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WO-2026090658-A1 - COMBINATION TREATMENT

WO2026090658A1WO 2026090658 A1WO2026090658 A1WO 2026090658A1WO-2026090658-A1

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.

Inventors

  • LOH, Kim Yong
  • ONDA, Danise Ann

Assignees

  • ST VINCENT'S INSTITUTE OF MEDICAL RESEARCH

Dates

Publication Date
20260507
Application Date
20251028
Priority Date
20241028

Claims (20)

  1. 1 . 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. 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. 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. 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. 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. 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. 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. 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 1481
  9. 9. 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. 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. 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. 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. 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. 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. 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. 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. 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 1481
  18. 18. 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. 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. 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.

Description

Combination treatment Related 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). Patients 100621 1481 having 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