Chemosensory Receptor Ligand-Based Therapies

• US 20120094942A1
• Filed: 10/18/2011
• Published: 04/19/2012
• Est. Priority Date: 10/19/2010
• Status: Active Grant

• Current Assignee: Ambra Bioscience LLC
• Original Assignee: Elcelyx Therapeutics, Inc.
• Inventors: BARON, Alain D., Brown, Martin R., Jones, Christopher R.G., Fineman, Mark S.
• Granted Patent: US 9,486,463 B2
• Time in Patent Office: Days
• US Class Current: 514/24
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/194 having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/353 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/575 substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• CPC Class Codes: A61K 31/7016 Disaccharides, e.g. lactose, lactulose lactobionic acid A61K31/7032
• CPC Class Codes: A61K 31/7032 attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/12 : Antidiuretics, e.g. drugs for diabetes insipidus ADH A61P5/10

Abstract

Provided herein are methods of modulating hormone concentrations in a subject comprising the administration of a composition comprising a chemosensory receptor ligand, wherein the composition is adapted to deliver the ligand to one or more regions of the intestine of said subject. Also provided are methods directed to the modulation of circulating concentrations of one or more of GLP-1 (total), GLP-1 (active), GLP-2, oxyntomodulin, PYY (total), PYY 3-36, CCK, GIP, insulin, C-peptide, glycentin, uroguanylin amylin, and ghrelin (total), ghrelin (active) and glucagon.

Claims

1. A method of modulating the concentration of one or more hormones in a subject comprising the administration of a composition comprising a chemosensory receptor ligand, said composition being adapted to deliver said ligand to one or more regions of the intestine of said subject, wherein modulating hormone concentration comprises modulating the circulating concentration of one or more of GLP-1 (total), GLP-1 (active), GLP-2, oxyntomodulin, PYY (total), PYY 3-36, CCK, GIP, insulin, C-peptide, amylin, glycentin, uroguanylin, ghrelin (total), ghrelin (active) and glucagon.

2. The method of claim 1, wherein the circulating concentration of one or more of GLP-1 (total), GLP-1 (active), GLP-2, oxyntomodulin, PYY (total), PYY 3-36, CCK, GIP, insulin, C-peptide, glycentin, uroguanylin and amylin is increased by about 0.5% to about 1000% compared to placebo-controlled circulating concentration.

3. The method of claim 1, wherein the circulating concentration of one or more of GLP-1 (total), GLP-1 (active), GLP-2, oxyntomodulin, PYY (total), PYY 3-36, CCK, GIP, insulin, C-peptide, glycentin, uroguanylin and amylin is increased by about 0.5% to about 100% compared to placebo-controlled circulating concentration.

4. The method of claim 1, wherein circulating the concentration of one or more of GLP-1 (total), GLP-1 (active), GLP-2, oxyntomodulin, PYY (total), PYY 3-36, CCK, GIP, insulin, C-peptide, glycentin, uroguanylin and amylin is increased by at least about 10% compared to placebo-controlled circulating concentration.

5. The method of claim 1, wherein the circulating concentrations of two or more of GLP-1 (total), GLP-1 (active), GLP-2, oxyntomodulin, PYY (total), PYY 3-36, CCK, GIP, insulin, C-peptide, glycentin, uroguanylin and amylin are increased by about 0.5% to about 1000% compared to placebo-controlled circulating concentrations.

6. The method of claim 1, wherein the circulating concentrations of two or more of GLP-1 (total), GLP-1 (active), GLP-2, oxyntomodulin, PYY (total), PYY 3-36, CCK, GIP, insulin, C-peptide, glycentin, uroguanylin and amylin are increased by about 0.5% to about 100% compared to placebo-controlled circulating concentrations.

7. The method of claim 1, wherein the circulating concentrations of two or more of GLP-1 (total), GLP-1 (active), GLP-2, oxyntomodulin, PYY (total), PYY 3-36, CCK, GIP, insulin, C-peptide, glycentin, uruguanylin and amylin are increased by at least about 10% compared to placebo-controlled circulating concentrations.

8. The method of claim 1, wherein the circulating concentrations of three or more of GLP-1 (total), GLP-1 (active), GLP-2, oxyntomodulin, PYY (total), PYY 3-36, CCK, GIP, insulin, C-peptide, glycentin, uroguanylin and amylin are increased by about 0.5% to about 1000% compared to placebo-controlled circulating concentrations.

9. The method of claim 1, wherein the circulating concentrations of three or more of GLP-1 (total), GLP-1 (active), GLP-2, oxyntomodulin, PYY (total), PYY 3-36, CCK, GIP, insulin, C-peptide, glycentin, uroguanylin and amylin are increased by about 0.5% to about 100% compared to placebo-controlled circulating concentrations.

10. The method of claim 1, wherein the circulating concentrations of three or more of GLP-1 (total), GLP-1 (active), GLP-2, oxyntomodulin, PYY (total), PYY 3-36, CCK, GIP, insulin, C-peptide, glycentin, uroguanylin and amylin are increased by at least about 10% compared to placebo-controlled circulating concentrations.

11. The method of claim 1, wherein the circulating concentrations of four or more of GLP-1 (total), GLP-1 (active), GLP-2, oxyntomodulin, PYY (total), PYY 3-36, CCK, GIP, insulin, C-peptide, glycentin, uroguanylin and amylin are increased by about 0.5% to about 1000% compared to placebo-controlled circulating concentrations.

12. The method of claim 1, wherein the circulating concentrations of four or more of GLP-1 (total), GLP-1 (active), GLP-2, oxyntomodulin, PYY (total), PYY 3-36, CCK, GIP, insulin, C-peptide, glycentin, uroguanylin and amylin are increased by about 0.5% to about 100% compared to placebo-controlled circulating concentrations.

13. The method of claim 1, wherein the circulating concentrations of four or more of GLP-1 (total), GLP-1 (active), GLP-2, oxyntomodulin, PYY (total), PYY 3-36, CCK, GIP, insulin, C-peptide, glycentin, uroguanylin and amylin are increased by at least about 10% compared to placebo-controlled circulating concentrations.

14. The method of claim 1, wherein the circulating concentrations of GLP-1 (total), GLP-1 (active), PYY (total), PYY3-36, oxyntomodulin, and insulin are increased by about 5% to about 25% compared to placebo-controlled circulating concentrations.

15. The method of claim 1, wherein the circulating concentration of one or more of ghrelin (total), ghrelin (active) and glucagon are decreased by about 2.5% to 15% compared to placebo-controlled circulating concentration.

16. The method of claim 1, wherein modulating hormone concentrations comprises one or more parameters selected from the group consisting of:

(a) an increase in circulating GLP-1 (total) concentration of at least about 0.5 pM to about 50 pM compared to placebo-controlled GLP-1 (total) concentration;

(b) an increase in circulating GLP-1 (active) concentration of at least about 0.5 pg/ml to about 60 pg/ml compared to placebo-controlled GLP-1 (active) concentration;

(c) an increase in circulating GLP-2 concentration of at least about 10 pM to about 200 pM compared to placebo-controlled GLP-2 concentration;

(d) an increase in circulating oxyntomodulin concentration of at least about 4 ng/ml to about 20 ng/ml compared to placebo-controlled oxyntomodulin concentration;

(e) an increase in circulating PYY total concentration of at least about 5 pg/ml to about 50 pg/ml compared to placebo-controlled PYY total concentration;

(f) an increase in circulating PYY 3-36 concentration of at least about 2.5 pg/ml to about 20 pg/ml compared to placebo-controlled PYY 3-36 concentration;

(g) an increase in circulating CCK concentration of at least about 0.5 pm to about 12 pM compared to placebo-controlled CCK concentration;

(h) an increase in circulating GIP concentration of at least about 5 pg/ml to about 200 pg/ml compared to placebo-controlled GIP concentration;

(i) an increase in circulating insulin concentration of at least about 5 μ

IU/ml to about 30 μ

IU/ml compared to placebo-controlled insulin concentration;

an increase in circulating C-peptide concentrations of at least about 50 pg/ml to about 120 pg/ml compared to placebo-controlled C-peptide concentrations;

(k) an increase in circulating amylin concentration of at least about 4 pM to about 100 pM compared to placebo-controlled amylin concentration;

(l) an increase in circulating glycentin concentration of at least about 10 pM to about 200 pM compared to placebo-controlled glycentin concentration;

(m) an increase in circulating uroguanylin concentration of at least about 1 pM to about 20 pM compared to placebo-controlled uroguanylin concentration;

(n) a decrease in circulating ghrelin (active) concentration of at least about 1 pg/ml to about 10 pg/ml compared to placebo-controlled ghrelin (active) concentration;

(o) a decrease in circulating ghrelin (total) of at least about 50 pg/ml to about 600 pg/ml compared to placebo-controlled ghrelin (total) concentration; and

(p) a decrease in circulating glucagon of at least about 10 pg/ml to about 300 pg/ml compared to placebo-controlled glucagon concentration.

17. The method of claim 1, wherein circulating concentrations of GLP-1 (active) and PYY (total) are increased by about 0.5% to about 1000% compared to placebo-controlled circulating concentrations.

18. The method of claim 1, wherein circulating concentrations of GLP-1 (active) and PYY (total) are increased by about 0.5% to about 100% compared to placebo-controlled circulating concentrations.

19. The method of claim 1, wherein circulating concentrations of GLP-1 (active) and PYY (total) are increased by at least about 10% compared to placebo-controlled circulating concentrations.

20. The method of claim 1, wherein circulating concentrations of GLP-1 (active) and PYY (total) are increased by at least about 25% compared to placebo-controlled circulating concentrations.

21. The method of claim 1, wherein the circulating concentration of one or more of GLP-1 (total), GLP-1 (active), GLP-2, oxyntomodulin, PYY (total), PYY 3-36, CCK, GIP, insulin, C-peptide, glycentin, uroguanylin and amylin is increased by at least about 2.5% to at least about 50% compared to baseline circulating concentration.

22. The method of claim 1, wherein the circulating concentration of one or more of ghrelin (total), ghrelin (active) and glucagon is decreased by at least about 2.5% to 50% compared to baseline circulating concentration.

23. The method of claim 1, wherein the circulating concentration of GLP-1 (active) is increased by at least about 2.5% to about 50% compared to baseline circulating concentration.

24. The method of claim 1, wherein the circulating concentration of PYY (total) is increased by at least about 2.5% to about 50% compared to baseline circulating concentration.

25. The method of claim 1, wherein the circulating concentrations of GLP-1 (active) and PYY (total) are increased by at least about 2.5% to about 50% compared to baseline circulating concentrations.

26. The method of claim 1, wherein the circulating hormone concentrations are determined by C_max values, AUC_last values, AUC_(0-∞

) values, and/or repeated measures values.

30. The method of claim 1, wherein the chemosensory receptor ligand is selected from the group consisting of a sweet receptor ligand, a bitter receptor ligand, an umami receptor ligand, a fat receptor ligand and a bile acid receptor ligand.

31. The method of claim 30, wherein the sweet receptor ligand is selected from the group consisting of sucralose, aspartame, Stevioside, Rebaudioside A, Rebaudioside B, Rebaudioside C, Rebaudioside D, Rebaudioside E, Rebaudioside F, Neotame, acesulfame-K and saccharin.

32. The method of claim 30, wherein the bitter receptor ligand is selected from the group consisting of a flavanone, a flavone, a flavonol, a flavan, a phenolic flavonoid, an isoflavone, a limonoid aglycone, metformin, metformin hydrochloride, a glucosinolate or hydrolysis product thereof and an organic isothiocyanate.

33. The method of claim 30, wherein the umami receptor ligand is selected from the group consisting of glutamate salt, glutamine, acetyl glycine and aspartame.

34. The method of claim 30, wherein the fat receptor ligand is selected from the group consisting of a linoleic acid, an oleic acid, an omega-3 fatty acid, a palmitate, an oleoylethanolamide, a mixed fatty acid emulsion and an N-acylphosphatidylethanolamine (NAPE).

35. The method of claim 30, wherein the sour receptor ligand is selected from the group consisting of citric acid and hydroxycitric acid.

36. The method of claim 30, wherein the bile acid receptor ligand is selected from the group consisting of deoxycholic acid, a taurocholic acid and a chenodeoxycholic acid.

37. The method of claim 30, wherein the chemosensory receptor ligand is an agonist.

38. The method of claim 30 wherein the chemosensory receptor ligand is an antagonist.

39. The method of claim 30, wherein the chemosensory receptor ligand is nonmetabolized.

40. The method of claim 30, wherein the chemosensory receptor ligand is an enhancer.

41. The method of claim 1, wherein one or more regions of the intestine are the duodenum, jejunum, ileum, caecum, colon, and/or rectum.

42. The method of claim 1, wherein one or more regions of the intestine are the jejunum, ileum caecum, colon, and/or rectum.

43. The method of claim 1, wherein the composition further releases at least some of the chemosensory receptor ligand in the stomach.

46. The method of claim 1, wherein the subject has a disorder or condition associated with chemosensory receptor.

47. The method of claim 46, wherein the disorder or condition associated with a chemosensory receptor is selected from metabolic syndrome, diabetes type I, diabetes type II, obesity, binge eating, undesired food cravings, food addiction, a desire to reduce food intake or to lose weight or maintain weight loss, desire to maintain healthy weight, desire to maintain normal blood glucose metabolism, anorexia, pre-diabetes, glucose intolerance, gestational diabetes mellitus (GDM), impaired fasting glycemia (IFG), post-prandial hyperglycemia, accelerated gastric emptying, dumping syndrome, delayed gastric emptying, dyslipidemia, post-prandial dyslipidemia, hyperlipidemia, post-prandial hypertriglyceridemia, post hypertriglyceridemia, insulin resistance, bone loss disorders, osteopenia, osteoporosis, muscle wasting disease, muscle degenerative disorders, polycystic ovary syndrome (PCOS), non-alcoholic fatty liver disease (NAFL), non-alcoholic steatohepatitis (NASH), immune disorders of the gut, celiac disease), bowel irregularity, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn'"'"'s disease, short bowel syndrome and peripheral neuropathy and diabetic neuropathy.

48. The method of claim 46, wherein the disorder or condition associated with a chemosensory receptor is selected from sadness, stress, grief, anxiety, anxiety disorder (e.g., generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder or social anxiety disorder or a mood disorder (e.g., depression, bipolar disorder, dysthymic disorder and cyclothymic disorder).

49. The method of claim 1, further comprising the administration of a second composition used in the treatment of a disorder or condition associated with a chemosensory receptor.

50. The method of claim 48, wherein the second composition comprises an agent used in the treatment of diabetes or obesity.

51. The method of claim 49, wherein the second composition comprises a DPP-IV inhibitor.

52. The method of claim 49, wherein the second composition comprises metformin or metformin hydrochloride.

53. The method of claim 50 wherein the subject has a body mass index (BMI) of less than about 40.

54. The method of claim 50 wherein the subject has a body mass index (BMI) between about 30 and about 35.

55. The method of claim 50 wherein the subject has a body mass index (BMI) between about 27 and about 30.

56. The method of claim 50 wherein the subject has a body mass index (BMI) between about 25 and about 27.

27. A method of modulating the T_max of the concentration of one or more hormones in a subject comprising the administration of a composition comprising a chemosensory receptor ligand, said composition being adapted to deliver said ligand to one or more regions of the intestine of said subject.

28. The method of claim 27, wherein the T_max of the circulating concentration of one or more of GLP-1 (total), GLP-1 (active), GLP-2, oxyntomodulin, PYY (total), PYY 3-36, CCK, GIP, insulin, C-peptide, glycentin, uroguanylin and amylin is increased by about 10% to about 200% compared to the placebo-controlled T_max of the circulating hormone concentration.

29. The method of claim 27, wherein the T_max of the circulating concentration of one or more of GLP-1 (total), GLP-1 (active), GLP-2, oxyntomodulin, PYY (total), PYY 3-36, CCK, GIP, insulin, C-peptide, glycentin, uroguanylin and amylin is decreased by about 10% to about 200% compared to the placebo-controlled T_max of the circulating hormone concentration.

44. A method of modulating the concentration of one or more hormones in a subject comprising the administration of a chemosensory receptor antagonist and a chemosensory receptor agonist.

45. The method of claim 44, wherein the chemosensory receptor antagonist is administered in a gastroretentive formulation and the chemosensory receptor agonist is adapted to deliver the chemosensoryreceptor agonist to one or more of the duodenum, jejunum, ileum, caecum, colon, and/or rectum.

57. A method of modulating glucose concentration in a subject comprising the administration of a composition comprising a chemosensory receptor ligand, said composition being adapted to deliver said ligand to one or more regions of the intestine of said subject.

58. The method of claim 57, wherein the circulating concentration of glucose is decreased by about 2.5% to about 50% compared to placebo-controlled circulating concentration.

59. A method of modulating concentration of triglycerides in a subject comprising the administration of a composition comprising a chemosensory receptor ligand, said composition being adapted to deliver said ligand to one or more regions of the intestine of said subject.

60. The method of claim 59, wherein the circulating concentration of triglycerides is decreased by about 2.5% to about 50% compared to placebo-controlled circulating concentration.

61. A method of modulating low-density lipoprotein concentration in a subject comprising the administration of a composition comprising a chemosensory receptor ligand, said composition being adapted to deliver said ligand to one or more regions of the intestine of said subject.

62. The method of claim 61, wherein the circulating concentration of low-density lipoprotein is decreased by about 2.5% to about 50% compared to placebo-controlled circulating concentration.

63. A method of modulating apolipoprotein B concentration in a subject comprising the administration of a composition comprising a chemosensory receptor ligand, said composition being adapted to deliver said ligand to one or more regions of the intestine of said subject.

64. The method of claim 63, wherein the circulating concentration of apolipoprotein B is decreased by about 2.5% to about 50% compared to placebo-controlled circulating concentration.

65. A method of modulating high-density lipoprotein concentration in a subject comprising the administration of a composition comprising a chemosensory receptor ligand, said composition being adapted to deliver said ligand to one or more regions of the intestine of said subject.

66. The method of claim 65, wherein the circulating concentration of high-density lipoprotein is increased by about 2.5% to about 50% compared to placebo-controlled circulating concentration.