PYY analogue in combination with an incretin for use in the treatment of obesity or an obesity-related disease or disorder

Abstract

The present invention provides a method for treating obesity or an obesity-related disease or disorder, comprising administering a PYY analog in combination with an incretin, wherein the patient's insulin sensitivity is improved with treatment.

Description

Ref. No. 31113_WOMETHODS FOR TREATING OBESITY OR AN OBESITY-RELATED DISEASE OR DISORDER

[0001] The present disclosure relates to the field of medicine. More particularly, the present disclosure relates to methods for treating obesity, obesity-related diseases or disorders, and / or obesity-associated morbidity. The present disclosure relates to administering a Peptide Tyrosine-Tyrosine (PYY) analog to a patient in need thereof, in combination with an incretin, wherein the patient’s insulin sensitivity is improved with treatment.

[0002] Obesity is a complex medical disorder resulting in excessive accumulation of adipose tissue mass. Today obesity is a global public health concern that is associated with undesired health outcomes and comorbidities. Treatments for patients with obesity attempt to reduce excess body weight, improve obesity-related diseases or disorders, and maintain long-term weight reduction. Treatment options for patients with severe obesity have fewer options due to the difficulty of achieving significant weight loss while maintaining a favorable side effect profile and effective glucose control. Therefore, there remains a need for treatment options to induce therapeutic weight loss in patients in need of such treatment.

[0003] PYY is a member of the pancreatic polypeptide family, which includes pancreatic polypeptide (PP) and neuropeptide Y (NPY). PYY exists in two endogenous forms, PYY(l-36) and PYY(3-36), due to enzymatic cleavage of PYY(l-36) by dipeptidyl peptidase-4 inhibitor (DPP4). Whereas PYY(l-36) binds all NPY receptors (NPY1R or Y1R, NPY2R or Y2R, NPY4R or Y4R, and NPY5R or Y5R) with similar affinity, PYY(3-36) acts as a selective NPY2R agonist whereby it reduces food intake leading to body weight loss (Holzer et al. Neuropeptides 2012: 46(6): 261-274). PYY(3-36) has also been proposed to play a role in glucose homeostasis, potentially by improving insulin sensitivity. (Pittner et al. International Journal of Obesity 2004: 28, 963-971; van den Hock et al. Diabetes 2004: 53(8): 1949-1952; see also Vrang et al. Am J Physiol Regul Integr Comp Physiol 2006: 291: R367-R375).

[0004] Glucagon-like peptide-1 (GLP-1) receptor agonists activate the GLP-1 receptor and are commercially available for the treatment of T2DM and / or obesity. ThroughRef. No. 31113_WOactivation of the GLP-1 receptor, drugs in this class stimulate insulin secretion after meals and may help reduce body weight by promoting satiety and delaying gastric emptying (See, e.g., Perez-Montes et al. Minerva Endocrinol 2021: 46(2): 168-176). Despite this, currently marketed GLP-1 receptor agonists are generally dose-limited by gastrointestinal side effects such as nausea and vomiting.

[0005] A variety of other incretins have been described. Tirzepatide, for example, is a dual GIP and GLP-1 receptor agonist. Other examples include retatrutide, a triple agonist of the GIP, GLP-1, and glucagon receptors, and mazdutide, a dual agonist of the glucagon and GLP-1 receptors.

[0006] Despite these advancements in obesity and diabetes medicine, there remains a need for effective treatments for people living with obesity and / or obesity-related disorders. Additionally, there is a need for patients who do not reach their optimal weight using currently marketed incretin treatments, such as semaglutide.

[0007] A combination of SEQ ID NO:1, also designated as Peptide A herein, may be combined with an incretin as disclosed herein. It has been shown that a combination of SEQ ID NO:1 with an incretin, such as tirzepatide, demonstrated a synergistic effect on weight loss by absolute and percentage change from baseline in body weight, and / or change from baseline in hip circumference and waist circumference. Furthermore, a combination of SEQ ID NO:1 with an incretin, such as tirzepatide, also resulted in a synergistic effect on insulin sensitivity.DETAILED DESCRIPTION OF THE DRAWINGS

[0008] Figure 1 shows Glucose Infusion Rate (GIR) (mg / kg / min) during a euglycemic clamp study in diet-induced obese mice treated with vehicle, SEQ ID NO:1 (Inmol / kg, qd), semaglutide “Sema” (lOnmol / kg, qd) or SEQ ID NO:1 (1 nmol / kg) and semaglutide (lOnmol / kg, qd).

[0009] Figure 2 shows average Glucose Infusion Rate (GIR) (mg / kg / min) over the last 30 minutes of the euglycemic clamp study.

[0010] Figure 3 and Figure 4 shows insulin-stimulated glucose disposal in skeletal muscles (Soleus, Gastronemius, and White Gastrocnemius) (Figure 3A-Figure 3C) and adipose tissues (Epididymal, Subcutaneous, Brown) (Figure 4A-Figure 4C) during aRef. No. 31113_WOeuglycemic clamp in diet-induced obese mice treated with vehicle, SEQ ID NO:1 (Inmol / kg, qd), Semaglutide (lOnmol / kg, qd) or SEQ ID NO:1 + Semaglutide (1 nmol / kg and lOnmol / kg, qd).

[0011] Figure 5 shows Glucose Infusion Rate (GIR) (mg / kg / min) during a euglycemic clamp study in diet-induced obese mice treated with vehicle, SEQ ID NO:1 (Inmol / kg, qd), Tirzepatide (3nmol / kg, qd) or SEQ ID NO:1 + Tirzepatide (1 nmol / kg and 3 nmol / kg, qd).

[0012] Figure 6 shows average Glucose Infusion Rate (GIR) (mg / kg / min) over the last 30 minutes of the euglycemic clamp study.

[0013] Figure 7 and Figure 8 shows insulin-stimulated glucose disposal in skeletal muscles (Soleus, Gastronemius, and White Gastrocnemius) (Figure 7A-7C) and adipose tissues (Epididymal, Subcutaneous, Brown) (Figure 8A-8C) during a euglycemic clamp in diet -induced obese mice treated with vehicle, SEQ ID NO:1 (Inmol / kg, qd), Tirzepatide (3nmol / kg, qd) or SEQ ID NO:1 + Tirzepatide (1 nmol / kg and 3nmol / kg, qd).

[0014] Figure 9 shows change from baseline mean (±SE) postprandial glucose during an oral glucose tolerance test on Days -1, 3, 38, and 80 following SC injection(s) of 0.5 mg Peptide A (SEQ ID NO: 1 ) (Figure 9A), 1.5 mg of dulaglutide alone (Figure 9B), or 0.5 mg Peptide A (SEQ ID NO:1) + 1.5 mg of dulaglutide (Figure 9C) in participants with T2D.

[0015] Figure 10 shows Peptide A (SEQ ID NO:1) additively lowers HbAlcin combination with 1.5 mg of dulaglutide in participants with T2D.Ref. No. 31113_WODETAILED DESCRIPTION

[0016] Herein, the PYY analog of the present disclosure is identified as Peptide A (SEQ ID NO:1), is:H H N N HN N H HO'P E— N H(SEQ ID NO: 1)

[0017] SEQ ID NO: 1 is beneficial in combination with incretins. Through weight loss and related metabolic improvements, SEQ ID NO: 1, when administered with an incretin, improves glycemic control beyond the effects of either SEQ ID NO: 1 or the incretin administered alone. Further, SEQ ID NO:1 may enhance insulin sensitization when combined with an incretin agonist beyond an additive effect of the two agents, i.e., SEQ ID NO:1 and an incretin, in addition to providing a weight loss benefit. Therefore, a combination treatment of SEQ ID NO: 1 and an incretin have one or more of the following characteristics: improved weight loss, measured by an absolute and percentage change from baseline in body weight and / or decreased hip circumference and waist circumference, weight-independent peripheral insulin sensitivity, and a favorable side effect profile.

[0018] In one embodiment, the present disclosure provides a method of improving glycemic control in a patient in need thereof with a condition selected from the group consisting of: Type 1 diabetes mellitus, obesity, and / or an obesity-related disease or disorder, comprising administering to said patient a once-weekly dose of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, in combination with a dose of an incretin.

[0019] In another embodiment, the present disclosure provides a method of improving insulin sensitivity in a patient in need thereof with a condition selected from the groupRef. No. 31113_WOconsisting of: Type 1 diabetes mellitus, obesity, and / or an obesity-related disease or disorder, comprising administering to said patient a once-weekly dose of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, in combination with a dose of an incretin.

[0020] In an embodiment, the present disclosure provides a method of improving chronic weight management in a patient in need thereof, comprising administering to said patient a once-weekly dose of 0.075-2 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, in combination with a dose of an incretin. In an embodiment, the present disclosure provides a method of improving chronic weight management in a patient in need thereof, comprising administering to said patient a once-weekly dose of 0.075-2 mg of a compound consisting of SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, in combination with a dose of an incretin. In an embodiment, the present disclosure provides a method of improving chronic weight management in a patient in need thereof, comprising administering to said patient a once-weekly dose of 0.075-2 mg of a compound consisting essentially of SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, in combination with a dose of an incretin.

[0021] In an embodiment, the present disclosure provides a method for providing non-therapeutic weight loss in a patient in need thereof, comprising administering to said patient a once-weekly dose of 0.075-2 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, in combination with a dose of incretin. In an embodiment, the present disclosure provides a method for providing non-therapeutic weight loss in a patient in need thereof, comprising administering to said patient a once-weekly dose of 0.075-2 mg of a compound consisting of SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, in combination with a dose of incretin. In an embodiment, the present disclosure provides a method for providing non-therapeutic weight loss in a patient in need thereof, comprising administering to said patient a once-weekly dose of 0.075-2 mg of a compound consisting essentially of SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, in combination with a dose of incretin.

[0022] In one embodiment, the present disclosure provides a method of treating obesity or an obesity-related disease or disorder in a patient in need thereof, comprisingRef. No. 31113_WOadministering to said patient a once-weekly dose of 0.075-2.0 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, in combination with a dose of an incretin. In one embodiment, the present disclosure provides a method of treating obesity or an obesity-related disease or disorder in a patient in need thereof, comprising administering to said patient a once-weekly dose of 0.075-2.0 mg of a compound consisting of SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, in combination with a dose of an incretin. In one embodiment, the present disclosure provides a method of treating obesity or an obesity-related disease or disorder in a patient in need thereof, comprising administering to said patient a once-weekly dose of 0.075-2.0 mg of a compound consisting essentially of SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, in combination with a dose of an incretin.

[0023] In one embodiment, the present disclosure provides a method of treating obesity and / or an obesity-related disease or disorder in a patient in need thereof, comprising administering to said patient a once-weekly dose of 0.075-2.0 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, in combination with a dose of an incretin, wherein the patient’s insulin sensitivity is improved with the treatment. In one embodiment, the present disclosure provides a method of treating obesity and / or an obesity-related disease or disorder in a patient in need thereof, comprising administering to said patient a once-weekly dose of 0.075-2.0 mg of a compound consisting of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, in combination with a dose of an incretin, wherein the patient’s insulin sensitivity is improved with the treatment. In one embodiment, the present disclosure provides a method of treating obesity and / or an obesity-related disease or disorder in a patient in need thereof, comprising administering to said patient a once-weekly dose of 0.075-2.0 mg of a compound consisting essentially of SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, in combination with a dose of an incretin, wherein the patient’s insulin sensitivity is improved with treatment.

[0024] In some embodiments, the present disclosure provides a method wherein the incretin is selected from the group consisting of: a GLP-1 receptor agonist, a dual agonist of the GIP and GLP-1 receptors, a tri-agonist of the GIP, GLP-1, and glucagon receptors,Ref. No. 31113_WOand a dual agonist of the glucagon and GLP-1 receptors. In a specific embodiment, the present disclosure provides a method wherein the incretin is a dual agonist of the GIP and GLP-1 receptors. In a more specific embodiment, the present disclosure provides a method wherein the dual agonist of the GIP and GLP-1 receptors is tirzepatide, or a pharmaceutically acceptable salt thereof.

[0025] In one embodiment, the present disclosure provides a method wherein the once-weekly dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 0.075 mg, and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5, 15 mg, 17.5 mg, 20 mg, 22.5 mg, and 25 mg.

[0026] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 0.075 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 2.5 mg.

[0027] In another embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 0.075 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 5 mg.

[0028] In another embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is 0.075 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 7.5 mg.

[0029] In another embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is 0.075 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 10 mg.

[0030] In another embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is 0.075 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 12.5 mg.Ref. No. 31113_WO

[0031] In another embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is 0.075 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 15 mg.

[0032] In another embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is 0.075 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 17.5 mg.

[0033] In another embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 0.075 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 20 mg.

[0034] In another embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 0.075 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 22.5 mg.

[0035] In another embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 0.075 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 25 mg.

[0036] In one embodiment, the present disclosure provides a method wherein the once-weekly dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 0.25 mg, and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5, 15 mg, 17.5 mg, 20 mg, 22.5 mg, and 25 mg.

[0037] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is 0.25 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 2.5 mg.Ref. No. 31113_WO

[0038] In another embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is 0.25 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 5 mg.

[0039] In another embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is 0.25 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 7.5 mg.

[0040] In another embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 0.25 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 10 mg.

[0041] In another embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 0.25 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 12.5 mg.

[0042] In another embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 0.25 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 15 mg.

[0043] In another embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 0.25 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 17.5 mg.

[0044] In another embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 0.25 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 20 mg.

[0045] In another embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable saltRef. No. 31113_WOthereof, is 0.25 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 22.5 mg.

[0046] In another embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 0.25 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 25 mg.

[0047] In one embodiment, the present disclosure provides a method wherein the once-weekly dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 0.5 mg, and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5, 15 mg, 17.5 mg, 20 mg, 22.5 mg, and 25 mg..

[0048] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 0.5 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 2.5 mg.

[0049] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 0.5 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 5 mg.

[0050] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is 0.5 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 7.5 mg.

[0051] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is 0.5 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 10 mg.

[0052] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 0.5 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 12.5 mg.Ref. No. 31113_WO

[0053] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is 0.5 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 15 mg.

[0054] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 0.5 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 17.5 mg.

[0055] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 0.5 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 20 mg.

[0056] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 0.5 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 22.5 mg.

[0057] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 0.5 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 25 mg.

[0058] In one embodiment, the present disclosure provides a method wherein the once-weekly dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 1.0 mg, and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5, 15 mg, 17.5 mg, 20 mg, 22.5 mg, and 25 mg.

[0059] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 1.0 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 2.5 mg.Ref. No. 31113_WO

[0060] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is 1.0 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 5.0 mg.

[0061] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 1.0 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 7.5 mg.

[0062] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 1.0 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 10 mg.

[0063] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 1.0 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 12.5 mg.

[0064] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 1.0 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 15 mg.

[0065] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 1.0 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 17.5 mg.

[0066] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 1.0 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 20 mg.

[0067] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, isRef. No. 31113_WO1.0 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 22.5 mg.

[0068] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 1.0 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 25 mg.

[0069] In one embodiment, the present disclosure provides a method wherein the once-weekly dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 2.0 mg, and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5, 15 mg, 17.5 mg, 20 mg, 22.5 mg, and 25 mg.

[0070] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 2.0 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 2.5 mg.

[0071] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 2.0 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 5.0 mg.

[0072] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 2.0 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 7.5 mg.

[0073] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 2.0 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 10 mg.

[0074] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, isRef. No. 31113_WO2.0 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 12.5 mg.

[0075] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 2.0 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 15 mg.

[0076] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 2.0 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 17.5 mg.

[0077] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 2.0 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 20 mg.

[0078] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 2.0 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 22.5 mg.

[0079] In one embodiment, the present disclosure provides a method wherein the dose of the compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is 2.0 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 25 mg.

[0080] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.075 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is selected from the group consisting of 2.5 mg, 5.0 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, and 25 mg.

[0081] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.075 mg of aRef. No. 31113_WOcompound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 2.5 mg.

[0082] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.075 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 5 mg.

[0083] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.075 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 7.5 mg.

[0084] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.075 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 10 mg.

[0085] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.075 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 12.5 mg.

[0086] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.075 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 15 mg.

[0087] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.075 mg of aRef. No. 31113_WOcompound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 17.5 mg.

[0088] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.075 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 20 mg.

[0089] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.075 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 22.5 mg.

[0090] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.075 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 25 mg.

[0091] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.25 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is selected from the group consisting of 2.5 mg, 5.0 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, and 25 mg.

[0092] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.25 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 2.5 mg.Ref. No. 31113_WO

[0093] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.25 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 5 mg.

[0094] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.25 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 7.5 mg.

[0095] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.25 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 10 mg.

[0096] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.25 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 12.5 mg.

[0097] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.25 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 15 mg.

[0098] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.25 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 17.5 mg.Ref. No. 31113_WO

[0099] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.25 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 20 mg.

[0100] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.25 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 22.5 mg.

[0101] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.25 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 25 mg.

[0102] In an embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.5 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, and a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is selected from the group consisting of 2.5 mg, 5.0 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, and 25 mg.

[0103] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.5 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 2.5 mg.

[0104] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.5 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, and a dose ofRef. No. 31113_WOtirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 5 mg.

[0105] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.5 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 7.5 mg.

[0106] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.5 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 10 mg.

[0107] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.5 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 12.5 mg.

[0108] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.5 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 15 mg.

[0109] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.5 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 17.5 mg.

[0110] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.5 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, and a dose ofRef. No. 31113_WOtirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 20 mg.

[0111] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.5 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 22.5 mg.

[0112] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 0.5 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 25 mg.

[0113] In an embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 1.0 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, and a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is selected from the group consisting of 2.5 mg, 5.0 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, and 25 mg.

[0114] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 1.0 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 2.5 mg.

[0115] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 1.0 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 5 mg.

[0116] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 1.0 mg of a compoundRef. No. 31113_WOcomprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 7.5 mg.

[0117] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 1.0 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 10 mg.

[0118] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 1.0 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 12.5 mg.

[0119] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 1.0 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 15 mg.

[0120] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 1.0 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 17.5 mg.

[0121] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 1.0 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 20 mg.

[0122] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 1.0 mg of a compoundRef. No. 31113_WOcomprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 22.5 mg.

[0123] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 1.0 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 25 mg.

[0124] In an embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 2.0 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, and a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is selected from the group consisting of 2.5 mg, 5.0 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, and 25 mg.

[0125] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 2.0 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 2.5 mg.

[0126] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 2.0 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 5 mg.

[0127] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 2.0 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 7.5 mg.Ref. No. 31113_WO

[0128] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 2.0 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 10 mg.

[0129] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 2.0 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 12.5 mg.

[0130] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 2.0 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 15 mg.

[0131] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 2.0 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 17.5 mg.

[0132] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 2.0 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 20 mg.

[0133] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 2.0 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 22.5 mg.Ref. No. 31113_WO

[0134] In one embodiment, the present disclosure provides a method of administering to a patient in need thereof a pharmaceutical composition comprising 2.0 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is 25 mg.

[0135] In an embodiment, the present disclosure provides 0.25-2 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an incretin in the treatment of a condition selected from the group consisting of: Type 1 diabetes, obesity, and / or an obesity -related disease or disorder.

[0136] In an embodiment, the present disclosure provides 0.25 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is selected from the group consisting of 2.5 mg, 5 mg, 10 mg, 15 mg, and 20 mg, in the treatment of obesity and / or an obesity-related disease or disorder.

[0137] In an embodiment, the present disclosure provides 0.5 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is selected from the group consisting of 2.5 mg, 5 mg, 10 mg, 15 mg, and 20 mg, in the treatment of obesity and / or an obesity-related disease or disorder.

[0138] In an embodiment, the present disclosure provides 1 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is selected from the group consisting of 2.5 mg, 5 mg, 10 mg, 15 mg, and 20 mg, in the treatment of obesity or an obesity-related disease or disorder.

[0139] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of skill in the art to which the disclosureRef. No. 31113_WOpertains. Although any methods and materials similar to or equivalent to those described herein can be used in the practice or testing of Peptide A in combination with an incretin, the preferred methods and materials are described herein.

[0140] Moreover, reference to an element by the indefinite article “a” or “an” does not exclude the possibility that more than one element is present, unless the context clearly requires that there be one and only one element. The indefinite article “a” or “an” thus usually means “at least one.”

[0141] When used herein in reference to one of more of the incretins, the terms “activity,” activate^]”, “activating]” and the like refers to the capacity of a compound, or a pharmaceutically acceptable salt thereof, to bind to and induce a response at the receptor(s), as measured using assays known in the art, such as the in vitro assays described below.

[0142] The term “in combination with”, as used herein, means administering at least one of Peptide A, or a pharmaceutically acceptable salt thereof, either simultaneously, sequentially or in a single combined formulation with one or more additional therapeutic agents, including, but not limited to, incretins. Non-limiting examples of the additional therapeutic agents that can be combined with Peptide A include insulin; incretins, such as glucagon-like-peptide-1 (GLP-1) or GLP-1 agonists; gastric inhibitory polypeptide (GIP) agonists; agonists of the GLP-1 and glucagon receptors, sometimes notated as GLP-1 / GCGR dual agonists; dual agonists of the GIP and GLP-1 receptors, sometimes notated as dual GIP / GLP-1 agonists; triagonists of the GIP, GLP-1 and glucagon receptors, sometimes notated as GIP / GLP-1 / GCGR triagonist; or combinations of any of the foregoing agents. Peptide A and the additional therapeutic agent(s) can be coadministered through the same delivery route and device such as a single pill, capsule, tablet, or injectable formulation; or separately administered either at the same time in separate delivery devices or routes; or administered sequentially.

[0143] The term “diabetes” refers to a disease in which the body’s ability to produce or respond to the hormone insulin is impaired, resulting in abnormal metabolism of carbohydrates and elevated levels of glucose in the blood and urine. As used herein, the term diabetes may refer to a chronic condition that affects the way the body processesRef. No. 31113_WOblood sugar, or glucose, e.g., type 2 diabetes mellitus (T2DM); a chronic condition in which the pancreas produces little or no insulin, e.g., type 1 diabetes mellitus (T1DM); a condition in which blood sugar is high, but not high enough to be type 2 diabetes, e.g., pre -diabetes; a form of high blood sugar affecting pregnant women, e.g., gestational diabetes.

[0144] The term “dose” as used herein means a quantity of a medicament taken or recommended to be taken. The term “incretin” as used herein refers to a group of endogenous metabolic hormones that are excreted from the enteroendocrine cells in the stomach and pancreas to stimulate a decrease in blood glucose, typically via regulation of the amount of insulin that is secreted after meals. The term “incretin” as used herein also refers to a group of synthetic hormone mimetics which are physiologically similar to incretins. Incretins may include, but are not limited to, GLP-1 receptor agonists, such as semaglutide, liraglutide, or dulaglutide; GIP receptor analogs; dual agonists of the glucagon and GLP-1 receptors, such as mazdutide; dual agonists of the GIP and GLP-1 receptors, such as tirzepatide; triagonists of the GIP, GLP-1 and glucagon receptors, such as retratrutide.

[0145] The term “insulin sensitivity” as used herein refers to the relationship between insulin exposure (concentration) and the efficacy of insulin, generally considered in terms of the glucose lowering capacity. Greater insulin sensitivity corresponds to lower insulin needs to achieve glucose control, which can result in lowered demand for endogenous insulin production or can be reflected in reduced need for exogenous insulin in individuals treated with insulin. Insulin sensitivity may be quantified, e.g., by using the Matsuda index, derived from the simultaneous assessment of insulin and glucose levels during an oral glucose tolerance test (OGTTS), mixed meal tolerance test (MMTT), or by using glucose clamp methodologies.

[0146] The term “obesity” as used herein refers to a disorder involving excess body fat that increases the risk of health problems. The term “obesity” also refers to weight that is higher than what is considered a healthy weight for a given height. The term “obesity” also refers to a BMI greater than 30.0. As used herein, body mass index (BMI) refers to a person’s weight in kilograms divided by the square of height in meters. The termRef. No. 31113_WO“obesity -related disease or disorders” as used herein also means any diseases or disorders that are induced / exacerbated by obesity including, but not limited to, cardiovascular disease, congestive heart failure, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), osteoarthritis (OA), polycystic ovarian syndrome (PCOS), type 2 diabetes mellitus (T2DM).

[0147] The term “patient” as used herein refers to an animal, and preferably to a human. In certain embodiments, the patient, preferably a human, is further characterized with a disease, disorder, or condition that would benefit from administration of Peptide A in combination with an incretin. Pharmaceutical compositions comprising Peptide A in combination with an incretin may be administered orally or parenterally to patients in need of such treatment. Parenteral administration may be performed by subcutaneous, intramuscular, or intravenous injection by means of a syringe, optionally a pen-like syringe, or a mechanically-driven injector. Alternatively, parenteral administration can be performed by means of an infusion pump.

[0148] As used herein, “PYY” means Peptide YY obtained or derived from any species, such as a mammalian species, especially a human. PYY includes both the native PYY (z'.e., full-length) and variations thereof (z.e., additions, deletions and / or substitutions of native PYY).

[0149] As used herein, “PYY analog” or “PYY analogs” means a PYY-like peptide or polypeptide that elicits one or more effects of native PYY at one or more NPY receptors such as the NPY2 receptor. Specific PYY analogs include, but are not limited to, Peptide A (SEQ ID NO:1).

[0150] As used herein, “treating” or “to treat” means attenuating, restraining, reversing, slowing or stopping progression or severity of an existing condition, disease, disorder or symptom.

[0151] “AOBPM” means automated office blood pressure measurement; “BP” means blood pressure; “CRU” means clinical research unit; “C-SSRS” means Columbia Suicide-Severity Rating Scale; “LTT” means lipid tolerance test; “OGTT” means oral glucose tolerance test; “HOMA-IR” means Homeostatic Model Assessment of Insulin Resistance; “i.v.” means intravenous; “GIR” means glucose infusion rate.Ref. No. 31113_WOEXAMPLESThe following non-limiting examples are offered for purposes of illustration, not limitation.Example 1: A dose-escalation study of Peptide A (SEQ ID NO:1) in combination with tirzepatide in overweight or obese participants

[0152] The study design is a Phase 1, randomized, placebo-controlled, investigator- and participant-blind, dose-escalation study that investigated the safety, tolerability, PK, and PD following multiple SC doses of Peptide A (SEQ ID NO:1) in combination with tirzepatide in overweight or obese participants. The study consisted of a screening period, a treatment period, and a follow-up period. The total study duration for each participant is planned to be approximately 14 weeks, including approximately 4 weeks for screening, 4 weeks of study intervention exposure, and 6 weeks of follow-up after the last SC administration of Peptide A and tirzepatide.

[0153] The study population includes participants with body mass index within the range of 27 to 45 kg / m2(inclusive) and had a stable body weight for 3 months prior to screening (<5% change in body weight).

[0154] A maximum of 45 participants will be enrolled to study intervention to ensure that approximately 12 participants per cohort complete the study.

[0155] Up to 3 dose-escalating cohorts of approximately 12 participants (9 Peptide A: 3 placebo in combination with tirzepatide) are planned. Cohorts will be dosed sequentially as shown in Table 1.Inclusion Criteria

[0156] Participants are eligible to be included in the study only if all of the following criteria apply:Age1. Participant must be 20 to 70 years of age inclusive at the time of signing of the informed consent.Type of Participant and Disease CharacteristicsRef. No. 31113_WO2. Participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring (vital signs and ECG).3. Participants must have venous access sufficient to allow for blood sampling as per the protocol.4. Participants are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures.Weight5. Participants have a BMI within the range 27 to 45 kg / m2(inclusive).6. Participants have had a stable body weight for at least 3 months prior to screening (<5% change in body weight).Sex and Contraceptive / Barrier Requirements7. Men agree to refrain from sperm donation and to use contraceptive methods throughout the study and for 21 weeks (90 days plus 5 projected half-lives of Peptide A - SEQ ID NO:1) after the last study intervention administration. 8. Women not of childbearing potential may participate in this study Informed Consent9. Participant must be capable of giving signed informed consent which includes compliances with the requirements and restrictions listed in the ICF and protocol.Other Inclusions10. Participants must not have modified diet, adopted or planned to make any nutritional lifestyle modification for 3 months prior to randomization.Exclusion Criteria

[0157] Participants are excluded from the study if any of the following criteria apply:(1) Are lactatingRef. No. 31113_WO(2) Have known allergies to Peptide A (SEQ ID NO:1), related compounds or any components of the formulation, tirzepatide, or history of atopy or clinically significant multiple or severe drug allergies, or intolerance to topical corticosteroids, or severe posttreatment hypersensitivity reactions including, but not limited to, erythema multiforme major, linear immunoglobulin A dermatosis, toxic epidermal necrolysis, anaphylaxis, angioedema, or exfoliative dermatitis. (3) Have a resting heart rate of <50 or >100 beats per minute. If a repeat measurement shows values within the range, the participant can be included in the study.(4) Have a mean sitting systolic BP, higher than 160 mm Hg and a mean sitting diastolic BP higher than 90 mm Hg from 3 measurements at screening, measured by following the automated office blood pressure measurement (AOBMP) instructionsa. The AOBPM will be performed using locally sourced automated BP measurement devices. The CRU staff should be trained on the correct positioning of the AOBPM device, use of the correct cuff size, and monitor calibration prior to the start of the study.b. The participant should avoid eating, drinking (except water), or smoking 30 minutes before AOBPM. The participant is seated comfortably in a chair with back support, legs uncrossed, feet touching the floor, and arm resting at heart level. The AOBPM will be performed by CRU staff that have appropriate training in collecting BP. After resting for at least 5 minutes, the BP measurements will occur.c. Four BP readings are recorded 1-2 minutes apart; the latter 3 are averaged and the first reading is discarded. The average of the 3 BP measurements will be considered for analysis. The assessment can be repeated once and if the repeat mean value is within the range, the participant can be included in the trial.d. Any AOBPM done after Day 1 should be done at approximately the same time of day as predose and done under similar conditions.Ref. No. 31113_WO(5) Have an abnormality in the 12-lead ECG at screening that, in the opinion of the investigator, increases the risks associated with participating in the study or may confound ECG data analysis(6) Have a history of or current cardiovascular, respiratory, hepatic, renal, hematological, or neurological disorders capable of signicificantly altering the absorption, metabolism, or elimination of drugs: of constituting a risk when taking the investigational product; or of interfering with the interpretation of data (7) Have any of the following within the past 6 months prior to screening: myocardial infarction, unstable angina, coronary artery bypass graft, percutaneous coronary intervention (diagnostic angiograms are permitted), transient ischemic attack, cerebrovascular accident or decompensated congestive heart failure, or currently have New York Heart Association Class III or IV heart failure(8) Have known or ongoing psychiatric disorders considered clinically significant in the opinion of the investigator(9) Are, in the judgment of the investigator, actively suicidal and therefore deemed to be at significant risk for suicide(10) Have answered “yes” to:a. Either Question 4 or Question 5 on the “Suicidal Ideation” portion of the C-SSRS; orb. Any of the suicide-related behaviors on the “suicidal behavior” portion of the C-SSRS; ANDc. The ideation or behavior occurred within the past month(11) Regularly use known drugs of abuse or show positive findings on urinary drug screening(12) Have a history or presence of a GI disorder that impacts gastric emptying (for example, relevant esophageal reflux, gastric bypass surgery, pyloric stenosis) or taking a medication known to increase or decrease gastric motility(13) Have obvious clinical signs or symptoms of liver disease and acute or chronic hepatitisRef. No. 31113_WO(14) Have serum AST or ALT >2 x ULN or total bilirubin > 1.5 x ULN except for participants diagnosed with Gilbert’s syndrome(15) Have anemia (defined by hemoglobin or hematocrit below the normal range) or any hematological condition that may interfere with glycated hemoglobin measurement (for example, hemolytic anemias, sickle cell disease) (16) Have evidence of hypothyroidism or hyperthyroidism based on clinical evaluation and / or an abnormal thyroid stimulating hormone that, in he opinion of the investigator, would pose a risk to patient safety(17) Have a history of acute or chronic pancreatitis or elevation in serum lipase and / or amylase >2 x ULN at screening(18) Show evidence of human immunodeficiency virus infection and / or positive human immunodeficiency virus antibodies(19) Have spontaneously cleared HCV infection, defined asa. A positive HCV antibody test, andb. A negative HCV RNA test.Participants with no history of HCV antibody (anti-HCV) treatment may be eligible for inclusion in the study, provided they have no detectable HCV RNA at screening for this study(20) Have a current infection with hepatitis B virus, that is, positive for Hepatitis B surface antigen and polymerase chain reaction positive for hepatitis B virus DNA or both.(21) Have obesity induced by other endocrine disorders (such as Cushing’s syndrome or Prader-Willi syndrome)(22) Have donated blood of more than 500 mL within the previous 3 months of study screening or intend to donate blood during the course of the study(23) Have had lyphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial cell carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 yearsRef. No. 31113_WO(24) Have an estimated glomerular filtration rate <60 mL / min / 1.73 m2, as determined by the local laboratory screening(25) Have a known self or family history (first-degree relative) of multiple endocrine neoplasia type2A or type 2B, thyroid C-cell hyperplasia, or MTC (26) Have a screening calcitonin >20.0 pg / mL(27) Fasting serum triglyceride level of >400 mg / dL at screening and total cholesterol >240 mg / dL at screeningPrior / Concomitant Therapy(28) Have used or intend to use medications that promote weight loss (including but limited to Saxenda® [liraglutide 3.0 mg], Xenical® [orlistat], Meridia® [sibutramine], Acutrim® [phenylpropanolamine], Sanorex® [mazindol], Apidex® [phentermine], BELVIQ® [lorcaserin], Qsymia™ [phentermine / topiramate combination], Contrave® [naltrexone / bupropion], Wegovy™ (semaglutide) or other similar body weight loss medication including over-the-counter medications (for example, all!®]), within 3 months prior to screening.a. Doses of prescription medications for the treatment of concurrent medical conditions should remain constant during the study whenever possible. The Sponsor should be contacted to clarify if an individual medication is allowed in the study. If the need for additional concomitant medication arises, the participant may be continued in the study and remain on study intervention if in the investigator’s opinion, the addition of the new medication does not pose a safety risk. If additional concomitant medication is started or doses ned to be changed of prescription medications, the Sponsor should be informed as soon as possible. b. Use of statins is allowed if the dose has been stable for 3 months prior to screening. Doses of antihypertensive and lipid-lowering therapies must be stable for 3 months prior to screening. Doses of antihypertensive and lipid- lowering agents should not be changed during this study unless necessaryRef. No. 31113_WOto protect participants’ safety on an emergency basis (for example, hypertensive crisis). Participants on a stable dose of thyroid replacement therapy for at least 3 months who are clinically euthyroid and anticipated to remain on this dose throughout the study may be eligible if they meet the other criteria.c. Nausea and / or vomiting during this study may be treated with antiemetics but these medications should not be used prophylactically. Nonsteroidal anti-inflammatory medications (including ibuprofen, aspirin), acetaminophen, cough suppressants, antihistamines, vitamin / mineral supplements, antibiotics, and topical ointments may be used on an as- needed basis without notifying the sponsor and are not restricted by the stable dosing requirements listed earlier.d. If acetaminophen treatment is needed for pain management, the maximal allowed dose will be 3 g / day from all acetaminophen-containing medicinal products. However, acetaminophen should not be allowed after midnight and throughout the remainder of the day on the day of the gastric emptying test. Any additional medication used during the course of the study (including those not requiring sponsor notifications) must be documented on the appropriate eCRF.e. Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and / or herbal supplements) that the participant is receiving at the time of enrollment or receives during the study must be recorded along withi. reason for useii. dates of administration including start and end dates, and iii. dosage information including dose and frequency for concomitant therapy of special interest.(29) The medical monitor should be contacted if there are any questions regarding concomitant or prior therapy.Ref. No. 31113_WO(30) Have taken within the last 3 months any medications that interfere with the absorportion of dietary cholesterol or fast (for example, bile acid sequestrants, orlistat).(31) Are currently taking a central nervous system stimulant (for example, methylphenidate SR) at screening.(32) Use of medications within 14 days of screening that reduce GI motility including, but not limited to, anticholinergics, antispasmodics, 5- hydroxytryptamine-3-receptor antagonists, dopamine antagonists, and opiates (33) Use of medications known to prolong the QT / QTc interval and / or with history of long QT syndromePrior / Concurrent Clinical Study Experience(34) Are currently enrolled in a clinical trial involving a study intervention or off-label use of a drug or device, or are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with his study(35) Have participated, within the last 30 days, in a clinical study involving an investigational product. If the previous investigational product has a long half-life, 5 half-lives or 30 days (whichever is longer) should have passed(36) Have previously completed or withdrawn from this study or any other study investigating Peptide A (SEQ ID NO:1)Other Exclusions(37) Have an average weekly alcohol intake that exceeds 21 units per week (males <65 years old) and 14 units per week (females and males over >65-year- old)a. 1 unit= 12 oz or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits(38) Smoke more than 10 cigarettes per day or the equivalent including electronic cigarettes, or regularly used other sources of nicotine in the last 3 months or are unable to abide by CRU smoking restrictionsRef. No. 31113_WO(39) Are investigate site personnel directly affiliated with this study and their immediate families (immediate family is defined as spouse, biological or legal guardian, child, or sibling)(40) Are unwilling to comply with the dietary restrictions required for this studya. Are unwilling to eat all the ingredients of the LTT or OGTT meal or unable to complete the meal within the predefined time(41) Are employees of Eli Lilly or the contract research organization(42) In the opinion of the investigator or Sponsor, are unsuitable for inclusion in the studyIntervention Groups and Duration:[01581 The total study duration for each participant is planned to be approximately 14 weeks, including approximately 4 weeks of screening, 4 weeks of study intervention exposure, and 6 weeks of follow-up after the last SC administration of Peptide A and tirzepatide. Up to 3 dose-escalating cohorts of approximately 12 participants (9 Peptide A: 3 placebo in combination with tirzepatide) are planned. Participants will receive SC doses of study interventions on a weekly basis for a total of 4 weeks. Cohorts will be dosed sequentially as shown below, Table 1.Table 1. Dosing Schedule for CohortsdWeek 1 Week 2 Week 3 Week 4 Cohort 0.25 mg Peptide 0.25 mg Peptide 0.25 mg Peptide 0.25 mg Peptide 1 A / Placebo + 2.5 mg A / Placebo + 5 mg A / Placebo + 10 mg A / Placebo + 10 TZP TZP TZP mg TZP Cohort 0.5 mg Peptide 0.5 mg Peptide 0.5 mg Peptide 0.5 mg Peptide 2 A / Placebo + 2.5 mg A / Placebo + 5 mg A / Placebo + 10 mg A / Placebo + 10 TZP TZP TZP mg TZPRef. No. 31113_WOWeekl Week 2 Week 3 Week 4 Cohort 0.5 mg Peptide 0.5 mg Peptide 1 mg Peptide 1 mg Peptide 3 A / Placebo + 2.5 A / Placebo + 5 mg A / Placebo + 10 mg A / Placebo + 10 mg TZP TZP TZP mg TZPAbbreviations: TZP= tirzepatide; Peptide A (SEQ ID NO:1)Table 2. Objectives and EndpointsObjectives EndpointsPrimary• To evaluate safety and tolerability • TEAEs and SAEsfollowing multiple SC doses of PeptideA (SEQ ID NO:1) in combination withtirzepatide in overweight or obeseparticipantsSecondary• To determine the PK following multiple • AUC(O-r)SC doses of Peptide A (SEQ ID NO:1)in combination with tirzepatide inoverweight or obese participantsExploratory• To assess the effects on body weight • Absolute and percentage change from following multiple SC doses of Peptide baseline in body weightA (SEQ ID NO:1) in combination with • Fasting appetite VAS tirzepatide compared to tirzepatide with • Postprandial glucose and insulin placebo in overweight or obese response following an OGTT, and participants measures of insulin sensitivity • To explore the effect on appetite • Postprandial lipid and amino acid following multiple SC doses of Peptide response following LTTA (SEQ ID NO: 1) in combination withRef. No. 31113_WOtirzepatide compared to tirzepatide with • Fasting biomarkers (glucose, insulin, C- placebo in overweight or obese peptide, BOHB, lipids, amino acid) participants • Change from baseline in hip• To explore other pharmacodynamic circumference and waist circumference effects following multiple SC doses of • PK of acetaminophenPeptide A (SEQ ID NO: 1) incombination with tirzepatide comparedto tirzepatide with placebo inoverweight or obese participants• To explore the effect on anthropometricmeasure following multiple SC doses ofPeptide A (SEQ ID NO: 1) incombination with tirzepatide comparedto tirzepatide with placebo inoverweight or obese participants• To explore the effect on gastricemptying following multiple SC dosesof Peptide A (SEQ ID NO: 1) incombination with tirzepatide comparedto tirzepatide with placebo inoverweight or obese participantsAbbreviations: AUC(O-r) = area under the drug plasma concentration versus time curve for a particular dosing interval; BOHB = (3-hydroxybutyrate; LTT = lipid tolerance test;OGTT = oral glucose tolerance test; PK = pharmacokinetics; SAE = serious adverseevent; SC = subcutaneous; TEAE = treatment-emergent adverse event; VAS = visualanalog scale.Follow-up periodThe participants will be followed for up to approximately 6 weeks following their lastdose of study intervention for safety assessments, PK, PD, and immunogenicitysamples / measures.Ref. No. 31113_WOExample 2: In vivo effects on body weights and insulin sensitivity in diet-induced obese mice

[0159] DIO male C57B1 / 6 mice (Taconic) at 20 weeks of age are maintained on a 60% fat (20% carbohydrate, 20% protein) diet (DI 2492; Research Diets, New Brunswich, NJ) upon arrival. Animals are individually housed in a temperature-controlled facility (74.0°F; 23.3°C) with a 12-hour light / dark cycle (lights on 22:00) and free access to food and water. After a one-week acclimation period of daily vehicle dosing, non-fasted body weights are measured and animals are randomized by body weight into experimental groups (n = 6-19). Animals are administered daily subcutaneous injections of vehicle, the PYY analog Peptide A, a GLP-1 receptor agonist semaglutide (SEQ ID NO:2), a dual GLP-1 and GIF receptor agonist tirzepatide (SEQ ID NO:3), a triagonist of the GLP-1, GIP, and GCGR receptors retratrutide (SEQ ID NO:4), and an oxyntomodulin GLP-1 and GCGR receptor agonist mazdutide (SEQ ID NO:5), or combinations of Peptide A (SEQ ID NO:1) plus each of the aforementioned compounds. In addition, to determine contributions of food intake to weight loss in combination treatments, pair-fed groups to a semaglutide or tirzepatide plus Peptide A (SEQ ID NO: 1) are included. After 2 weeks of dosing, non-fasted body weights are recorded and changes in average body weight versus vehicle are calculated. To determine additive or synergistic effects of PYY analogs in combination with semaglutide. tirzepatide, retratrutide, or mazdutide, net effects versus vehicle are calculated. In selected subsets of treatments, an oral glucose tolerance test (OGTT) or a euglycemic clamp is performed after 2 weeks of daily dosing.OGTT

[0160] After 2 weeks of treatment, animals are fasted overnight (16 hours). The following morning, animals receive an oral dose of glucose (2 g / kg using a 50% dextrose solution). Blood glucose concentrations are measured at 0, 15, 30, 60 and 120 min after glucose administration using glucometers, with whole blood collected in EDTA-plasma tubes for analysis of plasma insulin (Meso Scale Discovery, Rockville, MD) and c-peptide (Mercodia, Uppsala, Sweden). Data is used to calculate the area under the curve (AUC). To demonstrate improvements on insulin sensitivity, from both fasting conditions as well as in the context of an oral glucose challenge, we calculate HOMA-IR [(fasting glucoseRef. No. 31113_WO(mmol / L) * fasting insulin (microunits / mL)) / 22.5] and Matsuda Index [10000 / SQRT ([(fasting glucose (mmol / L) * fasting insulin (microunits / mL) * (average glucose in OGTT (mmol / L) * average insulin in OGTT (microunits / mL)].Euglycemic clamp

[0161] Catheters were placed in the left carotid artery and the right jugular vein seven to eight days prior to euglycemic clamp. Animals were fasted overnight and blood glucose (BG) was measured from arterial blood via glucometer every 5 minutes during the clamp period. An intravenous infusion of 3mU / kg / min Humulin R (Eli Lilly and Company) and 22.5% glucose was started and periodically adjusted (GIR; Glucose Infusion Rate) to maintain BG concentration at 115-125 mg / dL. Somatostatin (5 ug / kg / min, Bachem) was administered intravenously to inhibit endogenous insulin secretion and washed donor mouse erythrocytes were infused to maintain blood volume. At the end of the study, a bolus dose of 2-[ 1- 14C] Deoxy-D-glucose (PerkinElmer, Waltham, MA, 5pCi) was administered intravenously to measure tissue glucose uptake under steady state glucose concentrations.Ref. No. 31113_WOTable 3. Changes in Body Weight, Glucose, Insulin, HOMA-IR, Matsuda Index, and Glucose Infusion Rate Versus Vehicle in an OralGlucose Tolerance Test or Euglycemic Clamp Performed after 2-Week Treatment in Diet-Induced Obese Mice with Peptide A (SEQ IDNO:1) Alone or in Combination with SemaglutideTreatmen Dose Change Versus Vehicle Treatmentt (nmol / Body Fasting Fasting C- HOMA- Glucose Insulin C-Peptide Matsu Averagekg) Weigh Glucos Insulin Peptide IR AUC AUC AUC da GIR t(%) e (ng / mL) (pg / mL) (mg.min / dL (ng.min / m (pg.min / m Index (mg / kg / mi (mg / dL ) L) L) n))Peptide A 1 -2.8 0.04 1.1(SEQ IDNO:1) -7.8 -26.8 -1.1 -166.5 -29.4 -1967.1 0.4 Semagluti 1 -10.6 -22.4 0.21 26.3 -2.3 985.5 -281.9 -1444.4 3.2 - de 3 -11.6 -33.8 -1.26 -25.0 -14.6 -1471.5 -305.2 -6137.9 11.7 10.510 -17.7 -30.0 -1.08 20.7 -12.6 -2766.0 -290.4 -4634.5 14.7 - Semagluti 1 + 1 -19.8 -36.0 -1.25 -8.8 -14.6 -2439.0 -387.7 -4959.6 30.9 - de + 3 + 1 -23.8 -41.6 -2.40 -47.0 -23.0 -2056.5 -515.5 -7408.6 68.9 29.3Ref. No. 31113_WOPeptide A 10 + 1 -30.4 -1.94(SEQ IDNO:1) -36.8 -14.2 -19.5 -3727.5 -518.8 -5663.5 64.1 Pair-fed (1 + 1) -12.9 -31.4 0.60 -1.6 -0.8 -3841.5 -139.5 296.9 2.0 - (3 + 1) -18.3 -39.6 -0.48 -15.5 -10.1 -5692.5 -258.2 -5271.8 8.7 - (10 + -!)♦ -23.8 -41.6 -0.43 -54.9 -10.2 -4537.5 -301.4 -8815.5 9.9♦Achieved same body weight loss at 2 weeks of dosing as combination of semaglutide at 3 nmol / kg and Peptide A at 1 nmol / kgRef. No. 31113_WO

[0162] Peptide A (SEQ ID NO:1) at 1 nmol / kg daily (QD) alone leads to a small effect on reducing body weight while semaglutide at 1, 3, or 10 nmol / kg alone leads to dosedependent decrease in body weight. Combinations of semaglutide and Peptide A (SEQ ID NO:1) lead to a synergistic (more than additive) effect on reducing body weight in DIO mice. The magnitude of the body weight effect is not observed in mice pair-fed to the combination treatments, demonstrating that the effect of combinations of semaglutide and Peptide A is not based solely on food intake. In an OGTT, Peptide A (SEQ ID NO:1) at 1 nmol / kg QD alone does not greatly improve these indices of insulin sensitivity, with semaglutide dose-dependently improving these indices. Nevertheless, changes in both the HOMA-IR and Matsuda Index with combinations of semaglutide and Peptide A (SEQ ID NO:1) demonstrate a synergistic effect (more than additive of semaglutide or Peptide A alone) on insulin sensitivity. Moreover, these improvements are not simply due to weight loss, as demonstrated with pair-fed controls (including the weight-matched pair-fed group to semaglutide at 10 nmol / kg and Peptide A (SEQ ID NO:1) at 1 nmol / kg). Glucose infusion rate (GIR) is a measurement of the amount of glucose needing to be infused to keep blood glucose at a constant level. It reflects the animal’s ability to use endogenous insulin (i.e., insulin sensitivity). The higher the value, the more insulin sensitive the animal has become. The GIR using euglycemic clamps shows a marginal improvement with Peptide A (SEQ ID NO:1) alone at 1 nmol / kg, a further improvement with semaglutide at 3 nmol / kg alone, and a profound and synergic effect for the combination of semaglutide at 3 nmol / kg and Peptide A (SEQ ID NO:1) at 1 nmol / kg (See Figure 1 and Figure 2).

[0163] Overall, these data demonstrate a dual synergistic effect (body weight loss and insulin sensitivity above and beyond weight loss) of semaglutide (incretin) and Peptide A (SEQ ID NO:1) in DIO mice.Ref. No. 31113_WOTable 4. Changes in Body Weight, Glucose, Insulin, HOMA-IR, Matsuda Index, and Glucose Infusion Rate Versus Vehicle in an OralGlucose Tolerance Test or a Euglycemic Clamp Performed after 2-Week Treatment in Diet-Induced Obese Mice with Peptide A (SEQID NO: 1) Alone or in Combination with Tirzepatide (TZP)Treatme Dose Change Versus Vehicle Treatmentnt (nmol / k Body Fastin Fastin Fastin HOM Glucose Insulin C-peptide Matsu Averageg) Weig g g g c- A IR AUC AUC AUC da GIRht Glucos Insulin peptid (mg.min / d (ng.min / m (pg.min / m Index (mg / kg / mi(%) e (ng / m e L) L) L) n)(mg / d L) (pg / mL) L)Peptide 1 1.8A (SEQ 196.3ID NO:1) -2.3 -0.3 1.49 29.0 13.9 1430.0 641.3 -3.2Tirzepati 1 -9.2 -49.7 0.07 4.0 -11.2 -6558.8 -116.2 -3518.7 5.7 - de (TZP) 3 -13.5 -48.3 -1.47 -34.6 -17.8 -5741.3 -221.9 -6235.0 24.6 19.4TZP + 1 + 1 -22.8 -64.5 -2.01 18.4 -22.5 -8342.5 -374.5 717.9 78.8 - Peptide 3 + 1 -31.5 -79.0 -2.44 6.2 -25.4 -9811.3 -456.9 292.2 181.7 31.2Ref. No. 31113_WOA (SEQID NO:1)Pair-fed (1 + 1) -14.0 -29.2 0.23 31.5 -3.5 -3050.0 22.2 -3313.8 1.0 - (3 + 1) -19.1 -46.2 -1.52 -80.5 -18.8 -6430.0 -129.7 -5698.9 12.6 - TZP + (1 + 1) -17.5 -57.2 -0.82 -52.6 -16.5 -7040.0 -77.3 -3719.7 14.9Pair-fed (3 + 1) -22.9 -63.8 -2.46 -59.4 -25.5 -8450.0 -331.8 -4002.3 46.7Ref. No. 31113_WO

[0164] Peptide A (SEQ ID NO:1) at 1 nmol / kg QD alone leads to small effect on reducing body weight while tirzepatide at 1 or 3 nmol / kg QD alone leads to dosedependent decreases in body weight. Combinations of tirzepatide and Peptide A (SEQ ID NO:1) leads to a synergistic (more than additive) effect on reducing body weight in DIO mice. The magnitude of the body weight effect is not observed in mice pair-fed to the combination treatments, demonstrating that the effect of combinations of tirzepatide and Peptide A (SEQ ID NO: 1) is not based solely on food intake. Moreover, the magnitude of body weight loss in combinations of tirzepatide and Peptide A (SEQ ID NO:1) is not observed in mice pair-fed to combinations as well as dosed with tirzepatide. In an OGTT, Peptide A (SEQ ID NO:1) at 1 nmol / kg QD alone does not greatly improve indices of insulin sensitivity (HOMA-IR and Matsuda Index), while tirzepatide alone leads to dosedependent improvements in both these indices. However, the combinations of tirzepatide and Peptide A further improves HOMA-IR and profoundly increased Matsuda, demonstrating a synergistic effect (more than additive of tirzepatide or Peptide A (SEQ ID NO:1) alone) on insulin sensitivity. Moreover, these improvements are not simply due to weight loss, as demonstrated with pair-fed controls with or without co-treatment of tirzepatide. Tn further support of these findings, the GIR using euglycemic clamps shows only a marginal improvement with Peptide A alone at 1 nmol / kg, a further improvement with tirzepatide at 3 nmol / kg alone, but a profound and synergic effect for the combination of tirzepatide at 3 nmol / kg and Peptide A (SEQ ID NO:1) at 1 nmol / kg.

[0165] Overall, these data demonstrate a dual synergistic effect (body weight loss and insulin sensitivity above and beyond weight loss) of an incretin, e.g., tirzepatide, and Peptide A (SEQ ID NO: 1) in DIO mice (See Figure 5 and Figure 6).Ref. No. 31113_WOTable 5. Changes in Body Weight, Glucose, Insulin, HOMA-IR, and Matsuda Index Versus Vehicle in an Oral Glucose Tolerance Test Performed After 2-Week Treatment in Diet-Induced Obese Mice with Peptide A Alone or in Combination with Retatrutide.Treatmen Dose Change Versus Vehicle Treatmentt (nmol / kg Body Fasting Fasting Fasting HOMA Glucose Insulin C-peptide Matsud) Weigh Glucose Insulin C- -IR AUC AUC AUC a Indext(%) (mg / dL (ng / mL peptide (mg.min / dL (ng.min / mL (pg.min / mL) ) (pg / mL ) ) ))Peptide A 1 -1.6 -21.3 0.03 -0.6 -3.6 -888.8 -19.6 -4610.2 1.6Retatrutide 1 -19.9 -58.8 -0.98 -24.8 -16.2 -6352.5 -473.6 -6617.8 27.03 -29.0 -68.7 -2.84 14.3 -28.3 -7666.3 -580.3 -4726.1 122.4Retatrutide 1 + 1 -31.4 -101.5 -2.62 -1.5 -29.2 -8978.8 -636.3 -6331.6 148.8+ Peptide 3 + 1 -36.0 -100.0 -2.57 31.8 -29.0 -9652.5 -645.1 1101.3 165.0APair-fed (1 + 1) -24.7 -67.8 -1.42 -0.9 -20.6 -7661.3 -525.1 -6839.2 39.3(3 + 1) -26.9 -62.7 -1.62 -10.1 -21.4 -6891.3 -482.6 -5291.7 29.5(1 + D -30.1 -72.5 -2.09 22.6 -24.5 -8737.5 -534.0 170.4 62.6Ref. No. 31113_WORetatrutide (3 + 1) -33.8 -59.2 -2.86 -8.6 -28.2 -8250.0 -605.4 -4293.7 128.0+ Pair-fed□oRef. No. 31113_WO

[0166] Peptide A at 1 nmol / kg QD alone leads to small effect on reducing body weight while retatruide at 1 or 3 nmol / kg QD alone leads to dose-dependent decreases in body weight. Combinations of retatrutide and Peptide A leads to a synergistic (more than additive) effect on reducing body weight in DIO mice. The magnitude of the body weight effect is not observed in mice pair-fed to the combination treatments, demonstrating that the effect of combinations of retatrutide and Peptide A is not based solely on food intake. Moreover, the magnitude of body weight loss in combinations of retatrutide and Peptide A is not observed in mice pair-fed to combinations as well as dosed with retatrutide. In an OGTT, Peptide A at 1 nmol / kg QD alone does not greatly improve indices of insulin sensitivity (HOMA-IR and Matsuda Index), while retatrutide alone leads to dosedependent improvements in both these indices. However, the combinations of retatrutide and Peptide A further improves HOMA-IR and profoundly increased Matsuda, demonstrating a synergistic effect (more than additive of retatrutiide or Peptide A alone) on insulin sensitivity. Moreover, these improvements are not simply due to weight loss, as demonstrated with pair-fed controls with or without co-treatment of retatrutide.

[0167] Overall, these data demonstrate a dual synergistic effect (body weight loss and insulin sensitivity above and beyond weight loss) of retatrutide (incretin) and Peptide A in DIO mice.Ref. No. 31113_WOTable 6. Changes in Body Weight, Glucose, Insulin, HOMA-IR, and Matsuda Index Versus Vehicle in an Oral Glucose Tolerance Test Performed After 2-Week Treatment in Diet-Induced Obese Mice with Peptide A Alone or in Combination with MazdutideTreatmen Dose Change Versus Vehicle Treatmentt (nmol / kg Body Fasting Fasting Fasting HOMA Glucose Insulin C-peptide Matsud) Weigh Glucose Insulin C- -IR AUC AUC AUC a Indext(%) (mg / dL (ng / mL peptide (mg.min / dL (ng.min / mL (pg.min / mL) ) (pg / mL ) ) ))Peptide A 1 -2.4 -8.1 1.26 41.2 9.7 -2113.1 316.1 3196.4 -3.1Mazdutide 1 -11.4 -47.3 -0.72 -7.1 -13.5 -5421.2 -16.8 681.0 10.33 -37.0 -84.3 -2.54 -11.0 -26.8 -10233.7 -332.1 750.4 84.8Mazdutide 1 + 1 -28.7 -78.2 -2.19 15.6 -24.5 -8343.1 -351.9 2207.8 43.7+ Peptide 3 + 1 -40.7 -94.6 -3.05 -0.9 -29.5 -10606.9 -466.1 1960.2 174.6APair-fed (1 + 1) -20.9 -49.9 -0.84 -1.5 -14.8 -6879.4 -74.0 -2459.9 5.9(3 + 1) -31.5 -69.0 -2.00 -44.4 -23.7 -8835.0 -294.6 -2116.8 29.8(1 + D -23.6 -62.1 0.42 -12.2 -11.6 -7811.9 -49.9 -2494.4 5.1Ref. No. 31113_WOMazdutide (3 + 1) -34.6 -82.2 -2.91 -24.9 -28.7 -9978.7 -376.2 -907.3 82.1+ Pair-fedRef. No. 31113_WO

[0168] Peptide A at 1 nmol / kg QD alone leads to small effect on reducing body weight while mazdutide at 1 or 3 nmol / kg QD alone leads to dose-dependent decreases in body weight. Combinations of mazdutide and Peptide A leads to a synergistic (more than additive) effect on reducing body weight in DIO mice. The magnitude of the body weight effect is not observed in mice pair-fed to the combination treatments, demonstrating that the effect of combinations of mazdutide and Peptide A is not based solely on food intake. Moreover, the magnitude of body weight loss in combinations of mazdutide and Peptide A is not observed in mice pair-fed to combinations as well as dosed with mazdutide. In an OGTT, Peptide A at 1 nmol / kg QD alone does not greatly improve indices of insulin sensitivity (HOMA-IR and Matsuda Index), while mazdutide alone leads to dosedependent improvements in both these indices. However, the combinations of mazdutide and Peptide A further improves HOMA-IR and profoundly increased Matsuda, demonstrating a synergistic effect (more than additive of mazdutide or Peptide A alone) on insulin sensitivity. Moreover, these improvements are not simply due to weight loss, as demonstrated with pair-fed controls with or without co-treatment of mazdutide.

[0169] Overall, these data demonstrate a dual synergistic effect (body weight loss and insulin sensitivity above and beyond weight loss) of mazdutide (incretin) and Peptide A in DIO mice.Example 3: The effect of multiple doses of Peptide A (SEO ID NO:1) on postprandial glucose in participants with T2D

[0170] The effect of multiple doses of Peptide A (SEQ ID NO:1) on postprandial glucose was assessed on Days 3 (Week 1), 38 (Week 6), and 80 (Week 12) relative to Day -1 (baseline) in participants with T2D.

[0171] Following a multiple dosing, there were no statistically significant changes observed for change of the postprandial glucose AUC relative to the baseline (Day -1) for any of the Peptide A (SEQ ID NO: 1) monotherapy treatments versus placebo (Figure 9A). Similarly, no changes were observed for change of the postprandial glucose AUC relative to the baseline (Day -1) with dulaglutide alone (Figure 9B). Within each treatment group of Peptide A (SEQ ID NO:1) + 1.5 mg of dulaglutide, the change of theRef. No. 31113_WOpostprandial glucose AUC relative to the baseline (Day -1) was reduced compared to 1.5 mg dulaglutide alone (Figure 9C).

[0172] The treatment-related effects observed in the postprandial insulin response indicate that Peptide A (SEQ ID NO:1) improves insulin sensitivity.Example 4. The effect of multiple doses of Protein A (SEQ ID NO:1) on HbAlc was assessed alone or in combination with 1.5-mg weekly dose of dulaglutide in participants with T2D

[0173] The effect of multiple doses of Protein A (SEQ ID NO:1) on HbAlc was investigated alone or in combination with 1.5-mg weekly dose of dulaglutide in participants with T2D.

[0174] In comparing the same Protein A (SEQ ID NO:1) dosing regimen in monotherapy versus in combination with 1.5 mg dulaglutide, a greater HbAlc reduction was observed in combination with dulaglutide (Figure 10).Ref. No. 31113_WOSEQUENCE LISTING SEQ ID NO:1- PYY Analog (Peptide A)SEQ ID NO:2: GLP-1 Receptor Agonist (Semaglutide)H H H ifH— E G T F T S D V S S Y L E G Q A A— N^l— E F I A WL V RG RGSEQ ID NO:3: Dual GIP / GLP-1 Receptor Agonist (Tirzepatide)H E G T F T S D Y S I — NRef. No. 31113_WO SEQ ID NO:4: Triagonist GIP / GLP-1 / GCGR (Retatrutide)SEQ ID NO:5: Oxyntomodulin GLP-1 / GCGR Receptor Agonist (Mazdutide)

Claims

Ref. No. 31113_WOCLAIMS1. A method of treating obesity or an obesity -related disease or disorder in a patient in need thereof, comprising administering to said patient a once-weekly dose of 0.075-2 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, in combination with a dose of an incretin.

2. The method of claim 1, wherein the patient's insulin sensitivity is improved with treatment.

3. The method of any one of claims 1 and 2, wherein the incretin is selected from the group consisting of: a GLP-1 receptor agonist, a dual agonist of the GIP and GLP-1 receptors, a tri-agonist of the GIP, GLP-1, and glucagon receptors, and a dual agonist of the GLP-1 and glucagon receptors.

4. The method of any one of claims 1 and 2, wherein the incretin is a dual agonist of the GIP and GLP-1 receptors.

5. The method of claim 4 wherein the dual agonist of the GIP and GLP-1 receptors is tirzepatide, or a pharmaceutically acceptable salt thereof.

6. The method of claim 5, wherein the once-weekly dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 0.25 mg, and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of 2.5 mg, 5.0 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, and 25 mg7. The method of claim 5, wherein the once-weekly dose of the compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is 0.25 mg, and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of 2.5 mg, 5.0 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, and 25 mg.

8. The method of claim 7, wherein of dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 2.5 mg.

9. The method of claim 7, wherein the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 5.0 mg.Ref. No. 31113_WO10. The method of claim 7, wherein the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 10 mg.

11. The method of claim 7, wherein the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 12.5 mg.

12. The method of claim 7, wherein the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 15 mg.

13. The method of claim 7, wherein the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 20 mg.

14. The method of claim 5, wherein the once-weekly dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 0.5 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of 2.5 mg, 5.0 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, and 25 mg.

15. The method of claim 14 wherein the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 2.5 mg.

16. The method of claim 14 wherein the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 5.0 mg.

17. The method of claim 14 wherein the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 10 mg.

18. The method of claim 14, wherein the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 12.5 mg.

19. The method of claim 14 wherein the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 15 mg.

20. The method of claim 14 wherein the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 20 mg.

21. The method of claim 5 wherein the once-weekly dose of the compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, is 1 mg and the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of 2.5 mg, 5.0 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, and 25 mg.Ref. No. 31113_WO22. The method of claim 21 wherein the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 2.5 mg.

23. The method of claim 21 wherein the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 5.0 mg.

24. The method of claim 18 wherein the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 10 mg.

25. The method of claim 18 wherein the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 15 mg.

26. The method of claim 18 wherein the dose of tirzepatide, or a pharmaceutically acceptable salt thereof, is 20 mg.

27. A method of administering to a patient in need thereof a pharmaceutical composition comprising 0.25 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is selected from the group consisting of 2.5 mg, 5.0 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, and 25 mg.

28. A method of administering to a patient in need thereof a pharmaceutical composition comprising 0.5 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is selected from the group consisting of 2.5 mg, 5.0 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, and 25 mg.

29. A method of administering to a patient in need thereof a pharmaceutical composition comprising 1 mg of a compound comprising SEQ ID NO:1, or a pharmaceutically acceptable salt thereof, and a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is selected from the group consisting of 2.5 mg, 5.0 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, and 25 mg.

30. 0.075-2 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof for use in simultaneous, separate, or sequential combination withRef. No. 31113_WOan incretin or incretin in the treatment of obesity or an obesity-related disorder in a subject.

31. 0.25 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is selected from the group consisting of 2.5 mg, 5 mg, 10 mg, 15 mg, and 20 mg, in the treatment of obesity or an obesity-related disease or disorder.

32. 0.5 mg of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a dose of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the dose of tirzepatide is selected from the group consisting of 2.5 mg, 5 mg, 10 mg, 15 mg, and 20 mg, in the treatment of obesity or an obesity-related disease or disorder.

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