Methods for the prophylaxis and treatment of obesity and related conditions and disorders

Abstract

The present invention recognizes that, there is a need for the prophylaxis or treatment of obesity, glycemic control, and other metabolic disorders. A first aspect of the present invention generally relates to methods of prophylaxis or treatment of obesity, glycemic control, and other metabolic disorders, using various pharmaceutical compositions. A second aspect of the present invention generally relates to mono-therapy or combination therapy used for the prophylaxis or treatment of obesity, glycemic controh other metabolic disorders, and combinations thereof

Description

[0001] METHODS FOR THE PROPHYLAXIS AND TREATMENT OF OBESITY AND RELATED CONDITIONS AND DISORDERS

[0002] Cross Reference to Related Applications

[0003] The present application: claims benefit of priority to United States Provisional Application Serial No. 63 / 623,955, filed January 23, 2024; claims benefit of priority to United States Provisional Application Serial No. 63 / 661,027, filed June 17, 2024; claims benefit of priority to United States Provisional Application Serial No. 63 / 702,841, filed October 3, 2024; and claims benefit of priority to United States Provisional Application Serial No. 63 / 744,272, filed January 12, 2025; each of which is incorporated by reference herein in its entirety.

[0004] Technical Field

[0005] The present invention relates generally to the fields of treatment and prophylaxis of obesity, glycemic control, and other metabolic disorders.

[0006] Background

[0007] Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classified as obese when their body mass index (BMI) (a person's weight divided by the square of the person's height) is over 30 kg / m2; the range of 25 to 30 kg / m2 is defined as overweight. Some East Asian countries use lower values to calculate obesity. Obesity is a major cause of disability and is correlated with various diseases and conditions, particularly cardiovascular diseases, type 2 diabetes, obstructive sleep apnea, certain types of cancer, and osteoarthritis.

[0008] Obesity has individual, socioeconomic, and environmental causes. Some known causes are diet, physical activity, automation, urbanization, genetic susceptibility, medications, mental disorders, economic policies, endocrine disorders, and exposure to endocrine-disrupting chemicals.

[0009] Obesity is a leading preventable cause of death worldwide, with increasing rates in adults and children. According to World Health Organization, in 2016, more than 1.9 billion adults, 18 years and older, were overweight. Of these over 650 million were obese. 39% of adults aged 18 years and over were overweight in 2016, and 13% were obese. Most of the world's population live in countries where overweight and obesity kills more people than underweight. 39 million children under the age of 5 were overweight or obese in 2020. Over 340 million children and adolescents aged 5-19 were overweight or obese in 2016 (see, Obesity and overweight Fact sheet- World Health Organization- June 2021).

[0010] Obesity is associated with the impairment of normal GH (growth hormone) secretion and blunted responses to all stimuli such as GH-releasing hormone (GHRH), hypoglycemia, L-dopa, arginine, glucagon, physical exercise, and sleep, (see, William T, Berelowitz M, Joffe SN, Thorner MO, Rivier J, Vale W, Frohman LA. Impaired growth hormone responses to growth hormone- releasing factor in obesity. A pituitary defect reversed with weight reduction. N Engl J Med 1984; 311 : 1403-1407).

[0011] Based on the well-known GH hyposecretion in obesity, GH-dependent' insulin-like growth factor (IGF)-l concentrations would be expected to be subnormal in obesity. Circulating IGF-1 is predominantly bound in a ternary 150 kDa complex, consisting of IGF-1, IGF- binding protein (IGFBP)-3, and an acid-labile subunit. Thus IGFBP-3 and IGF-1 have relatively long half-lives in the circulation, and since they are GH dependent, they represent a stable index of long-term changes in GH availability and action. IGFBP-2 is the second most abundant IGF-binding protein in serum. The serum concentration of IGFBP-2 is known to be inversely related to GH secretion, being high in states of GH deficiency and low in states of GH excess. These reports have suggested that measurement of IGFBP-2 might be useful in detecting GH deficiency. In contrast, the serum concentrations of IGFBP-1 are lower than those of IGFBP-3 and IGFBP-2, and acutely regulated by food intake and fluctuation in serum insulin and glucose concentrations. Because of this unique property, IGFBP-1 is thought to play an important role in acute regulation of IGF-1 availability.

[0012] A small portion of circulating IGF-1 is detected in the free or readily dissociable state, which is thought to be the metabolically active form. The amount of free / dissociable IGF-1 in serum is dependent on a complex interplay between the production rate and concentrations of IGF-1 and IGFBPs.

[0013] Cyclic glycine-proline (cGP) is a small metabolite naturally cleaved from the N-terminal of IGF-1, cGP is neuroprotective and improves brain development and function following peripheral administration (Tran, US Patent 7232798). It is also known that cGP regulates the bioavailability of circulating IGF-1 by competing with the binding of IGF-1 to insulin-like growth factor binding protein (IGFBP)-3. (see, Guan J, Singh-Mallah G, Liu K, Thorstensen E, Shorten P, Mitchell EA, Taylor R, Harris P, Brimble M, Thompson JMD, Murphy R. The role for cyclic Glycine-Proline, a biological regulator of insulin-like growth factor- 1 in pregnancy- related obesity and weight changes. J Biol Regul Homeost Agents. 2018 May-Jun;32(3):465- 478. PMID: 29921371).

[0014] This competitive binding is concentration dependent, thus lower IGFBP-3 and higher cGP increases bioavailable IGF-1 (Guan et al., 2018). Endogenous cGP in brain tissues (Gudasheva et al., 1996) is generated from the same enzyme that cleaves cGP from plasma IGF- 1 (Yamamoto and Murphy, 1995).

[0015] IGF -I, predominantly synthesized in the liver upon stimulation by growth hormone (GH), is usually bound to IGF-binding protein 3 (IGFBP-3) in circulation, (see, Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 1995; 16:3-34 (PubMed) (Google Scholar)).

[0016] Indeed, several studies report that free IGF -I is elevated in obesity while the total IGF -I concentrations remain within the reference range or are even low-normal, with a normalization upon weight loss, (see, Nam SY, Lee EJ, Kim KR, et al. Effect of obesity on total and free insulinlike growth factor (IGF)-l, and their relationship to IGF-binding protein (BP)-l, IGFBP-2, IGFBP- 3, insulin, and growth hormone. Int J Obes Relat Metab Disord 1997;21:355-359 (PubMed) (Google Scholar)) (see, Rasmussen MH, Hvidberg A, Juul A, et al. Massive weight loss restores 24-hour growth hormone release profdes and serum insulin-like growth factor-I levels in obese subjects. J Clin Endocrinol Metab 1995;80:1407-1415 (PubMed) (Google Scholar)).

[0017] Glucagon-like peptide 1 (GLP-1) is classified as a peptide hormone with a sequence of 30 amino acids. It is produced and secreted by intestinal epithelial endocrine L-cells, pancreatic alpha cells, and neuronal units in the CNS. GLP-1 receptors are present throughout the brain, majorly in the arcuate nucleus, paraventricular nucleus, and dorsomedial nucleus of the hypothalamus, along with central amygdale (Cork et al., 2015).

[0018] Glucagon-like peptide- 1 (GLP-1) is an endogenous gut hormone and a key regulator in maintaining glucose homeostasis by stimulating insulin secretion. Its natural cleavage product GLP-1 (9-36), which was formerly considered a “bio-inactive” metabolite mainly due to its low affinity for GLP-1 receptor, possesses unique properties such as cardiovascular protection. Immunoprecipitation experiments showed that GLP-l(9-36) directly interacts with IGF-1 receptor in astrocytes. Western blot data indicated that GLP-l(9-36) activates IGF-1 receptor and downstream PI3K-AKT pathway in astrocytes upon OGD / R injury, which was abrogated by preincubation with IGF-1 receptor autophosphorylation inhibitor picropodophyllin. It was suggested that that GLP-1 (9-36) improved stroke outcome by reducing inflammation in astrocytes via interaction with IGF-1 receptor.

[0019] It can allude from the above data that IGF-1 and GLP-1 signaling mechanisms in the brain can be beneficial for treating various neurological diseases. The protective actions exerted by these two cellular targets in the brain are significant and will serve as the basis for future neurological research.

[0020] Gastric inhibitory polypeptide (GIP), also known as glucose-dependent insulinotropic polypeptide, is an inhibiting hormone of the secretin family of hormones. While it is a weak inhibitor of gastric acid secretion, its main role, being an incretin, is to stimulate insulin secretion.

[0021] GIP, along with glucagon-like peptide- 1 (GLP-1), belongs to a class of molecules referred to as incretins, which stimulate insulin release on oral food intake. GIP is known to inhibit apoptosis of the pancreatic beta cells and to promote their proliferation. It also stimulates glucagon secretion and fat accumulation. GIP receptors are expressed in many organs and tissues including the central nervous system enabling GIP to influence hippocampal memory formation and regulation of appetite and satiety.

[0022] The relationship of IGF-1, IGP-1, GIP and glucagon can be summarized as follows: Insulin and glucagon help maintain blood sugar levels. Glucagon helps prevent blood sugar from dropping, while insulin stops it from rising too high. Free Insulin like Growth Hormone (IGF-I) is elevated in obesity, having a critical role in weight loss. Glucagon-like peptide-1 (GLP-1) is a key regulator in maintaining glucose homeostasis by stimulating insulin secretion. GLP-1 and IGF-1 are interlinked having a primary role in metabolic functions, for treating Diabetes and Obesity. GIP is an incretin hormone produced in the gastrointestinal tract in response to nutrients. IGF-1 regulates GIP secretion to balance food dependence. Summary

[0023] The present invention recognizes that there is a need for the prophylaxis or treatment of obesity, glycemic control, and other metabolic disorders.

[0024] A first aspect of the present invention generally relates to methods of prophylaxis or treatment of obesity, glycemic control, other metabolic disorders, and combinations thereof, using various pharmaceutical compositions.

[0025] A second aspect of the present invention generally relates to pharmaceutical compositions used for the prophylaxis or treatment of obesity, glycemic control, other metabolic disorders, and combinations thereof.

[0026] Brief Description of the Figures

[0027] FIG. 1 generally depicts body weight change vs. concentration of cPG from baseline at week 12. **p<0.001 vs. placebo; ***p<0.0001 vs. placebo.

[0028] FIG. 2 generally depicts Body Weight Change of cPG, cGAL, cGMeP and Semaglutide vs. Vehicle.

[0029] FIG. 3 generally depicts change in Blood Glucose of cPG, cGAL, cGMeP and Semaglutide vs. Vehicle.

[0030] FIG. 4 generally depicts change in Plasma Triglycerides of cPG, cGAL, cGMeP and Semaglutide vs. Vehicle.

[0031] FIG. 5 generally depicts change in Liver Triglycerides of cPG, cGAL, cGMeP and Semaglutide vs. Vehicle.

[0032] FIG. 6 generally depicts body Weight Change of cPG, cGAL, cGMeP and Semaglutide vs. Vehicle.

[0033] FIG. 7 generally depicts change in Blood Glucose of cPG, cGAL, cGMeP and Semaglutide vs. Vehicle.

[0034] FIG. 8 generally depicts change in Plasma Triglycerides of cPG, cGAL, cGMeP and Semaglutide vs. Vehicle.

[0035] FIG. 9 generally depicts change in Liver Triglycerides of cPG, cGAL, cGMeP and Semaglutide vs. Vehicle. Detailed Description of the Invention

[0036] Definitions

[0037] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and the laboratory procedures in cell culture, chemistry, microbiology, molecular biology, cell science and cell culture described below are well known and commonly employed in the art. Conventional methods are used for these procedures, such as those provided in the art and various general references. Where a term is provided in the singular, the plural of that term is contemplated; and where a term is provided in the plural, the singular of that term is contemplated. The nomenclature used herein and the laboratory procedures described below are those well-known and commonly employed in the art. As employed throughout the disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0038] “Directly” refers to direct causation of a process that does not require intermediate steps.

[0039] “Indirectly” refers to indirect causation that requires intermediate steps.

[0040] “About” refers to plus or minus 10% of the indicated value.

[0041] Other technical terms used herein have their ordinary meaning in the art that they are used, as exemplified by a variety of technical dictionaries.

[0042] Introduction

[0043] The present invention recognizes that there is a need for the prophylaxis or treatment of obesity.

[0044] As a non-limiting introduction to the breath of the present invention, the present invention includes several general and useful aspects, including:

[0045] 1) a method of prophylaxis or treatment of obesity, glycemic control, and other metabolic disorders using various pharmaceutical compositions;

[0046] 2) a pharmaceutical composition used for the prophylaxis or treatment of obesity, glycemic control, and other metabolic disorders. These aspects of the invention, as well as others described herein, can be achieved by using the methods, articles of manufacture and compositions of matter described herein. To gain a full appreciation of the scope of the present invention, it will be further recognized that various aspects of the present invention can be combined to make desirable embodiments of the invention.

[0047] I. METHODS OF PROPHYLAXIS OR TREATMENT OF OBESITY, GLYCEMIC CONTROL, OTHER METABOLIC DISORDERS, OR COMBINATIONS THEREOF

[0048] The present invention includes methods of prophylaxis or treatment of obesity, glycemic control, other metabolic disorders, or combinations thereof, and related conditions and disorders, using various pharmaceutical compositions.

[0049] A first aspect of the present invention includes a method of prophylaxis or treatment of obesity, glycemic control, other metabolic disorders, or combinations thereof including: a) providing a subject in need of the prophylaxis or treatment of obesity; b) providing at least one pharmaceutical composition including one or more of the following components: 1) at least one cPG compound, optionally in combination with; 2) at least one GLP-1 compound; or 3) combinations thereof, wherein the components are administered together or separately; further wherein the components are provided together or separately; c) administering a pharmaceutically effective amount of the at least one pharmaceutical composition to the subject; wherein the subject is provided prophylaxis or treatment of obesity, glycemic control, other metabolic disorders, or combinations thereof.

[0050] A. COMPONENTS

[0051] An aspect of the present invention includes wherein the components are provided in a pharmaceutically acceptable diluent, adjuvant, excipient, or combinations thereof.

[0052] Another aspect of the present invention includes wherein the components are provided in a pharmaceutically acceptable salt.

[0053] A further aspect of the present invention includes wherein the components are administered separately. B. PROPHYLAXIS / TREATMENT OF OBESITY, GLYCEMIC CONTROL, OTHER METABOLIC DOSORDERS, OR COMBINATIONS THEREOF

[0054] Obesity is a highly prevalent, chronic, relapsing disease requiring long-term management. Lifestyle modification is recommended foundation of treatment for individuals with overweight or obesity, but typically achieves only modest weight loss that is often regained. Furthermore, the weight loss is challenging to maintain because of metabolic adaptation that promotes gradual weight regain. Pharmacological treatments for obesity provide a valuable adjunct to lifestyle interventions, but until recently the available agents only offered moderate weight loss over that achieved with lifestyle intervention. (Wadden TA, Tronieri JS, Butryn ML. Lifestyle modification approaches for the treatment of obesity in adults. Am Psychol. 2020, 75(2):235-251).

[0055] Obesity is associated with alterations in the quantity, distribution and function of adipose tissue. Most cases result from complex interactions between genetic, metabolic, neuroendocrine, behavioral and environmental factors involved in the regulation of energy balance and fat storage. (Theilade S, Christensen MB, Vilsboll T, Knop FK. An overview of obesity mechanisms in humans: endocrine regulation of food intake, eating behavior and common determinants of body weight. Diabetes Obes Metab. 2021;23(Suppl 1): 17-35). cPG compound is a metabolite of IGF-1 interlinking with GLP-1 has been shown to reduce energy intake, reduce hunger and increase feelings of satiety and fullness. cPG compound has been demonstrated to mimic GLP-1 that targets areas of the brain that regulate appetite and food intake.

[0056] An additional aspect of the present invention includes wherein the prophylaxis or treatment of obesity includes glycemic control, weight loss, inducing satiety, reducing body weight, reducing food intake and mitigating other metabolic disorders, or combinations thereof, wherein said prophylaxis or treatment of obesity comprises glycemic control, weight loss, inducing satiety, reducing body weight, reducing food intake and mitigating other metabolic disorders, or combinations thereof to maintain glycated hemoglobin Ale (HbAlc) of less than about 7% (53 mmol / mol), and to target preprandial capill ary plasma glucose of about 4.4 to about 12 mmol / 1 (about 80 to about 130 mg / dl), as well as to achieve a plasma triglyceride level below aobut 150 mg / dL (milligrams per deciliter). C. cPG COMPOUND

[0057] An aspect of the present invention includes wherein the at least one cPG compound includes Cyclic Prolyl Glycine, Cyclic Glycyl-2 -Allyl Proline, Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl- L-prolyl), or combinations thereof.

[0058] Another aspect of the present invention includes wherein the at least one cPG compound includes Cyclic Prolyl Glycine.

[0059] A further aspect of the present invention includes wherein the Cyclic Prolyl Glycine is provided in a dose between about 0.5 mg / kg to about 10.0 mg / kg.

[0060] An additional aspect of the present invention includes wherein the Cyclic Prolyl Glycine is provided in a dose between about 1.0 mg / kg to about 3.0 mg / kg.

[0061] An aspect of the present invention includes wherein the Cyclic Prolyl Glycine is provided in a dose between about 3.0 mg / kg to about 7.0 mg / kg.

[0062] Another aspect of the present invention includes wherein the Cyclic Prolyl Glycine is provided in a dose between about 7.0 mg / kg to about 10.0 mg / kg.

[0063] A further aspect of the present invention includes wherein the Cyclic Prolyl Glycine is administered about once a day, about twice a day, or combinations thereof.

[0064] An additional aspect of the present invention includes wherein the Cyclic Prolyl Glycine is administered orally, intranasally, or combinations thereof.

[0065] An aspect of the present invention includes wherein the at least one cPG compound includes Cyclic Glycyl-2-Allyl Proline.

[0066] Another aspect of the present invention includes wherein the Cyclic Glycyl-2-Allyl Proline is provided in a dose between about 0.5 mg to 10.0 mg / kg

[0067] A further aspect of the present invention includes wherein the Cyclic Glycyl-2-Allyl Proline is provided in a dose between about 1.0 mg / kg to about 3.0 mg / kg.

[0068] An additional aspect of the present invention includes wherein the Cyclic Glycyl-2-Allyl Proline is provided in a dose between about 3.0 mg / kg to about 7.0 mg / kg.

[0069] An aspect of the present invention includes wherein the Cyclic Glycyl-2-Allyl Proline is provided in a dose between about 7.0 mg / kg to about 10.0 mg / kg. Another aspect of the present invention includes wherein the pharmaceutical composition includes Cyclic Glycyl-2-Allyl Proline is administered about once a day, about twice a day, or combinations thereof.

[0070] A further aspect of the present invention includes wherein the pharmaceutical composition includes Cyclic Glycyl-2-Allyl Proline is administered orally, intranasally, or combinations thereof.

[0071] An additional aspect of the present invention includes wherein the at least one cPG compound includes Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl).

[0072] An aspect of the present invention includes wherein the pharmaceutical composition includes Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) is provided in a dose between about 0.5 mg / kg to about 10.0 mg / kg.

[0073] Another aspect of the present invention includes wherein the pharmaceutical composition includes Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) is provided in a dose between about 1.0 mg / kg to about 3.0 mg / kg.

[0074] A further aspect of the present invention includes wherein the pharmaceutical composition includes Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) is provided in a dose between about 3.0 mg / kg to about 7.0 mg / kg.

[0075] An additional aspect of the present invention includes wherein the pharmaceutical composition includes Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) is provided in a dose between about 7.0 mg / kg to about 10.0 mg / kg.

[0076] Another aspect of the present invention includes wherein the pharmaceutical composition includes Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) is administered about once a day, about twice a day, or combinations thereof.

[0077] A further aspect of the present invention includes wherein the pharmaceutical composition includes Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) is administered orally, intranasally, or combinations thereof.

[0078] D. GLP-1 COMPOUND

[0079] An additional aspect of the present invention includes wherein the at least one GLP-1 compound includes at least one GLP-1, at least one GLP-1 agonist, or combinations thereof. Another aspect of the present invention includes wherein the at least one GLP-1 includes tirzepatide (Zepbound®), semaglutide (Wegovy®), semaglutide (Rybelsus®), liraglutide (Saxenda®), maridebart cafraglutide (MariTide®), or combinations thereof.

[0080] 1) TIRZEPATIDE (ZEPBOUND® PREFERABLY BUT NOT NECESSARILY ADMINSTERED SUBCUTANEOUSLY)

[0081] A further aspect of the present invention includes wherein the at least one GLP-1 includes tirzepatide (Zepbound®).

[0082] An additional aspect of the present invention includes wherein the at least one pharmaceutical composition including tirzepatide (Zepbound®) is formulated for subcutaneous injection is provided in a dose is about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, or combinations thereof, for administration to a human subject.

[0083] An aspect of the present invention includes wherein the at least one pharmaceutical composition including tirzepatide (Zepbound®) is administered subcutaneously, orally, intranasally, or combinations thereof.

[0084] Another aspect of the present invention includes wherein the at least one pharmaceutical composition including tirzepatide (Zepbound®) is administered once a week, twice a week or combinations thereof.

[0085] 2) SEMAGLUTIDE (WEGOVY® PREFERABLY BUT NOT NECESSARILY ADMINISTERED SUBCUTANOUSLY)

[0086] A further aspect of the present invention includes wherein the GLP-1 includes semaglutide (Wegovy®).

[0087] An additional aspect of the present invention includes wherein the at least one pharmaceutical composition including semaglutide (Wegovy®) subcutaneous injection is provided in a dose of about 0.5 mg, about 1.0 mg, about 2.4 mg, about 4.8 mg, about 9.6 mg, about 19.2 mg or combinations thereof, for administration to a human subject. An aspect of the present invention includes wherein the at least one pharmaceutical compound including semaglutide (Wegovy®) is administered subcutaneously, orally, intranasally, or combinations thereof.

[0088] Another aspect of the present invention includes wherein the at least one pharmaceutical compound including semaglutide (Wegovy®) is administered about once a week, about twice a day, or combinations thereof.

[0089] 3) SEMAGLUTIDE (RYBELSUS® PREFERABLY ADMINISTERED ORALLY)

[0090] A further aspect of the present invention includes wherein the GLP-1 includes semaglutide (Rybelsus®) tablets.

[0091] An additional aspect of the present invention includes wherein the at least one pharmaceutical composition including semaglutide (Rybelsus®) is provided in an oral dose of about 1.5 mg, about 3 mg, about 4 mg, about 7 mg, about 9 mg, about 14 mg, about 28 mg, about 56 mg, about 112 mg, or combinations thereof, for administration to a human subject.

[0092] An aspect of the present invention includes wherein the at least one pharmaceutical compound including semaglutide (Rybelsus®) is administered orally, subcutaneously, intranasally, or combinations thereof.

[0093] Another aspect of the present invention includes wherein the at least one pharmaceutical composition including semaglutide (Rybelsus®) is administered about once per day, about twice a day, or combinations thereof.

[0094] 4) LIRAGLUTIDE (SAXENDA® PREFERABLY BUT NOT NECESSARILY ADMINISTERED SUBCUTANEOUSLY)

[0095] A further aspect of the present invention includes wherein the GLP-1 includes liraglutide (Saxenda®).

[0096] An additional aspect of the present invention includes wherein the at least one pharmaceutical composition including liraglutide (Saxenda®) is provided in a dose of about 0.6mg, about 1.2 mg, about 1.8 mg, about 2.4 mg, about 3 mg, about 6 mg, about 12 mg, about 24 mg, about 48 mg, or combinations thereof, for administration to a human subject. An aspect of the present invention includes wherein the at least one pharmaceutical compound including liraglutide (Saxenda®) is administered subcutaneously, orally, intranasally, or combinations thereof

[0097] Another aspect of the present invention includes wherein the at least one pharmaceutical compound including liraglutide (Saxenda®) is administered about once a week, about twice a week, or combinations thereof.

[0098] 5) MARIDEBART CAFRAGLUTIDE (MARITIDE®

[0099] PREFERABLY BUT NOT NECESSARILY ADMINISTERED SUBCUTANEOUSLY)

[0100] A further aspect of the present invention includes wherein the GLP-1 includes maridebart cafraglutide (MariTide®).

[0101] An additional aspect of the present invention includes wherein the at least one pharmaceutical composition including maridebart cafraglutide (MariTide®) is provided in a dose between about 21 mg to about 840 mg or about 1,680 mg, for administration to a human subject.

[0102] An aspect of the present invention includes wherein the at least one pharmaceutical compound including maridebart cafraglutide (MariTide®) is administered subcutaneously, orally, intranasally, or combinations thereof.

[0103] Another aspect of the present invention includes wherein the at least one pharmaceutical compound including maridebart cafraglutide (MariTide®) is administered about once a month, about twice a month, or combinations thereof.

[0104] E. OUTCOMES

[0105] A successful outcome with cPG treatment is considered to be a significant and sustained weight loss, typically defined as achieving a 5% or greater reduction in body weight compared to baseline, often accompanied by improvements in metabolic health markers like blood pressure and cholesterol levels, particularly in individuals with obesity or prediabetes. Beyond weight loss, cPG compound has been shown to provide positive changes in blood sugar control, and lipid profiles.

[0106] Glycemic control represents the primary target for people with T2I), regardless of the individual's body weight. Recent guideline recommendations suggest a glycated hemoglobin Ale (HbAlc) of less than 7% (53 mmol / mol) as a glycemic target for the majority of adults without significant hypoglycemia. However, glycemic treatment goals should be individualized based on patient preferences and goals, risk of adverse effects of therapy and patient characteristics, including frailty and comorbidities.

[0107] The American Diabetes Association (ADA) recommends target preprandial capillary plasma glucose of 4.4-7.2 mmol / l (80-130 mg / dl), and peak postprandial capillary plasma glucose levels of < 10.0 mmol / l (< 180 mg / dl).

[0108] (American Diabetes Association . 6. Glycemic targets: standards of medical care in diabetes — 2021. Diabetes Care. 2021 ;44(Supplement 1):S73-S84.)

[0109] When treating obesity, a typical plasma triglyceride goal is to achieve a level below 150 mg / dL (milligrams per deciliter), considered within the "normal" range, as lowering triglycerides is a key benefit of weight loss in obese individuals; however, specific goals may vary depending on individual factors and should be discussed with a healthcare provider.

[0110] (Qiao Q, Bouwman FG, van Baak MA, Roumans NJT, Vink RG, Mariman ECM. Plasma Levels of Triglycerides and IL -6 Are Associated With Weight Regain and Fat Mass Expansion. J Clin Endocrinol Metab. 2022 Jun 16; 107(7): 1920-1929. doi: 10.1210 / clinem / dgacl98. PM1D: 35366329;

[0111] PMCH): PMC9202711.).

[0112] A healthy goal for triglyceride levels is less than 150 milligrams per deciliter (mg / dL). Triglyceri de levels that are higher than this can increase the risk of heart attacks and strokes. Triglyceride level categories Normal: Less than 150 mg / dL. Borderline high: 150 to 199 mg / dL. High: 200 to 499 mg / dL. v ery high: 500 mg / dL or above (Alves-Bezerra M, Cohen DE. Triglyceride Metabolism in the Liver. Compr Physiol. 2017 Dec 12;8(1): 1-8. doi: 10.1002 / cphy.cl70012. PMID: 29357123; PMCID: PMC6376873).

[0113] The preferred outcome of the methods of the present invention, and use of the pharmaceutical compositions, to make progress towards these goals. The particular goals for a particular subject depend on the particularities of each subject and are subject to the discretion of the attending physician or other appropriate health care professional(s).

[0114] Goals also include maintaining glycated hemoglobin Ale (HbAlc) of less than about 7% (53 mmol / mol), and to target preprandial capillary plasma glucose of about 4.4 to about 7.2 mmol / l (about 80 to about 130 mg / dl), as well as to achieve a plasma triglyceride level below aobut 150 mg / dL (milligrams per deciliter). A further aspect of the present invention includes wherein the prophylaxis or treatment of obesity, glycemic control, and other metabolic disorders that includes but is not limited to reduction in plasma glucose, plasma triglycerides, liver triglycerides, or combinations thereof

[0115] An additional aspect of the present invention includes wherein the prophylaxis or treatment of obesity is prophylaxis.

[0116] An aspect of the present invention includes wherein the prophylaxis or treatment of obesity is treatment.

[0117] Another aspect of the present invention includes wherein the at least one pharmaceutical compound includes at least one cPG compound and at least one GLP-1 compound.

[0118] F. SUBJECT

[0119] A further aspect of the present invention includes wherein the subject is a human.

[0120] G. ADMINSTERED TOGETHER OR SEPARATELY

[0121] An additional aspect of the present invention includes wherein the components are administered together in a single or multiple doses.

[0122] An aspect of the present invention includes wherein the components are administered separately in a single or multiple doses.

[0123] H. PROVIDED TOGETHER OR SEPARATELY

[0124] Another aspect of the present invention includes wherein the components are provided together in a single or multiple containers.

[0125] A further aspect of the present invention includes wherein the components are provided separately in a single or multiple containers. I. GENERAL AND PREFERRED ASPECTS OF THE PRESENT INVENTION

[0126] An additional aspect of the present invention includes wherein the at least one cPG compound is provided in a dose between about 0.5 mg / kg to about 10.0 mg / kg.

[0127] An aspect of the present invention includes wherein the at least one cPG compound is provided by a route of administration of injection, orally, intranasally, intraperitoneal, intravenous, subcutaneous, or combinations thereof.

[0128] Another aspect of the present invention includes wherein the at least one cPG compound is provided in a regime of between once per hour to about once per three months.

[0129] A further aspect of the present invention includes wherein the at least one GLP-1 compound is provided in a dose between about 0.1 mg / kg to about 100 mg / kg.

[0130] An additional aspect of the present invention includes wherein the at least one GLP-1 compound is provided by a route of administration of injection, orally, intranasally, intraperitoneal, intravenous, subcutaneous, or combinations thereof.

[0131] An aspect of the present invention includes wherein the at least one GLP-1 compound is provided in a regime of between once per hour to about once per three months.

[0132] Another aspect of the present invention includes wherein the at least one GLP-1 compound is tirzepatide (Zepbound®) subcutaneous injection is provided in a dose of about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 30 mg , about 60 mg, about 120 mg or combinations thereof in about 0.5 ml to 2.00 ml solution.

[0133] A further aspect of the present invention includes wherein the at least one GLP-1 compound is semaglutide (Wegovy®) subcutaneous injection is provided in a dose of about 0.5 mg, about 1.0 mg, about 2.4 mg, about 4.8 mg, about 9.6 mg, about 19.2 mg, or combinations thereof, in about 1.5 ml of solution, for administration to a human subject.

[0134] An additional aspect of the present invention includes wherein the at least one GLP-1 compound is semaglutide (Rybelsus®) tablets is provided in an oral dose of about 1.5 mg, about 3 mg, about 4 mg, about 7 mg, about 9 mg, about 14 mg, about 28 mg, about 56 mg, about 112 mg, or combinations thereof, in about 1 ml to about 2.0 ml of solution, or combinations thereof, for administration to a human subject.

[0135] An aspect of the present invention includes wherein the at least one GLP-1 compound is liraglutide (Saxenda®) subcutaneous injection is provided in a dose of about 0.6 mg, about 1.2 mg, about 1.8 mg, about 2.4 mg, about 3 mg, about 6 mg, about 12 mg, about 24 mg, about 48 mg, or combinations thereof, in about 1.0 ml to about 2.0 ml of solution, or combinations thereof, for administration to a human subject.

[0136] Another aspect of the present invention includes wherein the at least one GLP-1 compound is maridebart cafraglutide (MariTide®) subcutaneous injection is provided in a dose between about 21 mg to about 840 mg or aboutl,680 mg, or combinations thereof, in about 1 .0 ml to about2.0 ml of solution, or combinations thereof, for administration to a human subject.

[0137] IL PHARMACEUTICAL COMPOSITIONS FOR THE PROPHYLAXIS OR TREATMENT OF OBESITY, GLYCEMIC CONTROL, OTHER METABOLIC DISORDERS, OR COMBINATIONS THEREOF

[0138] The present invention includes pharmaceutical compositions for the prophylaxis or treatment of obesity, glycemic control, other metabolic disorders, or combinations thereof, and related conditions and disorders.

[0139] A second aspect of the present invention includes a pharmaceutical composition for the prophylaxis or treatment of obesity, glycemic control, other metabolic disorders, or combinations thereof including: a) at least one cPG compound, optionally in combination with; b) at least one GLP-1 compound; or c) combinations thereof; wherein the components are provided together or separately; further wherein the pharmaceutical composition when administered to a subject in need of prophylaxis or treatment of obesity, glycemic control, other metabolic disorders, or combinations thereof, is so prevented from or treated for the obesity, glycemic control, other metabolic disorders, or combinations thereof

[0140] Any of the components disclosed and described herein can be used as components in this aspect of the present invention, including but not limited to the cPG compounds, the GLP-1 compounds, or combinations thereof.

[0141] III. Detailed Description of Certain Aspects and Embodiments of the Present Invention

[0142] The present invention is directed in part towards compounds that are effective in preventing and treating obesity.

[0143] The present disclosure relates to an improved use of cPG Compound as GLP-1 agonists in therapy. In one embodiment the disclosure relates to certain dosage regimes of cPG Compound which provide improved effect in diseases or conditions, such as prevention and / or treatment of type 2 diabetes and obesity.

[0144] One embodiment the method of the present disclosure provides surprisingly showed improved reduction of HbAlc and reduction of body weight as the result of the oral administration of cPG.

[0145] In one embodiment the disclosure relates to a method for treating or preventing obesity, for reducing body weight and / or food intake, or for inducing satiety, said method comprising administration of a cPG Compound to a subject in need thereof in an amount of at least about 0.5mg / kg to about 10.0 mg / kg per day.

[0146] In one embodiment the method is for reducing body weight and / or food intake. In one embodiment the method is for inducing satiety.

[0147] In one embodiment the cPG Compound is administered orally or by parenteral administration, such as subcutaneous injection.

[0148] In one embodiment the disclosure relates to a composition comprising a cPG Compound and one or more pharmaceutically acceptable excipients for use in the prevention or treatment of obesity, in the reduction of body weight and / or food intake, or in the induction satiety, wherein said cPG Compound is administered in an amount of at least about 1.0 mg / kg to about 3.0 mg / kg per day.

[0149] In one embodiment the disclosure relates to a composition comprising a cPG Compound and one or more pharmaceutically acceptable excipients for use in the prevention or treatment of obesity, in the reduction of body weight and / or food intake, or in the induction satiety, wherein said cPG Compound is administered in an amount of at least about 3.0 mg / kg to about 7.0 mg / kg per day.

[0150] In one embodiment the disclosure relates to a composition comprising a cPG Compound and one or more pharmaceutically acceptable excipients for use in the prevention or treatment of obesity, in the reduction of body weight and / or food intake, or in the induction satiety, wherein said cPG Compound is administered in an amount of at least about 7.0 mg / kg to about 10.0 mg / kg per day.

[0151] In one embodiment the cPG Compound agonist is administered with another therapeutic agent. Administration with another therapeutic agent may be carried out as administration of the GLP-1 agonist and the other therapeutic agent within the same therapeutic window. The treatment with a GLP-1 agonist according to the present disclosure may be combined with one or more additional therapeutic agents, e.g. selected from antidiabetic agents, anti-obesity agents, appetite regulating agents, antihypertensive agents, agents for the treatment and / or prevention of complications resulting from or associated with diabetes and agents for the treatment and / or prevention of complications and disorders resulting from or associated with obesity; examples of these therapeutic agents are: sulphonylureas, thiazolidinediones, biguanides, meglitinides, glucosidase inhibitors, glucagon antagonists, and DPP -IV (dipeptidyl peptidase-IV) inhibitors.

[0152] In one embodiment an "effective amount" of a cPG Compound as used herein means an amount sufficient to cure, alleviate, or partially arrest the clinical manifestations of a given disease or state and its complications. An amount adequate to accomplish this is defined as "effective amount". Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician or veterinary.

[0153] A. c?G COMPOUNDS

[0154] The present invention relates to a composition comprising of cyclic Prolyl Glycine (cPG) and its analogues collective referred herein as cPG Compound or at least one cPG Compound, for the treatment and prevention of obesity.

[0155] The present invention relates to a composition comprising a metabolite of IGF-1, known a cyclic Prolyl Glycine (cPG) and its analogues collective referred herein as cPG Compound, for the treatment and prevention of obesity.

[0156] Cyclic Prolyl Glycine, being a metabolite of IGF-1, regulates IGF-1 by competing with the binding of IGF-1 to insulin-like growth factor binding protein (IGFBP)-3.

[0157] As a result, cPG regulates the homeostasis of quadruple functions agonists: IGF-1, GLP- 1 and GIP and Glucagon receptors.

[0158] Cyclic Glycine-Proline (cGP) regulates the homeostasis of insulin-like growth factor (IGF)-l function and cGP / IGF-1 ratio determines IGF-1 bioactivity in vitro and in vivo. Plasma IGF-1 represents largely inactive IGF-1 and weakly associated with human obesity and hypertension, (see, Li, Fengxia; Liu, Karen; Wang, Ao; Harris, Paul W.R.; Vickers, Mark H.; Guan, Jian (2019). Cyclic glycine-proline administration normalizes high-fat diet-induced synaptophysin expression in obese rats. Neuropeptides, (), S0143417919300198-. doi: 10.1016 / j.npep.2019.05.006). Cyclic Prolyl Glycine (“cyclic PG” or “cPG”) has the following structure:

[0159] Structure 1 : cyclic Prolyl Glycine

[0160] The present invention includes novel diketopiperazines that are structurally related to cPG.

[0161] One aspect of this invention provides novel cyclic compounds having the structural formula and substituents described below.

[0162] Structure 2: cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl-Alkyl Proline referred herein as “cGAL”.

[0163] Where R can be an Alkyl” which refers to a saturated branched, straight chain or cyclic hydrocarbon radical. Exemplary alkyl groups include methyl, ethyl, isopropyl, cyclopropyl, tertbutyl, cyclopropylmethyl, hexyl and the like.

[0164] Where R can be an Ally, which refer to a group is a substituent with the structural formula H2OCH-CH2R, where R is the rest of the molecule.

[0165] With R is a methyl, an aspect of the present invention that includes Cyclic Glycyl-2- Alkyl Proline is (8aS)-Methyl-hexahydropyrrolo[l,2-a]pyrazine-l, 4-dione, which is referred to as Cyclic Glycyl-2- Methyl-Proline or cyclicGMeP or cGMeP.

[0166] Structure 3 : Cyclic G-2MeP (which is available for purchase from polypeptide suppliers such as Bachem Americas, Inc. (Torrance, California, USA)).

[0167] In general, c(PG)3 and cGAL can be prepared by methods such as are already well-known to persons of ordinary skill in the art of peptide and modified peptide synthesis. See for example, Bodanzsky: Principles of Peptide Synthesis, Berlin, New York: Springer- Verlag 1993. Synthesis of the diketopiperazine compounds of this invention may be by solution-phase synthesis as discussed in the Examples or via the solid-phase synthesis method exemplified by Merrifield et al 1963 J Amer. Chem. Soc.: 85, 2149-2156. Specific examples of diketopiperazine synthesis can be found in Fischer, 2003, J. Peptide Science: 9: 9-35 and references therein. A person of ordinary skill in the art will have no difficulty, taking account of that skill and the knowledge available, and of this disclosure, in developing one or more suitable synthetic methods for compounds of this invention.

[0168] In the present application, notably but not limited to this section where compound names and structures and abbreviations are provided, the various compounds can all be used in all aspects of the present invention included herein. For example, should cPG be indicted in the specification, then all other compounds of this section (and the application as a whole) that are cPG compounds and related derivatives such as but not limited to cGAL are included in that and other descriptions, notably but not limited to methods of treatment of a variety of conditions described herein.

[0169]

[0170] Structure 4: one possible structure for cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl)

[0171] The chemical synthesis of cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) was carried out as published in Israel Journal of Chemistry, Vol. 12, Nos. 1-2, 1974, pp. 15-29 “CYCLIC Peptides VII: The Synthesis and Characterization of Cyclic Peptides with Repeating Pro-Gly Sequences- by Charles M. Deber and Elkan R. Blout.

[0172] Synthesis of Cyc / o(glycyl-L -prolyl-glycyl-L -prolyl-glycyl-L -prolyl)

[0173] A solution of p-nitrophenyl ester hydrochloride (500 mg) dissolved in dimethyl-formamide (DMF) (20 ml, dried over sodium sulfate) was added dropwise with stirring over 6 hours to 500 ml of reagent-grade pyridine, at room temperature. The bright yellow mixture was constantly stirred over 48 hours at room temperature. Solvents were removed by rotary-evaporator-high vacuum pump system at 45°. The residue was washed with 20 ml of acetone which dissolved the p-nitrophenol and pyridine hydrochloride, but left the peptidic fraction insoluble. The insoluble materials and acetone were transferred to a flask and allow acetone to evaporate at 45°. The material was then dissolved in a minimum of DMF. The white microcrystalline precipitate was shown to be Cyc / o(glycyl-L -prolyl- glycyl-L -prolyl-glycyl-L -prolyl) (155 mg, with 28% yield), formed complexed with DMF. Crystallization from methanol-ether of 100 mg of this material gave crystalline cyclo(Pro-Gly)j (55 mg) free of DMF.

[0174] Chemical analysis: Calculated for C21H3ON6O6H2O : C, 52.49; H, 6.71; N, 17.49. Elemental analysis found C, 52.60; H, 6.81; N, 17.38.

[0175] In still other aspects, present invention provides pharmaceutical compositions including a pharmaceutically acceptable excipient or carrier and a therapeutically effective amount of cyclic GP or its analogues with structural formulas given above to treat a disease, disorder, or condition, including but not limited to Alzheimer’s disease and its related conditions such an impairment of cognitive function.

[0176] B, GITA. COMPOUNDS

[0177] 1. Tirzepatide, also known as ZEPBOUND® (Eli Lilly)

[0178] ZEPBOUND® is a glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide- 1 (GLP-1) receptor agonist indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of 30 kg / m2 or greater (obesity) or 27 kg / m2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea or cardiovascular disease).

[0179] The recommended starting dosage is 2.5 mg injected subcutaneously once weekly. The recommended maintenance dosages are 5 mg, 10 mg, or 15 mg injected subcutaneously once weekly. (United States Food and Drug Administration: https: / / www.fda.gov / drugsatfda)

[0180] 2. Semaglutide, also known as WEGOVY® (Novo Nordisk)

[0181] WEGOVY is a glucagon-like peptide- 1 (GLP-1) receptor agonist indicated as an adjunct to a reduced calorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index (BMI) of 30 kg / m2 or greater (obesity) or 27 kg / m2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e g., hypertension, type 2 diabetes mellitus, or dyslipidemia), or in pediatric patients aged 12 years and older with an initial BMI at the 95th percentile or greater for age and sex (obesity).

[0182] WEGOVY is administered once weekly, on the same day each week, at any time of day, with or without meals. (United States Food and Drug Administration: https: / / www.fda.gov / drugsatfda).

[0183] 3. Semaglutide oral- also known as RYBELSUS® (Novo Nordisk)

[0184] RYBELSUS is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Available as tablets: 3 mg, 7 mg and 14 mg. Recommended dosages: Start RYBELSUS with 3 mg once daily for 30 days. After 30 days on the 3 mg dose, increase the dose to 7 mg once daily. Dose may be increased to 14 mg once daily if additional glycemic control is needed after at least 30 days on the 7 mg dose (United States Food and Drug Administration: https: / / www.fda.gov / drugsatfda).

[0185] 4. Maridebart cafraglutide- also known as MariTide (Amgen)

[0186] MariTide is an investigational drug, an agonist of the GLP-1 receptor (GLP-1R) and an antagonist of the glucose-dependent insulinotropic polypeptide receptor (GIPR). Namely, MariTide consists of a monoclonal antibody against GIPR conjugated to two peptidic GLP-1R agonist molecules via amino acid linkers.

[0187] EXAMPLES

[0188] Experiment 1: Effect of cyclic Prolyl Glycine (cPG) on Blood Glucose and Body Weight

[0189] The purpose of the study is to verify the effect of cyclic Prolyl Glycine (cPG, or NA-931) on blood glucose (BG) and body weight (BW) in a diabetic setting. cPG was tested in a doseresponse study in an obese, diabetic mouse model (db / db mice) as described in the following.

[0190] The db / db mice are perfect animal models of type 2 diabetes. Mice that are homozygous for the diabetes spontaneous mutation (Leprdb) demonstrate morbid obesity, chronic hyperglycemia, pancreatic beta cell atrophy and come to be hypoinsulinemic fifty-six db / db mice fed from birth with the diet NIH31 (NIH 3 IM Rodent Diet, commercially available from Taconic Farms, Inc., US), are enrolled for the study at the age of 7-9 weeks. The mice are given free access to standard chow (e.g. Mazuri, San Jose, CA, USA) and tap water and kept at 24°C. After 1-2 weeks of acclimatization, the basal blood glucose is assessed twice on two consecutive days (i.e. at 9 am). The 8 mice with the lowest blood glucose values may be excluded from the experiments. Based on the mean blood glucose values, the remaining 56 mice may be selected for further experimentation and allocated to 6 groups (n=8) with matching blood glucose levels. The mice may be used in experiments with duration of 5 days for up to 4 times. After the last experiment the mice are euthanized.

[0191] The seven groups may receive treatment as follows:

[0192] 1 : Placebo, oral

[0193] 2: cPG: 0.1 mg / kg, oral 3: cPG: 0.5 mg / kg, oral

[0194] 4: cPG: 1.0 mg / kg, oral

[0195] 5: cPG: 1.5 mg / kg, oral

[0196] 6: cPG: 2.0 mg / kg, oral

[0197] On the day of dosing, blood glucose is assessed at the time right after the mice are weighed (about 8:30 am). Test solution cPG: 0.5 mg / kg, oral is dosed at approximately 9 am (time 0). On the day of dosing, blood glucose is assessed e.g. at times 1, 2, 4 and 7 h (10 am, 11 am, 1 pm and 4 pm).

[0198] On the following days, the blood glucose is assessed e.g. at time 24, 48, 72, and 96 hours after dosing (i.e. at 9 am on day 2, 3, 4, 5). On each day, the mice are weighed following blood glucose sampling.

[0199] Samples for the measurement of blood glucose are obtained from the tail tip capillary of conscious mice. Blood, 10 ml, is collected into heparinized capillaries and transferred to 500 ml glucose buffer (Millipore Sigma, New Zealand). The glucose concentration is measured using the glucose oxidase method (Mediray, New Zealand). The samples are kept at room temperature for up to 1 h until analysis. If analysis has to be postponed, samples are kept at 4°C for a maximum of 24 h.

[0200] ED50 is the dose giving rise to half-maximal effect in nmol / kg. This value is calculated on the basis of the ability of cPG to lower body weight as well as the ability to lower blood glucose, as explained below.

[0201] ED50 for body weight is calculated as the dose giving rise to half-maximum effect on delta BW 24 hours following the oral administration of cPG. For example, if the maximum decrease in body weight after 24 hours is 4.0 g, then ED50 bodyweight would be that dose in nmol / kg which gives rise to a decrease in body weight after 24 hours of 2.0 g. This dose (ED50 body weight) may be read from the dose-response curve.

[0202] Sample analysis:

[0203] HPLC analysis: 10 ml of the samples are analyzed by HPLC using a Waters System with a BEH C18 (1.7 mm 2.1 x 50 mm) column and a 30 to 65% gradient of 0.1% TFA and 0.07% TFA in acetonitrile over 5 minutes at a flow rate of 0.6 ml / min. After baseline subtraction the peak integrals of the intact compounds in the HPLC chromatogram recorded at a wavelength of 214 nm are determined.

[0204] FIG. 1 shows body weight change vs. concentration of cPG from baseline at week 12. **p<0.001 vs. placebo; ***p<0.0001 vs. placebo (based on adjusted means, f: Baseline values for information only: data are model-adjusted for baseline weight. Data are model-adjusted LS means, FAS LOCF. The estimates are from an ANOVA model with treatment, country and treatment as fixed effects and baseline weight as covariate.

[0205] Experiment 2: Animal Study of cPG, cGAL and cGMEP: Body Weight Change, Change in Blood Glucose, Change in Plasma Triglycerides and Change in Liver Triglycerides

[0206] Methods:

[0207] Studies were approved by and performed according to the guidelines of the Institutional Animal Care. Male C57BL / 6J mice (The Jackson Laboratory-Sacramento, California) were housed 4 per cage, exposed to a controlled 12 h / 12 h light-dark cycle at room temperature (22 °C), and provided ab libitum access to water and a 58% fat, high-sugar diet (D 12331, Research Diets) for 12 weeks. Mice exceeding 50 g of body weight were considered diet-induced obese (DIO) and included in studies, where they were randomized and evenly distributed to test groups (n = 8 per group) according to body weight.

[0208] Test compounds including: cyclic Prolyl Glycine (cPG), cyclic Glycyl-2-Allyl Proline (cGAL), and Cyclic Glycyl-2-Methyl-Proline (cGMeP) and Semaglutide at 10 nmol / kg dissolved in a vehicle (pH 7.4) containing 0.05% polysorbate-80, 50 mM sodium phosphate, and 70 mM sodium chloride were administered subcutaneously once daily, unless otherwise noted, during the light cycle for each day of treatment at a volume of 5 pL per gram of body weight as necessary to achieve the desired dose. Semaglutide was used as a positive reference control.

[0209] In a combination treatment, a solution containing cPG (5 nmol / kg) and Semaglutide (5 nmol / kg) in 5 pL was tested. Cohorts were then assessed for changes in BW, glucose, plasma triglycerides and liver triglycerides.

[0210] Body weight and food intake were measured immediately prior to dosing each day. The percent change in body was calculated individually for each mouse based on initial body weight prior to the first injection. For intraperitoneal (i.p.) glucose tolerance tests (IPGTT), animals were fasted for 6 h prior to the test but had access to water. Fasted blood glucose levels were measured, then mice were injected with an i.p. glucose load of 2 g / kg from a 200 mg / mL aqueous glucose solution. Tail blood glucose levels were measured 0, 15, 30, 60, 90, and 120 min following the glucose load using a handheld glucometer (FreeStyle Libre 3 System Abbott).

[0211] FIG. 2 shows Body Weight Change of cPG, cGAL, cGMeP and Semaglutide vs. Vehicle.

[0212] FIG. 3 shows Change in Blood Glucose of cPG, cGAL, cGMeP and Semaglutide vs. Vehicle. FIG. 4 shows Change in Plasma Triglycerides of cPG, cGAL, cGMeP and Semaglutide vs. Vehicle.

[0213] FIG. 5 shows Change in Liver Triglycerides of cPG, cGAL, cGMeP and Semaglutide vs.

[0214] Vehicle.

[0215] Conclusion:

[0216] The results of the animal studies of cPG Compound and Tirzepatide have demonstrated a proof of concept, leading to the following conclusions:

[0217] • A novel series of cPG Compounds produced significant reductions in body weight, plasma triglycerides, and liver triglycerides compared with the vehicle in a 14-day study conducted in DIO-NASH mice.

[0218] • Treatment with cPG Compounds resulted in reductions in body weight (up to 27%, p<0,0001), compared to Tirzepatide (30%), and a combination of cPG Compounds with Tirzepatide (34%) relative to vehicle treatment.

[0219] • Treatment with cPG Compounds reduced plasma glucose levels by 23%, compared to Tirzepatide (24%), and the combination therapy with Tirzepatide (30%).

[0220] • Treatment with cPG Compounds reduced plasma triglycerides by 35%, compared to Tirzepatide (31%), and the combination therapy with Tirzepatide (40%).

[0221] • Treatment with cPG Compounds reduced liver triglycerides by 29%, compared to Tirzepatide (21%), and the combination therapy with Tirzepatide (39%).

[0222] • There is evidence of potential synergy in the combination therapy of cPG Compounds and Tirzepatide.

[0223] Experiment 3: Animal Study of cPG, cGAL and cGMEP: Body Weight Change, Change in Blood Glucose, Change in Plasma Triglycerides and Change in Liver Triglycerides

[0224] Methods:

[0225] Studies were approved by and performed according to the guidelines of the Institutional Animal Care. Male C57BL / 6J mice (The Jackson Laboratory-Sacramento, California) were housed 4 per cage, exposed to a controlled 12 h / 12 h light-dark cycle at room temperature (22 °C), and provided ab libitum access to water and a 58% fat, high-sugar diet (D 12331, Research Diets) for 12 weeks. Mice exceeding 50 g of body weight were considered diet-induced obese (DIO) and included in studies, where they were randomized and evenly distributed to test groups (n = 8 per group) according to body weight.

[0226] Test compounds including: cyclic Prolyl Glycine (cPG), cyclic Glycyl-2-Allyl Proline (cGAL), and Cyclic Glycyl-2-Methyl-Proline (cGMeP) and Semaglutide at 10 nmol / kg dissolved in a vehicle (pH 7.4) containing 0.05% polysorbate-80, 50 mM sodium phosphate, and 70 mM sodium chloride were administered subcutaneously once daily, unless otherwise noted, during the light cycle for each day of treatment at a volume of 5 pL per gram of body weight as necessary to achieve the desired dose. Semaglutide was used as a positive reference control.

[0227] In a combination treatment, a solution containing cPG (5 nmol / kg) and Semaglutide (5 nmol / kg) in 5 pL was tested. Cohorts were then assessed for changes in BW, glucose, plasma triglycerides and liver triglycerides.

[0228] Body weight and food intake were measured immediately prior to dosing each day. The percent change in body was calculated individually for each mouse based on initial body weight prior to the first injection. For intraperitoneal (i.p.) glucose tolerance tests (IPGTT), animals were fasted for 6 h prior to the test but had access to water. Fasted blood glucose levels were measured, then mice were injected with an i.p. glucose load of 2 g / kg from a 200 mg / mL aqueous glucose solution. Tail blood glucose levels were measured 0, 15, 30, 60, 90, and 120 min following the glucose load using a handheld glucometer (FreeStyle Libre 3 System Abbott).

[0229] FIG. 6 shows Body Weight Change of cPG, cGAL, cGMeP and Semaglutide vs. Vehicle

[0230] FIG. 7 shows Change in Blood Glucose of cPG, cGAL, cGMeP and Semaglutide vs. Vehicle FIG. 8 shows Change in Plasma Triglycerides of cPG, cGAL, cGMeP and Semaglutide vs. Vehicle

[0231] FIG. 9 shows Change in Liver Triglycerides of cPG, cGAL, cGMeP and Semaglutide vs.

[0232] Vehicle

[0233] Conclusion:

[0234] The results of the animal studies of cPG Compound and Semaglutide have demonstrated a proof of concept, leading to the following conclusions:

[0235] • A novel series of cPG Compounds produced significant reductions in body weight, plasma triglycerides, and liver triglycerides compared with the vehicle in a 14-day study conducted in DIO-NASH mice. • Treatment with cPG Compounds resulted in reductions in body weight (26%, p<0.0001), compared to Semaglutide (28%), and a combination of cPG Compounds with Semaglutide (33%) relative to vehicle treatment.

[0236] • Treatment with cPG Compounds reduced plasma glucose levels by 22%, compared to Semaglutide (23%), and the combination therapy with Semaglutide (32%).

[0237] • Treatment with cPG Compounds reduced plasma triglycerides by 36%, compared to Semaglutide (29%), and the combination therapy with Semaglutide (43%).

[0238] • Treatment with cPG Compounds reduced liver triglycerides by 29%, compared to Semaglutide (24%), and the combination therapy with Semaglutide (45%).

[0239] • There is evidence of potential synergy in the combination therapy of cPG Compounds and Semaglutide

[0240] Experiment 4: Clinical trial of cPG Compound for the treatment of obesity over 28 days

[0241] A randomized, double-blind, placebo-controlled, dose escalation, human study was conducted to assess the safety and tolerability, of NA-931 when administered as single and multipleascending doses in overweight / obese participants and as multiple doses in patients with Type 2 Diabetes Mellitus. Reference: ClinicalTrials.gov ID NCT06615700 (https: / / clinicaltrials.gov / study / NCT06564753?term=NA-931&rank=l)

[0242] Cyclic Prolyl Glycine (herein referred as NA-931, a code name in clinical trial) has been found to act as a quadruple receptor agonist for Insulin Like Growth Factor 1 (IGF-1), Glucagon-like Peptide- 1 (GLP-1), Gastric Inhibitory Polypeptide (GIP) and Glucagon.

[0243] Participation Criteria:

[0244] 74 participants including male and female, 18 Years to 65 years old who met the following inclusion and exclusion criteria, are described in the Table 1.

[0245] Inclusion Criteria:

[0246] • Participants 18-65 years old, inclusive

[0247] • BMI of 25 - 40, inclusive

[0248] • Stable body weight for two months

[0249] • Participants must be capable of giving signed informed consent • Willing and able to comply with scheduled visits, treatment plan, laboratory

[0250] • tests and other clinical study procedures

[0251] • Willing to comply with contraception requirements

[0252] Exclusion Criteria:

[0253] • History of significant medical conditions and malignancy

[0254] • Uncontrollable hypertension

[0255] • History of alcoholism or drug addiction within 1 year prior to Screening

[0256] • Current or recent participation in an investigational clinical trial

[0257] • Any surgical or medical condition (active or chronic) that may interfere with

[0258] • IP distribution, metabolism, excretion, or drug absorption

[0259] Arms and Interventions

[0260] TABLE 1: Demographic Profile of Participants

[0261] BMI: Body Mass Index

[0262] HbAlc: A hemoglobin A1C (HbAlC) test is a blood test that shows what your average blood sugar (glucose) level was over the past two to three months

[0263] HOMA-IR: Homeostatic Model Assessment for Insulin Resistance

[0264] RESULTS

[0265] Efficacy Study

[0266] NA-931 is once-daily, oral small molecule quadruple receptor agonist being developed for the treatment of both type 2 diabetes and obesity.

[0267] The data showed that treatment with NA-931 in participants with obesity and without type 2 diabetes resulted in a clinically meaningful placebo-adjusted mean weight loss of -6.4%, and 4.7% relative to placebo, within four weeks (p <0.001).

[0268] NA-931 was well tolerated, with no significant gastrointestinal-related adverse events, which is safer than the profile of the incretin drug class. There was no treatment discontinuations related to the study drug. The study results also showed that blood levels of NA-931 were largely unaffected either during fasting or after a standardized high-fat meal. Thus, NA-931 could potentially be dosed without regard to meal timing, thereby affording greater dosing flexibility for patients.

[0269] Based on the study data, NA-931 is anticipated to be used not only as a therapy for achieving glycemic control and inducing weight loss, but also potentially for oral weight maintenance therapy following weight loss induced by injectables.

[0270] Body Weight Reductions

[0271] The 28-day MAD study results highlight positive signs of clinical activity following treatment with oral NA-931 . Cohorts receiving NA-931 demonstrated dose-dependent reductions in mean body weight from baseline, ranging up to 6.8% at 150 mg daily dosage, or 5.1% relative to placebo.

[0272] After 28-day study, an open label follow-up study for 8 weeks, a total of 12 weeks.

[0273] The 12-week MAD study showed NA-931 demonstrated dose-dependent reductions in mean body weight from baseline, ranging up to 12.7% at 150 mg daily dosage, or 10.4% % relative to placebo. . Based on a preliminary evaluation of weight loss trajectory, the company believes that treatment duration beyond 28 days may provide further reductions in body weight.

[0274] TABLE 2: 28 day- EFFICACY- Phase 1 to study NA-931 in participants who are overweight or obese, and patients with type 2 diabetes Notes:

[0275] 1) Population includes all randomized subjects who received at least one dose of study drug and had at least one planned post-baseline body weight assessment.

[0276] 2) Patients treated with NA-931 were titrated to final doses as indicated:

[0277] • 30 mg cohort = 30 daily x 4 weeks;

[0278] • 60 mg cohort = 30 mg daily x 1 wk, 60 mg daily x 3 wks;

[0279] • 90 mg cohort = 60 mg daily x 1 wk, 90 mg daily x 3 wks;

[0280] • 120 mg cohort =90 mg daily x 1 wk, 120 mg daily x 3 wks;

[0281] • 150 mg cohort = 120 mg daily x 1 wk, 150 mg daily x 3 wks.

[0282] 3) All subjects enrolled were required to have baseline BMI >30 kg / m2.

[0283] 4) Least squares mean.

[0284] 5) Two-sided t test using mixed model for repeated measures.

[0285] TABLE 3: 12 weeks- EFFICAY- Phase 1 to study NA-931 in participants who are overweight or obese, and patients with type 2 diabetes

[0286] After the initial 28 days, the study was continued as an open label for 8 weeks. A total of 12 week. Notes:

[0287] 1) Population includes all randomized subjects who received at least one dose of study drug and had at least one planned post-baseline body weight assessment.

[0288] 2) Patients treated with NA-931 were titrated to final doses as indicated:

[0289] • 60 mg cohort = 30 mg daily x 1 wk, 60 mg daily x 3 wks; opened label, treatment continued for 8 weeks

[0290] • 90 mg cohort = 60 mg daily x 1 wk, 90 mg daily x 3 wks; opened label, treatment continued for 8 weeks

[0291] • 120 mg cohort =90 mg daily x 1 wk, 120 mg daily x 3 wks; opened label, treatment continued for 8 weeks

[0292] • 150 mg cohort = 120 mg daily x 1 wk, 150 mg daily x 3 wks, opened label, treatment continued for 8 weeks

[0293] 3) All subjects enrolled were required to have baseline BMI >30 kg / m2.

[0294] 4) Least squares mean.

[0295] 5) Two-sided t test using mixed model for repeated measures.

[0296] SAFETY STUDY

[0297] 28 Day Study: Among subjects receiving NA-931, all treatment emergent adverse events (TEAEs) reported to date have been insignificant or mild, with the majority (85%) reported as insignificant.

[0298] Similarly, all observed gastrointestinal (GI) adverse events have been reported as insignificant or mild, with the majority (83%) reported as insignificant. Mild nausea was reported in two (5.8%) NA-931 -treated subjects at highest dose of 150 mg / day

[0299] Vomiting was reported in 1 subject (2.9%) at a high dose of 150 mg / day amongst 34 NA-931 -treated subjects. Diarrhea was reported in 1 subject (2.9%) receiving NA-931 compared with 1 subject (10%) receiving placebo. TABLE 4: 28 day- SAFETY- Phase 1 to study NA-931 in participants who are overweight or obese, and patients with type 2 diabetes

[0300] 12 Week Study: Among subjects receiving NA-931, all treatment emergent adverse events (TEAEs) reported to date have been insignificant or mild, with the majority (70%) reported as insignificant.

[0301] Similarly, all observed gastrointestinal (GI) adverse events have been reported as insignificant or mild, with the majority (75%) reported as insignificant. Mild nausea was reported in two (15.9%) NA-931 -treated subjects at highest dose of 150 mg / day

[0302] Vomiting was reported in 2 subject (5.8%) at a high dose of 150 mg / day amongst 34 NA-931 -treated subjects. Diarrhea was reported in 2 subject (5.8%) receiving NA-931 compared with one subjects (10%) receiving placebo. TABLE 5: 12 Week- SAFETY- Phase 1 to study NA-931 in participants who are overweight or obese, and patients with type 2 diabetes

[0303] FUNCTIONAL PROPERTIES

[0304] In a first functional aspect, the cPG Compound which acts as a GLP-1 agonist of the disclosure have a good potency. Also, or alternatively, in a second functional aspect, the GLP-1 agonists of the disclosure have a protracted pharmacokinetic profile. Also, or alternatively, in a third functional aspect, the GLP-1 agonists of the disclosure are stable against degradation by gastrointestinal enzymes.

[0305] The cPG Compound of the invention have GLP-1 activity. In one embodiment "a GLP-1 agonist" is understood to refer to any compound, including peptides and non-peptide compounds, which fully or partially activate the human GLP-1 receptor.

[0306] The diabetic db / db mouse is one example of a suitable animal model, and the blood glucose lowering effect may be determined in such mice in vivo. PHARMACEUTICAL DOSAGES - VARIOUS EMBODIMENTS

[0307] An administered dose may contain from 0.5mg to 1.5 mg / kg or between 30 mg to 150 mg for a typical adult of 70 kg weight, or between 60 mg to 150 mg for obese person normally weighing 80 -120 kg

[0308] An administered dose may range from 0.5 mg to 1.5 mg / kg, which corresponds to 30 mg to 90 mg for a typical 70 kg adult, or 60 mg to 180 mg for an obese individual weighing between 80 kg and 120 kg.

[0309] Pharmaceutical compositions comprising a pharmaceutically acceptable salt, amide, or ester thereof, and a pharmaceutically acceptable excipient may be prepared as is known in the art.

[0310] A composition may be administered in several dosage forms, for example as a solution; a suspension; emulsion; a microemulsion; multiple emulsions; a foam; a salve; a paste; a plaster; an ointment; a tablet; a coated tablet; a chewing gum; a rinse; a capsule such as hard or soft gelatin capsules; a suppositories; a rectal capsule; drops; a gel; a spray; a powder; an aerosol; an inhalant; eye drops; an ophthalmic ointment; an ophthalmic rinse; a vaginal pessary; a vaginal ring; a vaginal ointment; an injection solution; an in situ transforming solution such as in situ gelling, setting, precipitating, and in situ crystallization; an infusion solution; or as an implant.

[0311] A composition may further be compounded in a drug carrier or drug delivery system, e.g. in order to improve stability, bioavailability, and / or solubility. In a particular embodiment a composition may be attached to such system through covalent, hydrophobic, and / or electrostatic interactions. The purpose of such compounding may be, e.g., to decrease adverse effects, achieve chronotherapy, and / or increase patient compliance.

[0312] A composition may also be used in the formulation of controlled, sustained, protracting, retarded, and / or controlled release drug delivery systems.

[0313] The composition may be administered by parenteral administration. Parenteral administration may be performed by subcutaneous, intramuscular, intraperitoneal, or intravenous injection by means of a syringe, optionally a pen-like syringe, or by means of an infusion pump.

[0314] Pharmaceutical compositions are well known in the medical arts and can include formulations in solid form such as a tablet to be administered orally. Formulations of the present invention can also include liquid, gel, semisolid, colloidal, vapor and gas phase formulations capable of oral, nasal, bronchial, intestinal, or colonic (anal and perianal) delivery. In one embodiment, the compositions of the present invention are administered mucosally (for example, to the mucosa of the subject). By mucosa is meant anybody mucosa including oral, nasal, bronchial, esophageal, intestinal, and anal or perianal.

[0315] It will be recognized to the skilled clinician, choice of a carrier, including a physiologically acceptable compound, depends, for example, on the manner in which the peptide or encoding polynucleotide is to be administered, as well as on the route of administration of the composition and its dose. Where the composition is administered under immunizing conditions, for example, as a vaccine, it generally is administered intramuscularly, intradermally, or subcutaneously, but also can be administered parenterally such as intravenously, and can be administered by injection, intubation, or other such method known in the art. Where the desired modulation of the immune system is tolerization, the composition preferably is administered orally, or can be administered as above.

[0316] The term "therapeutically effective amount" or "effective amount" means the amount of a compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. Thus, the total amount of a composition to be administered in practicing a method of the present invention can be administered to a subject as a single dose, either as a bolus or by infusion over a relatively short period of time, and can be followed up with one or more booster doses over a period of time. The amount of the composition to stimulate an immune response in a subject depends on various factors including the age and general health of the subject, as well as the route of administration and the number of treatments to be administered. In view of these factors, the skilled clinician will know to adjust the particular dosage as necessary.

[0317] The total amount of a compound or composition to be administered in practicing a method of the present invention can be administered to a subject as a single dose, either as a bolus or by infusion over a relatively short period of time, or can be administered using a fractionated treatment protocol, in which multiple doses are administered over a prolonged period of time. One skilled in the art would know that the amount of the compositions of the present invention to treat SARS in a subject depends on many factors including the age and general health of the subject as well as the route of administration and the number of treatments to be administered. In view of these factors, the skilled artisan would adjust the particular dose as necessary. In general, the formulation of the pharmaceutical composition and the routes and frequency of administration are determined, initially, using Phase I and Phase II clinical trials. All of the compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and methods and in the steps or in the sequence of steps of the method described herein without departing from the spirit and scope of the present invention. More specifically, the described embodiments are to be considered in all respects only as illustrative and not restrictive. All similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit and scope of the present invention as defined by the appended claims.

[0318] Alternatively, or additionally, additional antiviral agent may optionally be unsuitable for the frequency of administration of the composition, for example, wherein the composition is formulated for administration once per day, and the additional antiviral agent is more suitable for administration once per week (for example., a PEGylated interferon-alpha).

[0319] The composition may be, for example, in the form of a liquid, a semi-solid (for example, gel), or solid.

[0320] In some embodiments of the present invention, the composition is in a solid form. Examples of solid forms for a composition include, without limitation, a tablet, a capsule (for example, comprising an encapsulated solid), a caplet, a powder, microspheroids, and granules.

[0321] The composition is preferably formulated in accordance with the intended frequency of administration of the composition. This, in turn, will depend on the properties of the active agents. As discussed herein, artemether and atazanavir may be administered, for example, once per day, but also at other frequencies (for example, twice or thrice a day).

[0322] It is to be appreciated that an active agent can be made more suitable for less frequent administration (for example, once per day, as is particularly convenient, instead of twice or more per day) by formulating a composition appropriately, for example, by formulating the composition for slow release of the active agents therein.

[0323] Slow release preparations typically include slow release biodegradable carriers. Slow release biodegradable carriers are well known in the art. These are materials that may form particles that may capture therein an active compound(s) and slowly degrade / dissolve under a suitable environment (for example, aqueous, acidic, basic, etc.) and thereby degrade / dissolve in body fluids and release the active compound(s) therein. The particles are preferably nanoparticles (for example, in the nanometer range, for example, in the range of about 1 to about 500 nm in diameter, preferably about 50 to about 200 nm in diameter, most preferably about 100 nm in diameter).

[0324] Oral slow-release forms are often designed to maintain therapeutic drug concentrations for greater than 12 hours. The absorption rate can be controlled by coating drug particles with wax or other water-insoluble material, by embedding the drug in a matrix from which it is released slowly during transit through the GI tract, or by complexing the drug with ion-exchange resins.

[0325] Thus, for example, a slow-release formulation in tablet form, can be based on the use of a hydrophilic polymer which swells in contact with gastrointestinal fluids, to form a gel, which creates a barrier that enrobes the tablet. The barrier limits physical exchanges between the inside of the tablet and the surrounding medium. As a consequence, intrusion of water towards the tablet matrix and diffusion of drug are slowed down, allowing a controlled slow release of the drug.

[0326] Various types of polymers may be used as a matrix for the slow-release of drugs, such as polyvinyl chloride, polyethylene polyamides, ethylcellulose, silicone, poly (hydroxyethyl methacrylate), other acrylic co-polymers, and polyvinylacetate-polyvinyl chloride copolymers.

[0327] In some embodiments of the present invention, the composition is a unit dosage form (for example, a unit dosage form formulated for oral administration).

[0328] Pharmaceutical compositions can be administered by an appropriate route of administration at an appropriate dose and an appropriate regime.

[0329] Pharmaceutical compositions for use in accordance with embodiments of the present invention thus may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredients (artemether and antiviral agents described herein) into preparations which, can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.

[0330] For injection, the active ingredient(s) of embodiments of the present invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer with or without organic solvents such as propylene glycol, polyethylene glycol.

[0331] For oral administration, the active ingredients can be formulated readily by combining the active ingredients described herein with pharmaceutically acceptable carriers well known in the art. Such carriers enable the active ingredient(s) to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient. Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose; and / or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0332] Pharmaceutical compositions, which can be used orally, include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active ingredients described herein may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration.

[0333] The active ingredients described herein can be formulated for parenteral administration, for example, by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, for example, in ampoules or in multidose containers with optionally, an added preservative. The compositions may be suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents.

[0334] Pharmaceutical compositions for parenteral administration include aqueous solutions of the active ingredients. Additionally, suspensions of the active ingredients may be prepared as appropriate oily injection suspensions and emulsions (for example, water-in-oil, oil-in-water or water-in-oil in oil emulsions). Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the active ingredients to allow for the preparation of highly concentrated solutions.

[0335] Alternatively, the active ingredients may be in powder form for constitution with a suitable vehicle, for example, sterile, pyrogen-free water, before use. The active ingredients of embodiments of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, for example, conventional suppository.

[0336] For administration by inhalation, the active ingredient(s) for use according to embodiments of the present invention are conveniently delivered in the form of an aerosol spray presentation (which typically includes powdered, liquefied and / or gaseous carriers) from a pressurized pack or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the active ingredient(s) and a suitable powder base such as, but not limited to, lactose or starch.

[0337] The choice of drug delivery methods requires understanding of tissue distribution, metabolism and cellular effects as well as an understanding of the interaction of the drug with the specific underlying pathological processes of the disease under treatment, for which general and specific teaching are available in the art.

[0338] Because the route of drug administration determines bioavailability and tissue levels and distribution, change in delivery may modify fundamentally the location, nature, extent and duration of disease condition, as well as alter dosing requirements and toxicities.

[0339] However, it was observed that when artemether is administered locally via nasal delivery system in vivo, the drug was adsorbed quickly with more bioavailability and short duration of action in treating the fever very quickly than when administered systemically.

[0340] For pulmonary delivery, a therapeutic composition of the invention can be formulated and administered to the patient in solid or liquid particulate form by direct administration for example, inhalation into the respiratory system.

[0341] Solid or liquid particulate forms of the active compound prepared for practicing the present invention include particles of respirable size: that is, particles of a size sufficiently small to pass through the mouth and larynx upon inhalation and into the bronchi and alveoli of the lungs. In general, particles ranging from about 1 to about 10 microns in size are within the general respirable range. The therapeutic composition containing the anti-malarial and antiviral compounds are preferably administered by direct inhalation into the respiratory system for delivery as a mist or other aerosol or dry powder. The dosage of active compound via this route may vary depending on the condition being treated and the state of the subject, but generally may be an amount sufficient to achieve dissolved concentrations of anti-malarial and antiviral compound on the airway surfaces of the subject. Depending upon the solubility of the particular formulation of active compound administered, the daily dose may be divided among one or several unit dose administrations. The daily dose administered via direct inhalation is normally much less than oral dose. For example, a daily dose of artemether administered via direct inhalation ranges from 20 to 40 mg per day and Atazanavir from about 25 mg to about 100 mg per day. The doses of the active compounds can be provided as one or several prepackaged units.

[0342] Aerosols of liquid particles can be produced by any suitable means, such as inhalatory delivery systems. One is a traditional nebulizer which works in a mechanism similar to the familiar perfume atomizer. The airborne particles are generated by a jet of air from either a compressor or compressed gas cylinder-passing through the device (pressure driven aerosol nebulizer) (U.S. Pat. No. 4,501,729- “Aerosolized amiloride treatment of retained pulmonary secretions”).

[0343] While various embodiments of the present invention have been described above, it should be understood that they have been presented by way of examples only, and not limitation. It will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the spirit and scope of the present invention as defined in the appended claims. Thus, the breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined in accordance with the following claims and their equivalents.

[0344] The present invention is described with reference to specific embodiments thereof. Other features and embodiments of the present invention can be produced by those of skill in the art without undue experimentation and a reasonably likelihood of success. All of those and other embodiments are considered to be part of the present invention.

[0345] All publication, including patent documents and scientific articles, referred to in this application, including any bibliography, are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication were individually incorporated by reference.

[0346] All headings are for the convenience of the reader and should not be used to limit the meaning of the text that follows the heading, unless so specified.

Claims

ClaimsWhat is claimed is:

1. A method of prophylaxis or treatment of obesity, glycemic control, other metabolic disorders, or combinations thereof comprising: a. providing a subject in need of said prophylaxis or treatment of obesity; b. providing at least one pharmaceutical composition comprising one or more of the following components: a) at least one cPG compound, optionally in combination with; b) at least one GLP-1 compound; or c) combinations thereof; wherein said components are administered together or separately; further wherein said components are provided together or separately; c. administering a pharmaceutically effective amount of said at least one pharmaceutical composition to said subject; wherein said subject is provided prophylaxis or treatment of obesity, glycemic control, other metabolic disorders, or combinations thereof.

2. The method of claim 1, wherein said components are provided in a pharmaceutically acceptable diluent, adjuvant, excipient, or combinations thereof.

3. The method of claim 1, wherein said components are provided in a pharmaceutically acceptable salt.

4. The method of claim 1, wherein said components are administered separately.

5. The method of claim 1, wherein said prophylaxis or treatment of obesity comprises glycemic control, weight loss, inducing satiety, reducing body weight, reducing food intake and mitigating other metabolic disorders, or combinations thereof.

6. The method of claim 1, wherein said at least one cPG compound comprises Cyclic Prolyl Glycine, Cyclic Glycyl-2-Allyl Proline, Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl- L-prolyl), or combinations thereof.

7. The method of claim 6, wherein said at least one cPG compound comprises Cyclic Prolyl Glycine.

8. The method of claim 7, wherein said Cyclic Prolyl Glycine is provided in a dose between about 0.5 mg / kg to about 10.0 mg / kg.

9. The method of claim 7, wherein said Cyclic Prolyl Glycine is provided in a dose between about 1.0 mg / kg to about 3.0 mg / kg10. The method of claim 7, wherein said Cyclic Prolyl Glycine is provided in a dose between about 3.0 mg / kg to about 7.0 mg / kg11. The method of claim 7, wherein said Cyclic Prolyl Glycine is provided in a dose between about 7.0 mg / kg to about 10.0 mg / kg.

12. The method of claim 7, wherein said Cyclic Prolyl Glycine is administered about once a day, about twice a day, or combinations thereof.

13. The method of claim 7, wherein said Cyclic Prolyl Glycine is administered orally, intranasally, or combinations thereof.

14. The method of claim 6, wherein said at least one cPG compound comprises Cyclic Glycyl-2-Allyl Proline.

15. The method of claim 14, wherein said Cyclic Glycyl-2-Allyl Proline is provided in a dose between about 0.5 mg to 10.0 mg / kg.

16. The method of claim 14, wherein said Cyclic Glycyl-2- Allyl Proline is provided in a dose between about 1.0 mg / kg to about 3.0 mg / kg.

17. The method of claim 14, wherein said Cyclic Glycyl-2-Allyl Proline is provided in a dose between about 3.0 mg / kg to about 7.0 mg / kg.

18. The method of claim 14, wherein said Cyclic Glycyl-2- Allyl Proline is provided in a dose between about 7.0 mg / kg to about 10.0 mg / kg.

19. The method of claim 14, wherein said pharmaceutical composition comprising Cyclic Glycyl-2-Allyl Proline is administered about once a day, about twice a day, or combinations thereof.

20. The method of claim 14, wherein said pharmaceutical composition comprising Cyclic Glycyl-2-Allyl Proline is administered orally, intranasally, or combinations thereof.

21. The method of claim 6, wherein said at least one cPG compound comprises Cyclic (glycyl-L- prolylglycyl-L-prolylglycyl-L-prolyl).

22. The method of claim 21, wherein said pharmaceutical composition comprises Cyclic (glycyl-L- prolylglycyl-L-prolylglycyl-L-prolyl) is provided in a dose between about 0.5 mg / kg to about 10.0 mg / kg.

23. The method of claim 21, wherein said pharmaceutical composition comprises Cyclic (glycyl-L- prolylglycyl-L-prolylglycyl-L-prolyl) is provided in a dose between about 1.0 mg / kg to about 3.0 mg / kg24. The method of claim 21, wherein said pharmaceutical composition comprises Cyclic (glycyl-L- prolylglycyl-L-prolylglycyl-L-prolyl) is provided in a dose between about 3.0 mg / kg to about 7.0 mg / kg25. The method of claim 21, wherein said pharmaceutical composition comprises Cyclic (glycyl-L- prolylglycyl-L-prolylglycyl-L-prolyl) is provided in a dose between about 7.0 mg / kg to about 10.0 mg / kg.

26. The method of claim 21, wherein said pharmaceutical composition comprising Cyclic (glycyl-L- prolylglycyl-L-prolylglycyl-L-prolyl) is administered about once a day, about twice a day, or combinations thereof.

27. The method of claim 21, wherein said pharmaceutical composition comprising Cyclic (glycyl-L- prolylglycyl-L-prolylglycyl-L-prolyl) is administered orally, intranasally, or combinations thereof.

28. The method of claim 1, wherein said at least one GLP-1 compound comprises at least one GLP-1, at least one GLP-1 agonist, or combinations thereof.

29. The method of claim 28, wherein said at least one GLP-1 comprises tirzepatide (Zepbound®), semaglutide (Wegovy®), semaglutide (Rybelsus®), liraglutide (Saxenda®), maridebart cafraglutide (MariTide®), or combinations thereof.

30. The method of claim 29, wherein said at least one GLP-1 comprises tirzepatide (Zepbound®).

31. The method of claim 30, wherein said at least one pharmaceutical composition comprising tirzepatide (Zepbound®) is formulated for subcutaneous injection is provided in a dose is about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, or combinations thereof, for administration to a human subject.

32. The method of claim 30, wherein said at least one pharmaceutical composition comprising tirzepatide (Zepbound®) is administered subcutaneously, orally, intranasally, or combinations thereof.

33. The method of claim 30, wherein said at least one pharmaceutical composition comprising tirzepatide (Zepbound®) is administered once a week, twice a week or combinations thereof.

34. The method of claim 29, wherein said GLP-1 comprises semaglutide (Wegovy®).

35. The method of claim 34, wherein said at least one pharmaceutical composition comprising semaglutide (Wegovy®) subcutaneous injection is provided in a dose of about 0.5 mg, about 1.0 mg, about 2.4 mg, about 4.8 mg, about 9.6 mg, about 19.2 mg or combinations thereof, for administration to a human subject.

36. The method of claim 34, wherein said at least one pharmaceutical compound comprising semaglutide (Wegovy®) is administered subcutaneously, orally, intranasally, or combinations thereof.

37. The method of claim 34, wherein said at least one pharmaceutical compound comprising semaglutide (Wegovy®) is administered about once a week, about twice a day, or combinations thereof.

38. The method of claim 29, wherein said GLP-1 comprises semaglutide (Rybelsus®) tablets.

39. The method of claim 38, wherein said at least one pharmaceutical composition comprising semaglutide (Rybelsus®) is provided in an oral dose of about 1.5 mg, about 3 mg, about 4 mg, about 7 mg, about 9 mg, about 14 mg, about 28 mg, about 56 mg, about 112 mg, or combinations thereof, for administration to a human subject.

40. The method of claim 38, wherein said at least one pharmaceutical compound comprising semaglutide (Rybelsus®) is administered orally, subcutaneously, intranasally, or combinations thereof.41 . The method of claim 38, wherein said at least one pharmaceutical composition comprising semaglutide (Rybelsus®) is administered about once per day, about twice a day, or combinations thereof.

42. The method of claim 29, wherein said GLP-1 comprises liraglutide (Saxenda®).

43. The method of claim 42, wherein said at least one pharmaceutical composition comprising liraglutide (Saxenda®) is provided in a dose of about 0.6 mg, about 1.2 mg, about 1.8 mg, about 2.4 mg, about 3 mg, about 6 mg, about 12 mg, about 24 mg, about 48 mg, or combinations thereof, for administration to a human subject.

44. The method of claim 42, wherein said at least one pharmaceutical compound comprising liraglutide (Saxenda®) is administered subcutaneously, orally, intranasally, or combinations thereof.

45. The method of claim 42, wherein said at least one pharmaceutical compound comprising liraglutide (Saxenda®) is administered about once a week, about twice a week, or combinations thereof.

46. The method of claim 29, wherein said GLP-1 comprises maridebart cafraglutide (MariTide®).

47. The method of claim 46, wherein said at least one pharmaceutical composition comprising maridebart cafraglutide (MariTide®) is provided in a dose between about 21 mg to about 840 mg or about 1,680 mg, for administration to a human subject.

48. The method of claim 46, wherein said at least one pharmaceutical compound comprising maridebart cafraglutide (MariTide®) is administered subcutaneously, orally, intranasally, or combinations thereof.

49. The method of claim 46, wherein said at least one pharmaceutical compound comprising maridebart cafraglutide (MariTide®) is administered about once a month, about twice a month, or combinations thereof.

50. The method of claim 1, wherein said prophylaxis or treatment of obesity, glycemic control, and other metabolic disorders comprises reduction in plasma glucose, plasma triglycerides, liver triglycerides, or combinations thereof.

51. The method of claim 1, wherein said prophylaxis or treatment of obesity is prophylaxis.

52. The method of claim 1, wherein said prophylaxis or treatment of obesity is treatment.

53. The method of claim 1, wherein said at least one pharmaceutical compound comprises at least one cPG compound and at least one GLP-1 compound.

54. The method of claim 1, wherein said subject is a human.

55. The method of claim 1, wherein said components are administered together in a single or multiple doses.

56. The method of claim 1, wherein said components are administered separately in a single or multiple doses.

57. The method of claim 1, wherein said components are provided together in a single or multiple containers.

58. The method of claim 1, wherein said components are provided separately in a single or multiple containers.

59. The method of claim 1, wherein said at least one cPG compound is provided in a dose between about 0.5 mg / kg to about 10.0 mg / kg.

60. The method of claim 1, wherein said at least one cPG compound is provided by a route of administration of injection, orally, intranasally, intraperitoneal, intravenous, subcutaneous, or combinations thereof.61 . The method of claim 1, wherein said at least one cPG compound is provided in a regime of between once per hour to about once per three months.

62. The method of claim 1, wherein said at least one GLP-1 compound is provided in a dose between about 0.1 mg / kg to about 100 mg / kg.

63. The method of claim 1, wherein said at least one GLP-1 compound is provided by a route of administration of injection, orally, intranasally, intraperitoneal, intravenous, subcutaneous, or combinations thereof.

64. The method of claim 1, wherein said at least one GLP-1 compound is provided in a regime of between once per hour to about once per three months.

65. The method of claim 1, wherein said at least one GLP-1 compound is tirzepatide (Zepbound®) subcutaneous injection is provided in a dose of about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg or combinations thereof in about 0.5 ml to 2 00 ml solution.

66. The method of claim 1, wherein said at least one GLP-1 compound is semaglutide (Wegovy®) subcutaneous injection is provided in a dose of about 0.5 mg, about 1.0 mg, about 2.4 mg, about 4.8 mg, about 9.6 mg, about 19.2 mg, or combinations thereof, in about 1.5 ml of solution, for administration to a human subject.

67. The method of claim 1, wherein said at least one GLP-1 compound is semaglutide (Rybelsus®) tablets is provided in an oral dose of about 1.5 mg, about 3 mg, about 4 mg, about 7 mg, about 9 mg, about 14 mg, about 28 mg, about 56 mg, about 112 mg, or combinations thereof, in about 1 ml to about 2.0 ml of solution, or combinations thereof, for administration to a human subject.

68. The method of claim 1, wherein said at least one GLP-1 compound is liraglutide (Saxenda®) subcutaneous injection is provided in a dose of about 0.6 mg, about 1.2 mg, about 1 .8 mg, about 2.4 mg, about 3 mg, about 6 mg, about 12 mg, about 24 mg, about 48 mg, or combinations thereof, in about 1.0 ml to about 2.0 ml of solution, or combinations thereof, for administration to a human subject.

69. The method of claim 1, wherein said at least one GLP-1 compound is maridebart cafraglutide (MariTide®) subcutaneous injection is provided in a dose between about 21 mg to about 840 mg or about 1,680 mg, or combinations thereof, in about 1.0 ml to about2.0 ml of solution, or combinations thereof, for administration to a human subject.

70. A pharmaceutical composition for the prophylaxis or treatment of obesity, glycemic control, other metabolic disorders, or combinations thereof, comprising: a) at least one cPG compound, optionally in combination with; b) at least one GLP-1 compound; or c) combinations thereof; wherein said components are provided together or separately, further wherein said pharmaceutical composition when administered to a subject in need of prophylaxis or treatment of obesity is so prevented from or treated for said obesity, glycemic control, other metabolic disorders, or combinations thereof.