Combination therapy including a long-acting GLP-1 / glucagon receptor agonist and an NPY2 receptor agonist

Abstract

Compound I (GLP-1R / glucagon receptor dual agonist): H-His-Ac4c-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Ala-Ala-Lys-Asp-Phe-Ile-Lys(HOOC-(CH2) 16 Provided is a combination therapy comprising -CO-γGlu-Gly-Ser-Gly-Ser-Gly-Gly-)-Trp-Leu-Glu-Ser-Ala-NH (I) and a long-acting NPY2 receptor agonist selected from Compounds A through L. The combination therapy may be useful for treating obesity and various obesity-related conditions, diseases, or comorbidities, for example, type 2 diabetes, liver disease such as NAFLD (non-alcoholic fatty liver disease) and NASH (non-alcoholic steatohepatitis), kidney disease, or cardiovascular disease.

Description

[Technical Field]

[0001] The present invention relates to the pharmacology and biology of long-acting acylated PYY analogs that are neuropeptide Y2 (NPY2) receptor agonists in combination with dual glucagon-like peptide-1 (GLP-1) / glucagon (GCG) receptor agonists, and their medical uses in the treatment and / or prevention of various diseases, conditions, or disorders, such as excessive food intake, excess weight, obesity, metabolic disease, and other conditions or disorders associated with excess weight or obesity, such as diabetes, kidney disease, non-alcoholic steatohepatitis, and cardiovascular disease. [Background technology]

[0002] obesity Obesity is a chronic, recurrent, and progressive disease and one of the greatest health care challenges of our time. In 2016, more than 1.9 billion adults aged 18 years and older were overweight, of which more than 650 million adults were obese (BMI ≥ 30 kg / m 2 Despite years of efforts, the number of overweight and obese people is still increasing, and the prevalence of obesity nearly tripled between 1975 and 2016. This equates to 39% of adults aged 18 years and older being overweight (39% of men and 40% of women) and 13% being obese. Overweight and obesity are defined as abnormal or excessive fat accumulation that poses a risk to health. In this regard, overweight and obesity are major risk factors for several chronic diseases directly (comorbidities) and indirectly (complications), including, but not limited to, cardiovascular disease (e.g., heart failure), cardiometabolic diseases such as insulin resistance, type 2 diabetes, atherosclerosis, cardiovascular disease, hypertension, dyslipidemia, hyperuricemia, chronic kidney disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), cirrhosis, depression, sleep apnea, musculoskeletal disorders (e.g., osteoarthritis), gallbladder disease, and certain types of cancer. In the United States, obesity is currently considered the second leading cause of preventable death, after smoking.

[0003] If current trends continue, it is estimated that by 2025, 2.7 billion adults will be overweight, more than 1 billion adults will be obese, and 177 million adults will be severely obese. Rising obesity is driving an increase in diabetes, with approximately 90% of people with type 2 diabetes being classified as obese. There are 246 million people with diabetes worldwide, and it is estimated that 380 million people will have diabetes by 2025. The first-line treatments available to overweight and obese patients consist of diet and exercise, but are often not fully effective. Second-line treatment options are bariatric surgery and drug therapy. Available pharmacological treatments appear to lack efficacy and / or safety, and only a limited number of approved treatments are available in the United States and Europe. Therefore, there remains a high medical need for more effective and safe treatment options.

[0004] Glucagon, GLP-1 and oxyntomodulin Preproglucagon is a 158-amino acid precursor polypeptide that is differentially processed in tissues to form several structurally related proglucagon-derived peptides, including glucagon (Glu), glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), and oxyntomodulin (OXM). These molecules are involved in a wide variety of physiological functions, including the regulation of glucose homeostasis, insulin secretion, gastric emptying and intestinal growth, and food intake. Glucagon is a 29-amino acid peptide corresponding to amino acids 53–81 of preproglucagon. Oxyntomodulin (OXM) is a 37-amino acid peptide that contains the complete 29-amino acid sequence of glucagon with an octapeptide carboxy-terminal extension (amino acids 82–89 of preproglucagon). The major biologically active fragment of GLP-1 is produced as a 30-amino acid C-terminal amidated peptide corresponding to amino acids 98–127 of preproglucagon. GLP-1 lowers elevated blood glucose levels by improving glucose-stimulated insulin secretion, promoting weight loss primarily by reducing food intake. Clinically, GLP-1 receptor agonists are established treatments for diabetes and obesity, but their therapeutic window is limited due to their mechanism-related gastrointestinal side effect profile (e.g., nausea and vomiting). Glucagon helps maintain blood glucose levels by binding to glucagon receptors on hepatocytes and triggering the release of glucose stored in the liver in the form of glycogen through glycogenolysis. When these stores are depleted, glucagon stimulates the liver to synthesize additional glucose through gluconeogenesis. Preclinical and clinical studies have shown that glucagon affects body weight by increasing energy expenditure. This glucose is released into the bloodstream, preventing the development of hypoglycemia. OXM is released into the blood in response to food intake in proportion to the amount of calories eaten. OXM activates both glucagon and GLP-1 receptors, and is somewhat more potent at the glucagon receptor than at the GLP-1 receptor, but less potent than native glucagon and GLP-1 at each receptor.Human glucagon can also activate both receptors, but has a strong preference for the glucagon receptor over the GLP-1 receptor. GLP-1, on the other hand, cannot activate the glucagon receptor. OXM has been shown to be involved in weight regulation and to suppress appetite, inhibiting food intake and energy expenditure in humans.

[0005] Other peptides have been described that bind to and activate both glucagon and GLP-1 receptors, inhibiting weight gain (see, e.g., WO2011 / 075393, WO2014 / 041195, WO2015 / 183054, WO2016 / 065090, WO2016 / 108617, WO2017 / 074798).

[0006] PYY Peptide YY (PYY) is a peptide consisting of 36 amino acids. It is secreted from endocrine cells (L cells) in the gastrointestinal tract upon food ingestion and exerts an appetite suppressant effect via the Y2 receptor (Inhibition of Food Intake in Obese Subjects by Peptide YY 3-36, N Engl J Med 2003;349;941-8). The mechanism of action of PYY(3-36) has been reported to be the entero-hypothalamic pathway mediated by Y2 receptors on NPY / AgRP-expressing neurons in the hypothalamic arcuate nucleus and the vagal afferent pathway mediated by Y2 receptors on vagus nerve terminals. Native PYY(3-36) has limited human tolerability due to dose-dependent nausea and vomiting when administered intranasally. PYY is cleaved to PYY(3-36) by dipeptidyl peptidase IV (DPP IV). Compared with PYY(1-36), PYY(3-36) shows a higher preference for the neuropeptide Y2 receptor over the neuropeptide Y1, Y4, and Y5 receptors, but retains some affinity for the neuropeptide Y1 and Y5 receptors. However, PYY and similarly PYY(3-36) have short half-lives in the body and exhibit undesirable chemical or physical properties, such as poor stability. Furthermore, their pharmacological effects, such as their effectiveness as weight-loss agents, appear to be limited. However, preclinical and clinical evidence has demonstrated that long-acting analogs of PYY3-36 offer a therapeutic window for achieving weight-loss effects with acceptable tolerability profiles. WO2014 / 178018 discloses PYY analogues and their ability to reduce food intake in mice. WO2011 / 033068 and WO2011 / 058165 disclose long-acting NPY2R agonists. WO2015 / 071355, WO2016 / 198682 and WO2020 / 092191 relate to PYY compounds that are selective NPY2R agonists. PYY compounds are disclosed that include covalently attached substituents or modifying groups, also referred to as extension moieties.

[0007] GLP-1 and NPY2 receptor agonism Coactivation of GLP-1R and NPY2R and synergistic food intake reduction and weight loss effects have been demonstrated in preclinical species, for example, mice (Neary NM et al. Endocrinology 2005; 146:5120; Talsania T et al. Endocrinology 2005; 146: 3748; Kjargaard M. et al. Neuropeptides 2019; 73: 89; WO2011 / 039096; WO2019 / 207505), rats (Reidelberger RD et al. Obesity 2011; 19: 121; Dischinger U et al. Frontiers in Endocrinology 2021; 11:598843; WO2017 / 035432), and pigs (WO2015 / 071355). In humans, the combined administration (continuous infusion) of GLP-1 and PYY3-36 (Schmidt JB et al. Am J Physiol Endocrinol Metab 2014; 306: E1248) or the combined administration (continuous infusion) of PYY3-36, GLP-1, and oxyntomodulin (Field BCT et al. Diabetes 2010 59:1635; Tan T et al. J. Clin. Endocrinol Metab 2017; 102: 2364; Tan T et al., Diabetes Care 2019, 42(8) :1446) has shown a synergistic effect in reducing energy intake.

[0008] The present invention provides a combination therapy comprising the administration of a long-acting GLP-1R / GCGR dual agonist and a long-acting NPY2R agonist. Simultaneous activation of the GLP-1R, GCGR, and NPY2 receptors may provide a highly effective treatment method for reducing food intake, appetite, and / or weight loss by simultaneously synergistically reducing energy intake via GLP-1R and NPY2R agonism and increasing energy expenditure via GCGR activation. According to the present invention, it is possible to activate the three receptors with a long-acting agent that allows for administration by subcutaneous injection. Furthermore, the combination therapy can be effectively administered by weekly injection of the agonists. The selection of an NPY2R agonist to be combined with a GLP-1R / GCGR dual agonist appears to be important, but selecting an effective NPY2R agonist is not easy given the data provided in the prior art (e.g., WO2021 / 094259 or WO2022 / 029231). Furthermore, combination treatments according to the present invention appear to provide a longer lasting effect on food intake inhibition when compared to a combination of a GLP-1R agonist and an NPY2R agonist, or when compared to GLP-1R / GCGR alone. Summary of the Invention

[0009] The present invention relates to combination therapy comprising administering a long-acting GLP-1 / glucagon receptor dual agonist and a long-acting NPY2 receptor agonist. More specifically, the present invention provides an effective amount of Compound I: H-His-Ac4c-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Ala-Ala-Lys-Asp-Phe-Ile-Lys(HOOC-(CH2) 16 -CO-γGlu-Gly-Ser-Gly-Ser-Gly-Gly-)-Trp-Leu-Glu-Ser-Ala-NH2 (SEQ ID NO: 01, SEQ ID NO: 02)

[0010] [ka] and -A long-acting NPY2 receptor agonist selected from the group consisting of compounds A to L to a patient. In one embodiment, the long-acting NPY2 receptor agonist is selected from the group consisting of compounds B, E, K and L. In one embodiment, the mass ratio of compound I to the NPY2 receptor agonist ranges from 1:5 to 5:1 (compound I:NPY2 receptor agonist). Use of a PYY analogue selected from the group consisting of compounds A-L in combination therapy with compound I. The compound may be administered once a week (qw) or more frequently.

[0011] In one embodiment, compound I and long-acting NPY2 receptor agonist are administered by subcutaneous injection, for example, by two separate injections, or by one injection that both compounds are administered simultaneously.When two separate injections are used, one compound can be administered first, and the other can be administered immediately thereafter, or there can be a period of 4, 3, 2 or 1 day between the two injections.Alternatively, the time between injections is 12, 6, 4, 2 or 1 hour. [Brief explanation of the drawings]

[0012] [Figure 1] Effect of Compound B on (A) food intake (grams) and (B) relative (percent) body weight in DIO mice. DIO animals were administered various doses of Compound B once daily. Relative body weight was measured as a percentage of each animal's baseline body weight per day for 28 days. Food intake was measured as grams per animal per day for 28 days. Data are shown as mean ± SEM. *p<0.05, **p<0.01, ***p<0.001 compared with vehicle group by one-way ANOVA followed by Dunnett's multiple comparison test. [Figure 2]Effect of Compound E on (A) food intake (grams) and (B) relative (percent) body weight in DIO mice. DIO animals were administered various doses of Compound E once daily. Relative body weight was measured as a percentage of each animal's baseline body weight per day for 28 days. Food intake was measured as grams per animal per day for 28 days. Data are shown as mean ± SEM. *p<0.001 compared with vehicle group by one-way ANOVA followed by Dunnett's multiple comparison test. [Figure 3] Effect of Compound K on (A) food intake (grams) and (B) relative (percent) body weight in DIO mice. DIO animals were administered various doses of Compound K once daily. Relative body weight was measured as a percentage of each animal's baseline body weight per day for 8 days. Food intake was measured as grams per animal per day for 8 days. Data are shown as mean ± SEM. *p<0.05, **p<0.01, ***p<0.001; by one-way ANOVA comparison to vehicle group followed by Dunnett's multiple comparison test. [Figure 4] Effect of Compound L on (A) food intake (grams) and (B) relative (percent) body weight in DIO mice. DIO animals were administered various doses of Compound L once daily. Relative body weight was measured as a percentage of each animal's baseline body weight per day for 8 days. Food intake was measured as grams per animal per day for 8 days. Data are shown as mean ± SEM. *p<0.05, **p<0.01, ***p<0.001; by one-way ANOVA comparison to vehicle group followed by Dunnett's multiple comparison test. [Figure 5]Effect of Compound B alone or in combination with semaglutide on (A) relative (percent) body weight, (B) food intake (grams), (C) cumulative food intake (grams) and (D) area under the curve of graph B in DIO mice. DIO animals were administered various doses of Compound B alone or in combination with semaglutide once daily. Relative body weight was measured as a % of each animal's baseline body weight per day for 28 days. Food intake was measured as grams per animal per day for 12 days. Data are shown as mean ± SEM. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001; by one-way ANOVA comparison with the semaglutide group followed by Dunnett's multiple comparison test. [Figure 6] Effect of Compound B alone or in combination with Compound I on (A) relative (percent) body weight, (B) food intake (grams), (C) cumulative food intake (grams), and (D) area under the curve of graph B in DIO mice. DIO animals were administered various doses of Compound B alone or in combination with Compound I once daily. Relative body weight was measured as a percentage of each animal's baseline body weight per day for 28 days. Food intake was measured as grams per animal per day for 11 days. Data are shown as mean ± SEM. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001; by one-way ANOVA comparison with Compound I group followed by Dunnett's multiple comparison test. [Figure 7] Effect of Compound E alone or in combination with semaglutide on (A) relative (percent) body weight, (B) food intake (grams), (C) cumulative food intake (grams), and (D) area under the curve in graph B in DIO mice. DIO animals were administered various doses of Compound E alone or in combination with semaglutide once daily. Relative body weight was measured as a % of each animal's baseline body weight per day for 28 days. Food intake was measured as grams per animal per day for 12 days. Data are shown as mean ± SEM. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001; by one-way ANOVA comparison with the semaglutide group followed by Dunnett's multiple comparison test. [Figure 8] Effect of Compound E alone or in combination with Compound I on (A) relative (percent) body weight, (B) food intake (grams), (C) cumulative food intake (grams), and (D) area under the curve in graph B in DIO mice. DIO animals were administered various doses of Compound E alone or in combination with Compound I once daily. Relative body weight was measured as a percentage of each animal's baseline body weight per day for 28 days. Food intake was measured as grams per animal per day for 11 days. Data are presented as mean ± SEM. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001; by one-way ANOVA comparison with Compound I group followed by Dunnett's multiple comparison test. [Figure 9] Effect of Compound K alone or in combination with semaglutide on (A) relative (percent) body weight, (B) food intake (grams), (C) cumulative food intake (grams), and (D) area under the curve in graph B in DIO mice. DIO animals were administered various doses of Compound K once daily. Relative body weight was measured as a % of each animal's baseline body weight per day for 28 days. Food intake was measured as grams per animal per day for 12 days. Data are shown as mean ± SEM. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001; by one-way ANOVA comparison to the semaglutide group followed by Dunnett's multiple comparison test. [Figure 10] Effect of Compound K alone or in combination with Compound I on (A) relative (percent) body weight, (B) food intake (grams), (C) cumulative food intake (grams), and (D) area under the curve in graph B in DIO mice. DIO animals were administered various doses of Compound K alone or in combination with Compound I once daily. Relative body weight was measured as a percentage of each animal's baseline body weight per day for 28 days. Food intake was measured as grams per animal per day for 12 days. Data are presented as mean ± SEM. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001; by one-way ANOVA comparison with Compound I group followed by Dunnett's multiple comparison test. DETAILED DESCRIPTION OF THE INVENTION

[0013] Additional abbreviations: gGlu or γGlu: L-γ-glutamyl iVal: 3-methylbutanoyl (isovalerianoyl) C18DA: 17-carboxy-heptadecanoyl (HOOC-(CH2) 16 -CO-). A synergistic improvement in treatment outcome may be greater than the additive improvement in overall efficacy obtained by coadministration compared with administration of either agent alone.

[0014] "Combination therapy" generally refers to the simultaneous or sequential administration of two or more active ingredients so that the concentrations of the individual active ingredients in the body are high enough to exhibit a synergistic effect. Combination therapy according to the present invention can be carried out with or without instructions for combined use. Thus, the two active ingredients may be administered completely separately or in completely separate pharmaceutical dosage forms. The individual active ingredients may be pharmaceutical compositions sold independently of each other, with only instructions for their combined use being provided for simultaneous or sequential use to be active together, for example, in packaging materials, such as leaflets, or in other information provided to physicians and healthcare professionals (e.g., oral communication, written communication, etc.). It can refer to either a fixed combination in one dosage unit form, or a kit of parts for combined administration, in which Compound I and a compound selected from the group consisting of Compounds A-L (or semaglutide and a compound selected from the group consisting of Compounds A-L) may be administered independently simultaneously or separately within time intervals, particularly those time intervals that allow the combination partners to exhibit a coordinated (synergistic) effect.

[0015] As used herein, terms such as "co-administration" or "administration in combination" are meant to encompass the administration of individual active ingredients to a single subject (e.g., patient) in need thereof, and are intended to include treatment regimens in which the agents are not necessarily administered at the same time or by the same route of administration. These terms also include methods for the treatment of disease in which two or more active ingredients are administered sequentially, such that the concentrations of the individual active ingredients in the body at a given time are high enough to exhibit a synergistic effect. The term "fixed combination" means that the active ingredients, e.g. Compound I and a compound selected from the group consisting of Compounds A-L (or semaglutide and a compound selected from the group consisting of Compounds A-L), are both administered to a patient simultaneously in the form of a single entity or dosage. In other words, the active ingredients are present in one dosage form, for example one tablet, one pre-filled syringe or one injection device, such as an autoinjector or pen. The present invention relates to combination therapy comprising administering a long-acting GLP-1 / glucagon receptor dual agonist and a long-acting NPY2 receptor agonist.

[0016] More specifically, the present invention provides an effective amount of Compound I: H-His-Ac4c-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Ala-Ala-Lys-Asp-Phe-Ile-Lys(HOOC-(CH2) 16 -CO-γGlu-Gly-Ser-Gly-Ser-Gly-Gly-)-Trp-Leu-Glu-Ser-Ala-NH2 (SEQ ID NO: 01, SEQ ID NO: 02),

[0017] [ka] and -A long-acting NPY2 receptor agonist selected from the group consisting of compounds A to L to a patient.

[0018] Compound A: N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-[2-(2-{2-[2-(2-{2-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]ethoxy}ethoxy)acetamido]ethoxy}ethoxy)acetamido]-[4A,6A,7K,9E,13T,18Q,22V,28Y,30W,31L]hPYY(4-36); iVal-APAK(C18DA-gGlu-OEG-OEG-)PEEDATPEELQRYYVSLRHYYNWLTRQRY-NH2 (SEQ ID NO: 03);

[0019] [ka]

[0020] Compound B: N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-[2-(2-{2-[2-(2-{2-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]ethoxy}ethoxy)acetamido]ethoxy}ethoxy)acetamido]-[4A,6A,7K,9E,18Q,22V,23A,28Y,30W,31L]hPYY(4-36); iVal-APAK(C18DA-gGlu-OEG-OEG-)PEEDASPEELQRYYVALRHYYNWLTRQRY-NH2 (SEQ ID NO: 04); [ka]

[0021] Compound C: N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-[2-(2-{2-[2-(2-{2-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]ethoxy}ethoxy)acetamido]ethoxy}ethoxy)acetamido]-[4A,6A,7K,9E,11E,18Q,22V,28Y,30W,31L]hPYY(4-36); iVal-APAK(C18DA-gGlu-OEG-OEG-)PEEEASPEELQRYYVSLRHYYNWLTRQRY-NH2 (SEQ ID NO: 05);

[0022] [ka]

[0023] Compound D: N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-[2-(2-{2-[2-(2-{2-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]ethoxy}ethoxy)acetamido]ethoxy}ethoxy)acetamido]-[4A,7K,9E,14A,18Q,22V,23A,28Y,30W,31L]hPYY(4-36); iVal-APEK(C18DA-gGlu-OEG-OEG-)PEEDASAEELQRYYVALRHYYNWLTRQRY-NH2 (SEQ ID NO: 06);

[0024] [ka]

[0025] Compound E: N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-[2-(2-{2-[2-(2-{2-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]ethoxy}ethoxy)acetamido]ethoxy}ethoxy)acetamido]-[4A,6A,7K,9E,17I,18Q,22V,28Y,30W,31L]hPYY(4-36); iVal-APAK(C18DA-gGlu-OEG-OEG-)PEEDASPEEIQRYYVSLRHYYNWLTRQRY-NH2 (SEQ ID NO: 07);

[0026] [ka]

[0027] Compound F: N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-[2-(2-{2-[2-(2-{2-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]ethoxy}ethoxy)acetamido]ethoxy}ethoxy)acetamido]-[4A,7K,9E,10A,13T,18Q,22V,28Y,30W,31L]hPYY(4-36); iVal-APEK(C18DA-gGlu-OEG-OEG-)PEADATPEELQRYYVSLRHYYNWLTRQRY-NH2 (SEQ ID NO: 08);

[0028] [ka]

[0029] Compound G: N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-[2-(2-{2-[2-(2-{2-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]ethoxy}ethoxy)acetamido]ethoxy}ethoxy)acetamido]-[4A,7K,9E,13T,17I,18Q,22V,28Y,30W,31L]hPYY(4-36); iVal-APEK(C18DA-gGlu-OEG-OEG-)PEEDATPEEIQRYYVSLRHYYNWLTRQRY-NH2 (SEQ ID NO: 09);

[0030] [ka]

[0031] Compound H: N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-[2-(2-{2-[2-(2-{2-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]ethoxy}ethoxy)acetamido]ethoxy}ethoxy)acetamido]-[4A,7K,9E,13T,18Q,19K,22V,28Y,30W,31L]hPYY(4-36); iVal-APEK(C18DA-gGlu-OEG-OEG-)PEEDATPEELQKYYVSLRHYYNWLTRQRY-NH2 (SEQ ID NO: 10)

[0032] [ka]

[0033] Compound J: N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-[2-(2-{2-[2-(2-{2-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]ethoxy}ethoxy)acetamido]ethoxy}ethoxy)acetamido]-[4A,7K,9E,10A,17I,18Q,22V,28Y,30W,31L]hPYY(4-36); iVal-APEK(C18DA-gGlu-OEG-OEG-)PEADASPEEIQRYYVSLRHYYNWLTRQRY-NH2 (SEQ ID NO: 11);

[0034] [ka]

[0035] Compound K: N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,13T,17I,18Q,22V,28Y,30W,31L]-hPYY(4-36); iVal-APEK(C18DA-gGlu-Ahx)PEADATPEEIQRYYVSLRHYYNWLTRQRY-NH2 (SEQ ID NO: 12);

[0036] [ka]

[0037] Compound L: N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,17I,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36); iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEEIQRYYVALRHYYNWLTRQRY-NH2 (SEQ ID NO: 13);

[0038] [ka]

[0039] In an alternative embodiment, the present invention provides a method for manufacturing a cellular membrane comprising: -Effective dose of semaglutide: [ka] (N-epsilon 26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37) (SEQ ID NO: 17)) and A long-acting NPY2 receptor agonist selected from the group consisting of compounds A to L to a patient. WO2021 / 094259 discloses the Ki of Compounds A to J measured in a radioligand binding (RLB) assay (Example 1), as well as the effect on short-term food intake (AFI) in normal NMRI mice (Example 6). WO2022 / 029231 discloses the Ki of compounds K and L measured in a radioligand binding (RLB) assay (Example 1) and their effects on acute food intake (AFI) in normal NMRI mice (Example 6). Example 1 herein describes the same radioligand binding (RLB) assay. The measured Ki for Compounds A-L and Reference 1-3 are reported in Table 1 below. Example 2 herein describes an experiment to measure the effect on short-term food intake (AFI) in normal NMRI mice. The AFI (%) relative to the vehicle group is shown in Table 1 below. Example 3 herein describes experiments to measure the effects on weight loss and food intake in diet-induced obese (DIO) mice.

[0040] All of these compounds exhibited good binding to the human NPY2 receptor (Example 1) and achieved strong inhibition of food intake after 24 hours (Example 2). In the DIO test, Compounds A to L achieved a weight loss ranging from 6.7% to 12.2% compared to the vehicle group (Example 3). However, the reference compounds Reference 1 to Reference 3 only achieved a weight loss of up to 2.7%. This indicates that not all PPY2 analogs that bind to the NPY2 receptor and inhibit short-term food intake can actually effectively reduce body weight. DIO experiments (Example 3) show that there is a synergistic effect on body weight for compounds B, E or K in combination with semaglutide (Figures 5A, 7A and 9A). Synergistic weight loss is also achieved for the combination of compounds B, E or K with compound I (Figures 6A, 8A and 10A). When semaglutide is administered in combination with compounds B, E or K, a synergistic effect, or an effect that is more than additive, may be observed.

[0041] The combination of Compound B with Compound I appears to result in a longer-lasting reduction in food intake (Figure 6B) compared to the combination of Compound B with semaglutide (Figure 5B). A more long-lasting effect on food intake is also observed for the combination of Compound E with Compound I (Figure 8B) compared to the combination of Compound E with semaglutide (Figure 7B). The longer-lasting reduction in food intake when Compounds B and E are combined with Compound I results in a greater weight loss effect (%BW, Figures 6A and 8A) and a significant reduction in total food intake (Figures 6D and 8D) compared to the combination of Compounds B or E with semaglutide, respectively (Figures 5A and 7A).

[0042] Combination DIO experiments have shown that synergistic effects can be achieved when a long-acting GLP-1 / glucagon receptor dual agonist is combined with a long-acting NPY2 receptor agonist in accordance with the present invention. Furthermore, the combination according to the present invention can provide a longer-lasting effect on significantly reducing food intake compared to combinations comprising a long-acting GLP-1 receptor agonist (semaglutide) and an NPY2 receptor agonist. In one embodiment, the long-acting NPY2 receptor agonist is selected from the group consisting of compounds B, E, K and L. In a further embodiment, the long-acting NPY2 receptor agonist is selected from the group consisting of compounds B, E and K. In a further embodiment, the long-acting NPY2 receptor agonist is selected from the group consisting of compounds E and K. In a further embodiment, the long-acting NPY2 receptor agonist is selected from the group consisting of compounds B and E. In a further embodiment, the long-acting NPY2 receptor agonist is Compound B. In a further embodiment, the long-acting NPY2 receptor agonist is Compound E. In a further embodiment, the long-acting NPY2 receptor agonist is Compound K. In one embodiment, the mass ratio of compound I (or semaglutide) to the NPY2 receptor agonist ranges from 1:10 to 10:1 (compound I:NPY2 receptor agonist). In one embodiment, the mass ratio of compound I (or semaglutide) to the NPY2 receptor agonist is in the range of 1:5 to 5:1 (compound I:NPY2 receptor agonist). In one embodiment, the mass ratio of compound I (or semaglutide) to the NPY2 receptor agonist ranges from 1:3 to 3:1. In one embodiment, the mass ratio of compound I (or semaglutide) to the NPY2 receptor agonist ranges from 1:2 to 2:1. For example, the mass ratio of compound I (or semaglutide) to compound E ranges from 1:3 to 3:1. Thus, the two compounds can be administered in a mass ratio of 1:2, 1:1 or 2:1. For example, the mass ratio of compound I (or semaglutide) to compound K ranges from 1:3 to 3:1. Thus, the two compounds can be administered in a mass ratio of 1:2, 1:1 or 2:1.

[0043] Any combination of doses can be used, but typically, the doses of Compound I and NPY2R agonist that provide synergistic effects or effects that are greater than additive benefit are used.For example, due to synergistic behavior, lower doses of Compound I and NPY2R agonist can be selected, thereby achieving appropriate effects on body weight and reducing the drug burden of patients.In addition, by achieving acceptable tolerability and safety, such combinations can provide a wide therapeutic range.In addition, lower doses can reduce the required amount of drug substance, which can bring economic benefits. A low dose of a compound (e.g., Compound I and / or an NPY2R agonist) can be administered initially in gradually increasing doses (dose escalation) until a certain dose (maintenance dose) is reached and maintained. The compounds can be administered once a week (qw) or more frequently, preferably once a week.

[0044] In one embodiment, Compound I (or semaglutide) and the long-acting NPY2 receptor agonist are administered subcutaneously, for example, by two separate injections (" free combination "), or by one injection in which both compounds are administered simultaneously, for example, by injection of a fixed dose combination of the two agonists.When administering two separate injections, one compound can be administered first, and the other can be administered immediately thereafter, or there can be a period of 4, 3, 2 or 1 day between the two injections.Alternatively, the period between injections is 12, 6, 4, 2 or 1 hour. In a further aspect, the present invention relates to the use of a PYY analogue selected from the group consisting of compounds A-L in combination therapy with compound I. Thus, the present invention relates to a method for treating the human body, comprising administering a PYY analogue selected from the group consisting of compounds A-L and compound I. Thus, the present invention relates to compound I for use in combination therapy together with a PYY analogue selected from the group consisting of compounds AL. In an alternative aspect, the invention relates to the use of a PYY analogue selected from the group consisting of compounds A to L in combination therapy with semaglutide. Thus, the present invention relates to a method for the treatment of the human body, comprising administering a (one) PYY analogue selected from the group consisting of compounds A to L and semaglutide. Thus, the present invention relates to semaglutide for use in combination therapy together with a PYY analogue selected from the group consisting of compounds AL. The combination therapy of the present invention can be administered in addition to treatment with another pharmacological treatment, e.g., an incretin-based therapy, as described in further detail below. In another embodiment, the combination therapy of the present invention is administered without the administration of an additional incretin-based therapy. In a more specific embodiment, the combination therapy of the present invention relates to the treatment of humans. In an alternative embodiment, the invention relates to a combination therapy comprising administering semaglutide and a long-acting NPY2 receptor agonist selected from the group consisting of compounds A to L, preferably compounds B, E, K or L.

[0045] Further embodiments include: E1. Combination therapy comprising administering a long-acting GLP-1 / glucagon receptor dual agonist and a long-acting NPY2 receptor agonist. E2.-An effective amount of compound I: H-His-Ac4c-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Ala-Ala-Lys-Asp-Phe-Ile-Lys(HOOC-(CH2) 16 -CO-γGlu-Gly-Ser-Gly-Ser-Gly-Gly-)-Trp-Leu-Glu-Ser-Ala-NH2 (SEQ ID NO: 01, SEQ ID NO: 02), and -A long-acting NPY2 receptor agonist selected from the group consisting of compounds A to L The combination treatment of E1, comprising administering to a patient E3. The combination treatment of embodiment E1 or E2, wherein the long-acting NPY2 receptor agonist is selected from the group consisting of compounds B, E, K and L. E4. The combination treatment of embodiment E1, E2, or E3, wherein the long-acting NPY2 receptor agonist is selected from the group consisting of compounds B, E, and K. E5. The combination treatment of any one of the preceding embodiments E1-E4, wherein the long-acting NPY2 receptor agonist is Compound B. E6. The combination treatment of any one of embodiments E1-E4, wherein the long-acting NPY2 receptor agonist is compound E. E7. The combination treatment of any one of embodiments E1-E4, wherein the long-acting NPY2 receptor agonist is Compound K. E8. The combination treatment of any one of embodiments E1-E7 above, wherein the compound can be administered once weekly. E9. The combination therapy of any one of the previous embodiments E1-E8, wherein the therapy is directed to the treatment and / or prevention of obesity and various obesity-related conditions, diseases, or comorbidities, such as type 2 diabetes, liver disease such as NAFLD (non-alcoholic fatty liver disease) and NASH (non-alcoholic steatohepatitis), kidney disease, or cardiovascular disease. E10. A combination treatment according to any one of the preceding embodiments E1-E9, which produces a synergistic therapeutic effect, eg, a synergistic effect on weight, weight management, or weight loss. E11. The combination treatment of embodiment E10, which produces a synergistic therapeutic effect compared to administration of compound I alone. E12. A long-acting GLP-1 / Glucagon receptor dual agonist for use in a method for the treatment of a disease, the method comprising co-administration of a long-acting GLP-1 / Glucagon receptor dual agonist and a long-acting NPY2 receptor agonist.

[0046] Treatment method The present invention is directed to combinations of PYY analogues and GLP-1R / GCGR dual agonists as described in the above embodiments that are useful for the prevention and / or treatment of diseases and / or conditions associated with or modulated by NPY2, GLP-1 and GCG receptor activity, including, but not limited to, the treatment and / or prevention of obesity and various obesity-related conditions, diseases or comorbidities such as type 2 diabetes, liver diseases such as NAFLD and NASH (non-alcoholic steatohepatitis), kidney diseases, or cardiovascular diseases.

[0047] The combination therapy described herein is particularly useful for preventing weight gain or promoting weight loss. "Preventing" means inhibiting or reducing weight gain compared to the absence of treatment, and does not necessarily mean completely halting weight gain. The combination therapy can reduce food intake and / or increase energy expenditure, each of which has beneficial effects on glucose control and / or lipid metabolism, including but not limited to the liver and circulating triglyceride and cholesterol levels, and can reduce circulating LDL levels and increase the HDL / LDL ratio. Thus, the combination therapy of the present invention can be used for the direct or indirect treatment of any condition caused or characterized by excess weight, such as the treatment and / or prevention of obesity, morbid obesity, obesity-related inflammation, obesity-related gallbladder disease, and obesity-related sleep apnea. Combination therapy can also be used to prevent or treat obesity-related comorbidities caused by or characterized by poor glucose control or dyslipidemia, type 2 diabetes, metabolic syndrome, hypertension, atherogenic dyslipidemia, coronary heart disease, peripheral artery disease, stroke or microvascular disease, heart failure, and cancer. Combinations can also be used to prevent or treat obesity-related comorbidities, such as liver disease (e.g., NAFLD and NASH), kidney disease, and central nervous system diseases, such as cognitive impairment, depression, psychiatric disorders including addictive behaviors (e.g., opioid addiction, overeating), or neurodegenerative diseases (e.g., Alzheimer's disease or Parkinson's disease). The effects of combination therapy in these diseases may be due to, related to, or unrelated to their effects on body weight.

[0048] Combination Therapy The combined therapy of a PYY analog and a dual-acting agonist for GLP-1 and GCG receptors can be administered together with another active agent for treating the disease or disorder in question, such as an anti-obesity agent, an anti-diabetic agent, an agent for treating metabolic syndrome, an anti-dyslipidemic agent, an anti-hypertensive agent, a proton pump inhibitor, or an anti-inflammatory agent. In such cases, the active agents can be administered together or separately, for example, as components in the same pharmaceutical composition or formulation, or as separate formulations. For example, the PYY analog and the GLP-1 / GCGR agonist can be administered together, and the additional active agent can be administered separately (e.g., as a background therapeutic agent).

[0049] Therefore, the combination according to the present invention can be used in combination with known anti-obesity agents. The anti-obesity agent may be amylin or an amylin analog, such as pramlintide, or a calcitonin analog. Alternatively, the anti-obesity agent may be a lipase inhibitor (Orlistat™), phentermine, a melanin-concentrating hormone receptor 1 antagonist, a GDF-15 analog, an FGF-21 analog, a urocortin analog, a leptin analog, a GOAT inhibitor, a ghrelin receptor antagonist, a neuromedin receptor 2 agonist, an NPY4 receptor agonist, an NPY5 receptor antagonist, a melanocortin receptor 4 agonist, and analogs thereof. Therefore, it will be understood that a combination of a dual-acting GLP-1R / GCGR agonist and a PYY analog can be administered to a subject suffering from a condition or disease characterized by inadequate appetite control or otherwise excessive eating, such as binge eating disorder and Prader-Willi syndrome. It will be apparent that the analogs may be used to treat a combination of the conditions or diseases described.

[0050] Furthermore, the combinations according to the invention may have some benefit when administered in combination with known types of antidiabetic agents selected, for example, from SGLT2 inhibitors (i.e., inhibitors of sodium-glucose transport, such as empagliflozin), GPR40 agonists (FFAR1 / FFA1 agonists), or insulin or insulin analogues. Examples of suitable insulin analogues include, but are not limited to, Lantus™, Novorapid™, Humalog™, Novomix™, Actraphane™ HM, Levemir™, Degludec™, and Apidra™.

[0051] The above-described invention relating to the combination of a PYY analog with a dual agonist of GLP-1R and GCGR can further be used in combination with therapeutic agents for cardiovascular diseases, such as those for treating hypertension, dyslipidemia, inflammation, and platelet function. Therapeutic agents for treating hypertension can be selected from the group including, but not limited to, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, diuretics, beta-blockers, or calcium channel blockers. Therapeutic agents for treating heart failure can be selected from the classes of angiotensin receptor-neprilysin inhibitors (ARNi), SGLT2 inhibitors (e.g., empagliflozin), soluble guanylate cyclase stimulators or activators (e.g., veruiguat), beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, or steroidal (spironolactone) and non-steroidal (e.g., finerenone) mineralocorticoid receptor antagonists, and aldosterone synthase inhibitors.

[0052] The above invention relating to the combination of a PYY analogue with a dual agonist of GLP-1R and GCGR may further be used in combination with known types of anti-dyslipidemic agents, including, but not limited to, statins, fibrates, niacin, PSCK9 (proprotein convertase subtilisin / kexin type 9) inhibitors, or cholesterol absorption inhibitors. The above invention relating to the combination of a PYY analog with a dual agonist of GLP-1R and GCGR also has utility in combination with known types of proton pump inhibitors (i.e., H + / K + -pharmaceutical agents having pharmacological activity as inhibitors of ATPase), including but not limited to benzimidazole- or imidazopyridine-derivative drugs such as Omeprazole™.

[0053] In addition, with regard to anti-inflammatory treatment, the above invention relating to the combination of a PYY analog with a dual agonist of GLP-1R and GCGR is effective against steroids and corticosteroids (e.g., prednisone, dexamethasone), non-steroidal anti-inflammatory drugs (NSAIDs) such as propionic acid derivatives (e.g., ibuprofen), acetic acid derivatives (e.g., indomethacin, diclofenac), fenamic acid derivatives (e.g., flufenamic acid, meclofenamic acid), biphenylcarboxylic acid derivatives (e.g., diflunisal and flufenisal), oxaliplatin, cyclospor ... It may be beneficial when administered in combination with known types of anti-inflammatory agents, including, but not limited to, cicams (e.g., isoxicam), salicylates (e.g., acetylsalicylic acid), and pyrazolones (e.g., apazone, bezupiperylone), COX-II inhibitors (e.g., rofecoxib), preparations of interferon beta (e.g., interferon beta-1a or interferon beta-1b), and certain other compounds, such as 5-aminosalicylic acid and its prodrugs and pharmaceutically acceptable salts. The above invention relating to the combination of a PYY analogue with a dual agonist of GLP-1R and GCGR can further be used in combination with a therapeutic agent for chronic kidney disease, including diabetic kidney disease. The therapeutic agent for treating chronic and diabetic kidney disease can be selected from the group including, but not limited to, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, diuretics, soluble guanylate cyclase stimulators or activators, aldosterone synthase inhibitors, and SGLT2 inhibitors (e.g., empagliflozin). [Example]

[0054] Compound I is disclosed in WO2015 / 055801 as Example 13 and has the following structure: HH-Ac4c-QGTFTSDYSKYLDERAAKDFI-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-WLESA-NH2 (SEQ ID NO: 01, SEQ ID NO: 02)

[0055] [ka] Compound A is disclosed as compound 106 in WO2021 / 094259. Compound B is disclosed as compound 117 in WO2021 / 094259. Compound C is disclosed as compound 234 in WO2021 / 094259. Compound D is disclosed as compound 74 in WO2021 / 094259. Compound E is disclosed as compound 23 in WO2021 / 094259. Compound F is disclosed as compound 14 in WO2021 / 094259. Compound G is disclosed as compound 171 in WO2021 / 094259. Compound H is disclosed as compound 231 in WO2021 / 094259. Compound J is disclosed as compound 53 in WO2021 / 094259. Compound K is disclosed as compound 7 in WO2022 / 029231. Compound L is disclosed as compound 84 in WO2022 / 029231.

[0056] Semaglutide has the following structure: [ka] (N-epsilon 26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37), (SEQ ID NO: 17))

[0057] Example 1 Radioligand binding competition assay (RLB) The filtered RLB assay was performed in a 96-well plate with a final volume of 100 μl per well. Lyophilized test peptides were dissolved in 100% dimethyl sulfoxide (DMSO) to a 1 mM stock solution and serially diluted in assay buffer (50 mM HEPES, 5 mM MgCl, 1 mM CaCl, pH 7.4) containing 0.2% ovalbumin. 10 μl / well of test peptide solution was added to the plate to give final concentrations ranging from 1 μM to 3 pM. This was followed by 10 μl of human IgG in assay buffer containing 0.2% ovalbumin. 125I-PYY(1-36) (Perkin Elmer) was added to the wells to a final concentration of 0.02 nM. Next, 80 μL of membrane (HTS066M, ChemiSCREEN™ Human Neuropeptide Y2 Receptor Membrane Preparation, CHEMICON) was added to each well to a final protein concentration of 0.5 μg / well. The plate was sealed and incubated for 2 hours at room temperature in a plate shaker set at 400 rpm. The incubation was terminated by vacuum filtration onto 0.5% polyethyleneamine (PEI)-presoaked GF / C filters using a 96-well FilterMate™ harvester (Perkin Elmer), followed by four washes with 300 μl / well of ice-cold wash buffer (50 mM HEPES, 500 mM NaCl, pH 7.4). The filter plate was then allowed to dry at room temperature for 60 minutes, and the bottom of the plate was sealed with UniFilter-96 backing tape. Finally, 50 μl / well of scintillation counter cocktail (Microscint20, Packard) was added and radioactivity was counted in a Packard TopCount NXT scintillation counter. 50 The K values (half-maximal inhibitory concentrations of agonists) were calculated by nonlinear regression analysis of sigmoidal dose-response curves. K values for binding affinity were calculated using the Cheng-Prusoff equation (K = IC 50 / (1 + [L] / Kd), where Kd is the receptor-specific dissociation constant previously measured (=0.07 nM for NPY2R) and [L] is 125 I-PYY(1-36) radioligand concentration. The Ki values are reported in Table 1 below.

[0058] Example 2 Effects on short-term food intake in normal NMRI mice Five-week-old male NMRI mice were obtained from Charles River (Charles River, Research Models & Services Germany GmbH) or JanVier (JanVier Labs, France). Animals were housed in groups of four mice per cage. Cages were kept under a 12 / 12-hour light / dark cycle with lights off at 3:00 PM. Room temperature was controlled at 21°C ± 1°C and humidity at 60% ± 20%. Animals were fed regular rodent chow (KLIBA Nafag 3430 or Altromin 1324, Brogaarden, Denmark) and tap water ad libitum.

[0059] To allow for acclimation to the experimental conditions, animals were transferred to a real-time food intake monitoring system, the HM-2 system (MBRose, Denmark), 5–7 days before the start of the study. Animals were uniquely identified using microchips, and each individual animal was identified by its microchip upon entry and exit from the food channel. Randomization of mice into each test group (n = 7–8) was based on body weight measured the day before the start of the study. A vehicle-treated group (50 mM phosphate buffer, pH 7, containing 5% mannitol) was included in each experiment. Animals were fasted 6 h before the onset of the night phase. Animals received a single subcutaneous dose of the test peptide (10 nmol / kg) 1 h before the dark phase. Food intake was reported hourly for 24 h. Food intake for the treatment groups was normalized (in %) to the mean food intake of the vehicle-receiving group (Table 1). Statistical significance was assessed using one-way analysis of variance with Turkey's multiple comparison test. P<0.05 was considered statistically significant.

[0060] Example 3 Effect on weight loss in wild-type diet-induced obese mice Male C57BL6 / J mice over 16 weeks old, pre-fed with a 60% high-fat diet, were obtained from Jackson Laboratories. Upon arrival of the diet-induced obese (DIO) mice, they were singly housed and assigned animal numbers to obtain accurate and individualized food intake measurements for each animal. Animals were housed at a room temperature of 21±2°C, a relative humidity of 60±20%, and a 12-hour reversed light / dark cycle (lights on at 10:00 AM). Animals had free access to food and water throughout the study period.

[0061] Prior to the start of treatment, stratified randomization was performed based on body weight measured during week -1 before the start of the study. Mice were approximately 20 weeks old at the start of the study. Body weight and food intake were measured daily before compound administration. Animals were dosed once daily by subcutaneous injection of 30 nmol / kg approximately 1 hour before the onset of the night phase for 5 to 28 days, depending on the experiment. Control animals received daily subcutaneous injections of vehicle.

[0062] RLB assay (NPY2R) [Table 1]

[0063] Reference 1: iVal-APEK(C18DA-gGlu-OEG-OEG)PEEDASPEEIQQYYVSLRHYYNWLTRQRY-NH2 (SEQ ID NO: 14) Reference 1 is disclosed as compound 11 in WO2021 / 094259. Reference 2: iVal-APEK(C18DA-gGlu-OEG-OEG)PGEDASPEELQRYYVSLRHYYHWLTRQRY-NH2 (SEQ ID NO: 15) Reference 3: iVal-RPEK(C18DA-gGlu-OEG-OEG)PEEDASPEELQRYYVSLRHYYNWLTRQRY-NH2 (SEQ ID NO: 16)

Claims

1. A pharmaceutical composition comprising compound I for use in a method for treating a disease, wherein the method is -Compound I: H-His-Ac4c-Gln-Gly-Thr-Phe -Thr-Ser-Asp-Tyr-Ser-Lys-Ty r-Leu-Asp-Glu-Arg-Ala-Ala-L ys-Asp-Phe-Ile-Lys(HOOC-(CH 2 ) 16 -CO-γGlu-Gly-Ser-Gly-Ser-Gly -Gly-)-Trp-Leu-Glu-Ser-Ala-NH 2 (Arrangement number 01, arrangement number 02), and - Compounds A to L below: Compound A: Compound B: Compound C: Compound D: Compound E: Compound F: Compound G: Compound H: Compound J: Compound K: Compound L: This includes the co-administration of a long-acting NPY2 receptor agonist selected from the group consisting of the following: The aforementioned pharmaceutical composition.

2. A pharmaceutical composition comprising compound I for use in a method for treating the disease described in claim 1, wherein a long-acting NPY2 receptor agonist is selected from the group consisting of compounds B, E, K, and L.

3. A pharmaceutical composition comprising compound I for use in a method for treating the disease described in claim 1, wherein the long-acting NPY2 receptor agonist is selected from the group consisting of compounds B, E, and K.

4. A pharmaceutical composition comprising compound I for use in a method for treating the disease described in claim 1, wherein compound B is a long-acting NPY2 receptor agonist.

5. A pharmaceutical composition comprising compound I for use in a method for treating the disease described in claim 1, wherein compound E is a long-acting NPY2 receptor agonist.

6. A pharmaceutical composition comprising compound I for use in a method for treating the disease described in claim 1, wherein compound K is a long-acting NPY2 receptor agonist.

7. A pharmaceutical composition comprising compound I for use in a method for treating the disease described in claim 1, wherein the compound may be administered once a week.

8. A pharmaceutical composition for use in a method for treating the disease described in claim 1, wherein the treatment targets obesity and various obesity-related conditions, diseases, or comorbidities such as type 2 diabetes, liver diseases such as NAFLD (non-alcoholic fatty liver disease) and NASH (non-alcoholic steatohepatitis), kidney diseases, or cardiovascular diseases.

9. A pharmaceutical composition comprising compound I for use in a method for treating a disease according to claim 1, wherein simultaneous administration has a synergistic effect in the patient, for example, a synergistic effect on weight, weight management, or weight loss.

10. A pharmaceutical composition comprising compound I for use in a method for treating the disease described in claim 1, wherein the use is for the treatment of obesity and / or obesity-related conditions, type 2 diabetes, liver disease (such as NAFLD (non-alcoholic fatty liver disease) or NASH (non-alcoholic steatohepatitis)), kidney disease or cardiovascular disease.

11. A pharmaceutical composition comprising compound I for use in a method for treating the disease described in claim 1, for the treatment of obesity or weight loss.

12. -Compound I: H-His-Ac4c-Gln-Gly-Thr-Phe -Thr-Ser-Asp-Tyr-Ser-Lys-Ty r-Leu-Asp-Glu-Arg-Ala-Ala-L ys-Asp-Phe-Ile-Lys(HOOC-(CH 2 ) 16 -CO-γGlu-Gly-Ser-Gly-Ser-Gly -Gly-)-Trp-Leu-Glu-Ser-Ala-NH 2 (Arrangement number 01, arrangement number 02), and - A long-acting NPY2 receptor agonist selected from the group consisting of compounds A to L described in claim 1. A pharmaceutical composition containing the following:

13. The pharmaceutical composition according to claim 12, wherein the long-acting NPY2 receptor agonist is selected from the group consisting of compounds B, E, and K.

14. The pharmaceutical composition according to claim 12 or 13, for use in the treatment of obesity and / or obesity-related conditions, for use in the treatment of type 2 diabetes, liver disease (such as NAFLD (non-alcoholic fatty liver disease) or NASH (non-alcoholic steatohepatitis)), kidney disease, or cardiovascular disease.

15. The composition according to claim 12 or 13, which produces a synergistic effect, for example, a synergistic effect on weight, weight management, or weight loss.

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