GLP-1R antagonism to improve nutrition after gastrointestinal surgery

Abstract

Disclosed are methods of improving nutrition in a subject, including an individual who has undergone gastrointestinal surgery, by an exenatide therapy. Exenatide can be administered subcutaneously or intravenously as part of a liquid pharmaceutical formulation. Exenatide therapy may improve body weight and / or nutrition intake / condition in a subject.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 497,502, filed April 21, 2023. The entire disclosure of the aforementioned provisional application is incorporated herein by reference for all purposes. Background Technology

[0003] Patients undergoing gastrointestinal (GI) surgery (gastrectomy, esophagectomy, etc.) to treat or prevent upper GI malignancies often experience undesirable weight loss in the early postoperative period. More than 15% of patients who have undergone total gastrectomy and more than 35% of patients who have undergone esophagectomy are affected. Weight loss and / or low body mass index (BMI) are associated with poorer response to chemotherapy, recurrence, and reduced survival. Therefore, preventing weight loss after upper GI surgery in cancer patients is extremely important. Low BMI is also associated with increased mortality in non-cancer patients, and therefore improving nutrition in underweight individuals may also benefit non-cancer patients. Summary of the Invention

[0004] As used in this document, the terms “invention,” “the invention,” “this invention,” and “the present invention” are intended to broadly refer to all subject matter of this patent application and the claims below. Statements containing these terms should be understood as not limiting the subject matter described herein or the meaning or scope of the following patent claims. The embodiments covered by this invention are defined by the claims, and not by this summary of the invention. This summary of the invention is a high-level overview of various aspects of the invention and introduces some concepts described and illustrated in this document and the accompanying drawings. This summary of the invention is not intended to identify key or essential features of the claimed subject matter, nor is it intended to be used alone to determine the scope of the claimed subject matter. The subject matter should be understood by referring to appropriate portions of the specification throughout, any or all of the drawings, and each claim. Some exemplary embodiments of the invention are described in detail below.

[0005] Embodiments of the present invention include, and are particularly described in this disclosure, the following non-limiting exemplary embodiments. Embodiments of the present invention include a method for improving the nutrition of a subject, the method comprising the step of administering to the subject a pharmaceutical preparation containing exenatide, wherein the subject has undergone at least one gastrointestinal surgical procedure. In some embodiments of the above method, administration of the pharmaceutical preparation improves the nutrition of the subject compared to the subject's nutrition before administration of the pharmaceutical preparation. In some embodiments of the above method, administration of the pharmaceutical preparation increases the subject's nutritional intake compared to the subject's nutritional intake before administration of the pharmaceutical preparation. In some embodiments of the above method, administration of the pharmaceutical preparation increases the subject's appetite compared to the subject's appetite before administration of the pharmaceutical preparation. In some embodiments of the above method, administration of the pharmaceutical preparation increases the subject's food tolerance compared to the subject's food tolerance before administration of the pharmaceutical preparation. In some embodiments of the above method, administration of the pharmaceutical preparation alleviates the subject's food and / or taste aversion compared to the subject's food and / or taste aversion before administration of the pharmaceutical preparation. In some embodiments of the above method, administration of the pharmaceutical preparation alleviates the subject's food intolerance compared to the subject's food intolerance before administration of the pharmaceutical preparation. In some embodiments of the above methods, administration of the drug formulation alleviates the subject's food avoidance compared to pre-administration food avoidance. In some embodiments of the above methods, the drug formulation increases the subject's calorie intake compared to pre-administration calorie intake. In some embodiments of the above methods, administration of the drug formulation increases the subject's eating behavior compared to pre-administration eating behavior. In some embodiments of the above methods, administration of the drug formulation alleviates the subject's fear of eating compared to pre-administration fear of eating. In some embodiments of the above methods, administration of the drug formulation alleviates the subject's eating-related anxieties compared to pre-administration food-related anxieties. In some embodiments of the above methods, administration of the drug formulation alleviates one or more gastrointestinal symptoms in the subject compared to pre-administration gastrointestinal symptoms. In some embodiments of the above methods, the subject experiences weight gain or a slower rate of weight loss after administration of the drug formulation. In some embodiments of the above methods, the subject experiences dietary freedom after administration of the drug formulation. In some embodiments of the above method, administration of the pharmaceutical preparation after administration of the pharmaceutical preparation reduces the incidence of hypoglycemic events.

[0006] Embodiments of the present invention also include a method for improving the nutritional intake of subjects requiring improved nutritional intake, the method comprising administering a pharmaceutical preparation containing exenatide to the subject, wherein the subject has undergone at least one gastrointestinal surgery. Embodiments of the present invention also include a method for improving the appetite of subjects requiring improved appetite, the method comprising administering a pharmaceutical preparation containing exenatide to the subject, wherein the subject has undergone at least one gastrointestinal surgery. Embodiments of the present invention also include a method for improving the food tolerance of subjects requiring improved food tolerance, the method comprising administering a pharmaceutical preparation containing exenatide to the subject, wherein the subject has undergone at least one gastrointestinal surgery. Embodiments of the present invention also include a method for alleviating food and / or taste aversion in subjects requiring reduced food and / or taste aversion, the method comprising administering a pharmaceutical preparation containing exenatide to the subject, wherein the subject has undergone at least one gastrointestinal surgery. Embodiments of the present invention also include a method for alleviating food intolerance in subjects requiring reduced food intolerance, the method comprising administering a pharmaceutical preparation containing exenatide to the subject, wherein the subject has undergone at least one gastrointestinal surgery. Embodiments of the present invention also include a method for alleviating food avoidance in subjects who need to reduce food avoidance, the method comprising administering a pharmaceutical preparation containing exenatide to the subject, wherein the subject has undergone at least one gastrointestinal surgery. Embodiments of the present invention also include a method for increasing calorie intake in subjects who need to increase calorie intake, the method comprising administering a pharmaceutical preparation containing exenatide to the subject, wherein the subject has undergone at least one gastrointestinal surgery. Embodiments of the present invention also include a method for increasing eating behavior in subjects who need to increase eating behavior, the method comprising administering a pharmaceutical preparation containing exenatide to the subject, wherein the subject has undergone at least one gastrointestinal surgery. Embodiments of the present invention also include a method for alleviating eating fear in subjects who need to reduce eating phobia, the method comprising administering a pharmaceutical preparation containing exenatide to the subject, wherein the subject has undergone at least one gastrointestinal surgery. Embodiments of the present invention also include a method for alleviating eating-related anxiety in subjects who need to reduce eating-related anxiety, the method comprising administering a pharmaceutical preparation containing exenatide to the subject, wherein the subject has undergone at least one gastrointestinal surgery. Embodiments of the present invention also include a method for alleviating one or more gastrointestinal symptoms in a subject who requires relief of one or more gastrointestinal symptoms, the method comprising administering a pharmaceutical preparation comprising exenatide to the subject, wherein the subject has undergone at least one gastrointestinal surgery. Embodiments of the present invention also include a method for increasing the weight of a subject who requires weight gain, the method comprising administering a pharmaceutical preparation comprising exenatide to the subject, wherein the subject has undergone at least one gastrointestinal surgery.Embodiments of the present invention also include a method for reducing the rate of weight loss in subjects who need to reduce the rate of weight loss, the method comprising administering a pharmaceutical preparation containing exenatide to the subject, wherein the subject has undergone at least one gastrointestinal surgery. Embodiments of the present invention also include a method for preventing weight loss in subjects who need to prevent weight loss, the method comprising administering a pharmaceutical preparation containing exenatide to the subject, wherein the subject has undergone at least one gastrointestinal surgery. Embodiments of the present invention also include a method for enabling dietary freedom in subjects who need dietary freedom, the method comprising administering a pharmaceutical preparation containing exenatide to the subject, wherein the subject has undergone at least one gastrointestinal surgery. Embodiments of the present invention also include a method for reducing the incidence of hypoglycemic events in subjects who need to reduce the incidence of hypoglycemic events, the method comprising administering a pharmaceutical preparation containing exenatide to the subject, wherein the subject has undergone at least one gastrointestinal surgery.

[0007] In some embodiments of the method of the present invention (some non-limiting examples of these embodiments are summarized above), administration of the pharmaceutical preparation reduces the incidence of hypoglycemic events in the subject. In some embodiments of the method of the present invention, prior to administration of the pharmaceutical preparation, the subject has elevated glucagon-like peptide-1 (GLP-1) levels compared to a reference population. In some embodiments of the method of the present invention, the subject has been diagnosed with one or more of the following prior to at least one gastric surgery: gastric cancer, esophageal cancer, gastroesophageal reflux, increased risk of gastric cancer, or increased risk of esophageal cancer. In some non-limiting examples, the at least one gastric surgery is a gastrectomy, esophagectomy, or Nissen fundoplication. In some non-limiting examples, the at least one gastric surgery is at least one bariatric surgery, such as, but not limited to, Roux-en-Y gastric bypass (RYGB), vertical sleeve gastrectomy (VSG), or BPD. In some embodiments of the method of the present invention, the subject has type 2 diabetes.

[0008] In some embodiments of the method of the present invention, the pharmaceutical preparation administered to the subject comprises exenatide at a concentration between about 2 and 225 mg / mL. In some embodiments of the method of the present invention, the pharmaceutical preparation is a buffered saline preparation. In some embodiments of the method of the present invention, the pharmaceutical preparation is administered subcutaneously. In some embodiments of the method of the present invention, the pharmaceutical preparation is administered to achieve a total daily dose of exenatide of about 40 mg to about 120 mg. In some embodiments of the method of the present invention, the pharmaceutical preparation is administered to achieve a total daily dose of exenatide of about 90 mg. In some embodiments of the method of the present invention, the pharmaceutical preparation is administered to achieve a total daily dose of exenatide of about 0.4 mg / kg to about 3 mg / kg. In some embodiments of the method of the present invention, the pharmaceutical preparation is administered once daily (QD) or twice daily (BID). In some embodiments of the method of the present invention, the pharmaceutical preparation is administered once daily (QD) at a dose of about 20 mg to about 120 mg, or about 90 mg. In some embodiments of the method of the present invention, the pharmaceutical preparation is administered once daily (QD) at a dose of about 90 mg. In some embodiments of the method of the present invention, the pharmaceutical preparation is administered twice daily (BID) at a dose of about 40 mg to about 60 mg. In some embodiments of the method of the present invention, the pharmaceutical preparation is administered twice daily (BID) at a dose of about 45 mg. These embodiments summarized in this section and other embodiments of this disclosure are described in detail below. Attached Figure Description

[0009] This disclosure includes the following drawings. The drawings are intended to illustrate certain embodiments and / or features of embodiments of the invention, and to supplement any description of embodiments of the invention. The drawings do not limit the scope of embodiments of the invention unless this is expressly indicated in the written description.

[0010] Figure 1 This is a schematic diagram of the design of a phase 2, 7-day clinical evaluation study (Study A) of exenatide (according to this disclosure) to improve eating behavior in cancer patients undergoing total gastrectomy or esophagectomy. The clinical assessments performed included a buffet test, MMTT, and surveys (VAS, SHS, CNAQ, GSRS, HFS-II, SF-36). A 10-day outpatient assessment was conducted using a Dexcompro blinded CGM and timer.

[0011] Figure 2This is a schematic diagram of the design of a Phase 2 28-day clinical evaluation study (Study B) of exenatide (according to this disclosure) to improve the nutritional status and prevent undesirable weight loss in cancer patients undergoing total gastrectomy or esophagectomy. The clinical assessments performed included anthropomorphic measurements; body composition analysis via BIA, DEXA, or CT; buffet testing via VAS and CNAQ; MMT via EHSS; and surveys (SHS, GSRS, HFS-II, SF-36). A 10-day outpatient assessment was conducted using a Dexcom pro blinded CGM and timer.

[0012] Figure 3 This is a schematic illustration of the design of a phase 2, 28-day clinical evaluation study (Study C) (according to this disclosure) of exenatide therapy in patients with severe hypoglycemia following gastrointestinal surgery, including Roux-en-Y gastric bypass (RYGB), vertical sleeve gastrectomy (VSG), esophagectomy, gastrectomy, and Nissen fundoplication. Patients were treated with exenatide in either of the following ways: 90 mg QD for two weeks followed by 45 mg BID for two weeks, or 45 mg BID for two weeks followed by 90 mg QD for two weeks. Eight patients were in each study group. Assessments performed at baseline, at the end of phase 1, and at the end of phase 2 included anthropometric assessments (Wt, Ht, BMI)*, surveys (SHS*, GSRS*, HFS-II*, SF-36, EQ-5D), and laboratory assessments. *Assessments were performed only in patients who had undergone gastrectomy or esophagectomy.

[0013] Figure 4 This is a bar graph showing the selected outcome of a phase 2 28-day clinical evaluation study (Study C) (according to this disclosure) of exenatide therapy in patients with severe hypoglycemia following gastrointestinal surgery (including RYGB, VSG, esophagectomy, gastrectomy, and Nissen fundoplication) – the percentage of time spent with hypoglycemia. The percentage of time hypoglycemia lasted in study participants was plotted on the y-axis. The bars are as follows: black – baseline; white – exenatide administered at a BID of 45 mg twice daily; gray – exenatide administered at a BID of 90 mg.

[0014] Figure 5This is a bar graph showing selected outcomes from a phase 28-day clinical evaluation study (according to this disclosure) of exenatide therapy in patients with severe hypoglycemia following gastrointestinal surgery (including RYGB, VSG, esophagectomy, gastrectomy, and Nissen fundoplication) – the number of hypoglycemic events (“event rate”) within 14 days. The number of hypoglycemic events recorded in study participants within 14 days is plotted on the y-axis. The bars are as follows: black – baseline; white – exenatide administered with a 45 mg BID; gray – exenatide administered with a 90 mg BID. The percentage of hypoglycemic time was defined as the total number of hours with continuous glucose monitoring (CGM) readings below 70 mg / L or 54 mg / dL divided by the total CGM wearing time. The event rate was defined as the number of episodes with blood glucose levels below the glucose range (70 mg / dL or 54 mg / dL) for at least 15 minutes during each treatment period normalized to 14 days.

[0015] Figure 6 This is a bar graph showing selected results from a phase 28-day clinical evaluation study (according to this disclosure) of exenatide therapy in patients with severe hypoglycemia following gastrointestinal surgery (including RYGB, VSG, esophagectomy, gastrectomy, and Nissen fundoplication) – the number of diurnal hypoglycemic events (“diurnal event rate”) within 14 days. The number of diurnal hypoglycemic events recorded in study participants within 14 days is plotted on the y-axis. The bars are as follows: black – baseline; white – exenatide administered with a 45 mg BID; gray – exenatide administered with a 90 mg BID. The event rate was defined as the number of episodes of hypoglycemia below the glucose range (70 mg / dL or 54 mg / dL) for at least 15 minutes during each treatment period normalized to 14 days. Diurnal was defined as events occurring from 8 a.m. to 10 p.m.

[0016] Figure 7 This is a bar graph showing the percentage of time with hypoglycemia (CGM value <70 mg / dL) in selected outcomes of a phase 28-day clinical evaluation study (according to this disclosure) of exenatide therapy in patients with severe hypoglycemia following RYGB, VSG, and gastrectomy (as indicated). The percentage of time hypoglycemia lasted in study participants was plotted on the y-axis. The bars are as follows: black - baseline; white - exenatide administered with a 45 mg BID; gray - exenatide administered with a 90 mg BID.

[0017] Figure 8This is a bar graph showing the percentage of time with hypoglycemia (CGM value <54 mg / dL) in selected outcomes of a phase 28-day clinical evaluation study (according to this disclosure) of exenatide therapy in patients with severe hypoglycemia following RYGB, VSG, and gastrectomy (as indicated). The percentage of time hypoglycemia lasted in study participants was plotted on the y-axis. The bars are as follows: black - baseline; white - exenatide administered with a 45 mg BID; gray - exenatide administered with a 90 mg BID.

[0018] Figure 9 This is a bar graph showing the percentage of time with hypoglycemia (CGM value <40 mg / dL) in selected outcomes of a phase 28-day clinical evaluation study (according to this disclosure) of exenatide therapy in patients with severe hypoglycemia following RYGB, VSG, and gastrectomy (as indicated). The percentage of time hypoglycemia lasted in study participants was plotted on the y-axis. The bars are as follows: black - baseline; white - exenatide administered with a 45 mg BID; gray - exenatide administered with a 90 mg BID.

[0019] Figure 10 This is a line graph showing selected results from animal studies according to this disclosure—the body weight of male animals. Body weight (in g) is plotted on the x-axis. These plots are for four different groups of animals administered different doses of exenatide as described in Example 5 of this disclosure.

[0020] Figure 11 This is a line graph showing selected results from animal studies according to this disclosure—the body weight of female animals. Body weight (in g) is plotted on the x-axis. These plots are for four different groups of animals administered different doses of exenatide as described in Example 5 of this disclosure. Detailed Implementation

[0021] Overview

[0022] This disclosure describes a method for improving the nutrition of subjects by administering a pharmaceutical formulation containing a GLP-1 antagonist (e.g., exenatide). Individuals undergoing gastrointestinal (GI) surgery (such as, but not limited to, gastrectomy, esophagectomy, etc.) (in some cases, these surgeries are performed to treat or prevent upper gastrointestinal malignancies) may experience undesirable and rapid weight loss postoperatively, especially in the early postoperative period. In patients undergoing cancer treatment, weight loss and / or low body mass index (BMI) are associated with poorer response to chemotherapy, recurrence, and reduced survival. Undesirable or excessive weight loss may also affect individuals undergoing upper GI surgery (including, but not limited to, Nissen fundoplication and bariatric surgeries such as Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG)) for indications other than malignancy. While low weight in these individuals is not necessarily associated with increased mortality, malnutrition associated with insufficient calorie, protein, or carbohydrate intake may lead to muscle wasting, fatigue, muscle weakness / exercise intolerance, and mood changes such as depression. The causes of weight loss are not fully elucidated. For example, postprandial GI symptoms (such as, but not limited to, nausea, early satiety, heartburn, indigestion, or bloating) are common in patients after GI surgery. In addition, patients may experience gastric reflux and / or gastric retention (gastroparesis), which may be accompanied by emesis / vomiting. Patients may also experience decreased appetite and taste aversion, as well as hypoglycemia-related anxiety and fear. Some patients may have elevated levels of glucagon-like peptide-1 (GLP-1), GIP, and / or PYY, which in particular promote insulin secretion, satiety, and / or inhibit gastric emptying, thereby reducing food consumption. Any or all of the above factors may lead to food avoidance and reduced food intake. Such factors result in insufficient nutritional intake in patients after GI surgery, leading to weight loss, impaired weight recovery, and / or malnutrition. The inventors particularly believe that the targeted antagonistic effect of exenatide on the GLP-1 receptor could be used as a treatment to improve nutrition in patients after GI surgery.

[0023] The inventors unexpectedly discovered that administration of exenatide to patients following GI surgery can lead to improved nutrition, including but not limited to: prevention of undesirable early postoperative weight loss or improvement of weight rebound; reduction of gastrointestinal symptoms; dietary freedom, improved nutrition / improved nutrient intake; improved appetite and eating attitudes; reduced taste aversion; and reduced hypoglycemia fear and related behaviors, including food avoidance. The inventors also surprisingly discovered that administration of exenatide to patients following GI surgery who are severely underweight, at high risk of malnutrition, and therefore have poor morbidity and mortality outcomes and / or cancer treatment (e.g., chemotherapy) responses. Therefore, the inventors believe that administration of exenatide to improve nutrition can improve patients' quality of life, improve their mental health, increase weight and / or prevent undesirable weight loss, reduce postprandial hypoglycemia, reduce GI symptoms, reduce the need for prolonged gastrostomy tube feeding, reduce the need for strict carbohydrate restriction, improve mental health, and may improve chemotherapy response and increase survival.

[0024] Compared to medical feeding procedures such as gastrostomy tubes and intravenous feeding, exenatide administration is less invasive, easier to self-administer, and has fewer potential side effects (such as increased risk of local and systemic infection, misalignment, or blockage), offering greater independence and psychological acceptance. The examples provided herein suggest that subcutaneous administration of exenatide to individuals undergoing upper GI surgery for cancer may prevent undesirable weight loss by mitigating the effects of surgically induced supraphysiological GLP-1 concentrations: central satiety, GI side effects due to altered gastrointestinal motility and gastric adaptation, and severe reactive hypoglycemia. Therefore, the inventors believe that GLP-1 receptor antagonistic administration, such as using the GLP-1 antagonist exenatide according to the method of this disclosure, should be incorporated into multimodal approaches for treating patients following GI surgery.

[0025] Terms and Concepts

[0026] The following discussion will cover some terms and concepts. These are intended to facilitate understanding of the various embodiments of the invention in conjunction with the remainder of this document and the accompanying drawings. These terms and concepts will be further clarified and understood according to generally accepted conventions in the art and the description provided throughout this document and / or the accompanying drawings. Some other terms may be explicitly or implicitly defined in other sections of this document and the accompanying drawings, and may be used and understood according to generally accepted conventions in the art, the description provided throughout this document, and / or the accompanying drawings. Terms not explicitly defined may also be defined and understood according to generally accepted conventions in the art and explained in conjunction with the context of this document and / or the accompanying drawings.

[0027] Unless the context otherwise requires, singular terms shall include plural terms and plural terms shall include singular terms. Generally, the names used to describe the methods of the present invention are well-known and commonly used names. Unless otherwise indicated, known methods and techniques are generally based on conventional methods well-known and described in various general and more specific references.

[0028] All numerical representations, such as pH, temperature, time, concentration, and molecular weight, including ranges, are approximate values ​​and are approximate values ​​varying in increments (+) or (-) of 0.1 or 1.0, depending on the circumstances (e.g., pH 5.4 or 5.5). It should be understood that, although not always explicitly stated, all numerical representations are preceded by the term "about". Unless otherwise indicated, references to ranges include the endpoints. For example, administration of exenatide at concentrations from 30 mg / mL to 180 mg / mL includes administration at 30 mg / mL or 180 mg / mL. Unless otherwise indicated, numerical ranges include all values ​​and subranges in this disclosure as if explicitly stated.

[0029] As used in this disclosure, the terms “about” and “approximately” generally mean the acceptable degree of error of a quantity measured given the nature or precision of the measurement. Exemplary degrees of error are within 20%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value or a range of given values. For example, any reference to “about X” or “approximately X” specifically indicates values ​​of at least X, 0.9X, 0.91X, 0.92X, 0.93X, 0.94X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, 1.05X, 1.06X, 1.07X, 1.08X, 1.09X, and 1.01X. In another instance, the term "about" or "approximately" in relation to a reference numerical value may include a range of values ​​from plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. Therefore, the expression "about X" or "approximately X" is intended to describe a limitation of the claim, such as "0.98X". Unless otherwise stated, all numerical values ​​given in this disclosure are approximate quantities, meaning that the term "about" or "approximately" can be inferred unless explicitly stated. When the term "about" or "approximately" is applied at the beginning of a numerical range, it applies to both ends of the range. When the term "about" or "approximately" is added before a series of values, these terms are intended to modify each value included in the series.

[0030] As used in this disclosure, the terms "a / an" and "described" may refer to one or more compounds, unless otherwise specified. For example, reference to "a compound" includes multiple compounds.

[0031] The term "or" is used to mean "and / or" unless explicitly indicated that it refers only to alternatives or that the alternatives are mutually exclusive; however, this disclosure supports the use of "and / or" only to alternatives and the definition of "and / or". As used in this disclosure, "another" may mean at least a second or more.

[0032] As used in this disclosure, and unless otherwise indicated, the term "include / including" and similar terms in certain circumstances (such as "have" or "having") mean "comprising". The term "comprising" is intended to mean that a compound, composition, or method includes the described elements but does not exclude other elements. When used to define a compound, composition, or method, "consistently of" means excluding other elements that would substantially affect the essential and novel features of the claimed invention. "Constitutes of" excludes any element, step, or ingredient not specified in the claims. Embodiments defined by each of these transitional terms are within the scope of the invention.

[0033] "Exenatide," also known as "exendin (9-39)," is a 31-amino acid polypeptide with the empirical formula C3. 149 H 234 N 40 O 47 Exenatide has a molecular weight of 3369.8 Daltons. It contains residues 9-39 of the GLP-1 receptor agonist ectosine-4 and is a GLP-1 receptor antagonist with inverse agonist properties. See Montrose-Rafizadeh et al. (1997). The amino acid sequence of exenatide is as follows: H-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Pro-Ser-NH2 (SEQ ID NO: 1). The predicted isoelectric point of exenatide is 4.69, and the net charge increases from -1 at pH 6 to +4 at pH 3.0. As used herein, the term "exenatide" also encompasses pharmaceutically acceptable salts of exenatide (Exexonine (9-39)), including but not limited to sulfates, hydrochlorides, phosphates, aminosulfonates, acetates, citrates, lactates, tartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylaminosulfonates, and quinates. In some embodiments, exenatide is in the form of acetate or trifluoroacetate. Unless otherwise specified herein, exenatide acetate is used. Exenatide (Exexonine (9-39)) and its pharmaceutically acceptable salts are commercially available.

[0034] As used herein, the term "formulation" or "pharmaceutical formulation," and other related terms and expressions, refers to a composition suitable for administration to a subject. Pharmaceutical formulations may be sterile and preferably free of contaminants that could elicit an undesirable response in a subject. The compounds included in a pharmaceutical formulation are typically pharmaceutical grade. Pharmaceutical formulations may be designed for administration to a subject or patient in need via a variety of different routes of administration, including oral, intravenous, oral, rectal, parenteral, intraperitoneal, intradermal, intramuscular, subcutaneous, and inhalation. In some embodiments, pharmaceutical formulations as described herein are formulated for subcutaneous or intravenous administration.

[0035] As used herein, "therapeutic effective amount" is the amount of an active ingredient (e.g., exenatide or a pharmaceutically acceptable salt thereof) that eliminates, improves, alleviates, or provides symptom relief or produces the clinical outcome expected from the administration of said active ingredient.

[0036] As used herein, the term "administer / administering / administration" (and related terms and expressions) means the introduction of a compound (e.g., exenatide), composition, or pharmaceutical agent into the body of a subject or patient (e.g., a human). As used herein, the term encompasses both direct administration (e.g., administration by the patient themselves or by a healthcare professional to the patient) and indirect administration (e.g., the act of prescribing a compound or composition to a subject).

[0037] "QD" and "BID" have the common meanings of once-daily or twice-daily administration of the composition (e.g., a buffered preparation of exenatide). In some embodiments, once-daily (QD) administration means an interval of at least 20 hours, at least 22 hours, or about 24 hours between administrations. In some embodiments, once-daily administration means administration about every 24 hours. In some embodiments, twice-daily (BID) administration means an interval of at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 11 hours, or about 12 hours between administrations. In some embodiments, twice-daily administration means administration about every 12 hours.

[0038] As used herein, the terms “individual,” “patient,” and “subject” are interchangeable in meaning of an individual (e.g., a human or a non-human mammal). The terms individual, subject, and patient do not, in themselves, indicate a specific age, sex, race, or clinical condition. The methods according to this disclosure are applicable to any race, including, for example, Caucasians (white race), African Americans (black race), Native Americans, Native Hawaiians, Hispanics, Latinos, Asians, and Europeans.

[0039] Gastric emptying (or stomach emptying) and related terms refer to the process by which stomach contents are emptied from the stomach. In healthy subjects, stomach contents enter the duodenum and are absorbed by the small intestine. The rate or time of gastric emptying refers to the time required for food to empty from the stomach and can be measured using various appropriate tests, such as scintillation. For example, the gastric emptying rate in healthy human subjects is approximately 1.5 to 2 hours, meaning the time it takes for stomach contents to move from the stomach to the small intestine. Delayed gastric emptying can be termed "gastroparesis." For example, Maurer et al. (2021) discussed gastric emptying.

[0040] The glucagon-like peptide-1 receptor (GLP1R) is a 7-transmembrane protein that acts as a receptor for the glucagon-like peptide-1 (GLP-1) hormone, which stimulates glucose-induced insulin secretion. GLP1R is internalized in response to GLP-1 and GLP-1 analogues and plays an important role in the signaling cascade leading to insulin secretion. See, for example, Brubaker et al. (2002).

[0041] Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino acid peptide hormone produced by L cells of the intestinal epithelial endocrine system through differential processing of proglucagon, the gene for which is expressed in these cells. GLP-1 is an endogenous intestinal hypoglycemic hormone secreted by L cells in the distal small and large intestine in response to luminal nutrients. GLP-1 (discussed in Holst (2007)) is known to have various physiological effects, including stimulating insulin secretion, inhibiting glucagon secretion, suppressing gastrointestinal motility, and promoting satiety. High GLP-1 concentrations alter gastrointestinal motility and gastric adaptability, promoting anorexia, nausea, acid reflux, and bloating, which may exacerbate weight loss. Satiety is the result of several processes, including vagal stimulation, gastric distension, and central nervous system effects. GLP-1 receptors are present in many parts of the brain, including areas involved in controlling food intake and energy balance, and infusion into the brain of rats inhibits feeding activity; this effect is blocked by co-infusion of exoxantrin 9-39 (a GLP-1 antagonist) (Turton 1996). Rodent data suggest that GLP-1 also promotes taste alterations, which may further contribute to weight loss. In humans, administration of synthetic analogues of GLP-1 effectively induces weight loss up to 15% of body weight. High GLP-1 concentrations can also promote excessive postprandial insulin secretion: this contributes to prolonged diabetes remission in 85% of patients receiving RYGB. However, in a small percentage of patients, very high GLP-1 levels lead to insulin secretion dysregulation and hypoglycemia (Salehi (2014)), which can be severe and frequent, resulting in food avoidance, carbohydrate depletion, and weight loss. Similar to what has been observed after RYGB, GLP-1 concentrations may increase after other upper gastrointestinal surgeries. Specifically, several studies have shown a 3-5 fold increase in GLP-1 levels after gastrectomy and esophagectomy, which is associated with dumping symptoms and hyperinsulinemic hypoglycemia. Therefore, GLP-1 antagonism is an attractive therapeutic possibility in cases of prevalent undesirable weight loss, particularly after upper gastrointestinal surgery with high GLP-1 concentrations. However, the success of such treatments has been limited, as a previous study involving intravenous infusion of ectoxantril 9-39 or saline for 240 minutes followed by a free-choice buffet meal test in post-weight-loss patients did not demonstrate an increase in food intake from ectoxantril 9-39 administration (Kittah et al. (2020)).

[0042] Treatment

[0043] This disclosure describes methods for improving the nutrition of a subject, the methods involving administering to the subject a pharmaceutical preparation comprising exenatide (which may be referred to as an "exenatide preparation"). Suitable pharmaceutical preparations are described elsewhere in this disclosure. According to this disclosure, methods for improving the nutrition of a subject may be referred to as "treatment methods," "exenatide therapy," and other related terms and expressions. When used according to embodiments of the invention, exenatide can exert its therapeutic effects through various mechanisms. Some of these mechanisms will be discussed below, but are not intended to limit any of the methods described in this disclosure. It should be understood that the treatment methods described in this disclosure may involve one or more mechanisms of action of exenatide.

[0044] For example, exenatide can improve nutrition in patients after GI surgery by preventing taste aversion and GLP-1R-mediated satiety through a central nervous system (CNS)-mediated mechanism. Several animal studies support the idea that the weight loss / anorexia effects of GLP-1 are CNS-mediated. In a study reported by Sisley et al. (2014), GLP-1R knockout mice did not consume more food than wild-type mice, but also did not lose weight after administration of liraglutide (a GLP-1 agonist), suggesting that the mechanism of weight loss / anorexia effects of GLP-1 agonism is CNS-mediated. As reported by Martin et al. (2009), GLP-1R knockout mice showed significantly reduced sensitivity to sweet tastes and increased sensitivity to umami stimuli. The animal data reported in these studies suggest that while the GLP-1 receptor is not essential for normal food intake or weight regulation, CNS GLP stimulation / agonism is necessary for weight loss / anorexia effects. Some studies have shown that GLP-1R antagonism does not stimulate appetite, increase eating behavior, or lead to weight gain. Melhorn et al. (2014) reported a study involving the infusion of exenatide or placebo in normal-weight subjects, which showed that GLP-1R blockade failed to suppress satiety or increase eating behavior in subjects. Kulve et al. (2017) reported the effect of RYGB on CNS activation induced by visual and gustatory food cues, which may be mediated by the central effects of GLP-1, but did not evaluate eating behavior induced by such visual and gustatory cues. However, a study by Kittah et al. (2020) investigated GI symptoms and carbohydrate intake in patients after GI surgery (RYGB patients and VSG patients) and weight-matched non-surgical controls with or without exenatide, and showed that carbohydrate intake or the incidence of GI symptoms did not change in surgical patients, while exenatide reduced carbohydrate intake in the non-surgical control group. In light of the above studies, the inventors found that exenatide therapy improved nutrition in patients after GI surgery, which was both surprising and unexpected.

[0045] Exenatide can improve nutrition in patients after GI surgery by alleviating GI symptoms such as nausea, indigestion, heartburn, and early satiety (fullness). Exenatide can also improve nutrition in patients after GI surgery by improving food intake-related fear and / or reducing food avoidance. The reduction of GI symptoms may be at least in part due to parasympathetic nervous system-mediated mechanisms, such as through the vagus nerve. The reduction of GI symptoms may also be at least in part due to an increased rate of nutrient passage through the GI pathway after exenatide administration. It has been previously shown that exenatide administration after RYGB accelerates gastric emptying. In a study reported by Shah et al. (2014), exenatide administration significantly increased the rate of gastric emptying of radiolabeled solid meals within the first 45 minutes after food intake in twelve RYGB patients, but no increase was observed in eight age-, sex-, and weight-matched controls. However, improvements in GI symptoms in patients after GI surgery have not been reported after exenatide administration. It is also possible that exenatide improves nutritional intake in patients after GI surgery by alleviating hypoglycemia-related fear and resulting food avoidance. For example, hypoglycemia is a common concern among people with insulin-dependent diabetes mellitus. There is data supporting a reduction in hypoglycemia-related anxiolytics and behaviors following exenatide administration (some of which is included in this disclosure).

[0046] Embodiments of the treatment methods according to this disclosure can result in improved nutrition in subjects receiving exenatide therapy. In the context of this disclosure, the term "nutrition" broadly encompasses all aspects of nutrient intake and eating, which may be objectively measured and / or subjectively experienced. The term "nutrition" encompasses, but is not limited to, the process by which a subject consumes (ingests, eats, or takes in) nutrients, particularly the process of eating, including chewing and swallowing, and the different stages of nutrient utilization, including aspects of digestion, nutrient absorption, excretion, etc. The term "nutrition" also encompasses the results of consuming and utilizing nutrients, such as, but not limited to, the subject's nutrient intake and the subject's nutritional status. For example, a subject may experience or expect to experience undesirable weight loss after undergoing GI surgery, as discussed elsewhere in this disclosure. In another instance, a subject may need to prevent undesirable weight loss after undergoing GI surgery. In yet another instance, a subject may or may expect to suffer from malnutrition (as discussed elsewhere in this disclosure, malnutrition or expected malnutrition) due to disruption of one or more aspects of nutrition. In another instance, the subject may have or is expected to have malnutrition after GI surgery (as discussed elsewhere in this disclosure), with or without malnutrition. In another instance, the subject may have or is expected to have cachexia and / or sarcopenia after GI surgery (both discussed elsewhere in this disclosure). In yet another instance, the subject may require or expect dietary liberalization, as discussed elsewhere in this disclosure.

[0047] In the context of this disclosure, "nutrient intake" broadly encompasses the composition of the food consumed by the subject. In this context, food composition (also referred to as "nutrient composition") covers various aspects of the food consumed by the subject, such as the calorie content, macronutrient content (e.g., the amount of one or more carbohydrates, protein, fat, fiber, fatty acids, cholesterol, amino acids, and water), and micronutrient content (e.g., the amount of various vitamins and minerals). "Improved nutrient intake" indicates an improvement in the composition of the food consumed by the subject. For example, improved nutrient intake refers to an increase in the calorie content consumed by the subject due to an increase in the total number of calories consumed per meal, per day, per week, per month, etc., or improved digestion and / or absorption of the food components consumed over a given period of time (per meal, per day, per week, per month, etc.).

[0048] As used in this disclosure, in addition to nutritional intake, the term "nutrition" also encompasses the nutritional status of the subject and subjective experiences and attitudes related to food and eating. Therefore, "nutritional improvement" encompasses various improvements in the nutritional status of the subject, as well as improvements in subjective experiences, attitudes, and behaviors related to food and eating. The nutritional status of the subject can be based on objective indicators such as weight, body mass index (BMI), body composition (such as the subject's body fat and muscle mass), and the levels of various macronutrients and micronutrients in the blood.

[0049] In the context of this disclosure, the term "nutrition" also encompasses subjective experiences, feelings, behaviors, and attitudes related to food and eating. Subjective feelings, experiences, and attitudes can manifest in a variety of ways, such as taste sensations (e.g., whether a subject perceives food as good or bad), appetite (which can be rated as "very poor," "poor," "average," "good," or "excellent," or expressed in numerical terms), satiety during or after meals and / or throughout the day, hunger during or after meals and / or throughout the day, emotions associated with eating food (e.g., mood during meals), food aversion, fear of eating, anxiety associated with eating food, etc. Subjective experiences can also encompass a variety of GI symptoms and physical reactions experienced before, during, or after eating food. Such GI symptoms and physical reactions may be physiological, psychosomatic, or both. For example, a subject may experience nausea after swallowing food, and in some cases, vomiting. In another instance, a subject may experience indigestion (not digesting food) after eating, including abdominal discomfort described as burning, bloating or gas, and / or nausea. In yet another instance, a subject may experience heartburn after eating. In yet another instance, a subject may experience satiety (fullness) soon after starting to eat. Subjective experiences (including various GI symptoms and physical reactions) can be triggered by one or more specific foods, all foods, the process of eating, or even the thought of eating. GI symptoms and unpleasant physical reactions may be triggered by specific foods and described as “food intolerance” to those foods. Conversely, “food tolerance” refers to the ability to eat a variety of foods without experiencing GI symptoms and unpleasant physical reactions. Higher or lower food tolerance can describe how many types of foods a subject can tolerate (a range of foods) and can also encompass the amount of a specific food tolerated. For example, a subject who can eat more dairy products than another subject without experiencing GI symptoms and unpleasant physical reactions may have higher dairy tolerance. Subjective experiences, feelings, and attitudes related to food and eating encompass food aversion, which is a very strong dislike of a specific food or food in general. In cases of food aversion, seeing, smelling, tasting, or even thinking about food (general or specific) can cause a subject to experience feelings of disgust and, in some cases, lead to unpleasant reactions such as nausea. Higher or lower levels of food aversion can describe how many types of food (a range of foods) cause a subject to experience aversion.

[0050] Subjective experiences, feelings, behaviors, and attitudes related to food and eating include food avoidance, which refers to a subject's potential restriction of the quantity and / or type of food intake (avoidance of specific foods), leading to nutritional deficiencies and negative health consequences. Food avoidance may be based on sensory aspects of food, fear of GI symptoms and unpleasant reactions, lack of interest in food, or other factors. Higher or lower levels of food avoidance can describe the level of restriction a subject places on the quantity and / or type of food consumed. Subjective experiences, feelings, behaviors, and attitudes related to food and eating include eating phobia, which refers to a subject's fear of eating general foods or specific foods. Eating phobia itself may manifest as physiological symptoms of fear and / or panic, such as increased heart rate, rapid or shallow breathing, sweating, trembling, etc. Higher or lower levels of eating phobia can describe the level (intensity) of a subject's fear symptoms. Subjective experiences, feelings, behaviors, and attitudes related to food and eating also include eating-related worry, which refers to a subject's worry (experiencing anxiety) about eating general foods or specific foods. Eating-related worry can have a variety of causes. For example, a subject may feel anxious about experiencing GI symptoms or unpleasant physical reactions after eating. Higher or lower levels of eating fear-related worries can describe the subject's anxiety level (intensity) and the quantity and circumstances of the food causing the eating-related worries. An example of food and eating-related behaviors is eating behavior, which broadly encompasses meal timing, including meal frequency, amount of food consumed, food preferences and choices, etc. Higher or lower levels of eating behavior may encompass one or more of the following: meal frequency, amount of food consumed, and variety of foods consumed. In one instance, embodiments of the treatment methods according to this disclosure can lead to improved or increased eating behavior.

[0051] As discussed throughout this disclosure, administration of a pharmaceutical preparation comprising exenatide to a subject can result in improvements in nutrition (including, but not limited to, nutritional intake, nutritional status, and attitudes, behaviors, and subjective experiences related to food and eating). It should be understood that improvements following exenatide therapy (which may be described as increases or decreases in various observable or subjectively experienced indicators and effects) are compared to various control values, such as corresponding control values ​​for the same subject before initiating exenatide therapy. For example, in some embodiments, treatment with exenatide therapy as described in this disclosure improves the nutrition of the subject compared to the subject's nutrition before exenatide therapy. In another example, in some embodiments, treatment with exenatide therapy as described in this disclosure improves the subject's nutritional intake compared to the subject's nutritional intake before exenatide therapy. In yet another example, subjects treated with exenatide therapy as described in this disclosure experienced either weight gain or a reduced rate of weight loss, respectively, compared to the subject's weight or rate of weight loss before exenatide therapy.

[0052] In some embodiments, treatment of a subject with exenatide therapy as described in this disclosure results in one or more of the following effects: increased appetite, increased food tolerance, reduced food intolerance, reduced food avoidance, reduced food aversion, increased calorie intake, increased eating behavior, dietary freedom, reduced fear of eating, or reduced eating-related anxieties, including but not limited to anxieties related to hypoglycemia. Therefore, some embodiments of the methods described in this disclosure may be referred to as methods for increasing or improving appetite, methods for increasing or improving food tolerance, methods for reducing food intolerance, methods for reducing food avoidance, methods for reducing food aversion, methods for increasing calorie intake, methods for increasing eating behavior, methods for dietary freedom, methods for reducing fear of eating, or methods for reducing eating-related anxieties, including but not limited to anxieties related to hypoglycemia. In some embodiments, treatment of a subject with exenatide therapy as described in this disclosure results in weight gain and / or prevention of postoperative weight loss (e.g., a reduction of more than 10% of preoperative weight). Therefore, some embodiments of the methods described in this disclosure may be referred to as methods for influencing or increasing weight gain, methods for treating or preventing postoperative weight loss, methods for treating or preventing undesirable weight loss, etc. In some embodiments, treatment of a subject with exenatide therapy as described in this disclosure results in the treatment or prevention of sarcopenia and / or cachexia, which can be measured by various physiological criteria such as body composition (e.g., lean body mass, fat mass, water ratio) or physical performance (e.g., total activity and / or grip strength)). Therefore, some embodiments of the methods described in this disclosure may be referred to as methods for preventing or alleviating sarcopenia or methods for preventing or alleviating sarcopenic cachexia. In some embodiments, treatment of a subject with exenatide therapy as described in this disclosure results in one or more of the following effects: improved taste and / or sensation of one or more foods, improved mood during, after, and / or throughout the day, reduced food and eating-related anxiety, or improved overall health. Therefore, some embodiments of the methods described in this disclosure may be referred to as methods for improving taste and / or sensation of one or more foods, methods for improving mood during, after, and / or throughout the day, methods for reducing food and eating-related anxiety, or methods for improving health. In some embodiments, treatment of a subject with exenatide therapy as described in this disclosure results in a reduction of one or more GI symptoms, such as nausea, indigestion, or heartburn. Therefore, some embodiments of the methods described in this disclosure may be referred to as methods for reducing one or more GI symptoms. In some embodiments, treatment of a subject with exenatide therapy results in an increase in the movement of food through the subject's GI tract (in some cases, this may be referred to as increased gastric emptying in this disclosure). Therefore, some embodiments of the methods described in this disclosure may refer to methods for improving or increasing the rate of movement of food through the GI tract, or methods for increasing or improving gastric emptying.

[0053] In some embodiments, the effects of treating a subject according to the methods of this disclosure can be monitored and / or measured by various physiological measurements. In one instance, the levels of various biomarkers are measured by various tests, such as blood tests. One example of a biomarker used to measure nutritional status is blood albumin levels. Physical performance can be measured by general activity and / or grip strength. In another instance, weight or body mass index (BMI) can be measured by various applicable procedures. For example, to monitor the extent of weight loss following a GI surgery (such as total gastrectomy or esophagectomy), weight or BMI can be measured immediately after the GI surgery and at different time points thereafter. The weight or BMI measured immediately after the GI surgery as a reference point will serve as a reference point for monitoring weight loss. In another instance, nutritional status can also be measured by quantifying the macronutrient composition of meals using various tools, such as diaries and computer / smartphone applications, some of which will be discussed elsewhere in this disclosure. Treating a subject according to the methods of this disclosure may result in one or more of the following: dietary liberalization, increased carbohydrate intake, and improved macronutrient balance.

[0054] In another instance, a reduction in the number (or incidence) of hypoglycemic events, either overall or, for example, diurnal (diurnal is defined as events occurring, for example, from 8 a.m. to 10 p.m.) hypoglycemic events, can be measured, for example, by the number of diurnal hypoglycemic events occurring within a specific time period. This time period can be from 1 to 20 days, such as one day, two days, three days, four days, five days, six days, seven days, eight days, nine days, ten days, eleven days, twelve days, thirteen days, sixteen days, seventeen days, eighteen days, nineteen days, or twenty days. The time period can also exceed 20 days, such as 20-100 days, 20-50 days, 20-25 days, etc. A hypoglycemic event can be defined as the number of episodes occurring below a defined glucose level (e.g., 70 mg / L, 54 mg / dL, or 40 mg / dL). The percentage of hypoglycemic events can be defined as, for example, the total number of hours during which a continuous glucose monitoring (CGM) reading was below a defined glucose level (e.g., 70 mg / L, 54 mg / dL, or 40 mg / dL) divided by the total CGM wearing time. The event incidence can also be measured via CGM, and in this case, the event incidence can be defined as the number of episodes during each time period where the glucose level was below a defined glucose level (e.g., 70 mg / L, 54 mg / dL, or 40 mg / dL) for at least 15 minutes. Treating subjects according to the methods of this disclosure can result in a reduction in the incidence of hypoglycemic events in the treated subjects by at least about 10%, at least about 20%, at least about 30%, at least about 40%, and at least about 30%.

[0055] It should be understood that changes (increases or decreases) related to the effect of exenatide therapy can be measured by comparison with various control values, such as comparison with corresponding control values ​​of the same subject before starting exenatide therapy. Other types of control values, such as placebo controls, can also be used. In one instance, a crossover design comparison using placebo controls (placebo versus exenatide in individual subjects) is used. In another instance, a parallel design comparison using placebo controls is used (placebo is used in one group of patients, and exenatide is used in another group of patients). For example, in some embodiments, treatment with exenatide therapy as described in this disclosure increases the appetite of a subject compared to the appetite of a subject before exenatide therapy. In another instance, in some embodiments, treatment with exenatide therapy as described in this disclosure increases the food tolerance of a subject compared to the food tolerance of a subject before exenatide therapy. In yet another instance, in some embodiments, treatment with exenatide therapy as described in this disclosure reduces the food aversion of a subject compared to the food aversion of a subject before exenatide therapy. In another example, in some embodiments, treating a subject with exenatide therapy as described in this disclosure reduces food intolerance compared to food intolerance prior to exenatide therapy. In another example, in some embodiments, treating a subject with exenatide therapy as described in this disclosure reduces food avoidance compared to food avoidance prior to exenatide therapy. In another example, in some embodiments, treating a subject with exenatide therapy as described in this disclosure increases calorie intake compared to calorie intake prior to exenatide therapy. In another example, in some embodiments, treating a subject with exenatide therapy as described in this disclosure improves or increases eating behavior compared to eating behavior prior to exenatide therapy. In another example, in some embodiments, treating a subject with exenatide therapy as described in this disclosure reduces eating fear compared to eating fear prior to exenatide therapy. In another instance, in some embodiments, treating a subject with exenatide therapy as described in this disclosure reduces the subject's eating-related concerns compared to the subject's prior eating-related concerns. In another instance, in some embodiments, treating a subject with exenatide therapy as described in this disclosure reduces one or more GI symptoms compared to the subject's prior GI symptoms.

[0056] Various subtypes of subjects following GI surgery, including those discussed in this disclosure, often experience similar and / or overlapping problems, such as, but not limited to, rapid emptying of food into the small intestine where GLP-1-secreting L cells reside, leading to excessive GLP-1 secretion, hyperinsulinemia, and consequently hypoglycemia. GLP-1 may then have direct effects on the CNS, impairing taste sensitivity and appetite, and on the GI system, slowing gastric passage, thus leading to satiety and nausea. Additionally, hypoglycemia (due to hyperinsulinemia) may cause autonomous symptoms (palpitations, diarrhea, sweating, tremors, nausea) and neurohypoglycemic symptoms (confusion, drowsiness, behavioral changes, motor incoordination, seizures, loss of consciousness, etc.). Treatment of subjects following GI surgery according to the methods of this disclosure can be performed to address one or more of the various post-GI surgery problems, including but not limited to those described in this disclosure.

[0057] The effects of the exenatide therapy according to this disclosure may be referred to as "therapeutic effects" or "therapeutic endpoints" and can be measured by various methods. For example, the nutritional intake of the subject can be recorded and measured by keeping a diary of the food consumed, using a computer or smartphone software, and calculating nutritional intake based on known data on the nutritional composition of various foods (manually or using software). The nutritional status of the subject can be assessed by measuring weight, body mass index (BMI), body composition (such as the subject's body fat and muscle mass), and the levels of various macronutrients and micronutrients in the blood. Various diaries, questionnaires, and rating scales can be used to assess GI symptoms. Gastric emptying rate can be measured by appropriate tests (such as scintillation). Subjective experiences and behaviors related to food and eating can be assessed using various diaries and questionnaires. Some examples of questionnaires suitable for measuring some effects of the exenatide therapy according to this disclosure include the Committee on Nutrition and Appetite Questionnaire (CNAQ) (Table 1), the Shortened Health Scale-GI (SHS-GI) questionnaire (Table 2), and the Hypoglycemia Fear Survey-II (HSF-II) questionnaire (Table 3). The CNAQ is an eight-item questionnaire designed to assess appetite and has been found to be effective in predicting clinically significant weight loss in older adults in community housing and long-term care (Wilson et al. (2005)). Each item is scored on a five-point scale, with the total score ranging from 8 (worst) to 40 (best). A score ≤28 indicates a significant risk of at least 5% weight loss over six months, and such patients are classified as being at risk of malnutrition because decreased appetite is a predictor of weight loss (Landi et al. (2010)). Responses to the CNAQ are scored numerically (a=1, b=2, c=3, d=4, e=5), and the sum of all individual item scores constitutes the CNAQ score. The SHS-GI is a four-item self-administered questionnaire. Each item covers a subjective health dimension: symptoms, social functioning, disease-related concerns, and overall health status. Responses are scored on a 100-mm visual analog scale, and the maximum total score for all items is 400, with higher scores indicating worse outcomes. The results are presented as a summary of the four items scored individually. The methods for measuring treatment effectiveness and endpoints are also described elsewhere in this disclosure (such as in the Examples section below). HFS-II is a 33-item questionnaire with two subscales that measure 1) behaviors to avoid hypoglycemia and its negative consequences and 2) concerns about hypoglycemia and its negative consequences.

[0058] Table 1. Committee on Nutrition and Appetite Questionnaire (CNAQ).

[0059]

[0060] Table 2. Short Health Scale - GI (SHS-GI) Questionnaire.

[0061]

[0062] Table 3. Hypoglycemia Fear Survey-II (HSF-II) Questionnaire.

[0063]

[0064] patient group

[0065] In some embodiments, the subject being treated according to the methods described in this disclosure is a subject who has previously undergone gastrointestinal (GI) surgery. In some embodiments, the subject has previously undergone non-weight-loss surgery involving the gastrointestinal system, including but not limited to esophagectomy (e.g., for the treatment or prevention of esophageal cancer), Nissen fundoplication (e.g., for the treatment of gastroesophageal reflux), or gastrectomy (e.g., for the treatment or prevention of gastric cancer). In some non-limiting embodiments, the subject has previously undergone weight-loss or metabolic surgery involving the gastrointestinal system, including but not limited to: Roux-en-Y gastric bypass (RYGB), vertical sleeve gastrectomy (VSG), placement of a colonic cannula device (such as the EndoBarrier gastrointestinal liner system, also known as an "intraluminal liner"), duodenal mucosal remodeling (also known as duodenal ablation), bile-pancreatic shunt (BPD), bile-pancreatic shunt with duodenal transposition (BPD-DS), partial duodenal bypass (involving duodeno-ileal or duodeno-jejunal anastomosis), vagus nerve block, and pyloroplasty. In some embodiments, subjects treated according to the methods described in this disclosure may be referred to herein as "post-gastrointestinal surgery" patients, "post-GI patients," "post-GI surgery," "post-GI surgery subjects," and other related expressions. In some embodiments, the subject has undergone at least one gastric surgery. In some embodiments, the subject receives treatment immediately after undergoing surgery (e.g., if the surgery was not a bariatric surgery). In some embodiments, the subject receiving treatment has undergone gastrointestinal surgery at least one year prior to starting treatment. In some embodiments, the subject is a person. In some embodiments, the subject is an adult. In some embodiments, the subject is an adolescent (i.e., a post-GI surgery adolescent).

[0066] In some embodiments, the subject has undergone gastrectomy. In some embodiments, the subject experiences post-gastrectomy syndrome, characterized by, for example, decreased tolerance to large meals, rapid emptying of food into the small intestine or "dumping," abdominal cramps, diarrhea, postprandial dizziness, and rapid heart rate and a sharp drop in blood glucose levels. In some embodiments, the subject has undergone esophagectomy. In some embodiments, the subject experiences post-esophagectomy syndrome, which may include various symptoms such as, but not limited to, dysphagia, regurgitation, delayed gastric emptying, dumping syndrome, weight loss, and chronic diarrhea.

[0067] In some embodiments, following GI surgery, subjects experience or are expected to experience various complications related to nutritional disorders. Some non-limiting examples of such complications are anemia due to vitamin B12, iron malabsorption, and osteoporosis. Anemia may occur if vitamin B12 is malabsorbed, and in some cases, neurological dysfunction may result. Iron deficiency anemia may occur because gastrectomy often results in a significant reduction in the production of gastric acid, which is necessary to convert dietary iron into a form more easily absorbed in the duodenum. Osteoporosis is caused by poor calcium absorption. After GI surgery, calcium absorption efficiency may be reduced due to the rapid emptying of the stomach.

[0068] Subjects treated according to the methods described in this disclosure can be identified by any suitable method. For example, a subject may experience unintended weight loss after undergoing GI surgery. Unintended weight loss encompasses unintentional weight loss and may also be referred to as involuntary or unintentional weight loss. Unintentional weight loss does not include certain types of weight loss: the expected outcome of treatment (weight loss in a patient with heart failure due to diuretic therapy) or the result of a known disease. However, some other types of weight loss as an expected outcome of treatment (such as weight loss after GI surgery) are still unintended and are included within the scope of the expression "unintended weight loss." For example, a subject may experience unintended weight loss after GI surgery, for example, because the patient was underweight or of normal weight before undergoing GI surgery. Subjects treated according to the methods described in this disclosure may experience clinically significant weight loss, which is generally defined as a weight loss of more than 5% of normal body weight over a period of 6 to 12 months.

[0069] Subjects treated according to the methods described in this disclosure may be malnourished. A variety of criteria can be used to diagnose malnutrition. For example, the Academy of Nutrition and Dietetics (Academy) and the American Society for Parenteral and Enteral Nutrition (ASPEN) recommended the following diagnostic criteria for malnutrition in a 2012 consensus statement. A diagnosis of malnutrition requires the presence of two or more of the following six characteristics: inadequate energy intake; weight loss; muscle mass loss; subcutaneous fat loss; localized or systemic fluid accumulation that may mask weight loss; and impaired functional status as measured by grip strength. In another instance, malnutrition criteria were introduced in 2018 from the Global Leaders Malnutrition Initiative (GLIM). GLIM was established to achieve global consensus on the identification and diagnostic criteria for malnutrition to facilitate comparisons of malnutrition prevalence, treatment, and outcomes. The aforementioned 2018 criteria include an assessment of the effects of acute and chronic inflammation, which is not reflected in the International Classification of Diseases, 10th Revision (ICD-10) coding. According to GLIM, a diagnosis of malnutrition requires a combination of at least one phenotypical criterion and one etiological criterion: phenotypical criterion – involuntary weight loss, low body mass index (BMI), or reduced muscle mass; etiological criterion – reduced food intake or absorption, or underlying inflammation due to acute illness / injury or chronic disease. In another instance, the clinically accepted definition of malnutrition includes involuntary weight loss (>5% over 3 months, or >10% over any period) as part of a set of diagnostic criteria. Following a diagnosis of malnutrition, a more comprehensive nutritional status assessment can be performed by a dietitian or nutritionist who can develop individualized care and treatment plans.

[0070] Subjects treated according to the methods described in this disclosure may develop malnutrition (inability to obtain sufficient amounts of required nutrients) after GI surgery, regardless of whether malnutrition is present or not. Malnutrition may or may not involve weight loss. Subjects treated according to the methods described in this disclosure are expected to develop malnutrition, which may or may not involve weight loss after GI surgery. Treating such subjects according to the methods described in this disclosure can prevent malnutrition. Subjects treated according to the methods described in this disclosure may have developed or are expected to develop cachexia and / or sarcopenia after GI surgery. In the latter case, treating such subjects according to the methods described in this disclosure can prevent cachexia and / or sarcopenia. Cachexia is generally defined as weight loss due to loss of muscle mass (with or without fat loss). Sarcopenia is characterized by a loss of muscle mass, strength, and performance.

[0071] In some embodiments, subjects treated according to the methods described in this disclosure experience food aversion, food avoidance, food phobia, and other related behavioral and / or psychological problems. In some embodiments, subjects treated according to the methods described in this disclosure experience one or more of the following: decreased appetite, food aversion, or taste aversion. In some embodiments, subjects treated according to the methods described in this disclosure experience postprandial GI symptoms, such as, but not limited to, nausea, early satiety, heartburn, indigestion, or bloating. In some embodiments, subjects treated according to the methods described in this disclosure experience gastric bypass and / or gastric retention (gastroparesis, which may be accompanied by vomiting). Gastroparesis is an objectively delayed gastric emptying syndrome without mechanical obstruction and whose main symptoms are nausea, vomiting, early satiety, belching, bloating, and / or epigastric pain. Gastroparesis can be classified by the degree of gastric bypass delay (mild to severe). In some embodiments, subjects treated according to the methods described in this disclosure experience hypoglycemia-related concerns. In some embodiments, subjects treated according to the methods described in this disclosure must follow a strict or restrictive diet involving frequent small low-glycemic index meals.

[0072] In some embodiments, subjects treated according to the methods described in this disclosure require dietary freedom. Following GI surgery, subjects typically have to strictly restrict their diet, such as adhering to frequent small, low-glycemic index meals and substantially avoiding carbohydrates. In the context of this disclosure, dietary freedom can mean the subject's ability to be less restricted and to introduce carbohydrates into their diet, resulting in a more balanced macronutrient composition.

[0073] In some embodiments, subjects treated according to the methods described in this disclosure have elevated GLP-1 levels before or after GI surgery. GLP-1 levels can be measured by a variety of methods, some of which are discussed in Holst (2007). GLP-1 levels are elevated compared to reference population levels. In humans, the fasting systemic plasma concentration of “total” GLP-1 (including metabolites produced by DPP-4-mediated degradation) is typically in the range of 5-10 pmol / L and can increase to 40 pmol / L after meals (Müller et al. (2019)).

[0074] Dosing regimen

[0075] In some embodiments, exenatide (which may be referred to herein as an "exenatide formulation") in a suitable pharmaceutical formulation is administered at a total daily dose ranging from about 40 mg to about 120 mg (e.g., subcutaneous administration), such as about 50 mg to about 120 mg per day, about 60 mg to about 120 mg per day, about 70 mg to about 120 mg per day, about 80 mg to about 120 mg per day, about 90 mg to about 120 mg per day, about 50 mg to about 110 mg per day, about 60 mg to about 110 mg per day, about 70 mg to about 110 mg per day, about 80 mg to about 110 mg per day, about 90 mg to about 110 mg per day, about 50 mg to about 100 mg per day, about 60 mg to about 100 mg per day, about 70 mg to about 100 mg per day, about 80 mg to about 100 mg per day, or about 90 mg to about 100 mg per day. For example, the total daily dose of exenatide may be about 40 mg to about 90 mg, about 40 mg to about 75 mg, about 40 mg to about 60 mg, about 50 mg to about 90 mg, about 45 mg to about 75 mg, about 60 mg to about 90 mg, or about 60 mg to about 75 mg. In some embodiments, exenatide is administered at a total daily dose of at least about 40 mg, such as at least about 45 mg, at least about 50 mg, at least about 60 mg, at least about 75 mg, or at least about 90 mg. In some embodiments, exenatide is administered at a total daily dose of about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, or about 120 mg. In some embodiments, exenatide is administered at a total daily dose of 85 mg or 95 mg.

[0076] In some embodiments of the method according to this disclosure, the subject's weight may be less than about 60 kg, less than about 59 kg, less than about 58 kg, less than about 57 kg, less than about 56 kg, less than about 55 kg, less than about 54 kg, less than about 53 kg, less than about 52 kg, less than about 51 kg, or less than about 50 kg, and such subjects may receive an exenatide dose of about 0.4 mg / kg / day to about 3 mg / kg / day. For example, subjects may receive an exenatide dose of about 0.4 mg / kg / day, about 0.75 mg / kg / day, about 1 mg / kg / day, about 1.125 mg / kg / day, about 1.2 mg / kg / day, about 1.5 mg / kg / day, about 2 mg / kg / day, or about 3 mg / kg / day. In some embodiments, subjects may receive an exenatide dose of about 0.375 mg / kg / day or about 0.75 mg / kg / day. In some embodiments, the subject may receive about 0.56 mg / kg / dose or about 1.125 mg / kg / day. In some embodiments of the method according to this disclosure, the subject's weight may be less than about 60 kg, less than about 59 kg, less than about 58 kg, less than about 57 kg, less than about 56 kg, less than about 55 kg, less than about 54 kg, less than about 53 kg, less than about 52 kg, less than about 51 kg, or less than about 50 kg, and they may receive an exenatide dose of about 0.4 mg / kg / day to about 3 mg / kg / day. In the above embodiments, exenatide may be administered BID (twice daily) or TID (three times daily).

[0077] In some embodiments, a therapeutically effective amount of exenatide (or a pharmaceutically acceptable salt thereof) is administered once daily (“QD”). QD administration is well known in the medical field. In some embodiments, the QD dose is administered at approximately 24-hour intervals (e.g., at 7 a.m. for several consecutive days) (e.g., subcutaneously). However, if the administrations are at least about 18 hours apart, the intervals between administrations can be shorter (e.g., about 8 a.m. and about 6 a.m. for several consecutive days) or longer (e.g., about 7 a.m. and about 9 a.m. for several consecutive days). Preferably, the administrations are at least about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 4 hours apart. Preferably, the administrations are at intervals not exceeding about 30 hours. For example, methods for determining the timing of QD dose administration are described in PCT patent applications PCT / US2016 / 033837 and PCT / US / 2019 / 0562778. In some cases, the dose may be administered at a higher frequency (e.g., twice a day) or a lower frequency (e.g., once every other day).

[0078] In some embodiments, the exenatide formulation is administered twice daily (“BID”) (e.g., subcutaneously or intravenously). BID administration is well known in the medical field. The formulation may be administered at specific times of day or on a schedule, such as in the morning, afternoon, evening, night, before meals, during or after meals, before bedtime, etc. In some embodiments, the formulation is administered approximately every 12 hours. In some embodiments, the BID dose is administered at approximately 12-hour intervals (e.g., approximately 7 a.m. and approximately 7 p.m.) (e.g., self-administered). However, the interval between administrations may be shortened (e.g., approximately 8 a.m. and approximately 6 p.m.) or lengthened (e.g., approximately 7 a.m. and approximately 10 p.m.). In some embodiments, administrations are at least about 4 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, or about 11 hours apart. Preferably, administrations are not more than about 15 hours apart. For example, methods for determining the timing of BID dosage are described in PCT patent applications PCT / US2016 / 033837 and PCT / US / 2019 / 0562778. In some embodiments, the exenatide formulation is administered three times daily (“TID”) (e.g., subcutaneously or intravenously).

[0079] The adult dose of exenatide can be from about 40 mg QD to about 120 mg QD. For example, the adult dose of exenatide can be from about 40 mg QD to about 100 mg QD, about 40 mg QD to about 75 mg QD, about 40 mg QD to about 60 mg QD, about 50 mg QD to about 90 mg QD, about 45 mg QD to about 75 mg QD, about 60 mg QD to about 100 mg QD, about 60 mg QD to about 75 mg QD, or about 85 mg QD to about 95 mg QD. The adult dose of exenatide can also be from about 20 mg BID to about 60 mg BID. For example, adult exenatide doses may be approximately 20 mg BID to approximately 55 mg BID, approximately 20 mg BID to approximately 50 mg BID, approximately 20 mg BID to approximately 45 mg BID, approximately 25 mg BID to approximately 50 mg BID, approximately 25 mg BID to approximately 47 mg BID, approximately 37 mg BID to approximately 47 mg BID, or approximately 40 mg BID to approximately 47 mg BID.

[0080] In some embodiments, the exenatide formulation is administered at a dose of about 20-65 mg BID or 25-50 mg BID (e.g., subcutaneous or intravenous administration). In some embodiments, the exenatide formulation is administered at a dose of about 20 mg BID. In some embodiments, the exenatide formulation is administered at a dose of about 25 mg BID. In some embodiments, the exenatide formulation is administered at a dose of about 30 mg BID. In some embodiments, the exenatide formulation is administered at a dose of about 35 mg BID. In some embodiments, the exenatide formulation is administered at a dose of about 40 mg BID. In some embodiments, the exenatide formulation is administered at a dose of about 45 mg BID. In some embodiments, the exenatide formulation is administered at a dose of about 50 mg BID. In some embodiments, the exenatide formulation is administered at a dose of about 55 mg BID. In some embodiments, the exenatide formulation is administered at a dose of about 60 mg BID. In some embodiments, the exenatide formulation is administered at a dose of about 65 mg BID. In some embodiments, a formulation comprising exenatide at a concentration of about 30 mg / ml or higher is administered at a dose of about 20 mg BID to about 65 mg BID (e.g., at a dose of about 45 mg BID).

[0081] In some embodiments, the exenatide formulation is administered at a total daily dose of about 40 mg to about 120 mg, or about 60 mg to about 100 mg, or about 85 mg to about 95 mg (e.g., subcutaneous or intravenous administration) and by BID. In some embodiments, the exenatide formulation is administered at a total daily dose of about 90 mg and by BID (i.e., about 45 mg BID). In some embodiments, the exenatide formulation is administered at a total daily dose of about 100 mg and by BID (i.e., about 50 mg BID). In some embodiments, the exenatide formulation is administered at a total daily dose of about 80 mg and by BID (i.e., about 40 mg BID); the exenatide formulation is administered at a total daily dose of about 120 mg and by BID (i.e., about 60 mg BID).

[0082] In some embodiments, the exenatide formulation is administered at a dose of about 40 mg QD to about 120 mg QD, such as about 60 mg QD to about 100 mg QD or about 85 mg QD to about 95 mg QD (e.g., subcutaneous or intravenous administration). In some embodiments, the exenatide formulation is administered at a dose of about 40 mg QD. In some embodiments, the exenatide formulation is administered at a dose of about 50 mg QD. In some embodiments, the exenatide formulation is administered at a dose of about 60 mg QD. In some embodiments, the exenatide formulation is administered at a dose of about 70 mg QD. In some embodiments, the exenatide formulation is administered at a dose of about 80 mg QD. In some embodiments, the exenatide formulation is administered at a dose of about 90 mg QD. In some embodiments, the exenatide formulation is administered at a dose of about 100 mg QD. In some embodiments, the exenatide formulation is administered at a dose of about 120 mg QD.

[0083] In some embodiments, the exenatide formulation is administered at a total daily dose of about 60 mg to about 120 mg (e.g., subcutaneous or intravenous administration) and QD. In some embodiments, the exenatide formulation is administered at a total daily dose of about 60 mg and QD (i.e., about 60 mg QD). In some embodiments, the exenatide formulation is administered at a total daily dose of about 70 mg and QD (i.e., about 70 mg QD). In some embodiments, the exenatide formulation is administered at a total daily dose of about 75 mg and QD (i.e., about 75 mg QD). In some embodiments, the exenatide formulation is administered at a total daily dose of about 80 mg and QD (i.e., about 80 mg QD). In some embodiments, the exenatide formulation is administered at a total daily dose of about 90 mg and QD (i.e., about 90 mg QD). In some embodiments, the exenatide formulation is administered at a total daily dose of about 120 mg and QD (i.e., about 120 mg QD).

[0084] In some embodiments, the exenatide formulation is administered at a total daily dose of about 60 mg to about 120 mg (e.g., subcutaneous or intravenous administration) and by BID or QD. In some embodiments, the exenatide formulation is administered at a total daily dose of about 60 mg and by QD (i.e., about 60 mg QD) or by BID (i.e., about 30 mg BID). In some embodiments, the exenatide formulation is administered at a total daily dose of about 70 mg and by QD (i.e., about 70 mg QD) or by BID (i.e., about 35 mg BID). In some embodiments, the exenatide formulation is administered at a total daily dose of about 80 mg and by QD (i.e., about 80 mg QD) or by BID (i.e., about 40 mg BID). In some embodiments, the exenatide formulation is administered at a total daily dose of about 90 mg and by QD (i.e., about 90 mg QD) or by BID (i.e., about 45 mg BID). In some embodiments, the exenatide formulation is administered at a total daily dose of 120 mg and administered via QD (i.e., about 120 mg QD) or BID (i.e., about 60 mg BID).

[0085] In some embodiments, the exenatide formulation is administered (e.g., subcutaneously or intravenously) about 60 minutes before breakfast and dinner (or before two main meals a day), twice daily (BID). In some embodiments, the exenatide formulation is administered at least about 60 minutes before meals (e.g., at least about 60 minutes before breakfast and / or at least about 60 minutes before dinner). In some embodiments, the administration of the formulation before breakfast and dinner (or before two main meals a day) is at least about 6 hours apart. In some embodiments, the administration of the formulation is independent of mealtime. In some embodiments, the exenatide formulation is administered once daily (QD) in the morning or evening (e.g., subcutaneously or intravenously) to maximize coverage of breakfast and dinner. For example, in some embodiments, the formulation is administered after evening dinner or before morning breakfast (e.g., at least about 60 minutes before breakfast).

[0086] As those skilled in the pharmaceutical art will know, the above dosages and dosage ranges are exemplary adult dosages and may vary depending on the subject's age and weight. It should be understood that in some embodiments, the dosage may be increased or decreased during treatment. For example, some physicians may expect to treat with a low or initial (starting) dose, gradually increasing the dose if the initial dose does not provide sufficient therapeutic benefit, and maintaining the starting dose if it provides sufficient therapeutic benefit.

[0087] Application route

[0088] In some embodiments, a pharmaceutical preparation containing exenatide (e.g., a buffered preparation as described elsewhere in this disclosure) is administered to a subject via subcutaneous administration. Subcutaneous administration includes subcutaneous injection and subcutaneous infusion. Subcutaneous injection involves injecting a liquid pharmaceutical preparation into subcutaneous adipose tissue using a syringe and a short needle. Subcutaneous infusion or subcutaneous perfusion is a subcutaneous technique that infuses liquid into a subcutaneous space using a small needle. Subcutaneous infusion can be performed by an infusion pump or manually (e.g., using a syringe). Injection or infusion sites include, but are not limited to, the thigh, abdomen, upper arm region, back, or upper buttock region. In some embodiments, exenatide is injected using insuflon. In some embodiments, a composition containing exenatide (e.g., a buffered preparation as disclosed elsewhere in this disclosure) is formulated for subcutaneous administration. In one embodiment, the exenatide composition is formulated for subcutaneous administration according to a once-daily (QD), twice-daily (BID), or three-daily (TID) regimen. In some embodiments, a pharmaceutical preparation containing exenatide (e.g., a buffered preparation as described elsewhere in this disclosure) is administered to a subject via intravenous administration, either as a bolus injection or a prolonged intravenous infusion. Intravenous administration can be performed using a syringe or catheter. Administration of the pharmaceutical preparation containing exenatide includes self-administration.

[0089] Exenatide preparations

[0090] In some embodiments, the treatment methods disclosed herein comprise a formulation comprising exenatide or a pharmaceutically acceptable salt thereof (“exenatide formulation”). In some embodiments, the formulation comprises exenatide at a concentration of at least 30 mg / mL. In some embodiments, the pharmaceutical formulation is a buffered saline formulation. For example, pharmaceutical formulations comprising exenatide are described in PCT patent applications PCT / US2016 / 033837 and PCT / US / 2019 / 0562778.

[0091] In some embodiments, the formulation comprises exenatide at the following concentrations: about 2-250 mg / mL, about 2-200 mg / mL, about 2-180 mg / mL, about 2-90 mg / mL, about 2-20 mg / mL, about 2-29 mg / mL, about 1-20 mg / mL, about 30-250 mg / mL, about 30-225 mg / mL, about 30-200 mg / mL, about 30-180 mg / mL, about 30-150 mg / mL, about 30-120 mg / mL, about 30-90 mg / mL, about 30-60 mg / mL, about 30-70 mg / mL, about 40-250 mg / mL, about 40-225 mg / mL, about 40-200 mg / mL, about 40-180 mg / mL, about 40-120 mg / mL, about 45-90 mg / mL, about 45-75 mg / mL. mg / mL, approximately 60-250 mg / mL, approximately 60-225 mg / mL, approximately 60-200 mg / mL, approximately 60-180 mg / mL, approximately 60-120 mg / mL, approximately 60-90 mg / mL, approximately 90-250 mg / mL, approximately 90-225 mg / mL, approximately 90-200 mg / mL, approximately 90-180 mg / mL, approximately 90-120 mg / mL, approximately 30-70 mg / mL, approximately (e.g., approximately 30 mg / mL, approximately 35 mg / mL, approximately 40 mg / mL, approximately 45 mg / mL, approximately 50 mg / mL, approximately 55 mg / mL, approximately 60 mg / mL, approximately 65 mg / mL, approximately 70 mg / mL, approximately 75 mg / mL, approximately 80 mg / mL, approximately 85 mg / mL, approximately 90 mg / mL, approximately 95 mg / mL, approximately 100 (The concentrations are approximately 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 200 mg / mL, 220 mg / mL, or approximately 220 mg / mL). In some embodiments, the formulation comprises exenatide at a concentration of approximately 30 mg / mL. In some embodiments, the formulation comprises exenatide at a concentration ranging from approximately 40 mg / mL to approximately 50 mg / mL. In some embodiments, the formulation comprises exenatide at a concentration of approximately 45 mg / mL. In some embodiments, the formulation comprises exenatide at a concentration ranging from approximately 30 mg / mL to approximately 60 mg / mL. In some embodiments, the formulation comprises exenatide at a concentration ranging from approximately 30 mg / mL to approximately 90 mg / mL.In some embodiments, the formulation comprises exenatide at a concentration ranging from about 45 mg / mL to about 90 mg / mL. In some embodiments, the formulation comprises exenatide at a concentration of about 60 mg / mL. In some embodiments, the formulation comprises exenatide at a concentration of about 75 mg / mL. In some embodiments, the formulation comprises exenatide at a concentration of about 90 mg / mL. In some embodiments, the formulation comprises exenatide at a concentration of about 120 mg / mL. In some embodiments, the formulation comprises exenatide at a concentration of about 175 mg / mL. In some embodiments, the formulation comprises exenatide at a concentration of about 200 mg / mL.

[0092] In some embodiments, the formulation comprises exenatide or a pharmaceutically acceptable salt thereof in a physiologically acceptable buffer solution with a pH range of about 5 to about 6. In some embodiments, the buffer solution is compatible with subcutaneous or intravenous administration. In some embodiments, a physiologically acceptable buffer solution is a buffer solution that brings the pH of the liquid formulation to or near a physiological pH, or within a relatively narrow pH range (e.g., between about 5.0 and about 8.0) close to a physiological pH. In one embodiment, the buffer body formulation comprises a physiologically acceptable buffer solution with a pH greater than 5.0 and at most about 6. In some embodiments, the physiologically acceptable buffer solution has a pH greater than 5.0 and at most about 5.5. In one embodiment, the physiologically acceptable buffer solution has a pH range of 5.2 to 5.8 (e.g., 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, or 5.8). In one embodiment, the physiologically acceptable buffer solution has a pH range of 5.0 to 5.5 (e.g., 5.1, 5.2, 5.3, 5.4, or 5.5). In one embodiment, the physiologically acceptable buffer solution has a pH in the range of about 5.5 to about 6 (e.g., 5.5, 5.6, 5.7, 5.8, 5.9, or 6). In one embodiment, the physiologically acceptable buffer solution has a pH of about 5.5. In one embodiment, the physiologically acceptable buffer solution has a pH of about 5.6. In one embodiment, the physiologically acceptable buffer solution has a pH of about 5.7. In one embodiment, the physiologically acceptable buffer solution has a pH of about 5.8.

[0093] In one embodiment, a physiologically acceptable buffer comprises acetate buffer, citrate buffer, phosphate buffer, histidine buffer, or a mixture thereof. In one embodiment, a physiologically acceptable buffer comprises sodium acetate, potassium acetate, trisodium citrate, magnesium citrate, potassium citrate, potassium phosphate, or a mixture thereof. In one embodiment, a physiologically acceptable buffer comprises a buffer (e.g., sodium acetate) at concentrations of about 5 mM to about 30 mM, about 10 mM to about 30 mM, about 15 mM to about 30 mM, about 20 mM to about 30 mM, or about 25 mM to about 30 mM (e.g., about 5 mM, about 8 mM, about 10 mM, about 12 mM, about 15 mM, about 18 mM, about 20 mM, about 22 mM, about 25 mM, about 28 mM, or about 30 mM). In some embodiments, a physiologically acceptable buffer comprises a buffer (e.g., sodium acetate) at a concentration of at least 10 mM.

[0094] In some embodiments, a physiologically acceptable buffer comprises an acetate buffer. In some embodiments, the buffer is sodium acetate. In some embodiments, the buffer is potassium acetate. In some embodiments, a physiologically acceptable buffer comprises an acetate buffer (e.g., sodium acetate or potassium acetate) at a concentration of about 5 mM to about 30 mM (e.g., about 10 mM to about 20 mM). In some embodiments, a physiologically acceptable buffer comprises an acetate buffer (e.g., sodium acetate or potassium acetate) at a concentration of about 10 mM.

[0095] In some embodiments, a physiologically acceptable buffer comprises a citrate buffer. In some embodiments, the buffer is trisodium citrate. In some embodiments, the buffer is magnesium citrate. In some embodiments, the buffer is potassium citrate. In one embodiment, a physiologically acceptable buffer comprises a citrate buffer (e.g., sodium citrate, magnesium citrate, or potassium citrate) at a concentration of about 5 mM to about 30 mM (e.g., about 10 mM to about 20 mM). In some embodiments, a physiologically acceptable buffer comprises a citrate buffer (e.g., sodium citrate, magnesium citrate, or potassium citrate) at a concentration of about 10 mM.

[0096] In one embodiment, the physiologically acceptable buffer comprises phosphate buffer. In one embodiment, the physiologically acceptable buffer comprises potassium phosphate. In one embodiment, the physiologically acceptable buffer comprises potassium phosphate at a concentration of about 5 mM to about 30 mM (e.g., about 10 mM to about 20 mM). In some embodiments, the physiologically acceptable buffer comprises phosphate buffer (e.g., potassium phosphate) at a concentration of about 10 mM.

[0097] In some embodiments, the buffer formulation comprises a tonicotinic agent. In some embodiments, the tonicotinic agent is mannitol, dextran, glycerol, lactose, sucrose, trehalose, or a mixture thereof. In some embodiments, the tonicotinic agent is mannitol. The use of tonicotinic agents is well known in the medical field, and those skilled in the art can use one or more of the tonicotinic agents disclosed herein to provide liquid pharmaceutical formulations suitable for subcutaneous or intravenous administration. See, for example, Pramanick et al., Pharma Times, Vol. 45, No. 3, (2013); see also Formulating Poorly Water Soluble Drugs, edited by Williams, Watts, and Miller, Springer Science and Business Media (2011).

[0098] In some embodiments, the tension modifier or combination of tension modifiers is present in the formulation at the following concentrations: about 20-75 mg / ml, about 20-60 mg / ml, about 25-55 mg / ml, about 30-75 mg / ml, about 30-50 mg / ml, about 35-45 mg / ml, about 40-45 mg / ml, about 45-75 mg / ml, or about 45-60 mg / ml (e.g., about 20 mg / ml, about 22 mg / ml, about 25 mg / ml, about 28 mg / ml, about 30 mg / ml, about 32 mg / ml, about 35 mg / ml, about 38 mg / ml, about 40 mg / ml, about 42 mg / ml, about 45 mg / ml, about 48 mg / ml, about 50 mg / ml, about 52 mg / ml, about 55 mg / ml, about 58 mg / ml, about 60 mg / ml, about 65 mg / ml, about 70 mg / ml, or about 75 mg / ml). In some embodiments, the formulation comprises a tension modulator in a concentration range of about 30 mg / ml to about 60 mg / ml.

[0099] In some embodiments, the tension modifier comprises mannitol. In some embodiments, mannitol is present at a concentration of about 40-50 mg / ml. In some embodiments, mannitol is present at a concentration range of about 40 mg / ml to about 45 mg / ml. In some embodiments, mannitol is present at a concentration of about 45 mg / ml. In some embodiments, mannitol is present at a concentration of at least 45 mg / ml.

[0100] In one embodiment, the tension modifier comprises dextrose. In one embodiment, dextrose is present at a concentration of about 20 mg / ml to about 60 mg / ml (e.g., about 20 mg / ml, about 40 mg / ml, about 45 mg / ml, or about 60 mg / ml).

[0101] In one embodiment, the tension modifier comprises glycerol. In some embodiments, glycerol is present at a concentration of about 20 mg / ml to about 60 mg / ml (e.g., about 20 mg / ml, about 40 mg / ml, about 45 mg / ml, or about 60 mg / ml).

[0102] In one embodiment, the tension modifier comprises lactose. On one hand, lactose is present at a concentration of about 20 mg / ml to about 60 mg / ml (e.g., about 20 mg / ml, about 40 mg / ml, about 45 mg / ml, or about 60 mg / ml).

[0103] In one embodiment, the tension modifier comprises sucrose. In some embodiments, the sucrose is present at a concentration of about 20 mg / ml to about 60 mg / ml (e.g., about 20 mg / ml, about 40 mg / ml, about 45 mg / ml, or about 60 mg / ml).

[0104] In one embodiment, the tension modifier comprises trehalose. On one hand, the trehalose is present at a concentration of about 20 mg / ml to about 60 mg / ml (e.g., about 20 mg / ml, about 40 mg / ml, about 45 mg / ml, or about 60 mg / ml).

[0105] In some embodiments, the buffer formulation comprises two or more tension modifiers. In some embodiments, the buffer formulation comprises two or more tension modifiers selected from the group consisting of mannitol, dextrose, glycerol, lactose, sucrose, and trehalose. In some embodiments, the buffer formulation comprises mannitol and at least one other tension modifier.

[0106] In some embodiments, the formulation further comprises one or more additional excipients, such as preservatives, surfactants (e.g., polysorbates or poloxamer), or colorants (e.g., pharmaceutically acceptable dyes, inorganic pigments, and natural colorants). A variety of pharmaceutically acceptable excipients are known in the art. Pharmaceutically acceptable excipients have been well described in a variety of publications, including, for example: A. Gennaro (2000) *Remington: The Science and Practice of Pharmacy*, 20th edition, Lippincott, Williams, & Wilkins; *Pharmaceutical Dosage Forms and Drug Delivery Systems* (1999), edited by HC Ansel et al., 7th edition, Lippincott, Williams, & Wilkins; and *Handbook of Pharmaceutical Excipients* (2000), edited by AH Kibbe et al., 3rd edition, Amer. Pharmaceutical Assoc., each of which is incorporated herein by reference.

[0107] In some embodiments, the exenatide formulation is provided as a single-use pre-filled syringe, for example, in a kit containing multiple single-use pre-filled syringes (e.g., 10, 20, 30, 40, 50, or 60 pre-filled syringes). In some embodiments, the single-use pre-filled syringe contains an exenatide formulation comprising exenatide at a concentration of at least 30 mg / mL, a tension modifier, and a buffer solution with a pH range of 5.0 to 6.0. In some embodiments, the single-use pre-filled syringe contains an amount of exenatide of at least 20 mg (e.g., 20-90 mg, 30-75 mg, 30-60 mg, 40-90 mg, or 60-90 mg, such as 20 mg, 25 mg, 30 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, or 90 mg). In some embodiments, the single-use pre-filled syringe contains an amount of exenatide of at least 30 mg. In some embodiments, the exenatide formulation optionally further comprises a preservative.

[0108] In some embodiments, the exenatide formulation is provided as a pen syringe device. In some embodiments, the pen syringe device is a glass device (e.g., a glass-tube pen syringe device). In some embodiments, the pen syringe device is a single-use device. In some embodiments, the pen syringe device comprises an exenatide formulation including exenatide at a concentration of at least 30 mg / mL, a tonic modulator, and a buffer solution with a pH range of 5.0 to 6.0. In some embodiments, the pen syringe device comprises an amount of exenatide of at least 20 mg (e.g., 20-90 mg, 30-75 mg, 30-60 mg, 40-90 mg, or 60-90 mg, such as 20 mg, 25 mg, 30 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, or 90 mg). In some embodiments, the pen syringe device comprises an amount of exenatide of at least 30 mg. As a non-limiting example, the pen injector device comprises a formulation including about 30-75 mg of exenatide (e.g., about 30 mg or about 60 mg of exenatide), a tension modifier, and a buffer solution with a pH range of about 5.0 to 6.0. In some embodiments, the exenatide formulation optionally further comprises a preservative.

[0109] In some embodiments, the exenatide formulation is provided in single-dose or multi-dose glass vials or ampoules for administration using a syringe similar to a glucagon emergency kit. In some embodiments, the exenatide formulation is provided in a disposable or reusable pen device. In some embodiments, a disposable or reusable pen device having the exenatide formulation contains multiple doses (e.g., 5, 8, 7, 8, 9, 10 or more) of exenatide. In some embodiments, the exenatide formulation is provided as an injectable solution in a single-dose disc containing a vial of the exenatide formulation as described herein, a tension modifier, a buffer solution with a pH range of 5.0 to 6.0 (e.g., 5.1–6.0, 5.2–5.8, or 5.5–6.0, including any one of 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or 6.0) and optionally an appropriate volume of antimicrobial preservative, a vial connector, a syringe, and one or more needles.

[0110] In some embodiments, each dose is administered as an injection in a total volume range of 0.25-2 ml. In some embodiments, each dose is administered in a total volume range of about 0.1 ml or even 0.5 ml, with most subjects receiving injection volumes in the range of 0.25-1.5 ml, or 0.5-1 ml, or 0.7-1 ml, or 0.1 ml or even 0.5 ml.

[0111] Example

[0112] The following examples are provided to illustrate, rather than limit, the claimed invention.

[0113] Example 1. The selected method.

[0114] A. Buffet Test

[0115] Total calorie intake and macronutrient distribution of selected foods were measured from a standard buffet with known nutrient composition. Participants chose two main dishes from a provided menu, and in addition, they received almond cookies (e.g., produced by Fat Snax, Brooklyn, New York) and guacamole (e.g., wholly produced by MegaMex Foods, Orange, California). ® Avocado salad dressing) and cheese sticks (e.g., low-moisture, partially defatted Lucerne). ® Mozzarella cheese, Guggisberg Cheese, Millersburg, Ohio. Record the amount of buffet food consumed (including partially eaten food) over the next hour. Via ESHA Food Processor (Salem, Oregon). ® Nutrition analysis software analyzes the total calories and macronutrients ingested from the food consumed.

[0116] B. Meal Tolerance Test (MTT)

[0117] If no prior screening was performed, subjects undergo an MTT to establish a baseline metabolic profile. The MTT can be performed at the Stanford University Clinical and Translational Research Unit (CTRU) or an equivalent institution. An indwelling catheter is inserted into the antecubital vein for blood collection. Blood samples are collected during the MTT by trained personnel. At time 0, subjects are given a pre-meal (e.g., Ensure) ®The Compact beverage (Abbott Laboratories, Abbott Park, Illinois) was to be consumed by the test subjects within 15 minutes. Blood glucose, insulin, C-peptide, glucagon, GIP, GLP-1, and other intestinal hypoglycemic hormone levels were measured at multiple time points over 3 hours. Symptoms of hypoglycemia were assessed during the administration of the test. The average total blood volume drawn per MTT was 100 mL.

[0118] C. CGM placement, guidance and data capture, adjustments for signal loss, and dietary liberalization.

[0119] Participants underwent continuous glucose monitoring (CGM) in an outpatient setting. Wearing the CGM device during the study allowed for comparison of the accuracy of the CGM meter in detecting large and rapid changes in blood glucose levels during metabolic stimulation. Registered participants were scheduled for a video training session with the study coordinator. During the initial training, the coordinator explained the study design, objectives, and potential risks associated with the CGM device. Participants wore the CGM device under the coordinator's supervision and were instructed on how to use the blood glucose meter to check their glucose levels in real time, as the CGM is blind. After the 7-day wearing period, participants had another video or in-person meeting with the coordinator to remove the CGM transmitter and return it to the research team for data capture. Once the research team received the CGM transmitter, the data was deidentified and uploaded to the Dexcom Clarity diabetes management application via a Dexcom receiver (a component of the Dexcom Mobile G6 Pro CGM system (Dexcom, Fort Lauderdale, Florida)). The raw data was exported to the appropriate software for data analysis.

[0120] CGM endpoints included the time to levels below 54 mg / dL and 70 mg / dL (adjusted for minutes of use) and the time to levels below 54 mg / dL and 70 mg / dL (adjusted for a glucose peak of 150 mg / dL or higher (indicating carbohydrate consumption)). Data were also adjusted for capture time. Dietary liberalization was estimated using the number of peaks. A glucose peak was defined as a rise in glucose to above 150 mg / dL sustained for at least 15 minutes, presumably indicating consumption of a carbohydrate-containing food / drink.

[0121] D. Cronometer application (Cronometer Software Inc., Revelstoke, British Columbia, Canada)

[0122] Use the Cronometer Pro smartphone app to track food and activity levels to quantify food consumption and nutritional data (macro and micronutrient composition, fiber, etc.), energy balance, and activity levels (minutes, levels).

[0123] Example 2. Seven-day proof-of-concept study: Evaluation of the effect of exenatide on eating behavior in cancer patients after total gastrectomy or esophagectomy.

[0124] A. Objective:

[0125] The main efficacy goals are as follows:

[0126] ●Evaluate the effect of exenatide on eating behavior during standardized outpatient buffet meals, using ESHA Food Processor (Salem, Oregon). ® Nutritional analysis software was used to measure total calorie intake and macronutrient distribution. Food interest was measured using a visual analog scale (VAS), which is a psychometric response scale that can be used in questionnaires (see, for example, the Committee on Nutrition and Appetite Questionnaire (CNAQ) Appetite and Hunger); and during randomized conditions in an outpatient setting, it was measured using the Cronometer Pro Nutrition Tracking app (Cronometer Software, Riverstock, British Columbia, Canada).

[0127] The main security objectives are as follows:

[0128] ●Evaluate the safety and tolerability of exenatide.

[0129] The secondary efficacy objective was to evaluate the effects of exenatide on the following:

[0130] ● Gastrointestinal symptoms were measured using the Short Form Gastrointestinal Health Scale (SHS-GI) and the Gastrointestinal Symptom Rating Scale (GSRS).

[0131] ● Hypoglycemia, fear of hypoglycemia, and related symptoms were measured in a clinic setting during the Standardized Mixed Meal Tolerance Test (MMTT) using plasma glucose nadir and the Edinburgh Hypoglycemia Symptom Scale (EHSS), the Hypoglycemia Fear Survey-II (HFS-II), and through continuous glucose monitoring (CGM), self-monitoring of blood glucose (SMBG), and electronic diary (eDiary) in an outpatient setting.

[0132] ●Evaluate the impact of exenatide on quality of life (QoL), such as through measurement using the 36-item Short Form Health Survey (SF-36).

[0133] B. Group:

[0134] (i) Inclusion criteria

[0135] Patients who meet all of the following criteria are eligible to participate in this study:

[0136] 1. Understand the purpose and risks of this study; be willing and able to comply with the planned visits, treatment plans, laboratory tests, procedures related to the use of smartphone applications, and other research evaluations and procedures, and provide written informed consent;

[0137] 2. Must be at least 18 years old;

[0138] 3. A record of total gastrectomy or esophagectomy within 12 months of registration; and

[0139] 4. At least one of the following: Unexpected weight loss, anticipated due to the patient being underweight or of normal weight before surgery (e.g., low BMI before surgery (BMI < 23 kg / m²)). 2 () or the doctor is concerned that the patient is currently or may be malnourished.

[0140] (ii) Exclusion criteria:

[0141] Patients meeting any of the following criteria were excluded from this study:

[0142] 1. Participated in another interventional clinical study within 30 days prior to screening;

[0143] 2. Donating or losing >500 mL of blood or blood products within 56 days prior to the first dose of the investigational drug;

[0144] 3. Clinically significant active infection within 14 days prior to the first dose of the study drug;

[0145] 4. Any clinically relevant acute or chronic mental abnormalities, renal abnormalities, hepatic abnormalities, pancreatic abnormalities, cardiovascular abnormalities, neurological abnormalities, hematological abnormalities, or gastrointestinal abnormalities (e.g., inflammatory bowel disease) or a history of malignant tumors, except for malignant tumors that have undergone upper GI surgery within 12 months prior to randomization, or basal cell or squamous cell skin cancer or cervical cancer in situ that have been adequately treated.

[0146] 5. Abnormal liver function, defined as transaminase (alanine aminotransferase (ALT), aspartate aminotransferase (AST)) levels >2 × upper limit of normal (ULN) and / or bilirubin levels >2 × ULN at screening; abnormal kidney function, defined as glomerular filtration rate (GFR) <60 mL / min / 1.73 m 2 (Calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation); electrolyte abnormalities, including potassium, magnesium, phosphorus, and sodium.

[0147] C. Research Design:

[0148] This randomized, placebo-controlled, crossover study aimed to evaluate the effects of exenatide treatment on eating behavior, gastrointestinal symptoms, hypoglycemia, and quality of life in patients who had previously undergone total gastrectomy or esophagectomy for the treatment or prevention of gastric or esophageal cancer. Figure 1 As shown, this study included a 3-day CGM induction period and two 7-day treatment periods with a 3-day washout period in between. Approximately 16 participants were randomly assigned in a 1:1 ratio to one of the two groups, with different dosing regimens in each group.

[0149] After randomization, baseline assessments were completed. Anthropometric measurements were performed, including height, weight, BMI, and body circumference. A standardized buffet meal test was conducted using the ESHA Food Processor to quantify energy intake and composition. Food interest, appetite, hunger, satiety, and taste aversion were assessed using the VAS and CNAQ. A standardized MMTT was performed to assess glucose and hormonal profiles, hypoglycemia and gastrointestinal symptoms at meal challenge, and hypoglycemic symptoms were assessed using the EHSS. In addition, patients completed the GSRS and SHS-GI questionnaires to assess GI symptoms, and completed the HFS-II and SF-36 to assess fear of hypoglycemia and health-related quality of life.

[0150] Starting from the CGM introductory phase and throughout Treatment Phase 1 and Treatment Phase 2 (including a 3-day washout period), participants received either exenatide or placebo twice daily for a total of 10 days in a crossover design and randomized sequence. Throughout each 7-day treatment period in a home setting, participants recorded randomized energy intake via a food diary using the Cronometer Pro app and recorded hypoglycemic events via an electronic diary (eDiary; Medpace, Inc., Cincinnati, Ohio), self-monitoring of blood glucose (SMBG), and blinded continuous glucose monitoring (CGM). At the end of each treatment phase, participants returned to the field for a repeat baseline assessment. A 3-day washout period existed between Treatment Phase 1 and Treatment Phase 2.

[0151] D. Research Procedure:

[0152] (i) Clinical assessment

[0153] Buffet Test: At baseline and at the end of each treatment period, subjects entered the clinic after fasting overnight to undergo a free-choice standard buffet test to measure their intake of a standard food with known nutrient composition (e.g., lasagna). ® Total calorie intake and macronutrient distribution of foods selected from the following meals will be recorded: Nestlé USA, Inc., Solon, OH; vanilla pudding (Hunts, KraftHeinz North America, Tarrytown, NY); and skim milk. The amount of food consumed at the buffet (including partially eaten buffet items) will be recorded over the next hour. This will be done using validated software (ProNutra™ 3.0; Viocare, Princeton, NJ). ® Technology company (Viocare) ® Technologies, Inc., Princeton, NJ) will analyze the total kilocalories consumed and the macronutrients ingested. Furthermore, VAS and CNAQ will be used to quantify food interest, appetite, hunger, and taste aversion.

[0154] Mixed Meal Tolerance Test (MMTT): At baseline and at the end of each treatment period, subjects entered the clinic after an overnight fast for a 180-minute MMTT. Following baseline blood draw, subjects consumed two servings of Ensure containing 64 g of carbohydrates within 10 minutes. ® Compact beverage (Abbott Laboratories, Abbott Science Park, Illinois) was used for laboratory blood draws every 15 minutes (for plasma glucose, insulin, C-peptide, GLP-1, and glucagon), and point-of-care glucose measurements were performed bedside for assessment every 30 minutes. If resuscitation parameters were met (point-of-care glucose ≤50 mg / dL with documented symptoms of neurogenic hypoglycemia or ≤40 mg / dL regardless of symptoms, whichever was earlier), a final blood sample was drawn, and the participant was resuscitated by intravenous dextran. Plasma glucose and hormones (glucose, insulin, glucagon, GLP-1, GIP) were collected every 30 minutes and analyzed according to standard methods.

[0155] To assess transient autonomous, neurohypoglycemic, and nonspecific symptoms and their severity, a five-point Likert severity scale (0 = none; 5 = severe) was used on the EHSS (a validated survey for identifying acute hypoglycemic symptoms in insulin-treated diabetic patients). During each oral glucose tolerance test (OGTT), participants completed the EHSS severity grading every 30 minutes prior to each blood draw. Assessed symptoms included autonomous symptoms (sweating, tremors, palpitations, hunger), neurohypoglycemic symptoms (blurred vision, confusion, drowsiness, bizarre behavior, speech difficulties, motor incoordination, dizziness, inattention), and discomfort (nausea, headache). For each participant, a composite score was recorded at all time points. To separate symptoms transiently associated with the glucose rise phase (from T = 0 to the individual participant's peak glucose level) and the glucose fall phase (from peak glucose level to trough), two sub-scores were included: "glucose rise" and "glucose fall" scores. Symptom scores were further analyzed by grouping according to symptom type: autonomous, neurohypoglycemic, or discomfort.

[0156] Questionnaires: Subjects completed SHS-GI, GSRS, HSF-II, and SF-36 at baseline and at the end of each treatment period. The questionnaires must be completed calmly and discreetly in a quiet, private environment using a black ballpoint pen, without any external assistance, before any study procedure or laboratory blood draw. Each questionnaire is checked to ensure all questions have been answered. If any question remains unanswered, the study participant will be asked if they wish to complete it. If a study participant does not wish to answer a question, no further action is taken, and the completed questionnaire is archived in the source document folder.

[0157] (ii) Outpatient assessment:

[0158] Use of CGM, SMBG, and eDiary in an outpatient setting: Throughout the two 7-day treatment periods, subjects used eDiary (an internet-connected web application) and CONTOUR. ® A Next One blood glucose meter (Ascensia Diabetes Care, Parsippany, New Jersey) and a blinded Dexcom Mobile G6 Pro CGM system (Dexcom, Fort Lauderdale, Florida) recorded hypoglycemic events in an outpatient setting. For each episode, patients recorded hypoglycemic symptoms / signs, the lowest SMBG reading during the episode, actions taken to treat or prevent the episode, requests for assistance, and whether the episode was postprandial. Study drug injections were also recorded, and adherence was monitored by counting returned study drug vials.

[0159] Cronometer Pro App: Throughout the two 7-day treatment periods, use the smartphone Cronometer Pro app and the nutrition tracking software Pro to track food and activity levels to quantify food consumption and nutritional data (macro and micronutrient composition, fiber, etc.), energy balance, and activity levels (minutes, levels).

[0160] E. End point:

[0161] The primary efficacy endpoint was total calorie intake (kcal) during the standardized buffet test.

[0162] Secondary endpoints supporting the primary objective include the following:

[0163] ●Food interest was measured using VAS prior to the buffet test.

[0164] ● Appetite and hunger, measured by CNAQ.

[0165] ● Taste aversion, measured using exploration tools.

[0166] ●Total energy intake is measured using a timer app by recording food logs over 7 days.

[0167] Secondary endpoints supporting the secondary objectives include the following:

[0168] ● Gastrointestinal symptoms were measured by SHS-GI and GSRS at the end of each treatment period.

[0169] ● The degree of hypoglycemia was measured by the lowest point of plasma glucose during the standardized MMTT.

[0170] ●Autonomic and neurogenic hypoglycemic symptoms, measured by EHSS score during MMTT challenge.

[0171] ● Fear and anxiety related to hypoglycemia, measured by HFS-II.

[0172] ●Incidence of hypoglycemic events (<70 mg / dl), measured by SMBG.

[0173] ● The incidence of clinically significant hypoglycemic events (<54 mg / dL) was measured by SMBG.

[0174] ● The time spent within the range (80-120 mg / dL) and the time spent below the range (<70 mg / dL; <54 mg / dL) were measured at home for 7 days in a blinded manner during each treatment period using Dexcom G6 CGM.

[0175] ● Quality of life, measured by SF36.

[0176] Example 3. Phase 2 28-day study: Evaluation of the improvement in nutritional status and prevention of unwanted weight loss in cancer patients after total gastrectomy or esophagectomy using exenatide.

[0177] A. Objective:

[0178] The primary efficacy objective is to assess the effects of exenatide on body weight, composition, and body mass index (BMI) by standardized methods of measurement at baseline and at the end of each treatment period, including height, weight, body circumference, and body impedance analysis (BIA), dual-energy X-ray absorptiometry (DEXA), or computed tomography (CT).

[0179] The primary safety objective is to evaluate the safety and tolerability of exenatide.

[0180] The secondary efficacy objective was to evaluate the effects of exenatide on the following:

[0181] ●Nutritional status is measured by the macronutrient composition of meals, blood albumin levels and / or other biomarkers;

[0182] ● Physical performance, measured by overall activity and / or grip strength;

[0183] ●Eating behavior and energy balance were measured in a clinic setting during standardized buffet meals using the ESHER foodprocessor for total calorie intake and macronutrient distribution. Food interest was measured using the Visual Analogue Scale (VAS), and appetite, taste, satiety, and hunger were measured using the Committee on Nutrition and Appetite Questionnaire (CNAQ).

[0184] ●Energy balance, dietary composition, and dietary freedom during randomized conditions in an outpatient setting, measured using the Cronometer Pro app, CGM, and eDiary;

[0185] ● Gastrointestinal symptoms were measured using the Short Form Gastrointestinal Health Scale (SHS-GI) and the Gastrointestinal Symptom Rating Scale (GSRS).

[0186] ● Hypoglycemia, fear of hypoglycemia, and related symptoms were measured in a clinic setting during the Standardized Mixed Meal Tolerance Test (MMTT) using plasma glucose nadir and the Edinburgh Hypoglycemia Symptom Scale (EHSS), the Hypoglycemia Fear Survey-II (HFS-II), and through continuous glucose monitoring (CGM), self-monitoring of blood glucose (SMBG), and electronic diary (eDiary) in an outpatient setting.

[0187] ● Quality of life (QoL), as measured by the Short Form Health Questionnaire (SF-36).

[0188] B. Group:

[0189] (i) Inclusion criteria

[0190] Patients who meet all of the following criteria will be eligible to participate in this study:

[0191] 1. Understand the purpose and risks of this study; be willing and able to comply with the planned visits, treatment plans, laboratory tests, procedures related to the use of smartphone applications, and other research evaluations and procedures, and provide written informed consent;

[0192] 2. Must be at least 18 years old;

[0193] 3. A record of total gastrectomy or esophagectomy within 12 months of registration; and

[0194] 4. At least one of the following: Unexpected weight loss, anticipated due to the patient being underweight or of normal weight before surgery (e.g., low BMI before surgery (BMI < 23 kg / m²)). 2 () or the doctor is concerned that the patient is currently or may be malnourished.

[0195] (ii) Exclusion criteria:

[0196] Patients meeting any of the following criteria were excluded from this study:

[0197] 1. Participated in another interventional clinical study within 30 days prior to screening;

[0198] 2. Donating or losing >500 mL of blood or blood products within 56 days prior to the first dose of the investigational drug;

[0199] 3. Clinically significant active infection within 14 days prior to the first dose of the study drug;

[0200] 4. Any clinically relevant acute or chronic mental abnormalities, renal abnormalities, hepatic abnormalities, pancreatic abnormalities, cardiovascular abnormalities, neurological abnormalities, hematological abnormalities, or gastrointestinal abnormalities (e.g., inflammatory bowel disease) or a history of malignant tumors, except for malignant tumors that have undergone upper GI surgery within 12 months prior to randomization, or basal cell or squamous cell skin cancer or cervical cancer in situ that have been adequately treated.

[0201] 5. Abnormal liver function, defined as transaminase (alanine aminotransferase (ALT), aspartate aminotransferase (AST)) levels >2 × upper limit of normal (ULN) and / or bilirubin levels >2 × ULN at screening; abnormal kidney function, defined as glomerular filtration rate (GFR) <60 mL / min / 1.73 m2 (Calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation); electrolyte abnormalities, including potassium, magnesium, phosphorus, and sodium.

[0202] C. Research Design:

[0203] This is a phase 2, single-center or multicenter, placebo-controlled, crossover study of exenatide injection, conducted in approximately 16 patients undergoing gastrointestinal surgery. Eligible participants must have undergone total gastrectomy or esophagectomy within 12 months of enrollment. Study participants also had at least one of the following: unintended weight loss, expected unintended weight loss due to preoperative underweight or normal weight (e.g., low preoperative BMI ≤23 kg / m²). 2 (), or the doctor is concerned about current or potential malnutrition. Registered participants were randomly assigned to one of two 28-day exenatide or placebo dosing regimens ( Figure 2 The dosage was administered self-administered via subcutaneous (SC) injection in an outpatient setting. Throughout the study, participants were instructed to follow dietary guidelines following GI surgery.

[0204] Prior to Treatment Phase 1 (at baseline) and at the end of Treatment Phase 1 and 2, participants underwent various clinical assessments, including height / weight / BMI, body composition assessments via BIA, DEXA, or CT, fasting and postprandial laboratory assessments to measure blood glucose, insulin, and enteroglycemic hormones (e.g., GLP-1), and measurements to assess nutritional status (e.g., albumin), performance (e.g., by general activity and / or grip strength), standardized buffet tests, and patient questionnaires (e.g., to assess gastrointestinal symptoms; appetite, taste, and satiety; fear of hypoglycemia-related behaviors). Throughout Treatment Phase 1 and 2, patients tracked eating behavior and energy balance using a timer app in addition to an electronic diary (eDiary). Furthermore, hypoglycemic events were tracked throughout the study using a blinded continuous glucose monitor (CGM), self-monitoring of blood glucose (SMBG), and electronic diary (eDiary) entries. At the end of Treatment Phase 2, participants returned used and unused vials of the study medication during a safety follow-up visit.

[0205] D. Research Procedure:

[0206] (i) Clinical assessment

[0207] Anthropometry: At baseline, height, weight, body mass index (BMI), and body circumference (waist, hips, and limbs) were measured after an overnight fast. At the end of the first and second treatment periods, weight, BMI, and body circumference were measured again after an overnight fast.

[0208] Body composition (lean body mass, fat mass, free fat mass, and water) was measured at baseline and at the end of the first and second treatment periods according to standard methods and analyzed by body impedance analysis (BIA), dual-energy X-ray absorptiometry (DEXA), or computed tomography (CT).

[0209] Buffet Test: At baseline and at the end of each treatment period, subjects entered the clinic after an overnight fast to participate in a free-choice standard buffet test to measure total calorie intake and macronutrient distribution from a selection of standard foods with known nutrient composition (e.g., vegetable lasagna (Stouffers®, Nestlé USA, Soren, OH), vanilla pudding (Hunts, Kraft Heinz North America, Tully, NY), and skim milk). The amount of food consumed (including partially consumed buffet food) was recorded over the next hour. Total kilocalories and macronutrient intake from the consumed food were analyzed using validated software (ProNutra 3.0; Viocare Technologies, Princeton, NJ). Additionally, food interest, appetite, hunger, and taste aversion were quantified using VAS and CNAQ.

[0210] Mixed Meal Tolerance Test (MMTT): At baseline and at the end of each treatment period, subjects entered the clinic after an overnight fast for a 180-minute MMTT. Following baseline blood draws, subjects consumed two servings of Ensure Compact beverage containing 64 g of carbohydrates within 10 minutes. Laboratory blood draws (for plasma glucose, insulin, C-peptide, GLP-1, and glucagon) were performed every 15 minutes, and point-of-care glucose measurements were performed bedside for assessment every 30 minutes. If resuscitation parameters were met (point-of-care glucose ≤50 mg / dL with documented symptoms of neurogenic hypoglycemia or ≤40 mg / dL regardless of symptoms, whichever was earlier), a final blood sample was drawn, and the participant was resuscitated by intravenous dextran. Plasma glucose and hormones (glucose, insulin, glucagon, GLP-1, GIP) were collected every 30 minutes and analyzed according to standard methods.

[0211] To assess transient autonomous, neurohypoglycemic, and nonspecific symptoms and their severity, a five-point Likert severity scale (0 = none; 5 = severe) was used on the EHSS (a validated survey for identifying acute hypoglycemic symptoms in insulin-treated diabetic patients). During each OGTT, participants completed the EHSS severity scale every 30 minutes prior to each blood draw. Assessed symptoms included autonomous symptoms (sweating, tremors, palpitations, hunger), neurohypoglycemic symptoms (blurred vision, confusion, drowsiness, bizarre behavior, speech difficulties, incoordination, dizziness, inattention), and discomfort (nausea, headache). For each participant, a composite score was recorded at all time points. To separate symptoms transiently associated with the glucose rise phase (from T = 0 to the individual participant's peak glucose level) and the glucose fall phase (from peak glucose level to trough), two sub-scores, "Glucose Rise" and "Glucose Fall," were included. Symptom scores were further analyzed by grouping according to symptom type: autonomous, neurohypoglycemic, or discomfort.

[0212] Questionnaires: Subjects completed SHS-GI, GSRS, HSF-II, and SF-36 at baseline and at the end of each treatment period.

[0213] (ii) Outpatient assessment:

[0214] Use of CGM, SMBG, and eDiary in the outpatient setting: Throughout both treatment periods, subjects used eDiary (an internet-connected web application) and CONTOUR. ® Hypoglycemic events occurring in the outpatient setting were recorded using a Next One blood glucose meter and a blinded Dexcom Mobile G6 ProCGM. For each episode, patients recorded hypoglycemic symptoms / signs, the lowest SMBG reading during the episode, actions taken to treat or prevent the episode, requests for assistance, and whether the episode was postprandial. Study drug injections were recorded, and adherence was monitored by counting returned study drug vials.

[0215] Cronometer Pro App: Throughout the two treatment periods, use the smartphone Cronometer Pro app and the nutrition tracking software Pro to track food and activity levels to quantify food consumption and nutritional data (macro and micronutrient composition, fiber, etc.), energy balance, and activity levels (minutes, levels).

[0216] E. End point:

[0217] The primary endpoint was the percentage change in body weight relative to baseline, measured at the end of each treatment period.

[0218] Secondary endpoints supporting the primary objective include:

[0219] ● The percentage change in BMI relative to baseline, measured at the end of each treatment period; and

[0220] ● Percentage change in body composition (lean body mass, fat mass, free fat mass, and water) relative to baseline, analyzed by body impedance analysis (BIA), dual-energy X-ray absorptiometry (DEXA), or computed tomography (CT).

[0221] Secondary endpoints supporting the secondary objective include percentage changes relative to the baseline:

[0222] ● Physical performance, such as through overall activity and grip strength measurements;

[0223] ●GI symptoms, such as those measured, for example, by the CNAQ questionnaire;

[0224] ●Appetite, taste, and satiety, for example, measured via the SHS-GI questionnaire;

[0225] ● Fears and behaviors related to hypoglycemia, such as those measured using the HSF-II questionnaire;

[0226] ●Liberalize eating behavior and carbohydrate intake, such as clinical assessment in an outpatient setting during standardized buffet testing, and use appropriate smartphone applications (such as Cronometer Pro, nutrition tracking software professional version) to quantify food consumption and nutritional data (macro and micronutrient composition, fiber, etc.), energy balance and activity status (minutes, levels).

[0227] ● Nutritional status, such as that measured by albumin or other biomarkers;

[0228] ● Fasting and postprandial glucose and hormone profiles during the MMTT test (e.g., peak, trough, and AUC of insulin, glucagon, GLP-1, and GIP levels).

[0229] ●Incidence of grade 1-3 hypoglycemia, as measured by CGM and SMBG / eDiary.

[0230] Example 4. A study of exenatide therapy in patients with severe hypoglycemia following gastrointestinal surgery (including RYGB, VSG, esophagectomy, gastrectomy, and Nissen fundoplication).

[0231] A. Study Description:

[0232] A phase 2b, single-center, open-label, crossover study of exenatide injection was conducted in 16 patients with surgically induced severe, diet-resistant hyperinsulinemic hypoglycemia (HH). Eligible participants were diagnosed with HH following upper GI surgery and exhibited severe diet-resistant HH, as documented, with at least two severe hypoglycemic events, at least one of which was characterized by a glucose level <54 mg / dL as measured by CGM during a 14-day introductory period of concurrent pharmaconutrient therapy.

[0233] Eligible participants include patients who develop HH following bariatric surgery (Roux-en-Y gastric bypass (RYGB) or vertical sleeve gastrectomy (VSG)) or other upper gastrointestinal surgeries (gastrectomy, esophagectomy, or Nissen fundoplication).

[0234] Eligible participants underwent a 14-day baseline initiation consisting of standard of care (SOC) therapy (medical nutrition therapy) and a standardized mixed meal consumption and screening test at the end of the 14-day SOC baseline period to confirm eligibility and establish a baseline within 90 days of randomization. Completed participants were randomized to one of two 14-day exenatide dosing regimens (…). Figure 3 The dosage was administered self-administered via subcutaneous (SC) injection in an outpatient setting. Participants were instructed to adhere to standard nursing medical nutrition therapy throughout all three treatment periods (baseline, treatment period 1, and treatment period 2) following standard dietary guidelines for hypoglycemia management (frequent small, low-glycemic index meals and snacks containing up to 30 g and 15 g of carbohydrates (CHO) respectively, with all monosaccharides eliminated). Hypoglycemia was assessed using blinded CGM, the patient's electronic diary (eDiary), and SMBG. At the end of each of the baseline, treatment period 1, and treatment period 2, participants completed a quality of life (QoL) assessment (SF-36, EQ-5D) and underwent laboratory blood draws, including trough pK samples. During a safety follow-up visit at the end of treatment period 2, used and unused vials of the study drug were returned and accounted for.

[0235] For a subset of patients who had undergone gastrectomy or esophagectomy, additional assessments were performed because this group was known to have experienced rapid and unconscious weight loss due to post-gastrectomy syndrome, characterized by decreased tolerance to large meals, rapid emptying of food into the small intestine or “dumping,” abdominal cramps, diarrhea, postprandial dizziness, and rapid heart rate and a sharp drop in blood glucose levels. Additional assessments performed in this cohort included anthropometric measurements, appetite and hunger assessments, GI symptom assessments, and QoL assessments at baseline and at the end of each of the first and second treatment periods, including weight, height, and BMI, the Committee on Nutrition and Appetite Questionnaire (CNAQ), the Shortened Health Scale-GI (SHS-GI) questionnaire, and the Hypoglycemia Fear Survey-II (HSF-II).

[0236] B. Result:

[0237] Baseline demographic and clinical characteristics of the participants are shown in Table 4. Metabolic responses of all study participants, as measured by SMBG, eDiary, and CGM, are shown in Table 5. Figure 4 , Figure 5 , Figure 6 , Figure 7 , Figure 8 and Figure 9 middle.

[0238] Table 4. Baseline demographic and clinical characteristics of participants.

[0239]

[0240] Table 5. Incidence of grade 1–3 hypoglycemia as measured by SMBG and eDiary.

[0241]

[0242] 1 Incidence was defined as the number of seizures in each treatment period normalized to 14 days.

[0243] 2 Grade 1 hypoglycemia is defined as an SMBG concentration <70 mg / dL.

[0244] 3 Grade 2 hypoglycemia is defined as an SMBG concentration <54 mg / dL.

[0245] 4 Grade 3 hypoglycemia is defined as a severe event characterized by alterations in mental and / or physical function requiring assistance from others for recovery. This applies regardless of whether the patent accepts external assistance.

[0246] Compared with baseline, both exenatide treatment regimens significantly reduced the incidence of grade 1 to 3 hypoglycemia. Compared with baseline, the incidence of SMBG <70 mg / dL (grade 1 hypoglycemia) was reduced by 54% (P = .003) and 68% (P = .001) during the exenatide 45 mg twice daily and 90 mg once daily treatment periods, respectively, and the incidence of SMBG <54 mg / dL (grade 2 hypoglycemia) was reduced by 57% (P = .003) and 53% (P = .004), respectively. During the exenatide 45 mg twice daily and 90 mg once daily treatment periods, the incidence of grade 3 events was reduced by 68% (P < .001) and 66% (P < .001), respectively.

[0247] Blinded CGM confirmed the results observed via SMBG and eDiary. Specifically, the mean percentage of time with glucose <54 mg / dL was reduced by 45% and 64% during exenatide treatment with 45 mg twice daily and 90 mg once daily, respectively. Similarly, the mean number of hypoglycemic events with glucose <54 mg / dL captured by CGM was reduced by 43% and 65% during exenatide treatment with 45 mg twice daily and 90 mg once daily, respectively.

[0248] When patients were evaluated according to surgical subtype, patients who underwent gastrectomy exhibited a more severe phenotype, with a greater percentage of time spent with CGM values ​​<70 mg / dL, <54 mg / dL, and <40 mg / dL at baseline compared to patients corresponding to weight loss (RYGB and VSG). A significantly enhanced effect of exenatide treatment was also observed in the total gastrectomy cohort compared to weight loss patients. Specifically, a greater reduction in the percentage of time spent with CGM values ​​<54 mg / dL and <40 mg / dL was observed in patients who underwent total gastrectomy. These results are presented in… Figure 7 , Figure 8 and Figure 9 middle.

[0249] The results of additional assessments (anthropometry, CNAQ, SGS-GI, HFS-II) performed on the two patients who underwent gastrectomy are summarized in Table 6.

[0250] (i) Patient 1

[0251] Patient 1 was a 23-year-old male with a germline CDH1 gene mutation who underwent prophylactic laparoscopic gastrectomy with Roux-en-Y reconstruction and esophagojejunostomy approximately 5 months prior to study participation. Within the first month post-surgery, he experienced postprandial hypoglycemia: fasting glucose ranged from approximately 60 to 69 mg / dL. After meals, blood glucose levels would peak as high as 200 mg / dL, and then drop to dangerously low levels (reportedly 37 mg / dL, measured by SMBG and CGM) within 1.5–2 hours. These episodes occurred multiple times daily, with the lowest values ​​appearing after the highest postprandial peak. The patient had no history of loss of consciousness, seizures, or requiring emergency medical assistance, but he reported “brain fog” and “extreme fatigue.” Review of CGM data revealed multiple glucose values ​​<54 mg / dL in the absence of symptoms. Therefore, the patient was diagnosed with asymptomatic hypoglycemia. The patient saw a nutritionist and was told to almost completely avoid carbohydrates and sugars, and to consume no more than 4-7 g of carbohydrates (CHO) per meal. He lost 14.8% of his weight (from 155 lbs to 122 lbs), which was the biggest concern for the patient, his family, and the medical team. The strict dietary restrictions were believed to have caused the patient's weight loss. He also complained of chronic nausea / vomiting, which further limited his oral intake and weight gain.

[0252] At baseline, the patient weighed 126 pounds. After 14 days of administration of exenatide at a 45 mg BID, the patient regained 4.6 pounds (3.6% weight gain). After an additional 14 days of administration of exenatide at a 90 mg QD, the patient regained another 0.8 pounds (4.3% total weight gain). Although the patient was instructed to adhere to the regimen and maintain a consistent diet throughout all treatment periods, a review of blinded CGM data indicated dietary liberalization during each of the 45 mg BID and 90 mg QD administration periods compared to baseline. Dietary liberalization was quantified as the number of times a glucose peak was ≥150 mg / dL, based on the assumption that an average 1 g of CHO raises blood glucose by 3–4 mg / dL and that fasting glucose is an average of 80 mg / dL, therefore an increase to 150 mg / dL represents approximately 20 CHO intakes. The number of daily peak glucose (representing higher CHO meals) increased from 1.44 / day at baseline to 3.57 / day with exenatide administered at 45 mg BID and 5.33 / day with exenatide administered at 90 mg QD, which represents a 270% increase in the number of high-carbohydrate meals treated with exenatide compared to baseline.

[0253] At baseline, the patient's CNAQ score was 23, indicating poor appetite and a high risk of at least 5% weight loss and malnutrition over 6 months. However, after 14 and 28 days of exenatide treatment, the CNAQ score increased to 24 and 26, respectively, indicating a reduced risk of weight loss and malnutrition. At 28 days of treatment, GI symptoms, as measured by SHS-GI, decreased by more than 5%. At baseline, the patient's HFS-II concern score was 49. After 14 and 28 days of exenatide treatment, their HFS-II scores decreased to 42 and 39, respectively, representing a 20.4% reduction in hypoglycemia-related concern by the end of the trial.

[0254] In summary, this 23-year-old male patient, who was underweight, had poor appetite, gastrointestinal symptoms, and frequent severe hypoglycemia, responded effectively to 28 days of exenatide treatment, preventing persistent weight loss and in fact promoting weight rebound. Based on CNAQ, SGS-GI, and HFS-II results, the mechanisms contributing to weight stabilization are likely multifactorial and complementary, including increased appetite, hunger, and taste sensitivity, reduced gastrointestinal symptoms, and reduced hypoglycemic fear due to effective prevention of hypoglycemia. Over the 28-day period, these effects collectively facilitated dietary freedom and improved the patient's weight and nutritional status.

[0255] Table 6. Response of individual gastrostomy patients to exenatide treatment, categorized by treatment period.

[0256]

[0257] (ii) Patient 2

[0258] Patient 2 was a 72-year-old male with a history of gastric cancer who underwent a total gastrectomy 2.75 years prior to participating in the study. He followed a liquid diet for 6 weeks post-surgery and initially lost 20 pounds, but otherwise was in good condition immediately after the surgery. However, over the next few months, he underwent two rounds of chemotherapy, and his weight continued to decrease uncontrollably, from 174 pounds to a low of 111 pounds. Dietary interventions involved frequent small, low-glycemic index meals, but failed to alleviate the weight loss. These meals triggered pain, gastrointestinal symptoms, and frequent diarrhea (according to the patient's report). The patient also complained of weakness, lethargy, and general depression. Approximately 1.5 years post-surgery, the patient's weight stabilized at 125 pounds; however, he continued to experience decreased appetite, taste and food aversion, low energy, and gastrointestinal symptoms during meals, including nausea and diarrhea. He began experiencing severe hypoglycemic events, including multiple episodes of loss of consciousness requiring emergency medical assistance. He was prescribed acarbose (which provided little improvement to his hypoglycemia), and his gastrointestinal symptoms worsened. This patient was recommended to participate in the trial.

[0259] In contrast to Patient 1, Patient 2 maintained a stable weight (-0.8% change) throughout baseline, treatment period 1, and treatment period 2. He also did not indicate dietary liberalization (consistent diet as instructed by the protocol). However, his CNAQ, SHS-GI, and HFS-II scores showed significant improvements across domains, indicating improved appetite / hunger and taste, reduced gastrointestinal symptoms, and decreased hypoglycemia-related concerns, enabling safe and well-tolerated dietary liberalization (as permitted by the protocol) while improving the patient's nutritional status.

[0260] The difference between Patient 2 and Patient 1 is that Patient 2 had more than 20 untreated severe hypoglycemic events at baseline. Over time, if discharged from the regimen, Patient 2 is expected to experience healthy weight regain due to prevention of hypoglycemic events, improved appetite, and reduced GI symptoms. Another difference between the two patients is that Patient 1 was in the early postoperative period (within 6 months after surgery), while Patient 2 was latent (approximately 2.75 years after surgery). The studies discussed above demonstrate that the methods according to this disclosure are particularly effective in treating early and involuntary weight loss or achieving weight regain in patients who have recently undergone gastrectomy.

[0261] Example 5. Animal experiments have shown that feeding behavior increases after administration of exenatide.

[0262] A. Overview:

[0263] An animal study was conducted involving the subcutaneous administration of exenatide to healthy Sprague Dawley rats. The results described below indicate that GLP1R antagonism can prevent undesirable weight loss in human subjects by increasing feeding behavior, thereby contributing to calorie intake and / or nutritional status. A large body of existing preclinical and clinical data (some of which are discussed elsewhere in this disclosure) shows that GLP1R agonism leads to weight loss and taste aversion via central mechanisms, but GLP1R antagonism does not stimulate appetite, increase feeding behavior, or lead to weight gain. In contrast, this study demonstrates that administration of the GLP1R antagonist exenatide increased food and calorie expenditure in study subjects. This study also shows that administration of the GLP1R antagonist exenatide increases feeding behavior without resulting in meaningful weight gain, suggesting that exenatide can prevent undesirable weight loss and improve nutritional status.

[0264] B. Study Description:

[0265] The aim of this study was to test the transmission of CD4 cells before commensalization, during mating, and during embryo implantation. ®Effects of SpragueDawley IGS (Crl:CD[SD]) twice daily (BID) subcutaneous (SC) administration of exenatide dose on male and female rats. The study design is summarized in Table 7. Among other parameters, body weight and food consumption data were collected throughout the study.

[0266] Table 7. Animal research design.

[0267]

[0268] a Administer the medication to animals via subcutaneous bolus injection twice daily. Administer to males 28 days before and during communal living, continuing until the day before euthanasia. Administer to females 15 days before and during communal living, continuing until day 7 of gestation. Administer to females who show no signs of mating after the communal living period until the day before autopsy.

[0269] b Based on recent weight measurements.

[0270] c Mannitol acetate buffer in sterile water for injection, USP, pH 5.5 ± 0.2.

[0271] C. Result:

[0272] No effects on body weight, weight gain, or organ weight associated with exenatide were observed. However, compared with the control group, food consumption increased in a dose-dependent manner in males as follows: on days 4–8, at all dose levels; on days 1–4 and 18–22, at dose levels of 150 mg / kg / day and 450 mg / kg / day; and on days 11–15, at a dose level of 450 mg / kg / day. In females, during the pre-mating dosing period, food consumption was observed to increase in a dose-dependent manner compared with the control group as follows: on days 4–8, at a dose level of 450 mg / kg / day; on days 8–11, at dose levels of 150 mg / kg / day and 450 mg / kg / day; and on days 11–15, at dose levels of 45 mg / kg / day and 450 mg / kg / day. During pregnancy, food consumption in female rats increased in a non-dose-dependent manner compared to the control group: at a dose level of 450 mg / kg / day from day 0 to day 3 of gestation (GD), and at dose levels of 150 mg / kg / day and 450 mg / kg / day from day 3 to day 7 and day 8 of GD. The results are summarized in Tables 8-10.

[0273] Table 8. Daily food consumption of males (g / animal / day).

[0274]

[0275] [G] - Kruskal-Wallis vs. Dunn: * = p ≤ 0.05; ** = p ≤ 0.01

[0276] [G1] - Anova and Dunnett: * = p ≤ 0.05

[0277] Table 9. Daily food consumption of females (g / animal / day).

[0278]

[0279] [G] - Anova and Dennehy: * = p ≤ 0.05

[0280] [G1] - Kruskar Wallis and Dunn

[0281] [I] - n - Not suitable for statistics

[0282] Table 10. Daily food consumption of females during pregnancy (g / animal / day).

[0283]

[0284] [G] - Kruskal Wallis vs. Dunn: ** = p ≤ 0.01

[0285] [G1] - Anova and Dennehy: * = p ≤ 0.05

[0286] It should be understood that the examples and embodiments described in this disclosure are for illustrative purposes only, and various modifications or changes made thereto will inspire those skilled in the art and will be included within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications referenced in this disclosure are incorporated herein by reference in their entirety for all purposes. No reference is acknowledged to constitute prior art, including any non-patent or patent documents referenced in this specification. In particular, it should be understood that unless otherwise stated, any document referenced herein does not constitute an admission that any document in such document constitutes part of general knowledge in the art in the United States or any other country. The discussion of the referenced documents illustrates the author's claims, and the applicant reserves the right to challenge the accuracy and relevance of any document referenced herein. In the event of any discrepancy between any definitions and / or descriptions found in the cited references, the contents of this disclosure shall prevail.

[0287] Publications cited in this disclosure

[0288] 1. Brubaker et al., “Structure-function of the glucagon receptor family of G protein-coupled receptors: the glucagon, GIP, GLP-1, and GLP-2 receptors”, *Receptors & Channels*, 8 (3-4):179-88 (2002), doi:10.1080 / 10606820213687

[0289] 2. Holst, “The Physiology of Glucagon-like Peptide 1,” Physiology Review (Physiol. Rev.), 87:1409-1439 (2007), doi:10.1152 / physrev.00034.2006

[0290] 3. Kittah et al., “A pilot study examining the effects of GLP-1 Receptor Blockade Using Exendin-(9,39) on gastric emptying and caloric intake in subjects with and without bariatric surgery.” Metabolic Syndrome Relat Disord. 18(9):406-412(2020). doi:10.1089 / met.2020.0049.

[0291] 4. Kulve et al. "Elevated Postoperative Endogenous GLP-1 Levels Mediate Effects of Roux-en-Y Gastric Bypass on Neural Responsivity to Food Cues". Diabetes Care. 40(11):1522-1529 (2017). doi:10.2337 / dc16-2113.

[0292] 5. Landi et al., “Anorexia, physical function, and incident disability among the frail elderly population: results from the ilSIRENTE study.” *Journal of the American Medical Association*, 11(4):268-274 (2010). doi:10.1016 / j.jamda.2009.12.088

[0293] 6. Martin et al. Ann NY Acad Sci. “Modulation of taste sensitivity by GLP-1 signaling intaste buds”. Ann NY Acad Sci. 1170:98-101 (2009) doi:10.1111 / j.1749-6632.2009.03920.x.

[0294] 7. Maurer et al., Chapter 11, “Gastric emptyingscintigraphy,” in *Gastroparesis*. Edited by McCallum and Parkman, Academic Press (2021), pp. 125–142. doi:10.1016 / B978-0-12-818586-5.00011-9

[0295] 8. Melhorn et al., Appetite, “Initial evidence that GLP-1 receptor blockade fails to suppress postprandial satiety or promote food intake in humans.” Appetite (2014) 82:85-90. doi:10.1016 / j.appet.2014.07.009.

[0296] 9. Montrose-Rafizadeh et al., “Highpotency antagonists of the pancreatic glucagon-like peptide-1 receptor,” *Journal of Biological Chemistry*, 272:21201-21206 (1997), doi:10.1074 / jbc.272.34.21201

[0297] 10. Müller et al. “Glucagon-like peptide 1 (GLP-1)”. Molecular Metabolism. 30:72-130 (2019). doi:10.1016 / j.molmet.2019.09.010.

[0298] 11. Salehi et al. “Blockade of glucagon-like peptide 1 receptor corrects postprandial hypoglycemia after gastric bypass”. Gastroenterology. 146(3):669-680.e2 (2014). doi:10.1053 / j.gastro.2013.11.044.

[0299] 12. Shah et al., “Contribution of endogenous glucagon-like peptide 1 to glucose metabolism after Roux-en-Y gastric bypass”. Diabetes 63:483-493 (2014).

[0300] 13. Sisley et al. “Neuronal GLP1R mediates liraglutide’s anorectic but not glucose-lowering effect.” J Clin Invest. 124(6):2456-63 (2014). doi:10.1172 / JCI72434.

[0301] 14. Wilson et al. “Appetite assessment: simple appetite questionnaire predicts weight loss in community-dwelling adults and nursing home residents”. American Journal of Clinical Nutrition. 82(5):1074-1081 (2005). doi:10.1093 / ajcn / 82.5.1074.

Claims

1. A method for improving the nutrition of a subject, the method comprising administering to the subject a pharmaceutical preparation containing exenatide, wherein the subject has undergone at least one gastrointestinal surgery.

2. The method of claim 1, wherein the administration of the pharmaceutical preparation improves the nutrition of the subject compared to the subject's nutrition prior to the administration of the pharmaceutical preparation.

3. The method according to claim 1 or 2, wherein the administration of the pharmaceutical preparation increases the nutritional intake of the subject compared to the subject's nutritional intake prior to the administration of the pharmaceutical preparation.

4. The method according to any one of claims 1 to 3, wherein the administration of the pharmaceutical preparation increases the appetite of the subject compared to the subject's appetite before the administration of the pharmaceutical preparation.

5. The method according to any one of claims 1 to 4, wherein the administration of the pharmaceutical preparation increases the subject's food tolerance compared to the subject's food tolerance prior to the administration of the pharmaceutical preparation.

6. The method according to any one of claims 1 to 5, wherein the administration of the pharmaceutical preparation reduces the subject's food and / or taste aversion compared to the subject's food and / or taste aversion prior to the administration of the pharmaceutical preparation.

7. The method according to any one of claims 1 to 6, wherein the administration of the pharmaceutical preparation alleviates the subject's food intolerance compared to the subject's food intolerance prior to the administration of the pharmaceutical preparation.

8. The method according to any one of claims 1 to 7, wherein the administration of the pharmaceutical preparation reduces the subject's food avoidance compared to the subject's food avoidance prior to the administration of the pharmaceutical preparation.

9. The method according to any one of claims 1 to 8, wherein the administration of the pharmaceutical preparation increases the calorie intake of the subject compared to the subject's calorie intake prior to the administration of the pharmaceutical preparation.

10. The method according to any one of claims 1 to 9, wherein the administration of the pharmaceutical preparation increases the subject's eating behavior compared to the subject's eating behavior before the administration of the pharmaceutical preparation.

11. The method according to any one of claims 1 to 10, wherein the administration of the pharmaceutical preparation reduces the subject's fear of eating compared to the subject's fear of eating prior to the administration of the pharmaceutical preparation.

12. The method according to any one of claims 1 to 11, wherein the administration of the pharmaceutical preparation reduces the subject's food-related concerns compared to food-related concerns prior to the administration of the pharmaceutical preparation.

13. The method according to any one of claims 1 to 12, wherein the administration of the pharmaceutical preparation alleviates one or more gastrointestinal symptoms of the subject compared to one or more gastrointestinal symptoms of the subject prior to the administration of the pharmaceutical preparation.

14. The method according to any one of claims 1 to 13, wherein the subject experienced a decrease in the rate of weight gain or weight loss after administration of the pharmaceutical preparation.

15. The method according to any one of claims 1 to 14, wherein the subject underwent dietary freedom after administration of the pharmaceutical preparation.

16. The method according to any one of claims 1 to 15, wherein the administration of the pharmaceutical preparation reduces the incidence of hypoglycemic events after the administration of the pharmaceutical preparation.

17. The method according to any one of claims 1 to 16, wherein prior to the administration of the pharmaceutical preparation, the subject has elevated glucagon-like peptide-1 (GLP-1) levels compared to a reference population level.

18. The method according to any one of claims 1 to 17, wherein the subject has been diagnosed with one or more of the following prior to at least one gastric surgery: gastric cancer, esophageal cancer, gastroesophageal reflux, increased risk of gastric cancer, or increased risk of esophageal cancer.

19. The method of claim 18, wherein the at least one gastric surgical procedure is a gastrectomy, an esophagectomy, or a Nissen fundoplication.

20. The method of claim 18, wherein the at least one gastric surgery is at least one bariatric surgery.

21. The method of claim 20, wherein the at least one bariatric surgical procedure is Roux-en-Y gastric bypass (RYGB), vertical sleeve gastrectomy (VSG), or BPD.

22. The method according to any one of claims 1 to 21, wherein the subject has type 2 diabetes.

23. The method according to any one of claims 1 to 22, wherein the pharmaceutical preparation comprises exenatide at a concentration between about 2 and 225 mg / mL.

24. The method according to any one of claims 1 to 23, wherein the pharmaceutical preparation is a buffer solution preparation.

25. The method according to any one of claims 1 to 24, wherein the pharmaceutical preparation is administered subcutaneously.

26. The method according to any one of claims 1 to 25, wherein the pharmaceutical preparation is administered to achieve a total daily dose of exenatide of about 40 mg to about 120 mg.

27. The method according to any one of claims 1 to 26, wherein the pharmaceutical preparation is administered to achieve a total daily dose of exenatide of about 90 mg.

28. The method according to any one of claims 1 to 27, wherein the pharmaceutical preparation is administered to achieve a total daily dose of exenatide of about 0.4 mg / kg to about 3 mg / kg.

29. The method according to any one of claims 1 to 28, wherein the pharmaceutical preparation is administered once daily (QD) or twice daily (BID).

30. The method according to any one of claims 1 to 29, wherein the pharmaceutical preparation is administered once daily (QD) at a dose of about 20 mg to about 120 mg.

31. The method of claim 30, wherein the pharmaceutical preparation is administered once daily (QD) at a dose of about 90 mg.

32. The method according to any one of claims 1 to 29, wherein the pharmaceutical preparation is administered twice daily (BID) at a dose of about 40 mg to about 60 mg.

33. The method of claim 32, wherein the pharmaceutical preparation is administered twice daily (BID) at a dose of about 45 mg.

34. A method for improving the nutritional intake of a subject who requires improved nutritional intake, the method comprising administering to the subject a pharmaceutical preparation comprising exenatide, wherein the subject has undergone at least one gastrointestinal surgery.

35. A method for improving the appetite of a subject who requires appetite improvement, the method comprising administering to the subject a pharmaceutical preparation comprising exenatide, wherein the subject has undergone at least one gastrointestinal surgery.

36. A method for improving food tolerance in a subject who requires improvement of food tolerance, the method comprising administering to the subject a pharmaceutical preparation comprising exenatide, wherein the subject has undergone at least one gastrointestinal surgery.

37. A method for alleviating food and / or taste aversion in a subject who requires relief of food and / or taste aversion, the method comprising administering to the subject a pharmaceutical preparation comprising exenatide, wherein the subject has undergone at least one gastrointestinal surgery.

38. A method for alleviating food intolerance in a subject who requires relief of food intolerance, the method comprising administering to the subject a pharmaceutical preparation comprising exenatide, wherein the subject has undergone at least one gastrointestinal surgery.

39. A method for alleviating food avoidance in a subject who needs to alleviate food avoidance, the method comprising administering to the subject a pharmaceutical preparation comprising exenatide, wherein the subject has undergone at least one gastrointestinal surgery.

40. A method for increasing calorie intake in a subject who requires increased calorie intake, the method comprising administering to the subject a pharmaceutical preparation comprising exenatide, wherein the subject has undergone at least one gastrointestinal surgery.

41. A method for increasing the eating behavior of a subject who requires increased eating behavior, the method comprising administering to the subject a pharmaceutical preparation comprising exenatide, wherein the subject has undergone at least one gastrointestinal surgery.

42. A method for alleviating eating phobia in a subject who needs to alleviate eating phobia, the method comprising administering to the subject a pharmaceutical preparation comprising exenatide, wherein the subject has undergone at least one gastrointestinal surgery.

43. A method for alleviating eating-related anxieties in a subject who requires relief of eating-related anxieties, the method comprising administering to the subject a pharmaceutical preparation comprising exenatide, wherein the subject has undergone at least one gastrointestinal surgery.

44. A method for alleviating one or more gastrointestinal symptoms in a subject who requires relief of one or more gastrointestinal symptoms, the method comprising administering to the subject a pharmaceutical preparation comprising exenatide, wherein the subject has undergone at least one gastrointestinal surgery.

45. A method for increasing the weight of a subject who needs to gain weight, the method comprising administering to the subject a pharmaceutical preparation comprising exenatide, wherein the subject has undergone at least one gastrointestinal surgery.

46. ​​A method for reducing the rate of weight loss in a subject who needs to reduce the rate of weight loss, the method comprising administering to the subject a pharmaceutical preparation comprising exenatide, wherein the subject has undergone at least one gastrointestinal surgery.

47. A method for preventing weight loss in a subject who requires prevention of weight loss, the method comprising administering to the subject a pharmaceutical preparation comprising exenatide, wherein the subject has undergone at least one gastrointestinal surgery.

48. A method for dietary liberalization of a subject requiring dietary liberalization, the method comprising administering to the subject a pharmaceutical preparation comprising exenatide, wherein the subject has undergone at least one gastrointestinal surgery.

49. A method for reducing the incidence of hypoglycemic events in a subject who requires a reduction in the incidence of hypoglycemic events, the method comprising administering to the subject a pharmaceutical preparation comprising exenatide, wherein the subject has undergone at least one gastrointestinal surgery.

50. The method according to any one of claims 34 to 49, wherein the administration of the pharmaceutical preparation reduces the incidence of the hypoglycemic event after the administration of the pharmaceutical preparation.

51. The method according to any one of claims 34 to 50, wherein prior to the administration of the pharmaceutical preparation, the subject has elevated glucagon-like peptide-1 (GLP-1) levels compared to a reference population.

52. The method according to any one of claims 34 to 51, wherein the subject has been diagnosed with one or more of the following prior to at least one gastric surgery: gastric cancer, esophageal cancer, gastroesophageal reflux, increased risk of gastric cancer, or increased risk of esophageal cancer.

53. The method of claim 52, wherein the at least one gastric surgical procedure is a gastrectomy, an esophagectomy, or a Nissen fundoplication.

54. The method of claim 52, wherein the at least one gastric surgery is at least one bariatric surgery.

55. The method of claim 54, wherein the at least one bariatric surgical procedure is Roux-en-Y gastric bypass (RYGB), vertical sleeve gastrectomy (VSG), or BPD.

56. The method according to any one of claims 34 to 55, wherein the subject has type 2 diabetes.

57. The method according to any one of claims 34 to 56, wherein the pharmaceutical preparation comprises exenatide at a concentration between about 2 and 225 mg / mL.

58. The method according to any one of claims 34 to 57, wherein the pharmaceutical preparation is a buffer solution.

59. The method according to any one of claims 34 to 58, wherein the pharmaceutical preparation is administered subcutaneously.

60. The method according to any one of claims 34 to 59, wherein the pharmaceutical preparation is administered to achieve a total daily dose of exenatide of about 40 mg to about 120 mg.

61. The method according to any one of claims 34 to 60, wherein the pharmaceutical preparation is administered to achieve a total daily dose of exenatide of about 90 mg.

62. The method according to any one of claims 34 to 61, wherein the pharmaceutical preparation is administered to achieve a total daily dose of exenatide of about 0.4 mg / kg to about 3 mg / kg.

63. The method according to any one of claims 34 to 62, wherein the pharmaceutical preparation is administered once daily (QD) or twice daily (BID).

64. The method according to any one of claims 34 to 63, wherein the pharmaceutical preparation is administered once daily (QD) at a dose of about 20 mg to about 120 mg, or about 90 mg.

65. The method of claim 64, wherein the pharmaceutical preparation is administered once daily (QD) at a dose of about 90 mg.

66. The method according to any one of claims 34 to 63, wherein the pharmaceutical preparation is administered twice daily (BID) at a dose of about 40 mg to about 60 mg.

67. The method of claim 66, wherein the pharmaceutical preparation is administered twice daily (BID) at a dose of about 45 mg.

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