# US 2014/0194352 A1 · Compositions and Methods for Treatment of Metabolic Disorders and Diseases

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- Number: US 2014/0194352 A1
- Document ID: US20140194352A1
- Status: Published application
- Kind: A1
- Application number: 14/091,085
- Filed: 2013-11-26
- Published: 2014-07-10
- Earliest claimed: 2012-11-28
- Assignees: NGM Biopharmaceuticals, Inc.
- Applicants: NGM Biopharmaceuticals, Inc.
- Inventors: Lei Ling; Darrin Anthony Lindhout
- Web page: https://patentgrep.com/patent/US20140194352A1

## CPC

- C07K 14/50: Fibroblast growth factor [FGF]
- A61K 38/1825: {Fibroblast growth factor [FGF]}
- 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)
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07K 2319/00: Fusion polypeptide
- 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)
- 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)

## 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.

## Claims

### Claim at position 1

-5. (canceled)

### Claim 6

A peptide sequence, comprising or consisting of
a) a fibroblast growth factor 19 (FGF19) sequence variant having one or more amino acid substitutions, insertions or deletions compared to a reference or wild type FGF19;
b) a portion of an FGF19 sequence fused to a portion of an FGF21 sequence, wherein the FGF19 and/or FGF21 sequence portion(s) have one or more amino acid substitutions, insertions or deletions compared to a reference or wild type FGF19 and/or FGF21;
wherein the peptide sequence comprises at least one amino acid substitution to amino acid residues 125-129 of SEQ ID NO:99 [FGF19], EIRPD; at least one amino acid substitution to amino acid residues 126-128 of SEQ ID NO:99 [FGF19], IRP; or at least one amino acid substitution to amino acid residues 127-128 of SEQ ID NO:99 [FGF19]. RP.

### Claim 7 (depends on 6)

The peptide sequence of claim 6, wherein the peptide sequence has amino-terminal amino acids 1-16 of SEQ ID NO:100 [FGF21] fused to carboxy-terminal amino acids 21-194 of SEQ ID NO:99 [FGF19], or wherein the peptide sequence has amino-terminal amino acids 1-147 of 860 ID NO:99 [FGF19] fused to carboxy-terminal amino acids 147-181 of SEQ ID NO:100 [FGF21] (M41).

### Claim 8

(canceled)

### Claim 9 (depends on 6)

The peptide sequence of claim 6, wherein the peptide sequence comprises at least one amino acid substitution to one of amino acid residues 127-128 of SEQ ID NO:99 [FGF19], RP, wherein at least one amino acid substitution is R127L or P128E.

### Claim 10

(canceled)

### Claim 11 (depends on 6)

The peptide sequence of claim 6, wherein the peptide sequence further comprises at least one amino acid substitution to amino acid residues 1-124 of SEQ ID NO:99 [FGF19] and/or to amino acid residues 130-194 of SEQ ID NO:99 [FGF19].

### Claim 12 (depends on 11)

The peptide sequence of claim 11, wherein the peptide sequence is RPLAFSDAGPHVHYGWGDPIRQRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSL LEIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEILEDGYNVYR SEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPEDLRGHLESDMFSSPLE TDSMDPFGLVTGLEAVRSPSFEK (M160).

### Claim 13 (depends on 6)

The peptide sequence of claim 6, wherein: (a) the peptide sequence has a WGDPI sequence motif corresponding to the WGDPI sequence of amino acids 16-20 of SEQ ID NO:99 [FGF19]; (b) the peptide sequence has a substituted, mutated or absent WGDPI sequence motif corresponding to FGF19 WGDPI sequence of amino acids 16-20 of FGF19; or (c) the peptide sequence is distinct from an FGF 19 variant sequence having any of GQV, GDI, WGPI, WGDPV, WGDI, GDPI, GPI, WGQPI, WGAPI, AGDPI, WADPI, WGDAI, WGDPA, WDPI, WGDI, WGDP or FGDPI substituted for the FGF19 WGDPI sequence at amino acids 16-20.

### Claim at position 10

-20. (canceled)

### Claim 21 (depends on 6)

The peptide sequence of claim 6 having an N-terminal region and a C-terminal region, wherein the N-terminal region comprises amino acid residues DSSPLLQ, and wherein the Q residue is the last amino acid position of the N-terminal region.

### Claim 22 (depends on 21)

The peptide sequence of claim 21, wherein the N-terminal region further comprises: RHPIP, wherein R is the first amino acid position of the N-terminal region; or HPIP, wherein H is the first amino acid position of the N-terminal region; or RPLAF, wherein R is the first amino acid position of the N-terminal region; or PLAF, wherein P is the first amino acid position of the N-terminal region; or R, wherein R is the first amino acid position of the N-terminal region.

### Claim 23 (depends on 6)

The peptide sequence or peptide sequence of claim 6, wherein
(a) the peptide sequence comprises or consists of any of M1-M98 variant peptide sequences, or a subsequence or fragment of any of the M1-M98 variant peptide sequences;
(b) amino acid residues HPIP are the first 4 amino acid residues of the N-terminal region;
(c) the first position of the N-terminal region is an R residue, or wherein the first position of the N-terminal region is an M residue, or wherein the first and second positions of the N-terminal region is an MR sequence, or wherein the first and second positions of the N-terminal region is an RM sequence, or wherein the first and second positions of the N-terminal region is an RD sequence, or wherein the first and second positions of the N-terminal region is an DS sequence, or wherein the first and second positions of the N-terminal region is an MD sequence, or wherein the first and second positions of the N-terminal region is an MS sequence, or wherein the first through third positions of the N-terminal region is an MDS sequence, or wherein the first through third positions of the N-terminal region is an RDS sequence, or wherein the first through third positions of the N-terminal region is an MSD sequence, or wherein the first through third positions of the N-terminal region is an MSS sequence, or wherein the first through third positions of the N-terminal region is an DSS sequence, or wherein the first through fourth positions of the N-terminal region is an RDSS sequence, or wherein the first through fourth positions of the N-terminal region is an MDSS sequence, or wherein the first through fifth positions of the N-terminal region is an MRDSS sequence, or wherein the first through fifth positions of the N-terminal region is an MSSPL sequence, or wherein the first through sixth positions of the N-terminal region is an MDSSPL sequence, or wherein the first through seventh positions of the N-terminal region is an MSDSSPL sequence;
(d) the last position of the C-terminal region corresponds to about residue 194 of SEQ ID NO:99 [FGF 19];
(e) the N-terminal region, or the C-terminal region, comprises or consists of an amino acid sequence of about 5 to 10, 10 to 20, 20 to 30, 30 to 40, 40 to 50, 60 to 70, 70 to 80, 80 to 90, 90 to 100 or more amino acids;
(f) the FGF19 sequence portion, or the FGF21 sequence portion, comprises or consists of an amino acid sequence of about 5 to 10, 10 to 20, 20 to 30, 30 to 40, 40 to 50, 50 to 60, 60 to 70, 70 to 80, 80 to 90, 90 to 100 or more amino acids of FGF19 or FGF21;
(g) the N-terminal region, or the C-terminal region, or the FGF19 sequence portion, or the FGF21 sequence portion, are joined by a linker or spacer;
(h) the N-terminus of the peptide sequence comprises or consists of any of:
HPIPDSSPLLQFGGQVRLRHLYTSG (M5);
DSSPLLQFGGQVRLRHLYTSG (M6);
RPLAFSDSSPLLQFGGQVRLRHLYTSG (M7);
HPIPDSSPLLQWGDPIRLRHLYTSG (M8);
HPIPDSSPLLQFGWGDPIRLRHLYTSG (M9);
HPIPDSSPHVHYGWGDPIRLRHLYTSG (M10);
RPLAFSDAGPLLQWGDPIRLRHLYTSG (M11);
RPLAFSDAGPLLQFGWGDPIRLRHLYTSG (M12);
RPLAFSDAGPLLQFGGQVRLRHLYTSG (M13);
HPIPDSSPHVHYGGQVRLRHLYTSG (M14);
RPLAFSDAGPHVHWGDPIRLRHLYTSG (M15);
RPLAFSDAGPHVHWGDPIRLRHLYTSG (M16);
RPLAFSDAGPHVGWGDPIRLRHLYTSG (M17);
RPLAFSDAGPHYGWGDPIRLRHLYTSG (M18);
RPLAFSDAGPVYGWGDPIRLRHLYTSG (M19);
RPLAFSDAGPVHGWGDPIRLRHLYTSG (M20);
RPLAFSDAGPVHYWGDPIRLRHLYTSG (M21);
RPLAFSDAGPHVHGWGDPIRLRHLYTSG (M22);
RPLAFSDAGPHHGWGDPIRLRHLYTSG (M23);
RPLAFSDAGPHHYWGDPIRLRHLYTSG (M24);
RPLAFSDAGPHVYWGDPIRLRHLYTSG (M25);
RPLAFSDSSPLVHWGDPIRLRHLYTSG (M26);
RPLAFSDSSPHVHWGDPIRLRHLYTSG (M22);
RPLAFSDAGPHVWGDPIRLRHLYTSG (M28);
RPLAFSDAGPHVHYWGDPIRLRHLYTSG (M29);
RPLAFSDAGPHVHYAWGDPIRLRHLYTSG (M30);
RHPIPDSSPLLQFGAQVRLRHLYTSG (M31);
RHPIPDSSPLLQFGDQV RLRHLYTSG (M32);
RHPIPDSSPLLQFGPQV RLRHLYTSG (M33);
RHPIPDSSPLLQFGGAVRLRHLYTSG (M34);
RHPIPDSSPLLQFGGEVRLRHLYTSG (M35);
RHPIPDSSPLLQFGGNV RLRHLYTSG (M36);
RHPIPDSSPLLQFGGQARLRHLYTSG (M37);
RHPIPDSSPLLQFGGQI RLRHLYTSG (M38);
RHPIPDSSPLLQFGGQT RLRHLYTSG (M39);
RHPIPDSSPLLQFGWGQPVRLRHLYTSG (M40);
DAGPHVHYGWGDPIRLRHLYTSG (M74);
VHYGWGDPIRLRHLYTSG (M75);
RLRHLYTSG (M77);
RHPIPDSSPLLQFGWGDPIRLRHLYTSG;
RHPIPDSSPLLQWGDPIRLRHLYTSG;
RHPIPDSSPHVHYGWGDPIRLRHLYTSG;
RHPIPDSSPHVHYGGQVRLRHLYTSG;
RPLAFSDAGPHVHYGGDIRLRHLYTSG; or
RDSSPLLQFGGQVRLRHLYTSG;
or any of the foregoing peptide sequences wherein the amino terminal R residue is deleted;
wherein optionally the peptide sequence further comprises the addition of amino acid residues 30-194 of SEQ ID NO:99 [FGF19] at the C-terminus, resulting in a chimeric polypeptide,
(i) the reference or wild type FGF19 sequence is set forth as:
(SEQ ID NO: 99)
RPLAFSDAGPHVHYGWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVD
CARGQSAHSLLEIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQY
SEEDCAFEEEIRPDGYNVYRSEKHRLPVSLSSAKQRQLYKNRGFLPLS
HFLPMLPMVPEEPEDLRGHLESDMFSSPLETDSMDPFGLVTGLEAVRS
PSFEK;
(j) the reference or wild type FGF21 sequence is set forth as:
(SEQ ID NO: 100)
RHPIPDSSPLLQFGGQVRQRYLYTDDAQQTEAHLEIREDGTVGGAAD
QSPESLLQLKALKPGVIQILGVKTSRFLCQRPDGALYGSLHFDPEACSF
RELLLEDGYNVYQSEAHGLPLHLPGNKSPHRDPAPRGPARFLPLPGLP
PALPEPPGILAPQPPDVGSSDPLSMVGPSQGRSPSYAS;
(k) the N-terminal region first amino acid position is a “M” residue, an “R” residue, a “S” residue, a “H” residue, a “P” residue, a “L” residue or an “D” residue, or wherein the peptide sequence does not have a “M” residue or an “R” residue at the first amino acid position of the N-terminal region;
(l) the N-terminal region comprises any one of the following sequences: MDSSPL, MSDSSPL, SDSSPL, MSSPL or SSPL; or
(m) the peptide sequence comprises one or more L-amino acids, D-amino acids, non-naturally occurring amino acids, amino acid mimetics, derivatives or analogues.

### Claim 24 (depends on 6)

The peptide sequence of claim 6, wherein the peptide sequence comprises or consists of any of:
RPLAFSDAGPHVHYGWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSL
LEIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEILPDGYNVYR
SEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPEDLRGHLESDMFSSPLE
TDSMDPFGLVTGLEAVRSPSFEK (M139);
PLAFSDAGPHVHYGWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSLL
EIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIREDGYNVYRS
EKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPEDLRGHLESDMFSSPLET
DSMDPFGLVTGLEAVRSPSFEK (M140);
RPLAFSDAGPHVHYGWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSL
LEIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEILCDGYNVYR
SEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPEDLRGHLESDMFSSPLE
TDSMDPFGLVTGLEAVRSPSFEK (M141); or
RPLAFSDAGPHVHYGWGDPIRQRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSL
LEIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEILEDGYNVYR
SEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPEDLRGHLESDMFSSPLE
TDSMDPFGLVTGLEAVRSPSFEK (M160),
or a subsequence or fragment of any of the foregoing peptide sequences,
or any of the foregoing peptide sequences wherein the R terminal residue is deleted.

### Claim at position 15

-29. (canceled)

### Claim 30 (depends on 23, 24)

The peptide sequence of claim 23 or 24, wherein the subsequence or fragment thereof has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more amino acid deletions from the amino terminus, the carboxy-terminus or internally.

### Claim at position 17

-43. (canceled)

### Claim 44 (depends on 6)

The peptide sequence of claim 6, wherein the peptide sequence:
(a) has reduced hepatocellular carcinoma (HCC) formation compared to FGF19, or an FGF 19 variant sequence having any of GQV, GDI, WGPI, WGDPV, WGDI, GDPI, GPI, WGQPI, WGAPI, AGDPI, WADPI, WGDAI, WGDPA, WDPI, WGDI, WGDP or FGDPI substituted for the WGDPI sequence at amino acids 16-20 of FGF19;
(b) has greater glucose lowering activity compared to FGF19, or an FGF 19 variant sequence having any of GQV, GDI, WGPI, WGDPV, WGDI, GDPI, GPI, WGQPI, WGAPI, AGDPI, WADPI, WGDAI, WGDPA, WDPI, WGDI, WGDP or FGDPI substituted for the WGDPI sequence at amino acids 16-20 of FGF19;
(c) has less lipid increasing activity compared to FGF19, or an FGF 19 variant sequence having any of GQV, GDI, WGPI, WGDPV, WGDI, GDPI, GPI, WGQPI, WGAPI, AGDPI, WADPI, WGDAI, WGDPA, WDPI, WGDI, WGDP or FGDPI substituted for the WGDPI sequence at amino acids 16-20 of FGF 19;
(d) has less triglyceride, cholesterol, non-HDL or HDL increasing activity compared to FGF19, or an FGF 19 variant sequence having any of GQV, GDI, WGPI, WGDPV, WGDI, GDPI, GPI. WGQPI, WGAPI. AGDPI, WADPI, WGDAI, WGDPA, WDPI, WGDI, WGDP or FGDPI substituted for the WGDPI sequence at amino acids 16-20 of FGF19; or
(e) has less lean mass reducing activity compared to FGF21;
wherein optionally the HCC formation, glucose lowering activity, lipid increasing activity, or lean mass reducing activity is ascertained in a db/db mouse.

### Claim at position 19

-49. (canceled)

### Claim 50 (depends on 6)

The peptide sequence of claim 6, wherein the peptide sequence: (a) binds to fibroblast growth factor receptor 4 (FGFR4) or activates FGFR4, or does not detectably bind to fibroblast growth factor receptor 4 (FGFR4) or activate FGFR4; (b) binds to FGFR4 with an affinity less than, comparable to or greater than FGF19 binding affinity for FGFR4; or (c) activates FGFR4 to an extent or amount less than, comparable to or greater than FGF19 the extent or amount that activates FGFR4.

### Claim at position 21

-52. (canceled)

### Claim 53 (depends on 6)

The peptide sequence of claim 6, wherein the peptide sequence has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or insertions.

### Claim 54 (depends on 53)

The peptide sequence of claim 53, wherein the amino acid deletions are at the N- or C-terminus, or internal; or wherein the amino acid substitution, or deletion is at any of amino acid positions 8-20 of FGF19 (AGPHVHYGWGDPI).

### Claim at position 24

-56. (canceled)

### Claim 57 (depends on 6)

A composition, comprising the peptide sequence of claim 6.

### Claim at position 26

-60. (canceled)

### Claim 61 (depends on 6)

A nucleic acid molecule encoding the peptide sequence of claim 6; wherein optionally the nucleic acid molecule further comprises an expression control element in operable linkage that confers expression of the nucleic acid molecule encoding the peptide in vitro, in a cell or in vivo.

### Claim 62

(canceled)

### Claim 63 (depends on 61)

A vector comprising the nucleic acid molecule of claim 61; wherein optionally the vector comprises a viral vector.

### Claim 64

(canceled)

### Claim 65 (depends on 6)

A transformed or host cell that expresses the peptide sequence of claim 6.

### Claim 66 (depends on 6)

A method of treating a subject having, or at risk of having, a disease or disorder treatable by the peptide sequence of claim 6, comprising administering the chimeric peptide sequence or peptide sequence to a subject in an amount effective for treating the disorder.

### Claim 67 (depends on 66)

The method of claim 66, wherein the disease or disorder comprises a hyperglycemic condition, insulin resistance, hyperinsulinemia, glucose intolerance, obesity, an undesirable body mass, or metabolic syndrome.

### Claim 68 (depends on 67)

The method of claim 67, wherein the hyperglycemic condition comprises diabetes.

### Claim 69 (depends on 67)

The method of claim 67, wherein the hyperglycemic condition comprises insulin-dependent (type I) diabetes, type II diabetes, or gestational diabetes.

### Claim 70

(canceled)

### Claim 71 (depends on 6)

A method of improving glucose metabolism in a subject in need thereof, comprising administering the peptide sequence of claim 6 to a subject in an amount effective to improve glucose metabolism in the subject; wherein optionally the subject has a fasting plasma glucose level greater than 100 mg/dl or has a hemoglobin A1c (HbA1c) level above 6%.

### Claim 72

(canceled)

### Claim 73 (depends on 68, 71)

The method of claim 68 or 71, wherein the method results in reduced glucose levels, increased insulin sensitivity, reduced insulin resistance, reduced glucagon, an improvement in glucose tolerance, or glucose metabolism or homeostasis, improved pancreatic function, a reduced triglyceride, cholesterol, IDL, LDL or VLDL levels, a decrease in blood pressure, a decrease in intimal thickening of the blood vessel, or a decrease in body mass or weight gain.

### Claim at position 40

-79. (canceled)