Methods for treating subjects with abdominal obesity, hypertriglyceridemia and / or glucose disorders - Patents.com

Abstract

The present specification relates to a CB1 receptor inhibitor compound of formula I, or a pharma- ceutically acceptable salt thereof, for the treatment of a patient population having abdominal obesity, hypertriglyceridemia and glucose disorders.

Description

[Background technology]

[0001] Cannabinoid CB 1 It is generally known that activation of the receptor increases appetite, increases lipid biosynthesis and storage, inhibits the action of insulin and leptin, and promotes inflammation and fibrosis. Therefore, research has been conducted to identify the role of CB12A1 and CB22A1 for the potential treatment of obesity and its associated metabolic disorders, called metabolic syndrome. 1 The focus was on developing receptor inhibitors. Rimonabant was shown to be effective in treating metabolic syndrome but caused neuropsychiatric (i.e., CNS-related) side effects that led to its removal from the market.

[0002] CB in peripheral tissues (e.g., adipose tissue, liver, muscle, lung, kidney, macrophages, pancreatic beta cells, and gastrointestinal tract) 1 Compounds that preferentially target the receptor were disclosed by George Kunos et al. in US Pat. No. 5,399,633.

[0003] One of the compounds is N-{[(S)-{[3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl][4-(trifluoromethyl)benzenesulfonamido]methylidene}amino]methanimidoyl}acetamide, also known as INV-202. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] U.S. Patent No. 9,765,031 Summary of the Invention

[0005] In some embodiments, the present disclosure relates to uses and methods for treating a patient population with abdominal obesity.Surprisingly, it has been found that daily oral administration of the compound of formula I in a patient population with abdominal obesity, hypertriglyceridemia, and glucose disorders results in significant weight loss combined with a significant reduction in triglycerides, without the patient experiencing non-specific suicidal thoughts during treatment.Statistically significant weight loss is seen after only 8 days of treatment.

[0006] In some embodiments, the disclosure relates to the use of a compound of formula I or a pharma- ceutically acceptable salt thereof for reducing body weight and triglycerides in a human subject determined to have abdominal obesity characterized by a waist circumference of ≧88 cm for a female subject or ≧102 cm for a male subject,

[0007] [ka] The reduction is relative to pre-treatment baseline levels and the compound of formula I is for oral administration to a human subject for a period of at least 28 days.

[0008] In some embodiments, the disclosure relates to the use of a compound of formula I or a pharma- ceutically acceptable salt thereof to reduce body weight, triglycerides, and impaired glucose tolerance in a human subject determined to have abdominal obesity characterized by a waist circumference of ≧88 cm for a female subject or ≧102 cm for a male subject, wherein the reduction is relative to pre-treatment baseline levels, and wherein the compound of formula I is for oral administration to the human subject for a period of at least 28 days.

[0009] In some embodiments, the disclosure relates to a compound of formula I or a pharma- ceutically acceptable salt thereof for use in reducing body weight and triglycerides in a human subject determined to have abdominal obesity characterized by a waist circumference of ≧88 cm for a female subject or ≧102 cm for a male subject, wherein the reduction is relative to pre-treatment baseline levels, and wherein the compound of formula I is for oral administration to the human subject for a period of at least 28 days.

[0010] In some embodiments, the disclosure relates to a compound of formula I or a pharma- ceutically acceptable salt thereof for use in reducing body weight, triglycerides, and impaired glucose tolerance in a human subject determined to have abdominal obesity characterized by a waist circumference of ≧88 cm for a female subject or ≧102 cm for a male subject, wherein the reduction is relative to pre-treatment baseline levels, and wherein the compound of formula I is for oral administration to the human subject for a period of at least 28 days.

[0011] In some embodiments, the disclosure relates to a method for reducing body weight and triglycerides in a human subject determined to have abdominal obesity characterized by a waist circumference of ≧88 cm for a female subject or ≧102 cm for a male subject, wherein the reduction is relative to a pre-treatment baseline level, the method comprising orally administering to the human subject a compound of formula I or a pharma- ceutically acceptable salt thereof for a period of at least 28 days.

[0012] In some embodiments, the disclosure relates to a method for reducing body weight, triglycerides, and impaired glucose tolerance in a human subject determined to have abdominal obesity characterized by a waist circumference of ≧88 cm for a female subject or ≧102 cm for a male subject, wherein the reduction is relative to a pre-treatment baseline level, the method comprising orally administering to the human subject a compound of formula I or a pharma- ceutically acceptable salt thereof for a period of at least 28 days.

[0013] In some embodiments, the disclosure relates to a method for reducing a subjective sensation of appetite in a subject in need thereof, the method comprising administering to the subject a compound of formula I or a pharma- ceutically acceptable salt thereof, wherein the reduction is relative to a baseline level.

[0014] In some embodiments, the reduction in subjective appetite sensation is determined by appetite and food intake questionnaires.

[0015] In some embodiments, the subject is a human subject and is a waist circumference of ≥88 cm for female subjects or ≥102 cm for male subjects; Present one or more of the following: fasting triglycerides (e.g., >1.5 mmol / L for men and women) and / or impaired glucose tolerance (e.g., an OGTT indicating impaired glucose tolerance as indicated by a 2-hour value >140 mg / dl, or any value at any time point >200 mg / dl, or an HbA1C level of ≧5.7% but ≦6.4%).

[0016] In some embodiments, the compound of formula I is for oral administration to a subject.

[0017] In some embodiments, the compound of formula I is for oral administration to a subject at a dose of 25 mg or greater.

[0018] In some embodiments, the compound of formula I is for daily oral administration to a subject at a dose of 25 mg or more.

[0019] In some embodiments, the compound of formula I is for daily oral administration to a subject at a dose of about 25 mg.

[0020] In some embodiments, the oral dosage form is a tablet, capsule, lozenge, lozenge, or granule.

[0021] In some embodiments, the compound of formula I is for daily oral administration in a unit dosage form.

[0022] In some embodiments, the pharmaceutical compositions are formulated as oral suspensions.

[0023] In some embodiments, the subject shows no significant changes versus baseline in bilirubin, AST, and / or ALT after 28 days of treatment with a compound of formula I.

[0024] In some embodiments, the subject exhibits a weight reduction relative to baseline of about 0.1 to about 7%, about 1 to about 6%, about 2 to about 5%, about 3 to about 5%, about 4%, about 3.5%, about 3%, or about 2.5%, about 2%, about 1%, about 0.5%, about 0.1% after 28 days of treatment with a compound of Formula I.

[0025] In some embodiments, the subject exhibits a triglyceride reduction relative to baseline of about 1 to about 10%, about 2 to about 9%, about 3 to about 8%, about 8%, about 7%, about 6%, or about 5% after 28 days of treatment with a compound of formula I.

[0026] In some embodiments, the subject exhibits a change in leptin levels relative to baseline of about 10% to about 20%, about 10%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% after 28 days of treatment with a compound of Formula I.

[0027] In some embodiments, the subject exhibits a reduction in LDL levels relative to baseline of at least about 0.1 mmol / L to about 1 mmol / L after 28 days of treatment with a compound of formula I.

[0028] In another aspect, there is provided a use of a compound of formula I as described herein or a pharmaceutical composition as described herein for the treatment of a disease or disorder selected from the group consisting of obesity (type I or type II), non-alcoholic and alcoholic fatty liver disease (risk factors for insulin resistance), comorbidities of obesity, comorbidities of diabetes, Prader-Willi syndrome (PWS), proopiomelanocortin (POMC) deficiency obesity, LepR deficiency obesity, POMC heterozygous deficiency obesity, POMC epigenetic disorders, Bardet-Biedl syndrome, Alström syndrome, dyslipidemia predisposing to atherosclerotic heart disease, diabetic nephropathy, fibrosis and fibrotic diseases such as idiopathic pulmonary fibrosis (IPF) and Hermansky-Pudlak syndrome pulmonary fibrosis (HPS-PF), gout, primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC).

[0029] In another aspect, there is provided a use of a compound of formula I as described herein or a pharmaceutical composition as described herein for the manufacture of a medicament for the treatment of a disease or disorder selected from the group consisting of obesity (Type I or Type II), non-alcoholic and alcoholic fatty liver disease (risk factors for insulin resistance), comorbidities of obesity, comorbidities of diabetes, Prader-Willi syndrome (PWS), proopiomelanocortin (POMC) deficiency obesity, LepR deficiency obesity, POMC heterozygous deficiency obesity, POMC epigenetic disorders, Bardet-Biedl syndrome, Alström syndrome, dyslipidemia predisposing to atherosclerotic heart disease, diabetic nephropathy, fibrosis and fibrotic diseases such as idiopathic pulmonary fibrosis (IPF) and Hermansky-Pudlak syndrome pulmonary fibrosis (HPS-PF), and gout.

[0030] In another aspect, there is provided a method for the treatment of a disease or disorder selected from the group consisting of obesity, diabetes mellitus (Type I or Type II), non-alcoholic and alcoholic fatty liver disease (risk factor for insulin resistance), comorbidities of obesity, comorbidities of diabetes, Prader-Willi syndrome (PWS), proopiomelanocortin (POMC) deficiency obesity, LepR deficiency obesity, POMC heterozygous deficiency obesity, POMC epigenetic disorders, Bardet-Biedl syndrome, Alström syndrome, dyslipidemia predisposing to atherosclerotic heart disease, diabetic nephropathy, fibrosis and fibrotic diseases such as idiopathic pulmonary fibrosis (IPF) and Hermansky-Pudlak syndrome pulmonary fibrosis (HPS-PF), and gout, comprising administering a compound of formula I as defined herein or a pharmaceutical composition as defined herein to a subject in need of treatment.

[0031] In some embodiments, the comorbidities of obesity are selected from metabolic syndrome, dementia, cardiac disease, hypertension, gallbladder disease, gastrointestinal disorders, menstrual irregularities, osteoarthritis, venous stasis ulcers, pulmonary hypoventilation syndrome, sleep apnea, snoring, coronary artery disease, arteriosclerosis, pseudotumor cerebri, osteoarthritis, high cholesterol, and increased incidence of malignancies of the liver, ovary, cervix, uterus, breast, prostate, or gallbladder.

[0032] In some embodiments, the comorbidities of diabetes (eg, Type I) are selected from diabetic nephropathy, chronic kidney disease, diabetic retinopathy, and peripheral and autonomic neuropathy.

[0033] In some embodiments, the disease or disorder is selected from diabetes (type 1 or type 2), obesity, and non-alcoholic fatty liver disease (eg, non-alcoholic steatohepatitis). [Brief description of the drawings]

[0034] [Figure 1] The difference in body weight (kg) between INV-202 (solid bars) and placebo (striped bars) is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] definition The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It should be noted that the singular forms "a," "an," and "the" include the plural unless the context clearly dictates otherwise. Thus, for example, reference to a composition containing a "compound" also contemplates a mixture of two or more compounds. It should also be noted that the term "or" is generally used in its sense including "and / or" unless the context clearly dictates otherwise. Furthermore, when the terms "including," "includes," "having," "has," "with," or variations thereof are used in either the detailed description and / or claims, such terms are intended to be inclusive in a manner similar to the term "comprising."

[0036] The term "about" or "approximately" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" may mean within one or more standard deviations, according to the practice in the art. Alternatively, "about" may mean within a range of up to 20%, preferably up to 10%, more preferably up to 5%, and even more preferably up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term may mean within 10-fold, preferably within 5-fold, and more preferably within 2-fold of a value. When a particular value is described in the present application and claims, the term "about" meaning within an acceptable error range for the particular value should be assumed, unless otherwise specified.

[0037] Provided herein are compounds of Formula I, or a pharma- ceutically acceptable salt thereof.

[0038] [ka]

[0039] The structures depicted for the compounds of formula I are also intended to include all tautomeric forms of the compounds of formula I. In addition, the structures depicted herein are also intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having the structure of the compound of formula I, except for the replacement of a carbon with a C-enriched carbon, are within the scope of this specification. The compound of formula (I) is also known as INV-202.

[0040] Formulations, Methods, and Uses As used herein, the term "effective amount" refers to an amount of a drug or pharmaceutical agent that induces a biological or medical response in a tissue, system, animal, or human that is desired, for example, by a researcher or clinician.Furthermore, the term "therapeutically effective amount" refers to any amount that results in improved treatment, cure, prevention, or amelioration of a disease, disorder, or side effect, or a reduction in the rate of progression of a disease or disorder, compared to a corresponding subject that does not receive such amount.This term also includes amounts within its range that are effective for enhancing normal physiological function.

[0041] As used herein, the terms "reduce," "reducing," "improve," "ameliorating," "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting the progression of a disease or disorder described herein, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have disappeared, for example, to prevent or delay the recurrence of symptoms.

[0042] The term "patient or subject" as used herein refers to a mammal. Thus, a subject refers to, for example, a dog, a cat, a horse, a cow, a pig, a guinea pig, etc. Preferably, the subject is a human. When the subject is a human, the subject can be either a patient or a healthy human. In one aspect, the subject is a human subject with metabolic syndrome. In one aspect, the subject is a human subject with abdominal obesity.

[0043] The term "metabolic syndrome" as used herein refers to subjects with hypertriglyceridemia, abdominal obesity, and impaired glucose tolerance.

[0044] The term "impaired glucose tolerance" as used herein refers to impaired glucose tolerance as indicated by an oral glucose tolerance test (OGTT) using a 75 g glucose load, with a 2 hour value of >140 mg / dl, or any value at any time point of >200 mg / dl, or an HbA1C level of ≥5.7% but ≤6.4%.

[0045] The term "baseline level" as used herein refers to the value before a subject begins treatment with a compound of formula (I). In some cases, the baseline value can also be the normal value of a comparable reference group.

[0046] The term "plasma lipid profile" as used herein refers to levels of total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), very low density lipoprotein (VLDL), and triglycerides.

[0047] The term "subjective appetite sensation" as used herein refers to that determined by appetite and food intake questionnaires as described herein taken before, during, and after treatment.

[0048] The present specification provides a method for treating a disorder (described herein) in a subject, comprising administering a compound of formula I to a subject identified as needing treatment.Identifying a patient who needs to treat the above-described disorder is well within the ability and knowledge of a person skilled in the art.Certain methods are understood in the medical arts for identifying patients at risk of developing the above-described disorder that can be treated by the subject method, such as family history and the presence of risk factors related to the development of the disease state in the subject patient.Clinicians in the art can easily identify such candidate patients, for example, by using clinical tests, physical examinations, medical / family history, and genetic determination.

[0049] The method of evaluating the effectiveness of treatment in a subject includes determining pre-treatment symptoms of the disorder by methods well known in the art, and then administering a therapeutically effective amount of a compound of the present invention to the subject. After an appropriate period (e.g., 1 week, 2 weeks, 1 month, 6 months) after administration of the compound, the symptoms of the disorder are determined again. Modulation (e.g., reduction) of the symptoms and / or biomarkers of the disorder indicates the effectiveness of the treatment. The symptoms and / or biomarkers of the disorder can be determined periodically throughout the treatment. For example, the symptoms and / or biomarkers of the disorder can be checked every few days, weeks, or months to evaluate the further effectiveness of the treatment. The reduction of the symptoms and / or biomarkers of the disorder indicates that the treatment is effective.

[0050] In some embodiments, the compound of formula I is for administration to a human subject for a period of at least 8 to 35 days, at least 8 days, at least 15 days, at least 22 days, at least 28 days, at least 29 days, or at least 35 days.

[0051] In some embodiments, the compound of formula I is for oral administration to a human subject for a period of at least 8 to 35 days, at least 8 days, at least 15 days, at least 22 days, at least 28 days, at least 29 days, or at least 35 days.

[0052] The compositions described herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques.

[0053] Liquid dosage forms for oral administration include, but are not limited to, pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.Other than inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings, and aromatics.

[0054] Injectable preparations, for example, sterile injectable aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution (USP), and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0055] The injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0056] To prolong the effect of the provided compound, it may be desirable to slow down the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with low water solubility. The absorption rate of the compound then depends on its dissolution rate, which in turn depends on the crystal size and crystalline form. Alternatively, the delayed absorption of parenterally administered compound forms is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the compound release rate can be controlled.

[0057] Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0058] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax, which is solid at ambient temperature but liquid at body temperature and thus will melt in the rectum or vaginal cavity and release the active compound.

[0059] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharma- ceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants, such as glycerol, d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite clay, and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include a buffering agent. In one embodiment, the compound of formula I is formulated as a solid dispersion as described in WO2021189141A1.

[0060] Solid compositions of similar form can also be used as fillers in soft and hard filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, lozenges, capsules, troches, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They can optionally contain opacifying agents, and can also be of a composition that releases the active ingredient only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of similar form can also be used as fillers in soft and hard filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0061] The provided compositions may also be in microencapsulated form, containing one or more of the excipients mentioned above. The solid dosage forms of tablets, dragees, lozenges, capsules, lozenges, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also contain, as is common practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents, and may also be of a composition that releases the active ingredient only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes.

[0062] The dosage form for topical or transdermal administration of the compound of the present invention includes ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches.The active ingredient is mixed under sterile conditions with a pharma- ceutically acceptable carrier, and any necessary preservatives or buffers, if necessary.Ophthalmic preparations, ear drops, and eye drops are also contemplated within the scope of the present invention.In addition, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body.Such dosage forms can be made by dissolving or dispensing the compound in a suitable medium.Absorption enhancers can also be used to increase the flux of the compound across the skin.The rate can be controlled by providing a rate-controlling membrane, or by dispersing the compound in a polymer matrix or gel.

[0063] The pharma- ceutically acceptable compositions provided herein may also be administered by nasal aerosol or inhalation.Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0064] The pharma- ceutically acceptable compositions provided herein can be formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharma- ceutically acceptable compositions of the present disclosure are administered without food. In other embodiments, the pharma- ceutically acceptable compositions of the present disclosure are administered with food.

[0065] The pharma- ceutically acceptable compositions provided herein can be formulated for oral administration. Such formulations can be administered with or without food. The compositions are formulated in unit dosage form for ease of administration and uniformity of dosage. The expression "unit dosage form" as used herein refers to a physically separate pharmaceutical unit suitable for the patient to be treated. However, it is understood that the total daily usage of the compositions of the present disclosure is determined by the attending physician within the scope of sound medical judgment.

[0066] The amount of the compound of formula I that may be included in a single dosage form will vary depending on the patient being treated (e.g., child vs. adult, etc.). Treatment regimens may include administration to a patient of a total amount of about 10 mg to about 200 mg, 25 mg to 150 mg, 25 mg to 125 mg, 25 mg to 100 mg, 25 mg to 75 mg, 25 mg to 50 mg, about 25 mg, about 50 mg of the compound herein per day, in a single dose or divided into multiple doses.

[0067] It is understood that the total daily dose of the compound of formula I is determined by the attending physician within the scope of sound medical judgment.For example, the specific dose or treatment regimen for any particular patient depends on various factors, including age, body weight, general health, sex, diet, administration time, excretion rate, drug combination, the judgment of the treating physician, and the severity of the symptoms related to disease or disorder.

[0068] Depending on the disease or disorder to be treated, additional therapeutic agents may also be present in the composition of the present disclosure or may be co-administered separately.Non-limiting examples of additional therapeutic agents that can be used in combination with the compound of formula I include antidiabetic drugs, cholesterol-lowering drugs, anti-inflammatory agents, antibacterial agents, matrix metalloproteinase inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressants, anticancer drugs, antiviral drugs, cytokines, growth factors, immunomodulators, prostaglandins, or anti-vascular hyperproliferation compounds.Treatment can also be complemented by other treatments or interventions, such as surgery, radiation therapy (e.g., gamma radiation, neutron radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and whole body radioisotopes), biological response modifiers (e.g., interferons, interleukins, tumor necrosis factor (TNF)), and agents used to attenuate the adverse effects of the compound or co-administered components.

[0069] The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiment or portions thereof. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiment or portions thereof.

[0070] In some embodiments, a therapeutically effective amount of a compound defined herein, or a pharma- ceutically acceptable salt thereof, may be administered to a patient, either alone or in admixture with a pharma- ceutically acceptable carrier.

[0071] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.The pharmaceutically acceptable carrier, adjuvant, or vehicle that can be used in the composition of the present disclosure includes, but is not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene block polymer, polyethylene glycol, and wool fat.

[0072] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound herein which is capable of providing, directly or indirectly, a compound herein, or an inhibitory active metabolite or residue thereof, upon administration to a recipient.

[0073] Embodiment Embodiment 1. Use of a compound of formula I or a pharma- ceutically acceptable salt thereof to reduce body weight and triglycerides in a human subject determined to have abdominal obesity characterized by a waist circumference of ≧88 cm for a female subject or ≧102 cm for a male subject, comprising:

[0074] [ka] The use, wherein the reduction is relative to a pre-treatment baseline level, and the compound of formula I is for oral administration to a human subject for a period of at least 28 days. Embodiment 2. Use of a compound of formula I or a pharma- ceutical acceptable salt thereof to reduce body weight, triglycerides, and impaired glucose tolerance in a human subject determined to have abdominal obesity characterized by a waist circumference of ≧88 cm for a female subject or ≧102 cm for a male subject, comprising:

[0075] [ka] The use, wherein the reduction is relative to a pre-treatment baseline level, and the compound of formula I is for oral administration to a human subject for a period of at least 28 days. Embodiment 3. A subject receives one of the following: a. Fasting triglycerides >1.5 mmol / L for men and women; and / or b. The use of embodiment 1 or 2, wherein the patient exhibits one or more of the following: an OGTT indicative of impaired glucose tolerance as indicated by a 2 hour value of >140 mg / dl, or any value at any time point of >200 mg / dl, or an HbA1C level of ≧5.7% but ≦6.4%. Embodiment 4. The use of any of embodiments 1-3, wherein the subject exhibits no significant changes relative to baseline in bilirubin, AST, and / or ALT after 28 days of treatment with the compound of formula I. Embodiment 5. The use of any of embodiments 1-4, wherein the subject exhibits a weight reduction relative to baseline of about 0.1 to about 7%, about 1 to about 6%, about 2 to about 5%, about 3 to about 5%, about 4%, about 3.5%, about 3%, or about 2.5% after 28 days of treatment with a compound of formula I. Embodiment 6. The use of any of embodiments 1-5, wherein the subject exhibits a triglyceride reduction relative to baseline of about 1 to about 10%, about 2 to about 9%, about 3 to about 8%, about 8%, about 7%, about 6%, or about 5% after 28 days of treatment with a compound of formula I. Embodiment 7. The use of any of embodiments 1-6, wherein the subject exhibits a change in leptin levels relative to baseline of about 10% to about 20% after 28 days of treatment with a compound of formula I. Embodiment 8. The use of any of embodiments 1-7, wherein the subject exhibits a reduction in LDL levels relative to baseline of at least about 0.1 mmol / L to about 1 mmol / L after 28 days of treatment with a compound of formula I. Embodiment 9. The use of any of embodiments 1-8, wherein the subject exhibits a reduction in VLDL levels relative to baseline of at least about 0.03 mmol / L to about 1 mmol / L after 28 days of treatment with a compound of formula I. Embodiment 10. The use of any of embodiments 1-9, wherein the subject exhibits a reduction in total cholesterol levels relative to baseline of at least about 0.1 mmol / L to about 1 mmol / L after 28 days of treatment with a compound of formula I. Embodiment 11. The use according to any of embodiments 1 to 10, wherein the subject does not show a significant change in subjective appetite sensation during treatment as determined by appetite and food intake questionnaires. Embodiment 12. The use of any of embodiments 1 to 11, wherein the compound of formula I is for oral administration to a subject at a dose of 25 mg or more. Embodiment 13. The use according to any one of embodiments 1 to 12, wherein the compound of formula I is for daily oral administration to a subject at a dose of 25 mg or more. Embodiment 14. The use according to any of embodiments 1 to 13, wherein the compound of formula I is for daily oral administration to a subject at a dose of about 25 mg. Embodiment 15. A compound of formula I or a pharma- ceutically acceptable salt thereof for use in reducing body weight and triglycerides in a human subject determined to have abdominal obesity characterized by a waist circumference of ≧88 cm for a female subject or ≧102 cm for a male subject,

[0076] [ka] The compound of formula I or a pharma- ceutically acceptable salt thereof, wherein the reduction is relative to a pre-treatment baseline level, and the compound of formula I is for oral administration to a human subject for a period of at least 28 days. Embodiment 16. A compound of formula I or a pharma- ceutically acceptable salt thereof for use in reducing body weight, triglycerides, and impaired glucose tolerance in a human subject determined to have abdominal obesity characterized by a waist circumference of ≧88 cm for a female subject or ≧102 cm for a male subject,

[0077] [ka] The compound of formula I or a pharma- ceutically acceptable salt thereof, wherein the reduction is relative to a pre-treatment baseline level, and the compound of formula I is for oral administration to a human subject for a period of at least 28 days. Embodiment 17. A subject receives one of the following: i. Fasting triglycerides >1.5mmol / L for men and women; and / or ii. A compound according to embodiment 15 or 16, which exhibits one or more of the following: an OGTT indicative of impaired glucose tolerance as indicated by a 2 hour value of >140 mg / dl, or any value at any time point of >200 mg / dl, or an HbA1C level of ≧5.7% but ≦6.4%. Embodiment 18. A compound for use according to embodiments 15-17, wherein the subject shows no significant changes relative to baseline in bilirubin, AST, and / or ALT after 28 days of treatment with a compound of formula I. Embodiment 19. The compound for use according to any of embodiments 15-18, wherein the subject exhibits a weight reduction relative to baseline of about 0.1 to about 7%, about 1 to about 6%, about 2 to about 5%, about 3 to about 5%, about 4%, about 3.5%, about 3%, or about 2.5% after 28 days of treatment with a compound of formula I. Embodiment 20. The compound for use according to any of embodiments 15-19, wherein the subject exhibits a triglyceride reduction relative to baseline of about 1 to about 10%, about 2 to about 9%, about 3 to about 8%, about 8%, about 7%, about 6%, or about 5% after 28 days of treatment with a compound of formula I. Embodiment 21. A compound for use according to any of embodiments 15-20, wherein the subject exhibits a change in leptin levels relative to baseline of about 10% to about 20% after 28 days of treatment with a compound of formula I. Embodiment 22. A compound for use according to any of embodiments 15-21, wherein the subject exhibits a reduction in LDL levels relative to baseline of at least about 0.1 mmol / L to about 1 mmol / L after 28 days of treatment with a compound of formula I. Embodiment 23. A compound for use according to any of embodiments 15-22, wherein the subject exhibits a reduction in VLDL levels relative to baseline of at least about 0.03 mmol / L to about 1 mmol / L after 28 days of treatment with a compound of formula I. Embodiment 24. A compound for use according to any of embodiments 15-23, wherein the subject exhibits a reduction in total cholesterol levels relative to baseline of at least about 0.1 mmol / L to about 1 mmol / L after 28 days of treatment with a compound of formula I. Embodiment 25. A compound for use according to any of embodiments 15-24, wherein the compound of formula I is for oral administration to a subject at a dose of 25 mg or more. Embodiment 26. A compound for use according to any of embodiments 15-25, wherein the compound of formula I is for daily oral administration to a subject at a dose of 25 mg or more. Embodiment 27. A compound for use according to any of embodiments 15 to 26, wherein the compound of formula I is for daily oral administration to a subject at a dose of about 25 mg. Embodiment 28. A method for reducing body weight and triglycerides in a human subject determined to have abdominal obesity characterized by a waist circumference of ≧88 cm for a female subject or ≧102 cm for a male subject, wherein the reduction is relative to a pre-treatment baseline level, the method comprising administering to a subject a compound of formula I or a pharma- ceutically acceptable salt thereof:

[0078] [ka] to a human subject for a period of at least 28 days. Embodiment 29. A method for reducing body weight, triglycerides, and impaired glucose tolerance in a human subject determined to have abdominal obesity characterized by a waist circumference of ≧88 cm for a female subject or ≧102 cm for a male subject, wherein the reduction is relative to a pre-treatment baseline level, the method comprising administering to a subject a compound of formula I or a pharma- ceutical acceptable salt thereof:

[0079] [ka] to a human subject for a period of at least 28 days. Embodiment 30. A subject receives the following: i. Fasting triglycerides >1.5mmol / L for men and women; and / or ii. The method of embodiment 28 or 29, wherein the patient exhibits one or more of the following: an OGTT indicative of impaired glucose tolerance as indicated by a 2 hour value of >140 mg / dl, or any value at any time point of >200 mg / dl, or an HbA1C level of ≧5.7% but ≦6.4%. Embodiment 31. The method of any of embodiments 28-30, wherein the subject exhibits no significant changes relative to baseline in bilirubin, AST, and / or ALT after 28 days of treatment with the compound of formula I. Embodiment 32. The method of any of embodiments 28-31, wherein the subject exhibits a weight reduction relative to baseline of about 0.1 to about 7%, about 1 to about 6%, about 2 to about 5%, about 3 to about 5%, about 4%, about 3.5%, about 3%, or about 2.5% after 28 days of treatment with a compound of formula I. Embodiment 33. The method of any of embodiments 28-32, wherein the subject exhibits a triglyceride reduction relative to baseline of about 1 to about 10%, about 2 to about 9%, about 3 to about 8%, about 8%, about 7%, about 6%, or about 5% after 28 days of treatment with a compound of formula I. Embodiment 34. The method of any of embodiments 28-33, wherein the subject exhibits a change in leptin levels relative to baseline of about 10% to about 20% after 28 days of treatment with a compound of formula I. Embodiment 35. The method of any of embodiments 28-34, wherein the subject exhibits a reduction in LDL levels relative to baseline of at least about 0.1 mmol / L to about 1 mmol / L after 28 days of treatment with a compound of formula I. Embodiment 36. The method of any of embodiments 28-35, wherein the subject exhibits a reduction in VLDL levels relative to baseline of at least about 0.03 mmol / L to about 1 mmol / L after 28 days of treatment with a compound of formula I. Embodiment 37. The method of any of embodiments 28-36, wherein the subject exhibits a reduction in total cholesterol levels relative to baseline of at least about 0.1 mmol / L to about 1 mmol / L after 28 days of treatment with a compound of formula I. Embodiment 38. The method of any of embodiments 28-37, wherein the compound of formula I is for oral administration to a subject at a dose of 25 mg or more. Embodiment 39. The method of any of embodiments 28-38, wherein the compound of formula I is for daily oral administration to a subject at a dose of 25 mg or more. Embodiment 40. The method of any of embodiments 28-39, wherein the compound of formula I is for daily oral administration to a subject at a dose of about 25 mg. Embodiment 41. A compound for use, use or method according to any of embodiments 1 to 40, wherein the compound of formula I is for daily oral administration to a subject at a dose of less than 25 mg. Embodiment 42. Use of a compound of formula I or a pharma- ceutically acceptable salt thereof for improving or reducing impaired glucose tolerance in a subject, comprising:

[0080] [ka] The improvement or reduction is relative to a baseline level. Embodiment 43. Use of a compound of formula I or a pharma- ceutically acceptable salt thereof for improving plasma lipid profile relative to baseline levels (e.g., total cholesterol, HDL, LDL, VLDL, and / or triglycerides) in a subject, comprising administering to said subject a therapeutically effective amount of a compound of formula I or a pharma- ceutically acceptable salt thereof,

[0081] [ka] Use, wherein the improvement is relative to a baseline level. Embodiment 44. Use of a compound of formula I or a pharma- ceutically acceptable salt thereof for reducing LDL, VLDL, and / or triglycerides in a subject, comprising:

[0082] [ka] The reduction is relative to a baseline level. Embodiment 45. Use of a compound of formula I or a pharma- ceutically acceptable salt thereof for reducing subjective appetite sensations in a subject with metabolic syndrome, comprising:

[0083] [ka] The reduction is relative to a baseline level. Embodiment 46. The use according to embodiment 45, wherein the reduction in subjective appetite sensation is determined by appetite and food intake questionnaires. Embodiment 47. The subject is a human subject, comprising: a waist circumference of ≥88 cm for female subjects or ≥102 cm for male subjects; Fasting triglycerides (e.g., >1.5 mmol / L for men and women) and / or 47. The use of any of the preceding embodiments 42-46, wherein the patient exhibits one or more of the following: impaired glucose tolerance (e.g., an OGTT indicative of impaired glucose tolerance as indicated by a 2-hour value of >140 mg / dl, or any value at any time point of >200 mg / dl, or an HbA1C level of ≧5.7% but ≦6.4%). Embodiment 48. The use of any of the preceding embodiments 42 to 47, wherein the compound of formula I is for oral administration to a subject. Embodiment 49. The use according to any of embodiments 42 to 48, wherein the compound of formula I is for oral administration to a subject at a dose of 25 mg or more. Embodiment 50. The use of any of the preceding embodiments 42-48, wherein the compound of formula I is for daily oral administration to a subject at a dose of 25 mg or more. Embodiment 51. The use of any of the preceding embodiments 42-49, wherein the compound of formula I is for daily oral administration to a subject at a dose of about 25 mg. Embodiment 52. A method for improving or reducing impaired glucose tolerance in an impaired glucose tolerance human subject, the method comprising administering to a subject a compound of formula I or a pharma- ceutically acceptable salt thereof:

[0084] [ka] to a subject in need thereof, wherein said improvement or reduction is relative to a baseline level. Embodiment 53. A method for improving plasma lipid profiles (e.g., total cholesterol, HDL, LDL, VLDL, and / or triglycerides), the method comprising administering to a patient a compound of formula I or a pharma- ceutically acceptable salt thereof:

[0085] [ka] to a subject, wherein the improvement is relative to a baseline level. Embodiment 54. A method for reducing LDL, VLDL, and / or triglycerides in a subject in need thereof, the method comprising administering to a subject a compound of formula I or a pharma- ceutically acceptable salt thereof:

[0086] [ka] to a subject, wherein the reduction is relative to a baseline level. Embodiment 55. A method for reducing a subjective sensation of appetite in a subject in need thereof, the method comprising administering to a subject a compound of formula I or a pharma- ceutically acceptable salt thereof:

[0087] [ka] to a subject, wherein the reduction is relative to a baseline level. Embodiment 56 The method of embodiment 55, wherein the reduction in subjective appetite sensation is determined by appetite and food intake questionnaires. Embodiment 57. The subject is a human subject, comprising: a waist circumference of ≥88 cm for female subjects or ≥102 cm for male subjects; Fasting triglycerides (e.g., >1.5 mmol / L for men and women) and / or 57. The method of any of the preceding embodiments 52-56, wherein the patient exhibits one or more of the following: impaired glucose tolerance (e.g., an OGTT indicative of impaired glucose tolerance as indicated by a 2-hour value of >140 mg / dl, or any value at any time point of >200 mg / dl, or an HbA1C level of ≧5.7% but ≦6.4%). Embodiment 58. The use of any of the preceding embodiments 52-57, wherein the compound of formula I is for oral administration to a subject. Embodiment 59. The method of any of embodiments 52-58, wherein the compound of formula I is for oral administration to a subject at a dose of 25 mg or more. Embodiment 60. The method of any of the preceding embodiments 52-58, wherein the compound of formula I is for daily oral administration to a subject at a dose of 25 mg or more. Embodiment 61. The method of any of the preceding embodiments 58-59, wherein the compound of formula I is for daily oral administration to a subject at a dose of about 25 mg.

[0088] Experiments and Examples A Phase 1b study was conducted to investigate the pharmacokinetic and pharmacodynamic effects of INV-202 in subjects with metabolic syndrome defined by hypertriglyceridemia, abdominal obesity, and impaired glucose tolerance over a 28-day period.

[0089] The results are reported in Tables 1-5 and FIG.

[0090] the purpose To examine the PK of INV-202 in subjects with evidence of metabolic syndrome over a 28 day period. To investigate the PD effects of INV-202 as measured by glucose metabolism and lipid profile over 28 days. To evaluate the safety and tolerability of INV-202 over a 28-day period.

[0091] Evaluation items PK evaluation items : PK parameters of INV-202 and its major metabolites.

[0092] Further details are available in the PK section of the protocol and additional details are included in the SAP.

[0093] PD evaluation items : -0-3 hour AUC blood glucose level during OGTT Change from baseline in: Plasma insulin levels C-peptide levels Plasma lipid profile (HDL, LDL, VLDL, and triglycerides) Adiponectin and leptin ·hs-CRP ·body weight Waist circumference Appetite and Food Intake Questionnaire scores Urinary albumin to creatinine ratio

[0094] Safety evaluation items : AEs: frequency, severity, time to onset, duration, and relationship to study drug SAEs: frequency, severity, time to onset, duration, and relationship to investigational drug Discontinuation due to AE Changes in clinical laboratory parameters

[0095] research design This is a single-center, phase 1B, randomized, double-blind, placebo-controlled, 28-day repeated-dose study.

[0096] The study will include subjects with evidence of metabolic syndrome and impaired glucose tolerance who will be randomized 1:1 to receive either INV-202 or placebo. For a total of 40 subjects, 20 subjects will receive 25 mg of INV-202 for 28 consecutive days and 20 subjects will receive a matching placebo.

[0097] Study population Rationale for study population The study will enroll subjects with metabolic syndrome as defined by hypertriglyceridemia, abdominal obesity, and impaired glucose tolerance.

[0098] The effects of INV-202 on body weight and food consumption were studied in DIO mouse models. After 10 days of administration, INV-202 was shown to reduce body weight in a dose-dependent manner. INV-202 also showed a reduction in glucose AUC in OGTT tests, showed a significant effect in reducing C-peptide and insulin levels, and also significantly reduced ALT and hepatic triglycerides after repeated administration for 28 days.

[0099] To date, no reproduction studies in animals have been conducted with INV-202. Because the risk to the developing human fetus following exposure to INV-202 is unknown at this time, only males and non-pregnant, non-lactating females will be included in the study. As a precaution for female subjects, pregnancy tests will be performed at different times during the study. Females of childbearing potential will be included if they use appropriate contraceptive methods.

[0100] In addition, non-surgically sterile male subjects who are sexually active with a non-infertile female partner must use effective contraception for the duration of the study and for 90 days after the last dose of study drug. All male subjects (including men who have had a vasectomy) who have a pregnant partner must agree to use condoms from dose (first, if applicable) until at least 90 days after dose (last, if applicable). In addition, all male subjects must be willing not to donate sperm until 90 days after dose (last, if applicable).

[0101] Sample size Approximately 40 male or female subjects are expected to be enrolled for participation in the study.

[0102] The study consists of one cohort randomized 1:1 to receive either INV-202 or placebo: for a total of 40 subjects, 20 subjects will receive INV-202 for 28 consecutive days and 20 subjects will receive a matching placebo.

[0103] The sample size for this study will not be determined based on statistical calculations, but rather on the probability of observing an AE. The number of subjects will be deemed sufficient to accomplish the study objectives.

[0104] Selection Criteria The subjects enrolled in this study are members of the general community. Subjects must meet all of the following criteria to be included in the study: 1) Provide a signed and dated ICF. 2) Willing and able to comply with all study procedures for the duration of the study. 3) Male or female aged ≥18 and ≤65 years. 4) Waist circumference of ≥88 cm for female subjects or ≥102 cm for male subjects. 5) Fasting triglycerides >1.5 mmol / L for men and women. 6) OGTT indicating impaired glucose tolerance as indicated by a 2-hour value >140 mg / dl or any value >200 mg / dl at any time point, or an HbA1C level ≥5.7% but ≤6.4%. 7) Females of childbearing potential who are sexually active with a non-infertile male partner (an infertile male partner is defined as a man who has had a vasectomy at least 6 months prior to the first study drug dose) must be willing to use one of the following acceptable methods of contraception throughout the study and for at least 30 days after the last study drug dose: a) must agree to concurrent use of hormonal contraception starting at least 4 weeks prior to administration of the study drug, and to use the same hormonal contraception throughout the study, and for male partners, condoms; b) Concomitant use of an intrauterine device placed at least 4 weeks prior to study drug administration and, for male partners, a condom; c) Concurrent use of a diaphragm or cervical cap with spermicide applied intravaginally and, for the male partner, a male condom, beginning at least 21 days prior to administration of the study drug. 8) Women who are not of childbearing potential must: a) Postmenopausal (absence of menstruation for at least 12 months prior to first study drug administration) with confirmation of postmenopausal status by documented FSH level ≥ 40 mIU / mL, or b) surgically infertile (total hysterectomy, bilateral oophorectomy, or tubal ligation at least 6 months prior to the first study drug administration). 9) Male subjects who have not had a vasectomy and who have been sexually active with a female partner of childbearing potential (a female of childbearing potential is defined as a female who is neither postmenopausal nor surgically sterile) for at least 6 months must be willing to use one of the following acceptable methods of contraception from the first study drug dose until at least 90 days after the last study drug dose: a) The simultaneous use of a male condom and, for the female partner, a hormonal contraceptive used at least four weeks later or an intrauterine device placed at least four weeks later; b) The simultaneous use of a male condom and, for the female partner, a diaphragm or cervical cap with spermicide applied intravaginally. 10) Male subjects (including men who have had a vasectomy) with a pregnant partner must agree to use condoms from the first dose of study drug and for 90 days after the last dose of study drug. 11) Male subjects must be willing not to donate sperm for 90 days after the last study drug dose.

[0105] Exclusion criteria Subjects who meet any of the following criteria will be excluded from the study. 1) Women who are breastfeeding at the time of screening. 2) Females who are pregnant according to a pregnancy test at screening or before administration of the study drug. 3) History of significant hypersensitivity to the investigational drug or its excipients. 4) History of severe hypersensitivity reactions such as anaphylaxis. 5) History of galactose and / or lactose intolerance, lactase deficiency, or rare genetic problems of glucose-galactose malabsorption. 6) Positive screening results for HIV antigen and antibody, HBsAg, or HCV tests. 7) Significant suicide risk as defined by C-SSRS score > type 1 ideation at screening. 8) Any clinically significant illness within 28 days prior to study drug administration. 9) Current or past history of significant gastrointestinal, hepatic, or renal disease, or surgery that may affect drug bioavailability. 10) History of severely uncontrolled or unstable cardiovascular, pulmonary, hematological, neurological, psychiatric, endocrine, immune, or skin disease. 11) History of seizures (epilepsy) of any kind. 12) History of cranial surgery. 13) Presence of clinically significant ECG abnormalities at the screening visit as defined by medical judgment (maximum QTcF of 450 ms). 14) Any other clinically significant abnormality in laboratory test results at screening that, in the opinion of the investigator, increases the risk of the subject's participation, jeopardizes full participation in the study, or impairs the interpretation of the study data. Mild elevations of AST / ALT, such as may be seen in NAFLD, are not exclusive. However, in these subjects, please follow the Hepatic Safety section. 15) New prescribed medication or change in medication regimen within 90 days prior to the first dose (i.e., stable dose of antihypertensive medication, etc. is permitted). 16) Use of the following medications for the time frames specified below, except for medications that may be waived by the investigator on a case-by-case basis because they are deemed unlikely to affect the PK profile of the investigational product or subject safety (e.g., topical drug products with no significant systemic absorption): a) any vaccination, including a COVID-19 vaccine within 14 days prior to the first dose; b) depot injection or implant of any drug within 3 months prior to the first dose; c) Any agent known to induce or inhibit hepatic drug metabolism within 30 days prior to the first dose. d) Any medication for the treatment of diabetes within 30 days prior to the first dose. e) Any medication that is prohibited by the investigator on a case-by-case basis because it is deemed likely to affect the PD profile of the investigational drug or subject safety within at least 5 half-lives of the drug and a minimum of 30 days prior to the first dose. 17) Positive urine drug screen or alcohol breath test at screening. 18) Significant alcohol abuse within 1 year prior to screening or regular use of alcohol (>14 units of alcohol per week [1 unit = 150 mL of wine, 360 mL of beer, or 45 mL of 40% alcohol]) within 6 months prior to screening visit. 19) Significant substance abuse within 1 year prior to screening, history of soft drug use within 3 months prior to screening, marijuana use within 1 month prior to screening, or hard drug use (e.g., cocaine, PCP, crack, opioid derivatives including heroin, and amphetamine derivatives) within 1 year prior to screening. 20) Use of any cannabinoid-containing product, including cannabis, by any route (e.g., oral, inhaled, topical) within 1 month prior to screening. 21) Administration of an investigational or marketed drug or device within 30 days (or at least 5 half-lives, whichever is longer) prior to the first dose, administration of a biological product in association with a clinical study within 90 days prior to the first dose, or participation in a clinical trial without concurrent administration of a drug or device. 22) Plasma donation within 7 days prior to first dose. Blood donation or blood loss of 50 mL to 499 mL within 30 days or >499 mL within 56 days prior to first dose (excluding the amount drawn at screening). 23) Any reason which, in the opinion of the investigator, prevents the subject from participating in the study.

[0106] Clinical Procedure Unless otherwise specified, procedures, data collection, and evaluations will be performed according to clinical site SOPs.

[0107] Screening Procedure Subject screening procedures will be conducted within 35 days preceding administration of the investigational drug. Subjects must provide written informed consent prior to the initiation of any screening procedures. Consent to conduct some general screening procedures may be obtained in consent forms other than the study-specific ICF, and thus some screening test results may be obtained prior to signing of the study-specific ICF. The study-specific ICF must be signed and dated by the subject prior to participation in any study-specific procedures.

[0108] Screening procedures include: demographic data, medical and medical history, complete physical examination, anthropometry, C-SSRS, OGTT, vital signs (BP, HR, RR, and OT), 12-lead ECG, hematology, biochemistry, coagulation, endocrinology (FSH only), serology (HIV antigen and antibody, HBsAg, and HCV antibody), urinalysis, serum pregnancy test, alcohol breath test, and urine drug screen.

[0109] FSH levels will be measured at screening unless documented results are available within the 6 months preceding dosing. For women using hormone replacement therapy and needing to have their FSH levels checked, these tests will be performed at least 1 week after withdrawal of therapy but before the first dose.

[0110] Subjects must meet all inclusion and exclusion criteria and have evidence of impaired glucose tolerance. If there is evidence of HbA1C ≥ 5.7% but ≤ 6.4% obtained within the past 3 months, an OGTT does not need to be performed at screening. If there is no such evidence, subjects will undergo an OGTT consisting of a 75g glucose load with blood draws at 30 minutes, 1 hour, and 2 hours post-ingestion.

[0111] For eligibility purposes, abnormal laboratory test or vital sign results may be repeated once if abnormal results are observed on the initial reading. Additionally, abnormalities found on the ECG may need to be confirmed by repeat measurements. In cases where a subject's enrollment in a study is delayed and some screening procedures were performed outside the prescribed screening window, outdated screening procedures may be repeated.

[0112] Research visit Participation in this study should last approximately 5-6 weeks. Subjects will undergo a screening visit and seven study visits.

[0113] First Baseline Visit on Day -1: Subjects will arrive at the clinic after an overnight fast of at least 8 hours.

[0114] Subjects undergo an OGTT consisting of a 75 g glucose load with blood drawn pre-load and 30 minutes, 1 hour, 2 hours, and 3 hours post-ingestion.

[0115] If the Screening C-SSRS was performed more than 21 days prior to day -1, a repeat C-SSRS should be performed on day -1. Otherwise, the Screening C-SSRS may be used as the baseline assessment.

[0116] Second Baseline Visit on Day 1: Subjects will arrive at the clinic after an overnight fast of at least 8 hours.

[0117] Blood and urine will be collected pre-dose for baseline clinical laboratory and PK / PD assessments. Subjects' weight and waist circumference will be measured, and subjects will undergo additional evaluations as outlined in Section 0, including a brief physical examination, vital sign measurements, and a 12-lead ECG.

[0118] Subjects complete an appetite and food intake questionnaire.

[0119] At this visit, subjects are randomized in a 1:1 ratio to receive either 25 mg of INV-202 or matching placebo. A dose of INV-202 (or matching placebo) sufficient for one week is dispensed to the subject. Food is provided and the first dose is taken at the site with food. Subjects are instructed to self-administer a dose of study drug once daily with food and to record the time of administration, any observations regarding the taste of the tablet, and any AEs that may be experienced on a subject diary card. Subjects are then discharged from the site.

[0120] Weekly study visits on days 8, 15, and 22: Once weekly, approximately every 7 days, subjects will return to the clinic after an overnight fast of at least 8 hours for PK / PD, safety, and tolerability evaluations.

[0121] Blood and urine will be collected pre-dose for clinical laboratory and PK / PD assessments. Subjects' weight and waist circumference will be measured, preferably using the same equipment as for baseline measurements. Subjects will undergo additional evaluations as outlined in Section 0, including a brief physical examination and vital signs. Diary cards will be collected and reviewed with the subject to document AEs, comments, and times of drug administration.

[0122] Subjects complete an appetite and food intake questionnaire.

[0123] A dose of INV-202 (or matching placebo) sufficient for one week will be dispensed to the subject. Food will be provided and the daily dose will be consumed with food at the site. Subjects will be instructed to self-administer a dose of study drug once daily with food and to record the time of administration, any observations regarding the taste of the tablet, and any AEs they may experience on a subject diary card. Subjects will then be discharged from the site.

[0124] EOT visit on day 29 (+2 days): Subjects will arrive at the clinic after an overnight fast of at least 8 hours for PK / PD, safety, and tolerability evaluations.

[0125] Blood and urine will be collected for clinical laboratory and PK / PD assessments. Subjects' weight and waist circumference will be measured, preferably using the same equipment as the baseline measurements. Subjects will undergo additional evaluations as outlined in Section 0, including a brief physical exam, vital signs, and a 12-lead ECG. Diary cards will be collected and reviewed with the subject to document AEs, comments, and times of drug administration.

[0126] Subjects undergo an OGTT consisting of a 75 g glucose load with blood drawn at 30 minutes, 1 hour, 2 hours, and 3 hours after ingestion. Subjects also complete an appetite and food intake questionnaire and are administered the C-SSRS questionnaire. Subjects are then discharged from the site.

[0127] EOS visit on day 35 (+2 days): Approximately 6 days after the Day 29 (+2) visit, subjects will arrive at the clinic after an overnight fast of at least 8 hours for terminal blood and urine collection for clinical laboratory and PK / PD evaluations. Additional evaluations will be preformed as outlined in Section 0, including a complete physical examination, vital sign measurements, and a 12-lead ECG. Subjects will complete the C-SSRS questionnaire.

[0128] At the end of this visit, subjects will have completed their participation in the study and may then be discharged from the site.

[0129] Randomization and blinding Subjects who are eligible to participate will be randomized (on Day 1) to receive either the active investigational drug or a matching placebo in a 1:1 ratio, for a total of 20 subjects receiving INV-202 and 20 subjects receiving a matching placebo. One randomization scheme will be generated for the study.

[0130] Subjects and clinical personnel involved in the collection, monitoring, revision, or evaluation of AEs, or who may affect the outcome of the study, will be blinded with respect to the subject's treatment assignment (INV-202 or placebo). Blinding will be maintained at least until the completion of the clinical phase of the study (i.e., when reporting and evaluation of all AEs is complete).

[0131] Designated pharmacy personnel at the clinical site not directly involved in the clinical aspects of the trial will prepare and dispense the study drug and will be aware of the randomization code. Study drug and placebo will have the same appearance to avoid compromising the blinding of the study.

[0132] In the event of an individual subject emergency where knowledge of the study treatment is critical to the subject's medical management, the investigator may break the blinding of that subject. An envelope for each subject containing the subject's treatment assignment will be available from pharmacy personnel. The investigator or other responsible study physician will make every effort to contact the sponsor before unblinding a subject's treatment assignment and will record the date and reason for unblinding in the study source documentation.

[0133] Pharmacy personnel will provide the bioanalytical laboratory with a list of subject numbers to be analyzed for each dose level so that only samples from subjects who received active drug are analyzed.

[0134] Investigational Drug Active investigational drug: 25 mg tablet of INV-202 (manufactured by Inversago Pharma Inc., Canada), given as 1 x 25 mg tablet administered orally. Placebo: A tablet identical in appearance to the active INV-202 (manufactured by Inversago Pharma Inc., Canada), administered orally.

[0135] Drug Supply and Accountability It is the sponsor's responsibility to ensure that the investigational product provided for this study is manufactured under good manufacturing practice (GMP) and is suitable for human use. The sponsor is responsible for shipping sufficient dose units to allow the clinical site to maintain adequate sample collection for the study.

[0136] Investigational medicinal products will be stored at the clinical site in accordance with applicable requirements. Medication will be stored in a locked, temperature-controlled medicine room with limited access. Containers will bear a label containing at least the investigational medicinal product name, lot number and / or batch number, and manufacturing date and / or expiration / retest date.

[0137] Individual doses for each subject will be distributed at the clinical site according to the appropriate SOPs. Individual doses will be distributed according to the randomization scheme in appropriate envelopes / containers denoted with at least the project number and subject / spare number.

[0138] All investigational medication received at the site will be inventoried and accounted for throughout the study and the results will be recorded in the medication accountability / custody record according to the clinical site's appropriate SOPs.

[0139] Administration of investigational drug Subjects will receive a daily oral dose of 25 mg of INV-202 or matching placebo for 28 consecutive days.

[0140] At the baseline and follow-up visits on days 8, 15, and 22, no food will be allowed for at least 8 hours prior to arrival at the clinic until completion of all scheduled assessments.

[0141] After completion of the evaluation, food will be provided and the daily dose will be taken on-site with food. The study drug will be administered to each subject with 240 mL of water and hand and mouth checks will be performed to ensure consumption of the medication. The administration time will be set equal to the time the tablet is administered to the subject.

[0142] For all other doses, subjects will be instructed to take the study drug independently and self-administer a dose of study drug once daily with food. Subjects will be required to record the time of administration and any observations regarding the taste of the tablet on the subject diary card.

[0143] Each study drug administration should be separated by approximately 24 hours and taken at approximately the same time each day. If a study drug dose is missed and the subject realizes this before 8:00 PM, the missed dose may still be taken. If the subject realizes the missed dose after 8:00 PM, the dose should be skipped and the next dose should be taken at the scheduled time.

[0144] Subjects are required to bring any unused study drug and / or empty study drug containers when they return to the clinic on Days 8, 15, 22, and 29. A post-dose inventory will be performed on dose containers.

[0145] Study limitations Food and Fluids The target person should refrain from the following: Foods and beverages containing grapefruit, starfruit, pomegranate, pineapple, or pomelo from 7 days prior to dosing until after the final PK blood sample collection in the study, At all study visits, food will not be allowed for at least 8 hours prior to arrival at the clinic until completion of all scheduled assessments. Food will be provided after completion of assessments. Water will be provided ad libitum at all times.

[0146] Alcohol and illegal drugs Subjects will be required to refrain from using soft or hard drugs from screening and throughout the study.

[0147] Consumption of alcohol-based products will be prohibited for 8 hours prior to each visit. Subjects will be asked to limit alcohol intake to moderate levels (<2 drinks per day) from Day -1 until study completion.

[0148] Concomitant medication Subjects should avoid new prescribed medications or changes in medication regimens, as well as medications likely to alter the PD profile of the investigational drug (e.g., diabetes medications), as outlined in the exclusion criteria15)16) and throughout the study.

[0149] From 90 days prior to the first dose until after the last PK / PD blood sample collection in the study, new concomitant medications or changes in medication regimens are not permitted, except for those required for medical management of AEs, medications waived by the investigator on a case-by-case basis that are judged unlikely to affect the PK profile of the investigational drug or subject safety (e.g., topical drug products with no significant systemic absorption), and the occasional use of acetaminophen.

[0150] Subjects should also avoid receiving any vaccinations, including COVID-19 vaccines, for 14 days prior to dosing and throughout the study. If vaccination is required for any reason, it must first be discussed with the investigator and waived by the investigator on a case-by-case basis to ensure that it does not compromise the PK profile of the investigational product or the safety of the subject.

[0151] All medications taken by the subject after screening through the last study date will be documented as concomitant medications. Use of any concomitant medications other than those permitted above will be reviewed and evaluated on a case-by-case basis by the Investigator to determine if it may potentially affect the subject's eligibility, continued participation in the study, or study outcomes.

[0152] Posture and physical activity OGTTs are performed at screening, day -1, and day 29 (day +2). Because activity can interfere with test results, subjects are required to remain seated from the time the glucose load is administered until the final blood draw is completed (2 hours after intake at screening and 3 hours after intake at other visits) unless medically necessary or required by procedure, as activity may interfere with test results.

[0153] Targeted Person Monitoring Subjects will be monitored throughout the study by clinical staff for AEs. The Investigator or designee will be present on-site for the first study drug administration. If necessary, the Investigator or designee at the clinical site, or medical personnel at a nearby hospital, will administer treatment for any AEs. An emergency cart or bag containing necessary rescue materials and appropriate medications will be available at the clinic to allow for rapid intervention in case of an emergency.

[0154] Safety parameters, including clinical laboratory results and ECGs, will be evaluated by the investigator or designee using clinical practice standards for biomedical laboratory tests and ECGs as the recommended guidelines for performing medical evaluations.

[0155] Scheduled safety measurements will be repeated according to the clinical site SOPs or upon request from the investigator or designee. Any abnormal repeat measurements will be evaluated by the investigator or designee and repeated if deemed necessary. Further measures may be taken upon request of the investigator or designee.

[0156] Unless otherwise specified or for subject safety, when timing of multiple procedures coincides, the following priority should be observed whenever possible: vital signs, ECG, blood samples for PK / PD analysis, clinical laboratory samples, physical examination, OGTT, appetite and food intake questionnaire, C-SSRS questionnaire, and diary card review.

[0157] Subjects are advised to inform their health care professionals (such as physicians, dentists, and / or pharmacists) that they are participating in a clinical study of a drug called INV-202 before taking any medicines or undergoing any medical procedures.

[0158] Physical Examination Complete physical examinations will be performed at screening and at the FU visit / EOS / ET on Day 35 (+2 days). Brief physical examinations will be performed pre-dose on Days 1, 8, 15, and 22, and on Day 29 (+2 days). Other physical examinations will be performed at the discretion of the investigator.

[0159] A complete physical examination includes evaluation of the following: head, eyes, ears, nose, and throat (HEENT), lymph nodes, neck, chest, lungs, abdomen, musculoskeletal, skin, cardiovascular / peripheral vascular, and general neurological examination. A brief physical examination includes evaluation of the following: HEENT, chest, lungs, abdomen, skin, cardiovascular / peripheral vascular, and areas of note elicited from the subject.

[0160] body measurements Physical measurements taken at screening include height and weight measurements, waist circumference, and BMI calculation. Height will be measured at screening only. Weight and waist circumference will also be measured prior to dosing on days 1, 8, 15, and 22, and on day 29 (+2). BMI will be calculated as appropriate.

[0161] Weight and waist circumference will be measured in triplicate using standard measurement methods. The same weighing scale should be used at all visits for a given subject. The weighing scale should be calibrated according to the manufacturer's recommendations. Medical grade weighing scales should be used.

[0162] Waist circumference should be measured around the top of the iliac crest at the level of the umbilicus. The same measuring device should be used at all visits for a given subject. The tape should go all the way around the subject and be parallel to the floor in a plane that includes the umbilicus and the top of the iliac crest.

[0163] Vital signs BP, HR, RR, and OT will be measured at screening, and pre-dose on days 1, 8, 15, and 22, on day 29 (+2 days), and at the FU visit / EOS / ET on day 35 (+2 days). Vital signs will be measured in the sitting position (except for safety reasons and when an ECG is planned at approximately the same time). Whenever possible, vital signs measurements should be performed prior to blood collection, preferably.

[0164] safety ecg 12-lead ECGs will be performed at screening, pre-dose on Day 1, FU visit / EOS / ET on Day 29 (+2), and Day 35 (+2). A standard 12-lead ECG will be performed after the subject has been in the supine position for at least 5 minutes. Whenever possible, an ECG should be performed prior to blood collection, preferably when consistent with blood draw.

[0165] Drug and Alcohol Screening A urine drug screen (for amphetamines, methamphetamines, barbiturates, benzodiazepines, tetrahydrocannabinol, cocaine, opiates, PCP, 3,4-methylenedioxymethamphetamine [MDMA], and methadone) and an alcohol breath test will be performed at screening.

[0166] Pregnancy test A serum pregnancy test will be performed at screening. A urine pregnancy test will be performed pre-dose on Day 1 and at the FU visit / EOS / ET on Day 35 (+2 days).

[0167] A urine pregnancy test that produces a positive result is confirmed by a serum pregnancy test. If the urine pregnancy test is positive, dosing is stopped. If the serum pregnancy test confirms the result, dosing is discontinued, otherwise dosing can proceed.

[0168] Clinical Laboratory Evaluation Clinical laboratory evaluations should be performed after at least an 8-hour fast.

[0169] hematology Hematology will be performed at screening, pre-dose on Days 1, 8, 15, and 22, at the FU visit / EOS / ET on Day 29 (+2 days), and at Day 35 (+2 days).

[0170] The following will be assessed: complete blood count with differential, hemoglobin, and hematocrit, mean corpuscular volume, red blood cell morphology, white blood cell morphology, platelet count, platelet morphology.

[0171] biochemistry Biochemistry will be performed at screening, pre-dose on days 1, 8, 15, and 22, on day 29 (+2 days), and at the FU visit / EOS / ET on day 35 (+2 days).

[0172] The following will be assessed: sodium, potassium, chloride, glucose, blood urea nitrogen, creatinine, creatinine clearance, direct bilirubin, indirect bilirubin, total bilirubin, ALP, AST, ALT, albumin, lactate dehydrogenase, calcium, lipase, amylase, phosphorus, HbA1C, serum ferritin, and total protein.

[0173] In addition, the lipid profile will be assessed: total cholesterol, HDL, LDL, VLDL, and triglycerides.

[0174] mL / min / 1.73m 2 Estimated glomerular filtration rate (eGFR), expressed as a percentage of body surface area, is calculated using the Modification of Diet in Renal Disease (MDRD4:4 variable) equation.

[0175] Considering that indirect bilirubin is calculated from the total and direct bilirubin values, if the direct bilirubin is below the limit of quantification, then the indirect bilirubin result will not be available.

[0176] coagulation Coagulation will be performed at screening, pre-dose on days 1, 8, 15, and 22, on day 29 (+2 days), and at the FU visit / EOS / ET on day 35 (+2 days).

[0177] The following will be assessed: INR, activated partial thromboplastin time (aPTT), prothrombin time (PT), partial thromboplastin time (PTT), and partial thromboplastin time control.

[0178] Endocrinology Endocrinology will be performed at screening, pre-dose on days 1, 8, 15, and 22, on day 29 (+2 days), and at the FU visit / EOS / ET on day 35 (+2 days).

[0179] The following will be assessed at screening only: FSH levels will be measured for postmenopausal women, with postmenopausal status confirmed by a documented FSH level ≧40 mIU / mL.

[0180] The following will be assessed pre-dose only on Days 1, 8, 15, and 22, at the FU visit / EOS / ET on Day 29 (+2 days), and Day 35 (+2 days): C-peptide, insulin, TSH, and T4.

[0181] Serology Serology will be performed at screening. The following will be assessed: HIV antigen and antibody, HBsAg, HCV antibody.

[0182] Urine tests Urine tests will be performed at screening, pre-dose on Days 1, 8, 15, and 22, on Day 29 (+2 days), and at the FU visit / EOS / ET on Day 35 (+2 days).

[0183] The following will be evaluated: gross examination, pH, specific gravity, protein, glucose, ketones, bilirubin, occult blood, nitrites, urobilinogen, leukocytes, albumin, and creatinine (to determine urinary albumin to creatinine ratio). Microscopic examination will be performed according to laboratory standards in accordance with internal procedures.

[0184] Oral glucose tolerance test An OGTT will be performed at screening, day -1, and day 29 (day +2). If there is evidence of an HbA1C of ≥ 5.7% but ≤ 6.4% obtained within the past 3 months, an OGTT does not need to be performed at screening.

[0185] For the OGTT performed at screening, a 75 g glucose load will be administered with blood drawn at 30 minutes, 1 hour, and 2 hours.

[0186] For the OGTT performed on day -1, a 75 g glucose load will be administered with blood drawn pre-load, 30 min, 1 hr, 2 hr, and 3 hr post-ingestion.

[0187] For the OGTT performed on day 29 (+2), a 75 g glucose load will be administered with blood drawn at 30 minutes, 1 hour, 2 hours, and 3 hours post-ingestion.

[0188] Subjects are required to remain seated until the final blood draw is completed, unless medically necessary or required by the procedure, as activity may interfere with test results.

[0189] Review of journal cards Throughout the treatment period, subjects will record time of administration, any observations regarding tablet taste, and any AEs they may experience on subject diary cards that will be collected and reviewed on days 8, 15, 22, and 29.

[0190] Appetite and Food Intake Questionnaire Appetite and food intake questionnaires will be completed prior to dosing on days 1, 8, 15, and 22, and on day 29 (+2 days). The questionnaires to be completed are presented in Section 18.

[0191] Columbia-Suicide Severity Rating Scale (C-SSRS) Suicide risk assessment will be performed using the C-SSRS questionnaire at screening, day -1 (if ≥21 days have passed since the screening C-SSRS), day 29 (+2 days), and day 35 (+2 days) FU visit / EOS / ET.

[0192] The scale will be administered by a member of the medical team, completed on-site, and in writing. The "Lifetime" C-SSRS questionnaire template will be used at the Screening Visit and Day -1 (if applicable), and the "Since Last Visit" C-SSRS questionnaire template will be used at Day 29 (Day +2) and at the FU Visit / EOS / ET. If the Investigator determines that the subject is at risk for suicide or self-harm, the subject must be immediately discontinued from the study and appropriate measures must be implemented to ensure the subject's safety and obtain a mental health evaluation. The event should be recorded as either an AE or SAE as determined by the Investigator, and reported to the sponsor within 24 hours.

[0193] FU / EOS / ET Examination Procedures The FU visit will occur on Day 35 (+2 days), approximately 168 hours after the last study drug administration.

[0194] The EOS procedure was scheduled to be performed at the time of the FU visit and consisted of the following assessments: complete physical examination, C-SSRS, vital signs, 12-lead ECG, hematology, biochemistry, coagulation, endocrinology, urinalysis, urine pregnancy test, PK / PD blood sampling, and AE monitoring.

[0195] These procedures will be performed within 14 days of the subject's last participation in the study in the case of ET. Subjects who discontinue the study early will receive an ET visit.

[0196] Liver Safety Measures If liver function markers and clinical findings suggest the development of liver injury during the study, the following instructions will be followed: Hepatic safety in all randomized subjects will be assessed through use of the following algorithm based on the FDA DILI Management Guideline (Center for Drug Evaluation and Research (CDER), FDA. Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation. July 2009).

[0197] An increase in serum ALT or AST >3 × ULN should be followed by repeat testing of all 4 of the routine serum measurements (ALT, AST, ALP, and TBL) within 48 to 72 hours to confirm the abnormality and to determine whether the abnormalities are increasing or decreasing, and the patient should be inquired about symptoms.

[0198] The need for prompt repeat testing is especially great when ALT or AST are much greater than 3 × ULN and / or TBL is greater than 2 × ULN.

[0199] If symptoms persist or repeat testing shows ALT or AST >3×ULN for subjects with normal baseline measurements, or a 2-fold increase above baseline for subjects with elevated values ​​prior to drug exposure, it is appropriate to begin close observation to determine whether the abnormality is improving or worsening. Close observation includes repeat testing two or three times weekly, detailed medical and medical history, exclusion of other causes, etc. If close monitoring is not possible, the drug should be discontinued. In addition, INV-202 should be discontinued in the following cases: ALT or AST >5×ULN ALT or AST >3×ULN and (TBL >2×ULN or INR >1.5) ALT or AST >3 x ULN with the development of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and / or eosinophilia (>5%).

[0200] Sample collection and processing Plasma samples are collected and processed according to the analytical method information sheet.

[0201] The total volume of blood, including that collected for eligibility, safety purposes, and repeat testing, should not exceed approximately 250 mL.

[0202] Blood sample collection for PK / PD analysis If applicable, blood samples for PK / PD analysis of INV-202 and its major metabolites will be collected as follows. Approximately six blood samples will be collected for PK / PD evaluation at the following time points: pre-dose on Days 1, 8, 15, and 22, at the FU / EOS / ET visit on Day 29 (+2 days), and at Day 35 (+2 days).

[0203] An intravenous cannula may be used for blood collection, where appropriate, to avoid multiple skin punctures; otherwise, blood samples are collected by direct venipuncture.

[0204] Data collection and evaluation All clinical raw data will be promptly, accurately, legibly and indelibly recorded by clinical staff on raw data sheets and / or electronically recorded using validated software and reported on case report forms (CRFs). All raw data will be stored to maintain data integrity. The investigator and / or clinical staff are responsible for ensuring the completeness and accuracy of the clinical data.

[0205] Details of the data management process will be described in a Data Management Plan (DMP).

[0206] Withdrawal and replacement of subjects Subjects are advised that they are free to withdraw from the study at any time. During the course of the study, the sponsor and investigator or designee may withdraw any subject from the study for one of the reasons described below, and withdrawal of subjects will be done in accordance with the clinical site SOPs. For safety reasons, Failure to comply with protocol requirements; Major protocol deviations, · A positive pregnancy test, drug screen, or alcohol test.

[0207] Clinical test results will be reviewed by the Investigator or designee when available. Subjects will be withdrawn from the study if their safety is deemed to be at risk based on these test results.

[0208] Subjects who withdraw or are withdrawn from the study after dosing will not be replaced. However, if the number of dropouts exceeds initial expectations, subjects who withdraw or are withdrawn may be replaced at the sponsor's discretion. Such replacements that result in dosing more subjects than planned in the protocol will be documented in a protocol amendment.

[0209] Subjects who are withdrawing or being withdrawn will be asked to remain in the clinic until the Investigator or designee agrees that the subject is OK and can be discharged. Blood sample collection will be stopped as soon as the subject's withdrawal is confirmed. PK blood draws may be collected at the time of withdrawal if deemed necessary by the Investigator. End-of-study procedures will be performed at the time of withdrawal from the study or as soon as possible thereafter.

[0210] Adverse events Definition of adverse events An AE is defined as any adverse medical occurrence in a clinical research subject after providing written informed consent to participate in the study that does not necessarily have a causal relationship to the study treatment. Thus, an AE can be any unfavorable unintended sign (including abnormal clinical laboratory findings), symptom, or disease that is temporally related to the use of a medicinal product (investigational product), whether or not related to the medicinal product (investigational product). This includes a worsening of a pre-existing condition or event, a concomitant illness, a drug interaction, or a significant worsening of the indication under investigation that is not recorded elsewhere on the CRF under a specific efficacy assessment. Anticipated variations in a pre-existing condition that do not represent a clinically significant worsening or deterioration need not be considered an AE.

[0211] Definition of serious adverse events An SAE is any AE that meets any of the following criteria: -Causing death, life-threatening (i.e., in the opinion of the investigator or designee, the subject is at imminent risk of death from the AE); -requires hospitalization or an extension of an existing hospital stay; · causes persistent or significant disability / incapacity (significantly impairs the subject's ability to carry out normal life functions); ·Causing birth defects / abortions; ·Constitutes a significant medical event. These may not result in death, be life-threatening, or require hospitalization, but may be considered severe when they endanger the subject's health and require medical or surgical intervention to prevent one of the outcomes listed. Any other event considered (by the Investigator or designee) to be serious (e.g., allergic bronchospasm requiring intensive care in the emergency room or at home, blood dyscrasias, seizures not resulting in hospitalization, or manifestations of drug dependence or abuse).

[0212] Recording of adverse events AEs will be recorded and evaluated for their severity, severity, and relationship to the study drug. AEs will be collected and documented during the course of the study starting with ICF signature. AEs will be followed until complete resolution or until the investigator determines it is safe to discontinue follow-up. Relationship to study drug will be classified according to clinical site SOPs and the following definitions:

[0213] [Table 1]

[0214] Adverse event categories to determine relationship to study drug connection AEs were probably, probably, or definitely related to the study drug.

[0215] Unrelated AEs were clearly unrelated or questionable to the study drug.

[0216] Serious Adverse Events Information about the SAE is recorded in the SAE Report. A blank copy is included in the Investigator's file. It is not acceptable for the Investigator to send a copy of the subject's medical record to the Sponsor or its representative in lieu of completing the appropriate AE CRF page or SAE Report. However, there may be instances where a copy of the medical record for a particular case is requested by the Sponsor or its representative. In this instance, all subject identifiers are redacted on the copy of the medical record before submission to the Sponsor or its representative (this is extremely rare).

[0217] The completed SAE form and SAE cover sheet should be sent via fax or email to Syneos Health Safety and Pharmacovigilance immediately upon completion. If the Investigator does not have all the information regarding the SAE, do not wait to receive additional information before completing and sending the form.

[0218] Any additional relevant information or clinical follow-up should be sent via fax or email to Syneos Health Safety and Pharmacovigilance as soon as it is available. Investigators should follow up subjects with events until resolution or stabilization of their condition. Follow-up reports (as many as required) should be completed following the same procedure above and sent via fax / email.

[0219] Once the condition has resolved or stabilized and no further information about the event is expected, a final report is required. The final report should be completed and faxed / emailed following the same procedures above.

[0220] The Investigator must keep copies of all documentation related to the event in the clinical site files.

[0221] Reporting serious adverse events to regulatory authorities The sponsor (or the sponsor's safety representative) is responsible for notifying the regulatory authority of any suspected unexpected serious adverse reactions (SUSARs) observed during the conduct of a study in which an investigational medicinal product is administered.

[0222] Notification of a fatal or life-threatening SUSAR must be made as soon as possible, but no later than seven (7) calendar days after becoming aware of the information. Notification of all other SUSARs that are not fatal or life-threatening must be made as soon as possible, but no later than fifteen (15) calendar days after becoming aware of the information.

[0223] The sponsor (or the sponsor's safety representative) is responsible for complying with any other applicable regulatory requirements related to reporting SAEs to regulatory authorities.

[0224] Reporting of serious adverse events to an independent ethics committee In addition to reporting the SAE to the sponsor (or the sponsor's safety representative), the investigator must also notify the IEC that he or she has approved the study in accordance with its requirements.

[0225] It is the responsibility of the site to report any fatal or life-threatening SUSARs occurring at the site to the IEC responsible for the study as soon as possible, but no later than 7 calendar days after the first observation by the investigator.

[0226] It is the site's responsibility to report all other SUSARs that are not fatal or life-threatening to the IEC as soon as possible, but no later than 15 calendar days after the first observation by the investigator.

[0227] The investigators and IEC will also be notified of any significant safety issues (SSIs) that arise during the clinical trial.

[0228] Copies of all correspondence related to the reporting of any SAE should be maintained on file at the study site and will be reviewed regularly by the study monitor.

[0229] Analysis method INV-202 and its metabolites, if applicable, will be analyzed in plasma samples from subjects receiving INV-202 alone using a validated LC-MS / MS method. Samples from subjects receiving placebo will not be analyzed.

[0230] A second set of aliquots may be sent once the bioanalytical laboratory has confirmed receipt of the first shipment. Samples should be packed on sufficient dry ice to remain frozen for at least 72 hours.

[0231] Bioanalytical work supporting research is performed in compliance with GCP using defined SOPs in Syneos Health's Bioanalytical Department. These SOPs are in accordance with applicable regulations within the industry: Guidelines on Bioanalytical Method Validation, Good Laboratory Practice (GLP), and the Guideline for GCP ICH E6(R2).

[0232] Safety and tolerability evaluation A complete description of the statistical analyses performed on the safety and tolerability data will be presented in the SAP.

[0233] Safety Group The safety population includes all subjects who received at least one dose of study drug (INV-202 or placebo). The safety population will be used to summarize all safety evaluations.

[0234] Safety and tolerability parameters and analyses The safety and tolerability of INV-202 will be assessed through evaluation of AEs (i.e., severity, severity, relationship to study drug, outcome, duration, and management), vital signs, 12-lead ECG, clinical laboratory parameters, and physical examination.

[0235] Demographic parameters are summarized descriptively.

[0236] TEAEs will be tabulated by study treatment and overall for all dosed subjects (safety population). Changes from baseline in vital signs, ECG, and clinical laboratory parameters will be assessed. Any findings or lack of findings on baseline physical examination for each subject will be documented. Any abnormal findings seen after dosing, if judged to be a clinically significant change from baseline, will be documented as an AE. AEs will be coded using the latest version of the Medical Dictionary for Clinical Practice (MedDRA).

[0237] Safety and tolerability data will be reported using descriptive statistics. No inferential statistical analyses of safety data are planned.

[0238] PK and PD assessment A complete description of the statistical analyses performed on the PK / PD data will be presented in the SAP.

[0239] PK Group The PK population includes all subjects receiving any amount of INV-202 and in which at least one PK parameter can be adequately characterized.

[0240] PK parameters The following PK parameters are calculated for INV-202 and its major metabolites in plasma concentrations: 1) C trough : The concentration reached just before the next dose is administered. Reported on days 8, 15, and 22. 2) Mean Concentrations: Mean value comparisons will be based on values ​​observed in healthy volunteers in the FIH Phase 1 study INV-202-CL-104. 3) Accumulation over the period of administration.

[0241] Additional PK analyses may be performed. Depending on the sponsor's requirements, replicate PK may be performed according to clinical site SOPs.

[0242] PK statistical analysis Descriptive statistics are provided.

[0243] The data will be used to assess differences / similarities with data obtained from healthy volunteers in the FIH Phase 1 study INV-202-CL-104 and to examine potential accumulation. Comparison of concentrations (C trough C observed in healthy volunteers min ) will be performed to assess PK differences.

[0244] PD population The PD population includes all subjects who receive any amount of INV-202 and in whom at least one PD parameter can be adequately characterized.

[0245] PD parameters The following PD parameters are evaluated: 1) 0-3 hour AUC blood glucose level during OGTT 2) Plasma insulin levels - change from baseline to EOS / ET 3) C-peptide levels - change from baseline to EOS / ET 4) Plasma lipid profile (HDL, LDL, VLDL, triglycerides) - Change from baseline to EOS / ET 5) Adiponectin and leptin – Change from baseline to EOS / ET 6) hs-CRP - Change from baseline to EOS / ET 7) Body weight - change from baseline to EOS / ET 8) Waist circumference - change from baseline to EOT / ET 9) Appetite and Food Intake Questionnaire Score - Change from Baseline to EOT / ET 10) Urinary albumin to creatinine ratio - change from baseline to EOS / ET

[0246] PD statistical analysis PD analyses are performed on the PD population.

[0247] All PD analyses are descriptive only and no formal statistical analysis is planned. Descriptive statistics will be used to describe changes from baseline in values ​​including glucose AUC during OGTT, fasting insulin and C-peptide levels, lipids (e.g., triglycerides, HDL), adiponectin, and other biomarkers. Exploratory analyses of PD vs. AE will be performed to assess exposure-response.

[0248] compliance The study will be conducted in accordance with the protocol, GCP, and all applicable regulations, including the Federal Food, Drug, and Cosmetic Act, applicable United States Code of Federal Regulations (Title 21), Canadian Food and Drug Act, and IEC requirements for clinical research. The study will also be conducted in compliance with the recommendations formulated in the latest version of the Declaration of Helsinki, except that registration of such Phase 1 studies in a publicly accessible database is not mandatory. As required by Canadian regulatory authorities, a Clinical Trial Application (CTA) must be submitted prior to the initiation of the study and a No Objection Letter (NOL) must be received prior to screening.

[0249] Quality Assurance Program The clinical site has established a quality control (QC) and quality assurance (QA) system with written SOPs to ensure studies are conducted and data are generated, recorded, and reported in compliance with protocols, GCP, and applicable regulatory requirements. A rigorous QC program is applied to ensure accuracy of all data and reports. QA oversees a complementary risk-based audit program to ensure compliance with applicable regulations and the clinical site's prescribing documentation.

[0250] Audits, Inspections and Monitoring In accordance with GCP and GLP principles, the study may be inspected by regulatory authorities, the sponsor, and Syneos Health. The sponsor will have access to information about the status of the study and the right to review the study documents.

[0251] Confidentiality and Retention of Research Records This document contains trade secrets and commercial information that is confidential and may not be disclosed to third parties. Any person to whom this study protocol is disclosed must be informed that all information herein is confidential and may not be divulged further. These restrictions also apply to all future communications if deemed privileged or confidential. Publication of study results is permissible only with written authorization from the sponsor.

[0252] All information about subjects obtained during the conduct of the study will be kept confidential. Subjects will be identified by anonymous identifiers on all samples and study records provided to the sponsor or designee. In compliance with ICH GCP, the sponsor's authorized representatives, monitors, auditors, IECs, and regulatory authorities will be given direct access to the subjects' original study-related records for verification of clinical trial procedures and / or data, to the extent permitted by applicable laws and regulations, without violating the subject's confidentiality. Consent from the subject for disclosure of such information will be obtained in writing in the ICF. In addition, if a subject requires medical care or hospitalization during the study, the clinical site may contact the treating physician with the subject's consent, except that consent may not be required if there are emergency circumstances. If the results of the study are published, the subject's identity will remain confidential.

[0253] The clinical site will maintain appropriate study records for 25 years after completion or termination of the study. After this period, the sponsor will be contacted to determine whether the study records will be transferred to the clinical site, destroyed, or stored at the clinical site or another facility for a longer period at the sponsor's expense.

[0254] [Table 2-1]

[0255] [Table 2-2]

[0256] [Table 3-1]

[0257]

Table 3-2

[0258]

Table 3-3

[0259]

Table 4-1

[0260]

Table 5-1

[0261] [Table 5-2]

[0262] [Table 5-3]

[0263] [Table 5-4]

[0264] [Table 6-1]

[0265] [Table 6-2]

[0266] Research results I. Changes in weight, waist circumference, and BMI INV-202 has been shown to induce weight loss and reduce waist circumference and BMI as shown in Figure 1 and Table 1 below. All patients who received INV-202 lost weight. The maximum percentage weight loss after 28 days of treatment was 6% and the minimum was 0.1%. A statistically significant change in weight was seen at the first visit (day 8), which was a mean weight loss of 1.4%.

[0267] [Table 7]

[0268] II. Lipids and Glucose The effects of INV-202 on lipids and glucose are shown in Table 2 below.

[0269] [Table 8]

[0270] III. Endocrine and renal test data The effects of INV-202 on endocrine and renal markers are shown below.

[0271] [Table 9]

[0272] IV. Overview of C-SSRS As shown below. None of the subjects had any active non-specific suicidal thoughts before or after treatment. None of the subjects had any actual, interrupted, planned, or aborted suicide attempts before or after treatment.

[0273] [Table 10]

[0274] V. Liver Safety All liver chemistries were within normal ranges for all patients throughout the study. There were no significant changes in bilirubin (total, direct, indirect) or transaminases (AST and ALT).

[0275] VI. Vital Signs

[0276] [Table 11] ***

[0277] While the present invention has been illustrated and described with respect to one or more implementations, equivalent alterations and modifications will occur to those skilled in the art upon reading and understanding this specification. In addition, while a particular feature of the present invention may be disclosed with respect to only one of several implementations, such feature may be combined with one or more other features of other implementations, as may be desirable and advantageous for any given or particular application.

[0278] It is understood, therefore, that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes therein will be suggested to those skilled in the art, which are within the spirit and scope of this application and the appended claims. Any publications, documents, patents, patent applications, or publications mentioned herein should each be construed as being incorporated by reference in their entirety for all purposes.

Claims

Claim 1: A compound of formula I: 【Chemistry 1】 1. A composition for treating metabolic syndrome in a human subject determined to have abdominal obesity characterized by a waist circumference of ≧88 cm for a female subject or ≧102 cm for a male subject, comprising the compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is orally administered to the human subject in an amount of 25 to 150 mg per day for a period of at least 28 days.

2. The composition described in claim 1, wherein the compound is administered in an amount of 25 to 75 mg per day.

3. The composition of claim 1, wherein the compound is administered in an amount of about 25 to about 50 mg per day.

4. The subject has one of the following: Fasting triglycerides >1.5 mmol / L for men and women, and / or 10. The composition of claim 1, wherein the composition exhibits one or more of the following: an OGTT indicative of impaired glucose tolerance as indicated by a 2-hour value of >140 mg / dl, or any value at any time point of >200 mg / dl, or an HbA1C level of ≥ 5.7% but ≤ 6.4%.

5. 10. The composition of claim 1, wherein the subject exhibits no significant changes in bilirubin, AST, and / or ALT relative to baseline after 28 days of treatment with the compound of formula I.

6. 10. The composition of claim 1, wherein the subject exhibits a weight reduction relative to baseline of about 0.1 to about 7%, about 1 to about 6%, about 2 to about 5%, about 3 to about 5%, about 4%, about 3.5%, about 3%, or about 2.5% after 28 days of treatment with the compound of Formula I.

7. 10. The composition of claim 1, wherein the subject exhibits a triglyceride reduction relative to baseline of about 1 to about 10%, about 2 to about 9%, about 3 to about 8%, about 8%, about 7%, about 6%, or about 5% after 28 days of treatment with the compound of formula I.

8. 10. The composition of claim 1, wherein the subject exhibits a change in leptin levels relative to baseline of about 10% to about 20% after 28 days of treatment with the compound of formula I.

9. 10. The composition of claim 1, wherein the subject exhibits a reduction in LDL levels relative to baseline of at least about 0.1 mmol / L to about 1 mmol / L after 28 days of treatment with the compound of formula I.

10. 10. The composition of claim 1, wherein the subject exhibits a reduction in VLDL levels relative to baseline of at least about 0.03 mmol / L to about 1 mmol / L after 28 days of treatment with the compound of formula I.

11. 10. The composition of claim 1, wherein the subject exhibits a reduction in total cholesterol levels relative to baseline of at least about 0.1 mmol / L to about 1 mmol / L after 28 days of treatment with the compound of formula I.

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