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CN-122003247-A - Methods for treating active and chronic thyroid eye diseases

CN122003247ACN 122003247 ACN122003247 ACN 122003247ACN-122003247-A

Abstract

Provided herein are methods of treating patients suffering from chronic thyroid eye disease, such as by administering antibodies and compositions that bind to and/or antagonize IGF-1R.

Inventors

  • Thomas Xiwula

Assignees

  • 维里迪安治疗公司

Dates

Publication Date
20260508
Application Date
20240703
Priority Date
20230707

Claims (20)

  1. 1. A method of treating fibrosis associated with Thyroid Eye Disease (TED), the method comprising administering to a patient in need of treatment a pharmaceutical composition comprising an IGF-1R inhibitor in a therapeutically effective dosing regimen.
  2. 2. The method of claim 1, wherein the patient has a Clinical Activity Score (CAS) of 2 or less prior to treatment.
  3. 3. A method of treating a patient suffering from Thyroid Eye Disease (TED), the method comprising administering to the patient an anti-IGF-1R inhibitor in a therapeutically effective dosing regimen, Wherein the patient has a Clinical Activity Score (CAS) of 2 or less prior to treatment.
  4. 4. The method of any one of the preceding claims, wherein the patient has had one or more symptoms of thyroid eye disease for at least 12 months prior to treatment.
  5. 5. A method of treating a patient suffering from Thyroid Eye Disease (TED), the method comprising administering to the patient an anti-IGF-1R inhibitor in a therapeutically effective dosing regimen, Wherein the patient has had one or more symptoms of thyroid eye disease for at least 12 months prior to treatment.
  6. 6. The method of any one of the preceding claims, wherein the IGF-1R inhibitor is selected from the group consisting of ganimumab, non-Ji Mushan antibody, MEDI-573, cetuximab, darotophyllizumab, luo Bamu MAB, BIIB022, zhtuzumab, ai Situo MAB, tetuzumab, IBI311, lonicera MAB (VB-421), PHP1003, MAB391, TZ-1, rhuMAb IGFR, H10H5, lixitinib (OSI-906), podophyllotoxin, bragg, ceritinib, emtrictinib, suradista, a-923573, a-928605, a-947864, AG1024 (tyrosine phosphorylation inhibitor )、ANT-429、AQIP (PQIP)、AXL1717、AZD3463、AZD9362、BI885578、BI893923、BMS-754807、BMS-536924 (BMS-536924)、BMS-554417、CHM-2133-P、GSK1838705A、GSK1904529A、GSK 552602A (NVP-ADW742)、GTx-134、IGF-1 ACL (IGF-1 anticancer ligand), IGF/p-2-13, INT-231, JDS-CR-004, LL-2450, LL-28, NT-157, NVP AEW541, PL 8, tee-226, tretinol-100, or XL-18-228.
  7. 7. The method of any one of the preceding claims, wherein the patient suffers from one or more symptoms of TED selected from the group consisting of eyelid withdrawal greater than 2mm, protruding eyes (herniation) greater than or equal to 3 mm beyond their normal range of race and gender, clinical Activity Score (CAS) of about 0 to about 7, and non-constancy or constancy review.
  8. 8. The method of claim 5, wherein the eye process is greater than or equal to 3 mm beyond its normal range of ethnicity and gender.
  9. 9. The method of any one of claims 1 or 4-8, wherein the patient has a Clinical Activity Score (CAS) of 0,1, 2, 3, or 4 or greater than 0,1, 2, 3, or 4 prior to treatment.
  10. 10. The method of any one of claims 1 or 4-9, wherein the patient has a Clinical Activity Score (CAS) of greater than 2 prior to treatment.
  11. 11. The method of any one of claims 1 or 4-10, wherein the patient has a Clinical Activity Score (CAS) of greater than 3 prior to treatment.
  12. 12. The method of any one of the preceding claims, wherein the patient has had one or more symptoms of thyroid eye disease for at least 15 months prior to treatment.
  13. 13. The method of any one of the preceding claims, wherein the patient further exhibits fibrosis.
  14. 14. The method of any one of the preceding claims, wherein the therapeutically effective dosing regimen comprises administering a first dose of 3.0 mg/kg to 20 mg/kg to the patient.
  15. 15. The method of claim 14, wherein the first dose is 3.0 mg/kg, 5.0 mg/kg, 10 mg/kg, or 20 mg/kg.
  16. 16. The method of any one of the preceding claims, wherein the therapeutically effective dosing regimen comprises administering a subsequent dose to the patient.
  17. 17. The method of claim 16, wherein the subsequent dose is 3.0 mg/kg to 20 mg/kg.
  18. 18. The method of claim 17, wherein the subsequent dose is 3.0 mg/kg, 5.0 mg/kg, 10 mg/kg, or 20 mg/kg.
  19. 19. The method of any one of claims 16-18, wherein the subsequent dose is administered to the patient once every two weeks, once every three weeks, once every four weeks, once every month, once every five weeks, or once every six weeks.
  20. 20. The method of claim 19, wherein the subsequent dose is administered to the patient once every three weeks.

Description

Methods for treating active and chronic thyroid eye diseases Cross Reference to Related Applications The present application claims the benefit of U.S. provisional patent application No. 63/512,468 filed 7 at 2023, which is hereby incorporated by reference in its entirety. Sequence listing The present application contains a sequence listing that has been submitted electronically in an XML file format and is hereby incorporated by reference in its entirety. The XML copy was created at 2024, 7, 3, named VRD-016WO2_SL and is 67,103 bytes in size. Background Thyroid-related eye lesions (TAOs) (also known as Thyroid Eye Disease (TED), graves' eye lesions, or orbital lesions (GO), thyrotoxic abrupt eyes, thyroid dysfunction eye lesions, and several other terms) are orbital diseases associated with thyroid dysfunction. TAOs fall into two categories. Active TAO, which typically lasts 1-3 years, is characterized by a persistent autoimmune/inflammatory response in the orbital soft tissue. Active TAO causes expansion and remodeling of ocular soft tissue. Autoimmune/inflammatory responses of active TAO spontaneously subside and the condition turns into inactive TAO. Inactivity TAO is a term used to describe the long-term/permanent sequelae of active TAO. The etiology of TAO is unknown. TAO is often associated with graves hyperthyroidism, but may also occur as part of other autoimmune disorders affecting the thyroid gland and producing pathology in the orbit and periorbital tissues and rarely in the pre-tibial skin (pre-tibial myxoedema) or fingers (thyroidism). TAO is an autoimmune orbital lesion in which the orbit and periocular soft tissues are primarily affected and secondarily affect the eye and vision. In TAO, the eyeball is forced forward (swelled) out of its orbital canal, a phenomenon known as herniation (proptosis) or abrupt eye (exophthalmos), due to inflammation and distention of the orbital soft tissue (mainly the eye muscles and fat). Although most cases of TAO do not cause vision loss, this condition can cause exposed keratopathy, troublesome double vision (diplopia/double vision), and pressing thyroid dysfunction optic neuropathy that endanger vision. TAO may occur before, contemporaneously with, or after the systemic complications of thyroid dysfunction. Ocular clinical manifestations of TAO include upper eyelid recession, eyelid hysteresis, swelling, redness (erythema), conjunctivitis and swollen eyes (protruding eyes or protruding eyeballs), bulbar conjunctival edema, periorbital edema and altered eye movements with significant functional, social and cosmetic consequences. Many signs and symptoms of TAO (including herniation and congestion of the eye) are caused by the expansion of orbital adipose tissue and periocular muscles. Part of the cause of the increased adipose tissue volume is new adipocyte development (adipogenesis) within the orbital fat. Accumulation of hydrophilic glycosaminoglycans (mainly hyaluronic acid) within the perimuscular connective tissue between the orbital adipose tissue and the extraocular muscle fibers further dilates the adipose compartment and enlarges the extraocular body. Hyaluronic acid is produced by fibroblasts residing in orbital fat and extraocular muscles, and its synthesis in vitro is stimulated by several cytokines and growth factors including IL-1 beta, interferon-gamma, platelet derived growth factors, thyroid Stimulating Hormone (TSH) and insulin-like growth factor I (IGF-I). Antibodies that activate insulin-like growth factor I receptor (IGF-IR) are also detected and are involved in active TAO. Without being bound by any theory, it is believed that the TSHR and IGF-IR form physiological and functional complexes in orbital fibroblasts, and blocking IGF-IR appears to attenuate IGF-1 and TSH-dependent signaling. Blocking IGF-IR with antibody antagonists has been shown to reduce TSHR and IGF-I dependent signaling and thus interrupt the pathological activity of autoantibodies acting as agonists of either receptor. IGF-IR is a widely expressed heterotetrameric protein involved in the regulation of proliferation and metabolic function in many cell types. Which is a tyrosine kinase receptor comprising two subunits. IGF-IR alpha contains ligand binding domains, while IGF-IR beta is involved in signaling and contains tyrosine phosphorylation sites. Current therapies for hyperthyroidism caused by graves' disease are not perfect because of the lack of therapies that target specific underlying pathogenic autoimmune mechanisms of the disease. Even more complex is the treatment of moderate to severe active TAO. Although a deeper understanding of its pathogenesis has been demonstrated in recent years, TAO remains a therapeutic challenge and challenge. There is no approved drug for the treatment of active TAO. Intravenous (ivGC) and oral glucocorticoids are used to treat patients with moderate to severe active TAO, but the results are less satisfactory. Partial reactions are