment according to the subject method, such as 15 minutes or longer, such as 30 minutes or longer, such as 60 minutes or longer, such as 2 hours or longer, such as 6 hours or longer, and including 12 hours or longer. In some embodiments, the patient's MDF score is determined the day before treatment according to the method described herein.

[0038] In some embodiments, the method includes determining the patient's MDF score after one or more rounds of treatment according to the subject method, such as two or more rounds, three or more rounds, four or more rounds, and including five or more rounds. In these embodiments, the MDF score may be determined immediately after the last dose of 25HC3S or a salt thereof or at a predetermined time thereafter, such as 5 minutes or more after the last dose of 25HC3S or a salt thereof, such as 10 minutes or more, such as 15 minutes or more, such as 30 minutes or more, such as 60 minutes or more, such as 2 hours or more, such as 6 hours or more, and including 12 hours or more. In some embodiments, the patient's MDF score is determined at a time on the same day as the last dose of 25HC3S or a salt thereof.

[0039] In some implementations, the subject method is sufficient to reduce the MDF score exhibited by the patient (e.g., 7 or 28 days after the start of treatment) by 5% or more, such as 10% or more, such as 15% or more, and including 20% ​​or more, the MDF score measured prior to treatment with 25HC3S or its salts as described herein.

[0040] In one embodiment, the use of 25HC3S or a salt thereof to treat or alleviate symptoms of acute hepatitis (AH) in an individual characterized by an MDF score ≥32 and a MELD score <25 prior to administration of 25HC3S or a salt thereof. In some cases, this method is sufficient to reduce an individual's MDF score by 1 or more, such as 2 or more, including a reduction of 5 or more. In some cases, this method is sufficient to reduce the score of an individual with an MDF score ≥32 to an MDF score <32. ABIC

[0041] While MDF can predict survival for one month, it is less accurate in the medium to long term. MELD scores, along with recently validated age, serum bilirubin, INR, and serum creatinine (ABIC) scores, provide more nuanced survival predictions by emphasizing impaired renal function and can be calculated at different time points. An ABIC score >9 indicates a high risk of death, 6.71 to 9 indicates an intermediate risk, and <6.71 indicates a low risk. Therefore, in some cases, patients have ABIC scores >9 or 6.71 to 9.

[0042] In some embodiments, the method includes determining the ABIC score of the patient to be treated. In these embodiments, the patient's ABIC score may be determined 10 minutes or longer, such as 15 minutes or longer, such as 30 minutes or longer, such as 60 minutes or longer, such as 2 hours or longer, such as 6 hours or longer, and including 12 hours or longer, before the patient is to be treated according to the method described herein. In some embodiments, the patient's ABIC score is determined the day before the patient is to be treated according to the method described herein.

[0043] In some embodiments, the method includes determining the patient's ABIC score after one or more rounds of treatment according to the subject method, such as two or more rounds, three or more rounds, four or more rounds, and including five or more rounds. In these embodiments, the ABIC score may be determined immediately after the last dose of 25HC3S or a salt thereof or at a predetermined time thereafter, such as 5 minutes or more after the last dose of 25HC3S or a salt thereof, such as 10 minutes or more, such as 15 minutes or more, such as 30 minutes or more, such as 60 minutes or more, such as 2 hours or more, such as 6 hours or more, and including 12 hours or more. In some embodiments, the patient's ABIC score is determined at a time on the same day as the last dose of 25HC3S or a salt thereof.

[0044] In some implementations, the subject method is sufficient to reduce the patient's ABIC score (e.g., 7 or 28 days after the start of treatment) by 5% or more, such as 10% or more, such as 15% or more, and including 20% ​​or more, the ABIC score measured prior to treatment with 25HC3S or its salts as described herein. Glasgow AH score

[0045] The Glasgow Alcoholic Hepatitis Score (GAHS) can be used to identify patients at risk of death (Forrest et al., Gut, 56:1743-1746 (2007)). A score of 9 or higher identifies patients at the highest risk of death.

[0046] In some embodiments, the method includes measuring the GAHS of the patient to be treated. In these embodiments, the patient's GAHS may be measured 10 minutes or longer, such as 15 minutes or longer, such as 30 minutes or longer, such as 60 minutes or longer, such as 2 hours or longer, such as 6 hours or longer, and including 12 hours or longer, before the patient is to be treated according to the method described herein. In some embodiments, the patient's GAHS is measured the day before the patient is to be treated according to the method described herein.

[0047] In some embodiments, the method includes measuring the patient's GAHS after one or more rounds of treatment according to the subject method, such as two or more rounds, three or more rounds, four or more rounds, and including five or more rounds. In these embodiments, GAHS may be measured immediately after the last dose of 25HC3S or a salt thereof or at a predetermined time thereafter, such as 5 minutes or longer after the last dose of 25HC3S or a salt thereof, such as 10 minutes or longer, such as 15 minutes or longer, such as 30 minutes or longer, such as 60 minutes or longer, such as 2 hours or longer, such as 6 hours or longer, and including 12 hours or longer. In some embodiments, the patient's GAHS is measured at a time on the same day as the last dose of 25HC3S or a salt thereof.

[0048] In some implementations, the subject method is sufficient to reduce the GAHS (e.g., 7 or 28 days after the start of treatment) of the patient as described herein prior to treatment with 25HC3S or its salts by 5% or more, such as 10% or more, such as 15% or more, and including 20% ​​or more.

[0049] Therefore, one aspect of this disclosure is to improve GAHS scores. One aspect involves treating or alleviating AH symptoms in an individual using 25HC3S or a salt thereof, wherein the individual is characterized by a reduced GAHS score after at least 7 days, at least 14 days, at least 21 days, at least 28 days, at least 42 days, or at least 90 days compared to before the first administration of 25HC3S or a salt thereof. Another aspect involves treating or alleviating AH symptoms in an individual using 25HC3S or a salt thereof, wherein the individual is characterized by a reduced GAHS score after at least 7 days, at least 14 days, at least 21 days, at least 28 days, at least 42 days, or at least 90 days compared to before the first administration of 25HC3S or a salt thereof.

[0050] The Lille score predicts mortality in patients with acute hemorrhage (AH). The Lille score is calculated using the following formula: Exp(-R) / [1 +exp(-R)] where R = [3.19 - (0.101 * age)] + (1.47 * albumin at baseline, in g / dL) + [0.28215 * (bilirubin at baseline - bilirubin on day 8, in mg / dL)] - [0.206 * (if creatinine at baseline >= 1.3 mg / dL)] - [0.11115 * bilirubin at baseline, in mg / dL] - (0.0096 * prothrombin time at baseline, in seconds)

[0051] Therefore, one aspect of this disclosure is to improve the Lille score. One aspect involves treating or alleviating AH symptoms in an individual using 25HC3S or a salt thereof, wherein the individual is characterized by a reduced Lille score 7 days after the first administration of 25HC3S or a salt thereof. Another aspect provides treatment or alleviation of AH symptoms in an individual using 25HC3S or a salt thereof, comprising administration of 25HC3S or a salt thereof, wherein the individual is characterized by a reduced Lille score 7 days after the first administration of 25HC3S or a salt thereof. In some cases, patients have a Lille score <0.45 7 days after the first administration of 25HC3S or a salt thereof. MELD + Lille

[0052] Combining static and dynamic models to enhance the prediction of AH, Louvet et al. demonstrated that the combined effect model of MELD plus Lille was superior to other combinations, thus the 2-month mortality risk was 1.9 times higher (23.7% vs. 12.5%) for patients with MELD 21 and Lille 0.45 compared to patients with MELD 21 and Lille 0.16. Therefore, in some cases, the combined effect model of MELD plus Lille has been used to diagnose individuals with AH.

[0053] In some cases, the Alcoholic Hepatitis Histological Score (AHHS) is used to diagnose an individual with AH. The AHHS is based on four histological parameters: degree of fibrosis, degree of neutrophil infiltration, type of bilirubin stasis, and presence of megamitochondria.

[0054] In some cases, patients have aspartate transaminase (AST) > alanine transaminase (ALT), but less than 300 IU / L. In some cases, patients have AST > 50, AST / ALT > 1.5, and both values ​​< 400 IU / L.

[0055] In some embodiments, the individual has an aspartate transaminase (AST) level of 50 to 400 IU / L. In some embodiments, the individual has an alanine transaminase (ALT) level of less than 400 IU / L, such as 390 IU / L or lower, such as 380 IU / L or lower, such as 370 IU / L or lower, such as 360 IU / L and including 350 IU / L. In some embodiments, the individual has an AST level greater than an ALT level, such as where the AST to ALT ratio (i.e., AST / ALT) is 1.05 or greater, such as 1.1 or greater, such as 1.15 or greater, such as 1.2 or greater, such as 1.25 or greater, such as 1.3 or greater, such as 1.35 or greater, such as 1.4 or greater, such as 1.45 or greater and including 1.5 or greater (e.g., preferably where AST / ALT is greater than 1.5). For example, in some implementation profiles, an individual may have a combination of two or more of these characteristics, such as AST of 50 to 400 IU / L, ALT of less than 400 IU / L, and an AST / ALT ratio greater than 1.5. Furthermore, the patient may have one or more other clinical features, such as jaundice onset within the previous 8 weeks, serum total bilirubin >3.0 mg / dL, a Maddrey discriminant function ≥32 for a presumed prothrombin time of 12 seconds in the control group, and / or a MELD score of 21 to 30.

[0056] In some cases, patients have albumin levels in the range of about 1 g / dL to about 5 g / dL, such as about 1 g / dL to about 4 g / dL or about 2 g / dL to about 3 g / dL.

[0057] In some cases, patients have an internationally normalized ratio (INR) of prothrombin formation time ranging from about 10 seconds to about 30 seconds, such as about 11 seconds to about 25 seconds or about 15 seconds to about 25 seconds. In some embodiments, the method includes measuring the internationally normalized ratio (INR) of prothrombin formation time of the patient to be treated. In these embodiments, the patient's internationally normalized ratio of prothrombin formation time may be measured 10 minutes or longer before treatment according to the subject method, such as 15 minutes or longer, such as 30 minutes or longer, such as 60 minutes or longer, such as 2 hours or longer, such as 6 hours or longer and including 12 hours or longer. In some embodiments, the patient's internationally normalized ratio of prothrombin formation time is measured the day before the patient is to be treated according to the method described herein.

[0058] In some embodiments, the method includes determining the international normalized ratio of the patient's prothrombin time after one or more rounds of treatment according to the subject method, such as two or more rounds, three or more rounds, four or more rounds, and including five or more rounds. In these embodiments, the international normalized ratio of the prothrombin time may be determined immediately after the last dose of 25HC3S or a salt thereof or at a predetermined time thereafter, such as 5 minutes or more after the last dose of 25HC3S or a salt thereof, such as 10 minutes or more, such as 15 minutes or more, such as 30 minutes or more, such as 60 minutes or more, such as 2 hours or more, such as 6 hours or more, and including 12 hours or more. In some embodiments, the international normalized ratio of the patient's prothrombin time is determined at a time on the same day as the last dose of 25HC3S or a salt thereof.

[0059] In some embodiments, the subject method is sufficient to reduce the international normalized ratio of prothrombin formation time (INR) exhibited by the patient (e.g., 7 or 28 days after the start of treatment) by 5% or more, such as 10% or more, such as 15% or more, and including 20% ​​or more, as described herein before treatment with 25HC3S or its salts.

[0060] In some cases, the patient has a serum creatinine level in the range of about 0.2 mg / dL to about 3 mg / dL, such as about 0.4 mg / dL to about 2.5 mg / dL or about 0.6 mg / dL to about 2 mg / dL. In some embodiments, the method includes measuring the serum creatinine level of the patient to be treated. In these embodiments, the patient's serum creatinine level may be measured 10 minutes or longer before treating the patient according to the subject method, such as 15 minutes or longer, such as 30 minutes or longer, such as 60 minutes or longer, such as 2 hours or longer, such as 6 hours or longer and including 12 hours or longer. In some embodiments, the patient's serum creatinine level is measured the day before the patient is to be treated according to the method described herein.

[0061] In some embodiments, the method includes measuring the patient's serum creatinine level after one or more rounds of treatment according to the subject method, such as two or more rounds, three or more rounds, four or more rounds, and including five or more rounds. In these embodiments, the serum creatinine level may be measured immediately after the last dose of 25HC3S or a salt thereof or at a predetermined time thereafter, such as 5 minutes or longer after the last dose of 25HC3S or a salt thereof, such as 10 minutes or longer, such as 15 minutes or longer, such as 30 minutes or longer, such as 60 minutes or longer, such as 2 hours or longer, such as 6 hours or longer, and including 12 hours or longer. In some embodiments, the patient's serum creatinine level is measured at a time on the same day as the last dose of 25HC3S or a salt thereof.

[0062] In some embodiments, the subject method is sufficient to reduce a patient’s serum creatinine level (e.g., 7 or 28 days after the start of treatment) by 2% or more, such as 5% or more, such as 10% or more and including 15% or more, as described herein before treatment with 25HC3S or its salts.

[0063] In some cases, patients suffer from acute AH, which presents as an acute exacerbation of chronic liver failure (ACLF).

[0064] In some cases, an individual is diagnosed with AH based on circulating fragments of major components of cytokeratin-18 (CK-18) and Mallory-Denk bodies (called M65 and M30).

[0065] In view of the above, the diagnosis of AH (i.e., identifying an individual who has experienced AH and who can benefit from the implementation of this method) is generally based on physical examination, laboratory test results, patient history, and established past medical history, such as altered mental status, coagulation disorders, rapid onset, and the absence of known prior liver disease. In some cases, patients with AH have other prior liver diseases, such as cholestatic liver dysregulation, autoimmune liver dysregulation, active viral hepatitis, Wilson's disease, or other non-alcohol-related liver dysregulation.

[0066] The definition of "rapid" depends on the specific conventions used. Different subdivisions exist based on the time from the earliest onset of liver symptoms to the onset of encephalopathy. In some cases, "AH" refers to the development of encephalopathy, jaundice, or a bilirubin level >3 mg / dL within 26 weeks of the onset of liver symptoms. This subdivision is "fulminant hepatic failure," which requires the onset of encephalopathy, jaundice, or a bilirubin level >3 mg / dL within 8 weeks; and "subfulminant," which describes the onset of encephalopathy, jaundice, or a bilirubin level >3 mg / dL after 8 weeks but before 26 weeks from the onset of liver symptoms. In other cases, "hyperacute" liver failure may be characterized by onset within 7 days of the onset of liver symptoms, "acute" liver failure by onset between 7 and 28 days of the onset of liver symptoms, and "subacute" liver failure by onset between 28 days and 24 weeks of the onset of liver symptoms. Individuals identified as experiencing acute liver failure by any of these criteria may be treated using the methods described herein.

[0067] In some cases, individuals treated with the methods described herein may or may not have the following symptoms and / or be diagnosed with: high cholesterol levels (hypercholesterolemia, e.g., serum cholesterol levels of approximately 200 mg / dL or higher); or conditions associated with high cholesterol levels, such as hyperlipidemia, atherosclerosis, heart disease, stroke, Alzheimer's disease, gallstones, cholestatic liver disease, etc. In some cases, individuals treated with the methods described herein may not have the following symptoms and / or be undiagnosed with: high cholesterol levels (hypercholesterolemia, e.g., serum cholesterol levels of approximately 200 mg / dL or higher); or conditions associated with high cholesterol levels, such as hyperlipidemia, atherosclerosis, heart disease, stroke, Alzheimer's disease, gallstones, cholestatic liver disease, etc. (Explanation of the Entries)

[0068] The implementation of these methods typically involves identifying patients with AH and administering 25HC3S or its salts in an acceptable form via an appropriate route. The exact amount to be administered (e.g., over a one-month period) may vary depending on the individual patient’s age, sex, weight and overall health status, as well as the precise cause of the disease.

[0069] In some implementation scenarios, the total amount of 25HC3S or its salts administered to patients was unexpectedly low. The total amount administered (e.g., over a one-month period) was typically in the range of about 0.01 mg / kg to about 50 mg / kg of body weight, more commonly about 0.05 mg / kg to about 20 mg / kg, such as about 0.1 mg / kg to about 10 mg / kg, about 0.2 mg / kg to about 6 mg / kg, about 0.2 mg / kg to about 2 mg / kg, or about 0.3 mg / kg to about 1.5 mg / kg of 25HC3S or its salts.

[0070] The total amount is typically from about 1 mg to about 1000 mg of 25HC3S or its salts. In some embodiments, the total amount of 25HC3S or its salts administered to the patient in these methods (e.g., over a one-month period) is from about 10 mg to about 500 mg. Typically, in some embodiments, the total amount of 25HC3S or its salts administered to the patient in these methods (e.g., over a one-month period) is from about 10 mg to about 400 mg. For example, in some embodiments, the total amount is at least about 20 mg. In some embodiments, the total amount is not more than about 300 mg, such as not more than about 200 mg, or even not more than about 140 mg. Specific examples of the total amount administered include about 10 mg to about 500 mg, about 10 mg to about 400 mg, about 20 mg to about 300 mg, about 20 mg to about 200 mg, and about 20 mg to about 140 mg. This total amount will vary depending on the route of administration, bioavailability, and the specific formulation being administered. For example, the total amount described herein is particularly useful for intravenous administration.

[0071] In some embodiments, the low dose number is unexpected (including, but not limited to, when 25HC3S or its salts are administered intravenously). In this regard, the total amount of 25HC3S or its salts to be administered in these methods may be administered in one dose or in multiple separate doses over a period of time (such as a month). In some embodiments, the total amount is administered in one to fifteen separate doses, for example, in one to five separate doses, such as in one dose or two separate doses. In some embodiments, the total amount is administered in a single dose. In other embodiments, the total amount is administered in two separate doses. In all methods described herein, the total amount administered includes at least a first dose (when the total amount is administered in a single dose, the first dose is a single dose, but in other embodiments, the first dose is followed by at least one other dose).

[0072] In some embodiments, at least one of one or more separate doses, preferably each dose, contains about 10 mg to about 200 mg of 25HC3S or a salt thereof. For example, in some embodiments, at least one of one or more separate doses, preferably each dose, contains about 10 mg to about 120 mg of 25HC3S or a salt thereof, such as about 20 mg to about 100 mg of 25HC3S or a salt thereof. Specific exemplary doses include the following: (a) about 20 mg to about 40 mg of 25HC3S or a salt thereof (such as about 30 mg); or (b) about 80 mg to about 100 mg of 25HC3S or a salt thereof (such as about 90 mg); or (c) about 140 mg to about 160 mg of 25HC3S or a salt thereof (such as about 150 mg). In some embodiments, the doses that are particularly useful may be (a) or (b) above. In some implementations, the number of separate doses that are particularly useful for this dosage may be one dose (i.e., a single dose) or two separate doses.

[0073] In some embodiments, the low dosing frequency is surprising. For example, in some embodiments, the total dose is administered in two or more separate doses, which are administered at a frequency ranging from once daily to once weekly, such as once every two days to once weekly, for example, once every two days to once every five days or once every two days to once every four days. An example of this dosing frequency is about once every three days. For example, when the total number of separate doses is two, the second dose may be administered one day to one week, two days to one week, two days to five days, two days to four days, or about three days after the first dose.

[0074] In some embodiments, one or more separate doses are administered within a single administration period (meaning the period during which 25HC3S or its salt is actually administered). For example, when the method includes a total administration period of one month from the start of the first dose measurement, the administration period may be shorter than one month. Therefore, in some embodiments, the administration period is followed by a "non-administration period" during which 25HC3S or its salt is not administered, and thus the administration period and the non-administration period are summed to a one-month period. In some such embodiments, the administration period does not exceed 21 days, such as not exceeding 14 days, for example, not exceeding 7 days or not exceeding 5 days.

[0075] In view of the above, the total amount of 25HC3S or its salts administered over a one-month period may range from about 0.01 mg / kg / month to about 50 mg / kg / month, more commonly from about 0.05 mg / kg / month to about 20 mg / kg / month, such as from about 0.1 mg / kg / month to about 10 mg / kg / month, for example from about 0.2 mg / kg / month to about 6 mg / kg / month or from about 0.3 mg / kg / month to about 1.5 mg / kg / month. The total amount of 25HC3S or its salts administered over a one-month period may range from about 1 mg / month to about 1000 mg / month, from about 5 mg / month to about 600 mg / month, from about 10 mg / month to about 400 mg / month, from about 20 mg / month to about 300 mg / month, from about 20 mg / month to about 200 mg / month, or from about 20 mg / month to about 140 mg / month.

[0076] The compound disclosed herein may be administered intermittently, or at a gradual or continuous, constant or controlled rate.

[0077] Administration may be administered via any route, such as non-gastrointestinal, including intravenous, intramuscular, or subcutaneous injection. The route of administration will depend on the nature of the condition being treated, such as the type or degree of liver injury and / or liver failure. For example, intravenous administration may be preferred to achieve the intended treatment before significant liver dysfunction or failure occurs. Therefore, when injury has occurred, especially when acute organ failure is diagnosed, the route of administration is usually non-gastrointestinal or intravenous to accelerate the delivery of 25HC3S or its salts.

[0078] 25HC3S can be administered in its pure form or as a pharmaceutically acceptable formulation including a suitable elixir (commonly referred to as a "carrier") or as a pharmaceutically acceptable salt (e.g., an alkali metal salt, such as sodium, potassium, calcium, or lithium salts, ammonium, etc.) or other complex. For example, salts of 25HC3S are preferred; sodium salts of 25HC3S are an example of such salts. It should be understood that pharmaceutically acceptable formulations include liquid materials conventionally used in the preparation of injectable dosage forms. 25HC3S or its salts are commonly administered as components of fluids suitable for injection and / or intravenous administration. Solid forms suitable for dissolving or suspending in a liquid prior to administration can also be prepared.

[0079] These active ingredients may be mixed with pharmaceutically acceptable and compatible excipients (e.g., pharmaceutically and physiologically acceptable carriers). Suitable excipients include, for example, water, saline (sodium chloride), cyclodextrins (e.g., hydroxypropyl-β-cyclodextrin), dextran, glycerol, ethanol, etc., or combinations thereof. In addition, the composition may contain small amounts of excipients, such as wetting agents or emulsifiers, pH buffers (e.g., phosphate buffers). Water may be used as a carrier for formulations of the composition (e.g., injectable compositions), and may also include conventional buffers and pharmaceuticals to make the composition isotonic. Other possible additives and other materials (preferably those generally considered GRAS) include: surfactants (TWEEN®, oleic acid, etc.); solvents, stabilizers, elixirs, and encapsulating agents (lactose, liposomes, etc.). Preservatives, such as methylparaben or benzalkium chloride, may also be used. The compositions disclosed herein may contain any such additional ingredients to provide a composition in a form suitable for the desired route of administration. Furthermore, these compounds may be formulated with aqueous or oil-based carriers.

[0080] Depending on the formulation, 25HC3S or a salt thereof is expected to constitute about 1 wt% to about 99 wt% of the composition, and the transport "carrier" will constitute about 1 wt% to about 99% of the composition. The pharmaceutical composition of the present invention may include any applicable pharmaceutically acceptable additives or adjuvants to the extent that such additives or adjuvants do not hinder or interfere with the therapeutic efficacy of 25HC3S or a salt thereof.

[0081] In some cases, alcoholic hepatitis is characterized by reduced liver function, resulting in an individual exhibiting a lower 25HC3S clearance rate than an individual without alcoholic hepatitis. In some cases, alcoholic hepatitis is characterized by reduced liver function, resulting in an individual exhibiting a 25HC3S clearance rate that is 50% or less, 40% or less, 30% or less, or 25% or less of the clearance rate of an individual without alcoholic hepatitis. In one illustrative but not limiting case, the 25HC3S clearance rate of an individual without alcoholic hepatitis, used to measure the reduced clearance rate of an individual with alcoholic hepatitis, is considered to be 25 L / hr (i.e., the individual exhibits a 25HC3S clearance rate below 25 L / hr, for example, below 50% or less, 40% or less, 30% or less, or 25% or less of 25 L / hr).

[0082] In some cases, alcoholic hepatitis is characterized by impaired liver function, resulting in an individual exhibiting a plasma half-life (T1 / 2) of 25HC3S that is 1.5 times or more, or 2 times or more, greater than that of an individual without alcoholic hepatitis. In an illustrative but not limiting case, the half-life of an individual without alcoholic hepatitis, used to measure the greater half-life of an individual with alcoholic hepatitis, is considered to be 1.6 hr (i.e., the individual exhibits a half-life greater than 1.6 hr, such as 1.5 times or more, or 2 times or more). In some cases, the time to reach maximum drug concentration (Tmax) is at the end of an infusion, for example, after a 2-hour infusion. In some embodiments, the half-life (t1 / 2) of 25HC3S or its salts is in the range of about 4 to about 6 hours. In some cases, individuals exhibited a 25HC3S half-life (T1 / 2) ranging from approximately 1.5 hours to approximately 6 hours or from approximately 2 hours to approximately 5 hours after administration.

[0083] In some cases, the average clearance rate of 25HC3S or its salts is about 5 L / hr to about 7 L / hr. In some cases, the clearance rate of 25HC3S observed by individuals is in the range of about 2 L to about 8 L / h, about 2.5 L / h to about 7.5 L / h, or about 3 L / h to about 7 L / h.

[0084] In some cases, the volume of distribution of 25HC3S observed in an individual ranges from about 10 L to about 50 L, from about 15 L to about 45 L, or from about 20 L to about 40 L. In some cases, the volume of distribution observed in an individual is lower than that observed in an individual without alcoholic hepatitis (which may be considered, for example, 55 L) – for example, 90% or less, 80% or less, 70% or less, or 60% or less.

[0085] In some cases, the Cmax of 25HC3S observed in individuals is in the range of about 500 ng / mL to about 10,000 ng / mL, about 600 ng / mL to about 7,000 ng / mL, or about 700 ng / mL to about 5,000 ng / mL. For example, in some cases, the Cmax of 25HC3S observed in individuals is in the range of about 500 ng / mL to about 10,000 ng / mL, about 600 ng / mL to about 7,000 ng / mL, or about 700 ng / mL to about 5,000 ng / mL per 100 mg intravenously administered.

[0086] In some cases, the AUCinf of 25HC3S observed in individuals ranges from about 3,000 ng*h / mL to about 50,000 ng*h / mL, from about 4,000 ng*h / mL to about 40,000 ng*h / mL, or from about 5,000 ng*h / mL to about 30,000 ng*h / mL. For example, in some cases, the AUCinf of 25HC3S observed in individuals is in the range of about 5,000 ng*h / mL to about 30,000 ng*h / mL or about 6,000 ng*h / mL to about 20,000 ng*h / mL for every 100 mg of 25HC3S or its salt administered intravenously.

[0087] In one implementation, 25HC3S or a salt thereof is used to treat or alleviate symptoms of acute hepatitis (AH) in an individual, wherein the individual has a reduced risk of death 90 days after the first administration of 25HC3S or a salt thereof compared to an individual who has not received 25HC3S or a salt thereof. In some implementations, the risk of death 90 days after the first administration of 25HC3S or a salt thereof is reduced by 5% or more, such as 10% or more, such as 25% or more, such as 50% or more, such as 75% or more, such as 90% or more, and includes cases where the individual's risk of death 90 days after the first administration of 25HC3S or a salt thereof is reduced by 99% or more compared to an individual who has not received 25HC3S or a salt thereof.

[0088] In one implementation, 25HC3S or a salt thereof is used to treat or alleviate symptoms of acute hemorrhage (AH) in an individual, wherein the individual has a reduced risk of death 28 days after the first administration of 25HC3S or a salt thereof compared to an individual who has not received 25HC3S or a salt thereof. In some implementations, the risk of death 28 days after the first administration of 25HC3S or a salt thereof is reduced by 5% or more, such as 10% or more, such as 25% or more, such as 50% or more, such as 75% or more, such as 90% or more, and includes cases where the individual has a 99% or more reduced risk of death 90 days after the first administration of 25HC3S or a salt thereof compared to an individual who has not received 25HC3S or a salt thereof.

[0089] In some embodiments, the methods and compositions disclosed herein are sufficient to reduce hospital stay compared to individuals who have not received 25HC3S or its salts. In some cases, these subject methods and compositions are sufficient to reduce hospital stay by, for example, 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, 6% or more, 7% or more, 8% or more, 9% or more, 10% or more, 11% or more, 12% or more, 13% or more, 14% or more, 15% or more, 16% or more, 17% or more, 18% or more, 19% or more, 20% or more, 25% or more, 30% or more, 35% or more, and include reducing hospital stay by 40% or more.

[0090] In some embodiments, the methods and compositions disclosed herein are sufficient to reduce the duration of intensive care unit (ICU) treatment compared to individuals who have not received 25HC3S or its salts. In some cases, these subject methods and compositions are sufficient to reduce ICU treatment time by, for example, 1% or more, such as 2% or more, such as 3% or more, such as 4% or more, such as 5% or more, such as 6% or more, such as 7% or more, such as 8% or more, such as 9% or more, such as 10% or more, such as 11% or more, such as 12% or more, such as 13% or more, such as 14% or more, such as 15% or more, such as 16% or more, such as 17% or more, such as 18% or more, such as 19% or more, such as 20% or more, such as 25% or more, such as 30% or more, such as 35% or more, and including reducing ICU treatment time by 40% or more.

[0091] The present invention will be further described by way of the following embodiments. These embodiments are non-limiting and do not limit the scope of the invention. Unless otherwise stated, all percentages, parts, etc., presented in the embodiments are by weight. Embodiment 1

[0092] As described in more detail below, a total of 19 patients were enrolled in the open-label phase 2a multicenter trial. Of these, 15 had a Maddrey discriminant function (MDF) ≥32 (severe alcoholic hepatitis (SAH)), 12 had a MELD score of 21 to 30, and 11 had baseline serum bilirubin levels >8 mg / dL. All patients received intravenous infusions of 25HC3S (30, 90, or 150 mg) on ​​days 1 and 4 (if still hospitalized) and were followed for 28 days. The final enrollment of 19 patients included: 8 patients receiving 30 mg (4 moderate and 4 severe), 7 patients receiving 90 mg (3 moderate and 4 severe), and 4 patients receiving 150 mg (4 severe). Methods: Research drugs 25HC3S sodium salt solution contains: • 30 mg / mL 25HC3S sodium salt; • 240 mg / mL hydroxypropyl-β-cyclodextrin; and • 50 mmole phosphate buffer The 25HC3S sodium salt solution was diluted in 100 mL of 5% dextrose or 0.9% sodium chloride infusion solution. • Dosage 1: 30 mg of 25HC3S sodium salt in 100 mL of 5% dextrose or 0.9% sodium chloride • Dosage 2: 90 mg of 25HC3S sodium salt in 100 mL of 5% dextrose or 0.9% sodium chloride. • Dosage 3: 150 mg of 25HC3S sodium salt in 100 mL of 5% dextrose or 0.9% sodium chloride. On days 1 and 4, 25HC3S sodium salt was administered via slow intravenous infusion (50 mL / h) over a 2-hour period until the full dose was given. If the patient met the discharge criteria before the second dose, the patient received only one dose instead of two. Research Procedures The study was conducted in two parts. Part A included patients with a MELD score of 11 to 20 (moderate acute hemorrhage), while Part B included patients with a MELD score of 21 to 30. The dosage of 25HC3S sodium salt administered was 30 mg and 90 mg in Part A, and 30 mg, 90 mg, and 150 mg in Part B, with four patients per dose group in each part (except for the 90 mg group in Part A, which had only three patients). All patients were followed up until day 28. The study began with four patients with moderate acute hemorrhage (AH) (Part A) at a dose level of 30 mg. After dosing, the dose escalation committee (DEC) reviewed the safety, tolerability, and pharmacokinetic (PK) data from all four patients and determined it was safe to proceed to the same dose level of 30 mg for the four patients with severe AH (Part B) and to escalate the dose level to 90 mg for the patients with moderate AH (Part A). The same dose escalation procedure was then followed in Part B until all four patients received a dose of 150 mg. The study process is illustrated in Figure 2. Up to four individuals were recruited for each dose group. Individuals received up to two doses of 25HC3S sodium salt. The first dose was administered on day 1, and the second dose was administered on day 4 if the individual remained hospitalized. Pharmacokinetic (PK) samples were collected at the following times: 0:00 (before administration), 1 hour after administration, 2 hours after administration (end of infusion), 3 hours after administration, 4 hours after administration, 8 hours after administration, 12 hours after administration, 24 hours after administration, and 50 hours after administration. Ethnicity: 1. In this clinical trial, patients diagnosed with alcoholic hepatitis were defined as follows: a. History of severe alcohol abuse: women >40 g / day or men >60 g / day for at least 6 months, and b. Drinking alcohol within 12 weeks of joining the study, and c. Serum bilirubin > 3 mg / dL and AST > ALT, but below 300 U / L, and d. MELD score between 11 and 30, including 11 and 30 The baseline laboratory characteristics of individuals in each group are listed in the table below. Evaluate: Evaluation of pharmacodynamic (PD) signals: Changes in Lille score, MELD score, and biochemical markers (such as bilirubin). Method and timing: The Lille score is calculated on day 7. The MELD score was calculated at screening, day 1 (before administration), day 7, and day 28. Biochemical and all safety laboratory parameters were collected at screening, on days 1 and 4 before administration, 12 hours after administration / infusion on days 1 and 4, on days 2, 7, and 28, and on days 3, 4, 5, and 6 if hospitalized. Security signal assessment: Safety is determined based on clinical and laboratory monitoring. Evaluation of PK: The plasma concentration data of 25HC3S from each patient were used to calculate the relevant PK parameters measured using the standard linear / logarithmic trapezoidal method and an appropriate PK data analysis program. PK samples were collected at the following time points (only after dose 1): 0 (before administration), 1 hour after administration, 2 hours after administration (end of infusion), and 3, 4, 8, 12, and 24 hours after administration. Results: All three doses of 25HC3S were safe, with no drug-related serious adverse events. All patients (including those with SAH) survived during the 28-day follow-up period. Some patients received one dose, while others received two doses. The dosage ranged from 30 mg to 300 mg. Of the 18 patients who returned on day 7, four received two doses and fourteen received one dose.

[0093] Drug exposure (both AUC and Cmax) in AH patients is dose-proportional. The time to reach maximum drug concentration (Tmax) is at the end of the 2-hour infusion. The mean plasma concentrations of 25HC3S sodium in individuals with moderate and severe AH are shown in Figures 3A and 3B, respectively. The half-life (t1 / 2) of 25HC3S sodium ranges from 4 to 6 hours. The mean clearance of 25HC3S sodium is approximately 5 to 7 L / hr. The PK parameters of 25HC3S sodium are similar between the moderate and severe AH groups. A summary of the PK parameters at various dose levels for individuals with moderate and severe AH is presented in the table below. Line graphs of Cmax (Figure 4A) and AUC (Figure 4B) for individuals with moderate and severe AH are plotted in Figure 4.

[0094] Compared to the pharmacokinetic parameters of 25HC3S sodium in healthy individuals, the same dose level (a single dose of 150 mg) increased the Cmax by 2-fold and the AUC by approximately 5-fold in AH patients. 25HC3S sodium clearance in AH patients was 80% lower than in healthy individuals from previous studies. A comparison of the pharmacokinetic parameters of 25HC3S administered to healthy individuals and individuals with alcoholic hepatitis is summarized in the table below. A comparison of the plasma concentrations of 25HC3S administered to healthy individuals and individuals with alcoholic hepatitis is depicted in Figure 5.

[0095] Among all AH patients treated with 25HC3S (one patient did not return on day 7), 89% had a treatment responder (Lille score < 0.45); among 15 SAH patients (MDF ≥ 32), 87% had a response; and among 12 patients with MELD 21 to 30, 83% had a response. In particular, 100% of SAH patients treated with 30 or 90 mg 25HC3S (n = 11) responded to the treatment, as shown in the table below.

[0096] Although patients received only 1 or 2 doses of 25HC3S, the MELD score of SAH patients on day 28 was significantly lower than baseline (-17.5%, p = 0.01). The median MELD score of SAH patients treated with 30 or 90 mg of 25HC3S on day 28 was reduced by -19.0% from baseline (p = 0.01). 25HC3S also significantly reduced serum bilirubin levels in AH patients on day 7, especially in patients with baseline bilirubin > 8.0 mg / dL (-25.1%, p = 0.02).

[0097] Comparing the data from this study with a set of data from 145 AH patients assessed using Louvet et al. to develop the Lille score (with DF score, prothrombin time, and serum creatinine, albumin, and bilirubin levels as compared in this study), the Lille score from this study (p < 0.0001) was significantly lower than the Lille score from historical data (0.24 (0.07, 0.60)). Louvet et al., Hepatology, 45:1348-1354 (2007); and Louvet et al., Gastroenterology, 149:398-406 (2015).

[0098] Compared to the historical control group (n = 15) from the University of Louisville (UL) AH study, clinical data from this trial also showed statistically significant reductions in baseline bilirubin (days 7 and 28) and MELD (day 28) in the 19 patients treated with 25HC3S, as well as statistically significant lower Lille scores. See Figure 1. UL shared anonymized data, in which 16 AH patients with initial MELD scores in the range of 15 to 30 received only supportive care (n = 9) or supportive care plus corticosteroids (n = 7). Of the 19 AH patients using 25HC3S, one patient did not return on day 7, therefore the Lille score could only be calculated from 18 of the 19 patients.

[0099] The Lille score is used in clinical practice to help determine the prognosis of AH patients 7 days after treatment. The lower the Lille score, the better the prognosis of AH patients. Patients with a Lille score below 0.45 have an 85% 6-month survival rate, while patients with a Lille score above 0.45 have only a 25% 6-month survival rate (Louvet A et al., Hepatology, 45: 1348-54 (2007)). In this study, the median Lille score of the 18 AH patients treated with 25HC3S who returned on day 7 was 0.10. 89% (16 / 18) had a Lille score below 0.45. Among the 16 patients in the UL group who received supportive care or supportive care plus corticosteroids, the median Lille score was 0.41, of whom 50% (8 / 16) had a Lille score below 0.45.

[0100] In this trial, the median Lille score of all 18 AH patients from 5 groups (both moderate and severe AH) treated with 25HC3S who returned on day 7 was 0.10, with an interquartile range of 0.04 to 0.20. In comparison, the median Lille score of 0.41 (shown as a historical control group) in 16 patient groups at the University of Louisville (UL) receiving supportive care (standard care [SOC]) with or without corticosteroids was 0.14 to 0.73, with 1-month and 3-month mortality rates of 12.5% ​​and 31.3%, respectively. Except for the absence of treatment-emergent serious adverse events, patients receiving 25HC3S had significantly lower Lille scores (p = 0.005) than those treated with SOC.

[0101] Figure 6 depicts the Lille scores measured on day 7 using AUC plotted from individuals diagnosed with moderate acute hemorrhage (AH) who received 30 mg and 90 mg of 25HC3S sodium, and the Lille scores of individuals diagnosed with severe AH who received 30 mg, 90 mg, and 150 mg of 25HC3S sodium. As shown in Figure 6, all individuals who received 30 mg and 90 mg of 25HC3S sodium had Lille scores below 0.45 on day 7. Two individuals with severe AH who received 150 mg of 25HC3S sodium had Lille scores greater than 0.45 on day 7.

[0102] Compared to -3% in UL patients on day 7, AH patients treated with 25HC3S also showed a statistically significant decrease in serum total bilirubin from baseline on day 7, -14% (n = 18).

[0103] All patients tolerated 25HC3S well, and no drug-related serious adverse events were reported at any dose level. Drug exposure was dose-proportionate and unaffected by disease severity. Conclusion:

[0104] In this Phase 2a trial, all patients with acute hemorrhage (AH), including those with subacute acute hemorrhage (SAH), tolerated the three tested doses of 25HC3S well. No study drug or study participant was discontinued, withdrawn early, or terminated due to adverse effects, and no adverse effects related to 25HC3S were observed. All patients survived during the 28-day follow-up period (i.e., 100% survival). The pharmacokinetics of 25HC3S in both moderate and severe AH patients were similar to and dose-proportional to the administered dose. At a given dose, systemic clearance of 25HC3S was approximately 5-fold lower in AH patients compared to healthy individuals.

[0105] One or two doses of the drug significantly reduced serum bilirubin levels on day 7 and MELD scores on day 28 after treatment. Patients administered 30 mg or 90 mg of 25HC3S had a 100% response rate (Lille score < 0.45), and all patients had an 89% response rate. The Lille scores of patients treated with 25HC3S were significantly better than those reported in historical data. Example 2

[0106] A randomized, double-blind, placebo-controlled phase 2b clinical trial will be conducted to evaluate the safety and efficacy of 25HC3S in patients with alcoholic hepatitis (AH). Trial Design

[0107] Individuals were randomly assigned to the following study treatment groups in a 1:1:1 ratio:

[0108] The first dose (day 1 dose) of the IV study treatment (experimental drug) assigned will be administered to the individual immediately in a hospital setting after randomization.

[0109] If the individual remains hospitalized, the second dose of the assigned IV study treatment (investigational drug) will be given on day 4 or 3 days after the first dose. If the patient meets the discharge criteria before day 4, the individual will receive only one dose of 25HC3S.

[0110] The study treatment (investigation drug) will be administered in an IV infusion of no more than two doses in total.

[0111] If the field investigator chooses to use corticosteroids (CS) as part of standard care, 32 mg methylprednisolone capsules (or a matched steroid placebo capsule) should be used. The administration of CS capsules or placebo capsules may be determined by the field investigator according to AASLD guidelines and may be started or stopped at any time, especially if the Lille score on day 7 is >0.45. Investigational drug, dosage, and administration method.

[0112] Dilute 30 and 90 mg (of 25HC3S free acid) of 25HC3S sodium salt in 100 mL of 5% dextrose or 0.9% sodium chloride and infuse over approximately 2 hours.

[0113] The sterile, ready-to-use 25HC3S for injection will be supplied in two specifications: • 30 mg / 1 mL in a single-dose 2 mL glass vial with a 13 mm stopper and crimp seal. • 90 mg / 3 mL (30 mg / mL) in a single-dose 5 mL glass vial with a 13 mm stopper and crimp seal.

[0114] The concentration of the DUR-928 injection product used in this study is 30 mg / mL of 25HC3S free acid, corresponding to 31.4 mg / mL of 25HC3S sodium salt.

[0115] 25HC3S injection or placebo will be diluted to a 100 mL infusion bag containing 5% dextran or 0.9% sodium chloride. The 25HC3S or placebo solution will be administered to the individual via IV infusion over approximately 2 hours. Comparative agent, dosage, and administration method:

[0116] Dilute 3 mL of sterile water for injection with 100 mL of 5% dextrose or 0.9% sodium chloride and infuse over approximately 2 hours. (Population)

[0117] In this clinical trial, patients with alcoholic hepatitis were defined as those who experienced jaundice within the previous 8 weeks, consumed an average of >40 (women) or >60 (men) grams of alcohol per day for 6 months or longer, and abstained from alcohol for <8 weeks prior to the onset of jaundice. Judgment regarding daily and long-term alcohol use and the onset of jaundice will be made by on-site investigators. Serum chemistry (measured by a local laboratory): Total bilirubin >3.0 mg / dL; 50 < AST < 400 IU / L; ALT < 400 IU / L; AST / ALT > 1.5; Assuming a prothrombin time of 12 seconds for the control group; Maddrey discriminant function ≥32; Model for End-Stage Liver Disease (MELD) score: 21 to 30.

[0118] Outcome Measures: Primary outcome measure: 90-day mortality rate between the efficacy group and the placebo (SOC) group (period: day 90) Secondary outcome measures: 28-day mortality rate between treatment groups (period: day 28) Lille score on day 7 after initiation of study drug treatment between treatment groups (period: day 7) MELD score on day 28 after initiation of study drug treatment between treatment groups (period: day 28) ICU days on day 28 (period: day 1 to day 28) [Simplified Explanation of the Diagram]

[0120] [Figure 1] Comparison of standard care (left) and treatment with 5-cholestyr-3,25-diol,3-sulfate (25HC3S) (right). Patients receiving standard care received supportive care with or without corticosteroids. Patients receiving 25HC3S received one or two doses of 25HC3S sodium salt, at doses of 30 mg, 90 mg, or 150 mg. [Figure 2] Depicting the 25HC3S treatment regimen for individuals with moderate and severe alcoholic hepatitis. [Figure 3A] Depicting the mean plasma concentration of 25HC3S in individuals with moderate AH. [Figure 3B] Depicting the mean plasma concentration of 25HC3S in individuals with moderate AH. [Figure 4A] Depicting the pharmacokinetic parameters of Cmax for 25HC3S administered to individuals with moderate and severe alcoholic hepatitis. [Figure 4B] Pharmacokinetic parameters of AUC for 25HC3S administered to individuals with moderate and severe alcoholic hepatitis. [Figure 5] Comparison of pharmacokinetic parameters of 25HC3S administered to healthy individuals and individuals with alcoholic hepatitis. [Figure 6] Plotting the Lille score measured on day 7, which is plotted based on the pharmacokinetic parameters AUC for individuals administered 30 mg, 90 mg, or 150 mg of 25HC3S.

Claims

1. Use of 5-cholesten-3,25-diol,3-sulfate (25HC3S) or a salt thereof in the manufacture of a medicament for treating alcoholic hepatitis in human individuals of need, wherein the medicament comprises 5-cholesten-3,25-diol,3-sulfate (25HC3S) or a salt thereof, wherein the human individual has a Maddrey discriminant function (MDF) of at least 32, and the medicament comprises administering to the individual a total amount of 10 mg to 400 mg of 5-cholesten-3,25-diol,3-sulfate (25HC3S) or a salt thereof over a one-month period, wherein: - The total amount is sufficient to treat the alcoholic hepatitis; - The total amount is administered in separate doses comprising at least one of the first doses or more; - The one-month period is measured from the start of administration of the first dose; and - Each of the one or more separate doses comprises 10 mg to 120 mg of 25HC3S or a salt thereof.

2. As in the purpose of request item 1, wherein, The total dose is administered in one dose or in two separate doses.

3. As in the purpose of request item 1 or 2, wherein, At least one of the one or more separate doses contains 10 mg to 100 mg of 25HC3S or a salt thereof.

4. As in the purpose of request item 1 or 2, wherein, At least one of the one or more separate doses contains 20 mg to 100 mg of 25HC3S or a salt thereof.

5. As in the purpose of request item 1 or 2, wherein, The total dose is administered in two or more separate doses, which are administered at a dose frequency of once daily to once weekly.

6. As in the purpose of request item 1, wherein: - The total dose is administered in one dose or in two separate doses; - The one dose contains 20 mg to 40 mg of 25HC3S or a salt thereof; - Each of the two separate doses contains 20 mg to 40 mg of 25HC3S or a salt thereof; and - The two separate doses are administered at a frequency ranging from once every two days to once every four days.

7. As in the purpose of request item 1 or 2, wherein, The administration can be done intravenously, intramuscularly, or subcutaneously.

8. As in the purpose of request item 1 or 2, wherein, The administration was carried out via injection.

9. As in the purpose of request item 1 or 2, wherein, The 25HC3S or its salt is administered as a formulation containing the 25HC3S or its salt and a pharmaceutically acceptable carrier.

10. As used in request item 1, wherein, In this application, the total amount of 25HC3S is administered in one to five separate doses.

11. As used in request item 10, wherein, In this application, the total amount of 25HC3S is administered in a single dose.

12. As used in request item 1, wherein, Each of these separate doses contains 10 mg to 100 mg of 25HC3S or its salt.

13. As used in request item 1, wherein, Each of these separate doses contains 20 mg to 100 mg of 25HC3S or its salt.

14. As used in request item 1, wherein, In this application, the total amount of 25HC3S or its salt is not more than 200 mg.

15. As in the purpose of request item 1, wherein: In this application, - the total amount is administered in one dose or in two separate doses; - the one dose contains 80 mg to 100 mg of 25HC3S or a salt thereof; - each of the two separate doses contains 80 mg to 100 mg of 25HC3S or a salt thereof; and - the two separate doses are administered at a frequency ranging from once every two days to once every four days.

16. As used in request item 1, wherein, The human individual had a MELD (Mechanism for End-Stage Liver Disease) score of at least 11.

17. As used in request item 1, wherein, The 25HC3S or its salts contain the sodium salt of 25HC3S.

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