Nutritional improvement after gastrointestinal surgery through GLP-1R antagonism

Abstract

A method for improving nutrition in subjects, including individuals who have undergone gastrointestinal surgery, by avexitide therapy is disclosed. Avexitide may be administered subcutaneously or intravenously as part of a liquid pharmaceutical formulation. Avexitide therapy may improve the subject's body weight and / or nutrient intake / nutritional status.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63 / 497,502, filed on 21 April 2023. The entire disclosure of the aforementioned Provisional Application is incorporated herein by reference for all purposes. [Background technology]

[0002] Patients undergoing gastrointestinal (GI) surgery (gastrectomy, esophagectomy, etc.) for the treatment or prevention of malignancies in the upper GI duct generally experience undesirable weight loss in the early postoperative period. This affects over 15% of patients who undergo total gastrectomy and over 35% of patients who undergo esophagectomy. Weight loss and / or low body mass index (BMI) are associated with a worse response to chemotherapy, recurrence, and reduced survival rates. Therefore, preventing weight loss after upper GI surgery in cancer patients is crucial. Low BMI is also associated with increased mortality in non-cancer patients, so the benefits of nutritional improvement in underweight individuals may extend to non-cancer patients as well. [Overview of the Initiative] [Means for solving the problem]

[0003] As used herein, the terms “invention,” “the invention,” “this invention,” and “the present invention” are intended to broadly refer to all the subject matter of this patent application and the following claims. Any statements containing these terms should be understood not to limit the subject matter described herein or the meaning or scope of the following claims. The covered embodiments of the invention are defined by the claims, not by this summary. This summary is a high-level overview of various aspects of the invention, introducing some of the concepts described and illustrated herein and in the accompanying drawings. This summary is not intended to identify any important 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 the entire specification, any or all of the drawings, and the appropriate portions of each claim. Some exemplary embodiments of the invention are discussed below.

[0004] Included in embodiments of the present invention and described herein are, in particular, the following non-limiting exemplary embodiments. Included in embodiments of the present invention are methods for improving the nutrition of a subject, comprising the step of administering a pharmaceutical formulation containing avexitide to the subject, wherein the subject has undergone at least one gastrointestinal surgery. In some embodiments of the above method, administration of the pharmaceutical formulation improves the nutrition of the subject compared to the nutrition of the subject before administration of the pharmaceutical formulation. In some embodiments of the above method, administration of the pharmaceutical formulation increases the nutritional intake of the subject compared to the nutritional intake of the subject before administration of the pharmaceutical formulation. In some embodiments of the above method, administration of the pharmaceutical formulation increases the appetite of the subject compared to the appetite of the subject before administration of the pharmaceutical formulation. In some embodiments of the above method, administration of the pharmaceutical formulation increases the food tolerance of the subject compared to the food tolerance of the subject before administration of the pharmaceutical formulation. In some embodiments of the above method, administration of the pharmaceutical formulation reduces food aversion and / or taste aversion in the subject compared to food aversion and / or aversion in the subject before administration of the pharmaceutical formulation. In some embodiments of the above method, administration of the pharmaceutical formulation reduces food intolerance in the subject compared to food intolerance in the subject before administration of the pharmaceutical formulation. In some embodiments of the above method, administration of the pharmaceutical formulation reduces food avoidance in the subject compared to food avoidance in the subject before administration of the pharmaceutical formulation. In some embodiments of the above method, administration of the pharmaceutical formulation increases the calorie intake in the subject compared to the calorie intake in the subject before administration of the pharmaceutical formulation. In some embodiments of the above method, administration of the pharmaceutical formulation increases eating behavior in the subject compared to eating behavior in the subject before administration of the pharmaceutical formulation. In some embodiments of the above method, administration of the pharmaceutical formulation reduces eating phobia in the subject compared to eating phobia in the subject before administration of the pharmaceutical formulation. In some embodiments of the above method, administration of the pharmaceutical formulation reduces eating anxiety in the subject compared to eating anxiety in the subject before administration of the pharmaceutical formulation.In some embodiments of the above method, administration of the pharmaceutical formulation reduces one or more gastrointestinal symptoms in the subject compared to one or more gastrointestinal symptoms in the subject before administration of the pharmaceutical formulation. In some embodiments of the above method, the subject experiences weight gain or a decrease in the rate of weight loss after administration of the pharmaceutical formulation. In some embodiments of the above method, the subject experiences a relaxation of dietary restrictions after administration of the pharmaceutical formulation. In some embodiments of the above method, administration of the pharmaceutical formulation reduces the incidence of hypoglycemic events after administration of the pharmaceutical formulation.

[0005] Furthermore, embodiments of the present invention include a method for improving nutritional intake in a subject who requires improvement in nutritional intake, comprising administering a pharmaceutical formulation containing abexitide to the subject, wherein the subject undergoes at least one gastrointestinal surgery. Furthermore, embodiments of the present invention include a method for improving appetite in a subject who requires improvement in appetite, comprising administering a pharmaceutical formulation containing abexitide to the subject, wherein the subject undergoes at least one gastrointestinal surgery. Furthermore, embodiments of the present invention include a method for improving food tolerance in a subject who requires improvement in food tolerance, comprising administering a pharmaceutical formulation containing abexitide to the subject, wherein the subject undergoes at least one gastrointestinal surgery. Furthermore, embodiments of the present invention include a method for reducing food aversion and / or taste aversion in a subject who requires reduction in food aversion and / or taste aversion, comprising administering a pharmaceutical formulation containing abexitide to the subject, wherein the subject undergoes at least one gastrointestinal surgery. Furthermore, embodiments of the present invention include a method for reducing food intolerance in a subject who requires reduction of food intolerance, comprising administering a pharmaceutical formulation containing abexitide to the subject, wherein the subject undergoes at least one gastrointestinal surgery. Furthermore, embodiments of the present invention include a method for reducing food avoidance in a subject who requires reduction of food avoidance, comprising administering a pharmaceutical formulation containing abexitide to the subject, wherein the subject undergoes at least one gastrointestinal surgery. Furthermore, embodiments of the present invention include a method for increasing calorie intake in a subject who requires increase in calorie intake, comprising administering a pharmaceutical formulation containing abexitide to the subject, wherein the subject undergoes at least one gastrointestinal surgery. Furthermore, embodiments of the present invention include a method for increasing eating behavior in a subject who requires increase in eating behavior, comprising administering a pharmaceutical formulation containing abexitide to the subject, wherein the subject undergoes at least one gastrointestinal surgery.Furthermore, embodiments of the present invention include a method for reducing eating phobia in a subject who requires a reduction in eating phobia, comprising administering a pharmaceutical formulation containing avexitide to the subject, wherein the subject undergoes at least one gastrointestinal surgery. Furthermore, embodiments of the present invention include a method for reducing eating anxiety in a subject who requires a reduction in eating anxiety, comprising administering a pharmaceutical formulation containing avexitide to the subject, wherein the subject undergoes at least one gastrointestinal surgery. Furthermore, embodiments of the present invention include a method for reducing one or more gastrointestinal symptoms in a subject who requires a reduction in one or more gastrointestinal symptoms, comprising administering a pharmaceutical formulation containing avexitide to the subject, wherein the subject undergoes at least one gastrointestinal surgery. Furthermore, embodiments of the present invention include a method for increasing weight in a subject who requires weight gain, comprising administering a pharmaceutical formulation containing avexitide to the subject, wherein the subject undergoes at least one gastrointestinal surgery. Furthermore, embodiments of the present invention include a method for reducing the rate of weight loss in a subject who requires a reduction in the rate of weight loss, comprising administering a pharmaceutical formulation containing abexitide to the subject, wherein the subject undergoes at least one gastrointestinal surgery. Furthermore, embodiments of the present invention include a method for preventing weight loss in a subject who requires prevention of weight loss, comprising administering a pharmaceutical formulation containing abexitide to the subject, wherein the subject undergoes at least one gastrointestinal surgery. Furthermore, embodiments of the present invention include a method for easing dietary restrictions in a subject who requires relaxation of dietary restrictions, comprising administering a pharmaceutical formulation containing abexitide to the subject, wherein the subject undergoes at least one gastrointestinal surgery. Furthermore, embodiments of the present invention include a method for reducing the incidence of hypoglycemic events in a subject who requires a reduction in the incidence of hypoglycemic events, comprising administering a pharmaceutical formulation containing abexitide to the subject, wherein the subject undergoes at least one gastrointestinal surgery.

[0006] In some embodiments of the method of the present invention, a small number of non-limiting examples are summarized above, the administration of the pharmaceutical formulation reduces the incidence of hypoglycemic events in subjects after administration of the pharmaceutical formulation. In some embodiments of the method of the present invention, prior to administration of the pharmaceutical formulation, subjects have elevated levels of glucagon-like peptide 1 (GLP1) compared to reference population levels. In some embodiments of the method of the present invention, subjects have been diagnosed with one or more of the following prior to at least one gastric surgery: gastric cancer, esophageal cancer, gastroesophageal reflux disease, increased risk of gastric cancer, or increased risk of esophageal cancer. In some non-limiting examples, at least one gastric surgery is a gastrectomy, esophagectomy, or Nissen fundoplication. In some non-limiting examples, at least one gastric surgery is, but is not limited to, a Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (VSG), or bariatric surgery such as biparietal dissection (BPD). In some embodiments of the method of the present invention, subjects have type 2 diabetes mellitus.

[0007] In some embodiments of the method of the present invention, the pharmaceutical formulation administered to a subject contains avexitide at a concentration of about 2 to 225 mg / mL. In some embodiments of the method of the present invention, the pharmaceutical formulation is a buffer formulation. In some embodiments of the method of the present invention, the pharmaceutical formulation is administered subcutaneously. In some embodiments of the method of the present invention, the pharmaceutical formulation is administered to achieve a total daily dose of avexitide from about 40 mg to about 120 mg. In some embodiments of the method of the present invention, the pharmaceutical formulation is administered to achieve a total daily dose of avexitide of about 90 mg. In some embodiments of the method of the present invention, the pharmaceutical formulation is administered to achieve a total daily dose of avexitide from about 0.4 mg / kg to about 3 mg / kg. In some embodiments of the method of the present invention, the pharmaceutical formulation is administered once daily (QD) or twice daily (BID). In some embodiments of the method of the present invention, the pharmaceutical formulation is administered once daily (QD) in doses from about 20 mg to about 120 mg, or about 90 mg. In some embodiments of the method of the present invention, the pharmaceutical formulation is administered once daily (QD) at a dose of about 90 mg. In some embodiments of the method of the present invention, the pharmaceutical formulation is administered twice daily (BID) at a dose ranging from about 40 mg to about 60 mg. In some embodiments of the method of the present invention, the pharmaceutical formulation is administered twice daily (BID) at a dose of about 45 mg. The embodiments summarized in this section and other embodiments of the present disclosure are described in detail below.

[0008] This disclosure includes the following figures. The figures are intended to illustrate certain embodiments and / or features of the embodiments of the present invention and to supplement any(s) of the embodiments of the present invention. The figures do not limit the scope of the embodiments of the present invention unless expressly indicated to that effect in the written description. [Brief explanation of the drawing]

[0009] [Figure 1]This is a schematic diagram of the design of the Phase 2 7-day clinical evaluation study (Study A) of avexitide (as disclosed herein) aimed at improving eating behavior in cancer patients who have undergone total gastrectomy or esophagectomy. The clinical evaluations performed were the buffet test, MMTT, and surveys (VAS, SHS, CNAQ, GSRS, HFS-II, SF-36). Outpatient evaluations over 10 days were performed using Dexcom pro blinded CGM and chronometer. [Figure 2] This is a schematic diagram of the design of the Phase 2 28-day clinical evaluation study (Study B) of avexitide (as disclosed herein) aimed at improving nutritional status and preventing undesirable weight loss in cancer patients undergoing total gastrectomy or esophagectomy. The clinical evaluations performed included anthropometric measurements, body composition by BIA, DEXA, or CT, buffet tests using VAS and CNAQ, MMT using EHSS, and surveys (SHS, GSRS, HFS-II, SF-36). Outpatient evaluations over 10 days were performed using Dexcom pro blinded CGM and chronometer. [Figure 3] This is a schematic diagram of the design of the Phase 2 28-day clinical evaluation study (Study C) of avexitide therapy in patients with severe hypoglycemia following gastrointestinal surgery, including Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (VSG), esophagectomy, gastrectomy, and Nissen fundoplication (JFCP). Patients received avexitide at a dose of 90 mg for 2 weeks on a quarterly dose (QD), followed by 45 mg for 2 weeks on a bilateral dose (BID), or 45 mg for 2 weeks on a bilateral dose (BID), followed by 90 mg for 2 weeks on a quarterly dose (QD). Each study arm had 8 patients. Assessments at baseline, end of Phase 1, and end of Phase 2 included anthropometric measurements (weight, height, BMI)*, surveys (SHS*, GSRS*, HFS-II*, SF-36, EQ-5D), and laboratory tests. *Assessments are relevant only to patients who have undergone gastrectomy or esophagectomy. [Figure 4]This bar graph shows the selection results, i.e., the percentage of time spent hypoglycemic, from the Phase 2 28-day clinical evaluation trial (Trial C) of avexitide therapy in patients with severe hypoglycemia following gastrointestinal surgery, including RYGB, VSG, esophagectomy, gastrectomy, and Nissen fundoplication (as disclosed herein). The percentage of time spent hypoglycemic by trial participants is plotted on the y-axis. The bars represent the following: black represents baseline, white represents avexitide 45 mg BID (twice daily), and gray represents avexitide 90 mg BID. [Figure 5] This bar graph shows the selection results of the (as disclosed) Phase 2 28-day clinical evaluation trial of avexitide therapy in patients with severe hypoglycemia following gastrointestinal surgery, including RYGB, VSG, esophagectomy, gastrectomy, and Nissen fundoplication, i.e., the number of hypoglycemic events over 14 days ("event rate"). The number of hypoglycemic events recorded over 14 days in trial participants is plotted on the y-axis. The bars are defined as follows: black represents baseline, white represents avexitide 45 mg BID administration, and gray represents avexitide 90 mg BID administration. The percentage of hypoglycemic time was defined as the total time during which continuous glucose monitoring (CGM) readings were below 70 mg / L or 54 mg / dL divided by the total CGM wearing time. The event rate was defined as the number of occurrences during each 14-day normalized treatment period in which glucose levels were below the 70 mg / dL or 54 mg / dL range for at least 15 minutes. [Figure 6]This bar graph shows the selection results of the (as disclosed) Phase 2 28-day clinical evaluation trial of avexitide therapy in patients with severe hypoglycemia following gastrointestinal surgery, including RYGB, VSG, esophagectomy, gastrectomy, and Nissen fundoplication, specifically the number of daytime hypoglycemic events ("daytime event rate") over 14 days. The number of daytime hypoglycemic events recorded over 14 days in trial participants is plotted on the y-axis. The bars are defined as follows: black represents baseline, white represents avexitide 45 mg BID administration, and gray represents avexitide 90 mg BID administration. The event rate was defined as the number of occurrences in which glucose levels fell below the glucose range (70 mg / dL or 54 mg / dL) for at least 15 minutes during each treatment period normalized to 14 days. Daytime events were defined as events beginning at 8 a.m. and occurring by 10 p.m. [Figure 7] This bar graph shows the selection results of the (as disclosed) Phase 2 28-day clinical evaluation trial of avexitide therapy in patients with severe hypoglycemia following RYGB, VSG, and gastrectomy (as shown), i.e., the percentage of time spent hypoglycemic with a CGM value < 70 mg / dL. The percentage of time spent hypoglycemic by trial participants is plotted on the y-axis. The bars are as follows: black represents baseline, white represents BID of 45 mg of avexitide, and gray represents BID of 90 mg of avexitide. [Figure 8] This bar graph shows the selection results of the (as disclosed) Phase 2 28-day clinical evaluation trial of avexitide therapy in patients with severe hypoglycemia following RYGB, VSG, and gastrectomy (as shown), i.e., the percentage of time spent hypoglycemic with a CGM value < 54 mg / dL. The percentage of time spent hypoglycemic by trial participants is plotted on the y-axis. The bars are as follows: black represents baseline, white represents BID of 45 mg of avexitide, and gray represents BID of 90 mg of avexitide. [Figure 9]This bar graph shows the selection results of the (as disclosed) Phase 2 28-day clinical evaluation trial of avexitide therapy in patients with severe hypoglycemia following RYGB, VSG, and gastrectomy (as shown), i.e., the percentage of time spent hypoglycemic with a CGM value < 40 mg / dL. The percentage of time spent hypoglycemic by trial participants is plotted on the y-axis. The bars are as follows: black represents baseline, white represents BID of 45 mg of avexitide, and gray represents BID of 90 mg of avexitide. [Figure 10] This is a line graph showing the selection results of the animal studies described herein, namely the body weight of male animals. Body weight in grams is plotted on the x-axis. The plots are for four different groups of animals administered different abexitide dose levels, as described in Example 5 of this disclosure. [Figure 11] This is a line graph showing the selection results of the animal studies described herein, namely the body weight of female animals. Body weight in grams is plotted on the x-axis. The plots are for four different groups of animals administered different avexitide dose levels, as described in Example 5 of this disclosure. [Modes for carrying out the invention]

[0010] overview This disclosure describes a method of improving the nutrition of a subject by administering a pharmaceutical formulation containing a GLP-1 antagonist, such as avexitide, to the subject. Individuals undergoing gastrointestinal (GI) surgery, such as (but not limited to) gastrectomy or esophagectomy, performed in some cases for the treatment or prevention of malignancies of the upper gastrointestinal tract, may experience rapid and undesirable weight loss in the postoperative period, particularly in the early postoperative period. In patients undergoing cancer treatment, weight loss and / or low body mass index (BMI) has been associated with a worse response to chemotherapy, recurrence, and reduced survival rates. Undesirable or excessive weight loss can also afflict individuals undergoing upper GI surgery, including but not limited to Nissen fundoplication and bariatric surgeries such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (VSG), for indications other than malignancies. While low body weight in these individuals does not necessarily lead to increased mortality, malnutrition associated with insufficient intake of calories, protein, or carbohydrates can cause muscle atrophy, fatigue, muscle weakness / exercise intolerance, and mood changes such as depression. The reasons for weight loss are not fully understood. For example, postprandial GI symptoms (nausea, early satiety, heartburn, indigestion, or abdominal bloating, etc.) are common in patients after GI surgery. Patients after GI surgery may also experience slow gastric passage and / or gastric stasis (gastroparesis), which can be accompanied by vomiting. Patients may also experience decreased appetite and aversion to taste, as well as anxiety and fear regarding hypoglycemia. Some patients may have elevated levels of glucagon-like peptide-1 (GLP-1), GIP, and / or PYY, which, among other things, promote insulin secretion and satiety, and / or inhibit gastric emptying, thereby reducing food consumption. Any or all of the above factors can lead to food avoidance and reduced food intake. Such factors contribute to nutritional deficiencies in patients after GI surgery, leading to weight loss, prevention of weight recovery, and / or malnutrition.In particular, the inventors of this invention conceived that the targeted antagonism of the GLP-1 receptor by abexitide is useful as a treatment to improve nutrition in patients after GI surgery.

[0011] The inventors unexpectedly discovered that administration of abexitide in patients after GI surgery can lead to improved nutrition in patients, including, but not limited to, prevention of undesirable weight loss in the early postoperative period or improvement in weight recovery, reduction of gastrointestinal symptoms, relaxation of dietary restrictions with improved nutrition / improvement of nutrient intake, improvement of appetite and eating attitude, reduction of taste aversion, and reduction of related behaviors, including hypoglycemia phobia and food avoidance. The inventors also made the surprising discovery that administration of abexitide in patients after GI surgery actively affected appetite (i.e., increased appetite was observed) and also affected GI symptoms (i.e., reduction of GI symptoms was observed), and that these patients were a severely underweight group after GI surgery who were at high risk of malnutrition, and consequently poor outcomes in morbidity and mortality, and / or poor response to cancer treatments such as chemotherapy. Therefore, the inventors have hypothesized that nutritional improvement through avexitide administration can improve patients' quality of life, enhance their psychological well-being, prevent weight gain and / or undesirable weight loss, reduce postprandial hypoglycemia, decrease GI symptoms, reduce the need for long-term gastrostomy tube feeding, reduce the need for strict carbohydrate restriction, improve psychological well-being, and potentially lead to improved response to chemotherapy and extended survival.

[0012] Compared with medical nutrition treatments such as gastric fistula tube nutrition and intravenous nutrition, administration of abexinotide is less invasive, easy for self - administration, has fewer potential side effects such as increased risk of local and systemic infections, malposition, or occlusion, and provides higher autonomy and higher psychological acceptability. The examples provided herein demonstrate that subcutaneous administration of abexinotide in individuals undergoing upper GI surgery for cancer likely mitigates the influence of supra - physiological GLP - 1 concentrations resulting from surgery (GI side effects due to changes in central satiety, motility, and gastric regulation, as well as severe reactive hypoglycemia), thereby preventing undesirable weight loss. Therefore, the inventors have devised that GLP - 1 receptor antagonist administration using, for example, abexinotide, a GLP - 1 antagonist, according to the methods of the present disclosure, should be incorporated into the multidisciplinary approach to the treatment of patients after GI surgery.

[0013] Terms and Concepts Several terms and concepts are discussed below. These are intended to facilitate the understanding of various embodiments of the present invention in conjunction with the remainder of this specification and the accompanying drawings. These terms and concepts can be further clarified and understood based on the accepted conventions in the field of the present invention and the explanations provided throughout this specification and / or the accompanying drawings. Some other terms can be defined explicitly or implicitly in other sections of this specification and the accompanying drawings and can be used and understood based on the accepted conventions in the field of the present invention and the explanations provided throughout this specification and / or the accompanying drawings. Terms not explicitly defined are defined and understood based on the accepted conventions in the field of the present invention and can also be interpreted in the context of this specification and / or the accompanying drawings.

[0014] Unless otherwise defined in context, singular terms shall include the plural and plural terms shall include the singular. In general, the nomenclature used when describing the methods of the present invention is well-known and commonly used. Unless otherwise indicated, known methods and techniques are generally carried out according to well-known conventional methods and as described in various general and more specific references.

[0015] All numerical designations, including ranges, e.g., pH, temperature, time, concentration, and molecular weight, are approximate values that change (+) or (-) in increments of 0.1 or 1.0 as necessary (e.g., pH 5.4 or 5.5). Although not always explicitly stated, it should be understood that the term "about" precedes all numerical designations. Unless otherwise specified, references to ranges include the endpoints. For example, administration of abecitide at a concentration 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 sub-ranges of the present disclosure as if explicitly recited.

[0016] As used herein, the terms “about” and “approximately” generally mean the degree of acceptable error in a measured quantity, taking into account 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 range of values. For example, any reference to “about X” or “approximately X” specifically refers to at least the values ​​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 example, the terms “about” or “approximately” with respect to a base number can include a range of plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that value. Thus, the expression “about X” or “approximately X” is intended to illustrate a limitation in the claimed range, such as “0.98X.” The quantities given in this disclosure are approximations unless otherwise stated, meaning that the terms “about” or “approximately” can be inferred even if not explicitly stated. When the terms “about” or “approximately” are applied to the beginning of a numerical range, they also apply to both ends of that range. When the terms “about” or “approximately” are preceded by a set of values, these terms are intended to modify each value included in that set.

[0017] Where used in this disclosure, the terms "a," "an," and "the" may refer to one or more unless otherwise specified. For example, a reference to "one compound" may include multiple compounds.

[0018] The use of the term “or” is used to mean “and / or” unless it is explicitly indicated that it refers only to the choices or the choices are not mutually exclusive, but this disclosure supports the definitions that refer only to the choices and “and / or.” Where used in this disclosure, “another” may mean at least a second or more.

[0019] Where used in this disclosure, unless otherwise indicated, the terms “include,” “including,” and, as may be similar terms (such as “have” or “having”) mean “comprising.” The term “comprising” is intended to mean that the compounds, compositions, and methods include the enumerated elements but do not exclude other elements. “Essentially consisting of,” when used in defining compounds, compositions, and methods, means excluding other elements that would materially affect the basic and novel characteristics of the claimed invention. “Consists of,” means excluding any elements, steps, or components not specified in the claims. Embodiments defined by each of these transitional terms are within the scope of this invention.

[0020] "Abexitide" is also called "Exendin (9-39)", and its empirical formula is C 149 H 234 N 40 O 47S refers to a 31-amino acid peptide with a molecular weight of 3369.8 daltons. Abexitide is a GLP-1 receptor antagonist that contains residues 9-39 of exendin-4, a GLP-1 receptor agonist, and possesses inverse agonist properties. See Montrose-Rafizadeh et al. (1997). The amino acid sequence of abexitide is shown as 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-Ser-NH2 (SEQ ID NO: 1). Abexitide has a predicted isoelectric point of 4.69, a net charge of -1 at pH 6, and an increase to +4 at pH 3.0. As used herein, the term “avexitide” also includes, but is not limited to, pharmaceutically acceptable salts of avexitide (exendin(9-39)), including sulfates, hydrochlorides, phosphates, sulfamates, acetates, citrates, lactates, tartrates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, cyclohexylsulfamates, and quinates. In some embodiments, avexitide is in the form of an acetate or trifluoroacetate. Unless otherwise specified herein, avexitide acetate is used. Avexitide (exendin(9-39)) and its pharmaceutically acceptable salts are commercially available.

[0021] As used herein, the terms “formulation” or “pharmaceutical formulation,” as well as other related terms and expressions, refer to a composition suitable for administration to a subject. Pharmaceutical formulations may be sterile and preferably free from contaminants that could cause undesirable reactions in a subject. The compounds contained in pharmaceutical formulations are typically pharmaceutical grade. Pharmaceutical compositions can be designed to be administered to a subject or patient in need through several different routes of administration, including oral, intravenous, oral cavity, rectal, parenteral, intraperitoneal, intradermal, intramuscular, subcutaneous, and inhalation. In some embodiments, the pharmaceutical formulations described herein are formulated for subcutaneous or intravenous administration.

[0022] As used herein, “therapeutic dose” means the amount of the active ingredient (e.g., avexitide or a pharmaceutically acceptable salt thereof) that eliminates, alleviates, reduces or soothes symptoms or produces the clinical outcome for which the administration is intended.

[0023] As used herein, the terms “administer,” “in administration,” and “dosage” (and related terms and expressions) refer to the introduction of a compound (e.g., avexitide), composition, or drug into a subject or patient, such as a human. As used herein, these terms encompass both direct administration (e.g., self-administration or administration to a patient by a healthcare professional) and indirect administration (e.g., the act of prescribing a compound or composition to a subject).

[0024] "QD" and "BID" have the usual meanings of administering the composition (e.g., a buffered preparation of avexitide) once or twice daily, respectively. In some embodiments, once-daily (QD) administration means that at least 20 hours, at least 22 hours, or about 24 hours elapse between administrations. In some embodiments, once-daily administration means administration approximately every 24 hours. In some embodiments, twice-daily (BID) administration means that at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 11 hours, or about 12 hours elapse between administrations. In some embodiments, twice-daily administration means administration approximately every 12 hours.

[0025] As used herein, the terms “individual,” “patient,” and “subject” are interchangeable to refer to an individual (e.g., human or non-human mammal). The terms “individual,” “subject,” and “patient” do not, by themselves, indicate a specific age, sex, race, or clinical condition. The methods described herein may be applied to any race, including, for example, Caucasians (white), African Americans (black), Native Americans, Native Hawaiians, Hispanics, Latinos, Asians, and Europeans.

[0026] "Gastric emptying," "removal of gastric contents," and related expressions refer to the process by which stomach contents leave the stomach. In healthy subjects, stomach contents move to the duodenum for absorption in the small intestine. The rate or time of gastric emptying is the time it takes for food to be completely emptied from the stomach and can be measured by various appropriate tests, such as scintigraphy. For example, the rate of gastric emptying in healthy human subjects is approximately 1.5 to 2 hours, which means the time it takes for stomach contents to leave the stomach and move into the small intestine. Delayed gastric emptying may be called "gastroparesis." Gastric emptying is discussed, for example, in Maurer et al. (2021).

[0027] The glucagon-like peptide 1 receptor (GLP1R) is a seven-transmembrane protein that functions as a receptor for the glucagon-like peptide 1 (GLP-1) hormone and stimulates glucose-induced insulin secretion. GLP1R is internalized in response to GLP-1 and GLP-1 analogs and plays a crucial role in the signaling cascade leading to insulin secretion. See, for example, Brubaker et al. (2002).

[0028] Glucagon-like peptide 1 (GLP-1) is a 30 or 31-amino acid amino acid peptide hormone produced by differential processing of proglucagon in intestinal epithelial endocrine L cells, and its gene is expressed in these cells. GLP-1 is an endogenous incretin hormone secreted from L cells of the distal small and distal large intestines in response to intraluminal nutrients. As discussed by Holst (2007), GLP-1 is known to have a variety of physiological effects, including stimulation of insulin secretion, inhibition of glucagon secretion, inhibition of gastrointestinal motility, and promotion of satiety. High GLP-1 concentrations can alter gastrointestinal motility and gastric regulation, promoting anorexia, nausea, acid reflux, and abdominal distension, and thus potentially enhancing weight loss. Satiety is the result of several processes, including vagus nerve stimulation, gastric dilation, and effects on the central nervous system. GLP-1 receptors are present in many parts of the brain, including areas involved in regulating feeding and energy balance. Injection into the rat brain suppresses feeding activity, and this effect is inhibited by co-injection of exendin 9-39 (a GLP-1 antagonist) (Turton 1996). Rodent data have demonstrated that GLP-1 also promotes altered taste perception and may further promote weight loss. In humans, administration of synthetic GLP-1 analogs effectively induces weight loss of up to 15% of body weight. High GLP-1 concentrations can also promote excessive postprandial insulin secretion, which contributes to long-term remission of diabetes in 85% of patients treated with RYGB. However, in a subset of patients, very high GLP-1 levels cause dysregulation of insulin secretion and hypoglycemia (Salehi (2014)), and these symptoms are severe and frequent, which can lead to food avoidance, carbohydrate deficiency, and weight loss. Similar to what was observed after RYGB, GLP-1 levels can also be elevated after other upper gastrointestinal surgeries. In particular, several studies have shown a 3- to 5-fold increase in GLP-1 levels after gastrectomy and esophagectomy, which is associated with dumping syndrome and hyperinsulinic hypoglycemia. Therefore, the antagonism of GLP-1 in situations where undesirable weight loss frequently occurs, such as after upper gastrointestinal surgery with high GLP-1 levels, presents an attractive therapeutic possibility.However, the success of such treatments is unclear, and one previous study in which patients who had undergone bariatric surgery were given intravenous infusion of exendin 9-39 or saline for 240 minutes followed by a free-choice buffet meal test did not demonstrate an increase in food intake with the administration of exendin 9-39 (Kittah et al. (2020)).

[0029] Treatment method This disclosure describes a method for improving the nutrition of a subject, which involves administering a pharmaceutical formulation containing avexitide (which may be referred to as "avexitide formulation") to the subject. Appropriate pharmaceutical formulations are described elsewhere in this disclosure. The method for improving the nutrition of a subject according to this disclosure may be referred to as "treatment method," "avexitide therapy," and other relevant terms and expressions. When used according to embodiments of the present invention, avexitide can exert its therapeutic effect through a variety of mechanisms. Some of these mechanisms are discussed below, but are not intended to limit any of the methods described in this disclosure. It should be understood that one or more mechanisms of action of avexitide may be involved in the treatment methods described in this disclosure.

[0030] For example, abexitide may improve nutrition in patients after GI surgery by preventing taste aversion and GLP-1R-mediated satiety through a central nervous system (CNS) mechanism. Results from several animal studies support the idea that the weight-loss / appetite-suppressing effect of GLP-1 is CNS-mediated. In a study reported by Sisley et al. (2014), GLP-1R knockout mice ingested less food than wild-type mice, but did not lose weight even when administered liraglutide (a GLP-1 agonist), suggesting that the weight-loss / appetite-suppressing effect of GLP-1 agonism is via a CNS-mediated mechanism. As reported by Martin et al. (2009), GLP-1R knockout mice have shown a dramatic decrease in sweetness sensitivity and an increase in sensitivity to umami stimuli. The animal data reported in the above studies suggest that while GLP-1 receptors are not required for normal food intake or weight regulation, GLP-stimulating / agonizing effects on the CNS are necessary for weight loss / appetite suppression. Several studies have shown that GLP-1R antagonism does not stimulate appetite, increase feeding behavior, or cause weight gain. Melhorn et al. (2014) reported a study on avexitide or placebo infusions in subjects with normal weight and showed that GLP-1R blockade failed to suppress satiety or increase feeding behavior in the subjects. Kulve et al. (2017) reported the effect of RYGB on CNS activation in response to visual and gustatory food cues, which may be mediated by the central action of GLP-1, but did not evaluate feeding behavior in response to such visual and gustatory cues. However, a study described by Kittah et al. (2020) investigated GI symptoms and carbohydrate intake in patients after GI surgery (RYGB patients and VSG patients) versus weight-matched non-surgical controls, with and without the presence of abexitide. While there was no change in carbohydrate intake or the occurrence of GI symptoms in surgical patients, carbohydrate intake decreased in non-surgical controls with abexitide.Considering the above tests, the inventors' discovery of avexitide therapy, which improves nutrition in patients after GI surgery, is both surprising and unexpected.

[0031] Abexitide may improve nutrition in patients after GI surgery by reducing GI symptoms such as nausea, indigestion, heartburn, and early satiety. Abexitide may also improve nutrition in patients after GI surgery by alleviating fear associated with food intake and / or reducing food avoidance. The reduction in GI symptoms may occur, at least in part, through parasympathetic nervous system-mediated mechanisms, such as the vagus nerve. The reduction in GI symptoms may also occur, at least in part, due to an increase in the rate of nutrient passage through the GI duct after abexitide administration. It has been previously shown that abexitide administration after RYGB promotes gastric emptying. In a study reported by Shah et al. (2014), abexitide administration significantly increased the gastric emptying rate of radiolabeled solid food during the first 45 minutes after food intake in 12 RYGB patients, but not in 8 age, sex, and weight-matched controls. However, improvement in GI symptoms after abexitide administration has not been reported in patients after GI surgery. Furthermore, avexitide can improve nutritional intake in patients after GI surgery by alleviating fear of hypoglycemia and associated food avoidance. For example, hypoglycemia phobia is common in patients with insulin-dependent diabetes. There is data supporting a reduction in hypoglycemia-related anxiety and behaviors after avexitide administration (some of which are included in this disclosure).

[0032] Embodiments of the therapeutic methods described herein may result in nutritional improvement in subjects receiving avexitide therapy. In the context of this disclosure, the term “nutrition” broadly encompasses objectively measurable and / or subjectively experienced nutrient intake and various aspects of eating. The term “nutrition” encompasses, but is not limited to, the processes by which a subject consumes (takes in, consumes, or inhales) nutrients, particularly the eating process including chewing and swallowing, as well as the different stages of nutrient utilization, including various aspects such as digestion, nutrient absorption, and excretion. The term “nutrition” also encompasses, but is not limited to, the results of nutrient intake and utilization, such as the subject’s nutrient intake and the subject’s nutritional status. For example, a subject may experience, or be expected to experience, undesirable weight loss after undergoing GI surgery, as discussed elsewhere in this disclosure. In another example, a subject may need to prevent undesirable weight loss after undergoing GI surgery. In another example, a subject may be malnourished or expected to be malnourished (with or expected to be malnourished, as discussed elsewhere in this disclosure) due to impairment in one or more aspects of nutrition. In yet another example, a subject may have or be expected to have malnutrition (as discussed elsewhere in this disclosure), whether or not they are malnourished, after GI surgery. In yet another example, a subject may have or be expected to have cachexia and / or sarcopenia (both as discussed elsewhere in this disclosure) after GI surgery. In yet another example, a subject may need or desire a relaxation of dietary restrictions, as discussed elsewhere in this disclosure.

[0033] In the context of this disclosure, “nutrient intake” broadly encompasses the components of food consumed by a subject. In this context, food components (which may also be called “nutrient components”) encompass various aspects of the food components consumed by a subject, such as calorie content, macronutrient content consumed by the subject (e.g., the amount of one or more carbohydrates, proteins, fats, dietary fiber, fatty acids, cholesterol, amino acids, and water), and micronutrient content consumed by the subject (e.g., the amounts of various vitamins and minerals). “Improved nutrient intake” indicates an improvement in the food components consumed by a subject. For example, improved nutrient intake is an increase in the calorie content consumed by a subject due to one or more of the following: an increase in the total calories consumed by the subject over a period of time (e.g., per meal, per day, per week, per month), or an improvement in the digestion and / or absorption of the food components consumed.

[0034] In addition to nutrient intake, the term “nutrition” as used in this disclosure also encompasses the subject’s nutritional status, as well as their subjective experiences and attitudes toward food and eating. Thus, “improvement in nutrition” encompasses various improvements in the subject’s nutritional status, as well as improvements in their subjective experiences, attitudes, and behaviors toward food and eating. The subject’s nutritional status can be determined based on objective indicators such as body weight, body mass index (BMI), body composition (including the subject’s body fat and muscle content), and blood levels of various macronutrients and micronutrients.

[0035] In the context of this disclosure, the term “nutrition” also encompasses subjective experiences, feelings, behaviors, and attitudes toward food and eating. Subjective feelings, experiences, and attitudes can manifest in various ways, including taste (e.g., whether the subject perceives food as good or bad), appetite (which may be rated as “very bad,” “bad,” “average,” “good,” or “very good,” or on a numerical scale), satiety during or after a meal and / or throughout the day, hunger during or after a meal and / or throughout the day, mood associated with food consumption (e.g., mood during a meal), food aversion, eating phobia, and anxiety associated with food consumption. Subjective experiences may also include various GI symptoms and physical reactions experienced before, during, or after food consumption. Such GI symptoms and physical reactions may be physiological, psychogenic, or both. For example, a subject may experience nausea and, in some cases, vomiting after swallowing food. In another example, a subject may experience indigestion (undigestion) after consuming food, including abdominal discomfort described as burning, bloating or gas, and / or nausea. In yet another example, a subject may experience heartburn after consuming food. In yet another example, a subject may experience fullness (satiety) shortly after starting a meal. Subjective experiences, including various GI symptoms and physical reactions, can be triggered by one or more specific foods, by all foods, by the process of eating, or even by the idea of ​​eating. GI symptoms and unpleasant physical reactions are triggered by specific foods and may be described as “food intolerance” to these foods. Conversely, “food tolerance” is the ability to eat a variety of foods without experiencing GI symptoms and unpleasant physical reactions. Higher or lower food tolerance may represent the number of foods (range of foods) a subject can tolerate, or it may include the amount of specific foods that a subject can tolerate. For example, a subject who can consume a higher amount of dairy products than other subjects without experiencing GI symptoms and unpleasant physical reactions may have a higher dairy tolerance. Subjective experiences, feelings, and attitudes toward food and eating include food aversion, which is a very strong aversion to specific foods or food in general.In cases of food aversion, the appearance, smell, taste, or even the thought of food (general food or specific food(s)) can cause subjects to experience feelings of disgust and, in some cases, unpleasant reactions such as nausea. Higher or lower levels of food aversion may describe how many foods(s) the subject experiences aversion to.

[0036] Subjective experiences, feelings, behaviors, and attitudes regarding food and eating include food avoidance, which means that a subject may limit their food intake by quantity and / or type (avoidance of specific foods), resulting in malnutrition and negative health outcomes. Food avoidance may be based on the 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 may explain the level of restriction on the quantity and / or type of food consumed by the subject. Subjective experiences, feelings, behaviors, and attitudes regarding food and eating also include eating phobia, which means that a subject fears consuming food in general or specific foods. Eating phobia may manifest as physiological symptoms of fear and / or panic, such as increased heart rate, faster breathing or shortness of breath, sweating, and tremors. Higher or lower levels of eating phobia may explain the level (intensity) of the subject's phobia symptoms. Subjective experiences, feelings, behaviors, and attitudes related to food and eating include eating anxiety, which means that a subject worries about (experiences anxiety about) consuming food in general or specific foods. Eating anxiety can arise from 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 fear of eating anxiety can explain not only the level (intensity) of the subject's anxiety, but also the number of foods and situations that trigger eating anxiety. An example of food and eating behavior is eating behavior, which broadly encompasses the timing of meals, including the frequency of meals, the amount of food consumed, and food preferences and choices. Higher or lower levels of eating behavior may encompass one or more of the frequency of meals, the amount of food consumed, and the variety of foods consumed. In one example, embodiments of the therapeutic methods described herein may result in improvement or increase of eating behavior.

[0037] As discussed throughout this disclosure, administering a pharmaceutical formulation containing avexitide to a subject may result in nutritional improvements including, but not limited to, nutrient intake, nutritional status, and attitudes, behaviors, and subjective experiences with food and meals. It should be understood that improvements following administration of avexitide therapy (which may be described as increases or decreases in various observable or subjectively experienced indicators and effects) are compared to various control values, e.g., the corresponding control values ​​in the same subject before the initiation of avexitide therapy. For example, in some embodiments, treatment of a subject with the avexitide therapy described in this disclosure improves the subject's nutrition compared to the subject's nutrition before administration of avexitide therapy. In another example, in some embodiments, treatment of a subject with the avexitide therapy described in this disclosure improves the subject's nutrient intake compared to the subject's nutrient intake before administration of avexitide therapy. In yet another example, a subject treated with the avexitide therapy described in this disclosure experiences an increase in body weight or a decrease in weight loss rate compared to the subject's body weight or weight loss rate before administration of avexitide therapy.

[0038] In some embodiments, treatment of a subject with avexitide therapy as described in this disclosure results in one or more effects, including but not limited to increased appetite, increased food tolerance, reduced food intolerance, decreased food avoidance, reduced food aversion, increased calorie intake, increased eating behavior, relaxation of dietary restrictions, reduced eating phobia, or reduced eating anxiety, including but not limited to concerns about hypoglycemia. Accordingly, some embodiments of the methods described in this disclosure may be referred to as methods for increasing or improving appetite, increasing or improving food tolerance, reducing food intolerance, decreasing food avoidance, reducing food aversion, increasing calorie intake, increasing eating behavior, relaxing dietary restrictions, reducing eating phobia, or reducing eating anxiety, including but not limited to concerns about hypoglycemia. In some embodiments, treatment of a subject with avexitide therapy as described in this disclosure results in prevention of weight gain and / or postoperative weight loss (e.g., a loss of more than 10% of preoperative weight). Accordingly, 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, and so on. In some embodiments, treatment of a subject with the abexitide therapy 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, and water content) or physical capacity (e.g., total activity level and / or grip strength). Accordingly, some embodiments of the methods described in this disclosure may be referred to as methods for preventing or mitigating sarcopenia, or methods for preventing or mitigating sarcopenic cachexia. In some embodiments, treatment of a subject with the abexitide therapy described in this disclosure results in one or more effects, including improved taste and / or perception of one or more foods, improved mood during, after, and / or throughout the day, reduced anxiety about food and meals, or improved overall well-being.Accordingly, some embodiments of the methods described in this disclosure may be referred to as methods for improving taste and / or perception of one or more foods, methods for improving mood during, after, and / or throughout the day, methods for reducing anxiety about food and meals, or methods for improving well-being. In some embodiments, treatment of a subject with the avexitide therapy described in this disclosure results in a reduction of one or more GI symptoms, such as nausea, indigestion, or heartburn. Accordingly, 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 the avexitide therapy results in an increase in the movement of food through the subject's GI duct (which may, in some cases, be referred to as an increase in gastric emptying in this disclosure). Accordingly, some embodiments of the methods described in this disclosure may be referred to as methods for improving or increasing the speed of food movement through the GI duct, or methods for increasing or improving gastric emptying.

[0039] In some embodiments, the therapeutic effect on a subject by the methods of this disclosure can be monitored by and / or by various physiological measures. In one example, levels of various biomarkers are measured by various tests, such as blood tests. An example of a biomarker for measuring nutritional status is serum albumin levels. Physical ability can be measured by total activity and / or grip strength. In another example, body weight or body mass index can be measured by various applicable procedures. For example, body weight or body mass index can be measured immediately after and at various points thereafter to monitor the degree of weight loss after GI surgery, such as total gastrectomy or esophagectomy. Body weight or body mass index measured as a baseline immediately after GI surgery can serve as a baseline for monitoring weight loss. In yet another example, nutritional status can also be measured by quantifying the major nutrient components of the diet using various tools, such as diaries and computer / smartphone applications, some examples of these tools are discussed elsewhere in this disclosure. The therapeutic effect on a subject by the methods of this disclosure may result in one or more of the following: relaxation of dietary restrictions, increased carbohydrate intake, and improved macronutrient balance.

[0040] In another example, a reduction in the number (or incidence) of hypoglycemic events, i.e., an overall reduction or a reduction in daytime hypoglycemic events ("daytime" is defined as events that begin, for example, at 8 a.m. and occur by 10 p.m.), can be measured, for example, as the number of daytime hypoglycemic events occurring over a specific period. For example, the period could be from 1 to 20 days, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 16, 17, 18, 19, or 20 days. The period can also exceed 20 days, for example, 20-100 days, 20-50 days, 20-25 days, etc. A hypoglycemic event can be defined as the number of occurrences of a specified glucose level, for example, 70 mg / L, 54 mg / dL, or 40 mg / dL. The proportion of hypoglycemic time can be defined, for example, as the total time during which continuous glucose monitoring (CGM) readings fall 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 rate can also be measured by CGM and in this case can be defined as the number of occurrences in each period during which the glucose level falls below a defined level, e.g., 70 mg / L, 54 mg / dL, or 40 mg / dL, for at least 15 minutes. Treatment of subjects using the methods of this disclosure may result in a reduction of at least approximately 10%, at least approximately 20%, at least approximately 30%, at least approximately 40%, and at least approximately 30% in the incidence of hypoglycemic events in treated subjects.

[0041] It should be understood that changes (increases or decreases) in the effect of avexitide therapy can be measured in comparison to various control values, for example, to the corresponding control value in the same subject before the initiation of avexitide therapy. Other types of control values, such as placebo controls, may also be used. In one example, a placebo control is used in a crossover design comparison (placebo versus avexitide in individual subjects). In another example, a placebo control is used in a parallel design comparison (placebo in one arm of the patient, avexitide in the other arm). For example, in some embodiments, treatment of a subject with the avexitide therapy described herein increases the subject's appetite compared to the subject's appetite before administration of avexitide therapy. In another example, in some embodiments, treatment of a subject with the avexitide therapy described herein increases the subject's food tolerance compared to the subject's food tolerance before administration of avexitide therapy. In another example, in some embodiments, treatment of a subject with the abexitide therapy described herein reduces food aversion in the subject compared to food aversion in the subject before administration of the abexitide therapy. In another example, in some embodiments, treatment of a subject with the abexitide therapy described herein reduces food intolerance in the subject compared to food intolerance in the subject before administration of the abexitide therapy. In another example, in some embodiments, treatment of a subject with the abexitide therapy described herein reduces food avoidance in the subject compared to food avoidance in the subject before administration of the abexitide therapy. In another example, in some embodiments, treatment of a subject with the abexitide therapy described herein increases the calorie intake in the subject compared to the calorie intake in the subject before administration of the abexitide therapy. In another example, in some embodiments, treatment of a subject with the abexitide therapy described herein improves or increases the eating behavior in the subject compared to eating behavior in the subject before administration of the abexitide therapy.In another example, in some embodiments, treatment of a subject with the abexitide therapy described herein reduces the subject's eating anxiety compared to the subject's eating anxiety before administration of the abexitide therapy. In yet another example, in some embodiments, treatment of a subject with the abexitide therapy described herein reduces the subject's eating anxiety compared to the subject's eating anxiety before administration of the abexitide therapy. In yet another example, in some embodiments, treatment of a subject with the abexitide therapy described herein reduces one or more GI symptoms in the subject compared to one or more GI symptoms in the subject before administration of the abexitide therapy.

[0042] Subjects of various subtypes after GI surgery, including those discussed in this disclosure, tend to experience similar and / or overlapping problems, which include, but are not limited to, excessive secretion of GLP-1 due to the rapid emptying of food into the small intestine where GLP-1 secreting L cells are present, excessive insulin secretion, and resulting hypoglycemia. Subsequently, GLP-1 can act directly on the CNS to reduce taste sensitivity and appetite, and directly on the GI system to slow the rate of gastric passage, causing satiety and nausea. Furthermore, hypoglycemia (due to hyperinsulinemia) can cause autonomic symptoms (palpitations, diarrhea, sweating, tremors, nausea) and neurohypoglycemic symptoms (confusion, lethargy, behavioral changes, coordination disorders, seizures, loss of consciousness, etc.). Treatment of subjects after GI surgery by the methods of this disclosure may be performed to treat one or more of the various post-GI surgery problems, including but not limited to those described in this disclosure.

[0043] The effects of avexitide therapy under this disclosure, referred to as “therapeutic effects” or “therapeutic endpoints,” may be measured by various methods. For example, a subject’s nutritional intake may be recorded and measured by entering the food consumed into a diary, computer, or smartphone software and calculating the nutritional intake (manually or using software) based on known data on the nutritional components of various foods. A subject’s nutritional status may be assessed by measuring weight, body mass index (BMI), body composition (such as the subject’s body fat and muscle content), and blood levels of various macronutrients and micronutrients. GI symptoms may be assessed using various diaries, questionnaires, and assessment scales. Gastric emptying rate may be measured by appropriate tests such as scintigraphy. Subjective experiences and behaviors regarding food and diet may be assessed using various diaries and questionnaires. Some examples of questionnaires suitable for measuring some of the effects of avexitide therapy as disclosed herein include the Council on Nutrition and Appetite Questionnaire (CNAQ) (Table 1), the Simplified Health Scale-Glycemic Index (SHS-GI) Questionnaire (Table 2), and the Hypoglycemia Fear-II Questionnaire (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 living in the community and in residents of long-term care facilities (Wilson et al. (2005)). Each item is scored on a 5-point scale, with possible total scores ranging from 8 (lowest) to 40 (highest). A score of 28 or less indicates a significant risk of 5% weight loss within at least six months, and such patients are classified as at risk of malnutrition, as anorexia 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 the scores for all individual items constitutes the CNAQ score. The SHS-GI is a four-item self-administered questionnaire. Each item deals with one of the subjective health dimensions: symptoms, social functioning, disease-related worries, and overall well-being.Responses are scored on a 100mm visual analog scale, with a maximum total score of 400 for all items, where higher values ​​indicate worse outcomes. Results are presented as individual scores for each of the four items, forming a profile. Methods for measuring treatment efficacy and treatment 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 adverse effects, and 2) concern about hypoglycemia and its adverse effects. [Table 1] JPEG2026514828000003.jpg59148 [Table 2] [Table 3]

[0044] Patient group In some embodiments, subjects treated according to the methods described herein are subjects who have previously undergone gastrointestinal (GI) surgery. In some embodiments, subjects have previously undergone non-obesity surgical procedures involving the gastrointestinal system, including but not limited to esophagectomy for the treatment or prevention of esophageal cancer, Nissen fundoplication for the treatment of gastroesophageal reflux disease, or gastrectomy (for the treatment, prevention or treatment of gastric cancer). In some non-limiting embodiments, subjects have previously undergone obesity or metabolic surgical procedures involving the gastrointestinal system, including but not limited to Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (VSG), placement of an endosleeve device such as an end-barrier gastrointestinal liner system also known as a "luminal liner," duodenal mucosal reconstruction (also known as duodenal ablation), biliary-pancreatic bypass (BPD), biliary-pancreatic bypass with duodenal switch (BPD-DS), partial duodenal bypass with duodenoileal anastomosis or duodenojejunal anastomosis, vagus nerve block, and pyloroplasty. In some embodiments, subjects treated according to the methods described herein may be referred to herein by the terms “post-gastrointestinal surgery” patient, “post-GI surgery patient,” “post-GI surgery,” “post-GI surgery subject,” and other related terms. In some embodiments, subjects have undergone at least one gastric surgery. In some embodiments, subjects are treated immediately after surgery (for example, if the surgery is not a bariatric surgery). In some embodiments, subjects to be treated have previously undergone gastrointestinal surgery at least one year prior to the start of treatment. In some embodiments, subjects are human. In some embodiments, subjects are adults. In some embodiments, subjects are minors (i.e., minors who have undergone GI surgery).

[0045] In some embodiments, subjects underwent gastrectomy. In some embodiments, subjects experienced post-gastrectomy syndrome, characterized by, for example, decreased tolerance to overeating, rapid emptying or "dumping" of food into the small intestine, abdominal cramps, diarrhea, postprandial dizziness, and increased heart rate and a sharp drop in blood glucose levels. In some embodiments, subjects underwent esophagectomy. In some embodiments, subjects experienced post-esophagectomy syndrome, which may include, but is not limited to, a variety of symptoms such as dysphagia, reflux, delayed gastric emptying, dumping syndrome, weight loss, and chronic diarrhea.

[0046] In some embodiments, after GI surgery, subjects may experience or be expected to experience a variety of complications related to nutritional deficiencies. Some non-limiting examples of such complications are anemia as a result of vitamin B12 deficiency, iron malabsorption, and osteoporosis. Insufficient absorption of vitamin B12 can lead to anemia and, in some cases, impaired nerve function. Iron deficiency anemia can develop because gastrectomy often significantly reduces the production of gastric acid necessary to convert dietary iron into a more easily absorbed form in the duodenum. Osteoporosis develops as a result of calcium malabsorption. After GI surgery, calcium absorption efficiency may be reduced as a result of rapid gastric emptying.

[0047] Subjects treated according to the methods described in this disclosure may be identified by any appropriate method. For example, a subject may have undesirable weight loss after undergoing GI surgery. Undesirable weight loss includes unintentional weight loss and may also be called involuntary or unintended weight loss. Unintentional weight loss does not include some types of weight loss that are expected outcomes of treatment (such as weight loss due to diuretic therapy in patients with heart failure) or weight loss as a result of a known disease. However, some other types of weight loss that are expected outcomes of treatment, such as weight loss after GI surgery, are still undesirable and fall within the scope of the expression “undesirable weight loss.” For example, a subject may be expected to have undesirable weight loss after GI surgery because, for example, the patient is underweight or normal weight before undergoing GI surgery. Subjects treated according to the methods described in this disclosure may have clinically significant weight loss, which is typically defined as a loss of more than 5% of normal weight over a period of 6 to 12 months.

[0048] Subjects treated according to the methods described in this disclosure may have malnutrition. Various criteria may be used to confirm the diagnosis of malnutrition. For example, the following criteria for the diagnosis of malnutrition were recommended in a 2012 consensus statement between the Academy of Nutrition and Diet and the American Society for Parenteral and Enteral Nutrition (ASPEN): A diagnosis of malnutrition requires the presentation of two or more of the following six features: insufficient energy intake, weight loss, decreased muscle mass, decreased subcutaneous fat, local or systemic fluid retention that may mask weight loss, and decreased functional status as measured by grip strength. In another example, criteria for malnutrition were introduced in 2018 by the Global Leadership Initiative on Malnutrition (GLIM). GLIM was established to develop a global consensus on the identification and diagnostic criteria for malnutrition to facilitate comparisons of malnutrition prevalence, treatment, and outcomes. The 2018 criteria mentioned above include an assessment of the role of acute and chronic inflammation, which is not represented in the International Classification of Diseases, 10th Revision (ICD-10) code. According to GLIM, a diagnosis of malnutrition requires a combination of at least one phenotypic criterion and one etiological criterion. The phenotypic criterion is involuntary weight loss, a low body mass index (BMI), or a decrease in muscle mass, while the etiological criterion is a decrease in food intake or absorption, or underlying inflammation due to an acute illness / injury or chronic disease. In another example, a clinically acceptable definition of malnutrition includes unintentional weight loss (more than 5% in 3 months, or more than 10% indefinitely) as a component of one set of diagnostic criteria. After a diagnosis of malnutrition has been made, a dietitian or nutritionist who can develop an individualized care and treatment plan can perform a more comprehensive assessment of the nutritional status.

[0049] Subjects treated according to the methods described in this disclosure may have malnutrition (not receiving sufficient amounts of necessary nutrients) after GI surgery, with or without malnutrition. Malnutrition may or may not be accompanied by weight loss. Subjects treated according to the methods described in this disclosure may be expected to have malnutrition, with or without weight loss, after GI surgery. Malnutrition may be prevented by treating such subjects according to the methods described in this disclosure. Subjects treated according to the methods described in this disclosure may have or be expected to have cachexia and / or sarcopenia after GI surgery. In the latter case, cachexia and / or sarcopenia may be prevented by treating such subjects according to the methods described in this disclosure. Cachexia is generally defined as weight loss due to a decrease in muscle mass (with or without fat loss). Sarcopenia is characterized by a decrease in muscle mass, muscle strength, and performance.

[0050] In some embodiments, subjects treated according to the methods of 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 of 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 of this disclosure experience postprandial GI symptoms, including, but not limited to, nausea, early satiety, heartburn, indigestion, or abdominal bloating. In some embodiments, subjects treated according to the methods of this disclosure experience slow gastric passage and / or gastric stasis (which may be accompanied by gastroparesis or vomiting). Gastroparalysis is a syndrome in which gastric emptying is objectively delayed, without mechanical obstruction, and the main symptoms are nausea, vomiting, early satiety, belching, abdominal bloating, and / or epigastric pain. Gastroparalysis can be classified according to the degree of delay in gastric passage (from mild to severe). In some embodiments, subjects treated according to the methods described herein experience concerns about hypoglycemia. In some embodiments, subjects treated according to the methods described herein must follow a strict or restrictive diet, including frequent, small, low-glycemic index meals.

[0051] In some embodiments, subjects treated according to the methods described herein require a relaxation of dietary restrictions. After GI surgery, subjects typically need to be very restricted in their diet, such as consuming small amounts of low-glycemic index foods frequently and generally avoiding carbohydrates. In the context of this disclosure, a relaxation of dietary restrictions may mean the subject's ability to be less restrictive and to introduce carbohydrates into their diet, resulting in a more balanced intake of macronutrients.

[0052] In some embodiments, subjects treated according to the methods described herein have elevated GLP-1 levels before or after GI surgery. GLP-1 levels can be measured in various ways, some of which are discussed in Holst (2007). GLP-1 levels are elevated compared to reference population levels. In humans, fasting total GLP-1 (including metabolites produced by DPP-4-mediated degradation) concentrations in whole-body plasma are typically in the range of 5–10 pmol / L and can increase up to 40 pmol / L in response to food (Mueller et al. (2019)).

[0053] Administration regimen In some embodiments, avexitide is available in the form of a suitable pharmaceutical formulation (which may be referred to herein as "avexitide formulation") in doses ranging from approximately 40 mg to approximately 120 mg per day, for example, approximately 50 mg to approximately 120 mg per day, approximately 60 mg to approximately 120 mg per day, approximately 70 mg to approximately 120 mg per day, approximately 80 mg to approximately 120 mg per day, approximately 90 mg to approximately 120 mg per day, approximately 50 mg to approximately 110 mg per day, and per day The drug is administered (e.g., subcutaneously) in a total daily dose within the range of approximately 60 mg to 110 mg, approximately 70 mg to 110 mg per day, approximately 80 mg to 110 mg per day, approximately 90 mg to 110 mg per day, approximately 50 mg to 100 mg per day, approximately 60 mg to 100 mg per day, approximately 70 mg to 100 mg per day, approximately 80 mg to 100 mg per day, or approximately 90 mg to 100 mg per day. For example, the total daily dose of avexitide may be approximately 40 mg to 90 mg, approximately 40 mg to 75 mg, approximately 40 mg to 60 mg, approximately 50 mg to 90 mg, approximately 45 mg to 75 mg, approximately 60 mg to 90 mg, or approximately 60 mg to 75 mg. In some embodiments, abexitide is administered in a total daily dose of at least about 40 mg, for example, 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, abexitide is administered in 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, abexitide is administered in a total daily dose of 85 mg or 95 mg.

[0054] In some embodiments of the methods according to this disclosure, subjects may have a body weight of 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 doses of abexitide ranging from about 0.4 mg / kg / day to about 3 mg / kg / day. For example, a subject may receive doses of abexitide ranging from 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, a subject may receive about 0.375 mg / kg / dose or about 0.75 mg / kg / day. In some embodiments, a subject may receive approximately 0.56 mg / kg / dose or approximately 1.125 mg / kg / day. In some embodiments of the method according to this disclosure, a subject may have a body weight of less than approximately 60 kg, less than approximately 59 kg, less than approximately 58 kg, less than approximately 57 kg, less than approximately 56 kg, less than approximately 55 kg, less than approximately 54 kg, less than approximately 53 kg, less than approximately 52 kg, less than approximately 51 kg, or less than approximately 50 kg, and may receive a dose of abexitide from approximately 0.4 mg / kg / day to approximately 3 mg / kg / day. In the above embodiments, abexitide may be administered as a BID (twice daily) or TID (three times daily).

[0055] In some embodiments, a therapeutically effective dose of avexitide (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 (e.g., subcutaneously) at intervals of approximately 24 hours (e.g., 7 a.m. on consecutive days). However, the intervals can be shorter (e.g., around 8 a.m. and 6 a.m. on consecutive days) or longer (e.g., around 7 a.m. and 9 a.m. on consecutive days), provided that the administrations are at least at intervals of approximately 18 hours. Preferably, the intervals between administrations are at least approximately 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours. Preferably, the intervals between administrations are no more than approximately 30 hours. Methods for determining the timing of QD administration are described, for example, in PCT patent applications PCT / US2016 / 033837 and PCT / US / 2019 / 0562778. In some cases, administration may be carried out more frequently (e.g., twice a day) or less frequently (e.g., once every other day).

[0056] In some embodiments, the avexitide formulation is administered twice daily ("BID") (e.g., subcutaneously or intravenously). BID administration is well known in the medical field. The formulation can be administered at specific points in the subject's day or schedule, e.g., morning, afternoon, evening, night, before or 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 (e.g., self-administered) at intervals of approximately 12 hours (e.g., around 7 a.m. and 7 p.m.). However, the administration interval can be shorter (e.g., around 8 a.m. and 6 p.m.) or longer (e.g., around 7 a.m. and 10 p.m.). In some embodiments, the administration is spaced at least 4 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, or 11 hours apart. Preferably, the administration interval does not exceed 15 hours. Methods for timing BID administration are described, for example, in PCT patent applications PCT / US2016 / 033837 and PCT / US / 2019 / 0562778. In some embodiments, the avexitide formulation is administered three times daily ("TID") (e.g., subcutaneously or intravenously).

[0057] The dosage of abexitide in adults ranges from approximately 40 mg QD to approximately 120 mg QD. For example, the dosage of abexitide in adults may range from approximately 40 mg QD to approximately 100 mg QD, approximately 40 mg QD to approximately 75 mg QD, approximately 40 mg QD to approximately 60 mg QD, approximately 50 mg QD to approximately 90 mg QD, approximately 45 mg QD to approximately 75 mg QD, approximately 60 mg QD to approximately 100 mg QD, approximately 60 mg QD to approximately 75 mg QD, or approximately 85 mg QD to approximately 95 mg QD. The dosage of abexitide in adults may range from approximately 20 mg BID to approximately 60 mg BID. For example, the dosage of abexitide in adults may range from 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.

[0058] In some embodiments, the avexitide preparation is administered in doses of approximately 20–65 mg BID or 25–50 mg BID (e.g., subcutaneous or intravenous). In some embodiments, the avexitide preparation is administered in doses of approximately 20 mg BID. In some embodiments, the avexitide preparation is administered in doses of approximately 25 mg BID. In some embodiments, the avexitide preparation is administered in doses of approximately 30 mg BID. In some embodiments, the avexitide preparation is administered in doses of approximately 35 mg BID. In some embodiments, the avexitide preparation is administered in doses of approximately 40 mg BID. In some embodiments, the avexitide preparation is administered in doses of approximately 45 mg BID. In some embodiments, the avexitide preparation is administered in doses of approximately 50 mg BID. In some embodiments, the avexitide preparation is administered in doses of approximately 55 mg BID. In some embodiments, the avexitide preparation is administered in doses of approximately 60 mg BID. In some embodiments, the avexitide preparation is administered in a dose of approximately 65 mg BID. In some embodiments, preparations containing avexitide at a concentration of approximately 30 mg / ml or higher are administered in doses ranging from approximately 20 to approximately 65 mg BID, for example, in a dose of approximately 45 mg BID.

[0059] In some embodiments, the avexitide preparation is administered in a total daily dose of about 40 to about 120 mg, or about 60 to about 100 mg, or about 85 to about 95 mg (e.g., subcutaneous or intravenous), and administered as a BID (Biochemical Intake). In some embodiments, the avexitide preparation is administered in a total daily dose of about 90 mg, and administered as a BID (i.e., about 45 mg BID). In some embodiments, the avexitide preparation is administered in a total daily dose of about 100 mg, and administered as a BID (i.e., about 50 mg BID). In some embodiments, the avexitide preparation is administered in a total daily dose of about 80 mg, and administered as a BID (i.e., about 40 mg BID), and the avexitide preparation is administered in a total daily dose of about 120 mg, and administered as a BID (i.e., about 60 mg BID).

[0060] In some embodiments, the avexitide preparation is administered in doses ranging from about 40 to about 120 mg QD, for example, from about 60 to about 100 mg QD, or from about 85 to about 95 mg QD (e.g., subcutaneous or intravenous). In some embodiments, the avexitide preparation is administered in a dose of about 40 mg QD. In some embodiments, the avexitide preparation is administered in a dose of about 50 mg QD. In some embodiments, the avexitide preparation is administered in a dose of about 60 mg QD. In some embodiments, the avexitide preparation is administered in a dose of about 70 mg QD. In some embodiments, the avexitide preparation is administered in a dose of about 80 mg QD. In some embodiments, the avexitide preparation is administered in a dose of about 90 mg QD. In some embodiments, the avexitide preparation is administered in a dose of about 100 mg QD. In some embodiments, the avexitide preparation is administered in a dose of about 120 mg QD.

[0061] In some embodiments, the avexitide preparation is administered in a total daily dose of about 60 to about 120 mg (e.g., subcutaneous or intravenous) and administered in QDs. In some embodiments, the avexitide preparation is administered in a total daily dose of about 60 mg and administered in QDs (i.e., about 60 mg QDs). In some embodiments, the avexitide preparation is administered in a total daily dose of about 70 mg and administered in QDs (i.e., about 70 mg QDs). In some embodiments, the avexitide preparation is administered in a total daily dose of about 75 mg and administered in QDs (i.e., about 75 mg QDs). In some embodiments, the avexitide preparation is administered in a total daily dose of about 80 mg and administered in QDs (i.e., about 80 mg QDs). In some embodiments, the avexitide preparation is administered in a total daily dose of about 90 mg and administered in QDs (i.e., about 90 mg QDs). In some embodiments, the avexitide preparation is administered in a total daily dose of approximately 120 mg, or in QDs (i.e., approximately 120 mg QDs).

[0062] In some embodiments, the avexitide preparation is administered in a total daily dose of about 60 to about 120 mg (e.g., subcutaneous or intravenous) and is administered as a BID or QD. In some embodiments, the avexitide preparation is administered in a total daily dose of about 60 mg and is administered as a QD (i.e., about 60 mg QD) or BID (i.e., about 30 mg BID). In some embodiments, the avexitide preparation is administered in a total daily dose of about 70 mg and is administered as a QD (i.e., about 70 mg QD) or BID (i.e., about 35 mg BID). In some embodiments, the avexitide preparation is administered in a total daily dose of about 80 mg and is administered as a QD (i.e., about 80 mg QD) or BID (i.e., about 40 mg BID). In some embodiments, the avexitide preparation is administered in a total daily dose of approximately 90 mg, either as a QD (i.e., approximately 90 mg QD) or BID (i.e., approximately 45 mg BID). In some embodiments, the avexitide preparation is administered in a total daily dose of 120 mg, either as a QD (i.e., approximately 120 mg QD) or BID (i.e., approximately 60 mg BID).

[0063] In some embodiments, the avexitide formulation is administered twice daily (BID) (e.g., subcutaneously or intravenously) within approximately 60 minutes before breakfast and dinner (or two major meals of the day). In some embodiments, the avexitide formulation is administered at least approximately 60 minutes before meals (e.g., at least approximately 60 minutes before breakfast and / or at least approximately 60 minutes before dinner). In some embodiments, the administration before breakfast and before dinner (or before two major meals of the day) is spaced at least approximately 6 hours apart. In some embodiments, the administration of the formulation is not timed with meals. In some embodiments, the avexitide formulation is administered once daily (QD) (e.g., subcutaneously or intravenously) in the morning or evening to best cover breakfast and dinner. For example, in some embodiments, the formulation is administered in the evening after dinner or in the morning before breakfast (e.g., at least approximately 60 minutes before breakfast).

[0064] The above dosages and dosage ranges are exemplary doses for adults and may vary depending on the age and weight of the subject, as is well known to those skilled in the pharmaceutical field. In some embodiments, it will be understood that the dosage may be increased or decreased during the course of treatment. For example, some physicians may wish to treat with a low dose or initial (starting) dose and escalate to an increased dose if the initial dose does not provide sufficient therapeutic effect, or maintain the initial dose if it does provide sufficient therapeutic effect.

[0065] Route of administration In some embodiments, a pharmaceutical formulation containing avexitide (e.g., a buffer formulation as described elsewhere in this disclosure) is administered to a subject by subcutaneous administration. Subcutaneous administration includes subcutaneous injection and subcutaneous infusion. Subcutaneous injection involves injecting a liquid pharmaceutical formulation into the subcutaneous adipose tissue using a syringe and a short needle. Subcutaneous infusion, or subcutaneous infusion method, is a subcutaneous technique for injecting a liquid into the subcutaneous cavity using a small-gauge needle. Subcutaneous infusion may be performed with an infusion pump or manually (e.g., using a syringe). Sites of injection or infusion include, but are not limited to, injections into the thigh, abdomen, upper arm region, back, or upper buttocks. In some embodiments, avexitide is injected using Insuflon. In some embodiments, a composition containing avexitide (e.g., a buffer formulation as disclosed elsewhere in this disclosure) is formulated for subcutaneous administration. In one embodiment, the avexitide composition is formulated for subcutaneous administration according to a once-daily (QD), twice-daily (BID), or three-daily (TID) regimen. In some embodiments, the avexitide-containing pharmaceutical formulation (e.g., a buffer formulation described elsewhere in this disclosure) is administered to a subject intravenously, either by bolus administration or by timed intravenous infusion. Intravenous administration can be performed using a syringe or catheter. Administration of the avexitide-containing pharmaceutical formulation includes self-administration.

[0066] Abexitide preparations In some embodiments, the therapeutic methods disclosed herein include a formulation containing avexitide or a pharmaceutically acceptable salt thereof ("avexitide formulation"). In some embodiments, the formulation contains avexitide at a concentration of at least 30 mg / mL. In some embodiments, the pharmaceutical formulation is a buffer formulation. Pharmaceutical formulations containing avexitide are described, for example, in PCT patent applications PCT / US2016 / 033837 and PCT / US / 2019 / 0562778.

[0067] In some embodiments, the formulations are approximately 2-250 mg / mL, approximately 2-200 mg / mL, approximately 2-180 mg / mL, approximately 2-90 mg / mL, approximately 2-20 mg / mL, approximately 2-29 mg / mL, approximately 1-20 mg / mL, approximately 30-250 mg / mL, approximately 30-225 mg / mL, approximately 30-200 mg / mL, approximately 30-180 mg / mL, approximately 30-150 mg / mL, approximately 30-120 mg / mL, and approximately 30-90 mg / mL. mg / mL, approx. 30~60mg / mL, approx. 30~70mg / mL, approx. 40~250mg / mL, approx. 40~225mg / mL, approx. 40~200mg / mL, approx. 40~180mg / mL, approx. 40~120m g / mL, approx. 45~90mg / mL, approx. 45~75mg / mL, approx. 60~250mg / mL, approx. 60~225mg / mL, approx. 60~200mg / mL, approx. 60~180mg / mL, approx. 60~120mg / 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 (for example, 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 The formulation contains avexitide at concentrations of 75 mg / mL, approximately 80 mg / mL, approximately 85 mg / mL, approximately 90 mg / mL, approximately 95 mg / mL, approximately 100 mg / mL, approximately 110 mg / mL, approximately 120 mg / mL, approximately 130 mg / mL, approximately 140 mg / mL, approximately 150 mg / mL, approximately 160 mg / mL, approximately 170 mg / mL, approximately 180 mg / mL, approximately 200 mg / mL, approximately 220 mg / mL, or approximately 220 mg / mL). In some embodiments, the formulation contains avexitide at a concentration of approximately 30 mg / mL. In some embodiments, the formulation contains avexitide at concentrations ranging from approximately 40 mg / mL to approximately 50 mg / mL. In some embodiments, the formulation contains avexitide at a concentration of approximately 45 mg / mL. In some embodiments, the formulation contains avexitide at concentrations ranging from approximately 30 mg / mL to approximately 60 mg / mL. In some embodiments, the formulation contains avexitide at a concentration ranging from about 30 mg / mL to about 90 mg / mL.In some embodiments, the formulation contains avexitide at a concentration ranging from about 45 mg / mL to about 90 mg / mL. In some embodiments, the formulation contains avexitide at a concentration of about 60 mg / mL. In some embodiments, the formulation contains avexitide at a concentration of about 75 mg / mL. In some embodiments, the formulation contains avexitide at a concentration of about 90 mg / mL. In some embodiments, the formulation contains avexitide at a concentration of about 120 mg / mL. In some embodiments, the formulation contains avexitide at a concentration of about 175 mg / mL. In some embodiments, the formulation contains avexitide at a concentration of about 200 mg / mL.

[0068] In some embodiments, the formulation contains avexitide or a pharmaceutically acceptable salt thereof in a physiologically acceptable buffer having a pH in the range of about 5 to about 6. In some embodiments, the buffer is suitable for subcutaneous or intravenous administration. In some embodiments, the physiologically acceptable buffer is a buffer that yields a liquid formulation having a pH at or near the physiological pH, or within a relatively narrow pH range close to the physiological pH (e.g., about 5.0 to about 8.0). In one embodiment, the buffer formulation contains a physiologically acceptable buffer having a pH greater than 5.0 and up to about 6. In some embodiments, the physiologically acceptable buffer has a pH greater than 5.0 and up to about 5.5. In one embodiment, the physiologically acceptable buffer has a pH in the 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, a physiologically acceptable buffer has a pH in the range of 5.0 to 5.5 (e.g., 5.1, 5.2, 5.3, 5.4, or 5.5). In one embodiment, a physiologically acceptable buffer 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, a physiologically acceptable buffer has a pH of about 5.5. In one embodiment, a physiologically acceptable buffer has a pH of about 5.6. In one embodiment, a physiologically acceptable buffer has a pH of about 5.7. In one embodiment, a physiologically acceptable buffer has a pH of about 5.8.

[0069] In one embodiment, the physiologically acceptable buffer comprises an acetate buffer, a citrate buffer, a phosphate buffer, a histidine buffer, or a mixture thereof. In one embodiment, the physiologically acceptable buffer comprises sodium acetate, potassium acetate, trisodium citrate, magnesium citrate, potassium citrate, potassium phosphate, or a mixture thereof. In one embodiment, the 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, the physiologically acceptable buffer contains a buffer (e.g., sodium acetate) at a concentration of at least 10 mM.

[0070] In some embodiments, the physiologically acceptable buffer contains an acetate buffer. In some embodiments, the buffer is sodium acetate. In some embodiments, the buffer is potassium acetate. In some embodiments, the physiologically acceptable buffer contains an acetate buffer (e.g., sodium acetate or potassium acetate) at a concentration of about 5 mM to about 30 mM, for example, about 10 mM to about 20 mM. In some embodiments, the physiologically acceptable buffer contains an acetate buffer (e.g., sodium acetate or potassium acetate) at a concentration of about 10 mM.

[0071] In some embodiments, the physiologically acceptable buffer contains 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, the physiologically acceptable buffer contains a citrate buffer (e.g., sodium citrate, magnesium citrate, or potassium citrate) at a concentration of about 5 mM to about 30 mM, for example, about 10 mM to about 20 mM. In some embodiments, the physiologically acceptable buffer contains a citrate buffer (e.g., sodium citrate, magnesium citrate, or potassium citrate) at a concentration of about 10 mM.

[0072] In one embodiment, the physiologically acceptable buffer contains a phosphate buffer. In one embodiment, the physiologically acceptable buffer contains potassium phosphate. In one embodiment, the physiologically acceptable buffer contains potassium phosphate at a concentration of about 5 mM to about 30 mM, for example, about 10 mM to about 20 mM. In some embodiments, the physiologically acceptable buffer contains a phosphate buffer (e.g., potassium phosphate) at a concentration of about 10 mM.

[0073] In some embodiments, the buffering formulation includes an isotonic agent. In some embodiments, the isotonic agent is mannitol, dextrose, glycerin, lactose, sucrose, trehalose, or a mixture thereof. In some embodiments, the isotonic agent is mannitol. The use of isotonic agents is well known in the pharmaceutical field, and those skilled in the art can use one or more of the isotonic 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), and also Formulating Poorly Water Soluble Drugs, Williams, Watts and Miller, eds., Springer Science and Business Media (2011).

[0074] In some embodiments, the isotonic agent or combination of multiple isotonic agents is present in the formulation at concentrations of approximately 20-75 mg / ml, approximately 20-60 mg / ml, approximately 25-55 mg / ml, approximately 30-75 mg / ml, approximately 30-50 mg / ml, approximately 35-45 mg / ml, approximately 40-45 mg / ml, approximately 45-75 mg / ml, or approximately 45-60 mg / ml (for example, approximately 20 mg / ml, approximately 22 mg / ml, approximately The isotonic agent is present in concentrations of approximately 25 mg / ml, approximately 28 mg / ml, approximately 30 mg / ml, approximately 32 mg / ml, approximately 35 mg / ml, approximately 38 mg / ml, approximately 40 mg / ml, approximately 42 mg / ml, approximately 45 mg / ml, approximately 48 mg / ml, approximately 50 mg / ml, approximately 52 mg / ml, approximately 55 mg / ml, approximately 58 mg / ml, approximately 60 mg / ml, approximately 65 mg / ml, approximately 70 mg / ml, or approximately 75 mg / ml. In some embodiments, the formulation contains an isotonic agent in a concentration range of approximately 30 mg / ml to approximately 60 mg / ml.

[0075] In some embodiments, the isotonic agent is 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 in the 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.

[0076] In one embodiment, the isotonic agent comprises dextrose. In one embodiment, the dextrose is present at a concentration of about 20 mg / ml to about 60 mg / ml (for example, about 20 mg / ml, about 40 mg / ml, about 45 mg / ml, or about 60 mg / ml).

[0077] In one embodiment, the isotonic agent is glycerin. In some embodiments, glycerin is present at concentrations ranging from 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).

[0078] In one embodiment, the isotonic agent is lactose. In one embodiment, lactose is present at a concentration of about 20 mg / ml to about 60 mg / ml (for example, about 20 mg / ml, about 40 mg / ml, about 45 mg / ml, or about 60 mg / ml).

[0079] In one embodiment, the isotonic agent is sucrose. In some embodiments, sucrose is present at concentrations ranging from 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).

[0080] In one embodiment, the isotonic agent comprises trehalose. In one embodiment, the trehalose is present at a concentration of about 20 mg / ml to about 60 mg / ml (for example, about 20 mg / ml, about 40 mg / ml, about 45 mg / ml, or about 60 mg / ml).

[0081] In some embodiments, the buffering formulation comprises two or more isotonic agents. In some embodiments, the buffering formulation comprises two or more isotonic agents selected from the group consisting of mannitol, dextrose, glycerin, lactose, sucrose, and trehalose. In some embodiments, the buffering formulation comprises mannitol and at least one other isotonic agent.

[0082] In some embodiments, the formulation further includes one or more additional excipients, such as preservatives, surfactants (e.g., polysorbates or poloxamers), or colorants (e.g., pharmaceutically acceptable dyes, inorganic pigments, and natural colorants). A wide variety of pharmaceutically acceptable excipients are known in the art. Pharmaceutically acceptable excipients are well described in various 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) H. Ansel et al., eds., 7th ed., Lippincott, Williams, & Wilkins; and Handbook of Pharmaceutical Excipients (2000) A. Kibbe et al., eds., 3rd ed. Amer. Pharmaceutical Assoc., each publication incorporated herein by reference.

[0083] In some embodiments, the avexitide formulation is provided as a disposable pre-filled syringe, for example, in a kit comprising a plurality of disposable pre-filled syringes (e.g., 10, 20, 30, 40, 50, or 60 pre-filled syringes). In some embodiments, the disposable pre-filled syringe contains the avexitide formulation comprising avexitide at a concentration of at least 30 mg / mL, an isotonic agent, and a buffer having a pH in the range of 5.0 to 6.0. In some embodiments, the disposable pre-filled syringe contains an amount of at least 20 mg of avexitide (e.g., 20-90 mg, 30-75 mg, 30-60 mg, 40-90 mg, or 60-90 mg, e.g., 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 disposable pre-filled syringe contains an amount of at least 30 mg of avexitide. In some embodiments, the avexitide formulation optionally further includes a preservative.

[0084] In some embodiments, the avexitide preparation is provided in a pen-type syringe device. In some embodiments, the pen-type syringe device is a glass device (e.g., a glass cartridge type pen-type syringe device). In some embodiments, the pen-type syringe device is a disposable device. In some embodiments, the pen-type syringe device contains an avexitide preparation comprising avexitide at a concentration of at least 30 mg / mL, an isotonic agent, and a buffer having a pH in the range of 5.0 to 6.0. In some embodiments, the pen-type syringe device contains an amount of at least 20 mg of avexitide (e.g., 20-90 mg, 30-75 mg, 30-60 mg, 40-90 mg, or 60-90 mg, e.g., 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-type syringe device contains an amount of at least 30 mg of avexitide. As a non-limiting example, a pen-type injector device may include a formulation comprising about 30 to 75 mg of abexitide (e.g., about 30 mg or about 60 mg of abexitide), an isotonic agent, and a buffer having a pH in the range of about 5.0 to 6.0. In some embodiments, the abexitide formulation may optionally further include a preservative.

[0085] In some embodiments, the avexitide formulation is provided in glass vials or ampoules of a single dose or multiple doses for administration using a syringe, similar to a glucagon emergency kit. In some embodiments, the avexitide formulation is provided as a disposable or reusable pen-type device. In some embodiments, the disposable or reusable pen-type device containing the avexitide formulation contains multiple doses (e.g., 5, 8, 7, 8, 9, 10, or more) of avexitide. In some embodiments, the avexitide formulation is provided as an injectable solution in a single-dose tray comprising a vial of the avexitide formulation described herein, an isotonic agent, and a buffer having a pH in the range of greater than 5.0 to 6.0 (e.g., 5.1-6.0, 5.2-5.8, or 5.5-6.0, including any 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 amount of antimicrobial preservative), a vial connector, a syringe, and one or more needles.

[0086] In some embodiments, each dose is administered in a total volume ranging from 0.25 to 2 ml of injection solution. In some embodiments, each dose is administered in a total volume ranging from about 0.1 ml or a further 0.5 ml, and most subjects are administered in injection volumes ranging from 0.25 to 1.5 ml, or 0.5 to 1 ml, or 0.7 to 1 ml, or 0.1 ml or a further 0.5 ml. [Examples]

[0087] The following examples are provided to illustrate, but not to limit, the claimed invention.

[0088] Example 1. Selected method. A. Buffet Test Using a free-choice standard buffet, the total calorie intake and macronutrient distribution of selected foods from a standard diet with known nutritional content will be measured. Participants will choose two main dishes from the provided meal list, and will also be offered almond crackers (e.g., Fat Snax, Brooklyn, New York), guacamole (e.g., Wholly® guacamole, MegaMex Foods, Orange, California), and string cheese (e.g., low-moisture, partially defatted Lucerne® mozzarella, Guggisberg Cheese, Millersburg, Ohio). The amount of items consumed from the buffet (including partially consumed buffet items) will be recorded over the following hour. The total kilocalories and macronutrients of the food consumed will be analyzed using Food Processor® Nutrition Analysis software from ESHA (Salem, Oregon).

[0089] B. Dietary Challenge Test (MTT) If subjects have not been previously screened, they will undergo a Metabolic Test (MTT) to establish a baseline metabolic profile. The MTT may be conducted at the Stanford University Clinical and Translational Research Unit (CTRU) or an equivalent facility. An indwelling catheter will be inserted into the median cubital vein for blood collection. Blood samples will be collected by trained staff throughout the MTT. At time 0, subjects will be given a standardized meal (e.g., Ensure® Compact Drink (Abbott Laboratories, Abbott Park, Illinois)) which must be consumed within 15 minutes. Blood glucose, insulin, c-peptide, glucagon, GIP, GLP-1, and other incretin hormone levels will be measured at multiple time points over a 3-hour period. Symptoms of hypoglycemia will be investigated during the test. The average total blood volume per MTT is 100 mL.

[0090] Installation, operation, and data collection of CGM, as well as coordination for signal loss and relaxation of dietary restrictions. Participants will receive continuous glucose monitoring (CGM) in an outpatient setting. Wearing a CGM device during the study period will allow for comparison of the accuracy of CGM meters to detect large and rapid changes in blood glucose levels during metabolic induction. Enrolled participants are scheduled to participate in a video training meeting with the study coordinator. During the initial training session, the coordinator will interpret the study design, objectives, and potential risks associated with the CGM device. Participants will wear the CGM device(s) under the coordinator's supervision and will be instructed on how to check glucose levels in real time using a glucometer, as the CGM will be blinded. After the 7-day wear period, participants will have another video or in-person meeting with the coordinator to remove the CGM transmitter(s) and return them to the study team for data collection. Once the study team receives the CGM transmitters, they will anonymize the data and upload it 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). Export the raw data to appropriate software for data analysis.

[0091] The CGM endpoint includes time spent below 54 mg / dL and 70 mg / dL, adjusted for usage time (minutes), and time spent below 54 mg / dL and 70 mg / dL, adjusted for glucose spikes of 150 mg / dL or more, which indicate carbohydrate consumption. Data are also adjusted for collection time. Relaxation of dietary restrictions is estimated by the number of spikes. A glucose spike is defined as glucose rising above 150 mg / dL and lasting for at least 15 minutes, which is assumed to indicate consumption of carbohydrate-containing food / drinks.

[0092] D.Cronometer application (Cronometer Software Inc., Levelstoke, British Columbia, Canada) Use the smartphone application Cronometer Pro to track your diet and activity levels, quantifying food consumption and nutritional data (major and micronutrient components, dietary fiber, etc.), energy balance, and activity levels (per minute, per level).

[0093] Example 2. 7-day proof-of-concept trial: Evaluation of avexitide for improving feeding behavior in cancer patients who underwent total gastrectomy or esophagectomy. A. Purpose: The primary objectives for evaluating effectiveness are as follows: The study evaluated the effects of avexitide on feeding behavior during standardized buffet meals in a clinic setting. These effects were measured as total calorie intake and macronutrient distribution using ESHA's (Salem, Oregon) Food Processor® Nutrition Analysis software, feeding motivation using a visual analog scale (VAS), a psychometric response scale usable on questionnaires, and appetite and hunger using the Council on Nutrition and Appetite Questionnaire (CNAQ). Furthermore, measurements were taken under free-feeding conditions in an outpatient setting using the Cronometer Pro nutrition tracking application (Cronometer Software Inc., Levelstoke, British Columbia, Canada).

[0094] The primary objectives of the safety evaluation are as follows: • Evaluate the safety and acceptability of abexitide.

[0095] A secondary objective of efficacy assessment is to evaluate the effects of avexitide on the following: • Gastrointestinal symptoms as measured by the Simplified Health Scale for the Gastrointestinal Tract (SHS-GI) and the Gastrointestinal Symptom Assessment Scale (GSRS). Hypoglycemia, hypoglycemia, and related symptoms as measured by minimum plasma glucose levels during standardized mixed-food challenge tests (MMTT) in a clinic setting, by the Edinburgh Hypoglycemia Symptom Scale (EHSS), by the Hypoglycemia Fear Study II (HFS-II), and by continuous glucose monitoring (CGM), self-monitoring of blood glucose (SMBG), and electronic diaries (eDiary) in an outpatient setting. • Evaluate the impact of abexitide on quality of life (QoL) as measured by the 36-item Short-Term Health Questionnaire (SF-36).

[0096] B. Group: (i) Inclusion criteria Patients who meet all of the following criteria are eligible to participate in the trial. 1. The participant must understand the purpose and risks of the trial, be willing and capable of complying with scheduled hospital visits, treatment plans, clinical tests, procedures related to the use of the smartphone application, and other trial evaluations and procedures, and provide written informed consent. 2. Must be at least 18 years old. 3. The patient must have a record of undergoing total gastrectomy or esophagectomy within 12 months of registration. 4. Undesirable weight loss, or anticipated undesirable weight loss due to the patient being underweight or normal weight before surgery (e.g., low BMI before surgery (BMI < 23 kg / m²)). 2 At least one of the following: )), or a physician's concern about current or potential malnutrition.

[0097] (ii) Exclusion criteria: Patients who meet any of the following criteria will be excluded from the study. 1. Participation in another interventional clinical trial within 30 days prior to screening. 2. Donation or loss of more than 500 mL of blood or blood products within 56 days prior to the first dose of the investigational drug. 3. A clinically significant active infection within 14 days prior to the first dose of the investigational drug. 4. Any clinically relevant acute or chronic psychiatric disorder, renal disorder, hepatic disorder, pancreatic disorder, cardiovascular disorder, neurological disorder, hematological disorder, or gastrointestinal disorder (e.g., inflammatory bowel disease), or a history of malignant tumor (excluding malignant tumors for which upper GI surgery was performed within 12 months prior to randomization, or appropriately treated basal cell carcinoma or squamous cell carcinoma, or cervical intraepithelial neoplasia). 5. Liver function abnormalities defined as transaminase (alanine transaminase (ALT), aspartate transaminase (AST)) levels exceeding twice the upper limit of normal (ULN) and / or bilirubin levels exceeding twice the ULN at screening, and a glomerular filtration rate (GFR) of 60 mL / min / 1.73 m² at screening. 2 Renal dysfunction defined as less than (calculated using the Chronic Kidney Disease Epidemiology Collaborative Study (CKD-EPI) formula), and abnormal electrolyte concentrations including potassium, magnesium, phosphorus, and sodium.

[0098] C. Examination Design: This randomized, placebo-controlled crossover trial is designed to evaluate the effects of avexitide treatment on eating behavior, gastrointestinal symptoms, hypoglycemia, and quality of life in patients who have previously undergone total gastrectomy or esophagectomy for the treatment or prevention of gastric or esophageal cancer. The trial includes two 7-day treatment periods, flanked by a 3-day continuous glucose monitoring (CGM) induction period and a 3-day washout period, as shown in Figure 1. Approximately 16 participants will be randomized in a 1:1 ratio to one of two arms, each with a different order of dosing regimens.

[0099] After randomization, baseline assessments are completed. Anthropometric measurements are taken, including height, weight, BMI, and body circumference. A standardized buffet meal test is performed, quantifying energy intake and components using the ESHA Food Processor. Willingness to eat, appetite, hunger, satiety, and taste aversion are assessed using the VAS and CNAQ. A standardized MMTT is performed to assess glucose and hormone profiles during meals, as well as hypoglycemic and gastrointestinal symptoms, with hypoglycemic symptoms assessed using the EHSS. In addition, patients complete the GSRS and SHS-GI questionnaires to assess GI symptoms, and complete the HFS-II and SF-36 to assess hypoglycemia and health-related quality of life.

[0100] At the start of the CGM initiation period and throughout treatment periods 1 and 2 (including a 3-day washout period), participants will receive either avexitide or placebo at a dose of 45 mg twice daily in a randomized order in a crossover design for a total of 10 days of avexitide or placebo treatment. Throughout each 7-day treatment period in the home environment, participants will document their ad libitum energy intake through a food diary using the Cronometer Pro application and document hypoglycemic events through 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 period, participants will return to the facility and repeat the baseline assessment. A 3-day washout period will occur between treatment periods 1 and 2.

[0101] D. Examination Procedure: (i) In-clinic evaluation Buffet Test: At baseline and at the end of each treatment period, subjects fasted overnight, then were admitted to the clinic to undergo a free-choice standard buffet test. Total calorie intake and macronutrient distribution were measured for selected foods from a standard diet of known nutritional content (e.g., vegetable lasagna (Stouffers®, Nestle USA, Inc., Solon, Ohio), vanilla pudding (Hunts, KraftHeinz North America, Tarrytown, New York), and skim milk). The amount of items consumed from the buffet (including partially consumed items) was recorded over the following hour. Total kilocalories and macronutrients consumed were analyzed using validated software (ProNutra® 3.0, Viocare® Technologies, Inc., Princeton, New Jersey). Additionally, feeding intent, appetite, hunger, and taste aversion were quantified using VAS and CNAQ.

[0102] Mixed Food Challenge (MMTT): At baseline and at the end of each treatment period, subjects will be admitted to the clinic after an overnight fast and undergo a 180-minute MMTT. Following baseline blood collection, subjects will consume two 64g Ensure® Compact Drinks (Abbott Laboratories, Abbott Park, Illinois) over 10 minutes, and bedside assessments of point-of-care glucose levels will be collected every 15 minutes in the laboratory (for plasma glucose, insulin, c-peptide, GLP-1, and glucagon) and every 30 minutes. If the rescue parameter is met (point-of-care glucose ≤ 50 mg / dL if neurogenic hypoglycemia symptoms are documented, or ≤ 40 mg / dL regardless of symptoms, whichever comes first), a final blood sample will be collected and the participant will be rescued with intravenous dextrose. Plasma glucose and hormones (glucose, insulin, glucagon, GLP-1, GIP) will be collected every 30 minutes and analyzed according to standard methods.

[0103] To assess the temporal presence and severity of autonomic symptoms, neurohypoglycemic symptoms, and nonspecific symptoms, a 5-point Likert severity scale (0=none, 5=severe) is applied to the EHSS, a study effective for use in insulin-treated diabetic patients for identifying symptoms of acute hypoglycemia. The EHSS with severity classification is completed by participants every 30 minutes before each blood draw during each oral glucose tolerance test (OGTT). Symptoms assessed include autonomic symptoms (sweating, tremors, palpitations, hunger), neurohypoglycemic symptoms (poor vision, confusion, drowsiness, bizarre behavior, speech difficulties, ataxia, dizziness, inability to concentrate), and fatigue (nausea, headache). For each participant, a composite score is recorded for all time points. Two subscores, a "glucose rise" score and a "glucose fall" score, are included to separate symptoms that are temporally related to the glucose rise period (from T=0 to the individual participant's glucose peak) and the glucose fall period (from the glucose peak to the lowest value). The analysis further classifies symptom scores according to the type of symptom, such as autonomic nervous system symptoms, neurohypoglycemic symptoms, or fatigue.

[0104] Questionnaires: At baseline and at the end of each treatment period, subjects will complete the SHS-GI, GSRS, HSF-II, and SF-36. Questionnaires must be completed unhurried in a quiet, private environment, using a black ink ballpoint pen, without any external assistance, prior to any study procedure or laboratory collection. Each questionnaire will be reviewed to ensure that all questions have been answered. If any questions are unanswered, the study subject will be asked if they are willing to complete the questions. If the study subject does not wish to answer the questions, no further action will be taken, and the completed questionnaire(s) will be stored in the source document folder.

[0105] (ii) Outpatient care evaluation: Use of CGM, SMBG, and eDiary in an outpatient setting: Throughout two 7-day treatment periods, subjects will use eDiary (an internet-connected web application), a CONTOUR® Next One glucometer (Ascensia Diabetes Care, Parsippany, New Jersey), and a blinded Dexcom Mobile G6 Pro CGM system (Dexcom, Fort Lauderdale, Florida) to record hypoglycemic events occurring in an outpatient setting. For each occurrence, patients will record symptoms / signs of hypoglycemia, the lowest SMBG reading during the occurrence, measures taken to treat or prevent the occurrence, the need for assistance, and whether the occurrence occurred after a meal. Investigational drug injections will also be recorded, and adherence will be monitored by accounting for returned investigational drug vials.

[0106] Cronometer Pro App: Throughout two 7-day treatment periods, use the Cronometer Pro app on your smartphone and professional nutrition tracking software to track your diet and activity levels, quantifying food consumption and nutritional data (major and micronutrient components, dietary fiber, etc.), energy balance, and activity levels (per minute, level).

[0107] E. Endpoint: The primary efficacy endpoint is total calorie intake (kcal) during a standardized buffet test.

[0108] Secondary endpoints supporting the primary objective include the following: • Eating intent before the buffet test, as measured by a Visual Analog Scale (VAS). Appetite and hunger as measured by CNAQ. • Taste aversion measured by exploratory tools. • Total energy intake measured over 7 days using the Chronometer application via food log.

[0109] Secondary endpoints supporting secondary objectives include the following: • Gastrointestinal symptoms as measured by SHS-GI and GSRS at the end of each treatment period. • The degree of hypoglycemia as measured by the lowest plasma glucose level during a standardized MMTT. • Autonomic and neuroglycemic symptoms of hypoglycemia as measured by the EHSS score during MMTT induction. • Worries and behaviors associated with hypoglycemia phobia as measured by HFS-II. • Hypoglycemic event rate (<70 mg / dL) as measured by SMBG. • Clinically significant hypoglycemic event rate (<54 mg / dL) as measured by SMBG. During each treatment period, 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 using a blinded Dexcom G6 CGM. • Quality of life as measured by SF36.

[0110] Example 3. Phase 2 28-day trial: Evaluation of avexitide for improving nutritional status and preventing undesirable weight loss in cancer patients who have undergone total gastrectomy or esophagectomy. A. Purpose: The primary objective of efficacy assessment is to evaluate the effects of avexitide on height, weight, and circumference using standardized methods, as well as on weight, body composition, and body mass index (BMI) measured by body impedance analysis (BIA), dual-energy X-ray absorptiometry (DEXA), or computed tomography (CT), at baseline and at the end of each treatment period.

[0111] The primary safety objective is to evaluate the safety and tolerability of avexitide.

[0112] A secondary objective of efficacy assessment is to evaluate the effects of avexitide on the following: Nutritional status as measured by major dietary nutrients, blood albumin levels, and / or other biomarkers. • Physical ability as measured by total activity level and / or grip strength. Feeding behavior and energy balance were measured during standardized buffet meals in a clinic setting, using the ESHER food processor for total calorie intake and macronutrient distribution, a visual analog scale (VAS) for feeding intent, and the Council on Nutrition and Appetite Questionnaire (CNAQ) for appetite, taste, satiety, and hunger. • Energy balance, dietary composition, and dietary restriction relaxation under ad libitum conditions in an outpatient setting, as measured by the Cronometer Pro application, CGM, and eDiary. • Gastrointestinal symptoms as measured by the Simplified Health Scale for the Gastrointestinal Tract (SHS-GI) and the Gastrointestinal Symptom Assessment Scale (GSRS). Hypoglycemia, hypoglycemia, and related symptoms as measured by minimum plasma glucose levels during standardized mixed-food challenge tests (MMTT) in a clinic setting, by the Edinburgh Hypoglycemia Symptom Scale (EHSS), by the Hypoglycemia Fear Study II (HFS-II), and by continuous glucose monitoring (CGM), self-monitoring of blood glucose (SMBG), and electronic diaries (eDiary) in an outpatient setting. • Quality of life (QoL) measured by a 36-item simplified health questionnaire (SF-36).

[0113] B. Group: (i) Inclusion criteria Patients who meet all of the following criteria are eligible to participate in the trial. 1. The participant must understand the purpose and risks of the study, be willing and capable of complying with scheduled hospital visits, treatment plans, clinical tests, procedures related to the use of smartphone applications, and other study evaluations and procedures, and provide written informed consent. 2. Must be at least 18 years old. 3. The patient must have a record of undergoing total gastrectomy or esophagectomy within 12 months of registration. 4. Undesirable weight loss, or anticipated undesirable weight loss due to the patient being underweight or normal weight before surgery (e.g., low BMI before surgery (BMI < 23 kg / m²)). 2 At least one of the following: )), or a physician's concern about current or potential malnutrition.

[0114] (ii) Exclusion criteria: Patients who meet any of the following criteria will be excluded from the study. 1. Participation in another interventional clinical trial within 30 days prior to screening. 2. Donation or loss of more than 500 mL of blood or blood products within 56 days prior to the first dose of the investigational drug. 3. A clinically significant active infection within 14 days prior to the first dose of the investigational drug. 4. Any clinically relevant acute or chronic psychiatric disorder, renal disorder, hepatic disorder, pancreatic disorder, cardiovascular disorder, neurological disorder, hematological disorder, or gastrointestinal disorder (e.g., inflammatory bowel disease), or a history of malignant tumor (excluding malignant tumors for which upper GI surgery was performed within 12 months prior to randomization, or appropriately treated basal cell carcinoma or squamous cell carcinoma, or cervical intraepithelial neoplasia). 5. Liver function abnormalities defined as transaminase (alanine transaminase (ALT), aspartate transaminase (AST)) levels exceeding twice the upper limit of normal (ULN) and / or bilirubin levels exceeding twice the ULN at screening, and a glomerular filtration rate (GFR) of 60 mL / min / 1.73 m² at screening. 2 Renal dysfunction defined as less than (calculated using the Chronic Kidney Disease Epidemiology Collaborative Study (CKD-EPI) formula), and abnormal electrolyte concentrations including potassium, magnesium, phosphorus, and sodium.

[0115] C. Examination Design: This is a Phase 2, single - or multi - center, placebo - controlled, crossover trial of abexicitide injection in approximately 16 patients who have undergone gastrointestinal surgery. Eligible participants must not have undergone total gastrectomy or esophagectomy within 12 months from enrollment. Also, the trial subjects must have at least one of the following: unwanted weight loss, expected unwanted weight loss due to the patient being underweight or normal weight before surgery (e.g., low preoperative BMI (BMI < 23 kg / m 2 )), or physician - diagnosed current or potential malnutrition concerns. Enrolled participants are randomized to one of two 28 - day abexicitide or placebo dosing regimens (Figure 2). The dose is self - administered by subcutaneous (SC) injection in an outpatient clinic setting. Throughout the study period, participants are instructed to maintain postoperative dietary guidelines for GI surgery.

[0116] Before treatment period 1 (baseline) and at the end of treatment periods 1 and 2, participants undergo various in - clinic evaluations including body composition by height / weight / BMI measurement, BIA, DEXA, or CT, fasting and post - meal clinical laboratory evaluations to measure glucose, insulin, and incretin hormones (e.g., GLP - 1), and measurements to assess nutritional status (e.g., albumin), physical ability assessments (e.g., by total activity and / or grip strength), standardized buffet tests, and patient questionnaires (e.g., to evaluate gastrointestinal symptoms, appetite, taste and satiety, and behaviors related to fear of hypoglycemia). Throughout treatment periods 1 and 2, patients track their eating behaviors and energy balance through the use of the Chronometer application in addition to an electronic diary (eDiary). Further, hypoglycemic events are tracked throughout the study by blinded continuous glucose monitoring (CGM), self - monitoring of blood glucose (SMBG), and entries in the electronic diary (eDiary). At the end of treatment period 2, participants return used and unused study drug vials during a safety follow - up visit.

[0117] D. Test Procedure: (i) In - clinic evaluations Anthropometric measurements: At baseline, after an overnight fast, height, weight, body mass index (BMI), and body circumference (waist, hips, and limbs) will be measured. At the end of treatment periods 1 and 2, after an overnight fast, weight, BMI, and body circumference will be measured again. Body composition: Body composition (lean body mass, fat mass, free fat mass, water) is measured at baseline and at the end of treatment periods 1 and 2, and analyzed according to standard methods by body impedance analysis (BIA), dual-energy X-ray absorptiometry (DEXA), or computed tomography (CT).

[0118] Buffet Test: At baseline and at the end of each treatment period, subjects fasted overnight, then were admitted to the clinic to undergo a free-choice standard buffet test. Total calorie intake and macronutrient distribution were measured for selected foods from a standard diet with known nutritional content (e.g., vegetable lasagna (Stouffers, Nestle USA, Inc., Solon, Ohio), vanilla pudding (Hunts, KraftHeinz North America, Tarrytown, New York), and skim milk). The amount of items consumed from the buffet (including partially consumed items) was recorded over the following hour. Total kilocalories and macronutrients consumed were analyzed using validated software (ProNutra 3.0, Viocare Technologies, Inc., Princeton, New Jersey). Additionally, VAS and CNAQ were used to quantify feeding intent, appetite, hunger, and taste aversion.

[0119] Mixed Food Challenge (MMTT): At baseline and at the end of each treatment period, subjects will be admitted to the clinic after an overnight fast and undergo a 180-minute MMTT. Following baseline blood collection, subjects will consume two Ensure Compact Drinks containing 64g of carbohydrates over 10 minutes, and bedside assessments of point-of-care glucose levels will be collected every 15 minutes in the laboratory (for plasma glucose, insulin, c-peptide, GLP-1, and glucagon) and every 30 minutes. If the rescue parameter is met (point-of-care glucose ≤ 50 mg / dL if neurogenic hypoglycemia symptoms are documented, or ≤ 40 mg / dL regardless of symptoms, whichever comes first), a final blood sample will be taken and the participant will be rescued with intravenous dextrose. Plasma glucose and hormones (glucose, insulin, glucagon, GLP-1, GIP) will be collected every 30 minutes and analyzed according to standard methods.

[0120] To assess the temporal presence and severity of autonomic symptoms, neurohypoglycemic symptoms, and nonspecific symptoms, a 5-point Likert severity scale (0=none, 5=severe) is applied to the EHSS, a survey effective for use in insulin-treated diabetic patients for identifying symptoms of acute hypoglycemia. The EHSS with severity classification is completed by participants every 30 minutes before each blood draw during each OGTT. Symptoms assessed include autonomic symptoms (sweating, tremors, palpitations, hunger), neurohypoglycemic symptoms (poor vision, confusion, drowsiness, bizarre behavior, speech difficulties, ataxia, dizziness, inability to concentrate), and fatigue (nausea, headache). For each participant, a composite score is recorded for all time points. Two subscores, a "glucose elevation" score and a "glucose decline" score, are included to separate symptoms that are temporally related to the glucose elevation period (T=0 to the individual participant's glucose peak) and the glucose decline period (glucose peak to the lowest value). The analysis further classifies symptom scores according to the type of symptom, such as autonomic nervous system symptoms, neurohypoglycemic symptoms, or fatigue. Questionnaire: At baseline and at the end of each treatment period, subjects will complete the SHS-GI, GSRS, HSF-II, and SF-36.

[0121] (ii) Outpatient care evaluation: Use of CGM, SMBG, and eDiary in an outpatient setting: Throughout two treatment periods, subjects will use eDiary (an internet-connected web application), a CONTOUR® Next One glucometer, and a blinded Dexcom Mobile G6 Pro CGM to record hypoglycemic events occurring in an outpatient setting. For each occurrence, patients will record symptoms / signs of hypoglycemia, the lowest SMBG reading during the occurrence, measures taken to treat or prevent the occurrence, the need for assistance, and whether the occurrence occurred after a meal. Adherence will be monitored by recording investigational drug injections and accounting for returned investigational drug vials.

[0122] Cronometer Pro application: Throughout two treatment periods, use the Cronometer Pro application on your smartphone and professional nutrition tracking software to track your diet and activity levels, quantifying food consumption and nutritional data (major and micronutrient components, dietary fiber, etc.), energy balance, and activity levels (per minute, level).

[0123] E. Endpoint: The primary endpoint is the percentage change in body weight from baseline, as measured at the end of each treatment period.

[0124] Secondary endpoints supporting the primary objective include the following: • The percentage change in BMI from baseline as measured at the end of each treatment period, and • Percentage change from baseline in body composition (lean body mass, fat mass and free fat mass, and water) as analyzed by body impedance analysis (BIA), dual-energy X-ray absorptiometry (DEXA), or computed tomography (CT).

[0125] Secondary endpoints supporting secondary objectives include the percentage change from baseline for the following items: For example, physical ability measured by total activity level and grip strength, For example, GI symptoms measured by the CNAQ questionnaire, For example, appetite, taste perception, and satiety perception as measured by the SHS-GI questionnaire, • Worries and behaviors associated with hypoglycemia phobia as measured by the HSF-II questionnaire. • Dietary behavior and relaxation of carbohydrate intake restrictions were assessed in-clinic during a standardized buffet test to quantify food consumption and nutritional data (major and micronutrient components, dietary fiber, etc.), energy balance, and activity levels (per minute, level), and continuously evaluated in an outpatient setting through food and activity tracking using appropriate smartphone applications such as Cronometer Pro and professional nutrition tracking software. • Nutritional status as measured by albumin or other biomarkers, • Fasting and postprandial glucose levels during the MMTT test, as well as hormone profiles (e.g., peak, minimum, and AUC values ​​of insulin, glucagon, GLP-1, and GIP). • Incidence of hypoglycemia levels 1-3 as measured by CGM and SMBG / eDiary.

[0126] Example 4. A study of avexitide therapy in patients with severe hypoglycemia after gastrointestinal surgery, including RYGB, VSG, esophagectomy, gastrectomy, and Nissen fundoplication. A. Exam Overview: A phase 2b single-center, open-label crossover trial of avexitide injection was conducted in 16 patients with surgically induced severe diet-resistant hyperinsulinic hypoglycemia (HH). Eligible participants had a confirmed diagnosis of HH after upper GI surgery and demonstrated severe diet-resistant HH, documented by the presence of at least two severe hypoglycemic events characterized by glucose <54 mg / dL as measured by CGM during a 14-day induction period while adhering to medical nutrition therapy.

[0127] Eligible participants included patients with HH resulting from bariatric surgery (Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (VSG)) or other upper gastrointestinal surgery (gastrectomy, esophagectomy, or Nissen fundoplication).

[0128] Participants who met the initial eligibility requirements underwent a 14-day baseline induction consisting of standardized mixed-food consumption as standardized care (SOC) therapy (medical nutrition therapy) and a screening examination performed at the end of the 14-day SOC baseline period to confirm eligibility and establish baseline within 90 days after randomization. Participants who completed enrollment were randomized to one of two 14-day avexitide administration regimen orders (Figure 3). Dosage was self-administered by subcutaneous (SC) injection in an outpatient setting. Participants were instructed to maintain standard 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, excluding all monosaccharides and containing up to 30g and 15g of carbohydrates (CHO), respectively). Hypoglycemia was assessed by blinded continuous glucose monitoring (CGM), patient electronic diaries (eDiary), and self-monitoring of blood glucose (SMBG). At the end of each of the baseline, treatment period 1, and treatment period 2, participants completed quality of life (QoL) assessments (SF-36, EQ-5D) and laboratory-collected samples, including trough PK samples. Used and unused investigational drug vials were returned accountably during safety follow-up visits that occurred at the end of treatment period 2.

[0129] Additional evaluations were completed for a subset of patients who underwent gastrectomy or esophagectomy, as this group is known to experience rapid and involuntary weight loss as a result of post-gastrectomy syndrome, characterized by decreased tolerance to overeating, rapid emptying of food into the small intestine or "dumping," abdominal cramps, diarrhea, postprandial dizziness, and increased heart rate and a sharp drop in blood glucose levels. Additional evaluations performed in this cohort included anthropometrics, assessments of appetite and hunger, and GI symptoms. Quality of life (QoL) assessments, including weight, height, and BMI, the Nutrition & Appetite Council Questionnaire (CNAQ), the Simplified Health Scale-GI (SHS-GI) Questionnaire, and the Hypoglycemia Fear Questionnaire II (HSF-II), were performed at baseline and at the end of treatment periods 1 and 2.

[0130] B. Results: Table 4 shows the baseline demographic and clinical characteristics of the participants. Metabolic responses of all study participants, measured by SMBG, eDiary, and CGM, are shown in Table 5, Figures 4, 5, 6, 7, 8, and 9. [Table 4] [Table 5] 1 The incidence rate is defined as the number of occurrences in each treatment period, normalized to 14 days. 2 Level 1 hypoglycemia is defined as an SMBG concentration <70 mg / dL. 3 Level 2 hypoglycemia is defined as an SMBG concentration < 54 mg / dL. 4 Level 3 hypoglycemia is defined as a serious event characterized by changes in mental and / or physical function that require assistance from others for recovery. This applies regardless of whether the patient is receiving external assistance.

[0131] Both avexitide treatment regimens significantly reduced the incidence of level 1 to 3 hypoglycemia compared to baseline. Between avexitide 45 mg twice daily and 90 mg once daily, the incidence of SMBG < 70 mg / dL (level 1 hypoglycemia) decreased by 54% (P=.003) and 68% (P=.001), respectively, compared to baseline, and the incidence of SMBG < 54 mg / dL (level 2 hypoglycemia) decreased by 57% (P=.003) and 53% (P=.004), respectively. Between avexitide 45 mg twice daily and 90 mg once daily, the incidence of level 3 events decreased by 68% (P<.001) and 66% (P<.001), respectively.

[0132] Blinded CGM supported the results observed by SMBG and eDiary. Specifically, the mean percentage of time spent with glucose <54 mg / dL decreased by 45% and 64%, respectively, during treatment with avexitide 45 mg twice daily and 90 mg once daily. Similarly, the mean number of hypoglycemic events with glucose <54 mg / dL collected by CGM decreased by 43% and 65%, respectively, between avexitide 45 mg twice daily and 90 mg once daily. When patients were evaluated by surgical subtype, gastrectomy patients showed a more severe phenotype, and the proportion of time spent with baseline CGM values ​​<70, <54, and <40 mg / dL was higher than in bariatric surgery (RYGB and VSG) controls. A significant amplification of the avexitide treatment effect was also observed in the total gastrectomy cohort compared to bariatric surgery patients. Specifically, a more pronounced reduction in the proportion of time spent with <54 mg / dL and <40 mg / dL was observed in total gastrectomy patients. These results are shown in Figures 7, 8, and 9.

[0133] Table 6 summarizes the results of additional evaluations (anthropometric measurements, CNAQ, SGS-GI, HFS-II) performed on two patients who underwent gastrectomy.

[0134] (i) Patient 1 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 joining the study. Within the first month post-surgery, he developed postprandial hypoglycemia, with fasting glucose levels ranging from approximately 60–69 mg / dL. Postprandially, blood glucose levels rose sharply to 200 mg / dL, and then became dangerously low within 1.5–2 hours postprandially (documented as 37 mg / dL by SMBG and CGM). Such episodes occurred multiple times per day, with the highest postprandial spike followed by the lowest value. The patient had no history of loss of consciousness, seizures, or requiring emergency medical attention, but reported "brain fog" and "extreme fatigue." A review of CGM data showed multiple glucose levels <54 mg / dL in the absence of symptoms. Therefore, the patient was determined to have asymptomatic hypoglycemia. The patient was consulted by a nutritionist and instructed to limit carbohydrates (CHO) to 4-7g or less per meal and to almost completely avoid carbohydrates and sugars. His weight decreased by 14.8% (from 155 pounds to 122 pounds), which was a major concern for the patient, family, and medical team. The strict dietary restrictions were thought to have contributed to the patient's weight loss. The patient also complained of chronic nausea / vomiting, which further limited oral intake and weight gain.

[0135] At baseline, the patient's weight was 126 pounds. After 14 days of administration of abexitide at 45 mg BID, the patient recovered 4.6 pounds (a 3.6% increase in body weight). After a further 14 days of administration of abexitide at 90 mg QD, the patient recovered another 0.8 pounds (a total increase of 4.3% in body weight). Although the patient was instructed to adhere to the protocol and maintain a consistent diet throughout the treatment period, a review of blinded CGM data demonstrated a relaxation of dietary restrictions during each administration period of 45 mg BID and 90 mg QD compared to baseline. The relaxation of dietary restrictions was quantified as the number of glucose spikes above 150 mg / dL, based on the assumption that, on average, 1 g of CHO raises blood glucose by 3–4 mg / dL, and fasting glucose is average 80 mg / dL, so an increase to 150 mg / dL corresponds to approximately 20 times the amount of CHO intake. The number of glucose spikes per day, reflecting a higher CHO diet, increased from 1.44 / day at baseline to 3.57 / day with abexitide administered at 45 mg BID and to 5.33 / day with abexitide administered at 90 mg QD, indicating a 270% increase in the number of higher carbohydrate meals during abexitide treatment compared to baseline.

[0136] The patient's baseline CNAQ score was 23, indicating a significant risk of anorexia and at least 5% weight loss and malnutrition within 6 months. However, 14 and 28 days after avexitide treatment, the CNAQ score increased to 24 and 26, respectively, demonstrating a reduced risk of weight loss and malnutrition. GI symptoms, as measured by SHS-GI, decreased by more than 5% at 28 days after treatment. At baseline, the patient's HFS-II worry score was 49. 14 and 28 days after avexitide treatment, his HFS-II score decreased to 42 and 39, respectively, indicating a 20.4% reduction in hypoglycemia-related worry by the end of the study.

[0137] In summary, in this 23-year-old male patient who had undergone gastrectomy and presented with low body weight, anorexia, gastrointestinal symptoms, and frequent severe hypoglycemia, 28 days of avexitide treatment effectively prevented continued weight loss and actually promoted weight recovery. Based on CNAQ, SGS-GI, and HFS-II results, the mechanisms mediating weight stabilization were likely multifactorial and complementary, including increased appetite, hunger, and taste sensitivity, reduced gastrointestinal symptoms, and reduced hypoglycemia phobia through effective prevention of hypoglycemia. Simultaneously, these effects facilitated a relaxation of dietary restrictions and improved the patient's body weight and nutritional status over the 28-day course. [Table 6]

[0138] (ii) Patient 2 Patient 2 was a 72-year-old male with a history of gastric cancer who underwent a total gastrectomy 2.75 years prior to joining the study. He consumed a liquid diet for six weeks post-surgery and initially lost 20 pounds, but otherwise progressed well in the immediate postoperative period. However, over the following months following two rounds of chemotherapy, his weight continued to decline uncontrollably, dropping from a low of 174 pounds to 111 pounds. A diet consisting of frequent, small, low-glycemic index meals failed to mitigate the weight loss. (According to the patient) the diet caused pain, gastrointestinal symptoms, and frequent diarrhea. The patient also complained of weakness, lethargy, and general depression. For approximately 1.5 years post-surgery, the patient's weight remained stable at 125 pounds, but he continued to experience poor appetite, aversion to taste and food, low energy, and gastrointestinal symptoms associated with 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 for his hypoglycemia), but his gastrointestinal symptoms worsened. The patient was referred to participate in a trial.

[0139] In contrast to Patient 1, Patient 2 maintained stable weight (-0.8% change) throughout baseline, treatment period 1, and treatment period 2. He also did not demonstrate any relaxation of dietary restrictions (he was instructed by protocol to maintain a consistent diet throughout). However, his CNAQ, SHS-GI, and HFS-II scores showed significant improvement in each area, demonstrating that improvements in appetite / hunger and taste, reduced gastrointestinal symptoms, and decreased anxiety associated with hypoglycemia allowed for a safe and well-tolerated relaxation of dietary restrictions (where permitted by protocol), thereby improving the patient's nutritional status.

[0140] In particular, Patient 2 differed from Patient 1 in that it had more than 20 severe hypoglycemic events at baseline, but no events during treatment. Over time, if deviated from the protocol, Patient 2 is expected to experience healthy weight recovery, including prevention of hypoglycemic events, improved appetite, and reduced GI symptoms. Another difference between the two patients was that Patient 1 was in the early postoperative period (within 6 months post-surgery), while Patient 2 was in the latent period (approximately 2.75 hours post-surgery). The trials discussed above demonstrated, among other things, the ability of the method disclosed herein to treat or promote weight recovery in patients who have recently undergone gastrectomy.

[0141] Example 5. Animal study demonstrating increased feeding behavior after administration of abexitide. A. Overview: Animal studies were conducted involving subcutaneous administration of avexitide to healthy Sprague Dolly rats. The results described below demonstrate that GLP1R antagonism may prevent undesirable weight loss in human subjects by increasing feeding behavior and thereby aiding calorie intake and / or nutritional status. A range of existing preclinical and clinical data (some of which are discussed elsewhere in this disclosure) indicate that GLP1R agonism leads to weight loss and taste aversion via central mechanisms, while GLP1R antagonism does not stimulate appetite, increase feeding behavior, or cause weight gain. In contrast, this study demonstrated that administration of the GLP1R antagonist avexitide increased food and calorie expenditure in the study subjects. Furthermore, this study demonstrated that administration of the GLP1R antagonist avexitide increased feeding behavior without causing significant weight gain, suggesting that avexitide may prevent undesirable weight loss and improve nutritional status.

[0142] B. Exam Overview: The objective of this study was to investigate the effects of twice-daily (BID) subcutaneous (SC) administration of CD® Sprague Dolly IGS (Crl:CD[SD]) avexitide in male and female rats before cohabitation, throughout mating, and up to embryo implantation. The study design is summarized in Table 7. Among other parameters, data on body weight and food consumption were also collected throughout the study. [Table 7] a The animals were administered subcutaneously twice a day by bolus injection. Males were administered 28 days before cohabitation, during cohabitation, and until the day before euthanasia. Females were administered 15 days before cohabitation, during cohabitation, and until the 7th day of gestation. After the end of the cohabitation period, females without evidence of mating were administered until the day before necropsy. b Based on the latest weight measurement. c Mannitol-containing acetate buffer in sterile water for injection, USP, pH 5.5 ± 0.2

[0143] C. Result: No avexitide-related effects on body weight, body weight gain, or organ weight were observed. However, an increase in food consumption was observed in a dose-dependent manner in males compared to controls, at all dose levels from days 4 to 8, at 150 and 450 mg / kg / day dose levels from days 1 to 4 and 18 to 22, and at 450 mg / kg / day dose level from days 11 to 15. In females, an increase in food consumption was observed in a dose-dependent manner compared to controls during the pre-mating administration period, at 450 mg / kg / day dose levels from days 4 to 8, at 150 and 450 mg / kg / day dose levels from days 8 to 11, and at 45 and 450 mg / kg / day dose levels from days 11 to 15. During pregnancy, increased food consumption was observed in a dose-independent manner in female rats compared to the control group, at a dose level of 450 mg / kg / day during days 0–3 of gestation (GD), and at dose levels of 150 and 450 mg / kg / day during days 3–7 and 3–8 of GD. The results of the study are summarized in Tables 8–10. [Table 8] [Table 9] [Table 10]

[0144] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes thereto are proposed to those skilled in the art and are understood to be within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are incorporated herein in their entirety by reference for all purposes. No reference, including any non-patent or patent literature cited herein, is considered to constitute prior art. In particular, unless otherwise stated, no reference to any document herein is considered to constitute any common general knowledge of the art in the United States or any other country. Any discussion of a reference is the assertion of its author, and the applicant reserves the right to object to the accuracy and validity of any document cited herein. This disclosure shall prevail in the event of any difference between any definition and / or description found in any cited reference. Publications cited in this disclosure 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 2. Holst”The Physiology of Glucagon-like Peptide 1”Physiol.Rev.87:1409-1439(2007)doi:10.1152 / physrev.00034.2006 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.”Metab Syndr Relat Disord.18(9):406-412(2020).doi:10.1089 / met.2020.0049。 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。 5. Landi et al.“Anorexia,physical function,and incident disability among the frail elderly population:results from the ilSIRENTE study.”J Am Med Dir Assoc.11(4):268-274(2010).doi:10.1016 / j.jamda.2009.12.088 6. Martin et al.Ann N Y Acad Sci”Modulation of taste sensitivity by GLP-1 signaling in taste buds.”Ann N Y Acad Sci.1170:98-101(2009)doi:10.1111 / j.1749-6632.2009.03920.x。 7. Maurer et al.Chapter 11”Gastric emptying scintigraphy,”Gastroparesis.Edited by McCallum,and Parkman,Academic Press(2021),pages 125-142.doi:10.1016 / B978-0-12-818586-5.00011-9 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。 9. Montrose-Rafizadeh et al.“High potency antagonists of the pancreatic glucagon-like peptide-1 receptor”Journal of Biological Chemistry.272:21201-21206(1997)doi:10.1074 / jbc.272.34.21201 10. Mueller et al.“Glucagon-like peptide 1(GLP-1).”Mol Metab.30:72-130(2019).doi:10.1016 / j.molmet.2019.09.010。 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。 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)。 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。 14. Wilson et al.“Appetite assessment:simple appetite questionnaire predicts weight loss in community-dwelling adults and nursing home residents.”Am J Clin Nutr.82(5):1074-1081(2005).doi:10.1093 / ajcn / 82.5.1074。

Claims

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

2. The method according to claim 1, wherein the administration of the pharmaceutical preparation improves the nutrition of the subject compared to the nutrition of the subject before the administration of the pharmaceutical preparation.

3. The method according to claim 1 or 2, wherein the administration of the pharmaceutical preparation increases the nutrient intake of the subject compared to the nutrient intake of the subject before 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 appetite of the subject before the administration of the pharmaceutical preparation.

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

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

7. The method according to any one of claims 1 to 6, wherein the administration of the pharmaceutical preparation reduces food intolerance in the subject compared to food intolerance in the subject before 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 avoidance of eating compared to the subject's avoidance of eating before 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 calorie intake of the subject before 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 feeding behavior of the subject compared to the feeding behavior of the subject 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 before 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 concerns regarding eating compared to concerns regarding eating before 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 reduces one or more gastrointestinal symptoms in the subject compared to one or more gastrointestinal symptoms in the subject before administration of the pharmaceutical preparation.

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

15. The method according to any one of claims 1 to 14, wherein the subject experiences a relaxation of dietary restrictions 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 administration of the pharmaceutical preparation.

17. The method according to any one of claims 1 to 16, wherein, prior to administration of the pharmaceutical preparation, the subject has an elevated level of glucagon-like peptide 1 (GLP-1) 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 disease, increased risk of gastric cancer, or increased risk of esophageal cancer.

19. The method according to claim 18, wherein the at least one gastric surgery is a gastrectomy, an esophagectomy, or a Nissen fundoplication.

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

21. The method according to claim 20, wherein the at least one bariatric surgery is Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (VSG), or biparietal dissection (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 avexitide at a concentration of about 2 to 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 abexitide ranging from 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 approximately 90 mg of abexitide.

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 abexitide ranging from 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) in a dose of approximately 20 mg to approximately 120 mg.

31. The method according to claim 30, wherein the pharmaceutical preparation is administered once daily (QD) in a dose of approximately 90 mg.

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

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

34. A method for improving nutritional intake in a subject requiring improvement in nutritional intake, comprising administering a pharmaceutical formulation containing abexitide to the subject, wherein the subject has undergone at least one gastrointestinal surgery.

35. A method for improving appetite in a subject requiring improvement of appetite, comprising administering a pharmaceutical formulation containing avexitide to the subject, wherein the subject has undergone at least one gastrointestinal surgery.

36. A method for improving food tolerance in a subject requiring improvement of food tolerance, comprising administering a pharmaceutical formulation containing avexitide to the subject, wherein the subject has undergone at least one gastrointestinal surgery.

37. A method for reducing food aversion and / or taste aversion in a subject requiring reduction of food aversion and / or taste aversion, comprising administering a pharmaceutical formulation containing avexitide to the subject, wherein the subject has undergone at least one gastrointestinal surgery.

38. A method for reducing food intolerance in a subject requiring reduction of food intolerance, comprising administering a pharmaceutical formulation containing avexitide to the subject, wherein the subject has undergone at least one gastrointestinal surgery.

39. A method for reducing food avoidance in a subject requiring a reduction in food avoidance, comprising administering a pharmaceutical formulation containing avexitide to the subject, wherein the subject has undergone at least one gastrointestinal surgery.

40. A method for increasing the calorie intake of a subject who requires an increase in calorie intake, comprising administering a pharmaceutical formulation containing avexitide to the subject, wherein the subject has undergone at least one gastrointestinal surgery.

41. A method for increasing feeding behavior in a subject requiring increased feeding behavior, comprising administering a pharmaceutical formulation containing avexitide to the subject, wherein the subject has undergone at least one gastrointestinal surgery.

42. A method for reducing eating phobia in a subject requiring reduction of eating phobia, comprising administering a pharmaceutical formulation containing avexitide to the subject, wherein the subject has undergone at least one gastrointestinal surgery.

42. A method for reducing eating anxiety in a subject requiring a reduction in eating anxiety, comprising administering a pharmaceutical formulation containing avexitide to the subject, wherein the subject has undergone at least one gastrointestinal surgery.

42. A method for reducing one or more gastrointestinal symptoms in a subject who requires reduction of one or more gastrointestinal symptoms, comprising administering a pharmaceutical formulation containing avexitide to the subject, wherein the subject has undergone at least one gastrointestinal surgery.

43. A method for increasing the weight of a subject who requires weight gain, comprising administering a pharmaceutical formulation containing avexitide to the subject, wherein the subject has undergone at least one gastrointestinal surgery.

44. A method for reducing the rate of weight loss in a subject requiring a reduction in the rate of weight loss, comprising administering a pharmaceutical formulation containing avexitide to the subject, wherein the subject has undergone at least one gastrointestinal surgery.

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

46. A method for easing dietary restrictions in a subject requiring relaxation of dietary restrictions, comprising administering a pharmaceutical formulation containing avexitide to the subject, wherein the subject has undergone at least one gastrointestinal surgery.

46. A method for reducing the incidence of hypoglycemic events in a subject requiring a reduction in the incidence of hypoglycemic events, comprising administering a pharmaceutical formulation containing avexitide to the subject, wherein the subject has undergone at least one gastrointestinal surgery.

47. The method according to any one of claims 34 to 46, wherein the administration of the pharmaceutical preparation reduces the incidence of hypoglycemic events after the administration of the pharmaceutical preparation.

48. The method according to any one of claims 34 to 47, wherein, prior to administration of the pharmaceutical preparation, the subject has an elevated level of glucagon-like peptide 1 (GLP-1) compared to a reference population level.

49. The method according to any one of claims 34 to 48, 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 disease, increased risk of gastric cancer, or increased risk of esophageal cancer.

50. The method according to claim 49, wherein the at least one gastric surgery is a gastrectomy, an esophagectomy, or a Nissen fundoplication.

51. The method according to claim 49, wherein the at least one gastric surgery is at least one bariatric surgery.

52. The method according to claim 51, wherein the at least one bariatric surgery is Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (VSG), or biparietal dissection (BPD).

53. The method according to any one of claims 34 to 52, wherein the subject has type 2 diabetes.

54. The method according to any one of claims 34 to 53, wherein the pharmaceutical preparation comprises abexitide at a concentration of about 2 to 225 mg / mL.

55. The method according to any one of claims 34 to 54, wherein the pharmaceutical preparation is a buffer solution preparation.

56. The method according to any one of claims 34 to 55, wherein the pharmaceutical preparation is administered subcutaneously.

57. The method according to any one of claims 34 to 56, wherein the pharmaceutical preparation is administered to achieve a total daily dose of abexitide ranging from about 40 mg to about 120 mg.

58. The method according to any one of claims 34 to 57, wherein the pharmaceutical preparation is administered to achieve a total daily dose of approximately 90 mg of abexitide.

59. The method according to any one of claims 34 to 58, wherein the pharmaceutical preparation is administered to achieve a total daily dose of abexitide ranging from about 0.4 mg / kg to about 3 mg / kg.

60. The method according to any one of claims 34 to 59, wherein the pharmaceutical preparation is administered once daily (QD) or twice daily (BID).

61. The method according to any one of claims 34 to 60, wherein the pharmaceutical preparation is administered once daily (QD) in a dose of about 20 mg to about 120 mg, or about 90 mg.

62. The method according to claim 61, wherein the pharmaceutical preparation is administered once daily (QD) in a dose of approximately 90 mg.

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

64. The method according to claim 63, wherein the pharmaceutical preparation is administered twice daily (BID) at a dose of approximately 45 mg.

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