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EP-4739392-A1 - METHODS OF TREATING ACTIVE AND CHRONIC THYROID EYE DISEASE

EP4739392A1EP 4739392 A1EP4739392 A1EP 4739392A1EP-4739392-A1

Abstract

Methods of treating patients with chronic thyroid eye disease are provided for herein, such as by administering antibodies and compositions that bind to and/or antagonize IGF-1R.

Inventors

  • CIULLA, Thomas

Assignees

  • Viridian Therapeutics, Inc.

Dates

Publication Date
20260513
Application Date
20240703

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 at a therapeutically effective dosing regimen.
  2. 2. The method of claim 1, wherein the patient, prior to treatment, had a Clinical Activity Score (CAS) of 2 or less.
  3. 3. A method of treating a patient suffering from thyroid eye disease (TED), the method comprising administering to the patient an anti-IGF-lR inhibitor at a therapeutically effective dosing regimen, wherein the patient, prior to treatment, had a Clinical Activity Score (CAS) of 2 or less.
  4. 4. The method of any one of the preceding claims, wherein the patient, prior to treatment, has had one or more symptoms of thyroid eye disease for at least 12 months.
  5. 5. A method of treating a patient suffering from thyroid eye disease (TED), the method comprising administering to the patient an anti-IGF-lR inhibitor at a therapeutically effective dosing regimen, wherein the patient, prior to treatment, has had one or more symptoms of thyroid eye disease for at least 12 months.
  6. 6. The method of any one of the preceding claims, wherein the IGF-1R inhibitor is selected from ganitumab, figitumumab, MEDI-573, cixutumumab, dalotuzumab, robatumumab, BIIB022, xentuzumab, istiratumab, teprotumumab, IB 1311, lonigutamab (VB-421), PHP1003, MAB391, TZ-1, rhuMAb IGFR, hlOH5, linsitinib (OSI-906), picropodophyllin, brigatinib, ceritinib, conteltinib, suradista, A-923573, A-928605, A-947864, AG1024 (tyrphostin), 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/IBP-2-13, INT-231, IDS-CR-004, KW-2450, LL-28, NT-157, NVP AEW541, PL 2258, TAE-226, TT-100 (masoprocol), XL-228, orNSM-18.
  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 lid retraction greater than 2 mm, exophthalmos (proptosis) of greater than or equal to 3 mm above the normal range for their race and gender, Clinical Activity Score (CAS) from about 0 to about 7, and inconstant or constant diplopia.
  8. 8. The method of claim 5, wherein the exophthalmos is greater than or equal to 3 mm above the normal range for their race and gender.
  9. 9. The method of any one of claims 1 or 4-8, wherein the patient, prior to treatment, had a Clinical Activity Score (CAS) of or greater than 0, 1, 2, 3, or 4.
  10. 10. The method of any one of claims 1 or 4-9, wherein the patient, prior to treatment, had a Clinical Activity Score (CAS) of greater than 2.
  11. 11. The method of any one of claims 1 or 4-10, wherein the patient, prior to treatment, had a Clinical Activity Score (CAS) of greater than 3.
  12. 12. The method of any one of the preceding claims, wherein the patient, prior to treatment, has had one or more symptoms of thyroid eye disease for at least 15 months.
  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 to the patient a first dose of 3.0 mg/kg to 20 mg/kg.
  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 to the patient a subsequent dose.
  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 OF TREATING ACTIVE AND CHRONIC THYROID EYE DISEASE CROSS-REFERENCE TO RELATED APPLICATIONS [0001] The present application claims benefit of U.S. Provisional Patent Application No. 63/512,468, filed on July 7, 2023, which is hereby incorporated by reference in its entirety. SEQUENCE LISTING [0002] The instant application contains a Sequence Listing which has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. Said XML copy, created on July 3, 2024, is named VRD-016WO2_SL and is 67,103 bytes. BACKGROUND [0003] Thyroid-associated ophthalmopathy (TAO), also known as thyroid eye disease (TED), Graves' ophthalmopathy or orbitopathy (GO), thyrotoxic exophthalmos, dysthyroid ophthalmopathy, and several other terms, is orbitopathy associated with thyroid dysfunction. TAO is divided into two types. Active TAO, which typically lasts 1-3 years, is characterized by an ongoing autoimmune/inflammatory response in the soft tissues of the orbit. Active TAO is responsible for the expansion and remodeling of the ocular soft tissues. The autoimmune/inflammatory response of active TAO spontaneously resolves and the condition transitions into inactive TAO. Inactive TAO is the term used to describe the long-term/permanent sequelae of active TAO. The cause of TAO is unknown. TAO is typically associated with Graves' hyperthyroidism, but can also occur as part of other autoimmune conditions that affect the thyroid gland and produce pathology in orbital and periorbital tissue, and, rarely, the pretibial skin (pretibial myxedema) or digits (thyroid acropachy). TAO is an autoimmune orbitopathy in which the orbital and periocular soft tissues are primarily affected with secondary effects on the eye and vision. In TAO, as a result of inflammation and expansion of orbital soft tissues, primarily eye muscles and adipose, the eyes are forced forward (bulge) out of their sockets— a phenomenon termed proptosis or exophthalmos. Although most cases of TAO do not result in loss of vision, this condition can cause vision-threatening exposure keratopathy, troublesome diplopia (double vision), and compressive dysthyroid optic neuropathy. TAO may precede, coincide with, or follow the systemic complications of dysthyroidism. The ocular manifestations of TAO include upper eyelid retraction, lid lag, swelling, redness (erythema), conjunctivitis, and bulging eyes (exophthalmos or proptosis), chemosis, periorbital edema, and altered ocular motility with significant functional, social, and cosmetic consequences. Many of the signs and symptoms of TAO, including proptosis and ocular congestion, result from expansion of the orbital adipose tissue and periocular muscles. The adipose tissue volume increases owing in part to new fat cell development (adipogenesis) within the orbital fat. The accumulation of hydrophilic glycosaminoglycans, primarily hyaluronic acid, within the orbital adipose tissue and the perimysial connective tissue between the extraocular muscle fibers, further expands the fat compartments and enlarges the extraocular muscle bodies. Hyaluronic acid is produced by fibroblasts residing within the orbital fat and extraocular muscles, and its synthesis in vitro is stimulated by several cytokines and growth factors, including IL-lbeta, interferon-gamma, platelet-derived growth factor, thyroid stimulating hormone (TSH) and insulin-like growth factor I (IGF-I). [0004] Antibodies that activate the insulin-like growth factor I receptor (IGF-IR) have also been detected and implicated in active TAO. Without being bound to any theory, it is believed that TSHR and IGF-IR form a physical and functional complex in orbital fibroblasts, and that blocking IGF-IR appears to attenuate both IGF-1 and TSH-dependent signaling. It has been suggested that blocking IGF-IR using an antibody antagonist might reduce both TSHR- and IGF-I-dependent signaling and therefore interrupt the pathological activities of autoantibodies acting as agonists on either receptor. [0005] IGF-IR is a widely expressed heterotetrameric protein involved in the regulation of proliferation and metabolic function of many cell types. It is a tyrosine kinase receptor comprising two subunits. IGF-IRalpha contains a ligand-binding domain while IGF-IRbeta is involved in signaling and contains tyrosine phosphorylation sites. [0006] Current therapies for hyperthyroidism due to Graves’ disease are imperfect because therapies targeting the specific underlying pathogenic autoimmune mechanisms of the disease are lacking. Even more complex is the treatment of moderate-to-severe active TAO. Although recent years have witnessed a better understanding of its pathogenesis, TAO remains a therapeutic challenge and dilemma. There are no approved drugs to treat active TAO. Intravenous glucocorticoids (ivGCs) and oral glucocorticoids are used to treat patients with moderate-to-severe active TAO, but results are seldom satisfactory. Partial responses ar