Method of treating diabetes using a GLP-1 receptor agonist

Abstract

The present disclosure relates to a GLP-1R agonist, Compound 1 for the treatment of diabetes, obesity, and / or hyperglycemia.

Description

METHOD OF TREATING DIABETES USING A GLP-1 RECEPTOR AGONISTTECHNICAL FIELD

[0001] The present disclosure relates to use of a GLP-1 receptor modulator, 2-(((2S,4S)-4-((2- ((2,4-difluorophenoxy)rnethyl)pyrimidin-4-yl)oxy)-2-rnethylpiperidin-l-yl)methyl)-l-(((S)- oxetan-2-yl)methyl)-lH-benzo[d]imidazole-6-carboxylic acid (Compound 1), for the treatment of diabetes, obesity, and others.BACKGROUND

[0002] Diabetes is a serious chronic disease that occurs when the pancreas does not produce enough insulin, or when the body cannot effectively use the insulin it produces. Complications of diabetes include damage to the heart, blood vessels, eyes, kidneys, and nerves. Diabetes can increase risk of heart disease, and stroke. The results include serious effects on quality of life, health, and mortality. WHO Global Report on Diabetes, 2016, World Health Organization. As of 2017, approximately 462 million individuals worldwide, about 6.28% of the population was affected by type 2 diabetes, and this prevalence was increasing measurably. Khan et al., 2020, J. Epidemiol. Glob. Health 10(1): 107-111. The global economic burden of diabetes in 2015 was estimated to be $1.3T and estimated to increase to $2. IT by 2030. Bommer et al., 2018, Diabetes Care 41(5):963-970. Approximately 90-95% of all diabetes cases are type 2 diabetes. Tripathi & Srivastava, 2016, Med. Sci. Monit. 12(7):RA130-147.

[0003] The glucagon-like peptide- 1 receptor (GLP-1 receptor, or GLP-1R) has emerged as a potential target for treating type 2 diabetes. Its ligand, glucagon-like peptide-1 (GLP-1) enhances glucose-induced insulin secretion and increases insulin synthesis among many other effects. Doyle and Egan, 2007, Pharmacol. Ther. 113(3):546-593. GLP-1 is known to delay gastric emptying, suppress food intake, increase satiety, and reduce weight in humans. Shah and Vella, 2014 Rev Endocr Metab Disord. 15(3): 181-187. Activating the GLP-1 receptor has been shown to have beneficial effects on insulin secretion and the maintenance of beta cell glucose sensing, transcription, synthesis, proliferation, and survival. Doyle and Egan, 2007, supra. While the GLP-1 receptor is a promising therapeutic target, only a handful of GLP-1 receptor drugs have been approved to date, and most, or all of these are peptide, or polypeptide drugs.

[0004] GLP-1 peptide-based agonists have several shortcomings. They require administration via subcutaneous injection, and concerns regarding their compliance for long-term use haveemerged. Elashoff et. al., 2011, Gastroenterology 141(1): 150-6. They lack effective long-term glucose control capability, and they can cause side effects and result in low quality of life in some patients. No small molecule agents acting as GLP-lRAs are currently available for clinical use. Hence, small molecule drugs suitable for oral administration that target GLP-1R are needed to circumvent this problemSUMMARY

[0005] The present disclosure provides a method for treating diabetes, obesity, and related disease using Compound 1, 2-(((2S,4S)-4-((2-((2,4-difluorophenoxy)methyl)pyrimidin-4- yl)oxy)-2-methylpiperidin-l-yl)methyl)-l-(((S)-oxetan-2-yl)methyl)-lH-benzo[d]imidazole-6- carboxylic acid (Compound 1), which has the following structure.Compound 1

[0006] Compound 1 is disclosed as Compound 485 in PCT Application No. PCT / US2022 / 014156, published as WO 2022165076.

[0007] Compound l is a biased agonist that activates cAMP signaling but does not recruit betaarrestin. These signaling properties provide strong promises in glycemic control, weight loss, and other uses of this compound.

[0008] In one aspect, the present disclosure is directed to a method of treating diabetes in a subject, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg to 250 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the method is for treating diabetes in a subject, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg to 200 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[0009] Another aspect of the present disclosure includes a method of treating hyperglycemia in a subject, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg to 250 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In someembodiments, the method is for treating hyperglycemia in a subject, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg to 200 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[0010] Another aspect of the present disclosure is directed to a method of reducing body weight in a subject, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg to 250 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the method is for reducing body weight in a subject, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg to 200 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[0011] Another aspect of the present disclosure is directed to a method of treating obesity or overweight in a subject with or without type 2 diabetes, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg to 250 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the method is for treating obesity or overweight in a subject with or without type 2 diabetes, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg to 200 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the method is for treating a subject with obesity or overweight and with at least one weight-related comorbidity, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg to 250 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[0012] A further aspect of the present disclosure relates to a method of maintaining body weight following weight loss in a subject, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg to 250 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the method is for maintaining body weight following weight loss in a subject, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg to 200 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[0013] A further aspect of the present disclosure relates to a method of chronic weight management in a subject with an initial body mass index (BMI) of 30 kg / m2or greater or 27 kg / m2or greater and with at least one weight-related comorbid condition, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg to 250 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[0014] The present disclosure also relates to Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of diabetes, obesity, overweight, and / or hyperglycemia, reduction of body weight, and weight management.

[0015] The present disclosure also includes the use of Compound 1 or a pharmaceutically acceptable salt thereof in the treatment of diabetes, obesity, overweight, and / or hyperglycemia, reduction of body weight, and weight management.

[0016] Also provided in the present disclosure is the use of Compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of diabetes, obesity, overweight, and / or hyperglycemia, reduction of body weight, and weight management.BRIEF DESCRIPTION OF THE FIGURES

[0017] FIG. 1 shows dose response curves for human GLP-1R cAMP accumulation (A), Human GLP-1R |3-arrestin recruitment (B), Cynomolgus monkey GLP-1R cAMP accumulation (C), and human GLP-1R internalization (D) in response to endogenous ligand GLP-1 or Compound 1.

[0018] FIG. 2 is a dose response curve of insulin secretion after stimulation with Compound 1 in the presence of 11 mM glucose. Abbreviations: nM is nanomolar, ug is microgram, and microIU is microintemational unit.

[0019] FIG. 3 shows mean (± SE) (A) glucose response to an MMTT and (B) the area under the glucose curves in hGLP-lR KI mice 30 minutes after vehicle and Compound 1 administration. Statistical differences were evaluated using a one-way ANOVA followed by Bonferroni post hoc test. ** p < 0.01, p < 0.0001.

[0020] FIG. 4 shows the effects of oral Compound 1 on GSIS during IVGTT in obese cynomolgus monkeys. Plasma insulin concentrations are represented as mean (± SE) following intravenous glucose challenge (2-3 hours after vehicle and Compound 1 administration).

[0021] FIG. 5 shows the effects of oral Compound 1 on postprandial glucose in obese cynomolgus monkeys. Plasma glucose change is represented as mean (± SE) from baseline. N = 6 / group. MMTT was administered on Day 1, 3 hours post Compound 1 administration.

[0022] FIG. 6 shows the effects of daily oral Compound 1 on chow intake and body weight in obese cynomolgus monkeys. (A) Daily chow consumption percent change [Mean (± SE)] from baseline; (B) weekly body weight percent change [Mean (± SE)] from baseline. N = 6 / group.

[0023] FIG. 7 shows the effects of daily oral Compound 1 on body composition in obese cynomolgus monkeys. Percent change from baseline [Mean (± SE)]. N = 6 / group. Abbreviations: BMC is bone mineral content and BMD is bone mineral density.

[0024] FIG. 8 shows the mean Compound 1 time-concentration profiles after a single dose of Compound 1 - linear scale.

[0025] FIG. 9 shows the incremental change in plasma glucose (mmol / L) and insulin (mIU / L) levels post-MMTT from corresponding Pre-MMTT values in Single Ascending Dose Cohorts 3, 4, 6.

[0026] FIG. 10A shows a single-centered MAD study of Compound 1 in three different dose escalation cohorts. FIG. 10B shows the mean Compound 1 time-concentration profiles after multiple ascending doses of Compound 1 - linear scale.

[0027] FIG. 11 shows the changes in body weight after administration of Compound 1 in multiple ascending dose cohorts. The legend 90 mg corresponds to Cohort 1 in Table 5, 120 mg (higher) corresponds to Cohort 2 in Table 5, and 120 mg (lower) corresponds to Cohort 3 in Table 5.

[0028] FIG. 12A and FIG. 12B show reductions in glucose and insulin Area under the Curve (AUC) during Mixed Meal Tolerance test (MMTT) on day 28 in the 120-mg dose groups relative to placebo.DETAILED DESCRIPTION

[0029] As used herein, the following definitions shall apply unless otherwise indicated.

[0030] “Subject” for the purposes of the present disclosure includes humans and any other animals, particularly mammals. Thus, the methods are applicable to both human therapy and veterinary applications. In a preferred embodiment, the subject is a mammal, and in a most preferred embodiment, the subject is human. Examples of the preferred mammals include mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, and primates.

[0031] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problem or complication, commensurate with a reasonable benefit risk ratio. In addition, guidelines forimpurities and residual solvents levels in crystalline and amorphous pharmaceuticals are provided by ICH in “Impurities: Guidelines for Residual Solvents Q3C(R6)” posted at https: / / database.ich.org / sites / default / fdes / Q3C-R6_Guideline_ErrorCorrection_2019 _0410_0.pdf (last visited December 01, 2023).

[0032] As used herein, the phrase “pharmaceutically acceptable excipient” refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid fdler, diluent, solvent, or encapsulating material. Excipients are generally safe, non-toxic and neither biologically nor otherwise undesirable and include excipients that are acceptable for veterinary use as well as human pharmaceutical use. In one embodiment, each component is “pharmaceutically acceptable” as defined herein. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al, Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

[0033] The terms “treat,” “treating,” “treatment,” and the like refer to eliminating, reducing, or ameliorating a disease or condition, and / or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated. The terms contemplate administering a therapeutically effective amount of a compound of the present disclosure to a subject in need of such treatment. The treatment can be orientated symptomatically, for example, to suppress symptoms. It can be achieved over a short period, be oriented over a medium term, or can be a long-term treatment, for example within the context of a maintenance therapy.

[0034] The terms “prevent,” “preventing,” and “prevention” refer to a method of preventing the onset of a disease or condition and / or its attendant symptoms or barring a subject from acquiring a disease. As used herein, “prevent,” “preventing,” and “prevention” also include delaying the onset of a disease and / or its attendant symptoms and reducing a subject's risk of acquiring a disease. The terms “prevent,” “preventing” and “prevention” may include “prophylactic treatment,” which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the diseaseor condition.EMBODIMENTS

[0035] Provided herein are methods for treating diabetes, obesity, and related disease using Compound 1, also known as 2-(((2S,4S)-4-((2-((2,4-difluorophenoxy)methyl)pyrimidin-4- yl)oxy)-2-methylpiperidin-l-yl)methyl)-l-(((S)-oxetan-2-yl)methyl)-lH-benzo[d]imidazole-6- carboxylic acid. Compound 1 has the structure depicted below.Compound 1

[0036] Compound 1 is useful for the treatment of a metabolic disease or condition. In some embodiments, the methods comprise orally administering a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof to a subject in need of such treatment. In some embodiments, the disease, or condition is any disease, or condition that benefits from modulation of GLP-1 receptor activity. In some embodiments, the disease, or condition is any disease, or condition that benefits from agonizing GLP-1 receptor activity. In some embodiments, the methods reduce blood glucose levels. In some embodiments, the methods promote insulin synthesis, stimulate insulin secretion, increase the mass of P-cells, modulate gastric acid secretion, modulate gastric emptying, and / or decrease glucagon production. In some embodiments, the disease, or condition is type 2 diabetes.

[0037] In some embodiments, the disease, or condition is obesity, or one, or more diseases, or conditions associated with obesity. According to the World health Organization, obesity is defined as a Body Mass Index (BMI) of 30 kg / m2or higher. Non-limiting examples of obesity, and obesity related conditions include symptomatic obesity, simple obesity, childhood obesity, morbid obesity, and abdominal obesity (central obesity characterized by abdominal adiposity). Non-limiting examples of symptomatic obesity include endocrine obesity (e.g., Cushing syndrome, hypothyroidism, insulinoma, obese type II diabetes, pseudohypoparathyroidism, hypogonadism), hypothalamic obesity, hereditary obesity (e.g., Prader-Willi syndrome,Laurence-Moon -Biedl syndrome), and drug-induced obesity (e.g., steroid, phenothiazine, insulin, sulfonylurea agent, or P-blocker-induced obesity). In some embodiments, the disease or condition is obesity with type 2 diabetes. In some embodiments, the disease or condition is obesity without type 2 diabetes.

[0038] Examples of such diseases, and conditions associated with obesity include, without limitation, glucose tolerance disorders, diabetes (e.g., type 2 diabetes, obese diabetes), lipid metabolism abnormality, hyperlipidemia, hypertension, cardiac failure, hyperuricemia, gout, fatty liver (including non-alcoholic steatohepatitis (NASH)), coronary heart disease (e.g., myocardial infarction, angina pectoris), cerebral infarction (e.g., brain thrombosis, transient cerebral ischemic attack), bone, or articular disease (e.g., knee osteoarthritis, hip osteoarthritis, spondylitis deformans, lumbago), sleep apnea syndrome, obesity hypoventilation syndrome (Pickwickian syndrome), menstrual disorder (e.g., abnormal menstrual cycle, abnormality of menstrual flow and cycle, amenorrhea, abnormal catamenial symptom), visceral obesity syndrome, and metabolic syndrome. In some embodiments, the compounds described herein can be used to treat subjects exhibiting symptoms of both obesity, and insulin deficiency.

[0039] In some embodiments, the disease, or condition is diabetes. Non-limiting examples of diabetes include, type 1 diabetes, type 2 diabetes (e.g., diet-treated type 2-diabetes, sulfonylurea- treated type 2-diabetes, a far-advanced stage type 2-diabetes, long-term insulin-treated type 2- diabetes), diabetes mellitus (e.g., non-insulin-dependent diabetes mellitus, insulin-dependent diabetes mellitus), gestational diabetes, obese diabetes, autoimmune diabetes, and borderline type diabetes.

[0040] In some embodiments, the disease or condition is associated with diabetes (e.g., a complication of diabetes). Non-limiting examples of disorders associated with diabetes include, obesity, obesity-related disorders, metabolic syndrome, neuropathy, nephropathy (e.g., diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infectious disease (e.g., respiratory infection, urinary tract infection, gastrointestinal infection, dermal soft tissue infections, inferior limb infection), diabetic gangrene, xerostomia, hypacusis, cerebrovascular disorder, diabetic cachexia, delayed wound healing, diabetic dyslipidemia peripheral blood circulation disorder, cardiovascular risk factors, (e.g., coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension, and risk factors related to unmanaged cholesterol, and / or lipid levels, and / orinflammation), NASH, bone fracture, and cognitive dysfunction

[0041] Other non-limiting examples of diseases, or conditions related to diabetes include, prediabetes, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, high LDL- cholesterolemia, low HDL-cholesterolemia, postprandial hyperlipemia), metabolic syndrome (e.g., metabolic disorder where activation of GLP-1R is beneficial, metabolic syndrome X), hypertension, impaired glucose tolerance (IGT), insulin resistance, and sarcopenia.

[0042] In some embodiments, the disease, or condition is diabetes, and obesity (diabesity). In certain embodiments, the compounds described herein are useful in improving the therapeutic effectiveness of metformin.

[0043] In some embodiments, Compound 1 is used to reduce or slow down the progression of borderline type, impaired fasting glucose, or impaired fasting glycemia into diabetes.

[0044] In some embodiments, Compound 1 is used to reduce body weight (e.g., excess body weight), prevent body weight gain, induce weight loss, decrease body fat, or reduce food intake in a subject (e.g., a subject in need thereof). In some embodiments, the weight increase in a subject may be attributed to excessive ingestion of food, or unbalanced diets, or may be weight increase derived from a concomitant drug (e.g., insulin sensitizers having a PPARy agonist-like action, such as troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone, and the like). Alternatively, the weight increase may be weight increase before reaching obesity, or may be weight increase in an obese subject. The weight increase may also be medication-induced weight gain, or weight gain subsequent to cessation of smoking.

[0045] In some embodiments, the condition, disease, or disorder is an eating disorder, such as hyperphagia, binge eating, bulimia, or compulsive eating.

[0046] In some embodiments, the disease or condition is a disorder of a metabolically important tissue.

[0047] In some embodiments, the disease, or condition is a fatty liver disease. Fatty liver diseases include, but are not limited to, non-alcoholic fatty acid liver disease (NAFLD), now referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), steatohepatitis, non-alcoholic steatohepatitis (NASH), now referred to as metabolic dysfunction-associated steatohepatitis (MASH), fatty liver disease resulting from hepatitis, fatty liver disease resulting from obesity, fatty liver disease resulting from diabetes, fatty liver disease resulting from insulin resistance, fatty liver disease resulting from hypertriglyceridemia, Abetalipoproteinemia,glycogen storage diseases, Weber-Christian disease, Wolmans disease, acute fatty liver of pregnancy, and lipodystrophy.

[0048] Non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD) represents a spectrum of disease occurring in the absence of alcohol abuse, and is typically characterized by the presence of steatosis (fat in the liver). NAFLD is believed to be linked to a variety of conditions, e.g., metabolic syndrome (including obesity, diabetes, and hypertriglyceridemia), and insulin resistance. It can cause liver disease in adults and children, and may ultimately lead to cirrhosis (Skelly et al., J Hepatol 2001; 35: 195-9; Chitturi et al., Hepatology 2002; 35(2):373-9). The severity of NAFLD or MAFLD ranges from the relatively benign isolated predominantly macrovesicular steatosis (i.e., nonalcoholic fatty liver or NAFL or MAFL) to non-alcoholic steatohepatitis (NASH) or metabolic dysfunction- associated steatohepatitis (MASH) (Angulo et al., J Gastroenterol Hepatol 2002; 17 SuppkS 186- 90). In some embodiments, the subject is a pediatric subject (e.g., 6-16 years old; or 6-12 years old; or 6-10 years old). In some embodiments, the subject is an adult subject.

[0049] Other non-limiting examples of diseases, or conditions in metabolically important tissues include, joint disorders (e.g., osteoarthritis, secondary osteoarthritis), steatosis (e.g. in the liver); gall stones; gallbladder disorders; gastroesophageal reflux; sleep apnea; hepatitis; fatty liver; bone disorder characterized by altered bone metabolism, such as osteoporosis, including postmenopausal osteoporosis, poor bone strength, osteopenia, Paget's disease, osteolytic metastasis in cancer patients, osteodistrophy in liver disease, and the altered bone metabolism caused by renal failure, or haemodialysis, bone fracture, bone surgery, aging, pregnancy, protection against bone fractures, and malnutrition polycystic ovary syndrome; renal disease (e.g., chronic renal failure, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease); muscular dystrophy, angina pectoris, acute, or chronic diarrhea, testicular dysfunction, respiratory dysfunction, frailty, sexual dysfunction (e.g., erectile dysfunction), and geriatric syndrome. In some embodiments, the chemical entities described herein can be used for treating surgical trauma by improving recovery after surgery, and / or by preventing the catabolic reaction caused by surgical trauma.

[0050] In some embodiments, the disease, or condition is a cardiovascular disease. Non-limiting examples of cardiovascular disease include, congestive heart failure, heart failure with preserved ejection fraction (HFpEF), atherosclerosis, arteriosclerosis, coronary heart disease, or peripheralartery disease, stroke, coronary artery disease, coronary heart disease, hypertension, cardiac failure, cerebrovascular disorder (e.g., cerebral infarction), vascular dysfunction, myocardial infarction, elevated blood pressure (e.g., 130 / 85 mm Hg or higher), and prothrombotic state (exemplified by high fibrinogen, or plasminogen activator inhibitor in the blood).

[0051] In some embodiments, the disease, or condition is a neurological disorder (e.g., neurodegenerative disorder), or a psychiatric disorder. Non-limiting examples of neurological disorders include, brain insulin resistance, mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety, dementia (e.g., senile dementia), traumatic brain injury, Huntington's chores, tardive dyskinesia, hyperkinesia, mania, Morbus Parkinson, steel-Richard syndrome, Down's syndrome, myasthenia gravis, nerve trauma, brain trauma, vascular amyloidosis, cerebral hemorrhage I with amyloidosis, brain inflammation, Friedrich's ataxia, acute confusion disorder, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated degenerative diseases of the central nervous system (e.g., Creutzfeld-Jakob Disease, bovine spongiform encephalopathy (mad cow disease), chronic wasting syndrome).

[0052] Non-limiting examples of psychiatric disorders include drug dependence / addiction (narcotics, amphetamines, and attention deficit / hyperactivity disorder (ADHD). The chemical entities described herein can be useful in improving behavioral response to addictive drugs, decreasing drug dependence, prevention drug abuse relapse, and relieving anxiety caused by the absence of a given addictive substance.

[0053] In some embodiments, the chemical entities described herein are useful in improving learning, and memory by enhancing neuronal plasticity, and facilitation of cellular differentiation, and also in preserving dopamine neurons, and motor function in Morbus Parkinson.

[0054] In some embodiments, the disease, or condition is impaired fasting glucose (IFG), impaired fasting glycemia (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, elevated blood levels of fatty acids, or glycerol, a hypoglycemic condition, insulin resistant syndrome, paresthesia caused by hyperinsulinemia, hyperlipidaemia, hypercholesteremia, impaired wound healing, leptin resistance, glucose intolerance, increased fasting glucose, dyslipidemia (e.g., hyperlipidemia, atherogenic dyslipidemia characterized by high triglycerides and low HDL cholesterol), glucagonoma, hyperuricacidemia, hypoglycemia (e.g., nighttime hypoglycemia), and concomitant comatose endpoint associated with insulin.

[0055] In some embodiments, the disease, or condition is an autoimmune disorder. Non-limiting examples of autoimmune disorders include, multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune disorder is associated with immune rejection, graft versus host disease, uveitis, optic neuropathies, optic neuritis, transverse myelitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, myasthenia gravis, and Graves disease.

[0056] In some embodiments, the disease, or condition is a stomach, or intestine related disorder. Non-limiting examples of these disorders include, ulcers of any etiology (e.g. peptic ulcers, Zollinger-Ellison syndrome, drug-induced ulcers, ulcers related to infections, or other pathogens), digestion disorders, malabsorption, short bowel syndrome, cul-de-sac syndrome, inflammatory bowel diseases (Crohn’s disease, and ulcerative colitis), celiac sprue, hypogammaglobulinemic sprue, chemotherapy, and / or radiation therapy-induced mucositis, and diarrhea, gastrointestinal inflammation, short bowel syndrome, colitis ulcerosa, gastric mucosal injury (e.g., gastric mucosal injury caused by aspirin), small intestinal mucosal injury, and cachexia (e.g., cancerous cachexia, tuberculous cachexia, cachexia associated with blood disease, cachexia associated with endocrine disease, cachexia associated with infectious disease, cachexia caused by acquired immunodeficiency syndrome).

[0057] In some embodiments, the disease, or condition is an inflammatory disorder. Nonlimiting examples of inflammatory disorders include, chronic rheumatoid arthritis, spondylitis deformans, arthritis deformans, lumbago, gout, post-operational or post-traumatic inflammation, bloating, neuralgia, laryngopharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory large bowel disease), inflammation in metabolically important tissues including liver, fat, pancreas, kidney, and gut, and a proinflammatory state (e.g., elevated levels of proinflammatory cytokines or, markers of inflammation-like C-reactive protein in the blood).

[0058] In some embodiments, the disease, or condition is cancer. Suitable examples of cancer include, breast cancer (e.g., invasive ductal breast cancer, noninvasive ductal breast cancer, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, hormone- independent prostate cancer), pancreatic cancer (e.g., ductal pancreatic cancer), gastric cancer (e.g., papillary adenocarcinoma, mucous adenocarcinoma, adenosquamous carcinoma), lung cancer (e.g., non-small cell lung cancer, small-cell lung cancer, malignant mesothelioma), coloncancer (e.g., gastrointestinal stromal tumor), rectal cancer (e.g., gastrointestinal stromal tumor), colorectal cancer (e.g., familial colorectal cancer, hereditary non-polyposis colorectal cancer, gastrointestinal stromal tumor), small intestinal cancer (e.g., non-Hodgkin's lymphoma, gastrointestinal stromal tumor), esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer (e.g., nasopharyngeal cancer, oropharynx cancer, hypopharyngeal cancer), salivary gland cancer, brain tumor (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma), neurilemmoma, liver cancer (e.g., primary liver cancer, extrahepatic bile duct cancer), renal cancer (e.g., renal cell cancer, transitional cell cancer of the renal pelvis and ureter), bile duct cancer, endometrial cancer, uterine cervical cancer, ovarian cancer (e.g., epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian tumor of low malignant potential), bladder cancer, urethral cancer, skin cancer (e.g., intraocular (ocular) melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g., medullary thyroid cancer), parathyroid cancer, nasal cavity cancer, sinus cancer, bone tumor (e.g., osteosarcoma, Ewing tumor, uterine sarcoma, soft tissue sarcoma), angiofibroma, sarcoma of the retina, penis cancer, testicular tumor, pediatric solid tumor (e.g., Wilms’ tumor, childhood kidney tumor), Kaposi's sarcoma, Kaposi's sarcoma caused by AIDS, tumor of maxillary sinus, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia).

[0059] In certain embodiments, provided herein are methods for the treatment that include, the administration of an effective amount of compounds provided herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the methods encompass the step of administering to the subject in need thereof an amount of a compound described herein effective for the treatment of disease, or condition in combination with a second agent effective for the treatment, or prevention of the disease, or condition. In certain embodiments, the compound is in the form of a pharmaceutical composition, or dosage form, as described elsewhere herein.

[0060] In some embodiments, the method is for treating diabetes in a subject, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg to 200 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, the method is for treating diabetes in a subject, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg to 250 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, the subject has type 2 diabetes.

[0063] In some embodiments, the subject has failed to achieve adequate glycemic control on diet and exercise alone.

[0064] In some embodiments, the subject has been on a stable dose of metformin, a sodiumglucose cotransporter-2 (SGLT-2) inhibitor, or metformin and SGLT-2 inhibitor.

[0065] In some embodiments, the subject has failed to achieve adequate glycemic control on a stable dose of metformin, SGLT-2 inhibitor, or metformin and SGLT-2 inhibitor.

[0066] In some embodiments, the SGLT-2 inhibitor is selected from Canagliflozin (Invokana®), Dapagliflozin (Farxiga®), Empagliflozin (Jardiance®), Ertugliflozin (Steglatro®), and Bexagliflozin (Brenzavvy®).

[0067] In some embodiments, the method is for treating hyperglycemia in a subject, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg to 200 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments, the method is for treating hyperglycemia in a subject, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg to 250 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments, the method is for reducing body weight in a subject, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg to 200 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[0070] In some embodiments, the method is for reducing body weight in a subject, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg to 250 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[0071] In some embodiments, the method is for treating obesity in a subject with or without type 2 diabetes, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg to 200 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the method is for treating obesity in a subject with or without type 2 diabetes, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg to 250 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a BMI of 30 kg / m2or higher. In some embodiments, the subject has type 2 diabetes. In some embodiments, the subject does not have type 2 diabetes.

[0072] In some embodiments, the method is for treating an overweight subject, the methodcomprising administering orally to the subject in need of such treatment an amount of 5 mg to 250 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a BMI of 25 kg / m2or higher but less than 30 kg / m2. In some embodiments, the subject has a BMI of 27 kg / m2or higher but less than 30 kg / m2.

[0073] In some embodiments, the subject has obesity or is overweight and has at least one weight-related comorbidity. In some embodiments, the subject has a BMI of 25 kg / m2or higher. In some embodiments, the weight-related comorbidity is selected from diabetes, hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease, cancer, hypertriglyceridemia, gastroesophageal reflux disease, osteoarthritis, and others. In some embodiments, the weight- related comorbidity is selected from hypertension, dyslipidemia, obstructive sleep apnea, and cardiovascular disease. In some embodiments, the weight-related comorbid condition is selected from hypertension, type 2 diabetes, and dyslipidemia. In some embodiments, the subject has obesity or is overweight and has at least one weight-related comorbidity but has no diabetes mellitus. In some embodiments, the subject has obesity or is overweight and has at least one weight-related comorbidity but has no type 2 diabetes mellitus.

[0074] In some embodiments, the method is for managing body weight in a subject, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg to 250 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has obesity or is overweight with at least one weight-related comorbidity.

[0075] In some embodiments, the method is for chronic weight management in a subject with an initial body mass index (BMI) of 30 kg / m2or greater or 27 kg / m2or greater and with at least one weight-related comorbid condition, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg to 250 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the weight-related comorbid condition is selected from hypertension, type 2 diabetes, and dyslipidemia.

[0076] A further aspect of the present disclosure relates to a method of maintaining body weight following weight loss in a subject, the method comprising administering orally to the subject in need of such treatment Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering orally to the subject in need of such treatment an amount of 5 mg to 250 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the weight loss is caused by injectable medications. In some embodiments,the injectable medication is selected from CT-388, CT-868, tirzepatide (Mounjaro®, Zepbound®), semaglutide (Wegovy®, Ozempic®), liraglutide (Victoza®, Saxenda®), and others. In some embodiments, the injectable medications are selected from CT-388, CT-868, Mounjaro, Zepbound, Wegovy, Ozempic, Zepbound, Victoza, Saxenda, and others. In some embodiments, the injectable medications are selected from CT-388, CT-868, Mounjaro, Zepbound, Wegovy, Ozempic, Zepbound, Saxenda, and others. In some embodiments, the injectable medication is semaglutide. In some embodiments, the injectable medication is CT-388. In some embodiments, the injectable medication is tirzepatide.

[0077] A further aspect of the present disclosure relates to a method of maintaining body in a subject, the method comprising administering orally to the subject in need of such treatment Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering orally to the subject in need of such treatment an amount of 5 mg to 250 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has received a prior incretin treatment. In some embodiments, the incretin treatment is selected from exenatide (Byetta®, Bydureon®), liraglutide (Victoza®, Saxenda®), sitagliptin (Januvia®, Janumet®, Janumet XR®, Juvisync®), saxagliptin (Onglyza®, Kombiglyze XR®), alogliptin (Nesina®, Kazano®, Oseni®), linagliptin (Tradjenta®, Jentadueto®), semaglutide (Wegovy®, Ozempic®, Rybelsus®), tirzepatide (Mounjaro®, Zepbound®), and others. In some embodiments, the prior incretin treatment is tirzepatide. In some embodiments, the prior incretin treatment is semaglutide.

[0078] In some embodiments, the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 0.01 mg to 500 mg. In some embodiments, the amount is 2 mg to 500 mg. In some embodiments, the amount is 1 mg to 450 mg. In some embodiments, the amount is 2 mg to 400 mg. In some embodiments, the amount is 3 mg to 350 mg. In some embodiments, the amount is 4 mg to 300 mg. In some embodiments, the amount is 5 mg to 250 mg. In some embodiments, the amount is 5 mg to 200 mg. In some embodiments, the amount is 5 mg to 180 mg.

[0079] In some embodiments, the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 5 mg to 150 mg. In some embodiments, the amount is 5 mg to 175 mg. In some embodiments, the amount is 5 mg to 120 mg. In some embodiments, the amount is 10 mg to 120 mg.

[0080] In some embodiments, the amount is 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg,40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, or 250 mg.

[0081] In some embodiments, the amount is 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 150 mg, 180 mg, 190 mg, or 200 mg.

[0082] In some embodiments, the amount is 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, or 150 mg.

[0083] In some embodiments, the amount is 5 mg, 10 mg, 15 mg, 30 mg, 60 mg, 90 mg, or 120 mg.

[0084] In some embodiments, the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 120 mg / day.

[0085] In some embodiments, the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 180 mg / day.

[0086] In some embodiments, the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 240 mg / day.

[0087] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered once daily.

[0088] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered twice daily.

[0089] In some embodiments, Compound 1 is administered orally as a solid dosage form or liquid dosage form.

[0090] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In some embodiments, the solid dosage form is a capsule or tablet.

[0091] In some embodiments, the solid dosage form is a capsule.

[0092] In some embodiments, the solid dosage form is a tablet.

[0093] In some embodiments, Compound 1 is administered orally as a tablet or capsule with water.

[0094] In some embodiments, Compound 1 is administered orally as a tablet or capsule after a meal.

[0095] In some embodiments, Compound 1 is administered orally as a tablet or capsule underfasted condition.

[0096] In some embodiments, Compound 1 is administered orally with or without food. In some embodiments, Compound 1 is administered orally under a fasting condition. In some embodiments, Compound 1 is administered after a meal.

[0097] In such solid dosage forms, the active compound is admixed with at least one inert customary excipient such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar- agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, magnesium stearate, and the like (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.

[0098] Solid dosage forms as described above can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain pacifying agents and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0099] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, and so on., Compound 1, and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3- butyleneglycol, and dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, com germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol,polyethyleneglycols and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a solution or suspension.

[0100] Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.

[0101] Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a crystalline form of Compound 1, and 99% to 1% by weight of a suitable pharmaceutical excipient. In one example, the composition will be between about 5% and about 75% by weight of a crystalline form of Compound 1, with the rest being suitable pharmaceutical excipients.

[0102] Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 21stEd., (Lippincott, Williams and Wilkins Philadelphia, PA, 2006). The composition to be administered will, in any event, contain a therapeutically effective amount of Compound 1 or a crystalline form of Compound 1 for treatment of a disease-state in accordance with the teachings of this disclosure.

[0103] In some embodiments, the subject has a Body Mass Index (BMI) of at least 25 kg / m2. In some embodiments, the subject has a Body Mass Index (BMI) of at least 27 kg / m2. In some embodiments, the subject has a BMI of at least 30.0 kg / m2. In some embodiments, the subject has a BMI of 25-40.0 kg / m2.

[0104] In some embodiments, the subject is a treatment naive subject. In further embodiments, the subject has previously received therapy. For instance, in some embodiments, the subject has not responded to a single agent treatment regimen.

[0105] In some embodiments, the subject is a subject that discontinued some other therapy because of one or more adverse events associated with the other therapy. In some embodiments, the subject has received some other therapy and discontinued that therapy prior to administration of a method provided herein. In further embodiments, the subject has received therapy and continues to receive that therapy along with administration of a compound provided herein. The compounds described herein can be co-administered with other therapy for treatment of the disease or condition according to the judgment of one of skill in the art. In some embodiments, the methods or compositions provided herein can be co-administered with a reduced dose of theother therapy for the treatment of the disease or condition.EXAMPLES

[0106] EXAMPLE 1: Preclinical StudiesEfficacy of Compound 1, an Oral Small Molecule GLP-1 Receptor Agonist, in Human GLP-1 Receptor Knock-in Mice and Obese Cynomolgus Monkeys

[0107] Injectable GLP-1 receptor agonists (GLP-1RA) such as semaglutide have demonstrated significant efficacy in glycemic control and weight management. However, while semaglutide is available in an oral peptide formulation, it requires specific timing and administration conditions. The increasing use of injectable incretin techniques underscores the urgent need for simpler, cost-effective solutions. Here, we describe Compound 1, a potent, oral small molecule GLP- 1TA, and present preclinical efficacy studies to support the daily oral use of Compound 1 in humans.

[0108] A series of in vitro and in vivo studies were performed to determine the primary, secondary, and safety pharmacology of Compound 1.

[0109] In Vitro Characterization

[0110] cAMP accumulation was measured in HEK293 cells expressing either human or cynomolgus monkey GLP-1R 30 minutes after stimulation. Maximal [3-arrestin recruitment after stimulation was measured in HEK293 cells expressing human GLP-lR-LgBit and SmBiT- human-P-arrestin-2. Internalization was measured in HEK293 cells expressing HiBiT-tagged human GLP-1R 60 minutes after stimulation.[0U1] Insulin secretion was measured in EndoC-PH5® cells, a human pancreatic 3-cell line, 40 minutes after stimulation in the presence of 11 mM glucose. Curves depict non-linear regression analysis of data normalized to vehicle and a high dose of GLP-1. Insulin data is also normalized to total protein content. Data are mean ± SD of 2-3 replicates per concentration.

[0112] Mixed Meal Tolerance Test (MMTT) in Humanized GLP-1R Knock-in Mice:

[0113] Male humanized GLP-1R knock-in (hGLP-lR KI; Taconic) mice, aged 8-14 weeks, were fasted overnight. Vehicle and Compound 1 were administered orally 30 minutes before the MMTT (Ensure, 10 ml / kg).

[0114] Glucose Stimulated Insulin Secretion (GSIS) in Obese Monkeys:

[0115] Male obese cynomolgus monkeys, > 8 years old (KB I), were fasted overnight. Vehicleand Compound 1 were administered orally 2-3 hours prior to intravenous glucose tolerance test (IVGTT; 0.5 g / kg).

[0116] 28-Day Daily Dose Study in Obese Monkeys:

[0117] Twenty-four (24) male cynomolgus monkeys, each weighing > 8 kg with BMI > 40 were included. Some of the animals had plasma glucose above 6 mmol / L. MMTT (Ensure, 5 ml / kg) was administered on Day 1, 3 hours post dose. Chow intake was recorded at each meal, and body weight was assessed weekly. Body composition was measured using dual-energy X-ray absorptiometry (DEXA) at baseline and Day 29.

[0118] Results

[0119] As depicted in FIG. 1, Compound 1 is a potent and cAMP -biased GLP-1R agonist. In addition, Compound 1 dose-dependently enhanced GSIS in human b-cells and obese monkeys (FIG. 2 and FIG. 4) and also improved glucose following MMTT in hGLP-lR KI mice and postprandial glucose following MMTT in obese monkeys (FIG. 3 and FIG. 5). Compound 1 preferentially reduced fat mass in obese monkeys and suppressed chow intake and progressively lowered body weight in obese monkeys (FIG. 6 and FIG. 7).

[0120] Discussion

[0121] Homology between the human GLP-1R with mouse, rat, and cynomolgus monkey GLP- 1R was high (92%, 91%, and 98%, respectively) as determined by a protein basic local alignment search tool (BLAST). Compound 1 was as potent and efficacious as GLP-1 on human and cynomolgus monkey GLP-1R in stimulating cAMP accumulation (ECso of 49 and 64 pM, Emax of 95% and 99%, respectively). Compound 1 demonstrated differentiated signaling properties on GLP-1R compared to the native ligand; while it exhibited full and potent agonism of cAMP signaling it exhibited partial and weak agonism of P-arrestin signaling and internalization. Compound 1 effectively stimulated insulin secretion in EndoC-PH5® cells, a human pancreatic P-cell line. Compound 1 was shown to be selective for GLP-1R, as it exhibited no detectable activity at GLP-1R homologs, human Glucose-dependent Insulinotropic Polypeptide Receptor, human Glucagon Receptor, or Glucagon-Like Peptide 2 Receptor.

[0122] These in vivo pharmacology studies demonstrated the effectiveness of orally dosed Compound 1 in improving glucose tolerance and promoting insulin secretion as assessed via intravenous glucose tolerance test (IVGTT) in male cynomolgus monkeys. Orally dosed Compound 1 was efficacious as demonstrated by a significant increase in insulin secretion. In the28-day PK / PD study performed in male cynomolgus monkeys, daily dosing of Compound 1 showed a dose-dependent decrease in food consumption of >30%. Dose-dependent reductions in body weight and percent body fat were also observed on Day 29 relative to vehicle-treated animals. In addition, a trend toward decreased fasting plasma glucose and HbAlc was observed on Day 29 at the higher Compound 1 doses.

[0123] Safety pharmacology studies in the Sprague Dawley rat and cynomolgus monkey evaluated the effects of Compound 1 on respiratory, cardiovascular, blood pressure, and central nervous system function. Compound 1 was well tolerated in the Sprague Dawley rat and cynomolgus monkey, up to 300 and 100 mg / kg, respectively. The inhibitory concentration at 50% (IC50) value of Compound 1 on the human ether-a-go-go (hERG) potassium current was 176.9 pM (101.9 pg / mL). Based on ICH guidance S7A, the maximum concentration (Cmax) in humans should be >30-fold the IC50 in the hERG assay. Even at the proposed high dose of 150 mg in this study, there are more than adequate margins (>137 fold) to the plasma exposures anticipated at this dose. No respiratory, cardiovascular, blood pressure, central nervous system effects, or other adverse effects were reported in the cynomolgus monkey after 28 days of daily dosing at 100 mg / kg.

[0124] Single-dose intravenous and oral studies in the Sprague Dawley rat and cynomolgus monkey were performed to characterize the PK of Compound 1 for oral dosing. In the Sprague Dawley rat, exposure to Compound 1 after oral administration was greater (3.6-fold) than intravenous administration (area under the concentration-time curve extrapolated to infinity [AUCinf] 2343 vs. 650 h-ng / mL). The mean oral bioavailability was 73.3%. In male monkeys, exposure to Compound 1 after oral administration of 5 mg / kg was greater (2.2-fold) than intravenous administration (AUCinf 5562 vs. 2484 hmg / mL). The mean oral bioavailability in monkeys was 46.9%.

[0125] Absorption, distribution, metabolism, and excretion studies determined the stability and metabolite profile of Compound 1 after incubation with rat, cynomolgus monkey, and human liver microsomes and hepatocytes. Compound 1 was highly stable in the Sprague Dawley rat and pooled human liver microsomes, and moderately metabolized in cynomolgus monkey liver microsomes (>10%). At a concentration of 1 pM, Compound 1 was highly stable in human hepatocytes. No other metabolites were identified, including no acyl-glucuronide (conjugation of the benzimidazole carboxylic acid). A glutathione (GSH) trapping assay detected no glucuronidemetabolites or GSH adducts after incubation of Compound 1 in human liver microsomes.

[0126] Compound 1 permeability in Caco-2 cells, and in vitro plasma protein binding indicate that Compound 1 may be classified as a low- to medium-permeability substrate in Caco-2 cells. Protein binding of Compound 1 was 97.6%, 97.4%, 96.4%, and 97.5%; in rat, dog, monkey, and human plasma, respectively.

[0127] A study in bile duct cannulated (BDC), and non-BDC male Sprague Dawley rats administered Compound 1 IV (1 mg / kg) indicated that Compound 1, as the parent molecule, is predominantly excreted in the bile and feces, with no urinary excretion, and with insignificant amounts of Compound 1 metabolites, including acyl-glucuronide.

[0128] Compound 1 exhibited no inhibition activity against 9 cytochrome P (CYP) isozymes tested (1 A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 / 5) at a test concentration of 50 pM (29 pg / mL). Compound 1 had no time-dependent inhibition of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 / in human liver microsomes at a test concentration of 50 pM (29 pg / mL). Compound 1 inhibited substrate transport mediated via multidrug resistance-associated peptide 2 (MRP2), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP)lBl, OATP1B3, organic anion transporter (OAT)l, OAT3, organic cation transporter (OCT)2, and multidrug and toxin extrusion (MATE)l, but not via multidrug resistance proteins (MRP)3, MRP4, sodium taurocholate cotransporting polypeptide (NTCP), OCTI, intestinal peptide transporter (PEPT)l, P-glycoprotein (P-gp) and MATE2K. R-values were calculated using the algorithms presented in the FDA guidance document for systemic drug-drug interactions (DDIs) except (OATPs) where the estimated inlet concentration post oral dosing was used. The cut-off values for significant potential DDIs are >1.02 for CYPs, >1.1 for OATPs and >0.1 for other transporters. Based on the R-values there should be no significant inhibition of any of these transporters at the doses proposed for the Phase 1 clinical studies. With uptake ratios and rRNA synthesis (RS) / renal impairment (RI) ratios of <2, Compound 1 was not a substrate of OAT1, OAT3, MATE1, or MATE2K. However, with uptake ratios and RS / RI ratios of >2, Compound 1 was a substrate of OATP1B3 and OCT2 at 1 pM (0.58 pg / mL) and a substrate of OATP1B1 at 1 pM (0.58 pg / mL) and 10 pM (5.8 pg / mL). Compound 1 is a substrate of P-gp but not BCRP. There was no Pregnane X receptor (PXR) activation potential or CYP3A4 observed with Compound 1 at 10 pM.

[0129] Taken together, these data indicate that Compound 1 has minimal to low DDI (drug-druginteraction) potential. Based on the anticipated plasma exposures from the Compound 1 doses proposed in this study, no clinically meaningful DDI with Compound 1 is anticipated.

[0130] The potential toxicity of Compound 1 was evaluated in a series of non-Good Laboratory (GLP) maximum tolerated dose studies and GLP 7- and 28-day repeat-dose toxicity studies in the Sprague Dawley rat and in the cynomolgus monkey.

[0131] In male and female Sprague Dawley rats, Compound 1 was well tolerated after daily oral dosing for 28 days at 30, 150, and 300 mg / kg. No animals were moribund or found dead during the study. No Compound 1 -related macroscopic or microscopic changes were noted at the end of the dosing or recovery phases. There was no difference in food consumption or body weights between the control and groups dosed with Compound 1 up to 300 mg / kg daily for 28 days. On Day 29, Compound 1-related organ weight changes consisted of increased liver weights in both sexes at >150 mg / kg / day, without correlating macroscopic or microscopic findings. No significant changes occurred in hematology, coagulation, or urinalysis parameters. No significant changes in any clinical chemistry parameters occurred except in total bilirubin, which was increase on Day 29 by 92.69% and 111.11%, males and females, respectively, at 300 mg / kg; by the end of the 14-day recovery period, bilirubin levels were no different than controls.

[0132] In male and female cynomolgus monkeys, the more sensitive and pharmacologically relevant species, Compound 1 was well tolerated after daily oral dosing for 28 days at 25, 50, and 100 mg / kg in GLP toxicology studies. No animals were moribund or found dead during the study. Inappetence was observed in males at 50 and 100 mg / kg / day and in females at 25, 50, and 100 mg / kg / day starting on Days 4 to 7, which lasted until the end of the dosing period (Day 28). A decrease in body weight was observed in all Compound 1 dose groups, both males and females, compared with controls. During the recovery period, there was a trend for recovery of body weight in all Compound 1 dose groups compared with controls. No significant changes in hematology, coagulation, clinical chemistry, and urinalysis parameters were noted. Compound 1- related organ weight changes at the end of the dosing phase (Day 29) consisted of decreased splenic weights in males at >50 mg / kg / day and females at >25 mg / kg / day and decreased thymic weights in both sexes at >25 mg / kg / day.

[0133] Genotoxicity results from a bacterial reverse mutation and in vitro chromosomal aberration assay in Chinese hamster ovary cells showed that Compound 1 is not genotoxic.

[0134] Conclusion

[0135] Daily oral dosing of Compound 1 enhanced glucose homeostasis and reduced weight and fat mass after four-week treatment in obese cynomolgus monkeys. All doses that were tested were well-tolerated. These observations corroborate the continued development of Compound 1 as a next generation GLP-1RA.

[0136] EXAMPLE 2: A Double-Blind, Randomized, Placebo-Controlled Phase 1 Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Doses of Compound 1 In Overweight / Obese Participants and in Patients With or Without Type 2 Diabetes Mellitus

[0137] This clinical trial is a multi-part, multi-cohort study comprising both single and multiple ascending doses administered to adults with obesity / overweight as well as multiple doses administered for up to 4 weeks in adults with obesity / overweight and type 2 diabetes (T2D). Compound 1 was supplied as oral capsules of 5 mg, 10 mg, 30mg, and 60 mg. Placebo was supplied as matching capsules. The objectives of the study are below.

[0138] Primary Objective:

[0139] To evaluate the safety and tolerability of Compound 1 administered as single and multiple ascending doses in overweight / obese participants and as multiple doses in patients with type 2 diabetes mellitus (T2DM).

[0140] Secondary Objective:• To determine the pharmacokinetic (PK) profile of Compound 1 following single ascending doses (SAD) and multiple ascending doses (MAD) over 28 days in overweight / obese participants and multiple doses up to 28 days in patients with T2DM.• To determine the effect of a high-fat meal on the PK of Compound 1 following a single dose in overweight / obese participants

[0141] Exploratory Objectives:

[0142] To evaluate the pharmacodynamic (PD) markers of Compound 1 activity following single and multiple (28 days) dosing in overweight / obese participants and in patients with T2DM.

[0143] The study will be conducted in 3 parts:

[0144] Part 1 - Single Ascending Dose

[0145] In Part 1 of the study (SAD), approximately 40 overweight / obese adult participants will be enrolled in up to 6 cohorts [40 total with 8 participants per cohort randomized 3: 1 (6 active:2placebo) with the same 8 participants completing SAD3 and SAD5],

[0146] Screening for Part 1 (SAD) of the study will occur within 28 days prior to enrollment and admission to the clinical research unit (CRU) on Day -1. Consenting participants who meet the eligibility criteria at Screening will be admitted to the CRU on Day -1. Participants will be randomized on the morning of Day 1 to receive Compound 1 or placebo by oral administration.

[0147] Study drug will be administered as a capsule or capsules of Compound 1 or matching placebo. The planned Compound 1 doses for Part 1 (SAD) of the study are as follows:MMTT = mixed meal tolerance test; SAD = single-ascending dose; SRC = SafetyReview CommitteeNote: After the first cohort has been fully dosed, safety / tolerability and full PK data will be reviewed by the SRC. Based on those data, doses in Cohorts 2 to 6 may be modified (increased, decreased, and / or not dosed at all). Additional adjustment may continue to be made to doses in subsequent cohorts based on review of safety, tolerability, and / or PK data from the preceding cohorts.Cohort SAD5 is planned to be dosed at an equivalent dose to SAD3 (10 mg) with a standardized high-fat breakfast to assess the effect of food on the PK of Compound 1. Participants enrolled into SAD3 will also be required to participate in SAD5. During SAD3 they will be dosed under fasted conditions and during SAD5 they will receive the same dose under high-fat fed conditions. There will be a minimum of 7 days between Cohort 3, Day 8 and Cohort 5, Day 1.

[0148] The first 2 participants in each SAD cohort will be sentinels (1 active, 1 placebo).Sentinel participants will receive study drug approximately 48 hours before the remaining participants in the cohort. In the absence of clinically significant safety signals in sentinel participants over this period, the remaining participants in the cohort will be randomized and dosed, at the Investigator’s discretion, with a sufficient minimum interval between participants to allow for monitoring of any acute postdose safety events. Following study drug administration, all Part 1 (SAD) participants will remain confined at the CRU and will undergo safety and other assessments as indicated in the Part 1 (SAD) Schedule of Assessments (SoA). Discharge from theCRU will occur on Day 3, in the absence of clinically significant safety signals, at the Investigator’s discretion, and following completion of all Day 3 assessments.

[0149] All Part 1 (SAD) participants will be followed for 30 (±3) days after study drug administration.

[0150] Participants will attend the CRU on an outpatient basis on Days 4, 5, and 8 (±1 day) for safety and other assessments and a final safety follow-up teleconference between site staff and the study participant will occur on Day 31 (±3 days). If required, following the teleconference, an onsite visit to the CRU will be scheduled, at the Investigator’s discretion.

[0151] Part 2 - Multiple Ascending Dose (28 Days of Dosing)

[0152] In Part 2 of the study (MAD), approximately 24 obese (BMI >30 kg / m2) adult participants will be sequentially enrolled in up to 3 cohorts [8 participants per cohort randomized 3: 1 (6 active:2 placebo)].

[0153] Following completion of Cohort 4 in Part 1 (SAD) and following review of all preceding Part 1 (SAD) cohort safety data and approval by the Safety Review Committee (SRC), dosing of Cohort 1 of Part 2 (MAD) of the study may commence.

[0154] Screening for Part 2 (MAD) of the study will occur within 28 days prior to enrollment and admission to the CRU on Day -2. Participants will be randomized on the morning of Day 1 to receive Compound 1 or placebo by oral administration. Sentinel participants will not be used for dosing of MAD cohorts unless required by the SRC.

[0155] Participants in the MAD cohorts will be randomized, and all participants will be administered a capsule or capsules of Compound 1 or placebo (per the randomization schedule) in the morning / day on Days 1 to 28 while confined to the CRU.

[0156] Compound 1 or matching placebo will be administered at a dose and regimen to be determined based on safety and PK data from the preceding SAD cohorts.

[0157] The proposed Compound 1 doses for the Part 2 (MAD) cohorts are currently as follows:MAD = multiple ascending dose; PK = pharmacokinetic; QD = once daily; SAD = single ascending doseNote: Within MAD Cohorts 1-3, both dose and / or regimen may be modified (e.g., dose(s) may be lowered / raised / held at the same dose, or a dosing holiday may be provided) and / or titration regimen may be shorter / longer) based on safety tolerability, PK, and any other data from the preceding SAD or MAD cohort(s) or current cohort.

[0158] Target doses will be attained using a gradual up-titration approach with flexibility provided to attain the target doses.

[0159] Participants will remain confined at the CRU and will undergo safety and other assessments. Discharge from the CRU will occur in the absence of clinically significant safety signals, at the Investigator’s discretion, and following completion of all Day 29 assessments.

[0160] All Part 2 (MAD) participants will be followed for 30 days (±3 days) after the last administered dose of study drug.

[0161] For follow-up, participants will attend the CRU on an outpatient basis for safety and other assessments, including blood sampling for PK, and a final safety follow-up teleconference between site staff and the study participant as specified below. If required, following the teleconference, an onsite visit to the CRU will be scheduled, at the Investigator’s discretion.

[0162] For participants in MAD cohorts• CRU visit on an outpatient basis: Days 30, 31, 32, 33, and 35 (±2 days).• Teleconference with site staff and study participant: Day 58 (±3 days).

[0163] Part 3 - Multiple-Dose Type 2 diabetes mellitus (T2DM) Patients (28 Days of Dosing)

[0164] In the multiple dose (MD) cohorts with T2DM patients, approximately 15 patients (12 active:3 placebo) with a diagnosis of T2DM will be enrolled in each of 2 cohorts. Cohorts will be enrolled sequentially, i.e., MD2 will only initiate after the SRC has reviewed safety and tolerability data from MD1 through Day 29.

[0165] Compound 1 or matching placebo in MD1 will be administered at the doses proposedbelow. These are the same doses that were demonstrated to be safe and well-tolerated in a population of obese otherwise healthy adults.MD=multiple dose; PK = pharmacokinetic s; T2DM = type 2 diabetes mellitusNote: Within each MD T2DM cohort, the target dose is achieved by initiating with a starting dose of either 5 mg (MD1) or 10 mg (MD2), and by using a gradual dose up-titration approach. Both dose(s) and / or regimen(s) may be modified (e.g., starting dose or other doses may be lowered / raised, held at the same dose, or dosing may be withheld) based on tolerability, PK, and any other data from preceding cohort(s). Further, slower / faster increments of up-titration, more frequent up-titrations, including escalating to a maximum of 150 mg dose in MD2 may also be required. The maximum dosing duration will remain at 28 days.

[0166] Following completion of the MAD2 cohort, and subject to review of all preceding safety and PK data, and SRC approval, screening activities for MD1 may be initiated. Screening should occur within 28 days prior to enrollment and admission to the CRU on Day -2.

[0167] In Part 3 (MD T2DM), all patients are required to have a confirmed diagnosis of T2DM documented in their medical record for at least 6 months prior to the Screening Visit (diagnosis per the American Diabetes Association Standards of Medical Care in Diabetes diagnostic criteria for type 2 diabetes [ADA 2024]). All patients enrolled into these cohorts must be maintained on a stable diet / exercise regimen, and / or on metformin-only monotherapy (metformin dose >500 mg) for at least 3 months prior to the Screening Visit, with a screening glycated hemoglobin (HbAlc) between 7.0% and 10.5% and body mass index (BMI) of >27.0 kg / m2.

[0168] Consenting patients who meet the eligibility criteria at Screening will be admitted to the CRU on Day -2. Various baseline assessments will be conducted during Day - 2 through Day 1 predose.

[0169] Eligible patients will be randomized on the morning of Day 1 to receive Compound 1 or placebo by oral administration. Patients will be administered a capsule or capsules of study drug(Compound 1 or matching placebo) once daily for 28 days based on the proposed dosing / titrations schedule indicated in Section 4.3.

[0170] Patients will remain confined at the CRU after their first dose and undergo safety and other assessments. Discharge from the CRU on Day 2 will occur in the absence of clinically significant safety signals and following demonstration of stable blood glucose levels, at the Investigator’s discretion, and after completion of the appropriate postdose assessments per the SoA.

[0171] At the time of discharge from the CRU, patients will be provided with sufficient supplies of study drug and glucose test strips until the next scheduled domiciled or outpatient visit. Following discharge from the CRU on Day 2, patients will return and be re-admitted to the CRU on Days 7 to 9, Days 14 to 16, Days 21 to 23, and Days 27 to 29 (±1 day) for all assessments as indicated in the SoA.

[0172] Following the last administration of study drug on Day 28, patients will remain confined at the CRU and undergo safety and other assessments. Discharge from the CRU will occur in the absence of clinically significant safety signals and following demonstration of stable blood glucose levels, at the Investigator’s discretion, and after completion of all Day 29 assessments.

[0173] All Part 3 (MD T2DM) patients will be followed for safety for 30 days (±3 days) after the last administered dose of study drug.

[0174] For follow-up, all T2DM patients will return to the CRU on Days 30, 31, 32, and 35 (±2 days) for safety and other assessments including blood sampling for PK. A final safety follow-up teleconference between site staff and the patient will occur on Day 58 (±3 days). If required, following the teleconference, an onsite visit to the CRU will be scheduled, at the Investigator’s discretion.

[0175] Rescue (MD T2DM Patient Cohorts Only)

[0176] Blood glucose levels will be monitored in the study. All enrolled patients in Part 3 will be provided with glucometers and adequate test strips and other supplies. Patients who demonstrate unstable metabolic control (i.e., fasting finger stick glucose >240 mg / dL [13.3 mmol / L] for 5 or more consecutive days as measured by self-monitored blood glucose [(SMBG]) will initially have their metformin doses adjusted up to the locally allowable maximum doses with continued evaluation of glycemic control by appropriate SMBG glucose measurements. If after maximally optimizing metformin doses (or they are already at their maximal allowable metformin dose),glycemia remains uncontrolled (i.e., fasting blood glucose remains >240 mg / dL [13.3 mmol / L] for 5 or more consecutive days), those patients will have their assigned study drug discontinued, and they will be provided with additional antidiabetic medications per local standards of care, including insulin if needed per the Investigator’s discretion, and remain under supervision until glycemic control is established. Such patients should be encouraged to remain in the study even after receiving the rescue therapy to allow for the assessment of safety of the investigational product.

[0177] Number of Participants:• Part 1: SAD Overwei ght / Obese Volunteer Cohorts o Approximately 40 participants o (up to 6 cohorts of 8 [6 active:2 placebo] with the same 8 participants completing SAD3 and SAD5)• Part 2: MAD Obese Volunteer Cohorts o Approximately 24 participants o (up to 3 cohorts of 8 [6 active: 2 placebo])• Part 3: MD Cohort in Patients with T2DM o Approximately 30 patients o (15 patients in each of 2 cohorts [12 active:3 placebo])

[0178] Inclusion Criteria:1. Male or female participants between 18 and 65 years of age, inclusive, at time of informed consent.2. Female participants must not be pregnant or breast feeding and be either: a. Not of childbearing potential, defined as surgically sterile (verbal confirmation through medical history review acceptable to confirm that participant is at least 6 weeks since having a surgical bilateral oophorectomy or at least 6 weeks since having a complete hysterectomy; tubal ligation only is not considered surgically sterile) or postmenopausal (no menses for 12 months and confirmed by follicle stimulating hormone [FSH] level >40 mIU / mL) b. Of childbearing potential and have a negative pregnancy test at Screening and Admission (Day -2) and agree to practice true abstinence or agree to use a highly effective method of contraception consistently from 30 days prior to Day 1 untilat least 30 days after the final dose of Compound 1. The reliability of abstinence from heterosexual intercourse should be evaluated in relation to the duration of the study and the usual and preferred lifestyle of the participant. Highly effective contraception includes oral, implantable, injectable, or transdermal hormonal contraception associated with inhibition of ovulation plus use of a condom, placement of an intrauterine device (IUD) or intrauterine system (IUS) plus use of a condom, or a vasectomized male partner (performed at least 6 months prior to the start of participation in the investigation) who has been documented to no longer produce sperm — verbal confirmation through medical history review is acceptable. Contraception requirements do not apply for participants in an exclusively same-sex relationship. Male participants must agree to practice true abstinence; be surgically sterilized (performed at least 6 months prior to the start of participation in the investigation and documented to no longer produce sperm — verbal confirmation through medical history review acceptable); or agree to use a condom plus effective contraception (i.e., established use of oral, injected, implanted or patch hormonal contraception; or placement or an IUD or IUS) for their female partner, if of childbearing potential, throughout the study if sexually active with a female partner of childbearing potential from Admission (Day -2) until 90 days after the final dose of Compound 1 (i.e., 1 spermatic cycle) and refrain from donating sperm during this same period. The reliability of abstinence from heterosexual intercourse should be evaluated in relation to the duration of the study and the usual and preferred lifestyle or the participant. Contraception requirements do not apply for participants in an exclusively same-sex relationship. BMI >25.0 to <40.0 kg / m2for Part 1 (SAD); BMI >30.0 kg / m2for Part 2 (MAD); BMI >27.0 kg / m2for Part 3 (MD T2DM) cohorts at Screening and Admission (Day -2) and prior to randomization (Day 1, predose). Stable body weight (defined as <5% gain or loss) in the 2 months prior to Screening as per verbal report by the participant and for the period between Screening and Admission (Day -2) as per measured weight. No clinically significant symptoms, signs, or active manifestations of stableconditions in the opinion of the Principal Investigator (PI) or delegate on the basis of medical history, physical examination, 12 lead electrocardiogram (ECG), vital signs, and laboratory findings at Screening and at SAD Day 1 (predose) or MAD / MD T2DM Admission (Day -2). Normal ECG findings or normal variants as determined by the PI or delegate, within the QT interval corrected for heart rate using Fridericia’s formula (QTcF) range of <450 msec for men and <470 msec for women, at Screening and at SAD Day 1 (predose) or MAD / MD T2DM Admission (Day -2). Resting heart rate by vital signs, in the range of 45-100 bpm at Screening and Admission (Day -2). Negative test for selected drugs of abuse at Screening and Admission (Day -2). Human immunodeficiency virus seronegative, hepatitis C virus antibody negative and negative hepatitis B surface antigen at Screening. Patients in Part 3 (MD T2DM cohorts) should have a documented diagnosis of T2DM in their medical record(s) as defined by ADA 2024 criteria for at least 6 months prior to the Screening Visit. Patients in Part 3 (MD T2DM cohorts) should be managed with diet and / or exercise alone or treated with a stable dose of metformin monotherapy (either immediate release or extended release >500 mg / day and not more than the locally approved dose) for at least 3 months prior to the Screening Visit. Patients in Part 3 (MD T2DM cohorts) should have an HbAlc between 7.0% and 10.5%, inclusive at the Screening and Day -2 Admission Visits. Patients in Part 3 (MD T2DM cohorts) should have a fasting blood glucose <240 mg / dL (13.3 mmoL / L) at the Screening and Day -2 Admission Visits. Patients in Part 3 (MD T2DM cohorts) with underlying hypertension or hyperlipidemia are allowed if they are stably controlled on a single oral antihypertensive or lipid lowering medication; however, they must be on a dose and regimen that has been stable for more than 3 months prior to the Screening Visit, and the medication dose / regimen is not anticipated to change during the course of the study. Able to comprehend and willing to sign an Informed Consent Form

[0179] Exclusion Criteria:

[0180] If any one of the following criteria are met, participants may be excluded:1. Clinically significant history or active clinical manifestation(s) of any significant metabolic, endocrine, allergic, dermatologic, hepatic, renal, hematologic, pulmonary, cardiovascular, gastrointestinal, neurologic, or psychiatric disorder (as determined by the PI or delegate).2. Current diagnosis (per ADA 2024) of any type of diabetes.Participants with pre-diabetes (as defined by ADA 2024 may be allowed, but only if they are controlled and maintained on diet / exercise alone (i.e., no pharmacotherapy of any type allowed including metformin, nor any other type of over-the-counter / herbal / nonprescription / supplement treatments).3. History of bariatric surgery (of any type) or gastric banding (including Lap-Band), or any gastrointestinal surgery that may induce malabsorption (e.g., bowel resection), or any gastrointestinal motility disorders, gastroparesis, delayed gastric emptying, inflammatory bowel disease, pancreatitis, malabsorption syndromes including Celiac disease, chronic diarrhea, chronic constipation, clinically significant irritable bowel syndrome, or planning any type of surgery during the study period.Note: History of routine cholecystectomy may be allowed if procedure was performed more than 6 months prior to Screening.4. Semi-supine blood pressure systolic >160 mm Hg and / or diastolic >100 mm Hg at Screening, Admission (Day -2), and Day 1 (predose). The Investigator or delegate has the discretion to repeat at least once based on clinical judgment.5. History or current diagnosis of acute or chronic pancreatitis, or risk factors for pancreatitis, such as history of alcoholism, cholelithiasis (without cholecystectomy), hypercalcemia, or severe hypertriglyceridemia.6. History of clinical depression and / or anxiety requiring inpatient admission / electroconvulsive therapy / previous treatment with antipsychotics and / or on treatment with any of the prohibited medications in Section 6.5.2.7. Have an active or untreated malignancy or have been in remission from aclinically significant malignancy (other than basal or squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) for <5 years prior to screening. Personal or family history (first degree relative) of medullary thyroid carcinoma (MTC), or a genetic condition that predisposes to MTC (i.e., thyroid C-cell hyperplasia, or multiple endocrine neoplasia type 2A or type 2B). Thyroid disease defined as having active symptoms (e.g., palpitations, lethargy, weight gain, or weight loss) and / or having a thyroid-stimulating hormone (TSH) value outside the normal reference range of the central laboratory at the Screening Visit. History of atopy (severe or multiple allergic manifestations) or clinically significant multiple or severe drug allergies, or intolerance to topical corticosteroids, or severe posttreatment hypersensitivity reactions; known allergy to any component of the study drug, GLP-1 analogs, or related compounds. History or presence of an abnormal ECG, which, in the opinion of the PI or delegate, is clinically significant. Any one of the following laboratory abnormalities at the Screening or Day -2 Admission Visits: i. Aspartate aminotransferase (AST), or alanine aminotransferase (ALT), alkaline phosphatase, or gamma glutamyl transpeptidase (GGT) >1.5* the upper limit of normal (ULN), or ii. Total bilirubin >ULN, or iii. Amylase and lipase >ULN, or iv. Fasting triglycerides >250 mg / dL (2.83 mmol / L), or v. Estimated glomerular filtration rate (eGFR) vi. <60 mL / min / 1.73 m2 as calculated by the central laboratory using the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) formula, or vii. Calcitonin >20 ng / L (>5.8 pmol / L), or viii. TSH >ULN, or ix. HbAlc level >6.5%, orx. Fasting glucose >126 mg / dL (6.9 mmol / L), or xi. Hemoglobin <11 g / dL (men) or <10 g / dL (women) History of alcoholism or drug addiction within 1 year prior to Screening. Current use or use within 3 months prior to Screening of tobacco containing or nicotine containing products (including but not limited to e cigarettes, cigarettes, pipes, cigars, chewing tobacco, nicotine patches, nicotine lozenges, or nicotine gum). Have an average alcohol intake that exceeds four units per day or 14 units per week (1 unit=360 mb of beer, 150 mL or wine, or 45 mL of distilled spirits). Current use or use within 3 months prior to Screening of any prescribed or nonprescribed drugs that are known to interfere with gut motility including but not limited to chronic opioids, anticholinergics, antispasmodics, linaclotide, 5HT3 antagonists. Participation in any other investigational study drug trial in which receipt of an investigational study drug occurred within 5 half-lives or 30 days, whichever is longer, prior to study entry. As long as the above requirement is met, participants in SAD cohorts are able to participate in future SAD or MAD cohorts. Use of hormone replacement therapy (other than oral contraceptive products / IUDs / IUSs) 60 days prior to the Screening Visit. Use of any medications or any other type of interventions (e.g., dietary, intense exercise program) that promote body weight changes (gain and / or loss) or changes in glucose metabolism within 3 months prior to Screening Visit.Note: Participants must not be on any type of unbalanced / extreme diets such as very low calorie / low carbohydrate / very high protein / ketogenic diets, time- restricted feeding, intermittent fasting, Weight Watchers, 5:2 diet, purely vegan, etc., within 3 months of Screening, nor plan to be on such diets during the study. Positive alcohol breath test at Screening or Admission (Day -2) Visits. Use of alcohol containing or caffeine containing foods or beverages within 48 hours prior to Admission (Day -2), unless deemed acceptable by the PI or delegate. Poor peripheral venous access.23. Donation of blood or severe blood loss from 30 days prior to Screening through the end of the study, inclusive, or of plasma from 2 weeks prior to Screening through end-of-study.24. History of any types of hemoglobinopathy, hemolytic anemia, sickle cell anemia, or any other condition known to interfere with accurate measurement of HbAlc.25. Receipt of blood products within 2 months prior to Screening.26. History of any infections of unexplained frequency or severity within 30 days prior to Screening, including any acute or chronic condition, which, in the opinion of the PI or delegate, may potentially interfere with or would limit the participant’s ability to complete and / or participate in this clinical study.Note: usual symptoms experienced secondary to post-COVID19 vaccinations are not exclusionary where the last vaccine dose was at least 14 days prior to Admission (Day -2).27. Participant who is unwilling to adhere to the protocol requirements during the study or unwilling to cooperate, or comply with the requirements of this study, or is considered by the Investigator or Sponsor to be an unsuitable candidate for the study.

[0181] Duration of the Study:

[0182] Part 1 Single Ascending Dose Cohorts

[0183] The expected duration of study participation for each participant in the SAD cohorts is ~9 weeks, including up to 4 weeks of screening, a single treatment with investigational product on Day 1, and a follow-up period, culminating in a final safety assessment by teleconference on Day 31 (±3 days).

[0184] Part 2 Multiple Ascending Dose Cohorts

[0185] The expected duration of study participation for each participant in the MAD cohorts is approximately 13 weeks, including up to 4 weeks of screening, multiple treatments (administered once daily from Day 1 over 28 days), and a follow-up period, culminating in a final safety assessment by teleconference on Day 58 (±3 days).

[0186] Part 3 (Multiple Dose Type 2 Diabetes Mellitus) Patient Cohort

[0187] The expected duration of study participation for each patient in the MD T2DM cohort is ~13 weeks, including up to 4 weeks of screening, multiple treatments (administered once dailyfrom Day 1 over 28 days), and a follow-up period, culminating in a final safety assessment by teleconference on Day 58 (±3 days).

[0188] Pharmacokinetics:

[0189] Part 1 (Single Ascending Dose)

[0190] The primary PK endpoints for this portion of the study will include maximum concentration (Cmax), time to maximum concentration (Tmax) relevant area under the concentration-time curve (AUC) parameters, elimination half-life, clearance, and volume of distribution.

[0191] Part 2 (Multiple Ascending Dose) and Part 3 (Multiple Dose Type 2 Diabetes Mellitus)

[0192] The primary PK endpoints for these portions of the study are as described in the SAD portion with the addition of evaluation of accumulation.

[0193] Pharmacodynamics:

[0194] Part 1 Single Ascending Dose

[0195] The primary PD endpoints for this portion of the study will include changes from baseline in PD parameters, including body weight, fasting glucose, fasting insulin, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), AUC and baseline-adjusted AUC, maximum value, and time to maximum value of glucose, insulin, C-peptide, glucagon, and HOMA-IR during the mixed meal tolerance test (MMTT).

[0196] Part 2 Multiple Ascending Dose

[0197] The primary PD endpoints for this portion of the study are as described in the SAD with the addition of changes from baseline in waist and hip circumference, HbAlc, and fasting lipids.

[0198] Part 3 (MD T2DM)

[0199] The primary PD endpoints for this portion of the study are as described in the SAD and MAD portions of the study with the addition of changes from baseline in 7-point SMBG values.

[0200] Statistical Methods:

[0201] Details of the statistical methods, statistical analysis, analysis populations, and data reporting will be provided in the Statistical Analysis Plan (SAP) to be finalized prior to database lock.

[0202] The sample size for each cohort is based on historical precedence for first-in-human studies. No formal power calculations or sample size estimates were conducted for this study.

[0203] The Intent to Treat (ITT) population will comprise all randomized participants.Participants will be analyzed according to treatment randomized. The Safety population will comprise participants who receive any amount of study drug (Compound 1 or placebo). Participants will be analyzed according to treatment received. The PK population will comprise all randomized participants who receive any amount of active study drug (Compound 1) with at least 1 measurable Compound 1 plasma concentration. The PD population will comprise all randomized participants who receive any amount of study drug (Compound 1 or placebo), with results from baseline and from >1 post-baseline PD assessment. Participants will be analyzed based on treatment randomized in line with the ITT principle.

[0204] Data will be summarized and listed separately for each study part.

[0205] Disposition, baseline and demographics characteristics, medical history, prior and concomitant medications, and treatment exposure will be summarized by treatment arm and overall with descriptive statistics using the ITT set and listed.

[0206] Safety and Tolerability:

[0207] AEs will be coded using MedDRA. AEs will be grouped by primary system organ class, high-level term, and preferred term and summarized, by study part and actual treatment group and overall. The summary tables will present the number and percentage of total participants and number of events, by system organ class and by preferred term.

[0208] Safety laboratory evaluations, vital sign assessments, ECG parameters, and other diseasespecific data will be listed by participant and summarized by treatment and protocol specified collection time point. A summary of change from baseline and counts of number of values out of normal range at each protocol specified time point by treatment will also be presented for laboratory data.

[0209] Physical examination abnormalities will be listed by treatment and time point and overall.

[0210] Pharmacokinetics

[0211] For each study part, individual and mean Compound 1 concentration-time data will be tabulated by dosing regimens.

[0212] PK parameters will be computed from the individual plasma concentrations of Compound 1 using a non-compartmental approach.

[0213] PK parameters will be tabulated and summarized by descriptive statistics (mean, standard deviation, median, minimum, maximum, and coefficient of variation [CV%], Geometric mean and geometric CV% will be calculated for Cmax and AUCs.

[0214] Potential correlations of relevant PK parameters with dose, demographics, safety, and PD measures may be explored, as data allow. Additional modelling, including population PK analysis, to characterize these correlations may be performed. The results of such additional analyses may be reported separately from the clinical study report.

[0215] The exposure to Compound 1 (using log-transformed Cmax and AUC values) in Part 1 (SAD) Cohorts 1, 2, and 4, dosed at 30 mg, will be compared using analysis of variance (ANOVA) with treatment condition as fixed effect.

[0216] The food effect will be evaluated by comparing the PK of Compound 1 following administration in the fed condition (SAD5, test) compared with the fasted condition (SAD3, reference). ANOVA tests with fed / fasted condition as fixed effect to compare Cmax and AUC will be performed.

[0217] Depending on the number of dose levels, dose proportionality will be analyzed using ANOVA or the power model with log-transformed PK parameter values and log-transformed dose. Details will be described in the SAP.

[0218] Pharmacodynamic Analysis

[0219] To explore the effect of Compound 1 between the treatment arms on the PD parameters, these parameters will be analyzed using analysis of covariance or mixed model repeated measures. All statistical analyses will be carried out using a 5% level of significance. Additional covariates / cofactors may be included in the modeling depending on the relevance to the endpoint analyzed and the model specifications will be further described in the SAP.

[0220] For each study part, all individual PD biomarkers will be presented in data listings and summarized by nominal sampling time point, and treatment group with descriptive statistics will be presented by Compound 1 dose, all Compound 1 doses combined and combined placebo group. Observed change from baseline and percent changes from baseline for PD biomarker parameters will be summarized at each protocol specified time point, by treatment.

[0221] Differences between treatment groups will be investigated for a subset of PD endpoints that will be defined in the SAP. A generalized linear mixed model approach will be used. Where endpoints are the results from the changes from baseline to each time-point, the model will include treatment, time point and the interaction between treatment and time point as fixed factors, the baseline value as a covariate and participant ID as the repeated factor. Estimates and 95% confidence intervals for the treatment means overall and at each time point and thedifferences between treatments will be presented.

[0222] Clinical Studies

[0223] Single Ascending Dose

[0224] As of 20 December 2023, 40 overweight or obese, otherwise healthy volunteers were enrolled, randomized, and received at least 1 dose of Compound 1 or placebo in 6 SAD cohorts.The Compound 1 dosing regimens in Single Ascending Dose cohorts are as follows:

[0225] Blinded and preliminary PK parameters from SAD Cohorts 1-6 are summarized in Table 1. The concentration-time profiles are depicted in FIG. 8.Table 1: Summary of Key PK Parameters from the Single Ascending Dose Cohorts (Preliminary, Blinded)AUCo-t = area under the concentration-time curve from time 0 to the last measurable concentration; AUCo- / = area under the concentrations-time curve from time 0 to infinity; CL / F = apparent clearance; Cmax= maximum concentration, MMTT = mixed meal tolerance test; SAD = single ascending dose; ti / 2 = terminal half-life; Tmax= time to maximum concentration, Vz / F = apparent volume of distribution a SADI dosing was with 240 mL water with scheduled breakfast and lunch 1 hour and 4 hours postdose, respectively.6SAD2 dosing was with 70 mL water with optional meals postdose. c SAD3 dosing was identical to SADI with MMTT at 3 hours postdose d SAD4 dosing was 70 mL water with dose / optional meals + MMTT at 3 hours postdose e SAD5 dosing was performed in the same participants as in SAD3 with the dose administered 30 minutes after a high-fat breakfastfSAD6 dosing was identical to SAD3.

[0226] The SAD PK data suggest a generally dose-proportional change in maximum observed concentration (Cmax) and AUC from 10 to 30 mg. A reduced amount of water consumed with the capsule and possibly prolonged fasting postdose appears to lower the exposure to Compound 1, as observed by the data from SAD2 (30 mg dosed with 70 mL of water with optional subject- driven meals) versus SADI (30 mg dosed with 240 mL of water with mandatory and scheduled meals). One plausible explanation for these findings may be that an adequate amount of water is necessary to ensure complete dissolution of the capsule, which consequently may affect bioavailability. Impact of a prolonged fast on the clearance and / or on bioavailability of Compound 1 cannot be ruled out at this time. Food intake with a high-fat meal 30 minutes prior to dosing (SAD5) did not appear to impact Cmax or AUC relative to the same dose consumed in the fasted state (SAD3), indicating no meaningful food effect. Dosing with food extended the Tmax by ~4 hours (Table 1). Across the various doses and dosing conditions tested (fasted, fed, different volume of water to administer drug), the observed mean terminal half-life (ti / z) of Compound 1 ranged from 14.3 hours to 18.5 hours, supportive of a once-daily dosing regimen with Compound 1.

[0227] These preliminary PK data from the SAD cohorts suggest that dosing should occur with adequate water (e.g., 240 mL) to ensure complete dissolution of the capsule to enable a more uniform absorption, and to provide post dose meals, and adequate hydration (i.e., avoid prolonged fasting periods).

[0228] The mixed meal tolerance test (MMTT) was performed in SAD Cohorts 3 (10 mg), 4 (30mg), and 6 (20 mg), 3 hours postdose (approaching Tmax of study drug) on Day 1 to assess the acute effects of Compound 1 on glucose homeostasis. Blood samples were collected at 0 hours of the MMTT, right before the test meal was ingested, and at frequent intervals of 15, 30, 60, 90, 120, 180, and 240 minutes after. Pharmacodynamic (PD) endpoints such as plasma glucose and insulin were measured at these time points. Based on the individual curves of change from 0 hours of MMTT to post-MMTT time points, the plasma glucose and insulin levels after MMTT were consistently attenuated in the majority of the participants as shown in FIG. 9.

[0229] In addition, the median percent change in body weight from baseline to Day 2 ranged from -1.2% to -0.4% in these 6 cohorts, further underscoring the potent PD activity of Compound 1, consistent with the broader GLP-1RA class effect in reducing body weight.

[0230] Multiple Ascending Dose

[0231] As of 20 December 2023, 16 obese, otherwise healthy volunteers were enrolled, randomized, and treated with Compound 1 or placebo daily for 28 days in 2 sequential MAD cohorts. The dosing regimens in multiple ascending dose Cohort 1 and Cohort 2 are as follows:

[0232] These blinded and preliminary data from the SAD and MAD cohorts indicate that the study drug appears to be safe and generally well tolerated. Starting at a low dose of the study drug (<20 mg) and gradually titrating up to both 90 mg and 120 mg over 28 days may provide a better and improved gastrointestinal-related tolerability profile given the relatively low rates and severity of nausea and vomiting that are commonly observed with this drug class. Additional cohorts in this protocol will use a more gradual up-titration of the study drug (i.e., from 30 to 50 mg and 50 to 80 mg in MAD3) as well as a starting dose of 5 mg (T2DM Cohort 1) to further delineate the tolerability profile and identify an optimal dosing regimen for Compound 1 in participants with obesity or T2DM.

[0233] Blinded and preliminary PK parameters from MAD1 and MAD2 cohorts are summarizedin Table 2. Time-concentration profiles are depicted in FIG. 10B.Table 2: Summary of Key Pharmacokinetic Parameters from Multiple Ascending Dose Cohorts (Preliminary, Blinded)AUCo-t = area under the concentration-time curve from time 0 to the last measurable concentration; AUCo-» = area under the concentrations-time curve from time 0 to infinity; CL / F = apparent clearance; Cmax = maximum concentration, MAD = multiple ascending dose; ti / 2 = terminal half-life; Tmax = time to maximum concentration; Vz / F = apparent volume of distributionaMAD1 : Compound 1 or placebo 10 / 30 / 60 / 90 mg, each dose was maintained for 7 days before escalating to the next higher dose.bMAD2: Compound 1 or placebo planned doses and titration scheme 10 / 30 / 60 / 90 / 120 mg, 10 mg x 3 days, 30 mg x 4 days, other doses for 7 days each. However, 2 participants needed 2 to 3 additional days on 90 mg before escalating to 120 mg, and 1 participant stayed on 60 mg from Week 2 onwards.

[0234] The MAD PK data suggest that Cmax and AUC are generally dose proportional across the doses within each cohort, without significant accumulation. Time-concentration profiles across doses are also generally well-behaved (i.e., no multiple peaks or delayed absorption patterns), suggesting no meaningful impact on Compound 1 from metabolizing pathways such as via cytochrome P450s. Observed Cmax and AUC after the 10 mg dose administration on Day 1 in both MAD Cohorts 1 and 2 are similar to each other, as well as that seen in SAD3. These data support the well-behaved and reproducible PK characteristics of Compound 1 across different populations in different cohorts. On Day 15, Compound 1 mean Cmax and AUC increased with dose. On Day 28, although mean Cmax increased with dose, AUCo-t means were similar for Compound 1 90 mg and 120 mg. It is important to note that while the planned titration path for the 120 mg dose was intended to be 10 mg x 3 days, 30 mg x 4 days, 60 mg x 7 days, 90 mg x 7 days, and 120 mg x7 days, 2 participants needed 2 to 3 additional days on 90 mg before escalating to 120 mg, and 1 participant stayed on 60 mg from Week 2 onwards. These dosing anomalies may have contributed to the slightly lower than expected exposure at the 120 mg dose.On Day 28, the mean ti / 2 for Compound 1 90 mg and 120 mg were similar - around 16 hours, with low variability, and these data continue to support a once-daily dosing regimen with Compound 1.

[0235] The MMTT procedures were also performed in both MAD Cohorts 1 and 2 on Day -1 (baseline, predose) and Day 28 (3 hours after the last dose of Compound 1 / placebo). Blood samples were collected in an identical manner to the procedures indicated above for the SAD cohorts. PD endpoints such as glucose and insulin were measured at these time points. Table 3 summarizes the AUCs of glucose and insulin on Day -1 and Day 28 as well as the change from baseline. These preliminary and blinded (i.e., Compound 1 and placebo participants combined) results suggest a likely dose-dependent reduction from baseline in AUC of both glucose and insulin after MMTT, corroborating the potent beneficial effects of the study drug on glucose homeostasis.Table 3: Median of Glucose and Insulin Area under the Curve after Mixed Meal ToleranceTest and Change from Baseline in Multiple Ascending Dose Cohorts (Preliminary, Blinded)AUCo-uomin = area under the concentration-time curve from time 0 to 120 minutes; MAD = multiple ascending doseaMAD1 : Compound 1 or placebo 10 / 30 / 60 / 90 mg, each dose was maintained for 7 days before escalating to the next higher dose.bMAD2: Compound 1 or placebo planned doses and titration scheme 10 / 30 / 60 / 90 / 120 mg, 10 mg x 3 days, 30 mg x 4 days, other doses for 7 days each. However, two participants needed 2 to 3 additional days on 90 mg before escalating to 120 mg, and one participant stayed on 60 mg from Week 2 onwards.

[0236] Medians and ranges of the percent change from baseline in body weight in MAD Cohorts1 and 2 are provided in Table 4. These preliminary and blinded (i.e., Compound 1 + placebo participants combined) results suggest a likely dose-dependent and continued (i.e., with noobvious plateau) weight reduction throughout the 28-day dosing period in both cohorts. By Day 28, the medians of percent change in body weight from baseline were -2.9% and -4.5% for Cohorts 1 and 2, respectively. The magnitude of the weight reduction seen in Table 4 is clinically meaningful, especially given that these data also reflect placebo-treated participants, with no suspected significant weight changes. Overall, these preliminary data are highly encouraging and underscore the potential of Compound 1 to provide a clinically meaningful benefit to people living with obesity and its many comorbidities, including those with T2DM.Table 4: Median of Percent Change from Baseline in Body Weight in Multiple AscendingDose Cohorts (Preliminary, Blinded)MAD = multiple ascending doseaMADl : Compound 1 or placebo 10 / 30 / 60 / 90 mg, each dose for 7 days.bMAD2: Compound 1 or placebo 10 / 30 / 60 / 90 mg, 10 mg x3 days, 30 mg x 4 days, other doses for 7 days each.Note: Two participants needed 2 to 3 additional days on 90 mg before escalating to 120 mg, and1 participant stayed on 60 mg from Week 2 onwards

[0237] In continuation of the MAD studies, a total of 25 participants with obesity (BMI >30 kg / m2) without type 2 diabetes were randomized 3 : 1 across three sequential MAD cohorts to receive either Compound 1 or placebo. MAD1 (n=6:2) received 90 mg titrated as 10 / 30 / 60 / 90 mg each dose for 7 days. MAD2 (n=7:2): 120 mg titrated as 10 mg x 3d, 30 mg x 4d, 60 mg x 7d, 90 mgx7d, 120 mg x 7d (higher dose step up from 30mg). MAD3 (n=6:2): 10 mg x 3d, 30 mg x 4d, 50 mg x 7d, 80 mg x 7d, 120 mg x 7d (lower dose step-up from 30mg). Primary endpoint was safety and tolerability of Compound 1. The secondary endpoints included PK parameters and effect on weight loss (WL) and glucose homeostasis after 4 weeks of treatment.

[0238] In this study, a total of 25 participants (60% female), mean (SD) age 37 (9.7) years, BMI 34.9 (3.48) kg / m2, weight 101.2 (17.24) kg, HbAlc 5.1 (0.39)% received at least one dose of Compound 1 (n=18) or placebo (n=6). All treatment-emergent adverse events (TEAEs) were mild or moderate, with no severe TEAEs or discontinuations related to study drug. Most common TEAEs with Compound 1 were gastrointestinal-related, which improved with shallower dose up-titrations to the final dose and over time (lower frequency to no events during Days 22- 28 in MAD3). No clinically significant abnormalities in safety labs were reported and there was no signals of liver injury (no GSH-adduct formation in preclinical studies). Decreased blood pressure and increased heart rate (6-15 bpm on average) were observed post dose. Mean half-life of Compound 1 ranged from 17-22 hours, supporting once-daily dosing. Placebo-adjusted least square mean (LSM) (95% CI) percent change in weight loss from baseline at Day 29 were -1.0% (-3.9, 1.9), -4.6% (-7.3, -1.8) (p<0.01), and -6.1% (-8.9, -3.3) (p <0.001) for MAD1, 2, 3, respectively. Concomitant reductions in AUCo-24Omin glucose and insulin were observed in the setting of a mixed meal tolerance test on Day 28 relative to baseline across all Compound 1 groups versus placebo.

[0239] FIG. 10A shows a single-centered MAD study to assess the safety and efficiency of Compound 1 in the three different dose escalation cohorts over four weeks:’ Cohort 1 (Compound 1 10 / 30 / 60 / 90): planned 10 / 30 / 60 / 90 mg: each dose for 7 days.* Cohort 2 (Compound 1 10 / 30 / 60 / 90 / 120): planned 10 mg x3d, 30 mg *4d, 60 mg *7d, 90 mg x7d, 120 mg x7d.• Cohort 3 (Compound 1 10 / 30 / 50 / 80 / 120): planned 10 mg x3d, 30 mg x4d, 50 mg x7d, 80 mg x7d, 120 mg x7d.

[0240] A brisk up-titration approach was used with a higher starting dose (10 mg), frequent (3 days to weekly), and 2-3x dose increases to reach relevant pharmacologic exposures.

[0241] The participants in the three sequential cohorts are shown in Table 5 below.Table 5: MAD Participants with Obesity and Without T2D

[0242] Overall, preliminary, blinded safety and tolerability data from the SAD and MAD cohorts indicate that Compound 1 / placebo appears to be safe and generally well -tolerated. Additionally, no signals for hypoglycemia, gastroparesis, pancreatitis, psychiatric- or retinal-related AEs have been reported in the study to date. Starting at doses < 10 mg with a shallower (smaller dose increments) and longer (e.g., 2-4 weeks at each dose level) titration regimen is expected to further improve the tolerability profile.

[0243] Preliminary, blinded PK data indicate a generally well-behaved and reproducible PK profile across populations and cohorts, that is generally dose proportional with minimal to no accumulation. Across the various doses, dosing regimens, and populations tested, ti / 2 supports a once-daily dosing regimen for Compound 1 . Table 6 below shows the PK parameters on day 28.Table 6: PK Parameters

[0244] Preliminary, blinded PD data also support a dose-dependent improvement in glucose homeostasis (i.e., concomitant reduction in glucose and insulin in the setting of a MMTT in both acute [following single dose] and sub-acute [over 28 days] settings), as well as dose-dependent and clinically meaningful weight loss (-2.9% and -4.5% for Cohorts 1 and 2, respectively).

[0245] In participants with obesity but without type 2 diabetes, the Phase 1 results showed that Compound 1 led to a clinically meaningful weight loss of 7.3%, while the weight loss in placebo group is 1.2% (p <0.001). Thus, the placebo-adjusted mean weight loss is 6.1% within four weeks. Weight loss magnitude appears to be time-and exposure-dependent. FIG. 1 1 shows thatthe percent change in body weight appears to be linear with changes observed within 1 week of dosing with continued separation from placebo over 4 weeks, and with no plateau. FIG. 12A and FIG. 12B also show that treatment with Compound 1 resulted in concomitant reductions in glucose and insulin during a mixed mean tolerance test (MMTT).

[0246] The results also showed that Compound 1 was well tolerated, with mostly mild or moderate gastrointestinal-related adverse events, consistent with the safety profile of the incretin drug class. There were no severe (Grade 3) treatment-emergent adverse events (TEAEs) and treatment discontinuations related to the study drug, as shown in table 7 below.Table 7: All TEAEs Mild or Moderate Across MAD CohortsdOne participant reported a Grade 2 psychotic disorder, not related to study drug.eOne participant reported a Grade 1 right bundle branch block, not related to study drug.

[0247] Table 8 below shows that all TEAEs were mild or moderate in severity. The frequency of Gl-related TEAEs is consistent with brisk up-titration and early stage of development. Higher- dose cohorts exhibited more frequent TEAEs, and a more gradual titration tended to improve tolerability.Table 8: All TEAEs Mild or Moderate Across MAD Cohortsa> 2 participants in any treatment group.bOther common (> 2 participants in any treatment group) AEs included dysmenorrhea, chills, photosensitivity reaction, and presyncope.

[0248] Table 9 below shows that the Gl-related TEAEs were mostly mild. No more than one participant in each cohort experienced Grade 2 AEs. The GI events tended to improve over time (lower frequency-to-no events during days 23-29.)Table 9: All TEAEs Mild or Moderate Across MAD Cohorts

[0249] The study results also showed that blood levels of Compound 1 were largely unaffected either during fasting or after a standardized high-fat meal. Thus, Compound 1 could potentially be dosed without regard to meal timing, thereby affording greater dosing flexibility for patients.Based on the study data, Compound 1 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 injectable medications.

[0250] These preliminary data are highly encouraging and underscore the potential of Compound 1 to provide a clinically meaningful benefit to people living with obesity and its many comorbidities. Thus, overweight / obese participants with T2DM with well-controlled hypertension and dyslipidemia are eligible to participate in this study as such metabolic comorbidities frequently coexist due to their shared pathophysiology. Additional studies are therefore warranted to continue to examine the effects of Compound 1 on both glucose homeostasis and weight reduction in not only those living with obesity but also in patients with T2DM.

[0251] EXAMPLE 3: A Randomized, Double-Blind, Placebo-and Open-Label Active Comparator-Controlled, Parallel-Group, Multi-Center Phase II Study to Evaluate the Efficacy, Safety, and Tolerability, Pharmacokinetics, and Pharmacodynamics of Once- Daily Compound 1 Administered for 30 Weks to Participants with Type 2 Diabetes Mellitus

[0252] Rationale: Compound 1 is an oral small molecule biased agonist of the glucagon-like peptide 1 receptor (GLP-1R) currently in development for glycemic control and obesity in conjunction with diet and exercise. Injectable peptide formulations of GLP-1R agonists (GLP-1 RAs) have been shown to be efficacious, but the injection method is a barrier to uptake and acceptability. An oral formulation of a peptide GLP-1 RA, semaglutide, is approved for the treatment of Type 2 diabetes (T2D), but it must be administered in a fasting state and no food, liquid, or other medication can be taken within 30 minutes of its administration. As a nonpeptide small molecule GLP-1 RA, Compound 1 has the potential for more convenient oral administration, which may improve uptake and adherence to treatment. This multicenter, randomized, double-blind, parallel-group, placebo- and open-label active comparator (14 mg oral semaglutidej-controlled, Phase II study aims to assess the efficacy, tolerability, and safety of five dose levels of Compound 1 administered once daily (QD) in adults with T2D. Participants must have failed to achieve adequate glycemic control on diet and exercise alone or when treated with a stable dose of metformin and / or sodium-glucose cotransporter-2 (SGLT-2) inhibitors. The primary objective of the study is to evaluate the effect of different doses of oral Compound 1,compared with placebo, on glycemic control, measured through glycated hemoglobin (HbAlc) after 30 weeks of treatment. The trial will also assess changes in body weight and other metabolic parameters.

[0253] Primary Objective: to evaluate the effect of Compound 1 compared with placebo, on glycated hemoglobin (HbAlc). Experimental arms (target doses) Compound 1 30, 60, 120, 180 and 240 mg QD. Control arm: Placebo QD.

[0254] Secondary Objectives: to evaluate the effect of Compound 1, compared with placebo and semaglutide on body weight and glucose homeostasis parameters. To evaluate the safety and tolerability of Compound 1 and to characterize the pharmacokinetics of Compound 1.

[0255] EXAMPLE 4: A Randomized, Double-Blind, Placebo-and Open-Label Active Comparator-Controlled, Parallel-Group, Multi-Center Phase II Study to Evaluate the Efficacy, Safety, and Tolerability, Pharmacokinetics, and Pharmacodynamics of Once- Daily Compound 1 Administered for 38 Weks to Participants with Obesity (BMI >30.0 kg / m2) or Overweight (BMI >27.0 kg / m2and <30.0 kg / m2) with at least one Weight-related Comorbidity

[0256] Rationale: Compound 1 is an oral small molecule biased agonist of the glucagon-like peptide 1 receptor (GLP-1R) currently in development for glycemic control and obesity. Unlike currently approved injectable peptide formulations of GLP-1R agonists (GLP-1 RAs), Compound 1 offers the convenience of oral administration, which may increase patient adherence to treatment to mediate efficacy in weight loss and improve weight loss maintenance compared with currently approved weight loss medications. This multicenter, randomized, double-blind, parallel-group, placebo- and open-label active comparator (14 mg oral semaglutide)-controlled, Phase II study aims to assess the efficacy, tolerability, and safety of five dose levels and two different up-titration schemes of Compound 1 administered once daily (QD) in adults with obesity or overweight with at least one weight-related comorbidity but without diabetes mellitus. The weight-related comorbidity includes hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease, and others. The primary objective of the study is to evaluate the effect of different doses and up-titration of oral Compound 1, compared with placebo, on the percent change in body weight after 30 weeks of treatment.

[0257] Primary Objective: to evaluate the effect of different doses and up-titration schemes of oral Compound 1 compared with placebo, on percent change in body weight after 30 weeks oftreatment. Experimental arms (target doses) Compound 1 30, 60, 120, 180 and 240 mg QD. Control arm: Placebo QD.

[0258] Secondary Objectives: to evaluate the effect of Compound 1, compared with placebo on body weight. To evaluate the safety and tolerability of Compound 1 and to characterize the pharmacokinetics of Compound 1.Other Embodiments

[0259] The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. The disclosure has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications can be made while remaining within the spirit and scope of the disclosure. It will be obvious to one of skill in the art that changes and modifications can be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive.

[0260] The scope of the disclosure should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.

Claims

CLAIMS1. A method of treating diabetes in a subject, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg to 250 mg of Compound 1Compound 1 or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 5 mg to 150 mg.

3. The method of claim 1 or claim 2, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 5 mg to 120 mg.

4. The method of any one of claims 1-3, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 5 mg, 10 mg, 30 mg, 60 mg, 90 mg, or 120 mg.

5. The method of claim 1, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 120 mg.

6. The method of claim 1, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 180 mg.

7. The method of claim 1, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 240 mg.

8. The method of any one of claims 1-7, wherein Compound 1 or the pharmaceuticallyacceptable salt thereof is administered once daily.

9. The method of any one of claims 1-8, wherein the subject has type 2 diabetes.

10. The method of claim 9, wherein the subject has failed to achieve adequate glycemic control on diet and exercise alone.

11. The method of claim 9, wherein the subject has been on a stable dose of metformin, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, or metformin and SGLT-2 inhibitor.

12. The method of claim 11, wherein the subject has failed to achieve adequate glycemic control on a stable dose of metformin, SGLT-2 inhibitor, or metformin and SGLT-2 inhibitor.

13. The method of claim 11 or claim 12, wherein the SGLT-2 inhibitor is selected from Canagliflozin (Invokana®), Dapagliflozin (Farxiga®), Empagliflozin (Jardiance®), Ertugliflozin (Steglatro®), and Bexagliflozin (Brenzavvy®).

14. A method of treating hyperglycemia in a subject, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg to 250 mg of Compound 1Compound 1 or a pharmaceutically acceptable salt thereof.

15. The method of claim 14, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 5 mg to 150 mg.

16. The method of claim 14 or claim 15, wherein the amount of Compound 1 or thepharmaceutically acceptable salt thereof is 5 mg to 120 mg.

17. The method of any one of claims 14-16, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 5 mg, 10 mg, 30 mg, 60 mg, 90 mg, or 120 mg.

18. The method of claim 14, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 120 mg.

19. The method of claim 14, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 180 mg.

20. The method of claim 14, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 240 mg.

21. The method of any one of claims 14-20, wherein Compound 1 or the pharmaceutically acceptable salt thereof is administered once daily.

22. A method of reducing body weight in a subject, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg to 250 mg of Compound 1Compound 1 or a pharmaceutically acceptable salt thereof.

23. The method of claim 22, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 5 mg to 150 mg.

24. The method of claim 22 or claim 23, wherein the amount of Compound 1 or thepharmaceutically acceptable salt thereof is 5 mg to 120 mg.

25. The method of any one of claims 22-24, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 5 mg, 10 mg, 30 mg, 60 mg, 90 mg, or 120 mg.

26. The method of claim 22, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 120 mg.

27. The method of claim 22, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 180 mg.

28. The method of claim 22, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 240 mg.

29. The method of any one of claims 22-28, wherein Compound 1 or the pharmaceutically acceptable salt thereof is administered once daily.

30. A method of treating obesity or overweight in a subject with or without type 2 diabetes, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg to 250 mg of Compound 1Compound 1 or a pharmaceutically acceptable salt thereof.31 . The method of claim 30, wherein the subject has type 2 diabetes.

32. The method of claim 30, wherein the subject has no type 2 diabetes.

33. The method of claim 32, wherein the subject has at least one weight-related comorbidity.

34. The method of claim 33, wherein the weight-related comorbidity is selected from hypertension, dyslipidemia, obstructive sleep apnea, and cardiovascular disease.

35. The method of any one of claims 30-34, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 5 mg to 150 mg.

36. The method of any one of claims 30-34, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 5 mg to 120 mg.

37. The method of any one of claims 30-36, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 5 mg, 10 mg, 30 mg, 60 mg, 90 mg, or 120 mg.

38. The method of claim 30, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 120 mg.

39. The method of claim 30, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 180 mg.

40. The method of claim 30, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 240 mg.

41. The method of any one of claims 30-40, wherein Compound 1 or the pharmaceutically acceptable salt thereof is administered once daily.

42. A method of maintaining body weight following weight loss in a subject, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg toCompound 1 or a pharmaceutically acceptable salt thereof.

43. The method of claim 42, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 5 mg to 150 mg.

44. The method of claim 42 or claim 43, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 5 mg to 120 mg.

45. The method of any one of claims 42-44, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 5 mg, 10 mg, 30 mg, 60 mg, 90 mg, or 120 mg.

46. The method of claim 42, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 120 mg.

47. The method of claim 42, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 180 mg.

48. The method of claim 42, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 240 mg.

49. The method of any one of claims 42-48, wherein Compound 1 or the pharmaceutically acceptable salt thereof is administered once daily.

50. The method of any one of claims 42-49, wherein the weight loss is caused by injectable medications.

51. The method of claim 50, wherein the injectable medications are selected from the group consisting of CT-388, CT-868, tirzepatide, semaglutide, and liraglutide.

52. A method of chronic weight management in a subject with an initial body mass index (BMI) of 30 kg / m2or greater or 27 kg / m2or greater in the presence of at least one weight-related comorbid condition, the method comprising administering orally to the subject in need of such treatment an amount of 5 mg to 250 mg of Compound 1Compound 1 or a pharmaceutically acceptable salt thereof.

53. The method of claim 52, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 5 mg to 150 mg.

54. The method of claim 52 or claim 53, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 5 mg to 120 mg.

55. The method of any one of claims 52-54, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 5 mg, 10 mg, 30 mg, 60 mg, 90 mg, or 120 mg.

56. The method of claim 52, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 120 mg.

57. The method of claim 52, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 180 mg.

58. The method of claim 52, wherein the amount of Compound 1 or the pharmaceutically acceptable salt thereof is 240 mg.

59. The method of any one of claims 52-58, wherein Compound 1 or the pharmaceutically acceptable salt thereof is administered once daily.

60. The method of any one of claims 52-59, wherein the comorbid condition is selected from hypertension, type 2 diabetes, and dyslipidemia.

61. The method of any one of claims 1-60, wherein Compound 1 or the pharmaceutically acceptable salt thereof is administered with or without food.

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