Methods of using compositions comprising variants and fusions of fgf19 polypeptides for reducing glucose levels in a subject

Patent metadata

Field	Value
Publication number	US-2016168216-A1
Application number	US-201514983324-A
Country	US
Kind code	A1
Filing date	Dec 29, 2015
Priority date	Jul 1, 2011
Publication date	Jun 16, 2016
Grant date	—

Abstract

The invention relates to variants and fusions of fibroblast growth factor 19 (FGF19), variants and fusions of fibroblast growth factor 21 (FGF21), fusions of fibroblast growth factor 19 (FGF19) and/or fibroblast growth factor 21 (FGF21), and variants or fusions of fibroblast growth factor 19 (FGF19) and/or fibroblast growth factor 21 (FGF21) proteins and peptide sequences (and peptidomimetics), having one or more activities, such as glucose lowering activity, and methods for and uses in treatment of hyperglycemia and other disorders.

First claim

1 .- 74 . (canceled)

75 . A method of reducing glucose levels in a subject, comprising administering to the subject an effective amount of a peptide having an amino acid sequence comprising or consisting of

(SEQ ID NO: 69)

RDSSPLVHYGWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAH

SLLEIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIR

PDGYNVYRSEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPE

DLRGHLESDMFSSPLETDSMDPFGLVTGLEAVRSPSFEK.

76 . The method of claim 75 , wherein the peptide has an amino acid sequence comprising SEQ ID NO:69.

77 . The method of claim 75 , wherein the peptide has an amino acid sequence consisting of SEQ ID NO:69.

78 . The method of claim 76 , wherein the peptide is fused with an immunoglobulin Fc region.

79 . The method of claim 77 , wherein the peptide is fused with an immunoglobulin Fc region.

80 . The method of claim 76 , wherein the peptide is formulated as a pharmaceutical composition, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

81 . The method of claim 76 , wherein the method further comprises administration of a supplementary therapy.

82 . The method of claim 81 , wherein said supplemental therapy is a weight loss surgery, gastric bypass, gastrectomy, gastric banding, gastric balloon, or gastric sleeve.

83 . The method of claim 81 , wherein said supplemental therapy is a glucose lowering agent, insulin, GLP1 analogue, biguanide, sulphonylurea, thiazolidinedione, a dipeptidyl peptidase-4 (DPP-4) inhibitor, a bromocriptine formulation, a bile acid sequestrant, metformin, a thiazolidinedione (TZD), a SGLT-2 inhibitor, or any combination thereof.

84 . The method of claim 83 , wherein said biguanide or sulphonylurea is selected from the group consisting of tolbutamide, chlorpropamide, acetohexamide, tolazamide, glibenclamide, glipizide or any combination thereof.

85 . The method of claim 83 , wherein said thiazolidinedione is rosiglitazone or pioglitazone, or combination thereof.

86 . The method of claim 83 , wherein said bile acid sequestrant is colesevelam.

87 . The method of claim 83 , wherein said insulin is bolus insulin, basal insulin, or an analogue thereof.

88 . The method of claim 81 , wherein said supplemental therapy is administered prior to, contemporaneously with or following said method.

89 . The method of claim 76 , wherein the glucose levels are blood glucose levels.

90 . The method of claim 76 , wherein the subject has a metabolic disorder.

91 . The method of claim 76 , wherein the subject has an insulin resistance disorder.

92 . The method of claim 76 , wherein the subject has hyperinsulinemia.

93 . The method of claim 76 , wherein the subject has glucose intolerance.

94 . The method of claim 76 , wherein the subject has a hyperglycemic disorder or is at risk of developing a hyperglycemic disorder.

95 . The method of claim 76 , wherein the subject has diabetes.

96 . The method of claim 76 , wherein the subject has insulin-dependent (type I) diabetes.

97 . The method of claim 76 , wherein the subject has type II diabetes.

98 . The method of claim 76 , wherein the subject has gestational diabetes.

99 . The method of claim 76 , wherein the subject is obese.

100 . The method of claim 76 , wherein the subject has nonalcoholic fatty liver disease (NAFLD).

101 . The method of claim 76 , wherein the subject has nonalcoholic steatohepatitis (NASH).

102 . The method of claim 76 , wherein the subject has a fasting plasma glucose (FPG) level of greater than 100 mg/dl.

103 . The method of claim 76 , wherein the subject has an FPG level of 125 mg/dl or greater.

104 . The method of claim 76 , wherein the subject has an FPG level between 100 and 125 mg/dl.

105 . The method of claim 76 , wherein the glucose levels are reduced by at least 5%.

106 . The method of claim 76 , wherein the subject has a hemoglobin A1c (HbA1c) level above 6%.

107 . The method of claim 77 , wherein the peptide is formulated as a pharmaceutical composition, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

108 . The method of claim 77 , wherein the method further comprises administration of a supplementary therapy.

109 . The method of claim 108 , wherein said supplemental therapy is a weight loss surgery, gastric bypass, gastrectomy, gastric banding, gastric balloon, or gastric sleeve.

110 . The method of claim 108 , wherein said supplemental therapy is a glucose lowering agent, insulin, GLP1 analogue, biguanide, sulphonylurea, thiazolidinedione, a DPP-4 inhibitor, a bromocriptine formulation, a bile acid sequestrant, metformin, a TZD, a SGLT-2 inhibitor, or any combination thereof.

111 . The method of claim 110 , wherein said biguanide or sulphonylurea is selected from the group consisting of tolbutamide, chlorpropamide, acetohexamide, tolazamide, glibenclamide, glipizide or any combination thereof.

112 . The method of claim 110 , wherein said thiazolidinedione is rosiglitazone or pioglitazone, or combination thereof.

113 . The method of claim 110 , wherein said bile acid sequestrant is colesevelam.

114 . The method of claim 110 , wherein said insulin is bolus insulin, basal insulin, or an analogue thereof.

115 . The method of claim 110 , wherein said supplemental therapy is administered prior to, contemporaneously with or following said method.

116 . The method of claim 77 , wherein the glucose levels are blood glucose levels.

117 . The method of claim 77 , wherein the subject has a metabolic disorder.

118 . The method of claim 77 , wherein the subject has an insulin resistance disorder.

119 . The method of claim 77 , wherein the subject has hyperinsulinemia.

120 . The method of claim 77 , wherein the subject has glucose intolerance.

121 . The method of claim 77 , wherein the subject has a hyperglycemic disorder or is at risk of developing a hyperglycemic disorder.

122 . The method of claim 77 , wherein the subject has diabetes.

123 . The method of claim 77 , wherein the subject has insulin-dependent (type I) diabetes.

124 . The method of claim 77 , wherein the subject has type II diabetes.

125 . The method of claim 77 , wherein the subject has gestational diabetes.

126 . The method of claim 77 , wherein the subject is obese.

Assignees

• Ngm Biopharmaceuticals Inc

Inventors

• Ling Lei
• Lindhout Darrin Anthony

Classifications

• A61P5/48

  of the pancreatic hormones · CPC title

• A61P3/08

  for glucose homeostasis (pancreatic hormones A61P5/48) · CPC title

• A61P9/08

  Vasodilators for multiple indications · CPC title

• A61P5/50

  for increasing or potentiating the activity of insulin · CPC title

• A61P9/12

  Antihypertensives · CPC title