Combination therapy

Abstract

The present invention relates to the use of an amyrin analog and a dual agonist of the gastric suppressor polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP-1R) for regulating body weight and for treating or preventing obesity and related conditions.

Description

Technical Field

[0001] The present invention relates to the use of amylin analogues, in combination with a dual agonist of gastric inhibitory polypeptide receptor (GIPR) and glucagon-like peptide-1 receptor (GLP-1R), for regulating body weight and for treating or preventing obesity and related conditions.

Background Art

[0002] Obesity is currently a major public health problem in most developed countries and is correlated with the development of several serious conditions such as cardiovascular disease, type 2 diabetes, sleep apnea, and certain cancers. The standard treatment for obesity is lifestyle intervention, including reducing energy intake and increasing exercise. However, while such interventions can achieve primary success, it is often difficult for patients to maintain such lifestyle changes over the long term to make the achieved weight loss permanent.

[0003] Amylin Amylin is one of a family of peptide hormones that includes amylin, calcitonin, calcitonin gene-related peptide, adrenomedullin, and intermedin (intermedin is also known as AFP-6) and has been associated with various metabolic diseases and disorders. Human amylin was first isolated, purified, and characterized as the major component of amyloid deposits in the islets of patients with type 2 diabetes.

[0004] Native human amylin is a peptide composed of 37 amino acids having the sequence: Hy-KC()NTATC()ATQRLANFLVHSSNNFGAILSSTNVGSNTY-NH2 (SEQ ID NO: 5) and In the formula, the N-terminus Hy- indicates a hydrogen atom corresponding to the presence of a free amino group at the N-terminal amino acid residue [i.e., the lysine (K) residue at sequence position 1 in the sequence shown above], the C-terminus -NH2 indicates that the C-terminal carboxyl group is in amide form, and the parentheses "()" surrounding the two cysteine ​​(C,Cys) residues at positions 2 and 7 of the sequence indicate the presence of an intramolecular disulfide bridge between the two Cys residues.

[0005] Amylin may be beneficial in the treatment of metabolic disorders such as diabetes and / or obesity. Amylin is thought to regulate the rate of glucose release into circulation by delaying gastric emptying, suppressing glucagon secretion, and reducing food intake. Amylin appears to complement the action of insulin. Compared to healthy adults, patients with type 1 diabetes have no circulating amylin, and patients with type 2 diabetes have low postprandial amylin concentrations. International Publication No. 93 / 10146 describes an amylin analog known as pramulintide, which has the following sequence: Lys-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Asn-Phe-Leu-Val-His-Ser-Ser-Asn-Asn-Phe-Gly-Pro-Ile-Leu-Pro-Pro-Thr-Asn-Val-Gly-Ser-Asn-Thr-Tyr (SEQ ID NO: 6) It holds.

[0006] Plumlintide also has a disulfide bridge between the cysteine ​​residues at positions 2 and 7, and has been shown in human studies to reduce body weight or reduce weight gain.

[0007] Another amyrin analog called IAPP-GI, which incorporates N-methylated residues and reduces the tendency towards microfibrillation, has been described by Yan et al. (PNAS, 103(7), 2046-2051, 2006; Angew. Chem. Int. Ed. 2013, 52, 10378-10383; International Publication No. 2006 / 042745). However, IAPP-GI appears to be less active than native amyrin.

[0008] International Publication No. 2018 / 046719 describes amyrin analogs that have lactam crosslinks instead of disulfide crosslinks, N-methylated residues, and deletions corresponding to native human amyrin residues Asn21 and Asn22, in particular. Such analogs have a much lower tendency to cause microfibrillation than native amyrin, while also having higher potency than the analogs described by Yan et al. (above).

[0009] GIP and GLP-1 GIP and GLP-1 are peptide hormones known as incretins, which play a role in glucose homeostasis.

[0010] Gastric inhibitory peptides (GIPs), also known as glucose-dependent insulinotropic polypeptides, are peptide hormones consisting of 42 amino acids produced by the mucosa of the small intestine. In the presence of glucose, GIPs bind to GIP receptors (GIPRs) on the surface of pancreatic β-cells and activate them, thereby stimulating insulin secretion from β-cells.

[0011] Glucagon-like peptide-1 (GLP-1) is a peptide hormone produced by intestinal tissue. When secreted from the gastrointestinal tract in response to nutrient intake, GLP-1 enhances glucose-stimulated insulin secretion from β-cells (Kim and Egan, 2008, Pharmacol. Rev. 470-512). Furthermore, GLP-1 or its analogs have been shown to increase somatostatin secretion and suppress glucagon secretion (Holst JJ, 2007, Physiol Rev. 1409-1439). The sequence of human GLP-1 is as follows. Hy-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly-NH2 (SEQ ID NO: 7) GLP-1 binds to the GLP-1 receptor (GLP-1R) expressed in pancreatic β-cells and brain neurons, and activates it.

[0012] In addition to its primary effect on glucose-stimulated insulin secretion, GLP-1 is known to be an important regulator of appetite, food intake, and body weight. Furthermore, GLP-1 can inhibit gastric emptying and gastrointestinal motility in both rodents and humans, most of which is likely mediated by GLP-1 receptors present in the gastrointestinal tract (Holst JJ, 2007, Physiol Rev. 1409-1439, Hellstrom et al., 2008, Neurogastroenterol Motil. Jun; 20(6):649-659). In addition, GLP-1 is thought to have insulin-like effects in major extrapancreatic tissues, and is involved in glucose homeostasis and lipid metabolism in tissues such as muscle, liver, and adipose tissue (Kim and Egan, 2008, Pharmacol. Rev. 470-512).

[0013] GLP-1 is released from the gastrointestinal tract in response to food intake and therefore acts as a signal of fullness, reducing food intake (Madsbad, S., 2014, Diabetes Obes Metab, 16: 9-21). There is evidence suggesting that the effects of GLP-1 may be reduced in obese individuals, which suggests that GLP-1 agonists may be promising in the treatment of obesity.

[0014] GLP-1 has been reported to increase the insulin response after oral intake of glucose or fat in most cases. However, it is generally known that GLP-1 lowers glucagon levels, has a beneficial effect on inhibiting rapid bowel motility (Tolessa et al., 1998, Dig. Dis. Sci. 43(10): 2284-90), and delays gastric emptying.

[0015] Molecules that exhibit both GIP and GLP-1 activity (i.e., activating both GIPR and GLP-1R) are known in the art (see, for example, International Publication No. 2011 / 119657, International Publication No. 2013 / 164483, and International Publication No. 2014 / 192284), and are referred to herein as GIPR / GLP-1R dual agonists. International Publication No. 2016 / 111971 describes a GIPR / GLP-1R dual agonist called tilzepatide, which is approved in the United States, Europe, Canada, and Australia for the treatment of type 2 diabetes. Tirzepatide is also described in Chavda et al. 2022 (Chavda et al. Tirzepatide, a New Era of Dual-Targeted Treatment for Diabetes and Obesity: A Mini-Review. Molecules 2022, 27, 4315). [Prior art documents] [Patent Documents]

[0016] [Patent Document 1] International Publication No. 93 / 10146 Pamphlet [Patent Document 2] International Publication No. 2006 / 042745 [Patent Document 3] International Publication No. 2018 / 046719 Brochure [Patent Document 4] International Publication No. 2011 / 119657 Pamphlet [Patent Document 5] International Publication No. 2013 / 164483 Pamphlet [Patent Document 6] International Publication No. 2014 / 192284 Pamphlet [Patent Document 7] International Publication No. 2016 / 111971 Pamphlet [Non-patent literature]

[0017] [Non-Patent Document 1] PNAS, 103(7), 2046-2051, 2006 [Non-Patent Document 2] Angew. Chem. Int. Ed. 2013, 52, 10378-10383 [Non-Patent Document 3] Kim and Egan, 2008, Pharmacol.Rev. 470-512 [Non-Patent Document 4] Holst JJ, 2007, Physiol Rev. 1409-1439 [Non-Patent Document 5] Hellstrom et al., 2008, Neurogastroenterol Motil. Jun; 20(6):649-659 [Non-Patent Document 6] Madsbad, S., 2014, Diabetes Obes Metab, 16: 9-21 [Non-Patent Document 7] Tolessa et al., 1998, Dig. Dis. Sci. 43(10): 2284-90 [Non-Patent Document 8] Chavda et al. Tirzepatide, a New Era of Dual-Targeted Treatment for Diabetes and Obesity: A Mini-Review. Molecules 2022, 27, 4315 [Overview of the project]

[0018] More broadly, the present invention relates to therapies and methods for treating or preventing diseases and disorders associated with excess body weight. More specifically, the present invention is based on the remarkable discovery that the combination of the use of amylin analogs and GIPR / GLP-1R dual agonists results in superior therapeutic efficacy compared to treatment with either agent alone.

[0019] Accordingly, the present invention provides a combination of an amyrin analog and a gastric suppressor polypeptide receptor (GIPR) / glucagon-like peptide-1 receptor (GLP-1R) dual agonist for use in the treatment or prevention of a disease in a subject, wherein the disease is overweight, obesity, morbid obesity, diabetes, or a disease associated with obesity or diabetes.

[0020] In one embodiment, the present invention provides a combination of an amyrin analog and a gastric suppressor polypeptide receptor (GIPR) / glucagon-like peptide-1 receptor (GLP-1R) dual agonist for use in the treatment or prevention of a disease in a subject, wherein the disease is overweight, obesity, morbid obesity, diabetes, or a disease associated with obesity or diabetes, and the amyrin analog and the gastric suppressor polypeptide receptor (GIPR) / glucagon-like peptide-1 receptor (GLP-1R) dual agonist are administered to the subject by one of the following methods: individual administration, simultaneous administration, sequential administration, incidental administration, co-administration, or administration in the same formulation.

[0021] The present invention also provides a combination of an amylin analog and a GIPR / GLP-1R dual agonist for use in methods for inhibiting and / or reducing weight gain in subjects.

[0022] In one embodiment, the present invention provides a combination of an amylin analog and a GIPR / GLP-1R dual agonist for use in a method of inhibiting and / or reducing weight gain in a subject, wherein the amylin analog and the GIPR / GLP-1R dual agonist are administered to the subject by one of the following methods: individual administration, simultaneous administration, sequential administration, incidental administration, co-administration, or administration in the same formulation.

[0023] The present invention also provides a kit including an Amilin analog and a GIPR / GLP-1R dual agonist.

[0024] Preferably, the amylin analog is a petrelin tide as described herein. [19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH2 (Sequence ID 2).

[0025] Preferably, the GIPR / GLP-1R dual agonist is Hy-Y[Aib]EGTFTSDYSI[Aib]LDKIAQ[K]AFVQWLIAGGPSSGAPPPS-NH2 (SEQ ID NO: 4) (Tilzepatide) as described herein. [Brief explanation of the drawing]

[0026] [Figure 1] This diagram schematically shows the research design used in Example 1. [Figure 2]This figure shows the average cumulative food intake per rat (in grams) ± SEM for rats administered the medium (Group 1, black circles); the medium followed by an amylin analog from day 14 (Group 2, white circles); tilzepatide followed by tilzepatide and the medium from day 14 (Group 3, black squares); or tilzepatide followed by tilzepatide and an amylin analog from day 14 (Group 4, white squares). [Figure 3] This figure shows the average cumulative water intake per rat (in grams) ± SEM for rats administered the medium (group 1, black circles); the medium and amylin analog from day 14 after the medium (group 2, white circles); tilzepatide and the medium from day 14 after tilzepatide (group 3, black squares); or tilzepatide and amylin analog from day 14 after tilzepatide (group 4, white squares). [Figure 4] This figure shows the mean body weight change %±SEM in rats administered the medium (group 1, black circles); the medium and amylin analog from day 14 after the medium (group 2, white circles); tilzepatide and the medium from day 14 after tilzepatide (group 3, black squares); or tilzepatide and amylin analog from day 14 after tilzepatide (group 4, white squares). [Figure 5] This figure shows the structure of tylzepatide, a GIPR / GLP-1R dual agonist. Most of the amino acids in the peptide portion of tylzepatide are shown using single-letter codes. Exceptionally, α-aminoisobutyric acid (Aib) at positions 2 and 13, and lysine at position 20, are shown using chemical structure notation. The linker and fatty acid portion ((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(isoGlu)1-CO-(CH2)18-COOH) conjugated to the side chain of lysine at position 20 are also shown using chemical structure notation. The N-terminal "H-" portion indicates the presence of a primary amine group, and the C-terminal "-NH2" portion indicates the presence of an amide (CONH2) group (rather than a carboxylic acid group -COOH) at the C-terminus. [Figure 6]This figure shows the average exposure to amylin analog on day 34 in rats administered either amylin analog alone (checkered bars) or amylin analog and tilzepatide (striped bars), as described in Example 1 of this specification. [Figure 7] This figure shows the average exposure to tilzepatide on day 34 in rats administered tilzepatide alone (diagonally intersecting bars) or amylin analog and tilzepatide (striped bars), as described in Example 1 of this specification. [Figure 8] This figure shows the individual exposure levels to amylin analogs on day 34 in rats administered either amylin analog alone (white circles) or amylin analog and tilzepatide (white squares), as described in Example 1 of this specification. [Figure 9] This figure shows the individual exposure levels to tilzepatide on day 34 in rats administered tilzepatide alone (black square) or amylin analog and tilzepatide (white square), as described in Example 1 of this specification. [Figure 10] This figure shows the mean body weight change on day 34 of rats administered the medium, amylin analog alone, tilzepatide alone, or amylin analog and tilzepatide, as described in Example 1 of this specification. [Modes for carrying out the invention]

[0027] Unless otherwise defined herein, scientific and technical terms used herein have the meanings generally understood by those skilled in the art. Overall, the terminology and techniques used herein in relation to chemistry, molecular biology, cell biology and cancer biology, immunology, microbiology, pharmacology, and protein chemistry and nucleic acid chemistry are well known and commonly used in the art.

[0028] All patents, published patent applications, and non-patent publications referenced herein are incorporated herein by reference. In case of any disagreement, this specification, including its specific definitions, shall prevail.

[0029] Each embodiment of the invention described herein may be carried out independently or in combination with one or more other embodiments of the invention.

[0030] definition Unless otherwise specified, the following definitions are given to the specific terms used herein. All other terms will be understood by those skilled in the art to have the general meaning in the art to which they pertain.

[0031] Throughout this specification, the word “comprise,” and its grammatical variations such as “comprises” or “comprising,” will be understood to mean that the integers or components, or groups of integers or components, described are included, but not that any other integers or components, or groups of integers or components, are excluded.

[0032] The singular forms "a," "an," and "the" include the plural form unless otherwise clearly indicated by the context.

[0033] The term "including" is used to mean "including but not limiting." "Including" and "including but not limiting" can be used interchangeably.

[0034] The terms “patient,” “subject,” and “individual” are used herein without distinction and refer to either human or non-human animals. These terms include mammals, e.g., humans, primates, domestic animals (e.g., cattle and pigs), companion animals (e.g., dogs and cats), and rodents (e.g., mice and rats).

[0035] The "amino acid sequence identity percentage (%)" for peptide sequences is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues of the wild-type (human) GLP-2 sequence after the sequence has been aligned and gaps introduced as necessary to obtain the maximum sequence identity percentage. Any conservative substitutions are not considered part of the sequence identity. Sequence alignment can be performed by those skilled in the art using techniques well known in the art, for example, using publicly available software such as BLAST, BLAST2, or Align software. See, for example, Altschul et al., Methods in Enzymology 266: 460-480 (1996), or Pearson et al., Genomics 46: 24-36, 1997.

[0036] The sequence identity percentage used herein in the context of the present invention can be determined by using these programs with their default settings. More generally, those skilled in the art can easily determine appropriate parameters for determining the alignment, including any algorithm necessary to obtain the maximum alignment over the full length of the sequences being compared.

[0037] Agonist peptide This invention relates to the therapeutic use of agonist peptides, particularly amylin analogs and GIPR / GLP-1R dual agonists. As used in the context of this invention, the term "agonist" refers to a substance (i.e., a peptide, molecule, or ligand) that activates a target receptor type. The terms "peptide," "compound," "molecule," and "agonist" may be used herein collectively to refer to both amylin analogs and GIPR / GLP-1R dual agonists.

[0038] Throughout this specification and the claims, when referring to agonist peptides, the conventional three-letter and one-letter codes of natural amino acids, namely: A(Ala), G(Gly), L(Leu), I(Ile), V(Val), F(Phe), W(Trp), S(Ser), T(Thr), Y(Tyr), N (Asn), Q(Gln), D(Asp), E(Glu), K(Lys), R(Arg), H(His), M(Met), C(Cys), and P(Pro), In addition, commonly recognized three-letter codes for other α-amino acids are used, for example, 4-hydroxyproline (e.g., (2S,4R)-4-hydroxyproline [(4R)-4-hydroxy-L-proline]) (Hyp or 4Hyp), also referred to herein as hydroxyproline, sarcosine (Sar), norleucine (Nle), α-aminoisobutyric acid (Aib), 1-naphthylalanine (1-Nal), 2,3-diaminopropanoic acid (Dap), 2,4-diaminobutanoic acid (Dab), and 2,5-diaminopentanoic acid (ornithine, Orn). When such other α-amino acids are used herein in general formulas or sequences, they may be indicated in square brackets "[]" (e.g., "[Aib]"), especially when the remainder of the formula or sequence is indicated using a single-letter code. Unless otherwise specified, the amino acid residues in the peptides of the present invention are in L-conceptual structures. However, D-structure amino acids may also be included. In this context, the amino acid codes written in lowercase represent the D-structure of the amino acid; for example, "k" represents the D-structure of lysine (K).

[0039] The sequences disclosed herein include sequences incorporating a "Hy-" or "H-" moiety at the amino terminus (N-terminus) and sequences incorporating either an "-OH" moiety or an "-NH2" moiety at the carboxyl terminus (C-terminus). In such cases, unless otherwise indicated, the "Hy-" or "H-" moiety at the N-terminus of the sequence in question is a hydrogen atom corresponding to the presence of a free primary or secondary amino group at the N-terminus [i.e., R in the general formula]. 1 =Hydrogen= indicates a hydroxyl group. The "-OH" portion at the C-terminus of the sequence corresponds to the presence of a carboxyl (COOH) group at the C-terminus.[For example, in the general formula R2 =OH] indicates the presence of an amino group at the C-terminus of the sequence. The "-NH2" part at the C-terminus corresponds to the presence of an amide (CONH2) group at the C-terminus [for example, in the general formula R 2 This represents [=NH2]. In each sequence of the present invention, the C-terminal "-OH" portion may be replaced by the C-terminal "-NH2" portion, and vice versa.

[0040] Agonist peptides (i.e., amyrin analogs or GIPR / GLP-1R dual agonists) may be in the form of pharmaceutically acceptable salts or solvates, such as pharmaceutically acceptable acid addition salts. Therefore, any reference herein to amyrin analogs is understood to include their pharmaceutically acceptable salts and solvates. Similarly, any reference herein to GIPR / GLP-1R dual agonists is understood to include their pharmaceutically acceptable salts and solvates.

[0041] Suitable salts formed with a base include metal salts, such as alkali metal salts or alkaline earth metal salts, such as sodium salts, potassium salts, or magnesium salts; ammonia salts and organic amine salts, such as morpholine, thiomorpholine, piperidine, pyrrolidine, lower mono-, di-, or tri-alkylamines (e.g., ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl-, or dimethylpropylamine), or lower mono-, di-, or tri-(hydroxyalkyl)amines (e.g., mono-, di-, or tri-ethanolamine). Intramolecular salts may also be formed. Similarly, if the compound of the present invention has a basic moiety, the salt can be formed using an organic or inorganic acid. For example, salts can be formed from the following acids: formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, oxalic acid, lactic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, phthalic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, benzoic acid, carbonic acid, uric acid, methanesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, p-toluenesulfonic acid (i.e., 4-methylbenzenesulfonic acid), camphosulfonic acid, 2-aminoethanesulfonic acid, aminomethylsulfonic acid, and trifluoromethanesulfonic acid (the last one also known as trifluic acid), as well as other known pharmaceutically acceptable acids. Amino acid addition salts can also be formed with amino acids such as lysine, glycine, or phenylalanine.

[0042] In the context of this invention, the term "solvate" refers to a complex with a defined stoichiometry formed between a solute (in this case, a peptide according to this invention or a pharmaceutically acceptable salt thereof) and a solvent. The solvent, in this regard, may be, for example, water, ethanol, or another pharmaceutically acceptable, typically low-molecular-weight organic species, such as, but not limited to, acetic acid or lactic acid. When the solvent in question is water, such a solvate is usually called a hydrate.

[0043] Array identity In some embodiments, the amylin analog and / or GIPR / GLP-1R dual agonist is defined as comprising a variant of an amino acid sequence (which may be referred to herein as the “reference sequence”), wherein the variant has at least a certain degree of sequence identity percentage with respect to the reference sequence. The terms “sequence identity percentage (%)”, “sequence identity”, and “identity” are used herein without distinction.

[0044] In some embodiments, the variant's "sequence identity percentage (%)" is defined as the percentage of amino acids in the variant's amino acid sequence that are identical to the amino acids of the reference sequence after the sequence has been aligned and gaps introduced as necessary to obtain the maximum sequence identity percentage, with no conservative substitutions being considered part of the sequence identity. Sequence alignment can be performed by those skilled in the art using techniques well known in the art, for example, using publicly available software such as BLAST, BLAST2, or Align software. See, for example, Altschul et al., Methods in Enzymology 266: 460-480 (1996), or Pearson et al., Genomics 46: 24-36, 1997. The sequence identity percentage used herein in the context of the present invention can be determined using these programs with their default settings. More generally, a person skilled in the art can easily determine appropriate parameters for determining alignment, including any algorithm necessary to obtain the maximum alignment over the full length of the arrays being compared.

[0045] In some embodiments, the variant has at least 80% sequence identity to the reference sequence, such as at least 85% sequence identity to the reference sequence, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least 96% sequence identity, such as at least 97% sequence identity, such as at least 98% sequence identity, such as at least 99% sequence identity, such as 100% identity.

[0046] Amylin analog An amylin analog is a molecule that is an amylin receptor agonist; that is, the molecule can bind to one or more receptors or receptor complexes that are thought to be the physiological receptors for human amylin and can induce signal transduction by the receptor or receptor complex. The terms "amylin analog" and "amylin receptor agonist" are used interchangeably herein. An amylin analog may also be described herein as a compound, molecule, or peptide.

[0047] An amylin analog according to the present invention has the formula: R 1 -Z-R 2 and can be a molecule of or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is hydrogen, C 1-4 acyl, benzoyl or C 1-4 alkyl, or a half-life extension moiety M, where M may be linked to Z via a linker moiety L, R 2 is OH or NHR 3 wherein, R 3 is hydrogen or C 1-3 alkyl and Z is 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-Ile(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly-Ser-X35-Thr-X37 (SEQ ID NO: 1) The amino acid sequence is as follows: 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 crosslink. X3 is selected from the group consisting of Gly, Gln, 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 Gln. X14 is selected from the group consisting of Aad, His, Asp, Asn, and Arg. X17 is selected from the group consisting of Gln, His, and Thr. X19-X20 are selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly, and Ala-Asn, or are not present. X27 is selected from the group consisting of Leu and Pro. X32 is selected from the group consisting of Val 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, for example (2S,4R)-4-hydroxyproline [also written as (4R)-4-hydroxy-L-proline], Gly(Me) is N-methylglycine [also known as sarcosine (Sar)], Ile(Me) is N-methylisoleucine, and Aad is 2-aminoadipic acid, also known as homoglutamic acid, for example, (2S)-2-aminoadipic acid [also known as (2S)-2-aminohexanediic acid].

[0048] In some embodiments, the amyrin analog includes the amino acid sequence RDGTATKATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp (SEQ ID NO: 9), or a variant thereof having at least 80% identity to SEQ ID NO: 9. In some embodiments, the variant of SEQ ID NO: 9 has 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. In some embodiments, the amyrin analog includes an amino acid sequence having 100% identity to SEQ ID NO: 9. SEQ ID NO: 9 may be considered the reference sequence for the amino acid sequence variant of the amyrin analog.

[0049] In a preferred embodiment, the amilin analog is [19CD]-IsoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH2 (SEQ ID NO: 2), or a pharmaceutically acceptable salt or solvate thereof. Here, The parentheses after an amino acid symbol indicate the residue whose side chain is involved in intramolecular lactam crosslinking. Gly(Me) is N-methylglycine [also known as sarcosine (Sar)], Ile(Me) is N-methylisoleucine, Aad is 2-aminoadipic acid, also known as homoglutamic acid, for example, (2S)-2-aminoadipic acid [also known as (2S)-2-aminohexanedioic acid], Hyp is 4-hydroxyproline, for example, (2S,4R)-4-hydroxyproline [also described as (4R)-4-hydroxy-L-proline], and [19CD]-isoGlu- is a 19-carboxy-nonadecanoyl group [19CD] covalently bonded to the alpha-amino group of the isoGlu linker via an amide bond, where the carboxyl group of the side chain of the isoGlu linker is covalently bonded via an amide bond to the nitrogen backbone of the Arg residue at position X1 of the Z peptide sequence of the amyrin analog (as described below).

[0050] The parentheses "()" shown after the symbol of a specific amino acid residue indicate the residue whose side chain is involved in intramolecular lactam crosslinking. Therefore, the amylin analog compounds present in the formulation of the present invention have intramolecular lactam crosslinking between the side chain of the residue at position X2 (e.g., aspartic acid, D) and the side chain of the residue at position X7 (e.g., lysine, K), as indicated by the parentheses.

[0051] The amylin analog of Sequence ID No. 2 may also be referred to as ZP8396 or petrelintide. ZP8396 is also described in detail in International Publication No. 2018 / 046719 (which is incorporated herein by reference), in which ZP8396 is also referred to as “Compound 35”.

[0052] In a preferred embodiment, the amilin analog is given by formula: [19CD]-IsoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH2(Sequence ID 2) Petrelintide or a pharmaceutically acceptable salt thereof having Here, an intramolecular lactam crosslink is formed between the side chains of residues indicated by parentheses "()", where [19CD]-isoGlu is a 19-carboxynonadecanoyl group covalently bonded to the alpha-amino group of the isoglutamic acid linker.

[0053] Amylin analogs may be in the form of pharmaceutically acceptable salts or solvates, such as pharmaceutically acceptable acid addition salts. Amylin analogs may also be in the form of pharmaceutically acceptable chloride salts. Any reference to “amilin analog” herein also includes pharmaceutically acceptable salts of amylin analogs.

[0054] Amyrin analogs can be adequately prepared by standard synthetic methods. Therefore, peptides can be synthesized, for example, by standard solid-phase or liquid-phase methodologies including stepwise or fragment assembly of peptide synthesis, and optional isolation and purification of the final peptide product. This method typically further includes the step of forming an amide bond between the 2- and 7-position side chains. In the case of solid-phase synthesis, cyclization may be performed in situ on a solid phase (e.g., a resin), i.e., before removing the peptide from the solid phase.

[0055] Half-life extension portion M As described herein, the N-terminal portion R of the amylin analog of the present invention 1This may be a half-life extension moiety M (sometimes referred to in the literature as a period extension moiety or albumin-binding moiety), which may be linked (covalently) to the peptide moiety Z via a linker moiety L. Suitable half-life extension moieties include certain types of lipid-soluble substituents. While we do not wish to be bound by any particular theory, such lipid-soluble substituents (and other classes of half-life extension moieties) are thought to bind to albumin in the bloodstream, thereby protecting the compound of the present invention from renal filtration and enzymatic degradation, and thus possibly extending the half-life of the compound in vivo. Lipid-soluble substituents may also modulate the potency of the compound as an agonist to the amyrin (calcitonin) receptor.

[0056] Lipid-soluble substituents can be attached to an N-terminal amino acid residue or linker L via an ester, sulfonyl ester, thioester, amide, amine, or sulfonamide. Therefore, it is understood that the lipid-soluble substituents preferably include an acyl group, sulfonyl group, N atom, O atom, or S atom that forms part of an ester, sulfonyl ester, thioester, amide, amine, or sulfonamide. Preferably, the acyl group within the lipid-soluble substituent, together with the amino acid residue or linker, forms part of an amide or ester.

[0057] Lipid-soluble substituents may include hydrocarbon chains having 10 to 24 carbon atoms, for example, 14 to 22 carbon atoms, for example, 16 to 20 carbon atoms. Preferably, the hydrocarbon chain has at least 14 carbon atoms, and preferably 20 or fewer carbon atoms. For example, the hydrocarbon chain may have 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The hydrocarbon chain may be linear or branched, and may be saturated or unsaturated. Furthermore, the hydrocarbon chain may contain functional groups at its ends, such as carboxylic acid groups that may or may not be protected during synthesis. From the above discussion, it will also be understood that the hydrocarbon chain may be preferably substituted with a moiety that forms part of the bond of the peptide moiety Z to the N-terminal amino acid residue or to the linker L, for example, an acyl group, a sulfonyl group, an N atom, an O atom, or an S atom.

[0058] Most preferably, the hydrocarbon chain is substituted with an acyl group, and therefore the hydrocarbon chain may be part of an alkanoyl group, such as dodecanoyl, 2-butyloctanoyl, tetradecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, or eicosaenoyl group. Examples of functionalized hydrocarbon chains are 15-carboxypentadecanoyl, 17-carboxyheptadecanoyl, and 19-carboxynonadecanoyl.

[0059] As described above, the lipophilic substituent M may be linked to the N-terminal amino acid residue of Z via a linker L. In the embodiment, the linker portion L is itself a small portion L linked to one, two, three or more other small portions L 1 , L 2 , L 3 This may include the following. If linker L contains only one such moiety, it is bonded to the lipophilic substituent and the N-terminal amino acid residue of Z. The linker may then be independently bonded to the lipophilic substituent and the N-terminal amino acid residue of Z by an ester bond, sulfonyl ester bond, thioester bond, amide bond, amine bond, or sulfonamide bond. Thus, it may contain two moieties independently selected from acyl, sulfonyl, N, O, and S atoms. The linker may be linear or branched C 1-10 hydrocarbon chains, or more preferably linear C 1-5 It can be composed of hydrocarbon chains. Furthermore, the linker is C 1-6 Alkyl, amino C 1-6 Alkyl, hydroxy C 1-6 Alkyl and carboxyl C 1-6 It may be substituted with one or more substituents selected from alkyl groups.

[0060] In some embodiments, the linker may comprise one or more linked amino acid residues (e.g., one, two, or three), each of which may independently be any natural or non-natural amino acid residue. For example, the linker may contain one, two, or three linked amino acid residues, each of which may independently be the residues Gly, Pro, Ala, Val, Leu, Ile, Met, Cys, Phe, Tyr, Trp, His, Lys, Arg, Gln, Asn, α-Glu, γ-Glu, ε-Lys, Asp, β-Asp, Ser, Thr, Gaba, Aib, β-Ala (i.e., 3-aminopropanoyl), 4-aminobutanoyl, 5-aminopentanoyl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-aminononanoyl, 10-aminodecanoyl, or 8Ado (i.e., 8-amino-3,6-dioxaoctanoyl).

[0061] References to γ-Glu, ε-Lys, and β-Asp refer to amino acid residues involved in the binding via the carboxyl or amine functional groups of their side chains. Therefore, γ-Glu and β-Asp are involved in the binding via their alpha-amino group and side-chain carboxyl group, while ε-Lys is involved via its carboxyl group and side-chain amino group. In the context of the present invention, γ-Glu and isoGlu are used without distinction.

[0062] In certain embodiments, the linker comprises or is composed of one, two, or three independently selected residues: Glu, γ-Glu, ε-Lys, β-Ala, 4-aminobutanoyl, 8-aminooctanoyl, or 8Ado.

[0063] Linkers composed of isoGlu and isoGlu-isoGlu may be particularly preferred.

[0064] An example of a lipophilic substituent including the lipophilic moiety M and linker L is shown by the following formula: [ka] In the formula, the skeletal nitrogen of the Arg residue (located at position X1 in the Z peptide sequence of the amyrin analog) is covalently bonded to the carboxyl group of the side chain of the Glu moiety via an amide bond. The 19-carboxy-nonadecanoyl group is covalently bonded to the alpha-amino group of the Glu linker via an amide bond. Thus, the Glu linker has an iso-Glu (or γ-Glu) stereostructure. This combination of the lipophilic moiety bonded to the Arg residue and the linker can be written in the simple notation [19CD]-isoGlu-R, for example, when shown in the formula of a particular compound.

[0065] Those skilled in the art will recognize appropriate techniques for preparing the compounds used in the context of the present invention. For examples of appropriate chemistry, see, for example, International Publication No. 98 / 08871, International Publication No. 00 / 55184, International Publication No. 00 / 55119, Madsen et al. (J. Med. Chem. 2007, 50, 6126-32), and Knudsen et al., 2000 (J. Med. Chem. 43, 1664-1669).

[0066] The hydrocarbon chain in the lipophilic substituent may be further substituted. For example, it may be further substituted with up to three substituents selected from NH2, OH, and COOH. If the hydrocarbon chain is further substituted, it is preferably substituted with only one substituent. Alternatively, the hydrocarbon chain may further include a cycloalkane or heterocycloalkane moiety, for example, as shown below. [ka]

[0067] In some embodiments, the cycloalkane or heterocycloalkane moiety is a six-membered ring, such as a piperidine ring.

[0068] In alternative embodiments of the present invention, the N-terminal amino acid Z in the compound of the present invention may be covalently linked to a biotinyl substituent, which may be via a linker moiety L. While we do not wish to be bound by any particular theory, it is similarly believed that such a biotinyl substituent binds to albumin in the bloodstream, thereby protecting the compound of the present invention from enzymatic degradation, and thus potentially extending the half-life of the compound in vivo. The linker, if present, may provide a space between the peptide moiety Z and the biotinyl substituent.

[0069] Biotinyl substituents can be attached to N-terminal amino acid residues or linkers via maleimide ester bonds, sulfonyl ester bonds, thioester bonds, amide bonds, amine bonds, or sulfonamide bonds. Therefore, it will be understood that biotinyl substituents preferably include maleimide groups, acyl groups, sulfonyl groups, N atoms, O atoms, or S atoms that form part of the ester bond, sulfonyl ester bond, thioester bond, amide bond, amine bond, or sulfonamide bond.

[0070] Examples of biotinyl substituents may include the following: [ka]

[0071] Biotin, also known as vitamin H or coenzyme R, is a water-soluble vitamin B (vitamin B7). It has been shown to increase the oral uptake rate of certain drugs.

[0072] Amylin receptor agonist activity As described herein, amyrin analogs are molecules that are amyrin receptor agonists, that is, molecules that can bind to one or more receptors or receptor complexes that are thought to be physiological receptors for human amyrin, and can induce signal transduction by such receptors or receptor complexes.

[0073] The physiological receptors for human amyrin include the human calcitonin receptor hCT-R, and complexes comprising the human calcitonin receptor hCT-R and at least one of the human receptor activity regulatory proteins called hRAMP1, hRAMP2, and hRAMP3. The complexes between hCT-R and hRAMP1, hRAMP2, and hRAMP3 are called hAMYR1, hAMYR2, and hAMYR3, respectively (i.e., human amyrin receptors 1, 2, and 3). A compound can be considered an amyrin receptor agonist if it exhibits agonist activity with respect to one or more of hAMYR1, hAMYR2, and hAMYR3, for example, hAMYR3 with respect to hAMYR1 and / or hAMYR3.

[0074] Typically, amyrin receptor agonists also exhibit agonist activity in hCT-R when expressed in the absence of hRAMP1, hRAMP2, and hRAMP3. Typically, agonists exhibit activity in hCT-R (when expressed in the absence of hRAMP1, hRAMP2, and hRAMP3) at a ratio less than 10 times that of their activity in any one of hAMYR1, hAMYR2, and hAMYR3 (i.e., their activity in all of these receptors) in comparable assays. The agonist activity at hCT-R may be less than five times that at hAMYR1, hAMYR2, and hAMYR3, substantially equal to (e.g., + / - 10%), or lower than that at hAMYR1, hAMYR2, and hAMYR3. In this regard, it may be sufficient to simply compare the activity between hCT-R and hAMYR3.

[0075] The ability to induce cAMP formation (i.e., induce adenylyl cyclase activity) as a result of binding to the relevant receptor or receptor complex is typically considered an indicator of agonist activity. Other intracellular signaling pathways or events may also be used as information read for amyrin receptor agonist activity. These may include calcium release, β-arrestin recruitment, receptor internalization, kinase activation or inactivation, lipase activation, inositol phosphate release, diacylglycerol release, or nuclear transcription factor transfer.

[0076] The cells utilized by a suitable equivalent assay format express hCT-R, differing only in their expression of hRAMP1, 2, and 3. For example, by manipulating a “base” cell line that does not express any of hCT-R, hRAMP1, hRAMP2, and hRAMP3, cells can be produced that express (i) hCT-R and (ii) one of hAMYR1, hAMYR2, and hAMYR3 (i.e., in addition to hCT-R, one of hRAMP1, hRAMP2, and hRAMP3), for example, hAMYR3. The base cells are typically mammalian cells and may be primate cells. These may be non-human primate cells. Preferably, the base cells do not express any of CT-R, RAMP1, RAMP2, or RAMP3 (human, or native to the base cells if the base cells are non-human). The base cells may be fibroblasts. Suitable non-human fibroblast-based cells include African green monkey COS7 cells, which do not express native CT-R or RAMP.

[0077] Equivalent activity is provided by the EC described below. 50 The value can be measured by any appropriate means, for example, through the determination of the value. It should be obvious that identical biological readout information must exist for both receptor types.

[0078] The compounds of the present invention may exhibit many advantageous properties of human amyrin and its existing analogs, such as plumrintide, IAPP-GI, and analogs, as described in International Publication No. 2012 / 168430, International Publication No. 2012 / 168431, and International Publication No. 2012 / 168432. Compared to human amyrin or any of these analogs, the compounds of the present invention may exhibit, for example, improved efficacy (e.g., in the form of improved in vitro activity or potency at one or more of the receptors hCT-R, hAMYR1, hAMYR2, or hAMYR3). Furthermore, or / or, the compounds of the present invention may exhibit improved solubility, particularly in aqueous media with pH values ​​in the range of 4 to 7.5, or a variety of pH values ​​within that range. Furthermore, the compounds of the present invention may further, or / or, exhibit reduced tendency to undergo microfibrillation, particularly in pharmaceutically relevant aqueous media with pH values ​​in the range of 4 to 7, or a variety of pH values ​​within that range. Furthermore, the compounds of the present invention may also exhibit improved chemical stability (i.e., reduced tendency to undergo chemical degradation) in aqueous media with pH values ​​in the range of 4 to 9, or a variety of pH values ​​within that range.

[0079] Thus, in contrast to plumrintide, which typically exhibits low chemical stability and rapid fibrillation in pharmaceutically relevant aqueous media, for example, at a neutral pH, the compounds of the present invention are well-suited for formulation in acidic media (e.g., pH 4) and neutral or near-neutral media (e.g., pH 7 or 7.4).

[0080] Generally, as described above, it is preferable to use biological assays that measure intracellular signaling resulting from the binding of compounds to the relevant receptors. Activation of the calcitonin / amyrin receptor by the compound of the present invention (which acts as an agonist of the receptor) induces cAMP formation, as well as activation of other intracellular signaling pathways and events. Therefore, cAMP production in appropriate cells expressing the receptor, or any other appropriate parameter, can be used to monitor agonist activity against the receptor.

[0081] Appropriate assay formats will be recognized by those skilled in the art, and examples are given below. For example, the assay can use the human calcitonin receptor (hCT-R, e.g., isoform 2 of hCT-R) or the hAMYR3 receptor (see Examples below). Where the sequence of the precursor protein is referenced, it should be understood that the assay may use mature proteins lacking the signal sequence.

[0082] EC 50 The value can be used as a numerical measure of agonist potency at a given receptor. 50 The value is a measure of the compound concentration required to achieve half of the compound's maximum activity in a particular assay. Therefore, for example, the EC of native human amylin... 50 [hCT-R] is lower than or the EC of plumlintide 50 Lower EC than [hCT-R] 50 Compounds containing [hCT-R] can be considered to have higher receptor potency or activity than native human amyrin or pramulintide, respectively, in certain assays.

[0083] In some embodiments of the compounds of the present invention, EC against hCT-R 50 This is less than approximately 1.5 nM (for example, 0.001 to 1.5 nM).

[0084] In some embodiments of the compounds of the present invention, EC against hCT-R 50 This is less than approximately 0.9 nM (for example, 0.001 to 0.9 nM).

[0085] In some embodiments of the compounds of the present invention, EC against hCT-R 50 This is less than approximately 0.5 nM (for example, 0.001 to 0.5 nM).

[0086] In some embodiments of the compounds of the present invention, EC against hCT-R 50This is less than approximately 0.3 nM (for example, 0.001 to 0.3 nM).

[0087] In some embodiments of the compounds of the present invention, EC against hCT-R 50 This is less than approximately 0.2 nM (for example, 0.001 to 0.2 nM).

[0088] EC in hCT-R 50 This can be an indicator of the compound's effect on food intake, weight gain, and / or weight loss. EC in hCT-R 50 Compounds with low values ​​may have superior effects on these parameters.

[0089] In some embodiments of the compounds of the present invention, EC against hAMYR3 50 This is approximately less than 1.0 nM (for example, 0.001 to 1.0 nM).

[0090] In some embodiments of the compounds of the present invention, EC against hAMYR3 50 This is less than approximately 0.5 nM (for example, 0.001 to 0.5 nM).

[0091] In some embodiments of the compounds of the present invention, EC against hAMYR3 50 This is less than approximately 0.4 nM (for example, 0.001 to 0.4 nM).

[0092] In some embodiments of the compounds of the present invention, EC against hAMYR3 50 This is less than approximately 0.3 nM (for example, 0.001 to 0.3 nM).

[0093] In some embodiments of the compounds of the present invention, EC against hAMYR3 50 This is less than approximately 0.2 nM (for example, 0.001 to 0.2 nM).

[0094] EC in hCT-R (when expressed in the absence of hRAMP1, hRAMP2, and hRAMP3) 50This refers to EC in any or all of hAMYR1, hAMYR2, and hAMYR3, for example, in hAMYR3. 50 It may be lower than that.

[0095] For example, EC in hCT-R (when expressed in the absence of hRAMP1, hRAMP2, and hRAMP3) 50 This refers to EC in any or all of hAMYR1, hAMYR2, and hAMYR3, for example, in hAMYR3. 50 It can sometimes exceed one-tenth of that.

[0096] EC in hCT-R (when expressed in the absence of hRAMP1, hRAMP2, and hRAMP3) 50 This refers to EC in any or all of hAMYR1, hAMYR2, and hAMYR3, for example, in hAMYR3. 50 This can sometimes exceed one-fifth.

[0097] EC in hCT-R (when expressed in the absence of hRAMP1, hRAMP2, and hRAMP3) 50 This refers to EC in any or all of hAMYR1, hAMYR2, and hAMYR3, for example, in hAMYR3. 50 It may be substantially equal to (for example, + / - 50%).

[0098] EC in hCT-R (when expressed in the absence of hRAMP1, hRAMP2, and hRAMP3) 50 This refers to EC in any or all of hAMYR1, hAMYR2, and hAMYR3, for example, in hAMYR3. 50 It may be higher than that.

[0099] GIPR / GLP-1R Dual Agonist GIPR / GLP-1R dual agonists are molecules that possess agonist activity at both the gastric suppressor polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP-1R). In other words, GIPR / GLP-1R dual agonists can bind to both GIPR and GLP-1R, and can induce signaling by both GIPR and GLP-1R. Therefore, GIPR / GLP-1R dual agonists have activity at both GIP and GLP-1. The term "dual agonist" is synonymous with "coagonist." GIPR / GLP-1R dual agonists may be referred to herein as "compounds," "peptides," or "dual agonists."

[0100] GIPR / GLP-1R dual agonists may be in the form of pharmaceutically acceptable salts or solvates, such as pharmaceutically acceptable acid addition salts. Any reference herein to “GIPR / GLP-1R dual agonist” also includes pharmaceutically acceptable salts of GIPR / GLP-1R dual agonists.

[0101] A GIPR / GLP-1R dual agonist may be any GIPR / GLP-1R dual agonist known in the art, for example, any GIPR / GLP-1R dual agonist described in International Publication No. 2011 / 119657, International Publication No. 2013 / 164483, and International Publication No. 2014 / 192284.

[0102] In some embodiments, the GIPR / GLP-1R dual agonist includes 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. In some embodiments, the variant of SEQ ID NO: 10 has 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. In some embodiments, the GIPR / GLP-1R dual agonist includes an amino acid sequence having 100% identity to SEQ ID NO: 10. Sequence ID 10 can be considered a reference sequence for a variant of the amino acid sequence of a GIPR / GLP-1R dual agonist.

[0103] Chilzepatid In preferred embodiments, the GIPR / GLP-1R dual agonist is tilzepatide or a pharmaceutically acceptable salt or solvate thereof. Tilzepatide (described in International Publication No. 2016 / 111971) is also known as LY3298176 or GIP / GLP-1 RA and is marketed under the trade names Manjaro and Zepbound.

[0104] Chilzepatide is a peptide containing an amidated C-terminus and a fatty acid moiety conjugated to the lysine side chain at position 20 via a linker. More specifically, chilzepatide has the following structure: Hy-Y[Aib]EGTFTSDYSI[Aib]LDKIAQ[K]AFVQWLIAGGPSSGAPPPS-NH2(Sequence ID 4) It has, and here, [Aib] is α-aminoisobutyric acid, and [K] is (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(isoGlu)1-CO-(CH2) 18 This is lysine in which the -COOH group is conjugated to the epsilon-amino group of the lysine side chain.

[0105] Therefore, in some embodiments, the GIPR / GLP-1R dual agonist is Hy-Y[Aib]EGTFTSDYSI[Aib]LDKIAQ[K]AFVQWLIAGGPSSGAPPPS-NH2(Sequence ID 4) (Tilzepatide) or a pharmaceutically acceptable salt or solvate thereof, where, [Aib] is α-aminoisobutyric acid, and [K] is (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(isoGlu)1-CO-(CH2) 18 This is lysine in which the -COOH group is conjugated to the epsilon-amino group of the lysine side chain.

[0106] The lysine at position 20 of tylzepatide is conjugated to the fatty acid moiety via a linker. The linker is (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(isoGlu)1, and the fatty acid moiety is -CO-(CH2) 18 -CO2H (i.e., 19-carboxynonadecanoyl). In total, the linker and lipid portion is (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(isoGlu)1-CO-(CH2) 18 It is written as -COOH, which has the following chemical structure: [ka] The formula has the following characteristics, where the dotted line crosses the bond that is connected to the nitrogen atom of the epsilon-amino group of lysine at position 20 of the peptide portion of tilzepatide.

[0107] The structure of tilzepatide is shown in Figure 5, using a combination of chemical structure notation and single-letter amino acid codes.

[0108] In some embodiments, the GIPR / GLP-1R dual agonist is expressed by the formula: Y[Aib]EGTFTSDYSI[Aib]LDKIAQ[K]AX-VQWLIAGGPSSGAPPPS(Sequence ID 3) A compound of or a pharmaceutically acceptable salt or solvate thereof, where, [Aib] is α-aminoisobutyric acid, and [K] is (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(isoGlu) a -CO-(CH2) b -COOH is conjugated to the epsilon-amino group of the lysine side chain, and this is lysine. a is 1 or 2, and b is between 10 and 20. X is Phe or 1-Nal, Furthermore, the C-terminal amino acid may be amidated as the first C-terminal amide.

[0109] In some embodiments, the C-terminal amino acid is amidated as the C-terminal first amide. In some embodiments, X is Phe. In some embodiments, a is 1. In some embodiments, b is 16-18. In some embodiments, b is 16 or 18. In some embodiments, b is 18.

[0110] GIPR / GLP-1R dual agonist activity GIPR / GLP-1R dual agonists have at least one GIP biological activity and at least one GLP-1 biological activity. GIPR / GLP-1R dual agonists have agonist activity at the GIPR receptor and the GLP-1R receptor, for example, human GIPR and GLP-1R.

[0111] Whether a given compound has GIPR agonist activity and / or GLP-1R agonist activity can be tested using assays known in the art, for example, those described in International Publication No. 2013 / 164483, International Publication No. 2014 / 192284, and International Publication No. 2016 / 111971.

[0112] For example, the ability of a given compound to bind to GIPR and GLP-1R (i.e., the affinity of the compound to the receptor) can be measured using an in vitro binding assay, and the dissociation constant (K) can be determined. d It can be expressed as ).

[0113] Preferably, the GIPR and GLP-1R agonizing effect of a given compound can be measured using in vitro functional assays, such as measuring signal transduction from GIPR and GLP-1R expressed intracellularly and stimulated by the compound. Signal transduction can be quantified, for example, by measuring changes in cellular cAMP levels. EC of receptor agonist activity in vitro 50 The value can be used as a numerical measure of agonist activity / potency at a given receptor. EC 50 The value is a measure of the compound concentration (e.g., mol / L) required to achieve half of the compound's maximum activity in a particular assay. 50 The reference compound EC 50 Compounds with a lower value than the reference compound can be considered to have higher efficacy at that receptor than the reference compound.

[0114] GIP activity In some embodiments, dual agonists, when evaluated using the GIP receptor activity assay described in, for example, International Publication No. 2013 / 164483, exhibit EC levels of less than approximately 2.0 nM, less than approximately 1.5 nM, less than approximately 1.0 nM, less than approximately 0.9 nM, less than approximately 0.8 nM, less than approximately 0.7 nM, less than approximately 0.6 nM, less than approximately 0.5 nM, less than approximately 0.4 nM, less than approximately 0.3 nM, less than approximately 0.2 nM, less than approximately 0.1 nM, less than approximately 0.09 nM, less than approximately 0.08 nM, less than approximately 0.07 nM, less than approximately 0.06 nM, less than approximately 0.05 nM, less than approximately 0.04 nM, less than approximately 0.03 nM, less than approximately 0.02 nM, or less than approximately 0.01 nM at the GIP receptor (e.g., human GIP receptor). 50 It holds.

[0115] In some embodiments, dual agonists, when evaluated using the GIP receptor activity assay described in, for example, International Publication No. 2013 / 164483, range from approximately 0.005 to approximately 2.0 nM, approximately 0.01 to approximately 2.0 nM, approximately 0.025 to approximately 2.0 nM, approximately 0.005 to approximately 1.5 nM, approximately 0.01 to approximately 1.5 nM, and approximately 0. EC at GIP receptors in the following ranges: 0.025 to approximately 1.5 nM, approximately 0.005 to approximately 1.0 nM, approximately 0.01 to approximately 1.0 nM, approximately 0.025 to approximately 1.0 nM, approximately 0.005 to approximately 0.5 nM, approximately 0.01 to approximately 0.5 nM, approximately 0.025 to approximately 0.5 nM, approximately 0.005 to approximately 0.25 nM, approximately 0.01 to approximately 0.25 nM, and approximately 0.025 to approximately 0.25 nM. 50 It holds.

[0116] Another measure of GIPR agonist activity can be derived by comparing the potency of a dual agonist to the potency of a known (or reference) GIPR agonist when both are measured in the same assay. Therefore, relative potency in GIPR can be defined as follows: [EC 50 (Reference Agonist)] / [EC 50 (Dual Agonist)

[0117] Therefore, a value of 1 indicates that the dual agonist and the reference agonist have equal efficacy, and a value greater than 1 indicates that the dual agonist has higher efficacy than the reference agonist (i.e., lower EC). 50 This indicates that the dual agonist has lower potency (i.e., higher EC) than the reference agonist, and a value less than 1 indicates that the dual agonist has lower potency than the reference agonist. 50 This indicates that it has ).

[0118] A reference GIP agonist is, for example, human GIP. Typically, the relative potency is about 0.001 to about 100, for example, about 0.001 to about 10, about 0.001 to about 5, about 0.001 to about 1, about 0.001 to about 0.5, about 0.001 to about 0.1, about 0.001 to about 0.05, or about 0.001 to about 0.01; about 0.01 to about 10, about 0.01 to about 5, about 0.01 to about 1, about 0.01 to about 0.5, about 0.01 to about 0.1, or It will be approximately 0.01 to approximately 0.05; approximately 0.05 to approximately 10, approximately 0.05 to approximately 5, approximately 0.05 to approximately 1, approximately 0.05 to approximately 0.5, or approximately 0.05 to approximately 0.1; approximately 0.1 to approximately 10, approximately 0.1 to approximately 5, approximately 0.1 to approximately 1, or approximately 0.1 to approximately 0.5; approximately 0.5 to approximately 10, approximately 0.5 to approximately 5, or approximately 0.5 to approximately 1; approximately 1 to approximately 10, or approximately 1 to approximately 5; or approximately 5 to approximately 10.

[0119] GLP-1 activity In some embodiments, dual agonists, when evaluated using the GLP-1 receptor efficacy assay described, for example, in International Application No. PCT / EP2022 / 074420, exhibit EC levels of less than approximately 2.0 nM, less than approximately 1.5 nM, less than approximately 1.0 nM, less than approximately 0.9 nM, less than approximately 0.8 nM, less than approximately 0.7 nM, less than approximately 0.6 nM, less than approximately 0.5 nM, less than approximately 0.4 nM, less than approximately 0.3 nM, less than approximately 0.2 nM, less than approximately 0.1 nM, less than approximately 0.09 nM, less than approximately 0.08 nM, less than approximately 0.07 nM, less than approximately 0.06 nM, less than approximately 0.05 nM, and less than approximately 0.04 nM at the GLP-1 receptor (e.g., human GLP-1 receptor). 50 It holds.

[0120] In some embodiments, dual agonists, when evaluated using the GLP-1 receptor potency assay described, for example, in International Application No. PCT / EP2022 / 074420, range from approximately 0.005 to approximately 2.5 nM, approximately 0.01 to approximately 2.5 nM, approximately 0.025 to approximately 2.5 nM, approximately 0.005 to approximately 2.0 nM, approximately 0.01 to approximately 2.0 nM, approximately 0.025 to approximately 2.0 nM, and approximately 0.005 to approximately EC at the GLP-1 receptor at 1.5 nM, approximately 0.01 to 1.5 nM, approximately 0.025 to 1.5 nM, approximately 0.005 to 1.0 nM, approximately 0.01 to 1.0 nM, approximately 0.025 to 1.0 nM, approximately 0.005 to 0.5 nM, approximately 0.01 to 0.5 nM, approximately 0.025 to 0.5 nM, approximately 0.005 to 0.25 nM, approximately 0.01 to 0.25 nM, and approximately 0.025 to 0.25 nM. 50 It holds.

[0121] Another measure of GLP-1 agonist activity can be derived by comparing the potency of a dual agonist to the potency of a known (or reference) GLP-1 agonist when both are measured in the same assay. Therefore, relative potency at the GLP-1 receptor can be defined as follows: [EC 50 (Reference Agonist)] / [EC 50 (Dual Agonist)

[0122] Therefore, a value of 1 indicates that the dual agonist and the reference agonist have equal efficacy, and a value greater than 1 indicates that the dual agonist has higher efficacy than the reference agonist (i.e., lower EC). 50 This indicates that the dual agonist has lower potency (i.e., higher EC) than the reference agonist, and a value less than 1 indicates that the dual agonist has lower potency than the reference agonist. 50 This indicates that it has ).

[0123] The reference GLP-1 agonist may be, for example, human GLP-1(7-37), liraglutide (NN2211, Victoza), or exendin-4, but liraglutide is preferred.

[0124] Typically, the relative effects are about 0.001 to about 100, for example, about 0.001 to about 10, about 0.001 to about 5, about 0.001 to about 1, about 0.001 to about 0.5, about 0.001 to about 0.1, about 0.001 to about 0.05, or about 0.001 to about 0.01; about 0.01 to about 10, about 0.01 to about 5, about 0.01 to about 1, about 0.01 to about 0.5, about 0.01 to about 0.1, or It will be approximately 0.01 to approximately 0.05; approximately 0.05 to approximately 10, approximately 0.05 to approximately 5, approximately 0.05 to approximately 1, approximately 0.05 to approximately 0.5, or approximately 0.05 to approximately 0.1; approximately 0.1 to approximately 10, approximately 0.1 to approximately 5, approximately 0.1 to approximately 1, or approximately 0.1 to approximately 0.5; approximately 0.5 to approximately 10, approximately 0.5 to approximately 5, or approximately 0.5 to approximately 1; approximately 1 to approximately 10 or approximately 1 to approximately 5; or approximately 5 to approximately 10.

[0125] The dual agonists described in the following examples have slightly lower GLP-1 potency than liraglutide, and therefore may have relative potency of, for example, about 0.01 to about 1, about 0.01 to about 0.5, or about 0.01 to about 0.1.

[0126] It will be understood that the absolute potency of dual agonists at each receptor is not as important as the balance between GIP agonist activity and GLP-1 agonist activity. Therefore, as long as the dual agonist compound exhibits an acceptable relative potency level at both receptors, it is not a problem if the absolute potency of GIP or GLP-1 at these receptors is lower than that of known agonists. Any apparent deficiency in absolute potency can be compensated for by increasing the dose as needed.

[0127] The GIPR / GLP-1R dual agonists used in the present invention may exhibit balanced GIP activity and GLP-1 activity. "Balanced GIPR activity and GLP-1R activity" refers to compounds that have affinity for GIPR and GLP-1R in a molar ratio close to 1:1 in an in vitro binding assay, for example, 1:1 GIPR / GLP-1R, 2:1 GIPR / GLP-1R, 3:2 GIPR / GLP-1R, 1:2 GIPR / GLP-1R, or 2:3 GIPR / GLP-1R.

[0128] The GIPR / GLP-1R dual agonists used in the present invention may exhibit selectivity for GIP receptors and GLP-1 receptors more than for glucagon receptors and GLP-2 receptors. The terms "selectivity" or "selective to" as used herein, relative to reference GIP and GLP-1 activity compared to glucagon activity, refer to compounds that, when normalized from their respective in vitro binding assays, exhibit 1000-fold, 500-fold, or approximately 100-fold higher potency for GIP and GLP-1 than for glucagon. The terms "selectivity" or "selective to" as used herein, relative to reference GIP and GLP-1 activity compared to GLP-2 activity, refer to compounds that, when normalized from their respective in vitro functional assays, exhibit 250-fold, 200-fold, 100-fold, or approximately 50-fold higher potency for GIP and GLP-1 than for GLP-2.

[0129] therapeutic use In a broader embodiment, the present invention provides an amylin analog and a GIPR / GLP-1R dual agonist for therapeutic use. The present invention provides an amylin analog and a GIPR / GLP-1R dual agonist for use in the treatment or prevention of disease in a subject. The present invention provides an amylin analog and a GIPR / GLP-1R dual agonist for use in methods of treating or preventing disease in a subject. The present invention provides a combination of an amylin analog and a GIPR / GLP-1R dual agonist for use in methods of treating or preventing disease in a subject. The present invention provides an amylin analog and a GIPR / GLP-1R dual agonist for use in methods of treating or preventing disease in a subject, comprising the step of administering the amylin analog and a GIPR / GLP-1R dual agonist to a subject.

[0130] In other words, the present invention provides the use of amylin analogs and GIP / GLP-1R dual agonists in the preparation of pharmaceuticals for treating or preventing diseases in a subject.

[0131] In other words, the present invention provides a combination of an amylin analog and a GIPR / GLP-1R dual agonist for therapeutic use. The present invention provides a combination of an amylin analog and a GIPR / GLP-1R dual agonist for use in the treatment or prevention of disease in a subject. The present invention provides a combination of an amylin analog and a GIPR / GLP-1R dual agonist for use in a method for treating or preventing disease in a subject. The present invention provides a combination of an amylin analog and a GIPR / GLP-1R dual agonist for use in a method for treating or preventing disease in a subject, comprising the step of administering the amylin analog and the GIPR / GLP-1R dual agonist to a subject.

[0132] The present invention provides the use of a combination of amylin analog and a GIP / GLP-1R dual agonist in the preparation of a pharmaceutical for treating or preventing a disease in a target.

[0133] The present invention may also be described as a method of treatment. Accordingly, the present invention provides a method for treating or preventing a disease in a subject, comprising the step of administering an amylin analog and a GIPR / GLP-1R dual agonist to the subject.

[0134] The methods and uses of the present invention can be performed in vitro, in vivo, or ex vivo.

[0135] As used in the context of this invention, the term “treatment” (and “treating” and other grammatical variations thereof) refers to an approach to obtain a favorable or desired clinical outcome. For the purposes of this invention, favorable or desired clinical outcomes include, but are not limited to, symptom reduction, disease severity reduction, stabilization of the disease state (i.e., prevention of exacerbation), delay or slowing of disease progression, improvement or reduction of the condition, and remission (partial or complete), whether detectable or undetectable. “Treatment” may also refer to an extension of survival compared to expected survival in the absence of treatment. “Treatment” is an intervention undertaken with the aim of preventing the onset of a disability or altering the pathology of a disability. Thus, “treatment” refers to both therapeutic treatment and prophylactic or preventative measures. When used in the context of prophylactic or preventative measures, the pharmaceutical formulation does not need to completely prevent the onset of the disease or disability. Subjects requiring treatment include those already suffering from the disability and those whose onset of the disability is to be prevented. "Treatment" also means inhibiting or reducing the increase of a pathology or symptom (e.g., weight gain or hypoglycemia) compared to the absence of treatment, and does not necessarily mean including the complete cessation of the associated condition.

[0136] The terms “disease,” “disorder,” and “condition” are synonymous and are used interchangeably herein to refer to a state of physical dysfunction. The term “disease” therefore encompasses “disorder” and “condition.”

[0137] In the context of the present invention, the disease to be treated or prevented is any disease associated with overweight. Accordingly, the present invention provides an amylin analog and a GIPR / GLP-1R dual agonist for use in the treatment or prevention of a disease in a subject, wherein the disease is overweight, obesity, morbid obesity, diabetes, or a disease associated with obesity or diabetes. Diabetes may be type 1 diabetes or type 2 diabetes. In other words, the present invention provides a method for treating or preventing a disease in a subject, comprising the step of administering an amylin analog and a GIPR / GLP-1R dual agonist to the subject, wherein the disease is overweight, obesity, morbid obesity, diabetes, or a disease associated with obesity or diabetes.

[0138] In some embodiments, the disease is overweight. In some embodiments, the disease is obesity. In some embodiments, the disease is morbid obesity. In some embodiments, the disease is diabetes. In some embodiments, the disease is type 1 diabetes. In some embodiments, the disease is type 2 diabetes. In some embodiments, the disease is obesity or a disease associated with diabetes.

[0139] The subject's weight may be stated using the Body Mass Index (BMI), which for human subjects is calculated by dividing the subject's weight in kilograms by the square of the subject's height in meters.

[0140] In some embodiments, the subjects are obese. In some embodiments, the subjects are obese, ranging from 30.0 to 39.9 kg / m². 2 He has a BMI of [value missing].

[0141] In some embodiments, the subject is morbidly obese. In some embodiments, the subject is 40.0 kg / m², which corresponds to morbidly obese. 2 Or have a BMI of or higher.

[0142] In some embodiments, diseases associated with obesity or diabetes are selected from the group consisting of obesity-related inflammation, obesity-related gallbladder disease, obesity-induced sleep apnea, obesity-related respiratory problems, cartilage degeneration, osteoarthritis, infertility, Alzheimer's disease, pre-diabetes, gestational diabetes, insulin resistance syndrome, inadequate glucose control, impaired glucose tolerance (IGT), conditions associated with elevated blood glucose levels, metabolic diseases, metabolic syndrome, hyperglycemia, hypertension, dyslipidemia, atherosclerosis, renal failure, arteriosclerosis, atherosclerosis, macrovascular disease, microvascular disease, diabetic heart disease, diabetic cardiomyopathy, heart failure as a complication of diabetes, coronary heart disease, peripheral artery disease, and stroke.

[0143] The compounds of the present invention may also be useful in reducing circulating LDL levels and / or increasing the HDL / LDL ratio.

[0144] The effects of the compounds of the present invention may be mediated, in whole or in part, by an effect on body weight, or they may be unrelated to an effect on body weight.

[0145] Metabolic syndrome is characterized by a group of metabolic risk factors in an individual. These include abdominal obesity (excess adipose tissue around internal organs), atherosclerosis (high triglycerides, low HDL cholesterol, and / or high LDL cholesterol, which promote plaque buildup in arterial walls), elevated blood pressure (hypertension), insulin resistance and glucose intolerance, pro-thrombogenic conditions (e.g., high levels of fibrinogen or plasminogen activator-1 in the blood), and inflammatory conditions (e.g., elevated levels of C-reactive protein in the blood).

[0146] Individuals with metabolic syndrome have an increased risk of coronary heart disease, as well as other diseases associated with other signs of arteriosclerosis (e.g., stroke and peripheral vascular disease). Abdominal obesity is considered to be the primary underlying risk factor for this syndrome.

[0147] Obesity is associated with low-grade inflammation (sometimes referred to as "obesity-related inflammation"). It is also commonly recognized that obesity (as with other syndromes) leads to increased vascular permeability, which allows pathogens and toxins such as LPS to enter the intestinal cell wall and cause inflammation. The changes resulting from the inflammatory response are essentially the same regardless of the cause and the location of the damage. The inflammatory response can be acute (short-lived) or chronic (long-lasting).

[0148] The dual agonist activity of the GIPR / GLP-1R dual agonists described herein may be particularly advantageous in many of the described conditions because the two activities can complement each other.

[0149] For example, malabsorption is a condition resulting from abnormalities in the absorption of water and / or nutrients from food, such as amino acids, sugars, fats, vitamins, or minerals, through the gastrointestinal (GI) tract, leading to malnutrition and / or dehydration. Malabsorption can be a result of physical (e.g., trauma) or chemical damage to the intestinal tract. The dual agonists described herein can simultaneously normalize intestinal transit time, improve intestinal barrier function, reduce gastric emptying, and increase intestinal absorption. This not only helps increase the absorption of nutrients and fluids in patients but also alleviates the social problems patients face regarding bowel movements stimulated by food.

[0150] Furthermore, disorders of intestinal function and metabolism can be closely related to each other, with one contributing to the onset or symptoms of the other.

[0151] Weight loss The present invention provides amylin analogs and GIPR / GLP-1R dual agonists for use in methods for inhibiting and / or reducing weight gain in subjects.

[0152] In other words, the present invention provides a combination of an amylin analog and a GIPR / GLP-1R dual agonist for use in a method for inhibiting and / or reducing weight gain in a subject.

[0153] In other words, the present invention provides a method for inhibiting weight gain and / or reducing weight in a subject, comprising the step of administering an amylin analog and a GIPR / GLP-1R dual agonist to the subject.

[0154] In other words, the present invention provides a method for inhibiting and / or reducing weight gain in a subject, comprising the step of administering a combination of an amylin analog and a GIPR / GLP-1R dual agonist to the subject. "Inhibition of weight gain" may also be described as "reduction of weight gain." "Reduction of weight" may also be described as "promotion of weight loss."

[0155] Amylin analogs and GIPR / GLP-1R dual agonists can increase or prolong the feeling of fullness experienced by a subject, thereby reducing their appetite and thus reducing food intake. Therefore, the present invention can also be expressed as amylin analogs and GIPR / GLP-1R dual agonists for use in methods of reducing food intake and / or appetite.

[0156] The amylin analog and GIPR / GLP-1R dual agonist of the present invention can be used for therapeutic or cosmetic purposes. Therefore, inhibition of weight gain or reduction of weight in a subject may be cosmetic (i.e., non-therapeutic). The effect of the compounds of the present invention on body weight may be therapeutic or cosmetic.

[0157] Accordingly, the present invention provides a non-therapeutic method for inhibiting and / or reducing weight gain in a subject, comprising the step of administering an amylin analog and a GIPR / GLP-1R dual agonist to the subject. The present invention also provides a cosmetic method for inhibiting and / or reducing weight gain in a subject, comprising the step of administering an amylin analog and a GIPR / GLP-1R dual agonist to the subject.

[0158] These non-therapeutic methods aim to reduce the weight of individuals who are neither obese nor morbidly obese.

[0159] In some embodiments of the non-therapeutic methods of the present invention, the subjects are of healthy weight. In other words, in some embodiments, the subjects are neither overweight, obese, nor morbidly obese. In some embodiments, the subjects are of healthy weight, ranging from 18.5 to 24.9 kg / m². 2 He has a BMI of [value missing].

[0160] In some embodiments of the non-therapeutic methods of the present invention, the subjects are overweight. In other words, in some embodiments, the subjects are not at a healthy weight, but are neither obese nor morbidly obese. In some embodiments, the subjects are overweight, corresponding to 25.0–29.9 kg / m². 2 He has a BMI of [value missing].

[0161] The present invention further relates to amylin analogs and GIPR / GLP-1R dual agonists for use in methods that are not for the treatment of disease themselves. Such uses and methods can be considered for disease prevention, insofar as they are used before the onset of disease (e.g., before diagnosis), for example, to improve undesirable physiological characteristics or to alter certain physiological parameters. Furthermore, such uses or methods can also be considered for cosmetic purposes.

[0162] The effects of the above compounds may be mediated, in whole or in part, by effects on body weight, or may be unrelated to effects on body weight. Regardless of those effects on body weight, the compounds of the present invention may have beneficial effects on glucose loading and / or glucose control.

[0163] In some embodiments, subjects show weight loss when treated with an amylin analog and a GIPR / GLP-1R dual agonist. In some embodiments, subjects show a weight loss of at least 1%, e.g., at least 5%, at least 10%, at least 15%, at least 20%, at least 22.5%, or at least 25% compared to the subject's weight before treatment. In some embodiments, subjects show a weight loss of at least 0.5% per month (i.e., a weight loss of 0.5% at the end of each month compared to the weight at the beginning of that month), e.g., at least 0.75% per month, at least 1% per month, at least 1.25% per month, or at least 1.3% per month. In some embodiments, subjects show a weight loss of 0.5%, 0.75% per month, 1% per month, 1.25% per month, or 1.3% per month.

[0164] Methods to increase weight loss The present invention also provides a method for increasing weight loss in subjects requiring it, (i) A step of preparing a subject who has been treated with a GIPR / GLP-1R dual agonist as described herein for a certain period of time, during which time the subject's weight loss has plateaued, and / or the subject is resistant to or will become resistant to the GIPR / GLP-1R dual agonist, and (ii) After step (i), administer to the subject (a) a GIPR / GLP-1R agonist and (b) an amylin analog as described herein, in an amount sufficient to increase the weight loss in the subject when combined. This provides a method that includes this.

[0165] The present invention also provides a method for increasing weight loss in subjects requiring it, (i) the step of preparing subjects who do not respond to treatment with the GIPR / GLP-1R dual agonists described herein, and (ii) The step of administering to a subject (a) a GIPR / GLP-1R dual agonist and (b) an amylin analog, as described herein, in an amount sufficient to increase the subject's weight loss when combined. This provides a method that includes this.

[0166] The present invention also provides a method for increasing weight loss in subjects requiring it, (i) the step of preparing subjects who have been treated with a GIPR / GLP-1R dual agonist as described herein for at least one month, and (ii) After step (i), administer to the subject (a) a GIPR / GLP-1R dual agonist and (b) an amylin analog as described herein, in an amount sufficient to increase the weight loss in the subject when combined. This provides a method that includes this.

[0167] The present invention also provides a method for maintaining weight loss in a subject that requires it, (i) A step of preparing subjects who have been treated with a GIPR / GLP-1R dual agonist as described herein and have lost weight, and (ii) After step (i), administer to the subject (a) a GIPR / GLP-1R dual agonist and (b) an amylin analog as described herein, in an amount sufficient to maintain weight loss in the subject when combined. This provides a method that includes this.

[0168] The present invention also provides a method for increasing weight loss in subjects requiring it, (i) A step of preparing a subject who has been treated with a GIPR / GLP-1R dual agonist as described herein for a certain period of time, during which the subject's weight loss has plateaued, and / or the subject has become resistant to or resistant to the GIPR / GLP-1R dual agonist, and further weight loss is required in the subject, and (ii) After step (i), administer to the subject (a) a GIPR / GLP-1R dual agonist and (b) an amylin analog as described herein, in an amount sufficient to achieve further weight loss in the subject when combined. This provides a method that includes this.

[0169] The present invention also provides a method for achieving further weight loss in subjects requiring it, (i) A step of preparing subjects who have been treated with a GIPR / GLP-1R dual agonist as described herein for a certain period of time, during which weight loss has been achieved and further weight loss is required for the subjects, and (ii) After step (i), administer to the subject (a) a GIPR / GLP-1R dual agonist and (b) an amylin analog as described herein, in an amount sufficient to achieve further weight loss in the subject when combined. This provides a method that includes this.

[0170] As described elsewhere in this specification, preferably the amylin analog is petrelintide. Preferably the GIPR / GLP-1R dual agonist is tilzepatide. Most preferably, the amylin analog is petrelintide and the GIPR / GLP-1R dual agonist is tilzepatide.

[0171] Administration method The administration of the amylin analogs and GIPR / GLP-1R dual agonists described herein to subjects may be any common or standard mode of administration in the art, such as oral, intravenous, intramuscular, subcutaneous, sublingual, intranasal, intradermal, suppository, or implantable. In preferred embodiments, administration is by subcutaneous injection.

[0172] In some embodiments, the amylin analog is administered to the subject by injection. In some embodiments, the amylin analog is administered to the subject by subcutaneous injection. The amylin analog may be in any form suitable for administration to the subject. Preferably, the amylin analog is in a form suitable for subcutaneous (s / c or sc) administration to the subject.

[0173] In some embodiments, the GIPR / GLP-1R dual agonist is administered to the subject by injection. In some embodiments, the GIPR / GLP-1R dual agonist is administered to the subject by subcutaneous injection. The GIPR / GLP-1R dual agonist may be in any form suitable for administration to the subject. Preferably, the GIPR / GLP-1R dual agonist is in a form suitable for subcutaneous (s / c or sc) administration to the subject.

[0174] In some embodiments, both the amylin analog and the GIPR / GLP-1R dual agonist are administered to the subject via injection, preferably subcutaneously.

[0175] In a preferred embodiment, the amilin analog is [19CD]-IsoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH2(Sequence ID 2) or a pharmaceutically acceptable salt or solvate thereof, administered to the subject by subcutaneous injection. In a preferred embodiment, the GIPR / GLP-1R dual agonist is tilzepatide or a pharmaceutically acceptable salt or solvate thereof (as described elsewhere herein), administered to the subject by subcutaneous injection.

[0176] In some embodiments, the subject is a human subject.

[0177] In some embodiments, the subject suffers from a disease or disorder described herein. In some embodiments, the subject is overweight, obese, morbidly obese, has diabetes, or has a disease associated with obesity or diabetes. In some embodiments, the subject does not suffer from a disease or disorder described herein. In some embodiments, the subject is at risk of developing a disease or disorder described herein.

[0178] dose In this specification, the term "dose" refers to the amount of a given compound (amyrin analog or GIPR / GLP-1R dual agonist) administered to a subject in each administration event. The term "dosage" refers to both the amount and frequency of administration of a given compound to a subject.

[0179] The doses of the amylin analog and the GIPR / GLP-1R dual agonist can be selected independently. Any dose of the amylin analog described herein can be combined with any dose of the GIPR / GLP-1R dual agonist described herein.

[0180] In the context of the present invention, the subject is administered a therapeutically effective dose of an amylin analog and a therapeutically effective dose of a GIPR / GLP-1R dual agonist. The amylin analog is administered to the subject in a therapeutically effective dose. The GIPR / GLP-1R dual agonist is administered to the subject in a therapeutically effective dose. Both the amylin analog and the GIPR / GLP-1R dual agonist are administered to the subject in therapeutically effective doses.

[0181] The precise dose of amylin analog or GIPR / GLP-1R dual agonist administered to the subject depends, in particular, on the nature and severity of the disease or disorder being treated, the subject's sex, age, weight, and overall condition, any other concomitant diseases or disorders that are being treated or are likely to be treated, and other factors known to a physician with the skills in the art.

[0182] Amylin analog dosage In some embodiments, the amylin analog is administered to the subject in doses up to approximately 10 mg, for example, up to approximately 9.5 mg, 9 mg, 8.5 mg, 8 mg, 7.5 mg, 7 mg, 6.5 mg, 6 mg, 5.5 mg, 5 mg, 4.5 mg, 4 mg, 3.5 mg, 3 mg, 2.5 mg, 2 mg, 1.5 mg, 1 mg, 0.5 mg, or 0.25 mg.

[0183] In some embodiments, the amylin analog is administered to the subject in doses ranging from approximately 0.04 mg to approximately 10 mg, for example, approximately 0.04 mg to approximately 7 mg, approximately 0.04 mg to approximately 6 mg, approximately 0.04 mg to approximately 4.4 mg, or approximately 0.04 mg to approximately 2.4 mg.

[0184] In some embodiments, the amylin analog is administered to the subject in doses of approximately 0.6 mg to 10 mg, approximately 0.6 mg to 7 mg, approximately 0.6 mg to 6 mg, approximately 0.6 mg to 4.4 mg, or approximately 0.6 mg to 2.4 mg.

[0185] In some embodiments, the amylin analog is administered to the subject in doses of approximately 0.7 mg to 10 mg, approximately 0.7 mg to 7 mg, approximately 0.7 mg to 6 mg, approximately 0.7 mg to 4.4 mg, or approximately 0.7 mg to 2.4 mg.

[0186] In some embodiments, the amylin analog is administered to the subject in doses of approximately 0.5 mg to approximately 10.0 mg, preferably approximately 0.6 mg to approximately 7.5 mg, preferably approximately 1.2 mg to approximately 7.5 mg, preferably approximately 1.2 to approximately 6.0 mg, preferably approximately 2.4 to approximately 6.0 mg, preferably approximately 2.4 to approximately 4.0 mg, and preferably approximately 2.4 to approximately 3.5 mg.

[0187] In some embodiments, the amylin analog is administered to the subject in doses of approximately 10 mg, for example, approximately 9.5 mg, 9 mg, 8.5 mg, 8 mg, 7.5 mg, 7 mg, 6.5 mg, 6 mg, 5.5 mg, 5 mg, 4.5 mg, 4.4 mg, 4 mg, 3.5 mg, 3.4 mg, 3 mg, 2.5 mg, 2.4 mg, 2 mg, 1.5 mg, 1.4 mg, 1 mg, 0.5 mg, 0.35 mg, 0.25 mg, 0.16 mg, 0.08 mg, or 0.04 mg.

[0188] In some embodiments, the amylin analog is administered to the subject in a dose of approximately 0.0001 to 1 mg per kg of body weight, for example, approximately 0.0005 to 1 mg per kg of body weight, approximately 0.001 to 1 mg per kg of body weight, approximately 0.01 to 1 mg per kg of body weight, approximately 0.1 to 1 mg per kg of body weight, approximately 0.2 to 1 mg per kg of body weight, approximately 0.3 to 1 mg per kg of body weight, approximately 0.4 to 1 mg per kg of body weight, or approximately 0.5 to 1 mg per kg of body weight.

[0189] In some embodiments, the amylin analog is administered to the subject at a dose of approximately 0.0001 to 0.5 mg per kg of body weight, for example, approximately 0.0005 to 0.5 mg per kg of body weight, approximately 0.001 to 0.5 mg per kg of body weight, approximately 0.01 to 0.5 mg per kg of body weight, approximately 0.1 to 0.5 mg per kg of body weight, approximately 0.2 to 0.5 mg per kg of body weight, approximately 0.3 to 0.5 mg per kg of body weight, or approximately 0.4 to 0.5 mg per kg of body weight.

[0190] In some embodiments, the amylin analog is administered to the subject at a dose of approximately 0.0001 to 0.15 mg per kg of body weight, for example, approximately 0.0005 to 0.15 mg per kg of body weight, approximately 0.001 to 0.15 mg per kg of body weight, or approximately 0.01 to 0.15 mg per kg of body weight.

[0191] In some embodiments, the amylin analog is administered to the subject at a dose of approximately 0.0001 to 0.1 mg per kg of body weight, for example, approximately 0.0005 to 0.1 mg per kg of body weight, approximately 0.001 to 0.1 mg per kg of body weight, or approximately 0.01 to 0.1 mg per kg of body weight.

[0192] In some embodiments, the amylin analog is administered to the subject in doses ranging from approximately 10 nmol to approximately 500 nmol per kg of body weight, for example, approximately 10 to approximately 100 nmol per kg of body weight, or approximately 10 to approximately 50 nmol per kg of body weight. In some embodiments, the amylin analog is administered to the subject in doses ranging from approximately 10, 50, or 100 nmol per kg of body weight.

[0193] In some embodiments, the dose of the amylin analog is not the same with each administration. In some embodiments, the dose of the amylin analog increases with each sequential administration. In some embodiments, the dose of the amylin analog increases with each sequential administration until a desired maximum dose is reached. The desired maximum dose may be maintained over a given time (i.e., a plateau dose). In some embodiments, the dose of the amylin analog is the same with each administration.

[0194] Preferably, the amilin analog is [19CD]-IsoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH2(Sequence ID 2), Or a pharmaceutically acceptable salt or solvate thereof, administered to the subject in any of the doses described herein.

[0195] Dosage of GIPR / GLP-1R dual agonist In some embodiments, the GIPR / GLP-1R dual agonist is administered to subjects in doses of up to approximately 15 mg, up to approximately 12.5 mg, up to approximately 10 mg, up to approximately 7.5 mg, up to approximately 5 mg, up to approximately 2.5 mg, up to approximately 2 mg, or up to approximately 1 mg.

[0196] In some embodiments, the GIPR / GLP-1R dual agonist is administered to the subject in doses of approximately 1 mg to 15 mg, approximately 2.5 mg to 15 mg, approximately 5 mg to 15 mg, approximately 7.5 mg to 15 mg, approximately 10 mg to 15 mg, or approximately 12.5 mg to 15 mg.

[0197] In some embodiments, the GIPR / GLP-1R dual agonist is administered to the subject in doses of approximately 0.5 mg to 10 mg, 1 mg to 10 mg, 2.5 mg to 10 mg, 5 mg to 10 mg, or 7.5 mg to 10 mg.

[0198] In some embodiments, the GIPR / GLP-1R dual agonist is administered to the subject in doses of approximately 1 mg to approximately 5 mg, or approximately 2.5 mg to approximately 5 mg.

[0199] In some embodiments, the GIPR / GLP-1R dual agonist is administered to subjects in doses of approximately 15 mg, 12.5 mg, 10 mg, 7.5 mg, 5 mg, 2.5 mg, or 1 mg. In some embodiments, the GIPR / GLP-1R dual agonist is administered to subjects in doses of approximately 15 mg, 10 mg, or 5 mg.

[0200] In some embodiments, the GIPR / GLP-1R dual agonist is administered to the subject at a dose of approximately 0.0001 to 1 mg per kg of body weight, for example, approximately 0.0005 to 1 mg per kg, approximately 0.001 to 1 mg per kg, approximately 0.01 to 1 mg per kg, approximately 0.1 to 1 mg per kg, approximately 0.2 to 1 mg per kg, approximately 0.3 to 1 mg per kg, approximately 0.4 to 1 mg per kg, or approximately 0.5 to 1 mg per kg.

[0201] In some embodiments, the GIPR / GLP-1R dual agonist is administered to the subject at a dose of approximately 0.0001 to 0.5 mg per kg of body weight, for example, approximately 0.0005 to 0.5 mg per kg of body weight, approximately 0.001 to 0.5 mg per kg of body weight, approximately 0.01 to 0.5 mg per kg of body weight, approximately 0.1 to 0.5 mg per kg of body weight, approximately 0.2 to 0.5 mg per kg of body weight, approximately 0.3 to 0.5 mg per kg of body weight, or approximately 0.4 to 0.5 mg per kg of body weight.

[0202] In some embodiments, the GIPR / GLP-1R dual agonist is administered to the subject at a dose of approximately 0.0001 to 0.15 mg per kg of body weight, for example, approximately 0.0005 to 0.15 mg per kg of body weight, approximately 0.001 to 0.15 mg per kg of body weight, or approximately 0.01 to 0.15 mg per kg of body weight.

[0203] In some embodiments, the GIPR / GLP-1R dual agonist is administered to the subject at a dose of approximately 0.0001 to 0.1 mg per kg of body weight, for example, approximately 0.0005 to 0.1 mg per kg of body weight, approximately 0.001 to 0.1 mg per kg of body weight, or approximately 0.01 to 0.1 mg per kg of body weight.

[0204] In some embodiments, the GIPR / GLP-1R dual agonist is administered to the subject at a dose of approximately 1 nmol to approximately 100 nmol per kg of body weight, for example, approximately 1 to approximately 50 nmol per kg of body weight, or approximately 1 to approximately 10 nmol per kg of body weight. In some embodiments, the amylin analog is administered to the subject at a dose of approximately 1, 5, or 10 nmol per kg of body weight.

[0205] In some embodiments, the GIPR / GLP-1R dual agonist is administered to subjects at doses ranging from approximately 5 mg / mL to approximately 30 mg / mL. In some embodiments, the GIPR / GLP-1R dual agonist is administered to subjects at doses of approximately 5 mg / mL, approximately 10 mg / mL, approximately 15 mg / mL, approximately 20 mg / mL, approximately 25 mg / mL, or approximately 30 mg / mL.

[0206] Preferably, the GIPR / GLP-1R dual agonist is Hy-Y[Aib]EGTFTSDYSI[Aib]LDKIAQ[K]AFVQWLIAGGPSSGAPPPS-NH2(Sequence ID 4) (Tilzepatide) or a pharmaceutically acceptable salt or solvate thereof, Here, [K] is (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(isoGlu)1-CO-(CH2) 18 -COOH is conjugated to the epsilon-amino group of the lysine side chain, and this is lysine. Furthermore, GIPR / GLP-1R dual agonists are administered to the subject at any of the doses described herein.

[0207] In preferred embodiments, the GIPR / GLP-1R dual agonist is tilzepatide or a pharmaceutically acceptable salt or solvate thereof, administered to the subject in doses of about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, or about 15 mg.

[0208] Timing of administration An amylin analog and / or a GIPR / GLP-1R dual agonist can be administered to a subject a specific number of times “per day” or a specific number of times “per day”. “One day” means approximately 24 hours, for example, approximately 20, 21, 22, 23, 24, 25, 26, 27, or 28 hours.

[0209] An amylin analog and / or a GIPR / GLP-1R dual agonist can be administered to a subject a specific number of times “per week” or a specific number of times “per week”. “One week” means approximately 7 days, for example, approximately 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, or 9 days, and each “day” is counted as approximately 24 hours.

[0210] As is understood in the art, the time between administrations can vary somewhat, so each and all of the administrations are not exactly equally spaced in time (i.e., not exactly one day or exactly one week). This is often at the discretion of the physician. Thus, the administrations can be spaced in time by a clinically acceptable time range.

[0211] Thus, in some embodiments, the recitation “day” can mean 24 hours ± 8 hours. That is, the administration can be made up to about 8 hours before or up to about 8 hours after the recited time.

[0212] In some embodiments, the recitation “week” can mean 7 days ± 2 days. That is, the administration can be made up to about 2 days before or up to about 2 days after the recited day. Thus, the administration can be made about 2 days or about 1 day before, or about 1 day or about 2 days after, the recited day. Thus, the administration can be made 2 days or 1 day before, or 1 day or 2 days after, the recited day.

[0213] Timing of the Amylin Analogue The amylin analog can be administered continuously (e.g., by intravenous administration or another continuous drug administration method).

[0214] In some embodiments, the amylin analog is administered at regular intervals. In some embodiments, the amylin analog is administered at regular intervals.

[0215] In some embodiments, the amylin analog is administered to the subject at least about once a day (i.e., at least about once every day). In some embodiments, the amylin analog is administered to the subject once a day, once every two days, once every three days, once every four days, once every five days, or once every six days. In some embodiments, the amylin analog is administered to the subject once a week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the amylin analog is administered to the subject once a month.

[0216] In some embodiments, the amylin analog is administered to the subject twice a day, twice a week, or twice a month.

[0217] In some embodiments, the amylin analog is administered to the subject every other day (i.e., once every two days).

[0218] In preferred embodiments, the amylin analog is administered to the subject once a week (i.e., once each week or once every week). In preferred embodiments, the amylin analog is SEQ ID NO: 2 or a pharmaceutically acceptable salt or solvate thereof (as described elsewhere herein), and is administered to the subject once a week (i.e., once every week).

[0219] Timing of GIPR / GLP-1R dual agonist GIPR / GLP-1R dual agonists can be administered sequentially (for example, by intravenous administration or another sequential drug administration method).

[0220] In some embodiments, the GIPR / GLP-1R dual agonist is administered at regular intervals. In some embodiments, the GIPR / GLP-1R dual agonist is administered at regular intervals.

[0221] In some embodiments, the amylin analog is administered to the subject at least about once a day (i.e., at least about once daily). In some embodiments, the GIPR / GLP-1R dual agonist is administered to the subject once a day, once every two days, once every three days, once every four days, once every five days, or once every six days. In some embodiments, the GIPR / GLP-1R dual agonist is administered to the subject once a week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the GIPR / GLP-1R dual agonist is administered to the subject once a month.

[0222] In some embodiments, the GIPR / GLP-1R dual agonist is administered to the subject twice daily, twice weekly, or twice monthly.

[0223] In some preferred embodiments, the GIPR / GLP-1R dual agonist is administered to the subject once a week (i.e., once a week). In preferred embodiments, the GIPR / GLP-1R dual agonist is tilzepatide or a pharmaceutically acceptable salt or solvate thereof (as described elsewhere herein), and is administered to the subject once a week (i.e., once a week).

[0224] Timing of administration of both compounds The present invention encompasses, but is not limited to, medical uses and therapeutic methods for simultaneously administering amylin analogs and GIPR / GLP-1R dual agonists to a subject. Amylin analogs and GIPR / GLP-1R dual agonists can be administered to a subject at different times according to different dosing regimens (i.e., timing). For example, amylin analogs may be administered daily while GIPR / GLP-1R dual agonists are administered weekly. Amylin analogs and GIPR / GLP-1R dual agonists may be administered at different times on the same day.

[0225] The present invention provides an amylin analog and a GIPR / GLP-1R dual agonist for use in a method of treating or preventing a disease in a subject, comprising the step of administering the amylin analog and the GIPR / GLP-1R dual agonist to the subject at different time points or simultaneously. Accordingly, in some embodiments, the amylin analog and the GIPR / GLP-1R dual agonist are administered to the subject at different time points. In some embodiments, the amylin analog and the GIPR / GLP-1R dual agonist are administered to the subject simultaneously.

[0226] The present invention provides an amylin analog and a GIPR / GLP-1R dual agonist for use in a method of treating or preventing a disease in a subject, comprising the step of administering the amylin analog and the GIPR / GLP-1R dual agonist to the subject individually or together. In some embodiments, the amylin analog and the GIPR / GLP-1R dual agonist are administered to the subject individually. In some embodiments, the amylin analog and the GIPR / GLP-1R dual agonist are administered to the subject together.

[0227] In some embodiments, the amylin analog and the GIPR / GLP-1R dual agonist are administered to the subject at different intervals. In some embodiments, the amylin analog and the GIPR / GLP-1R dual agonist are administered to the subject at the same interval.

[0228] Duration of administration The term “duration of administration” may be used herein to refer to the entire period of administration of an amylin analog or GIPR / GLP-1R dual agonist to a subject. In other words, the duration of administration is the period that begins with the first administration event (i.e., the first time the compound is administered to the subject) and ends with the last administration event (i.e., the last time the compound is administered to the subject). In other words, the duration of administration is the period during which the subject is treated with the compound.

[0229] In some embodiments, the amylin analog is administered to the subject for at least one month (i.e., the administration period of the amylin analog is at least one month). In some embodiments, the amylin analog is administered to the subject for at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months.

[0230] In some embodiments, the amylin analog is administered to the subject for at least one year (i.e., the administration period of the amylin analog is at least one year). In some embodiments, the amylin analog is administered to the subject for at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, or at least ten years.

[0231] In some embodiments, the amylin analog is administered to the subject for more than ten years. In some embodiments, the amylin analog is administered to the subject indefinitely. In some embodiments, the amylin analog is administered to the subject for the remainder of the subject's life.

[0232] In some embodiments, the GIPR / GLP-1 dual agonist is administered to the subject for at least one month (i.e., the administration period of the GIPR / GLP-1 dual agonist is at least one month). In some embodiments, the GIPR / GLP-1 dual agonist is administered to the subject for at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months.

[0233] In some embodiments, the GIPR / GLP-1 dual agonist is administered to the subject for at least one year (i.e., the duration of GIPR / GLP-1 dual agonist administration is at least one year). In some embodiments, the GIPR / GLP-1 dual agonist is administered to the subject for at least two years, at least three years, at least four years, at least five years, at least six years, at least eight years, at least nine years, or at least ten years.

[0234] In some embodiments, GIPR / GLP-1 dual agonists are administered to subjects for more than 10 years. In some embodiments, GIPR / GLP-1 dual agonists are administered to subjects indefinitely. In some embodiments, GIPR / GLP-1 dual agonists are administered to subjects for the remainder of their lives.

[0235] Duration of administration of both compounds The present invention does not require that the administration of amylin analogs and GIPR / GLP-1R dual agonists begin or end simultaneously. In other words, amylin analogs and GIPR / GLP-1R dual agonists may have different administration periods. The present invention therefore relates to the period during which the administration of amylin analogs to a subject overlaps with the administration of GIPR / GLP-1R dual agonists to a subject.

[0236] In some embodiments, the administration period of the amylin analog begins simultaneously with the administration period of the GIPR / GLP-1R dual agonist. In other words, administration of the amylin analog and the GIPR / GLP-1R dual agonist to the subject begins at the same time.

[0237] In some embodiments, the administration period of the amylin analog begins before the administration period of the GIPR / GLP-1R dual agonist. In other words, the subject is being treated with the amylin analog, and then administration of the GIPR / GLP-1R dual agonist to the subject begins. Alternatively, additional treatment with the GIPR / GLP-1R dual agonist is initiated to a subject who is already being treated with the amylin analog.

[0238] In a preferred embodiment, the administration period of the GIPR / GLP-1R dual agonist begins before the administration period of the amylin analog. In other words, the subject is being treated with the GIPR / GLP-1R dual agonist, and then administration of the amylin analog to the subject is initiated. Alternatively, additional treatment with the amylin analog is initiated to a subject receiving treatment with the GIPR / GLP-1R dual agonist.

[0239] In a particularly preferred embodiment, the subject is administered tilzepatide or a pharmaceutically acceptable salt or solvate thereof, and then administration of the amylin analog to the subject is initiated, where the amylin analog is [19CD]-IsoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH2(Sequence ID 2) or a pharmaceutically acceptable salt or solvate thereof. In other words, the subject is being treated with tilzepatide, and then treatment with a specific amylin analog as defined in the preceding sentence is added to the tilzepatide treatment.

[0240] Titration regimen In some embodiments, the GIPR / GLP-1R dual agonist is administered to the subject according to a titration regimen.

[0241] In some embodiments, the amylin analog is administered to the subject according to a titration regimen.

[0242] A titration regimen consists of an initial set of one or more doses of the dual agonist during the "titration period," and subsequent sets of one or more doses of the dual agonist during the "treatment period." Typically, the dose of the dual agonist in each dose during the titration period is less than the dose in each dose during the treatment period.

[0243] The primary objective of the titration period is to allow the patient to become accustomed to the side effects of the dual agonist. The initial dose of a dual agonist may cause side effects, but these tend to decrease in severity with subsequent doses as the patient adapts. Administering low doses of the dual agonist during the titration period can reduce the initial severity of these side effects. A secondary objective of the titration period may be to determine the appropriate dual agonist dose for the patient. The dual agonist dose can be increased throughout the titration period, allowing the physician to observe side effects at different doses, thus determining the appropriate dose for treatment.

[0244] Therefore, in some embodiments, the GIPR / GLP-1R dual agonist is administered to the subject once or twice or more in an initial dose, and then once or twice or more in a second dose. In some embodiments, the GIPR / GLP-1R dual agonist is administered to the subject once or twice or more in additional doses (i.e., a third dose, a fourth dose, a fifth dose, etc.). In some embodiments, the GIPR / GLP-1R dual agonist is administered to the subject once or twice or more in a third, fourth, fifth, or sixth dose.

[0245] Each dose of the GIPR / GLP-1R dual agonist can be administered any number of times. In some embodiments, each dose of the GIPR / GLP-1R dual agonist is administered a number of times independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 times.

[0246] Each dose of the dual agonist may be any of the dual agonist doses described elsewhere in this specification.

[0247] Therefore, in some embodiments, the amylin analog is administered to the subject once or twice or more in an initial dose, and then once or twice or more in a second dose. In some embodiments, the amylin analog is administered to the subject once or twice or more in additional doses (i.e., a third dose, a fourth dose, a fifth dose, etc.). In some embodiments, the amylin analog is administered to the subject once or twice or more in a third, fourth, fifth, or sixth dose.

[0248] Each dose of the amylin analog can be administered any number of times. In some embodiments, each dose of the amylin analog is administered a number of times independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 times.

[0249] Each dose of an amylin analog may be any of the doses of amylin analogs described elsewhere in this specification.

[0250] The timing of each dose may be any of the timings of administration described elsewhere in this specification. In a preferred embodiment, each dose of the GIPR / GLP-1R dual agonist is once weekly.

[0251] Advantageously, subjects do not experience nausea or vomiting (or other adverse gastrointestinal effects) during the titration period. This allows for shorter or faster titration periods before administering higher doses.

[0252] For tilzepatide, an initial titration dose of approximately 2.5 mg is recommended and administered once a week for four weeks. After four weeks, the dose can be increased to approximately 5 mg (this provides therapeutic effect). However, if a stronger therapeutic effect is needed, the dose may be increased to approximately 7.5 mg after at least four weeks of administration at approximately 5 mg. The dose of tilzepatide can be increased by approximately 2.5 mg at each dose for at least four weeks, up to a maximum dose of approximately 15 mg, until the final therapeutic dose is identified. Once the final therapeutic dose is identified, tilzepatide can be continued indefinitely at that dose or until treatment is completed.

[0253] Therefore, in a preferred embodiment, the GIPR / GLP-1R dual agonist is tilzepatide or a pharmaceutically acceptable salt or solvate thereof (as described elsewhere herein), and is administered to the subject at a dose of approximately 2.5 mg once weekly for 4 weeks, and thereafter at a dose of approximately 5 mg once weekly.

[0254] In a preferred embodiment, the GIPR / GLP-1R dual agonist is tilzepatide or a pharmaceutically acceptable salt or solvate thereof (as described elsewhere herein), and is administered to the subject at a dose of approximately 2.5 mg once weekly for 4 weeks, then at a dose of approximately 5 mg once weekly for 4 weeks, and then at a dose of approximately 7.5 mg once weekly.

[0255] In a preferred embodiment, the GIPR / GLP-1R dual agonist is tilzepatide or a pharmaceutically acceptable salt or solvate thereof (as described elsewhere herein), and is administered to the subject at a dose of about 2.5 mg once weekly for 4 weeks, then at a dose of about 5 mg once weekly for at least 4 weeks, then at a dose of about 7.5 mg once weekly for at least 4 weeks, and then at a dose of about 10 mg once weekly.

[0256] In a preferred embodiment, the GIPR / GLP-1R dual agonist is tilzepatide or a pharmaceutically acceptable salt or solvate thereof (as described elsewhere herein), and is administered to the subject at a dose of about 2.5 mg once weekly for 4 weeks, then at a dose of about 5 mg once weekly for at least 4 weeks, then at a dose of about 7.5 mg once weekly for at least 4 weeks, then at a dose of about 10 mg once weekly for at least 4 weeks, and then at a dose of about 12.5 mg once weekly.

[0257] In a preferred embodiment, the GIPR / GLP-1R dual agonist is tilzepatide or a pharmaceutically acceptable salt or solvate thereof (as described elsewhere herein), and is administered to the subject at a dose of about 2.5 mg once weekly for 4 weeks, then at a dose of about 5 mg once weekly for at least 4 weeks, then at a dose of about 7.5 mg once weekly for at least 4 weeks, then at a dose of about 10 mg once weekly for at least 4 weeks, then at a dose of about 12.5 mg once weekly for at least 4 weeks, and thereafter at a dose of about 15 mg once weekly.

[0258] Pharmaceutical composition Amylin analogs and GIPR / GLP-1R dual agonists can each be formulated as pharmaceutical compositions.

[0259] A pharmaceutical composition containing an amylin analog may be referred to herein as an "amylin analog pharmaceutical composition." Similarly, a pharmaceutical composition containing a GIPR / GLP-1R dual agonist may be referred to herein as a "GIPR / GLP-1R dual agonist pharmaceutical composition." This terminology distinguishes the types of pharmaceutical compositions. As used herein, the expressions "pharmaceutical composition" and "pharmaceutical composition of the present invention" encompass both amylin analog pharmaceutical compositions and GIPR / GLP-1R dual agonist pharmaceutical compositions.

[0260] Accordingly, the present invention provides pharmaceutical compositions comprising an amylin analog and a GIPR / GLP-1R dual agonist for use in the treatment or prevention of a disease in a subject, wherein the disease is overweight, obesity, morbid obesity, diabetes, or a disease associated with obesity or diabetes.

[0261] In other words, the present invention provides the use of a pharmaceutical composition comprising an amylin analog and a pharmaceutical composition comprising a GIPR / GLP-1R dual agonist in the preparation of a pharmacopoeia for the treatment or prevention of a disease in a subject, wherein the disease is overweight, obesity, morbid obesity, diabetes, or a disease associated with obesity or diabetes.

[0262] The present invention also provides a method for treating or preventing a disease in a subject, comprising the step of administering to the subject a pharmaceutical composition comprising an amylin analog and a pharmaceutical composition comprising a GIPR / GLP-1R dual agonist, wherein the disease is overweight, obesity, morbid obesity, diabetes, or a disease associated with obesity or diabetes.

[0263] The present invention also provides pharmaceutical compositions comprising amylin analogs and GIPR / GLP-1R dual agonists for use in methods of inhibiting and / or reducing weight gain in subjects.

[0264] The present invention also provides a method for inhibiting weight gain and / or reducing weight in a subject, comprising the step of administering to the subject a pharmaceutical composition comprising an amylin analog and a pharmaceutical composition comprising a GIPR / GLP-1R dual agonist.

[0265] In a preferred embodiment, the combination of the present invention includes separate administration of an amylin analog pharmaceutical composition and a GIPR / GLP-1R dual agonist pharmaceutical composition to a subject.

[0266] It will be understood that when formulated as a pharmaceutical composition, amylin analogs and GIPR / GLP-1R dual agonists may be in the form of pharmaceutically acceptable salts or solvates, such as pharmaceutically acceptable acid addition salts, as described elsewhere in this specification.

[0267] The pharmaceutical composition may be suitable for administration with or without storage.

[0268] The pharmaceutical composition may contain a therapeutically effective amount of the compound (i.e., an amylin analog or a GIPR / GLP-1R dual agonist).

[0269] A pharmaceutical composition may include a carrier, excipients, and / or a medium. In other words, a compound is mixed with a carrier, excipients, and / or a medium. In some embodiments, the carrier is a pharmaceutically acceptable carrier.

[0270] The term “pharmaceutically acceptable carrier” includes any standard pharmaceutically acceptable carrier. pharmaceutically acceptable carriers for therapeutic use are well known in the pharmaceutical field and are described, for example, in “Remington's Pharmaceutical Sciences,” 17th edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985. For example, sterile salines and phosphate-buffered salines of slightly acidic or physiological pH can be used. Suitable pH buffers may be, for example, phosphates, citrates, acetates, tris(hydroxymethyl)aminomethane (TRIS), N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS), ammonium bicarbonate, diethanolamine, histidine, arginine, lysine, or acetates (e.g., sodium acetate), or mixtures thereof. The term further encompasses all carriers listed in the United States Pharmacopeia for use in animals, including humans.

[0271] The pharmaceutical compositions of the present invention may be in unit dosage form. In such form, the composition is divided into unit doses containing an appropriate amount of one or more active components. The unit dosage form may be provided as a packaged preparation, the packaging containing individual amounts of the preparation, for example, packaged tablets, capsules, or powder in vials or ampoules. The unit dosage form may also be itself, for example, a capsule, cachet, or tablet, or an appropriate number of any of these packaged forms. The unit dosage form may also be provided in a single-dose injectable form, for example, in the form of a pen-type device containing a liquid-phase (typically aqueous) composition. The composition can be formulated for any appropriate route and means of administration. Pharmaceutically acceptable carriers or diluents include, for example, those used in formulations suitable for oral, intravitreal, rectal, vaginal, nasal, topical, intestinal, or parenteral administration (including subcutaneous, intramuscular, intravenous, intradermal, and transdermal administration), or inhalation. The formulations can be conveniently provided in unit dose forms and can be prepared by any method well known in the field of pharmaceutical formulations. Subcutaneous or transdermal administration may be suitable for the compounds of the present invention in some cases.

[0272] Further embodiments relate to devices, dosage forms, and packaging used to deliver the pharmaceutical formulations of the present invention. Thus, at least one peptide in a stable or stored formulation or solution described herein can be administered to a patient in accordance with the present invention by various delivery methods, including by SC or IM injection, or by transdermal, pulmonary, or transmucosal administration, or by implantation, or by the use of an osmotic pump, cartridge, micropump, or other means recognized by those skilled in the art.

[0273] The pharmaceutical composition can be formulated as a liquid suitable for administration by injection or infusion. In some embodiments, the pharmaceutical composition of the present invention is formulated as a 1 mL injectable solution. In some embodiments, the pharmaceutical composition is formulated as a 0.5 mL injectable solution.

[0274] Further embodiments relate to oral formulations and oral administration. Formulations for oral administration may rely on the co-administration of an adjuvant (e.g., resorcinol and / or a nonionic surfactant, e.g., polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether) to artificially increase the permeability of the intestinal wall, and / or on the co-administration of an enzyme inhibitor (e.g., a pancreatic trypsin inhibitor, diisopropyl fluorophosphate (DFF), or trazilol) to inhibit enzymatic degradation. The active constituent compound of a solid-type dosage form for oral administration may be mixed with at least one additive, e.g., sucrose, lactose, cellulose, mannitol, trehalose, raffinose, maltitol, dextran, starch, agar, alginate, chitin, chitosan, pectin, tragacanth gum, acacia gum, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymer, or glyceride. These dosage forms may also contain other types of additives, such as inert diluents, lubricants (e.g., magnesium stearate), parabens, preservatives (e.g., sorbic acid, ascorbic acid, or alpha-tocopherol), antioxidants (e.g., cysteine), disintegrants, binders, thickeners, buffers, pH adjusters, sweeteners, flavorings, or fragrances.

[0275] The pharmaceutical composition may contain an isotonic agent. The pharmaceutical composition may contain a preservative.

[0276] In some embodiments, the pharmaceutical composition comprises one or more further activators, such as one or more further peptides.

[0277] Amylin analog pharmaceutical composition In some embodiments, the amylin analog is formulated as an amylin analog pharmaceutical composition.

[0278] The amylin analog pharmaceutical composition comprises any of the doses of the amylin analog described herein.

[0279] In some embodiments, the amylin analog pharmaceutical composition includes a buffer with a concentration of about 0.5 mM to 25 mM.

[0280] In some embodiments, the amylin analog pharmaceutical composition has a pH of about 5.8 to about 6.9.

[0281] In some embodiments, the amylin analog pharmaceutical composition consists of the following components. [Table 1]

[0282] GIPR / GLP-1R dual agonist pharmaceutical composition In some embodiments, the GIPR / GLP-1R dual agonist is formulated as a GIPR / GLP-1R dual agonist pharmaceutical composition.

[0283] A GIPR / GLP-1R dual agonist pharmaceutical composition comprises a GIPR / GLP-1R dual agonist as described herein, in any of the doses described herein.

[0284] In some embodiments, the GIPR / GLP-1R dual agonist pharmaceutical composition comprises the following components: [Table 2]

[0285] Chilzepatide (trade name Zepbound) is clinically formulated for subcutaneous injection as 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg of chilzepatide in 0.5 mL of solution with the following excipients: sodium chloride (4.1 mg), sodium phosphate dibasic heptahydrate (0.7 mg), and water for injection. Hydrochloric acid solution and / or sodium hydroxide solution may be added to adjust the pH. The formulation has a pH of 6.5 to 7.5.

[0286] Therefore, in some embodiments, the GIPR / GLP-1R dual agonist pharmaceutical composition comprises tilzepatide or a pharmaceutically acceptable salt or solvate thereof, and sodium phosphate buffer.

[0287] In some embodiments, the GIPR / GLP-1R dual agonist pharmaceutical composition has a pH of 6.5 to 7.5.

[0288] Kits and devices The present invention provides a kit comprising the amylin analog and the GIPR / GLP-1R dual agonist of the present invention. The amylin analog and GIPR / GLP-1R dual agonist in the kit of the present invention may have any of the characteristics of the amylin analog and GIPR / GLP-1R dual agonist described herein. In some embodiments, the kit further includes packaging and / or instructions for use.

[0289] The present invention also provides a device comprising the amylin analog and the GIPR / GLP-1R dual agonist of the present invention for delivery to a subject. The amylin analog and GIPR / GLP-1R dual agonist in the device of the present invention may have any of the features of the amylin analog and GIPR / GLP-1R dual agonist described herein. Through such a device, the amylin analog and GIPR / GLP-1R dual agonist can be administered to a subject by a variety of delivery methods, including intravenous, subcutaneous, intramuscular, or intraperitoneal injection; oral administration; transdermal administration; pulmonary or transmucosal administration; administration by implant, osmotic pump, cartridge, or micropump; or other means recognized by those skilled in the art.

[0290] Sequence List SEQ ID NO: 1 - Amylin analog identifying possible amino acid substitutions Sequence ID 2 - Specific amylin analog Sequence ID 3 - GIPR / GLP-1R dual agonist identifying possible amino acid substitutions SEQ ID NO: 4-Tilzepatide Sequence ID 5-Amylin Sequence ID 6-Plumlintide Sequence ID 7-GLP-1 Sequence ID 8 - Variant amylin analog sequence [Examples]

[0291] The following examples are provided to illustrate preferred embodiments of the present invention and are not intended to limit the scope of the invention.

[0292] Summary - The potent weight-loss effect of amylin analog ZP8396 combined with tilzepatide in DIO rats. Over-the-counter hormonal therapies for the treatment of obesity include liraglutide and semaglutide, both of which are GLP-1R agonists.

[0293] Tilzepatide, GIPR, and GLP-1R dual agonists are approved for both the treatment of type 2 diabetes (Manjaro) and weight loss (Zepbound). Combination therapy consisting of complementary hormonal therapies can add further weight loss to liraglutide, semaglutide, and tilzepatide without compromising safety and tolerability.

[0294] ZP8396, or petrelintide, a novel amylin analog designed for weekly administration, has been shown to potentially reduce body weight and improve glycosylation in rat models of obesity and diabetes. In this study, we investigate the combined weight-reducing effect of ZP8396 and tilzepatide in diet-induced obese (DIO) rats.

[0295] DIO rats were treated with either the medium or 10 nmol / kg of tilzepatide by subcutaneous injection once daily for two weeks. Between days 14 and 34, medium-treated rats were either continued with the medium or switched to 10 nmol / kg of ZP8396 subcutaneously every other day. Similarly, tilzepatide-treated rats were either continued with tilzepatide or switched to tilzepatide + ZP8396. The weight loss effect was evaluated by measuring body weight and food intake.

[0296] Combination treatment with ZP8396 (petrelintide) and tilzepatide resulted in a significant, sustained, and substantial reduction in cumulative food intake and a corresponding significant, sustained, and substantial weight loss compared to the media treatment group and each monotherapy group (ZP8396: -5.2% ± 0.7, tilzepatide: -8.2% ± 1.1, combination: -15.3% ± 0.9, media: 6.5% ± 0.4; ± SEM relative to initial body weight). When exposure was determined for ZP8396 and tilzepatide, it was similar between the comparison groups for each compound.

[0297] In conclusion, the combination of ZP8396 (petrelintide) and tilzepatide in DIO rats resulted in significantly greater weight loss compared to monotherapy. The combination of ZP8396 and tilzepatide could potentially be a future therapeutic approach for weight management in people living with overweight and obesity. [Examples]

[0298] Effects of GIPR / GLP-1R dual agonist alone and in combination with amylin analog in feed-induced obesity rats. This study was conducted to evaluate the effects of amylin analog treatment in addition to treatment with the GIPR / GLP-1R dual agonist tilzepatide in diet-induced obesity (DIO) rats.

[0299] The amylin analog used in this embodiment is petrelintide[19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH2 (SEQ ID NO: 2), as described elsewhere in this specification.

[0300] The GIPR / GLP-1R dual agonist used in this embodiment is tilzepatide Hy-Y[Aib]EGTFTSDYSI[Aib]LDKIAQ[K]AFVQWLIAGGPSSGAPPPS-NH2 (SEQ ID NO: 4), as described elsewhere in this specification.

[0301] Healthy male Sprague Dolly rats were obtained from Charles River, Germany. The rats were 6 weeks old upon arrival and were acclimated for 2 weeks. To create research DIO rats, the animals were fed ad libitum for 18 weeks on a high-fat diet (D12492, Research Diet Inc., New Brunswick, USA) in which 60% of the total energy came from fat. The animals were housed in groups of two under standard temperature and humidity conditions (20-23°C, 50-80% relative humidity) with a 12-hour light-12-hour dark cycle (lighting from 10pm to 10am), and had free access to domestic quality tap water.

[0302] DIO animals (n=12 / group) were stratified based on body weight on day -12. Starting on day 0, rats were treated once daily for 13 days by subcutaneous injection with the medium (groups 1 and 2) or 10 nmol / kg of tilzepatide (groups 3 and 4).

[0303] From day 14 to day 34, rats administered the media continued their media treatment. Every other day (Q2D), Group 1 received a second media injection, while Group 2 received an additional injection of 10 nmol / kg of amylin analog every other day in addition to the media. Simultaneously, rats administered tilzepatide continued their tilzepatide treatment and also received an additional injection of the media (Group 3) or 10 nmol / kg of amylin analog (Group 4) every other day.

[0304] The research design is schematically shown in Figure 1.

[0305] Food and fluid intake were measured daily from day 4 onwards and throughout the experiment, and the cumulative food and fluid intake for each treatment group was calculated (Figures 2 and 3).

[0306] On day 34, blood samples were collected to determine the plasma exposure concentrations of both amylin analog and tilzepatide. Blood samples were collected before the final administration of both compounds, and then 6 and 24 hours after administration. At each sampling time, rat samples were collected by tail-cutting and processed into plasma by centrifugation at 8300 × g for 5 minutes at 4°C.

[0307] Plasma samples were analyzed by solid-phase extraction (SPE) followed by liquid chromatography-mass spectrometry (LC-MS / MS). The bioanalysis assay range was 1–1000 nmol / L, and for acceptance, at least 75% of the calibration samples and at least 4 of the 6 QC samples showed accuracy within ±15%, except for ±20% at LLOQ. At least one QC sample at each level (high, medium, low) was accepted as a valid assay result. A summary of the measured exposures is provided in T1. [Table 3]

[0308] Animals were weighed on day 4 and daily throughout the study. The percentage change in body weight from baseline was calculated for each day from day 0 to day 34 (Figure 4). Figure 4 shows that treatment with tilzepatide initially reduces body weight, but then plateaus around day 11 (i.e., stops further reduction and is maintained at the same body weight). However, in contrast to continued treatment with tilzepatide alone (in which case body weight remains essentially the same for the remainder of the study), combination treatment with tilzepatide and petrelintide (started on day 14) further reduces body weight. Therefore, additional treatment with petrelintide may be a useful option for further weight reduction, especially for subjects receiving tilzepatide but whose body weight has plateaued.

[0309] The average weight change on day 34 is also shown in Figure 10.

[0310] Combination treatment with amylin analogs and tilzepatide achieved significant, sustained, and substantial inhibition of cumulative food intake and corresponding significant, sustained, and substantial weight loss compared to the media treatment group and each monotherapy group (amylin analog: -5.2% ± 0.7, tilzepatide: -8.2% ± 1.1, combination: -15.3% ± 0.9, media: 6.5% ± 0.4; ± SEM relative to initial body weight).

[0311] Exposure to amylin analogs and tilzepatide was assessed at three different time points on the final day of the experiment (day 34). The measured exposures were similar among the comparison groups for each compound (Figures 6-9).

[0312] In conclusion, in DIO rats, combination treatment with amylin analogs and tilzepatide resulted in significantly greater weight loss compared to treatment with either peptide alone, clearly demonstrating the potential use of this combination therapy for the management of overweight, obesity, and obesity-related comorbidities.

[0313] All publications described in the above specification are incorporated herein by reference. Various modifications and variations of the methods and systems described in the present invention will be obvious to those skilled in the art, without departing from the scope and spirit of the invention. Although the present invention has been described in terms of specific preferred embodiments, it should be understood that the invention described in the claims should not be unduly limited to such specific embodiments. In fact, various modifications of the described embodiments for carrying out the present invention, which will be obvious to those skilled in the art in biochemistry, molecular biology, or related fields, are included within the scope of the following embodiments.

Claims

1. Amyrin analog and gastric suppressor polypeptide receptor (GIPR) / glucagon-like peptide-1 receptor (GLP-1R) dual agonist for use in the treatment or prevention of disease in the subject, wherein the amyrin analog is of formula: R １ -Z-R ２ A compound of or a pharmaceutically acceptable salt or solvate thereof, in which, R １ However, hydrogen, C １－４ Acyl, benzoyl, or C １－４ The alkyl group or half-life extension portion M may be linked to Z via a linker portion L. R ２ is OH or NHR ３ where R ３ is hydrogen or C １－３ alkyl, and Z is given by equation 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-Ile(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly-Ser-X35-Thr-X37 (SEQ ID NO: 1) This is the amino acid sequence, and in the sequence, 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 crosslink. X3 is selected from the group consisting of Gly, Gln, 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 Glun. X14 is selected from the group consisting of Aad, His, Asp, Asn, and Arg. X17 is selected from the group consisting of Gln, His, and Thr. X19-X20 are selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly, and Ala-Asn, or they do not exist. X27 is selected from the group consisting of Leu and Pro. X32 is selected from the group consisting of Val 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)], Ile(Me) is N-methylisoleucine, and Aad is 2-aminoadipic acid, also known as homoglutamic acid, for example, (2S)-2-aminoadipic acid [also known as (2S)-2-aminohexanediic acid], Amylin analog and gastric suppressor polypeptide receptor (GIPR) / glucagon-like peptide-1 receptor (GLP-1R) dual agonist for use, wherein the disease is overweight, obesity, morbid obesity, diabetes, or a disease associated with obesity or diabetes.

2. Amylin analogs and GIPR / GLP-1R dual agonists for use according to claim 1, wherein the diseases associated with obesity or diabetes are selected from the group consisting of obesity-related inflammation, obesity-related gallbladder disease, obesity-induced sleep apnea, obesity-related respiratory problems, cartilage degeneration, osteoarthritis, infertility, Alzheimer's disease, prediabetes, gestational diabetes, insulin resistance syndrome, inadequate glucose control, impaired glucose tolerance (IGT), conditions associated with elevated blood glucose levels, metabolic diseases, metabolic syndrome, hyperglycemia, hypertension, dyslipidemia, atherosclerosis, renal failure, arteriosclerosis, atherosclerosis, macrovascular disease, microvascular disease, diabetic heart disease, diabetic cardiomyopathy, heart failure as a complication of diabetes, coronary heart disease, peripheral artery disease, and stroke.

3. Amylin analog and GIPR / GLP-1R dual agonist for use in methods of inhibiting weight gain and / or reducing weight in subjects, wherein the amylin analog is of formula: R １ -Z-R ２ A compound of or a pharmaceutically acceptable salt or solvate thereof, in which, R １ However, hydrogen, C １－４ Acyl, benzoyl, or C １－４ The alkyl group or half-life extension portion M may be linked to Z via a linker portion L. R ２ However, OH or NHR ３ And R ３ However, hydrogen or C １－３ It is alkyl, and Z is given by equation 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-Ile(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly-Ser-X35-Thr-X37 (SEQ ID NO: 1) This is the amino acid sequence, and in the sequence, 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 crosslink. X3 is selected from the group consisting of Gly, Gln, 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 Glun. X14 is selected from the group consisting of Aad, His, Asp, Asn, and Arg. X17 is selected from the group consisting of Gln, His, and Thr. X19-X20 are selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly, and Ala-Asn, or they do not exist. X27 is selected from the group consisting of Leu and Pro. X32 is selected from the group consisting of Val 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)], Ile(Me) is N-methylisoleucine, and Aad is 2-aminoadipic acid, also known as homoglutamic acid, for example, (2S)-2-aminoadipic acid [also known as (2S)-2-aminohexanediic acid]. Amilin analog and GIPR / GLP-1R dual agonist for use.

4. A non-therapeutic method for inhibiting weight gain and / or reducing weight in a subject, comprising the step of administering an amylin analog and a GIPR / GLP-1R dual agonist to the subject, wherein the amylin analog is of formula: R １ -Z-R ２ The compound or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, R １ However, hydrogen, C １－４ Acyl, benzoyl, or C １－４ The alkyl group or half-life extension portion M may be linked to Z via a linker portion L. R ２ However, OH or NHR ３ And R ３ However, hydrogen or C １－３ It is alkyl, and Z is given by equation 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-Ile(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly-Ser-X35-Thr-X37 (SEQ ID NO: 1) This is the amino acid sequence, and in the sequence, 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 crosslink. X3 is selected from the group consisting of Gly, Gln, 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 Glun. X14 is selected from the group consisting of Aad, His, Asp, Asn, and Arg. X17 is selected from the group consisting of Gln, His, and Thr. X19-X20 are selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly, and Ala-Asn, or they do not exist. X27 is selected from the group consisting of Leu and Pro. X32 is selected from the group consisting of Val 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)], Ile(Me) is N-methylisoleucine, and Aad is 2-aminoadipic acid, also known as homoglutamic acid, for example, (2S)-2-aminoadipic acid [also known as (2S)-2-aminohexanediic acid]. The aforementioned method.

5. Amylin analogs, amino acid sequence Amylin analogs and GIPR / GLP-1R dual agonists for use according to any one of claims 1 to 3, comprising RDGTATKATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp (SEQ ID NO: 9) or variants thereof having at least 80% identity to SEQ ID NO: 9, preferably at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NO: 9, or the method according to claim 4.

6. Amilin analog, Petrelintide: [19CD]-IsoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH 2 (Sequence No. 2) or a pharmaceutically acceptable salt or solvate thereof, In the sequence, the parentheses after the amino acid symbol indicate the residue whose side chain is involved in intramolecular lactam crosslinking, and [19CD]-isoGlu is a 19-carboxynonadecanoyl group ([19-CD]-) that is covalently bonded to the alpha-amino group of the isoglutamic acid linker. Amylin analog and GIPR / 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 5.

7. Amylin analog and GIPR / GLP-1R dual agonist for use according to any one of claims 1 to 3, 5, or 6, wherein the amylin analog is administered to the subject in a maximum dose of about 10 mg, preferably in a dose selected from 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, or the method according to any one of claims 4 to 6.

8. An amylin analog and a GIPR / GLP-1R dual agonist for use according to any one of claims 1 to 3 or 5 to 7, wherein the amylin analog is administered to the subject once a week, or the method according to any one of claims 4 to 7.

9. Amylin analog and GIPR / GLP-1R dual agonist for use according to any one of claims 1 to 3 or 5 to 8, comprising a variant thereof having at least 80% identity to the amino acid sequence Y[Aib]EGTFTSDYSI[Aib]LDKIAQKAFVQWLIAGGPSSGAPPPS (SEQ ID NO: 10) or 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, or the method according to any one of claims 4 to 8.

10. The GIPR / GLP-1R dual agonist is formulated as follows: Y[Aib]EGTFTSDYSI[Aib]LDKIAQ[K]AX-VQWLIAGGPSSGAPPPS (Sequence ID 3) A GIPR / GLP-1R dual agonist or a pharmaceutically acceptable salt or solvate thereof, in the sequence, [Aib] is α-aminoisobutyric acid, [K] is (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ - (IsoGlu) ａ -CO-(CH ２ ) ｂ -CO ２ This is lysine in which H is 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 may be amidated as the first C-terminal amide. Amylin analog and GIPR / GLP-1R 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.

11. GIPR / GLP-1R dual agonist, tilzepatide: Hy-Y[Aib]EGTFTSDYSI[Aib]LDKIAQ[K]AFVQWLIAGGPSSGAPPPS-NH 2 (Sequence No. 4) or a pharmaceutically acceptable salt or solvate thereof, in the sequence, [Aib] is α-aminoisobutyric acid, and [K] is (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ - (IsoGlu) １ -CO-(CH ２ ) １８ This is lysine in which the -COOH group is conjugated to the epsilon-amino group of the lysine side chain. Amylin analog and GIPR / GLP-1R 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.

12. An amylin analog and a GIPR / GLP-1R dual agonist for use according to any one of claims 1 to 3 or 5 to 11, wherein the amylin analog is petrelintide and the GIPR / GLP-1R dual agonist is tilzepatide, or the method according to any one of claims 4 to 11.

13. Amylin analog and GIPR / GLP-1R dual agonist for use according to any one of claims 1 to 3 or 5 to 12, wherein the GIPR / GLP-1R dual agonist is administered to the subject in a maximum dose of approximately 15 mg, preferably a dose selected from one of approximately 2.5 mg, approximately 5 mg, approximately 7.5 mg, approximately 10 mg, approximately 12.5 mg, and approximately 15 mg, or the method according to any one of claims 4 to 12.

14. An amylin analog and a GIPR / GLP-1R dual agonist for use according to any one of claims 1 to 3 or 5 to 13, wherein the GIPR / GLP-1R dual agonist is administered to the subject once weekly, or the method according to any one of claims 4 to 13.

15. An amylin analog and GIPR / GLP-1R dual agonist for use according to any one of claims 1 to 3 or 5 to 14, wherein an amylin analog or a pharmaceutically acceptable salt or solvate thereof is formulated as an amylin analog pharmaceutical composition, or the method according to any one of claims 4 to 14.

16. Amylin analog and GIPR / GLP-1R dual agonist for use according to any one of claims 1 to 3 or 5 to 15, wherein a GIPR / GLP-1R dual agonist or a pharmaceutically acceptable salt or solvate thereof is formulated as a GIPR / GLP-1R dual agonist pharmaceutical composition, or the method according to any one of claims 4 to 15.

17. Amylin analog and GIPR / GLP-1R dual agonist for use according to any one of claims 1 to 3 or 5 to 16, wherein the amylin analog and GIPR / GLP-1R dual agonist are administered to a subject by injection, preferably by subcutaneous injection, or the method according to any one of claims 4 to 16.

18. A kit comprising an amylin analog and a GIPR / GLP-1R dual agonist, wherein the amylin analog and / or the GIPR / GLP-1R dual agonist is as described in any one of claims 1 to 17.

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