Processing

Please wait...

Settings

Settings

Goto Application

1. WO2016149111 - TREATING LATENT AUTOIMMUNE DIABETES OF ADULTS WITH FARNESOID X RECEPTOR AGONISTS TO ACTIVATE INTESTINAL RECEPTORS

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

We claim:

1. A method of treating or preventing latent autoimmune diabetes of adults (LADA) in a subject, comprising administering to a gastrointestinal tract of the subject a therapeutically effective amount of one or more farnesoid X receptor (FXR) agonists, thereby activating FXR receptors in the intestine of the subject.

2. The method of claim 1, wherein the one or more FXR agonists is minimally absorbed systemically.

3. The method of claim 1 or 2, wherein the method substantially restores pancreatic beta cell function in the subject, increases glucose-stimulated insulin secretion (GSIS), increases glucagon-like peptide 1 (GLP1) secretion in enteroendrocrine L cells of the subject, increases expression of glucagon-like peptide- 1 receptor (GLP-1R) in pancreatic beta cells of the subject, or combinations thereof, relative to no administration of the one or more FXR agonists.

4. The method of any of claims 1-3, wherein the method improves glucose homeostasis in the subject.

5. The method of any of claims 1-4, further comprising detecting one or more markers of pancreatic beta cell damage in the subject.

6. The method of claim 5, wherein the one or more markers of pancreatic beta cell damage comprises thioredoxin-interacting protein (Txnip).

7. The method of any one of claims 1-6, wherein the one or more FXR agonists has the following structure:

wherein,

R is selected from

Ra is selected from aryl, heteroaryl, alkyl, alkenyl, cycloalkyl, heterocyclic, or polycyclic;

Rb is selected from hydrogen, alkyl, alkenyl, or cycloalkyl; Y is CRg, N or N-O (N- oxide);

Rc, Rd, Re and Rg are each independently selected from hydrogen, deuterium, halide, alkyl, alkenyl, alkoxy, alkylthio, amino, sulfonyl, aminosulfonyl, aminocarbonyl, acyl, hydroxyl or nitro;

Rfa and Rfb are each independently selected from hydrogen, deuterium, halide or alkyl; La and Lb are each independently selected from hydrogen, deuterium, alkyl or cycloalkyl, or together form a pi-bond;

Lc and Ld are each independently selected from hydrogen, deuterium, alkyl or cycloalkyl; W is selected from O or ‒(C(Lc)(Ld))s-;

s is 1, 2, 3, 4, 5 or 6;

n is 0 or 1 ; and

X is aryl, heterocyclic or heteroaryl.

8. The method of any of claims 1-7, wherein the one or more FXR agonists is deuterated.

9. The method of claim 8, wherein the one or more FXR agonists is

10. The method of any of claims 19, wherein the subject has a body mass index (BMI) of 25 of higher, is hyperglycemic, produces no insulin or is insulin resistant, has a decreased number of pancreatic beta cells, has persistent islet cell antibodies, has high frequency of thyroid and gastric autoimmunity, has DR3 and DR4 human leukocyte antigen haplotypes, shows progressive loss of beta cells, has adult disease onset, has low levels of C-peptide, or combinations thereof.

11. The method of any of claims 1-10, wherein the subject is a mammal.

12. The method of claim 11, wherein the mammal is a human.

13. The method of any of claims 1-12, wherein the one or more FXR agonists is administered in combination with a therapeutically effective amount of one or more additional therapeutic compounds.

14. The method of claim 13, wherein the one or more additional therapeutic compounds is an insulin-sensitizing drug, an insulin secretagogue, an alpha-glucosidase inhibitor, an amylin agonist, a dipeptidyl-peptidase 4 (DPP-4) inhibitor, a glucagon-like peptide (GLP) agonist, meglitinide, sulfonylurea, a peroxisome proliferator-activated receptor (PPAR)-gamma agonist, nicotinamide ribonucleoside, analogs of nicotinamide ribonucleoside, or combinations thereof.

15. The method of claim 14, wherein the PPAR- gamma agonist is a thiazolidinedione (TZD), aleglitazar, farglitazar, muraglitazar, or tesaglitazar.

16. The method of claim 15, wherein the TZD is pioglitazone, rosiglitazone, rivoglitazone, or troglitazone.

17. The method of any of claims 1-16, wherein the one or more FXR agonists is administered daily, twice daily, every other day, bi-weekly, weekly, or monthly.

18. The method of any of claims 1-17, wherein the one or more FXR agonists is administered at a dose of at least 1 mg/kg.

19. The method of any of claims 1-18, wherein the method further comprises: determining if the subject produces insulin;

determining a level of C-peptide in the subject;

determining a level of islet cell antibodies (ICA), glutamic acid decarboxylase autoantibodies (GADA), insulinoma-associated (IA-2) autoantibodies, and/or zinc transporter autoantibodies (ZnT8) in the subject; or

combinations thereof.