Combination of cvn-766 and a GLP-1 receptor agonist for use in the treatment of obesity and overweight

Abstract

The present invention provides methods of treating and / or managing obesity and / or overweight and methods of losing weight, which comprise administering to a subject N-[2-{[3-ethyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3- triazol-2-yl)pyridine-2-carboxamide ("Compound A"), or an enantiomer or mixture of enantiomers, a tautomer, an isotopolog, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, in combination with a GLP-1 receptor agonist.

Description

[0001] Novel Treatment

[0002] Field of the invention

[0003] The present invention provides methods of treating and / or managing obesity and / or overweight and methods of losing weight, which comprise administering to a subject / V-[2-{[3-ethyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-l,2,3-triazol-2-yl)pyridine-2-carboxamide ("Compound A"), or an enantiomer or mixture of enantiomers, a tautomer, an isotopolog, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, in combination with a GLP-1 receptor agonist.

[0004] Background of the invention

[0005] Obesity is a complex and multifactorial condition characterized by excessive body fat accumulation, which poses significant health risks, including cardiovascular diseases, diabetes, and certain cancers. Despite various available treatments, the prevalence of obesity continues to rise globally, highlighting the need for more effective and sustainable solutions.

[0006] Compared with normal weight, individuals with a body mass index (BMI) of 30-34.9 carry a 40% increased risk of overall premature mortality, rising to 100% with a BMI >40. The causes of obesity can be environmental, genetic or a combination of the two. The contribution of genetic factors to BMI is estimated to be about 40-70%.

[0007] Environmental factors accounting for the steep rise in global obesity include increased access to energy-dense food coupled with reduced physical activity, sleep deprivation, circadian desynchronization, chronic stress and use of certain prescribed drugs.

[0008] Monogenic obesity is observed in individuals with loss-of-function mutations in genes encoding for leptin, the leptin receptor (LEPR), pro-opiomelanocortin (POMC) and the melanocortin 4 receptor (MC4R). The most common polygenic risk factors for obesity include mutations in the fat mass and obesity-associated gene (FTO), MC4R, ADRB3, BDNF, CNR1, PCSK1 and PPARG. Notably, monogenic obesity affects only around 5% of the obesity population with the remaining 95% developing common polygenic obesity, which is multifactorial.

[0009] Physiologically we defend body weight both peripherally and centrally. Body weight control is based on the ability of the brain, hypothalamus in particular, to integratebehavioural, endocrine and autonomic responses via afferent and efferent pathways from and to the brainstem and peripheral organs. Communication between peripheral areas and the brain is mediated through afferent fibres of the vagus nerve projecting to the hindbrain or via the circulation by way of the median eminence of the hypothalamus or area postrema of the brainstem. Various intestinal signals are involved including GLP-1. Its ability to decrease food intake is mainly via direct activation of POMC / CART neurons but it also activates neurons in area postrema (AP) and nucleus tractus solitarius (NTS). GLP-1 receptor agonists can also modulate hedonic feeding by acting on dopaminergic neurons of the ventral tegmental area (VTA), nucleus accumbens (NAcc) and lateral septum.

[0010] Glucagon-like peptide-1 (GLP-1) receptor agonists are glucose-lowering drugs that induce clinically significant reductions in body weight. However, GLP-1 receptor agonists not only reduce fat mass, but have also been shown to reduce lean mass and skeletal muscle. After treatment with GLP-1 receptor agonists is stopped, fat mass is typically regained faster than lean mass and skeletal muscle.

[0011] Improved treatments for obesity and / or overweight and methods of losing weight that include GLP-1 receptor agonists, but prevent lean mass and skeletal muscle loss and / or limit the increase in fat mass after treatment with the GLP-1 receptor agonist is stopped, are therefore required. Such improved treatments and methods may also make a reduced dose or a reduced dosing frequency of the GLP-1 receptor agonist possible.

[0012] Summary of the invention

[0013] A first aspect of the present invention provides a method of treating or managing obesity or overweight or a method of losing weight, comprising administering to an obese or overweight subject: (a) a therapeutically effective amount of a compound, wherein the compound is Compound A:

[0014]

[0015] Compound A

[0016] or an enantiomer or mixture of enantiomers, a tautomer, an isotopolog, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof; in combination with (b) a therapeutically effective amount of a GLP-1 receptor agonist.

[0017] A second aspect of the present invention provides a compound for use in the treatment or management of obesity or overweight or for use in a method of losing weight, wherein the treatment, management or method comprises administering to an obese or overweight subject: (a) a therapeutically effective amount of the compound, wherein the compound is Compound A:

[0018]

[0019] Compound A

[0020] or an enantiomer or mixture of enantiomers, a tautomer, an isotopolog, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; in combination with (b) a therapeutically effective amount of a GLP-1 receptor agonist.

[0021] The second aspect of the present invention also provides use of a compound in the manufacture of a medicament for treating or managing obesity or overweight or for losing weight, wherein the medicament comprises: (a) the compound, wherein the compound is Compound A:

[0022]

[0023] Compound A

[0024] or an enantiomer or mixture of enantiomers, a tautomer, an isotopolog, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; and (b) a GLP-1 receptor agonist.

[0025] A third aspect of the present invention provides a GLP-1 receptor agonist for use in the treatment or management of obesity or overweight or for use in a method of losing weight, wherein the treatment, management or method comprises administering to an obese or overweight subject: (a) a therapeutically effective amount of a compound, wherein the compound is Compound A:

[0026]

[0027] Compound A

[0028] or an enantiomer or mixture of enantiomers, a tautomer, an isotopolog, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; in combination with (b) a therapeutically effective amount of the GLP-1 receptor agonist.

[0029] The third aspect of the present invention also provides use of a GLP-1 receptor agonist in the manufacture of a medicament for treating or managing obesity or overweight or for losing weight, wherein the medicament comprises: (a) a compound, wherein the compound is Compound A:

[0030]

[0031] Compound A

[0032] or an enantiomer or mixture of enantiomers, a tautomer, an isotopolog, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; and (b) the GLP-1 receptor agonist.

[0033] A fourth aspect of the present invention provides a compound and a GLP-1 receptor agonist for use in the treatment or management of obesity or overweight or for use in a method of losing weight, wherein the treatment, management or method comprises administering to an obese or overweight subject: (a) a therapeutically effective amount of the compound, wherein the compound is Compound A:

[0034]

[0035] Compound A

[0036] or an enantiomer or mixture of enantiomers, a tautomer, an isotopolog, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; in combination with (b) a therapeutically effective amount of the GLP-1 receptor agonist.The fourth aspect of the present invention also provides use of a compound and a GLP-1 receptor agonist in the manufacture of a medicament for treating or managing obesity or overweight or for losing weight, wherein the medicament comprises: (a) the compound, wherein the compound is Compound A:

[0037]

[0038] Compound A

[0039] or an enantiomer or mixture of enantiomers, a tautomer, an isotopolog, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; and (b) the GLP-1 receptor agonist.

[0040] A fifth aspect of the present invention provides a pharmaceutical composition or kit comprising: (a) a compound, wherein the compound is Compound A:

[0041]

[0042] Compound A

[0043] or an enantiomer or mixture of enantiomers, a tautomer, an isotopolog, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; and (b) a GLP-1 receptor agonist.

[0044] The pharmaceutical composition of the fifth aspect provides the compound and the GLP-1 receptor agonist together in one dosage form.

[0045] The kit of the fifth aspect provides the compound and the GLP-1 receptor agonist in separate dosage forms. The kit may further comprise a device for separately retaining the compound and the GLP-1 receptor agonist, such as a divided bottle or a divided foil packet. An example of such a kit is a blister pack used for the packaging of tablets or capsules. The kit can be suitable for administering different types of dosage forms (e.g., oral and subcutaneous), or suitable for administering different pharmaceutical compositions at separate dosing intervals, or suitable for titrating the different pharmaceutical compositions against one another. To assist with patient compliance, the kit typically comprises directions for administration and may be provided with a memory aid.In one embodiment of the first, second, third, fourth or fifth aspect, the compound is Compound A-SS:

[0046]

[0047] Compound A-SS

[0048] or a tautomer, an isotopolog, a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof.

[0049] In one embodiment of the first, second, third, fourth or fifth aspect, the compound is formulated as a pharmaceutical composition comprising the compound and one or more pharmaceutically acceptable carriers or excipients.

[0050] In one embodiment of the first, second, third, fourth or fifth aspect, the GLP-1 receptor agonist is selected from AMG 133, Amycretin (NNC0487-0111), CagriSema, CT-388, CT-996, Danuglipron, Dapiglutide, Dulaglutide, Efinopegdutide, Exenatide, HM15211, Liraglutide, Lixisenatide, Mazdutide, Orforglipron, Pemvidutide, Retatrutide, SCO-094, Semaglutide, Survodutide, Tirzepatide, or VK2735. In one embodiment of the first, second, third, fourth or fifth aspect, the GLP-1 receptor agonist is selected from Dulaglutide, Exenatide, Liraglutide, Lixisenatide, Semaglutide, or Tirzepatide.

[0051] In one embodiment of the first, second, third, fourth or fifth aspect, the GLP-1 receptor is formulated as a pharmaceutical composition comprising the GLP-1 receptor and one or more pharmaceutically acceptable carriers or excipients.

[0052] In one embodiment of the first, second, third or fourth aspect, the compound is administered orally or subcutaneously. In one embodiment of the first, second, third or fourth aspect, the compound is administered orally.

[0053] In one embodiment of the first, second, third or fourth aspect, the compound is administered once or twice per day.

[0054] In one embodiment of the first, second, third or fourth aspect, the compound is administered in an amount of from about 30 mg to about 200 mg per day.

[0055] In one embodiment of the first, second, third or fourth aspect, the GLP-1 receptor agonist is administered orally or subcutaneously.In one embodiment of the first, second, third or fourth aspect, the GLP-1 receptor agonist is administered once per month, twice per month, once per week, twice per week, once per day, or twice per day.

[0056] In one embodiment of the first, second, third or fourth aspect, the GLP-1 receptor agonist is administered in an amount of from about 0.1 mg to about 200 mg per administration dose.

[0057] In one embodiment of the first, second, third or fourth aspect, the compound and the GLP-1 receptor agonist are administered simultaneously, separately or sequentially.

[0058] In one embodiment of the first, second, third or fourth aspect, administration of the compound is initiated on the same day as administration of the GLP-1 receptor agonist.

[0059] In another embodiment of the first, second, third or fourth aspect, administration of the compound is initiated one or more days (such as one, two, three, four, five, six, seven, eight, nine, ten or more days, or one, two, three, four, five, six, seven, eight, nine, ten or more weeks, or one, two, three, four, five, six or more months) after administration of the GLP-1 receptor agonist. Optionally the administration amount and / or the administration frequency of the GLP-1 receptor agonist is reduced when administration of the compound is initiated.

[0060] Weight loss effected by GLP-1 receptor agonists tends to plateau after a few months of treatment (such as one, two, three, four, five, six or more months). Therefore, in one embodiment of the first, second, third or fourth aspect, administration of the compound is initiated after administration of the GLP-1 receptor agonist when weight loss effected by the GLP-1 receptor agonist has plateaued. Optionally the administration amount and / or the administration frequency of the GLP-1 receptor agonist is reduced when administration of the compound is initiated.

[0061] In one embodiment of the first, second, third or fourth aspect, administration of the compound is continued after administration of the GLP-1 receptor agonist has ceased.

[0062] Generally, subjects are considered overweight if they have a BMI of 25 or greater, and obese if they have a BMI of 30 or greater. Although weight loss therapies provide a treatment of weight-gain induced comorbidities, such as obesity-associatedcomorbidities, weight loss therapies can have an impact on body composition. Body composition includes free mass, fat free mass, lean mass, skeletal muscle, bone mineral content, and total body water. Free mass is a mass of all adipose tissue; fat free mass is total body mass minus total fat mass; lean mass includes organs, skin, bones, total body water, and muscle mass minus total fat mass; skeletal muscle includes lean mass minus connective tissue, skin, and other organs; and total body water includes intra- and extracellular water. A GLP-1 receptor agonist used to induce weight loss in a subject, can also induce loss of lean mass and / or skeletal muscle which can make the subject susceptible to muscle atrophies, sarcopenia, and physical frailty. A subject who is overweight and recommended for weight loss therapy may already have an increased risk of conditions such as diabetes, insulin resistance, muscle atrophies, sarcopenia, and physical frailty.

[0063] The present inventors discovered that co-administration of Compound A-SS with a GLP-1 receptor agonist can induce or increase total weight loss (e.g., fat mass loss) but also preserve muscle function and muscle mass, and thus reduce or prevent the loss of skeletal muscle and / or lean mass that usually follows treatment with a GLP-1 receptor agonist. The present inventors discovered that the combination therapy can lead to increased total weight loss, reduction of fat mass percentage, increase in lean mass percentage, and / or improvement in body composition (higher lean mass / fat mass ratio) relative to that caused by administration of the GLP-1 receptor agonist alone, i.e. the combination therapy can be synergistic.

[0064] Definitions

[0065] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, and other publications are incorporated by reference in their entirety.

[0066] The term "GLP-1 receptor agonist" includes compounds which act only as GLP-1 receptor agonists (such as Semaglutide) as well as compounds that have a mixed pharmacology which includes GLP-1 receptor agonism (such as Tirzepatide which is a mixed GIP / GLP-1 receptor agonist). A protocol of how to measure GLP-1 receptor agonism can be found in Willard et al, JCI Insight, 2020 (https: / / doi.org / 10.1172 / jci.insight.140532).

[0067] / V-[2-{[3-Ethyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-l,2,3-triazol-2-yl)pyridine-2-carboxamide ("Compound A") has two chiral centres. InCompound A-SS, both chiral centres are in the S-configuration. An enantiomer of Compound A (such as Compound A-SS) can be enantiomerically enriched or enantiomerically pure. A typical "enantiomerically pure" compound comprises greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, in one embodiment greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and in one embodiment greater than about 98% by weight of one stereoisomer of the compound and less than about 2% by weight of the other stereoisomers of the compound. A typical "enantiomerically enriched" compound comprises greater than about 60% by weight of one stereoisomer of the compound and less than about 40% by weight of the other stereoisomers of the compound, in one embodiment greater than about 70% by weight of one stereoisomer of the compound and less than about 30% by weight of the other stereoisomers of the compound, and in one embodiment greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomers of the compound.

[0068] The term "solvate" means a compound provided herein or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.

[0069] The term "pharmaceutically acceptable salt" encompasses non-toxic acid and base addition salts of the compound to which the term refers. Acid addition salts include those derived from organic and inorganic acids known in the art, see for example, Remington's Pharmaceutical Sciences, 18thed, Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19thed, Mack Publishing, Easton PA (1995). Base addition salts may be alkali metal or alkaline earth metal salts or salts with suitable organic bases.

[0070] The term "subject" or "patient" refers to an animal, including but not limited to a mammal, including a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject.

[0071] The terms "treat", "treating" and "treatment" refer to the eradication or amelioration of a disease, disorder or condition, or of one or more symptoms associated with the disease, disorder or condition. In certain embodiments, the terms refer to minimizing the spread or worsening of the disease, disorder or condition.The terms "manage", "managing" and "management" refer to preventing or slowing the progression or worsening of a disease, disorder or condition, or of one or more symptoms thereof. Often, the beneficial effects that a patient derives from a prophylactic and / or therapeutic agent do not result in a cure of the disease, disorder or condition.

[0072] A "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A "therapeutically effective amount" of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of the disease, disorder or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease, disorder or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0073] The terms "combination therapy" and "in combination with" refer to the use of more than one therapeutic agent to treat a particular disease, disorder or condition. The terms are not intended to imply that the therapeutic agents must be administered at the same time and / or formulated for delivery together, although these methods of delivery are within the scope of this disclosure. A therapeutic agent (such as Compound A) can be administered concurrently with, prior to, or subsequent to, one or more other additional agents (such as a GLP-1 receptor agonist). The administration of a therapeutic agent (such as Compound A) "in combination with" another therapeutic agent (such as a GLP-1 receptor agonist) includes, but is not limited to, simultaneous, separate and sequential administration of the two agents. In general, each therapeutic agent is administered at a dose and / or on a time schedule determined for that particular agent.

[0074] Subjects are considered "obese" if they have a body mass index (BMI) of 30 or greater. Obese subjects suffer from the disease, disorder or condition known as "obesity". Obesity is classified by the World Health Organization (WHO) as a chronic, relapsing disease arising from complex interactions between genetics, neurobiology, eating behaviours, access to healthy diet, market forces, and the broader

[0075] environment.Subjects are considered "overweight" if they have a body mass index (BMI) of 25 or greater. Overweight subjects suffer from the condition known as "overweight".

[0076] Overweight is a condition of excessive fat deposits.

[0077] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, disintegrating agent, binding agent, lubricating agent, solvent, adjuvant, sweetening agent, flavouring agent, colouring agent, encapsulating material, or preservative. In one embodiment, each ingredient is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. (See, Remington: The Science and Practice of Pharmacy, 21sted, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5thed, Rowe et al., The Pharmaceutical Press and The American Pharmaceutical Association: 2005; Handbook of Pharmaceutical Additives, 3rded, Ash and Ash, Gower Publishing Company: 2007; and Pharmaceutical Preformulation and Formulation, Gibson, CRC Press LLC: Boca Raton, FL, 2004).

[0078] Brief description of the figures

[0079] Figure 1 is a bar chart showing the body weights on Day -1 before the start of the study.

[0080] Figure 2A is a graph showing the body weights over the course of the study. Figure 2B is a bar chart showing the percentage change in body weights from baseline.

[0081] Figures 3A and 3B are bar charts showing the percentage fat mass and the percentage lean mass respectively, as measured by Echo MRI.

[0082] Figure 4 is a graph showing the food intake over the course of the study.

[0083] Example

[0084] Compound A-SS was tested in combination with Semaglutide, a GLP-1 receptor agonist, in a mouse model of obesity.OBJECTIVE

[0085] The objective of this preclinical study was to measure the changes in body weight and body fat composition following treatment with Compound A-SS and / or Semaglutide when given via subcutaneous injection to C57BL / 6J and C57BL / 6J DIO (diet induced obesity) male mice.

[0086] TEST MATERIALS

[0087] The following test articles were used:

[0088] • Vehicle consisting of 10% Kolliphor EL and 90% saline

[0089] • Compound A-SS as a suspension in Vehicle

[0090] • Semaglutide as a solution in 5mM sodium phosphate, 5% mannitol, pH 8.0

[0091] ANIMALS

[0092] Species: Mouse

[0093] Strain: C57BL / 6J C57BL / 6J DIO

[0094] Number of males: 24 48

[0095] Age at pre-dose

[0096] assessments: 19-20 weeks

[0097] FOOD

[0098] Diet: Control Mice

[0099] PMI Nutrition International Certified Rodent Chow No. 5CR4 (14% kcal from fat)

[0100] DIO Mice

[0101] Research Diet: D12492 (high fat diet - 60% kcal from fat) DIO Mice fed on high fat diet from 6 weeks

[0102] Diet Frequency: Ad libitum, except during designated procedures.

[0103] EXPERIMENTAL DESIGN

[0104] Table - Experimental Design

[0105]

[0106] No. = number; Cone. = concentration; - = not applicable; QD = once daily; BID = twice daily; SC = subcutaneous injection

[0107] Administration of Test Articles (Semaglutide)

[0108] Route of Administration: Subcutaneous Bolus

[0109] Treatment Frequency per day: Groups 3-4: QD (lx)

[0110] Treatment Duration: 28 days

[0111] Administration of Test Articles (Compound A-SS and Vehicle)

[0112] Route of Administration: Subcutaneous Bolus

[0113] Treatment Frequency per day: Groups 1-2 and 4-6: BID (2x)

[0114] 12 hours between doses (+ / - lhr).

[0115] 2nddose about 45 minutes before lights off Treatment Duration: 28 days

[0116] MEASUREMENTS AND RESULTS

[0117] Body Weight

[0118] Individual body weights were recorded three times weekly from Week -1 and throughout the study.

[0119] Figures 2A and 2B show that administration of a combination of Compound A-SS and Semaglutide led to a statistically significant additional decrease in body weight compared to all other groups including Semaglutide alone, and that the combination of Compound A-SS and Semaglutide has a synergistic effect I more than additive effect on loss of body weight.

[0120] Body Composition

[0121] Body composition was analysed on Days -1 and 27. The animals were taken from their home cage and placed into a plastic restrainer compatible with the body composition analysis machine (Echo MRI). The restrainer was placed into the Echo MRI and body composition was assessed.

[0122] Figures 3A and 3B show that administration of a combination of Compound A-SS and Semaglutide led to a statistically significant additional decrease in the percentage fat mass and a statistically significant increase in the percentage lean mass compared to all other groups including Semaglutide alone. Figures 3A and 3B also show that the combination of Compound A-SS and Semaglutide has a synergistic effect I more than additive effect on decrease in the percentage fat mass and increase in the percentage lean mass.Food Consumption

[0123] Food consumption was recorded twice weekly from Week -1 and throughout the study. Food consumption was measured quantitatively with food spillage being recorded.

[0124] Figure 4 shows that mice treated with Semaglutide alone initially consumed less food, but that this did not last beyond 9 days, whereas mice treated with a combination of Compound A-SS and Semaglutide consumed less food throughout the study period of 28 days. Hence administration of a combination of Compound A-SS and Semaglutide led to a superior reduction in food intake.

[0125] It will be understood that the present invention has been described above by way of example only. The examples are not intended to limit the scope of the invention. Various modifications and embodiments can be made without departing from the scope and spirit of the invention, which is defined by the following claims only.

Claims

Claims1. A method of treating or managing obesity or overweight or a method of losing weight, comprising administering to an obese or overweight subject: (a) a therapeutically effective amount of a compound, wherein the compound is Compound A:Compound Aor an enantiomer or mixture of enantiomers, a tautomer, an isotopolog, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; in combination with (b) a therapeutically effective amount of a GLP-1 receptor agonist.

2. The method of claim 1, wherein the compound is Compound A-SS:Compound A-SSor a tautomer, an isotopolog, a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof.

3. The method of claim 1 or 2, wherein the GLP-1 receptor agonist is selected from AMG 133, Amycretin (NNC0487-0111), CagriSema, CT-388, CT-996, Danuglipron, Dapiglutide, Dulaglutide, Efinopegdutide, Exenatide, HM15211, Liraglutide, Lixisenatide, Mazdutide, Orforglipron, Pemvidutide, Retatrutide, SCO-094, Semaglutide, Survodutide, Tirzepatide, or VK2735.

4. The method of any one of claims 1 to 3, wherein the compound is administered orally or subcutaneously.

5. The method of any one of claims 1 to 4, wherein the compound is administered once or twice per day.

6. The method of any one of claims 1 to 5, wherein the compound is administered in an amount of from about 30 mg to about 200 mg per day.

7. The method of any one of claims 1 to 6, wherein the GLP-1 receptor agonist is administered orally or subcutaneously.

8. The method of any one of claims 1 to 7, wherein the GLP-1 receptor agonist is administered once per month, twice per month, once per week, twice per week, once per day, or twice per day.

9. The method of any one of claims 1 to 8, wherein the GLP-1 receptor agonist is administered in an amount of from about 0.1 mg to about 200 mg per administration dose.

10. The method of any one of claims 1 to 9, wherein the compound and the GLP-1 receptor agonist are administered simultaneously, separately or sequentially.

11. The method of any one of claims 1 to 10, wherein administration of the compound is initiated on the same day as administration of the GLP-1 receptor agonist.

12. The method of any one of claims 1 to 10, wherein administration of the compound is initiated one or more days after administration of the GLP-1 receptor agonist.

13. The method of any one of claims 1 to 12, wherein administration of the compound is continued after administration of the GLP-1 receptor agonist has ceased.

14. A compound for use in the treatment or management of obesity or overweight or for use in a method of losing weight, wherein the treatment, management or method comprises administering to an obese or overweight subject: (a) the compound, wherein the compound is Compound A:Compound Aor an enantiomer or mixture of enantiomers, a tautomer, an isotopolog, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; in combination with (b) a GLP-1 receptor agonist.

15. A GLP-1 receptor agonist for use in the treatment or management of obesity or overweight or for use in a method of losing weight, wherein the treatment, management or method comprises administering to an obese or overweight subject: (a) a compound, wherein the compound is Compound A:Compound Aor an enantiomer or mixture of enantiomers, a tautomer, an isotopolog, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; in combination with (b) the GLP-1 receptor agonist.

16. A compound and a GLP-1 receptor agonist for use in the treatment or management of obesity or overweight or for use in a method of losing weight, wherein the treatment, management or method comprises administering to an obese or overweight subject: (a) the compound, wherein the compound is Compound A:Compound Aor an enantiomer or mixture of enantiomers, a tautomer, an isotopolog, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; in combination with (b) the GLP-1 receptor agonist.

17. The compound for use of claim 14, the GLP-1 receptor agonist for use of claim 15, or the compound and the GLP-1 receptor agonist for use of claim 16, wherein the compound is CompoundCompound A-SSor a tautomer, an isotopolog, a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof.

18. The compound for use of claim 14 or 17, the GLP-1 receptor agonist for use of claim 15 or 17, or the compound and the GLP-1 receptor agonist for use of claim 16 or 17, wherein the GLP-1 receptor agonist is selected from AMG 133, Amycretin (NNC0487-0111), CagriSema, CT-388, CT-996, Danuglipron, Dapiglutide, Dulaglutide, Efinopegdutide, Exenatide, HM15211, Liraglutide, Lixisenatide, Mazdutide, Orforglipron, Pemvidutide, Retatrutide, SCO-094, Semaglutide, Survodutide, Tirzepatide, or VK2735.

19. The compound for use of any one of claims 14 or 17-18, the GLP-1 receptor agonist for use of any one of claims 15 or 17-18, or the compound and the GLP-1 receptor agonist for use of any one of claims 16-18, wherein the compound is administered orally or subcutaneously.

20. The compound for use of any one of claims 14 or 17-19, the GLP-1 receptor agonist for use of any one of claims 15 or 17-19, or the compound and the GLP-1 receptor agonist for use of any one of claims 16-19, wherein the compound is administered once or twice per day.

21. The compound for use of any one of claims 14 or 17-20, the GLP-1 receptor agonist for use of any one of claims 15 or 17-20, or the compound and the GLP-1 receptor agonist for use of any one of claims 16-20, wherein the compound is administered in an amount of from about 30 mg to about 200 mg per day.

22. The compound for use of any one of claims 14 or 17-21, the GLP-1 receptor agonist for use of any one of claims 15 or 17-21, or the compound and the GLP-1 receptor agonist for use of any one of claims 16-21, wherein the GLP-1 receptor agonist is administered orally or subcutaneously.

23. The compound for use of any one of claims 14 or 17-22, the GLP-1 receptor agonist for use of any one of claims 15 or 17-22, or the compound and the GLP-1 receptor agonist for use of any one of claims 16-22, wherein the GLP-1 receptor agonist is administered once per month, twice per month, once per week, twice per week, once per day, or twice per day.

24. The compound for use of any one of claims 14 or 17-23, the GLP-1 receptor agonist for use of any one of claims 15 or 17-23, or the compound and the GLP-1 receptor agonist for use of any one of claims 16-23, wherein the GLP-1 receptor agonist is administered in an amount of from about 0.1 mg to about 200 mg per administration dose.

25. The compound for use of any one of claims 14 or 17-24, the GLP-1 receptor agonist for use of any one of claims 15 or 17-24, or the compound and the GLP-1 receptor agonist for use of any one of claims 16-24, wherein the compound and the GLP-1 receptor agonist are administered simultaneously, separately or sequentially.

26. The compound for use of any one of claims 14 or 17-25, the GLP-1 receptor agonist for use of any one of claims 15 or 17-25, or the compound and the GLP-1 receptor agonist for use of any one of claims 16-25, wherein administration of the compound is initiated on the same day as administration of the GLP-1 receptor agonist.

27. The compound for use of any one of claims 14 or 17-25, the GLP-1 receptor agonist for use of any one of claims 15 or 17-25, or the compound and the GLP-1 receptor agonist for use of any one of claims 16-25, wherein administration of the compound is initiated one or more days after administration of the GLP-1 receptor agonist.

28. The compound for use of any one of claims 14 or 17-27, the GLP-1 receptor agonist for use of any one of claims 15 or 17-27, or the compound and the GLP-1 receptor agonist for use of any one of claims 16-27, wherein administration of the compound is continued after administration of the GLP-1 receptor agonist has ceased.

29. A pharmaceutical composition or kit comprising: (a) a compound, wherein the compound is Compound A:Compound Aor an enantiomer or mixture of enantiomers, a tautomer, an isotopolog, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; and (b) a GLP-1 receptor agonist.

30. The pharmaceutical composition or kit of claim 29, wherein the compound is Compound A-SS:>Compound A-SSor a tautomer, an isotopolog, a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof.

31. The pharmaceutical composition or kit of claim 29 or 30, wherein the GLP-1 receptor agonist is selected from AMG 133, Amycretin (NNC0487-0111), CagriSema, CT-388, CT-996, Danuglipron, Dapiglutide, Dulaglutide, Efinopegdutide, Exenatide, HM15211, Liraglutide, Lixisenatide, Mazdutide, Orforglipron, Pemvidutide, Retatrutide, SCO-094, Semaglutide, Survodutide, Tirzepatide, or VK2735.

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