Combination therapy

Abstract

The present invention relates to methods of treatment using acylated compounds and peptide hormones having dual agonist activity for the GLP-1 (glucagon-like peptide 1) and GLP-2 5 (glucagon-like peptide 2) receptors. In particular, the present invention relates to the administration of a dual GLP-1 / GLP-2 agonist peptide and amylin for modulating body weight and preventing or treating obesity and related conditions.

Description

Technical Field

[0001] The present invention relates to therapeutic methods using a combination of acylated compounds and peptide hormones having dual agonist activity at the GLP-1 (glucagon-like peptide 1) and GLP-2 (glucagon-like peptide 2) receptors. In particular, the present invention relates to a combination of dual GLP-1 / GLP-2 agonist peptides and amylin analogs for use in regulating body weight and in preventing or treating obesity and related disorders. Background Art

[0002] Obesity is a major public health problem in many current developed countries and is associated with the occurrence of several serious conditions (e.g., 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, although such intervention can achieve temporary success, it is usually challenging for patients to maintain such lifestyle changes for a long time so as to achieve permanent weight loss.

[0003] GLP-1 is released from the intestine in response to food intake and thus acts as a satiety signal, resulting in reduced food intake (Madsbad, S., 2014, Diabetes Obes Metab, 16: 9-21). There is evidence that the effects of GLP-1 may be impaired in obese subjects, suggesting that GLP-1 agonists may have promise in treating obesity.

[0004] Intestinal tissue is responsible for the production of both human glucagon-like peptide 1 (GLP-1 (7-36)) and human glucagon-like peptide 2 (GLP-2 (1-33)), which are produced by the same cells. Human GLP-2 is a 33 amino acid peptide with the following sequence:

[0005] Hy-His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-OH (SEQ ID NO: 1).

[0006] GLP-2 is derived from specific post-translational processing of proglucagon in enteroendocrine L cells of the intestine and in specific regions of the brainstem. GLP-2 binds to a single G protein-coupled receptor belonging to the class II glucagon secretin family.

[0007] GLP-2 is co-secreted with GLP-1, oxyntomodulin, and glicentin in response to nutrient intake. Human GLP-1 is produced as a 30 amino acid peptide with the following sequence:

[0008] Hy-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-IIe-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly-NH2 (SEQ ID NO: 2).

[0009] GLP-1 has been described as a physiological incretin hormone and has therefore been primarily reported to enhance the insulin response after oral intake of glucose or fat. However, it is generally understood that GLP-1 reduces glucagon concentrations, has a beneficial effect on inhibiting rapid intestinal motility (Tolessa et al., 1998, Dig. Dis. Sci. 43 (10): 2284-90), and slows gastric emptying.

[0010] The main disadvantage of GLP-1 therapy is that a significant proportion of patients receiving known GLP-1 agonists suffer from side effects of nausea and vomiting (Filippatos et al, 2014 / 15, Rev Diabet Stud., 11(3): 202-230). These side effects usually require that the dose of the GLP-1 agonist be gradually increased from a low starting dose to minimize such side effects. In fact, clinical trial data of the GLP-1 agonist Semaglutide showed that nausea and vomiting were commonly observed in patients when administered, even when low doses of the drug were initially administered (Wilding et al, 2021, N Engl J Med; 384: 989-1002). These side effects are undesirable because they tend to reduce patient compliance with treatment.

[0011] Thus, there remains a need for therapeutic agents having GLP-1 agonist activity that are effective in treating obesity and related disorders while not exhibiting the expected side effects of nausea and vomiting following administration.

[0012] WO2013 / 164484 discloses GLP-2 analogues and their medical uses, which GLP-2 analogues comprise one or more substitutions compared to h[Gly2]GLP-2 and may have altered properties of GLP-1 activity.

[0013] WO 2018 / 104561 discloses peptides having dual GLP-1 and GLP-2 agonist activity and proposes their medical uses, and PCT / EP2022 / 074420 discloses specific dosing regimens for treating obesity and related disorders.

[0014] Amylin is a member of a family of peptide hormones that includes amylin, calcitonin, calcitonin gene-related peptide, adrenomedullary peptide, and mesenteric hormone (mesenteric hormone also known as AFP-6), and has been implicated in a variety of metabolic diseases and disorders. Human amylin was first isolated, purified, and characterized as a major component of amyloid deposits in islets of the pancreas from patients with type 2 diabetes.

[0015] Native human amylin is a 37 amino acid peptide with the following formula:

[0016] H-KC()NTATC()ATQRLANFLVHSSNNFGAILSSTNVGSNTY-NH2

[0017] (SEQ ID NO: 3)

[0018] wherein the H- at the N-terminus represents a hydrogen atom, corresponding to the free amino group present on the N-terminal amino acid residue [i.e., the lysine (K) residue at position 1 in the sequence shown above]; wherein the -NH2 at the C-terminus represents that the carboxyl group at the C-terminus is in amide form; and wherein the brackets "()"" connected to the two cysteine ​​(C, Cys) residues at positions 2 and 7 of the sequence represent the presence of an intramolecular disulfide bridge between the two Cys residues involved.

[0019] Amylin may be beneficial in treating metabolic disorders such as diabetes and / or obesity. It is believed that amylin regulates gastric emptying and inhibits glucagon secretion and food intake, thereby regulating the rate of glucose release into the circulation. Amylin has been shown to complement the effects of insulin. Compared to healthy adults, patients with type 1 diabetes have no circulating amylin, while patients with type 2 diabetes show reduced postprandial amylin concentrations. WO 93 / 10146 describes an amylin analog called pramlintide, which has the following sequence:

[0020] 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: 4).

[0021] Pramlintide also has a disulfide bridge between the cysteine ​​residues at positions 2 and 7 and has been shown to reduce body weight or decrease body weight gain in human trials.

[0022] Yan et al. (PNAS, 103 (7), 2046-2051, 2006; Angew. Chem. Int. Ed. 2013, 52, 10378-10383; WO2006 / 042745) have described an alternative amylin analogue incorporating N-methylated residues and having a reduced tendency to fibrillate, which was named IAPP-GI. However, IAPP-GI was shown to have lower activity than native amylin.

[0023] WO 2018 / 046719 describes such amylin analogs, which have, in particular, lactam bridges instead of disulfide bridges, N-methylated residues, and deletions of residues Asn21 and Asn22 corresponding to natural human amylin. Such analogs have a significantly lower tendency to fibrillate than natural amylin, while also having a higher potency than the analogs described by Yan et al. (supra). Summary of the invention

[0024] In general, the present invention relates to treatments and methods for preventing or treating diseases and disorders, such as obesity and obesity-related disorders. More specifically, the present invention is based on the unexpected discovery that the combined use of a dual agonist of the GLP-1 (glucagon-like peptide 1) and GLP-2 (glucagon-like peptide 2) receptors and a long-acting amylin analog achieves better therapeutic efficacy than treatment with either agent alone.

[0025] In one aspect, a GLP-1 / GLP-2 dual agonist and an amylin analog are provided for use in a method of preventing or treating a disease or disorder, wherein the GLP-1 / GLP-2 dual agonist and an amylin analog are administered to a subject.

[0026] In one embodiment, the subject is a human subject.

[0027] In one embodiment, the subject is a human subject suffering from a disease or disorder.

[0028] In one embodiment, the subject is a human subject at risk for developing a disease or disorder.

[0029] In one embodiment, the dose of the GLP-1 / GLP-2 dual agonist and the dose of the amylin analog are selected independently.

[0030] In one embodiment, the GLP-1 / GLP-2 dual agonist may be administered at a dose of 100 nmol / kg and the amylin analog may be administered at a dose of 10 nmol / kg.

[0031] In one embodiment, the disease or condition is obesity, morbid obesity, obesity-related gallbladder disease, obesity-induced sleep apnea, poor glycemic control, glucose tolerance, dyslipidemia, diabetes, prediabetes, metabolic syndrome, or hypertension.

[0032] The present invention also relates to the use of GLP-1 / GLP-2 dual agonists and amylin analogs for methods that are not intended to treat a disease or condition per se. Such uses and methods may be considered prevention of a disease or condition, provided that they can be used prior to the onset of the disease (e.g., pre-diagnosis), for example, to improve undesirable physiological characteristics or to alter certain physiological parameters.

[0033] In some embodiments, the uses or methods of the invention may be considered cosmetic.

[0034] In one embodiment, the subject to whom the GLP-1 / GLP-2 dual agonist and the amylin analog are administered does not have a disease or disorder.

[0035] In one aspect, a combination of a GLP-1 / GLP-2 dual agonist and an amylin analog is provided for use in a method of reducing or inhibiting weight gain, reducing gastric emptying or intestinal transit, reducing food intake, reducing appetite, or promoting weight loss, wherein a GLP-1 / GLP-2 dual agonist and an amylin analog are administered.

[0036] The present invention also provides a combination of a GLP-1 / GLP-2 dual agonist and an amylin analog for use in treatment. In another aspect, a combination of a GLP-1 / GLP-2 dual agonist and an amylin analog is provided for use as a medicament. A combination of a GLP-1 / GLP-2 dual agonist and an amylin analog is also provided for use in a medical treatment method.

[0037] The present invention also provides a combination of a GLP-1 / GLP-2 dual agonist and an amylin analog for use in a method of reducing or inhibiting weight gain, reducing gastric emptying or intestinal transit, reducing food intake, reducing appetite or promoting weight loss.

[0038] The present invention also provides a combination of a GLP-1 / GLP-2 dual agonist and an amylin analog for use in a method for preventing or treating obesity, morbid obesity, obesity-related gallbladder disease, obesity-induced sleep apnea, poor blood sugar control, glucose tolerance, dyslipidemia (e.g., elevated LDL levels or decreased HDL / LDL ratio), diabetes (e.g., type 2 diabetes, gestational diabetes), prediabetes, metabolic syndrome, or hypertension.

[0039] The present invention also provides a method for reducing or inhibiting weight gain, reducing gastric emptying or intestinal transit, reducing food intake, reducing appetite or promoting weight loss in a subject in need thereof, the method comprising administering to the subject a GLP-1 / GLP-2 dual agonist and an amylin analog.

[0040] The present invention also provides a method for preventing or treating obesity, morbid obesity, obesity-related gallbladder disease, obesity-induced sleep apnea, poor glycemic control, glucose tolerance, dyslipidemia (e.g., elevated LDL levels or decreased HDL / LDL ratio), diabetes (e.g., type 2 diabetes, gestational diabetes), prediabetes, metabolic syndrome, or hypertension in a subject in need thereof, the method comprising administering to the subject a GLP-1 / GLP-2 dual agonist and an amylin analog.

[0041] The present invention also provides a GLP-1 / GLP-2 dual agonist and an amylin analog for use in the preparation of one or more medicaments for administering the GLP-1 / GLP-2 dual agonist and the amylin analog. In this aspect, the GLP-1 / GLP-2 dual agonist and the amylin analog can be in the same medicament or in different medicaments. In a preferred aspect, the GLP-1 / GLP-2 dual agonist and the amylin analog are in separate medicaments. In a preferred aspect, the GLP-1 / GLP-2 dual agonist is in one medicament, which optionally comprises one or more carriers, diluents, and excipients (sometimes referred to as a "GLP-1 / GLP-2 dual agonist medicament" or "dual agonist medicament" or "GLP-1 / GLP-2 dual agonist medicament" or "dual agonist medicament"); and wherein the amylin analog is in another medicament, which optionally comprises one or more carriers, diluents, excipients (sometimes referred to as an "amylin analog medicament" or "amylin analog medicament"). The GLP-1 / GLP-2 dual agonist medicament can be in any form suitable for administration to a subject. In a preferred aspect, the GLP-1 / GLP-2 dual agonist medicament is in a form suitable for subcutaneous (s / c or sc) administration to a subject. The amylin analog medicament can be in any form suitable for administration to a subject. In a preferred aspect, the amylin analog drug is in a form suitable for subcutaneous (s / c or sc) administration to a subject. The GLP-1 / GLP-2 dual agonist drug and the amylin analog drug can be delivered to the subject simultaneously or at different times. In a preferred aspect, the GLP-1 / GLP-2 dual agonist drug is delivered to the subject daily. In a preferred aspect, the GLP-1 / GLP-2 dual agonist drug is delivered to the subject once a day. In a preferred aspect, the amylin analog drug is delivered to the subject every other day. In a preferred aspect, the amylin analog drug is delivered to the subject once every other day.

[0042] For some embodiments, preferably, the method comprises administering to the subject a GLP-1 / GLP-2 dual agonist at a dose of about 0.5 mg to about 10.0 mg.

[0043] For some embodiments, preferably, the method comprises administering to the subject a GLP-1 / GLP-2 dual agonist at a dose of about 0.5 mg to about 7.5 mg, preferably about 1.0 mg to about 7.5 mg, preferably about 1.0 to about 6.0 mg, preferably about 1.0 to about 4.0 mg, preferably about 1.0 to about 3.5 mg.

[0044] For some embodiments, preferably, the method comprises administering to the subject a GLP-1 / GLP-2 dual agonist once daily at a dosage of about 0.5 mg to about 10.0 mg / day.

[0045] For some embodiments, preferably, the method comprises administering to the subject a GLP-1 / GLP-2 dual agonist once a day at a dose of about 0.5 mg to about 7.5 mg / day, preferably once a day at a dose of about 1.0 mg to about 7.5 mg / day, preferably once a day at a dose of about 1.0 to about 6.0 mg / day, preferably once a day at a dose of about 1.0 to about 4.0 mg / day, preferably once a day at a dose of about 1.0 to about 3.5 mg / day.

[0046] For some embodiments, preferably, the GLP-1 / GLP-2 dual agonist is in a pharmaceutical composition, wherein the pharmaceutical composition comprises one or more of the following:

[0047] (i) at least about 1 mg / mL of one or more GLP-1 / GLP-2 dual agonists

[0048] (ii) 5 mM to about 50 mM phosphate buffer component

[0049] (iii) about 190 mM to about 240 mM mannitol and / or

[0050] (iv) The pH is about pH 8.0.

[0051] For some embodiments, preferably, the method comprises administering to the subject an amylin analog at a dose of about 0.5 mg to about 10.0 mg, preferably about 0.6 mg to about 7.5 mg, preferably about 1.2 mg to about 7.5 mg, preferably about 1.2 to about 6.0 mg, preferably about 2.4 to about 6.0 mg, preferably about 2.4 to about 4.0 mg, preferably about 2.4 to about 3.5 mg.

[0052] For some embodiments, preferably, the method comprises administering to the subject an amylin analog at a dose of about 0.5 mg to about 10.0 mg / day every other day, preferably at a dose of about 0.6 mg to about 7.5 mg / day every other day, preferably at a dose of about 1.2 mg to about 7.5 mg / day every other day, preferably at a dose of about 1.2 to about 6.0 mg / day every other day, preferably at a dose of about 2.4 to about 6.0 mg / day every other day, preferably at a dose of about 2.4 to about 4.0 mg / day every other day, preferably at a dose of about 2.4 to about 3.5 mg / day every other day.

[0053] For some embodiments, preferably, the amylin analog is in a pharmaceutical composition, wherein the pharmaceutical composition comprises one or more of the following:

[0054] (i) one or more amylin analogs at a concentration of about 0.4 mg / ml to about 25 mg / ml;

[0055] (ii) present in a solution having a buffer concentration of about 0.5 mM to 25 mM;

[0056] (iii) is present in a solution having a pH of about 5.8 to about 6.9; and / or

[0057] (iv) Supplied as the hydrochloride salt.

[0058] For some embodiments, preferably, the method comprises administering to the subject a GLP-1 / GLP-2 dual agonist once daily at a dose of about 0.5 mg to about 7.5 mg / day, preferably once daily at a dose of about 1.0 mg to about 7.5 mg / day, preferably once daily at a dose of about 1.0 to about 6.0 mg / day, preferably once daily at a dose of about 1.0 to about 4.0 mg / day, preferably once daily at a dose of about 1.0 to about 3.5 mg / day;

[0059] And wherein the method comprises administering to the subject an amylin analog at a dose of about 0.5 mg to about 10.0 mg / day every other day, preferably at a dose of about 0.6 mg to about 7.5 mg / day every other day, preferably at a dose of about 1.2 mg to about 7.5 mg / day every other day, preferably at a dose of about 1.2 to about 6.0 mg / day every other day, preferably at a dose of about 2.4 to about 6.0 mg / day every other day, preferably at a dose of about 2.4 to about 4.0 mg / day every other day, preferably at a dose of about 2.4 to about 3.5 mg / day every other day.

[0060] For some embodiments, preferably, the method comprises administering to the subject a GLP-1 / GLP-2 dual agonist once daily at a dose of about 0.5 mg to about 7.5 mg / day, preferably once daily at a dose of about 1.0 mg to about 7.5 mg / day, preferably once daily at a dose of about 1.0 to about 6.0 mg / day, preferably once daily at a dose of about 1.0 to about 4.0 mg / day, preferably once daily at a dose of about 1.0 to about 3.5 mg / day;

[0061] wherein the GLP-1 / GLP-2 dual agonist is in a first pharmaceutical composition, wherein the first pharmaceutical composition comprises one or more of the following:

[0062] (i) at least about 1 mg / mL of one or more GLP-1 / GLP-2 dual agonists

[0063] (ii) 5 mM to about 50 mM phosphate buffer component

[0064] (iii) about 190 mM to about 240 mM mannitol and / or

[0065] (iv) a pH of about pH 8.0;

[0066] wherein the method comprises administering to the subject an amylin analog at a dose of about 0.5 mg to about 10.0 mg / day every other day, preferably at a dose of about 0.6 mg to about 7.5 mg / day every other day, preferably at a dose of about 1.2 mg to about 7.5 mg / day every other day, preferably at a dose of about 1.2 to about 6.0 mg / day every other day, preferably at a dose of about 2.4 to about 6.0 mg / day every other day, preferably at a dose of about 2.4 to about 4.0 mg / day every other day, preferably at a dose of about 2.4 to about 3.5 mg / day every other day; and

[0067] wherein the amylin analog is in a second pharmaceutical composition, wherein the second pharmaceutical composition comprises one or more of:

[0068] (i) one or more amylin analogs at a concentration of about 0.4 mg / ml to about 25 mg / ml;

[0069] (ii) present in a solution having a buffer concentration of about 0.5 mM to 25 mM;

[0070] (iii) is present in a solution having a pH of about 5.8 to about 6.9; and / or

[0071] (iv) The amylin analog is provided as the hydrochloride salt.

[0072] For some embodiments, preferably, the method comprises administering to the subject a GLP-1 / GLP-2 dual agonist once daily at a dose of about 0.5 mg to about 7.5 mg / day, preferably once daily at a dose of about 1.0 mg to about 7.5 mg / day, preferably once daily at a dose of about 1.0 to about 6.0 mg / day, preferably once daily at a dose of about 1.0 to about 4.0 mg / day, preferably once daily at a dose of about 1.0 to about 3.5 mg / day;

[0073] Wherein the GLP-1 / GLP-2 dual agonist is in the first pharmaceutical composition, wherein the first pharmaceutical composition comprises:

[0074] (i) at least about 1 mg / mL of one or more GLP-1 / GLP-2 dual agonists

[0075] (ii) 5 mM to about 50 mM phosphate buffer component

[0076] (iii) about 190 mM to about 240 mM mannitol and / or

[0077] (iv) a pH of about pH 8.0;

[0078] wherein the method comprises administering to the subject an amylin analog at a dose of about 0.5 mg to about 10.0 mg / day every other day, preferably at a dose of about 0.6 mg to about 7.5 mg / day every other day, preferably at a dose of about 1.2 mg to about 7.5 mg / day every other day, preferably at a dose of about 1.2 to about 6.0 mg / day every other day, preferably at a dose of about 2.4 to about 6.0 mg / day every other day, preferably at a dose of about 2.4 to about 4.0 mg / day every other day, preferably at a dose of about 2.4 to about 3.5 mg / day every other day; and

[0079] Wherein the amylin analog is in a second pharmaceutical composition, wherein the second pharmaceutical composition comprises:

[0080] (i) one or more amylin analogs at a concentration of about 0.4 mg / ml to about 25 mg / ml;

[0081] (ii) present in a solution having a buffer concentration of about 0.5 mM to 25 mM;

[0082] (iii) is present in a solution having a pH of about 5.8 to about 6.9; and / or

[0083] (iv) The amylin analog is provided as the hydrochloride salt.

[0084] The present invention also provides the use of a GLP-1 / GLP-2 dual agonist and an amylin analog in the preparation of a drug for reducing or inhibiting weight gain, reducing gastric emptying or intestinal transit, reducing food intake, reducing appetite or promoting weight loss.

[0085] The present invention also provides the use of a GLP-1 / GLP-2 dual agonist and an amylin analog in the preparation of a medicament for preventing or treating obesity, morbid obesity, obesity-related gallbladder disease, obesity-induced sleep apnea, poor blood sugar control, glucose tolerance, dyslipidemia (e.g., elevated LDL levels or decreased HDL / LDL ratio), diabetes (e.g., type 2 diabetes, gestational diabetes), prediabetes, metabolic syndrome or hypertension.

[0086] In another aspect there is provided a therapeutic kit comprising a dual agonist according to the invention or a pharmaceutically acceptable salt or solvate thereof.

[0087] The methods and uses of the present invention may be performed in vitro, in vivo or ex vivo.

[0088] Compounds that have agonist activity (e.g., as assessed in an in vitro potency assay) at GLP-1 (glucagon-like peptide 1) and GLP-2 (glucagon-like peptide 2) receptors. Such compounds are referred to herein as "GLP-1 / GLP-2 dual agonists," or simply "dual agonists." Therefore, the compounds of the present invention have both GLP-1 and GLP-2 activity.

[0089] In one embodiment, the GLP-1 / GLP-2 dual agonist is:

[0090] Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH (SEQ ID NO: 5).

[0091] The dual agonist may be in the form of a pharmaceutically acceptable salt or solvate (eg, a pharmaceutically acceptable acid addition salt).

[0092] The present invention also provides a composition comprising a dual agonist of the present invention or a pharmaceutically acceptable salt or solvate thereof, and a carrier, excipient or carrier. The carrier may be a pharmaceutically acceptable carrier. The composition may be a pharmaceutical composition. The pharmaceutical composition may be formulated into a liquid suitable for administration by injection or infusion.

[0093] In one embodiment, the amylin analog is:

[0094] [19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH2 (SEQ ID NO: 6).

[0095] The amylin analog may be in the form of a pharmaceutically acceptable salt or solvate (eg, a pharmaceutically acceptable acid addition salt).

[0096] The present invention also provides a composition comprising an amylin analog of the present invention or a pharmaceutically acceptable salt or solvate thereof, and a carrier, excipient or carrier. The carrier may be a pharmaceutically acceptable carrier. The composition may be a pharmaceutical composition. The pharmaceutical composition may be formulated into a liquid suitable for administration by injection or infusion. It may be formulated to achieve slow release of the dual agonist. BRIEF DESCRIPTION OF THE DRAWINGS

[0097] Figure 1 : Effects of sc treatment with vehicle, GLP-1 / GLP-2 dual agonist, amylin analog and combination treatment on cumulative food intake in Sprague Dawley diet-induced obese (DIO) rats. Data are shown as mean values ​​(n=9 / group). Statistics: Cumulative food intake on day 28 (from day 0 to 28) was compared by one-way ANOVA followed by Bonferroni's multiple comparison test (95% confidence interval).

[0098] Figure 2 : Effects of sc treatment with vehicle, GLP-1 / GLP-2 dual agonist or amylin analog monotherapy and GLP-1 / GLP-2 dual agonist and amylin analog combination treatment on % change in body weight (BW) compared to baseline day 0 in Sprague Dawley diet-induced obese (DIO) rats. Data are shown as mean (n=9 / group); A) % change in BW daily; B) BW change on day 28. Statistics: Data in B) were compared by one-way ANOVA followed by Bonferroni's multiple comparison test (95% confidence intervals).

[0099] Figure 3 : Effects of subcutaneous (sc) treatment with vehicle, GLP-1 / GLP-2 dual agonist or amylin analog monotherapy and combination treatment of GLP-1 / GLP-2 dual agonist and amylin analog on overnight fasting blood glucose levels at day 29 in Sprague Dawley diet-induced obese (DIO) rats. Data are shown as means (n=9 / group). The dashed line shows the mean fasting blood glucose level at baseline from all animals in the study. Statistics: Data were compared by one-way ANOVA followed by Bonferroni's multiple comparison test (95% confidence intervals).

[0100] Figure 4 : Plasma exposure in nmol / L measured using LC-MS / MS for the following:

[0101] A. Administration of 100 nmol / kg of GLP-1 / GLP-2 dual agonist alone or in combination with 10 nmol / kg of amylin analog.

[0102] B. Amylin analogs were administered at 10 nmol / kg alone or in combination with GLP-1 / GLP-2 dual agonist 100 nmol / kg. Data are shown as mean values ​​(n=9 / group), with error bars representing one standard deviation. DETAILED DESCRIPTION

[0103] Unless otherwise defined herein, the scientific and technical terms used in this application shall have the meanings commonly understood by those of ordinary skill in the art. Generally speaking, the nomenclature and techniques used in connection with the chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry described herein are those well known and commonly used in the art.

[0104] All patents, published patent applications, and non-patent publications mentioned in this application are specifically incorporated herein by reference. In case of conflict, the present specification, including its specific definitions, will control.

[0105] Each embodiment of the present invention described herein may be used alone or in combination with one or more other embodiments of the present invention.

[0106] definition

[0107] Unless otherwise indicated, the following definitions are provided for specific terms used in this written description.

[0108] Throughout this specification, the word "comprise" and grammatical variations (e.g., "comprises" or "comprising") will be understood to mean including the specified integer or component, or group of integers or components, but not excluding any other integer or component, or group of integers or components.

[0109] Unless the context clearly dictates otherwise, a noun without a quantifier means one or more than one.

[0110] The term "including" is used to mean "including, but not limited to." "Including" and "including, but not limited to" are used interchangeably.

[0111] The terms "patient," "subject," and "individual" are used interchangeably and refer to humans or non-human animals. These terms include mammals, such as humans, primates, livestock animals (e.g., cattle and pigs), companion animals (e.g., dogs and cats), and rodents (e.g., mice and rats).

[0112] The term "solvate" in the context of the present invention refers to a complex of defined stoichiometry formed between a solute (here, a peptide according to the present invention or a pharmaceutically acceptable salt thereof) and a solvent. In this case, the solvent may be, for example, water, ethanol or other pharmaceutically acceptable, usually small molecule organic substances, such as, but not limited to, acetic acid or lactic acid. When the solvent involved is water, such a solvate is usually referred to as a hydrate.

[0113] The term "agonist" as used in the context of the present invention refers to a substance (ligand) which activates the receptor type in question.

[0114] Throughout the specification and claims, the conventional three-letter and one-letter codes for the naturally occurring amino acids are used, namely:

[0115] A(Ala), G(Gly), L(Leu), l(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);

[0116] As well as the generally accepted three-letter codes for other α-amino acids, such as sarcosine (Sar), norleucine (Nle), α-aminoisobutyric acid (Aib), 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab) and 2,5-diaminopentanoic acid (ornithine; Orn). When used in the general formula or sequence in the present specification, especially when the rest of the formula or sequence is shown using a single-letter code, such other α-amino acids may be shown in square brackets "[]" (e.g., "[Aib]"). Unless otherwise indicated, the amino acid residues in the peptides of the present invention are in the L-configuration. However, D-configuration amino acids may be incorporated. In the context of the present invention, amino acid codes written in lowercase letters represent the D-configuration of the amino acid, for example, "k" represents the D-configuration of lysine (K).

[0117] The sequences disclosed herein are sequences that incorporate a "Hy-" moiety at the amino terminus (N-terminus) of the sequence and an "-OH" moiety or "-NH2" moiety at the carboxyl terminus (C-terminus) of the sequence. In such cases, and unless otherwise indicated, the "Hy-" moiety at the N-terminus of the sequence in question represents a hydrogen atom [i.e., in the general formula R 1 = hydrogen = Hy; corresponding to the presence of a free primary or secondary amino group at the N-terminus], and the "-OH" or "-NH2" portion at the C-terminus of the sequence represents a hydroxyl group [e.g., in the general formula R 2 =OH; corresponding to the presence of a carboxyl group (COOH) at the C-terminus] or an amino group [for example, in the general formula R 2 =[NH2]; corresponding to the presence of an amide group (CONH2) at the C-terminus]. In each sequence of the present invention, the C-terminal "-OH" moiety can be replaced by a C-terminal "-NH2" moiety, and vice versa.

[0118] "Percent (%) amino acid sequence identity" with respect to a GLP-2 polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the wild-type (human) GLP-2 sequence, after aligning the sequences and introducing gaps (if necessary) to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Sequence alignments can be performed by a skilled artisan using techniques well known in the art, such as using publicly available software such as BLAST, BLAST2 or Align software. For example, see Altschul et al., Methods in Enzymology 266: 460-480 (1996) or Pearson et al., Genomics 46: 24-36. 1997.

[0119] The percentage of sequence identity used herein can be determined in the context of the present invention using these programs with their default settings. More generally, the skilled person can readily determine appropriate parameters for determining an alignment, including any algorithm required to achieve maximum alignment over the full length of the compared sequences.

[0120] Dual agonist compounds

[0121] Compounds that have agonist activity (e.g., as assessed in an in vitro potency assay) at both GLP-1 (glucagon-like peptide 1) and GLP-2 (glucagon-like peptide 2) receptors. Such compounds are referred to herein as "GLP-1 / GLP-2 dual agonists" or "dual agonists." Therefore, the compounds of the present invention have both GLP-1 and GLP-2 activity.

[0122] The dual agonist compounds according to the present invention possess both GLP-1 (7-36) and GLP-2 (1-33) activities.

[0123] The GLP-1 / GLP-2 dual agonist of the present invention can be represented by the following formula or a pharmaceutically acceptable salt or solvate thereof:

[0124] R 1 -X*-UR 2

[0125] in:

[0126] ·R 1 is hydrogen (Hy), C 1-4 Alkyl (e.g. methyl), acetyl, formyl, benzoyl or trifluoroacetyl;

[0127] ·R 2 It is NH2 or OH;

[0128] X* is a peptide of formula I:

[0129] H-X2-EG-X5-F-X7-X8-E-X10-X11-TIL-X15-X16-X17-A-X19-X20-X21-FI-X24-WL-X27-X28-X29-KIT-X33(I)(SEQ ID NO: 7)

[0130] in:

[0131] οX2 is Aib or G

[0132] οX5 is T or S;

[0133] οX7 is T or S;

[0134] o X8 is S, E or D;

[0135] οX10 is L, M, V or Ψ;

[0136] οX11 is A, N or S;

[0137] ο X15 is D or E;

[0138] οX16 is G, E, A or Ψ;

[0139] οX17 is Q, E, K, L or Ψ;

[0140] ο X19 is A, V or S;

[0141] οX20 is R, K or Ψ;

[0142] ο X21 is D, L or E;

[0143] o X24 is A, N or S;

[0144] o X27 is I, Q, K, H or Y;

[0145] o X28 is Q, E, A, H, Y, L, K, R or S;

[0146] οX29 is H, Y, K or Q;

[0147] ο X33 is D or E;

[0148] U is absent or is a sequence of 1 to 15 residues, each of which is independently selected from K, k, E, A, T, I, L and Ψ;

[0149] The molecule contains one and only one Ψ, where Ψ is a side chain with a 1 - or Z 1 -Z 2-a substituent conjugated to a residue of K, K, R, Orn, Dap or Dab, wherein:

[0150] οZ 1 - is CH3-(CH2) 10-22 -(CO)- or HOOC-(CH2) 10-22 -(CO)-; and

[0151] ο-Z 2 -Selected from

[0152] -Z S1 -, -Z S1 -Z S2 -, -Z S2 -Z S1 , -Z S2 -, -Z S3 -, -Z S1 Z S3 -, -Z S2 Z S3 -, -Z S3 Z S1 -, -Z S3 Z S2 -, -Z S1 Z S2 Z S3 -, -Z S1 Z S3 Z S2 -, -Z S2 Z S1 Z S3 -, -Z S2 Z S3 Z S1 -, -Z S3 Z S1 Z S2 -, -Z S3 Z S2 Z S1 -, -Z S2 Z S3 Z S2 -;

[0153] in

[0154] οZ S1 isoGlu, β-Ala, isoLys or 4-aminobutyryl;

[0155] οZ S2 Yes - (Peg3) m -, where m is 1, 2 or 3; and

[0156] ο-Z S3- is a peptide sequence of 1 to 6 amino acid units, said amino acid units being independently selected from A, L, S, T, Y, Q, D, E, K, K, R, H, F and G;

[0157] and wherein at least one of X5 and X7 is T.

[0158] In one embodiment, the GLP-1 / GLP-2 dual agonist is:

[0159] Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH (SEQ ID NO: 5).

[0160] The dual agonist may be in the form of a pharmaceutically acceptable salt or solvate (eg, a pharmaceutically acceptable acid addition salt).

[0161] The present invention also provides a composition comprising a dual agonist of the present invention or a pharmaceutically acceptable salt or solvate thereof, and a carrier, excipient or carrier. The carrier may be a pharmaceutically acceptable carrier. The composition may be a pharmaceutical composition. The pharmaceutical composition may be formulated into a liquid suitable for administration by injection or infusion.

[0162] Dual agonist activity

[0163] According to the present invention, dual agonists have at least one GLP-1 and at least one GLP-2 biological activity. Exemplary GLP-1 physiological activities include reducing intestinal transit rate, reducing gastric emptying rate, reducing appetite, food intake or body weight, and improving glucose control and glucose tolerance. Exemplary GLP-2 physiological activities include causing an increase in intestinal mass (e.g., mass of the small intestine or colon), intestinal repair, and improving intestinal barrier function (i.e., reducing intestinal permeability). These parameters can be assessed in an in vivo assay, in which the mass and permeability of the intestine or a portion thereof are determined after a test animal has been treated with a dual agonist.

[0164] Dual agonists have agonist activity at both GLP-1 and GLP-2 receptors (e.g., human GLP-1 and GLP-2 receptors). The EC of in vitro receptor agonist activity 50 The EC value can be used as a numerical measure of the potency of an agonist at a given receptor. 50 The EC value is a measure of the concentration of a compound (e.g., mol / L) required to achieve half of the maximal activity of that compound in a particular assay. 50 Lower than the EC of the reference compound 50 A compound having a higher potency at the receptor than the reference compound can be considered.

[0165] GLP-1 activity

[0166] In some embodiments, the EC of the dual agonist at the GLP-1 receptor (e.g., human GLP-1 receptor) is 50 Less than 2.0 nM, less than 1.5 nM, less than 1.0 nM, less than 0.9 nM, less than 0.8 nM, less than 0.7 nM, less than 0.6 nM, less than 0.5 nM, less than 0.4 nM, less than 0.3 nM, less than 0.2 nM, less than 0.1 nM, less than 0.09 nM, less than 0.08 nM, less than 0.07 nM, less than 0.06 nM, less than 0.05 nM, less than 0.04 nM, for example when assessed using a GLP-1 receptor potency assay as described in PCT / EP2022 / 074420.

[0167] In some embodiments, the EC of the dual agonist at the GLP-1 receptor is 50 0.005 to 2.5 nM, 0.01 nM to 2.5 nM, 0.025 to 2.5 nM, 0.005 to 2.0 nM, 0.01 nM to 2.0 nM, 0.025 to 2.0 nM, 0.005 to 1.5 nM, 0.01 nM to 1.5 nM, 0.025 to 1.5 nM, 0.005 to 1.0 nM, 0.01 nM to 1.0 nM 0.025 to 0.25 nM, for example when assessed using the GLP-1 receptor potency assay as described in PCT / EP2022 / 074420.

[0168] A surrogate measure of GLP-1 agonist activity can be obtained 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. Thus, the relative potency at the GLP-1 receptor can be defined as:

[0169] [EC 50 (reference agonist)] / [EC 50 (dual agonist)].

[0170] Thus, a value of 1 indicates that the dual agonist and the reference agonist have equal potency, and a value > 1 indicates that the dual agonist has higher potency (i.e., lower EC 50 ), and values ​​< 1 indicate that the dual agonist has lower potency (i.e., higher EC 50 ).

[0171] The reference GLP-1 agonist may be, for example, human GLP-1 (7-37), liraglutide (NN2211; Victoza) or Exendin-4, but is preferably liraglutide.

[0172] Generally, the relative potency will be from 0.001 to 100, e.g., 0.001 to 10, 0.001 to 5, 0.001 to 1, 0.001 to 0.5, 0.001 to 0.1, 0.001 to 0.05, or 0.001 to 0.01; 0.01 to 10, 0.01 to 5, 0.01 to 1, 0.01 to 0.5, 0.01 to 0.1, or 0.01 to 0.05; 0.05 to 10, 0.05 to 5, 0.05 to 1, 0.05 to 0.5, or 0.05 to 0.1; 0.1 to 10, 0.1 to 5, 0.1 to 1, or 0.1 to 0.5; 0.5 to 10, 0.5 to 5, or 0.5 to 1; 1 to 10, or 1 to 5; or 5 to 10.

[0173] The dual agonists described in the Examples below have slightly lower GLP-1 potency than liraglutide, and thus may, for example, have a relative potency of 0.01 to 1, 0.01 to 0.5, or 0.01 to 0.1.

[0174] In contrast, the dual agonists of the present invention have a higher potency at the GLP-1 receptor (e.g., human GLP-1 receptor) than wild-type human GLP-2 (hGLP-2(1-33)) or [Gly2]-hGLP-2(1-33) (i.e., human GLP-2 with glycine at position 2, also known as teduglutide). Thus, the relative potency of the dual agonists at the GLP-1 receptor compared to hGLP-2(1-33) or teduglutide is greater than 1, typically greater than 5 or greater than 10, and can be as high as 100, as high as 500, or even higher.

[0175] GLP-2 activity

[0176] In some embodiments, the EC of the dual agonist at a GLP-2 receptor (e.g., a human GLP-2 receptor) is 50Less than 2.0 nM, less than 1.5 nM, less than 1.0 nM, less than 0.9 nM, less than 0.8 nM, less than 0.7 nM, less than 0.6 nM, less than 0.5 nM, less than 0.4 nM, less than 0.3 nM, less than 0.2 nM, less than 0.1 nM, less than 0.09 nM, less than 0.08 nM, less than 0.07 nM, less than 0.06 nM, less than 0.05 nM, less than 0.04 nM, less than 0.03 nM, less than 0.02 nM or less than 0.01 nM, for example when assessed using a GLP-2 receptor potency assay as described in PCT / EP2022 / 074420.

[0177] In some embodiments, the EC of the dual agonist at the GLP-2 receptor is 50 0.005 to 2.0 nM, 0.01 nM to 2.0 nM, 0.025 to 2.0 nM, 0.005 to 1.5 nM, 0.01 nM to 1.5 nM, 0.025 to 1.5 nM, 0.005 to 1.0 nM, 0.01 nM to 1.0 nM, 0.025 to 1.0 nM, 0.005 to 0.5 nM, 0.01 nM to 0.5 nM, 0.025 to 0.5 nM, 0.005 to 0.25 nM, 0.01 nM to 0.25 nM, 0.025 to 0.25 nM, for example when assessed using a GLP-2 receptor potency assay as described in PCT / EP2022 / 074420.

[0178] A surrogate measure of GLP-2 agonist activity can be obtained by comparing the potency of a dual agonist to the potency of a known (or reference) GLP-2 agonist when both are measured in the same assay. Thus, the relative potency at the GLP-2 receptor can be defined as:

[0179] [EC 50 (reference agonist)] / [EC 50 (dual agonist)].

[0180] Thus, a value of 1 indicates that the dual agonist and the reference agonist have equal potency, and a value > 1 indicates that the dual agonist has higher potency (i.e., lower EC 50 ), and values ​​< 1 indicate that the dual agonist has lower potency (i.e., higher EC 50 ).

[0181] The reference GLP-2 agonist may be, for example, human GLP-2(1-33) or teduglutide ([Gly2]-hGLP-2(1-33)), but is preferably teduglutide. Generally, the relative potency will be from 0.001 to 100, e.g., 0.001 to 10, 0.001 to 5, 0.001 to 1, 0.001 to 0.5, 0.001 to 0.1, 0.001 to 0.05, or 0.001 to 0.01; 0.01 to 10, 0.01 to 5, 0.01 to 1, 0.01 to 0.5, 0.01 to 0.1, or 0.01 to 0.05; 0.05 to 10, 0.05 to 5, 0.05 to 1, 0.05 to 0.5, or 0.05 to 0.1; 0.1 to 10, 0.1 to 5, 0.1 to 1, or 0.1 to 0.5; 0.5 to 10, 0.5 to 5, or 0.5 to 1; 1 to 10, or 1 to 5; or 5 to 10.

[0182] The dual agonists described in the Examples below have slightly lower GLP-2 potency than teduglutide, and thus may, for example, have a relative potency of 0.01 to 1, 0.01 to 0.5, or 0.01 to 0.1.

[0183] In contrast, the dual agonists of the present invention have a higher potency at the GLP-2 receptor (e.g., human GLP-2 receptor) than human GLP-1 (7-37), liraglutide (NN2211; Victoza), or exendin-4. Thus, the relative potency of the dual agonists at the GLP-2 receptor compared to human GLP-1 (7-37), liraglutide (NN2211; Victoza), or exendin-4 is greater than 1, typically greater than 5 or greater than 10, and can be as high as 100, as high as 500, or even higher (if the reference GLP-1 agonist even exerts detectable activity at the GLP-2 receptor).

[0184] It will be appreciated that the absolute potency of a dual agonist at each receptor is far less important than the balance between GLP-1 and GLP-2 agonist activity. Thus, it is perfectly acceptable for the absolute GLP-1 or GLP-2 potency to be lower than that of known agonists at those receptors, as long as the dual agonist compound exerts an acceptable relative potency level at both receptors. Any apparent deficiency in absolute potency can be compensated for by increasing the dosage, if necessary.

[0185] Pharmaceutical composition

[0186] One aspect of the present invention relates to a composition comprising a dual agonist according to the present invention or a pharmaceutically acceptable salt or solvate thereof, and a carrier. In one embodiment of the present invention, the composition is a pharmaceutical composition and the carrier is a pharmaceutically acceptable carrier. The present invention also relates to a pharmaceutical composition comprising a dual agonist according to the present invention or a salt or solvate thereof, and a carrier, excipient or carrier. Therefore, the dual agonist of the present invention, or a salt or solvate thereof (especially a pharmaceutically acceptable salt or solvate thereof) can be formulated into a composition or pharmaceutical composition prepared for storage or administration, and it comprises a therapeutically effective amount of the dual agonist of the present invention or a salt or solvate thereof.

[0187] Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts, such as sodium, potassium or magnesium salts; ammonium salts and organic amine salts, such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, lower monoalkylamine, lower dialkylamine or lower trialkylamine (e.g., ethyl-tert-butylamine, diethylamine, diisopropylamine, triethylamine, tributylamine or dimethylpropylamine), or lower mono(hydroxyalkyl)amine, lower di(hydroxyalkyl)amine or lower tri(hydroxyalkyl)amine (e.g., monoethanolamine, diethanolamine or triethanolamine). Inner salts can also be formed. Similarly, when the compounds of the present invention contain a basic moiety, organic or inorganic acids can be used to form salts. For example, salts can be formed from 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), camphorsulfonic acid, 2-aminoethanesulfonic acid, aminomethylphosphonic acid, and trifluoromethanesulfonic acid (trifluoromethanesulphonic acid) (the latter is also known as triflicacid), 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.

[0188] In one embodiment, the pharmaceutical composition of the invention is one wherein the dual agonist is in the form of a pharmaceutically acceptable acid addition salt.

[0189] In some embodiments, the pharmaceutical composition of the present invention is formulated as a 1 mL solution for injection.

[0190] In some embodiments, the pharmaceutical compositions of the present invention are formulated as follows:

[0191] (i) at least about 1 mg / mL of one or more GLP-1 / GLP-2 dual agonists

[0192] (ii) 5 mM to about 50 mM phosphate buffer component

[0193] (iii) about 190 mM to about 240 mM mannitol

[0194] and a pH of about pH 8.0.

[0195] In some aspects, the compositions of the present invention include the following ingredients:

[0196]

[0197] GLP-1 / GLP-2 dual agonists are

[0198] A pharmaceutically acceptable salt of Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH (SEQ ID NO: 5).

[0199] In some aspects, the compositions of the present invention include the following ingredients:

[0200]

[0201]

[0202] GLP-1 / GLP-2 dual agonists are

[0203] Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-

[0204] isoGlu)]QAARDFIAWLIQHKITD-OH (SEQ ID NO: 5)]a pharmaceutically acceptable salt.

[0205] Dosage regimen

[0206] It will be appreciated that the dose of the GLP-1 / GLP-2 dual agonist and the dose of the amylin analogue may be selected independently. The dose of the GLP-1 / GLP-2 dual agonist may be selected as described herein.

[0207] According to the present invention, dual GLP-1 / GLP-2 agonists are used in methods of reducing or inhibiting weight gain, reducing food intake, reducing appetite, promoting weight loss, or treating obesity, morbid obesity, obesity-related gallbladder disease, or obesity-induced sleep apnea. The present invention includes methods of administering the dual agonist to a patient at a dose of about 0.1 mg to 10.0 mg.

[0208] A dual agonist of about 0.1 mg to 10.0 mg dose is administered to a patient in a single administration (i.e., a single administration event). In other words, the dual agonist is administered to a patient in a single dose formulation of about 0.1 mg to about 10.0 mg. The single dose formulation can be administered to a patient once or more, wherein each of the multiple dose formulations administered to the patient does not need to contain the same amount of dual agonist. In other words, the dual agonist can be administered to a patient in a series of single administrations, wherein each of the single administrations may not contain the same amount of dual agonist. Each dual agonist administration performed on a patient can be independently selected to be administered at a dose of about 0.1 mg to about 10.0 mg.

[0209] Therefore, the present invention provides a GLP-1 / GLP-2 dual agonist as described herein or a pharmaceutically acceptable salt or solvate thereof, wherein the GLP-1 / GLP-2 dual agonist or a pharmaceutically acceptable salt or solvate thereof is used in such a method: reducing or inhibiting weight gain, reducing food intake, reducing appetite, promoting weight loss, or treating obesity, morbid obesity, obesity-related gallbladder disease, or obesity-induced sleep apnea; wherein the method comprises administering the dual agonist to the patient at least once at a dose of about 0.1 mg to 10.0 mg.

[0210] dose

[0211] In one aspect, the dual agonist is administered to a patient at a dosage of about 0.1 mg to about 10.0 mg. In one aspect, the dual agonist is administered to a patient at a dosage of about 1.0 mg to about 10.0 mg. In one aspect, the dual agonist is administered to a patient at a dosage of about 1.1 mg to about 10.0 mg, about 1.2 mg to about 10.0 mg, about 1.3 mg to about 10.0 mg, or about 1.4 mg to about 10.0 mg. In one aspect, the dual agonist is administered to a patient at a dosage of about 1.5 mg to about 10.0 mg. In one aspect, the dual agonist is administered to a patient at a dosage of about 1.6 mg to about 10.0 mg, about 1.7 mg to about 10.0 mg, about 1.8 mg to about 10.0 mg, or about 1.9 mg to about 10.0 mg. In one aspect, the dual agonist is administered to a patient at a dosage of about 2.0 mg to about 10.0 mg. In one aspect, the dual agonist is administered to a patient at a dose of about 2.1 mg to about 10.0 mg, or about 2.2 mg to about 10.0 mg. In one aspect, the dual agonist is administered to a patient at a dose of about 2.25 mg to about 10.0 mg. In one aspect, the dual agonist is administered to a patient at a dose of about 3.0 mg to about 10.0 mg, about 4.0 mg to about 10.0 mg, about 5.0 mg to about 10.0 mg, about 6.0 mg to about 10.0 mg, about 7.0 mg to about 10.0 mg, about 8.0 mg to about 10.0 mg, or about 9.0 mg to about 10.0 mg.

[0212] In one aspect, the dual agonist is administered to a patient at a dosage of about 0.1 mg to about 9.0 mg. In one aspect, the dual agonist is administered to a patient at a dosage of about 1.0 mg to about 9.0 mg. In one aspect, the dual agonist is administered to a patient at a dosage of about 1.1 mg to about 9.0 mg, about 1.2 mg to about 9.0 mg, about 1.3 mg to about 9.0 mg, or about 1.4 mg to about 9.0 mg. In one aspect, the dual agonist is administered to a patient at a dosage of about 1.5 mg to about 9.0 mg. In one aspect, the dual agonist is administered to a patient at a dosage of about 1.6 mg to about 9.0 mg, about 1.7 mg to about 9.0 mg, about 1.8 mg to about 9.0 mg, or about 1.9 mg to about 9.0 mg. In one aspect, the dual agonist is administered to a patient at a dosage of about 2.0 mg to about 9.0 mg. In one aspect, the dual agonist is administered to a patient at a dose of about 2.1 mg to about 9.0 mg, or about 2.2 mg to about 9.0 mg. In one aspect, the dual agonist is administered to a patient at a dose of about 2.25 mg to about 9.0 mg. In one aspect, the dual agonist is administered to a patient at a dose of about 3.0 mg to about 9.0 mg, about 4.0 mg to about 9.0 mg, about 5.0 mg to about 9.0 mg, about 6.0 mg to about 9.0 mg, about 7.0 mg to about 9.0 mg, or about 8.0 mg to about 9.0 mg.

[0213] In one aspect, the dual agonist is administered to a patient at a dosage of about 0.1 mg to about 8.0 mg. In one aspect, the dual agonist is administered to a patient at a dosage of about 1.0 mg to about 8.0 mg. In one aspect, the dual agonist is administered to a patient at a dosage of about 1.1 mg to about 8.0 mg, about 1.2 mg to about 8.0 mg, about 1.3 mg to about 8.0 mg, or about 1.4 mg to about 8.0 mg. In one aspect, the dual agonist is administered to a patient at a dosage of about 1.5 mg to about 8.0 mg. In one aspect, the dual agonist is administered to a patient at a dosage of about 1.6 mg to about 8.0 mg, about 1.7 mg to about 8.0 mg, about 1.8 mg to about 8.0 mg, or about 1.9 mg to about 8.0 mg. In one aspect, the dual agonist is administered to a patient at a dosage of about 2.0 mg to about 8.0 mg. In one aspect, the dual agonist is administered to a patient at a dose of about 2.1 mg to about 8.0 mg, or about 2.2 mg to about 8.0 mg. In one aspect, the dual agonist is administered to a patient at a dose of about 2.25 mg to about 8.0 mg. In one aspect, the dual agonist is administered to a patient at a dose of about 3.0 mg to about 8.0 mg, about 4.0 mg to about 8.0 mg, about 5.0 mg to about 8.0 mg, about 6.0 mg to about 8.0 mg, or about 7.0 mg to about 8.0 mg.

[0214] In one aspect, the dual agonist is administered to a patient at a dose of about 1.0 mg to about 7.5 mg, about 1.0 mg to about 7.0 mg, about 1.0 mg to about 6.0 mg, about 1.0 mg to about 5.0 mg, about 1.0 mg to about 4.0 mg, or about 1.0 mg to about 3.5 mg. In one aspect, the dual agonist is administered to a patient at a dose of about 1.5 mg to about 7.5 mg. In one aspect, the dual agonist is administered to a patient at a dose of about 1.5 mg to about 7.0 mg, about 1.5 mg to about 6.0 mg, about 1.5 mg to about 5.0 mg, about 1.5 mg to about 4.0 mg, or about 1.5 mg to about 3.5 mg. In one aspect, the dual agonist is administered to a patient at a dose of about 2.0 mg to about 7.5 mg, about 2.0 mg to about 7.0 mg, about 2.0 mg to about 6.0 mg, about 2.0 mg to about 5.0 mg, about 2.0 mg to about 4.0 mg, or about 2.0 mg to about 3.5 mg. In one aspect, the dual agonist is administered to a patient at a dose of about 2.25 mg to about 7.5 mg, about 2.25 mg to about 7.0 mg, about 2.25 mg to about 6.0 mg, about 2.25 mg to about 5.0 mg, about 2.25 mg to about 4.0 mg, or about 2.25 mg to about 3.5 mg. In one aspect, the dual agonist is administered to a patient at a dose of about 4.0 mg to about 7.5 mg. In one aspect, the dual agonist is administered to a patient at a dose of about 4.0 mg to about 6.0 mg.

[0215] In one aspect, the dual agonist is administered to a patient at a dosage of 1.0 mg to 7.5 mg, 1.0 mg to 7.0 mg, 1.0 mg to 6.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 4.0 mg, or 1.0 mg to 3.5 mg. In one aspect, the dual agonist is administered to a patient at a dosage of 1.5 mg to 7.5 mg. In one aspect, the dual agonist is administered to a patient at a dosage of 1.5 mg to 7.0 mg, 1.5 mg to 6.0 mg, 1.5 mg to 5.0 mg, 1.5 mg to 4.0 mg, or 1.5 mg to 3.5 mg. In one aspect, the dual agonist is administered to a patient at a dosage of 2.0 mg to 7.5 mg, 2.0 mg to 7.0 mg, 2.0 mg to 6.0 mg, 2.0 mg to 5.0 mg, 2.0 mg to 4.0 mg, or 2.0 mg to 3.5 mg. In one aspect, the dual agonist is administered to a patient at a dose of 2.25 mg to 7.5 mg, 2.25 mg to 7.0 mg, 2.25 mg to 6.0 mg, 2.25 mg to 5.0 mg, 2.25 mg to 4.0 mg, or 2.25 mg to 3.5 mg. In one aspect, the dual agonist is administered to a patient at a dose of 4.0 mg to 7.5 mg. In one aspect, the dual agonist is administered to a patient at a dose of 4.0 mg to 6.0 mg.

[0216] In one aspect, the dose is greater than 0.6 mg. In one aspect, the dual agonist is administered to a patient at a dose of about 1.5 mg.

[0217] In some aspects, the dual agonist is administered to a patient at a dose of about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 7.5 mg, about 8.0 mg, about 9.0 mg, or about 10.0 mg. In some aspects, the dual agonist is administered to a patient at a dose of 1.0 mg, 1.5 mg, 2.0 mg, 2.25 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 9.0 mg, or 10.0 mg.

[0218] Application

[0219] Administration of the dual agonists described herein can be carried out by any mode of administration common or standard in the art, such as oral, intravenous, intramuscular, subcutaneous, sublingual, intranasal, intradermal, suppository routes or implantation. In a preferred embodiment of the invention described herein, administration is carried out by subcutaneous injection.

[0220] The dosing regimen of the present invention may involve administering more than one dose of a dual agonist. Therefore, in some aspects, the present invention provides a GLP-1 / GLP-2 dual agonist or a pharmaceutically acceptable salt or solvate thereof as described herein, wherein the GLP-1 / GLP-2 dual agonist or a pharmaceutically acceptable salt or solvate thereof is used in such a method: reducing or inhibiting weight gain, reducing food intake, reducing appetite, promoting weight loss, or treating obesity, morbid obesity, obesity-related gallbladder disease, or obesity-induced sleep apnea, wherein the method comprises administering the dual agonist to the patient once or more at a dose of about 0.1 mg to 10.0 mg. In some aspects, the method comprises administering the dual agonist to the patient twice or more at a dose of about 0.1 mg to 10.0 mg. In some aspects, the dose of each dual agonist administered to the patient is about 0.1 mg to 10.0 mg.

[0221] In some aspects of the invention, wherein the method comprises administering the dual agonist to the patient more than once, the dose of the dual agonist may be different at each administration. In other words, the dose of the dual agonist need not be the same at each administration. However, in other aspects of the invention, wherein the method comprises administering the dual agonist to the patient more than once, the dose of the dual agonist may be the same or substantially the same at each administration.

[0222] For some aspects of the invention, a series of single administrations are delivered to the patient, wherein the initial course of a single administration may have a subsequent increase in the dose of the dual agonist in the single dose formulation. In some aspects, the initial course may include any of the following: 2, 3, 4, 5, 6, 7, 8, 9, 10 or more administrations of an increase in the amount of the dual agonist in the single administration formulation. In some aspects, after the initial course, the amount of the subsequent dose of the dual agonist in the single dose formulation may be the same as the last dose of the initial course, or may be less than the dose of the last dose of the initial course, or may be higher than the last dose of the initial course. In some aspects, after the initial course, the amount of the subsequent dose of the dual agonist in the single dose formulation may be the same or approximately the same as the last dose of the initial course.

[0223] Administration may involve administration of a dual agonist weekly. Reference to "weekly" is intended to mean about every 7 days, for example, about every 5 days, 5.5 days, 6 days, 6.5 days, 7 days, 7.5 days, 8 days, 8.5 days or 9 days, wherein each "day" is considered to be about a 24-hour period. As will be understood in the art, the time between doses may vary to a certain extent so that each dose is not separated by the exact same time from each dose. This will generally be guided at the discretion of the physician. Therefore, the doses may be separated in time by a clinically acceptable time range. In one aspect of the invention described herein, reference to "weekly" may mean 7 days ± 2 days. That is, administration may be performed until and including two days before the prescribed date or until and including two days after the prescribed date. Therefore, administration may be performed 2 days or 1 day before the prescribed date, or 1 day or 2 days after the prescribed date. In one aspect, the dual agonist is administered weekly at a dose of about 1.5 mg to about 10.0 mg, such as about 1.5 mg to about 7.5 mg, such as about 1.5 mg to about 6.0 mg, such as about 1.5 mg to about 4.0 mg, such as about 1.5 mg to about 3.5 mg. In one aspect, the dual agonist is administered weekly at a dose of about 2.0 mg to about 7.5 mg, such as about 2.0 mg to about 6.0 mg, such as about 2.0 mg to about 4.0 mg, such as about 2.0 mg to about 3.5 mg. In one aspect, the dual agonist is administered weekly at a dose of about 2.25 mg to about 3.5 mg. In one aspect, the dual agonist is administered weekly at a dose of 1.5 mg to 10.0 mg, such as about 1.5 mg to about 7.5 mg, such as 1.5 mg to 6.0 mg, such as 1.5 mg to 4.0 mg, such as 1.5 mg to 3.5 mg. In one aspect, the dual agonist is administered weekly at a dose of 2.0 mg to 7.5 mg, such as 2.0 mg to 6.0 mg, such as 2.0 mg to 4.0 mg, such as 2.0 mg to 3.5 mg. In one aspect, the dual agonist is administered weekly at a dose of 2.25 mg to 3.5 mg.

[0224] In one aspect, the number of doses administered to a patient can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or more doses. In other words, in some aspects, the dual agonist is administered to a patient 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times or more. In some aspects, the method comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times or more of dual agonist administration. In some aspects, the dual agonist is administered to a patient 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times or more at a dose of about 0.1 to 10.0 mg (or at any other dose described herein) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times or more. In some aspects, the method comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 or more administrations of the dual agonist at a dose of about 0.1 to 10.0 mg (or at any other dose described herein). In one aspect, 4 doses are administered to the patient. In one aspect, the method comprises 4 administrations of the dual agonist at a dose of about 0.1 to 10.0 mg (or at any other dose described herein). In one aspect, 12 doses are administered to the patient. In one aspect, the method comprises 12 administrations of the dual agonist at a dose of about 0.1 to 10.0 mg (or at any other dose described herein).

[0225] In one aspect, the agonist may be administered at the same dose each time. In one aspect, the dose of each administration of the dual agonist to the patient is about 0.1 mg to 10.0 mg.

[0226] In one aspect, multiple doses are administered to the patient over a period of weeks, or months, or 1 year or more.

[0227] In one aspect, multiple doses are administered to the patient each week over a period of weeks, or months, or 1 year or more.

[0228] In one aspect, the agonist may be administered in ascending doses.

[0229] Titration and treatment

[0230] The dosage of the dual agonists according to the invention may be a titration dose or a therapeutic dose.

[0231] The term "titration dose" refers to the dose of the dual agonist administered to the patient at each administration during the titration period, prior to administration at the therapeutic dose. Each titration dose is an amount of 0.1 mg to 10.0 mg of the dual agonist. The doses, dosing regimens, and administration regimens set forth herein are equally applicable to one or more titration doses.

[0232] The term "therapeutic dose" refers to the dose of the dual agonist administered to the patient at each administration during the treatment period. Each therapeutic dose is an amount of 0.1 mg to 10.0 mg of the dual agonist. The doses, dosing regimens, and administration regimens set forth herein are equally applicable to one or more therapeutic doses.

[0233] In some aspects, the dual agonist is administered to the patient according to a titration regimen. The titration regimen includes an initial set of one or more administrations of the dual agonist during a "titration period," followed by one or more administrations of the dual agonist during a "treatment period." Generally, the dose of the dual agonist at each administration during the titration period is lower than the dose at each administration during the treatment period.

[0234] The first purpose of the titration period is to acclimate the patient to the side effects of the dual agonist. The initial administration of the dual agonist may produce side effects that decrease in severity after further administration as the patient acclimates. Administering the dual agonist at a lower dose during the titration period may reduce the initial severity of these side effects. A second purpose of the titration period may be to determine the appropriate dose of the dual agonist for the patient. The dose of the dual agonist may be increased throughout the titration period, allowing the physician to observe side effects at different doses and thereby determine the appropriate dose for treatment.

[0235] Therefore, in some aspects, the present invention provides a GLP-1 / GLP-2 dual agonist as described herein, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of reducing or inhibiting weight gain, reducing food intake, reducing appetite, promoting weight loss, or treating obesity, morbid obesity, obesity-related gallbladder disease, or obesity-induced sleep apnea; wherein the method comprises administering the dual agonist to the patient at least once at a dose of about 0.1 mg to 10.0 mg, and wherein the method comprises administering the dual agonist to the patient at least once at a titrated dose, and administering the dual agonist to the patient at least once at a therapeutic dose. In other words, in some aspects, the method comprises administering the dual agonist to the patient at least once at a titrated dose, and administering the dual agonist to the patient at least once at a therapeutic dose.

[0236] In some aspects, the method includes administering more than one administration of a dual agonist to a patient at a titration dose (i.e., 2 or more administrations). In some aspects, the method includes administering 3 or more, 4 or more, or 5 or more dual agonists to a patient at a titration dose. In some aspects, the method includes administering 1, 2, 3, 4, or 5 dual agonists to a patient at a titration dose. In some preferred aspects, the method includes administering 2 dual agonists to a patient at a titration dose. In some preferred aspects, the method includes administering 5 dual agonists to a patient at a titration dose.

[0237] In one aspect, there may be at least one initial titration period of a lower dose before the dose is increased. In one aspect, the titration period may consist of 1, 2, 3 or 4 doses of the lower dose, wherein preferably each dose is the same. In one aspect, the titration period consists of 1 dose of the lower dose. In one aspect, the titration period consists of 2 doses of the lower dose.

[0238] In a preferred aspect, the titrated dose is administered weekly. In other words, in some aspects, the method comprises administering the dual agonist to the patient once a week at a titrated dose.

[0239] The titration dose can be any dose of the dual agonist as described elsewhere herein. In some aspects, the titration dose is about 0.1 mg to about 10.0 mg. In some aspects, the titration dose is about 1.0 mg to about 6.0 mg, for example, about 1.5 mg to about 6.0 mg. Therefore, in some aspects, the method includes administering at least one dual agonist to the patient at a titration dose of about 1.5 mg to about 6.0 mg. In one aspect, the titration dose is about 1.0 mg to about 4.0 mg, for example, about 1.5 mg to about 4.0 mg. In one aspect, the titration dose is about 1.0 mg to about 3.5 mg, for example, about 1.5 mg to about 3.5 mg, or about 1.5 mg to about 3.0 mg. In one aspect, the titration dose is 1.0 mg, 2.0 mg, 2.25 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, or 6.0 mg, or is about 1.0 mg, 2.0 mg, 2.25 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, or 6.0 mg. In some aspects, the titration dose is 2.0 mg. In some aspects, the titration dose is 2.0 mg, administered once a week. In some aspects, the titration dose is 4.0 mg. In some aspects, the titration dose is 4.0 mg, administered once a week.

[0240] The titration dose administered each time need not be the same. In other words, different titration doses may be administered to the patient during the titration period. Therefore, in some aspects, the present invention provides a GLP-1 / GLP-2 dual agonist or a pharmaceutically acceptable salt or solvate thereof as described herein, wherein the GLP-1 / GLP-2 dual agonist or a pharmaceutically acceptable salt or solvate thereof is used in the following method: reducing or inhibiting weight gain, reducing food intake, reducing appetite, promoting weight loss, or treating obesity, morbid obesity, obesity-related gallbladder disease, or obesity-induced sleep apnea; wherein the method comprises administering the dual agonist to the patient at least once at a dose of about 0.1 mg to 10.0 mg, and wherein the method comprises administering the dual agonist to the patient at least once at one or more titration doses, and administering the dual agonist to the patient at least once at a therapeutic dose.

[0241] In some aspects, the method includes 2 or more, 3 or more, or 4 or more different titration doses. In some aspects, the method includes 2, 3 or 4 different titration doses. In some preferred aspects, the method includes 2 different titration doses. Each titration dose can be any one of the doses of the dual agonist described elsewhere herein.

[0242] In some aspects, all titration doses are the same (ie, there is one titration dose that is the same for all administrations of the dual agonist to the patient during the titration period).

[0243] In some aspects, the method comprises administering to the patient one dual agonist at a titrated dose of 3.5 mg. In some aspects, the method comprises administering to the patient two dual agonist at a titrated dose of 2.0 mg. In some aspects, the method comprises administering to the patient two dual agonist at a titrated dose of 2.0 mg, and administering to the patient three dual agonist at a titrated dose of 4.0 mg.

[0244] In some aspects, the method includes administering more than one administration of a dual agonist to a patient at a therapeutic dose (i.e., 2 or more administrations). In some aspects, the method includes administering 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more dual agonist administrations to a patient at a therapeutic dose. In some aspects, the method includes administering 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 dual agonist administrations to a patient at a therapeutic dose. In some preferred aspects, the method includes administering 3 dual agonists to a patient at a therapeutic dose. In some preferred aspects, the method includes administering 10 dual agonists to a patient at a therapeutic dose. In some preferred aspects, the method includes administering 7 dual agonists to a patient at a therapeutic dose.

[0245] Therapeutic doses can continue to be administered as long as necessary. Therapeutic doses of the dual agonist can be administered to a patient for a period of, for example, one month to twenty years, such as one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, eleven years, twelve years, thirteen years, fourteen years, fifteen years, sixteen years, seventeen years, eighteen years, nineteen years, or twenty years.

[0246] For example, a therapeutic dose can be administered to a patient weekly for a period of, e.g., one month to twenty years, e.g., for a period of one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, eleven years, twelve years, thirteen years, fourteen years, fifteen years, sixteen years, seventeen years, eighteen years, nineteen years, or twenty years.

[0247] The therapeutic dose can be any dose of the dual agonist described herein. In some aspects, the therapeutic dose is about 0.1 mg to about 10.0 mg. In some aspects, the therapeutic dose is about 1.0 mg to about 10.0 mg, about 1.5 mg to about 10.0 mg, about 2.0 mg to about 10.0 mg, about 2.25 mg to about 10.0 mg, about 3.0 mg to about 10.0 mg, about 4.0 mg to about 10.0 mg, about 5.0 mg to about 10.0 mg, about 6.0 mg to about 10.0 mg, about 7.0 mg to about 10.0 mg, about 8.0 mg to about 10.0 mg, or about 9.0 mg to about 10.0 mg. In some aspects, the therapeutic dose is about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 7.5 mg, about 8.0 mg, about 9.0 mg, or about 10.0 mg. In some aspects, the therapeutic dose is 1.0 mg, 1.5 mg, 2.0 mg, 2.25 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 9.0 mg, or 10.0 mg.

[0248] Generally speaking, in aspects where the dual agonist is administered to a patient more than once at a therapeutic dose (i.e., the dual agonist is administered multiple times at a therapeutic dose), all administrations within a treatment period are at the same dose. Thus, in some aspects, all therapeutic doses are the same (i.e., there is one therapeutic dose that is the same for all administrations of the dual agonist to a patient within a treatment period).

[0249] However, the therapeutic dose does not need to be the same for each administration. In other words, different therapeutic doses can be administered to the patient during the treatment period. The therapeutic dose can be varied depending on the patient's response to the dual agonist. For example, if a patient experiences severe side effects at a given therapeutic dose, the therapeutic dose can be reduced in future administrations to reduce the severity of the side effects.

[0250] Therefore, in some aspects, the present invention provides a GLP-1 / GLP-2 dual agonist as described herein, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of reducing or inhibiting weight gain, reducing food intake, reducing appetite, promoting weight loss, or treating obesity, morbid obesity, obesity-related gallbladder disease, or obesity-induced sleep apnea; wherein the method comprises administering the dual agonist to the patient at least once at a dose of about 0.1 mg to 10.0 mg, and wherein the method comprises administering the dual agonist to the patient at least once at one or more titration doses, and administering the dual agonist to the patient at least once at one or more therapeutic doses.

[0251] In some aspects, the method comprises 2 or more, 3 or more, or 4 or more different therapeutic doses. In some aspects, the method comprises 2, 3 or 4 different therapeutic doses. Each therapeutic dose can be any one of the doses of the dual agonist described elsewhere herein.

[0252] Generally speaking, the therapeutic dose is higher than the titration dose. Thus, in some aspects, the therapeutic dose is higher than the titration dose. In some aspects, the therapeutic dose is higher than some or all of the titration dose.

[0253] However, the therapeutic dose may be lower than the titration dose. This may be the case, for example, where the titration dose increases as the titration period progresses (i.e., the titration dose becomes higher with continued administration), but then the dose is reduced for the therapeutic dose in view of the side effects experienced by the patient as the titration dose increases. Thus, in some aspects, the therapeutic dose is lower than the titration dose. In some aspects, the therapeutic dose is lower than some or all of the titration dose.

[0254] As described herein, one purpose of titration is to determine an appropriate therapeutic dose. Thus, in some aspects, the therapeutic dose is determined by a physician observing the effect of the titration on the patient. In other words, the therapeutic dose may depend on the titration dose.

[0255] In a preferred aspect, the therapeutic dose is administered weekly. In other words, in some aspects, the method comprises administering the dual agonist to the patient once a week at a therapeutic dose. In some aspects, the method comprises administering the dual agonist to the patient once a week at a titrated dose and once a week at a therapeutic dose. In other words, administering the dual agonist once a week at a therapeutic dose is a continuation of administering it once a week at a titrated dose.

[0256] In one aspect, the titration period can be followed by one or more doses, which are doses higher than the titration dose. In one aspect, the titration period is followed by 1, 2, 3 or 4 doses, which are doses higher than the titration dose. In one aspect, the titration period is followed by 3 doses, which are doses higher than the titration dose. In one aspect, the titration period is followed by 10 doses, which are doses higher than the titration dose. In one aspect, the titration period is followed by 7 doses, which are doses higher than the titration dose. In one aspect, the titration period is composed of 1 dose and is followed by 3 doses at a dose higher than the titration dose. In one aspect, the titration period is composed of 2 doses and is followed by 10 doses at a dose higher than the titration dose. In one aspect, a higher dose is about 3 mg to about 8 mg. In one aspect, a higher dose is about 3 mg to about 8 mg.

[0257] In some aspects, the method comprises administering to the patient one dual agonist at a titrated dose of 3.5 mg and administering to the patient three dual agonist administrations at a therapeutic dose of 6.0 mg, wherein each administration is performed once per week.

[0258] In some aspects, the method comprises administering to the patient two dual agonist administrations at a titrated dose of 2.0 mg and administering to the patient ten dual agonist administrations at a therapeutic dose of 4.0 mg, wherein each administration is performed once per week.

[0259] In some aspects, the method comprises administering to the patient two dual agonist administrations at a titrated dose of 2.0 mg, administering to the patient three dual agonist administrations at a titrated dose of 4.0 mg, and administering to the patient seven dual agonist administrations at a therapeutic dose of 6.0 mg, wherein each administration is performed once per week.

[0260] In one aspect, the higher dose (after the titration period) is or is about 6.0 mg, 7.0 mg, 7.5 mg or 8.0 mg, preferably 6.0 mg.

[0261] Titrated doses may be administered daily, every other day, or weekly.

[0262] After titration, the dose is administered daily, every other day, or weekly.

[0263] Advantageously, the subject may not experience nausea or vomiting (or other adverse gastrointestinal effects) during the titration period. This allows for a shorter or accelerated titration period before administering a higher dose.

[0264] In one aspect, there may be more than one titration period.

[0265] In one aspect of the invention, further doses are administered after the above doses, ie, the subject may continue to receive doses after the initial dose described herein.

[0266] Additional dosing may be given weekly.

[0267] Administration of the dual agonist may continue as long as necessary.

[0268] The above additional dosages can be administered as needed for a period of, for example, one month to twenty years, such as one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, eleven years, twelve years, thirteen years, fourteen years, fifteen years, sixteen years, seventeen years, eighteen years, nineteen years, or twenty years.

[0269] In a preferred aspect, the dual agonist is administered to the subject daily.

[0270] Medical conditions

[0271] The dual agonists described in this specification have the biological activities of both GLP-1 and GLP-2.

[0272] GLP-1 is a peptide hormone known for its important role in glucose homeostasis. When secreted by 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). In addition, GLP-1 or its analogs have been shown to increase somatostatin secretion and inhibit glucagon secretion (Holst JJ, 2007, Physiol Rev. 1409-1439).

[0273] In addition to its primary effect on glucose-stimulated insulin secretion, GLP-1 is also known to be a key regulator of appetite, food intake, and body weight. In addition, GLP-1 can inhibit gastric emptying and gastrointestinal motility in both rodents and humans, most likely through GLP-1 receptors present in the gastrointestinal tract (Holst JJ, 2007, Physiol Rev. 1409-1439; et al., 2008, Neurogastroenterol Motil. Jun; 20(6): 649-659). In addition, GLP-1 appears to have insulin-like effects in major extrapancreatic tissues, participating in glucose homeostasis and lipid metabolism in tissues such as muscle, liver, and adipose tissue (Kim and Egan, 2008, Pharmacol. Rev. 470-512).

[0274] The dual agonist compounds described herein in combination with amylin analogs are also particularly useful for reducing or inhibiting weight gain, reducing gastric emptying rate or intestinal transit rate, reducing food intake, reducing appetite, or promoting weight loss. The effect on body weight may be mediated in part or in whole by reducing food intake, appetite, or intestinal transit.

[0275] Therefore, the dual agonists of the present invention can be used to prevent or treat obesity, morbid obesity, obesity-related gallbladder disease, and obesity-induced sleep apnea.

[0276] Independent of its effect on body weight, the dual agonists of the invention may have a beneficial effect on glucose tolerance and / or glucose control. They may also be used to modulate (e.g., improve) circulating cholesterol levels, can reduce circulating triglyceride or LDL levels, and increase the HDL / LDL ratio.

[0277] Therefore, it can be used to prevent or treat poor glycemic control, glucose tolerance or dyslipidemia (e.g., elevated LDL levels or reduced HDL / LDL ratio) and related conditions, including diabetes (e.g., type 2 diabetes, gestational diabetes), prediabetes, metabolic syndrome and hypertension.

[0278] Many of these conditions are also associated with obesity or being overweight. Thus, the effects of dual agonists on these conditions may be due in whole or in part to the effects of the dual agonists on body weight, or may be independent thereof.

[0279] The effect on body weight may be therapeutic or cosmetic.

[0280] The dual agonist activity of the compounds described herein may be particularly beneficial in many of the described conditions because the two activities may complement each other.

[0281] For example, malabsorption is a condition caused by abnormal absorption of water and / or food nutrients (e.g., amino acids, sugars, fats, vitamins, or minerals) through the gastrointestinal (GI) tract, leading to malnutrition and / or dehydration. Malabsorption can be the result of physical (e.g., traumatic) or chemical damage to the intestine. The dual agonists described in this specification may be able to improve intestinal barrier function, reduce gastric emptying, and increase intestinal absorption while normalizing intestinal transit time. This will not only help patients improve absorption of nutrients and fluids, but will also alleviate patients' social problems associated with dietary-stimulated intestinal motility.

[0282] Furthermore, intestinal function and metabolic disorders may be closely related, each contributing to the occurrence or symptoms of the other.

[0283] As mentioned above, obesity is associated with low-grade inflammation (sometimes referred to as "obesity-associated inflammation"). It is also widely recognized that obesity (along with other syndromes) leads to increased vascular permeability, which allows pathogens and toxins (such as LPS) to enter the cell walls of the intestine and thus trigger inflammation. Regardless of the cause and regardless of where the insult occurs, the changes caused by the inflammatory response are essentially the same. The inflammatory response can be acute (short-term) or chronic (longer lasting).

[0284] It has been shown, for example, that obese mice (ob / ob and db / db mice) have impaired mucosal barrier function and exhibit elevated low-grade inflammation (Brun et al., 2007, Am. J. Physiol. Gastrointest. Liver Physiol., 292: G518-G525, Epub 5 Oct 2006). These observations also extend to C57BL6 / J mice maintained on a high-fat diet (Cani et al., 2008, Diabetes, vol. 57, 1470-1481) and to non-obese diabetic mice (Hadjiyanni et al., 2009, Endocrinology, 150(2): 592–599).

[0285] Cani and colleagues (Gut; 2009, 58: 1091-1103,) reported that in ob / ob mice, modulation of the intestinal microbiota reduced intestinal barrier dysfunction and systemic inflammation through a GLP-2-dependent pathway. In addition, the increased intestinal permeability observed in obese and diabetic patients may play a more important role in disease progression than previously expected. Increased intestinal permeability leads to increased bacterial lipopolysaccharide (LPS) transport across the intestinal barrier. This increased LPS activates immune cells, such as circulating macrophages and macrophages present in organs in the body, causing low-grade chronic inflammation that can participate in the pathogenesis of many diseases. This phenomenon is called metabolic endotoxemia (ME).

[0286] In obese individuals, inflammatory processes may also play a role in causing metabolic dysfunction, such as insulin resistance and other metabolic disorders.

[0287] Thus, the dual agonist compounds of the invention are particularly useful for preventing or treating low-grade inflammation, especially in obese or overweight individuals, through the beneficial effects of their active GLP-1 agonist component and / or their active GLP-2 component.

[0288] The therapeutic efficacy of treatment with the dual agonists of the invention can be monitored by intestinal biopsy to examine villus morphology, by biochemical assessment of nutrient absorption, by non-invasive determination of intestinal permeability, by patient weight gain, or by improvement in symptoms associated with these conditions.

[0289] Amylin analogs

[0290] Amylin analogs (which may also be referred to as compounds or peptides) may be suitably prepared by standard synthetic methods. Thus, the peptides may be synthesized, for example, by a method comprising synthesizing the peptide stepwise or by fragment assembly by standard solid phase or liquid phase methods, and optionally isolating and purifying the final peptide product. For example, as described below, the method typically also includes a step of forming an amide bond between the side chains at positions 2 and 7. 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).

[0291] The amylin analogs according to the present invention may have the following formula or a pharmaceutically acceptable salt or solvate thereof:

[0292] R 1 -ZR 2

[0293] in:

[0294] R 1It is hydrogen, C 1-4 Acyl, benzoyl or C 1-4 alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L;

[0295] R 2 Is OH or NHR 3 , where R 3 is hydrogen or C 1-3 Alkyl; and

[0296] Z is an amino acid sequence of formula I:

[0297] 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(SEQID NO:8)

[0298] in:

[0299] X1 is selected from the group consisting of Arg, Lys and Glu;

[0300] X3 is selected from the group consisting of Gly, Gln and Pro;

[0301] X4 is selected from Thr and Glu;

[0302] X5 is selected from Ala and Leu;

[0303] X6 is selected from Thr and Ser;

[0304] X10 is selected from Glu and Gln;

[0305] X14 is selected from the group consisting of Aad, His, Asp, Asn and Arg;

[0306] X17 is selected from the group consisting of Gln, His and Thr;

[0307] X19-X20 are selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly and Ala-Asn, or are absent;

[0308] X27 is selected from Leu and Pro;

[0309] X32 is selected from Val and Thr;

[0310] X35 is selected from Asn and Ser;

[0311] X37 is selected from Hyp and Pro; and

[0312] X2 and X7 are amino acid residues whose side chains together form a lactam bridge;

[0313] Gly(Me) is N-methylglycine [also known as sarcosine (Sar)]

[0314] Ile(Me) is N-methylisoleucine

[0315] Aad is a 2-aminoadipic acid, such as (2S)-2-aminoadipic acid [also known as (2S)-2-aminoadipic acid], also known as homo-glutamic acid.

[0316] In a preferred embodiment, the amylin analog is: [19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-lle(Me)-LSSTEVGSNT-Hyp-NH2 (SEQ ID NO: 6).

[0317] in:

[0318] Gly(Me): N-methylglycine [also known as sarcosine (Sar)]

[0319] Ile(Me): N-methylisoleucine

[0320] Aad: 2-aminoadipic acid, such as (2S)-2-aminoadipic acid [also known as (2S)-2-aminoadipic acid], also known as homoglutamic acid

[0321] Hyp: 4-hydroxyproline, such as (2S,4R)-4-hydroxyproline [also known as (4R)-4-hydroxy-L-proline]

[0322] The backbone nitrogen of the [19CD]-isoGlu Arg residue (present in position X1 of the peptide sequence Z of the amylin analog) is covalently linked to the side chain carboxyl group of the Glu moiety via an amide linkage. The 19-carboxy-nonadecanoyl group is covalently linked to the alpha amino group of the Glu linker via an amide linkage (described below).

[0323] The brackets "()" shown after the symbol of a particular amino acid residue indicate the residue whose side chain participates in the intramolecular lactam bridge. Thus, the amylin analog compound present in the formulation of the present invention has an intramolecular lactam bridge formed between the side chains of the residues indicated by the brackets (aspartic acid and lysine, respectively).

[0324] The amylin analog may be in the form of a pharmaceutically acceptable salt or solvate (eg, a pharmaceutically acceptable acid addition salt).

[0325] Half-life extension part M

[0326] As described herein, the N-terminal portion R 1 It may be a half-life extending moiety M (particularly sometimes referred to in the literature as a duration enhancing moiety or an albumin binding moiety), which is optionally linked (covalently linked) to the peptide moiety Z via a linker moiety L. Among suitable half-life extending moieties are certain types of lipophilic substituents. Without wishing to be bound by any particular theory, it is believed that such lipophilic substituents (as well as other types of half-life extending moieties) bind to albumin in the bloodstream, thereby protecting the compounds of the invention from renal filtration and enzymatic degradation, and thus may increase the half-life of the compound in vivo. The lipophilic substituent may also modulate the potency of the compound as an amylin (calcitonin) receptor agonist.

[0327] The lipophilic substituent may be linked to the N-terminal amino acid residue or to the linker L via an ester, sulfonyl ester, thioester, amide, amine or sulfonamide. It will therefore be appreciated that preferably the lipophilic substituent comprises an acyl group, a sulfonyl group, a N atom, an O atom or a S atom forming part of an ester, sulfonyl ester, thioester, amide, amine or sulfonamide. Preferably, the acyl group in the lipophilic substituent forms part of an amide or ester with the amino acid residue or linker.

[0328] The lipophilic substituent may comprise a hydrocarbon chain having 10 to 24 C atoms, for example 14 to 22 C atoms, for example 16 to 20 C atoms. Preferably it has at least 14 C atoms, and preferably has 20 C atoms or less. For example, the hydrocarbon chain may comprise 14, 15, 16, 17, 18, 19 or 20 carbon atoms. The hydrocarbon chain may be straight or branched, and may be saturated or unsaturated. In addition, it may comprise a functional group at the end of the hydrocarbon chain, such as a carboxylic acid group that may or may not be protected during synthesis. Through the above discussion, it will also be understood that the hydrocarbon chain is preferably substituted with a portion that forms a portion connected to the N-terminal amino acid residue of the peptide portion Z or to the linker L, such as an acyl group, a sulfonyl group, an N atom, an O atom or an S atom.

[0329] Most preferably, the hydrocarbon chain is substituted with an acyl group, and thus the hydrocarbon chain may be part of an alkanoyl group, such as dodecanoyl, 2-butyloctanoyl, tetradecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl or eicosanoyl. Some examples of functionalized hydrocarbon chains are 15-carboxy-pentadecanoyl, 17-carboxy-heptadecanoyl and 19-carboxy-nonadecanoyl.

[0330] As described above, the lipophilic substituent M can be linked to the N-terminal amino acid residue of Z via a linker L. In some embodiments, the linker moiety L itself can comprise one, two, three or more linked sub-moieties L 1 , L 2 , L 3 When the linker L comprises only one such part, it is linked to the lipophilic substituent and to the N-terminal amino acid residue of Z. The linker can then be independently linked to the lipophilic substituent and to the N-terminal amino acid residue of Z via an ester, sulfonyl ester, thioester, amide, amine or sulfonamide bond. Thus, it can comprise two parts independently selected from the following: acyl, sulfonyl, N atom, O atom and S atom. The linker can be composed of a straight or branched C 1-10 A hydrocarbon chain or more preferably a straight chain C 1-5 In addition, the linker may be substituted with one or more substituents selected from the following: 1-6 Alkyl, amino C 1-6 Alkyl, hydroxyl C 1-6 Alkyl and carboxyl C 1-6 alkyl.

[0331] In some embodiments, the linker may comprise one or more (e.g., one, two, or three) linked amino acid residues, each of which may independently be the residue of any naturally occurring or non-naturally occurring amino acid. For example, the linker may comprise one, two, or three linked amino acid residues, each of which may independently be the following residues:

[0332] 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-aminopropionyl), 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-aminononanoyl, 10-aminodecanoyl or 8Ado (i.e., 8-amino-3,6-dioxaoctanoyl).

[0333] Mentioning γ-Glu, ε-Lys and β-Asp represents the residue of the amino acid participating in the bond through its side chain carboxyl or amine functional group.Therefore, γ-Glu and β-Asp participate in the bond through its α amino group and side chain carboxyl group, while ε-Lys participates through its carboxyl group and side chain amino group.In the context of the present invention, γ-Glu and isoGlu are used interchangeably.

[0334] In certain embodiments, the linker comprises or consists of one, two or three independently selected residues of Glu, γ-Glu, ε-Lys, β-Asp, 4-aminobutyryl, 8-aminooctanoyl or 8Ado.

[0335] Linkers consisting of isoGlu and isoGlu-isoGlu may be particularly preferred.

[0336] One example of a lipophilic substituent comprising a lipophilic moiety M and a linker L is shown in the following formula:

[0337]

[0338] Here, the backbone nitrogen of the Arg residue (present in the X1 position of the peptide sequence Z of the amylin analog) is covalently linked to the side chain carboxyl group of the Glu portion via an amide linkage. The 19-carboxy-nonadecanoyl group is covalently linked to the α-amino group of the Glu linker via an amide linkage. Thus, the Glu linker is in an iso-Glu (or γ-Glu) configuration. For example, when shown in the formula of a particular compound, this combination of a lipophilic moiety linked to an Arg residue and a linker can be represented by the abbreviated symbol [19CD]-isoGlu-R.

[0339] The skilled person will be well aware of suitable techniques for preparing the compounds employed in the context of the present invention. Examples of suitable chemical processes are described in, for example, WO98 / 08871, WO00 / 55184, WO00 / 55119, Madsen et al (J. Med. Chem. 2007, 50, 6126-32) and Knudsen et al. 2000 (J. Med Chem. 43, 1664-1669).

[0340] 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 further substituted with only one substituent. Alternatively or in addition, the hydrocarbon chain may contain a cycloalkane or heterocycloalkane moiety, such as shown below:

[0341]

[0342] In some embodiments, the cycloalkane or heterocycloalkane moiety is a six-membered ring, such as a piperidine ring.

[0343] In some alternative embodiments of the invention, the N-terminal amino acid of Z in the compounds of the invention may be linked (covalently linked) to a biotinylated substituent, optionally via a linker moiety L. Without wishing to be bound by any particular theory, it is also believed that such a biotinylated substituent binds to albumin in the bloodstream, thereby protecting the compounds of the invention from enzymatic degradation and thus may increase the half-life of the compound in vivo. When present, the linker may provide a spacer between the peptide moiety Z and the biotinylated substituent.

[0344] The biotinylation substituent may be linked to the N-terminal amino acid residue or to the linker via a maleimido ester bond, a sulfonyl ester bond, a thioester bond, an amide bond, an amine bond or a sulfonamide bond. It will therefore be appreciated that the biotinylation substituent preferably comprises a maleimido group, an acyl group, a sulfonyl group, a N atom, an O atom or a S atom forming part of the ester, sulfonyl ester, thioester, amide, amine or sulfonamide bond involved.

[0345] Some examples of biotinylation substituents may include:

[0346]

[0347] Biotin is known as vitamin H or coenzyme R and is a water-soluble B-complex vitamin (vitamin B7). It has been shown to enhance the oral uptake of certain drugs.

[0348] Potency of the compound

[0349] The compounds of the present invention are amylin receptor agonists, i.e., they are capable of binding to and initiating signal transduction by one or more receptors or receptor complexes considered as physiological receptors for human amylin. These include: human calcitonin receptor hCT-R, and complexes comprising human calcitonin receptor hCT-R and at least one human receptor activity modifying protein designated hRAMP1, hRAMP2, and hRAMP3. The complexes between hCT-R and hRAMP1, hRAMP2, and hRAMP3 are designated hAMYR1, hAMYR2, and hAMYR3 (i.e., human amylin receptors 1, 2, and 3), respectively.

[0350] A compound is considered to be an amylin receptor agonist if it has agonist activity at one or more of hAMYR1, hAMYR2, and hAMYR3 (eg, at hAMYR1 and / or hAMYR3, eg, at hAMYR3).

[0351] Typically, when expressed in the absence of hRAMP1, hRAMP2, and hRAMP3, an amylin receptor agonist will also have agonist activity on hCT-R. Typically, the agonist will be less than 10-fold more active on hCT-R (when expressed in the absence of hRAMP1, hRAMP2, and hRAMP3) than its activity on any one of hAMYR1, hAMYR2, and hAMYR3 in a comparative assay (i.e., its activity on all of these receptors). The agonist activity on hCT-R may be less than 5-fold more active, substantially equal (e.g., + / - 10%) to the agonist activity on hAMYR1, hAMYR2, and hAMYR3, or less active than the agonist activity on hAMYR1, hAMYR2, and hAMYR3. In this regard, it is sufficient to compare the activity between hCT-R and hAMYR3 alone.

[0352] The ability to induce cAMP formation (i.e., inducing adenylate cyclase activity) as a result of binding to a relevant receptor or receptor complex is generally considered to be an indication of agonist activity. Other intracellular signaling pathways or events can also be used as read-outs for amylin receptor agonist activity. These may include calcium release, beta-arrestin recruitment, receptor internalization, kinase activation or inactivation, lipase activation, phosphoinositide release, diacylglycerol release, or nuclear transcription factor translocation.

[0353] A suitable equivalent assay format would utilize cells that express hCT-R and differ only in their expression of hRAMP1, 2, and 3. For example, a "base" cell line that does not express any of hCT-R, hRAMP1, hRAMP2, and hRAMP3 can be engineered to produce cells that express (i) hCT-R, and (ii) one of hAMYR1, hAMYR2, and hAMYR3 (i.e., hCT-R plus one of hRAMP1, hRAMP2, and hRAMP3) (e.g., hAMYR3). The base cells will typically be mammalian cells and may be primate cells. They may be non-human primate cells. Preferably, the base cells do not express any of CT-R, RAMP1, RAMP2, or RAMP3 (whether human or native to the base cell if the base cell is non-human). The base cells may be fibroblasts. Suitable non-human fibroblast basal cells include COS7 cells from African green monkeys, which do not express native CT-R or RAMP.

[0354] The activity of the comparison can be measured by any appropriate means, for example by EC 50Obviously, the biological readout must be the same for both receptor types.

[0355] The compounds of the present invention may exhibit many advantageous properties relative to human amylin and its existing analogs (e.g., pramlintide, IAPP-GI, and analogs described in WO2012 / 168430, WO2012 / 168431, and WO2012 / 168432). Compared to human amylin or any of these analogs, the compounds of the present invention may, for example, exhibit improved efficacy (e.g., in the form of improving the in vitro activity or efficacy of one or more of the receptors hCT-R, hAMYR1, hAMYR2, or hAMYR3). In addition or as an alternative, the compounds of the present invention may exhibit improved solubility in aqueous media (especially at a pH of 4 to 7.5, or at a pH range within this range). In addition, the compounds of the present invention may, as a supplement or alternative, exhibit a reduced tendency to fibrillate in pharmaceutically relevant aqueous media (especially at a pH of 4 to 7, or at a pH range within this range). Furthermore, the compounds of the invention may additionally or alternatively exhibit improved chemical stability (ie, reduced tendency to undergo chemical degradation) in aqueous media, particularly at a pH of 4 to 9, or within this range.

[0356] Thus, the compounds of the invention may be well suited for formulation in acidic media (e.g., pH 4) and in neutral or near-neutral media (e.g., pH 7 or 7.4). This is in contrast to, for example, pramlintide, which generally exhibits poor chemical stability and rapid fibrillation in pharmaceutically relevant aqueous media at neutral pH, and thus, the compounds of the invention may be well suited for co-formulation with, for example, insulin, various insulin analogs, and / or other therapeutic (e.g., anti-diabetic or anti-obesity) agents that require a neutral or near-neutral formulation pH.

[0357] In general, it is preferred to use a bioassay that measures intracellular signaling caused by the binding of a compound to a relevant receptor as discussed above. Calcitonin / amylin receptor activation by a compound of the invention (which acts as an agonist of the receptor) induces cAMP formation and activates other intracellular signaling pathways and events. Therefore, the generation of cAMP or any other suitable parameter in a suitable cell expressing the receptor can be used to monitor the agonist activity of the receptor.

[0358] The skilled artisan will be aware of suitable assay formats, and examples are provided below. For example, the assay may utilize the human calcitonin receptor (hCT-R, e.g., isoform 2 of hCT-R) or the hAMYR3 receptor (see Examples below). Where reference is made to the sequence of a precursor protein, it is understood that the assay may utilize the mature protein lacking a signal sequence.

[0359] EC 50 The EC value can be used as a numerical measure of the potency of an agonist at a given receptor. 50 The EC value is a measure of the concentration of a compound required to achieve half of its maximal activity in a particular assay. Thus, for example, in a particular assay, the EC 50 [hCT-R] is lower than the EC of native human amylin 50 [hCT-R], or less than the EC of pramlintide 50 The compounds of [hCT-R] have a higher potency or activity at the receptor than native human amylin, or higher potency or activity at the receptor than pramlintide, respectively.

[0360] In some embodiments of the compounds of the invention, the EC of hCT-R 50 Less than 1.5 nM (eg, 0.001 to 1.5 nM).

[0361] In some embodiments of the compounds of the invention, the EC of hCT-R 50 Less than 0.9 nM (eg, 0.001 to 0.9 nM).

[0362] In some embodiments of the compounds of the invention, the EC of hCT-R 50 Less than 0.5 nM (eg, 0.001 to 0.5 nM).

[0363] In some embodiments of the compounds of the invention, the EC of hCT-R 50 Less than 0.3 nM (eg, 0.001 to 0.3 nM).

[0364] In some embodiments of the compounds of the invention, the EC of hCT-R 50 Less than 0.2 nM (eg, 0.001 to 0.2 nM).

[0365] EC for hCT-R 50 May be an indication of the compound's effect on food intake, weight gain and / or weight loss. Has a lower EC for hCT-R 50 Compounds with higher values ​​may have greater effects on these parameters.

[0366] In some embodiments of the compounds of the invention, the EC for hAMYR3 50 Less than 1.0 nM (eg, 0.001 to 1.0 nM).

[0367] In some embodiments of the compounds of the invention, the EC for hAMYR3 50 Less than 0.5 nM (eg, 0.001 to 0.5 nM).

[0368] In some embodiments of the compounds of the invention, the EC for hAMYR3 50 Less than 0.4 nM (eg, 0.001 to 0.4 nM).

[0369] In some embodiments of the compounds of the invention, the EC for hAMYR3 50 Less than 0.3 nM (eg, 0.001 to 0.3 nM).

[0370] In some embodiments of the compounds of the invention, the EC for hAMYR3 50 Less than 0.2 nM (eg, 0.001 to 0.2 nM).

[0371] EC for hCT-R (when expressed in the absence of hRAMP1, hRAMP2, and hRAMP3) 50 may be less than the EC for any or all of hAMYR1, hAMYR2, and hAMYR3 (e.g., for hAMYR3) 50 .

[0372] For example, EC for hCT-R (when expressed in the absence of hRAMP1, hRAMP2, and hRAMP3) 50 It can be an EC for any one or all of hAMYR1, hAMYR2 and hAMYR3 (e.g., for hAMYR3). 50 is lower than one tenth.

[0373] EC for hCT-R (when expressed in the absence of hRAMP1, hRAMP2, and hRAMP3) 50 It can be an EC for any one or all of hAMYR1, hAMYR2 and hAMYR3 (e.g., for hAMYR3). 50 is lower than one-fifth.

[0374] EC for hCT-R (when expressed in the absence of hRAMP1, hRAMP2, and hRAMP3) 50 The EC for any or all of hAMYR1, hAMYR2, and hAMYR3 (eg, for hAMYR3) may be substantially equal (eg, + / - 50%). 50 .

[0375] EC for hCT-R (when expressed in the absence of hRAMP1, hRAMP2, and hRAMP3) 50 The EC for any or all of hAMYR1, hAMYR2, and hAMYR3 (e.g., for hAMYR3) may be higher than 50 .

[0376] Therapeutic Uses

[0377] Amylin analogs in combination with dual agonists are particularly useful for reducing food intake, promoting weight loss, and inhibiting or reducing weight gain. Thus, they can provide attractive treatment options for, in particular, obesity and metabolic diseases caused by, characterized by, or associated with excess body weight. Thus, the compounds can be used in methods for treating, inhibiting or reducing weight gain, promoting weight loss, reducing food intake, and / or reducing excess body weight. Treatment can be achieved, for example, by controlling appetite, eating, food intake, calorie intake, and / or energy expenditure.

[0378] The compounds can be used in methods of treating obesity and related diseases, disorders and health conditions, including but not limited to morbid obesity, pre-surgical obesity, obesity-related inflammation, obesity-related gallbladder disease, and obesity-induced sleep apnea and breathing problems, cartilage degeneration, osteoarthritis, and reproductive health complications of obesity or overweight (e.g., infertility).

[0379] The compounds may also be used in methods of preventing or treating Alzheimer's disease, diabetes, type 1 diabetes, type 2 diabetes, prediabetes, insulin resistance syndrome, impaired glucose tolerance (IGT), disease states associated with elevated blood glucose levels, metabolic diseases including metabolic syndrome, hyperglycemia, hypertension, atherogenic dyslipidemia, hepatic steatosis ("fatty liver"; including non-alcoholic fatty liver disease (NAFLD), which itself includes non-alcoholic steatohepatitis (NASH)), renal failure, arteriosclerosis (e.g., atherosclerosis), macrovascular disease, microvascular disease, diabetic heart disease (including diabetic cardiomyopathy and heart failure as complications of diabetes), coronary heart disease, peripheral arterial disease, or stroke.

[0380] The compounds may also be used to lower circulating LDL levels and / or increase the HDL / LDL ratio.

[0381] The effects of the above compounds may be mediated in whole or in part through an effect on body weight, or may be independent thereof.

[0382] Metabolic syndrome is characterized by a group of metabolic risk factors in a person. They include abdominal obesity (excess fat tissue around the internal organs in the abdomen), atherogenic dyslipidemia (a lipid disorder including high triglycerides, low HDL cholesterol and / or high LDL cholesterol that promotes plaque formation in the artery walls), elevated blood pressure (hypertension), insulin resistance and glucose intolerance, a prothrombotic state (e.g., high fibrinogen or plasminogen activator inhibitor-1 in the blood), and a proinflammatory state (e.g., elevated C-reactive protein in the blood).

[0383] Individuals with metabolic syndrome have an increased risk of developing coronary heart disease and other diseases associated with other clinical manifestations of atherosclerosis, such as stroke and peripheral vascular disease. The major underlying risk factor for this syndrome appears to be abdominal obesity.

[0384] Pharmaceutical composition

[0385] The invention also extends to compositions (eg pharmaceutical compositions) comprising an amylin analogue.As with all aspects of the invention, it will be understood that reference to an amylin analogue encompasses a reference to pharmaceutically acceptable salts and solvates.

[0386] The amylin analogs of the present invention can be formulated into pharmaceutical compositions suitable for administration with or without storage, and generally comprise a therapeutically effective amount of at least one peptide of the present invention, and a pharmaceutically acceptable carrier, excipient, or vehicle.

[0387] The term "pharmaceutically acceptable carrier" includes any standard pharmaceutical carrier. Pharmaceutically acceptable carriers for therapeutic use are well known in the pharmaceutical field and are described in, for example, "Remington's Pharmaceutical Sciences", 17th edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985. For example, sterile saline and phosphate buffered saline at slightly acidic or physiological pH can be used. Suitable pH buffers can 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 acetate (e.g., such as sodium acetate), or mixtures thereof. The term also encompasses any carrier agent listed in the US Pharmacopoeia for animals (including humans).

[0388] The pharmaceutical composition of the present invention can be in unit dosage form. In such a form, the composition is divided into unit doses containing an appropriate amount of one or more active ingredients. The unit dosage form can exist as a packaged preparation, and the package contains a discrete amount of preparations, such as packaged tablets, capsules, or powders in vials or ampoules. The unit dosage form can also be, for example, a capsule, a cachet, or a tablet itself, or it can be any of these packaged forms in an appropriate number. The unit dosage form can also be provided in a single dose injection form, such as in the form of a pen device containing a liquid phase (usually aqueous) composition. The composition can be formulated for any suitable route of administration and mode. Pharmaceutically acceptable carriers or diluents are included in those suitable for use in, for example, the following preparations: oral, intravitreal, rectal, vaginal, nasal, surface, enteral or parenteral (including subcutaneous, sc), intramuscular (intramuscular, im), intravenous (intravenous, iv), intradermal and transdermal) administration or by inhalation. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmaceutical formulation.

[0389] In some cases, subcutaneous or transdermal modes of administration may be suitable for the peptides of the present invention.

[0390] Other embodiments relate to devices, dosage forms and packaging for delivering the pharmaceutical preparations of the present invention. Therefore, at least one peptide in a stable or preserved formulation or solution as described herein can be administered to a patient according to the present invention by a variety of delivery methods, including by sc or im injection, or by transdermal, pulmonary or transmucosal administration, or by implants, or by using osmotic pumps, cartridges, micro-pumps or other means recognized by those skilled in the art.

[0391] Other embodiments relate to oral preparations and oral administration. Preparations for oral administration can rely on the co-application of excipients (e.g., resorcinol and / or nonionic surfactants (e.g., polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether)) to artificially increase the permeability of the intestinal wall, and / or the co-application of enzyme inhibitors (e.g., pancreatic trypsin inhibitor, diisopropylfluorophosphate (DFF) or aprotinin (trasylol)) to inhibit enzymatic degradation. The active ingredient compound of the solid dosage form for oral administration can be mixed with at least one additive, such as sucrose, lactose, cellulose, mannitol, trehalose, raffinose, maltitol, dextran, starch, agar, alginate, chitin, chitosan, pectin, tragacanth, gum arabic, gelatin, collagen, casein, albumin, synthetic or semisynthetic polymers, or glycerides. These dosage forms may also contain other types of additives, such as inactive diluents, lubricants (e.g., magnesium stearate), parabens, preservatives (e.g., sorbic acid, ascorbic acid, or α-tocopherol), antioxidants (e.g., cysteine), disintegrants, binders, thickeners, buffers, pH adjusters, sweeteners, flavoring agents, or perfuming agents.

[0392] dose

[0393] It will be appreciated that the dose of the GLP-1 / GLP-2 dual agonist and the dose of the amylin analogue may be selected independently. The dose of the amylin analogue may be selected as described herein.

[0394] Typical dosages of amylin analogs employed in the context of the present invention may be from about 0.0001 to about 100 mg / kg body weight per day or every other day, such as from about 0.0005 to about 50 mg / kg body weight per day or every other day, such as from about 0.001 to about 10 mg / kg body weight per day or every other day, such as from about 0.01 to about 1 mg / kg body weight per day or every other day, administered in one or more doses (e.g., one to three doses). The precise dose employed will depend, among other things, on the nature and severity of the disease or condition to be treated; the sex, age, weight and general condition of the subject to be treated; possible other concurrent diseases or conditions that are being or will be treated, and other factors that will be known to medical practitioners in the art.

[0395] Typical dosages of amylin analogs employed in the context of the present invention may be from about 0.5 mg to about 10.0 mg per day or every other day, from about 0.6 mg to about 7.5 mg per day or every other day, preferably from about 1.2 mg to about 7.5 mg per day or every other day, preferably from about 1.2 mg to about 6.0 mg per day or every other day, preferably from about 2.4 mg to about 6.0 mg per day or every other day, preferably from about 2.4 mg to about 4.0 mg per day or every other day, preferably from about 2.4 mg to about 3.5 mg per day or every other day.

[0396] The amylin analogs of the present invention may be administered continuously (e.g., by intravenous administration or other continuous drug administration methods) or may be administered to a subject at intervals (usually at regular time intervals), depending on the desired dose and pharmaceutical composition selected by a skilled practitioner for a particular subject. Regular administration dosing intervals include, for example, once a day, twice a day, once every two, three, four, five or six days, once or twice a week, once or twice a month, etc. In some cases (e.g., such as during chronic long-term administration), such a regular peptide administration regimen may be advantageously interrupted for a period of time so that the subject can reduce the level of medication or stop taking the medication, which is generally referred to as taking a "drug holiday". Drug holidays can be used, for example, to maintain or restore sensitivity to a drug (especially during long-term chronic treatment), or to reduce the undesirable side effects of long-term chronic treatment on a subject using the drug. The timing of the drug holiday depends on the timing of the regular dosing regimen and the purpose of the drug holiday (e.g., to restore drug sensitivity and / or reduce the undesirable side effects of continuous long-term administration). In some embodiments, a drug holiday may reduce the dose of the drug (e.g., below the therapeutically effective amount for a certain time interval). In other embodiments, the administration of the drug is stopped for a certain time interval before administration is started again using the same or different dosing regimen (e.g., with a lower or higher dose and / or frequency of administration). Thus, the drug holiday of the present invention can be selected according to a wide range of time periods and dosing regimens. An exemplary drug holiday is a drug holiday of two or more days, one or more weeks, or one or more months, up to about 24 months. Thus, for example, a regular daily dosing regimen of the peptides of the present invention may be interrupted, for example, by a drug holiday of one week, or two weeks, or four weeks, after which time the aforementioned regular dosing regimen (e.g., a daily or weekly dosing regimen) continues. A variety of other drug holiday regimens that can be used to administer the peptides of the present invention are contemplated.

[0397] Thus, the peptide may be delivered via an administration regimen comprising two or more administration phases separated by respective drug holiday phases.

[0398] During each administration phase, the peptide is administered to the recipient subject in a therapeutically effective amount according to a predetermined administration pattern. The administration pattern may include continuous administration of the drug to the recipient subject during the administration phase. Alternatively, the administration pattern may include administering multiple doses of the peptide to the recipient subject, wherein the doses are separated by dosing intervals.

[0399] The dosing pattern can include at least two doses per administration phase, at least five doses per administration phase, at least 10 doses per administration phase, at least 20 doses per administration phase, at least 30 doses per administration phase, or more.

[0400] The dosing interval can be a regular dosing interval, which can be as described above, including once a day, twice a day, once every two, three, four, five or six days, once or twice a week, once or twice a month, or regular and even less frequent dosing intervals, depending on the specific dosage formulation, bioavailability and pharmacokinetic profile of the peptide.

[0401] The duration of the administration phase can be at least two days, at least one week, at least 2 weeks, at least 4 weeks, at least one month, at least 2 months, at least 3 months, at least 6 months, or longer.

[0402] When the administration pattern comprises multiple doses, it is possible that the duration after the drug holiday phase is longer than the dosing interval used in the administration pattern. When the dosing interval is irregular, the duration of the drug holiday phase may be greater than the average interval between doses during the administration phase. Alternatively, the duration of the drug holiday may be longer than the longest interval between consecutive doses during the administration phase.

[0403] The duration of a possible drug holiday phase may be at least 2 times the duration of the relevant dosing interval (or its average), may be at least 3 times, at least 4 times, at least 5 times, at least 10 times or at least 20 times the duration of the relevant dosing interval or its average.

[0404] Within these constraints, the duration of the drug holiday phase can be at least 2 days, at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, at least 6 months, or longer, depending on the administration pattern during the prior administration phase.

[0405] The administration regimen requiring the use of a drug holiday comprises at least 2 administration phases. Consecutive administration phases are separated by respective drug holiday phases. Thus, the administration regimen may comprise at least 3, at least 4, at least 5, at least 10, at least 15, at least 20, at least 25 or at least 30 administration phases, or more, each separated by a respective drug holiday phase.

[0406] The continuous administration phase can utilize the same mode of administration, but this may not always be desirable or necessary. However, if other drugs or active agents are administered in combination with the peptides of the present invention, the same combination of drugs or active agents is usually given in the continuous administration phase. In certain embodiments, the recipient subject is a human.

[0407] In a preferred aspect, the amylin analog is administered to the subject every other day.

[0408] Medical conditions

[0409] The preparations of the invention are particularly useful for reducing food intake, promoting weight loss and inhibiting or reducing weight gain. Therefore, they can provide attractive treatment options for metabolic diseases caused by, characterized by or associated with excess body weight, in particular obesity.

[0410] Therefore, the formulation can be used in a method of treating, inhibiting or reducing weight gain, promoting weight loss, reducing food intake and / or reducing excess body weight. Treatment can be achieved, for example, by controlling appetite, eating, food intake, calorie intake and / or energy expenditure.

[0411] The formulations can be used in methods of treating obesity and related diseases, disorders and health conditions, including but not limited to morbid obesity, pre-surgical obesity, obesity-related inflammation, obesity-related gallbladder disease, and obesity-induced sleep apnea and breathing problems, cartilage degeneration, osteoarthritis, and reproductive health complications of obesity or overweight (e.g., infertility).

[0412] The formulations may also be used in methods of preventing or treating Alzheimer's disease, diabetes, type 1 diabetes, type 2 diabetes, prediabetes, insulin resistance syndrome, impaired glucose tolerance (IGT), disease states associated with elevated blood glucose levels, metabolic diseases including metabolic syndrome, hyperglycemia, hypertension, atherogenic dyslipidemia, hepatic steatosis ("fatty liver"; including non-alcoholic fatty liver disease (NAFLD), which itself includes non-alcoholic steatohepatitis (NASH)), renal failure, arteriosclerosis (e.g., atherosclerosis), macrovascular disease, microvascular disease, diabetic heart disease (including diabetic cardiomyopathy and heart failure as complications of diabetes), coronary heart disease, peripheral arterial disease, or stroke.

[0413] The formulations may also be used to lower circulating LDL levels and / or increase the HDL / LDL ratio.

[0414] These effects may be mediated in whole or in part through effects on body weight, or may be independent thereof.

[0415] Metabolic syndrome is characterized by a group of metabolic risk factors in a person. They include abdominal obesity (excess fat tissue around the internal organs in the abdomen), atherogenic dyslipidemia (a lipid disorder including high triglycerides, low HDL cholesterol and / or high LDL cholesterol that promotes plaque formation in the artery walls), elevated blood pressure (hypertension), insulin resistance and glucose intolerance, a prothrombotic state (e.g., high fibrinogen or plasminogen activator inhibitor-1 in the blood), and a proinflammatory state (e.g., elevated C-reactive protein in the blood).

[0416] Individuals with metabolic syndrome have an increased risk of developing coronary heart disease and other diseases associated with other clinical manifestations of atherosclerosis, such as stroke and peripheral vascular disease. The major underlying risk factor for this syndrome appears to be abdominal obesity.

[0417] The term "treatment" (and other grammatical variants thereof) used in the context of the present invention refers to a method for obtaining a beneficial or desired clinical result. For the purposes of the present invention, a beneficial or desired clinical result includes, but is not limited to, relief of symptoms, reduction of disease extent, stabilization of the disease state (i.e., no deterioration), delay or slowing of disease progression, improvement or alleviation of the disease state, and relief (whether partial or complete), whether detectable or undetectable. "Treatment" may also refer to an extension of survival compared to the expected survival in the absence of treatment. "Treatment" is an intervention for the purpose of preventing the occurrence of a disease or altering the pathological condition of a disease. Therefore, "treatment" refers to both therapeutic treatment and preventive or preventive measures. As used in the context of preventive or preventive measures, a pharmaceutical preparation does not need to completely prevent the occurrence of a disease or disease. Those that need treatment include those that already have a disease, and those that are to be prevented from occurring. "Treatment" also means to suppress or reduce the increase in a pathological condition or symptom (e.g., weight gain or hypoglycemia) compared to the absence of treatment, and does not necessarily mean to imply a complete cessation of the associated disease.

[0418] Devices and kits

[0419] In some embodiments, the present invention relates to a device comprising an amylin analog or pharmaceutical composition of the present invention and / or a dual agonist or pharmaceutical composition of the present invention for delivering the analog to a subject. Through such a device, a dual agonist and / or amylin analog 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, box or mini pump; or by other means recognized by those skilled in the art.

[0420] In some embodiments, the invention relates to a kit comprising a dual agonist of the invention and / or an amylin analog or a pharmaceutical composition of the invention. In certain embodiments, the kit further comprises packaging and / or instructions for use.

[0421] Pharmaceutical compositions and administration

[0422] One aspect of the present invention relates to separate compositions, wherein the first composition comprises a GLP-1 / GLP-2 dual agonist according to the present invention and / or a pharmaceutically acceptable salt or solvate thereof, and a carrier; and the second composition comprises an amylin analogue according to the present invention and / or a pharmaceutically acceptable salt or solvate thereof, and a carrier. The first composition and the second composition can be prepared for storage or administration, and they respectively comprise a therapeutically effective amount of a GLP-1 / GLP-2 dual agonist according to the present invention and an amylin analogue or a salt or solvate thereof.

[0423] In one embodiment, the pharmaceutical composition of the present invention is a pharmaceutical composition wherein the dual agonist is in the form of a pharmaceutically acceptable acid addition salt; and wherein the pharmaceutical composition optionally comprises one or more pharmaceutically acceptable carriers, diluents or excipients. The pharmaceutical composition is sometimes referred to as a dual agonist pharmaceutical composition or a dual agonist drug.

[0424] In one embodiment, the pharmaceutical composition of the present invention is a pharmaceutical composition wherein the amylin analog is in the form of a pharmaceutically acceptable acid addition salt; and wherein the pharmaceutical composition optionally comprises one or more pharmaceutically acceptable carriers, diluents or excipients. The pharmaceutical composition is sometimes referred to as an amylin analog pharmaceutical composition or an amylin analog drug.

[0425] In a preferred aspect, the combination of the invention comprises separately administering to a subject an amylin analog pharmaceutical composition and an amylin analog pharmaceutical composition.

[0426] Therapeutic uses, methods and dosing regimens

[0427] In a broad aspect the invention provides a GLP-1 / GLP-2 dual agonist and an amylin analogue according to the invention for use as one or more medicaments.

[0428] In one aspect the invention relates to a GLP-1 / GLP-2 dual agonist according to the invention and an amylin analogue for use in therapy.

[0429] In one aspect the invention relates to a GLP-1 / GLP-2 dual agonist and an amylin analogue according to the invention for use in treating or preventing a disease or disorder.

[0430] In some preferred embodiments, the disease or disorder is obesity or obesity-related.

[0431] In one aspect, the invention relates to a GLP-1 / GLP-2 dual agonist and an amylin analogue according to the invention for use in a method of treating or preventing a disease or disorder.

[0432] In one aspect the invention relates to a GLP-1 / GLP-2 dual agonist according to the invention and an amylin analogue for use in reducing body weight in a subject.

[0433] The GLP-1 / GLP-2 dual agonists and amylin analogs according to the present invention may be used for therapeutic or cosmetic purposes.

[0434] The present invention also relates to GLP-1 / GLP-2 dual agonists and amylin analogs for use in methods that are not intended per se to treat a disease or condition. Such uses and methods may be considered prevention of a disease or condition, provided that they can be used prior to the onset of the disease (e.g., pre-diagnosis), for example to improve undesirable physiological characteristics or to alter certain physiological parameters. Furthermore, such uses or methods may be considered cosmetic.

[0435] It will be understood that the GLP-1 / GLP-2 dual agonists and amylin analogs used according to the invention will be useful for any disease or condition disclosed herein (e.g., with respect to each of the GLP-1 / GLP-2 dual agonists and amylin analogs).

[0436] It will be appreciated that the uses of the GLP-1 / GLP-2 dual agonists and amylin analogues of the invention described herein may be represented as methods. All features of the uses of the invention described herein are applicable to the corresponding methods of the invention.

[0437] Thus, the present invention provides a method for preventing or treating a disease or condition, the method comprising administering to a subject a GLP-1 / GLP-2 dual agonist and an amylin analog. In some embodiments, the disease or condition is obesity, morbid obesity, obesity-related gallbladder disease, obesity-induced sleep apnea, poor glycemic control, glucose tolerance, dyslipidemia, diabetes, prediabetes, metabolic syndrome, or hypertension.

[0438] The present invention also provides a method of reducing or inhibiting weight gain, reducing food intake, reducing appetite or promoting weight loss, the method comprising administering a GLP-1 / GLP-2 dual agonist and an amylin analog to a subject. The method can be therapeutic or non-therapeutic (i.e., cosmetic).

[0439] Likewise, it should be understood that the uses of the GLP-1 / GLP-2 dual agonist and amylin analogues of the invention described herein may be expressed as a dosing regimen. All features of the uses of the invention described herein apply to the corresponding dosing regimens of the invention.

[0440] Thus, the present invention provides a dosing regimen for preventing or treating a disease or condition, the dosing regimen comprising administering to a subject a GLP-1 / GLP-2 dual agonist and an amylin analog. In some embodiments, the disease or condition is obesity, morbid obesity, obesity-related gallbladder disease, obesity-induced sleep apnea, poor glycemic control, glucose tolerance, dyslipidemia, diabetes, prediabetes, metabolic syndrome, or hypertension.

[0441] The present invention also provides a dosage regimen for reducing or inhibiting weight gain, reducing food intake, reducing appetite or promoting weight loss, the dosage regimen comprising administering a GLP-1 / GLP-2 dual agonist and an amylin analog to a subject. The dosage regimen can be therapeutic or non-therapeutic (i.e., cosmetic).

[0442] Example

[0443] The following examples are provided to illustrate some preferred aspects of the invention and are not intended to limit the scope of the invention.

[0444] Example 1: Effects of GLP-1 / GLP-2 Dual Agonists Alone and in Combination with Amylin Analogs in DIO Rats

[0445] The dual GLP-1 / GLP-2 agonist used in this example is the GLP-1 / GLP-2 dual agonist Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH (SEQ ID NO: 5).

[0446] The amylin analog used in this example is the amylin analog [19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH2 (SEQ ID NO: 6).

[0447] This study was conducted to evaluate the effects of treatment with a GLP-1 / GLP-2 dual agonist in combination with an amylin analog in diet-induced obese (DIO) rats.

[0448] Healthy male Sprague Dawley rats were obtained from Taconic Denmark (Taconic Biosciences A / S). Rats weighed approximately 225 to 275 g upon arrival and were allowed to acclimate for 4 weeks. In order to produce diet-induced obesity (DIO) rats for research, animals were fed a high diet (D12492, ResearchDiet Inc., New Brunswick, USA) in which 60% of the total energy came from fat without restriction. Animals were housed in 2 groups under standard temperature and humidity conditions (20 to 23° C.; 50% to 80% relative humidity) with 12-hour light and 12-hour dark cycles (with 6.00 AM to 6:00 PM light), and free access to household quality tap water.

[0449] DIO animals (n=9 / group) were categorized based on body weight on the first 3 days and treated for 4 weeks starting from day 0 with vehicle (once a day (qd)), GLP-1 / GLP-2 dual agonist (100 nmol / kg, qd), amylin analog (10 nmol / kg, every other day (qod)), or a combination of GLP-1 / GLP-2 dual agonist plus amylin analog (100 nmol / kg, qd and 10 nmol / kg, qod, respectively).

[0450] Results included cumulative food intake, body weight (BW), and fasting blood glucose levels. Food intake was measured from day -2 and every other day throughout the experiment, and the cumulative food intake ( Figure 1 ).

[0451] For BW results, animals were weighed on Day -2 (baseline body weight) and daily throughout the study. Figure 2 A) and on day 28 (the day before termination) from baseline (day 0) ( Figure 2 B) Percent change (%) in BW relative to baseline.

[0452] Overnight fasting blood glucose levels (mmol / L) at baseline (day -1) and termination (day 29) in overnight fasted animals were determined. Blood samples (10 μl) were sampled from the tail vein in Na-heparin coated capillaries using an S-line Biosen glucose analyzer (EKF diagnostics, US). The average fasting blood glucose levels (mmol / L) measured for each group on day 29 and the average blood glucose levels for all animals on day -1 (dashed horizontal line) are shown in Table 1. Figure 3The exposure of both compounds in plasma was measured using LC-MS / MS.

[0453] Combination treatment with a GLP-1 / GLP-2 dual agonist and an amylin analog resulted in significant, sustained, and greater reductions in cumulative food intake compared with vehicle (p<0.0001) and compared with GLP-1 / GLP-2 dual agonist monotherapy (p<0.05). Figure 1 ), and achieved significant, sustained and greater BW reductions compared to vehicle and either monotherapy ( Figure 2 A and B). Data show: -12.4% ± 0.9 for GLP-1 / GLP-2 dual agonist, -5.9% ± 0.4 for amylin analog, -18.9% ± 1.8 for combination treatment, and +4.4% ± 0.7 for vehicle, all changes relative to initial body weight of DIO animals; p<0.0001 for all groups compared to vehicle; p<0.01 for combination compared to GLP-1 / GLP-2 dual agonist; and p<0.0001 for combination compared to amylin analog.

[0454] GLP-1 / GLP-2 dual agonist monotherapy and combination therapy resulted in a significant reduction in fasting blood glucose levels compared to vehicle; p<0.001 ( Figure 3 ).

[0455] Treatment with the GLP-1 / GLP-2 dual agonist, amylin analog, and the combination of the two was observed to be well tolerated. The measured exposure of the GLP-1 / GLP-2 dual agonist and amylin analog in plasma showed no difference between administration as a single compound or as a combination of the two compounds ( Figure 4 ).

[0456] In conclusion, in the DIO rat model, GLP-1 / GLP-2 dual agonists enhanced the weight loss effects of amylin analog monotherapy, suggesting that this combination therapy has an additive effect in the management of overweight, obesity, and obesity-related complications.

[0457] All publications mentioned in the above description are incorporated herein by reference. The various modifications and variations of the methods and systems described in the present invention are obvious to those skilled in the art, and do not depart from the scope and spirit of the present invention. Although the present invention has been described in conjunction with some specific preferred embodiments, it should be understood that the claimed invention should not be unduly limited to such specific embodiments. In fact, the various modifications of the methods for implementing the present invention that are obvious to those skilled in the art of biochemistry, molecular biology or related fields are intended to be within the scope of the appended claims.

Claims

1. A GLP-1 / GLP-2 dual agonist and an amylin analogue for use in a method for preventing or treating a disease or condition, wherein the GLP-1 / GLP-2 dual agonist and the amylin analogue are administered to a subject.

2. The GLP-1 / GLP-2 dual agonist and amylin analog for use according to claim 1, wherein the disease or condition is obesity, morbid obesity, obesity-related gallbladder disease, obesity-induced sleep apnea, poor blood sugar control, glucose tolerance, dyslipidemia, diabetes, prediabetes, metabolic syndrome or hypertension.

3. A GLP-1 / GLP-2 dual agonist and an amylin analogue for use in a method of reducing or inhibiting weight gain, reducing food intake, reducing appetite or promoting weight loss.

4. The GLP-1 / GLP-2 dual agonist and amylin analogue for use according to any one of claims 1 to 3, wherein the GLP-1 / GLP-2 dual agonist is Hy-H[Aib]EGSFTSEKATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH (SEQ ID NO: 5) or a pharmaceutically acceptable salt or solvate thereof.

5. A GLP-1 / GLP-2 dual agonist and an amylin analogue for use according to any one of claims 1 to 4, wherein the method comprises administering to the subject the GLP-1 / GLP-2 dual agonist at a dose of about 0.5 mg to about 10.0 mg.

6. A GLP-1 / GLP-2 dual agonist and an amylin analogue for use according to any one of claims 1 to 5, wherein the method comprises administering to the subject the GLP-1 / GLP-2 dual agonist at a dose of about 0.5 mg to about 7.5 mg, preferably about 1.0 mg to about 7.5 mg, preferably about 1.0 to about 6.0 mg, preferably about 1.0 to about 4.0 mg, preferably about 1.0 to about 3.5 mg.

7. A GLP-1 / GLP-2 dual agonist and an amylin analogue for use according to any one of claims 1 to 6, wherein the method comprises administering the GLP-1 / GLP-2 dual agonist to the subject once a day at a dose of about 0.5 mg to about 10.0 mg / day.

8. A GLP-1 / GLP-2 dual agonist and an amylin analogue for use according to any one of claims 1 to 7, wherein the method comprises administering to the subject the GLP-1 / GLP-2 dual agonist once a day at a dose of about 0.5 mg to about 7.5 mg / day, preferably once a day at a dose of about 1.0 mg to about 7.5 mg / day, preferably once a day at a dose of about 1.0 to about 6.0 mg / day, preferably once a day at a dose of about 1.0 to about 4.0 mg / day, preferably once a day at a dose of about 1.0 to about 3.5 mg / day.

9. The GLP-1 / GLP-2 dual agonist and amylin analog for use according to any one of claims 1 to 8, wherein the amylin analog is [19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH2 (SEQ ID NO: 6) or a pharmaceutically acceptable salt or solvate thereof.

10. A GLP-1 / GLP-2 dual agonist and an amylin analogue for use according to any one of claims 1 to 9, wherein the method comprises administering to the subject the amylin analogue at a dose of about 0.5 mg to about 10.0 mg, preferably about 0.6 mg to about 7.5 mg, preferably about 1.2 mg to about 7.5 mg, preferably about 1.2 to about 6.0 mg, preferably about 2.4 to about 6.0 mg, preferably about 2.4 to about 4.0 mg, preferably about 2.4 to about 3.5 mg.

11. A GLP-1 / GLP-2 dual agonist and an amylin analogue for use according to any one of claims 1 to 10, wherein the method comprises administering to the subject the amylin analogue at a dose of about 0.5 mg to about 10.0 mg / day every other day, preferably at a dose of about 0.6 mg to about 7.5 mg / day every other day, preferably at a dose of about 1.2 mg to about 7.5 mg / day every other day, preferably at a dose of about 1.2 to about 6.0 mg / day every other day, preferably at a dose of about 2.4 to about 6.0 mg / day every other day, preferably at a dose of about 2.4 to about 4.0 mg / day every other day, preferably at a dose of about 2.4 to about 3.5 mg / day every other day.

12. The GLP-1 / GLP-2 dual agonist and amylin analogue for use according to any one of claims 1 to 11, wherein the GLP-1 / GLP-2 dual agonist and / or the amylin analogue or a pharmaceutically acceptable salt or solvate thereof is independently mixed with a carrier, excipient and / or vehicle.

13. The GLP-1 / GLP-2 dual agonist and amylin analogue for use according to claim 12, wherein the carrier is a pharmaceutically acceptable carrier.

14. A GLP-1 / GLP-2 dual agonist and an amylin analogue for use according to any one of claims 1 to 13, wherein the amylin analogue is in a pharmaceutical composition, wherein the pharmaceutical composition comprises one or more of the following: (i) one or more amylin analogs at a concentration of about 0.4 mg / ml to about 25 mg / ml; (ii) present in a solution having a buffer concentration of about 0.5 mM to 25 mM; (iii) is present in a solution having a pH of about 5.8 to about 6.9; and / or (iv) the amylin analog is provided as a hydrochloride salt.

15. A GLP-1 / GLP-2 dual agonist and an amylin analogue for use according to any one of claims 1 to 14, wherein the GLP-1 / GLP-2 dual agonist is in a pharmaceutical composition, wherein the pharmaceutical composition comprises one or more of the following: (i) at least about 1 mg / mL of one or more GLP-1 / GLP-2 dual agonists (ii) 5 mM to about 50 mM phosphate buffer component (iii) about 190 mM to about 240 mM mannitol; and / or (iv) The pH is about pH 8.

0.

16. A GLP-1 / GLP-2 dual agonist and an amylin analogue for use according to any one of claims 1 to 15, wherein the subject is a human.

17. The GLP-1 / GLP-2 dual agonist and amylin analogue for use according to any one of claims 1 to 16, wherein the GLP-1 / GLP-2 dual agonist and the amylin analogue are administered by injection, preferably by subcutaneous injection.

18. A dosing regimen for preventing or treating a disease or condition, the dosing regimen comprising administering to a subject a GLP-1 / GLP-2 dual agonist and an amylin analog.

19. A dosing regimen for reducing or inhibiting weight gain, reducing food intake, reducing appetite, or promoting weight loss, the dosing regimen comprising administering to a subject a GLP-1 / GLP-2 dual agonist and an amylin analog.

20. A dosing regimen according to claim 18 or claim 19 comprising the features of any one of claims 1 to 17.

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