Treatment of insomnia or sleep disorders in dermatitis patients

Abstract

The present invention provides an anti-IL-13Rα1 antibody or an antigen-binding fragment thereof, and a pharmaceutical preparation comprising the same, for use in treating patients with skin diseases such as atopic dermatitis who are experiencing insomnia or sleep disorders due to pruritus. Also provided is a method for treating insomnia or sleep disorders due to pruritus in a patient in need thereof, comprising administering to the patient an anti-IL-13Rα1 antibody or an antigen-binding fragment thereof, or a pharmaceutical preparation comprising the same.

Description

[Technical Field]

[0001] The present disclosure relates to the use of anti-IL-13Rα1 antibodies or binding fragments thereof, and pharmaceutical formulations containing them, in the treatment of patients experiencing insomnia or sleep disorders. [Background technology]

[0002] It is common for all individuals to experience occasional insomnia or sleep disturbances due to, for example, stress or anxiety, shift work that can disrupt sleep cycles, or the use of certain medications. However, some individuals, such as those with high allergies, regularly experience insomnia or sleep disturbances due to underlying medical conditions.

[0003] Hyperallergic patients often suffer from skin conditions such as atopic dermatitis and eczema. Chronic itch is a hallmark and primary symptom of atopic dermatitis and other type 2 inflammatory skin diseases. These conditions can cause patients to experience discomfort on a daily basis, making it particularly difficult to fall asleep or stay asleep.

[0004] Itch signaling in atopic dermatitis (AD) has recently been postulated to be exacerbated by pro-inflammatory cytokines present in the skin, which disrupt the skin barrier and trigger immune responses that promote disease pathology. The role of some cytokines, such as IL-31 and IL-4, in itch signaling is well documented. However, for other cytokines, such as IL-13, there is less evidence for a direct role in the pathophysiology of pruritus.

[0005] One way to inhibit IL-13 activity is to block the binding of IL-13 to its receptor, IL-13R, using antibodies specific for IL-13R, such as those specific for IL-13Rα1. Effective antibody antagonists to IL-13Rα1 may block IL-13 binding and potentially prevent heterodimerization between IL-4Rα and IL-13Rα1. Such antibodies could block both IL-13 and IL-4 signaling through the type II receptor while maintaining IL-4 signaling through the type I receptor. Signaling through the type I receptor is essential for the induction stage of the immune response, leading to Th2 cell differentiation. Because T cells do not express IL-13Rα1, the type II receptor is not involved in Th2 differentiation. Therefore, IL-13Rα1 antibodies should not affect the overall Th1 / Th2 balance. Signaling through the type II IL-4 / IL-13 receptor is important during the effector A phase of the immune response in established allergic inflammation. Thus, blockade of the type II receptor should have beneficial effects on many symptoms of IL-13R-mediated conditions and should therefore be an effective disease-modifying agent.

[0006] Antibodies (both monoclonal and polyclonal) against IL-13Rα1 have been described in the art. For example, WO 97 / 15663, WO 03 / 80675; WO 03 / 46009; WO 06 / 072564; Gauchat et al, 1998 Eur. J. Immunol. 28:4286-4298; Gauchat et al, 2000 Eur.J.Immunol.30:3157-3164;Clement et al,1997 Cytokine 9(11):959(Meeting Abstract);Ogata et al,1998 J.Biol.Chem.273:9864-9871;Graber et al,1998 Eur.J.Immunol.28:4286-4298;C.Vermot-Desroches et al,2000 Tissue Antigens 5(Supp.l):52-53(Meeting Abstract);Poudrier et al,2000 Eur.J.Immunol.30:3157-3164;Akaiwa et al,2001 Cytokine 13:75-84;Cancino-Diaz et al,2002 J.Invest.Dermatol.119:1114-1120; and Krause et al, 2006 MoI.Immunol.43:1799-1807.

[0007] A particularly promising anti-IL-13Rα1 antibody is described in WO 2008 / 060813 as antibody 10G5-6. 10G5-6 is an IgG4 antibody with a hinge-stabilizing serine-to-proline mutation (S241P Kabat numbering). This antibody is now known as ebrasakimab (previously called ASLAN004; both names are used interchangeably herein). Ebrasakimab has been shown to bind to human IL-13Rα1 with high affinity (e.g., Kd can be 500 pM). Ebrasakimab effectively antagonizes IL-13 function by inhibiting the binding of IL-13 to its receptor, IL-13Rα1, and has also been shown to inhibit IL-13- and IL-4-induced eotaxin release in NHDF cells, IL-13- and IL-4-induced STAT6 phosphorylation in NHDF cells, and IL-13-stimulated TARC release in blood or peripheral blood mononuclear cells.

[0008] Long-term insomnia is known to result in impaired cognitive performance, increased irritability, and daytime sleepiness, all of which have a significant negative impact on quality of life. Furthermore, the long-term cumulative effects of insomnia and sleep disorders have been linked to a wide range of adverse health outcomes, including an increased risk of diabetes, depression, heart attack, and stroke.

[0009] Thus, there is a need for alternative therapies to manage and treat sleep deprivation or sleep disorders, such as, for example, insomnia or sleep disorders in highly allergic patients. Summary of the Invention

[0010] The following items summarize this disclosure. Item 1. An antibody or antigen-binding fragment thereof that is an inhibitor of IL-13Rα1-mediated signaling by binding to IL-13Rα1, for use in treating insomnia or a sleep disorder in a patient by parenteral administration in a treatment cycle comprising a dose in the range of 200 mg to 600 mg (e.g., 300, 400, 500, or 600 mg, e.g., 400-600 mg), wherein treatment results in a reduction in the sleep disturbance (SD) score of the Patient Assessment of Eczema Severity (POEM) in the range of -50 to -100% from baseline, e.g., a reduction of 2 to 4 points from baseline. Item 1A. An antibody or antigen-binding fragment thereof that inhibits signal transduction mediated by IL-13Rα1 by binding to IL-13Rα1, for use in reducing the Patient Assessment of Eczema Severity (POEM) sleep disturbance (SD) score in patients with insomnia, by parenteral administration in a treatment cycle comprising a dose in the range of 200 mg to 600 mg (e.g., 400 to 600 mg), to reduce the sleep disturbance score by -50 to -100%, e.g., a reduction of 2 to 4 points from baseline. Item 1B. An antibody or antigen-binding fragment thereof that is an inhibitor of IL-13Rα1-mediated signaling by binding to IL-13Rα1, for use in reducing the sleep deprivation component of the SCORAD in the range of -20 to -100% from baseline, e.g., a reduction of 2 or more points, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 points from baseline. Item 1C. An antibody or antigen-binding fragment thereof that is an inhibitor of IL-13Rα1-mediated signaling by binding to IL-13Rα1, for use in reducing the Sleep Disorder Numeric Rating Scale (SD NRS) in the range of -20 to -100% from baseline, e.g., a reduction of 4 or more points, e.g., 4, 5, 6, 7, 8, 9, or 10 points from baseline. Item 2. The antibody or antigen-binding fragment thereof of any one of items 1 to 1C, wherein treatment results in a reduction in the Patient Assessment of Eczema Severity (POEM) Sleep Disturbance (SD) score by -50 to -100% from baseline, e.g., a 2 to 4 point reduction from baseline. Item 3. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 2, wherein the patient has a baseline SD score of at least 3, e.g., 3 or 4. Item 4. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 3, wherein the patient has a baseline SD score of 3. Item 5. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 4, wherein the patient has a baseline SD score of 4. Item 6. The antibody or antigen-binding fragment thereof for use according to any one of Items 1 to 5, wherein the reduction in SD score from baseline is 2 to 4 points, such as a 2, 3, or 4 point reduction. Item 7. The antibody or antigen-binding fragment thereof for use according to any one of Items 1 to 6, wherein the reduction in SD score from baseline is 2 points. Item 8. The antibody or antigen-binding fragment thereof for use according to any one of Items 1 to 7, wherein the reduction in SD score from baseline is 3 points. Item 9. The antibody or antigen-binding fragment thereof for use according to any one of Items 1 to 8, wherein the reduction in SD score from baseline is 4 points. Item 10. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 9, wherein the reduction in SD score is at least -50% from baseline, for example, a 2-point reduction from a baseline SD score of 4. Item 11. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 10, wherein the reduction in SD score is at least -66% from baseline, for example, a 2-point reduction from a baseline SD score of 3. Item 12. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 11, wherein the reduction in SD score is at least -75% from baseline, for example, a 3-point reduction from a baseline SD score of 4. Item 13. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 12, wherein the reduction in SD score is 100% from baseline, e.g., a 2-point reduction from a baseline SD score of 2, a 3-point reduction from a baseline SD score of 3, or a 4-point reduction from a baseline SD score of 4. Item 14. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 13, wherein treatment results in a reduction in the sleep deprivation component of the SCORAD, for example, a reduction of -20% to -100% from baseline, such as a reduction of 2 to 10 points from baseline. Item 15. The antibody or antigen-binding fragment thereof for use according to item 14, wherein treatment results in a reduction from baseline of at least -30% in the sleep deprivation component of the SCORAD, e.g., -30%, -35%, -40%, -45%, -50%, -55%, -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95%, or -100%. Item 16. The antibody or antigen-binding fragment thereof for use according to Item 14 or Item 15, wherein treatment results in a reduction from baseline in the sleep deprivation component of the SCORAD by -35% to -55%, e.g., -35%, -40%, -50%, or -55%. Item 17. The antibody or antigen-binding fragment thereof for use according to any one of items 14 to 16, wherein treatment results in a reduction in the SCORAD sleep deprivation component of 4 or more points from baseline, e.g., 4, 5, 6, 7, 8, 9, or 10 points. Item 18. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 17, wherein the patient has a baseline sleep deprivation component of SCORAD of at least 4 points, e.g., 4, 5, 6, 7, 8, 9, or 10 points. Item 19. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 18, wherein treatment results in a reduction in the Sleep Disorder Numerical Rating Scale (SD NRS), for example, a reduction of -20% to -100% from baseline, such as a reduction of 2 to 10 points from baseline. Item 20. The antibody or antigen-binding fragment thereof for use according to Item 19, wherein treatment results in a decrease from baseline in SD NRS of at least -30%, such as, for example, -30%, -35%, -40%, -45%, -50%, -55%, -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95%, or -100%. Item 21. The antibody or antigen-binding fragment thereof for use according to item 19 or item 20, wherein treatment results in a reduction in SD NRS from baseline of 4 or more points, e.g., 4, 5, 6, 7, 8, 9, or 10 points. Item 22. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 21, wherein the patient has a baseline Sleep Disorder Numerical Rating Scale (SD NRS) of at least 4 points, e.g., 4, 5, 6, 7, 8, 9, or 10 points. Item 23. The antibody or antigen-binding fragment thereof for use according to any one of Items 1 to 22, wherein the patient is a highly allergic patient, for example, the patient has a confirmed baseline IgE level of at least 10,000 KU / L ± 2,000. Item 24. The antibody or antigen-binding fragment thereof for use according to Item 23, wherein the baseline IgE level is in the range of 10,000±2,000 to 30,000±6,000 KU / L. Item 25. The antibody or antigen-binding fragment thereof for use according to Item 23 or 24, wherein treatment reduces IgE levels by at least 15% from baseline. Item 26. The antibody or antigen-binding fragment thereof for use according to Item 25, wherein treatment reduces IgE levels by at least 20% from baseline. Item 27. The antibody or antigen-binding fragment thereof for use according to Item 25 or 26, wherein treatment results in a reduction in IgE levels of at least 30% from baseline, for example a 30-40% reduction from said levels, such as 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40% from baseline. Item 28. The antibody or antigen-binding fragment of any one of items 1 to 27, wherein a decrease is observed by about day 15. Item 29. The antibody or antigen-binding fragment thereof of any one of items 1 to 27, wherein a decrease is observed by about day 29. Item 30. The antibody or antigen-binding fragment thereof according to any one of items 1 to 27, wherein a decrease is observed by about day 57. Item 31. The antibody or antigen-binding fragment thereof for use according to any one of Items 1 to 30, wherein the patient has pruritus. Item 32. The antibody or antigen-binding fragment thereof for use according to Item 21, wherein the pruritus is mediated by one or more of histamine, 5-HT (serotonin), acetylcholine, substance P (SP), leukotrienes, bradykinin, proteases (e.g., typsin, tryptase, cathepsin S, or kallikrein-related peptidase (such as KLK4 or KLK14)), IL-31, lysophosphatidic acid, autotaxin, and / or toll-like receptor 7 (TLR7). Item 33. The antibody or antigen-binding fragment thereof for use according to Item 31 or 32, wherein the pruritus is mediated by histamine. Item 34. The antibody or antigen-binding fragment thereof for use according to any one of Items 31 to 33, wherein the pruritus is mediated by IL-13, IL-4, or a combination of both. Item 35. The antibody or antigen-binding fragment thereof for use according to any one of items 31 to 34, wherein the pruritus is mediated by both IL-13 and IL-4. Item 36. The antibody or antigen-binding fragment thereof for use according to any one of Items 1 to 35, wherein the patient has a skin disease selected from the group consisting of dermatitis, such as atopic dermatitis (AD), contact dermatitis, neurodermatitis, or seborrheic dermatitis; eczema; hand, foot, and mouth disease; urticaria (including urticaria associated with lupus); psoriasis; infections, such as fungal or bacterial infections, e.g., impetigo or folliculitis; allergic skin reactions; Ehlers-Danlos syndrome; asthma; and angioedema, such as hereditary angioedema (HAE). Item 37. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 36, wherein the patient has dermatitis, such as atopic dermatitis (AD), contact dermatitis, neurodermatitis, or seborrheic dermatitis. Item 38. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 37, wherein the patient has atopic dermatitis (AD), e.g., moderate to severe atopic dermatitis. Item 39. The antibody or antigen-binding fragment thereof for use according to any one of Items 1 to 38, wherein the patient has Ehlers-Danlos syndrome (EDS), asthma, or angioedema (such as HAE). Item 40. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 39, wherein the patient has asthma. Item 41. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 40, wherein the patient has angioedema. Item 42. The antibody or antigen-binding fragment thereof for use according to any one of Items 1 to 41, wherein the patient does not have atopic dermatitis or psoriasis. Item 43. The antibody or antigen-binding fragment thereof for use according to any one of Items 1 to 42, wherein the patient does not have atopic dermatitis. Item 44. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 42, wherein the patient does not have psoriasis. Item 45. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 44, wherein the patient has previously received dupilumab. Item 46. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 45, wherein the patient had insomnia or a sleep disorder that was not adequately controlled by dupilumab. Item 47. The antibody or antigen-binding fragment thereof for use according to any one of Items 1 to 46, wherein the patient has atopic dermatitis and insomnia or a sleep disorder that is not adequately controlled by dupilumab. Item 48. The antibody or antigen-binding fragment thereof for use according to any one of Items 1 to 47, wherein there is a decrease in SD score, the sleep deprivation component of SCORAD, or SD NRS about 2 weeks (e.g., on day 15) after the first administration. Item 49. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 47, wherein there is a decrease in SD score, the sleep deprivation component of SCORAD, or SD NRS about 4 weeks (e.g., day 29) after the first administration. Item 50. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 47, wherein there is a decrease in SD score, the sleep deprivation component of SCORAD, or SD NRS about 6 weeks after the first administration (e.g., on day 43). Item 51. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 47, wherein there is a decrease in SD score, the sleep deprivation component of SCORAD, or SD NRS about 8 weeks after the first administration (e.g., day 57). Item 52. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 51, wherein the treatment is administered intravenously. Item 53. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 51, wherein the treatment is administered subcutaneously. Item 54. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 53, wherein the antibody or antigen-binding fragment is administered multiple times in a treatment cycle (e.g., a treatment cycle of 4 to 8 weeks, such as 8 weeks). Item 55. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 54, wherein multiple treatment cycles are administered, e.g., 2, 3, 4 or more treatment cycles are administered. Item 56. The antibody or antigen-binding fragment thereof for use according to Item 41 or 42, wherein following the treatment cycle or cycles and disease modification, maintenance therapy is administered, e.g., the same dose administered less frequently (e.g., monthly) or a lower dose (e.g., 200 mg) administered at the same or less frequent frequency (e.g., about twice weekly, about three times weekly, or about four times weekly). Item 57. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 56, wherein the antibody or antigen-binding fragment thereof is administered approximately once every week (particularly for a single treatment cycle, particularly for 8 weeks). Item 58. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 55, wherein the antibody or antigen-binding fragment thereof is administered approximately once every two weeks (particularly for a single treatment cycle, particularly for 8 weeks). Item 59. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 55, wherein the antibody or antigen-binding fragment thereof is administered approximately once every 3 weeks (particularly for a single treatment cycle, particularly for 8 weeks). Item 60. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 55, wherein the antibody or antigen-binding fragment thereof is administered approximately once every four weeks (e.g., monthly) (particularly for a single treatment cycle, particularly for 8 weeks). Item 61. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 60, wherein an initial loading dose in the range of 400 to 900 mg, for example, 400, 500, 600, 700, 800, or 900 mg, is used prior to administration of a treatment cycle. Item 62. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 61, wherein an initial loading dose of 600 mg is used prior to administration of the therapeutic dose. Item 63. The antibody or antigen-binding fragment thereof for use according to Item 61 or Item 62, wherein the loading dose is administered 1 to 3 weeks, such as 1 week, 2 weeks, or 3 weeks before the administration of the therapeutic dose. Item 64. The antibody or antigen-binding fragment thereof for use according to any one of Items 61 to 63, wherein the loading dose is administered only at week 0, for example, 600 mg at week 0. Item 65. The antibody or antigen-binding fragment thereof for use according to any one of Items 61 to 63, wherein an initial loading dose is administered at weeks 0 and 1, for example, 600 mg at week 0 and 600 mg at week 1. Item 66. The antibody or antigen-binding fragment thereof for use according to any one of Items 61 to 65, wherein an initial loading dose is administered at weeks 0, 1, and 2, for example, 600 mg at week 0, 600 mg at week 1, and 600 mg at week 2. Item 67. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 60, wherein the treatment does not include a loading dose. Item 68. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 67, wherein the dose is 200 mg. Item 69. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 67, wherein the dose is 300 mg, for example, administered once every two weeks. Item 70. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 67, wherein the dose is 400 mg, for example, administered once every two weeks or once a month. Item 71. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 67, wherein the dose is 600 mg, for example, administered monthly. Item 72. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 71, wherein the therapeutic amount of the anti-IL13R antibody or binding fragment thereof is 400 mg administered every two weeks (400 mg Q2W). Item 73. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 71, wherein the therapeutic amount of the anti-IL13R antibody or binding fragment thereof is 600 mg administered every two weeks (600 mg Q2W). Item 74. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 71, wherein the therapeutic amount of the anti-IL13R antibody or binding fragment thereof is 300 mg administered every two weeks (300 mg Q2W). Item 75. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 71, wherein an initial loading dose of 600 mg is administered at weeks 0 and 1, followed by a therapeutic dose of 300 mg every two weeks (300 mg Q2W). Item 76. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 71, wherein an initial loading dose of 600 mg is administered at weeks 0 and 1, followed by a therapeutic dose of 400 mg every two weeks (400 mg Q2W). Item 77. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 71, wherein an initial loading dose of 600 mg is administered at weeks 0, 1, and 2, followed by a therapeutic dose of 600 mg every 4 weeks (400 mg Q4W). Item 78. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 77, wherein the treatment cycle comprises an initial administration of 600 mg, followed by 400 mg three times a week, and wherein, for example, the treatment cycle is repeated twice, i.e., two treatment cycles last 8 weeks, and in particular, 600 mg is administered on day 1, 400 mg on about day 8, 400 mg on about day 15, 400 mg on about day 22, 600 mg on about day 29, 400 mg on about day 36, 400 mg on about day 43, and 400 mg on about day 50. Item 79. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 78, wherein day 1 is the first administration of the antibody or antigen-binding fragment thereof and disease modification occurs by day 8. Item 80. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 79, wherein the disease modification is a reduction in the POEM SD score, for example, a reduction in percentage from baseline of -50 to -100%. Item 81. The antibody or antigen-binding fragment thereof for use according to Item 80, wherein disease modification in the range of -50 to -100% is achieved about 57 days after the first administration on day 1, e.g., maximum disease modification is achieved by about day 57. Item 82. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 81, wherein the antibody or antigen-binding fragment binds to the FFYQ epitope (e.g., the same epitope as an antibody having a VH set forth in SEQ ID NO: 51 and a VL set forth in SEQ ID NO: 53, or an antibody having a sequence at least 95% identical to either of them). Item 83. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 82, wherein the antibody or antigen-binding fragment is an anti-IL13Rα1 antibody or antigen-binding fragment thereof. Item 84. The antibody or antigen-binding fragment thereof for use according to any one of Items 1 to 83, wherein the antibody or antigen-binding fragment thereof comprises a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 10. Item 85. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 84, wherein the antibody or antigen-binding fragment thereof comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 51 or a sequence at least 95% identical thereto, in particular SEQ ID NO: 51. Item 86. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 85, wherein the antibody or antigen-binding fragment thereof comprises a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 31, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 32, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45. Item 87. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 86, wherein the antibody or antigen-binding fragment thereof comprises a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 53 or a sequence at least 95% identical thereto, in particular SEQ ID NO: 53. Item 88. The antibody or antigen-binding fragment thereof for use according to any one of items 1 to 87, wherein the antibody comprises a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 53 or a sequence at least 95% identical thereto, particularly SEQ ID NO: 53, and a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 51 or a sequence at least 95% identical thereto, particularly SEQ ID NO: 51. Item 89. A pharmaceutical formulation comprising an antibody or antigen-binding fragment thereof for use according to any one of Items 1 to 88, wherein the formulation comprises an anti-IL-13R antibody or antigen-binding fragment thereof at a concentration of 150 to 210 mg / ml, for example, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, or 210 mg / ml, particularly 150 mg / ml, 175 mg / ml, or 200 mg / ml; an arginine (e.g., Arg-HCl or Arg-Glu) at a concentration of 170 to 250 mM, for example, 170, 175, 180, 185, 190, 195, 200, 205, or 210 mg / ml, particularly 150 mg / ml, 175 mg / ml, or 200 mg / ml; the histidine buffer is 20 to 50 mM, for example 20, 25, 30, 35, 40, 45 or 50 mM, for example 20 mM or 50 mM; the formulation contains 0.01 to 0.03% non-ionic surfactant, for example 0.02% w / w; and the pH of the formulation is in the range of 6.0 to 7.0, for example 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0, in particular 6.5. Item 90. A pharmaceutical formulation comprising the antibody or antigen-binding fragment thereof for use according to any one of Items 1 to 88, wherein the formulation comprises an anti-IL-13R antibody or antigen-binding fragment thereof at 175 to 250 mg / ml, for example, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, or 225 mg / ml, particularly 200 mg / ml, 225 mg / ml, or 250 mg / ml; tryptophan at 15 to 75 mM, for example, 15 to 60 mM, particularly 25 to 50 mM; and arginine (e.g., Arg-HCl or Arg-Glu) at 190 to 270 mM. , for example 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, or 270 mM, in particular 200, 210, 225, 235, 250 or 260 mM; a non-ionic surfactant is present at 0.01 to 0.03%, for example 0.01 to 0.03% w / w, for example 0.02% w / w; a buffer (e.g., a histidine buffer); and the pH of the formulation is in the range of 6.0 to 7.0, for example 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0, in particular 6.4. Item 91. A pharmaceutical formulation comprising an antibody or binding fragment thereof for use according to any one of items 1 to 88, wherein the formulation comprises an anti-IL-13R antibody or antigen-binding fragment thereof at a concentration of 175 to 250 mg / ml, for example 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245 or 250 mg / ml, in particular 190, 200 mg / ml, 210 mg / ml, 225 mg / ml or 250 mg / ml, for example 200 mg / ml of the anti-IL-13R antibody or antigen-binding fragment thereof; Tryptophan was added to 5–100 mM (15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 mM), for example, tryptophan at 15 to 75 mM, for example, 15 to 60 mM, particularly 25 to 50 mM, for example, 20 mM, 50 mM or 80 mM; arginine at 140 to 290 mM (including 150 or 151 to 290 nM), for example, arginine (e.g., Arg-HCl or Arg-Glu) at 160 to 290 mM, for example, 160, 165, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220 , 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, or 290 mM, in particular 150, 185, 215, 225, 250, 260, or 280 mM; non-ionic surfactants (e.g., polysorbates) at 0.01 to 0.03%, for example, 0.01%, 0.015%, 0.020%, 0.025%, or 0.030% w / w, in particular 0.02% w / w; buffers (e.g., histidine buffers), for example, histidine buffers at 15 to 55 mM (25 or 26 to 55 mM and the pH of the formulation is 5.5 to 7.2 (including 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0, for example, 6.0 to 7.0, for example, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0, in particular 5.8, 6.3, 6.4, 6.5, 6.6, 6.7, or 6.8. Item 92. A method for treating a patient suffering from insomnia or a sleep disorder, comprising parenteral administration of an antibody or antigen-binding fragment thereof, for example, according to any one of Items 1 to 88, or a pharmaceutical formulation comprising the same, which is an inhibitor of IL13Rα1-mediated signal transduction by binding to IL-13Rα1, in a treatment cycle comprising a dose in the range of 200 mg to 600 mg (e.g., 300, 400, 500, or 600 mg, such as 400 to 600 mg), wherein, for example, the treatment results in a reduction in the sleep disturbance (SD) score on the Patient Assessment of Eczema Severity (POEM), for example, a reduction in the range of -50 to -100% from baseline, such as a reduction of 2 to 4 points from baseline. Item 93. Use in the manufacture of a medicament for treating insomnia or a sleep disorder in a patient by parenterally administering a treatment cycle comprising a dose in the range of 200 mg to 600 mg (e.g., 300, 400, 500, or 600 mg, such as 400 to 600 mg) of, for example, the antibody or antigen-binding fragment thereof described in any one of Items 1 to 88, which is an inhibitor of IL-13Rα1-mediated signal transduction by binding to IL-13Rα1, or a pharmaceutical preparation comprising the same, wherein, for example, the treatment results in a reduction in the sleep disorder (SD) score on the Patient Assessment of Eczema Severity (POEM), for example, a reduction in the range of -50 to -100% from baseline, such as a reduction of 2 to 4 points from baseline.

[0011] Surprisingly, the inventors have discovered that the symptoms and severity of insomnia or sleep disorders can be treated and / or ameliorated by administering an anti-IL13R antibody or antigen-binding fragment, such as eblasiximab, to a subject in need thereof.

[0012] In one embodiment, there is provided a method of treating a patient with insomnia or a sleep disorder, such as a hyperallergenic patient as defined herein, with an antibody or binding fragment thereof, or pharmaceutical formulation as defined herein. In one embodiment there is provided the use of an antibody or binding fragment thereof, or pharmaceutical formulation as defined herein for the manufacture of a medicament for the treatment of insomnia or sleep disorders, for example in hyperallergenic patients.

[0013] In one embodiment, the improvement in sleep is independent of improvement in an underlying condition, such as allergies (eg, as disclosed herein). In one embodiment, improved sleep is associated with improvement in an underlying condition (eg, as disclosed herein), such as allergies.

[0014] In one embodiment, treatment with ebrasakimab reduces the overall burden of disease, e.g., reduces the overall burden of insomnia or sleep disorders in a patient. In one embodiment, treatment with ebrasakimab improves the quality of life of patients with insomnia or sleep disorders, for example, highly allergic patients. In one embodiment, the patient has a type 2 inflammatory skin disease, for example, a skin disease exacerbated by pro-inflammatory cytokines present in the skin. Thus, in one embodiment, ebrasakimab is suitable for treating patients with type 2 inflammatory skin disease. In one embodiment, the type 2 inflammatory skin disease is atopic dermatitis (AD). In one embodiment, the patient has pruritus. In one embodiment, pruritus signaling in the patient is exacerbated by pro-inflammatory cytokines present in the patient's skin, which can disrupt the skin barrier and trigger an immune response that promotes disease pathology. Thus, in one embodiment, ebrasakimab can reduce or inhibit pruritus signaling in the patient. In one embodiment, treatment with ebrasakimab prevents or reduces skin barrier disruption in the patient. In one embodiment, ebrasakimab suppresses or inhibits the immune response that promotes disease pathology in a patient with pruritus. Without wishing to be bound by theory, ebrasakimab may inhibit the signaling pathway for pruritus and / or inhibit the signaling pathway for neuropathic pain (particularly peripheral neuropathic pain and / or central neuropathic pain, particularly peripheral neuropathic pain), thereby resulting in improved sleep. In one embodiment, the pro-inflammatory cytokine is IL-13, IL-4, or a combination of both IL-13 and IL-4. In one embodiment, IL-13, IL-4, or both act as neural enhancers for amplification of the itch pathway via the 13Rα1 subunit of the type 2 receptor. Thus, in one embodiment, ebrasakimab inhibits or suppresses neural enhancers for amplification of the itch pathway, such as IL-13 and / or IL-4. In one embodiment, treatment with ebrasakimab reduces pruritic neurological responses, for example, due to the dual type 2 receptor-mediated inhibition of both IL-4 and IL-13 by ebrasakimab.

[0015] Improving sleep has significant health benefits, including improved mood, improved focus, reduced common inflammatory markers in the body, increased energy, reduced obesity levels, reduced risk of heart disease, reduced risk of diabetes, improved relationships, improved self-esteem, improved immune system, and improved ability to cope with stress.

[0016] In one embodiment, a combination therapy comprising an antibody, antigen-binding fragment thereof, or formulation according to the present disclosure and an additional pharmaceutical agent is used. In one embodiment, the additional pharmaceutical agent is a drug for treating insomnia, e.g., a sleep aid, including, but not limited to, melatonin, zolpidem, zaleplon, eszopiclone, ramelteon, suvorexant, lemborexant, or doxepin. In one embodiment, the additional pharmaceutical agent is a drug for treating a condition of insomnia, such as narcolepsy. Examples of such pharmaceutical agents include, but are not limited to, stimulants or wake-promoting agents, e.g., modafinil, armodafinil, pitolisant, or solimfetol.

[0017] Surprisingly, disease modification following treatment with an anti-IL-13Rα1 antibody or antigen-binding fragment thereof according to the present disclosure closely follows the reduction in TARC; indeed, the reduction in TARC and the reduction in EASI are closely correlated.

[0018] In one embodiment, the patient has a skin disease selected from the group including, for example, dermatitis such as atopic dermatitis (AD), contact dermatitis, neurodermatitis, or seborrheic dermatitis; eczema; hand, foot, and mouth disease; urticaria (including urticaria associated with lupus); psoriasis; infections such as fungal or bacterial infections, e.g., impetigo or folliculitis; allergic skin reactions; Ehlers-Danlos syndrome; asthma; and angioedema, such as hereditary angioedema (HAE). In one embodiment, the patient has dermatitis, e.g., atopic dermatitis (AD), contact dermatitis, neurodermatitis, or seborrheic dermatitis. In one embodiment, the patient has atopic dermatitis (AD), e.g., moderate to severe atopic dermatitis. In one embodiment, the patient has eczema. In one embodiment, the insomnia or sleep disturbance is due to the patient's eczema. In one embodiment, the patient has hives. In one embodiment, the patient has Ehlers-Danlos syndrome (EDS), asthma, or angioedema (e.g., HAE). In one embodiment, the patient has Ehlers-Danlos syndrome. In one embodiment, the patient has asthma. In one embodiment, the patient has angioedema, such as HAE.

[0019] The inventors have also determined that the antibodies, antigen-binding fragments and compositions of the invention can be employed in the treatment of other diseases that have an allergic component, for example, allergic asthma and allergic epithelial diseases such as eosinophilic esophagitis. Thus, in a separate aspect, there is provided treatment of allergic diseases, e.g., in which IgE levels are elevated (elevated compared to normal), by binding to the receptor using, e.g., antibodies, binding fragments, or compositions comprising same that are inhibitors of signal transduction through IL-13Rα1 (e.g., as described elsewhere herein for atopic dermatitis). Without wishing to be bound by theory, the inventors believe that the same cytokines and similar or corresponding mechanisms are at work in these allergic diseases as in this atopic dermatitis population.

[0020] In one embodiment, the allergic disorder is manifested in epithelial tissue. In one embodiment, the allergic disease is allergic asthma, e.g., poorly controlled and / or moderate to severe asthma. In one embodiment, the allergic disease is, e.g., poorly controlled and / or moderate to severe eosinophilic esophagitis. In one embodiment, the treatment of the present disclosure is administered to a patient having an acute allergic reaction. In one embodiment, the patient is confirmed to be allergic prior to treatment, eg, a baseline is established, with a level of at least 10,000 KU / L±2,000. The principles described herein for atopic dermatitis, such as dosage, apply equally to allergic disease indications. In one embodiment, the allergic disease is not atopic dermatitis. In one embodiment, the allergic disease is not eosinophilic esophagitis. In one embodiment, the allergic disease is not psoriasis. DETAILED DESCRIPTION OF THE INVENTION

[0021] As used herein, "insomnia," "sleep deprivation," or "sleep disorder" refers to the inability to fall asleep or maintain sleep, for example, due to disruption of the sleep-wake cycle. In one embodiment, the patient wakes up one or more times during the night, for example, an average of 1, 2, 3, 4, 5 or more times per night. In one embodiment, the patient takes an average of at least 45 minutes to fall asleep, for example, 1 hour, 1.5 hours, 2 hours. In one embodiment, the patient wakes up on average for at least 30 minutes (for example, 1 hour, 1.5 hours, 2 hours or more) during the night, for example, 3 times per week. In one embodiment, the patient wakes up one or more times during the night. For example, the patient wakes up on average 1, 2, 3, 4, 5 or more times per night, and takes an average of at least 45 minutes, for example, 1 hour, 1.5 hours, 2 hours to fall asleep. In one embodiment, the patient wakes up one or more times during the night. For example, the patient wakes up on average 1, 2, 3, 4, 5 or more times per night, and on average, wakes up for at least 30 minutes (for example, 1 hour, 1.5 hours, 2 hours or more) at night, for example, 3 times per week. In one embodiment, the patient takes at least 45 minutes, for example, 1 hour, 1.5 hours, 2 hours, etc., to fall asleep, and on average, wakes up for at least 30 minutes (for example, 1 hour, 1.5 hours, 2 hours, etc.) at night, for example, 3 times per week. In one embodiment, the patient wakes up one or more times at night. For example, the patient wakes up on average 1, 2, 3, 4, 5 or more times per night, and on average, wakes up for at least 45 minutes to fall asleep. For example, the patient wakes up for 1 hour, 1.5 hours, 3 times per week, and on average, wakes up for at least 30 minutes (for example, 1 hour, 1.5 hours, 2 hours or more) at night, for example, 3 times per week.

[0022] As used herein, "Patient-Assessed Eczema Severity (POEM)" refers to a seven-item patient questionnaire that assesses the presence of disease symptoms (dryness, itching, peeling, cracking, insomnia, bleeding, and weeping) over the past week using a scoring system ranging from 0 (never) to 4 (every day). Total scores range from 0 to 28, with higher scores indicating greater severity of eczema.

[0023] As used herein, the sleep disturbance (SD) score refers to the score for the sleep disturbance question on the POEM questionnaire. Scores range from 0 (no sleep disturbance days) to 4 (sleep disturbance every day). The relevant question is typically phrased as follows: Over the past week, how many nights was your sleep disturbed because of your eczema? Possible answers include, for example, 0 days (SD score 0), 1-2 days (SD score 1), 3-4 days (SD score 2), 5-6 days (SD score 3), or every day (SD score 4).

[0024] As used herein, SCORAD refers to a clinical tool used to assess the degree and severity of atopic dermatitis (SCORing Atopic Dermatitis). Within the context of this disclosure, SCORAD is an alternative scoring tool that can be used instead of POEM. To calculate the SCORAD index, the extent of disease is first determined using nine rules to estimate the percentage of body surface area affected. The maximum extent of disease is 100%. Disease severity is then calculated based on six features: erythema, edema, exudation / crusting, excoriation, lichenification, and dryness. Each feature is given a score from 0 to 3, with 0 representing no symptoms and 3 representing severe. The scores for each feature are summed to calculate a total severity score of up to 18. Subjective symptoms, such as insomnia and pruritus, are measured using a 10-cm visual analog scale, with a total maximum score of 20. Finally, the SCORAD index is calculated using the following formula: extent / 5 + 7 x severity / 2 + subjective symptoms. As used herein, the sleep deprivation component of the SCORAD refers to the score on the SCORAD insomnia question, which reflects the average of what a patient experienced over the last three days or nights and ranges from 0 (no insomnia) to 10 (worst insomnia imaginable).

[0025] As used herein, the Sleep Disorder Numerical Rating Scale (SD-NRS) refers to a single-item patient-reported outcome (PRO) measure for quantifying sleep disturbance / insomnia. The SD-NRS asks patients to rate their insomnia the previous night on a scale of 0 ("no insomnia") to 10 ("no sleep at all").

[0026] In one embodiment, the reduction in SD score during or after treatment ranges from -50% to -100% from baseline, e.g., -50%, -55%, -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95%, or -100%. In one embodiment, the reduction in SD score during or after treatment ranges from -55% to -100% from baseline, e.g., -55%, -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95%, or -100%. In one embodiment, the reduction in SD score during or after treatment ranges from -60% to -100% from baseline, e.g., -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95%, or -100%. In one embodiment, the reduction in SD score during or after treatment ranges from -65% to -100% from baseline, e.g., -65%, -70%, -75%, -80%, -85%, -90%, -95%, or -100%. In one embodiment, the reduction in SD score during or after treatment ranges from -70% to -100% from baseline, e.g., -70%, -75%, -80%, -85%, -90%, -95%, or -100%. In one embodiment, the reduction in SD score during or after treatment ranges from -75% to -100%, e.g., -75%, -80%, -85%, -90%, -95%, or -100%. In one embodiment, the reduction in SD score during or after treatment is in the range of -80% to -100% from baseline, e.g., -80%, -85%, -90%, -95%, or -100%. In one embodiment, the reduction in SD score during or after treatment is in the range of -85% to -100% from baseline, e.g., -85%, -90%, -95%, or -100%. In one embodiment, the reduction in SD score during or after treatment is in the range of -90% to -100% from baseline, e.g., -90%, -95%, or -100%. In one embodiment, the reduction in SD score during or after treatment is in the range of -95% to -100% from baseline, e.g., -95% or -100%.In one embodiment, the reduction in SD score during or after treatment is in the range of -15% to -25%, e.g., -15%, -16%, -17%, -18%, -19%, -20%, -21%, -22%, -23%, -24%, or -25%. In one embodiment, the reduction in SD score during or after treatment is in the range of -25% to -35% from baseline, e.g., -25%, -26%, -27%, -28%, -29%, -30%, -31%, -32%, -33%, -34%, or -35%. In one embodiment, the reduction in SD score during or after treatment ranges from -35% to -45% from baseline, e.g., -35%, -36%, -37%, -38%, -39%, -40%, -41%, -42%, -43%, -44%, -45%. In one embodiment, the reduction in SD score during or after treatment ranges from 45% to -55% from baseline, e.g., -45%, -46%, -47%, -48%, -49%, -50%, -51%, -52%, -53%, -54%, -55%. In one embodiment, the reduction in SD score during or after treatment ranges from 55% to -65% from baseline, e.g., -55%, -56%, -57%, -58%, -59%, -60%, -61%, -62%, -63%, -64%, -65%. In one embodiment, the reduction in SD score during or after treatment ranges from 65% to -75% from baseline, e.g., -65%, -66%, -67%, -68%, -69%, -70%, -71%, -72%, -73%, -74%, -75%. In one embodiment, the reduction in SD score during or after treatment is in the range of 75% to -85% from baseline, e.g., -75%, -76%, -77%, -78%, -79%, -80%, -81%, -82%, -83%, -84%, or -85%. In one embodiment, the reduction in SD score during or after treatment is in the range of 85% to -95% from baseline, e.g., -85%, -86%, -87%, -88%, -89%, -90%, -91%, -92%, -93%, -94%, or -95%. In one embodiment, the reduction in SD score during or after treatment is in the range of 95% to -100% from baseline, e.g., -95%, -96%, -97%, -98%, -99%, or -100%.

[0027] In one embodiment, the reduction in SD score during or after treatment is 1 to 4 points from baseline, e.g., 1, 2, 3, or 4 points. In one embodiment, the reduction in SD score during or after treatment is 2 or more points from baseline, e.g., 2, 3, or 4 points. In one embodiment, the reduction in SD score during or after treatment is 3 or more points from baseline, e.g., 3 or 4 points.

[0028] In one embodiment, the reduction in the SCORAD sleep deprivation component during or after treatment ranges from -20% to -100% from baseline, e.g., -20%, -25%, 30%, -35%, -40%, -45%, -50%, -55%, -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95%, or -100%. In one embodiment, the reduction in the SCORAD sleep deprivation component during or after treatment ranges from -30% to -100% from baseline, e.g., 30%, -35%, -40%, -45%, -50%, -55%, -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95%, or -100%. In one embodiment, the reduction in the SCORAD sleep deprivation component during or after treatment ranges from -40% to -100% from baseline, e.g., -40%, -45%, -50%, -55%, -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95%, -100%. In one embodiment, the reduction in the SCORAD insomnia or sleep deprivation component during or after treatment ranges from -50% to -100% from baseline, e.g., -50%, -55%, -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95%, or -100%. In one embodiment, the reduction in the SCORAD sleep deprivation component during or after treatment ranges from -60% to -100% from baseline, e.g., -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95%, or -100%. In one embodiment, the reduction in the SCORAD sleep deprivation component during or after treatment ranges from -70% to -100% from baseline, e.g., -70%, -75%, -80%, -85%, -90%, -95%, or -100%. In one embodiment, the reduction in the SCORAD sleep deprivation component during or after treatment ranges from -80% to -100%, e.g., -80%, -85%, -90%, -95%, or -100%. In one embodiment, the reduction in the SCORAD sleep deprivation component during or after treatment ranges from -20% to -70% from baseline, for example, -20%, -25%, -30%, -35%, -40%, -50%, -55%, -60%, -65%, or -70%.In one embodiment, the reduction in the SCORAD sleep deprivation component during or after treatment ranges from −30% to −60% from baseline, e.g., −30%, −35%, −40%, −50%, −55%, −60%, etc. In one embodiment, the reduction in the SCORAD sleep deprivation component during or after treatment ranges from −35% to −55% from baseline, e.g., −35%, −40%, −50%, or −55%.

[0029] In one embodiment, the reduction in the SCORAD sleep deprivation component is 1 to 10 points from baseline, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the reduction in the SCORAD sleep deprivation component is 2 or more points from baseline, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the reduction in SCORAD sleep deprivation is 3 or more points from baseline, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the reduction in SCORAD sleep deprivation is 4 or more points from baseline, e.g., 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the reduction in SCORAD sleep deprivation is 5 or more points from baseline, e.g., 5, 6, 7, 8, 9, or 10 points. In one embodiment, the reduction in SCORAD sleep deprivation is 6 or more points from baseline, e.g., 6, 7, 8, 9, or 10 points. In one embodiment, the reduction in SCORAD sleep deprivation is 7 points or more from baseline, e.g., 7, 8, 9, or 10 points. In one embodiment, the reduction in SCORAD sleep deprivation is 8 points or more from baseline, e.g., 8, 9, or 10 points. In one embodiment, the reduction in SCORAD sleep deprivation is 9 points or more from baseline, e.g., 9 or 10 points.

[0030] In one embodiment, the reduction in SD NRS during or after treatment ranges from -20% to -100% from baseline, e.g., -20%, -25%, 30%, -35%, -40%, -45%, -50%, -55%, -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95%, or -100%. In one embodiment, the reduction in SD NRS during or after treatment ranges from -30% to -100% from baseline, e.g., -30%, -35%, -40%, -45%, -50%, -55%, -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95%, or -100%. In one embodiment, the decrease in SD NRS during or after administration ranges from -40% to -100% from baseline, e.g., -40%, -45%, -50%, -55%, -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95%, or -100%. In one embodiment, the decrease in SD NRS during or after treatment ranges from -50% to -100% from baseline, e.g., -50%, -55%, -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95%, or -100%. In one embodiment, the reduction in SD NRS during or after treatment ranges from -60% to -100% from baseline, e.g., -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95%, or -100%. In one embodiment, the reduction in SD NRS during or after treatment ranges from -70% to -100% from baseline, e.g., -70%, -75%, -80%, -85%, -90%, -95%, or -100%. In one embodiment, the reduction in SD NRS during or after treatment ranges from -80% to -100% from baseline, e.g., -80%, -85%, -90%, -95%, or -100%. In one embodiment, the reduction in SD NRS during or after treatment ranges from -20% to -70% from baseline, for example, -20%, -25%, -30%, -35%, -40%, -50%, -55%, -60%, -65%, or -70%.In one embodiment, the decrease in SD NRS during or after treatment ranges from -30% to -60% from baseline, e.g., -30%, -35%, -40%, -50%, -55%, or -60%. In one embodiment, the decrease in SD NRS during or after treatment ranges from -35% to -55% from baseline, e.g., -35%, -40%, -50%, or -55%.

[0031] In one embodiment, the decrease in the SD NRS is 1 to 10 points from baseline, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the decrease in the SD NRS is 2 or more points from baseline, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the decrease in the SD NRS is 3 or more points from baseline, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the decrease in the SD NRS is 4 or more points from baseline, e.g., 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the decrease in the SD NRS is 5 or more points from baseline, e.g., 5, 6, 7, 8, 9, or 10 points. In one embodiment, the decrease in the SD NRS is 6 or more points from baseline, e.g., 6, 7, 8, 9, or 10 points. In one embodiment, the decrease in the SD NRS is 7 or more points from baseline, e.g., 7, 8, 9, or 10 points. In one embodiment, the reduction in the SD NRS is 8 points or more from baseline, e.g., 8, 9, 10 points. In one embodiment, the reduction in the SD NRS is 9 points or more from baseline, e.g., 9 or 10 points.

[0032] In one embodiment, the patient has a baseline SD score of at least 1, e.g., 1, 2, 3, or 4. In one embodiment, the patient has a baseline SD score of at least 2, e.g., 2, 3, or 4. In one embodiment, the patient has a baseline SD score of at least 3, e.g., 3 or 4. In one embodiment, the patient has a baseline SD score of 4.

[0033] In one embodiment, the patient has a baseline sleep deprivation component of the SCORAD of at least 1 point, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the patient has a baseline sleep deprivation component of the SCORAD of at least 2 points, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the patient has a baseline sleep deprivation component of the SCORAD of at least 3 points, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the patient has a baseline sleep deprivation component of the SCORAD of at least 4 points, e.g., 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the patient has a baseline sleep deprivation component of the SCORAD of at least 5 points, e.g., 5, 6, 7, 8, 9, or 10 points. In one embodiment, the patient has a baseline sleep deprivation component of the SCORAD of at least 6 points, e.g., 6, 7, 8, 9, or 10 points. In one embodiment, the patient has a baseline sleep deprivation component of the SCORAD of at least 7 points, e.g., 7, 8, 9, or 10 points. In one embodiment, the patient has a baseline sleep deprivation component of the SCORAD of at least 8 points, e.g., 8, 9, or 10 points. In one embodiment, the patient has a baseline sleep deprivation component of the SCORAD of at least 9 points, e.g., 9 or 10 points.

[0034] In one embodiment, the patient has a baseline SD NRS score of at least 1 point, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the patient has a baseline SD NRS score of at least 2 points, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the patient has a baseline SD NRS score of at least 3 points, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the patient has a baseline SD NRS score of at least 4 points, e.g., 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the patient has a baseline SD NRS score of at least 5 points, e.g., 5, 6, 7, 8, 9, or 10 points. In one embodiment, the patient has a baseline SD NRS score of at least 6 points, e.g., 6, 7, 8, 9, or 10 points. In one embodiment, the patient has a baseline SD NRS score of at least 7 points, e.g., 7, 8, 9, or 10 points. In one embodiment, the patient has a baseline SD NRS of at least 8 points, e.g., 8, 9, or 10. In one embodiment, the patient has a baseline SD NRS of at least 9 points, e.g., 9 or 10.

[0035] As used herein, disease modification refers to an improvement in disease state, as measured, for example, by a reduction in clinically relevant scores, particularly the sleep disturbance score of the POEM. Thus, in one embodiment, disease modification is a reduction in the sleep disturbance score of the POEM. In another embodiment, disease modification is a reduction in the sleep deprivation component of the SCORAD. In another embodiment, disease modification is a reduction in the sleep disturbance numeric rating scale (SD NRS). A clinically relevant score is one that is used in a doctor's office, for example, by a physician.

[0036] As used herein, "pruritus" or "pruritis" refers to a condition in which the skin becomes itchy. Pruritus can be very uncomfortable and irritating, forcing an individual to scratch their skin. Pruritus can be caused by a range of different conditions, including skin diseases (such as atopic dermatitis and psoriasis), internal diseases (such as liver or kidney disease and lymphoma), neurological disorders (such as multiple sclerosis), psychiatric disorders (such as anxiety and obsessive-compulsive disorder), and allergic reactions.

[0037] As used herein, the pruritus numerical score / scale (P-NRS) refers to a patient's assessment of the intensity of itch over the past 24 hours on a scale of 0 to 10, with a score of 0 meaning "no itch" and a maximum score of 10 meaning "worst itch imaginable." As used herein, the mean pruritus numerical score / scale (mean P-NRS) refers to a patient's assessment of the average intensity of itch experienced over the past 24 hours on a scale of 0 to 10, with a score of 0 meaning "no itch" and a score of 10 meaning "worst itch imaginable." As used herein, the "peak itch numerical score / scale (peak P-NRS)" or "worst itch numerical score / scale (worst P-NRS)" refers to a patient's assessment of the worst intensity of itch experienced over the past 24 hours on a scale of 0 to 10, with a score of 0 meaning "no itch" and a score of 10 meaning "worst itch imaginable."

[0038] In one embodiment, the disease is modified by a percentage decrease in the Eczema Area and Severity Index (EASI) score from baseline ranging from -20 to -100%, e.g., EASI 50, EASI 75, or EASI 90. As used herein, EASI score and EASI are used interchangeably. The Eczema Area and Severity Index (EASI) score, as used herein, is a tool used to measure the area (indicating the extent of disease) and severity of atopic eczema. The number following the term "EASI" indicates the percentage reduction in score from baseline. Thus, for example, an EASI of 50 means a 50% reduction in score, and an EASI of 90 means a 90% reduction in score.

[0039] In one embodiment, disease modification is measured as a decrease in IGA. In one embodiment, during or after treatment with the present disclosure, a decrease in Investigator Global Assessment (IGA) is achieved, for example, a rating of 0, 1, or 2 (none, almost none, and mild signs of inflammation, respectively). In particular, an IGA score of 0 or 1 is achieved. As used herein, Investigator Global Assessment (IGA) refers to an assessment tool for atopic dermatitis, using a 0-5 point scale depending on the severity of the patient's symptoms. [Table 1]

[0040] In another aspect, there is provided a use of an antibody, antigen-binding fragment or pharmaceutical formulation disclosed herein for the treatment or amelioration of allergic food reactions, particularly severe allergic food reactions such as peanut allergy.

[0041] In one embodiment, the hyperallergic patient has a confirmed baseline IgE level of at least 10,000 KU / L ± 2,000, for example, at a level of 8,000, 8,500, 9,000, 9,500, 10,000, 10,500, 11,000, 11,500 or 12,000 KU / L. In one embodiment, for example, a patient is identified as a hyperallergic patient before treatment is administered if the patient's baseline IgE level is determined and is at a level of at least 10,000 KU / L ± 2,000. Thus, in one embodiment, a patient is identified as a highly allergic patient if, prior to administration of the antibody or binding fragment thereof, antibody or binding fragment thereof defined herein, pharmaceutical formulation, or medicament, the patient's baseline IgE level is determined and is at a level of at least 10,000 KU / L ± 2,000. Thus, in one embodiment, the treatment target population is highly allergic patients whose baseline IgE level is determined and is at a level of at least 10,000 KU / L ± 2,000.

[0042] In one embodiment, the patient is identified as hyperallergic by clinical observation. As used herein, inadequate control refers to inadequate control with existing approved medications, such as topical medications and / or dupilumab. The results suggest that ebrasakimab has similar or potentially greater efficacy than dupilumab, demonstrating the potential of ebrasakimab as an alternative therapy for the treatment and management of insomnia. Thus, in one embodiment, treatment is provided for patient populations whose symptoms and / or adverse side effects are inadequately controlled when treated with dupilumab, i.e., patient populations who have failed treatment with dupilumab. Thus, in one embodiment, the patient has previously received dupilumab. In one embodiment, the patient has insomnia or a sleep disorder that is not adequately controlled by dupilumab. In one embodiment, the patient has atopic dermatitis that is not adequately controlled by dupilumab. In one embodiment, the patient has atopic dermatitis and insomnia or a sleep disorder that is not adequately controlled by dupilumab.

[0043] As used herein, asthma is a respiratory disease characterized by inflammation and bronchospasm, and the muscles around the airway tighten and contract to keep the airway open.This causes patients to cough, wheeze, feel chest tightness, and shortness of breath.When breathing difficulties become severe, this is usually called an asthma attack.Typical asthma may be characterized by dry cough or a feeling of blockage in the throat.

[0044] As used herein, "allergic asthma (synonymous with allergy-induced asthma)" refers to a form of asthma in which a patient's lungs become inflamed and constrict their airways in response to inhaled allergens. Common allergens include pollen, dust, animal dander, and mold. Patients with allergic asthma often experience the same symptoms as those with non-allergic asthma, namely coughing, wheezing, chest tightness, and shortness of breath. Thus, the main difference between the two is that patients with allergic asthma typically experience symptoms after inhaling an allergen.

[0045] As used herein, "eosinophilic esophagitis (EOE)" refers to a chronic immune system disorder in which eosinophils accumulate in the esophagus (eosinophils are not normally present there). This accumulation occurs as a response to food, allergens, or acid reflux and can cause inflammation and damage to esophageal tissue. This can result in narrowing of the esophagus, making swallowing difficult. In severe cases, food can get stuck in the throat, leading to an emergency. Most EOE patients are atopic. Therefore, individuals with atopic dermatitis, food allergies, or other environmental allergies are at higher risk for developing EOE. A family history of EOE is also a risk factor for the disease. Currently, there are no medications approved by the U.S. Food and Drug Administration (FDA) for the treatment of EOE. However, proton pump inhibitors (PPIs) have been shown to reduce esophageal inflammation in some EOE patients and are therefore often used as first-line treatment. Corticosteroids may also be administered to suppress inflammation.

[0046] As used herein, atopic dermatitis (AD) refers to inflammation of the skin, including dry / sensitive skin, red rash, etc. AD is an extremely painful, demoralizing, and psychologically damaging disease. The most common side effect of AD is pruritus, and a diagnosis of active AD cannot be made without a history of pruritus. In fact, AD patients often report that pruritus is their most bothersome and difficult-to-treat symptom.

[0047] Psoriasis, as used herein, refers to a skin disease in which skin cells grow much faster than normal. This results in red, itchy, scaly patches, which are usually found on the scalp, knees, elbows, and trunk. There are different categories of plaque psoriasis, such as pustular psoriasis, guttate psoriasis, inverse psoriasis, and erythrodermic psoriasis. Most types of psoriasis go through periods of symptoms lasting several weeks or months, followed by periods of temporary remission or remission.

[0048] As used herein, angioedema refers to rapid swelling (edema) of the skin or areas under the mucous membranes due to fluid accumulation, usually in response to an allergic trigger. Angioedema can affect various parts of the body, but it usually appears in the eyes, lips, genitals, hands, and feet. Angioedema can occur simultaneously with hives or alone. In more severe cases, angioedema can cause difficulty breathing, abdominal pain, and dizziness.

[0049] As used herein, Ehlers-Danlos syndrome (EDS) refers to a group of genetic disorders affecting connective tissues such as tendons, ligaments, and blood vessels. There are 13 types of EDS, including hyperactive EDS (the most common), classic EDS, vascular EDS, and kyphoscoliotic EDS. The different types of EDS share several common symptoms, such as increased joint range of motion (hyperactive type) and stretchy, brittle skin. There is no known cure for EDS, and treatment is primarily supportive, including physical therapy.

[0050] Hives (urticaria), as used herein, refers to the sudden appearance of itchy, light pink bumps or welts on the skin. There are several types of hives, including acute hives, which last less than six weeks and are generally caused by food, medications, or infection; chronic hives, which last six weeks or more; and physical hives, which are caused by anything that irritates the skin (e.g., cold, heat, pressure, sweating, etc.). In one embodiment, a treatment according to the present disclosure is administered for acute hives.

[0051] As used herein, the interleukin-13 receptor (IL-13R) is a type I cytokine receptor that binds to interleukin-13. It consists of two subunits, encoded by IL13Rα1 and IL4R, respectively. These two genes encode the IL-13Rα1 and IL-4Rα proteins. IL-13 binds to the IL-13Rα1 chain to form a dimer, and IL-4Rα stabilizes this interaction. The presence of the IL-4R subunit also allows IL13R to initiate IL-4 signaling. In both cases, this occurs via activation of the Janus kinase (JAK) / signal transducer and activator of transcription (STAT) pathway, resulting in the phosphorylation of STAT6. Human IL-13Rα1 has the Uniprot designation P3597.

[0052] IL-13Rα2, previously referred to as IL-13R and IL-13Rα, is another receptor that can bind to IL-13. However, in contrast to IL-13Rα1, this protein binds IL-13 with high affinity but not IL-4. Human IL-13Rα2 has the Uniprot number Q14627.

[0053] In one embodiment, the anti-IL-13R antibody or binding fragment thereof of the present disclosure binds to IL-13Rα1. In one embodiment, the antibody or binding fragment thereof binds only to IL-13Rα1 and not to IL-13Rα2.

[0054] In one embodiment, CDRH1 is the amino acid sequence GYSFTSYWIG (SEQ ID NO: 1). In one embodiment, CDRH2 is the amino acid sequence VIYPGDSYTR (SEQ ID NO: 2). In one embodiment, CDRH3 has the formula: SEQ ID NO: 3 X1Pro Asn Trp Gly X6X7Asp X9 X1 represents Phe, Met, Gln, Leu or Val. X6 represents Ser or Ala. X7 represents Phe, Leu, Ala or Met. X9 represents Tyr, Gln, Lys, Arg, Trp, His, Ala, Thr, Ser, Asn, or Gly.

[0055] In one embodiment, the anti-IL13R antibody or binding fragment used in the formulation of the present disclosure comprises a CDRH3 independently selected from SEQ ID NOs: 4-30. In one embodiment, an anti-IL13R antibody or binding fragment used in the present disclosure comprises a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:3. In one embodiment, an anti-IL13R antibody or binding fragment used in the present disclosure comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In one embodiment, an anti-IL13R antibody or binding fragment used in the present disclosure comprises a CDRH3 having the amino acid sequence MPNWGSLDH (SEQ ID NO: 10). In one embodiment, an anti-IL13R antibody or binding fragment used in the present disclosure comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO:2, and a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:10.

[0056] In one embodiment, CDRL1 is the amino acid sequence RASQSISSSYLA (SEQ ID NO: 31). In one embodiment, CDRL2 is the amino acid sequence GASSRAT (SEQ ID NO: 32). In one embodiment, CDL3 has the formula: SEQ ID NO: 33 Gln X2X3X4X5 X2 represents Gln, Arg, Met, Ser, Thr or Val. X3 represents Tyr or Val. X4 represents Glu, Ala, Gly or Ser. X5 represents Thr, Ala or Ser.

[0057] In one embodiment, the IL-13Rα1 antibody used in the formulation of the present disclosure comprises a CDRL3 independently selected from SEQ ID NOs: 34-47. In one embodiment, an anti-IL13R antibody or binding fragment used in the present disclosure comprises a CDL3 having the amino acid sequence QQYAS (SEQ ID NO: 45). In one embodiment, an anti-IL13R antibody of the present disclosure comprises a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 31, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 32, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 45. In one embodiment, an IL-13R antibody used in the present disclosure comprises a CDRL3 independently selected from the sequence comprising SEQ ID NOs: 34-47. In one embodiment, CDRL3 comprises the amino acid sequence set forth in SEQ ID NO:33.

[0058] In one embodiment, the VH regions are independently selected from a sequence from the group comprising: SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; and a sequence at least 95% identical to any one of these. SEQ ID NO:51 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met Gly Val Ile Tyr Pro Gly Asp Ser Tyr Thr Arg Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Met Pro Asn Trp Gly Ser Leu Asp His Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

[0059] In one embodiment, the VL is selected from the group comprising SEQ ID NO: 52, SEQ ID NO: 53 and SEQ ID NO: 54, and a sequence at least 95% identical to any one of these ( * K is deleted by post-translational modification). SEQ ID NO:53 EIVLTQSPGTLSLSPGERATLSCRASQSISSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYASFGQGTKVEI *

[0060] In one embodiment, the VH sequence is SEQ ID NO:48 (or a sequence at least 95% identical thereto), and the VL sequence is SEQ ID NO:52, SEQ ID NO:53, or SEQ ID NO:54 (or a sequence at least 95% identical to any one of these). In one embodiment, the VH sequence is SEQ ID NO:49 (or a sequence at least 95% identical thereto), and the VL sequence is SEQ ID NO:52, SEQ ID NO:53, or SEQ ID NO:54 (or a sequence at least 95% identical to any one of these). In one embodiment, the VH sequence is SEQ ID NO:50 (or a sequence at least 95% identical thereto), and the VL sequence is SEQ ID NO:52, SEQ ID NO:53, or SEQ ID NO:54 (or a sequence at least 95% identical to any one of these). In one embodiment, the VH sequence is SEQ ID NO:51 (or a sequence at least 95% identical thereto), and the VL sequence is SEQ ID NO:52, SEQ ID NO:53, or SEQ ID NO:54 (or a sequence at least 95% identical to any one of these). In one embodiment, the VL sequence is SEQ ID NO:52 (or a sequence at least 95% identical thereto), and the VH sequence is SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, or SEQ ID NO:51 (or a sequence at least 95% identical to any one of these). In one embodiment, the VL sequence is SEQ ID NO:53 (or a sequence at least 95% identical thereto), and the VH sequence is SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, or SEQ ID NO:51 (or a sequence at least 95% identical to any one of these). In one embodiment, the VL sequence is SEQ ID NO:54 (or a sequence at least 95% identical thereto), and the VH sequence is SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, or SEQ ID NO:51 (or a sequence at least 95% identical to any one of these).

[0061] In one embodiment, the VH sequence is SEQ ID NO: 51 (or a sequence at least 95% identical thereto) and the VL sequence is SEQ ID NO: 53 (or a sequence at least 95% identical thereto). As used herein, a variable region refers to the region of an antibody chain comprising the CDRs and an appropriate framework.

[0062] In one embodiment, the heavy chain comprises a sequence independently selected from the group consisting of SEQ ID NOs: 55, 56, 57, 58, 59 and 60 (or a sequence at least 95% identical to any one of these), and the light chain is independently selected from SEQ ID NOs: 61, 62 and 63 (or a sequence at least 95% identical to any one of these).

[0063] In one embodiment, the light chain is independently selected from the group comprising SEQ ID NO: 61; SEQ ID NO: 62; SEQ ID NO: 63 and a sequence at least 95% identical to any one of these.

[0064] In one embodiment, the heavy chains are independently selected from SEQ ID NOs: 55, 56, 57, 58, 59 and 60 (or a sequence at least 95% identical to any one of these), and the light chains are independently selected from SEQ ID NOs: 61, 62 and 63 (or a sequence at least 95% identical to any one of these).

[0065] In one embodiment, the heavy chain is SEQ ID NO: 55 (or a sequence at least 95% identical thereto), and the light chain is independently selected from SEQ ID NOs: 61 or 62 and 63 (or a sequence at least 95% identical to any one of these). In one embodiment, the heavy chain is SEQ ID NO: 56 (or a sequence at least 95% identical thereto), and the light chain is independently selected from SEQ ID NOs: 61 or 62 and 63 (or a sequence at least 95% identical to any one of these). In one embodiment, the heavy chain is SEQ ID NO: 57 (or a sequence at least 95% identical thereto), and the light chain is independently selected from SEQ ID NOs: 62 or 63 (or a sequence at least 95% identical to any one of these). In one embodiment, the heavy chain is SEQ ID NO: 58 (or a sequence at least 95% identical thereto), and the light chain is independently selected from SEQ ID NOs: 61, 62, and 63 (or a sequence at least 95% identical to any one of these). In one embodiment, the heavy chain is SEQ ID NO:59 (or a sequence at least 95% identical thereto), and the light chain is independently selected from SEQ ID NOs:61, 62, and 63 (or a sequence at least 95% identical to any one of these). In one embodiment, the heavy chain is SEQ ID NO:60 (or a sequence at least 95% identical thereto), and the light chain is independently selected from SEQ ID NOs:61 and 63 (or a sequence at least 95% identical to any one of these). In one embodiment, the heavy chain is SEQ ID NO:58 or 60 (or a sequence at least 95% identical to any one of these), and the light chain has the sequence set forth in SEQ ID NO:61 (or a sequence at least 95% identical thereto). In one embodiment, the heavy chain is SEQ ID NO:58 (or a sequence at least 95% identical to any one of these), and the light chain has the sequence set forth in SEQ ID NO:61 (or a sequence at least 95% identical thereto). In one embodiment, the heavy chain has the sequence set forth in SEQ ID NO: 60 (or a sequence at least 95% identical to any one of these) and the light chain has the sequence set forth in SEQ ID NO: 61 (or a sequence at least 95% identical thereto).

[0066] In one embodiment, an anti-IL13R antibody of the disclosure comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 10, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 31, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 32, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 45.

[0067] In one embodiment, the anti-IL13R antibody is ebrasakimab (formerly known as ASLAN004).

[0068] As used herein, "derived from" means that the sequence employed, or a sequence closely similar to the sequence employed, is obtained from the original genetic material, such as the light or heavy chain of an antibody.

[0069] As used herein, "at least 95% identical" is intended to refer to an amino acid sequence that is 95% or more identical to a reference sequence over its entire length, for example, an amino acid sequence that is 96, 97, 98, or 99% identical. Software programs can be used to calculate the percentage of identity.

[0070] It will be understood that any discussion herein of a protein, antibody, or amino acid sequence includes any variant of the protein, antibody, or amino acid sequence produced during production and / or storage. For example, during production or storage, an antibody may be deamidated (e.g., at asparagine or glutamine residues), and / or its glycosylation may be altered, and / or glutamine residues may be converted to pyroglutamic acid, and / or N- or C-terminal residues may be removed or "trimmed" (C-terminal lysine residues of encoded antibodies are often removed during the manufacturing process), and / or some or all of the signal sequence may be incompletely processed and thus remain at the end of the antibody. It will be understood that an antibody comprising a particular amino acid sequence, or binding fragment thereof, may be a heterogeneous mixture of the designated or encoded sequence and / or variants of the designated or encoded sequence or binding fragment thereof.

[0071] In one embodiment, the present disclosure extends to sequences expressly disclosed herein where the C-terminal lysine has been truncated.

[0072] In one embodiment, the antibody or binding fragment thereof used in the formulations of the present disclosure is humanized. As used herein, "humanized antibody (including CDR-grafted antibody)" refers to a molecule having one or more complementarity-determining regions (CDRs) from a non-human species and the framework regions of a human immunoglobulin molecule (see, e.g., U.S. Pat. No. 5,585,089; WO 91 / 09967). It will be understood that it may be necessary to transfer the specificity-determining residues of a CDR rather than the entire CDR (see, e.g., Kashmiri et al. 2005, Methods, 36, 25-34). A humanized antibody may optionally further comprise one or more framework residues from the non-human species from which the CDRs are derived. For a review, see Vaughan et al., Nature Biotechnology, 16, 535-539, 1998.

[0073] When CDRs or specificity-determining residues are grafted, any suitable receptor variable region framework sequence, including mouse, primate, or human framework regions, can be used, taking into account the class / type of the donor antibody from which the CDRs are derived. Examples of human frameworks that can be used in the present invention include KOL, NEWM, REI, EU, TUR, TEI, LAY, and POM (Kabat et al.). For example, KOL and NEWM can be used for the heavy chain, REI can be used for the light chain, and EU, LAY, and POM can be used for both the heavy and light chains. Alternatively, human germline sequences can be used, which are available at http: / / vbase.mrc-cpe.cam.ac.uk / .

[0074] In the humanized antibodies used in the present invention, the receptor heavy and light chains do not necessarily have to be derived from the same antibody, and may, if desired, comprise composite chains having framework regions derived from different chains.

[0075] The framework regions need not be exactly identical in sequence to those of the acceptor antibody. For example, unusual residues may be changed to more frequently occurring residues for that acceptor chain class or type. Alternatively, selected residues in the acceptor framework regions may be altered to correspond to residues at the same positions in the donor antibody (see Reichmann et al., 1998, Nature, 332, 323-324). Such alterations should be kept to the minimum necessary to restore the affinity of the donor antibody. Protocols for selecting residues in acceptor framework regions that need to be altered are described in WO 91 / 09967.

[0076] In one embodiment, the anti-IL13R antibodies of the present disclosure are fully human, particularly one or more variable domains. A fully human molecule is one in which the variable and constant regions (if present) of both the heavy and light chains are all of human origin or are substantially identical to sequences of human origin, although not necessarily from the same antibody. Examples of fully human antibodies include, for example, antibodies produced by the phage display method described above, and antibodies produced in mice in which mouse immunoglobulin variable regions and, optionally, constant region genes have been replaced with human counterparts (e.g., as outlined in EP 0 546 073, U.S. Pat. Nos. 5,545,806, 5,569,825, 5,625,126, 5,633,425, 5,661,016, 5,770,429, EP 0 438 474, and EP 0 463 151).

[0077] Thus, the anti-IL13R antibodies disclosed herein may comprise one or more constant regions, such as naturally occurring constant domains or derivatives of naturally occurring domains.

[0078] As used herein, a derivative of a naturally occurring domain is intended to refer to one in which 1, 2, 3, 4 or 5 amino acids in the naturally occurring sequence have been substituted or deleted, e.g., to optimize the properties of the domain by removing undesirable properties, but retain the properties that characterize the domain.

[0079] If necessary, the antibody used in the present invention may be conjugated to one or more effector molecules. It will be understood that the effector molecules can be a single effector molecule or two or more effector molecules can be linked to form a single molecule that can bind to the antibody of the present invention. If an antibody fragment conjugated to an effector molecule is desired, it can be prepared by standard chemical or recombinant DNA procedures, in which the antibody fragment is directly or indirectly conjugated to the effector molecule (including via a coupling agent). Techniques for conjugating such effector molecules to antibodies are well known in the art (see Hellstrom et al., Controlled Drug Delivery, 2nd Ed., Robinson et al., eds., 1987, pp. 623-53; Thorpe et al., 1982, Immunol. Rev., 62:119-58 and Dubowchik et al., 1999, Pharmacology and Therapeutics, 83, 67-123). Particular chemical procedures include, for example, those described in WO 93 / 06231, WO 92 / 22583, WO 89 / 00195, WO 89 / 01476, WO 03 / 031581. Alternatively, where the effector molecule is a protein or polypeptide, attachment may be achieved using recombinant DNA procedures, for example, as described in WO 86 / 01533 and EP 0392745.

[0080] The term "effector molecule" as used herein includes, for example, biologically active proteins, e.g., enzymes, other antibodies or antibody fragments, synthetic or naturally occurring polymers, nucleic acids and fragments thereof, e.g., DNA, RNA and fragments thereof, radionuclides, particularly radioactive iodides, radioisotopes, chelated metals, nanoparticles, and reporter groups such as fluorescent compounds or compounds that can be detected by NMR or ESR spectroscopy.

[0081] Other effector molecules can include, for example, detectable substances useful for diagnosis.Examples of detectable substances include various enzymes, prosthetic groups, fluorescent substances, luminescent substances, bioluminescent substances, radionuclides, positron-emitting metals (used in positron emission tomography), and non-radioactive paramagnetic metal ions.For the metal ions that can be bound to antibodies for use as diagnostic agents, see generally U.S. Patent No. 4,741,900. Suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; suitable prosthetic groups include streptavidin, avidin, and biotin; suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride, and phycoerythrin; suitable luminescent materials include luminol; suitable bioluminescent materials include luciferase, luciferin, and aequorin; and suitable radionuclides include 125I, 131I, 111In, and 99Tc.

[0082] In another example, the effector molecule may increase the half-life of the antibody in vivo, and / or reduce the immunogenicity of the antibody, and / or facilitate delivery of the antibody across an epithelial barrier to the immune system. Examples of suitable effector molecules of this type include polymers, albumin, albumin-binding proteins, or albumin-binding compounds such as those described in WO 05 / 117984. When the effector molecule is a polymer, it may generally be a synthetic or natural polymer, such as an optionally substituted linear or branched polyalkylene, polyalkenylene, or polyaloxyalkylene polymer, or a branched or unbranched polysaccharide, such as a homo- or heteropolysaccharide.

[0083] Particular optional substituents which may be present on the synthetic polymers include one or more hydroxy, methyl, or methoxy groups. Examples of synthetic polymers include optionally substituted linear or branched poly(ethylene glycol), poly(propylene glycol), poly(vinyl alcohol) or derivatives thereof, in particular optionally substituted poly(ethylene glycol), such as methoxypoly(ethylene glycol), or derivatives thereof. Examples of naturally occurring polymers include lactose, amylose, dextran, glycogen, or derivatives thereof.

[0084] As used herein, "derivative" is intended to include reactive derivatives, e.g., thiol-selective reactive groups such as maleimides. The reactive group can be attached to the polymer directly or via a linker segment. It will be understood that the residue of such a group will, in some instances, form part of the product, as the linking group between the antibody fragment and the polymer. Suitable polymers include polyalkylene polymers such as poly(ethylene glycol) or especially methoxypoly(ethylene glycol) or derivatives thereof, especially those having a molecular weight in the range of about 15,000 Da to about 40,000 Da.

[0085] In one example, the antibody used in the present invention is conjugated to a poly(ethylene glycol) (PEG) moiety. In one particular example, the antibody is an antibody fragment, and the PEG molecule can be attached via any available amino acid side chain or terminal amino acid functional group located on the antibody fragment, such as any free amino, imino, thiol, hydroxyl, or carboxyl group. Such amino acids may occur naturally in the antibody fragment or may be incorporated into the fragment using recombinant DNA methods (see, e.g., U.S. Pat. Nos. 5,219,996; 5,667,425; WO 98 / 25971; WO 2008 / 038024). In one example, the antibody molecule of the present invention is a modified Fab fragment in which one or more amino acids have been added to the C-terminal end of its heavy chain to enable attachment of an effector molecule. Optionally, the added amino acids form a modified hinge region containing one or more cysteine ​​residues to which an effector molecule can be attached. Multiple sites can be used to attach two or more PEG molecules.

[0086] In cancer-related lymphedema (BCRL) in patients with cancer, such as breast cancer, the formulations of the present disclosure may prevent lymphedema-related effects such as fibrosis, hyperkeratosis, fibroadipose tissue deposition, fluid accumulation, limb swelling, loss of skin elasticity, pain, etc. By reducing excess volume, the formulations may improve lymphatic and, for example, limb function.

[0087] The development of lymphedema after lymphatic injury is associated with tissue inflammation, infiltration of CD4+ cells, and their differentiation into the type 2 helper T cell (Th2) phenotype. Th2 cells produce IL-4 and IL-13, which play important roles in the development of lymphedema-related symptoms as well as other Th2-mediated diseases.

[0088] In one embodiment, the formulations described herein are administered in combination with another therapy. As used herein, "in combination" is intended to encompass when an anti-IL13R antibody is administered before, simultaneously with, or after another therapy, in the same or a different formulation. Thus, combination refers to when the pharmacological effects of a first therapy are present in the body at the same time as the pharmacological effects of a second therapy, and / or when the two therapies are part of a treatment plan designed to be used together.

[0089] In one embodiment, an initial loading dose of 600 mg of the anti-IL13R antibody or binding fragment thereof is administered. In one embodiment, the loading dose is administered for 1 to 3 weeks, such as 1 week, 2 weeks, or 3 weeks. In one embodiment, the loading dose is administered only at week 0. In one embodiment, the loading dose is administered at weeks 0 and 1, e.g., 600 mg at week 0 and 600 mg at week 1. In one embodiment, the loading dose is administered at weeks 0, 1, and 2, e.g., 600 mg at week 0, 600 mg at week 1, and 600 mg at week 2.

[0090] As used herein, a "loading dose" refers to a higher and / or more frequently administered dose at the beginning of a treatment cycle. The purpose of the loading dose is to quickly "saturate" the system in vivo to provide a drug level that is therapeutically effective and can be maintained with lower and / or less frequent "therapeutic" doses. In some embodiments, this may be achieved locally and rapidly by administering the doses simultaneously to the same part of the body. Subsequent doses administered after the loading dose are referred to herein as therapeutic doses.

[0091] As used herein, "therapeutic amount" refers to an amount of an anti-IL13R antibody, such as ASLAN004, that is adequate to achieve the intended therapeutic effect when used in an appropriate treatment regimen, e.g., an amount that ameliorates a disease symptom or condition without causing any particular dose-limiting side effects. An appropriate therapeutic amount is generally a balance between therapeutic effect and acceptable toxicity, e.g., when the side effects and toxicity are acceptable given the benefits obtained by the treatment.

[0092] In one embodiment, the therapeutic dose of an anti-IL13R antibody or binding fragment thereof is 300 mg. In one embodiment, the therapeutic dose of an anti-IL13R antibody or binding fragment thereof is 300 mg administered every two weeks (300 mg Q2W). In one embodiment, the therapeutic dose of an anti-IL13R antibody or binding fragment thereof is 300 mg administered every four weeks (300 mg Q4W). In one embodiment, the therapeutic dose of the anti-IL13R antibody or binding fragment thereof is 400 mg. In one embodiment, the therapeutic dose of the anti-IL13R antibody or binding fragment thereof is 400 mg administered every two weeks (400 mg Q2W). In one embodiment, the therapeutic dose of the inhibitor is 400 mg administered every four weeks (400 mg Q4W). In one embodiment, the therapeutic dose of the anti-IL13R antibody or binding fragment thereof is 600 mg. In one embodiment, the therapeutic dose of the anti-IL13R antibody or binding fragment thereof is administered at 600 mg every two weeks (600 mg Q2W). In one embodiment, the therapeutic dose of the anti-IL13R antibody or binding fragment thereof is administered at 600 mg every four weeks (600 mg Q4W).

[0093] In one embodiment, the anti-IL13R antibody or binding fragment thereof is administered at 300 mg Q2W, 400 mg Q2W, 400 mg Q4W, or 600 mg Q4W. In one embodiment, the anti-IL13R antibody or binding fragment thereof is administered at 300 mg Q2W, 400 mg Q2W, or 600 mg Q4W. In one embodiment, the anti-IL13R antibody or binding fragment thereof is not administered at 400 mg once every four weeks (400 mg Q4W).

[0094] In one embodiment, an initial loading dose of 600 mg of anti-IL13R antibody or binding fragment thereof is administered at weeks 0 and 1, followed by 300 mg of anti-IL13R antibody or binding fragment thereof every two weeks. In one embodiment, an initial loading dose of 600 mg of anti-IL13R antibody or binding fragment thereof is administered at weeks 0 and 1, followed by 400 mg of anti-IL13R antibody or binding fragment thereof every two weeks. In one embodiment, an initial loading dose of 600 mg of anti-IL13R antibody or binding fragment thereof is administered at weeks 0, 1, and 2, followed by 400 mg of anti-IL13R antibody or binding fragment thereof every four weeks. In one embodiment, an initial loading dose of 600 mg of anti-IL13R antibody or binding fragment thereof is administered at weeks 0, 1, and 2, followed by 600 mg of anti-IL13R antibody or binding fragment thereof every four weeks.

[0095] In one embodiment, a formulation according to the present disclosure (including formulations containing same) is administered monthly, for example, during a treatment cycle or as maintenance therapy. As used herein, a "treatment cycle" refers to a complete cycle including a loading dose and a treatment dose for a defined period of time, e.g., 1 month or more, 2 months or more, or 3 months or more, e.g., 4 months, 5 months, 6 months, etc. The cycle may be repeated after treatment has ceased, starting again with the loading dose. In one embodiment, the treatment cycle is followed by a maintenance dose aimed at maintaining the disease in remission.

[0096] As used herein, a unit dose generally refers to a product containing an amount of an anti-IL13R antibody or antigen-binding fragment thereof of the present disclosure, including any excess, to be administered in a single dose. A unit dose of an anti-IL13R antibody or antigen-binding fragment thereof claimed herein may refer to a commercially available form in which the product is divided into the amount of anti-IL13R antibody or binding fragment thereof required for a single administration, such as a pharmaceutical formulation of the anti-IL13R antibody or binding fragment thereof. Thus, the manufacturer can determine and control the exact amount of anti-IL13R antibody or binding fragment thereof contained in each unit dose. The product can be provided in a variety of forms familiar to those skilled in the art, such as vials, ampoules, infusion bags, or devices (including automatic injection devices). As used herein, exact amount refers to the amount administered as a dose to a patient and any overages. In one embodiment, a unit dose or multiple unit doses are used in accordance with the methods of the present disclosure.

[0097] In this specification, "comprising" is to be interpreted as "including." Embodiments of the invention comprising particular features / elements are intended to extend to alternative embodiments "consisting of" or "consisting essentially of" the associated elements / functions. Where technically appropriate, embodiments of the invention may be combined.

[0098] Technical literature, such as patents and applications, is incorporated herein by reference. Any embodiment specifically and explicitly described herein may be the basis for the disclaimer, either alone or in combination with one or more additional embodiments. The Background section of this specification contains relevant technical information which may be used as a basis for amendment. This application claims priority to U.S. Patent Application No. 63 / 374,678, filed September 6, 2022, the contents of which are incorporated herein by reference and may be used to correct any errors herein. Individual values ​​or elements in the examples may be extracted and combined with the general elements of the disclosure, i.e., used as the basis for a particular correction without reference to other features of the examples. Headings herein are used to divide the document into sections and are not intended to be used to interpret the meaning of the disclosure provided herein. The invention is further described, by way of example only, in the following examples. [Brief explanation of the drawings]

[0099] [Figure 1A] 1 is a table showing the demographics of the full analysis population. [Figure 1B] 1 is a table showing baseline disease characteristics of the full analysis set. [Figure 1C] 1 is a table showing baseline disease characteristics of the efficacy evaluable set (EES). [Figure 2A] 1 is a table showing the percent change from baseline in EASI score at day 57 in the EES. [Figure 2B] 1 is a graph showing the percent change from baseline in EASI score at day 57 in EES (ASLAN004 200 mg, 400 mg and 600 mg). [Figure 2C] Graph showing the % change from baseline in EASI score at day 57 in EES (ASLAN004 low and high doses). [Figure 3A] 1 is a table showing the percent change from baseline in EASI score at day 29 in the EES. [Figure 3B] 1 is a graph showing the percent change from baseline in EASI score at day 29 in EES (ASLAN004 200 mg, 400 mg, 600 mg). [Figure 4A] 1 is a graph showing the percent change in EASI score over time for EES (ASLAN004 200 mg, 400 mg, 600 mg). [Figure 4B]Graph showing % change in EASI score over time in EES (low and high doses of ASLAN004). [Figure 5A] FIG. 1 is a graph showing the percent change from baseline in EASI scores over time in EES (placebo). [Figure 5B] 1 is a graph showing the percent change from baseline in EASI score over time on EES (ASLAN004 200 mg). [Figure 5C] 1 is a graph showing the percent change from baseline in EASI score over time on EES (ASLAN004 400 mg). [Figure 5D] 1 is a graph showing the percent change from baseline in EASI score over time on EES (ASLAN004 600 mg). [Figure 6A] 1 is a table showing sensitivity analysis at day 57 in a modified intention-to-treat population (mITT). [Figure 6B] Graph showing sensitivity analysis at day 57 in mITT (ASLAN004 200 mg, 400 mg, 600 mg). [Figure 6C] Sensitivity analysis at day 57 in mITT (ASLAN004 low and high doses). [Figure 7A] 1 is a summary table showing EASI 50, EASI 75, and EASI 90 on day 57 in the EES. [Figure 7B] 1 is a graph showing EASI 50 on day 57 for EES (ASLAN004 200 mg, 400 mg, 600 mg). [Figure 7C] 1 is a graph showing EASI 50 at day 57 of EES (low and high doses of ASLAN004). [Figure 7D] 1 is a graph showing EASI 75 on day 57 of EES (ASLAN004 200 mg, 400 mg, 600 mg). [Figure 7E] 1 is a graph showing EASI 75 at day 57 in EES (low and high doses of ASLAN004). [Figure 7F]1 is a graph showing EASI 90 on day 57 of EES (ASLAN004 200 mg, 400 mg, 600 mg). [Figure 7G] 1 is a graph showing EASI 90 at day 57 in EES (low and high doses of ASLAN004). [Figure 8A] Graph showing the percentage of patients who achieved EASI 50. [Figure 8B] Graph showing the percentage of patients who achieved EASI 75. [Figure 8C] Graph showing the percentage of patients who achieved EASI 90. [Figure 9] Summary table showing the proportion of patients achieving EASI 50, 75, and 90 in EES and mITT. [Figure 10A] 1 is a summary table showing the proportion of patients with an IGA score of 0 or 1 at day 57 in the ESS. [Figure 10B] 1 is a graph showing the proportion of patients with an IGA score of 0 or 1 at day 57 in the ESS. [Figure 10C] 1 is a graph showing the change over time in the proportion of patients with an IGA score of 0 or 1 in the ESS. [Figure 11] 1 is a table showing patient baseline TARC and IgE levels. [Figure 12A] Graph showing mean % change from baseline TARC (ASLAN004 200 mg and 400 mg). [Figure 12B] Graph showing mean % change from baseline TARC (ASLAN004 400 mg and placebo). [Figure 12C] Graph showing individual patient % change from baseline TARC (ASLAN004 400 mg). [Figure 13A] Graph showing % change from baseline for ASLAN004 200 mg and 400 mg. [Figure 13B]1 is a graph showing the mean IgE % change from baseline at ASLAN004 200 mg and 400 mg. [Figure 13C] 1 is a graph showing the IgE % change from baseline for individual patients receiving placebo. [Figure 13D] 1 is a graph showing the change in IgE% from baseline in individual patients administered ASLAN004 200 mg. [Figure 13E] 1 is a graph showing the change in IgE% from baseline in individual patients administered ASLAN004 400 mg. [Figure 14] 1 is a graph showing a comparison over time between ASLAN004 exposure, EASI, TARC, and IgE in patients administered ASLAN004 400 mg. [Figure 15] 1 is a table showing a comparison of ASLAN004 and dupilumab. [Figure 16] 1 is a flowchart showing the number of subjects in each test group. [Figure 17] Table showing baseline demographic and disease characteristics of the intent-to-treat population (ITT), modified intent-to-treat population (mITT), and excluded center group. [Figure 18] Table showing a comparison of adverse events (AEs) between the mITT group and the excluded center group. [Figure 19A] FIG. 1 is a graph showing improvement in worst itch (median) over time in the mITT group. [Figure 19B] Graph showing improvement in worst itch (median) at week 8 in the mITT group. [Figure 20A] 1 is a graph showing improvement in mean itching (median) over time in the mITT group. [Figure 20B] Graph showing improvement in mean itch (median) at week 8 in the mITT population. [Figure 21] Graph showing improvement over time in POEM score change from baseline (CFBL). [Figure 22] FIG. 10 is a graph showing a 2-point improvement in sleep disturbance (SD) score at week 8 in the mITT group. [Figure 23] Table showing baseline characteristics of the intent-to-treat (ITT) patient population in the TREK-AD trial. a = Ebla 400mg Q4W (n=59), Ebla 600mg Q4W (n=57), Ebla 300mg Q2W (n=58), Ebla 400mg Q2W (n=55), placebo Q2W (n=56), all Ebla groups (n=229); b = Ebla 400mg Q4W (n=24), Ebla 600mg Q4W (n=21), Ebla 300mg Q2W (n=20), Ebla 400mg Q2W (n=19), placebo Q2W (n=23), all Ebla groups (n=84); c = Ebla 400mg Q4W (n=24), Ebla 600mg Q4W (n=20), Ebla 300mg Q2W (n=20), Ebla 400mg Q2W (n=19), placebo Q2W (n=23), all Ebla groups (n=83) BSA: body surface area; DLQI: index assessing the impact of skin disease on quality of life; EASI: eczema area and severity index; IGA: investigator's global assessment (5-point scale); NRS: numerical rating scale; POEM: patient-assessed eczema severity; Q2W: once every 2 weeks, Q4W: once every 4 weeks; SD: standard deviation. [Figure 24] 1 is a graph showing the % mean change from baseline in the sleep deprivation component of SCORAD for ITT patients in the TREK-AD trial over 16 weeks. [Figure 25A] 1 is a graph showing the proportion of ITT patients with a baseline sleep disturbance numeric rating scale (SD NRS) who achieved a change of 4 or more points on the SD NRS over the 16-week study period. [Figure 25B] 1 is a graph showing the proportion of ITT patients with a baseline sleep disturbance numeric rating scale (SD NRS) who achieved a 4 or greater point change in SD NRS at week 16.

[0100] Example Example 1 Research Protocol (Initial MAD Escalation) Patients were enrolled in multiple dose escalation cohorts of ASLAN004 (SEQ ID NOS: 51, 53, 59 herein): 200 mg, 400 mg, 600 mg. Initially, doses were administered QW. Within each cohort, patients were randomized in a 3:1 ratio of ASLAN004:placebo. [Table 2] Figure 13A shows the % change from baseline for days 15, 29, 43, and 57 or for all patients treated. Figure 13B shows the mean % change from baseline over the same time periods. Figures 13C-E show data from individual patients. [Table 3] In a highly allergic patient population (IgE 41.6% cfbl), ASLAN004 reduced IgE levels by -34%, which is substantially more significant than the -15 to -30% reduction seen in the low-allergic population with dupilumab.

[0101] Example 2 Among the 32 patients who completed at least 29 days of treatment at all sites, defined as the efficacy population by protocol, the mean reduction from baseline in EASI at week 8 was 73% (n=19) compared with 44% (n=13) in placebo-treated patients (p=0.007 1 ). The proportion of patients with adverse events and treatment-related adverse events was similar between the treatment and placebo groups. No cases of conjunctivitis were observed in the expansion cohort. [Table 4] ASLAN004 achieved a statistically significant improvement (p<0.025) compared to placebo in the primary endpoint of percent change from baseline in the Eczema Area and Severity Index (EASI), and also demonstrated significant improvements (p<0.05) in the other primary efficacy endpoints of EASI-50, EASI-75, peak pruritus, and patient-assessed eczema severity (POEM).

[0102] Prior to unblinding, a modified intention-to-treat (ITT) population (RITT, n=29) was defined by excluding one study site where all patients enrolled appeared atypical for moderate-to-severe AD based on biomarkers such as TARC and patient history. The RITT population, which is more similar to other published studies of moderate-to-severe AD, also achieved a statistically significant improvement (p<0.025) compared with placebo in percent change from baseline in the EASI, demonstrating greater improvement than placebo in the primary efficacy endpoint compared with the ITT population.

[0103] Example 3 The objective of this study was to evaluate the effects of ebrasakimab on pruritus and sleep scores in AD.

[0104] method Three patient cohorts were randomized to receive 200, 400, or 600 mg of ebrasakimab or placebo subcutaneously once weekly for 8 weeks in a multiple-ascending dose study design. Adult patients had chronic AD present for ≥3 years prior to screening, with the following AD parameters at screening and baseline: Eczema Area and Severity Index (EASI) ≥16, Investigator Global Assessment (IGA) score ≥3 (on a scale of 0–4), and ≥10% body surface area (BSA) associated with AD. Rescue medications (active moisturizers, topical corticosteroids, topical calcineurin inhibitors) were not permitted, and LOCF was used for participants using rescue medications.

[0105] Patient-reported outcomes were measured including the Pruritus Numerical Scale (P-NRS) for both worst and average pruritus, and the Patient-Rated Eczema Severity Scale (POEM), which includes a single-item insomnia component. Inferential statistical analyses were performed for the comparison of the 600 mg dose group with the placebo group at week 8 only. Results for the 200 mg and 400 mg dose groups were described descriptively due to small sample sizes. The efficacy analysis in the Phase 1b study used a modified intention-to-treat (mITT) population (excluded center group), in which nine study patients from one center were excluded from the ITT analysis before unblinding because the participants did not have disease characteristics consistent with moderate to severe AD (Figure 16).

[0106] result The excluded center group differed significantly from the mITT group at baseline, with significantly lower serum TARC / CCL17 (7,350 pg / mL and 461 pg / mL, respectively), serum IgE (12,225 kU / I vs. 527 kU / I), and EASI scores (mean 31.2 vs. 19.3), indicating a lower extent and severity of disease. Other notable differences included older age and lower IGA, BSA, and POEM scores. Participants at this center had no history of atopic disease but reported other comorbidities, including diabetes and hypertension (Figure 17).

[0107] In the mITT analysis group, improvements in percent change from baseline in P-NRS for median worst itch (%CFBL) were evident over time in the ebrasakimab-treated group compared with the placebo group, and were also evident at week 8 (Figures 19A and 19B) and in mean median itch (Figures 20A and 20B) (worst itch: -48% vs. -13%, mean itch: -49% vs. -6% (ebrasakimab 600 mg vs. placebo, respectively)).

[0108] Excluded facilities *Participants who received 600 mg of ebrasakimab experienced improvement in mean itch, but not in worst itch, compared with placebo. Improvements in POEM scores were evident over time with ebrasakimab treatment compared with placebo in the mITT population, with greater responses for the 400 mg and 600 mg doses than for the 200 mg dose (Figure 21). At week 8, median POEM CFBLs were -12 and -9 for 400 mg and 600 mg ebrasakimab, respectively, compared with -1 for placebo in the mITT population. No improvement versus placebo was observed in the excluded center group.

[0109] In the mITT analysis group, but not the excluded-center analysis group, a 4-point improvement in POEM score was observed at week 8 in the 600 mg ebrasakimab group compared to the placebo group (81% vs. 23%, and 50% vs. 100%, respectively). POEM sleep scores improved more in the ebrasakimab group compared to the placebo group (Figure 22). In the mITT analysis population, a mean 2-point improvement in insomnia (POEM item) was observed at week 8 in the 400 mg and 600 mg ebrasakimab groups (43% and 56% vs. 15% in the placebo group) and in the 600 mg ebrasakimab group at the excluded centers (33% vs. 0% in the placebo group).

[0110] Importantly, these improvements were seen in patients with a baseline sleep disturbance score of 3 or 4. The majority of patients in the 600 mg group (75% [12 / 16]) reported more than 5 nights of sleep disturbance at baseline compared with placebo (54% [7 / 13]). At week 8, a higher proportion of patients in the ebrasakimab-treated group reported "no days" or "1-2 days" with no sleep disturbance (63% [10 / 16]) compared with the placebo group (38% [5 / 13]).

[0111] Rescue medication use was low but high in the placebo group (data not shown). Rates of moderate to severe adverse events (AEs) were comparable between the 600 mg and placebo groups. Treatment-related AEs were similar in both groups (Figure 18).

[0112] Interestingly, AEs leading to treatment discontinuation were higher in the placebo group. One serious adverse event (SAE) reported in the study (mild abdominal pain, 400 mg) was considered unrelated to treatment. No deaths were reported.

[0113] conclusion This study demonstrated that ebrasakimab was well tolerated and demonstrated significant improvements compared with placebo in several efficacy endpoints in adults with moderate to severe AD. Notably, ebrasakimab-treated patients demonstrated significant improvements in sleep disturbance scores compared with placebo-treated patients. The robustness of the data from the small study was supported by a sensitivity analysis of the primary analysis population. Including data from excluded centers did not alter the primary endpoint or conclusions.

[0114] These significant improvements observed within the 8-week study period suggest the possibility of even greater benefits with extended treatment duration and support further investigation in an ongoing Phase 2b clinical trial.

[0115] Example 4 The TREK-AD (Study of Ebrasakimab in Atopic Dermatitis) study is a randomized, double-blind, placebo-controlled, dose-ranging Phase 2b clinical trial designed to evaluate the efficacy and safety of ebrasakimab monotherapy in biologic-naive adult patients with moderate to severe AD who are candidates for systemic therapy. Baseline characteristics of the intent-to-treat (ITT) population are shown in Figure 23.

[0116] The TREK-AD study conducted various clinical analyses, including change in EASI, SCORAD, DLQI, POME, EQ-5D-5L, and HAD, and the proportion of patients achieving a 4-point reduction in SD-NRS from baseline to week 16. The results of change in the sleep deprivation component of SCORAD and the proportion of patients achieving a 4-point reduction in SD-NRS from baseline to week 16 are shown in Figure 24 and Figure 25, respectively.

[0117] Figure 24 clearly demonstrates that ebrasakimab improves sleep disturbances as measured by the individual component scores of the SCORAD quality of life measure. Specifically, ebrasakimab 400 mg Q4W, 600 mg Q4W, 300 mg Q2W, and 400 mg Q4W demonstrated changes from baseline in insomnia scores of -37.7%, -50.6%, -37.3%, and -52.2%, respectively.

[0118] Figure 25 shows that a significantly higher proportion of patients achieved a greater than 4-point reduction in SD-NRS from baseline (a 4-point reduction in SD-NRS indicates a clinically meaningful improvement) at week 16. In particular, in the treatment group receiving ebrasakimab 300 mg every 2 weeks, 32.3%, or nearly one-third, of patients achieved an improvement of 4 or more points in SD-NRS. Thus, the results of the TREK-AD trial further demonstrate that ebrasakimab has the potential to significantly improve insomnia / sleep deprivation in patients.

Claims

1. A composition comprising an anti-IL-13Rα1 antibody for use in the treatment of insomnia or sleep disorder in a patient, wherein the treatment comprises subcutaneous administration of a treatment cycle comprising doses ranging from 300 mg to 600 mg of the antibody administered once every two weeks or once every four weeks, wherein the treatment results in a patient-assessed sleep disorder (SD) score of eczema severity (POEM) ranging from baseline to -50 to -100%, wherein the antibody is evrasakimab, and the patient has atopic dermatitis.

2. The composition for use according to claim 1, wherein the patient has at least 3 baseline SD scores.

3. The composition for use according to claim 1, wherein the reduction in the SD score is 2 to 4 points from the baseline.

4. The composition for use according to claim 1, wherein the treatment results in a -20 to -100% reduction from baseline in the sleep deprivation component of SCORAD.

5. The composition for use according to claim 4, wherein the patient has at least four baseline sleep deprivation components of SCORAD.

6. The composition for use according to claim 4 or 5, wherein the reduction in the sleep deprivation component of SCORAD is in the range of -30 to -60% from baseline.

7. The composition for use according to claim 1, wherein the treatment results in a -20 to -100% reduction from baseline on the Sleep Disorder Numerical Rating Scale (SD NRS).

8. The composition for use according to claim 7, wherein the patient has a baseline SD NRS of at least 4 points from baseline.

9. The composition for use according to claim 4 or 5, wherein there is a decrease of 4 points or more in SD NRS from baseline.

10. The composition for use according to claim 1, wherein the patient is a highly allergic patient having a baseline IgE level of at least 10,000 KU / L ± 2,000.

11. The composition according to claim 1, wherein a decrease in the SD score, the SCORAD sleep deprivation score, or the SD NRS is observed by approximately 15 days.

12. The composition for use according to claim 1, wherein the patient has pruritus.

13. The composition for use according to claim 1, wherein the patient has moderate to severe atopic dermatitis.

14. The composition for use according to claim 1, wherein an initial loading dose in the range of 400 to 900 mg is administered before administration of the aforementioned treatment cycle.

15. The composition for use according to claim 14, wherein the initial loading amount is administered in weeks 0 and 1.

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