Granted Patent B2

US 12,642,805 · App. 18/008,588 · Granted Jun 2, 2026

Inventors: Shunlin Ren (Richmond, VA); Yaping Wang (Richmond, VA); WeiQi Lin (Emerald Hills, CA); James E. Brown (Los Gatos, CA); Terrence Blaschke (Stanford, CA)

Assignees: Medicis Pharmaceutical Corporation; Virginia Commonwealth University; The United States Government as Represented by the Department of Veterans Affairs

A61K31/575A61P3/10A61P29/00A61P35/00A61P37/02

Abstract

Claims (33)

1 . A method of treating insulin resistance in a human subject in need thereof, the method comprising orally administering to the subject at least one compound selected from 25-hydroxycholesterol-3-sulfate (25HC3S), 25-hydroxycholesterol-disulfate (25HCDS), 27-hydroxycholesterol-3-sulfate (27HC3S), 27-hydroxycholesterol-disulfate (27HCDS), 24-hydroxycholesterol-3-sulfate (24HC3S), 24-hydroxycholesterol-disulfate (24HCDS), and 24,25-epoxycholesterol-3-sulfate, or salt thereof in an amount ranging from 1 mg/day to 300 mg/day, wherein the human subject has a magnetic resonance imaging-proton density fat fraction (MRI-PDFF) prior to treatment of at least 5%, or a magnetic resonance elastography (MRE) prior to treatment≥2.75 kPa.

2 . A method of treating diabetes in a human subject in need thereof, the method comprising orally administering to the subject at least one compound selected from 25-hydroxycholesterol-3-sulfate (25HC3S), 25-hydroxycholesterol-disulfate (25HCDS), 27-hydroxycholesterol-3-sulfate (27HC3S), 27-hydroxycholesterol-disulfate (27HCDS), 24-hydroxycholesterol-3-sulfate (24HC3S), 24-hydroxycholesterol-disulfate (24HCDS), and 24,25-epoxycholesterol-3-sulfate, or salt thereof in an amount ranging from 1 mg/day to 300 mg/day, wherein the human subject has a magnetic resonance imaging-proton density fat fraction (MRI-PDFF) prior to treatment of at least 5%, or a magnetic resonance elastography (MRE) prior to treatment≥2.75 kPa.

3 . The method of claim 2 , wherein the diabetes is type I diabetes.

4 . The method of claim 2 , wherein the diabetes is type II diabetes.

5 . The method of claim 1 , wherein the human subject has non-alcoholic steatohepatitis (NASH).

6 . A method of treating non-alcoholic steatohepatitis (NASH) and at least one of insulin resistance, diabetes and prediabetes, in a human subject in need thereof, the method comprising orally administering to the subject at least one compound selected from 25-hydroxycholesterol-3-sulfate (25HC3S), 25-hydroxycholesterol-disulfate (25HCDS), 27-hydroxycholesterol-3-sulfate (27HC3S), 27-hydroxycholesterol-disulfate (27HCDS), 24-hydroxycholesterol-3-sulfate (24HC3S), 24-hydroxycholesterol-disulfate (24HCDS), and 24,25-epoxycholesterol-3-sulfate, or salt thereof in an effective amount, wherein the human subject has a magnetic resonance imaging-proton density fat fraction (MRI-PDFF) prior to treatment of at least 5%, or a magnetic resonance elastography (MRE) prior to treatment≥2.75 kPa.

7 . The method of claim 1 , wherein the orally administering comprises orally administering the at least one compound in an amount ranging from 1 mg/day to 100 mg/day.

8 . The method of claim 1 , wherein the orally administering comprises orally administering the at least one compound in an amount ranging from 5 mg/day to 90 mg/day or 10 mg/day to 80 mg/day.

9 . The method of claim 1 , wherein the orally administering comprises orally administering the at least one compound in an amount ranging from 30 mg/day to 70 mg/day.

10 . The method of claim 1 , wherein a total amount per kg of the at least one compound that is orally administered to the subject: (a) ranges from 0.1 mg/kg/day to 5 mg/kg/day; or (b) ranges from 0.2 mg/kg/day to 4 mg/kg/day; or (c) ranges from 0.3 mg/kg/day to 3 mg/kg/day; or (d) ranges from 0.4 mg/kg/day to 2 mg/kg/day.

11 . The method of claim 1 , wherein the orally administering comprises orally administering a plurality of doses of the at least one compound.

12 . The method of claim 11 , wherein:

(a) the doses are orally administered at a frequency ranging from once weekly to three times a day, or once a day, or twice a day; and/or

(b) the orally administering comprises orally administering for a dosing period of at least 7 days.

13 . The method of claim 1 , wherein the at least one compound is orally administered in a formulation comprising the at least one compound and a pharmaceutically acceptable carrier.

14 . The method of claim 1 , wherein:

(a) the at least one compound comprises a salt; or

(b) the at least one compound comprises a salt of 25HC3S; or

(c) the at least one compound comprises a salt that is sodium salt; or

(d) the at least one compound comprises a sodium salt of 25HC3S.

15 . The method of claim 1 , wherein the subject exhibits one or more of:

(a) a half-life time of the at least one compound in the plasma after administration (T1/2) ranging from 1 hour to 5 hours or from 1.5 hour to 4 hours;

(b) a C max of the at least one compound ranging from 25 ng/mL to 4000 ng/mL, 25 ng/mL to 200 ng/mL, from 50 ng/mL to 150 ng/mL, from 75 ng/mL to 125 ng/mL, from 300 ng/mL to 1500 ng/mL, from 400 ng/mL to 1250 ng/mL, or from 500 ng/mL to 1000 ng/mL;

(c) a C max of the at least one compound ranging from 100 ng/mL to 300 ng/mL, from 120 ng/mL to 250 ng/mL, from 150 ng/mL to 200 ng/mL, from 100 ng/mL to 300 ng/mL, from 120 ng/mL to 250 ng/mL, or from 150 ng/mL to 200 ng/mL, per 100 mg of orally administered at least one compound;

(d) an AUCinf of the at least one compound ranging from 300 ng*h/mL to 1000 ng*h/mL, 400 ng*h/mL to 900 ng*h/mL, from 500 ng*h/mL to 800 ng*h/mL, 2700 ng*h/mL to 9000 ng*h/mL, 3000 ng*h/mL to 8000 ng*h/mL, or from 3500 ng*h/mL to 7000 ng*h/mL;

(e) an AUCinf of the at least one compound ranging from 600 ng*h/mL to 1000 ng*h/mL, 700 ng*h/mL to 900 ng*h/mL, or from 800 ng*h/mL to 900 ng*h/mL, per 100 mg of orally administered at least one compound;

(f) an apparent volume of distribution (Vz/F) of the at least one compound ranging from 300 L to 1000 L, 400 L to 900 L, or from 500 L to 800 L; and

(g) an apparent clearance (CL/F) of the at least one compound ranging from 100 L to 200 L/h, 110 L/h to 180 L/h, or from 120 L/h to 160 L/h.

16 . The method of claim 1 , wherein the human subject is taking a lipid lowering drug, or further comprising administering to the human subject a lipid lowering drug.

17 . The method of claim 1 , wherein the human subject is taking at least one of insulin, a glitazone, GLP-1, glucagon, DDP-4 inhibitor, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin, or further comprising administering to the human subject at least one of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

18 . The method of claim 12 , wherein the dosing period is at least 14 days.

19 . The method of claim 12 , wherein the dosing period is at least 28 days.

20 . The method of claim 16 , wherein the lipid lowering drug is at least one of a statin, fenofibrate, omega-3 fatty acid, icosapent ethyl, and fish oil.

Assignments (4)

Continuity (11)

References Cited (279)