# US 9,751,924 B2 · Methods of using compositions comprising fusion variants of FGF19 polypeptides for reducing glucose levels in a subject

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- Number: US 9,751,924 B2
- Document ID: US9751924B2
- Status: Granted
- Kind: B2
- Application number: 14/983,324
- Filed: 2015-12-29
- Published: 2016-06-16
- Granted: 2017-09-05
- Earliest claimed: 2011-07-01
- Assignees: NGM Biopharmaceuticals, Inc.
- Applicants: NGM Biopharmaceuticals, Inc.
- Inventors: Lei Ling; Darrin Anthony Lindhout
- Web page: https://patentgrep.com/patent/US9751924B2

## CPC

- A61K 38/1825: {Fibroblast growth factor [FGF]}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/08: for glucose homeostasis (pancreatic hormones A61P5/48)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/48: of the pancreatic hormones
- A61P 5/50: for increasing or potentiating the activity of insulin
- A61P 9/08: Vasodilators for multiple indications
- A61P 9/12: Antihypertensives
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 14/50: Fibroblast growth factor [FGF]
- A61K 31/14: Quaternary ammonium compounds, e.g. edrophonium, choline (betaines A61K31/205)
- A61K 31/155: Amidines ([IMAGE cpc-sch-A61K-1029.gif]), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
- A61K 31/785: Polymers containing nitrogen
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07K 2319/00: Fusion polypeptide
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- G01N 33/5088: {of vertebrates}
- G01N 33/66: involving blood sugars, e.g. galactose
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The invention relates to methods for and uses in reducing glucose levels in subjects in need thereof with variants and fusions of fibroblast growth factor 19 (FGF19) proteins and peptide sequences (and peptidomimetics).

## Claims

### Claim 1

A method of reducing glucose levels in a subject in need thereof, 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.

### Claim 2 (depends on 1)

The method of claim 1, wherein the peptide has an amino acid sequence comprising SEQ ID NO:69.

### Claim 3 (depends on 2)

The method of claim 2, wherein the peptide is fused with an immunoglobulin Fc region.

### Claim 4 (depends on 3)

The method of claim 3, wherein the peptide is formulated as a pharmaceutical composition, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

### Claim 5 (depends on 3)

The method of claim 3, wherein the method further comprises administration of a supplemental therapy.

### Claim 6 (depends on 5)

The method of claim 5, wherein said supplemental therapy is a weight loss surgery, gastric bypass, gastrectomy, gastric banding, gastric balloon, or gastric sleeve.

### Claim 7 (depends on 5)

The method of claim 5, 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.

### Claim 8 (depends on 7)

The method of claim 7, wherein said biguanide or sulphonylurea is selected from the group consisting of tolbutamide, chlorpropamide, acetohexamide, tolazamide, glibenclamide, glipizide or any combination thereof.

### Claim 9 (depends on 7)

The method of claim 7, wherein said thiazolidinedione is rosiglitazone or pioglitazone, or combination thereof.

### Claim 10 (depends on 7)

The method of claim 7, wherein said bile acid sequestrant is colesevelam.

### Claim 11 (depends on 7)

The method of claim 7, wherein said insulin is bolus insulin, basal insulin, or an analogue thereof.

### Claim 12 (depends on 5)

The method of claim 5, wherein said supplemental therapy is administered prior to said method.

### Claim 13 (depends on 5)

The method of claim 5, wherein said supplemental therapy is administered contemporaneously with said method.

### Claim 14 (depends on 5)

The method of claim 5, wherein said supplemental therapy is administered following said method.

### Claim 15 (depends on 3)

The method of claim 3, wherein the glucose levels are blood glucose levels.

### Claim 16 (depends on 3)

The method of claim 3, wherein the subject has a metabolic disorder.

### Claim 17 (depends on 3)

The method of claim 3, wherein the subject has an insulin resistance disorder.

### Claim 18 (depends on 3)

The method of claim 3, wherein the subject has hyperinsulinemia.

### Claim 19 (depends on 3)

The method of claim 3, wherein the subject has glucose intolerance.

### Claim 20 (depends on 3)

The method of claim 3, wherein the subject has a hyperglycemic disorder or is at risk of developing a hyperglycemic disorder.

### Claim 21 (depends on 3)

The method of claim 3, wherein the subject has diabetes.

### Claim 22 (depends on 3)

The method of claim 3, wherein the subject has insulin-dependent (type I) diabetes.

### Claim 23 (depends on 3)

The method of claim 3, wherein the subject has type II diabetes.

### Claim 24 (depends on 3)

The method of claim 3, wherein the subject has gestational diabetes.

### Claim 25 (depends on 3)

The method of claim 3, wherein the subject is obese.

### Claim 26 (depends on 3)

The method of claim 3, wherein the subject has a FPG level of greater than 100 mg/dl.

### Claim 27 (depends on 3)

The method of claim 3, wherein the subject has an FPG level of 125 mg/dl or greater.

### Claim 28 (depends on 3)

The method of claim 3, wherein the subject has an FPG level between 100 and 125 mg/dl.

### Claim 29 (depends on 3)

The method of claim 3, wherein the glucose levels are reduced by at least 5%.

### Claim 30 (depends on 3)

The method of claim 3, wherein the subject has a HbA1c level above 6%.

### Claim 31 (depends on 2)

The method of claim 2, wherein the peptide is formulated as a pharmaceutical composition, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

### Claim 32 (depends on 2)

The method of claim 2, wherein the method further comprises administration of a supplemental therapy.

### Claim 33 (depends on 32)

The method of claim 32, wherein said supplemental therapy is a weight loss surgery, gastric bypass, gastrectomy, gastric banding, gastric balloon, or gastric sleeve.

### Claim 34 (depends on 32)

The method of claim 32, 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.

### Claim 35 (depends on 34)

The method of claim 34, wherein said biguanide or sulphonylurea is selected from the group consisting of tolbutamide, chlorpropamide, acetohexamide, tolazamide, glibenclamide, glipizide or any combination thereof.

### Claim 36 (depends on 34)

The method of claim 34, wherein said thiazolidinedione is rosiglitazone or pioglitazone, or combination thereof.

### Claim 37 (depends on 34)

The method of claim 34, wherein said bile acid sequestrant is colesevelam.

### Claim 38 (depends on 34)

The method of claim 34, wherein said insulin is bolus insulin, basal insulin, or an analogue thereof.

### Claim 39 (depends on 32)

The method of claim 32, wherein said supplemental therapy is administered prior to said method.

### Claim 40 (depends on 32)

The method of claim 32, wherein said supplemental therapy is administered contemporaneously with said method.

### Claim 41 (depends on 32)

The method of claim 32, wherein said supplemental therapy is administered following said method.

### Claim 42 (depends on 2)

The method of claim 2, wherein the glucose levels are blood glucose levels.

### Claim 43 (depends on 2)

The method of claim 2, wherein the subject has a metabolic disorder.

### Claim 44 (depends on 2)

The method of claim 2, wherein the subject has an insulin resistance disorder.

### Claim 45 (depends on 2)

The method of claim 2, wherein the subject has hyperinsulinemia.

### Claim 46 (depends on 2)

The method of claim 2, wherein the subject has glucose intolerance.

### Claim 47 (depends on 2)

The method of claim 2, wherein the subject has a hyperglycemic disorder or is at risk of developing a hyperglycemic disorder.

### Claim 48 (depends on 2)

The method of claim 2, wherein the subject has diabetes.

### Claim 49 (depends on 2)

The method of claim 2, wherein the subject has insulin-dependent (type I) diabetes.

### Claim 50 (depends on 2)

The method of claim 2, wherein the subject has type II diabetes.

### Claim 51 (depends on 2)

The method of claim 2, wherein the subject has gestational diabetes.

### Claim 52 (depends on 2)

The method of claim 2, wherein the subject is obese.

### Claim 53 (depends on 2)

The method of claim 2, wherein the subject has a fasting plasma glucose (FPG) level of greater than 100 mg/dl.

### Claim 54 (depends on 2)

The method of claim 2, wherein the subject has an FPG level of 125 mg/dl or greater.

### Claim 55 (depends on 2)

The method of claim 2, wherein the subject has an FPG level between 100 and 125 mg/dl.

### Claim 56 (depends on 2)

The method of claim 2, wherein the glucose levels are reduced by at least 5%.

### Claim 57 (depends on 2)

The method of claim 2, wherein the subject has a hemoglobin A1c (HbA1c) level above 6%.

### Claim 58 (depends on 1)

The method of claim 1, wherein the peptide has an amino acid sequence consisting of SEQ ID NO:69.

### Claim 59 (depends on 58)

The method of claim 58, wherein the peptide is fused with an immunoglobulin Fc region.

### Claim 60 (depends on 59)

The method of claim 59, wherein the peptide is formulated as a pharmaceutical composition, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

### Claim 61 (depends on 59)

The method of claim 59, wherein the method further comprises administration of a supplemental therapy.

### Claim 62 (depends on 61)

The method of claim 61, wherein said supplemental therapy is a weight loss surgery, gastric bypass, gastrectomy, gastric banding, gastric balloon, or gastric sleeve.

### Claim 63 (depends on 61)

The method of claim 61, 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.

### Claim 64 (depends on 63)

The method of claim 63, wherein said biguanide or sulphonylurea is selected from the group consisting of tolbutamide, chlorpropamide, acetohexamide, tolazamide, glibenclamide, glipizide or any combination thereof.

### Claim 65 (depends on 63)

The method of claim 63, wherein said thiazolidinedione is rosiglitazone or pioglitazone, or combination thereof.

### Claim 66 (depends on 63)

The method of claim 63, wherein said bile acid sequestrant is colesevelam.

### Claim 67 (depends on 63)

The method of claim 63, wherein said insulin is bolus insulin, basal insulin, or an analogue thereof.

### Claim 68 (depends on 61)

The method of claim 61, wherein said supplemental therapy is administered prior to said method.

### Claim 69 (depends on 61)

The method of claim 61, wherein said supplemental therapy is administered contemporaneously with said method.

### Claim 70 (depends on 61)

The method of claim 61, wherein said supplemental therapy is administered following said method.

### Claim 71 (depends on 59)

The method of claim 59, wherein the glucose levels are blood glucose levels.

### Claim 72 (depends on 59)

The method of claim 59, wherein the subject has a metabolic disorder.

### Claim 73 (depends on 59)

The method of claim 59, wherein the subject has an insulin resistance disorder.

### Claim 74 (depends on 59)

The method of claim 59, wherein the subject has hyperinsulinemia.

### Claim 75 (depends on 59)

The method of claim 59, wherein the subject has glucose intolerance.

### Claim 76 (depends on 59)

The method of claim 59, wherein the subject has a hyperglycemic disorder or is at risk of developing a hyperglycemic disorder.

### Claim 77 (depends on 59)

The method of claim 59, wherein the subject has diabetes.

### Claim 78 (depends on 59)

The method of claim 59, wherein the subject has insulin-dependent (type I) diabetes.

### Claim 79 (depends on 59)

The method of claim 59, wherein the subject has type II diabetes.

### Claim 80 (depends on 59)

The method of claim 59, wherein the subject has gestational diabetes.

### Claim 81 (depends on 59)

The method of claim 59, wherein the subject is obese.

### Claim 82 (depends on 59)

The method of claim 59, wherein the subject has a FPG level of greater than 100 mg/dl.

### Claim 83 (depends on 59)

The method of claim 59, wherein the subject has an FPG level of 125 mg/dl or greater.

### Claim 84 (depends on 59)

The method of claim 59, wherein the subject has an FPG level between 100 and 125 mg/dl.

### Claim 85 (depends on 59)

The method of claim 59, wherein the glucose levels are reduced by at least 5%.

### Claim 86 (depends on 59)

The method of claim 59, wherein the subject has a HbA1c level above 6%.

### Claim 87 (depends on 58)

The method of claim 58, wherein the peptide is formulated as a pharmaceutical composition, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

### Claim 88 (depends on 58)

The method of claim 58, wherein the method further comprises administration of a supplemental therapy.

### Claim 89 (depends on 88)

The method of claim 88, wherein said supplemental therapy is a weight loss surgery, gastric bypass, gastrectomy, gastric banding, gastric balloon, or gastric sleeve.

### Claim 90 (depends on 88)

The method of claim 88, 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.

### Claim 91 (depends on 90)

The method of claim 90, wherein said biguanide or sulphonylurea is selected from the group consisting of tolbutamide, chlorpropamide, acetohexamide, tolazamide, glibenclamide, glipizide or any combination thereof.

### Claim 92 (depends on 90)

The method of claim 90, wherein said thiazolidinedione is rosiglitazone or pioglitazone, or combination thereof.

### Claim 93 (depends on 90)

The method of claim 90, wherein said bile acid sequestrant is colesevelam.

### Claim 94 (depends on 90)

The method of claim 90, wherein said insulin is bolus insulin, basal insulin, or an analogue thereof.

### Claim 95 (depends on 90)

The method of claim 90, wherein said supplemental therapy is administered prior to said method.

### Claim 96 (depends on 90)

The method of claim 90, wherein said supplemental therapy is administered contemporaneously with said method.

### Claim 97 (depends on 90)

The method of claim 90, wherein said supplemental therapy is administered following said method.

### Claim 98 (depends on 58)

The method of claim 58, wherein the glucose levels are blood glucose levels.

### Claim 99 (depends on 58)

The method of claim 58, wherein the subject has a metabolic disorder.

### Claim 100 (depends on 58)

The method of claim 58, wherein the subject has an insulin resistance disorder.

### Claim 101 (depends on 58)

The method of claim 58, wherein the subject has hyperinsulinemia.

### Claim 102 (depends on 58)

The method of claim 58, wherein the subject has glucose intolerance.

### Claim 103 (depends on 58)

The method of claim 58, wherein the subject has a hyperglycemic disorder or is at risk of developing a hyperglycemic disorder.

### Claim 104 (depends on 58)

The method of claim 58, wherein the subject has diabetes.

### Claim 105 (depends on 58)

The method of claim 58, wherein the subject has insulin-dependent (type I) diabetes.

### Claim 106 (depends on 58)

The method of claim 58, wherein the subject has type II diabetes.

### Claim 107 (depends on 58)

The method of claim 58, wherein the subject has gestational diabetes.

### Claim 108 (depends on 58)

The method of claim 58, wherein the subject is obese.

### Claim 109 (depends on 58)

The method of claim 58, wherein the subject has a FPG level of greater than 100 mg/dl.

### Claim 110 (depends on 58)

The method of claim 58, wherein the subject has an FPG level of 125 mg/dl or greater.

### Claim 111 (depends on 58)

The method of claim 58, wherein the subject has an FPG level between 100 and 125 mg/dl.

### Claim 112 (depends on 58)

The method of claim 58, wherein the glucose levels are reduced by at least 5%.

### Claim 113 (depends on 58)

The method of claim 58, wherein the subject has a HbA1c level above 6%.