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WO-2026092583-A1 - THR-BETA MODULATORS, ALONE OR IN COMBINATION WITH GLP-1R\GIPR\GCGR MODULATORS FOR THE TREATMENT OF METABOLIC DISEASES AND ALOPECIA AREATA DISEASES

WO2026092583A1WO 2026092583 A1WO2026092583 A1WO 2026092583A1WO-2026092583-A1

Abstract

Provided herein are method of thyroid hormone receptor beta (THRβ) agonist and combinations comprising a glucagon-like peptide-1 receptor (GLP-1R) agonist and a thyroid hormone receptor beta (THRβ) agonist and methods comprising administering to a subject in need thereof such combinations.

Inventors

  • WU, JINZI JASON

Assignees

  • ASCLETIS PHARMA (CHINA) CO., LIMITED

Dates

Publication Date
20260507
Application Date
20251030
Priority Date
20241030

Claims (20)

  1. A method for preventing, treating, or ameliorating obesity, overweight or alopecia areata disease, comprising administering to a subject in need thereof an effective amount of a THR-βmodulator, wherein the THR-βmodulator is selected from the group consisting of Resmetirom (MGL-3196) , Tiratricol, ALG-055009, ABX-002, HSK31679, TERN-501, CS-060380, Kylo-0603, ECC-4703, CS-060304, HPG-7233, HP-515, CS-27109, Sobetirome, KY-41111 and or stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterium substitutes thereof, isomers thereof, prodrugs thereof, or metabolites thereof.
  2. A method for weight management or chronic weight management, comprising administering to a subject in need thereof an effective amount of a THR-βmodulator of claim 1.
  3. Use of a THR-βmodulator of claim 1 in the preparation of a medicament for the treatment of obesity, alopecia areata disease, or overweight.
  4. Use of a THR-βmodulator of claim 1 in the preparation of a medicament for weight management or chronic weight management.
  5. A method for preventing, treating, or ameliorating obesity or overweight, comprising administering to a subject in need thereof an effective amount of a GLP-1R\GIPR\GCGR modulator, in combination with an effective amount of a THR-βmodulator of claim 1.
  6. A method for weight management or chronic weight management, comprising administering to a subject in need thereof an effective amount of a GLP-1R\GIPR\GCGR modulator, in combination with an effective amount of a THR-βmodulator of claim 1.
  7. Use of a GLP-1R\GIPR\GCGR modulator, in combination with a THR-βmodulator of claim 1 in preparation of a medicament for the treatment of obesity or overweight.
  8. Use of a GLP-1R\GIPR\GCGR modulator, in combination with a THR-βmodulator of claim 1 in preparation of a medicament for weight management or chronic weight management.
  9. The method or the use of any one of the preceding claims, wherein the GLP-1R\GIPR\GCGR modulator and THR-βmodulator are co-formulated into a pharmaceutical composition comprising a GLP-1R\GIPR\GCGR modulator, a THR-βmodulator, and a pharmaceutically acceptable excipient.
  10. The method or the use of any one of the preceding claims, wherein the GLP-1R\GIPR\GCGR modulator is formulated into a pharmaceutical composition comprising a GLP-1R\GIPR\GCGR modulator and a pharmaceutically acceptable excipient, the THR-βmodulator is formulated into a pharmaceutical composition comprising a THR-β modulator and a pharmaceutically acceptable excipient.
  11. The method or the use of any one of the preceding claims, wherein the GLP-1R\GIPR\GCGR modulator is one to three modulators selected from the group consisting of (1) a GLP-1R agonist, (2) a GLP-1R antagonist, (3) a GIPR agonist, (4) a GIPR antagonist, (5) a GCGR agonist, (6) a GCGR antagonist, (7) a GLP-1\GIPR dual agonist, (8) a GLP-1R\GCGR dual agonist (9) a GLP-1R\GIPR dual antagonist, (10) a GLP-1R\GCGR dual antagonist, (11) a GLP-1R\GIPR\GCGR tripe agonist, (12) a GLP-1R\GIPR\GCGR tripe antagonist, (13) a GLP-1R agonist\GIPR antagonist, (14) a GLP-1R agonist\GCGR antagonist, (15) a GLP-1R antagonist\GCGR agonist, (16) a GLP-1R antagonist\GIPR agonist, (17) GLP-1R antagonist\GIPR antagonist, (18) GLP-1R antagonist\GCGR antagonist, (19) a GLP-1R agonist\GIPR antagonist\GCGR agonist, (20) a GLP-1R agonist\GIPR antagonist\GCGR antagonist, and (21) a GLP-1R agonist\GIPR agonist\GCGR antagonist.
  12. The method or the use of any one of the preceding claims, wherein the GLP-1R\GIPR\GCGR modulator is selected from the group consisting of a GLP-1R agonist, a GIPR agonist, a GIPR antagonist, a GLP-1R\GIPR dual agonist, a GLP-1R\GCGR dual agonist, a GLP-1R agonist\GIPR antagonist, a GLP-1R agonist\GCGR antagonist, a GLP-1R\GIPR\GCGR tripe agonist, a GLP-1R agonist\GIPR antagonist\GCGR agonist, a GLP-1R agonist\GIPR antagonist\GCGR antagonist, and a GLP-1R agonist\GIPR agonist\GCGR antagonist.
  13. The method or the use of any one of the preceding claims, wherein the GLP-1R\GIPR\GCGR modulator is selected from the group consisting of Tirzepatide, PEG-Loxenatide, Semaglutide, Beinaglutide, Liraglutide, Dulaglutide, Lixisenatide, Exenatide, Supaglutide, Mazdutide, Albenatide, Visepegenatide, HR-17031, Retatrutide, Ecnoglutide, Survodutide, Efpeglenatide, Glutazumab, Orforglipron, Danuglipron, Lotiglipron, HRS-7535, CagriSema, Exendin-4, HRS-9531, NA-931, RGT-075, NN-9541, GMA106, HDM1002, Efocipegtrutide, ROSE-010, Noiiglutide, Cotadutide, Froniglutide, Amycretin, RAY1225, ZT002, SAL0112, CT-388, Efinopegdutide, Dapiglutide, Pemvidutide, Bofanglutide, Olatorepatide, VK2735, AMG133, CT-868, Aleniglipron, AZD-9550, AZD5004, PB-718, HM-15275, HDM-1005, NN-6177, LY3493269, RAY002, XW-014, XW-015, Utreglutide, PF-06954522, BI3006337, Bamadutide, DR10627, KN056, TERN-601, CT-996, GS-4571, ID110521156, LY3437943, HS-10501, LY-3537031, and or stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterium substitutes thereof, isomers thereof, prodrugs thereof, or metabolites thereof.
  14. The method or the use of any one ofthe preceding claims, wherein the GLP-1R\GIPR\GCGR modulator is selected from the group consisting of Tirzepatide, Semaglutide, Liraglutide, Dulaglutide, VK2735, AMG133 and Retatrutide, Orforglipron, Aleniglipron, AZD5004, or stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterium substitutes thereof, isomers thereof, prodrugs thereof, or metabolites thereof.
  15. The method or the use of any one ofthe preceding claims, wherein the GLP-1R\GIPR\GCGR modulator is selected from those listed in Table 1, or stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterium substitutes thereof, isomers thereof, prodrugs thereof, or metabolites thereof.
  16. The method or the use of any one ofthe preceding claims, wherein the THR-βmodulator is selected from the group consisting of or stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterium substitutes thereof, isomers thereof, prodrugs thereof, or metabolites thereof.
  17. The method or the use of any one ofthe preceding claims, wherein the THR-βmodulator is selected from those listed in Table 2, or stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterium substitutes thereof, isomers thereof, prodrugs thereof, or metabolites thereof.
  18. The method or the use of any one ofthe preceding claims, wherein the GLP-1R\GIPR\GCGR modulator is selected from the group consisting of Tirzepatide, PEG-Loxenatide, Semaglutide, Beinaglutide, Liraglutide, Dulaglutide, Lixisenatide, Exenatide, Supaglutide, Mazdutide, Albenatide, Visepegenatide, HR-17031, Retatrutide, Ecnoglutide, Survodutide, Efpeglenatide, Glutazumab, VK2735, AMG133, Orforglipron, Aleniglipron, AZD5004, Danuglipron, Lotiglipron, CT-996 and or stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterium substitutes thereof, isomers thereof, prodrugs thereof, or metabolites thereof, and the THR-βmodulator is Resmetirom (MGL-3196) or stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterium substitutes thereof, isomers thereof, prodrugs thereof, or metabolites thereof.
  19. The method or the use of any one ofthe preceding claims, wherein the GLP-1R\GIPR\GCGR modulator is selected from the group consisting of Tirzepatide, PEG-Loxenatide, Semaglutide, Beinaglutide, Liraglutide, Dulaglutide, Lixisenatide, Exenatide, Supaglutide, Mazdutide, Albenatide, Visepegenatide, HR-17031, Retatrutide, Ecnoglutide, Survodutide, Efpeglenatide, Glutazumab, VK2735, AMG133, Orforglipron, Aleniglipron, AZD5004, Danuglipron, Lotiglipron, CT-996 and or stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterium substitutes thereof, isomers thereof, prodrugs thereof, or metabolites thereof, and the THR-βmodulator which is ALG-055009, or stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterium substitutes thereof, isomers thereof, prodrugs thereof, or metabolites thereof.
  20. The method or the use of any one ofthe preceding claims, wherein the GLP-1R\GIPR\GCGR modulator is selected from the group consisting of Tirzepatide, PEG-Loxenatide, Semaglutide, Beinaglutide, Liraglutide, Dulaglutide, Lixisenatide, Exenatide, Supaglutide, Mazdutide, Albenatide, Visepegenatide, HR-17031, Retatrutide, Ecnoglutide, Survodutide, Efpeglenatide, Glutazumab, VK2735, AMG133, Orforglipron, Aleniglipron, AZD5004, Danuglipron, Lotiglipron, CT-996 and or stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterium substitutes thereof, isomers thereof, prodrugs thereof, or metabolites thereof, and the THR-βmodulator is or stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterium substitutes thereof, isomers thereof, prodrugs thereof, or metabolites thereof.

Description

THR-BETA MODULATORS, ALONE OR IN COMBINATION WITHGLP-1R\GIPR\GCGR MODULATORS FOR THE TREATMENT OF METABOLIC DISEASES AND ALOPECIA AREATA DISEASES CROSS-REFERENCE TO RELATED APPLICATIONS The present disclosure claims the benefits of the PCT application No. PCT/CN2024/128509 entitled “A compound or a method for the treatment of metabolic diseases and alopecia areata diseases” filed October 30, 2024, the PCT application No. PCT/CN2024/130172 entitled “A compound or a method for the treatment of metabolic diseases and alopecia areata diseases” filed November 06, 2024, and the PCT application No. PCT/CN2024/139943 entitled “A compound or a method for the treatment of metabolic diseases and alopecia areata diseases” filed December 17, 2024, which are incorporated herein by their entireties. Field The present invention is related to a combination therapy or a method for the treatment of metabolic diseases or alopecia areata diseases (AGA) . And the metabolic diseases is including obesity, chronic weight management, weight management and overweight. Background Thyroid hormones are critical for normal growth and development and for maintaining metabolic homeostasis (Paul M. Yen Physiological Review, Vol. 81 (3) : pp. 1097-1126 (2001) ) . Circulating levels of thyroid hormones are tightly regulated by feedback mechanisms in the hypothalamus/pituitary/thyroid (HPT) axis. Thyroid dysfunction leading to hypothyroidism or hyperthyroidism clearly demonstrates that thyroid hormones exert profound effects on cardiac function, body weight, metabolism, metabolic rate, body temperature, cholesterol, bone, muscle and behavior. The thyroid hormone receptors are derived from two separate genes, αandβ. These distinct gene products produce multiple forms of their respective receptors through differential RNA processing. The major thyroid receptor isoforms areαl, α2, βl and β2. Thyroid hormone receptorsαl, βl andβ2 bind thyroid hormone. It has been shown that the thyroid hormone receptor subtypes can differ in their contribution to particular biological responses. Recent studies suggest that TRβl plays an important role in regulating TRH (thyrotropin releasing hormone) and on regulating thyroid hormone actions in the liver. TRβ2 plays an important role in the regulation of TSH (thyroid stimulating hormone) . TRβl plays an important role in regulating heart rate. GIP (Glucose-Dependent Insulinotropic Polypeptide) , GLP-1 (Glucagon-Like Peptide-1) , and GCGR (Glucagon Receptor) are hormones and receptors closely related to the regulation of blood glucose levels. These three hormones and receptors in the body is crucial for maintaining glucose homeostasis and regulating energy balance. GIP and GLP-1 are typically secreted in increased amounts after meals, working synergistically on pancreaticβ-cells to promote insulin secretion, while GCGR promotes glycogenolysis and gluconeogenesis through the action of glucagon when blood glucose levels are low, to maintain blood glucose levels. Research on these receptors and hormones provides important targets and strategies for the treatment of metabolic diseases such as diabetes and obesity. Obesity, chronic weight management, weight management or over weight is a common metabolic disease characterized by excessive accumulation of body fat to the extent that it becomes detrimental to health. Obesity is typically associated with a variety of health issues, including but not limited to: cardiovascular diseases: such as coronary heart disease, hypertension, stroke, etc. Metabolic syndrome: a cluster of symptoms that includes high blood pressure, high blood sugar, abnormal cholesterol levels, and abdominal obesity. Type 2 diabetes: obesity is a significant risk factor for type 2 diabetes. Respiratory problems: such as sleep apnea. Certain cancers: including breast, colon, and endometrial cancers. Musculoskeletal and joint problems: such as osteoarthritis. Psychological impacts: such as depression and anxiety. Given the significant health risks associated with obesity, patients with weight imbalance require chronic weight management strategies. Although various methods for weight management exist, they often fail to fully meet clinical needs. This shortfall highlights the necessity for new and effective therapies that can prevent, treat, or ameliorate obesity, chronic weight management, weight management and overweight. Androgenetic alopecia, also known male pattern baldness, occurs not only in men but also in women. Current treatments such as minoxidil and finasteride are only efficacious in a small percentage of subjects. Novel mechanisms with robust efficacy and long-term safety are still needed for the treatment of androgenetic alopecia. Thyroid hormone receptor agonists (thyromimetics) are closely associated with hair growth. Topical triiodo-thyronine (T3) stimulates epidermal proliferation, dermal thickening, and hair growth in both mice and rats. Some human subjects given with thyroxine (T4) to