Treatment of alcoholic hepatitis

Abstract

Methods of treating alcoholic hepatitis (AH) are provided. For example, the method may comprise administering a 5-cholestene-3, 25-diol, a 3-sulfate ester (25HC3S), or a salt thereof.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application date of September 29, 2020, application number 202080068770.3, and invention name “Treatment of alcoholic hepatitis”. Background Art

[0002] Alcoholic hepatitis (AH) is an alcoholic liver disease caused by chronic alcohol (ethanol) intake. Signs and symptoms of AH include acute jaundice, fever, and weight loss, as well as multiple complications such as ascites and hepatic encephalopathy, leading to cirrhosis. AH is associated with a high mortality burden, up to 15% at 30 days, depending on the severity of the disease at the time of presentation. Severe AH has a 1-month mortality rate as high as 30%-50%.

[0003] Corticosteroids are often used to treat severe cases of AH. However, corticosteroid treatment has shown inconsistent results, is associated with an increased risk of infection, and is not suitable for patients with gastrointestinal bleeding or those who are allergic to steroids. Corticosteroids are typically administered in amounts such as 30 mg to 40 mg per day, depending on the specific corticosteroid used. Patient compliance is often low because patients often do not take their medication when they should.

[0004] Liver transplantation is a curative treatment option for AH, but patients must be abstinent for 6 months to qualify. 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 transplant criteria.

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

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

[0007] U.S. Pat. No. 10,272,097, which is incorporated herein by reference, discloses oxidized cholesterol sulfates, e.g., 25HC3S and salts thereof, for use in preventing and / or treating 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 has published an investigational study to evaluate the safety, pharmacokinetics, and pharmacodynamics of 25HC3S in patients with AH, with dose escalation including three doses: 30 mg, 90 mg, and 150 mg. See ClinicalTrials.gov identifier: NCT03432260.

[0009] Improved treatments for AH are urgently needed. Summary of the invention

[0010] The present disclosure provides a variety of methods for treating alcoholic hepatitis (AH). The methods involve administering an effective amount of 5-cholestene-3,25-diol, 3-sulfate (25HC3S) or a salt thereof. In some cases, the methods involve administering an effective amount of 5-cholestene-3,25-diol, 3β-sulfate or a salt thereof.

[0011] The results of the present disclosure are surprising for several reasons. For example, in certain embodiments, the low doses of the present disclosure are surprising. In addition, in certain embodiments, the low dose frequency is surprising. In addition, in certain embodiments, the number of low doses that achieve therapeutic effects in AH treatment is surprising. The results of the present disclosure are also surprising, to the extent that low dose amounts, low dose frequencies, and low dose totals can provide results similar to or better than corticosteroids, which require larger dose amounts, more frequent dosing, and / or higher dose totals. In addition, the present disclosure can also achieve effective results in AH patients characterized by specific diagnostic criteria (such as end-stage liver disease model (MELD) scores and / or other criteria discussed elsewhere herein).

[0012] Other aspects of the disclosure:

[0013] 1. A method of treating alcoholic hepatitis in a human subject in need thereof, the method comprising administering to the subject 5-cholestene-3,25-diol, 3-sulfate (25HC3S) or a salt thereof in an amount sufficient to treat the alcoholic hepatitis.

[0014] 2. The method according to aspect 1, wherein the administering comprises administering a total amount of 25HC3S or a salt thereof in the range of about 1 mg to about 1000 mg.

[0015] 3. The method according to aspect 1 or 2, wherein the administration comprises administering a total amount of 25HC3S or a salt thereof in the following range: (a) about 10 mg / month to about 500 mg / month; or (b) about 10 mg / month to about 400 mg / month.

[0016] 4. The method according to any one of aspects 1-3, comprising administering to the human subject a total amount of 25HC3S or a salt thereof of: (a) about 10 mg / month to about 400 mg / month; or (b) about 10 mg to about 400 mg over a period of 1 month; wherein:

[0017] - the total amount is sufficient to treat alcoholic hepatitis;

[0018] - said total amount is administered in one or more divided doses, said doses comprising at least a first dose; and

[0019] - The 1 month period is measured from the start of administration of the first dose.

[0020] 5. The method of any one of aspects 2-4, wherein the total amount is administered in 1-15 divided doses.

[0021] 6. The method of any one of aspects 2-4, wherein the total amount is administered in 1 to 5 divided doses.

[0022] 7. The method according to any one of aspects 2 to 4, wherein the total amount is administered in one dose or in two divided doses, preferably as a single dose.

[0023] 8. The method of any one of aspects 2-7, wherein the total amount is at least about 20 mg.

[0024] 9. The method of any one of aspects 2-8, wherein the total amount does not exceed about 300 mg.

[0025] 10. The method of any one of aspects 2-8, wherein the total amount does not exceed about 200 mg.

[0026] 11. The method of any one of aspects 2-8, wherein the total amount does not exceed about 140 mg.

[0027] 12. The method of any one of aspects 4 to 11, wherein at least one and preferably each of the one or more divided doses comprises from about 10 mg to about 200 mg of 25HC3S or a salt thereof.

[0028] 13. The method of any one of aspects 4 to 12, wherein at least one and preferably each of the one or more divided doses comprises from about 10 mg to about 120 mg of 25HC3S or a salt thereof.

[0029] 14. The method of any one of aspects 4 to 13, wherein at least one and preferably each of the one or more divided doses comprises from about 20 mg to about 100 mg of 25HC3S or a salt thereof.

[0030] 15. The method of any one of aspects 2-14, wherein the total amount is administered in two or more divided doses at a dose frequency ranging from daily to once per week.

[0031] 16. The method of aspect 15, wherein the dosage frequency ranges from once every 2 days to once per week.

[0032] 17. The method of aspect 15, wherein the dosage frequency ranges from once every 2 days to once every 5 days.

[0033] 18. The method of aspect 15, wherein the dosage frequency ranges from once every 2 days to once every 4 days.

[0034] 19. The method of aspect 4, wherein:

[0035] - administering the total amount in one dose or in two divided doses;

[0036] - one dose comprises about 10 mg to about 200 mg of 25HC3S or a salt thereof;

[0037] - each of the two separate doses contains from about 10 mg to about 200 mg of 25HC3S or a salt thereof; and

[0038] - The two divided doses are administered at a dosage frequency ranging from once every 2 days to once every 4 days.

[0039] 20. The method of aspect 19, wherein the total amount is administered in one dose and wherein the one 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.

[0040] 21. The method of aspect 19, wherein the total amount is administered in two divided doses and wherein each of the two divided 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.

[0041] 22. The method of any one of aspects 4 to 21, wherein the total amount per kilogram of 25HC3S or a salt thereof administered during the period ranges from about 0.05 mg / kg to about 20 mg / kg.

[0042] 23. The method of aspect 22, wherein the total amount per kilogram ranges from about 0.1 mg / kg to about 10 mg / kg.

[0043] 24. The method of aspect 22, wherein the total amount per kilogram ranges from about 0.2 mg / kg to about 6 mg / kg.

[0044] 25. The method of aspect 22, wherein the total amount per kilogram ranges from about 0.3 mg / kg to about 1.5 mg / kg.

[0045] 26. The method of any one of aspects 1-25, wherein the administration is performed parenterally, intravenously, intramuscularly or subcutaneously.

[0046] 27. The method of any one of aspects 1-26, wherein the administering is by injection.

[0047] 28. The method of any one of aspects 1 to 27, wherein the 25HC3S or a salt thereof is administered in a formulation comprising 25HC3S or a salt thereof and a pharmaceutically acceptable carrier.

[0048] 29. The method of any one of aspects 1-28, wherein the 25HC3S or its salt comprises a salt of 25HC3S, wherein the salt of 25HC3S is preferably a sodium salt.

[0049] 30. The method of any one of aspects 4-29, wherein the one or more divided doses are administered over an administration period of no more than 14 days.

[0050] 31. The method of any one of aspects 1-30, wherein the human subject has a Model for End-Stage Liver Disease (MELD) score of at least 11.

[0051] 32. The method of any one of aspects 1-31, wherein the human subject has a MELD score in the range of 11-45.

[0052] 33. The method of any one of aspects 1-32, wherein the human subject has a MELD score in the range of 15-40.

[0053] 34. The method of any one of aspects 1-33, wherein the human subject has a MELD score of at least 20.

[0054] 35. The method of any one of aspects 1-34, wherein the human subject has a MELD score of at least 30.

[0055] 36. The method of any one of aspects 1-35, wherein the human subject has a Maddrey's discriminant function (MDF) of at least 32.

[0056] 37. The method of any one of aspects 1-36, wherein the alcoholic hepatitis is characterized by decreased liver function occurring within 13 weeks of onset.

[0057] 38. The method of any one of aspects 1-36, wherein the alcoholic hepatitis is characterized by decreased liver function occurring within 10 weeks of onset.

[0058] 39. The method of any one of aspects 1 to 38, wherein the alcoholic hepatitis is characterized by reduced liver function such that the subject exhibits a reduced clearance rate of 25HC3S compared to a subject not suffering from alcoholic hepatitis.

[0059] 40. The method of aspect 39, wherein the alcoholic hepatitis is characterized by reduced liver function such that the subject exhibits a 25HC3S clearance rate that is 50% or less, 40% or less, 30% or less, or 25% or less of the clearance rate of 25HC3S from plasma in a subject without alcoholic hepatitis.

[0060] 41. The method of any one of aspects 1 to 40, wherein the alcoholic hepatitis is characterized by decreased liver function such that the subject exhibits a half-life (T ) of 25HC3S in plasma after administration of 1:1, compared to a subject not suffering from alcoholic hepatitis. 1 / 2 ) is 1.5 times or more or 2 times or more.

[0061] 42. The method of any one of aspects 1 to 41, wherein the subject exhibits a half-life (T 1 / 2 ) is in the range of about 1.5 hours to about 6 hours or about 2 hours to about 5 hours.

[0062] 43. The method of any one of aspects 1-42, wherein the subject 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 7000 ng / mL, or about 700 ng / mL to about 5000 ng / mL.

[0063] 44. The method of any one of aspects 1-43, wherein for each 100 mg of 25HC3S or a salt thereof administered intravenously, the subject 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 7000 ng / mL, or about 700 ng / mL to about 5000 ng / mL.

[0064] 45. The method of any one of aspects 1-44, wherein the subject exhibits an AUCinf of 25HC3S in the range of 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.

[0065] 46. ​​The method of any one of aspects 1-45, wherein for each 100 mg of 25HC3S or a salt thereof administered intravenously, the subject exhibits an AUCinf of 25HC3S in the range of 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.

[0066] 47. The method of any one of aspects 1-46, wherein the subject exhibits a volume of distribution of 25HC3S in the range of about 10 L to about 50 L, about 15 L to about 45 L, or about 20 L to about 40 L.

[0067] 48. The method of any one of aspects 1-47, wherein the subject exhibits a clearance of 25HC3S 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.

[0068] 49. The method of any one of aspects 1-48, wherein the alcoholic hepatitis is characterized by loss of liver function occurring within 13 weeks of onset.

[0069] 50. The method of any one of aspects 1-48, wherein the alcoholic hepatitis is characterized by loss of liver function occurring within 10 weeks of onset.

[0070] 51. 5-cholestene-3,25-diol, 3-sulfate (25HC3S) or a salt thereof for use in a method of treating alcoholic hepatitis in a human subject in need thereof, wherein the method is as defined in any one of aspects 1-50.

[0071] 52. Use of 5-cholestene-3,25-diol, 3-sulfate (25HC3S) or a salt thereof in a method for preparing a medicament for use in a method of treating alcoholic hepatitis in a human subject in need thereof, wherein the method is as defined in any one of aspects 1-50. BRIEF DESCRIPTION OF THE DRAWINGS

[0072] Figure 1Standard of care treatment (left) and 5-cholestene-3,25-diol, 3-sulfate (25HC3S) treatment (right) were compared. Standard of care patients received supportive care with or without corticosteroids. 25HC3S patients received one or two doses of 25HC3S sodium salt, each dose of 30 mg, 90 mg, or 150 mg.

[0073] Figure 2 Flowchart depicting the 25HC3S treatment regimen for subjects with moderate and severe alcoholic hepatitis.

[0074] Figure 3 A depicts mean plasma concentrations of 25HC3S in subjects with moderate AH. Figure 3 B depicts mean plasma concentrations of 25HC3S in subjects with moderate AH.

[0075] Figure 4 A depicts the pharmacokinetic parameters of Cmax of 25HC3S administered to subjects with moderate and severe alcoholic hepatitis. Figure 4 B depicts the pharmacokinetic parameters of AUC of 25HC3S administered to subjects with moderate and severe alcoholic hepatitis.

[0076] Figure 5 Depicted is a comparison of the pharmacokinetic parameters of 25HC3S administered to healthy subjects versus subjects with alcoholic hepatitis.

[0077] Figure 6 Depicted are the Lille scores determined on day 7 plotted against the pharmacokinetic parameter AUC for subjects administered 30 mg, 90 mg, or 150 mg of 25HC3S. DETAILED DESCRIPTION

[0078] Methods for treating alcoholic hepatitis (AH) are described herein. The methods include contacting the liver with 25HC3S or a salt thereof. The contacting generally involves administering to a human patient an amount of 25HC3S or a salt thereof that is effective or sufficient to treat AH.

[0079] As discussed above, the results of the present disclosure are surprising for several reasons. For example, in certain embodiments, the low doses of the present disclosure are surprising. In addition, in certain embodiments, the low dose frequency is surprising. In addition, in certain embodiments, the number of low doses that achieve therapeutic effects in AH treatment is surprising. The results of the present disclosure are also surprising, to the extent that low dose amounts, low dose frequencies, and low dose totals can provide results similar to or better than corticosteroids, which require larger dose amounts, more frequent dosing, and higher dose totals. In addition, the present disclosure can also achieve effective results in AH patients characterized by specific diagnostic criteria (such as MELD scores and / or other criteria discussed elsewhere herein).

[0080] definition

[0081] The following definitions are used throughout:

[0082] As used herein, "treat", "treatment", "treating", etc., means administering 25HC3S or a salt thereof to a human subject who: (1) has exhibited at least one symptom of AH; and / or (2) has been diagnosed as having AH, for example, by a trained clinical professional; and / or (3) has been determined to have AH based on laboratory tests (e.g., molecular markers) of one or more body fluids (such as blood) or clinical tests. In certain embodiments, the subject is diagnosed as having AH by liver tissue biopsy. In other words, at least one parameter known to be associated with AH has been measured, detected, or observed in the subject. "Treatment" of AH includes alleviation or reduction, or in some cases, complete eradication of at least one symptom of AH that was present prior to or at the time of administration of 25HC3S or a salt thereof. In certain embodiments, treating AH according to the present disclosure is sufficient to improve laboratory or clinical indicators of AH in the subject, as described in more detail below. In some cases, the improvement of laboratory or clinical indicators of AH in the subject is such that the subject is no longer considered to have AH. In one example, a subject method is sufficient to reduce a Maddrey Discriminant Function (MDF) score of a subject having a score of ≥32 to an MDF score of <32.

[0083] "Liver dysfunction" refers to a condition or health state in which the liver does not perform its expected function, for example, in which certain biological or molecular parameters are measured outside the normal physiological range. Liver function represents the expected function of the liver within the physiological range. Those skilled in the art are aware of the corresponding functions of the liver during medical examinations. Liver dysfunction generally refers to a clinical syndrome in which a progressive and potentially reversible physiological dysfunction occurs in the liver, optionally in the absence of anatomical damage.

[0084] "Liver failure" means liver dysfunction to such an extent that normal homeostasis cannot be maintained without external clinical intervention.

[0085] "Acute liver dysfunction" means a decrease in liver function that occurs rapidly - 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) - usually in a person without pre-existing disease.

[0086] "Acute liver failure" means a loss of liver function that occurs rapidly - 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) - typically in a person without pre-existing disease. Acute liver failure is discussed in more detail below.

[0087] "Pharmaceutically acceptable" means a material that does not interfere with the effectiveness of the biological activity of the active ingredient and is non-toxic to the host to which it is administered.

[0088] Patient population

[0089] Overview of Alcoholic Hepatitis

[0090] Alcoholic hepatitis (AH) can range from mild hepatitis (abnormal laboratory tests are the only indication of the disease) to severe liver dysfunction, with complications such as jaundice (yellowing of the skin caused by bilirubin retention), hepatic encephalopathy (neurological dysfunction caused by liver failure), ascites (fluid accumulation in the abdomen), bleeding esophageal varices (varicose veins in the esophagus), abnormal coagulation and coma. In some cases, patients develop jaundice within the first 8 weeks, such as within the first 7 weeks, such as within the first 6 weeks, such as within the first 5 weeks, such as within the first 4 weeks, such as within the first 3 weeks, such as within the first 2 weeks, and including cases where the patient has an attack of jaundice within the previous week. AH is usually reversible if the patient stops drinking, but hepatitis usually takes several months to subside. AH can lead to liver scarring and cirrhosis. Typical findings of liver histology include hepatocyte necrosis and ballooning degeneration, and alcoholic Mallory's hyaline bodies (abnormal aggregation of cellular intermediate filament proteins, indicating fibrosis). Cholestasis is usually obvious. The severity of the disease can be classified according to the Maddrey's 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 creatinine, bilirubin and prothrombin time international normalized ratio (INR)) (Lucey et al., N. Engl. J. Med., 360 (26), 2758-2769 (2009); Vergis et al., Gastroenterology, 152 (5): 1068-1077 (2017)). When MDF>32, AH is classified as severe.

[0091] Alcohol intake

[0092] In some cases, the patient has a history of heavy alcohol abuse of >40 g / day (in females) or >60 g / day (in males) over a period of at least 6 months, e.g., abstinence <60 days (e.g., <8 weeks) prior to the onset of jaundice. Excessive alcohol intake over many years can lead to alcoholic liver disease and AH. In some cases, excessive alcohol intake involves alcohol intake of >80 g / day (for males) or >60 g / day (for females). Thus, one embodiment is the use of 25HC3S or a salt thereof to treat AH in male or female subjects who have consumed excessive alcohol, wherein male subjects consume >80 g of alcohol per day or female subjects consume >60 g of alcohol per day. In other embodiments, the disclosure relates to the use of 25HC3S or a salt thereof to treat or alleviate AH in male or female subjects with a history of excessive drinking, such as subjects who have experienced one or more such situations: wherein the subject consumes an average of 40 g or more per day over a period of 6 months or more. In certain embodiments, the subject has experienced one or more instances in which the subject consumed an average of 60 g or more per day for 6 months or longer.

[0093] Bilirubin

[0094] AH is characterized by elevated bilirubin, which reflects impaired liver metabolic function in the absence of biliary obstruction. In some cases, the patient has a serum bilirubin of>3mg / dL. Therefore, one embodiment is to use 25HC3S or its salt to treat or alleviate the AH symptoms in subjects with a serum bilirubin level of>50μmol / L (such as>60μmol / L or>80μmol / L) before applying 25HC3S or its salt. In some cases, the patient to be treated has a bilirubin level in the range of about 2mg / dL to 50mg / dL (such as about 3mg / dL to about 40mg / dL or about 4mg / dL to about 30mg / dL). In some cases, the patient to be treated is determined to have a bilirubin level of>8mg / dL.

[0095] In certain embodiments, method comprises determining the serum bilirubin of the patient to be treated.Any convenient scheme can be used, such as determining the serum bilirubin of the patient with colorimetric analysis or fluorescence analysis.In these embodiments, can be before treating the patient according to the subject method 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, determine the serum bilirubin of the patient.In certain embodiments, the day before treating the patient according to the method described herein, determine the serum bilirubin of the patient.

[0096] In some cases, the method includes determining the patient's serum bilirubin after one or more treatment cycles (such as 2 or more cycles, such as 3 or more cycles, such as 4 or more cycles, and including 5 or more cycles) according to the subject method. In these embodiments, serum bilirubin can be determined immediately after the last administration dose of 25HC3S or its salt or at a predetermined time thereafter, such as 5 minutes or more after the last administration dose of 25HC3S or its salt, 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 certain embodiments, the patient's serum bilirubin is determined at a certain time on the same day as the last administration dose of 25HC3S or its salt. In some cases, the patient's bilirubin rises suddenly, for example, by ≥3 mg / dL within 8 weeks. In some cases, the methods of the present invention are sufficient to reduce the serum bilirubin of the subject, such as by reducing the serum bilirubin in the subject by 1 mg / dL or more, such as 2 mg / dL or more, and including 3 mg / dL or more. In some cases, in the case where the subject exhibits a sudden increase in bilirubin, the methods of the present invention are sufficient to reduce the increase in bilirubin by the amount of increase, such as 1 mg / dL or more, such as 2 mg / dL or more, and including 3 mg / dL or more. In certain embodiments, compared to the serum bilirubin determined before treatment with 25HC3S or its salt as described herein, the subject method is sufficient to reduce the serum bilirubin in the patient (e.g., 7 days or 28 days after the start of treatment) by 10% or more, such as 15% or more, such as 20% or more, such as 25% or more, such as 30% or more, such as 35% or more, such as 40% or more, such as 45% or more, and including 50% or more.

[0097] MELD

[0098] The Model for End-Stage Liver Disease (MELD) is a scoring system used to assess the severity of liver disease. An increasing MELD score reflects a greater risk of death, while a decreasing MELD score reflects a decreased risk. MELD uses a patient's values ​​for serum bilirubin, serum creatinine, and the international normalized ratio (INR) of prothrombin time to predict survival and is calculated according to the following formula:

[0099] MELD=3.78xln[serum bilirubin (mg / dL)]+11.2xln[INR]+9.57xln[serum creatinine (mg / dL)]+6.43

[0100] In some cases, the patient has a MELD score in the range of about 11 to about 40, such as a MELD score in the range of about 11 to about 35, about 11 to about 33, or about 21 to about 30. In some cases, the patient has a MELD score of ≥11, such as ≥15 or ≥21. In some cases, the patient has a MELD score of <35, such as <30, <25, <20, or <15. Thus, one embodiment is to use 25HC3S or a salt thereof to treat or alleviate AH symptoms in a subject, wherein the subject is characterized by a MELD score in the range of about 11 to about 30 or about 21 to about 30 prior to administration of 25HC3S or a salt thereof.

[0101] In certain embodiments, the method includes determining the MELD score of the patient to be treated. In these embodiments, the MELD score of the patient can be determined 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, before treating the patient according to the subject method. In certain embodiments, the MELD score of the patient is determined one day before treating the patient according to the methods described herein.

[0102] In some cases, the method includes determining the patient's MELD score after one or more treatment cycles (such as 2 or more cycles, such as 3 or more cycles, such as 4 or more cycles, and including 5 or more cycles) according to the subject method. In these embodiments, the MELD score can be determined immediately after the last administered dose of 25HC3S or its salt or at a predetermined time thereafter, such as 5 minutes or more after the last administered dose of 25HC3S or its salt, 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 certain embodiments, the patient's MELD score is determined at a time on the same day as the last administered dose of 25HC3S or its salt.

[0103] In certain embodiments, the subject methods are sufficient to reduce the MELD score exhibited by the patient (e.g., 7 days or 28 days after initiation of treatment) by 5% or more, such as 10% or more, such as 15% or more, and including 20% ​​or more, compared to the MELD score determined prior to treatment with 25HC3S or a salt thereof as described herein.

[0104] MDF

[0105] The Maddrey discriminant function (MDF) is a model for evaluating the severity and prognosis of AH. The MDF score is a statistical model that can be used to predict the short-term prognosis of a subject, especially mortality within 30 or 90 days. A score of 32 or greater (severe alcoholic hepatitis (SAH)) means a poor outcome, with a 30-day mortality rate in the range of 35% to 45%. In contrast, an MDF of <32 identifies those with mild / moderate AH, with a low, but non-zero risk of mortality with supportive care.

[0106] Calculate the MDF using the following formula:

[0107] MDF = 4.6 x (prothrombin time (PT 患者 -PT 对照 )+serum bilirubin (μmol / L) / 17.1

[0108] Thus, one embodiment is the use of 25HC3S or a salt thereof to treat or alleviate AH symptoms in a subject, wherein the subject is characterized by an MDF score of ≥ 32 prior to administration of 25HC3S or a salt thereof. Thus, in some cases, the patient has an MDF score of ≥ 32. In other cases, the patient has an MDF score of < 32.

[0109] In certain embodiments, the method includes determining the MDF score of the patient to be treated. In these embodiments, the MDF score of the patient can be determined 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, before treating the patient according to the subject method. In certain embodiments, the MDF score of the patient is determined one day before treating the patient according to the method described herein.

[0110] In some cases, the method includes determining the patient's MDF score after one or more treatment cycles (such as 2 or more cycles, such as 3 or more cycles, such as 4 or more cycles, and including 5 or more cycles) according to the subject method. In these embodiments, the MDF score can be determined immediately after the last administration dose of 25HC3S or its salt or at a predetermined time thereafter, such as 5 minutes or more after the last administration dose of 25HC3S or its salt, 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 certain embodiments, the patient's MDF score is determined at a certain time on the same day as the last administration dose of 25HC3S or its salt.

[0111] In certain embodiments, the subject methods are sufficient to reduce the MDF score exhibited by a patient (e.g., 7 days or 28 days after initiation of treatment) by 5% or more, such as 10% or more, such as 15% or more, and including 20% ​​or more, compared to the MDF score determined prior to treatment with 25HC3S or a salt thereof as described herein.

[0112] In one embodiment, the use of 25HC3S or a salt thereof to treat or reduce AH symptoms in a subject is provided, wherein the subject is characterized by an MDF score of ≥32 and a MELD score of <25 prior to administration of 25HC3S or a salt thereof. In some cases, the methods of the invention are sufficient to reduce the subject's MDF score by 1 or more, such as 2 or more, and including 5 or more. In some cases, the methods of the invention are sufficient to reduce the MDF score of a subject having a score of ≥32 to an MDF score of <32.

[0113] ABIC

[0114] Although MDF is predictive at 1 month, it is less accurate in the medium and long term. MELD score and the age, serum bilirubin, INR and serum creatinine (ABIC) score of recent verification provide more detailed survival prediction by emphasizing that renal function is impaired, and can be calculated at different time points.> 9 ABIC score indicates high mortality risk, 6.71-9 indicates medium mortality risk, and <6.71 indicates low mortality risk. Therefore, in some cases, the patient has> 9 or 6.71-9 ABIC score.

[0115] In certain embodiments, the method includes determining the ABIC score of the patient to be treated. In these embodiments, the ABIC score of the patient can be determined 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, before treating the patient according to the subject method. In certain embodiments, the ABIC score of the patient is determined one day before treating the patient according to the methods described herein.

[0116] In some cases, the method includes determining the patient's ABIC score after one or more treatment cycles (such as 2 or more cycles, such as 3 or more cycles, such as 4 or more cycles, and including 5 or more cycles) according to the subject method. In these embodiments, the ABIC score can be determined immediately after the last administered dose of 25HC3S or its salt or at a predetermined time thereafter, such as 5 minutes or more after the last administered dose of 25HC3S or its salt, 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 certain embodiments, the patient's ABIC score is determined at a time on the same day as the last administered dose of 25HC3S or its salt.

[0117] In certain embodiments, the subject methods are sufficient to reduce the ABIC score exhibited by a patient (e.g., 7 or 28 days after initiation of treatment) by 5% or more, such as 10% or more, such as 15% or more, and including 20% ​​or more, compared to the ABIC score determined prior to treatment with 25HC3S or a salt thereof as described herein.

[0118] Glasgow AH score

[0119] The Glasgow Alcoholic Hepatitis Score (GAHS) can be used to identify patients at risk of death (Forrest et al., Gut, 56: 1743-1746 (2007)). Scores of 9 or higher identify patients at greatest risk of death.

[0120] In certain embodiments, the method includes determining the GAHS of the patient to be treated. In these embodiments, the GAHS of the patient can be determined 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, before the patient is treated according to the subject method. In certain embodiments, the GAHS of the patient is determined one day before the patient is treated according to the methods described herein.

[0121] In some cases, the method includes determining the patient's GAHS after one or more treatment cycles (such as 2 or more cycles, such as 3 or more cycles, such as 4 or more cycles, and including 5 or more cycles) according to the subject method. In these embodiments, GAHS can be determined immediately after the last administered dose of 25HC3S or its salt or at a predetermined time thereafter, such as 5 minutes or more, 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 after the last administered dose of 25HC3S or its salt. In certain embodiments, the patient's GAHS is determined at a time on the same day as the last administered dose of 25HC3S or its salt.

[0122] In certain embodiments, the subject methods are sufficient to reduce GAHS exhibited by a patient (e.g., 7 or 28 days after initiation of treatment) by 5% or more, such as 10% or more, such as 15% or more, and including 20% ​​or more, compared to GAHS determined prior to treatment with 25HC3S or a salt thereof as described herein.

[0123] Thus, one aspect of the present disclosure is to improve the GAHS score. One embodiment is the use of 25HC3S or a salt thereof to treat or alleviate AH symptoms in a subject, wherein the subject is characterized by a reduced GAHS score for 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 embodiment is the use of 25HC3S or a salt thereof to treat or alleviate AH symptoms in a subject, wherein the subject is characterized by a reduced GAHS score for 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.

[0124] Lille

[0125] The Lille score predicts the mortality of AH patients. The Lille score is calculated according to the following formula:

[0126] Exp(-R) / [1+exp(-R)]

[0127] in

[0128] R = [3.19-(0.101*age)]+(1.47*albumin at baseline (g / dL))+[0.28215*(bilirubin at baseline-bilirubin at day 8 (mg / dL))]-[0.206*(if creatinine at baseline>=1.3mg / dL)]-[0.11115*bilirubin baseline (mg / dL)]-(0.0096*prothrombin time at baseline (seconds))

[0129] Thus, one aspect of the present disclosure is to improve the Lille score. One embodiment is the use of 25HC3S or a salt thereof to treat or alleviate symptoms of AH in a subject, and wherein the subject is characterized by a reduced Lille score 7 days after the first administration of 25HC3S or a salt thereof. In another embodiment, there is provided the use of 25HC3S or a salt thereof to treat or alleviate symptoms of AH in a subject, comprising administering 25HC3S or a salt thereof, and wherein the subject is characterized by a reduced Lille score 7 days after the first administration of 25HC3S or a salt thereof. In some cases, 7 days after the first administration of 25HC3S or a salt thereof, the patient has a Lille score of <0.45.

[0130] MELD+Lille

[0131] Louvet et al. combined static and dynamic models to enhance AH prediction and confirmed that the combined effect model of MELD+Lille was superior to other combinations, so that patients with MELD 21 and Lille 0.45 had a 1.9-fold higher risk of death at 2 months than those with MELD 21 and Lille 0.16 (23.7% vs. 12.5%). Therefore, in some cases, subjects were diagnosed with AH by using the combined effect model of MELD+Lille.

[0132] In some cases, subjects have been diagnosed as having AH by using the Alcoholic Hepatitis Histology Score (AHHS). The AAHS is based on four histological parameters: the extent of fibrosis, the extent of neutrophil infiltration, the type of bilirubinostasis, and the presence of giant mitochondria.

[0133] In some cases, the patient has aspartate aminotransferase (AST)> alanine aminotransferase (ALT), but less than 300 IU / L. In some cases, the patient has AST>50, AST / ALT>1.5, and both values ​​are <400 IU / L.

[0134] In certain embodiments, the subject has an aspartate aminotransferase (AST) of 50-400IU / L. In certain embodiments, the subject has an alanine aminotransferase (ALT) of less than 400IU / L, such as 390IU / L or lower, such as 380IU / L or lower, such as 370IU / L or lower, such as 360IU / L, and includes 350IU / L. In certain embodiments, the AST that the subject has is greater than ALT, such as wherein the ratio of AST to ALT (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 includes 1.5 or greater (e.g., preferably wherein greater than 1.5 AST / ALT). For example, in certain embodiments, the subject may have a combination of two or more of these features, such as AST of 50-400 IU / L, ALT of less than 400 IU / L, and AST / ALT greater than 1.5. In addition, the patient may also have one or more additional clinical features, such as onset of jaundice within the previous 8 weeks, serum total bilirubin>3.0 mg / dL, Maddrey's discriminant function ≥32 (assuming a control prothrombin time of 12 seconds) and / or a MELD score of 21-30.

[0135] In certain instances, the patient has an albumin level within 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.

[0136] In some cases, the patient has within the range of about 10 seconds to about 30 seconds, such as about 11 seconds to about 25 seconds or about 15 seconds to about 25 seconds of the prothrombin time international normalized ratio (INR).In certain embodiments, method includes determining the prothrombin time international normalized ratio (INR) of the patient to be treated.In these embodiments, can be before according to the subject method treatment patient 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, determine the prothrombin time international normalized ratio of the patient.In certain embodiments, according to the method treatment patient described herein before determining the prothrombin time international normalized ratio of the patient.

[0137] In some cases, the method includes determining the patient's prothrombin time international normalized ratio after one or more treatment cycles (such as 2 or more cycles, such as 3 or more cycles, such as 4 or more cycles, and including 5 or more cycles) according to the subject method. In these embodiments, the prothrombin time international normalized ratio can be determined immediately after the last administration dose of 25HC3S or its salt, or at a predetermined time thereafter, such as 5 minutes or more after the last administration dose of 25HC3S or its salt, 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 to determine the prothrombin time international normalized ratio. In certain embodiments, the patient's prothrombin time international normalized ratio is determined at a time on the same day as the last administration dose of 25HC3S or its salt.

[0138] In certain embodiments, the subject methods are sufficient to reduce the international normalized ratio of prothrombin time exhibited by a patient (e.g., 7 days or 28 days after initiation of treatment) by 5% or more, such as 10% or more, such as 15% or more, and including 20% ​​or more, compared to the international normalized ratio of prothrombin time determined prior to treatment with 25HC3S or a salt thereof as described herein.

[0139] 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 certain embodiments, the method includes determining the serum creatinine level of the patient to be treated. In these embodiments, the serum creatinine level of the patient can be determined 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, before treating the patient according to the subject method. In certain embodiments, the serum creatinine level of the patient is determined one day before treating the patient according to the methods described herein.

[0140] In some cases, the method includes determining the patient's serum creatinine level after one or more treatment cycles (such as 2 or more cycles, such as 3 or more cycles, such as 4 or more cycles, and including 5 or more cycles) according to the subject method. In these embodiments, the serum creatinine level can be determined immediately after the last administered dose of 25HC3S or its salt, or at a predetermined time thereafter, such as 5 minutes or more after the last administered dose of 25HC3S or its salt, 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 certain embodiments, the patient's serum creatinine level is determined at a time on the same day as the last administered dose of 25HC3S or its salt.

[0141] In certain embodiments, the subject methods are sufficient to reduce a patient's serum creatinine level (e.g., 7 or 28 days after initiation of treatment) by 2% or more, such as 5% or more, such as 10% or more, and including 15% or more, compared to the serum creatinine level determined prior to treatment with 25HC3S or a salt thereof as described herein.

[0142] In certain instances, the patient has acute AH manifesting as acute on chronic liver failure (ACLF).

[0143] In certain instances, subjects have been diagnosed with AH based on circulating fragments of cytokeratin-18 (CK-18) and the major components of Mallory-Denk bodies, known as M65 and M30.

[0144] In view of the above, the diagnosis of AH (i.e., identification of subjects who experience AH and may benefit from the implementation of the methods of the present invention) is generally based on physical examination, laboratory findings, patient history, and past medical history to determine, for example, changes in mental status, coagulopathy, rapidity of onset, and the absence of known past liver disease. In some cases, AH patients may have other past liver disease, such as cholestatic liver disease, autoimmune liver disease, active viral hepatitis, Wilson's disease, or other liver disease not caused by alcohol intake.

[0145] The definition of "rapid" depends on the specific convention used. There are different subdivisions, which are based on the time from the first onset of liver symptoms to the onset of encephalopathy. In some cases, "AH" involves the occurrence of encephalopathy, jaundice, or bilirubin increased to> 3mg / dL within 26 weeks of any liver symptom onset. This is further subdivided into: "fulminant hepatic failure", which requires encephalopathy, jaundice, or bilirubin increased to> 3mg / dL within 8 weeks; and "subfulminant" liver failure, which describes the occurrence of encephalopathy, jaundice, or bilirubin increased to> 3mg / dL 8 weeks after the onset of liver symptoms but before 26 weeks. In other cases, the characteristics of "hyperacute" liver failure can be onset within 7 days after the onset of liver symptoms, "acute" liver failure is between 7 and 28 days after the onset of liver symptoms, and "subacute" liver failure is between 28 days and 24 weeks after the onset of liver symptoms. Subjects determined to experience acute liver failure by any of these criteria can be treated with the methods described herein.

[0146] In certain aspects, the subject population treated by the methods described herein may or may not have symptoms of high cholesterol levels and / or have been diagnosed as having high cholesterol levels (hypercholesterolemia, e.g., cholesterol levels in serum in the range of about 200 mg / dl or more), or have been diagnosed as having a condition associated with high cholesterol levels, e.g., hyperlipidemia, atherosclerosis, heart disease, stroke, Alzheimer's disease, gallstone disease, cholestatic liver disease, etc. In certain aspects, the subject population treated by the methods described herein do not have symptoms of high cholesterol levels and / or have not been diagnosed as having high cholesterol levels (hypercholesterolemia, e.g., cholesterol levels in serum in the range of about 200 mg / dl or more), or have not been diagnosed as having a condition associated with high cholesterol levels, e.g., hyperlipidemia, atherosclerosis, heart disease, stroke, Alzheimer's disease, gallstone disease, cholestatic liver disease, etc.

[0147] Description of administration

[0148] The implementation of the method generally comprises: identifying a patient suffering from AH, and administering 25HC3S or a salt thereof in an acceptable form by an appropriate route. The exact total amount to be administered (e.g., over a period of 1 month) may vary with the age, sex, weight and general health of the individual patient and the precise etiology of the disease.

[0149] In certain embodiments, the total amount of 25HC3S or its salt administered to the patient is surprisingly low. The total amount administered (e.g., over a period of 1 month) is typically in the range of about 0.01 mg / kg to about 50 mg / kg per kilogram of body weight, more typically 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 salt.

[0150] The total amount generally ranges from about 1 mg to about 1000 mg of 25HC3S or a salt thereof. In certain embodiments, the total amount of 25HC3S or a salt thereof administered to the patient in the method (e.g., over a period of 1 month) is about 10 mg to about 500 mg. Typically, in certain embodiments, the total amount of 25HC3S or a salt thereof administered to the patient in the method (e.g., over a period of 1 month) is about 10 mg to about 400 mg. For example, in certain embodiments, the total amount is at least about 20 mg. In certain embodiments, the total amount is no more than about 300 mg, such as no more than about 200 mg, or even no 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. The total amount will vary with the route of administration, bioavailability, and the specific formulation administered. For example, for intravenous administration, the total amount described herein may be particularly useful.

[0151] In certain embodiments, the low dose number is surprising (including but not limited to when 25HC3S or a salt thereof is administered by intravenous administration). In this regard, the total amount of 25HC3S or a salt thereof administered in the method can be administered in one dose or in multiple divided doses over a period of time (such as a period of one month). In certain embodiments, the total amount is administered in 1-15 divided doses, for example, in 1-5 divided doses, such as in one dose or in two divided doses. In certain embodiments, the total amount is administered in a single dose. In other embodiments, the total amount is administered in two divided doses. In all methods described herein, the total amount administered comprises 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 it is a first dose followed by at least one other dose).

[0152] In certain embodiments, at least one and preferably each of the one or more separate doses contains about 10 mg to about 200 mg of 25HC3S or a salt thereof. For example, in certain embodiments, at least one and preferably each of the one or more separate doses 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 dosage amounts include the following doses: (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 certain embodiments, a particularly useful dosage amount may be (a) or (b) above. In certain embodiments, a particularly useful number of separate doses for such a dosage amount may be one dose (i.e., a single dose) or two separate doses.

[0153] In certain embodiments, low dosing frequency is surprising. For example, in certain embodiments, the total amount is applied with two or more separate dosages, and the dosage is applied with a dosage frequency within the range of once a day to once a week, such as once every 2 days to once a week, for example once every 2 days to once every 5 days, or once every 2 days to once every 4 days. An example of such dosage frequency is to apply once approximately every 3 days. For example, when the total number of the separated dosages is 2, the second dosage can be applied 1 day to 1 week, 2 days to 1 week, 2 days to 5 days, 2 days to 4 days or about 3 days after the first dosage.

[0154] In certain embodiments, one or more separate doses are administered within an administration period (referring to the period during which the actual administration of 25HC3S or its salt is performed). For example, when the method includes administering the total amount over a period of 1 month measured from the administration of the first dose, the administration period may be less than a period of 1 month. Thus, in certain embodiments, the administration period is followed by a "non-administration period" during which 25HC3S or its salt is not administered, such that the administration period and the non-administration period total a period of 1 month. In certain such embodiments, administration is no more than 21 days, such as no more than 14 days, for example, no more than 7 days or no more than 5 days.

[0155] In view of the above, the total amount of 25HC3S or its salt administered over a period of 1 month may be in the range of about 0.01 mg / kg / month to about 50 mg / kg / month, more typically about 0.05 mg / kg / month to about 20 mg / kg / month, such as about 0.1 mg / kg / month to about 10 mg / kg / month, for example about 0.2 mg / kg / month to about 6 mg / kg / month, or about 0.3 mg / kg / month to about 1.5 mg / kg / month. The total amount of 25HC3S or its salt administered over a period of 1 month may be in the range of about 1 mg / month to about 1000 mg / month, about 5 mg / month to about 600 mg / month, about 10 mg / month to about 400 mg / month, about 20 mg / month to about 300 mg / month, about 20 mg / month to about 200 mg / month, or about 20 mg / month to about 140 mg / month.

[0156] Administration of the compounds of the disclosure may be intermittent, or at a gradual or continuous, constant or controlled rate.

[0157] Administration can be by any route, such as parenteral administration, including intravenous, intramuscular and / or subcutaneous injection. The route of administration will depend on the nature of the condition being treated, for example, the type or degree of liver damage and / or liver failure. For example, in order to achieve rapid treatment before obvious liver dysfunction or failure occurs, administration by intravenous injection may be preferred. Therefore, when damage has occurred, especially when acute organ failure is diagnosed, the route of administration is usually parenteral or intravenous to accelerate the delivery of 25HC3S or its salt.

[0158] 25HC3S can be administered in pure form or in a pharmaceutically acceptable formulation containing a suitable elixir (commonly referred to as a "carrier") or the like, or as a pharmaceutically acceptable salt (e.g., an alkali metal salt such as a sodium, potassium, calcium or lithium salt, ammonium, etc.) or other complex. For example, a salt of 25HC3S may be preferably utilized; the sodium salt of 25HC3S is an exemplary such salt. It should be understood that pharmaceutically acceptable formulations include liquid materials conventionally used to prepare injectable dosage forms. 25HC3S or its salt is typically administered as a liquid composition suitable for injection and / or intravenous administration. Solid forms suitable for dissolution or suspension in a liquid prior to administration may also be prepared.

[0159] The active ingredient can be mixed with a pharmaceutically acceptable and compatible excipient (e.g., a pharmaceutically and physiologically acceptable carrier). Suitable excipients include, for example, water, saline (sodium chloride), cyclodextrin (e.g., hydroxypropyl-β-cyclodextrin), glucose (dextrose), glycerol, ethanol, etc., or a combination thereof. In addition, the composition may contain a small amount of auxiliary substances such as wetting agents or emulsifiers, pH buffers (e.g., phosphate buffer), etc. Water can be used as a carrier for preparing a composition (e.g., an injectable composition), which may also include conventional buffers and agents that make the composition isotonic. Other possible additives and other materials (preferably those that are generally recognized as safe [GRAS]) include: surfactants ( oleic acid, etc.); solvents, stabilizers, elixirs and encapsulating agents (lactose, liposomes, etc.). Preservatives such as methyl paraben or benzalkonium chloride may also be used. The compositions of the present disclosure may contain any such additional ingredients to provide the composition in a form suitable for the intended route of administration. In addition, the compounds may be formulated with aqueous or oil-based vehicles.

[0160] Depending on the formulation, it is expected that 25HC3S or its salt will be present in about 1% to about 99% by weight of the composition, and the "carrier" as a solvent will account for about 1% to about 99% by weight of the composition. The pharmaceutical composition of the present disclosure may include any suitable pharmaceutically acceptable additives or excipients, as long as they do not hinder or interfere with the therapeutic effect of 25HC3S or its salt.

[0161] In some cases, the alcoholic hepatitis is characterized by decreased liver function, such that the subject exhibits a decreased clearance rate of 25HC3S compared to a subject without alcoholic hepatitis. In some cases, the alcoholic hepatitis is characterized by decreased liver function, such that the subject exhibits a 25HC3S clearance rate that is 50% or less, 40% or less, 30% or less, or 25% or less of the clearance rate of 25HC3S by a subject without alcoholic hepatitis. In an exemplary but non-limiting case, the clearance rate of 25HC3S by a subject without alcoholic hepatitis (compared to which the decreased clearance rate is measured in a subject with alcoholic hepatitis) is considered to be 25 L / h (i.e., a subject of the present invention exhibits a 25HC3S clearance rate of less than 25 L / h, such as 50% or less, 40% or less, 30% or less, or 25%, or less than 25 L / h).

[0162] In certain instances, the alcoholic hepatitis is characterized by decreased liver function such that the subject exhibits a decreased half-life (T ) of 25HC3S in plasma following administration compared to a subject not suffering from alcoholic hepatitis. 1 / 2) is 1.5 times or more or 2 times or more. In an exemplary but non-limiting case, the half-life of a subject without alcoholic hepatitis (compared with which a greater half-life is measured in a subject with alcoholic hepatitis) is considered to be 1.6 hours (i.e., the subject of the present invention exhibits a half-life greater than 1.6 hours, such as 1.5 times or more, or 2 times or more). In some cases, the time to maximum drug concentration (T max ) is at the end of an infusion (e.g., a 2-hour infusion). In certain embodiments, the half-life (t 1 / 2 ) ranges from about 4 to about 6 hours. In some cases, subjects exhibit a 25HC3S half-life (T) after administration in the range of about 1.5 hours to about 6 hours or about 2 hours to about 5 hours. 1 / 2 ).

[0163] In some cases, the average clearance of 25HC3S or a salt thereof is about 5 L / h to about 7 L / h. In some cases, the subject exhibits a 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.

[0164] In some cases, the subject exhibits a volume of distribution of 25HC3S in the range of about 10 L to about 50 L, about 15 L to about 45 L, or about 20 L to about 40 L. In some cases, the subject exhibits a volume of distribution that is lower than the volume of distribution of 25HC3S exhibited by a subject without alcoholic hepatitis (which can be, for example, considered to be 55 L) - e.g., 90% or less, 80% or less, 70% or less, or 60% or less).

[0165] In some cases, the subject 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 7000 ng / mL, or about 700 ng / mL to about 5000 ng / mL. For example, in some cases, for each 100 mg of 25HC3S or a salt thereof administered intravenously, the subject 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 7000 ng / mL, or about 700 ng / mL to about 5000 ng / mL.

[0166] In some cases, the subject exhibits an AUCinf of 25HC3S in the range of 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. For example, in some cases, for each 100 mg of 25HC3S or a salt thereof administered intravenously, the subject exhibits an AUCinf of 25HC3S in the range of about 5000 ng*h / mL to about 30,000 ng*h / mL or about 6000 ng*h / mL to about 20,000 ng*h / mL.

[0167] In one embodiment, 25HC3S or a salt thereof is used to treat or alleviate AH symptoms in a subject, wherein the subject has a reduced risk of death 90 days after the first administration of 25HC3S or a salt thereof compared to a subject who did not receive 25HC3S or a salt thereof. In certain embodiments, 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, compared to a subject who did not receive 25HC3S or a salt thereof, and includes a case where the risk of death of the subject 90 days after the first administration of 25HC3S or a salt thereof is reduced by 99% or more compared to a subject who did not receive 25HC3S or a salt thereof.

[0168] In one embodiment, 25HC3S or a salt thereof is used to treat or alleviate AH symptoms in a subject, wherein the subject has a reduced risk of death 28 days after the first administration of 25HC3S or a salt thereof compared to a subject who did not receive 25HC3S or a salt thereof. In certain embodiments, 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, compared to a subject who did not receive 25HC3S or a salt thereof, and includes a case where the risk of death of the subject is reduced by 99% or more 90 days after the first administration of 25HC3S or a salt thereof compared to a subject who did not receive 25HC3S or a salt thereof.

[0169] In certain embodiments, the methods and compositions of the present disclosure are sufficient to reduce the duration of hospitalization compared to subjects who do not receive 25HC3S or its salt. In some cases, the subject methods and compositions are sufficient to reduce hospitalization, such as 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 include reducing the duration of hospitalization by 40% or more.

[0170] In certain embodiments, the methods and compositions of the present disclosure are sufficient to reduce the duration of intensive care unit treatment compared to subjects who have not received 25HC3S or its salt. In some cases, the subject methods and compositions are sufficient to reduce the duration of intensive care unit treatment, such as 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 include reducing the duration of intensive care unit treatment by 40% or more.

[0171] The present invention will be further illustrated by the following examples. These examples are non-limiting and do not limit the scope of the present invention. Unless otherwise stated, all percentages, parts, etc. presented in the examples are by weight.

[0172] Example

[0173] Example 1

[0174] As described in more detail below, a total of 19 patients were enrolled in an open-label Phase 2a multicenter trial, 15 of whom had a Maddrey's discriminant function (MDF) of ≥32 (severe alcoholic hepatitis (SAH)), 12 had a MELD score between 21-30, and 11 had a baseline serum bilirubin level of >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 up for 28 days. The final 19 patients enrolled included: 8 patients (4 moderate and 4 severe) were administered 30 mg, 7 patients (3 moderate and 4 severe) were administered 90 mg, and 4 patients (4 severe) were administered 150 mg.

[0175] method:

[0176] The study drug 25HC3S sodium salt solution contained:

[0177] 30 mg / mL 25HC3S sodium salt;

[0178] 240 mg / mL hydroxypropyl-β-cyclodextrin; and

[0179] 50 mmol phosphate buffer

[0180] Dissolve 25HC3S sodium salt in 100 mL of 5% glucose or 0.9%

[0181] Dilute in Sodium Chloride Infusion Solution:

[0182] ●Dose 1: 30 mg 25HC3S sodium salt in 100 mL 5% dextrose or 0.9% sodium chloride

[0183] ●Dose 2: 90 mg 25HC3S sodium salt in 100 mL 5% dextrose or 0.9% sodium chloride

[0184] ●Dose 3: 150 mg 25HC3S sodium salt in 100 mL 5% dextrose or 0.9% sodium chloride

[0185] 25HC3S sodium salt was administered by slow intravenous infusion (50 mL / h) over 2 hours until all doses were administered on Days 1 and 4. If a patient met discharge criteria before the second dose, the patient received only one dose, not two.

[0186] Study Procedures This study was conducted in two parts. Part A included patients with a MELD score of 11-20 (moderate AH patients) and Part B included patients with a MELD score of 21-30. The dose of 25HC3S sodium salt administered was 30

[0187] mg and 90 mg (for Part A) and 30 mg, 90 mg and 150 mg

[0188] (For Part B), there were 4 patients in each dose group in each part (with the exception of only 3 patients in the 90 mg cohort in Part A). All patients were followed up to Day 28.

[0189] This study enrolled 4 patients with moderate AH (Part A) at 30 mg

[0190] Dose level initiated. After dosing was completed, the Dose Escalation Committee (DEC) reviewed the safety, tolerability, and pharmacokinetic (PK) data from all 4 patients and determined that it was safe to continue dosing at the same dose level (30 mg) to the 4 severe AH patients (Part B) and to increase the dose level to 90 mg for the moderate patients (Part A).

[0191] The same dose escalation schedule was then followed in Part B until all 4 patients received the 150 mg dose.

[0192] The flow chart of the study is as follows Figure 2 As shown. A maximum of 4 subjects were enrolled in each dose cohort. Study subjects received up to 2 doses of 25HC3S sodium salt. The first dose was administered on day 1, and if still hospitalized, the second dose was administered on day 4. Pharmacokinetic (PK) samples were collected at the following times: time 0 (pre-dose), 1 day after the start of dosing

[0193] 1 hour, 2 hours (end of infusion), 3 hours after the start of dosing, 4 hours after the start of dosing, 8 hours after the start of dosing, 12 hours after the start of dosing, 24 hours after the start of dosing, and 50 hours after the start of dosing.

[0194] group:

[0195] 1. Patients with alcoholic hepatitis in this clinical trial were defined as:

[0196] a. History of severe alcohol abuse: >40 g / day for women or >60 g / day for men,

[0197] lasting for a period of at least 6 months, and

[0198] b. Alcohol use within 12 weeks of study entry, and

[0199] c. Serum bilirubin>3mg / dL and AST>ALT, but less than 300

[0200] U / L, and

[0201] d. MELD score between 11-30, inclusive The following table shows a list of the baseline laboratory characteristics of the subjects in each cohort.

[0202]

[0203]

[0204] Evaluation: Assessment of pharmacodynamic (PD) signal:

[0205] Changes in Lille score, MELD score, biochemistry (such as bilirubin)

[0206] Method and timing:

[0207] Calculation of Lille score on day 7

[0208] MELD scores were calculated at screening, day 1 (pre-dose), day 7, and day 28.

[0209] Biochemistry and all safety laboratory parameters were collected at Screening, on Days 1 and 4 prior to dosing, 12 hours after completion of dosing / end of infusion on Days 1 and 4, Days 2, 7, Day 28, and if hospitalized, on Days 3, 4, 5, and 6.

[0210] Evaluation of Safety Signals:

[0211] Safety was determined based on clinical and laboratory monitoring.

[0212] PK assessment:

[0213] The plasma concentration data of 25HC3S from each patient were used to calculate relevant PK parameters determined using standard linear / log trapezoidal non-compartmental methods with an appropriate PK data analysis program.

[0214] PK samples were collected at the following time points (only after dose 1): 0 (pre-dose), 1 hour after the start of dosing, 2 hours (end of infusion), 3, 4, 8, 12, 24 hours after dosing

[0215] result:

[0216] 25HC3S was safe at all 3 doses, with no drug-related serious adverse events. All patients, including those with SAH, were alive during the 28-day follow-up period. Some patients received one dose and some received two doses. Dosing ranged from 30 mg to 300 mg. Of the 18 patients who returned for their day 7 visit, 4 received two doses and 14 received one dose.

[0217] Drug exposure (AUC and C max ) is proportional to the dose. The time to reach maximum drug concentration (T max) was at the end of the 2-hour infusion. The mean plasma concentrations of 25HC3S sodium in subjects with moderate AH and severe AH were Figure 3 A and Figure 3 B. The half-life of 25HC3S sodium (t 1 / 2 ) was 4-6 hours. The mean clearance of 25HC3S sodium was approximately 5-7 L / h. The PK parameters of 25HC3S sodium were similar between the moderate and severe AH groups. The following table summarizes the PK parameters at each dose level for subjects with moderate AH and severe AH. Cmax ( Figure 4 A) and AUC( Figure 4 B) Figure 4 shown.

[0218]

[0219] Compared with the PK parameters of 25HC3S sodium in healthy subjects, at the same dose level (single dose of 150 mg), C max The AUC increased by about 5-fold and the clearance of 25HC3S sodium was reduced by 80% in AH patients compared to healthy subjects from earlier studies. The following table summarizes the pharmacokinetic parameters of 25HC3S administered to healthy subjects and subjects with alcoholic hepatitis. Figure 5 Depicted is the comparison of plasma concentrations of 25HC3S administered to healthy subjects versus subjects with alcoholic hepatitis.

[0220]

[0221] Of all 25HC3S treated AH patients (1 patient did not return for the Day 7 visit), treatment responders (Lille score < 0.45) were 89%; of the 15 SAH patients (MDF ≥ 32), 87%; and of the 12 patients with MELD 21-30, 83%. In particular, 100% of SAH patients (n = 11) treated with 30 or 90 mg 25HC3S responded to treatment, as shown in the table below.

[0222]

[0223] Although patients received only 1 or 2 doses of 25HC3S, the MELD scores of SAH patients on day 28 were significantly reduced compared with baseline (-17.5%, p = 0.01). In SAH patients treated with 30 or 90 mg 25HC3S, the median reduction in MELD on day 28 compared with baseline was -19.0% (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).

[0224] Comparing our data with a set of data from Louvet et al. that evaluated 145 AH patients for the development of the Lille score (where the DF score, prothrombin time, and serum creatinine, albumin, and bilirubin levels were the same as those in this study), the Lille score from our study was significantly lower than the historical data by 0.24 (0.07, 0.60), p<0.0001. Louvet et al., Hepatology, 45:1348-1354 (2007); and Louvet et al., Gastroenterology, 149:398-406 (2015).

[0225] Clinical data from the trial also showed that the 19 patients treated with 25HC3S had statistically significantly greater reductions from baseline in bilirubin (Day 7 and Day 28) and MELD (Day 28), as well as statistically significantly lower Lille scores, compared to the historical control group (n=15) from the University of Louisville (UL) AH study. Figure 1 UL shared anonymized data of 16 AH patients with initial MELD scores between 15 and 30 who received supportive care alone (n = 9) or supportive care with corticosteroids (n = 7). Of the 19 AH patients who received 25HC3S, one patient did not return for the Day 7 visit, so Lille scores were calculated for only 18 of the 19 patients.

[0226] The Lille score is used in clinical practice to help determine the prognosis of AH patients after 7 days of treatment. The lower the Lille score, the better the prognosis of AH patients. Patients with a Lille score below 0.45 had an 85% 6-month survival rate, while patients with a Lille score above 0.45 had only a 25% 6-month survival rate (Louvet A et al., Hepatology, 45: 1348-54 (2007)). In this study, the median Lille score of 18 AH patients treated with 25HC3S who returned for a 7th day visit was 0.10. 89% (16 / 18) had a Lille score below 0.45. In the UL group of 16 patients treated with supportive care or corticosteroid supportive care, the median Lille score was 0.41, of which 50% (8 / 16) had a Lille score below 0.45.

[0227] In this trial, the median Lille score for all 18 AH patients treated with 25HC3S from 5 cohorts (moderate and severe AH) who returned for the Day 7 visit was 0.10, with an interquartile range of 0.04-0.20. In comparison, the median Lille score in the cohort of 16 patients treated with supportive care (standard of care [SOC]) with or without corticosteroids at the University of Louisville (UL) was 0.41 (shown as historical control), with an interquartile range of 0.14-0.73, and 1-month or 3-month mortality rates of 12.5% ​​and 31.3%, respectively. In addition to the absence of treatment-emergent serious adverse events, patients receiving 25HC3S had significantly lower Lille scores than those treated with SOC, p=0.005.

[0228] Figure 6 Depicted are the Lille scores determined on day 7 plotted against the AUC for subjects diagnosed with moderate AH administered 30 mg and 90 mg 25HC3S sodium, and the Lille scores for subjects diagnosed with severe AH administered 30 mg, 90 mg, and 150 mg 25HC3S sodium. Figure 6 As shown in Figure 2, all subjects taking 30 mg and 90 mg 25HC3S sodium had a Lille score of less than 0.45 on Day 7. Two subjects with severe AH taking 150 mg 25HC3S sodium had a Lille score greater than 0.45 on Day 7.

[0229] AH patients treated with 25HC3S also showed a statistically significant decrease from baseline in serum total bilirubin levels at day 7 of -14% compared to -3% at day 7 for UL patients (n=18).

[0230] 25HC3S was well tolerated by all patients, with no drug-related serious adverse events reported at any dose level. Drug exposure was proportional to dose and was not affected by disease severity.

[0231] in conclusion:

[0232] In this Phase 2a trial, all AH patients (including SAH patients) tolerated 25HC3S at all three doses tested. There were no interruptions, early withdrawals, or terminations of study drug or study participation due to adverse reactions, and no serious adverse reactions related to 25HC3S were found. All patients survived the 28-day follow-up period (i.e., 100% survival rate). The pharmacokinetics of 25HC3S in moderate AH and severe AH patients were similar and dose-proportional to the dose administered. For a given dose, the systemic clearance of 25HC3S in AH patients was as low as about 1 / 5 compared to healthy subjects.

[0233] One or two doses of the drug significantly reduced serum bilirubin levels on day 7 after treatment and MELD scores on day 28. There was a 100% treatment response rate (Lille score <0.45) in patients administered 30 mg or 90 mg of 25HC3S, and an 89% response rate in all patients. The Lille scores of patients treated with 25HC3S were significantly better than published comparative historical data.

[0234] Example 2

[0235] 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).

[0236] Experimental Design

[0237] Subjects will be randomized in a 1:1:1 ratio to the following study treatment groups:

[0238] Study Treatment (IV Infusion) Optional corticosteroid or placebo capsule 25HC3S(30mg) Placebo 25HC3S(90mg) Placebo Sterile water for injection (placebo) Methylprednisolone (32 mg)

[0239] The first dose (Day 1 dose) of the assigned intravenous study treatment (trial drug) is administered in the hospital setting immediately after subject randomization.

[0240] If the subject remains hospitalized, a second dose of the assigned intravenous study treatment (trial drug) will be administered on Day 4 or 3 days after the first dose. If the subject meets discharge criteria prior to Day 4, the subject will receive only one dose of 25HC3S.

[0241] No more than two doses total of intravenous infusions of study treatment (trial drug) were administered.

[0242] If the site investigator chooses to use corticosteroids (CS) as part of standard of care, 32 mg methylprednisolone capsules (or matching steroid placebo capsules) should be used. Based on the AASLD guidelines, administration of CS capsules or placebo capsules can be started at any time at the site investigator's discretion and can also be stopped at any time, especially if their Lille score on Day 7 is >0.45.

[0243] Study drugs, doses, and modes of administration

[0244] 25HC3S sodium salt was diluted at 30 and 90 mg (of 25HC3S free acid) in 100 mL of 5% dextrose or 0.9% sodium chloride and infused over approximately 2 hours.

[0245] Sterile, ready-to-use 25HC3S injection will be available in two strengths:

[0246] - 30 mg / 1 mL in a single-dose 2 mL glass vial with a 13 mm stopper and crimp seal.

[0247] 90 mg / 3 mL (30 mg / mL) in a single-dose 5 mL glass vial with a 13 mm stopper and crimp seal

[0248] The concentration of the DUR-928 injectable product to be used in this study was 30 mg / mL of 25HC3S free acid, corresponding to 31.4 mg / mL of 25HC3S sodium salt.

[0249] 25HC3S injection or placebo was diluted into a 100 mL infusion bag containing 5% dextrose or 0.9% sodium chloride intravenous solution. 25HC3S or placebo solution was administered to subjects by intravenous infusion over approximately 2 hours.

[0250] Comparators, Dosages and Modes of Administration:

[0251] Dilute 3 mL of Sterile Water for Injection in 100 mL of 5% dextrose or 0.9% sodium chloride and infuse over approximately 2 hours.

[0252] group

[0253] Patients with alcoholic hepatitis in this clinical trial were defined as:

[0254] Onset of jaundice within the first 8 weeks

[0255] Consumption of >40 g (females) or >60 g (males) of alcohol per day on average for 6 months or longer, with abstinence from alcohol for <8 weeks prior to the onset of jaundice. Daily and chronic alcohol consumption and onset of jaundice will be determined by site investigators.

[0256] Serum chemistry (determined by local laboratory):

[0257] Serum total bilirubin > 3.0 mg / dL

[0258] 50 <AST<400IU / L

[0259] ALT<400 IU / L

[0260] AST / ALT>1.5

[0261] Maddrey's discriminant function ≥ 32, assuming a control prothrombin time of 12 seconds

[0262] Model for End-Stage Liver Disease (MELD) score: 21-30

[0263] Outcome measures

[0264] Main outcome measures:

[0265] 90-day mortality between active and placebo (SOC) groups (time frame: day 90)

[0266] Secondary outcome measures:

[0267] 28-day mortality between treatment groups (time frame: day 28)

[0268] Lille scores on day 7 after initiation of study drug treatment between treatment groups (time frame: day 7)

[0269] MELD scores on day 28 after initiation of study drug treatment between treatment groups (time frame: day 28)

[0270] Number of ICU days on day 28 (time range: day 1 to day 28).

Claims

1. A method of treating alcoholic hepatitis in a human subject in need thereof, the method comprising administering to the subject 5-cholestene-3,25-diol, 3-sulfate (25HC3S) or a salt thereof in an amount sufficient to treat the alcoholic hepatitis.

2. The method of claim 1, wherein the administering 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 claim 1 or 2, wherein the administering comprises administering a total amount of 25HC3S or a salt thereof in the range of about 10 mg / month to about 400 mg / month.

4. The method according to any one of claims 1-3, comprising administering to the human subject a total amount of about 10 mg to about 400 mg of 25HC3S or a salt thereof over a period of 1 month, wherein: - the total amount is sufficient to treat alcoholic hepatitis; - said total amount is administered in one or more divided doses, said doses comprising at least a first dose; and - The 1 month period is measured from the start of administration of the first dose.

5. The method according to any one of claims 2 to 4, wherein the total amount is administered in one dose or in two divided doses, preferably as a single dose.

6. The method according to any one of claims 4-5, wherein at least one and preferably each of the one or more divided doses comprises from about 10 mg to about 200 mg of 25HC3S or a salt thereof.

7. The method according to any one of claims 4 to 6, wherein at least one and preferably each of the one or more divided doses comprises from about 20 mg to about 100 mg of 25HC3S or a salt thereof.

8. The method according to any one of claims 2-7, wherein the total amount is administered in two or more divided doses at a dosage frequency ranging from daily to once per week.

9. The method according to claim 4, wherein: - administering the total amount in one dose or in two divided doses; - one dose comprises about 10 mg to about 200 mg of 25HC3S or a salt thereof; - each of the two separate doses contains from about 10 mg to about 200 mg of 25HC3S or a salt thereof; and - The two divided doses are administered at a dosage frequency ranging from once every 2 days to once every 4 days.

10. The method according to any one of claims 1-9, wherein the administration is performed parenterally, intravenously, intramuscularly or subcutaneously.

11. The method according to any one of claims 1-10, wherein the administration is performed by injection.

12. The method according to any one of claims 1-11, wherein the 25HC3S or its salt is administered in a formulation comprising 25HC3S or its salt and a pharmaceutically acceptable carrier.

13. The method according to any one of claims 1 to 12, wherein the 25HC3S or a salt thereof comprises a salt of 25HC3S, wherein the salt of 25HC3S is preferably a sodium salt.

14. 5-cholestene-3,25-diol, 3-sulfate (25HC3S) or a salt thereof for use in a method of treating alcoholic hepatitis in a human subject in need thereof, wherein the method is as defined in any one of claims 1 to 13.

15. Use of 5-cholestene-3,25-diol, 3-sulfate (25HC3S) or a salt thereof in a process for preparing a medicament for use in a method for treating alcoholic hepatitis in a human subject in need thereof, wherein the method for treating alcoholic hepatitis is as defined in any one of claims 1 to 13.

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