Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
  • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
  • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• SHAH et al. “Pharmacokinetic and Pharmacodynamic Response in Individual NASH Patients Receiving Two Dose Levels of DUR-928,” NASH Summit – 2019 (April 22-25, 2019) discloses oral administration of 5-cholesten-3 ⁇ ,25-diol 3-sulfate (25HC3S) to NASH patients. The patients received both 50 mg and 200 mg doses administered approximately two months apart. SHAH et al. concludes that there were no dose- dependent changes of biological responses between 50 mg and 200 mg dose levels. There is an urgent need for improved methods to treat NASH. SUMMARY The present disclosure provides a variety of methods of treating non-alcoholic steatohepatitis (NASH).
• NASH non-alcoholic steatohepatitis
• any one of aspects 12 to 15, wherein the orally administering comprises orally administering for a dosing period of at least 7 days, such as at least 14 days, at least 28 days, at least 3 months, at least 6 months, or at least 1 year.
• the orally administering comprises orally administering for a dosing period of at least 7 days, such as at least 14 days, at least 28 days, at least 3 months, at least 6 months, or at least 1 year.
• the 25HC3S or salt thereof is orally administered in a formulation comprising the 25HC3S or salt thereof and a pharmaceutically acceptable carrier.
• the 25HC3S or salt thereof comprises a salt of 25HC3S.
• the method of aspect 18, wherein the salt of 25HC3S is sodium salt. 20.
• NASH non-alcoholic steatohepatitis
• At least one parameter that is known to be associated with NASH has been measured, detected or observed in the subject.
• “Treatment” of NASH involves the lessening or attenuation, or in some instances, the complete eradication, of at least one symptom of NASH that was present prior to or at the time of administration of 25HC3S or salt thereof.
• treating NASH according to the present disclosure is sufficient to improve laboratory or clinical indicators of NASH in the subject as described in greater detail below. In certain instances, the improvement in the laboratory or clinical indicators of NASH in the subject is such that the subject is considered to no longer have NASH.
• a “human subject [is] receiving statin therapy” when defining a subject to be treated according to the disclosure, typically refers to a human subject who is receiving/has received statin therapy prior to commencing a method of the disclosure, e.g. prior to commencing administration of the 25HC3S or salt thereof.
• the human subject may or may not continue to receive statin therapy during the period of treatment with the 25HCS3 or salt thereof, and any continued statin therapy may be identical to or different from the statin therapy prior to commencing the period of treatment with the 25HCS3 or salt thereof.
• treatment according to the methods described herein results in an improvement (i.e., a reduction) in hepatocyte ballooning.
• hepatocyte ballooning is visualized using hematoxylin and eosin straining.
• treatment according to the methods described herein results in an improvement in one or more biomarkers of NASH, such as but not limited to markers of apoptosis (e.g., CK-18 fragments), adipokines (e.g., adiponectin, leptin, resistin, or visfatin), inflammatory markers (e.g., TNF-a, IL-6, chemo-attractant protein- 1, or high sensitivity C-reactive protein).
• markers of apoptosis e.g., CK-18 fragments
• adipokines e.g., adiponectin, leptin, resistin, or visfatin
• inflammatory markers e.g., TNF-a, IL-6, chemo-
• biomarker values are measured using a sample that comprises a fluid, e.g., blood, plasma, serum, urine, or cerebrospinal fluid.
• biomarker values are measured using a sample that comprises cells and/or tissues, e.g., hepatocytes or liver tissue.
• treatment results in an improvement in the biomarker CK-18.
• treatment results in a reduction in plasma CK-18 levels in the subject.
• methods include treating a subject in a manner sufficient to reduce the level of an adiponectin, HMW biomarker, such as by 1% or more, such as by 2% or more, such as by 3% or more, such as by 4% or more, such as by 5% or more, such as by 6% or more, such as by 7% or more, such as by 8% or more, such as by 9% or more, such as by 10% or more, such as by 11% or more, such as by 12% or more, such as by 13% or more, such as by 14% or more, such as by 15% or more, such as by 16% or more, such as by 17% or more, such as by 18% or more, such as by 19% or more, such as by 20% or more, such as by 25% or more, such as by 30% or more, such as by 35% or more and including by 40% or more.
• administering 25HC3S is sufficient to reduce the amount of serum AST to an amount that is below the upper limit of normal levels of AST.
• compositions, unit dosage forms, pharmaceutical packages, and kits comprising 25HC3S or salt thereof for use in the methods described herein are provided.
• the formulations, unit dosage forms, pharmaceutical packages, and/or kits are for use in treating NASH.
• oral 25HC3S or salt thereof formulations are formulated as immediate release preparations, and are conveniently packaged, for example, in unit dosage forms in the form of a pill, capsule, or tablet, which in turn may be in a pill bottle or blister packaging.
• Dosages and desired drug concentration of pharmaceutical compositions of the disclosure may vary depending on the particular use envisioned. The determination of the appropriate dosage or route of administration is well within the skill of one in the art.
• Low and high dose groups showed statistically significant median reductions from baseline of serum ALT levels at -16% and -17%, respectively.
• the high dose group also showed statistically significant median reductions from baseline of serum AST (-18%) and GGT (-8%) levels, as well as FIB-4 (-15%) and APRI (-26%) scores.
• the low dose group had a statistically significant reduction at day 28 from baseline in liver stiffness as measured by Fibroscan (-10%).
• Patients in the low and medium dose groups also had statistically significant median reduction at day 28 from baseline of serum triglycerides (-13% in the 50 mg group) or LDL-C (-11% in the 150 mg group).

Landscapes

• Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Epidemiology (AREA)
• General Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Gastroenterology & Hepatology (AREA)
• Nutrition Science (AREA)
• Physiology (AREA)
• Emergency Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Steroid Compounds (AREA)

Priority Applications (9)

Applications Claiming Priority (8)

Publications (1)

Family

ID=78707644

Family Applications (1)

Country Status (11)

Families Citing this family (1)

Citations (4)

Family Cites Families (6)

• 2021
  • 2021-05-21 BR BR112022022737A patent/BR112022022737A2/pt not_active Application Discontinuation
  • 2021-05-21 US US17/924,101 patent/US20230181601A1/en active Pending
  • 2021-05-21 JP JP2022570474A patent/JP2023527153A/ja active Pending
  • 2021-05-21 CA CA3195103A patent/CA3195103A1/en active Pending
  • 2021-05-21 WO PCT/US2021/033743 patent/WO2021237143A1/en not_active Ceased
  • 2021-05-21 KR KR1020227043976A patent/KR20230015939A/ko active Pending
  • 2021-05-21 CN CN202180049351.XA patent/CN115916181A/zh active Pending
  • 2021-05-21 AU AU2021273936A patent/AU2021273936A1/en active Pending
  • 2021-05-21 MX MX2022014575A patent/MX2022014575A/es unknown
  • 2021-05-21 EP EP21808175.0A patent/EP4153164A4/en active Pending
  • 2021-05-21 TW TW110118457A patent/TW202210081A/zh unknown

Patent Citations (4)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events