Methods and uses for treating nausea and vomiting

Abstract

The GIP receptor agonists of this disclosure have antiemetic properties and can therefore be used to reduce or inhibit the frequency or severity of episodes of nausea or vomiting in patients in need.

Description

[Technical Field]

[0001] (Priority) This application claims the benefits and priority of U.S. Provisional Patent Application No. 63 / 493,384 filed on 31 March 2023 and U.S. Provisional Patent Application No. 63 / 585,493 filed on 26 September 2023, the entirety of which is incorporated herein by reference.

[0002] (Reference to a sequence listing by reference) The sequence listing was created on February 15, 2024, and is provided with this specification as a sequence listing XML file "30286_WO" with a size of 25KB. The entire sequence listing XML is incorporated herein by reference.

[0003] (Field of invention) This disclosure relates to compositions having activity in the human glucose-dependent insulin secretion-stimulating polypeptide receptor (GIP-R), more particularly to long-acting peptide compounds, and to methods of use for treating and preventing nausea and vomiting, or symptoms or conditions associated with nausea and vomiting, in patients. [Background technology]

[0004] Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are two of the major incretin peptide hormones that are secreted from the intestines in response to glucose or nutrient intake and stimulate insulin secretion from pancreatic β-cells. GIP and GLP-1 exert their effects by binding to their specific receptors, the GIP receptor (GIP-R) and the GLP-1 receptor (GLP-1R), which belong to the G protein-coupled receptor family. While GIP is the major incretin peptide hormone for improving glycemic control, other therapies that focus on GLP-1 receptor agonism (e.g., liraglutide, semaglutide, and dulaglutide) are effective in managing blood glucose levels and reducing weight, making them ideal treatments for type 2 diabetes or obesity. However, a major problem with these GLP-1 receptor peptide agonists is that they can be associated with adverse side effects such as nausea and vomiting.

[0005] Similarly, nausea and vomiting are common adverse side effects in patients undergoing chemotherapy for cancer treatment. These include the administration of high- and moderate-risk emetogenic chemotherapy that results in chemotherapy-induced nausea and vomiting (CINV). The need for novel therapies to prevent and treat nausea and vomiting in patients is of particular priority in patients with type 2 diabetes, obesity, and cancer. Various aspects and embodiments of this disclosure provide compositions and methods for preventing and treating nausea and vomiting. [Overview of the project] [Means for solving the problem]

[0006] In some embodiments, the present disclosure provides a method for treating or preventing nausea or vomiting in a patient, comprising administering a therapeutically effective amount of a GIP receptor agonist peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof.

[0007] In some embodiments, the therapeutically effective amount of a GIP receptor agonist peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is from about 0.3 mg to 30 mg.

[0008] In some embodiments, the therapeutically effective amount of a GIP receptor agonist peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is from about 5 mg to 30 mg.

[0009] In some embodiments, the therapeutically effective amount of a GIP receptor agonist peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is 7.5 mg.

[0010] In some embodiments, the therapeutically effective amount of a GIP receptor agonist peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is 20 mg.

[0011] In some embodiments, the therapeutically effective amount of a GIP receptor agonist peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is 25 mg.

[0012] In some embodiments, the therapeutically effective amount of a GIP receptor agonist peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is formulated as a medicament.

[0013] In some embodiments, the treatment of nausea or vomiting is in a patient taking a medicament for treating a metabolic syndrome disorder.

[0014] In some embodiments, the metabolic syndrome disorder is type 2 diabetes or obesity.

[0015] In some embodiments, the agent for treating metabolic syndrome disease is selected from the group consisting of a GLP-1 receptor agonist peptide, a dual agonist peptide of GLP-1 and glucagon (GCG) receptor, a long-acting agonist peptide of amylin receptor, a dual agonist peptide of amylin and calcitonin receptor, a monoclonal antibody against leptin receptor, urocortin peptide, or a peptide tyrosine-tyrosine (PYY) analog for a patient.

[0016] In some embodiments, the agent for treating metabolic syndrome disease is selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9, or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments, the patient's tolerance to treatment that induces nausea or vomiting of metabolic syndrome disease is improved.

[0018] In some embodiments, the agent for treating metabolic syndrome disease is administered without titration.

[0019] In some embodiments, the treatment of nausea or vomiting is in patients taking chemotherapeutic agents.

[0020] In some embodiments, the chemotherapeutic agent is selected from the group consisting of anthracycline, cyclophosphamide, carboplatin, carmustine, cisplatin, cyclophosphamide, dacarbazine, doxorubicin, epirubicin, fam-trastuzumab deruxtecan-nxki, ifosfamide, mechlorethamine, melphalan, sacituzumab govitecan-hzly, and streptozocin.

[0021] In some embodiments, the chemotherapeutic agent is selected from the group consisting of aldezleukin, amifostine, bendamustine, busulfan, carboplatin, carmustine, clopharabine, cyclophosphamide, cytarabine, dactinomycin, daunorubicin, dinutuximab, doxorubicin, cytarabine and daunorubicin in dual drug liposome encapsulation, epirubicin, idarubicin, ifosfamide, irinotecan, irinotecan (liposome), lurubinectedin, melphalan, methotrexate, milbetuximab soratansine-gynx, naxitamab-gqgk, oxaliplatin, romidepsin, temozolomide, and trabectedin.

[0022] In some embodiments, the chemotherapeutic agent is cisplatin.

[0023] In some embodiments, the chemotherapeutic agent is a combination of cyclophosphamide and anthracycline.

[0024] In some embodiments, the anthracycline is selected from the group consisting of doxorubicin, daunorubicin, and idarubicin.

[0025] In some embodiments, patient tolerance to nausea or vomiting-inducing treatments using chemotherapeutic agents is improved.

[0026] In some embodiments, the chemotherapeutic agent is administered without titration.

[0027] In some embodiments, a therapeutically effective dose of a GIP receptor agonist peptide containing SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is administered subcutaneously, intravenously, intramuscularly, intraperitoneally, orally, or by inhalation.

[0028] In some embodiments, a therapeutically effective dose of a GIP receptor agonist peptide containing SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is administered to the patient once, once weekly, twice monthly, once every three weeks, once monthly, or once a year.

[0029] In some embodiments, a therapeutically effective dose of a GIP receptor agonist peptide containing SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is administered subcutaneously to the patient once a week.

[0030] In some embodiments, the use of a pharmaceutical composition comprising SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, for treating or preventing nausea or vomiting in a patient.

[0031] In some embodiments, the use of a compound comprising SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a drug for treating or preventing nausea or vomiting in a patient.

[0032] In some embodiments, a pharmaceutical composition comprising the compound of SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of nausea or vomiting in a patient. [Modes for carrying out the invention]

[0033] In various aspects and embodiments, the Disclosure provides compositions and methods for treating or preventing nausea or vomiting. According to aspects of the Disclosure, the compositions comprise a long-acting GIP receptor agonist peptide that targets GIP-R. In some embodiments, the long-acting GIP receptor agonist peptide comprises SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof. In some embodiments, a long-acting GIP receptor agonist peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is effective in treating nausea or vomiting.

[0034] Furthermore, this disclosure also provides methods for clinically managing nausea or vomiting caused by the administration of therapeutic agents that induce nausea and vomiting (e.g., GLP-1 receptor agonist peptides and chemotherapeutic agents) (e.g., treating, preventing, and / or reducing the incidence of nausea or vomiting). Compositions disclosed herein, including SEQ ID NO: 1 or SEQ ID NO: 2, or pharmaceutically acceptable salts and methods thereof, have been shown to treat, prevent, and / or reduce the incidence of the negative side effect of nausea and vomiting and to improve the tolerability of nausea-inducing therapy. The improved tolerability of nausea-inducing therapies in patients disclosed herein, in particular in the examples, is measured by counting the number of vomiting episodes characterized by strong, rhythmic abdominal contractions accompanied by either oral emptying from the gastrointestinal tract (i.e., vomiting) or no passage of substance (i.e., nausea) in patients receiving treatment for cancer (e.g., chemotherapy) or type 2 diabetes or obesity (e.g., GLP-1 agonist peptide) in conjunction with a long-acting GIP receptor agonist peptide, e.g., SEQ ID NO: 1 or SEQ ID NO: 2.

[0035] In some embodiments, the present disclosure provides a method for treating or preventing nausea or vomiting in a patient, comprising administering a therapeutically effective amount of a GIP receptor agonist peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof.

[0036] In one embodiment, the disclosure provides a GIP receptor agonist peptide comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of nausea or vomiting. In another embodiment, the disclosure provides a GIP receptor agonist peptide comprising SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of nausea or vomiting.

[0037] In one embodiment, the Disclosure provides a GIP receptor agonist peptide containing SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of nausea or vomiting, the GIP receptor agonist peptide containing SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, administered in at least one dose of about 0.3 mg to 30 mg. In another embodiment, the Disclosure provides a GIP receptor agonist peptide containing SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, for use in the treatment of nausea or vomiting, the GIP receptor agonist peptide containing SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, administered in at least one dose of about 0.3 mg to 30 mg.

[0038] In one embodiment, the Disclosure provides a GIP receptor agonist peptide comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of nausea or vomiting, wherein the compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is administered once weekly at a dose of approximately 0.3 mg to 30 mg. In another embodiment, the Disclosure provides a GIP receptor agonist peptide comprising SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, for use in the treatment of nausea or vomiting, wherein the GIP receptor agonist peptide comprising SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is administered once weekly at a dose of approximately 0.3 mg to 30 mg.

[0039] In one embodiment, the present disclosure provides the use of a pharmaceutical composition comprising SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, for treating or preventing nausea or vomiting in a patient.

[0040] In some embodiments, the disclosure provides the use of a compound comprising SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a drug for treating or preventing nausea or vomiting in a patient.

[0041] In some embodiments, the present disclosure provides pharmaceutical compositions comprising the compound of SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of nausea or vomiting in patients.

[0042] In some embodiments described herein, the GIP receptor agonist peptide comprises SEQ ID NO: 1. The chemical structure of SEQ ID NO: 1 is shown below using standard single-letter amino acid codes, with the exception of the amino acid residues Aib2, αMeL13, Orn16, Aib20, K26, and Ser39, whose structures have been extended.

[0043] [ka]

[0044] The chemical structure of Sequence ID No. 2 is shown below using standard single-letter amino acid codes, with the exception of amino acid residues Aib2, αMeL13, K17, Aib20, 4-Pal25, and Ser39, whose structures have been extended.

[0045] [ka]

[0046] In some embodiments, the therapeutically effective dose of a GIP receptor agonist peptide for preventing or treating nausea or vomiting in patients requiring prevention or treatment of nausea or vomiting may be in the range of about 0.3 to 30 mg, or about 5.0 to 50 mg.

[0047] In some embodiments, the present disclosure provides a method for treating or preventing nausea or vomiting in a patient requiring treatment for nausea or vomiting, comprising administering a therapeutically effective dose of a GIP receptor agonist peptide comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective dose of the GIP receptor agonist peptide comprising SEQ ID NO: 1 is about 0.3 mg to 30 mg. In some embodiments, the therapeutically effective dose of the GIP receptor agonist peptide comprising SEQ ID NO: 1 is 7.5 mg. In other embodiments, the therapeutically effective dose of the GIP receptor agonist peptide comprising SEQ ID NO: 1 is 20 mg. In other embodiments, the therapeutically effective dose of the GIP receptor agonist peptide comprising SEQ ID NO: 1 is 25 mg.

[0048] In some embodiments, the present disclosure provides a method for treating or preventing nausea or vomiting in a patient requiring treatment for nausea or vomiting, comprising administering a therapeutically effective dose of a GIP receptor agonist peptide containing SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective dose of the GIP receptor agonist peptide containing SEQ ID NO: 2 is about 0.3 mg to 30 mg. In some embodiments, the therapeutically effective dose of the GIP receptor agonist peptide containing SEQ ID NO: 2 is 7.5 mg. In other embodiments, the therapeutically effective dose of the GIP receptor agonist peptide containing SEQ ID NO: 2 is 20 mg. In other embodiments, the therapeutically effective dose of the GIP receptor agonist peptide containing SEQ ID NO: 2 is 25 mg.

[0049] In some embodiments, the present disclosure provides a method for treating or preventing nausea or vomiting in a patient requiring treatment for nausea or vomiting, comprising administering a therapeutically effective dose of the GIP receptor agonist peptide comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective dose of the GIP receptor agonist peptide comprising SEQ ID NO: 1 is about 0.3 mg to 30 mg. In some embodiments, the therapeutically effective dose of the GIP receptor agonist peptide comprising SEQ ID NO: 1 is 7.5 mg. In some embodiments, the therapeutically effective dose of the GIP receptor agonist peptide comprising SEQ ID NO: 1 is 25 mg. In some embodiments, the therapeutically effective dose of the GIP receptor agonist peptide comprising SEQ ID NO: 1 is 25 mg.

[0050] In some embodiments, the present disclosure provides a method for treating or preventing nausea or vomiting in a patient requiring treatment for nausea or vomiting, comprising administering a therapeutically effective dose of the GIP receptor agonist peptide comprising SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective dose of the GIP receptor agonist peptide comprising SEQ ID NO: 2 is about 0.3 mg to 30 mg. In some embodiments, the therapeutically effective dose of the GIP receptor agonist peptide comprising SEQ ID NO: 2 is 7.5 mg. In some embodiments, the therapeuticly effective dose of the GIP receptor agonist peptide comprising SEQ ID NO: 2 is 20 mg. In some embodiments, the therapeuticly effective dose of the GIP receptor agonist peptide comprising SEQ ID NO: 2 is 25 mg.

[0051] In some embodiments, the present disclosure provides a method for treating or preventing nausea or vomiting in a patient requiring treatment for nausea or vomiting, comprising administering a therapeutically effective dose of a GIP receptor agonist peptide essentially derived from SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective dose of the GIP receptor agonist peptide essentially derived from SEQ ID NO: 1 is about 0.3 mg to 30 mg. In some embodiments, the therapeutically effective dose of the GIP receptor agonist peptide essentially derived from SEQ ID NO: 1 is 7.5 mg. In some embodiments, the therapeuticly effective dose of the GIP receptor agonist peptide essentially derived from SEQ ID NO: 1 is 20 mg. In some embodiments, the therapeuticly effective dose of the GIP receptor agonist peptide essentially derived from SEQ ID NO: 1 is 25 mg.

[0052] In some embodiments, the present disclosure provides a method for treating or preventing nausea or vomiting in a patient requiring treatment for nausea or vomiting, comprising administering a therapeutically effective dose of a GIP receptor agonist peptide essentially derived from SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective dose of the GIP receptor agonist peptide essentially derived from SEQ ID NO: 2 is about 0.3 mg to 30 mg. In some embodiments, the therapeutically effective dose of the GIP receptor agonist peptide essentially derived from SEQ ID NO: 2 is 7.5 mg. In some embodiments, the therapeuticly effective dose of the GIP receptor agonist peptide essentially derived from SEQ ID NO: 2 is 20 mg. In some embodiments, the therapeuticly effective dose of the GIP receptor agonist peptide essentially derived from SEQ ID NO: 2 is 25 mg.

[0053] In some embodiments, the GIP receptor agonist peptide of this disclosure, including SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is formulated as a drug.

[0054] In some embodiments, the GIP receptor agonist peptides of the Disclosure, including SEQ ID NO: 1 or SEQ ID NO: 2, or pharmaceutically acceptable salts thereof, are administered as monotherapy to treat or prevent nausea or vomiting in a patient. In some examples, the GIP receptor agonist peptides of the Disclosure, e.g., SEQ ID NO: 1 or SEQ ID NO: 2, may be administered, for example, weekly, twice weekly, every other week, every three weeks, monthly, every two months, every three months, every four months, every five months, or every six months. In some embodiments, the GIP receptor agonist peptides of the Disclosure may be administered to a patient once a week for one to five weeks, one to five months, or one to five years. In some embodiments, the GIP receptor agonist peptides of the Disclosure, including SEQ ID NO: 1 or SEQ ID NO: 2, or pharmaceutically acceptable salts thereof, are administered to treat nausea or vomiting in a patient without co-administration, post-administration, or pre-administration of a GLP-1 receptor agonist.

[0055] In some embodiments, the GIP receptor agonist peptides of the present disclosure, such as SEQ ID NO: 1 or SEQ ID NO: 2, may be administered to patients in need, for example, in combination with other agents that do not adversely affect the GIP receptor agonist peptides of the present disclosure, for purposes such as enhancing the action of the GIP receptor agonist peptides of the present disclosure (antiemetic effect) or reducing the dose of the GIP receptor agonist peptides of the present disclosure.

[0056] In some embodiments, patients who require it are administered a GIP receptor agonist peptide simultaneously with another drug used to treat metabolic syndrome. In other embodiments of this specification, patients who require it are administered a GIP receptor agonist peptide followed by another drug used to treat metabolic syndrome. In yet another embodiment, patients who require it are administered a GIP receptor agonist peptide followed by another drug used to treat metabolic syndrome. In yet another embodiment of this specification, patients who require it are administered a combination of a GIP receptor agonist and another drug used to treat metabolic syndrome sequentially, simultaneously, or separately.

[0057] In some embodiments, metabolic syndrome is defined as type 2 diabetes or obesity.

[0058] Examples of therapeutic agents that can be administered in combination with the GIP receptor agonist peptide of this disclosure, for example, SEQ ID NO: 1 or SEQ ID NO: 2, along with a second therapeutic agent (hereinafter sometimes abbreviated as "combination drug") include anti-obesity drugs, antidiabetic drugs, antidiabetic complication drugs, antihyperlipidemia drugs, antihypertensive drugs, diuretics, and chemotherapeutic agents.

[0059] In some embodiments, the GIP receptor agonist peptides of this disclosure, such as SEQ ID NO: 1 or SEQ ID NO: 2, are administered before the administration of anti-obesity drugs, antidiabetic drugs, antidiabetic complication drugs, antihyperlipidemic drugs, antihypertensive drugs, diuretics, and chemotherapeutic agents.

[0060] In some embodiments of the present disclosure, a second therapeutic agent selected from the group consisting of GLP-1 receptor agonist peptides (SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5), GLP-1 receptor and glucagon (GCG) receptor dual agonist peptides (SEQ ID NO: 6), amyrin receptor long-acting agonist peptide (SEQ ID NO: 7), amyrin receptor and calcitonin receptor dual agonist peptide (SEQ ID NO: 8), a monoclonal antibody against leptin receptor, urocortin peptide, or peptide tyrosine-tyrosine (PYY) analog (SEQ ID NO: 9) is further administered to the patient in need.

[0061] In some embodiments of the present disclosure, a second therapeutic agent selected from the group consisting of SEQ ID NOs: 3, 4, 5, 6, 7, 8, and 9, or pharmaceutically acceptable salts thereof, is further administered to the patient in need.

[0062] In some embodiments, the GLP-1 receptor agonist peptide containing SEQ ID NO: 3 is administered in combination with the GIP receptor agonist peptide of the Disclosure, for example, SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, patients who require it are administered a sequential, simultaneous, or separate treatment regimen of SEQ ID NO: 3 in combination with the GIP receptor agonist peptide of the Disclosure, for example, SEQ ID NO: 1 or SEQ ID NO: 2, for the treatment of nausea or vomiting. In some embodiments, the GLP-1 receptor agonist peptide containing SEQ ID NO: 4 is administered in combination with the GIP receptor agonist peptide of the Disclosure, for example, SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, patients who require it are administered a sequential, simultaneous, or separate treatment regimen of SEQ ID NO: 4 in combination with the GIP receptor agonist peptide of the Disclosure, for example, SEQ ID NO: 1 or SEQ ID NO: 2, for the treatment of nausea or vomiting. In some embodiments, the GLP-1 receptor agonist peptide containing SEQ ID NO: 5 is administered in combination with the GIP receptor agonist peptide of the Disclosure, for example, SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, patients requiring treatment for nausea or vomiting are administered sequentially, concurrently, or separately in a therapeutic regimen of SEQ ID NO: 5 in combination with the GIP receptor agonist peptide of the Disclosure, e.g., SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, a GLP-1 receptor and glucagon (GCG) receptor dual agonist peptide, including SEQ ID NO: 6, is administered in combination with the GIP receptor agonist peptide of the Disclosure, e.g., SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, patients requiring treatment for nausea or vomiting are administered sequentially, concurrently, or separately in a therapeutic regimen of SEQ ID NO: 6 in combination with the GIP receptor agonist peptide of the Disclosure, e.g., SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, a long-acting amyrin receptor agonist peptide, including SEQ ID NO: 7, is administered in combination with the GIP receptor agonist peptide of the Disclosure, e.g., SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, patients in need are administered sequential, simultaneous, or separate therapeutic regimens of the GIP receptor agonist peptide of this disclosure for the treatment of nausea or vomiting, for example, SEQ ID NO: 7 in combination with SEQ ID NO: 1 or SEQ ID NO: 2.In some embodiments, a dual agonist peptide for the amyrin receptor and calcitonin receptor, including SEQ ID NO: 8, is administered in combination with a GIP receptor agonist peptide of the Disclosure, e.g., SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, patients who require it are administered a sequential, simultaneous, or separate treatment regimen of SEQ ID NO: 8 in combination with a GIP receptor agonist peptide of the Disclosure, e.g., SEQ ID NO: 1 or SEQ ID NO: 2, for the treatment of nausea or vomiting. In some embodiments, a peptide tyrosine-tyrosine (PYY) analog, including SEQ ID NO: 9, is administered in combination with a GIP receptor agonist peptide of the Disclosure, e.g., SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, patients who require it are administered a sequential, simultaneous, or separate treatment regimen of SEQ ID NO: 9 in combination with a GIP receptor agonist peptide of the Disclosure, e.g., SEQ ID NO: 1 or SEQ ID NO: 2, for the treatment of nausea or vomiting.

[0063] In some embodiments of the present invention, a second therapeutic agent is further administered to patients who require it, and the second therapeutic agent is a chemotherapeutic agent.

[0064] In some embodiments of the present invention, the chemotherapeutic agent is altretamine, bendamustine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, mechloretamine, melphalan, oxaliplatin, procarbazine, temozolomide, thiotepa, trabectedin, carmustine, lomustine, streptozosin, 5-fluorouracil, 6-mercaptopurine, azacitidine, capecitabine, cladribine, clopharabine, cytarabine, decitabine, phloxuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, nelarabine, pemetrexed, pentostatin, pralatrexate, thioguanine, or trifluridine / tipiracil combination. The following are selected from the group consisting of a combination of etoposide, irinotecan, irinotecan liposomal preparations, mitoxantrone, teniposide, topotecan, cabazitaxel, docetal, nab-paclitaxel, paclitaxel, vinblastine, vincristine, vincristine liposomal preparations, vinorelbine, daunorubicin, doxorubicin, doxorubicin liposomal preparations, epirubicin, idarubicin, mitoxantrone, barurubicin, bleomycin, dactinomycin, mitomycin-C, all-trans retinoic acid, arsenic trioxide, asparaginase, eribulin, isabepyrone, mitotane, omasetaxin, pegaspargase, procarbazine, romidepsin, vorinostat, or any combination thereof.

[0065] In some embodiments, the chemotherapeutic agent is selected from the group consisting of anthracyclines, cyclophosphamide, carboplatin, carmustine, cisplatin, cyclophosphamide, dacarbazine, doxorubicin, epirubicin, fam-trastuzumab deruxtecan-NXKI, ifosfamide, mechloretamine, melphalan, sacituzumab govitecan-HZLY, and streptozocin, and is a chemotherapeutic agent with a high emetogenic risk (e.g., a vomiting rate of more than 90%).

[0066] In some other embodiments, the chemotherapeutic agent is a chemotherapeutic agent having a moderate emetic risk (e.g., vomiting frequency of more than 30% to 90%) selected from the group consisting of aldezleukin, amifostine, bendamustine, busulfan, carboplatin, carmustine, clofarabine, cyclophosphamide, cytarabine, dactinomycin, daunorubicin, dinutuximab, doxorubicin, cytarabine and daunorubicin in dual drug liposome encapsulation, epirubicin, idarubicin, ifosfamide, irinotecan, irinotecan (liposome formulation), rurivinectin, melphalan, methotrexate, milbetuximab soratansine-gynx, naxitamab-gqgk, oxaliplatin, romidepsin, temozolomide, and trabectedin.

[0067] In some embodiments, the chemotherapeutic agent is cisplatin.

[0068] In some other embodiments, the chemotherapeutic agent is a combination of cyclophosphamide and anthracycline.

[0069] In some embodiments, the anthracycline is selected from the group consisting of doxorubicin, daunorubicin, and idarubicin.

[0070] In some embodiments, patients are administered sequential, simultaneous, or separate treatment regimens of GIP receptor agonist peptides in combination with chemotherapeutic agents for the treatment of nausea or vomiting.

[0071] In some embodiments, the Disclosure provides a method for improving a patient's tolerance to treatment with a second therapeutic agent. In another embodiment, a patient's tolerance to treatment with a chemotherapeutic agent is improved. In yet another embodiment, the Disclosure provides a method for improving a patient's tolerance to treatment with a second therapeutic agent administered to treat metabolic syndrome. In one embodiment, the Disclosure provides a method for improving a patient's tolerance to treatment with a second therapeutic agent, selected from the group consisting of GLP-1 receptor agonist peptides (SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5), a GLP-1 receptor and glucagon (GCG) receptor dual agonist peptide (SEQ ID NO: 6), a long-acting amyrin receptor agonist peptide (SEQ ID NO: 7), amyrin receptor and calcitonin receptor dual agonist peptide (SEQ ID NO: 8), a monoclonal antibody against the leptin receptor, urocortin peptide, or a peptide tyrosine-tyrosine (PYY) analog (SEQ ID NO: 9).

[0072] In one embodiment, the disclosure provides a method for administering a second therapeutic agent without titration. In one embodiment, the disclosure provides a method for administering a chemotherapeutic agent without titration. In one embodiment, the disclosure provides a method for administering a second therapeutic agent administered to treat metabolic syndrome without titration. In one embodiment, the disclosure provides a method for administering a second therapeutic agent selected from the group consisting of GLP-1 receptor agonist peptides (SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5), a GLP-1 receptor and glucagon (GCG) receptor dual agonist peptide (SEQ ID NO: 6), a long-acting amyrin receptor agonist peptide (SEQ ID NO: 7), amyrin receptor and calcitonin receptor dual agonist peptide (SEQ ID NO: 8), a monoclonal antibody against leptin receptor, urocortin peptide, or a peptide tyrosine-tyrosine (PYY) analog (SEQ ID NO: 9), without titration.

[0073] In a more specific embodiment, the GIP receptor agonist peptide containing SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is administered in at least one dose of 7.5 mg. In a more specific embodiment, the GIP receptor agonist peptide containing SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is administered in at least one dose of 7.5 mg.

[0074] In a more specific embodiment, the GIP receptor agonist peptide containing SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is administered in at least one dose of 20 mg. In a more specific embodiment, the GIP receptor agonist peptide containing SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is administered in at least one dose of 20 mg.

[0075] In a more specific embodiment, the GIP receptor agonist peptide containing SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is administered in at least one dose of 25 mg. In a more specific embodiment, the GIP receptor agonist peptide containing SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is administered in at least one dose of 25 mg.

[0076] In another specific embodiment, the GIP receptor agonist peptide containing SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is administered in a once-weekly dose of 7.5 mg. In yet another specific embodiment, the GIP receptor agonist peptide containing SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is administered in a once-weekly dose of 7.5 mg.

[0077] In another specific embodiment, the GIP receptor agonist peptide containing SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is administered in a once-weekly dose of 20 mg.

[0078] In another specific embodiment, the GIP receptor agonist peptide containing SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is administered in a once-weekly dose of 20 mg.

[0079] In another specific embodiment, the GIP receptor agonist peptide containing SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is administered in a once-weekly dose of 25 mg.

[0080] In another specific embodiment, the GIP receptor agonist peptide containing SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is administered in a once-weekly dose of 25 mg.

[0081] In one embodiment, the disclosure provides the use of a GIP receptor agonist peptide comprising SEQ ID NO: 1 in the manufacture of a drug for the treatment of nausea or vomiting. In another embodiment, the disclosure provides the use of a GIP receptor agonist peptide comprising SEQ ID NO: 1 in the manufacture of a drug for the treatment of nausea only. In yet another embodiment, the disclosure provides the use of a GIP receptor agonist peptide comprising SEQ ID NO: 1 in the manufacture of a drug for the treatment of vomiting only.

[0082] In one embodiment, the disclosure provides the use of a GIP receptor agonist peptide comprising SEQ ID NO: 2 in the manufacture of a drug for the treatment of nausea or vomiting. In another embodiment, the disclosure provides the use of a GIP receptor agonist peptide comprising SEQ ID NO: 2 in the manufacture of a drug for the treatment of nausea alone. In one embodiment, the disclosure provides the use of a GIP receptor agonist peptide comprising SEQ ID NO: 2 in the manufacture of a drug for the treatment of vomiting alone.

[0083] In some embodiments disclosed herein, nausea or vomiting is acute. In other embodiments disclosed herein, nausea or vomiting is chronic. In yet another embodiment disclosed herein, nausea or vomiting is predictable.

[0084] In embodiments disclosed herein, the GIP receptor agonist peptide, for example, SEQ ID NO: 1 or SEQ ID NO: 2, is administered once. In other embodiments disclosed herein, the GIP receptor agonist peptide is administered once a week. In other embodiments disclosed herein, the GIP receptor agonist peptide is administered twice a month. In other embodiments disclosed herein, the GIP receptor agonist peptide is administered once every three weeks. In other embodiments disclosed herein, the GIP receptor agonist peptide is administered once a month. In other embodiments disclosed herein, the GIP receptor agonist peptide is administered once a year.

[0085] In embodiments disclosed herein, a therapeutically effective dose of a GIP receptor agonist peptide, such as SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is administered subcutaneously to the patient once a week.

[0086] In certain embodiments disclosed herein, the patient requiring treatment has one or more symptoms selected from the group consisting of (1) pregnancy, (2) cyclic vomiting syndrome, (3) infection, (4) ingestion of a toxic substance, (5) motion sickness, and (6) chemotherapy-induced nausea and vomiting (CINV). In certain embodiments disclosed herein, nausea or vomiting is caused by hyperemesis gravidarum during pregnancy.

[0087] The indefinite article "a" or "an" does not rule out the possibility of multiple elements unless the context explicitly requires that there be only one or one element. Therefore, the indefinite article "a" or "an" usually means "at least one."

[0088] Where disclosed herein, “administration” means the act of giving a substance to a patient for the purpose of diagnosing, treating, or preventing a medical disease or condition. Where used herein, the administration of a GIP receptor agonist peptide, including SEQ ID NO: 1 or SEQ ID NO: 2, may be simultaneous with, before, or after a second therapeutic agent. The timing of administration may be simultaneous with, before, or after the onset of nausea or vomiting.

[0089] Where disclosed herein, the term “amino acid” means both naturally occurring and unnatural amino acids. Amino acids are generally represented by standard single-letter codes (e.g., L = leucine), as well as by the α-methyl substitution residues of natural amino acids (e.g., α-methylleucine (or αMeL) and α-methylphenylalanine (or αMeF)), and other specific unnatural amino acids (e.g., α-aminoisobutyric acid (or “Aib”), “4Pal”, “Orn”, etc.). The structures of these amino acids are shown below.

[0090] [ka]

[0091] As disclosed herein, “Orn” means L-ornithine. As disclosed herein, “4Pal” means 3-(4-pyridyl)-L-alanine. As disclosed herein, “αMeF(2F)” means alpha-methyl2-fluoro-L-phenylalanine. As disclosed herein, “αMeY” and “αMeL” mean alpha-methyl-L-tyrosine and alpha-methyl-L-leucine, respectively. As disclosed herein, “e” and “D-Glu” mean D-glutamic acid. As disclosed herein, “D-Tyr” and “y” mean D-tyrosine, respectively. As disclosed herein, “D-Ala” and “a” mean D-alanine, respectively. As disclosed herein, “αMeF” means alpha-methyl-F and alpha-methyl-Phe. As disclosed herein, “Iva” means L-isovaline.

[0092] Where disclosed herein, the term “chemotherapeutic agent” means a drug used to treat cancer by killing malignant cells or preventing their growth.

[0093] Chemotherapy agents are toxic to rapidly proliferating cells and may cause side effects such as nausea and vomiting. Physicians classify chemotherapeutic agents as having high emetogenic risk, moderate emetogenic risk, low emetogenic risk, or minimal emetogenic risk, according to their emetogenicity (i.e., the likelihood of the drug causing nausea or vomiting).

[0094] Non-exclusive examples of chemotherapy agents include altretamine, bendamustine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, mechloretamine, melphalan, oxaliplatin, procarbazine, temozolomide, thiotepa, trabectedin, carmustine, lomustine, streptozocin, 5-fluorouracil, 6-mercaptopurine, azacitidine, capecitabine, cladribine, clopharabine, cytarabine, decitabine, phloxuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, nelarabine, pemetrexed, pentostatin, pralatrexate, thioguanine, and trifluridine / tipiracil combinations. Examples include etoposide, irinotecan, irinotecan liposomal preparations, mitoxantrone, teniposide, topotecan, cabazitaxel, docetal, nab-paclitaxel, paclitaxel, vinblastine, vincristine, vincristine liposomal preparations, vinorelbine, daunorubicin, doxorubicin, doxorubicin liposomal preparations, epirubicin, idarubicin, mitoxantrone, barurubicin, bleomycin, dactinomycin, mitomycin-C, all-trans retinoic acid, arsenic trioxide, asparaginase, eribulin, isabepyrone, mitotane, omasetaxin, pegaspargase, procarbazine, romidepsin, vorinostat, or any combination thereof.

[0095] Non-exclusive examples of chemotherapeutic agents with a high emetogenic risk (vomiting frequency exceeding 90%) include anthracyclines, cyclophosphamide, carboplatin, and carmustine (250 mg / m²). 2 Ultra-, cisplatin, cyclophosphamide (1500 mg / m²)2 hyper), dacarbazine, doxorubicin (60 mg / m 2 or more), epirubicin (90 mg / m 2 hyper) fam-trastuzumab deruxtecan-nxki, ifosfamide (2 g / m per dose 2 or more), mechlorethamine, melphalan (140 mg / m 2 or more), sacituzumab govitecan-hzly, streptozocin, or any combination thereof.

[0096] Non-limiting examples of chemotherapeutic agents with a moderate emetic risk (vomiting frequency > 30% to 90%) are aldesleukin (over 12 million to 15 million IU / m 2 ), amifostine (300 mg / m 2 or more), bendamustine, busulfan, carboplatin (AUC < 4), carmustine (250 mg / m 2 or more), clofarabine, cyclophosphamide (1500 mg / m 2 or more), cytarabine (200 mg / m 2 or more), dactinomycin, daunorubicin, dinutuximab, doxorubicin, a dual-drug liposomal encapsulated formulation of cytarabine and daunorubicin, epirubicin (90 mg / m 2 or less), idarubicin, ifosfamide (2 g / m per dose 2 less than), irinotecan, irinotecan (liposomal formulation), lurbinectedin, melphalan (140 mg / m 2 less than), methotrexate (250 mg / m 2 or more), miltefosine, naxitamab-gqgk, oxaliplatin, romidepsin, temozolomide, trabectedin, or any combination thereof.

[0097] The term "chemotherapy-induced nausea and vomiting" or "CINV" refers to a side effect of cancer treatment. CINV can be classified as acute, anticipatory, breakthrough, delayed, or refractory.

[0098] As disclosed herein, the term “cyclic vomiting syndrome” refers to a syndrome characterized by episodes of severe vomiting without apparent cause. These episodes may last for several hours or several days and may alternate with asymptomatic periods.

[0099] As disclosed herein, the term “dosage” refers to the amount (e.g., concentration) of a drug that is taken or recommended to be taken.

[0100] The terms “vomiting” or “vomiting episode” as disclosed herein refer to strong, rhythmic abdominal contractions accompanied by either oral expulsion from the gastrointestinal tract (i.e., vomiting or diarrhea) or no passage of substance (i.e., nausea). Vomiting may be caused by chemotherapy drugs, such as cisplatin. In some embodiments, nausea and vomiting may be caused by an underlying condition such as hyperemesis gravidarum, cyclic vomiting syndrome, or infection. In some embodiments, nausea and vomiting may be caused by opioid analgesics, ingestion of toxic substances, motion sickness, or concomitant treatment with drugs that induce or may induce nausea or vomiting, such as drugs used to treat metabolic syndrome.

[0101] As used herein, “fatty acid” refers to a linear chain of even carbon atoms, the chain having hydrogen atoms along its length, and having a carboxyl group (-COOH) at one end (monoacid) or both ends (diacid). In a preferred embodiment, the “fatty acid” portion is C 20 It is a diacid.

[0102] Where disclosed herein, “hyperemesis gravidarum” refers to the most severe form of nausea and vomiting during pregnancy. Hyperemesis gravidarum is a condition characterized by severe nausea, vomiting, weight loss, and electrolyte abnormalities.

[0103] Where disclosed herein, “long-acting” means that the binding affinity and activity of the compositions described herein persist for a longer period than that of natural peptides or proteins. Dosage and administration schedules may vary depending on the patient’s condition and the chemical properties of the long-acting GIP agonist peptides, e.g., SEQ ID NO: 1 and SEQ ID NO: 2. In various embodiments, the long-acting GIP agonist peptides are administered approximately weekly, approximately every other month (i.e., approximately every other week), approximately monthly, or approximately quarterly or annually. Dosage and administration schedules may further include varying the frequency of dosing and administration based on the patient’s response.

[0104] Where disclosed herein, “metabolic syndrome” refers to any of a group of conditions that often occur together and increase the risk of heart disease, stroke, and type 2 diabetes. These conditions include hyperglycemia, hypertension, low levels of HDL cholesterol, high levels of blood triglycerides, and a large waist circumference. Non-exclusive examples of drugs used to treat metabolic syndrome include GLP-1 receptor agonist peptides such as liraglutide, semaglutide, or dulaglutide; GLP-1 receptor and GCG receptor dual agonists; amyrin receptor agonist peptides; dual agonists of both amyrin receptor and calcitonin receptor; monoclonal antibodies against leptin receptors; peptide tyrosine-tyrosine (PYY) analogs; or urocortin peptides.

[0105] Where disclosed herein, “motion sickness” means motion sickness. Motion sickness refers to repetitive motion during travel, such as driving over bumps in a car or being rocked by a boat.

[0106] Where disclosed herein, the term “nausea” refers to an unpleasant sensation accompanied by an urge to vomit. Nausea is a subjective discomfort in the back of the throat and stomach that may cause vomiting. There are many words to describe nausea, but they are not limited to those listed below, including stomach upset, nausea, or indigestion. Nausea may have other accompanying symptoms, such as increased saliva production, dizziness, lightheadedness, difficulty swallowing, changes in skin temperature, and a rapid heart rate.

[0107] As used herein, the term “patient” refers to a human or animal. In preferred embodiments, the patient is human. In certain embodiments, the patient is further characterized by having or being at risk of nausea or vomiting. In further embodiments, the patient benefits from the therapeutic effect of a long-acting GIP agonist that treats or prevents nausea or vomiting.

[0108] The terms “reduce” or “inhibit” refer to the ability to produce an overall reduction of 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or more. In some embodiments, “reduce” or “inhibit” may refer to a relative reduction compared to a standard (e.g., a standard level of biological activity (e.g., the number of episodes of nausea and / or vomiting and / or diarrhea after administering a prescribed dose of chemotherapy, e.g., a prescribed dose of a chemotherapy agent known to cause nausea or vomiting)). In some embodiments, “reduce” or “inhibit” may refer to a relative reduction of side effects (i.e., nausea and / or vomiting and / or diarrhea) associated with the treatment of a condition or disease.

[0109] As used herein, “prevention,” “prevent,” and / or “preventing” are interchangeable and refer to all processes, including but not limited to pre-treatment, that prevent something from happening or occurring, or that prevent events such as vomiting or nausea from occurring. As used herein, prevention is not necessarily intended to indicate complete prevention of all disease symptoms.

[0110] As used herein, the term “vomiting” refers to the contraction of the abdominal or diaphragmatic muscles that induces the expulsion of stomach contents. Vomiting is also expressed as “spitting up.” When a person vomits, the abdominal muscles contract (compress) to push the stomach contents out of the mouth. Nausea may or may not be present.

[0111] As used herein, the term “nausea” refers to episodes of vomiting that do not involve the passage of any substance, such as reflux of gastric and esophageal material without regurgitation. As used herein, the term “nausea” also refers to the sensation of nausea without the actual production of vomit.

[0112] As used herein, “therapeutic dose” means, for example, an amount of the compound sufficient to treat nausea and / or vomiting when administered to a patient in need.

[0113] As used herein, "titration" refers to a drug initiated at a low dose. The dose is gradually increased until the maximum desired dose is reached.

[0114] As used herein, "tolerance" refers to the ability to readily tolerate drug treatment.

[0115] As used herein, “to treat” or “to treat” means to reduce, suppress, reverse, slow down or stop the progression or severity of an existing condition, disease, disorder or symptom.

[0116] As used herein, the term “approximately” means the value ± the value of the relevant value, unless the context should interpret it otherwise.

[0117] Other aspects and embodiments of this disclosure will become apparent from the following examples. [Examples]

[0118] Example 1: Emeticity test of peptide A (SEQ ID NO: 1), cisplatin, and aprepitant after single oral, subcutaneous, or intraperitoneal administration in male ferrets. method During the experiment, adult male ferrets (n=5 / group (0.9–1.8 kg), Marshall Farms), aged 16 weeks or older, were individually housed in a temperature-controlled environment (20–26°C) with a relative humidity of 50±20% and a 12-hour light / 12-hour dark cycle. Animals were pre-treated with a solvent (Tris-HCl / 0.02% PS-80) or peptide A (SEQ ID NO: 1) (doses 0.012 mg / kg, 0.125 mg / kg, and 0.497 mg / kg, subcutaneously (SC)) 16 hours prior to administration of cisplatin (10 mg / kg, IP) or the antiemetic aprepitant (CAS170729-80-3) (dosage 2 mg / kg) or saline injection. Vomiting episodes were measured by blinded observers for each treatment group. A vomiting episode is characterized by strong, rhythmic abdominal contractions accompanied by either oral expulsion from the gastrointestinal tract (i.e., vomiting or diarrhea) or no passage of material (i.e., nausea). The latency to the first vomiting episode and the total number of intervals between vomiting episodes (with and without oral expulsion) are quantified.

[0119] [Table 1]

[0120] Ferrets were treated with cisplatin alone, cisplatin in combination with peptide A, or cisplatin in combination with aprepitant, a known antiemetic. Adult male ferrets were pre-administered low (0.012 mg / kg), medium (0.125 mg / kg), and high (0.491 mg / kg) doses of peptide A 16 hours prior to administration of cisplatin (10 mg / kg) or aprepitant (n=5 per group). Data are shown as mean ± SEM. Statistical analysis was performed by Student's t-test. Solvent * or cisplatin # For this, P = < 0.05.

[0121] The data shows that in adult male ferrets, peptide A (SEQ ID NO: 1) does not induce vomiting when administered alone, but pretreatment with peptide A reduced vomiting and nausea induced by the known emetic cisplatin.

[0122] Example 2: A study to investigate the safety and tolerability of peptide A (SEQ ID NO: 1) in combination with a GLP-1 receptor (GLP-1R) agonist in healthy subjects. In a Phase 1 randomized, placebo-controlled, double-blind trial, the safety and tolerability of a single dose (25 mg) of peptide A (SEQ ID NO: 1) or placebo in combination with the GLP-1 receptor agonist liraglutide were investigated in healthy subjects. It was hypothesized that pretreatment with peptide A (SEQ ID NO: 1) could reduce adverse gastrointestinal (GI) events associated with GLP-1 receptor agonist administration.

[0123] Study selection criteria: Participants must be healthy individuals aged 11 to 60 years, weigh at least 55 kg, and have a BMI of 23 to 40 kg / m². 2 Female subjects were assumed to be free from the possibility of pregnancy, and male subjects were instructed to use appropriate contraception.

[0124] Study Exclusion Criteria: Subjects were excluded if they had a significant medical history including malignancy, HIV infection and / or positive human immunodeficiency virus antibodies, evidence of hepatitis C and / or positive hepatitis C antibodies, or a known personal or family history of multiple endocrine neoplasia type 2A or 2B, thyroid C-cell hyperplasia, or medullary thyroid carcinoma. Subjects were also excluded if they had undergone any debilitating surgery. Subjects were also excluded if they had received any systemic or inhaled glucocorticoid therapy (excluding topical, intra-articular, and intraocular formulations) for more than 14 consecutive days within two weeks prior to screening, or if they planned to use any commercially available or prescription medications other than vitamin / mineral supplements and acetaminophen within 7 days prior to the planned administration. Subjects were also excluded if they had a known allergy to liraglutide, peptide A (SEQ ID NO: 1), or any GIP or GLP-1R agonist, related compounds, or any formulation component of the study, or a significant history of atopic dermatitis. Subjects were excluded if they were currently enrolled in another clinical trial that was not relevant to this study, had participated in another clinical trial within 30 days of screening (or longer if the investigational drug had a half-life longer than 30 days), or had previously completed or discontinued this study. Subjects were also excluded if they had abnormal 12-lead ECG findings that increased the risk associated with participation in the study, serum AST or ALT levels greater than 2×ULN or TBL levels greater than 1.5ULN, serum triglyceride levels of at least 5 mmol / L (442.5 mg / dL), amylase or lipase levels greater than 2.5×ULN, or screening calcitonin levels greater than 20 pg / mL. Subjects were also excluded if they had donated blood in the previous month or more than 450 mL of blood in the past three months. Participants were excluded if they consumed more than 21 units of alcohol per week (for men) or 14 units per week (for women), or if they did not wish to abstain from alcohol consumption from 24 hours before medication until discharge from the clinical trial site.

[0125] Study design. The study was conducted in two parts. Part A evaluated the tolerability of a combination of liraglutide with a 25 mg dose of peptide A (SEQ ID NO: 1) or placebo, following daily administration of liraglutide (intrahorat dose escalation every two days), in a parallel-group design in a population of treatment-naive, healthy subjects.

[0126] Using an accelerated dose escalation regimen, the dose of liraglutide was increased every two days for each subject from a starting dose of 0.6 mg to a final dose of 2.4 mg by day 8, followed by a two-week rest period (Part A, Period 1). This accelerated regimen was designed to increase the frequency of GI events and thus allow for the potential demonstration of a reduction in GI events by peptide A (SEQ ID NO: 1) pretreatment. After the rest period, subjects were readmitted the day before administration and randomly assigned to either a 25 mg dose of peptide A (SEQ ID NO: 1) or placebo pretreatment on day 1. The following day, subjects began an eight-day course of liraglutide administration (daily), similar to the first treatment period. Using the accelerated dosing regimen, the dose of liraglutide was increased every two days for each subject (Part A, Period 2).

[0127] Part B evaluated the tolerability of liraglutide administered daily to a population of treatment-naive, healthy subjects, along with a 25 mg dose of peptide A (SEQ ID NO: 1) or placebo as a pretreatment, in a crossover design that allowed for intra-patient repeated measures while avoiding order bias.

[0128] On day 1, subjects were randomly assigned to receive either a 25 mg dose of peptide A (SEQ ID NO: 1) or a placebo as pretreatment. The following day, subjects began daily administration of liraglutide for 8 days. In Part B, an accelerated dosing regimen was used. The dose of liraglutide was increased daily in each subject, followed by an 8-week rest period. After the rest period, subjects crossed over to the same 25 mg dose of peptide A (SEQ ID NO: 1) or placebo as in the first treatment period, alternating as pretreatment.

[0129] In Parts A and B, the incretin response to 25 mg of peptide A (SEQ ID NO: 1) alone or in combination with liraglutide was evaluated by graded glucose infusion (GGI). Hyperglycemia was induced using intravenous glucose to stimulate endogenous insulin secretion. By performing this procedure on different days during the dose escalation schedule, the incretin effects from placebo, 25 mg of peptide A (SEQ ID NO: 1), 1.8 mg of liraglutide (Part A), 2.4 mg of liraglutide (Part B), and peptide A + liraglutide could be measured. GGI was performed during both treatment periods of Part A (Period 2) and Part B. GGI was performed before the first dose of liraglutide on day 2 (to measure the peptide A (SEQ ID NO: 1) or placebo response) and again on day 6 (to measure the liraglutide or liraglutide + peptide A (SEQ ID NO: 1) response).

[0130] Participants. 44 participants were randomly assigned to the study intervention; 12 participants completed Part A and 32 participants completed Part B.

[0131] [Table 2] * The p-values ​​are derived from a generalized linear model assuming a negative binomial distribution, comparing the mean events per patient in the placebo group and the protein A (SEQ ID NO: 1) group, after accounting for repeated measures in the same patients. Some p-values ​​are unavailable due to the small number of events.

[0132] [Table 3] † The p-values ​​are from the McNemar test, which compares paired binomial data between the Protein A (SEQ ID NO: 1) group and the placebo group. Some p-values ​​are unavailable due to the small number of events.

[0133] Results. The drug was administered to 32 healthy subjects, and 31 completed both periods of the trial. All 32 patients were included in the safety data analysis. In the placebo-treated phase of the trial, the total number of gastrointestinal adverse events was 73 (average 2.28 events per subject). 23 out of 32 subjects (72%) experienced gastrointestinal adverse events. In the GIP receptor agonist pretreatment phase, the frequency of gastrointestinal adverse events was 41 (average 1.28 events per subject). 17 out of 32 subjects (53%) experienced gastrointestinal adverse events (p=0.02 comparing the combined event rates of peptide A and placebo; no evidence of order effect).

[0134] The number of subjects experiencing the three most common GI events (nausea, vomiting, and gastroesophageal reflux) decreased by approximately 20–65%. The total number of the three most common GI events (nausea, vomiting, and gastroesophageal reflux) also decreased by approximately 45–65%.

[0135] Example 3: Phase 1b, Part 2, Double-Blind, Multiple Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Peptide B (SEQ ID NO: 2) in Subjects with Type 2 Diabetes (T2DM) A Phase 1b randomized, single-center, double-blind, two-part multi-dose escalation (MAD) trial of peptide B (SEQ ID NO: 2) was conducted in subjects with T2DM. The trial consisted of a screening period, an induction period, a treatment period, and a follow-up period. Part A of the trial consisted of two cohorts (7.5 mg dose, once weekly (QW) and 20 mg dose, QW), with approximately 9 subjects in each cohort randomized in a 6:3 ratio to either peptide B (SEQ ID NO: 2) or placebo. At week 9, 1.5 mg of dulaglutide (QW) was added to the treatment regimen of all subjects.

[0136] Part B of the study consisted of three cohorts in which subjects were randomized in a 2:2:1 ratio. Each cohort received either a placebo matched to 1.5 mg of dulaglutide (QW) + peptide B, 20 mg of peptide B (SEQ ID NO: 2(QW)) + 1.5 mg of dulaglutide QW (24 subjects), or a placebo matched to 20 mg of peptide B(QW) + dulaglutide (12 subjects).

[0137] Selection Criteria: To be considered for participation in the study, participants must be healthy, between 18 and 70 years of age, weigh less than 150 kg, and have a BMI between 23 and 45 kg / m². 2 The following conditions were met: Female subjects had no possibility of pregnancy, and male subjects had given their consent to use highly effective / effective contraception.

[0138] Study Design. The study was conducted in two parts. Part A consisted of two cohorts (7.5 mg (QW) and 20 mg (QW)), with approximately 9 subjects in each cohort randomized in a 6:3 ratio to either peptide B or placebo. From week 9 onward, dulaglutide 1.5 mg (QW) was added to the treatment regimen of all subjects. Part B consisted of three cohorts, randomized in a 2:2:1 ratio, with subjects receiving either dulaglutide 1.5 mg (QW) + placebo (24 subjects), peptide B 20 mg (QW) + dulaglutide 1.5 mg (QW) (24 subjects), or peptide B 20 mg (QW) + placebo (12 subjects).

[0139] Part A. Eligible subjects were randomized in a 6:3 ratio to receive subcutaneous injections of peptide B or placebo (QW). The doses for Part A were 7.5 mg for cohort 1 and 20 mg for cohort 2. The treatment duration was 12 weeks. All subjects received dulaglutide 1.5 mg (QW) from week 9 onward.

[0140] The primary objective of Part A was to investigate the safety and tolerability of multiple quarterly doses of peptide B and placebo with and without dulaglutide after saturation therapy (SC) in subjects with T2DM. Endpoints included therapeutic adverse events (TEAEs) and serious adverse events (SAEs). Secondary objectives of Part A were to characterize the pharmacokinetic profile after multiple QW doses and to characterize the effects on glucose management and glucagon secretion. Endpoints included Cmax and AUC, and the change from baseline in fasting and postprandial blood glucose levels during sMMTT (total AUC and incremental AUC). 0~240分 ), change from baseline in HbA1c, baseline changes in fasting and postprandial glucagon concentrations during sMMTT (total AUC and increase AUC) 0~240分 The exploratory objectives included characterizing the effects of multiple QW doses on body weight and lipid parameters, characterizing the effects on appetite and food intake, characterizing the immunogenicity of peptide B after multiple QW doses, and characterizing the effects of peptide B on target-binding blood markers. Exploratory endpoints included changes from baseline in body weight, waist circumference, body composition (BIA), and lipid parameters, changes in fasting appetite (VAS), changes in appetite (VAS) score at sMMTT, incidence of ADA during treatment, CTX-1, and pancreatic polypeptide levels.

[0141] Part B. Eligible subjects were randomized in a 2:2:1 ratio to receive either dulaglutide 1.5 mg + placebo, peptide B + dulaglutide 1.5 mg (QW), or peptide B + placebo via SC injection. The treatment duration was 12 weeks.

[0142] The primary objective of Part B was to characterize the effects of peptide B on the composite outcome of insulin secretion and insulin sensitivity. The primary endpoint of Part B was the change in total clamped glucose processing index (cDI).

[0143] Secondary objectives of Part B included investigating the safety and tolerability of multiple QW doses of peptide B, dulaglutide, or peptide B + dulaglutide after SC administration in subjects with T2DM, and characterizing the effects on insulin secretion, insulin sensitivity, glucose management, and glucagon secretion. Secondary endpoints of Part B included the frequency of TEAEs and SAEs, changes from baseline in ISR and β-cell glucose sensitivity (GS) in hyperglycemic clamps, changes from baseline in hyperinsulinemia-euglycemic clamp M values, and changes from baseline in fasting and postprandial blood glucose levels at sMTT (total AUC and incremental AUC). 0~240分 ), change from baseline in HbA1c, change from baseline in fasting and postprandial glucagon concentrations during sMMTT (total AUC and increase AUC) 0~240分 ) included.

[0144] The exploratory objectives of Part B included characterizing the effects on body weight and lipid parameters after multiple QW administrations, characterizing the effects on appetite and food intake, characterizing the immunogenicity of peptide B after multiple QW administrations, and characterizing the effects on insulin secretion. The exploratory endpoints of Part B included changes from baseline in body weight, waist circumference, body composition (BIA), and lipid parameters; changes in fasting appetite (VAS); changes in appetite (VAS) score during sMMTT; the incidence of ADA during treatment; and changes from baseline in insulin response to arginine during hyperglycemic clamps (increase in AUC arginine). 0~10分 and increased AUC arginine 0~30分 This included changes in β-cell GS in sMMT, changes from baseline in ISRg in sMMTT, CTX-1, and pancreatic polypeptide levels.

[0145] Results: In Part A, adverse events such as nausea (n=1) and vomiting (n=0) occurred very rarely after the dulaglutide and peptide B treatment regimen. In Part B, subjects treated with dulaglutide and peptide B had fewer instances of nausea and vomiting than subjects treated with dulaglutide and placebo.

[0146] [Table 4]

[0147] [Table 5]

[0148] Sequence List Peptide A (SEQ ID NO: 1) Y-Aib-EGTFISDYSI-αMeL-LD-Orn-IHQ-Aib-DFVEYK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)LEGGPSSGAPPPS-NH2

[0149] Peptide B (SEQ ID NO: 2) Y-Aib-EGTFISDYSI-αMeL-LDKK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)HQ-Aib-DFVE-4-Pal-LLEAGPSSGAPPPS-NH2

[0150] Semaglutide (SEQ ID NO: 3) H-Aib-EGTFTSDVSSYLEGQAAK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)-CO-(CH2) 16 -CO2H)EFIAWLVRGRG

[0151] Liraglutide (CAS Registry Number: 204656-20-2) (Sequence ID: 4) HAEGTFTSDVSSYLEGQAAK(γGlu-CO-(CH2) 14 -CH3)EFIAWLVRGRG

[0152] Dulaglutide (SEQ ID NO: 5) Dulaglutide is a human GLP-1 receptor agonist containing a GLP-1 analog dimer, fused at its C-terminus to the N-terminus of an immunoglobulin analog via a peptide linker, and is identified as CAS Registry No. 923950-08-7, providing the following chemical name: 7-37-glucagon-like peptide I[8-glycine, 22-glutamic acid, 36-glycine](synthetic human) fusion protein, dimer, containing immunoglobulin G4 (synthetic human Fc fragment), peptide (synthetic 16-amino acid linker). Each monomer of dulaglutide has the amino acid sequence described in SEQ ID NO: 13: HGEGTFTSDVSSYLEEQAAKEFIAWLVKGGGGGGGSGGGGGSGGGGSAESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTV LHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG

[0153] Mazdutid (SEQ ID NO: 6) H-Aib-QGTFTSDYSKYLDEKKAK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)-CO-(CH2) 18 -CO2H)EFVEWLLEGGPSSG-NH2

[0154] Long-acting amylin receptor agonist (SEQ ID NO: 7) γE-CNTATCATG-Orn-LAE-αMeF-LVRSSN-NMeN-FGPKLPPTEVGSNTY-NH2 A thioacetal bridge exists between the cysteine ​​at position 2 and the cysteine ​​at position 7. Lysine, ranked 26th, has the formula (γE)2-CO-(CH2). 18 - It is bound to the fatty acid linker portion that follows CO2H.

[0155] Dual agonist of calcitonin receptor and amyrin receptor (SEQ ID NO: 8) Acetyl-ASHLSTAVLGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)LS-Aib-ELHKLEDYPRTDVGAESP-NH2

[0156] Peptide tyrosine-tyrosine (PYY) analog (SEQ ID NO: 9)

[0157] [ka]

Claims

1. A pharmaceutical composition for use in methods for treating or preventing nausea or vomiting in patients, The pharmaceutical composition comprises a GIP receptor agonist peptide containing SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof. The method comprises administering a therapeutically effective amount of a GIP receptor agonist peptide containing SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, to a pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the therapeutically effective amount of the GIP receptor agonist peptide containing SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is about 0.3 to 30 mg.

3. The pharmaceutical composition according to claim 1, wherein the therapeutically effective amount of the GIP receptor agonist peptide containing SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is about 5.0 to 30 mg.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the therapeutically effective amount of the GIP receptor agonist peptide containing SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is 7.5 mg.

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein the therapeutically effective amount of the GIP receptor agonist peptide containing SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is 20 mg.

6. The pharmaceutical composition according to any one of claims 1 to 3, wherein the therapeutically effective amount of the GIP receptor agonist peptide containing SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is 25 mg.

7. The pharmaceutical composition according to any one of claims 1 to 3, wherein the treatment of the nausea or vomiting is performed in a patient taking a drug for the treatment of metabolic syndrome.

8. The pharmaceutical composition according to claim 7, wherein the metabolic syndrome disease is type 2 diabetes or obesity.

9. The pharmaceutical composition according to claim 7, wherein the agent for treating the metabolic syndrome disease is selected from the group consisting of a GLP-1 receptor agonist peptide, a GLP-1 and glucagon (GCG) receptor dual agonist peptide, a long-acting amyrin receptor agonist peptide, amyrin and calcitonin receptor dual agonist peptide, a monoclonal antibody against the leptin receptor, urocortin peptide, or a peptide tyrosine-tyrosine (PYY) analog.

10. The pharmaceutical composition according to claim 9, wherein the agent for treating the metabolic syndrome disease is selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9, or pharmaceutically acceptable salts thereof.

11. The pharmaceutical composition according to claim 9, wherein the patient's tolerance to treatments that induce nausea or vomiting in the metabolic syndrome disease is improved.

12. The pharmaceutical composition according to claim 9, wherein the agent for treating the metabolic syndrome disease is administered without titration.

13. The pharmaceutical composition according to any one of claims 1 to 3, wherein the treatment of the nausea or vomiting is performed in a patient taking a chemotherapy agent.

14. The pharmaceutical composition according to claim 13, wherein the chemotherapeutic agent is selected from the group consisting of anthracycline, cyclophosphamide, carboplatin, carmustine, cisplatin, cyclophosphamide, dacarbazine, doxorubicin, epirubicin, fam-trastuzumab deruxtecan-nxki, ifosfamide, mechloretamine, melphalan, sacituzumab govitecan-hzly, and streptozocin.

15. The pharmaceutical composition according to claim 13, wherein the chemotherapeutic agent is selected from the group consisting of aldezleukin, amifostine, bendamustine, busulfan, carboplatin, carmustine, clopharabine, cyclophosphamide, cytarabine, dactinomycin, daunorubicin, dinutuximab, doxorubicin, cytarabine and daunorubicin in a dual drug liposome encapsulation, epirubicin, idarubicin, ifosfamide, irinotecan, irinotecan (liposome), lurubinectedin, melphalan, methotrexate, milbetuximab soratansine-gynx, naxitamab-gqgk, oxaliplatin, romidepsin, temozolomide, and trabectedin.

16. The pharmaceutical composition according to claim 14, wherein the chemotherapeutic agent is cisplatin.

17. The pharmaceutical composition according to claim 14, wherein the chemotherapeutic agent is a combination of cyclophosphamide and an anthracycline.

18. The pharmaceutical composition according to claim 17, wherein the anthracycline is selected from the group consisting of doxorubicin, daunorubicin, and idarubicin.

19. The pharmaceutical composition according to claim 13, wherein the patient's tolerance to treatment that induces nausea or vomiting using the aforementioned chemotherapeutic agent is improved.

20. The pharmaceutical composition according to claim 13, wherein the chemotherapeutic agent is administered without titration.

21. The pharmaceutical composition according to any one of claims 1 to 3, wherein the GIP receptor agonist peptide containing SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is administered subcutaneously, intravenously, intramuscularly, intraperitoneally, orally, or by inhalation.

22. The pharmaceutical composition according to any one of claims 1 to 3, wherein a GIP receptor agonist peptide containing SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is administered to the patient once, once a week, twice a month, once every three weeks, once a month, or once a year.

23. The pharmaceutical composition according to claim 22, wherein a GIP receptor agonist peptide containing SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is administered subcutaneously to the patient once a week.

24. The use of a compound comprising SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical composition for use in a method for treating or preventing nausea or vomiting in a patient, The pharmaceutical composition comprises a GIP receptor agonist peptide containing SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof. The method described above involves administering a therapeutically effective amount of a GIP receptor agonist peptide containing SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof.

25. The use according to claim 24, wherein the therapeutically effective amount of the GIP receptor agonist peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is about 0.3 to 30 mg.

26. The use according to claim 24, wherein the therapeutically effective dose of the GIP receptor agonist peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is about 5.0 to 30 mg.

27. ​​The use according to any one of claims 24 to 26, wherein the therapeutically effective dose of the GIP receptor agonist peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is 7.5 mg.

28. The use according to any one of claims 24 to 26, wherein the therapeutically effective dose of the GIP receptor agonist peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is 20 mg.

29. The use according to any one of claims 24 to 26, wherein the therapeutically effective dose of the GIP receptor agonist peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is 25 mg.

30. The use according to any one of claims 24 to 26, wherein the treatment of nausea or vomiting is in a patient taking a drug for the treatment of metabolic syndrome.

31. The use according to claim 30, wherein the metabolic syndrome disease is type 2 diabetes or obesity.

32. The use according to claim 30, wherein the agent for treating the metabolic syndrome disease is selected from the group consisting of a GLP-1 receptor agonist peptide, a GLP-1 and glucagon (GCG) receptor dual agonist peptide, an amyrin receptor long-acting agonist peptide, an amyrin and calcitonin receptor dual agonist peptide, a monoclonal antibody against the leptin receptor, a urocortin peptide, or a peptide tyrosine-tyrosine (PYY) analog for the patient.

33. The use according to claim 32, wherein the agent for treating metabolic syndrome is selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9, or pharmaceutically acceptable salts thereof.

34. The use according to claim 32, wherein the patient's tolerance to the treatment that induces nausea or vomiting in the metabolic syndrome disease is improved.

35. The use according to claim 32, wherein the agent for treating metabolic syndrome is administered without titration.

36. The use according to any one of claims 24 to 26, wherein the treatment of nausea or vomiting is in a patient taking a chemotherapy agent.

37. The use according to claim 36, wherein the chemotherapeutic agent is selected from the group consisting of anthracycline, cyclophosphamide, carboplatin, carmustine, cisplatin, cyclophosphamide, dacarbazine, doxorubicin, epirubicin, fam-trastuzumab deruxtecan-nxki, ifosfamide, mechloretamine, melphalan, sacituzumab govitecan-hzly, and streptozocin.

38. The use according to claim 36, wherein the chemotherapeutic agent is selected from the group consisting of aldezleukin, amifostine, bendamustine, busulfan, carboplatin, carmustine, clopharabine, cyclophosphamide, cytarabine, dactinomycin, daunorubicin, dinutuximab, doxorubicin, cytarabine and daunorubicin in a dual drug liposome encapsulation, epirubicin, idarubicin, ifosfamide, irinotecan, irinotecan (liposome), lurubinectedin, melphalan, methotrexate, milbetuximab soratansine-gynx, naxitamab-gqgk, oxaliplatin, romidepsin, temozolomide, and trabectedin.

39. The use according to claim 37, wherein the chemotherapeutic agent is cisplatin.

40. The use according to claim 37, wherein the chemotherapeutic agent is a combination of cyclophosphamide and an anthracycline.

41. The use according to claim 40, wherein the anthracycline is selected from the group consisting of doxorubicin, daunorubicin, and idarubicin.

42. The use according to claim 36, wherein the patient's tolerance to treatments that induce nausea or vomiting using the chemotherapeutic agent is improved.

43. The use according to claim 36, wherein the chemotherapeutic agent is administered without titration.

44. The use according to any one of claims 24 to 26, wherein the GIP receptor agonist peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is administered subcutaneously, intravenously, intramuscularly, intraperitoneally, orally, or by inhalation.

45. The use according to any one of claims 24 to 26, wherein the GIP receptor agonist peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is administered to the patient once, once a week, twice a month, once every three weeks, once a month, or once a year.

46. The use according to claim 45, wherein the GIP receptor agonist peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, is administered subcutaneously to the patient once a week.