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EP-4735021-A1 - COMBINATION THERAPY

EP4735021A1EP 4735021 A1EP4735021 A1EP 4735021A1EP-4735021-A1

Abstract

The present invention relates to use of an amylin analogue and a dual agonist of the gastric inhibitory polypeptide receptor (GIPR) and the glucagon-like peptide- 1 receptor (GLP-1R) to regulate body weight and to treat or prevent obesity and related conditions.

Inventors

  • VESTERGAARD, Bill

Assignees

  • Zealand Pharma A/S

Dates

Publication Date
20260506
Application Date
20240628

Claims (18)

  1. 1. An amylin analogue and a gastric inhibitory polypeptide receptor (GIPR) I glucagon- like peptide-1 receptor (GLP-1R) dual agonist for use in treating or preventing a disease in a subject, wherein the amylin analogue is a compound of the formula: R 1 -Z-R 2 wherein: R 1 is hydrogen, CM acyl, benzoyl or C1-4 alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L; R 2 is OH or NHR 3 , wherein R 3 is hydrogen or Ci-3-alkyl; and Z is an amino acid sequence of formula I: X1-X2-X3-X4-X5-X6-X7-Ala-Thr-X10-Arg-Leu-Ala-X14-Phe-Leu-X17-Arg-X19-X20- Phe-Gly(Me)-Ala-lle(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly-Ser-X35-Thr-X37 (SEQ ID NO: 1) wherein: X1 is selected from the group consisting of Arg, Lys and Glu; X2 and X7 are amino acid residues whose side chains together form a lactam bridge; X3 is selected from the group consisting of Gly, Gin and Pro; X4 is selected from the group consisting of Thr and Glu; X5 is selected from the group consisting of Ala and Leu; X6 is selected from the group consisting of Thr and Ser; X10 is selected from the group consisting of Glu and Gin; X14 is selected from the group consisting of Aad, His, Asp, Asn and Arg; X17 is selected from the group consisting of Gin, His and Thr; X19-X20 is selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly and Ala-Asn or is absent; X27 is selected from the group consisting of Leu and Pro; X32 is selected from the group consisting of Vai and Thr; X35 is selected from the group consisting of Asn and Ser; X37 is selected from the group consisting of Hyp and Pro; and Hyp is 4-hydroxyproline, Gly(Me) is N-methylglycine [also known as sarcosine (Sar)], lle(Me) is N-methylisoleucine, and Aad is 2-aminoadipic acid, e.g. (2S)-2-aminoadipic acid [also (2S)-2- aminohexanedioic acid], also known as homo-glutamic acid; or a pharmaceutically acceptable salt or solvate thereof, and wherein the disease is overweight, obesity, morbid obesity, diabetes, or a disease linked to obesity or to diabetes.
  2. 2. The amylin analogue and GIPR I GLP-1R dual agonist for use according to claim 1 , wherein the disease linked to obesity or to diabetes is selected from the group consisting of: obesity-linked inflammation, obesity-linked gallbladder disease, obesity-induced sleep apnea, obesity-linked respiratory problems, degeneration of cartilage, osteoarthritis, infertility, Alzheimer’s disease, pre-diabetes, gestational diabetes, insulin resistance syndrome, inadequate glucose control, impaired glucose tolerance (IGT), disease states associated with elevated blood glucose levels, metabolic disease, metabolic syndrome, hyperglycemia, hypertension, dyslipidaemia, atherogenic dyslipidemia, kidney failure, arteriosclerosis, atherosclerosis, macrovascular disease, microvascular disease, diabetic heart disease, diabetic cardiomyopathy, heart failure as a diabetic complication, coronary heart disease, peripheral artery disease and stroke.
  3. 3. An amylin analogue and a GIPR / GLP-1R dual agonist for use in a method of inhibiting weight gain and/or reducing body weight in a subject, wherein the amylin analogue is a compound of the formula: R 1 -Z-R 2 wherein: R 1 is hydrogen, CM acyl, benzoyl or C1-4 alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L; R 2 is OH or NHR 3 , wherein R 3 is hydrogen or Ci-3-alkyl; and Z is an amino acid sequence of formula I: X1-X2-X3-X4-X5-X6-X7-Ala-Thr-X10-Arg-Leu-Ala-X14-Phe-Leu-X17-Arg-X19-X20- Phe-Gly(Me)-Ala-lle(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly-Ser-X35-Thr-X37 (SEQ ID NO: 1) wherein: X1 is selected from the group consisting of Arg, Lys and Glu; X2 and X7 are amino acid residues whose side chains together form a lactam bridge; X3 is selected from the group consisting of Gly, Gin and Pro; X4 is selected from the group consisting of Thr and Glu; X5 is selected from the group consisting of Ala and Leu; X6 is selected from the group consisting of Thr and Ser; X10 is selected from the group consisting of Glu and Gin; X14 is selected from the group consisting of Aad, His, Asp, Asn and Arg; X17 is selected from the group consisting of Gin, His and Thr; X19-X20 is selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly and Ala-Asn or is absent; X27 is selected from the group consisting of Leu and Pro; X32 is selected from the group consisting of Vai and Thr; X35 is selected from the group consisting of Asn and Ser; X37 is selected from the group consisting of Hyp and Pro; and Hyp is 4-hydroxyproline, Gly(Me) is N-methylglycine [also known as sarcosine (Sar)], lle(Me) is N-methylisoleucine, and Aad is 2-aminoadipic acid, e.g. (2S)-2-aminoadipic acid [also (2S)-2- aminohexanedioic acid], also known as homo-glutamic acid; or a pharmaceutically acceptable salt or solvate thereof.
  4. 4. A non-therapeutic method of inhibiting weight gain and/or reducing body weight in a subject, wherein the method comprises administering an amylin analogue and a GIPR / GLP-1R dual agonist to the subject, wherein the amylin analogue is a compound of the formula: R 1 -Z-R 2 wherein: R 1 is hydrogen, CM acyl, benzoyl or C1-4 alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L; R 2 is OH or NHR 3 , wherein R 3 is hydrogen or Ci-3-alkyl; and Z is an amino acid sequence of formula I: X1-X2-X3-X4-X5-X6-X7-Ala-Thr-X10-Arg-Leu-Ala-X14-Phe-Leu-X17-Arg-X19-X20- Phe-Gly(Me)-Ala-lle(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly-Ser-X35-Thr-X37 (SEQ ID NO: 1) wherein: X1 is selected from the group consisting of Arg, Lys and Glu; X2 and X7 are amino acid residues whose side chains together form a lactam bridge; X3 is selected from the group consisting of Gly, Gin and Pro; X4 is selected from the group consisting of Thr and Glu; X5 is selected from the group consisting of Ala and Leu; X6 is selected from the group consisting of Thr and Ser; X10 is selected from the group consisting of Glu and Gin; X14 is selected from the group consisting of Aad, His, Asp, Asn and Arg; X17 is selected from the group consisting of Gin, His and Thr; X19-X20 is selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly and Ala-Asn or is absent; X27 is selected from the group consisting of Leu and Pro; X32 is selected from the group consisting of Vai and Thr; X35 is selected from the group consisting of Asn and Ser; X37 is selected from the group consisting of Hyp and Pro; and Hyp is 4-hydroxyproline, Gly(Me) is N-methylglycine [also known as sarcosine (Sar)], lle(Me) is N-methylisoleucine, and Aad is 2-aminoadipic acid, e.g. (2S)-2-aminoadipic acid [also (2S)-2- aminohexanedioic acid], also known as homo-glutamic acid; or a pharmaceutically acceptable salt or solvate thereof.
  5. 5. The amylin analogue and GIPR I GLP-1R dual agonist for use according to any one of claims 1 to 3 or the method according to claim 4, wherein the amylin analogue comprises the amino acid sequence RDGTATKATERLA-Aad-FLQRSSF-Gly(Me)-A-lle(Me)-LSSTEVGSNT-Hyp (SEQ ID NO: 9) or a variant thereof having at least 80% identity to SEQ ID NO: 9, preferably at least 85% identity, at least 86% identity, at least 87% identity, at least 88% identity, at least 89% identity, at least 90% identity, at least 91% identity, at least 92% identity, at least 93% identity, at least 94% identity, at least 95% identity, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 9.
  6. 6. The amylin analogue and GIPR I GLP-1R dual agonist for use according to any one of claims 1 to 3 or 5, or the method according to claim 4 or claim 5, wherein the amylin analogue is petrelintide: [19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-lle(Me)- LSSTE GSNT-Hyp-NH 2 (SEQ ID NO: 2), wherein () after amino acid symbols indicate residues whose side chains participate in an intramolecular lactam bridge, and [19CD]-isoGlu is a 19-carboxynonadecanoyl group ([19-CD]-) covalently attached to the alpha amino group of an iso-glutamic acid linker, or a pharmaceutically acceptable salt or solvate thereof.
  7. 7. The amylin analogue and GIPR I GLP-1R dual agonist for use according to any one of claims 1 to 3, 5 or 6, or the method according to any one of claims 4 to 6, wherein the amylin analogue is administered to the subject at a dose of up to about 10 mg, preferably a dose selected from any one of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg and about 10 mg.
  8. 8. The amylin analogue and GIPR I GLP-1 R dual agonist for use according to any one of claims 1 to 3 or 5 to 7, or the method according to any one of claims 4 to 7, wherein the amylin analogue is administered to the subject once a week.
  9. 9. The amylin analogue and GIPR I GLP-1 R dual agonist for use according to any one of claims 1 to 3 or 5 to 8, or the method according to any one of claims 4 to 8, wherein the GIPR I GLP-1 R dual agonist comprises the amino acid sequence Y[Aib]EGTFTSDYSI[Aib]LDKIAQKAFVQWLIAGGPSSGAPPPS (SEQ ID NO: 10) or a variant thereof having at least 80% identity to SEQ ID NO: 10, preferably at least 85% identity, at least 86% identity, at least 87% identity, at least 88% identity, at least 89% identity, at least 90% identity, at least 91% identity, at least 92% identity, at least 93% identity, at least 94% identity, at least 95% identity, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 10.
  10. 10. The amylin analogue and GIPR I GLP-1 R dual agonist for use according to any one of claims 1 to 3 or 5 to 9, or the method according to any one of claims 4 to 9, wherein the GIPR I GLP-1 R dual agonist is of the formula: Y[Aib]EGTFTSDYSI[Aib]LDKIAQ[K]A-X-VQWLIAGGPSSGAPPPS (SEQ ID NO: 3) wherein: [Aib] is a-aminoisobutyric acid, [K] is lysine with (2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(isoGlu) a -CO-(CH2)b-CO2H conjugated to the epsilon-amino group of the lysine side-chain, a is 1 or 2, b is 10 to 20, X is Phe or 1-Nal, and the C-terminal amino acid is optionally amidated as a C-terminal primary amide; or a pharmaceutically acceptable salt or solvate thereof.
  11. 11. The amylin analogue and GIPR I GLP-1 R dual agonist for use according to any one of claims 1 to 3 or 5 to 10, or the method according to any one of claims 4 to 10, wherein the GIPR I GLP-1 R dual agonist is tirzepatide: Hy-Y[Aib]EGTFTSDYSI[Aib]LDKIAQ[K]AFVQWLIAGGPSSGAPPPS-NH 2 (SEQ ID NO: 4) wherein [Aib] is a-aminoisobutyric acid, and [K] is lysine with (2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(isoGlu)i-CO-(CH2)i8-COOH conjugated to the epsilon-amino group of the lysine side-chain; or a pharmaceutically acceptable salt or solvate thereof.
  12. 12. The amylin analogue and GIPR I GLP-1 R dual agonist for use according to any one of claims 1 to 3 or 5 to 11 , or the method according to any one of claims 4 to 11 , wherein the amylin analogue is petrelintide and the GIPR I GLP-1 R dual agonist is tirzepatide.
  13. 13. The amylin analogue and GIPR I GLP-1 R dual agonist for use according to any one of claims 1 to 3 or 5 to 12, or the method according to any one of claims 4 to 12, wherein the GIPR I GLP-1 R dual agonist is administered to the subject at a dose of up to about 15 mg, preferably a dose selected from any one of about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg and about 15 mg.
  14. 14. The amylin analogue and GIPR I GLP-1 R dual agonist for use according to any one of claims 1 to 3 or 5 to 13, or the method according to any one of claims 4 to 13, wherein the GIPR I GLP-1 R dual agonist is administered to the subject once a week.
  15. 15. The amylin analogue and GIPR I GLP-1 R dual agonist for use according to any one of claims 1 to 3 or 5 to 14, or the method according to any one of claims 4 to 14, wherein the amylin analogue, or the pharmaceutically acceptable salt or solvate thereof, is formulated as an amylin analogue pharmaceutical composition.
  16. 16. The amylin analogue and GIPR I GLP-1 R dual agonist for use according to any one of claims 1 to 3 or 5 to 15, or the method according to any one of claims 4 to 15, wherein the GIPR I GLP-1 R dual agonist, or the pharmaceutically acceptable salt or solvate thereof, is formulated as a GIPR / GLP-1 R dual agonist pharmaceutical composition.
  17. 17. The amylin analogue and GIPR I GLP-1 R dual agonist for use according to any one of claims 1 to 3 or 5 to 16, or the method according to any one of claims 4 to 16, wherein the amylin analogue and GIPR I GLP-1 R dual agonist are administered to the subject by injection, preferably by subcutaneous injection.
  18. 18. A kit comprising an amylin analogue and a GIPR / GLP-1 R dual agonist, preferably wherein the amylin analogue and/or the GIPR I GLP-1 R dual agonist are as defined in any one of claims 1 to 17.

Description

COMBINATION THERAPY FIELD OF THE INVENTION The present invention relates to the use of a combination of an amylin analogue and a dual agonist of the gastric inhibitory polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP-1R) to regulate body weight and to treat or prevent obesity and related conditions. BACKGROUND TO THE INVENTION Obesity is a currently a significant public health issue across much of the developed world and is correlated with the development of several serious conditions, such as cardiovascular disease, type 2 diabetes, sleep apnoea, and certain cancers. The standard treatment for obesity is lifestyle intervention, including the reduction of energy intake and the increase of exercise. However, while such interventions can achieve temporary success, it is often challenging for patients to sustain such lifestyle changes over a long period such that the weight loss achieved is permanent. Amylin Amylin is one of a family of peptide hormones that includes amylin, calcitonin, calcitonin gene-related peptide, adrenomedullin and intermedin (intermedin also being known as AFP- 6), and has been implicated in various metabolic diseases and disorders. Human amylin was first isolated, purified and characterized as the major component of amyloid deposits in the islets of pancreases from type 2 diabetes patients. Native human amylin is a 37-amino acid peptide having the sequence: Hy-KC()NTATC()ATQRLANFLVHSSNNFGAILSSTNVGSNTY-NH2 (SEQ ID NO: 5) wherein Hy- at the N-terminus designates a hydrogen atom, corresponding to the presence of a free amino group on the N-terminal amino acid residue [i.e. the lysine (K) residue at sequence position number 1 in the sequence shown above], wherein -NH2 at the C-terminus indicates that the C-terminal carboxyl group is in the amide form, and wherein the parentheses “()” associated with the two cysteine (C, Cys) residues at sequence positions 2 and 7 indicate the presence of an intramolecular disulfide bridge between the two Cys residues. Amylin may be beneficial in treating metabolic disorders such as diabetes and/or obesity. Amylin is believed to slow gastric emptying, suppress glucagon secretion and reduce food intake, thereby regulating the rate of glucose release to the circulation. Amylin appears to complement the actions of insulin. Compared to healthy adults, type 1 diabetes patients have no circulating amylin, and type 2 diabetes patients exhibit reduced postprandial amylin concentrations. WO 93/10146 describes an amylin analogue known as pramlintide, which has the sequence: Lys-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-GIn-Arg-Leu-Ala-Asn-Phe-Leu-Val-His-Ser- Ser-Asn-Asn-Phe-Gly-Pro-lle-Leu-Pro-Pro-Thr-Asn-Val-Gly-Ser-Asn-Thr-Tyr (SEQ ID NO: 6). Pramlintide also possesses a disulphide bridge between the cysteine residues at positions 2 and 7, and, in human trials, has been shown to reduce body weight or reduce weight gain. An alternative amylin analogue incorporating N-methylated residues and having a reduced tendency to fibrillation, designated IAPP-GI, has been described by Yan et al. (PNAS, 103(7), 2046-2051, 2006; Angew. Chem. Int. Ed. 2013, 52, 10378-10383; W02006/042745). IAPP-GI appears to have lower activity than native amylin, however. WO 2018/046719 describes amylin analogues having, inter alia, a lactam bridge instead of a disulfide bridge, N-methylated residues, and a deletion corresponding to the residues Asn21 and Asn22 of native human amylin. Such analogues have considerably lower tendency towards fibrillation than native amylin, while also having higher potency than the analogues described by Yan et al. (supra). GIP and GLP-1 GIP and GLP-1 are peptide hormones known as incretins which have roles in glucose homeostasis. Gastric inhibitory polypeptide or gastric inhibitory peptide (GIP), also known as glucosedependent insulinotropic polypeptide, is a 42-amino acid peptide hormone produced by the mucosa of the small intestine. In the presence of glucose, GIP stimulates insulin secretion from pancreatic p-cells by binding and agonising the GIP receptor (GIPR) on the p-cell surface. Glucagon-like peptide-1 (GLP-1) is a peptide hormone produced by intestinal tissue. When secreted from the gastrointestinal tract in response to nutrient ingestion, GLP-1 potentiates glucose-stimulated insulin secretion from p-cells (Kim and Egan, 2008, Pharmacol. Rev. 470- 512). Furthermore, GLP-1 or it analogues has been shown to increase somatostatin secretion and suppress glucagon secretion (Holst JJ, 2007, Physiol Rev. 1409-1439). The sequence of human GLP-1 is: Hy-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-GIn-Ala-Ala- Lys-Glu-Phe-lle-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly-NH2 (SEQ ID NO: 7) GLP-1 binds and agonises the GLP-1 receptor (GLP-1 R), which is expressed on pancreatic P-cells and brain neurons. Besides the primary actions of GLP-1 on glucose-stimulated insulin secretion, GLP-1 is also known as a key regulator of appetite, food in