Treatment of alcoholic hepatitis

Abstract

Methods for treating alcoholic hepatitis (AH) are provided. For example, the methods can include administering 5-cholestene-3,25-diol, 3-sulfate (25HC3S) or a salt thereof.

Description

[Technical Field]

[0001] A method for treating alcoholic hepatitis (AH) is provided. For example, the method may include administering 5-cholesten-3,25-diol,3-sulfate (25HC3S) or a salt thereof. [Background technology]

[0002] Alcoholic hepatitis (AH) is an alcoholic liver disease caused by long-term consumption of alcohol (ethanol). Signs and symptoms of AH include acute jaundice, fever and weight loss, as well as several complications such as ascites and hepatic encephalopathy, which can lead to cirrhosis. AH is associated with a high mortality burden of up to 15% in 30 days, depending on the severity of the disease at the time of medical attention. 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 pulmonary hemorrhage (AH). However, treatment with corticosteroids has conflicting outcomes, is associated with an increased risk of infection, and is unsuitable for patients with gastrointestinal bleeding or steroid allergies. Corticosteroids are typically taken daily in doses of around 30-40 mg, depending on the specific corticosteroid used. Patient compliance tends to be low because patients often fail to take their medication when they should.

[0004] Liver transplantation is a curative treatment option for alpha halal hypertension (AH), but patients must abstain from alcohol for six months to meet the requirements. However, the six-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, incorporated herein by reference, discloses the use of 5-cholestene-3,25-diol, 3-sulfate (25HC3S) and its salts for the treatment of 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, incorporated herein by reference, discloses the use of 25HC3S and its salts for the prevention and treatment of liver injury or liver disease.

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

[0008] ClinicalTrials.gov contains disclosures of a research study evaluating the safety, pharmacokinetics, and pharmacodynamics of 25HC3S in patients with avian heartburn using dose escalation, including three doses: 30 mg, 90 mg, and 150 mg. See ClinicalTrials.gov ID: NCT03432260.

[0009] Improved methods for treating AH are urgently needed. [Prior art documents] [Patent Documents]

[0010] [Patent Document 1] U.S. Patent No. 8,399,441 [Patent Document 2] U.S. Patent No. 9,034,859

Patent Document 3

Non-Patent Document

[0011]

Non-Patent Document 1

Summary of the Invention

[0012] The present disclosure provides various methods for treating alcoholic hepatitis (AH). The methods involve administering an effective amount of 5-cholesten-3,25-diol, 3-sulfate (25HC3S) or a salt thereof. In certain cases, the method involves administering an effective amount of 5-cholesten-3,25-diol, 3β-sulfate or a salt thereof.

[0013] The results of the present disclosure are surprising for several reasons. For example, the low doses in some embodiments of the present disclosure are surprising. Further, the low dosing frequency in some embodiments is surprising. Still further, the low number of doses to obtain an effect in the treatment of AH in some embodiments is surprising. The results of the present disclosure are even more surprising in that such low doses, low dosing frequencies, and low number of doses can provide the same or better results as corticosteroids that require more doses, more frequent dosing, and / or a greater total number of doses. Still further, the present disclosure can also obtain effective results in AH patients characterized by certain diagnostic criteria, such as the Model for End-stage Liver Disease (MELD) score and / or other criteria discussed elsewhere in this specification.

[0014] Further aspects of the present disclosure are as follows:

[0015] 1. A method for treating alcoholic hepatitis in a human subject in need, the method comprising administering to the subject 5-cholesten-3,25-diol,3-sulfate (25HC3S) or a salt thereof in an amount sufficient to treat the alcoholic hepatitis.

[0016] 2. The method according to embodiment 1, wherein the administration comprises administering a total amount of 25HC3S or a salt thereof, which is approximately 1 mg to approximately 1000 mg.

[0017] 3. The method according to embodiment 1 or 2, wherein the administration comprises administering either (a) or (b), namely (a) about 10 mg / month to about 500 mg / month, or (b) about 10 mg / month to about 400 mg / month, in total amounts of 25HC3S or a salt thereof.

[0018] 4. The method comprises administering to the human subject either (a) or (b) below, namely (a) about 10 mg / month to about 400 mg / month, or (b) about 10 mg to about 400 mg of 25HC3S or a salt thereof, over a period of one month, where - The total amount is sufficient to treat the alcoholic hepatitis, - The total amount is administered in one or more separate doses, including at least the first dose, and - The one-month period is measured from the start of administration of the first dose. The method according to any one of embodiments 1 to 3.

[0019] 5. One of the methods described in embodiments 2 to 4, wherein the total amount is administered in 1 to 15 separate doses.

[0020] 6. One of the methods described in embodiments 2 to 4, wherein the total amount is administered in 1 to 5 separate doses.

[0021] 7. Any one of embodiments 2 to 4, wherein the total amount is administered as one dose or as two separate doses, preferably as a single dose.

[0022] 8. Any one of embodiments 2 to 7, wherein the total amount is at least about 20 mg.

[0023] 9. Any one of the methods described in Embodiments 2 to 8, wherein the total amount is approximately 300 mg or less.

[0024] 10. Any one of the methods described in Embodiments 2 to 8, wherein the total amount is approximately 200 mg or less.

[0025] 11. Any one of the methods described in Embodiments 2 to 8, wherein the total amount is approximately 140 mg or less.

[0026] 12. Any one of embodiments 4 to 11, wherein at least one of the one or more separate doses described above, preferably each, contains about 10 mg to about 200 mg of 25HC3S or a salt thereof.

[0027] 13. Any one of embodiments 4 to 12, wherein at least one of the one or more separate doses described above, preferably each, contains about 10 mg to about 120 mg of 25HC3S or a salt thereof.

[0028] 14. Any one of embodiments 4 to 13, wherein at least one of the one or more separate doses described above, preferably each, contains about 20 mg to about 100 mg of 25HC3S or a salt thereof.

[0029] 15. One of the methods described in embodiments 2 to 14, wherein the total amount is administered in two or more separate doses at a frequency of once daily to once weekly.

[0030] 16. The method according to embodiment 15, wherein the administration frequency is once every two days to once a week.

[0031] 17. The method according to embodiment 15, wherein the administration frequency is once every two days to once every five days.

[0032] 18. The method according to embodiment 15, wherein the administration frequency is once every two days to once every four days.

[0033] 19. The following, that is, - The total amount may be administered in one dose or in two separate doses. -The said dose contains approximately 10 mg to approximately 200 mg of 25HC3S or a salt thereof. -Each of the two separate doses contains approximately 10 mg to approximately 200 mg of 25HC3S or a salt thereof, -These two separate doses are administered at a frequency of once every two to four days. The method of embodiment 4.

[0034] 20. The method of embodiment 19, wherein the total amount is administered as one dose, and the one dose comprises (a) to (c) below, namely (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.

[0035] 21. The method of embodiment 19, wherein the total amount is administered in two separate doses, and each of the two separate doses comprises (a) to (c) below, namely (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.

[0036] 22. Any one of embodiments 4 to 21, wherein the total amount / kg of 25HC3S or its salt administered during the aforementioned period is approximately 0.05 mg / kg to approximately 20 mg / kg.

[0037] 23. The method according to embodiment 22, wherein the total amount / kg is approximately 0.1 mg / kg to approximately 10 mg / kg.

[0038] 24. The method according to embodiment 22, wherein the total amount / kg is approximately 0.2 mg / kg to approximately 6 mg / kg.

[0039] 25. The method according to embodiment 22, wherein the total amount / kg is approximately 0.3 mg / kg to approximately 1.5 mg / kg.

[0040] 26. Any one of embodiments 1 to 25, wherein the administration is carried out parenterally, intravenously, intramuscularly, or subcutaneously.

[0041] 27. One of the methods described in Embodiments 1 to 26, wherein the administration is carried out by injection.

[0042] 28. Any one of embodiments 1 to 27, wherein the 25HC3S or a salt thereof is administered in a formulation comprising the 25HC3S or a salt thereof and a pharmaceutically acceptable carrier.

[0043] 29. Any one of embodiments 1 to 28, wherein the 25HC3S or its salt comprises a salt of 25HC3S, and the salt of 25HC3S is preferably a sodium salt.

[0044] 30. One of the methods described in any of embodiments 4 to 29, wherein one or more separate doses are administered over a period of administration of 14 days or less.

[0045] 31. Any one of embodiments 1 to 30, wherein the human subject has at least 11 end-stage liver disease (MELD) scores.

[0046] 32. Any one of embodiments 1 to 31, wherein the human subject has a MELD score of 11 to 45.

[0047] 33. Any one of embodiments 1 to 32, wherein the human subject has a MELD score of 15 to 40.

[0048] 34. Any one of embodiments 1 to 33, wherein the human subject has at least 20 MELD scores.

[0049] 35. Any one of embodiments 1 to 34, wherein the human subject has a MELD score of at least 30.

[0050] 36. Any one of embodiments 1 to 35, wherein the human subject has at least 32 Maddrey discriminant functions (MDFs).

[0051] 37. Any one of embodiments 1 to 36, wherein the alcoholic hepatitis is characterized by a decline in liver function occurring within 13 weeks of onset.

[0052] 38. Any one of embodiments 1 to 36, wherein the alcoholic hepatitis is characterized by a decline in liver function occurring within 10 weeks of onset.

[0053] 39. Any one of embodiments 1 to 38, wherein the alcoholic hepatitis is characterized by a decrease in liver function such that the subject shows a decrease in the clearance rate of 25HC3S compared to a subject that does not have alcoholic hepatitis.

[0054] 40. The method of embodiment 39, wherein the alcoholic hepatitis is characterized by a decrease in liver function such that the subject exhibits a 25HC3S clearance rate of 50% or less, 40% or less, 30% or less, or 25% or less compared to the 25HC3S clearance rate from plasma of a subject that does not have alcoholic hepatitis.

[0055] 41. The half-life time (T) of 25HC3S in plasma after administration is 1.5 times or longer, or 2 times longer, in the case of alcoholic hepatitis compared to a case without alcoholic hepatitis. 1 / 2 One of the methods described in embodiments 1 to 40, characterized by a decline in liver function such as that shown by ).

[0056] 42. The half-life of 25HC3S in the plasma after administration is approximately 1.5 hours to approximately 6 hours or approximately 2 hours to approximately 5 hours for the subject (T 1 / 2 A method that demonstrates any one of embodiments 1 to 41.

[0057] 43. Any one of the methods from Embodiments 1 to 42, wherein the subject is 25HC3S with a Cmax of approximately 500 ng / mL to approximately 10,000 ng / mL, approximately 600 ng / mL to approximately 7,000 ng / mL, or approximately 700 ng / mL to approximately 5,000 ng / mL.

[0058] 44. Any one of methods of embodiments 1-43, wherein the subject exhibits a Cmax of 25HC3S that is 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 per 100 mg of intravenously administered 25HC3S or a salt thereof.

[0059] 45. The subject is 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, and any one of methods of embodiments 1-44 exhibits an AUCinf of 25HC3S.

[0060] 46. Any one of methods of embodiments 1-45, wherein the subject exhibits an AUCinf of 25HC3S that is 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 per 100 mg of intravenously administered 25HC3S or a salt thereof.

[0061] 47. Any one of methods of embodiments 1-46, wherein the subject exhibits a volume of distribution of 25HC3S that is about 10 L to about 50 L, about 15 L to about 45 L, or about 20 L to about 40 L.

[0062] 48. Any one of methods of embodiments 1-47, wherein the subject exhibits a clearance of 25HC3S that is 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.

[0063] 49. Any one of embodiments 1 to 48, wherein the alcoholic hepatitis is characterized by loss of liver function occurring within 13 weeks of onset.

[0064] 50. Any one of embodiments 1 to 48, wherein the alcoholic hepatitis is characterized by loss of liver function occurring within 10 weeks of onset.

[0065] 51. 5-Cholesten-3,25-diol, 3-sulfate (25HC3S) or a salt thereof for use in a method of treating alcoholic hepatitis in human subjects in need thereof, wherein the method is defined in any one of embodiments 1 to 50.

[0066] 52. Use of 5-cholesten-3,25-diol, 3-sulfate (25HC3S) or a salt thereof in a method for manufacturing a medicament for use in a method of treating alcoholic hepatitis in human subjects in need thereof, wherein the method is defined in any one of embodiments 1 to 50. [Brief explanation of the drawing]

[0067] [Figure 1] Figure 1 compares treatment with standard therapy (left) and treatment with 5-cholesten-3,25-diol, 3-sulfate (25HC3S) (right). Patients receiving standard therapy received supportive care with or without corticosteroids. Patients receiving 25HC3S were administered one or two doses of 25HC3S sodium salt, each dose being 30 mg, 90 mg, or 150 mg. [Figure 2] Figure 2 shows a flow diagram of the treatment protocol for 25HC3S in patients with moderate and severe alcoholic hepatitis. [Figure 3] Figure 3A shows the mean plasma concentration of 25HC3S in subjects with moderate AH. Figure 3B shows the mean plasma concentration of 25HC3S in subjects with moderate AH. [Figure 4] Figure 4A shows the pharmacokinetic parameters of Cmax for 25HC3S administered to subjects with moderate and severe alcoholic hepatitis. Figure 4B shows the pharmacokinetic parameters of AUC for 25HC3S administered to subjects with moderate and severe alcoholic hepatitis. [Figure 5] Figure 5 shows a comparison of the pharmacokinetic parameters of 25HC3S administered to healthy subjects and subjects with alcoholic hepatitis. [Figure 6] Figure 6 shows the Lille score measured on day 7, plotted against the pharmacokinetic parameter AUC for subjects administered 30 mg, 90 mg, or 150 mg of 25HC3S. [Modes for carrying out the invention]

[0068] Methods for treating alcoholic hepatitis (AH) are described herein. These methods include contacting the liver with 25HC3S or a salt thereof. The contact generally involves administering to a human patient an amount of 25HC3S or a salt thereof that is effective or sufficient to treat AH.

[0069] As stated above, the results of this disclosure are surprising for several reasons. For example, the low doses of this disclosure in some embodiments are surprising. Furthermore, the low administration frequency in some embodiments is surprising. Furthermore, the low number of doses required to achieve efficacy in the treatment of AH in some embodiments is surprising. The results of this disclosure are even more surprising in that such low doses, low administration frequency, and / or low number of doses may produce results similar to or better than those of corticosteroids requiring higher doses, higher administration, and higher total number of doses. Furthermore, this disclosure may also yield effective results in AH patients characterized by certain diagnostic criteria, such as the MELD score and / or other criteria discussed elsewhere in this specification.

[0070] definition The following definitions will be used throughout this specification: As used herein, “to treat” (including “treatment” and “to treat”) means administering 25HC3S or a salt thereof to (1) to (3) below, namely (1) a human subject already exhibiting at least one symptom of AH, and / or (2) a human subject diagnosed with AH by, for example, a trained clinical professional, and / or (3) a human subject determined to have AH based on laboratory tests (e.g., molecular indicators) of one or more bodily fluids, such as blood, or clinical tests. In certain embodiments, the subject is diagnosed with AH by liver tissue biopsy. In other words, at least one parameter known to be associated with AH is measured, detected, or observed in the subject. “Treatment” of AH involves reduction or attenuation, or in some cases, complete eradication, of at least one symptom of AH that was present before or at the time of administration of 25HC3S or a salt thereof. In some embodiments, the treatment of AH according to the present disclosure is sufficient to improve laboratory or clinical indicators of AH in the subject, as will be described in more detail later. In certain cases, such improvement of laboratory or clinical indicators of AH in the subject means that the subject is deemed to no longer have AH. In one example, the method of the present disclosure is sufficient to reduce the Maddrey Discriminant Function (MDF) score of a subject with a score of ≥32 to an MDF score of <32.

[0071] "Hepatic dysfunction" refers to a condition or state of health in which the liver does not perform its expected functions, for example, a condition or state of health in which certain biological or molecular indicators are measured outside the normal physiological range. Hepatic function refers to the expected functions of the liver within the physiological range. Those skilled in the art recognize the various functions of the liver during medical examinations. Hepatic dysfunction typically involves a clinical syndrome that develops progressive and potentially reversible physiological dysfunction of the liver, sometimes in the absence of anatomical damage.

[0072] "Liver failure" refers to liver dysfunction to the extent that normal homeostasis cannot be maintained without external clinical intervention.

[0073] "Acute liver dysfunction" refers to a rapid decline in liver function that occurs within days or weeks (e.g., within 26 weeks, 13 weeks, 10 weeks, 5 weeks, 4 weeks, 3 weeks, 2 weeks, 1 week, 5 days, 4 days, 3 days, or 2 days) in people who do not have underlying medical conditions.

[0074] "Acute liver failure" refers to a rapid loss of liver function that occurs—within days or weeks (for example, within 26 weeks, 13 weeks, 10 weeks, 5 weeks, 4 weeks, 3 weeks, 2 weeks, 1 week, 5 days, 4 days, 3 days, or 2 days)—usually in people without underlying medical conditions. Acute liver failure will be discussed in more detail later.

[0075] "Pharmaceutically acceptable" refers to a substance that does not interfere with the effectiveness of the biological activity of the active ingredient and does not exhibit toxicity to the recipient of the active ingredient.

[0076] Patient group Overview of Alcoholic Hepatitis Alcoholic hepatitis (AH) can range from mild hepatitis, where abnormal clinical tests only show signs of the disease, to severe liver dysfunction accompanied by 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 (varices in the esophagus), abnormal blood clotting, and coma. In some cases, the patient may have developed jaundice within the past 8 weeks, e.g., within the past 7 weeks, e.g., within the past 6 weeks, e.g., within the past 5 weeks, e.g., within the past 4 weeks, e.g., within the past 3 weeks, e.g., within the past 2 weeks, and also includes cases where the patient developed jaundice within the past 1 week. AH is typically reversible if the patient stops drinking, but hepatitis usually takes several months to resolve. AH can lead to liver scarring and cirrhosis. Typical findings in liver tissue include hepatocyte necrosis and ballooning degeneration, as well as alcoholic Mallory hyaline bodies (abnormal aggregates of cellular intermediate filament proteins, a sign of fibrosis). Cholestasis is typically prominent. The severity of this 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 end-stage liver disease model (MELD) score (based on creatinine, bilirubin, and the international normalized ratio (INR) of prothrombin time) (Lucey et al., N. Engl. J. Med., 360(26), 2758-2769 (2009); Vergis et al., Gastroenterology, 152(5):1068-1077 (2017)). If the MDF is >32, AH is classified as severe.

[0077] Alcohol consumption In some cases, the patients have a history of severe alcohol abuse of >40 g / day for women or >60 g / day for men for a period of at least 6 months, coupled with abstinence from alcohol for <60 days (e.g., <8 weeks) prior to the onset of jaundice. Long-term excessive alcohol consumption can cause alcoholic liver disease and AH. In some cases, excessive alcohol consumption is accompanied by alcohol intake of >80 g / day for men or >60 g / day for women. Thus, one embodiment is the use of 25HC3S or a salt thereof in treating AH in male or female subjects who consume excessive alcohol, wherein the male subject consumes >80 g of alcohol per day, or the female subject consumes >60 g of alcohol per day. In other embodiments, the disclosure relates to the use of 25HC3S or a salt thereof to treat or mitigate AH in male or female subjects with a history of excessive alcohol consumption, for example, when the subject has experienced consuming an average of 40 g / day or more over a period of six months or more on one or more occasions. In specific embodiments, the subject has experienced consuming an average of 60 g / day or more over a period of six months or more on one or more occasions.

[0078] Bilirubin AH is characterized by elevated bilirubin, reflecting impaired hepatic metabolic function in the absence of biliary obstruction. In some cases, the patient exhibits serum bilirubin >3 mg / dL. Thus, one embodiment involves the use of 25HC3S or a salt thereof to treat or alleviate the symptoms of AH in subjects whose serum bilirubin levels prior to administration of 25HC3S or a salt thereof are >50 μmol / L, e.g., >60 μmol / L or >80 μmol / L. In some cases, the treated patient has bilirubin levels of approximately 2 mg / dL to 50 mg / dL, e.g., approximately 3 mg / dL to approximately 40 mg / dL or approximately 4 mg / dL to approximately 30 mg / dL. In specific cases, the treated patient is judged to have a bilirubin level of >8 mg / dL.

[0079] In some embodiments, the method includes measuring the serum bilirubin of the patient to be treated. The serum bilirubin of the patient can be measured using any convenient protocol, for example, by colorimetric analysis or fluorescence analysis. In these embodiments, the serum bilirubin of the patient may be measured at least 10 minutes, for example, at least 15 minutes, for example, at least 30 minutes, for example, at least 60 minutes, for example, at least 2 hours, for example, at least 6 hours, and for example, at least 12 hours before treating the patient according to the method of this disclosure. In certain embodiments, the serum bilirubin of the patient is measured the day before treating the patient according to the method described herein.

[0080] In some examples, the method includes measuring the patient's serum bilirubin after one or more cycles of treatment by the method of the present disclosure, for example, after two or more cycles, for example, after three or more cycles, for example, after four or more cycles and for example, after five or more cycles. In these embodiments, the serum bilirubin may be measured immediately after or at a predetermined time thereafter following the last dose of 25HC3S or its salt, for example, five minutes or more after the last dose of 25HC3S or its salt, for example, ten minutes or more, for example, fifteen minutes or more, for example, thirty minutes or more, for example, sixty minutes or more, for example, two hours or more, for example, six hours or more and for example, twelve hours or more. In certain embodiments, the patient's serum bilirubin is measured at some point on the same day as the last dose of 25HC3S or its salt. In some cases, the patient shows a rapid increase in bilirubin, for example, an increase of ≥3 mg / dL within eight weeks. In some cases, the method is sufficient to reduce the serum bilirubin of a subject by, for example, reducing the serum bilirubin of the subject by 1 mg / dL or more, e.g., 2 mg / dL or more and e.g., 3 mg / dL or more. In certain cases, if the subject shows a rapid increase in bilirubin, the method is sufficient to reduce the increase in bilirubin by the amount that increased, e.g., 1 mg / dL or more, e.g., 2 mg / dL or more and e.g., 3 mg / dL or more. In some embodiments, the method of the disclosure is sufficient to reduce the serum bilirubin of the patient by 10% or more, e.g., 15% or more, e.g., 20% or more, e.g., 25% or more, e.g., 30% or more, e.g., 35% or more, e.g., 40% or more, e.g., 45% or more and e.g., 50% or more, compared to the serum bilirubin measured before treatment with 25HC3S or a salt of the specification (e.g., 7 or 28 days after the start of treatment).

[0081] MELD The End-Stage Liver Disease (MELD) model is a scoring system for assessing the severity of liver disease. An increasing MELD score reflects a higher risk of death, while a decreasing MELD score reflects a reduced risk. MELD utilizes patient values ​​for serum bilirubin, serum creatinine, and prothrombin time international normalized ratio (INR) to predict survival, using the following formula: [Mathematics 1] MELD = 3.78xln [Serum bilirubin (mg / dL)] + 11.2xln [INR] + 9.57xln [Serum creatinine (mg / dL)] + 6.43 It is calculated according to the following.

[0082] In some cases, the patient has a MELD score of approximately 11 to approximately 40, for example, approximately 11 to approximately 35, approximately 11 to approximately 33, or approximately 21 to approximately 30. In some cases, the patient has a MELD score of ≥11, for example, ≥15 or ≥21. In some cases, the patient has a MELD score of <35, for example, <30, <25, <20, or <15. Accordingly, one embodiment is the use of 25HC3S or a salt thereof in treating or alleviating the symptoms of AH in a subject, wherein the subject is characterized by a MELD score of approximately 11 to approximately 30 or approximately 21 to approximately 30 prior to administration of 25HC3S or a salt thereof.

[0083] In some embodiments, the method includes measuring the MELD score of the patient to be treated. In these embodiments, the MELD score of the patient may be measured at least 10 minutes, for example, at least 15 minutes, for example, at least 30 minutes, for example, at least 60 minutes, for example, at least 2 hours, for example, at least 6 hours, and for example, at least 12 hours before treating the patient according to the method of the Disclosure. In certain embodiments, the MELD score of the patient is measured the day before treating the patient according to the method described herein.

[0084] In some embodiments, the method includes measuring the patient's MELD score after one or more cycles of treatment by the method of the present disclosure, for example, after two or more cycles, for example, after three or more cycles, for example, after four or more cycles and for example, after five or more cycles. In these embodiments, the MELD score may be measured immediately after or at a predetermined time thereafter following the last administration of 25HC3S or its salt, for example, five minutes or more after the last administration of 25HC3S or its salt, for example, ten minutes or more, for example, fifteen minutes or more, for example, thirty minutes or more, for example, sixty minutes or more, for example, two hours or more, for example, six hours or more and for example, twelve hours or more. In certain embodiments, the patient's MELD score is measured at a point in time on the same day as the last administration of 25HC3S or its salt.

[0085] In some embodiments, the methods of the present disclosure are sufficient to reduce the MELD score indicated by the patient (for example, on day 7 or 28 from the start of treatment) by 5% or more, e.g., 10% or more, e.g., 15% or more, and e.g., 20% or more, compared to the MELD score measured before treatment with 25HC3S or a salt thereof as described herein.

[0086] MDF The Maddrey discriminant function (MDF) is a model for assessing the severity and prognosis of alcoholic hepatitis (AH). The MDF score is a useful statistical model for predicting the short-term prognosis of a patient, particularly mortality within 30 or 90 days. A score of 32 or higher (severe alcoholic hepatitis (SAH)) indicates a poor outcome with a 30-day mortality rate of 35%–45%. In contrast, an MDF < 32 identifies patients with mild to moderate AH who have a low but non-zero mortality risk with supportive care.

[0087] The aforementioned MDF is given by the following formula: [Math 2] MDF = 4.6 x (Prothrombin time (PT) 患者 -PT 対照 ) + serum bilirubin (μmol / L) / 17.1 It is calculated according to the following.

[0088] Accordingly, one embodiment is the use of 25HC3S or a salt thereof in treating or alleviating the symptoms of AH 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 ≥32. In other cases, the patient has an MDF score <32.

[0089] In some embodiments, the method includes measuring the MDF score of the patient to be treated. In these embodiments, the patient's MDF score may be measured at least 10 minutes, for example, at least 15 minutes, for example, at least 30 minutes, for example, at least 60 minutes, for example, at least 2 hours, for example, at least 6 hours, and for example, at least 12 hours before treating the patient according to the method of the Disclosure. In certain embodiments, the patient's MDF score is measured the day before treating the patient according to the method described herein.

[0090] In some embodiments, the method includes measuring the patient's MDF score after one or more cycles of treatment by the method of the present disclosure, for example, after two or more cycles, for example, after three or more cycles, for example, after four or more cycles and for example, after five or more cycles. In these embodiments, the MDF score may be measured immediately after or at a predetermined time thereafter following the last administration of 25HC3S or its salt, for example, five minutes or more after the last administration of 25HC3S or its salt, for example, ten minutes or more, for example, fifteen minutes or more, for example, thirty minutes or more, for example, sixty minutes or more, for example, two hours or more, for example, six hours or more and for example, twelve hours or more. In certain embodiments, the patient's MDF score is measured at some point on the same day as the last administration of 25HC3S or its salt.

[0091] In some embodiments, the methods of the present disclosure are sufficient to reduce the MDF score indicated by the patient (for example, on day 7 or 28 from the start of treatment) by 5% or more, e.g., 10% or more, e.g., 15% or more, and e.g., 20% or more, compared to the MDF score measured before treatment with 25HC3S or a salt of the herein.

[0092] Provided in one embodiment is the use of 25HC3S or a salt thereof for treating or alleviating symptoms of AH in a subject, wherein the subject is characterized by an MDF score ≥ 32 and a MELD score < 25 prior to administration of 25HC3S or a salt thereof. In some examples, the method is sufficient to reduce the subject's MDF score by 1 or more, e.g., 2 or more and e.g., 5 or more. In certain examples, the method is sufficient to reduce the subject's MDF score from a score ≥ 32 to an MDF score < 32.

[0093] ABIC The aforementioned MDF predicts survival at one month, but its accuracy is not very high in the medium and long term. The aforementioned MELD score, as well as age, serum bilirubin, INR, and serum creatinine (ABIC) scores, which have been validated more recently, provide a more granular survival prediction by emphasizing renal impairment and can be calculated at various time points. An ABIC score >9 indicates a high risk of death, 6.71–9 indicates a moderate risk of death, and <6.71 indicates a low risk of death. Therefore, in some cases, the patient may have an ABIC score >9 or 6.71–9.

[0094] In some embodiments, the method includes measuring the ABIC score of the patient to be treated. In these embodiments, the ABIC score of the patient may be measured at least 10 minutes, for example, at least 15 minutes, for example, at least 30 minutes, for example, at least 60 minutes, for example, at least 2 hours, for example, at least 6 hours, and for example, at least 12 hours before treating the patient according to the method of the Disclosure. In certain embodiments, the ABIC score of the patient is measured the day before treating the patient according to the method described herein.

[0095] In some embodiments, the method includes measuring the patient's ABIC score after one or more cycles of treatment by the method of the present disclosure, for example, after two or more cycles, for example, after three or more cycles, for example, after four or more cycles and for example, after five or more cycles. In these embodiments, the ABIC score may be measured immediately after the last dose of 25HC3S or its salt, or at a predetermined time thereafter, for example, five minutes or more after the last dose of 25HC3S or its salt, for example, ten minutes or more, for example, fifteen minutes or more, for example, thirty minutes or more, for example, sixty minutes or more, for example, two hours or more, for example, six hours or more and for example, twelve hours or more. In certain embodiments, the patient's ABIC score is measured at some point on the same day as the last dose of 25HC3S or its salt.

[0096] In some embodiments, the methods of the present disclosure are sufficient to reduce the ABIC score indicated by the patient (for example, on day 7 or 28 from the start of treatment) by 5% or more, e.g., 10% or more, e.g., 15% or more, and e.g., 20% or more, compared to the ABIC score measured before treatment with 25HC3S or a salt thereof as described herein.

[0097] Glasgow AH score 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.

[0098] In some embodiments, the method includes measuring the GAHS of the patient to be treated. In these embodiments, the GAHS of the patient may be measured at least 10 minutes, for example, at least 15 minutes, for example, at least 30 minutes, for example, at least 60 minutes, for example, at least 2 hours, for example, at least 6 hours, and for example, at least 12 hours before treating the patient according to the method of the Disclosure. In certain embodiments, the GAHS of the patient is measured the day before treating the patient according to the method described herein.

[0099] In some examples, the method includes measuring the patient's GAHS after one or more cycles of treatment by the method of the present disclosure, for example, after two or more cycles, for example, after three or more cycles, for example, after four or more cycles and for example, after five or more cycles. In these embodiments, the GAHS may be measured immediately after the last dose of 25HC3S or its salt, or at a predetermined time thereafter, for example, five minutes or more after the last dose of 25HC3S or its salt, for example, ten minutes or more, for example, fifteen minutes or more, for example, thirty minutes or more, for example, sixty minutes or more, for example, two hours or more, for example, six hours or more and for example, twelve hours or more. In a particular embodiment, the patient's GAHS is measured at some point on the same day as the last dose of 25HC3S or its salt.

[0100] In some embodiments, the methods of the present disclosure are sufficient to reduce the GAHS indicated by the patient (for example, on day 7 or 28 from the start of treatment) by 5% or more, e.g., 10% or more, e.g., 15% or more, and e.g., 20% or more, compared to the GAHS measured before treatment with 25HC3S or a salt thereof as described herein.

[0101] Accordingly, improving the GAHS score is one aspect of the present disclosure. One embodiment is the use of 25HC3S or a salt thereof to treat or alleviate symptoms of AH in a subject, characterized by a reduction in the GAHS score 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 symptoms of AH in a subject, characterized by a reduction in the GAHS score 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.

[0102] Lille The Lille score predicts mortality in patients with anemic heart disease (AH). The Lille score is calculated using the following formula: [Math 3] Exp(-R) / [1+exp(-R)] During the ceremony, R=[3.19-(0.101 * Age (years)) + (1.47 * Baseline albumin (g / dL) + [0.28215 * (Baseline bilirubin - Day 8 bilirubin (mg / dL)) - [0.206 * (Baseline creatinine >= 1.3 mg / dL)] - [0.11115 * Bilirubin baseline (mg / dL): -(0.0096) * Baseline prothrombin time (seconds) It is calculated according to the following.

[0103] Accordingly, improving the Lille score is one aspect of the present disclosure. One embodiment is the use of 25HC3S or a salt thereof to treat or alleviate symptoms of AH in a subject, wherein the subject is characterized by a decrease in the Lille score on day 7 from the first administration of 25HC3S or a salt thereof. Another embodiment provides 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, wherein the subject is characterized by a decrease in the Lille score on day 7 from the first administration of 25HC3S or a salt thereof. In some cases, the patient has a Lille score of <0.45 on day 7 from the first administration of 25HC3S or a salt thereof.

[0104] MELD+Lille By combining static and dynamic models to improve prediction in AH, Louvet et al. demonstrated that the MELD+Lille joint-effect model was superior to other combinations, showing that patients with MELD 21 and Lille 0.45 had a 1.9 times higher mortality risk at 2 months than patients with MELD 21 and Lille 0.16 (23.7% vs. 12.5%). Therefore, in some cases, the aforementioned subjects can be diagnosed with AH by using the MELD+Lille joint-effect model.

[0105] In some cases, the aforementioned individuals are diagnosed with alcoholic hepatitis (AH) using the Alcoholic Hepatitis Histological Score (AHHS). The AHHS is based on four histological parameters: the degree of fibrosis, the degree of neutrophil infiltration, the type of bilirubin stasis, and the presence of giant mitochondria.

[0106] In some cases, the patient may have aspartate aminotransferase (AST) > alanine transaminase (ALT) but with a value less than 300 IU / L. In other cases, the patient may have AST > 50, AST / ALT > 1.5, and both values ​​< 400 IU / L.

[0107] In certain embodiments, the subject has aspartate aminotransferase (AST) in a concentration of 50 to 400 IU / L. In certain embodiments, the subject has alanine transaminase (ALT) in a concentration of less than 400 IU / L, for example, 390 IU / L or less, for example, 380 IU / L or less, for example, 370 IU / L or less, for example, 360 IU / L and for example, 350 IU / L. In certain embodiments, the subject has more AST than ALT, for example, in which case the ratio of AST to ALT (i.e., AST / ALT) is 1.05 or greater, for example, 1.1 or greater, for example, 1.15 or greater, for example, 1.2 or greater, for example, 1.25 or greater, for example, 1.3 or greater, for example, 1.35 or greater, for example, 1.4 or greater, for example, 1.45 or greater and for example, 1.5 or greater (for example, preferably here AST / ALT is greater than 1.5). For example, in certain embodiments, the subject may have two or more combinations of these features, e.g., an AST of 50–400 IU / L, an ALT of less than 400 IU / L, and an AST / ALT ratio greater than 1.5. Furthermore, the patient may also have one or more additional clinical features, e.g., onset of jaundice within the past 8 weeks, serum total bilirubin > 3.0 mg / dL, a Maddrey discriminant function ≥ 32 assuming a control prothrombin time of 12 seconds, and / or a MELD score of 21–30.

[0108] In some cases, the patient has albumin levels of approximately 1 g / dL to approximately 5 g / dL, for example, approximately 1 g / dL to approximately 4 g / dL or approximately 2 g / dL to approximately 3 g / dL.

[0109] In some cases, the patient has an International Normalized Ratio (INR) of prothrombin time that is approximately 10 to 30 seconds, for example, approximately 11 to 25 seconds or approximately 15 to 25 seconds. In some embodiments, the method includes measuring the International Normalized Ratio (INR) of the patient to be treated. In these embodiments, the patient's International Normalized Ratio of prothrombin time may be measured at least 10 minutes, for example, at least 15 minutes, for example, at least 30 minutes, for example, at least 60 minutes, for example, at least 2 hours, for example, at least 6 hours and for example, at least 12 hours before treating the patient according to the method of the Disclosure. In certain embodiments, the patient's International Normalized Ratio of prothrombin time is measured the day before treating the patient according to the method described herein.

[0110] In some examples, the method includes measuring the patient's prothrombin time international normalized ratio after one or more cycles of treatment by the method of the present disclosure, for example, after two or more cycles, for example, after three or more cycles, for example, after four or more cycles and for example, after five or more cycles. In these embodiments, the prothrombin time international normalized ratio may be measured immediately after the last dose of 25HC3S or its salt, or at a predetermined time thereafter, for example, five minutes or more after the last dose of 25HC3S or its salt, for example, ten minutes or more, for example, fifteen minutes or more, for example, thirty minutes or more, for example, sixty minutes or more, for example, two hours or more, for example, six hours or more and for example, twelve hours or more. In certain embodiments, the patient's prothrombin time international normalized ratio is measured at some point on the same day as the last dose of 25HC3S or its salt.

[0111] In some embodiments, the methods of the present disclosure are sufficient to reduce the prothrombin time international normalized ratio (ICU) shown by the patient (for example, on day 7 or 28 from the start of treatment) by 5% or more, e.g., 10% or more, e.g., 15% or more, and e.g., 20% or more, compared to the ICU measured before treatment with 25HC3S or a salt thereof as described herein.

[0112] In some cases, the patient has a serum creatinine level of approximately 0.2 mg / dL to approximately 3 mg / dL, for example, approximately 0.4 mg / dL to approximately 2.5 mg / dL or approximately 0.6 mg / dL to approximately 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 at least 10 minutes, for example, at least 15 minutes, for example, at least 30 minutes, for example, at least 60 minutes, for example, at least 2 hours, for example, at least 6 hours and for example, at least 12 hours before treating the patient according to the method of the Disclosure. In certain embodiments, the patient's serum creatinine level is measured the day before treating the patient according to the method described herein.

[0113] In some examples, the method includes measuring the patient's serum creatinine level after one or more cycles of treatment by the method of the present disclosure, for example, after two or more cycles, for example, after three or more cycles, for example, after four or more cycles and for example, after five or more cycles. In these embodiments, the serum creatinine level may be measured immediately after the last dose of 25HC3S or its salt, or at a predetermined time thereafter, for example, five minutes or more after the last dose of 25HC3S or its salt, for example, ten minutes or more, for example, fifteen minutes or more, for example, thirty minutes or more, for example, sixty minutes or more, for example, two hours or more, for example, six hours or more and for example, twelve hours or more. In certain embodiments, the patient's serum creatinine level is measured at some point on the same day as the last dose of 25HC3S or its salt.

[0114] In some embodiments, the methods of the present disclosure are sufficient to reduce the patient's serum creatinine level (for example, on day 7 or day 28 from the start of treatment) by 2% or more, e.g., 5% or more, e.g., 10% or more, and e.g., 15% or more, compared to the serum creatinine level measured before treatment with 25HC3S or a salt thereof as described herein.

[0115] In some cases, the patient presents with acute acute hepatic heart disease (AH), which manifests as acute exacerbation of chronic liver failure (ACLF).

[0116] In some cases, the subject is diagnosed with AH based on circulating fragments of the main components of cytokeratin-18 (CK-18) and Mallory-Denk bodies, referred to as M65 and M30.

[0117] Considering the above, the diagnosis of AH (i.e., the identification of individuals who have AH and could benefit from the practice of this method) is generally based on physical examination, laboratory findings, patient history, and medical history to confirm, for example, changes in mental state, coagulation disorders, rate of onset, and the absence of pre-existing liver disease. In some cases, such AH patients may have other past liver diseases, such as cholestatic liver disease, autoimmune liver disease, active viral hepatitis, Wilson's disease, or other liver disorders not caused by alcohol consumption.

[0118] The definition of "rapid" depends on the specific convention used. There are various subcategories based on the time from the onset of the first liver symptom to the onset of encephalopathy. In some cases, "AH" is accompanied by the onset of encephalopathy, jaundice, or an increase in bilirubin to >3 mg / dL within 26 weeks of the onset of any liver symptom. This is further subdivided into "fulminant hepatic failure," which requires the onset of encephalopathy, jaundice, or an increase in bilirubin to >3 mg / dL within 8 weeks, and "subfulminant," which represents the onset of encephalopathy, jaundice, or an increase in bilirubin to >3 mg / dL after 8 weeks but before 26 weeks from the onset of liver symptoms. In other cases, "hyperacute" hepatic failure may be characterized by onset within 7 days of liver symptoms, "acute" hepatic failure by onset within 7 to 28 days of liver symptoms, and "subacute" hepatic failure by onset within 28 days to 24 weeks of liver symptoms. Subjects who are found to have developed acute liver failure according to any of these criteria may be treated by the methods described herein.

[0119] In some embodiments, the population treated by the methods described herein may or may not have high cholesterol (hypercholesterolemia, e.g., serum cholesterol levels in the range of about 200 mg / dL or higher) or conditions associated with high cholesterol, e.g., hyperlipidemia, atherosclerosis, heart disease, stroke, Alzheimer's disease, cholelithiasis, cholestatic liver disease, etc., and / or may not be diagnosed with such high cholesterol or condition. In some embodiments, the population treated by the methods described herein may not have high cholesterol (hypercholesterolemia, e.g., serum cholesterol levels in the range of about 200 mg / dL or higher) or conditions associated with high cholesterol, e.g., hyperlipidemia, atherosclerosis, heart disease, stroke, Alzheimer's disease, cholelithiasis, cholestatic liver disease, etc., and / or may not be diagnosed with such high cholesterol or condition.

[0120] Instructions for administration The implementation of the above method generally involves identifying patients suffering from AH and administering 25HC3S or a salt thereof in an acceptable form via an appropriate route. The exact total amount administered (e.g., over a one-month period) may vary depending on the individual patient's age, sex, weight, and overall health, as well as the exact etiology of the disease.

[0121] In some embodiments, the total amount of 25HC3S or its salt administered to the patient is surprisingly small. The total amount administered (e.g., over a one-month period) is typically about 0.01 mg / kg to about 50 mg / kg, more commonly about 0.05 mg / kg to about 20 mg / kg, for example, 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 per kg of body weight.

[0122] The total amount is generally about 1 mg to about 1000 mg of 25HC3S or a salt thereof. In some embodiments, the total amount of 25HC3S or a salt thereof administered to the patient in the method (for example, over a period of one month) is about 10 mg to about 500 mg. Typically, in some embodiments, the total amount of 25HC3S or a salt thereof administered to the patient in the method (for example, over a period of one month) is 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 about 300 mg or less, for example, about 200 mg or less, or even more than about 140 mg or less. Specific examples of total amounts to administer 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 varies depending on the route of administration, bioavailability, and the specific formulation being administered. For example, the total amount described herein may be particularly useful for intravenous administration.

[0123] In some embodiments (including, for example, cases where the 25HC3S or a salt thereof is administered intravenously), a low number of doses (fewer administrations) is remarkable. In this regard, the total amount of 25HC3S or a salt thereof administered in the above method may be administered in one dose or in multiple separate doses over a period of time (e.g., a period of one month). In some embodiments, the total amount is administered in 1 to 15 separate doses, for example, 1 to 5 separate doses, for example, 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 (where the total amount is administered in a single dose, the first dose is the single dose; however, in other embodiments, at least one further dose is administered after the first dose).

[0124] In some embodiments, at least one of the one or more separate doses described above, preferably each, contains about 10 mg to about 200 mg of 25HC3S or a salt thereof. For example, in some embodiments, at least one of such one or more separate doses, preferably each, contains about 10 mg to about 120 mg of 25HC3S or a salt thereof, for example, about 20 mg to about 100 mg of 25HC3S or a salt thereof. Specific example doses include (a) to (c) below, namely (a) about 20 mg to about 40 mg of 25HC3S or a salt thereof (e.g., about 30 mg), or (b) about 80 mg to about 100 mg of 25HC3S or a salt thereof (e.g., about 90 mg), or (c) about 140 mg to about 160 mg of 25HC3S or a salt thereof (e.g., about 150 mg). In some embodiments, particularly useful doses may be (a) or (b) above. In some embodiments, a particularly useful number of separate doses with respect to such dosage may be one dose (i.e., a single dose) or two separate doses.

[0125] In some embodiments, the low frequency of administration is remarkable. For example, in some embodiments, the total amount is administered in two or more separate doses at a frequency of administration daily to once a week, for example, every two days to once a week, for example, every two days to once every five days, or every two days to once every four days. One example of such a frequency of administration is once every three days. For example, if the total number of separate doses is two, the second dose may be administered 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 dose.

[0126] In some embodiments, one or more separate doses are administered over a period of administration (meaning the period over which 25HC3S or a salt thereof is actually administered). For example, if the method involves administering the total amount within a period of one month measured from the start of administration of the first dose, the resulting period of administration may be shorter than that one month. Thus, in some embodiments, the period of administration is followed by a "non-administration period" during which 25HC3S or a salt thereof is not administered, and the sum of the administration period and the non-administration period equals the aforementioned one month. In some such embodiments, the administration is 21 days or less, for example, 14 days or less, for example, 7 days or less, or 5 days or less.

[0127] Considering the above, the total amount of 25HC3S or its salt administered within a one-month period may be 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, for example, 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 within a one-month period may be 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.

[0128] The administration of the compounds of this disclosure may be intermittent, stepwise, continuous, constant, or controlled.

[0129] Administration may be via any route, including parenteral routes such as intravenous, intramuscular, and / or subcutaneous injection. The route of administration depends on the nature of the condition being treated, e.g., the type or degree of hepatic impairment and / or hepatic failure. For example, intravenous administration may be preferred to achieve rapid treatment before significant hepatic impairment or failure occurs. Therefore, if damage has already occurred, and especially if acute organ failure is diagnosed, the route of administration is generally parenteral or intravenous to facilitate the delivery of 25HC3S or its salts.

[0130] The 25HC3S may be administered in pure form, or in a pharmaceutically acceptable formulation containing a suitable elixir (generally referred to as a “carrier”), or as a pharmaceutically acceptable salt (e.g., alkali metal salts such as sodium, potassium, calcium, or lithium salts, ammonium, etc.) or other complex. For example, it may be preferable to use a salt of 25HC3S, and the sodium salt of 25HC3S is one example of such a salt. It should be understood that a pharmaceutically acceptable formulation may include liquid materials conventionally used to prepare an injectable dosage form. The 25HC3S or a salt thereof is typically administered as a composition that is a liquid suitable for injection and / or intravenous administration. A solid form suitable for dissolution in a liquid or suspension before administration may be prepared.

[0131] The active ingredient may be mixed with excipients that are pharmaceutically acceptable and compatible with the active ingredient, such as pharmaceutically and physiologically acceptable carriers. Suitable excipients include, for example, water, physiological saline (sodium chloride), cyclodextrin (e.g., hydroxypropyl-beta-cyclodextrin), dextrose, glycerol, ethanol, or combinations thereof. In addition, the composition may contain small amounts of auxiliary substances, such as wetting agents or emulsifiers, pH buffers (e.g., phosphate buffer). Water may be used as a carrier for preparing the composition (e.g., an injectable composition), and the composition may further contain conventional buffers and agents to make the composition isotonic. Other possible additives and other materials (preferably those generally considered safe [GRAS]) include, namely, surfactants (e.g., TWEEN®, oleic acid), solvents, stabilizers, elixirs, and capsule materials (e.g., lactose, liposomes). Preservatives such as methylparaben or benzalkonium chloride may also be used. The compositions of this disclosure may contain any additional components to provide the compositions in a form suitable for the intended route of administration. In addition, the compounds may be formulated with aqueous or oily vehicles.

[0132] Depending on the formulation, the 25HC3S or its salt is expected to be present in an amount of about 1 wt% to about 99 wt% of the composition, and the "carrier" which serves as the medium is expected to account for about 1 wt% to about 99 wt% of the composition. The pharmaceutical compositions of this disclosure may contain any suitable pharmaceutically acceptable additives or adducts to the extent that they do not interfere with or impede the therapeutic effect of the 25HC3S or its salt.

[0133] In some cases, alcoholic hepatitis is characterized by impaired liver function such that the subject exhibits a reduced 25HC3S clearance rate compared to subjects without alcoholic hepatitis. In some cases, alcoholic hepatitis is characterized by impaired liver function such that the subject exhibits a 25HC3S clearance rate of 50% or less, 40% or less, 30% or less, or 25% or less of the 25HC3S clearance rate of subjects without alcoholic hepatitis. In some exemplary, but non-limiting, cases, the 25HC3S clearance rate of subjects without alcoholic hepatitis is considered to be 25 L / hr, while a reduced clearance rate is measured in subjects with alcoholic hepatitis (i.e., subjects with alcoholic hepatitis exhibit a 25HC3S clearance rate of less than 25 L / hr, for example, 50% or less, 40% or less, 30% or less, or 25% or less of 25 L / hr).

[0134] In some cases, the alcoholic hepatitis is characterized by a half-life time (T) of 25HC3S in plasma after administration that is 1.5 times or more greater in the subject compared to a subject without alcoholic hepatitis. 1 / 2 It is characterized by impaired liver function, such as ). In some exemplary, but non-limiting cases, the half-life of a subject without alcoholic hepatitis is considered to be 1.6 hours, while a longer half-life is measured for subjects with alcoholic hepatitis (i.e., subjects with alcoholic hepatitis show a half-life greater than 1.6 hours, e.g., 1.5 times or more, or 2 times or more). In some cases, the time to reach peak drug concentration (T max ) is the end of the injection, for example, a 2-hour injection. In some embodiments, the half-life (t) of 25HC3S or its salt is given. 1 / 2 The half-life of 25HC3S after administration (T) is approximately 4 to 6 hours. In some cases, the half-life of 25HC3S after administration is approximately 1.5 to 6 hours or approximately 2 to 5 hours. 1 / 2 ) indicates.

[0135] In some cases, the average clearance of 25HC3S or its salts is approximately 5 L / hr to approximately 7 L / hr. In other cases, the subject exhibits 25HC3S clearances of approximately 2 L to approximately 8 L / h, approximately 2.5 L / h to approximately 7.5 L / h, or approximately 3 L / h to approximately 7 L / h.

[0136] In some cases, the subjects exhibit a 25HC3S distribution volume of approximately 10 L to 50 L, 15 L to 45 L, or 20 L to 40 L. In some cases, the subjects exhibit a distribution volume lower than that of subjects without alcoholic hepatitis (which may be considered to be, for example, 55 L)—for example, 90% or less, 80% or less, 70% or less, or 60% or less.

[0137] In some cases, the subject exhibits a Cmax of 25HC3S of approximately 500 ng / mL to approximately 10,000 ng / mL, approximately 600 ng / mL to approximately 7,000 ng / mL, or approximately 700 ng / mL to approximately 5,000 ng / mL. For example, in some cases, the subject exhibits a Cmax of 25HC3S of approximately 500 ng / mL to approximately 10,000 ng / mL, approximately 600 ng / mL to approximately 7,000 ng / mL, or approximately 700 ng / mL to approximately 5,000 ng / mL per 100 mg of intravenously administered 25HC3S or its salt.

[0138] In some cases, the aforementioned substance is approximately 3000 ng * h / mL ~ approximately 50,000 ng * h / mL, approximately 4000 ng * h / mL ~ approximately 40,000 ng * h / mL or approximately 5000 ng * h / mL ~ approximately 30,000 ng * This shows the AUCinf of 25HC3S at h / mL. For example, in some cases, the subject may have approximately 5000 ng per 100 mg of 25HC3S or its salt administered intravenously. * h / mL ~ approximately 30,000 ng * h / mL or approximately 6000 ng * h / mL ~ approximately 20,000 ng* This shows the AUCinf of 25HC3S at h / mL.

[0139] In one embodiment, 25HC3S or a salt thereof is used in a subject to treat or alleviate symptoms of AH, wherein the subject exhibits a reduced risk of death 90 days after the first dose of 25HC3S or a salt thereof compared to a subject that has not received 25HC3S or a salt thereof. In a particular embodiment, the risk of death 90 days after the first dose of 25HC3S or a salt thereof, compared to a subject that has not received 25HC3S or a salt thereof, is reduced by 5% or more, e.g., 10% or more, e.g., 25% or more, e.g., 50% or more, e.g., 75% or more, e.g., 90% or more, and also includes cases where the subject exhibits a 99% or greater reduction in the risk of death 90 days after the first dose of 25HC3S or a salt thereof compared to a subject that has not received 25HC3S or a salt thereof.

[0140] In one embodiment, 25HC3S or a salt thereof is used in a subject to treat or alleviate symptoms of AH, wherein the subject shows a reduced risk of death 28 days after the first dose of 25HC3S or a salt thereof compared to a subject that has not been administered 25HC3S or a salt thereof. In a particular embodiment, the risk of death 28 days after the first dose of 25HC3S or a salt thereof, compared to a subject that has not been administered 25HC3S or a salt thereof, is reduced by 5% or more, e.g., 10% or more, e.g., 25% or more, e.g., 50% or more, e.g., 75% or more, e.g., 90% or more, and the subject also shows a reduction of 99% or more in the risk of death 90 days after the first dose of 25HC3S or a salt thereof compared to a subject that has not been administered 25HC3S or a salt thereof.

[0141] In certain embodiments, the methods and compositions of the Disclosure are sufficient to shorten hospital stays compared to subjects who have not been administered 25HC3S or a salt thereof. In some examples, the methods and compositions of the Disclosure are sufficient to shorten hospital stays by, for example, 1% or more, for example, 2% or more, for example, 3% or more, for example, 4% or more, for example, 5% or more, for example, 6% or more, for example, 7% or more, for example, 8% or more, for example, 9% or more, for example, 10% or more, for example, 11% or more, for example, 12% or more, for example, 13% or more, for example, 14% or more, for example, 15% or more, for example, 16% or more, for example, 17% or more, for example, 18% or more, for example, 19% or more, for example, 20% or more, for example, 25% or more, for example, 30% or more, for example, 35% or more, and also include shortening the hospital stay by 40% or more.

[0142] In certain embodiments, the methods and compositions of the present disclosure are sufficient to shorten the duration of treatment in the intensive care unit compared to subjects that have not been administered 25HC3S or a salt thereof. In some examples, such subjects' methods and compositions are sufficient to shorten the duration of treatment in the intensive care unit by, for example, 1% or more, for example, 2% or more, for example, 3% or more, for example, 4% or more, for example, 5% or more, for example, 6% or more, for example, 7% or more, for example, 8% or more, for example, 9% or more, for example, 10% or more, for example, 11% or more, for example, 12% or more, for example, 13% or more, for example, 14% or more, for example, 15% or more, for example, 16% or more, for example, 17% or more, for example, 18% or more, for example, 19% or more, for example, 20% or more, for example, 25% or more, for example, 30% or more, for example, 35% or more, and also include shortening such duration of treatment in the intensive care unit by 40% or more.

[0143] The present invention will be further illustrated by the following examples. These examples are non-limiting and do not restrict the scope of the present invention. Unless otherwise specified, all percentages, parts, etc., presented in these examples are based on weight. (Examples) [Examples]

[0144] As detailed below, a total of 19 patients were enrolled in an open-label, multicenter phase 2a trial. Of these, 15 had a Maddrey discriminant function (MDF) ≥ 32 (severe alcoholic hepatitis (SAH)), 12 had a MELD score of 21–30, and 11 had baseline serum bilirubin levels > 8 mg / dL. All patients received an IV infusion of 25HC3S (30, 90, or 150 mg) on ​​day 1 and day 4 (if still hospitalized) and were followed for 28 days. The final enrollment consisted of 19 patients: 8 patients who received 30 mg (4 moderate and 4 severe), 7 patients who received 90 mg (3 moderate and 4 severe), and 4 patients who received 150 mg (4 severe).

[0145] method: Test reagent The 25HC3S sodium salt solution is as follows: • 30 mg / mL of 25HC3S sodium salt · 240 mg / mL of hydroxypropyl-beta-cyclodextrin, and 50 mM phosphate buffer It contained [something].

[0146] The 25HC3S sodium salt solution was diluted with 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.

[0147] 25HC3S sodium salt was administered by slow intravenous infusion (50 mL / h) over 2 hours until the full dose was administered on days 1 and 4. If a patient met the discharge criteria before the second dose, only one dose was administered instead of two.

[0148] Examination Procedure The aforementioned study was conducted in two parts. Part A included patients with MELD scores of 11–20 (moderate AH patients), and Part B included patients with MELD scores of 21–30. The doses of 25HC3S sodium salt administered were 30 mg and 90 mg for Part A, and 30 mg, 90 mg, and 150 mg for Part B, with 4 patients per dose group per part (except for the 90 mg cohort in Part A, which had 3 patients). All patients were followed up until day 28.

[0149] The aforementioned study was initiated in four patients with moderate acute heartburn (AH) at a dose level of 30 mg (Part A). After completion of administration, the Dose Elevation Committee (DEC) evaluated the safety, tolerability, and pharmacokinetic (PK) data obtained from all four patients and determined that it was safe to proceed to administer the same dose level of 30 mg to four patients with severe AH (Part B), and to escalate the dose level to 90 mg in the moderate patients (Part A). Subsequently, the same dose escalation procedure was followed until all four patients in Part B received a dose of 150 mg.

[0150] The flow diagram of the aforementioned study is shown in Figure 2. Up to four subjects were enrolled in each dose cohort. Subjects were administered up to two doses of 25HC3S sodium salt. The first dose was administered on day 1, and if the subject was still hospitalized, the second dose was administered on day 4. Pharmacokinetic (PK) samples were collected at the following time points, namely 0 hours (before administration), 1 hour after the start of administration, 2 hours after the start of administration (end of infusion), 3 hours after the start of administration, 4 hours after the start of administration, 8 hours after the start of administration, 12 hours after the start of administration, 24 hours after the start of administration, and 50 hours after the start of administration.

[0151] Group: 1. In this clinical trial, the following a to d, i.e. a. A history of severe alcohol abuse for a period of at least 6 months: >40 g / day for women or >60 g / day for men, b. Alcohol consumption within 12 weeks prior to participation in the aforementioned test, and c. Serum bilirubin > 3 mg / dL and AST > ALT, but less than 300 U / L, d. MELD score 11-30 (including the numbers at both ends) A patient suffering from alcoholic hepatitis, as defined by the following criteria.

[0152] The table below shows a list of baseline test characteristics for each cohort. [Table 1]

[0153] evaluation: Evaluation of pharmacodynamic (PD) signals: Changes in Lille score, MELD score, and biochemistry (e.g., bilirubin) Method and timing: The Lille score was calculated on the 7th day. The MELD score was calculated at screening, on day 1 (pre-administration), on day 7, and on day 28.

[0154] Biochemical and all safety laboratory parameters were collected at screening, before administration on days 1 and 4, 12 hours after completion of administration / infusion on days 1 and 4, on days 2, 7, and 28, and on days 3, 4, 5, and 6 if the patient was hospitalized. Assessment of safety signals: Safety was assessed based on clinical and laboratory monitoring. PK's rating: Using plasma concentration data of 25HC3S obtained from each patient, the relevant PK parameters were calculated using the standard linear / logarithmic-trapezoidal non-compartment method in conjunction with an appropriate PK data analysis program. PK samples were collected at the following times (only after dose 1): 0 (before administration), 1 hour after the start of administration, 2 hours after administration (end of infusion), 3 hours, 4 hours, 8 hours, 12 hours, and 24 hours.

[0155] result: The aforementioned 25HC3S was safe in all three doses, with no serious drug-related adverse events observed. All patients, including those with SAH, survived the 28-day follow-up period. Some patients received one dose, while others received two doses. The administered doses ranged from 30 mg to 300 mg. Of the 18 patients who visited the hospital on day 7, 4 received two doses, and 14 received one dose.

[0156] Drug exposure to AH patients (AUC and C max Both of the two were dose-proportional. Time to reach peak drug concentration (T max The value was obtained at the end of the 2-hour infusion. The mean plasma concentrations of 25HC3S sodium in subjects with moderate and severe AH are shown in Figures 3A and 3B, respectively. The half-life of 25HC3S sodium (t 1 / 2 The time between administrations was 4–6 hours. The mean clearance of 25HC3S sodium was approximately 5–7 L / hr. The PK parameters of 25HC3S sodium were similar between the moderate and severe AH groups. A summary of the PK parameters in subjects with moderate and severe AH at each dosage level is shown in the table below. Figure 4 shows plots of Cmax (Figure 4A) and AUC (Figure 4B) for subjects with moderate and severe AH.

[0157] [Table 2]

[0158] Compared to the PK parameters of 25HC3S sodium in healthy subjects, C was observed in AH patients at the same dose level (single dose of 150 mg). maxA twofold increase in and an approximately fivefold increase in AUC were observed. The clearance of 25HC3S sodium was 80% lower in AH patients compared to the clearance obtained in healthy subjects in previous studies. The table below summarizes the comparison of pharmacokinetic parameters of 25HC3S administered to healthy subjects and subjects with alcoholic hepatitis. Figure 5 shows a comparison of plasma concentrations of 25HC3S administered to healthy subjects and subjects with alcoholic hepatitis.

[0159] [Table 3]

[0160] Among all AH patients treated with 25HC3S (one patient did not return for a visit on day 7), 89% responded to the treatment (Lille score < 0.45), 87% among 15 SAH patients (MDF ≥ 32), and 83% among 12 patients with a MELD of 21-30. In particular, 100% of SAH patients treated with 30 or 90 mg of 25HC3S (n=11) responded to the treatment, as shown in the table below.

[0161] [Table 4]

[0162] Patients received either one or two doses of 25HC3S, and in SAH patients, the MELD score at day 28 was significantly reduced from baseline (-17.5%, p=0.01). In SAH patients treated with 30 or 90 mg of 25HC3S, the median reduction in MELD at day 28 from baseline was -19.0% (p=0.01). The 25HC3S also significantly reduced serum bilirubin levels at day 7 in AH patients, particularly in patients with baseline bilirubin >8.0 mg / dL (-25.1%, p=0.02).

[0163] When comparing our data with a series of data used by Louvet et al. to develop the Lille score, which evaluated 145 AH patients (using comparative DF score, prothrombin time, and serum creatinine, albumin, and bilirubin levels, as in this study), the Lille score obtained in our study was significantly lower than the historical Lille score of 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).

[0164] The clinical data obtained in this study also show that the aforementioned 19 patients treated with 25HC3S had statistically significantly greater decreases from baseline in bilirubin (days 7 and 28) and MELD (day 28), as well as statistically significantly lower Lille scores, compared to the historical control group (n=15) in the University of Louisville (UL) AH study. See Figure 1. UL shared anonymized data from 16 AH patients with initial MELD scores of 15–30 who received supportive care alone (n=9) or supportive care with corticosteroids (n=7). Of the aforementioned 19 AH patients using 25HC3S, one patient did not return to the clinic on day 7, so Lille scores could only be calculated for 18 of the 19 patients.

[0165] The Lille score is used in clinical practice to help determine the prognosis of AH patients 7 days after treatment. A lower Lille score indicates a better prognosis for the AH patient. Patients with a Lille score of less than 0.45 have an 85% 6-month survival rate compared to patients with a Lille score above 0.45, who have a 6-month survival rate of only 25% (Louvet A et al., Hepatology, 45:1348-54 (2007)). In this study, the median Lille score of the 18 AH patients treated with 25HC3S and who visited the hospital 7 days later was 0.10. 89% (16 / 18) had a Lille score of less than 0.45. Among the 16 patients in the UL cohort treated with supportive care or supportive care with corticosteroids, the median Lille score was 0.41, and 50% (8 / 16) had a Lille score of less than 0.45.

[0166] In this study, the median Lille score for all 18 AH patients treated with 25HC3S and presenting at day 7, taken from five cohorts (both moderate and severe AH), was 0.10, with an interquartile range of 0.04–0.20. For comparison, the median Lille score between cohorts of 16 patients treated with or without corticosteroids (standard of care [SOC]) at the University of Louisville (UL) was 0.41 (shown as a historical control), with an interquartile range of 0.14–0.73, and the 1-month and 3-month mortality rates were 12.5% ​​and 31.3%, respectively. In addition to no serious adverse events occurring under treatment, patients receiving 25HC3S had significantly lower Lille scores (p=0.005) than patients treated with SOC.

[0167] Figure 6 shows the Lille score measured on day 7, plotted against the AUC of subjects diagnosed with moderate pulmonary hemorrhage (AH) administered 30 mg and 90 mg of 25HC3S sodium, as well as the Lille score of subjects diagnosed with severe AH administered 30 mg, 90 mg, and 150 mg of 25HC3S sodium. As shown in Figure 6, all subjects administered 30 mg and 90 mg of 25HC3S sodium had a Lille score of less than 0.45 on day 7. Two of the subjects with severe AH who received 150 mg of 25HC3S sodium had a Lille score greater than 0.45 on day 7.

[0168] AH patients treated with the aforementioned 25HC3S also showed a statistically significant decrease of -14% (n=18) in serum total bilirubin levels from baseline on day 7, compared to -3% on day 7 in the aforementioned UL patients.

[0169] The aforementioned 25HC3S was well tolerated in all patients, and no serious drug-related adverse events were reported at any dose level. Drug exposure was dose-proportional and not affected by disease severity.

[0170] Conclusion: In this Phase 2a trial, 25HC3S was well tolerated at the three doses tested in all AH patients, including those with SAH. There were no interruptions of the study drug or participation due to adverse effects, early withdrawal, or discontinuation, and no serious adverse effects associated with 25HC3S were observed. All patients survived the 28-day follow-up period (i.e., 100% survival rate). The pharmacokinetics of 25HC3S in both moderate and severe AH patients were similar and dose-proportional with respect to the doses administered. At a given dose, systemic clearance of 25HC3S was approximately five times lower in AH patients compared to healthy controls.

[0171] One or two doses of the aforementioned drugs significantly reduced serum bilirubin levels at day 7 post-treatment and MELD scores at day 28. A 100% treatment response rate (Lille score < 0.45) was observed in patients treated with 30 mg or 90 mg of 25HC3S, and an 89% response rate was observed in all patients. Lille scores in patients treated with 25HC3S were significantly better than those in previously published historical data used for comparison. [Examples]

[0172] 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).

[0173] Exam design The subjects were selected for the following test treatment groups: [Table 5] They are randomly assigned in a 1:1:1 ratio.

[0174] The first dose (day 1 dose) of the assigned IV test treatment (investigation drug) is administered in the hospital setting immediately after the subjects are randomized.

[0175] The second dose of the assigned IV test treatment (investigation drug) is administered on the fourth day, or three days after the first dose, if the subject is still hospitalized. If the subject meets the discharge criteria before the fourth day, only one dose of 25HC3S is administered to the subject.

[0176] Administer a total of two or fewer intravenous injection test treatments (test drug).

[0177] If the investigator at the site decides to use corticosteroids (CS) as part of standard treatment, then 32 mg methylprednisolone capsules (or the corresponding steroid placebo capsules) should be used. Administration of the CS capsules or placebo capsules may be initiated at any time at the discretion of the investigator at the site, in accordance with the AASLD guidelines, and may also be discontinued at any time, particularly if the Lille score on day 7 is >0.45.

[0178] Test drug, dosage, and mode of administration 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 then inject over approximately 2 hours.

[0179] Sterile, ready-to-use 25HC3S for injection is available in the following two sizes: • 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. It will be supplied by [this method].

[0180] The concentration of the DUR-928 injection product to be used in this study is 30 mg / mL of the 25HC3S free acid, which corresponds to 31.4 mg / mL of the 25HC3S sodium salt.

[0181] The aforementioned 25HC3S injection or placebo is diluted in a 100 mL infusion bag containing 5% dextrose or 0.9% sodium chloride intravenous solution. This 25HC3S or placebo solution is administered to the subject by IV infusion over approximately 2 hours.

[0182] Control drug, dosage, and mode of administration: Dilute 3 mL of sterile water for injection with 100 mL of 5% dextrose or 0.9% sodium chloride, then inject over approximately 2 hours.

[0183] group In this clinical trial, the following occurred: Onset of jaundice within the past 8 weeks The average daily alcohol consumption for a period of 6 months or longer is >40 grams (women) or >60 grams (men), including <8 weeks of abstinence prior to the onset of jaundice. Decisions regarding daily and long-term alcohol consumption and the onset of jaundice will be made by the clinical trial physician at the facility. Serum chemistry (measured at the local laboratory): Serum total bilirubin > 3.0 mg / dL 50 <AST<400 IU / L ALT < 400 IU / L AST / ALT > 1.5 Assuming a control prothrombin time of 12 seconds, the Maddrey discriminant function is ≥ 32. End-Stage Liver Disease (MELD) score: 21-30 A patient suffering from alcoholic hepatitis, as defined by the following criteria.

[0184] Evaluation items Primary evaluation criteria: 90-day mortality rate between the active drug group and the placebo (SOC) group (time frame: day 90) Secondary evaluation items: 28-day mortality rate between the aforementioned treatment groups (time frame: day 28) Lille score on day 7 after the start of treatment with the investigational drug between the aforementioned treatment groups (time frame: day 7) MELD scores (time frame: day 28) on day 28 after the start of treatment with the investigational drug between the aforementioned treatment groups. ICU stay duration on day 28 (time frame: Day 1 to Day 28). This disclosure includes the following embodiments. [1] A method for treating alcoholic hepatitis in a human subject in need of treatment for alcoholic hepatitis, comprising administering to the subject 5-cholesten-3,25-diol,3-sulfate(25HC3S) or a salt thereof in an amount sufficient to treat the alcoholic hepatitis. [2] The method according to Embodiment 1, wherein the administration comprises administering a total amount of 25HC3S or a salt thereof, which is approximately 1 mg to approximately 1000 mg. [3] The method according to Embodiment 1 or 2, wherein the administration comprises administering a total amount of 25HC3S or a salt thereof, which is approximately 10 mg / month to approximately 400 mg / month. [4] The method comprises administering to the human subject a total amount of approximately 10 mg to approximately 400 mg of 25HC3S or a salt thereof over a period of one month, where - The total amount is sufficient to treat the alcoholic hepatitis, - The total amount is administered in one or more separate doses, including at least the first dose, and - The one-month period is measured from the start of administration of the first dose. The method according to any one of Embodiments 1 to 3. [5] The method according to any one of Embodiments 2 to 4, wherein the total amount is administered in one dose or in two separate doses, preferably as a single dose. [6] The method according to any one of Embodiments 4 to 5, wherein at least one of the one or more separate doses described above, preferably each, contains about 10 mg to about 200 mg of 25HC3S or a salt thereof. [7] The method according to any one of Embodiments 4 to 6, wherein at least one of the one or more separate doses described above, preferably each, contains about 20 mg to about 100 mg of 25HC3S or a salt thereof. [8] The method according to any one of Embodiments 2 to 7, wherein the total amount is administered in two or more separate doses at a frequency of daily to once a week. [9] The following, that is, - The total amount may be administered in one dose or in two separate doses. -The said dose contains approximately 10 mg to approximately 200 mg of 25HC3S or a salt thereof. -Each of the two separate doses contains approximately 10 mg to approximately 200 mg of 25HC3S or a salt thereof, -These two separate doses are administered at a frequency of once every two to four days. The method described in Embodiment 4.

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

[11] The method according to any one of embodiments 1 to 10, wherein the administration is carried out by injection.

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

[13] The method according to any one of Embodiments 1 to 12, wherein the 25HC3S or its salt comprises a salt of 25HC3S, and the salt of 25HC3S is preferably a sodium salt.

[14] 5-Cholesten-3,25-diol, 3-sulfate (25HC3S) or a salt thereof for use in a method of treating alcoholic hepatitis in human subjects in need thereof, wherein the method is the method described in any of Embodiments 1 to 13.

[15] Use of 5-cholesten-3,25-diol,3-sulfate(25HC3S) or a salt thereof in a method for manufacturing a medicament for use in a method for treating alcoholic hepatitis in human subjects in need thereof, wherein the method is one of the methods described in any of Embodiments 1 to 13.

Claims

1. A pharmaceutical composition for treating alcoholic hepatitis in human subjects who require treatment for alcoholic hepatitis, The aforementioned compositions include 5-cholestene-3,25-diol, 3-sulfate (25HC3S) or a salt thereof. The aforementioned treatment includes administering 5-cholesten-3,25-diol,3-sulfate (25HC3S) or a salt thereof to the subject in a total amount of 20 mg to 200 mg over a period of one month. The aforementioned total amount is sufficient to treat the alcoholic hepatitis. The total amount is administered as one or more individual doses, including at least the first dose. The aforementioned one-month period is measured from the start of administration of the first dose. The above one or more individual doses are 20 mg to 100 mg of 5-cholestene-3,25-diol, 3-sulfate (25HC3S) or a salt thereof. The composition.

2. The composition according to claim 1, wherein the total amount is administered in one dose or in two separate doses.

3. The composition according to claim 1 or 2, wherein the total amount is administered in two or more individual doses administered at a frequency of daily to once a week.

4. In the above measures, - The total amount is administered as one dose, or as two separate doses. - The said dose contains 20 mg to 40 mg of 25HC3S or a salt thereof, - Each of the two individual doses is 20 mg to 40 mg of 25HC3S or a salt thereof, and - The two individual doses are administered at a frequency of once every two to four days. The composition according to claim 1.

5. The composition according to any one of claims 1 to 4, wherein the administration in the treatment is carried out parenterally, intravenously, intramuscularly, or subcutaneously.

6. The composition according to any one of claims 1 to 5, wherein the administration in the aforementioned procedure is carried out by injection.

7. The composition according to any one of claims 1 to 6, wherein in the treatment, the 25HC3S or a salt thereof is administered in a formulation comprising the 25HC3S or a salt thereof and a pharmaceutically acceptable carrier.

8. The composition according to any one of claims 1 to 7, wherein the 25HC3S or its salt comprises a salt of 25HC3S.

9. The composition according to claim 1, wherein in the treatment, the total amount of 25HC3S is administered in individual doses of 1 to 5.

10. The composition according to claim 9, wherein in the treatment, the total amount of 25HC3S is administered in a single dose.

11. In the aforementioned study, The total amount is administered in one dose or in two separate doses. The aforementioned dose 1 contains 80 mg to 100 mg of 25HC3S or a salt thereof. The two individual doses are 80 mg to 100 mg of 25HC3S or a salt thereof, and The two individual doses mentioned above are administered at a dose frequency ranging from once every two days to once every four days. The composition according to claim 1.

12. The composition according to any one of claims 1 to 11, wherein the human subject has at least 11 end-stage liver disease model (MELD) scores in the treatment described above.

13. The composition according to any one of claims 1 to 12, wherein the human subject has at least 32 Maddrey discriminant functions (MDFs) in the above treatment.

14. The composition according to any one of claims 1 to 13, wherein the 25HC3S or its salt comprises a sodium salt of 25HC3S.

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