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EA-053299-B1 - Dual Amyline and Calcitonin Receptor Agonists and Their Uses

EA053299B1EA 053299 B1EA053299 B1EA 053299B1EA-053299-B1

Abstract

The present invention relates to the field of medicine. More specifically, the present invention relates to the treatment of diabetes, obesity and/or dyslipidemia. The present invention relates to the use of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, in combination with a GLP-1 agonist, a dual GIP/GLP-1 agonist, a triagonist of glucagon, GIP, and GLP-1, or an oxyntomodulin analogue, for the treatment of diabetes, obesity, non-alcoholic steatohepatitis (NASH) and/or dyslipidemia.

Inventors

  • Коскун Тамер
  • Цюй Хунчан
  • КАРСДАЛ Мортен Ассер
  • АНДРЕАССЕН Ким Витц
  • ХЕНРИКСЕН Ким

Assignees

  • ЭЛИ ЛИЛЛИ ЭНД КОМПАНИ
  • КИБАЙОСАЙНС СА

Dates

Publication Date
20260504
Application Date
20211217
Priority Date
20201218

Claims (12)

  1. 1. Use of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, in combination with a GLP-1 agonist, for the treatment of a condition selected from the group consisting of diabetes, obesity, non-alcoholic steatohepatitis (NASH) and dyslipidemia.
  2. 2. The use according to claim 1, wherein the GLP-1 agonist is selected from the group consisting of compound III (SEQ ID NO: 6), compound VIII (SEQ ID NO: 12) and compound IX (SEQ ID NO: 13) or pharmaceutically acceptable salts thereof.
  3. 3. The use according to claim 1 or 2, wherein the compound comprising SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof is intended for separate, simultaneous or sequential administration in combination with a GLP-1 agonist.
  4. 4. Use of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, in combination with a dual GIP/GLP-1 agonist, for the treatment of a condition selected from the group consisting of diabetes, obesity, NASH and dyslipidemia.
  5. 5. The use according to claim 4, wherein the dual GIP/GLP-1 agonist is selected from the group consisting of compound VI (SEQ ID NO: 9) and compound VII (SEQ ID NO: 10) or pharmaceutically acceptable salts thereof. - 20 053299
  6. 6. The use according to claim 4 or 5, wherein the compound comprising SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof is intended for separate, simultaneous or sequential administration in combination with a dual GIP/GLP-1 agonist.
  7. 7. Use of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, in combination with a glucagon triagonist, GIP, and GLP-1, for the treatment of a condition selected from the group consisting of diabetes, obesity, NASH, and dyslipidemia.
  8. 8. The use according to claim 7, wherein the triagonist of glucagon, GIP, and GLP-1 is compound V (SEQ ID NO: 8) or a pharmaceutically acceptable salt thereof.
  9. 9. The use according to claim 7 or 8, wherein the compound comprising SEQ ID NO: 1 is intended for separate, simultaneous or sequential administration in combination with a glucagon triagonist, GIP, and GLP-1.
  10. 10. Use of a compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, in combination with an oxyntomodulin analogue, for the treatment of a condition selected from the group consisting of diabetes, obesity, NASH and dyslipidemia.
  11. 11. The use according to claim 10, wherein the oxyntomodulin analogue is compound IV (SEQ ID NO: 7) or a pharmaceutically acceptable salt thereof.
  12. 12. The use according to claim 10 or 11, wherein the compound comprising SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is intended for separate, simultaneous or sequential administration in combination with an oxyntomodulin analogue.

Description

The present invention relates to the field of medicine. More specifically, the present invention relates to the treatment of diabetes, obesity, non-alcoholic steatohepatitis (NASH), and/or dyslipidemia. The present invention relates to compounds that agonize both amylin and calcitonin receptors and, therefore, can reduce food intake, body weight, glucose and/or triglyceride levels and can be used to treat diabetes, obesity, NASH, and/or dyslipidemia. The present disclosure also includes pharmaceutical compositions containing such compounds and the therapeutic use of such compounds and pharmaceutical compositions. Amylin is a peptide hormone secreted by pancreatic β cells in conjunction with insulin and is deficient in people with diabetes. It inhibits glucagon secretion, delays gastric emptying, and acts as a satiety agent. An amylin analogue, pramlintide, is available for the treatment of diabetic patients using insulin because it lowers blood sugar. This medication has a half-life of less than an hour and is administered with meals, requiring patients to take multiple doses in one day to utilize this medication. Calcitonin is a hormone produced by the thyroid gland that plays a role in regulating calcium and phosphate levels in the blood. Salmon calcitonin is available for the treatment of conditions associated with high blood calcium levels, such as hypercalcemia. Salmon calcitonin has a short half-life of less than two hours, so patients must take a dose once daily or several times daily to utilize this peptide in their therapy. Compounds that agonize both amylin and calcitonin receptors have been shown to have beneficial effects, such as lowering blood glucose and inducing weight loss. See WO 2016/034604, WO 2015/071229, and WO 2010/085700. The natural half-life of known amylin and calcitonin receptor agonists is short, so prolonged action is desirable. However, chemical modifications intended to increase the time of action have also been shown to decrease efficacy. Furthermore, amylin and calcitonin receptor agonists have stability issues due to their tendency to fibrillate and the presence of a labile disulfide bond at neutral pH. There is a need for alternative compounds that agonize both amylin and calcitonin receptors. Furthermore, there is a need for dual amylin and calcitonin receptor agonists with a prolonged duration of action and maintained efficacy. Therapeutically desirable compounds will agonize both amylin and calcitonin receptors and provide one or more beneficial properties, such as decreased food intake, weight loss, lower blood glucose, lower triglyceride levels, and/or lower insulin levels. Furthermore, therapeutically desirable compounds may have one or more additional beneficial properties, such as a prolonged duration of action with maintained or improved potency in agonizing both amylin and calcitonin receptors, a low risk of immunogenicity, chemical stability at neutral pH, and/or a low risk of fibrillation. Furthermore, the treatment of diabetes, obesity, NASH, and/or dyslipidemia requires a combination of a dual amylin receptor agonist and calcitonin, as described herein, optionally in combination with an incretin or incretin analog. Such a combination will also preferably be more effective than either molecule alone. For example, treatment with such a combination may allow for lower doses of one or both molecules compared to either molecule alone, potentially resulting in fewer side effects (or a shorter duration of one or the other therapy) while maintaining efficacy. It is believed that the novel combination(s) proposed herein will be an effective treatment for diabetes, obesity, NASH, and/or dyslipidemia. Accordingly, the present invention provides a method for treating diabetes, obesity, NASH and/or dyslipidemia, comprising administering to a patient in need of such treatment an effective amount of a dual amylin and calcitonin receptor agonist with an effective amount of an incretin or incretin analogue. The present invention also provides a method for treating clinical or preclinical diabetes, obesity, NASH and/or dyslipidemia, comprising administering to a patient in need of such treatment an effective amount of a dual amylin and calcitonin receptor agonist in combination with an effective amount of an incretin or incretin analogue. Certain compounds disclosed herein that agonize amylin and calcitonin receptors demonstrate effective reductions in food intake and body weight, as well as glucose and insulin levels. Furthermore, certain compounds disclosed herein demonstrate reduced immunogenicity and a low incidence of atrial fibrillation. - 1 053299 The pharmacokinetic properties of some compounds disclosed herein demonstrate significantly increased half-lives, allowing for once-weekly dosing for therapeutic use. Other embodiments of the present invention are applicable to the preparation of such compounds for therapeutic use. Methods for combining the compounds disclose