Combination treatment

Abstract

The present invention relates to methods for treating overweight or obese in individuals in need thereof, and / or individuals with fatty liver disease or diabetes. In particular, the present invention relates to a method of treating obesity, fatty liver disease or diabetes in an individual in need thereof, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual.

Description

Combination treatmentRelated application

[0001] This application is related to Australian provisional application no 2024903494 filed on 28 October 2024, the contents of which are incorporated herein by reference in their entirety.Field of the invention

[0002] The present invention relates to methods for treating overweight or obese in individuals in need thereof, and I or individuals with fatty liver disease or diabetes.Sequence listing

[0003] A sequence listing in ST. 26 format is filed herewith, the entire contents of which are incorporated herein by reference.Background of the invention

[0004] More than 1 .9 billion people are overweight or obese worldwide. The prevalence of obesity has reached epidemic levels and is increasing rapidly. Chronic diseases associated with obesity such as diabetes and cardiovascular disease are leading causes of morbidity and mortality. Weight loss strategies focused on lifestyle modifications are difficult to maintain due to rebound weight gain. Moreover, there are limited treatment options currently available.

[0005] The development of obesity is primarily due to an imbalance in energy homeostasis, whereby energy intake exceeds energy expenditure. The maintenance of energy balance is under strict control by a complex system involving endocrine and neural pathways. The hypothalamus is a critical regulator of energy balance as it senses information about peripheral energy availability, comparing it to the actual value of body fat and adjusting food intake or expenditure as required. The molecular mechanisms involved in hypothalamic nutrient sensing are poorly defined. A lack of understanding about the fundamental mechanisms that regulate energy balance is a critical roadblock to the development of effective anti-obesity treatments.100621 1481

[0006] Body weight is tightly regulated within a specific range. In order to prevent excessive weight gain or chronic weight loss, a complex neuronal regulatory network has developed in the brain, specifically in the hypothalamus. This system has the capacity to sense the amount of fat accumulated in the body and adjust food intake and fuel consumption so that body weight stays reasonably constant despite variations in daily food intake and energy expenditure. To elicit appropriate responses, the hypothalamus, in particular the arcuate nucleus (ARC), needs to obtain accurate information about the body’s energy status from the periphery. The hypothalamic ARC contains two major neuronal populations responsible for control of energy homeostasis: neurons that express orexigenic (appetite-inducing) neuropeptide Y (NPY)Zagouti- related protein (AgRP) and another set of neurons that produce anorexigenic (appetitesuppressing) pro-opiomelanocortin (POMC). When this system is disrupted, obesity or the other extreme, anorexia, can develop. Identifying endogenous regulators within the arcuate network that control body weight and energy balance is critical to understand the pathology of obesity. This may in turn provide the means for the development of more effective and safer therapeutic approaches.

[0007] Obesity and overconsumption of calories is known to lead to ectopic lipid deposition around and within tissue and organs, such as the muscle, heart, liver and pancreas.

[0008] Heavy alcohol use is known to lead to liver complications, including alcoholic hepatitis which is often characterized by fatty liver and inflammation. Alcoholic hepatitis can ultimately lead to cirrhosis of the liver (scarring) and hardening of the liver tissue. However, individuals that do not consume excessive amounts of alcohol can also be found to have liver disease complications. Non-alcoholic fatty liver disease (NAFLD) is understood to encompass a variety of liver diseases, including steatosis (simple fatty liver), non-alcoholic steatohepatitis (NASH) and advanced scarring of the liver (cirrhosis). NASH has traditionally been diagnosed by means of a liver biopsy to characterize the liver histology, particularly with respect to the characteristics of inflammation, fibrosis and steatosis (fat accumulation). NASH then generally refers to clinical findings based upon the liver biopsy of a patient with steatohepatitis, combined with the absence of significant alcohol consumption.

[0009] In NASH, fat accumulation is seen in varying degrees of inflammation (hepatitis) and may lead to more serious conditions involving scarring (fibrosis). Patients100621 1481having NASH are also often characterized by abnormal levels of liver enzymes, such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT).

[0010] There exists a need for new and / or improved treatments for overweight and / or obese individuals.

[0011] There exists a need for new and / or improved treatments for obese individuals having a further obesity-related disease or disorder.

[0012] Separately, or in addition to the above needs, there exists a need for new and / or improved treatments for fatty liver disease.

[0013] Separately, or in addition to the above needs, there exists a need for new and / or improved treatments for diabetes.

[0014] Reference to any prior art in the specification is not an acknowledgment or suggestion that this prior art forms part of the common general knowledge in any jurisdiction or that this prior art could reasonably be expected to be understood, regarded as relevant, and / or combined with other pieces of prior art by a skilled person in the art.Summary of the invention

[0015] Surprisingly the inventors have found that administration of a SIK-3 inhibitor and a metabolic modulator has numerous benefits in overweight or obese individuals including increasing resistance to weight gain, and promotion of weight loss. Further, the benefits have been shown arise from a synergistic effect of the different molecules. Further, the inventors have found that administration of a SIK-3 inhibitor and a metabolic modulator has a beneficial effect on fatty liver disease, including NAFLD and NASH, and on diabetes.

[0016] In an aspect of the disclosure there is provided a method of treating obesity in an individual in need thereof, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby treating obesity in the individual.

[0017] In another aspect there is provided a method of treating, or minimising the risk of, an obesity-related disease or disorder, the method comprising administering to an individual suffering from or at risk of suffering from an obesity-related disease or100621 1481disorder a SIK-3 inhibitor and a metabolic modulator to the individual, thereby treating, or minimising the risk of, an obesity in the individual.

[0018] In a further aspect there is provided a method of reducing adiposity in an individual in need thereof, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby reducing adiposity in the individual.

[0019] In a further aspect there is provided a method of reducing the body weight of an individual in need thereof, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby reducing body weight of the individual.

[0020] In a further aspect there is provided a method of increasing white adipose tissue browning in an individual in need thereof, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby increasing white adipose tissue browning in the individual.

[0021] Advantageously, the methods of the present invention may result in reduction in body weight and adiposity without a corresponding decrease in lean mass, ie no or minimal reduction in muscle and / or bone mass.

[0022] In a further aspect there is provided a method of preventing or minimising the weight gain of an individual consuming a high energy / caloric diet, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby preventing or minimising the weight gain of the individual consuming a high energy / caloric diet.

[0023] In a further aspect there is provided a method of preventing or minimising adiposity in an individual consuming a high energy / caloric diet, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby preventing or minimising adiposity in the individual consuming a high energy / caloric diet.

[0024] In a further aspect there is provided a method of enhancing energy expenditure in an individual in need thereof, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby enhancing energy expenditure in the individual.100621 1481

[0025] In preferred embodiments the method of enhancing energy expenditure does not require the individual to increase their level of exercise. In embodiments the method of enhancing energy expenditure does not require the individual to modify their diet. Alternatively, in other embodiments the method includes modification to the exercise and diet regimen of the individual. Preferably the administration of a SIK-3 inhibitor and a metabolic modulator in combination with modification to the exercise and diet regimen of the individual has an additive effect or a synergistic effect.

[0026] Advantageously in some embodiments the methods of the disclosure can contribute to a reduction in body weight and adiposity without requiring a change in activity level or caloric intake of the individual in need thereof.

[0027] In a further aspect there is provided a method of promoting weight loss in an individual in need thereof, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby promoting weight loss in the individual.

[0028] In a further aspect there is provided a method of treating a disease or disorder associated with dysregulated leptin signalling in an individual in need thereof, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby treating the disease or disorder associated with dysregulated leptin signalling in the individual.

[0029] In a further aspect there is provided a method of increasing sensitization of leptin action and / or signalling in an individual in need thereof, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby increasing sensitization of leptin action and / or signalling in the individual.

[0030] In some embodiments, the disease or disorder associated with dysregulated leptin signalling is leptin resistance (or leptin insensitivity), or abnormally low levels of leptin (hypoleptinemia). In a further embodiment, the individual with leptin resistance (or leptin insensitivity) has elevated levels of leptin. In another further embodiment, the individual with leptin resistance (or leptin insensitivity) has pre-diabetes or diabetes, and / or is overweight and / or is obese. In another further embodiment, the individual with abnormally low levels of leptin (hypoleptinemia) has lipodystrophy and / or congenital leptin deficiency.100621 1481

[0031] In a further aspect there is provided a method of promoting or improving insulin secretion in an individual in need thereof, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby improving insulin secretion in the individual. Preferably the individual is an overweight or obese individual.

[0032] In a further aspect there is provided a method of promoting blood glucose clearance in an individual in need thereof, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby promoting blood glucose clearance in the individual.

[0033] In a further aspect there is provided a method of promoting or improving glycaemic control in an individual in need thereof, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby promoting glycaemic control in the individual.

[0034] In a further aspect there is provided a method of treating pre-diabetes or diabetes in an individual in need thereof, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby treating pre-diabetes or diabetes in the individual.

[0035] In a further aspect there is provided a method of treating type 1 diabetes (T1 D) in an individual in need thereof, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby treating T1 D in the individual.

[0036] In a further aspect there is provided a method of promoting blood glucose clearance in an overweight or obese individual, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby promoting blood glucose clearance in the individual.

[0037] In a further aspect there is provided a method of promoting or improving glycaemic control in an overweight or obese individual, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby promoting glycaemic control in the individual.

[0038] In a further aspect there is provided a method of treating pre-diabetes or diabetes in an overweight or obese individual, the method comprising administering a100621 1481S IK-3 inhibitor and a metabolic modulator to the individual, thereby treating pre-diabetes or diabetes in the individual.

[0039] In a further aspect there is provided a method of treating type 1 diabetes (T1 D) in an overweight or obese individual, the method comprising administering a SIK- 3 inhibitor and a metabolic modulator to the individual, thereby treating T1 D in the individual.

[0040] In a further aspect there is provided a method of treating insulin resistance in an individual in need thereof, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby treating the insulin resistance.Preferably the individual is an overweight or obese individual.

[0041] In a further aspect there is provided a method of decreasing food intake in an individual in need thereof comprising the step of administering to the individual a SIK-3 inhibitor and a metabolic modulator. Preferably the individual is an overweight or obese individual.

[0042] In a further aspect there is provided a method of reducing caloric intake in an individual in need thereof comprising the step of administering to the individual a SIK-3 inhibitor and a metabolic modulator. Preferably the individual is an overweight or obese individual.

[0043] In a further aspect there is provided a method of reducing or inhibiting appetite in an individual in need thereof, the method comprising administering to the individual a SIK-3 inhibitor and a metabolic modulator, thereby inhibiting appetite in the individual. Preferably the individual is an overweight or obese individual.

[0044] In a further aspect there is provide a method of treating fatty liver disease in an individual in need thereof, the method comprising administering to the individual a SIK-3 inhibitor and a metabolic modulator, thereby treating fatty liver disease in the individual in need thereof. In one embodiment, the individual is an overweight or obese individual, for example an overweight or obese individual as defined herein. In another embodiment, the individual is not an overweight or obese individual, for example not an overweight or obese individual as defined herein. In embodiments the fatty liver disease may be any one described herein, including non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).100621 1481

[0045] The present disclosure also provides the use of a SIK-3 inhibitor and a metabolic modulator in the manufacture of a medicament for: treating obesity; in an individual in need thereof; treating or minimising the risk of, an obesity-related disease or disorder in an individual suffering from or at risk of suffering from an obesity-related disease or disorder reducing the body weight of an individual in need thereof; preventing or minimising the weight gain of an individual consuming a high energy / caloric diet; preventing or minimising adiposity in individual consuming a high energy / caloric diet; enhancing energy expenditure; improving insulin secretion in an individual in need thereof; promoting blood glucose clearance in an individual in need thereof; promoting or improving glycaemic control in an individual in need thereof; treating pre-diabetes or diabetes in an individual in need thereof; treating type 1 diabetes (T1 D) in an individual in need thereof; promoting blood glucose clearance in an overweight or obese individual; promoting or improving glycaemic control in an overweight or obese individual; treating pre-diabetes or diabetes in an overweight or obese individual; treating type 1 diabetes (T1 D) in an overweight or obese individual; treating insulin resistance in an individual; decreasing food intake in an individual; decreasing caloric intake in an individual; inhibiting appetite in an individual; or treating fatty liver disease in an individual.

[0046] In embodiments the SIK-3 inhibitor and metabolic modulator are separate medicaments. In embodiments the SIK-3 inhibitor and metabolic modulator are to be administered sequentially. In embodiments the SIK-3 inhibitor and metabolic modulator are to be administered simultaneously.

[0047] In embodiments there is provided the use of a SIK-3 inhibitor in the manufacture of a medicament for:100621 1481treating obesity; in an individual in need thereof; treating or minimising the risk of, an obesity-related disease or disorder in an individual suffering from or at risk of suffering from an obesity-related disease or disorder reducing the body weight of an individual in need thereof; preventing or minimising the weight gain of an individual consuming a high energy / caloric diet; preventing or minimising adiposity in individual consuming a high energy / caloric diet; enhancing energy expenditure; improving insulin secretion in an individual in need thereof; promoting blood glucose clearance in an individual in need thereof; promoting or improving glycaemic control in an individual in need thereof; treating pre-diabetes or diabetes in an individual in need thereof; treating type 1 diabetes (T1 D) in an individual in need thereof; promoting blood glucose clearance in an overweight or obese individual; promoting or improving glycaemic control in an overweight or obese individual; treating pre-diabetes or diabetes in an overweight or obese individual; treating type 1 diabetes (T1 D) in an overweight or obese individual; treating insulin resistance in an individual; decreasing food intake in an individual; decreasing caloric intake in an individual; inhibiting appetite in an individual; or treating fatty liver disease in an individual; wherein the medicament is to be administered with a metabolic modulator.

[0048] In embodiments there is provided the use of a metabolic modulator in the manufacture of a medicament for: treating obesity; in an individual in need thereof; treating or minimising the risk of, an obesity-related disease or disorder in an individual suffering from or at risk of suffering from an obesity-related disease or disorder reducing the body weight of an individual in need thereof;100621 1481preventing or minimising the weight gain of an individual consuming a high energy / caloric diet; preventing or minimising adiposity in individual consuming a high energy / caloric diet; enhancing energy expenditure; improving insulin secretion in an individual in need thereof; promoting blood glucose clearance in an individual in need thereof; promoting or improving glycaemic control in an individual in need thereof; treating pre-diabetes or diabetes in an individual in need thereof; treating type 1 diabetes (T1 D) in an individual in need thereof; promoting blood glucose clearance in an overweight or obese individual; promoting or improving glycaemic control in an overweight or obese individual; treating pre-diabetes or diabetes in an overweight or obese individual; treating type 1 diabetes (T1 D) in an overweight or obese individual; treating insulin resistance in an individual; decreasing food intake in an individual; decreasing caloric intake in an individual; inhibiting appetite in an individual; or treating fatty liver disease in an individual; wherein the medicament is to be administered with a SIK-3 inhibitor.

[0049] In another aspect of the present disclosure there is provided a SIK-3 inhibitor and a metabolic modulator for use for: treating obesity; in an individual in need thereof; treating or minimising the risk of, an obesity-related disease or disorder in an individual suffering from or at risk of suffering from an obesity-related disease or disorder reducing the body weight of an individual in need thereof; preventing or minimising the weight gain of an individual consuming a high energy / caloric diet; preventing or minimising adiposity in individual consuming a high energy / caloric diet; enhancing energy expenditure;100621 1481improving insulin secretion in an individual in need thereof; promoting blood glucose clearance in an individual in need thereof; promoting or improving glycaemic control in an individual in need thereof; treating pre-diabetes or diabetes in an individual in need thereof; treating type 1 diabetes (T1 D) in an individual in need thereof; promoting blood glucose clearance in an overweight or obese individual; promoting or improving glycaemic control in an overweight or obese individual; treating pre-diabetes or diabetes in an overweight or obese individual; treating type 1 diabetes (T1 D) in an overweight or obese individual; treating insulin resistance in an individual; decreasing food intake in an individual; decreasing caloric intake in an individual; inhibiting appetite in an individual; or treating fatty liver disease in an individual.

[0050] In another aspect of the present disclosure there is provided a SIK-3 inhibitor and a metabolic modulator when used for: treating obesity; in an individual in need thereof; treating or minimising the risk of, an obesity-related disease or disorder in an individual suffering from or at risk of suffering from an obesity-related disease or disorder; reducing the body weight of an individual in need thereof; preventing or minimising the weight gain of an individual consuming a high energy / caloric diet; preventing or minimising adiposity in individual consuming a high energy / caloric diet; enhancing energy expenditure; improving insulin secretion in an individual in need thereof; promoting blood glucose clearance in an individual in need thereof; promoting or improving glycaemic control in an individual in need thereof; treating pre-diabetes or diabetes in an individual in need thereof; treating type 1 diabetes (T1 D) in an individual in need thereof; promoting blood glucose clearance in an overweight or obese individual; promoting or improving glycaemic control in an overweight or obese individual;100621 1481treating pre-diabetes or diabetes in an overweight or obese individual; treating type 1 diabetes (T1 D) in an overweight or obese individual; treating insulin resistance in an individual; decreasing food intake in an individual; decreasing caloric intake in an individual; inhibiting appetite in an individual; or treating fatty liver disease in an individual.

[0051] In any aspect of the present invention, the individuals in need thereof are typically those that are overweight, obese, morbidly obese or extremely obese. Preferably, the individual has a BMI greater than 20, 21 , 22, 23, 24, 25, 26, 27, 28 or 29 kg / m2. The individual may have a BMI of between 25 kg / m2to 29.9 kg / m2The individual may have a BMI of 30 kg / m2or greater, or a BMI of 40 kg / m2or greater.

[0052] In any aspect of the present invention, the individuals in need thereof may have been diagnosed with insulin deficiency. In embodiments the individuals have an insulin resistance. In embodiments the individuals have both insulin deficiency and insulin resistance. In embodiments the individuals are pre-diabetic or may have hyperinsulinemia.

[0053] In embodiments the individuals may have mild insulin deficiency, and not require specific treatment with insulin. In embodiments the individuals may have moderate insulin deficiency. In embodiments the individuals may have severe insulin deficiency. In embodiments the individuals have absolute insulin deficiency.

[0054] In any aspects of the present invention the SIK-3 inhibitor and a metabolic modulator is administered to the individual in need thereof after disease onset or diagnosis.

[0055] In any aspects of the present invention, the individual in need thereof may be one who has been identified as being in need of treatment for a prescribed period of time prior to starting treatment according to the methods as described herein. In some embodiments the individual in need thereof has been obese for a prescribed period prior to starting treatment.100621 1481

[0056] In some embodiments the individual in need thereof has been treated by other methods for a prescribed period prior to starting treatment with the methods as described herein.

[0057] In some embodiments the prescribed period is at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months or at least 12 months. In some embodiments the prescribed period is from about 6 months to about 2 years, or from about 1 year to about 5 years. In some embodiments the prescribed period is more than 5 years.

[0058] In an embodiment of any one of the aspects as herein described the obesity- related disease or disorder is selected from the group consisting of obesity, pre-obesity, morbid obesity, Prader-Willi Syndrome, Hypothalamic Injury Associated Obesity, hyperlipidemia, hypertension, pre-diabetes, diabetes, lipodystrophy, lipodema, Bardet- Biedl Syndrome, Cohen Syndrome, cardiovascular disease, arthritis, stroke, metabolic syndrome, hypothyroid and MOMO Syndrome.

[0059] In an embodiment of any one of the aspects as herein described the obesity- related disease or disorder is a disorder the causes or is concomitant with increased adiposity or obesity. For example the obesity-related disease or disorder may be a thyroid condition.

[0060] In an embodiment of any one of the aspects as herein described the individual is an obese and diabetic individual.

[0061] In any method of the disclosure, the obesity is treated, adiposity is reduced, weight gain may be prevented or minimised, or body weight may be reduced without an additional change in diet, or an increase in exercise. However, in any method of the disclosure, the method may further comprise the step of reducing the caloric intake in the individual and / or increasing the level of exercise undertaken by the individual.

[0062] In embodiments of the aspects as herein described the administration of the SIK-3 inhibitor and a metabolic modulator to an individual may suppress appetite in the individual, thereby leading to a reduction of caloric and / or food intake, contributing to treatment of obesity, reduction of adiposity or prevention or minimisation of body weight gain.100621 1481

[0063] In any aspect or embodiment, treating fatty liver disease, such as NAFLD or NASH, may be the partial or complete alleviation, suppression, delay (onset), prevention, amelioration and / or alleviation of fatty liver disease (such as NAFLD or NASH), or one or more symptoms of fatty liver disease (such as NAFLD or NASH).

[0064] In one embodiment, the individual who receives the SIK-3 inhibitor and a metabolic modulator for treating fatty liver disease is an overweight or obese individual, for example an overweight or obese individual as defined herein.

[0065] In another embodiment, the individual who receives the SIK-3 inhibitor and a metabolic modulator for treating fatty liver disease is not an overweight or obese individual, for example not an overweight or obese individual as defined herein.

[0066] In any aspect or embodiment, the fatty liver disease may be any one described herein, including steatosis, nonalcoholic fatty liver disease (NAFLD), Alcoholic fatty liver disease (AFLD), Nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), liver fibrosis caused by fatty liver disease typically NASH, cirrhosis caused by fatty liver disease typically NASH, or hepatocellular carcinoma (HCC) caused by fatty liver disease typically NASH. Preferably the fatty liver disease is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

[0067] In any aspect or embodiment, the SIK-3 inhibitor may be any one described herein.

[0068] In any aspect or embodiment, the metabolic modulator may be any one described herein, including a molecule that acts to increase resistance to weight gain by suppressing appetite and reducing food intake, increase metabolism and / or enhance energy expenditure (for example by acting on adipose tissue), act directly or indirectly in the hypothalamus and / or other tissues to decrease appetite, slow gastric emptying (and therefore prolonging fullness), and / or act through other mechanisms referred to herein. In one embodiment, the metabolic modulator is an appetite suppressant. In a preferred embodiment, the metabolic modulator is a GLP-1 agonist or a leptin receptor agonist.

[0069] In any embodiment, the metabolic modulator may be an appetite suppressant, a weight loss enhancer, a metabolic enhancer, and / or a body fat reducer. In particular, any reference to “a metabolic modulator” in this disclosure may be substituted with “an appetite suppressant”, “a weight loss enhancer”, “a metabolic100621 1481enhancer”, and / or “a body fat reducer”. For example, in the statement above referring to the aspect of the invention that is a method of treating obesity in an individual in need thereof, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby treating obesity in the individual, also provides basis for a method comprising administering a SIK-3 inhibitor and “an appetite suppressant”, “a weight loss enhancer”, “a metabolic enhancer”, and / or “a body fat reducer”. In embodiments the metabolic modulator may act through central appetite regulating mechanisms to improve metabolic health. In embodiments the metabolic modulator is a hormonal therapy.

[0070] As used herein, except where the context requires otherwise, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude further additives, components, integers or steps.

[0071] Further aspects of the present invention and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example and with reference to the accompanying drawings.Brief description of the drawings

[0072] Figure 1 : Expression of SIK-3 in relation to metabolic stress in the hypothalamic ARC. mRNA levels of SIK-1 , SIK-2, and SIK-3 in the hypothalamus of chow- and HFD-fed mice, leptin receptor deficient db / db mice and their heterozygous db / + counterpart. Immunostaining for SIK-3 in the mediobasal hypothalamus of Chow vs HFD-fed 16-week-old male mice and 8-10-week-old male lean db / + and obese db / db mice. Data are mean ± s.e.m, *p < 0.05, **p < 0.01 , ***p<0.001 by two-tailed t- test.

[0073] Figure 2: Diagram of the generation of neuronal specific SIK3 knockout mice (SIK3-NPYKO). Exon 5 was flanked by loxP sites, and a neomycin resistance cassette flanked by FRT sites was inserted upstream from the 5’ loxP site. The neomycin resistance cassette was excised by the expression of the FLP recombinase in vivo. Live disruption of exon 5 flanked by loxP sites was achieved by crossing SIK3 floxed mice with NPY-Cre transgenic mice. DNA was extracted from different tissues (HY: Hypothalamus, HIP: Hippocampus, BS: Brain Stem, CER: Cerebrum, OB: Olfactory100621 1481Bulb, PG: Pituitary gland, BR: Whole brain, LIV: Liver). Recombination of the floxed SIK3 allele was assessed by PCR. Recombination was detected in the hypothalamus, hippocampus, cerebrum, brain stem, olfactory bulb, and brain of SIK3-NPYKO mice. Immunofluorescence analysis showing colocalization of SIK-3 (green) and NPY;Ai9- expression (Red) in the central ARC (Bregma 1 .58-1 .94) of WT vs KO mice.

[0074] Figure 3: WT and SIK3-NPYKO mice were fed on a high fat diet for 10 weeks. Weekly body weight were recorded and fat mass and lean mass were determined by EchoMRI. Dissected weights of individual fat pads from epididymal (eWAT) and inguinal (iWAT) were measured. Data are mean ± s.e.m. *p < 0.05, **p < 0.01 , ***p<0.001 by two-tailed t-test.

[0075] Figure 4: WT and SIK3-NPYKO mice were fed on a high fat diet for 10 weeks. Mice were placed into the Promethion metabolic cages and energy expenditure, daily food intake, RER and Pedestrian meters were recorded. Hypothalamic neuropeptide (AgRP, NPY and POMC) were assessed by qRTPCR. Data are mean ± s.e.m. *p < 0.05, **p < 0.01 , ***p<0.001 by two-tailed t-test.

[0076] Figure 5: WT and SIK3-NPYKO mice were fed on a high fat diet for 10 weeks. Intraperitoneal (i.p.) glucose tolerance test (2g / kg body weight) on 6 h fasted 16- week-old mice fed with HFD. i.p. pyruvate tolerance test (1 g / kg body weight) on 16 h fasted 18-week-old mice fed with HFD. Intraperitoneal insulin tolerance test (0.75 lll / kg body weight) on 6 h fasted 17-week-old mice fed with HFD. Blood glucose levels during each tolerance tests were monitored at 0, 15, 30, 16, 90, and 120 minutes. Results are expressed over the time course as the area under the curve. 16 h / overnight fasted, and 30 minutes re-fed blood glucose levels were measured from WT v SIK3-NPYKO HFD fed mice. Data ± s.e.m. P values by two-way repeated ANOVA or student t test. *p < 0.05, **p < 0.01, ***p<0.001

[0077] Figure 6: Following SIK-3 overexpression in SHSY5Y cells for 72 hours and overnight serum starvation, cells were treated with 100 nm insulin for 15 minutes. Phosphorylated IRS1 (Ser789), Phosphorylated AKT were assessed by Western blot analysis. Western blot analysis showing overexpression of SIK3 in SHSY5Y cells. In p- AKT (S473) densitometry analysis, total-AKT was used as loading control. In p-IRS1 (S789) densitometry analysis, beta-actin was used as a loading control. Data ± s.e.m., n100621 1481= 3-per conditions. P values by student t test. Experiments were repeated in 3 independent biological replicates. *p < 0.05, **p < 0.01 , ***p<0.001

[0078] Figure 7: 8-10-week-old male chow-fed WT v SIK3-NPYKO mice on NPY Ai9TdTomato background were fasted overnight and intraperitoneally injected with 2.5 mll / g insulin for 15 minutes. Consequently, brains were extracted for ARC p-AKT (Ser 473) immunohistochemistry and p-AKT positive NPY neurons quantified across the rostral-caudal extent of the hypothalamus. Data ± s.e.m., P values by student t test. *p < 0.05, **p < 0.01, ***p<0.001.

[0079] Figure 8: SIK-3 inhibitors have similar effects to SIK3-NPYKO knockouts on mRNA and protein expression levels of thermogenic and mitochondrial function / biogenesis markers (UCP-1 ) in Brown adipose tissue (BAT) and hypothalamic neuropeptides. (A) WT and SIK3-NPYKO mice were fed a high fat diet for 10 weeks. Western blot analyses of UCP-1 protein levels in BAT of WT and SIK3-NPYKO mice. Alpha-tubulin was used as a control. Data ± s.e.m., P values by student t test. *p < 0.05, **p < 0.01 , ***p<0.001. (B) BAT from obese mice treated with placebo or YKL-05-099 were isolated. Western blot analysis for UCP-1 protein levels in BAT normalised to Tubulin. Data presented as mean ± SEM (n = 7 placebo vs n = 7 treated with YKL-05- 099), p-values by Student’s t test. *p < 0.05. (C) Hypothalamic neuropeptide (AgRP, NPY and POMC) in SIK3-NPYKO knockout mice were assessed by qRTPCR. Data are mean ± s.e.m. *p < 0.05, **p < 0.01 , ***p<0.001 by two-tailed t-test. (D) Relative hypothalamic mRNA expression of Agrp and Npy of obese mice treated with placebo or YKL-05-099. Results were normalised to the house keeping gene Ppia and shown as fold change relative to the placebo group. Data presented as mean ± SEM (n = 7-9 placebo vs n = 7 treated with YKL-05-099), p-values by Student’s t test. *p < 0.05.

[0080] Figure 9: SIK3-NPYKO mice have less weight gain compared to WT mice when fed a high fat diet and obese mice treated with SIK-3 inhibitors lose weight. (A) Weekly body weight were recorded for SIK3-NPYKO mice and WT mice fed a high fat diet for 10 weeks. (B) Obese mice were treated with YKL-05-099 (18mg / kg of body weight) or placebo for 4 weeks and body weights were measured. (C) Body weights from baseline of placebo or GLPG3970 treatment. Fat mass, lean mass, eWAT, and iWAT in (D) SIK3-NPYKO mice and WT mice fed a high fat diet, (E) Obese mice treated with placebo or YKL-05-099, and (F) Obese mice treated with placebo or GLPG3970.100621 1481

[0081] Figure 10: SIK3-NPYKO mice and mice treated with SIK-3 inhibitors have improved whole body glucose control and clearance compared to WT mice or mice treated with placebo. Intraperitoneal glucose tolerance tests (1 g / kg of body weight) were performed and fasted, and postprandial induced insulin secretion were determined. Blood glucose levels during each tolerance tests were monitored at 0, 15, 30, 16, 90, and 120 minutes. Results are expressed over the time course as the area under the curve. Glucose tolerance test data for (A) SIK3-NPYKO mice compared to WT mice, (B) Mice treated with YKL-05-099 compared to placebo, and (C) Mice treated with GLPG3970 compared to placebo. (D) Insulin secretion in mice treated with YKL-05-099 compared to placebo. Data ± s.e.m. P values by two-way repeated ANOVA or student t test. *p < 0.05, **p < 0.01 , ***p<0.001 .

[0082] Figure 11 : Effects of SIK3 knockout and SIK-3 inhibitors on liver. Photographs of liver and hematoxylin and eosin (H&E) stain of liver tissue from high fat- fed obese mice treated with (A) placebo or YKL-05-099 or (B) placebo or GLPG-3970. (C) Primary hepatocytes were harvested from WT (Sik3lox / lox) and liver-specific SIK3- KO (AlbCre / +Sik3lox / lox) mice. Lipogenesis (lipid production) in WT and liver-specific SIK3-KO primary hepatocytes in response to basal and SIK-3 inhibitor Pterosin B was determined by measuring the incorporation of radiolabelled acetate in the primary hepatocytes. Data presented as mean ± SEM, n = 3 independent experiments (each experiment contains at least three replicates), p-values by two-way ANOVA with Sidak post-hoc test: *p < 0.05 for the difference between genotypes. (D) Primary hepatocytes were harvested from WT (Sik3lox / lox) and liver-specific SIK3-KO (AlbCre / +Sik3lox / lox) mice. Rates of oxygen consumption (JO2) were determined in permeabilised primary hepatocytes isolated from WT and liver-specific SIK3-KO mice. Hepatocytes were incubated in the presence of buffer alone (basal) and 25 or 50 pM palmitoyl-CoA (P- CoA). Data presented as mean ± SEM, n = 3-4 independent experiment per genotype, p-values by Student’s t-test: *p< 0.05. Liver triglyceride levels from (E) high fat-fed obese mice treated with placebo or GLPG397, or (F) with placebo or YKL-05-099.

[0083] Figure 12: Combination treatment with GLPG3970 and Semaglutide offers improved effects in reducing body weight. WT C57BL / 6J mice were fed a high fat diet for 12 weeks starting from 8 weeks of age, and placebo, semaglutide (10 nmol / kg), GLPG3970 (25 mg / kg) or semaglutide+GLPG3970 treatment began at 20 weeks of age. (A) Body weights and (B) percentage body weight loss from baseline of placebo,100621 1481semaglutide, GLPG3970 or semaglutide+GLPG3970 treatment. (C) Mice body weight 17 days after placebo, semaglutide, GLPG3970 or semaglutide+GLPG3970 treatment. Body compositions were measured by Echo MRI. (D) Fat mass and (E) lean mass. Data presented as mean ± SEM (n = 6 from each group), p-values by Student’s t test. *p < 0.05, **p < 0.01, ***p < 0.001.

[0084] Figure 13: Combination treatment with GLPG3970 and leptin offers improved effects in reducing body weight. WT C57BL / 6J mice were fed a high fat diet for 12 weeks starting from 8 weeks of age, and placebo, leptin (0.75 g / kg), GLPG3970 (25mg / kg) or leptin+GLPG3970 treatment began at 20 weeks of age. (A) Body weights and (B) percentage body weight loss from baseline of placebo, leptin, GLPG3970 or leptin+GLPG3970 treatment. Body compositions were measured by Echo MRI. (C) Fat mass and (D) lean mass. Data presented as mean ± SEM (n = 5 from each group), p- values by Student’s t test. *p < 0.05, **p < 0.01 , ***p < 0.001 .

[0085] Figure 14: Co-treatment with SIK-3 inhibitor GLPG3970 and GLP1 therapy Semaglutide offers synergistic effects in improving glycaemic control. C57BL / 6J mice were fed a high fat diet for 12 weeks starting from 8 weeks of age to induce obesity and diabetes. Mice were treated with Semaglutide (Serna, 10nmol / kg), or Semaglutide + GLPG3970 (25mg / kg) at 20 weeks of age. (A) Fasted blood glucose levels from Semaglutide, or Semaglutide + GLPG3970 treated group. (B-C) Oral glucose tolerance tests were performed and area under the curve were determined. Results are expressed over the time course as the area under the curve. Data ± s.e.m. (n=5) P values by two-way repeated ANOVA or student t test. *p < 0.05.

[0086] Figure 15: SIK-3 inhibitor GLPG3970 treatment led to a significant reduction in hepatic steatosis and reverses steatohepatitis (MASH). C57BL / 6J mice were fed a western diet supplemented with cholesterol for 16 weeks. Mice were treated with vehicle or GLPG3970 (25mg / kg) for 4 weeks. (A) Representative photos of liver sections stained with Hematoxylin and Eosin (H&E) or Oil Red O (ORO). (B) Reduced liver steatosis as determined by Oil Red O staining in GLPG3970 treated mice. (C-F) NAFLD activity score (NAS) was calculated based on the assessment of (D) hepatic steatosis, (E) lobular inflammation, and (F) hepatocyte ballooning in H&E-stained liver sections, which were reduced in GLPG3970 treated mice. Data presented as mean ± SEM (n=7-9 / group), P values by two-way repeated ANOVA or student t test. *p < 0.05, **p < 0.01 , ***p < 0.001 , **** p < 0.0001 .100621 1481

[0087] Figure 16: SIK-3 inhibitor GLPG3970 treatment led to a significant reduction in liver fibrosis. C57BL / 6J mice were fed a western diet supplemented with cholesterol for 16 weeks. Mice were treated with vehicle or GLPG3970 (25mg / kg) for 4 weeks. (A) Representative photos of liver sections stained with Picrosirius Red. (B) Reduced liver fibrosis as determined by Picrosirius Red staining in GLPG3970 treated mice. (C) Reduced liver injury in GLPG3970 treated mice as determined by reduced serum ALT levels. Data presented as mean ± SEM (n=7-9 / group), P values by two-way repeated ANOVA or student t test. *p < 0.05, **p < 0.01 , ***p < 0.001 , **** p < 0.0001 .

[0088] Figure 17: Liver-specific SIK3-knockout (SIK3lox / lox, ALBcre / +) led to a significant reduction in hepatic steatosis and suppresses steatohepatitis (MASH) WT (SIK3lox / lox) and liver-specific SIK3-knockout (SIK3lox / lox, ALBcre / +) mice were fed a western diet supplemented with cholesterol for 16 weeks. (A) Representative photos of liver sections stained with Hematoxylin and Eosin (H&E) or Oil Red O (ORO). (B) Reduced liver steatosis as determined by Oil Red O staining in SIK3lox / lox, ALBcre / + mice. (C-F) NAFLD activity score (NAS) was calculated based on the assessment of (D) hepatic steatosis, (E) lobular inflammation, and (F) hepatocyte ballooning in H&E- stained liver sections, which were decreased in SIK3lox / lox, ALBcre / + mice. Data presented as mean ± SEM (n=7-8 / group), P values by two-way repeated ANOVA or student t test. *p < 0.05, **p < 0.01 , ***p < 0.001 , **** p < 0.0001 .

[0089] Figure 18: WT (SIK3lox / lox) and liver-specific SIK3-knockout (SIK3lox / lox, ALBcre / +) mice were fed a western diet supplemented with cholesterol for 16 weeks. (A) Representative photos of liver sections stained with Picrosirius Red. (B) Reduced liver fibrosis as determined by Picrosirius Red staining in SIK3lox / lox, ALBcre / + mice. (C) Reduced liver injury in SIK3lox / lox, ALBcre / + mice as determined by reduced serum ALT levels. Data presented as mean ± SEM (n=7-8 / group), P values by two-way repeated ANOVA or student t test. *p < 0.05, **p < 0.01 , ***p < 0.001 , **** p < 0.0001 .Sequence information

[0090] Table 1 : Sequence details100621 148110062114811006211481Detailed description of the embodiments

[0091] It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.

[0092] One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described.

[0093] All of the patents and publications referred to herein are incorporated by reference in their entirety.

[0094] For purposes of interpreting this specification, terms used in the singular will also include the plural and vice versa.

[0095] The present disclosure relates to methods of treating obesity, reducing body weight and increasing energy expenditure in an individual in need thereof, the method comprising administering a SIK-3 inhibitor and a metabolic modulator, preferably a GLP-1 agonist or a leptin receptor agonist. Surprisingly the inventor(s) have found that administration of a SIK-3 inhibitor and a metabolic modulator to an individual suffering from obesity or an obesity related disorder positively affects the individual thereby treating the obesity or obesity related disorder. Further, the inventor(s) have shown that this beneficial effect is synergistic.

[0096] The synergistic effect of a SIK-3 inhibitor and a metabolic modulator may be more effective in promoting weight loss in severely obese patients. The synergistic effect may also be used to reduce the dose of metabolic modulators that are currently used clinically (e.g. GLP-1 agonist therapy), thereby achieving the same or greater efficacy while reducing side effects. Further, as SIK-3 inhibitors have previously undergone clinical trials for ulcerative colitis and demonstrated improvement, they may reduce gastrointestinal side effects that are associated with currently used metabolic modulators (e.g. GLP-1 agonist therapy). A SIK-3 inhibitor and a metabolic modulator may also be used in individuals who are intolerant of existing treatments with metabolic modulators (for example GLP-1 agonists at a high or low dose). Leptin is the100621 1481most potent appetite suppressing hormone in humans, but a number of clinical trials for use of leptin in weight loss have failed due to leptin resistance. A SIK-3 inhibitor may also sensitize leptin signaling, and increase the efficacy of leptin signaling-based therapies for weight loss.Definitions

[0097] As used herein, the term “condition” refers to a disruption of or interference with normal function, and is not to be limited to any specific condition, and will include diseases or disorders.

[0098] As used herein, ‘preventing’ or ‘prevention’ is intended to refer to at least the reduction of likelihood of the risk of (or susceptibility to) acquiring a disease or disorder (i.e. , causing at least one of the clinical symptoms of the disease not to develop in a patient that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease). Biological and physiological parameters for identifying such patients are provided herein and are also well known by physicians.

[0099] The terms ‘treatment’ or ‘treating’ of a subject includes the application or administration of an inhibitor or composition comprising the inhibitor, as described herein, to a subject (or application or administration of inhibitor or composition comprising the inhibitor to a cell or tissue from a subject) with the purpose of delaying, slowing, stabilizing, curing, healing, alleviating, relieving, altering, remedying, less worsening, ameliorating, improving, or affecting the disease or condition, the symptom of the disease or condition, or the risk of (or susceptibility to) the disease or condition. The term "treating" refers to any indication of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; lessening of the rate of worsening; lessening severity of the disease; stabilization, diminishing of symptoms or making the injury, pathology or condition more tolerable to the subject; slowing in the rate of degeneration or decline; or making the final point of degeneration less debilitating.

[0100] As used herein, the term “subject” or “individual” shall be taken to mean any animal including humans, for example a mammal. Exemplary subjects include but are not limited to humans and non-human primates. For example, the subject is a human.100621 1481

[0101] It will be clearly understood that, although this specification refers specifically to applications in humans, the invention is also useful for veterinary purposes. Thus in all aspects the invention is useful for domestic animals such as cattle, sheep, horses and poultry; for companion animals such as cats and dogs; and for zoo animals. Therefore, the general term "individual” or “individual to be I being treated" is understood to include all animals (such as humans, apes, dogs, cats, horses, and cows).Overweight and obesity

[0102] In any method of the disclosure, the method may further comprise identifying an individual in need thereof. Typically the individual is in need of a reduction in body weight, or reduction in adiposity. The individual may be one who has not displayed a significant reduction in body weight after consuming a reduced caloric diet. The individual may have one or more conditions requiring treatment. For example, the individual may overweight or obese, and also have an impaired ability to clear glucose from the blood. The individual may need a reduction in adiposity and also have insulin resistance.

[0103] In any aspect of the present disclosure, the individuals in need thereof are typically those that are overweight, obese, morbidly obese or extremely obese. Unless the context suggests otherwise, any statement herein referring to “obese” may also equally refer to “morbidly obese” or “extremely obese”. Preferably, the individual has a BMI greater than 20, 21 , 22, 23, 24, 25, 26, 27, 28 or 29 kg / m2. The individual may have a BMI of between 25 kg / m2to 29.9 kg / m2. The individual may have a BMI of 30 kg / m2or greater, or a BMI of 40 kg / m2or greater. Preferably, the individual may have a BMI of 40 kg / m2or greater.

[0104] In any aspect of the present disclosure, the individuals may have been diagnosed as overweight or obese by a physician.

[0105] In any aspect of the present disclosure, the individuals in need thereof may also have an impaired ability to clear glucose from the blood, display a level of insulin resistance and / or be diagnosed with pre-diabetes or type 2 diabetes.

[0106] The term “glycaemic control” refers to maintaining, restoring, or achieving normal or near normal blood glucose levels.100621 1481

[0107] In any aspect of the present disclosure the method of treatment comprising administration of a SIK-3 inhibitor and a metabolic modulator may additionally lead to improved glycaemic control in the individual.

[0108] In any aspect of the present disclosure the individual may be one that has been identified as having an elevated level of circulating insulin. Preferably the level of circulating insulin that is elevated is at a fasting state or is a basal level.

[0109] In any aspect of the present disclosure the individual may be one that has been identified as having an insulin deficiency.

[0110] In embodiments the individuals may have mild insulin deficiency, and not require specific treatment with insulin. In embodiments the individuals may have moderate insulin deficiency. In embodiments the individuals may have severe insulin deficiency. In embodiments the individuals have absolute insulin deficiency. In embodiments the individual may be being administered insulin.

[0111] The terms “obesity” and “being overweight” refers to an excess of fat in proportion to lean body mass. Excess fat accumulation is associated with an increase in size (hypertrophy) as well as number (hyperplasia) of adipose tissue cells. Obesity is variously measured in terms of absolute weight, weightheight ratio, degree of excess body fat, distribution of subcutaneous fat, and societal and aesthetic norms. A common measure of body fat is Body Mass Index (BMI). The BMI refers to the ratio of body weight (expressed in kilograms) to the square of height (expressed in meters). Body mass index may be accurately calculated using the formulas: SI units: BMI=weight(kg) / (height2(m2), or US units: BMI=(weight(lb)*703) / (height2(in2).

[0112] In accordance with the U.S. Centers for Disease Control and Prevention (CDC), an overweight adult has a BMI of 25 kg / m2to 29.9 kg / m2, and an obese adult has a BMI of 30 kg / m2or greater. A BMI of 40 kg / m2or greater is indicative of morbid obesity or extreme obesity. A BMI of 40 kg / m2 or greater may be indicative of morbid obesity or extreme obesity. The individual may be unable to conduct any exercise or be limited in their capacity to do so. In any aspect of the invention, any degree of obesity is diet-induced. For children, the definitions of overweight and obese take into account age and gender effects on body fat.100621 1481

[0113] BMI does not account for the fact that excess adipose can occur selectively in different parts of the body, and development of adipose tissue can be more dangerous to health in some parts of the body rather than in other parts of the body. For example, “central obesity”, typically associated with an “apple-shaped” body, results from excess adiposity especially in the abdominal region, including belly fat and visceral fat, and carries higher risk of co-morbidity than “peripheral obesity”, which is typically associated with a “pear-shaped” body resulting from excess adiposity especially on the hips. Measurement of waist / hip circumference ratio (WHR) can be used as an indicator of central obesity. A minimum WHR indicative of central obesity has been variously set, and a centrally obese adult typically has a WHR of about 0.85 or greater if female and about 0.9 or greater if male.

[0114] In any method of the invention, a reduction in adiposity may be a reduction in central obesity and / or peripheral obesity. In particular, the reduction in adiposity may be a reduction in subcutaneous adiposity. The subcutaneous adiposity may be abdominally located. Alternatively, the reduction in adiposity may be a reduction in visceral adiposity.

[0115] Methods of determining whether a subject is overweight or obese that account for the ratio of excess adipose tissue to lean body mass may involve obtaining a body composition of the subject. Body composition can be obtained by measuring the thickness of subcutaneous fat in multiple places on the body, such as the abdominal area, the subscapular region, arms, buttocks and thighs. These measurements are then used to estimate total body fat with a margin of error of approximately four percentage points. Another method is bioelectrical impedance analysis (BIA), which uses the resistance of electrical flow through the body to estimate body fat. Another method is using a large tank of water to measure body buoyancy. Increased body fat will result in greater buoyancy, while greater muscle mass will result in a tendency to sink. Another method is fan-beam dual energy X-ray absorptiometry (DEXA). DEXA allows body composition, particularly total body fat and / or regional fat mass, to be determined non-invasively.

[0116] The existence of, improvement in, treatment of or prevention of obesity may be by any clinically or biochemically relevant method (e.g. as described herein) of the subject or a biopsy therefrom. For example, treatment may result in a reduction in excess fat, either a reduction in size (hypertrophy) or number (hyperplasia) of adipose100621 1481tissue cells. In addition, or alternatively, there may be an improvement in various measurements of absolute weight, weightheight ratio, degree of excess body fat, distribution of subcutaneous fat, and societal and aesthetic norms. Further, there may be a reduction in Body Mass Index (BMI). Treatment may result in a reduction in adiposity throughout the entire individual or at certain sites. There may be a reduction in central obesity and / or peripheral obesity. In particular, the reduction in adiposity may be a reduction in subcutaneous adiposity. The subcutaneous adiposity may be abdominally located. Alternatively, the reduction in adiposity may be a reduction in visceral adiposity.

[0117] In addition, an improvement in exercise capacity or mobility may be observed. The improvement in exercise capacity or mobility may be a result of a reduction in adiposity and / or body weight.

[0118] An advantage of an aspect of the present invention is that the reduction in body weight and adiposity does not result in a substantial decrease in lean muscle mass nor a substantial reduction in bone density. In one embodiment, the individual retains substantially more muscle mass as compared to body fat reduction in a subject using an energy restricted diet alone. Typically for an effective therapy for treating a subject having an overweight or obese condition, the treatment should reduce adipose tissue without resulting in substantial deleterious side effects, for example, significant wasting. Wasting is characterized by degradation and loss of a substantial amount of lean body mass (muscle tissue, bones, and / or organs) in addition to adipose tissue. In particular, lean body mass refers to structural and functional elements in cells, body water, muscle, bones, and other body organs such as the heart, liver, and kidneys. Although weight loss may involve loss of fat along with slight loss of muscle or fluid, weight loss for the purposes of maintaining health should aim to lose fat while conserving lean body mass. Wasting involves uncontrollable weight loss.

[0119] In an embodiment of any one of the aspects as herein described the obesity- related disease or disorder is selected from the group consisting of obesity, preobesity, morbid obesity, Prader-Willi Syndrome, Hypothalamic Injury Associated Obesity, hyperlipidemia, hypertension, pre-diabetes, diabetes, lipodystrophy, lipodema, Bardet-Biedl Syndrome, Cohen Syndrome, cardiovascular disease, arthritis, stroke, metabolic syndrome, hypothyroid and MOMO Syndrome.100621 1481Browning of white adipose tissue

[0120] Brown adipose tissue is a type of fat that is activated in response to cold temperature. The heat produced by brown and beige adipocytes is essential for the survival of small mammals in cold environments, clothing and adequate shelter in modem humans have largely diminished the need for cold-induced brown and beige thermogenesis.

[0121] White adipose tissue is a fat tissue which stores extra energy. In contrast brown or beige adipose tissue breaks down blood sugar and fat molecules to create heat. The capacity of brown / beige adipocytes to utilise lipids and glucose as a fuel source, and to expend the energy as heat, accompanied by their decreased abundance in older and overweight individuals, has garnered interest in promoting brown and beige fat thermogenesis to combat the obesity epidemic.

[0122] In embodiments of the disclosure, administration of a SIK-3 inhibitor and a metabolic modulator may lead to increased browning of white adipose tissue. In embodiments of the disclosure, administration of a SIK-3 inhibitor and a metabolic modulator may lead to increase in thermogenic gene markers, for example llcp-1 , Dio2, Cidea, Prdm16, Pgc-1a and / or PPARy.

[0123] Advantageously increasing the browning of white adipose tissue in an individual is proposed to increase the energy expenditure of the individual when exposed to cold, subsequently leading to a decrease in body weight.

[0124] In embodiments of the disclosure the method of treatment may increase the energy expenditure of the individual.

[0125] Without wishing to be bound by theory is it proposed that administration of a SIK-3 inhibitor and a metabolic modulator can result in increased energy expenditure due increased browning of white fat and increased thermogenesis of brown fat.Insulin resistance and diabetes

[0126] In another embodiment, the individual in need thereof also has insulin resistance, pre-diabetes or Type II diabetes.100621 1481

[0127] Insulin resistance (IR) is a condition in which the body's cells become less sensitive to the glucose-lowering effects of the hormone insulin. Environmental factors such as physical inactivity, abdominal obesity, diet (e.g., high calorie intake), medications (e.g., Cortisol), hyperglycaemia (glucose toxicity), increased free fatty acids, and the aging process may also contribute. The most common type of insulin resistance is associated with obesity resulting in a condition known as metabolic syndrome.

[0128] In an insulin-resistant person, normal levels of insulin do not have the same effect in controlling blood glucose levels. During the compensated phase in insulin resistance insulin levels are higher, and blood glucose levels are largely maintained. Therefore, in most people with insulin resistance there are normal levels of glucose in the blood but high levels of insulin in the blood. If compensatory insulin secretion fails, then either fasting (impaired fasting glucose) or postprandial (impaired glucose tolerance) blood glucose concentrations increase. Eventually, Type 2 diabetes occurs when blood glucose levels become higher throughout the day as the resistance increases and compensatory insulin secretion fails.

[0129] Type 2 diabetes mellitus is generally characterized by the body's resistance to insulin, caused by the loss or diminished function of insulin receptors that mediate the entrance of insulin into the body's cells. Type 2 diabetes occurs commonly in association with other disorders such as hypertension, dyslipidaemia (includes high LD1 cholesterol, low HDL cholesterol, and high triglycerides) and hypercoagulability. All these problems usually occur in association with obesity, especially abdominal obesity.

[0130] Without wishing to be bound by theory it is proposed that SIK-3 may be a negative regulator of insulin signalling in the brain. Accordingly, SIK-3 inhibition may lead to increased insulin signalling thereby potentially improving glucose regulation, and energy homeostasis.

[0131] Disruption in the normal regulation of glucose can lead to blood glucose levels deviating from, i.e. , elevated or low compared to, normal blood glucose levels. Chronically elevated blood glucose levels, characteristic, for example, of hyperglycaemia, diabetes, can impose multiple detrimental effects on various organs, tissue, and systems of the body. Diabetes, hyperglycaemia, or elevated blood glucose100621 1481levels are associated with numerous disorders and conditions, including accelerated atherosclerosis, increased chronic heart disease, myocardial infarction, stroke, microangiopathy, damage to blood vasculature, peripheral vascular disease leading to decreased circulation in the arms and legs, macrovascular complication, ocular disorders, such as, for example, diabetic retinopathy, macular degeneration, cataracts, etc., kidney disorders, including, diabetic nephropathy, kidney damage, etc., damage to nerves and other neuropathies, including diabetic neuropathy, peripheral neuropathy, damage to nerves of the autonomic nervous system, etc., hyperinsulinaemia, hyperlipidaemia, insulin resistance, skin and connective tissue disorders, foot wounds and ulcerations, diabetic ketoacidosis, etc.

[0132] Altered or impaired glucose regulation, and the presence of or risk for development of disorders including diabetes, hyperglycaemia, etc., can be identified by measurement of circulating glucose or determination of blood / plasma glucose levels. Blood glucose levels are most often measured by a fasting blood glucose test, a random blood glucose test, or an oral glucose tolerance test.

[0133] The methods and compositions of the invention described herein are for promoting, accelerating, increasing the rate of, or improving the clearance, depletion or reduction in blood glucose. Typically, that means that at each time point after an event that leads to an increase in the fasting or basal glucose level of an individual, the level of blood glucose in an individual who has received a SIK-3 inhibitor and a metabolic modulator is less than in an individual that has not received a SIK-3 inhibitor and a metabolic modulator (i.e. a control individual).

[0134] The term "hyperglycaemia" as used herein refers generally to blood glucose concentrations or levels that are above normal. Hyperglycaemia can be determined by any measure accepted and utilized by those of skill in the art. Currently, in humans, normal blood glucose is considered to be between about 70 and 120 mg / dl (3.9 - 6.6 mmol / L), but varies depending on the fasting state. Before a meal, blood glucose can range from about 80 to 120 mg / dl (4.4 - 6.6 mmol / L), whereas two hours after a meal, blood glucose can be at or below about 180 mg / dl (10 mmol / L). Additionally, in fasted individuals, normal blood glucose is below about 110 mg / dl (6.1 mmol / L). A subject having a blood glucose value of about 126 mg / dl (7 mmol / L) or greater is generally considered hyperglycaemic, and a subject whose blood glucose is above about 200 mg / dl (11.1 mmol / L) is generally considered diabetic.100621 1481

[0135] The existence of, improvement in, treatment of or prevention of a disease associated with, or arising from, an impaired ability to clear glucose from the blood may be determined by any clinically or biochemically relevant method of the subject or a biopsy therefrom. For example, a parameter measured may be the presence of a certain level of glucose in the blood or rate or degree of decline of glucose in the blood after a glucose challenge. Typically, that includes blood glucose levels measured by a fasting blood glucose test, a random blood glucose test, or an oral glucose tolerance test.

[0136] A method of treating insulin resistance may result in reversing one or more clinical or biochemical characteristics, or symptoms, of insulin resistance.

[0137] A subject or individual “in need thereof” includes a subject or individual that has (a) an impaired ability to clear glucose from the blood, (b) an elevated fasting level of glucose or insulin, (c) any other condition or disease described herein including, but not limited to, insulin resistance, pre-diabetes, diabetes (preferably type 2 diabetes). Typically, an individual that has (a), (b) and / or (c) is overweight or obese.Fatty liver disease

[0138] Fatty liver disease encompasses a spectrum of liver conditions and is typically classified as either alcoholic or nonalcoholic. In either case, fatty liver disease ranges from simple hepatic steatosis (lipid accumulation and deposition) to steatohepatitis (ASH or NASH), which often progresses to hepatic fibrosis, cirrhosis, and probably hepatocellular carcinoma. Alcoholic fatty liver disease (AFLD) and nonalcoholic fatty liver disease (NAFLD) are histologically indistinguishable; however, by definition NAFLD develops in patients who consume little or no alcohol. Nonalcoholic fatty liver disease (NAFLD) consists of a spectrum of conditions ranging from relatively benign steatosis to more severe non-alcoholic steatohepatitis (NASH), which when untreated can lead to fibrosis, cirrhosis, liver failure, or hepatocellular carcinoma. Updated clinical definitions of fatty liver disease refer to metabolic disfunction- associated steatohepatitis (MASH) and metabolic dysfunction-associated steatotic liver disease (MASLD). In the context of this disclosure, NASH and MASH, and NAFLD and MASLD, are used interchangeably.100621 1481

[0139] As used herein, fatty liver disease means any disease or other deleterious condition characterized by and / or caused by the accumulation of excess liver fat, including (but not limited to) steatosis, nonalcoholic fatty liver disease (NAFLD), Alcoholic fatty liver disease (AFLD), Nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), liver fibrosis caused by fatty liver disease typically NASH, cirrhosis caused by fatty liver disease typically NASH, or hepatocellular carcinoma (HCC) caused by fatty liver disease typically NASH.

[0140] In some embodiments, the NAFLD is steatosis. In some embodiments, the NAFLD is non-alcoholic steatohepatitis (NASH). In some embodiments, the NAFLD is liver fibrosis caused by NASH. In some embodiments, the NAFLD is liver cirrhosis caused by NASH. In some embodiments, the NAFLD is hepatocellular carcinoma (HCC) caused by NASH.

[0141] Non-alcoholic steatohepatitis (NASH) is usually a silent disease with few or no symptoms. Patients generally feel well in the early stages and only begin to have symptoms — such as fatigue, weight loss, and weakness — once the disease is more advanced or cirrhosis develops. The progression of NASH can take years, even decades. NASH can slowly worsen, causing scarring or “fibrosis” to appear and accumulate in the liver. As fibrosis worsens, cirrhosis develops; the liver becomes seriously scarred, hardened, and unable to function normally. A person with cirrhosis experiences fluid retention, muscle wasting, bleeding from the intestines, and liver failure.

[0142] The term "liver fibrosis" means the formation or development of excess fibrous connective tissue (fibrosis) in the liver thereby resulting in the development of scarred (fibrotic) tissue. The scarred tissue replaces healthy tissue by the process of fibrosis and leads to subsequent cirrhosis of the liver.

[0143] The invention includes methods of delaying or reducing progression to liver fibrosis caused by or associated with fatty liver diseases. The liver fibrosis may be associated with or co-morbid to cirrhosis, and associated conditions, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH).

[0144] Severe liver fibrosis, if untreated, may lead to cirrhosis. Cirrhosis may be compensated cirrhosis, where the liver is able to continue working more of less100621 1481normally, and decompensated cirrhosis, where the liver is failing. Symptoms of liver fibrosis may include appetite loss, difficulty thinking clearly, fluid buildup in the legs of stomach, jaundice, nausea, unexplained weight loss and / or weakness. Symptoms of decompensated cirrhosis include ascites, hepatic encephalopathy, bleeding, and jaundice.

[0145] The terms "treatment, treat and treating" of fatty liver disease, such as NAFLD or NASH, refers to the partial or complete alleviation, suppression, delay (onset), prevention, stabilization, amelioration and / or alleviation of fatty liver disease (such as NAFLD or NASH), or one or more symptoms of fatty liver disease (such as NAFLD or NASH). In some embodiments, treatment may be administered after one or more symptoms have occurred.

[0146] In some embodiments, the term "treating" includes preventing or halting the progression of fatty liver disease, such as NAFLD or NASH. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to susceptible individuals prior to the onset of symptoms (eg, due to history of symptoms and / or due to genetic or other predisposition factors).Treatment may also be continued after symptoms have resolved, for example, to prevent or delay their recurrence. Thus, in some embodiments, the term "treating" includes preventing the recurrence of fatty liver disease, such as NAFLD or NASH.

[0147] In one embodiment, the present invention provides a method of reducing or delaying progression of, or worsening of, fatty liver disease in an individual comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby reducing or delaying progression of, or worsening of, fatty liver disease in the individual. In this embodiment, the progression or worsening may be:- NAFLD to NASH;- AFLD to ASH;NAFLD or NASH to liver fibrosis;AFLD to ASH to liver fibrosis;NAFLD or NASH to liver cirrhosis;AFLD or ASH to liver cirrhosis;NAFLD or NASH to hepatocellular carcinoma; or AFLD or ASH to hepatocellular carcinoma.100621 1481

[0148] In an embodiment of the invention, there is provided a method of reducing or supressing steatohepatitis, the method comprising administering to the individual a SIK-3 inhibitor and a metabolic modulator.

[0149] In an embodiment of the invention, there is provided a method of reversing steatohepatitis (MASH), the method comprising administering to the individual a SIK-3 inhibitor and a metabolic modulator.

[0150] Indications of steatohepatitis may include hepatic steatosis, lobular inflammation and hepatocyte ballooning in the liver. It is proposed that administration of a SIK-3 inhibitor and a metabolic modulator can reduce steatosis, inflammation and ballooning, thereby reducing or reversing steatohepatitis.

[0151] In an embodiment of the invention, there is provided a method of reducing or supressing liver fibrosis the method comprising administering to the individual a SIK-3 inhibitor and a metabolic modulator.

[0152] In an aspect of the invention there is provided a method of treating nonalcoholic fatty liver disease in an individual in need thereof, the method comprising administering to the individual a SIK-3 inhibitor and a metabolic modulator.

[0153] In any method of the invention, the method optionally further comprises the step of identifying or diagnosing an individual having fatty liver disease, preferably a fatty liver disease described herein, including NAFLD or NASH.

[0154] In embodiments of the invention the individual in need of treatment has been diagnosed with NAFLD. In embodiments the individual in need of treatment has been diagnosed with NASH. In embodiments the individual in need of treatment has been diagnosed with liver fibrosis. In embodiments the individual in need of treatment has been diagnosed with liver cirrhosis.

[0155] NAFLD can be differentiated from NASH by the assessment of NAFLD activity (NAS), the sum of the histopathology ratings of a liver biopsy for steatosis (0 to 3), lobular inflammation (0 to 2), and hepatocellular embolism (0 to 2). A NAS of <3 corresponds to NAFLD, 3-4 corresponds to bordering NASH, and> 5 corresponds to NASH. Biopsy is also evaluated for fibrosis (0 to 4).100621 1481

[0156] Fibrosis may be characterized by a liver biopsy in 5 stages (0 to 4). The biopsy sample is evaluated and given a score with 0 being no fibrosis, 1 being portal fibrosis without septa, 2 being portal fibrosis with few septa, 3 being numerous septa without cirrhosis and 4 being cirrhosis.

[0157] In embodiments the individual in need of treatment has been diagnosed with a fatty liver disease, such as NAFLD or NASH, and at least one other obesity related disorder. In embodiments the individual is obese.

[0158] In some embodiments, the individual with a fatty liver disease, such as NAFLD or NASH, has pre-diabetes or diabetes, preferably type 2 diabetes.

[0159] In some embodiments, the individual with a fatty liver disease also has insulin resistance.

[0160] There are instances where individuals who are not obese have fatty liver disease, such as those fatty liver diseases defined herein, for example NAFLD or NASH. The administration of a SIK-3 inhibitor and a metabolic modulator is also beneficial for these individuals.

[0161] In alternative embodiments, the individual in need of treatment for a fatty liver disease, such as NAFLD or NASH, is not obese.

[0162] In alternative embodiments, the individual with a fatty liver disease, such as NAFLD or NASH, does not have pre-diabetes or diabetes, preferably type 2 diabetes.

[0163] In alternative embodiments, the individual with a fatty liver disease does not have insulin resistance.Salt-inducible kinase 3

[0164] Salt-inducible kinase 3 (SIK3 or SIK-3) is a serine / threonine protein kinase that regulates multiple signalling pathways involved in metabolic regulation in response to changes in hormonal and nutrient status. SIK3 is widely expressed in the brain, particularly in the arcuate nucleus (ARC) of the hypothalamus, in subsets of anorexigenic pro-opiomelanocortin (POMC) and orexigenic neuropeptide Y (NPY) / agouti-related protein (AgRP)-expressing neurons. Although these two populations of neurons play critical roles in the coordination of energy balance, the100621 1481physiological role of SIK3 in regulating energy balance in NPY / AgRP and POMC neurons remains unknown.

[0165] The inventors have shown that hypothalamic SIK-3 expression is significantly upregulated in diet-induced and genetically obese mice. And that genetic ablation of SIK3 in orexigenic NPY neurons leads to reduced diet-induced weight gain attributed to an increase in energy expenditure. It is therefore proposed that increased SIK-3 may be a key factor contributing to obesity development.

[0166] Without wishing to be bound by theory it is proposed that SIK3 in NPY and POMC neurons is critical for the regulation of body weight through control of energy balance. It is further proposed that inhibition of hypothalamic SIK-3 increases energy expenditure and BAT thermogenesis, resulting in decreasing adiposity and promoting weight loss.SIK-3 inhibitors

[0167] In any aspect of the disclosure, the SIK-3 inhibitor is any inhibitor as described herein. Typically, the inhibitor of SIK-3 is any compound, e.g. small molecule, that inhibits the activity of SIK-3. Preferably, the inhibitor binds to the active of site of SIK-3. Typically SIK-3 inhibitors may also inhibit SIK-1 and / or SIK-2.

[0168] The inhibitor may be specific for SIK family (eg SIK-1 , SIK-2 and SIK-3), and in particular SIK-3, and only have some low level inhibitory activity against other kinases (for example, an Ki of more than about 100pM, preferably more than 1 mM against other kinases as measured using an assay as described herein, or otherwise known in the art). Preferably the inhibitor of SIK-3 is a substance that limits the activity of SIK-3 to 25% or less in comparison with control. Control is a solvent, in which the inhibitor is tested, used at the same quantity however without the inhibitor.

[0169] In embodiments of the disclosure the SIK-3 inhibitor has an Ki value of less than 1 mM, less than 10OpM, less than 10pM, or less than 1 pM.

[0170] In preferred embodiments of the disclosure the SIK-3 inhibitor has an Ki value of less than 100nM, less than 90nM, less than 80nM, less than 70nM, less than 60nM less than 50nM, or less than 40nM.100621 1481

[0171] In preferred embodiments of the disclosure the SIK-3 inhibitor has a Ki for SIK-2 and / or SIK-1 of less than 1 mM, less than 100pM, less than 10pM, less than 1 M, less than 100nM, less than 90nM, less than 80nM, less than 70nM, less than 60nM less than 50nM, or less than 40nM.

[0172] In some embodiments of the disclosure the SIK-3 inhibitor has an Ki of about 30nM. In some embodiments the SIK-3 inhibitor also inhibitors SIK-1 and SIK-2 with a nanomolar Ki.

[0173] In embodiments the potency of the SIK-3 inhibitor is measured in a binding assay measuring the binding to hSIK3. The binding assay may be a commercially available binding assay, for example LanthaScreen® kinase assay. The binding assay may be determined by measuring the binding and displacement of a fluorescence label with a labelled anti-tag antibody which binds to the kinase of interest.Simultaneous binding of both the tracer and antibody to the kinase results in a high degree of FRET (fluorescence resonance energy transfer). Binding of the inhibitor to the kinase competes for binding with the tracer resulting in a loss of FRET. Detailed protocol information may be found from the manufacturer (Life Technologies, catalogue numbers PV6403, PV6404 and PV6405 for example https: / / tools.thermofisher.com / content / sfs / manuals / PV6403_PV6404_PV6405_SIK3_P l.pdf).

[0174] Alternatively, the potency of the SIK-3 inhibitor may be determined by any known assay that measured SIK-3 activity. For example, the SIK3 Kinase System (Promega) contains SIK3 Kinase, 10pg (Human, recombinant; amino acids 1-307). MW: ~62kDa, AMARA Peptide Substrate (1mg / ml), (AMARAASAAALARRR; SEQ ID NO: 11 ), and 5X Reaction Buffer, 0.1 M DTT. It can be used with the ADP-Glo™ kinase assay (Promega). The ADP-Glo™ Kinase Assay is a luminescent kinase assay that measures ADP formed from a kinase reaction; ADP is converted into ATP, which is a substrate in a reaction catalyzed by Ultra-Gio™ Luciferase that produces light. The luminescent signal positively correlates with ADP amount and kinase activity.

[0175] Alternatively, SIK-3 enzymatic activity may be assessed by transfecting cells with PCDNA5-Flag SIK3 vector and cultured for 48 hr to produce SIK3 overexpressed cells. After 48h, SIK3 overexpressed cells are treated with SIK-3 inhibitors. Following FLAG immunoprecipitation, purified SIK3 proteins are subjected to kinase assay for 10100621 1481minutes at 32°C in the presence of [Y-32P]-ATP using AMARAASAAALARRR (SEQ ID NO: 11 ) peptide as a substrate. The reaction is stopped by spotting 15 pL of reaction mix onto p81 phosphocellulose paper and placing it in 1 % phosphoric acid and measuring using a scintillation counter.

[0176] In a further alternative SIK-3 inhibitor activity may be measured by western blotting with a phosphorylation SIK-3 antibody (eg Invitrogen, Cat# PA5-105914) in the catalytic site.

[0177] In some embodiments the inhibitor is selective for SIK-3 and demonstrates higher inhibitory activity for SIK-3 over S IK-1 or SIK-2 or both. For example, the SIK-3 inhibitor may have higher inhibitory activity for SIK-3 and SIK-2 over S IK-1 , or the SIK- 3 inhibitor may have higher inhibitory activity for SIK-3 and S IK-1 over SIK-2.

[0178] In some embodiments the SIK-3 inhibitor has at least the same inhibitory activity for SIK-3 as for SIK-1 and / or SIK-2. In embodiments ICso of the SIK-3 inhibitor for SIK-3 inhibition is the same order of magnitude compared to the ICso for SIK-1 and / or SIK-2.

[0179] In some embodiments the SIK-3 inhibitor has at least 2, or at least 5 or at least 10 or at least 20 or at least 50 times higher inhibitory activity for SIK-3 over SIK- 1 . Alternatively or additionally, the SIK-3 inhibitor has at least 2, or at least 5, or at least 10 times high inhibitory activity for SIK-3 over SIK-2.

[0180] In embodiments the SIK-3 inhibitor is not bosutinib. In embodiments the SIK- 3 inhibitor is not dasatinib.

[0181] In alternative embodiments the SIK-3 inhibitor may also be an inhibitor of related family kinases, for example SIK-1 or SIK-2 or both. In alternative embodiments the SIK-3 inhibitor may inhibit SIK-1 , SIK-2 and SIK-3. In one embodiment, the SIK-3 inhibitor has the same, or similar, selectivity for SIK-3 compared to SIK-1 and / or SIK-2 as any one of the inhibitors described herein, preferably YKL-05-099 or GLPG3970.

[0182] In some embodiments, the SIK-3 inhibitor shows selectivity for SIK family kinases, ie the SIK-3 inhibitor is more potent for inhibition of SIK family kinases, preferably SIK-3 kinase, compared inhibition of other kinases. For example, the SIK-3 inhibitor does not exhibit significant inhibitory activity for kinase ABL (or tyrosine kinase100621 1481ABL). In some embodiments the SIK-3 inhibitor does not show significant activity for BTK (Bruton’s tyrosine kinase) or Src kinase. For example in some embodiments, the SIK-3 inhibitor is more than 50 times, 100 times, 200 times or 250 times less potent against ABL, BTK and / or Src compared to SIK-3. Alternatively, the SIK-3 inhibitor exhibits similar potency as any inhibitor described herein (e.g. GLPG-4399, GLPG- 3970, OMX-0407, Tenalsib, Pterosin B, YKL-05-099, Dasatinib, Bosutinib, Crenolanib, HG-9-91-01 , YKL-06-061 , MRT-199665, ARN-3261 , GLPG 3312, MRIA9, ARN-3236, and YKL-06-062) against ABL, BTK and / or Src compared to SIK-3.

[0183] In some instances, administration of kinase inhibitors with broad activities may have off-target effects. Without wishing to be bound by theory, it is proposed that a SIK-3 inhibitor with a high degree of selectivity for SIK family kinases and particularly SIK-3 may have reduced side effects compared to an inhibitor of multiple kinases.

[0184] The SIK-3 inhibitor may be any inhibitor that inhibits the activity of SIK-3 or reduces the level of SIK-3 in a cell. The inhibitor may be a direct inhibitor of the SIK-3 active site, may act allosterically to inhibit SIK-3 activity, inhibit interaction of SIK-3 with its substrate, or reducing the amount of SIK-3 mRNA or protein present in the cell. For example, the amount of SIK-3 protein levels can be reduced through ubiquitin degradation.

[0185] An inhibitor of SIK-3 may be selected from the group consisting of a small molecule, an antibody, a peptide, an interfering RNA (including an antisense RNA, siRNA, microRNA, or shRNA or a gRNA), a PROTAC, or may be a gRNA for gene editing (for example using CRISPR-Cas9 genome editing methods).

[0186] In any aspect of the present disclosure, the SIK-3 inhibitor is a small molecule. Examples of small molecule SIK-3 inhibitors can be found, for example, as described in US11339166B2, US2022 / 0402911 A1 , US10954242B2, US 20230167116 and US9914735B2.

[0187] Further and non-limiting examples of SIK-3 inhibitors include GLPG-4399, GLPG-3970, OMX-0407, Tenalsib, Pterosin B, YKL-05-099, Dasatinib, Bosutinib, Crenolanib, HG-9-91-01 , YKL-06-061 , MRT-199665, ARN-3261 , GLPG 3312, MRIA9, ARN-3236, and YKL-06-062.100621 1481Chemical structure of Pterosin BChemical structure of YKL-06-061Chemical structure of Dasatinib100621 1481Chemical structure of BosutinibChemical structure of CrenolanibChemical structure of TenalisibChemical structure of MRT199665100621 1481Chemical structure of MRIA9Chemical structure of HG-9-91-01100621 1481of ARN-3236Chemical structure of YKL-06-062Metabolic modulators

[0188] It will be understood that a metabolic modulator may act through a range of mechanisms in an individual. A metabolic modulator may act on the brain, nervous system, pancreas, adipose tissue, or gut, through hormones, neurotransmitters, neuropeptides, and / or signaling peptides. The skilled person will understand that because metabolism and appetite interact through regulatory and feedback pathways that maintain energy homeostasis, action through one mechanism often has effects through other mechanisms. For example, a metabolic modulator may increase resistance to weight gain by suppressing appetite and reducing food intake, increase metabolism and / or enhance energy expenditure (for example by acting on adipose tissue), act directly in the hypothalamus to decrease appetite, slow gastric emptying (and therefore prolonging fullness), and / or act through other mechanisms. The skilled person will understand that the examples described are not limiting, and that action of the metabolic modulator may occur through one or multiple mechanisms.

[0189] In one embodiment, the metabolic modulator is an appetite suppressant. In an embodiment the metabolic modulator is an anorectic.100621 1481

[0190] In one embodiment the metabolic modulator is a hormonal therapy. The hormone may be a peptide. In one embodiment, the metabolic modulator is an endogenous hormone. In one embodiment the hormonal therapy acts via hypothalamic appetite and energy balance pathways.

[0191] In some embodiments, the metabolic modulator may be a GLP-1 agonist, a leptin receptor agonist, an amphetamine-type stimulant, Naltrexone / bupropion, phenterm ine / topiramate, metformin, a sodium-glucose transport protein 2 (SGLT2) inhibitor, sulfonylureas, insulin, and / or other molecules that modulate metabolic pathways.

[0192] In one embodiment, the metabolic modulator is a GLP-1 agonist or a leptin receptor agonist.

[0193] In another embodiment, the metabolic modulator is metformin.

[0194] In an embodiment, the metabolic modulator is not a senolytic. In an embodiment the metabolic modulator is not quercetin.Combination of SIK-3 and metabolic modulators

[0195] Without wishing to be bound by theory it is proposed that SIK-3 inhibition engages a unique molecular mechanism which, advantageously, when combined with a metabolic modulator is surprisingly efficacious. SIK-3 functions as a central regulator of the leptin and insulin signalling axis, integrating metabolic cues across multiple tissues, including hypothalamic neurons, liver, adipose tissue, and pancreatic [3-cells. It is proposed that selective inhibition of SIK-3 modulates these pathways and may restore leptin sensitivity, increase energy expenditure and reduce appetite to promote weight loss and improve metabolic health.

[0196] It is therefore proposed that combination of SIK-3 inhibitors with a metabolic modulator such as leptin can further promote appetite reduction to promote weight loss and improve metabolic health compared to sole administration of SIK-3 or leptin, or administration of alternative metabolic modulators which do not restore leptin sensitivity, or even reduce leptin sensitivity.

[0197] Without wishing to be bound by theory it is proposed that the advantageous combination of SIK-3 inhibitor with a metabolic modulator may arise from action on100621 1481neuroendocrine circuits in the arcuate nucleus of the hypothalamus, directly regulating appetite, satiety and energy expenditure. Metabolic modulators such as leptin agonists, GLP-1 receptor agonists or other appetite suppressants may promote weight loss primarily via central appetite suppression and energy balance modulation.

[0198] This is in contrast to antioxidants or senolytic compounds which do not have known activity on central appetite controlling pathways.In embodiments of the invention the metabolic modulator is a leptin agonist. Without wishing to be bound by theory it is proposed that administration of a leptin agonist directly enhances leptin receptor signalling and administration of a SIK-3 inhibitor modulates key metabolic pathways to restore leptin sensitivity. Accordingly, it is proposed that the dual administration is able to synergistically enhance appetite suppression and increase energy expenditure.GLP-1 agonists

[0199] The term “GLP-1 agonist” as used herein refers to a compound, which fully or partially activates the human GLP-1 receptor. The term is thus equal to the term “GLP-1 receptor agonist”. The term GLP-1 agonist as well as the specific GLP-1 agonists described herein are meant to encompass also salt forms thereof.

[0200] It follows that the GLP-1 agonist should display “GLP-1 activity” which refers to the ability of the compound, i.e. a GLP-1 analogue or a compound comprising a GLP- 1 analogue, to bind to the GLP-1 receptor and initiate a signal transduction pathway resulting in insulinotropic action or other physiological effects as is known in the art. In some embodiments the “GLP-1 agonist” binds to a GLP-1 receptor, e.g., with an affinity constant (KD) or activate the receptor with a potency (ECso) of below 1 mM, e.g. below 100 nM as measured by methods known in the art (see e.g. WO 98 / 08871 ) and exhibits insulinotropic activity, where insulinotropic activity may be measured in vivo or in vitro assays known to those of ordinary skill in the art. For example, the GLP-1 agonist may be administered to an animal with increased blood glucose (e.g. obtained using an Intravenous Glucose Tolerance Test (IVGTT). A person skilled in the art will be able to determine a suitable glucose dosage and a suitable blood sampling regime, e.g. depending on the species of the animal, for the IVGTT) and measure the plasma insulin concentration over time.100621 1481

[0201] Suitable assays have been described in such as WO2015 / 155151 .

[0202] The term half maximal effective concentration (ECso) generally refers to the concentration which induces a response halfway between the baseline and maximum, by reference to the dose response curve. ECso is used as a measure of the potency of a compound and represents the concentration where 50% of its maximal effect is observed.

[0203] The in vitro potency of the GLP-1 agonist may be determined as described in WO201 5 / 155151 , Example 29 (without HSA) and the ECso determined. The lower the ECso value, the better the potency. In one embodiment the potency (EC50) as determined (without HSA) is 5-1000 pM, such as 10-750 pM, 10-500 pM or 10-200 pM. In one embodiment the EC50 (without HSA) is at most 500 pM, such as at most 300 pM, such as at most 200 pM.

[0204] In one embodiment the EC50 (without HSA) is comparable to human GLP-1 (7-37).

[0205] In one embodiment the EC50 (without HSA) is at most 50 pM. In a further such embodiment the EC50 is at most 40 pM, such as at most 30 pM such as at most 20 pM, such as at most 10 pM. In one embodiment the EC50 is around 10 pM.

[0206] If desired, the fold variation in relation to a known GLP-1 receptor agonist may be calculated as ECso(test analogue) / EC5o(known analogue), and if this ratio is such as 0.5- 1 .5, or 0.8-1 .2 the potencies are considered to be equivalent.

[0207] Semaglutide and tirzepatide (a GLP-1 and glucose-dependent insulinotropic polypeptide dual agonist) have been approved by the FDA for use in type 2 diabetes and chronic weight management in obese adults. A number of other GLP-1 agonists have also been approved (for example lixisenatide for type 2 diabetes), or are undergoing clinical trials, for example orforglipron for weight loss. Without being limited by the examples described, the skilled person understands that other GLP-1 agonists that are known that may also be used in some embodiments of the invention.

[0208] In one embodiment the potency, EC50 (without HSA), is equivalent to the potency of liraglutide.100621 1481

[0209] In one embodiment the potency, ECso (without HSA), is equivalent to the potency of semaglutide.

[0210] In one embodiment the potency, ECso (without HSA), is equivalent to the potency of tirzepatide.

[0211] In some embodiments the GLP-1 agonist is a GLP-1 analogue, optionally comprising one substituent. The term "analogue" as used herein referring to a GLP-1 peptide (hereafter “peptide”) means a peptide wherein at least one amino acid residue of the peptide has been substituted with another amino acid residue and / or wherein at least one amino acid residue has been deleted from the peptide and / or wherein at least one amino acid residue has been added to the peptide and / or wherein at least one amino acid residue of the peptide has been modified. Such addition or deletion of amino acid residues may take place at the N-terminal end of the peptide and / or at the C- terminal end of the peptide. In some embodiments a simple nomenclature is used to describe the GLP-1 agonist, e.g., [AibS] GLP-1 (7-37) designates an analogue of GLP-1 (7-37) wherein the naturally occurring Ala in position 8 has been substituted with Aib. In some embodiments the GLP-1 agonist comprises a maximum of twelve, such as a maximum of 10, 8 or 6, amino acids which have been altered, e.g., by substitution, deletion, insertion and / or modification, compared to e.g. GLP-1 (7-37). In some embodiments the analogue comprises up to 10 substitutions, deletions, additions and / or insertions, such as up to 9 substitutions, deletions, additions and / or insertions, up to 8 substitutions, deletions, additions and / or insertions, up to 7 substitutions, deletions, additions and / or insertions, up to 6 substitutions, deletions, additions and / or insertions, up to 5 substitutions, deletions, additions and / or insertions, up to 4 substitutions, deletions, additions and / or insertions or up to 3 substitutions, deletions, additions and / or insertions, compared to e.g. GLP-1 (7-37). Unless otherwise stated the GLP-1 comprises only L-amino acids.

[0212] In some embodiments the term “GLP-1 analogue” or “analogue of GLP-1” as used herein refers to a peptide, or a compound, which is a variant of the human Glucagon-Like Peptide-1 (GLP-1 (7-37)). GLP-1 (7-37) has the sequence HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG (SEQ ID NO: 1 ). In some embodiments the term “variant” refers to a compound which comprises one or more amino acid substitutions, deletions, additions and / or insertions.100621 1481

[0213] In one embodiment, the GLP-1 agonist is an orthologue or paralogue of a human Glucagon-Like Peptide-1.

[0214] In one embodiment the GLP-1 agonist exhibits at least 60%, 65%, 70%, 80% or 90% sequence identity to GLP-1 (7-37) over the entire length of GLP-1 (7-37). As an example of a method for determination of sequence identity between two analogues the two peptides [Aib8] GLP-1 (7-37) and GLP-1 (7-37) are aligned. The sequence identity of [Aib8] GLP-1 (7-37) relative to GLP-1 (7-37) is given by the number of aligned identical residues minus the number of different residues divided by the total number of residues in GLP-1 (7-37).

[0215] Accordingly, in said example the sequence identity is (31 -1 ) / 31 .

[0216] In one embodiment the C-terminal of the GLP-1 agonist is an amide.

[0217] In some embodiments the GLP-1 agonist is GLP-1 (7-37) or GLP-1 (7-36) amide. In some embodiments the GLP-1 agonist is exendin-4, the sequence of which is HGEGTFITSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS (SEQ ID NO: 3).

[0218] In order to prolong the effect of the GLP-1 agonist it is preferred that the GLP-1 agonist have an extended half-life. The half-life can be determined by method known in the art and in an appropriate model, such as in Male Sprague Dawley rats or minipigs as described in W02012 / 140117. In one embodiment the GLP-1 agonist according to the invention has a half-life above 24 hours in minipig. In one embodiment the GLP-1 agonist according to the invention has a half-life above 30 hours, such as above 36 hours, such as above 42 hours, such as above 48 hours, such as above 54 hours or such as above 60 hours in minipig.

[0219] In some embodiments the GLP-1 agonist comprises one substituent which is covalently attached to the peptide. In some embodiments the substituent comprises a fatty acid or a fatty diacid. In some embodiments the substituent comprises a C16, C18 or C20 fatty acid. In some embodiments the substituent comprises a C16, C18 or C20 fatty diacid.100621 1481

[0220] In some embodiments the substituent comprises formula (X)wherein n is at least 13, such as n is 13, 14, 15, 16,17, 18 or 19. In some embodiments the substituent comprises formula (X), wherein n is in the range of 13 to 19, such as in the range of 13 to 17. In some embodiments the substituent comprises formula (X), wherein n is 13, 15 or 17. In some embodiments the substituent comprises formula (X), wherein n is 13. In some embodiments the substituent comprises formula (X), wherein n is 15. In some embodiments the substituent comprises formula (X), wherein n is 17.

[0221] In some embodiments the substituent comprises formula (Xia) HOOC- (C6H4)-O-(CH2)m-CO-* (Xia), wherein m is an integer in the range of 6-14.

[0222] In some embodiments the substituent comprises formula (Xlb)(Xlb), wherein the carboxy group is in position 2, 3 or 4 of the (CeH4) group and wherein m is an integer in the range of 8-11 .

[0223] In some embodiments the substituent comprises formula (Xia) or formula (Xlb), wherein m is in the range of 6 to 14, such as in the range of 8 to 11 . In some embodiments the substituent comprises formula (Xia) or formula (Xlb), wherein m is 8, 10 or 12. In some embodiments the substituent comprises formula (Xia) or formula (Xlb), wherein m is 9. In some embodiments the substituent comprises formula (Xia) or formula (Xlb), wherein m is 11.

[0224] In some embodiments the substituent comprises one or more 8-amino-3,6- dioxaoctanoic acid (OEG), such as two OEG.100621 1481

[0225] In some embodiments the substituent is [2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17- carboxyheptadecanoylamino) butyrylamino]ethoxy}ethoxy)acetylamino] ethoxy}ethoxy)acetyl].

[0226] In some embodiments the substituent is [2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4- [(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl} am ino)butyrylam ino]ethoxy}ethoxy)acetylam ino]ethoxy}ethoxy)acetyl].

[0227] In some embodiments the GLP-1 agonist is semaglutide, also known as N- epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17- carboxyheptadecanoylam ino)butyrylam ino]ethoxy}ethoxy)acetylam ino]ethoxy}ethoxy)ac etyl][Aib8,Arg34]GLP-1 (7-37) which may be prepared as described in W02006 / 097537, Example 4 with the following structure:

[0228] In some embodiments the GLP-1 agonist is tirzepatide (LY3298176, UNII: OYN3CCI6QE, CAS: 2023788-19-2), which may be prepared as described in WO201 6 / 111971 , or in Frederick et al (2021 ) Organic Process Research & Development, 25(7): 1628-1636, and has the following structure:100621 1481

[0229] In some embodiments the GLP-1 agonist is Liraglutide, the sequence of which is HAEGTFTSDVSSYLEGQAAKEEFIAWLVRGRG (SEQ ID NO: 2). Liraglutide and methods of preparing liraglutide are known in the art (for example, as described in WO201 6 / 046753 or WO2017 / 162650).

[0230] In some embodiments the GLP-1 agonist is exenatide, a synthetic formulation of Exendin-4 (SEQ ID NO: 3). Exenatide and methods of preparing exenatide are known in the art (for example, as described in US2013 / 0289241 ).

[0231] In some embodiments the GLP-1 agonist is dulaglutide, the sequence of which is HGEGTFTSDVSSYLEEQAAKEFIAWLVKGGGGGGGSGGGGSGGGGSAESKYGPPC PPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKG QPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO: 4). The structure, function, production and use of dulaglutide are described in US 7 , 452 , 966 and U S2010 / 0196405.

[0232] In some embodiments the GLP-1 agonist is lixisenatide, the sequence of which is HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK (SEQ ID NO: 5). The structure, function, production and use of lixisenatide are described in WO 01 / 04156 (as SEQ ID NO: 93), USRE45313, WO2010 / 043566, WO2011 / 058082, WO201 1 / 058083, WO2016 / 092026.

[0233] In some embodiments the GLP-1 agonist is albiglutide, the sequence of which is HGEGTFTSDVSSYLEGQAAKEFIAWLVKGRHGEGTFTSDVSSYLEGQAAKEFIAWLVK GRDAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVAD ESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLP RLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAA DKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFA EVSKLVTDLTKVHTECCHGDLLECADDRADLAKYICENQDSISSKLKECCEKPLLEKSH CIAEVENDEMPADLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSVVLL LRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQN ALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAEDYLSWLNQLCVL100621 1481HEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHADICTLSEKERQ IKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLVAASQ AALGL (SEQ ID NO: 6). Albiglutide is a GLP-1 receptor agonist developed by fusion of two DPP-4- resistant human GLP-1 analogs to human albumin as described in Matthews et al. (2008) J Clin Endocrinol Metab., 93(12):4810-7. The structure, function, production and use of albiglutide are described in WO 2007 / 056681 and WO201 0 / 068735.

[0234] In one embodiment the GLP-1 agonist is GLP-1 agonist B, which is diacylated [Aib8,Arg34,Lys37]GLP-1 (7-37) as shown in Example 2 of WO2011 / 080103 and named A / s262-[2-(2-{2-[2-(2-{(S)-4-Carboxy-4-[10-(4- carboxyphenoxy)decanoylam ino]butyrylam ino}- ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl}, A / s37{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4- [10-(4- carboxyphenoxy)decanoylam ino]butyrylam ino}ethoxy)ethoxy]acetylam ino}ethoxy)ethox y]- acetyl}-[Aib8,Arg34,Lys37]GLP-1 (7-37)-peptide with the following structure.

[0235] In one embodiment the GLP-1 agonist is GLP-1 agonist C which is Diacylated [Aib8,Glu22,Arg26,Lys27,Glu30,Arg34,Lys36]-GLP-1 -(7-37)-peptidyl-Glu-Gly as shown in Example 31 of W02012 / 140117 and named Ns27-[2-[2-[2- [[2-[2-[2-[[(4S)-4- carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino] ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]-acetyl], A / s36-[2-[2-[2-[[2-[2-[2-[[(4S)-4- carboxy-4- [10-(4-carboxyphenoxy)decanoylamino]- butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]- [Aib8,Glu22,Arg26,Lys27, Glu30,Arg34,Lys36]-GLP-1-(7-37)-peptidyl-Glu-Gly with the following structure100621 1481

[0236] In general the term GLP-1 agonist is meant to encompass the GLP-1 agonist and any pharmaceutically acceptable salt, amide, or ester thereof.

[0237] In some embodiments the composition comprises the GLP-1 agonist or a pharmaceutically acceptable salt, amide, or ester thereof.

[0238] In some embodiments the composition comprises the GLP-1 agonist and one or more pharmaceutically acceptable counter ions.

[0239] In some embodiments the GLP-1 agonist is selected from one or more of the GLP-1 agonists mentioned in WO93 / 19175, WO96 / 29342, WO98 / 08871 , WO99 / 43707, WO99 / 43706, WO99 / 43341 , WO99 / 43708, W02005 / 027978, W02005 / 058954, W02005 / 058958, W02006 / 005667, W02006 / 037810, W02006 / 037811 , W02006 / 097537, W02006 / 097538, W02008 / 023050, W02009 / 030738, W02009 / 030771 and W02009 / 030774.

[0240] In some embodiments the GLP-1 agonist is selected from the group consisting of N- epsilon37{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1 -(19-carboxynonadecanoyl) piperidine-4- carbonyl]am inojpropionylam ino)ethoxy]ethoxy}acetylam ino)ethoxy]ethoxy}acetyl[desam inoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1 (7-37)amide; N-epsilon26{2-[2-(2-{2-[2-((R)- 3-carboxy-3-{[1 -(19-carboxynonadecanoyl) piperidine-4- carbonyl]am inojpropionylam ino)ethoxy]ethoxy}acetylam ino)ethoxy] ethoxyjacetyl [desaminoHis7, Arg34] GLP-1 -(7-37); N-epsilon37{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1 - (19-carboxy-nonadecanoyl) piperidine-4-carbonyl]amino}propionylamino)ethoxy] ethoxy} acetylamino)ethoxy]ethoxy}acetyl[Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1 -(7- 37)amide; N-epsilon37-[2-(2-[2-(2-[2- (2-((R)-3-[1 -(17-carboxyheptadecanoyl)piperidin-100621 14814-ylcarbonylamino]3- carboxypropionylamino)ethoxy)ethoxy]acetylamino)ethoxy] ethoxy )acetyl][,DesaminoHis7, Glu22 Arg26, Arg 34, Phe(m-CF3)28]GLP-1 -(7-37)amide; N- epsilon26-[(S)-4-carboxy-4- ({trans-4-[(19- carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyryl][Aib8,Arg34]GL P-1 -(7-37); N-epsilon26-{4-[(S)-4- carboxy-4-({trans-4-[(19-carboxynonadecanoylamino) methyl]cyclohexanecarbonyl} amino)butyrylamino]butyryl}[Aib8,Arg34]GLP-1 -(7-37); N- epsilon26-[2-(2-{2-[(S)-4-carboxy-4- ({trans-4-[(19-carboxy-nonadecanoylamino) methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP -1 -(7-37); N-epsilon26-[2-(2-{2-[2- (2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy- nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)ac etylamino]ethoxy}ethoxy) acetyl][Aib8,Arg34]GLP-1 -(7-37)amide; N-epsilon37-[2-(2-{2- [2-(2-{2-[(S)-4-carboxy-4- ({trans-4-[(19-carboxy- nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)ac etylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1 -(7-37)amide; N- epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4- [(19-carboxy- nonadecanoylam ino)methyl]cyclohexanecarbonyl}am ino) butyrylam ino] ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Ly s37]GLP-1 -(7-37)amide; N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({4- [(trans-19- carboxy- nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)ac etylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Arg26,Arg34,L ys37]GLP-1 -(7- 37)amide; N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19- carboxy- nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)ac etylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,A rg34, Lys37]GLP-1 -(7- 37); N-epsilon26[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({4-[(19-carboxy- nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino] ethoxyjethoxy) acetylamino]ethoxy}ethoxy)acetyl[Aib8, Lys 26]GLP-1 (7-37)amide; N-epsilon26 [2-(2- [2-(2- [2-(2-((S)-2-[trans-4-((9-carboxynonadecanoylamino] methyl) cyclohexylcarbonylam ino]-4- carboxybutanoylam ino)ethoxy)ethoxy]acetylam ino) ethoxy]ethoxy)acetyl][Aib8, Lys26] GLP-1 (7-37)amide; N-epsilon37-[2-(2-{2-[2-(2-{2- [(S)-4-carboxy-4-({trans-4-[(19-carboxy- nonadecanoylamino)methyl]cyclohexane- carbonyljam ino)butyrylam ino]ethoxy}ethoxy)acetylam ino]ethoxy}ethoxy)acetyl][Desam in 0His7,Arg26,Arg34,Lys37]GLP-1 -(7-37); N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4- carboxy-4- ({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}100621 1481am ino)butyrylam ino]ethoxy}ethoxy)acetylam ino]ethoxy}ethoxy)acetyl][Desam inoH is7, Gl u22, Arg26,Glu30,Arg34,Lys37]GLP-1 -(7-37); N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4- ((S)-4- carboxy-4-{4-[4-(16-(1 H-tetrazol-5-yl)-hexadecanoylsulfamoyl)butyrylamino]- butyrylaminojbutyrylamino) butyrylamino] ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1 -(7- 37); N- epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1 H-tetrazol-5- yl)hexadecanoyl- sulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)ace tyl][Aib8,Arg34]GLP-1 -(7-37); N-epsilon26-[2-(2-{2-[(S)-4- carboxy-4-((S)-4-carboxy-4- {6-[4-(16-(1 H-tetrazol-5-yl)hexadecanoyl- sulfamoyl)butyrylamino]hexanoylamino} butyrylamino)butyrylamino]ethoxy}ethoxy) acetyl][Aib8,Arg34]GLP-1 -(7-37); N- epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{4- [4-(16-(1 H-tetrazol-5- yl)hexadecanoylsulfamoyl)butyrylamino]butyrylamino}butyrylamino)butyrylamino]ethoxy} ethoxy)acetyl][Aib8,Arg34]GLP-1 -(7-34); N- epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4- carboxy-4-{12-[4-(16-(1 H-tetrazol-5- yl)hexadecanoylsulfamoyl)butyrylamino]- dodecanoylaminojbutyrylamino) butyrylamino] ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1 - (7-34); N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4- carboxy-4-{6-[4-(16-(1 H-tetrazol-5- yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino) butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1 -(7-34); N-epsilon26-[2-(2-{2-[(S)- 4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16- (1 H-tetrazol-5-yl)hexadecanoyl- sulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)ace tyl][Aib8,Arg34]GLP-1 -(7-35); N-epsilon26-[2- (2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4- {6-[4-(16-(1 H-tetrazol-5- yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino} butyrylamino)butyrylamino] ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1 -(7-35); N- epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4- carboxy-4-{6-[4-(16-(1 H-tetrazol-5- yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]etho xy}ethoxy)acetyl][Aib8,Arg34]GLP-1 -(7- 36)amide; N-epsilon26-[2-(2-{2-[(S)-4-carboxy- 4-((S)-4-carboxy-4-{6-[4-(16-(1 H-tetrazol-5- yl)hexadecanoylsulfamoyl) butyrylam ino]hexanoylam inojbutyrylam ino)butyrylam ino]ethoxy}ethoxy)acetyl][Aib8, Arg 34]GLP-1 -(7-35); N-epsilon26-[2-(2-{2-[(S)-4- carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1 H-tetrazol-5-yl)hexadecanoyl- sulfamoyl)butyrylamino]dodecanoylamino}butyryl- amino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Lys33,Arg34]GLP-1-(7-34); N- epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4- carboxy-4-{12-[4-(16-(1 H-tetrazol-5- yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]et hoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1 -(7- 36)amide; N-epsilon26-[2-(2-{2-[2-(2-{2-[2-(2-100621 1481{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4- ((S)-4-carboxy-4-{12-[4-(16-(1 H-tetrazol-5- yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino) butyrylam ino]ethoxy}ethoxy)acetylam ino]ethoxy}ethoxy)acetylam ino]ethoxy}ethoxy)acet ylam ino]ethoxy}ethoxy)acetylam ino]ethoxy}ethoxy)acetylam ino]ethoxy}ethoxy)acetyl][Ai b8,Lys26,Arg34]GLP-1 -(7-36)amide; N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4- carboxy-4-{12-[4-(16-(1 H-tetrazol-5- yl)hexadecanoylsulfamoyl)butyrylamino] dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,A rg34,Lys37]GLP-1 -(7-37)amide; N- epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy- 4-{12-[4-(16-(1 H-tetrazol-5- yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino) butyrylamino] ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1 -(7-37)amide; N- epsilon37{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1 -(19-carboxy-nonadecanoyl) piperidine-4- carbonyl]am inojpropionylam ino)ethoxy]ethoxy} acetylam ino)ethoxy] ethoxy}acetyl[desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1 (7-37)amide; N- epsilon37{2-[2-(2-{2-[2-((S)- 3-carboxy-3-{[1 -(19-carboxynonadecanoyl) piperidine-4- carbonyl]amino} propionylamino) ethoxy]ethoxy}acetylamino)ethoxy] ethoxy} acetyl [Aib8,Glu22, Arg26,Arg34, Lys37]GLP-1 - (7-37)amide; N-epsilon37-[2-(2-[2-(2-[2-(2- ((R)-3-[1 -(17-carboxyhepta-decanoyl)piperidin-4- ylcarbonylamino]3-carboxy- propionylamino) ethoxy)ethoxy] acetylamino) ethoxy]ethoxy)acetyl] [DesaminoHis7, Glu22,Arg26, Arg34,Phe(m-CF3)28] GLP-1 -(7-37)amide; N- epsilon37-[2-(2-{2-[2-(2-{2- [(S)-4-carboxy-4-({trans-4-[(19-carboxy- nonadecanoylamino)methyl] cyclohexanecarbonyl} am ino)butyrylam ino]ethoxy}ethoxy )acetylam ino] ethoxy}ethoxy)acetyl] [Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1 -(7- 37)amide; N- epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy- nonadecanoylamino)methyl]cyclohexane-carbonyl} amino)butyrylamino]ethoxy}ethoxy) acetylamino]ethoxy}ethoxy)acetyl] [DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1 -(7- 37)amide; N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy- nonadecanoylamino)methyl] cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy) acetylam ino]ethoxy} ethoxy)acetyl] [DesaminoHis7,Glu22,Arg26,Arg34, Lys37]GLP-1 - (7-37); N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy- nonadecanoylamino) methyl]cyclohexane-carbonyl}amino)butyrylamino]ethoxy}ethoxy) acetylamino]ethoxy}ethoxy)acetyl] [DesaminoHis7,Glu22,Arg26,Glu30,Arg34, Lys37]GLP-1 -(7-37); N- epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16- (1 H-tetrazol-5- yl)hexadecanoyl-sulfamoyl) butyrylam ino]dodecanoylam ino}100621 1481butyrylamino) butyrylamino] ethoxy}ethoxy)acetyl] [Aib8,Glu22,Arg26,Arg34,Lys37]GLP- 1-(7-37)amide; N-epsilon37-[2- (2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1 H- tetrazol-5-yl)hexadecanoylsulfamoyl) butyrylamino]dodecanoylamino}butyrylamino) butyrylamino] ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7- 37)amide; N-epsilon37-(3-((2-(2-(2-(2- (2-Hexadecyloxyethoxy)ethoxy)ethoxy) ethoxy) ethoxy))propionyl)[DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1 (7-37)-amide; N- epsilon37-{2-(2- (2-(2-[2-(2-(4-(hexadecanoylamino)-4-carboxybutyryl-amino)ethoxy) ethoxy]acetyl)ethoxy)ethoxy)acetyl)}-[desaminoHis7,Glu22,Arg26, Glu30,Arg34,Lys37] GLP-1 -(7- 37)amide; N-epsilon37-{2-(2-(2-(2-[2-(2-(4-(hexadecanoylamino)-4-carboxy- butyryl-amino) ethoxy )ethoxy]acetyl)ethoxy)ethoxy) acetyl)}-[desaminoHis7,Glu22, Arg26, Arg34,Lys37]GLP-1-(7-37)amide; N-epsilon37-(2-(2-(2-(2-(2-(2-(2-(2-(2- (octadecanoyl- amino)ethoxy)ethoxy) acetylamino)ethoxy) ethoxy)acetylamino) ethoxy )ethoxy)acetyl)[desaminoHis7,Glu22,Arg26,Arg34,Lys37] GLP-1 (7-37)amide; N- epsilon37-[4-(16- (1 H-Tetrazol-5-yl)hexadecanoylsulfamoyl) butyryl] [DesaminoHis7,Glu22,Arg26, Arg34, Lys37]GLP-1-(7-37)amide; N-epsilon37-[2-(2-{2- [2-(2-{2-[(S)-4-carboxy-4-(19- carboxynonadecanoylamino) butyrylamino] ethoxyjethoxy) acetylamino]ethoxy}ethoxy)acetyl] [DesaminoHis7,Glu22,Arg26, Arg34,Lys37]GLP-1-(7-37); N-epsilon37-(2-{2- [2-((S)-4-ca rboxy-4-{(S )-4-ca rboxy-4- [(S)-4-ca rboxy-4-( 19-ca rboxy- nonadecanoylamino)butyrylamino]butyrylamino} butyrylamino)ethoxy]ethoxy}acetyl)[DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7- 37); N-epsilon37-{2-[2-(2-{(S)-4- [(S)-4-(12-{4-[16-(2-tert-Butyl-2H-tetrazol-5-yl)- hexadecanoylsulfamoyl]butyrylamino}dodecanoylamino)-4-carboxybutyrylamino]-4- carboxybutyrylamino}ethoxy)ethoxy]acetyl}[DesaminoHis7,Glu22,Arg26,Arg34,Lys37] GLP-1 (7-37); N-epsilon37- [2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy- heptadecanoylam ino)-butyrylam ino]-ethoxy}- ethoxy )-acetylam ino]-ethoxy}-ethoxy)- acetyl] [Aib8,Glu22, Arg26,Arg34,Lys37]GLP-1-(7-37); N-alpha37-[2-(2-{2-[2-(2-{2-[(S)- 4-carboxy-4-(17-carboxy-heptadecanoylamino)- butyrylamino]-ethoxy}-ethoxy)- acetylamino]-ethoxy}-ethoxy)-acetyl][Aib8,Glu22,Arg26,Arg34,epsilon-Lys37]GLP-1-(7- 37)peptide; N-epsilon37-[2-(2-{2-[2-(2-{2- [(S)-4-carboxy-4-(17-carboxy- heptadecanoylam ino)-butyrylam ino]-ethoxy}-ethoxy)- acetylam ino]-ethoxy}-ethoxy)- acetyl] [desaminoHis7, Glu22,Arg26,Arg34,Lys37] GLP-1 -(7- 37); N-epsilon36-[2-(2-{2- [2-(2-{2-[(S)-4-carboxy-4-(15-carboxy-pentadecanoylamino)- butyrylamino]-ethoxy}- ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl] [desaminoHis7,Glu22,Arg26,Glu30,Arg34,Lys36] GLP-1 -(7-37)-Glu-Lys peptide; N-100621 1481epsilon37-[2-(2-{2-[2-(2- {2-[(S)-4-carboxy-4-({trans-4-[(19- carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyryl- amino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37] GLP -1 -(7-37); N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy- heptadecanoylamino)- butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)- acetyl]-[Aib8,Glu22,Arg26,Arg34,Aib35,Lys37]GLP-1-(7-37); N-epsilon37-[(S)-4- carboxy-4-(2-{2-[2-(2-{2-[2-(17- carboxyheptadecanoylamino) ethoxy] ethoxy} acetylamino) ethoxy] ethoxy} acetylamino) butyryl] [Aib8,Glu22,Arg26,34,Lys37] GLP-1 (7-37); N-epsilon37-[2-(2-[2-(2-[2-(2-[4-(17- carboxyheptadecanoylamino)-4(S)- carboxybutyry- lamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [lmPr7,Glu22, Arg26,34,Lys37], GLP-1 -(7-37); N-epsilon26-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4- carboxyphenoxy) decanoylam ino]butyrylam ino}ethoxy)ethoxy] acetylam inojethoxy) ethoxy]acetyl}, N- epsilon37-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxy-phenoxy) decanoylam ino] butyrylam ino}ethoxy)ethoxy]acetylam inojethoxy) ethoxy]acetyl}- [Aib8,Arg34,Lys37]GLP-1 (7- 37)-OH; N-epsilon26 (17-carboxyhepta-decanoyl)- [Aib8,Arg34]GLP-1 -(7-37)-peptide; N- epsilon26-(19-carboxynonadecanoyl)- [Aib8,Arg34]GLP-1 -(7-37); N-epsilon26-(4-{[N-(2- carboxyethyl)-N-(15-carboxypenta- decanoyl)amino]methyl}benzoyl[Arg34]GLP-1-(7-37); N- epsilon26-[2-(2-[2-(2-[2-(2-[4- (17-carboxyheptadecanoylamino)-4(S)- carboxybutyrylamino]ethoxy)ethoxy] acetylamino) ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1 - (7-37); N-epsilon26-[2-(2-[2-(2- [2-(2-[4-(19-carboxynonadecanoylamino)-4(S)- carboxybutyrylamino]ethoxy)ethoxy] acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1 - (7-37); N-epsilon26-[2-(2-[2-(2-[2- (2-[4-(17-carboxyheptadecanoylamino)-4(S)- carboxybutyrylamino]ethoxy)ethoxy] acetylamino)ethoxy]ethoxy)acetyl][3-(4- lmidazolyl)Propionyl7,Arg34]GLP-1 -(7-37); N- epsilon26-[2-(2-[2-(2-[2-(2-[4-(17- carboxyheptadecanoylamino)-(carboxymethyl- amino)acetylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1- (7- 37); N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-3(S)- Sulfopropionylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP- 1-(7- 37); N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)- carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34] GLP-1 - (7-37); N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)- carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP- 1-(7- 37)-amide; N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)- carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34,Pro3100621 14817]GLP-1-(7-37)amide; Aib8,Lys26(N-epsilon26-{2-(2-(2-(2-[2-(2-(4- (pentadecanoylamino)-4-carboxybutyrylamino)ethoxy)ethoxy]acetyl)ethoxy) ethoxy)acetyl)}), Arg34)GLP-1 H(7-37)-OH; N-epsilon26-[2-(2-[2-(2-[2-(2-[4-{[N-(2- carboxyethyl)-N-(17- carboxyheptadecanoyl)amino]methyl}benzoyl)amino]ethoxy)ethoxy]acetylamino)ethoxy] ethoxy)acetyl][Aib8,Arg34]GLP-1 (7-37); N-alpha7 -formyl, N- epsilon26-[2-(2-[2-(2-[2-(2- [4-(17-carboxyheptadecanoyl-amino)-4(S)-carboxy- butyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [Arg34]GLP-1 -(7-37); N- epsilon2626-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxy- butyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8, Glu22, Arg34] GLP-1- (7-37); N-epsilon26{3-[2-(2-{2-[2-(2-{2-[2-(2-[4-(15-(N-((S)-1 ,3- dicarboxypropyl)carbamoyl)pentadecanoylamino)-(S)-4-carboxybutyrylamino] ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]propionyl} [Aib8,Arg34]GLP- 1 -(7-37); N- epsilon26-[2-(2-[2-(2-[2-(2-[4-{[N-(2-carboxyethyl)-N-(17-carboxy- heptadecanoyl)amino]methyl}benzoyl)amino](4(S)-carboxybutyryl- amino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34] GLP-1 (7-37); N- epsilon26-{(S)-4- carboxy-4-((S)-4-carboxy-4-((S)-4-carboxy-4-((S)-4-carboxy-4-(19- carboxy- nonadecanoylam ino)butyrylam ino)butyrylam ino)butyrylam ino) butyrylamino}[Aib8,Arg34]GLP-1-(7-37); N-epsilon26-4-(17-carboxyheptadecanoyl- amino)-4(S)- carboxybutyryl-[Aib8,Arg34]GLP-1 -(7-37); N-epsilon26-{3-[2-(2-{2-[2-(2-{2- [2-(2-[4-(17- carboxyheptadecanoylamino)-4(S)- carboxybutyrylamino]ethoxy)ethoxy]ethoxy}ethoxy )ethoxy]ethoxy}ethoxy)ethoxy]propionyl}[Aib8,Arg34]GLP-1 -(7-37); N-epsilon26-{2-(2- (2-(2-[2-(2-(4-(17-carboxyheptadecanoylamino)-4- carboxybutyrylamino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}-[Aib8,22,27,30,35,Arg34,Pro37, Lys26] GLP-1 (7-37)amide; N-epsilon26-[2-(2-[2-[4-(21- carboxyuneicosanoylam ino)-4(S)- carboxybutyrylamino]ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1 -(7-37); and N-epsilon26- [2-(2- [2-(2-[2-(2-[4-(21-carboxyuneicosanoylamino)-4(S)-carboxybutyrylamino]ethoxy )ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1 -(7-37).

[0241] Delivery agent

[0242] Salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid100621 1481

[0243] The delivery agent may be a salt of N-(8-(2- hydroxybenzoyl)amino)caprylic acid (NAC). The structural formula of N-(8-(2- hydroxybenzoyl)amino)caprylate is shown in formula (I).

[0244] In some embodiments the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid comprises one monovalent cation, two monovalent cations or one divalent cation. In some embodiments the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is selected from the group consisting of the sodium salt, potassium salt and / or calcium salt of N-(8- (2- hydroxybenzoyl)amino)caprylic acid.

[0245] In one embodiment the salt of N-(8-(2- hydroxybenzoyl)amino)caprylic acid is selected from the group consisting of the sodium salt, potassium salt and / or the ammonium salt.

[0246] In one embodiment the salt of N-(8-(2- hydroxybenzoyl)amino)caprylic acid is the sodium salt or the potassium salt. Salts of N-(8-(2- hydroxybenzoyl)amino)caprylate may be prepared using the method described in e.g. W096 / 030036, WO00 / 046182, W001 / 092206 or W02008 / 028859. The salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid may be crystalline and / or amorphous.

[0247] In some embodiments the delivery agent comprises the anhydrate, monohydrate, dihydrate, trihydrate, a solvate or one third of a hydrate of the salt of N-(8- (2- hydroxybenzoyl)amino)caprylic acid as well as combinations thereof. In some embodiments the delivery agent is a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid as described in W02007 / 121318.100621 1481

[0248] In some embodiments the delivery agent is sodium N-(8-(2- hydroxybenzoyl)amino)caprylate (referred to as“SNAC” herein), also known as sodium 8- (salicyloylamino)octanoate.

[0249] GLP-1 agonists and delivery agents are also described in WO2019 / 149880A1.Leptin receptor agonists

[0250] The term “leptin agonist” as used herein refers to a compound, which fully or partially activates the human leptin receptor (ObR). The term is thus equal to the term “leptin receptor agonist”. The term leptin agonist as well as the specific leptin agonists described herein are meant to encompass also salt forms thereof.

[0251] It follows that the leptin agonist should display “leptin activity” which refers to the ability of the compound, i.e. a leptin molecule, a variant of leptin, a leptin analogue, or a compound comprising a leptin molecule, a variant of leptin, a leptin analogue, to bind to the leptin receptor and initiate signal transduction pathways that activate anorexigenic pathways, suppress orexigenic pathways, or result in other physiological effects, for example lipolysis and thermogenesis, as is known in the art. In some embodiments, the leptin receptor agonist comprises a leptin, a recombinant leptin, a leptin derivative, a leptin variant, an analogue of a leptin agonist, and / or leptin receptor antibodies, antigen-binding fragments, or variants thereof that act as a leptin agonist (such as those described in WO2019 / 195796, WO2017 / 66204, and W02022 / 060827).

[0252] In some embodiments the “leptin agonist” binds to a leptin receptor, e.g., with an affinity constant (KD) or activate the receptor with a potency (ECso) of below 1 mM, e.g. below 100 nM as measured by methods known in the art (see e.g.WO201 7 / 66204). Leptin agonist activity may be measured using in vivo or in vitro assays known to those of ordinary skill in the art. For example, leptin agonist activity may be assessed using cell-based reporter assays such as luciferase expression in HEK293 cell lines expressing the human leptin receptor (WO2017 / 66204) or may be assessed in an animal by monitoring food consumption and / or change in body weight (WO2019 / 195796).

[0253] The term half maximal effective concentration (ECso) generally refers to the concentration which induces a response halfway between the baseline and maximum,100621 1481by reference to the dose response curve. EC50 is used as a measure of the potency of a compound and represents the concentration where 50% of its maximal effect is observed.

[0254] The in vitro potency of the leptin agonist may be determined as described in WO201 9 / 195796, Example 7 and the EC50 determined (in the presence or absence of leptin). The lower the EC50 value, the better the potency. In one embodiment the potency (EC50) as determined is 5 pM - 1 mM, such as 10 - 750 pM, 10 - 500 pM or 10 - 200 pM. In one embodiment the EC50 is at most 1 mM, such as at most 1 nM, such as at most 600 pM, such as at most 300pM, such as at most 70 pM, such as at most 60 pM, such as at most 30 pM.

[0255] In one embodiment the EC50 is comparable to human leptin.

[0256] If desired, the fold variation in relation to a known leptin receptor agonist may be calculated as ECso(test analogue) / EC5o(known analogue), and if this ratio is such as 0.5- 1 .5, or 0.8-1 .2 the potencies are considered to be equivalent.

[0257] In one embodiment the potency, EC50, is equivalent to the potency of human leptin.

[0258] In some embodiments the leptin agonist is a leptin analogue, optionally comprising one substituent. The term "analogue" as used herein referring to a leptin peptide (hereafter “peptide”) means a peptide wherein at least one amino acid residue of the peptide has been substituted with another amino acid residue and / or wherein at least one amino acid residue has been deleted from the peptide and / or wherein at least one amino acid residue has been added to the peptide and / or wherein at least one amino acid residue of the peptide has been modified. Such addition or deletion of amino acid residues may take place at the N-terminal end of the peptide and / or at the C- terminal end of the peptide. In some embodiments the leptin agonist comprises a maximum of twelve, such as a maximum of 10, 8 or 6, amino acids which have been altered, e.g., by substitution, deletion, insertion and / or modification, compared to human leptin. In some embodiments the analogue comprises up to 10 substitutions, deletions, additions and / or insertions, such as up to 9 substitutions, deletions, additions and / or insertions, up to 8 substitutions, deletions, additions and / or insertions, up to 7 substitutions, deletions, additions and / or insertions, up to 6 substitutions, deletions,100621 1481additions and / or insertions, up to 5 substitutions, deletions, additions and / or insertions, up to 4 substitutions, deletions, additions and / or insertions or up to 3 substitutions, deletions, additions and / or insertions, compared to e.g. human leptin. Unless otherwise stated the human leptin comprises only L-amino acids.

[0259] In some embodiments the term “leptin analogue” or “analogue of leptin” as used herein refers to a peptide, or a compound, which is a variant of the human leptin hormone. Human leptin hormone is 167 amino acids in length and has the sequence MHWGTLCGFLWLWPYLFYVQAVPIQKVQDDTKTLIKTIVTRINDISHTQSVSSKQKVTG LDFIPGLHPILTLSKMDQTLAVYQQILTSMPSRNVIQISNDLENLRDLLHVLAFSKSCHLP WASGLETLDSLGGVLEASGYSTEWALSRLQGSLQDMLWQLDLSPGC (SEQ ID NO: 7), which may be accessed using the UniProt database (primary accession number P41159). In some embodiments, the term “variant” refers to a homologous variant of human leptin hormone, for example recombinant mouse leptin, which has the sequence MVPIQKVQDDTKTLIKTIVTRINDISHTQSVSAKQRVTGLDFIPGLHPILSLSKMDQTLAV YQQVLTSLPSQNVLQIANDLENLRDLLHLLAFSKSCSLPQTSGLQKPESLDGVLEASLY STEWALSRLQGSLQDILQQLDVSPEC (SEQ ID NO: 8). In some embodiments the term “variant” refers to a compound which comprises one or more amino acid substitutions, deletions, additions and / or insertions in human leptin hormone.

[0260] In some embodiments, the leptin agonist is full length human leptin or mature human leptin, i.e. amino acids 22-167 of human leptin. Mature human leptin is 146 amino acids in length and has the sequenceMVPIQKVQDDTKTLIKTIVTRINDISHTQSVSSKQKVTGLDFIPGLHPILTLSKMDQTLAV YQQILTSMPSRNVIQISNDLENLRDLLHVLAFSKSCHLPWASGLETLDSLGGVLEASGY STEWALSRLQGSLQDMLWQLDLSPGC (SEQ ID NO: 9). In some embodiments the term “variant” refers to a compound which comprises one or more amino acid substitutions, deletions, additions and / or insertions in mature human leptin.

[0261] Variants of human leptin, which may be a leptin analogue, have been described. These include variants of uncertain significance and benign variants, such as the variants listed for P41159 on the UniProt database. In some embodiments a simple nomenclature is used to describe such variants, such as the variant rs17151919 (which may be represented as V94L), VAR_004197 (which may be represented as V94M), and rs28954113 (which may be represented as N103K). It will be appreciated that the variants of leptin that are listed on UniProt for P41159 are not limiting, and that other100621 1481variants of the human leptin hormone that have uncertain clinical effects or are benign have been characterised but have not been indexed on UniProt, or will be characterised. The skilled person will understand that such variants may also be leptin analogues.

[0262] In one embodiment, the leptin is an orthologue or paralogue of a human leptin.

[0263] In any embodiment, a variant of any amino acid sequence referred to or recited herein may not have an N-terminal methionine.

[0264] In one embodiment the leptin agonist exhibits at least 60%, 65%, 70%, 80% or 90% sequence identity to human leptin over human leptin hormone (SEQ ID NO: 7) and / or mouse recombinant leptin (SEQ ID NO: 8). As an example of a method for determination of sequence identity, the sequence of an analogue (for example rs17151919) and human leptin hormone are aligned. The sequence identity of the analogue relative to human leptin hormone is given by the number of aligned identical residues minus the number of different residues divided by the total number of residues in human leptin hormone.

[0265] In one embodiment the leptin agonist is Metreleptin, a recombinant / V- methionyl- analogue of human leptin that is approved by the FDA for treatment of complications of leptin deficiency, as an adjunct to diet, in patients with congenital or acquired generalised lipodystrophy. Metreleptin is 147 amino acids in length, and has the sequence MVPIQKVQDDTKTLIKTIVTRINDISHTQSVSSKQKVTGLDFIPGLHPILTLSKMDQTLAV YQQILTSMPSRNVIQISNDLENLRDLLHVLAFSKSCHLPWASGLETLDSLGGVLEASGY STEWALSRLQGSLQDMLWQLDLSPGC (SEQ ID NO: 10).

[0266] In one embodiment the leptin agonist exhibits at least 60%, 65%, 70%, 80% or 90% sequence identity to human leptin hormone (SEQ ID NO: 7), mature human leptin (SEQ ID NO: 9), or recombinant mouse leptin (SEQ ID NO: 8). As an example of a method for determination of sequence identity, an analogue (for example Metreleptin) and mature human leptin (SEQ ID NO: 9) are aligned. The sequence identity of the analogue relative to mature human leptin is given by the number of aligned identical100621 1481residues minus the number of different residues divided by the total number of residues in mature human leptin.

[0267] In some embodiments, the leptin agonist is a leptin receptor antibody, antigen-binding fragment, or variant thereof that act as a leptin agonist.

[0268] In one embodiment, the leptin receptor antibody, antigen-binding fragment, or variant thereof that act as a leptin agonist is an leptin receptor antibody, antigen-binding fragment, or variant thereof as described in WO2019 / 195796, WO2017 / 66204, or W02022 / 060827.

[0269] In one embodiment, the leptin receptor antibody, antigen-binding fragment, or variant thereof that act as a leptin agonist is Mibavademab (REGN4461 ), Record UNII PHL2UDY3AB, accessible here: https: / / gsrs.ncats.nih.gov / ginas / app / ui / su stances / PHL2UDY3AB. M i bavadem ab (REGN4461 ) and methods of generating Mibavademab are also described in WO201 9 / 195796 (for H4H17319P2).Administration

[0270] The term ‘administered’ means administration of a therapeutically effective dose of the aforementioned inhibitor(s) or composition(s) to an individual. By ‘therapeutically effective amount’ is meant a dose that produces the effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques. As is known in the art and described above, adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the seventy of the condition may be necessary, and will be ascertainable with routine experimentation by those skilled in the art.

[0271] The skilled person will appreciate that varying doses of SIK-3 and an metabolic modulator will be effective at treating individuals in need thereof, depending on, for example the level of seventy of the obesity, or adiposity in the individual being treated. The skilled person will be readily able to determine the appropriate dose of SIK- 3 and an metabolic modulator for promoting reduction in body weight or increased energy expenditure in an individual in need thereof.100621 1481

[0272] It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific SIK-3 inhibitor and a metabolic modulator employed, the metabolic stability and length of action of that SIK-3 inhibitor, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the seventy of the particular condition, and the host undergoing therapy.

[0273] Moreover, the skilled person will be familiar with methods for determining an appropriate human dose based on the disclosure provided herein in relation to therapeutically effective doses for use in mice. For example, Human dose conversion can be by any of the relevant methods described in U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. Rockville, MD 2005, incorporated herein by reference.

[0274] The human equivalent doses described herein are derived using the methods described in the CDER ‘Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers’ for dose conversion based on body surface area. It will be appreciated that any variation on the methods described in the CDER document may also be utilised for determining an appropriate human dose from the dosages administered to mice, as described herein (for example, in some circumstances it may be appropriate to dose scaling based on body weight rather than on body surface area). Moreover, the skilled person will also be familiar with methods for determining the appropriate dose for a juvenile human (i.e. , non-adult human), as well as methods for determining the appropriate dose in a non-human organism, to which the methods of the present invention may be applied. The skilled person will also be familiar with methods for adjusting the appropriate dose depending on the intended method of administration (for example, intravenous, intramuscular, subcutaneous, topical, oral or other method of administration).

[0275] Human Equivalent Dose (HED in mg / kg) = Animal Dose (mg / kg) x Animal K - Human K, where K is a correction factor reflecting the relationship between body weight and body surface area.100621 1481

[0276] For a typical adult (body weight 60 kg, body surface area 1 .6m2), K is 37 and mouse K is 3.

[0277] An adult suffering from obesity will likely weigh more than 60 kg and the skilled person will be familiar with appropriate methods for adjusting the dose of SIK-3 and a metabolic modulator accordingly to account for the increased body surface area as compared with a 60 kg adult.

[0278] For example in some embodiments the SIK-3 inhibitor may be administered as an injection, and the injection dose levels may range from about 0.01 mg / kg / h to at least 10 mg / kg / h, all for from about 1 to about 120 h and especially 24 to 96 h. In embodiments a preloading bolus of from about 0.24 mg / kg to about 240 mg / kg or more may also be administered to achieve adequate steady state levels. In preferred embodiments a preloading bolus about 7 mg / kg or more may also be administered to achieve adequate steady state levels.

[0279] For example in some embodiments the metabolic modulator may be administered as an injection. For example, the injection dose of the GLP-1 agonist semaglutide may range from about 0.10 mg once weekly to about 3 mg once weekly. In preferred embodiments the injection dose may rangef from about 0.25 mg once weekly to about 2 - 2.4 mg once weekly, or more may also be administered to achieve adequate steady state levels.

[0280] In another example, the injection dose of Metreleptin may range from about 1 mg once daily to about 7 mg once daily. In preferred embodiments the injection dose may range from about 2.5 mg once daily to about 5 mg once daily, or more may also be administered to achieve adequate steady state levels.

[0281] In another example, the injection dose of Mibavademab may range from about 150 mg once weekly to about 750 mg once weekly. In preferred embodiments the injection dose may range from about 300 mg once weekly to about 600 mg once daily, or more may also be administered to achieve adequate steady state levels.

[0282] In some embodiments the metabolic modulator may be administered orally, for example semaglutide. Oral formulations for GLP-1 agonists are known in the art, for example Rybelsus, an oral tablet formulation of semaglutide. Such formulations and100621 1481methods of use are described in W02006 / 097537, WO2012 / 080471 , WO2013 / 139694, and WO2014 / 177683.

[0283] For the prophylaxis and / or treatment of long-term conditions, such as degenerative conditions, the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance.

[0284] With oral dosing, one to four (1 -4) regular doses daily, especially one to three (1-3) regular doses daily, typically one to two (1 -2) regular doses daily, and most typically one (1 ) regular dose daily are representative regimens. Alternatively for long lasting effect drugs, with oral dosing, once every other week, once weekly, and once a day are representative regimens. In particular, dosage regimen can be every 1 -14 days, more particularly 1-10 days, even more particularly 1 -7 days, and most particularly 1-3 days.

[0285] Using these dosing patterns, each dose provides from about 1 to about 1000 mg of a compound of the invention, with particular doses each providing from about 10 to about 500 mg and especially about 30 to about 250 mg.

[0286] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.Pharmaceutical composition

[0287] In embodiments of the disclosure the SIK-3 inhibitor and a metabolic modulator may be provided as a pharmaceutical composition, comprising a SIK-3 inhibitor, a metabolic modulator and optionally a pharmaceutically acceptable diluent, excipient or carrier.

[0288] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a SIK-3 inhibitor, preferably as described herein, and a metabolic modulator, preferably as described herein.

[0289] In embodiments of the disclosure, the SIK-3 inhibitor and a metabolic modulator may be present in different compositions or medicaments and separately administered to the individual.100621 1481

[0290] In embodiments of the disclosure, the SIK-3 inhibitor and a metabolic modulator may be present in the same composition or medicament and simultaneously administered to the individual.

[0291] In any method or use of the disclosure, SIK-3 inhibition and metabolic modulation may be achieved by administering a composition or pharmaceutical composition as described herein.

[0292] Generally, a composition of this invention may be administered orally or parenterally (eg subcutaneously), however, any other suitable route of administration is contemplated, for example topical (for example, transdermal or ocular), oral, buccal, nasal, vaginal or rectal administration.

[0293] The term parenteral as used herein includes subcutaneous, intradermal, intravascular (for example, intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial and intraperitoneal injection, as well as any similar injection or infusion technique.

[0294] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersion and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that easy syri ngabil ity exists.

[0295] In certain embodiments, compositions in a form suitable for oral use or parenteral use are preferred. Suitable oral forms include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Within yet other embodiments, compositions provided herein may be formulated as a lyophilisate.

[0296] A composition may further include one or more components adapted to improve the stability or effectiveness of the applied formulation, such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters, gelling agents, preservatives, antioxidants, skin penetration enhancers, moisturizers and sustained release materials. Examples of such components are described in Martindale - The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Martin (ed.), Remington's Pharmaceutical Sciences. Formulations may comprise microcapsules,100621 1481such as hydroxymethylcellulose or gelatine-microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsules.Kits

[0297] In another embodiment there is provided a kit or article of manufacture comprising: a container holding a SIK-3 inhibitor, or a pharmaceutical composition comprising a SIK-3 inhibitor; and a container holding an metabolic modulator, or a pharmaceutical composition comprising an metabolic modulator; a label or package insert with instructions for use.

[0298] In another embodiment there is provided a kit or article of manufacture comprising: a container holding a SIK-3 inhibitor and a metabolic modulator, or a pharmaceutical composition comprising a SIK-3 inhibitor and a metabolic modulator; and a label or package insert with instructions for use.

[0299] In certain embodiments the present disclosure provides a kit for use in: treating obesity in an individual in need thereof; treating or minimising the risk of, an obesity-related disease or disorder in an individual suffering from or at risk of suffering from an obesity-related disease or disorder; reducing the body weight of an individual in need thereof; preventing or minimising the weight gain of an individual consuming a high energy / caloric diet; preventing or minimising adiposity in individual consuming a high energy / caloric diet; enhancing energy expenditure; improving insulin secretion in an individual in need thereof; promoting blood glucose clearance in an individual in need thereof; promoting or improving glycaemic control in an individual in need thereof; treating pre-diabetes or diabetes in an individual in need thereof; treating type 1 diabetes (T1 D) in an individual in need thereof;100621 1481promoting blood glucose clearance in an obese individual; promoting or improving glycaemic control in an obese individual; treating pre-diabetes or diabetes in an obese individual; treating type 1 diabetes (T1 D) in an overweight or obese individual; treating insulin resistance in an individual,; or treating a fatty liver disease in an individual, the kit comprising a SIK-3 inhibitor and a metabolic modulator, preferably a SIK-3 inhibitor and a metabolic modulator as described herein.

[0300] Preferably, the kit also comprises written instructions for use of the kit in a method of the disclosure as described herein.

[0301] The kit or “article of manufacture” may comprise a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, blister pack, etc. The containers may be formed from a variety of materials such as glass or plastic. The container holds a therapeutic composition which is effective for treating the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The label or package insert indicates that the therapeutic composition is used for treating the condition of choice. In one embodiment, the label or package insert includes instructions for use and indicates that the therapeutic or prophylactic composition can be used to treat a disease described herein.

[0302] The kit may comprise (a) a therapeutic or prophylactic composition; and (b) a second container with a second active principle or ingredient contained therein. The kit in this embodiment of the invention may further comprise a package insert indicating the composition and other active principle can be used to treat a disorder or prevent a complication stemming from obesity or an obesity related disorder. Alternatively, or additionally, the kit may further comprise a second (or third) container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.100621 1481

[0303] In certain embodiments the therapeutic composition may be provided in the form of a device, disposable or reusable, including a receptacle for holding the therapeutic, prophylactic or pharmaceutical composition. In one embodiment, the device is a syringe. The device may hold 1 -2 mL of the therapeutic composition. The therapeutic or prophylactic composition may be provided in the device in a state that is ready for use or in a state requiring mixing or addition of further components.

[0304] The present disclosure also provide for the use of a SIK-3 inhibitor and a metabolic modulator in the manufacture of a kit as described herein.

[0305] It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.Examples

[0306] The inventors have shown the therapeutic potential of SIK-3 inhibition in combination with an metabolic modulator in promoting weight loss and improving glucose and insulin tolerance in an in vivo preclinical model through pharmacological inhibition. Relevantly, multiple structurally distinct metabolic modulators have been tested and beneficial effects observed.

[0307] Example 1 : SIK3 knockout studies and methods

[0308] The inventors have shown the therapeutic potential of SIK-3 inhibition in promoting weight loss and improving glucose and insulin tolerance in an in vivo preclinical model through two distinct mechanisms - (1 ) genetic manipulation of SIK-3 and separately through (2) pharmacological inhibition.

[0309] In vivo NPY neuron specific SIK3 knockout studies and pharmacological inhibition studies were performed according to the methods explained below. Data that shows the characterisation of the SIK3 knockout mice are represented in Figures: 1 -7.Animal and Experimental Design

[0310] All animal care and experiments were performed in accordance with protocols approved by the St Vincent’s institute Animal ethics committee (AEC No.100621 1481015 / 18, 017 / 19, and GBNML849). All mice were housed in a temperature-controlled room of 22 °C with a 12-hour light / dark cycle (lights on from 0700-1900 hours) and were allowed free access to food and water. All experimental mice used in this study were on a C57NL / 6J background. Age- and sex- matched mice were used for all experiments. Male mice were used in all studies. Mice were fed a standard chow (19% protein, 4.6% fat and 4.8% crude fibre) or a high-fat diet (23% fat, 45% of total energy from fat; SF04- 027; Specialty Feeds, Australia) for the entirety of the experiments except during experiments where fasting is required.

[0311] Mouse body weight is dependent on mouse age and sex. For the mice used in this study, a mouse having a body weight of about 35g or more is considered an overweight mouse, and a mouse having a body weight of more than about 40g is considered an obese mouse. More specifically a mouse having a total body fat mass of about 5-7g and / or 15-20% of fat mass / body weight is considered an overweight mouse, and a mouse having a total body fat mass of >7g and / or >20% of fat mass / body weight is considered an obese mouse.Generation of NPY neuron specific SIK3 KO mice

[0312] To generate NPY neuron-specific SIK3 deficient mice, SIK3fl / fl were mated with NPY-cre mice to generate NPYcre / +; SIK3fl / fl mice. NPYcre / +;SIK3fl / fl mice were then subsequently crossed with Gt(ROSA)26Sortm9 to generate NPYcre / +; SIK3fl / fl;Ai9 mice. SIK3fl / fl mice were used as control.Isolation of genomic DNA

[0313] Mouse tail tips and tissues (Hypothalamus, hippocampus, brain stem, cerebrum, olfactory Bulb, pituitary gland, and liver) were digested in 250 pL tail digestion buffer (100 mM Tris-HCI, pH 8.5, 5 mM EDTA, 0.2% (w / v) SDS, 200 mM NaCI) containing 20 pg proteinase K and incubated overnight at 55 C. Digested tissues were centrifuged at room temperature at 13 000 rpm for 5 mins. Resulting supernatant were transferred to fresh tubes. 100 % isopropanol were added and mixed gently by inverting. 100% isopropanol were removed from the precipitated genomic DNA by centrifugation at 13 000 for 3 mins. Clinging isopropanol were removed by pipette then samples were left to dry for 30 minutes. 250 pL of 1x TE buffer were added. Routine100621 1481PCR was conducted to confirm recombination of SIK3 allele in these tissues using the following primers:Genotyping and primers

[0314] Routine genotyping was carried out to confirm the presence of SIK3 floxed alleles and presence of NPY ere transgenes. PCR reactions were conducted using PCR master mix and protocol as indicated in the table below:Table 2. Primer sequenceTable 3. PCR Master Mix100621 1481Table 4. PCR Reaction ProtocolMetabolic Measurements and Body Composition

[0315] Body composition such as whole-body fat mass and lean mass were measured at 8, and 16 weeks of age using nuclear magnetic resonance imaging (Whole Body Composition Analyzer, Echo MRI, Houston, USA). Blood glucose levels were determined using blood collected from tail tip and measured with Accu-check Performa glucose meter (Roche, Switzerland). These measurements were taken at the same time of the day between 9:00 h - 11 :00 h. Physical activity, food intake and energy expenditure measures were determined using a computer-controlled indirect calorimetry system (Promethion®, Sable Systems, Las Vegas, NV). The calorimetry system consists of 16 metabolic cages, reflecting their home cages, which are equipped with indirect open circuit calorimetry, food consumption & activity monitors. Mice were put in the cages for 72 hours. Data presented were averaged for two dark and two light cycles. Energy expenditure and the respiratory exchange ratio were calculated from the gas exchange data (Rate of oxygen consumption (VO2) in ml / min and Rate of carbon dioxide emission (VCO2) in ml / min). Gas exchange data was used to calculate carbohydrate and fat oxidation rates. Respiratory exchange ratio (RER) reflects the percentage use of fuel substrate at the cellular level at any time (carbohydrate or lipids). RER of 0.7 for fats, 0.8 for proteins, 1 .0 for carbohydrates. Ambulatory movements were measured by pedestrian meters, which sums all of the directed ambulatory locomotion of 1 cm / sec or above within the x,y,z beam-break system, excluding the wheel activity. Feeding was determined by measuring the mass of food consumed.100621 1481Glucose tolerance test (GTT)

[0316] Whole body glucose clearance was assessed by intraperitoneal glucose tolerance test (IPGTT) on 6 h fasted conscious mice at 8- and 16-weeks of age. Briefly, mice were weighed and after taking basal blood glucose levels, injected intraperitoneally with 1 g / kg body weight of D-glucose. Blood glucose levels were determined at basal and, 15, 30, 60, 90- and 120-minutes following glucose administration, using blood collected from tail tip and measured with Accu-check Performa glucose meter (Roche Diagnostics, Switzerland). Area under the curve was calculated using prism software to determine glucose tolerance.Insulin tolerance test (ITT)

[0317] Whole body insulin sensitivity was assessed by intraperitoneal insulin tolerance test (IPITT) on 6 h fasted conscious mice at 9- and 17-weeks of age. Briefly, mice were weighed and after taking basal blood glucose levels, injected intraperitoneally with 0.75U / kg body weight human insulin (Actrapid, Novo Nordisk Pharmaceuticals). Blood glucose levels were determined at basal and, 15, 30, 60, 90- and 120-minutes following insulin administration, using blood collected from tail tip and measured with Accu-check Performa glucose meter (Roche Diagnostics, Switzerland). Area under the curve was calculated using prism software to determine insulin sensitivity.Pyruvate tolerance test (PTT)

[0318] Pyruvate tolerance test was conducted to test the hepatic gluconeogenesis, in which the intraperitoneal pyruvate injection was administered on 16 h fasted 10- and 19 weeks old mice. Briefly, mice were weighed and after taking basal blood glucose levels, injected intraperitoneally with 1 g / kg body weight sodium pyruvate. Blood glucose levels were determined at basal and, 15, 30, 60, 90- and 120-minutes following pyruvate administration, using blood collected from tail tip and measured with Accu- check Performa glucose meter (Roche Diagnostics, Switzerland). Area under the curve was calculated using prism software.100621 1481Fed and fasted serum collection

[0319] Overnight (16 h) fasted and 30-miuntes re-fed blood were collected by retro- orbital bleeding (Performed by Ms Rhiannon Walder from Bioresource Centre Animal Facility. Briefly, a small amount of blood collected was used to measure fasting and refeeding blood glucose levels using Accu-check Performa glucose meter (Roche Diagnostics, Switzerland). The remainder blood, approximately 200 pL, were put on heparinised 1.5 mL Eppendorf tubes, stored on ice then centrifuged at 13,000 rpm for 10 minutes at 4°C. Serum was collected and stored at -20° C.Insulin Concentration Determination

[0320] Plasma insulin levels were measured in duplicates from serum obtained from the 16 h fasted and 30 mins re-fed mice using a commercially available sandwich type insulin ELISA assay: mouse specific ultrasensitive insulin ELISA (ALPCO Diagnostics, Salem, NH, USA).Tissue isolation and Homogenisation

[0321] After completing all metabolic characterizations, mice at 16-20 weeks of age were fasted for 3-4 hours then sacrificed by cervical dislocation. Tissues were collected. The skull was then pierced and dissected exposing the brain. The brain was carefully flipped to expose the hypothalamus located on the underside of the brain.Hypothalamus were excised and snap frozen in liquid nitrogen and stored at -80 °C for storage. Other tissues including gastrocnemius, soleus and quadricep muscles, liver, and individual fat pads were weighed and either put into 1 .5 mL Eppendorf tubes, snap frozen in liquid nitrogen, and stored at -80 °C or put into histology cassettes and fixed in 4% PBS-buffered paraformaldehyde for 72 h before processing and embedded in paraffin. Tissues were mechanically homogenised. For protein extraction, ice cold RIPA lysis buffer containing 20 mM Tris-HCI (pH 7.5), 150 mM NaCI, 1 mM Na2EDTA, 1 mM EGTA, 1 % NP-40, 1 % sodium deoxycholate, 2.5 mM sodium pyrophosphate, 1 mM beta-glycerophosphate, 1 mM Na3VO4, 1 pg / ml leupeptin, supplemented with protease and phosphatase inhibitors (Cell Signalling Technology) was used. For RNA extraction, RNAzol® RT (Sigma, St. Louise, MO) was used.100621 1481RNA extraction, reverse transcription, and quantitative real-time PCR

[0322] Total RNA of hypothalamic tissues was extracted using RNAzol reagent (Sigma, St. Louis, MO) following the manufacturer’s instructions. Whole hypothalamic was resuspended in 250 pL RNAzol followed by vigorous homogenisation using beads and TissueLyser LT (QIAGEN). Homogenates were centrifuge at 12,000 x g for 5 minutes at 4°C. Supernatant containing RNA were transferred into a fresh tube. 100 pL of RNase-free water were added to the homogenates. Samples were mixed vigorously for 15 seconds. Samples were allowed to stand for 15 minutes at RT. The resulting mixture was centrifuged at 12,000 x g for 15 minutes at 4°C. Supernatant was transferred to a new tube then equal volumes of 100% isopropanol was added to precipitate 100%. Samples were centrifuged at 12,000 x g for 10 minutes. RNA pellets were washed twice with 75% ethanol. RNA pellets were solubilised in 50uL RNAse-free water. RNA quality and concentration was determined using nanodrop. Purified RNA was stored at -20 C. Isolated RNA was reverse transcribed into cDNA using the Superscript IV First-Strand Synthesis System (Invitrogen, Australia). In a 20 pL reaction, RNA samples were incubated with 1 pL of random hexamers, 1 pl of 10 mM dNTP mix plus 2-5 pg of the template RNA. To facilitate annealing of primers to the template RNA, the above mixture was incubated at 65°C for 5 minutes, and then incubate on ice for at least 1 minute. Subsequently, annealed template RNA was combined with 4 pL of 5x SSIV buffer, 1 pL of 100mM DTT, 1 pL of ribonuclease inhibitor, and 1 pL of Superscript Reverse Transcriptase (Invitrogen, Australia). Annealed RNA and reverse transcription reaction mix were combined and incubated at 23 °C for 10 mins, 50 °C for 10 mins and 80 °C for 10 mins. Primer annealing and reverse transcription was carried out in a thermocycler (Bio-Rad). A control for the genomic DNA contamination was prepared as a reaction without the addition of reverse transcriptase. The resulting cDNA samples were stored at -20 °C for subsequent quantitative real-time PCR analysis. Quantitative Real-Time PCR was conducted using TaqMan® Gene Expression System (Thermo Fisher). Quantitative real-time PCR was performed using the Light-Cycler 480 Real- Time PCR system (Roche, Switzerland). Reactions were set up in a 384-well PCR plate. Each reaction performed in a 10 pL volume containing 5 pL of 2x TaqMan® Universal PCR Master Mix, 0.5 pL 1x TaqMan Gene Expression Assay, 3.5 pL RNAse free H2O, and 1 pL cDNA template. GAPDH was utilised as internal control to evaluate the relative amount of target gene expression levels.100621 1481

[0323] The cycling conditions used in all the RT-qPCR experiments were as follows: 95 °C for 10m in, 95 °C for 15s, and 60 °C for 60s for 40 cycles. The relative gene expression of SIK3 was performed under the assumption that the binding efficiency of the probes are equal. GAPDH was used as the housekeeping gene for the normalization of SIK3 expression. Prism software was utilised to quantify the comparative Ct (AACt) method and the results were reported as fold change from the controls.Immunohistochemistry

[0324] For brain immunohistochemistry, mice were anaesthetised. Incisions were made through both sides of the rib cage up to the collarbone, exposing the lung and the heart. Trimmed needle was then inserted towards the tip of the left ventricle at an angle parallel to the midline of the heart. Needle is then clamped to secure position within the left aorta. A small incision was then made on the right atrium to let blood flow out. Immediately, heparinised saline [10,000 units / l heparin in 0.9% (w / v) NaCI] was perfused at a constant speed (10 rpm) using a peristaltic pump. After blood is flushed out, indicated by the liver gradually turning pale (approximately 20 mL of heparinised saline), 4% (w / v) paraformaldehyde in phosphate buffer (0.1 M, pH 7.4) is subsequently perfused (approximately 50 mL). Mice were then decapacitated, the skull was pierced and dissected exposing the brain.

[0325] The brain was carefully removed from the skull and post fixed in 4% (w / v) paraformaldehyde in phosphate buffer for 24 hours at 4 C. Following post-fixation, brains were then washed twice for 15 minutes in 1x PBS. Subsequently, brains were transferred to 30% sucrose (w / v) in 1x PBS for four days until they sink at the bottom for cryoprotection. Brains were frozen and stored at -80 C. Fixed brains were embedded in Tissue-Tek O.C.T. compound (ProScieTech) and allowed to acclimatise in the cryostat for 1-2hours prior to sectioning. Using cryostat, brains were cut in the coronal plane and sectioned into 30 urn thickness 120 urn apart. Brains were collected into 12 well plate containing anti-freeze media (for 500 mL: mix 250 mL of 0.05 M sodium phosphate buffer, 150 mL ethylene glycol, and 100 mL glycerol). Brains can be stored at -20 °C until ready for staining.

[0326] For detection of SIK3, samples were removed from the freezer and allowed to equilibrate at room temperature for 30 minutes. Sections were transferred into fresh100621 148112 well plate containing 1 xPBS. Sections were washed with 1 x PBS 3x 10 m inutes each on an orbital shaker using low speed at room temperature. Sections were then placed in freshly prepared 1 %NaOH, 1 %H2O2 in 1X PBS for 20 min. Sections were then washed 3x for 5 mins in 1X PBS. Subsequently, sections were incubated in 0.3% glycine in PBS for 10 min then washed 3x for 5 mins in 1x PBS. After, sections were placed into 0.73 ul of 10% S DS to 25 ml 1X PBS for another 10 minutes. Sections were washed 3x for 5 minutes. Sections were then blocked for 2 hours in blocking-permeabilising solution (1x PBS, 0.3% Triton X-100, and 3% normal goat serum).

[0327] For primary antibody incubation, sections were incubated in 800 pL of 1 :300 SIK3 primary antibody diluted appropriately in 1x PBS with 0.3% Triton X-100 and 3% normal goat serum on an orbital shaker rotating at low speed (e.g., speed 7 rpm) overnight at 4C. The following day, brains were poured into well inserts. Sections were then washed once for 30 secs and 2x for 10 minutes with 1xPBS with 0.3% Triton X- 100, and 3% normal goat serum. Sections were then incubated in secondary antibody solution (1 :250 Goat anti-rabbit alexa-fluor488) for 2 hours shaking on an orbital shaker at RT. Sections were protected against light during the secondary antibody incubation. Sections were washed 1x for 30s then 2x for 10 minutes in 1xPBS while continuing to protect against light exposure. Sections were poured into a 150 mm petri dish filled with 1xPBS with 0.3% Triton X-100. Glass slides were submerged into solution.

[0328] Fine paint brush was used to mount free floating brain sections towards the slides. Brain sections were carefully positioned on to the slides. Following mounting, sections were dried onto the slides for about 10-15 minutes while being shielded against the light. Aqueous mounting medium containing DAPI were then added to the mounted slides. Using tweezers, coverslip was placed on top of the medium. Edges of the cover slipped slides were then sealed with clear nail polish. Slides were stored in a dark slide box at 4C until visualised using a Leica Thunder fluorescent microscope at magnifications 10x, 20x, and 40x.

[0329] Example 2: SIK-3 inhibitors have similar effects on UCP-1 expression and hypothalamic neuropeptides to SIK3 knockouts

[0330] WT and SIK3-NPYKO mice were fed on a high fat diet (HFD) for 10 weeks. mRNA expression levels of thermogenic and mitochondrial function / biogenesis markers in intrascapular BAT tissue of HFD-fed WT v SIK3-NPYKO mice, and UCP-1 protein100621 1481levels in BAT of WT and SIK3-NPYK0 mice were measured. mRNA and protein levels of UCP-1 were increased in SIK3-NPYK0 mice (Figure 8A). YKL-05-099 (SIK-3 inhibitor) treatment similarly enhanced UCP-1 levels in brown adipose tissue in obese mice compared to placebo treatment (Figure 8B).

[0331] Hypothalamic neuropeptide (AgRP, NPY and POMC) in WT and SIK3- NPYKO mice that were fed a high fat diet (HFD) were assessed by qRTPCR. Levels of Npy and AgRP were significantly decreased in SIK3-NPYKO mice (Figure 8C).Similarly, treatment with YKL-05-099 significantly decreased hypothalamic mRNA expression of Agrp and Npy of obese mice compared to placebo (Figure 8D).

[0332] Example 3: Obesity and fat mass in SIK3 knockouts and treatment of obesity in mice using SIK-3 inhibitors

[0333] WT and SIK3-NPYKO mice were fed on a high fat diet for 10 weeks. Weekly body weight were recorded and fat mass and lean mass were determined by EchoMRI. SIK3-NPYKO mice have less weight gain compared to WT mice when fed a high fat diet (Figure 9A). Dissected weights of individual fat pads from epididymal (eWAT) and inguinal (iWAT) were measured. SIK3-NPYKO mice had significantly lower fat mass compared to WT mice (Figure 9D).

[0334] Additionally, mice were fed on a high fat diet for up to 12 weeks to achieve a body weight of above 40g, which reflects clinical obesity with a BMI >30. Obese mice treated with YKL-05-099 exhibited reduced body weight over 4 weeks of treatment (Figure 9B). The body weight reduction in obese mice treated with YKL-05-099 was found to be due to reduced adiposity, with minimal reduction in lean mass (Figure 9E).

[0335] Using the same animal model as the YKL-05-099 study, WT C57BL / 6J mice were fed a high fat diet for 12 weeks starting from 8 weeks of age, and placebo or GLPG3970 treatment (50mg / kg or 25mg / kg) began at 20 weeks of age. GLPG3970 treatment led to significant reduction in body weight for both the 25 mg / kg dose and the 50 mg / kg dose compared to the placebo group (Figure 9C). Obese mice treated with GLPG3970 also exhibit decreased adiposity (Figure 9F).

[0336] GLPG3970 is well tolerated with acceptable safety profile in humans.100621 1481

[0337] Compared to placebo, obese mice treated with YKL-05-099 or GLPG3970 exhibited significant body weight loss due to reduced adiposity.

[0338] Without wishing to be bound by theory, it is proposed that a key underlying explanation for the reduction in body weight and adiposity could be a reduction in caloric intake (food intake) and increase in energy expenditure. Mice treated with YKL-05-099 also exhibited significantly increased in thermogenesis, as indicated by upregulation of the thermogenic marker UCP-1 .

[0339] Collectively, these results indicate that pharmacological inhibition of SIK-3 promotes weight loss in obese subjects.

[0340] Example 4: Glucose tolerance in SIK3 knockouts and obese mice treated with SIK-3 inhibitors

[0341] WT and SIK3-NPYKO mice were fed on a high fat diet for 10 weeks. Intraperitoneal (i.p.) glucose tolerance test (2g / kg body weight) on 6 h fasted 16-week- old mice. Blood glucose levels during each tolerance tests were monitored at 0, 15, 30, 16, 90, and 120 minutes. Results are expressed over the time course as the area under the curve. 16 h / overnight fasted, and 30 minutes re-fed blood glucose levels were measured from WT v SIK3-NPYKO HFD fed mice. SIK3-NPYKO mice showed superior glucose clearance ability compared to WT mice (Figure 10A).

[0342] High-fat diet (HFD) & Streptozotocin (STZ) induced type II diabetic mice model. A cohort of wild type male C57 / BL6 mice were purchased from The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. These mice were treated with high-fat diet (46% of calories from fat, 20% calories from protein and 34% calories from carbohydrate, Specialty Feeds, Australia) for 4 weeks prior to streptozotocin (STZ, Sigma) injection. Mice were fasted for 4 hours and intraperitoneally injected 5 doses of 40 mg / kg of STZ within 2 weeks. STZ was dissolved in sodium citrate buffer (pH=4.5) right before the injection. Body weight and blood glucose was measured weekly since HFD, blood was collected from mouse tail tips and blood glucose was determined via Accu-check Performa glucometers (Roche, Switzerland). Two weeks after STZ injection, the average blood glucose level spike up to 15.4 mmol / L. These mice were randomly allocated into two groups, one group treated with placebo and the other group treated with YKL-05-099 (YKL). Diabetic mice were100621 1481randomly allocated for either YKL or placebo. YKL (18 mg / kg of body weight) or placebo (6.25 mM HCL + PBS) was administrated through oral gavage once per day for 4 weeks.

[0343] After 4 weeks of placebo / YKL treatment, an intraperitoneal glucose tolerance test (IPGTT) was performed to investigate glucose clearance ability. Mice were fasted for 6 hours, prior to glucose injection, mice were weighted, and basal blood glucose level was measured and recorded. Then the mice were intraperitoneally injected with 1 g / kg body weight of glucose (dissolved in saline). Blood glucose levels were measured at 15, 30, 60, 90, 120 mins time point post glucose injection. Blood glucose levels were measured by Accu-check Performa glucometers (Roche, Switzerland) by assessing blood from tail tip.

[0344] Fasting / Re-fed blood glucose level measurement. Glucose sensitivity was assessed through fast / refed blood glucose test and insulin secretion level was measured. Mice were fasted overnight (16 hours) and 30 mins of refed time, blood glucose was measured before and after refed by collecting blood from tail tips. To determine insulin secretion level, mouse eye bleed was collected before and after refed and centrifuged at 4 °C 14,800 RPM for 10 mins to separate plasma for insulin level measurement. 10pl of neat fasting plasma and 10 pl of 1 in 3 diluted refed plasma were added to mouse ultrasensitive insulin ELISA kit (ALPCO Diagnostics, Salem, NH USA) to investigate insulin secretion level.

[0345] Insulin ELISA. Mouse ultrasensitive insulin ELISA kit (ALPCO Diagnostics, Salem, NH, USA) was used to measure insulin secretion both in vitro and in vivo. 10pl of sample was added to the ELISA plate with 75 pl of conjugate buffer and shake it at room temperature with 900 RPM for 2 hours. Then, washed the ELISA plate using the ELISA wash for 6 times and 100 pl of TMB was added to each well. Shaked for another 15 mins and added stop buffer. Then ELISA result was read by Enspire Plate Reader and analysed by Prism 10.0.

[0346] Data are presented as means ± SEM. Differences between YKL or Vehicle treated group under different experimental condition was assessed using Student-t test. Differences between groups of mice were assessed by two-way ANOVA or repeated- measures ANOVA. Correlation coefficient was calculated using Spearman’s rank correlation coefficient. Statistical analyses were assessed using Prism software 10.0.100621 1481Differences were regarded as statistically significant if *P < 0.05; **P < 0.01 ; ***P < 0.001 ; ****P < 0.0001.

[0347] The effect of YKL-05-099 (YKL) on glucose tolerance is shown in Figure 10B. Mice administered with the pharmacological SIK-3 inhibitor had improved glucose tolerance. The effect of YKL-05-099 on insulin secretion is shown in Figure 10D. This experiment demonstrates that YKL-05-099 increases insulin secretion, and improves glycaemic control in high fat diet (HFD) + streptozotocin (STZ) mice a widely used model for obese and type 2 diabetes (reduced beta-cell mass).

[0348] Using the same animal model as the YKL-05-099 study, WT C57BL / 6J mice were fed a high fat diet for 12 weeks starting from 8 weeks of age, and placebo or GLPG3970 treatment (50mg / kg or 25mg / kg) began at 20 weeks of age. Similarly, the mice treated with GLPG3970 exhibit exhibited improved glycaemic control (Figure 10C).

[0349] Example 5: Liver metabolism in SIK3 knockouts and reversing and treating fatty liver disease in obese mice using SIK-3 inhibitors

[0350] An assay was performed to investigate the effect of SIK-3 inhibition. Primary hepatocytes were harvested from WT (Sik3lox / lox) and liver-specific SIK3-KO (AlbCre / +Sik3lox / lox) mice. Lipogenesis (lipid production) in WT and liver-specific SIK3- KO primary hepatocytes in response to basal and SIK-3 inhibitor Pterosin B was determined by measuring the incorporation of radiolabelled acetate in the primary hepatocytes. The results are shown in Figure 11 C with data presented as mean ± SEM, n = 3 independent experiments (each experiment contains at least three replicates), p- values by two-way ANOVA with Sidak post-hoc test: *p < 0.05 for the difference between genotypes.

[0351] These results indicate that inhibition of SIK3 in hepatocytes is able to reduce hepatocyte lipogenesis through either genetic manipulation (SIK3 KO hepatocytes) or through administration of a pharmacological inhibitor (Pterosin B). Furthermore, when the SIK3 KO hepatocytes were treated with a pharmacological SIK-3 inhibitor (Pterosin B) a further reduction lipid production was observed, likely due to inhibition of other SIK isoforms such as SIK1 and SIK2. The experiments showed decreased lipid synthesis in hepatocytes with SIK3 inhibition, indicating that SIK3 inhibition may be useful for100621 1481reducing excessive fat synthesis, a major driver of fatty liver disease in obese subjects, and therefore reducing fat accumulation in the liver.

[0352] A second assay was performed to investigate the effect of lipid utilization in SIK-3 inhibited hepatocytes. Primary hepatocytes were harvested from WT (Sik3lox / lox) and liver-specific SIK3-KO (AlbCre / +Sik3lox / lox) mice. Rates of oxygen consumption (JO2) were determined in permeabilised primary hepatocytes isolated from WT and liver-specific SIK3-KO mice. Hepatocytes were incubated in the presence of buffer alone (basal) and 25 or 50 pM palmitoyl-CoA (P-CoA). The results of the lipid utilization assay are shown in Figure 11 D. All data are shown as the mean ± SEM, n = 3-4 independent experiment per genotype, p-values by Student’s t-test: *p< 0.05.

[0353] The results of the lipid utilization assay show that hepatocytes harvested from SIK-3 KO mice had increased lipid oxidation when treated with 25pM and 50pM palmityl-CoA compared to the wild type mice. This indicates that SIK3 inhibition is able to enhance lipid utilization in the liver, and useful for treating or preventing fatty liver diseases associated with fat storage in the liver, or reversing or ameliorating fat storage in the liver.

[0354] WT C57BL / 6J mice were fed a high fat diet for 11 weeks starting from 9 weeks of age, and placebo or YKL-05-099 (18 mg / kg), or GLPG-3970 (50mg / kg) treatment began at 20 weeks of age. The mice were euthanized at 26 weeks of age and the livers collected for analysis. Photographs of the livers of the placebo treated and SIK-3 inhibitor treated mice are shown in Figures 11 A and 11 B (left most insert). The placebo livers show increased discoloration (the whiteness indicates more fat accumulation and storage in the liver) compared to the livers of the mice treated with the SIK-3 inhibitor (the darker and reddish appearance indicates less fat stored in the liver).

[0355] The extracted livers were biopsied and images of hematoxylin and eosin (H&E) stain of biopsied liver tissue from high fat-fed obese mice treated with placebo or YKL-05-099 or GLPG-3970 are shown in Figures 11 A and 11 B. Lipid droplets appear white and round in H&E staining. In both Figures 11 A and 11 B it can be seen that the livers of the placebo treated mice have significant fat deposits (in the white / round specifical regions indicated in the central and right hand side panels of the image) where as the livers of the SIK-3 inhibitor treated mice have significantly less fat deposits100621 1481(there are less white / round regions visible in the central and right hand side panels of the images). In particular the GLPG-3970 treated mice have very few visible fat deposits in the liver samples.

[0356] These results indicate that administration of a pharmacological SIK-3 inhibitor is able to treat and reverse the build-up of fatty deposits in the liver in mice on a high-fat diet. This indicates the utility of SIK3 inhibition in both suppressing the progression and treating fatty liver disease.

[0357] The liver fat content in high-fat fed mice was measured by looking at the liver triglyceride levels in placebo treated vs GLPG-3970 or YKL-05-099 treated mice.

[0358] WT C57BL / 6J mice were fed a high fat diet for 11 weeks starting from 9 weeks of age, and placebo or YKL-05-099 treatment began at 20 weeks of age. Liver triglyceride levels from high fat-fed obese mice treated with placebo or YKL-05-099. The results are shown in Figure 11 E. YKL-05-099 treatment led to a significant reduction in liver triglyceride levels.

[0359] WT C57BL / 6J mice were fed a high fat diet for 12 weeks starting from 8 weeks of age, and placebo or GLPG3970 treatment (25mg or 50mg / kg) began at 20 weeks of age. Liver triglyceride levels from high fat-fed obese mice treated with placebo or GLPG3970. These results are shown in Figure 11 F. The GLPG2970 treatment led to a significant reduction in liver triglyceride levels.

[0360] These results indicate that administration of a pharmacological SIK-3 inhibitor is able to potentially reverse triglyceride accumulation in the liver of mice on a high-fat diet and inhibit the progression of fatty liver disease. This indicates the benefit of administration of a SIK-3 inhibitor to treat fatty liver disease.

[0361] Example 6: Combination treatment of an SIK-3 inhibitor and a GLP-1 agonist for obesity

[0362] Typically, the dosage range of the GLP-1 agonist semaglutide that is used in the clinic is 2 - 2.4 mg, once weekly in obese patients. The inventors compared the use of a combination treatment of a sub-clinical dosage of semaglutide and a SIK-3 inhibitor on weight loss and body composition to treatment with semaglutide only, SIK-3 inhibitor only, or placebo.100621 1481

[0363] WT C57BL / 6J mice were fed a high fat diet for 12 weeks starting from 8 weeks of age, and placebo, semaglutide (10 nmol / kg), GLPG3970 (25 mg / kg), or combination (10 nmol / kg semaglutide + 25 mg / kg GLPG3970) treatment began at 20 weeks of age. Body weight, fat mass, and lean mass were measured. Combination treatment led to a significant reduction in body weight compared to semaglutide only, GLPG3970 only, or placebo treatment (Figure 12A, 12B, and 12C).

[0364] The lean mass of the combination treatment group was maintained compared to semaglutide only, GLPG3970 only, or placebo treatments (Figure 12E), while fat mass was significantly decreased (Figure 12D).

[0365] Collectively, this result suggests that combination treatment using a SIK-3 inhibitor and a GLP-1 agonist has a synergistic effect on weight loss and obesity in obese subjects.

[0366] Example 7: Combination treatment of an SIK-3 inhibitor and leptin for obesity

[0367] Typically, the dosage range of the leptin receptor agonist, leptin, that is used clinically is 2.5 - 5 mg once daily. The inventors compared the use of a combination treatment of a sub-clinical dosage of leptin and a SIK-3 inhibitor on weight loss and body composition to treatment with leptin only, SIK-3 inhibitor only, or placebo.

[0368] WT C57BL / 6J mice were fed a high fat diet for 12 weeks starting from 8 weeks of age, and placebo, leptin (0.75 g / kg), GLPG3970 (25 mg / kg), or combination (0.75 g / kg eptin + 25 mg / kg GLPG3970) treatment began at 20 weeks of age. Body weight, fat mass, and lean mass were measured. Combination treatment led to a significant reduction in body weight compared to leptin only, GLPG3970 only, or placebo treatment (Figure 13A and 13B).

[0369] The lean mass of the combination treatment group was maintained compared to leptin only or GLPG3970 only treatments (Figure 13D), while fat mass was significantly decreased (Figure 13C).

[0370] Collectively, this result suggests that combination treatment using a SIK-3 inhibitor and a leptin receptor agonist has a synergistic effect on weight loss and obesity in obese subjects.100621 1481

[0371] Example 8: Combination treatment of a SIK-3 inhibitor and a GLP-1 agonist for diabetes

[0372] The effect of treatment of a combination of a SIK-3 inhibitor and a GLP-1 agonist was tested in a HFD-induced insulin resistance and type II diabetic mice model. A cohort of wild type male C57 / BL6 mice was purchased from The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. These mice were treated with high-fat diet (46% of calories from fat, 20% calories from protein and 34% calories from carbohydrate, Specialty Feeds, Australia) for 12 weeks. These mice were randomly allocated into two groups, to be treated with a GLP-1 agonist only or with a combination treatment with a GLP-1 agonist and a SIK-3 inhibitor. Treatments were administrated through oral gavage once every 48h for GLP1 agonist and twice daily for SIK-3 inhibitor for up to 3 weeks.

[0373] After 3 weeks of treatment, mice were fasted for 6 hours and fasting blood glucose level measured and recorded. Blood glucose levels were measured by Accu- check Performa glucometers (Roche, Switzerland) by assessing blood from tail tip. The fasted blood glucose levels from Semaglutide, or Semaglutide + GLPG3970 treated mice are shown in figure 14A. It can be seen that mice treated with the combination had lower blood glucose levels compared to mice treated with only Semaglutide.

[0374] Oral glucose tolerance tests were also performed, and the results are shown in figures 14B and 14C. Administration of the combination of the SIK-3 inhibitor GLPG3970 and GLP-1 resulted in lower blood glucose levels as measured in oral glucose tolerance tests, indicative of improved glycaemic control.

[0375] Fasting / Re-fed blood glucose level measurement.

[0376] Glucose sensitivity will be assessed through fast / refed blood glucose test and insulin secretion level will be measured. Mice will be fasted overnight (16 hours) and 30 mins of refed time, blood glucose will be measured before and after refed by collecting blood from tail tips. To determine insulin secretion level, mouse eye bleed will be collected before and after refed and centrifuged at 4 °C 14,800 RPM for 10 mins to separate plasma for insulin level measurement. 10 pl of neat fasting plasma and 10 pl of 1 in 3 diluted refed plasma will be added to mouse ultrasensitive insulin ELISA kit to investigate insulin secretion level.100621 1481

[0377] Insulin ELISA.

[0378] Mouse ultrasensitive insulin ELISA kit will be used to measure insulin secretion both in vitro and in vivo. 10 l of sample will be added to the ELISA plate with 75 pl of conjugate buffer and shaken at room temperature with 900 RPM for 2 hours. Then, the ELISA plate will be washed using the ELISA wash for 6 times and 100 pl of TMB will be added to each well. The sample will be shaken for another 15 mins and stop buffer will be added. Then the ELISA result will be read by Enspire Plate Reader and analysed by Prism 10.0.

[0379] Data is presented as means ± SEM. Differences between treatment groups under different experimental conditions are assessed using Student-t test. Differences between groups of mice are assessed by two-way ANOVA or repeated-measures ANOVA. Correlation coefficient is calculated using Spearman’s rank correlation coefficient. Statistical analyses are assessed using Prism software 10.0. Differences are regarded as statistically significant if *P < 0.05; **P < 0.01 ; ***P < 0.001 ; ****P < 0.0001 .

[0380] Mice administered with the combination treatment are expected to have improved glucose tolerance and / or insulin secretion compared to placebo or SIK-3 inhibitor only, and do display improved glucose tolerance and glycaemic control compared to administration of GLP-1 agonist only.

[0381] Example 9: Combination treatment of an SIK-3 inhibitor and a leptin receptor agonist for diabetes

[0382] The effect of treatment of a combination of a SIK-3 inhibitor and a leptin receptor agonist will be tested in a HFD & STZ induced type II diabetic mice model. A cohort of wild type male C57 / BL6 mice will be purchased from The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. These mice will be treated with high-fat diet (46% of calories from fat, 20% calories from protein and 34% calories from carbohydrate, Specialty Feeds, Australia) for 4 weeks prior to streptozotocin (STZ, Sigma) injection. Mice will be fasted for 4 hours and intraperitoneally injected with 5 doses of 40 mg / kg of STZ within 2 weeks. STZ will be dissolved in sodium citrate buffer (pH = 4.5) right before the injection. Body weight and blood glucose will be measured weekly since HFD, blood will be collected from mouse tail tips and blood glucose will be determined via Accu-check Performa glucometers (Roche, Switzerland). Two weeks100621 1481after STZ injection, the average blood glucose level will spike up to 15.4mmol / L. These mice will randomly allocated into four groups, to be treated with placebo, a leptin receptor agonist only, a SIK-3 inhibitor only, and a combination treatment with a leptin receptor agonist and a SIK-3 inhibitor. Treatments will be administrated through oral gavage once per day for 4 weeks.

[0383] After 4 weeks of treatment, an intraperitoneal glucose tolerance test (IPGTT) will be performed to investigate glucose clearance ability. Mice will be fasted for 6 hours prior to glucose injection, weighed, and basal blood glucose level measured and recorded. Then the mice will be intraperitoneally injected with 1 g / kg body weight of glucose (dissolved in saline). Blood glucose levels will be measured at 15, 30, 60, 90, 120 mins time point post glucose injection. Blood glucose levels will be measured by Accu-check Performa glucometers (Roche, Switzerland) by assessing blood from tail tip.

[0384] Fasting / Re-fed blood glucose level measurement. Glucose sensitivity will be assessed through fast / refed blood glucose test and insulin secretion level will be measured. Mice will be fasted overnight (16 hours) and 30 mins of refed time, blood glucose will be measured before and after refed by collecting blood from tail tips. To determine insulin secretion level, mouse eye bleed will be collected before and after refed and centrifuged at 4°C 14,800 RPM for 10 mins to separate plasma for insulin level measurement. 10 pl of neat fasting plasma and 10 pl of 1 in 3 diluted refed plasma will be added to mouse ultrasensitive insulin ELISA kit to investigate insulin secretion level.

[0385] Insulin ELISA. Mouse ultrasensitive insulin ELISA kit will be used to measure insulin secretion both in vitro and in vivo. 10 pl of sample will be added to the ELISA plate with 75 pl of conjugate buffer and shaken at room temperature with 900 RPM for 2 hours. Then, the ELISA plate will be washed using the ELISA wash for 6 times and 100 pl of TMB will be added to each well. The sample will be shaken for another 15 mins and stop buffer will be added. Then the ELISA result will be read by Enspire Plate Reader and analysed by Prism 10.0.

[0386] Data will be presented as means ± SEM. Differences between treatment groups under different experimental conditions will be assessed using Student-t test. Differences between groups of mice will be assessed by two-way ANOVA or repeated-100621 1481measures ANOVA. Correlation coefficient will be calculated using Spearman’s rank correlation coefficient. Statistical analyses will be assessed using Prism software 10.0. Differences will be regarded as statistically significant if *P < 0.05; **P < 0.01 ; ***P < 0.001 ; ****p< O.QQO1.

[0387] Mice administered with the combination treatment are expected to have improved glucose tolerance and / or insulin secretion compared to SIK-3 inhibitor only, leptin receptor agonist only, or placebo treatment.

[0388] Example 10: Combination treatment of an SIK-3 inhibitor and a GLP-1 agonist for NASH / NAFLD

[0389] WT C57BL / 6J mice will be fed a high fat diet for 11 weeks starting from 9 weeks of age, and placebo, a GLP-1 agonist only, a SIK-3 inhibitor only, or a combination of a GLP-1 agonist and a SIK-3 inhibitor treatment will begin at 20 weeks of age. The mice will be euthanized at 26 weeks of age and the livers collected for analysis. Photographs of the livers of the combination treatment are expected to show less discoloration (a darker and reddish appearance indicates less fat stored in the liver) compared to the livers of mice treated with placebo, a GLP-1 agonist only, or a SIK-3 inhibitor only. More whiteness indicating more fat accumulation and storage in the liver is expected to be observed in the livers of mice treated with placebo, a GLP-1 agonist only, or a SIK-3 inhibitor only.

[0390] The extracted livers will be biopsied and images of hematoxylin and eosin (H&E) stain of biopsied liver tissue will be obtained from high fat-fed obese mice treated with placebo, a GLP-1 agonist only, a SIK-3 inhibitor only, or a combination of a GLP-1 agonist and a SIK-3 inhibitor. Lipid droplets will appear white and round in H&E staining. The livers of the placebo treated mice will have significant fat deposits (the white / round specifical regions of the image) whereas the livers of the mice treated with the combination will have significantly less fat deposits (there are less white / round regions visible). In particular the mice treated with the combination are expected to have very few visible fat deposits in the liver samples.

[0391] These results are expected to indicate that administration of a combination of a GLP-1 agonist and a SIK-3 inhibitor is able to treat and reverse the build-up of fatty deposits in the liver in mice on a high-fat diet. This is expected to indicate the utility of100621 1481the combination treatment in both suppressing the progression of and treatment of fatty liver disease.

[0392] The liver fat content in high-fat fed mice will be measured by looking at the liver triglyceride levels in mice treated with placebo, a GLP-1 agonist only, a SIK-3 inhibitor only, or a combination of a GLP-1 agonist and a SIK-3 inhibitor treatment.

[0393] WT C57BL / 6J mice will be fed a high fat diet for 12 weeks starting from 8 weeks of age, and placebo, a GLP-1 agonist only, a SIK-3 inhibitor only, or a combination of a GLP-1 agonist and a SIK-3 inhibitor treatment will begin at 20 weeks of age. Liver triglyceride levels will be measured in high fat-fed obese mice treated with placebo, a GLP-1 agonist only, a SIK-3 inhibitor only, or a combination of a GLP-1 agonist and a SIK-3 inhibitor. These results are expected to show that the combination treatment leads to a significant reduction in liver triglyceride levels compared to mice treated with placebo, a GLP-1 agonist only, or a SIK-3 inhibitor only.

[0394] These results are expected to indicate that administration of a combination treatment of a GLP-1 agonist and a SIK-3 inhibitor is able to potentially reverse triglyceride accumulation in the liver of mice on a high-fat diet and inhibit the progression of fatty liver disease. This will indicate the benefit of administration of a combination treatment of a GLP-1 agonist and a SIK-3 inhibitor to treat fatty liver disease.

[0395] Data showing reduction in fatty liver disease following the administration of a SIK-3 inhibitor only is shown in figures 15A-D and 16A-B. Data showing reduced liver disease in liver-specific SIK-3 knockout mice is shown in figure 17A-D and 18A-C. This data confirms that inhibition of SIK-3 is able to supress or reverse fatty liver disease. It is expected that administration of the combination of a SIK-3 inhibitor and a GLP-1 agonist will show enhanced suppression or reversal of fatty liver disease.

[0396] Example 11 : Combination treatment of an SIK-3 inhibitor and leptin for NASH / NAFLD

[0397] WT C57BL / 6J mice will be fed a high fat diet for 11 weeks starting from 9 weeks of age, and placebo, a leptin receptor agonist only, a SIK-3 inhibitor only, or a combination of a leptin receptor agonist and a SIK-3 inhibitor treatment will begin at 20 weeks of age. The mice will be euthanized at 26 weeks of age and the livers collected100621 1481for analysis. Photographs of the livers of the combination treatment are expected to show less discoloration (a darker and reddish appearance indicates less fat stored in the liver) compared to the livers of mice treated with placebo, a leptin receptor agonist only, or a SIK-3 inhibitor only. More whiteness indicating more fat accumulation and storage in the liver is expected to be observed in the livers of mice treated with placebo, a leptin receptor agonist only, or a SIK-3 inhibitor only.

[0398] The extracted livers will be biopsied and images of hematoxylin and eosin (H&E) stain of biopsied liver tissue will be obtained from high fat-fed obese mice treated with placebo, a leptin receptor agonist only, a SIK-3 inhibitor only, or a combination of a leptin receptor agonist and a SIK-3 inhibitor. Lipid droplets will appear white and round in H&E staining. The livers of the placebo treated mice will have significant fat deposits (the white / round specifical regions of the image) whereas the livers of the mice treated with the combination will have significantly less fat deposits (there are less white / round regions visible). In particular the mice treated with the combination are expected to have very few visible fat deposits in the liver samples.

[0399] These results are expected to indicate that administration of a combination of a leptin receptor agonist and a SIK-3 inhibitor is able to treat and reverse the build-up of fatty deposits in the liver in mice on a high-fat diet.

[0400] The liver fat content in high-fat fed mice will be measured by looking at the liver triglyceride levels in mice treated with placebo, a leptin receptor agonist only, a SIK-3 inhibitor only, or a combination of a leptin receptor agonist and a SIK-3 inhibitor treatment.

[0401] WT C57BL / 6J mice will be fed a high fat diet for 12 weeks starting from 8 weeks of age, and placebo, a leptin receptor agonist only, a SIK-3 inhibitor only, or a combination of a leptin receptor agonist and a SIK-3 inhibitor treatment will begin at 20 weeks of age. Liver triglyceride levels will be measured in high fat-fed obese mice treated with placebo, a leptin receptor agonist only, a SIK-3 inhibitor only, or a combination of a leptin receptor agonist and a SIK-3 inhibitor. These results are expected to show that the combination treatment leads to a significant reduction in liver triglyceride levels compared to mice treated with placebo, a leptin receptor agonist only, or a SIK-3 inhibitor only.100621 1481

[0402] These results are expected to indicate that administration of a combination treatment of a leptin receptor agonist and a SIK-3 inhibitor is able to potentially reverse triglyceride accumulation in the liver of mice on a high-fat diet and inhibit the progression of fatty liver disease.

[0403] Data showing reduction in fatty liver disease following the administration of a SIK-3 inhibitor only is shown in figures 15A-D and 16A-B. Data showing reduced liver disease in liver-specific SIK-3 knockout mice is shown in figure 17A-D and 18A-C. This data confirms that inhibition of SIK-3 is able to supress or reverse fatty liver disease. It is expected that administration of the combination of a SIK-3 inhibitor and a leptin receptor agonist will show enhanced suppression or reversal of fatty liver disease.100621 1481

Claims

CLAIMS1 . A method of treating obesity in an individual in need thereof, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby treating obesity in the individual.

2. A method of treating, or minimising the risk of, an obesity-related disease or disorder, the method comprising administering to an individual suffering from or at risk of suffering from an obesity-related disease or disorder a SIK-3 inhibitor and a metabolic modulator to the individual, thereby treating, or minimising the risk of, an obesity related disorder in the individual.

3. A method of reducing adiposity in an individual in need thereof, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby reducing adiposity in the individual.

4. A method of reducing the body weight of an individual in need thereof, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby reducing body weight of the individual.

5. A method of increasing white adipose tissue browning in an individual in need thereof, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby increasing white adipose tissue browning in the individual.

6. A method of preventing or minimising the weight gain of an individual consuming a high energy / caloric diet, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby preventing or minimising the weight gain of the individual consuming a high energy / caloric diet.

7. A method of preventing or minimising adiposity in individual consuming a high energy / caloric diet, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby preventing or minimising adiposity in the individual consuming a high energy / caloric diet.

8. A method of enhancing energy expenditure in an individual in need thereof, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby enhancing energy expenditure in the individual.100621 14819. A method of promoting weight loss in an individual in need thereof, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby promoting weight loss in the individual.

10. A method of improving insulin secretion in an individual in need thereof, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby improving insulin secretion in the individual.

11. A method of promoting blood glucose clearance in an overweight or obese individual, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby promoting blood glucose clearance in the individual.

12. A method of promoting or improving glycaemic control in an overweight or obese individual, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby promoting glycaemic control in the individual.

13. A method of treating pre-diabetes or diabetes in an individual, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby treating diabetes in individual in need thereof.

14. A method of treating a disease or disorder associated with dysregulated leptin signalling in an individual in need thereof, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby treating the disease or disorder associated with dysregulated leptin signaling in the individual.

15. A method of increasing sensitization of leptin action and / or signalling in an individual in need thereof, the method comprising administering a SIK-3 inhibitor and a metabolic modulator to the individual, thereby increasing sensitization of leptin action and / or signalling in the individual.

16. The method of any one of the preceding claims, wherein the SIK-3 inhibitor is more potent for inhibition of SIK family kinases, preferably SIK-3 kinase, compared inhibition of other kinases.

17. The method of any one of the preceding claims, wherein the SIK-3 inhibitor does not exhibit significant inhibitory activity for kinase ABL and / or the SIK-3 inhibitor does not exhibit significant activity for Bruton’s tyrosine kinase and / or Src kinase.100621 148118. The method of any one of the preceding claims, wherein the SIK-3 inhibitor demonstrates higher inhibitory activity for SIK-3 over SIK-1 or SIK-2 or both.

19. The method of any one of the preceding claims, wherein the SIK-3 inhibitor has at least 2, preferably at least 5, times higher inhibitory activity for SIK-3 over SIK- 1.

20. The method of any one of the preceding claims, wherein the SIK-3 inhibitor has at least 2, preferably at least 5, times high inhibitory activity for SIK-3 over SIK-2.21 . The method of any one of the preceding claims, wherein the individual is overweight or obese.

22. The method of any one of the preceding claims, wherein the individual has a BMI greater than 20, 21 , 22, 23, 24, 25, 26, 27, 28 or 29 kg / m2.

23. The method of any one of the preceding claims, wherein the individual in need thereof has been overweight or obese for at least 6 months prior to starting treatment.

24. The method of any one of the preceding claims, wherein the individual is insulin resistant.

25. The method of any one of the preceding claims, wherein the individual has been diagnosed with insulin deficiency.

26. The method of any one of the preceding claims, wherein the individual has a moderate, severe or absolute insulin deficiency.

27. The method of any one of the preceding claims, wherein the individual has been diagnosed as pre-diabetic or diabetic.

28. The method of any one of the preceding claims, wherein the individual has one or more obesity related diseases or disorders.

29. The method of claim 2 or claim 28, wherein the obesity-related disease or disorder is selected from the group consisting of obesity, pre-obesity, morbid obesity, Prader-Willi Syndrome, Hypothalamic Injury Associated Obesity, hyperlipidemia, hypertension, diabetes, lipodystrophy, lipodema, Bardet-Biedl100621 1481Syndrome, Cohen Syndrome, cardiovascular disease, arthritis, stroke, metabolic syndrome, hypothyroid, and MOMO Syndrome.

30. The method of claims 2 or 28 or 29, wherein the method of treatment commenced after the onset of the disease or disorder.31 . Use of a SIK-3 inhibitor and a metabolic modulator in the manufacture of a medicament for treating obesity or an obesity related disorder in an individual in need thereof.

32. Use of a SIK-3 inhibitor and a metabolic modulator in the manufacture of a medicament for reducing adiposity in an individual in need thereof.

33. Use of a SIK-3 inhibitor and a metabolic modulator in the manufacture of a medicament for reducing the body weight of an individual in need thereof.

34. Use of a SIK-3 inhibitor and a metabolic modulator in the manufacture of a medicament for increasing white adipose tissue browning in an individual in need thereof.

35. Use of a SIK-3 inhibitor and a metabolic modulator in the manufacture of a medicament for preventing or minimising the weight gain, or preventing or minimising adiposity, in an individual consuming a high energy / caloric diet.

36. Use of a SIK-3 inhibitor and a metabolic modulator in the manufacture of a medicament for enhancing energy expenditure in an individual in need thereof.

37. Use of a SIK-3 inhibitor and a metabolic modulator in the manufacture of a medicament for promoting weight loss in an individual in need thereof.

38. Use of a SIK-3 inhibitor and a metabolic modulator in the manufacture of a medicament for improving insulin secretion in an individual in need thereof.

39. Use of a SIK-3 inhibitor and a metabolic modulator in the manufacture of a medicament for promoting blood glucose clearance in an overweight or obese individual.100621 148140. Use of a SIK-3 inhibitor and a metabolic modulator in the manufacture of a medicament for promoting or improving glycaemic control in an overweight or obese individual.41 . Use of a SIK-3 inhibitor and a metabolic modulator in the manufacture of a medicament for treating diabetes in an overweight or obese individual.

42. Use of a SIK-3 inhibitor and a metabolic modulator in the manufacture of a medicament for treating a disease or disorder associated with dysregulated leptin signalling in an individual.

43. Use of a SIK-3 inhibitor and a metabolic modulator in the manufacture of a medicament for increasing sensitization of leptin action and / or signalling in an individual.

44. A SIK-3 inhibitor and a metabolic modulator for use in treating obesity or an obesity related disorder in an individual in need thereof.

45. A SIK-3 inhibitor and a metabolic modulator for use in reducing adiposity in an individual in need thereof.

46. A SIK-3 inhibitor and a metabolic modulator for use in reducing the body weight of an individual.

47. A SIK-3 inhibitor and a metabolic modulator for use in increasing white adipose tissue browning.

48. A SIK-3 inhibitor and a metabolic modulator for use in preventing or minimising the weight gain, or preventing or minimising adiposity, in an individual consuming a high energy / caloric diet.

49. A SIK-3 inhibitor and a metabolic modulator for use in enhancing energy expenditure in an individual in need thereof.

50. A SIK-3 inhibitor and a metabolic modulator for use in promoting weight loss in an individual in need thereof.51 . A SIK-3 inhibitor and a metabolic modulator for use in improving insulin secretion in an individual in need thereof.100621 148152. A SIK-3 inhibitor and a metabolic modulator for use in promoting blood glucose clearance in an overweight or obese individual.

53. A SIK-3 inhibitor and a metabolic modulator for use in promoting or improving glycaemic control in an overweight or obese individual.

54. A SIK-3 inhibitor and a metabolic modulator for use in treating pre-diabetes or diabetes in an overweight or obese individual.

55. A SIK-3 inhibitor and a metabolic modulator for use in treating a disease or disorder associated with dysregulated leptin signalling in an individual.

56. A SIK-3 inhibitor and a metabolic modulator for use in increasing sensitization of leptin action and / or signalling in an individual.

57. A method of decreasing food intake in an individual in need thereof comprising the step of administering to the individual a SIK-3 inhibitor and a metabolic modulator.

58. A method of reducing or inhibiting appetite in an individual in need thereof, the method comprising administering to the individual a SIK-3 inhibitor and a metabolic modulator, thereby inhibiting appetite in the individual.

59. The method of claim 57 or 58, wherein the individual is an overweight or obese individual.

60. The method of any one of claims 57 to 59, wherein the individual has prediabetes or diabetes.61 . Use of a SIK-3 inhibitor and a metabolic modulator in the manufacture of a medicament for decreasing food intake in an individual in need thereof.

62. Use of a SIK-3 inhibitor and a metabolic modulator in the manufacture of a medicament for reducing or inhibiting appetite in an individual in need thereof.

63. A SIK-3 inhibitor and a metabolic modulator for use in decreasing food intake in an individual in need thereof.100621 148164. A SIK-3 inhibitor and a metabolic modulator for use in reducing or inhibiting appetite in an individual in need thereof.

65. A method of treating fatty liver disease in an individual in need thereof, the method comprising administering to the individual a SIK-3 inhibitor and a metabolic modulator, thereby treating fatty liver disease in the individual in need thereof.

66. The method of claim 65 wherein the SIK-3 inhibitor is more potent for inhibition of SIK family kinases, preferably SIK-3 kinase, compared inhibition of other kinases.

67. The method of claim 65 or 66 wherein the SIK-3 inhibitor does not exhibit significant inhibitory activity for kinase ABL and / or the SIK-3 inhibitor does not show significant activity for Bruton’s tyrosine kinase and / or Src kinase.

68. The method of any one of claims 65 to 67, wherein the SIK-3 inhibitor demonstrates higher inhibitory activity for SIK-3 compared to SIK-1 or SIK-2, or both SIK-1 and SIK-2.

69. The method of any one of claims 65 to 68, wherein the SIK-3 inhibitor has at least 2, preferably at least 5, times higher inhibitory activity for SIK-3 than SIK-1 .

70. The method of any one of claims 65 to 69, wherein the SIK-3 inhibitor has at least 2, preferably at least 5, times high inhibitory activity for SIK-3 than SIK-2.71 . The method of claim any one of claims 65 to 70, wherein the fatty liver disease is non-alcoholic fatty liver disease (NAFLD).

72. The method of claim any one of claims 65 to 70, wherein the fatty liver disease is non-alcoholic steatohepatitis (NASH).

73. The method of any one of claims 65 to 72, wherein the individual is an overweight or obese individual.

74. The method of any one of claims 65 to 73, wherein the individual with a fatty liver disease also has insulin resistance.

75. The method of any one of claims 65 to 74, wherein the individual with a fatty liver disease has pre-diabetes or diabetes.100621 14817Q. The method of any one of claims 65 to 72, wherein the individual is not an overweight or obese individual.

77. The method of any one of claims 65 to 73, wherein the individual with a fatty liver disease does not have insulin resistance.

78. The method of any one of claims 65 to 73, wherein the individual with a fatty liver disease does not have diabetes.

79. Use of a SIK-3 inhibitor and a metabolic modulator in the manufacture of a medicament for treating fatty liver disease in an individual in need thereof.

80. A SIK-3 and an metabolic modulator for use in treating fatty liver disease in an individual in need thereof.81 . A pharmaceutical composition comprising a SIK-3 inhibitor and a metabolic modulator.

82. A kit comprising: a pharmaceutical composition comprising a SIK-3 inhibitor; and a pharmaceutical composition comprising a metabolic modulator; and optionally a label or package insert with instructions for use.

83. The metabolic modulator as defined in any one of the proceeding claims, wherein the metabolic modulator is not quercetin.

84. The method of any one of claims 1 to 30 or 68-78 wherein the metabolic modulator is a leptin agonist.

85. The method of any one of claims 1 to 30 or 68-78 wherein the metabolic modulator is a GLP-1 agonist.100621 1481

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