Method for treating prurigo nodularis

Abstract

The invention provides a method for treating prurigo nodularis by administering an anti-OX40 or anti- OX40L inhibitor, and an article of manufacture with instructions for such use. In particular the invention relates to a dosage regiment wherein an anti-OX40 antibody is administered at a dose of between about 150 mg and 300 mg once every 4 weeks, with an additional loading dose of anti-OX40 antibody between about 150 mg and 300 mg at week 2.

Description

[0001] METHOD FOR TREATING PRURIGO NODULARIS

[0002]

[0001] This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 672,905, filed July 18, 2024.

[0003] INCORPORATION BY REFERENCE OF MATERIAL SUBMITTED ELECTRONICALLY

[0004] [2] Incorporated by reference in its entirety is a computer-readable nucleotide / amino acid sequence listing submitted concurrently herewith and identified as follows: 35,332 byte XML file named “01017- 70509_Sequence_Listing.xmr'; created on July 14, 2024.

[0005] FIELD OF THE INVENTION

[0006] [3] The present invention relates to the use of 0X40 or OX40L inhibitors for the treatment of Prurigo Nodularis.

[0007] BACKGROUND

[0008] [4] Prurigo nodularis, also known as chronic nodular prurigo, is defined by pruritus for more than 6 weeks, evidence of chronic scratching, and the presence of multiple pruriginous lesions and excoriated nodules that cause a profound negative impact on quality of life. Topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI) are often used initially. While there is a mechanistic rationale for their use, no rigorous clinical studies confirming their efficacy were identified. Nearly all adult patients have treatment failure with topical glucocorticoids.

[0009] [5] To date, there is only one US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved targeted therapy indicated for the treatment of prurigo nodularis (Dupilumab). However, around 61% to 68% of patients do not respond sufficiently to dupilumab in both reduction in itch and lesions after 24 weeks of treatment (Yosipovitch et al., Dupilumab in patients with prurigo nodularis: two randomized, double-blind, placebo-controlled phase 3 trials. Nat Med. 2023 May;29(5):1 180-1190). Therefore, there is still a large unmet need for novel biologic therapies with different mechanisms of action and with improved safety profile for this population.

[0010] SUMMARY

[0011] [6] Based on the disclosure provided herein, those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following embodiments (E). [7] The use of section headings herein is merely for the convenience of reading, and not intended to be limiting per se. The entire document is intended to be viewed as a unified disclosure, and it should be understood that all combinations of features described herein are contemplated.

[0012] E1 . A method for treating prurigo nodularis (PN), comprising administering to a subject in need thereof an 0X40 or OX40L inhibitor, at a dose of from about 150 mg to about 300 mg, once every 4 weeks (Q4W).

[0013] E1 a. A method for treating prurigo nodularis (PN), comprising administering to a subject in need thereof an 0X40 or OX40L inhibitor, at a dose of from about 150 mg to about 300 mg, once every 2 weeks (Q2W), once every 6 weeks (Q6W), or once every 8 weeks (Q8W).

[0014] E2. The method of E1 or E1 a, further comprising administering to said subject an additional loading dose of the 0X40 or OX40L inhibitor, at a dose of.from about 150 mg to about 300 mg at week 2 (W2).

[0015] E3. The method of E1 , E1 a, or E2, wherein said OX40L inhibitor is an antibody that binds to human OX-40L.

[0016] E4. The method of E1 , E1 a, or E2, wherein said 0X40 inhibitor is an antibody that binds to human QX-40.

[0017] E5. The method of E4, wherein said anti-OX 40 antibody comprises: (a) a heavy chain variable region (VH) that comprises: (i) a VH complementarity determining region one (CDR-H1 ) comprising the amino acid sequence of any one of SEQ ID NOs:1 -5; (ii) a CDR-H2 comprising the amino acid sequence of any one of SEQ ID NOs:6-10; and (Hi) a CDR-H3 comprising the amino acid sequence of any one of SEQ ID NOs:11 -15; and (b) a light chain variable region (VL) that comprises: (i) a VL complementarity determining region one (CDR-L1 ) comprising the amino acid sequence of any one of SEQ ID NQs:16-20; (II) a CDR-L2 comprising the amino acid sequence of any one of SEQ ID NOs:21 -25; and (Hi) a CDR-L3 comprising the amino acid sequence of any one of SEQ ID NQs:26-30.

[0018] E6. The method of E4, wherein said anti-OX 40 antibody comprises: (a) a heavy chain variable region (VH) that comprises the CDR-H1 , CDR-H2, and CDR-H3 of SEQ ID NO:31 ; and (b) a light chain variable region (VL) that comprises the CDR-L1 , CDR-L2, and CDR-L3 of SEQ ID NO:32.

[0019] E7. The method of any one of E4-E6, wherein said anti-OX 40 antibody comprises: a VH that comprises the amino acid sequence of SEQ ID NO:31 , and a VL that comprises the amino acid sequence of SEQ ID NO:32.

[0020] E8. The method of any one of E4-E6, wherein said anti-OX 40 antibody further comprises a human IgG 1 heavy chain constant region. E9. The method of any one of E4-E7, wherein said anti-OX 40 antibody further comprises human kappa chain constant region.

[0021] E10. The method of any one of E4-E9, wherein said anti-OX 40 antibody comprises: a heavy chain that comprises the amino acid sequence of SEQ ID NO:33, and a light chain that comprises the amino acid sequence of SEQ ID NO:34.

[0022] E11 . The method of any one of E7-E10, wherein the lysine residue (K) at the C-terminus of the heavy chain is deleted.

[0023] E12. The method of any one of E7-E10, wherein the lysine residue (K) at the C-terminus of the heavy chain is present.

[0024] E13. The method of any one of E7-E10, wherein the glycine and lysine residues (GK) at the C- terminus of the heavy chain is deleted.

[0025] E14. The method of any one of E7-E10, wherein the glycine and lysine residues (GK) at the C- terminus of the heavy chain is present.

[0026] E15. The method of any one of E1 -E14, wherein the dose is about 150 mg.

[0027] E16. The method of any one of E1 -E14, wherein the dose is about 200 mg.

[0028] E17. The method of any one of E1 -E14, wherein the dose is about 250 mg.

[0029] E18. The method of any one of E1 -E14, wherein the dose is about 300 mg.

[0030] E19. The method of any one of E1 -E18, wherein the 0X40 or OX40L inhibitor is administered subcutaneously.

[0031] E20. The method of any one of E1 -E18, wherein the 0X40 or OX40L inhibitor is administered intravenously.

[0032] E21 . The method of any one of E1 -E20, wherein the 0X40 or OX40L inhibitor is administered once every 4 weeks (Q4W) for at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, or at least 52 weeks.

[0033] E22. The method of any one of E1 -E21 , wherein the 0X40 or OX40L inhibitor is administered once every 4 weeks (Q4W) for at least 24 weeks, with an additional loading dose of the 0X40 or OX40L inhibitor administered at week 2. E23. The method of any one of E1 -E21 , wherein the 0X40 or OX40L inhibitor is administered once every 4 weeks (Q4W) for at least 28 weeks, with an additional loading dose of the 0X40 or OX40L inhibitor administered at week 2.

[0034] E24. The method of any one of E1 -E21 , wherein the 0X40 or OX40L inhibitor is administered once every 4 weeks (Q4W) for at least 32 weeks, with an additional loading dose of the 0X40 or OX40L inhibitor administered at week 2.

[0035] E25. The method of any one of E1 -E21 , wherein the 0X40 or OX40L inhibitor is administered once every 4 weeks (Q4W) for at least 36 weeks, with an additional loading dose of the 0X40 or OX40L inhibitor administered at week 2.

[0036] E26. The method of any one of E1 -E21 , wherein the 0X40 or OX40L inhibitor is administered once every 4 weeks (Q4W) for at least 40 weeks, with an additional loading dose of the 0X40 or OX40L inhibitor administered at week 2.

[0037] E27. The method of any one of E1 -E21 , wherein the 0X40 or OX40L inhibitor is administered once every 4 weeks (Q4W) for at least 44 weeks, with an additional loading dose of the 0X40 or OX40L inhibitor administered at week 2.

[0038] E28. The method of any one of E1 -E21 , wherein the 0X40 or OX40L inhibitor is administered once every 4 weeks (Q4W) for at least 48 weeks, with an additional loading dose of the 0X40 or OX40L inhibitor administered at week 2.

[0039] E29. The method of any one of E1 -E21 , wherein the 0X40 or OX40L inhibitor is administered once every 4 weeks (Q4W) for at least 52 weeks, with an additional loading dose of the 0X40 or OX40L inhibitor administered at week 2.

[0040] E30. The method of any one of E1 -E29, wherein said subject shows a change in weekly average of daily Worst Itch Numeric Rating Scale (WI-NRS) score after one or more doses of said 0X40 or OX40L inhibitor have been administered, as compared to a baseline.

[0041] E31 . The method of any one of E1 -E30, wherein said subject’s weekly average of daily Worst Itch Numeric Rating Scale (WI-NRS) score is reduced by 4 points or more after one or more doses of said 0X40 or OX40L inhibitor have been administered, preferably at week 24 or earlier, as compared to a baseline.

[0042] E31 a. The method of any one of E1 -E30, wherein said subject’s weekly average of daily Worst Itch Numeric Rating Scale (WI-NRS) score is reduced by 4 points or more after one or more doses of said 0X40 or OX40L inhibitor have been administered, preferably at week 16 or earlier, at week 36 or earlier, or at week 52 or earlier, as compared to a baseline.

[0043] E31 b. The method of any one of E1 -E30, wherein said subject’s weekly average of daily Worst Itch Numeric Rating Scale (WI-NRS) score is reduced by 3 points or more after one or more doses of said 0X40 or OX40L inhibitor have been administered, preferably at week 24 or earlier, as compared to a baseline.

[0044] E32. The method of E30, E31 , E31 a, or E31 b, wherein said baseline is the subject’s weekly average of daily WI-NRS score before the first dose of the 0X40 or OX40L inhibitor is administered, or is a predetermined baseline value.

[0045] E33. The method of any one of E1 -E32, wherein said subject shows a change in Investigator's Global Assessment for Chronic Nodular Prurigo-Stage (IGA CNPG-S) score after one or more doses of said 0X40 or OX40L inhibitor have been administered, as compared to a baseline.

[0046] E34. The method of E33 wherein said baseline is the subject's IGA CNPG-S score before the first dose of the 0X40 or OX40L inhibitor is administered, or is a pre-determined baseline value.

[0047] E35. The method of any one of E1 -E34, wherein said subject’s IGA CNPG-S score is 0 (clear) or 1 (almost clear) (IGA CNPG-S 0 / 1 ) after one or more doses of said 0X40 or OX40L inhibitor have been administered, preferably at week 24 or earlier.

[0048] E35a. The method of any one of E1 -E34, wherein said subject’s IGA CNPG-S score is 0 (clear) or 1 (almost clear) (IGA CNPG-S 0 / 1 ) after one or more doses of said 0X40 or OX40L inhibitor have been administered, preferably at week 36 or earlier, or at week 52 or earlier.

[0049] E36. The method of any one of E1 -E35a, wherein said subject shows a reduction in weekly average of daily WI-NRS score of 4 points or more, as compared to a baseline; and an IGA CNPG-S score of 0 (clear) or 1 (almost clear) (IGA CNPG-S 0 / 1 ), after one or more doses of said 0X40 or OX40L inhibitor have been administered, preferably at week 24 or earlier.

[0050] E36a. The method of any one of E1 -E35a, wherein said subject shows a reduction in weekly average of daily WI-NRS score of 4 points or more, as compared to a baseline; and an IGA CNPG-S score of 0 (clear) or 1 (almost clear) (IGA CNPG-S 0 / 1 ), after one or more doses of said 0X40 or OX40L inhibitor have been administered, preferably at week 36 or earlier, or week 52 or earlier.

[0051] E36b. The method of any one of E1 -E35a, wherein said subject shows a reduction in weekly average of daily WI-NRS score of 3 points or more, as compared to a baseline; and an IGA CNPG-S score of 0 (clear) or 1 (almost clear) (IGA CNPG-S 0 / 1 ), after one or more doses of said 0X40 or OX40L inhibitor have been administered, preferably at week 24 or earlier.

[0052] E36c. The method of any one of E1 -E35a, wherein said subject shows a reduction in weekly average of daily WI-NRS score of 3 points or more, as compared to a baseline; and an IGA CNPG-S score of 0 (clear) or 1 (almost clear) (IGA CNPG-S 0 / 1 ), after one or more doses of said 0X40 or OX40L inhibitor have been administered, preferably at week 36 or earlier, or week 52 or earlier.

[0053] E37. The method of any one of E36 to E36c, wherein said baseline is the subject’s weekly average of daily WI-NRS score before the first dose of the 0X40 or OX40L inhibitor is administered, or is a predetermined baseline value.

[0054] E38. The method of any one of E1 -E37, wherein said subject shows a change in Dermatology Life Quality Index (DLQI) score after one or more doses of said 0X40 or OX40L inhibitor have been administered, as compared to a baseline.

[0055] E39. The method of any one of E1 -E38, wherein said subject shows a reduction in DLQI score of 4 points or more after one or more doses of said 0X40 or OX40L inhibitor have been administered, as compared to a baseline, preferably at week 24 or earlier, at week 36 or earlier, or at week 52 or earlier.

[0056] E40. The method of E38 and E39, wherein said baseline is the subject’s DLQI score before the first dose of the 0X40 or OX40L inhibitor is administered, or is a pre-determined baseline value.

[0057] E41 . The method of any one of E1 -E40, wherein said subject shows a change in weekly average of daily prurigo nodularis skin pain NRS score after one or more doses of said 0X40 or OX40L inhibitor have been administered, as compared to a baseline.

[0058] E42. The method of any one of E1 -E41 , wherein said subject shows a reduction in weekly average of daily prurigo nodularis skin pain NRS score of 4 points or more after one or more doses of said 0X40 or OX40L inhibitor have been administered, as compared to a baseline, preferably at week 24 or earlier, at week 36 or earlier, or at week 52 or earlier.

[0059] E42a. The method of any one of E1 -E41 , wherein said subject shows a reduction in weekly average of daily prurigo nodularis skin pain NRS score of 3 points or more as compared to a baseline, and an IGA CNPG-S score of 0 (clear) or 1 (almost clear) (IGA CNPG-S 0 / 1 ), after one or more doses of said 0X40 or QX40L inhibitor have been administered, preferably at week 24 or earlier, at week 36 or earlier, or at week 52 or earlier.

[0060] E42b. The method of any one of E1 -E41 , wherein said subject shows a reduction in weekly average of daily prurigo nodularis skin pain NRS score of 4 points or more as compared to a baseline, and an IGA CNPG-S score of 0 (clear) or 1 (almost clear) (IGA CNPG-S 0 / 1 ), after one or more doses of said 0X40 or OX40L inhibitor have been administered, preferably at week 24 or earlier, at week 36 or earlier, or at week 52 or earlier.

[0061] E43. The method of E41 , E42, E42a, or E42b, wherein said baseline is the subject’s weekly average of daily prurigo nodularis skin pain NRS score before the first dose of the 0X40 or OX40L inhibitor is administered, or is a pre-determined baseline value.

[0062] E44. The method of any one of E1 -E43, wherein said subject shows a change in weekly average of daily sleep disturbance-NRS score after one or more doses of said 0X40 or OX40L inhibitor have been administered, as compared to a baseline.

[0063] E45. The method of any one of E1 -E41 , wherein said subject shows a reduction in weekly average of daily sleep disturbance-NRS score of 4 points or more after one or more doses of said 0X40 or OX40L inhibitor have been administered, as compared to a baseline.

[0064] E46. The method of E41 and E42, wherein said baseline is the subject’s weekly average of daily sleep disturbance-NRS score before the first dose of the 0X40 or OX40L inhibitor is administered, or is a predetermined baseline value.

[0065] E47 The method of any one of E1 -E46, wherein said subject shows a change in Hospital Anxiety and Depression Scale (HADS) score after one or more doses of said 0X40 or OX40L inhibitor have been administered, as compared to baseline.

[0066] E48. The method of E47, wherein said subject shows a change in HADS anxiety subscale score or in HADS depression subscale score after one or more doses of said 0X40 or OX40L inhibitor have been administered, as compared to a baseline.

[0067] E48a. The method of E47 and E48, wherein said baseline is the subject’s HADS anxiety subscale score or HADS depression subscale score before the first dose of the 0X40 or OX40L inhibitor is administered, or is a pre-determined baseline value.

[0068] E48b. The method of any one of E1 -E48a, wherein said subject shows any one of the following after one or more doses of said 0X40 or OX40L inhibitor have been administered: (1 ) a reduction in weekly average of daily prurigo nodularis skin pain NRS score of 4 points or more as compared to a baseline; (2) a weekly average of daily Wl NRS score less than 2, preferably at week 24 or earlier; (3) a weekly average of daily Wl NRS score of 0 or 1 ; (4) a weekly average of daily Wl NRS score of 0, 1 , or 2; or (5) a combination thereof. E48c. The method of E48b, wherein said baseline is the subject’s weekly average of daily prurigo nodularis skin pain NRS score before the first dose of the 0X40 or OX40L inhibitor is administered, or is a pre-determined baseline value.

[0069] E48d. The method of any one of E1 -E48c, wherein said subject shows a change in EQ-5D visual analog scale (VAS) score after one or more doses of said 0X40 or OX40L inhibitor have been administered, as compared to baseline.

[0070] E48e. The method of E48d, wherein said baseline is the subject’s EQ-5D visual analog scale (VAS) score before the first dose of the 0X40 or OX40L inhibitor is administered, or is a pre-determined baseline value.

[0071] E48f. The method of any one of E1 -E48e, wherein said subject shows a change number of lesions in a representative area, as determined from PAS, after one or more doses of said 0X40 or OX40L inhibitor have been administered, as compared to baseline.

[0072] E48g. The method of E48f , wherein the subject achieves 76% or more healed lesions, as determined from PAS.

[0073] E48h. The method of E48f or E48g, wherein said baseline is the subject’s number of lesions in a representative area, determined from PAS, before the first dose of the 0X40 or OX40L inhibitor is administered, or is a pre-determined baseline value.

[0074] E49. The method of any one of E1 -E48 and E48a-E48h, wherein said subject is a human.

[0075] E50. The method of any one of E1 -E49, wherein said subject further receives topical treatment, such as a topical calcineurin inhibitor (TCI) or a topical corticosteroid (TCS).

[0076] E51 . The method of E50, wherein said subject further receives one or more of the following treatments: an antihistamine, topical capsaicin, an intralesional glucocorticosteroid, cryotherapy, phototherapy, a gabapentinoid, an antidepressant, an immunosuppressants (such as cyclosporine or methotrexate), a neurokinin-1 receptor antagonist, an l-opioid receptor antagonist, and dupilumab.

[0077] E52. A method for treating prurigo nodularis (PN), comprising administering to a subject in need thereof an anti-OX40 antibody at a dose of 150 mg, once every 4 weeks (Q4W) for at least 12 weeks, and an additional loading dose of anti-OX40 antibody at a dose of 150 mg at week 2 (W2); wherein said anti- 0X40 antibody comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:33, 37, 38, or a combination thereof; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 34. E52a. A method for treating prurigo nodularis (PN), comprising administering to a subject in need thereof an anti-OX40 antibody at a dose of 150 mg, once every 2 weeks (Q2W) for at least 12 weeks, once every 6 weeks (Q6W) for at least 12 weeks, or once every 8 weeks (Q8W) for at least 12 weeks, and an additional loading dose of anti-OX40 antibody at a dose of 150 mg at week 2 (W2); wherein said anti- 0X40 antibody comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:33, 37, 38, or a combination thereof; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 34.

[0078] E53. A method for treating prurigo nodularis (PN), comprising administering to a subject in need thereof an anti-OX40 antibody at a dose of 200 mg, once every 4 weeks (Q4W) for at least 12 weeks, and an additional loading dose of 200 mg at week 2 (W2); wherein said anti-OX40 antibody comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:33, 37, 38, or a combination thereof; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 34.

[0079] E53a. A method for treating prurigo nodularis (PN), comprising administering to a subject in need thereof an anti-QX40 antibody at a dose of 200 mg, once every once every 2 weeks (Q2W) for at least 12 weeks, once every 6 weeks (Q6W) for at least 12 weeks, or once every 8 weeks (Q8W) for at least 12 weeks, and an additional loading dose of 200 mg at week 2 (W2); wherein said anti-QX40 antibody comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:33, 37, 38, or a combination thereof; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 34.

[0080] E54. A method for treating prurigo nodularis (PN), comprising administering to a subject in need thereof an anti-QX40 antibody at a dose of 250 mg, once every 4 weeks (Q4W) for at least 12 weeks, and an additional loading dose of 250 mg at week 2 (W2); wherein said anti-QX40 antibody comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:33, 37, 38, or a combination thereof; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 34.

[0081] E54a. A method for treating prurigo nodularis (PN), comprising administering to a subject in need thereof an anti-QX40 antibody at a dose of 250 mg, once every once every 2 weeks (Q2W) for at least 12 weeks, once every 6 weeks (Q6W) for at least 12 weeks, or once every 8 weeks (Q8W) for at least 12 weeks, and an additional loading dose of 250 mg at week 2 (W2); wherein said anti-QX40 antibody comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:33, 37, 38, or a combination thereof; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 34.

[0082] E55. A method for treating prurigo nodularis (PN), comprising administering to a subject in need thereof an anti-QX40 antibody at a dose of 300 mg, once every 4 weeks (Q4W) for at least 12 weeks, and an additional loading dose of 300 mg at week 2 (W2); wherein said anti-QX40 antibody comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:33, 37, 38, or a combination thereof; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 34. E55a. A method for treating prurigo nodularis (PN), comprising administering to a subject in need thereof an anti-OX40 antibody at a dose of 300 mg, once every once every 2 weeks (Q2W) for at least 12 weeks, once every 6 weeks (Q6W) for at least 12 weeks, or once every 8 weeks (Q8W) for at least 12 weeks, and an additional loading dose of 300 mg at week 2 (W2); wherein said anti-OX40 antibody comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:33, 37, 38, or a combination thereof; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 34.

[0083] E56. The method of any one of E52-E55a, wherein said anti-OX40 antibody is administered for at least 16 weeks.

[0084] E57. The method of any one of E52-E55a, wherein said anti-OX40 antibody is administered for at least 20 weeks.

[0085] E58. The method of any one of E52-E55a, wherein said anti-OX40 antibody is administered for at least 24 weeks.

[0086] E59. The method of any one of E52-E55a, wherein said anti-OX40 antibody is administered for at least 28 weeks.

[0087] E60. The method of any one of E52-E55a, wherein said anti-OX40 antibody is administered for at least 32 weeks.

[0088] E61 . The method of any one of E52-E55a, wherein said anti-OX40 antibody is administered for at least 36 weeks.

[0089] E62. The method of any one of E52-E55a, wherein said anti-OX40 antibody is administered for at least 40 weeks.

[0090] E63. The method of any one of E52-E55a, wherein said anti-OX40 antibody is administered for at least 44 weeks.

[0091] E64. The method of any one of E52-E55a, wherein said anti-OX40 antibody is administered for at least 48 weeks.

[0092] E65. The method of any one of E52-E55a, wherein said anti-OX40 antibody is administered for at least 52 weeks.

[0093] E66. The method of any one of E52-E65, wherein said subject shows a change in weekly average of daily Worst Itch Numeric Rating Scale (WI-NRS) score after one or more doses of said anti-OX40 antibody have been administered, as compared to a baseline. E67. The method of any one of E52-E65, wherein said subject’s weekly average of daily Worst Itch Numeric Rating Scale (WI-NRS) score is reduced by 4 points or more after one or more doses of said anti-OX40 antibody have been administered, preferably at week 24 or earlier, as compared to a baseline. E67a. The method of any one of E52-E65, wherein said subject’s weekly average of daily Worst Itch Numeric Rating Scale (WI-NRS) score is reduced by 4 points or more after one or more doses of said 0X40 or OX40L inhibitor have been administered, preferably at week 16 or earlier, at week 36 or earlier, or at week 52 or earlier, as compared to a baseline.

[0094] E67b. The method of any one of E52-E65, wherein said subject’s weekly average of daily Worst Itch Numeric Rating Scale (WI-NRS) score is reduced by 3 points or more after one or more doses of said 0X40 or OX40L inhibitor have been administered, preferably at week 24 or earlier, as compared to a baseline.

[0095] E68. The method of E66, E67, E67a or E67b, wherein said baseline is the subject’s weekly average of daily WI-NRS score before the first dose of the anti-OX40 antibody is administered, or is a pre-determined baseline value.

[0096] E69. The method of any one of E52-E68, wherein said subject shows a change in Investigator's Global Assessment for Chronic Nodular Prurigo-Stage (IGA CNPG-S) score after one or more doses of said anti- 0X40 antibody have been administered, as compared to a baseline.

[0097] E70. The method of E69, wherein said baseline is the subject’s IGA CNPG-S score before the first dose of the anti-OX40 antibody is administered, or is a pre-determined baseline value.

[0098] E71 . The method of any one of E52-E68, wherein said subject’s IGA CNPG-S score is 0 (clear) or 1 (almost clear) (IGA CNPG-S 0 / 1 ) after one or more doses of said anti-OX40 antibody have been administered, preferably at week 24 or earlier.

[0099] E71 a. The method of any one of E52-E71 , wherein said subject’s IGA CNPG-S score is 0 (clear) or 1 (almost clear) (IGA CNPG-S 0 / 1 ) after one or more doses of said 0X40 or OX40L inhibitor have been administered, preferably at week 36 or earlier, or at week 52 or earlier.

[0100] E72. The method of any one of E52-E71 a, wherein said subject shows a reduction in weekly average of daily WI-NRS score of 4 points or more, as compared to a baseline; and an IGA CNPG-S score of 0 (clear) or 1 (almost clear) (IGA CNPG-S 0 / 1 ), after one or more doses of said anti-OX40 antibody have been administered, preferably at week 24 or earlier.

[0101] E72a. The method of any one of E52-E71 a, wherein said subject shows a reduction in weekly average of daily WI-NRS score of 4 points or more, as compared to a baseline; and an IGA CNPG-S score of 0 (clear) or 1 (almost clear) (IGA CNPG-S 0 / 1 ), after one or more doses of said 0X40 or OX40L inhibitor have been administered, preferably at week 36 or earlier, or week 52 or earlier.

[0102] E72b. The method of any one of E52-E71 a, wherein said subject shows a reduction in weekly average of daily WI-NRS score of 3 points or more, as compared to a baseline; and an IGA CNPG-S score of 0 (clear) or 1 (almost clear) (IGA CNPG-S 0 / 1 ), after one or more doses of said 0X40 or OX40L inhibitor have been administered, preferably at week 24 or earlier.

[0103] E72c. The method of any one of E52-E71 a, wherein said subject shows a reduction in weekly average of daily WI-NRS score of 3 points or more, as compared to a baseline; and an IGA CNPG-S score of 0 (clear) or 1 (almost clear) (IGA CNPG-S 0 / 1 ), after one or more doses of said 0X40 or OX40L inhibitor have been administered, preferably at week 36 or earlier, or week 52 or earlier.

[0104] E73. The method of any one of E72 to E72c, wherein said baseline is the subject’s weekly average of daily WI-NRS score before the first dose of the anti-OX40 antibody is administered, or is a pre-determined baseline value.

[0105] E74. The method of any one of E52-E73 wherein said subject shows a change in Dermatology Life Quality Index (DLQI) score after one or more doses of said anti-OX40 antibody have been administered, as compared to a baseline.

[0106] E75. The method of any one of E52-E73, wherein said subject shows a reduction in DLQI score of 4 points or more after one or more doses of said anti-QX40 antibody have been administered, as compared to a baseline, preferably at week 24 or earlier, at week 36 or earlier, or at week 52 or earlier.

[0107] E76. The method of E74 and E75, wherein said baseline is the subject’s DLQI score before the first dose of the anti-QX40 antibody is administered, or is a pre-determined baseline value.

[0108] E77. The method of any one of E52-E76, wherein said subject shows a change in weekly average of daily prurigo nodularis skin pain NRS score after one or more doses of said anti-QX40 antibody have been administered, as compared to a baseline.

[0109] E78. The method of any one of E52-E76, wherein said subject shows a reduction in weekly average of daily prurigo nodularis skin pain NRS score of 4 points or more after one or more doses of said anti-QX40 antibody have been administered, as compared to a baseline, preferably at week 24 or earlier, at week 36 or earlier, or at week 52 or earlier.

[0110] E78a. The method of any one of E78-E77, wherein said subject shows a reduction in weekly average of daily prurigo nodularis skin pain NRS score of 3 points or more as compared to a baseline, and an IGA CNPG-S score of 0 (clear) or 1 (almost clear) (IGA CNPG-S 0 / 1 ), after one or more doses of said 0X40 or OX40L inhibitor have been administered, preferably at week 24 or earlier, at week 36 or earlier, or at week 52 or earlier.

[0111] E78b. The method of any one of E78-E77, wherein said subject shows a reduction in weekly average of daily prurigo nodularis skin pain NRS score of 4 points or more as compared to a baseline, and an IGA CNPG-S score of 0 (clear) or 1 (almost clear) (IGA CNPG-S 0 / 1 ), after one or more doses of said 0X40 or OX40L inhibitor have been administered, preferably at week 24 or earlier, at week 36 or earlier, or at week 52 or earlier.

[0112] E79. The method of E77, E78a and E78b, wherein said baseline is the subject’s weekly average of daily prurigo nodularis skin pain NRS score before the first dose of the anti-OX40 antibody is administered, or is a pre-determined baseline value.

[0113] E80. The method of any one of E52-E79, wherein said subject shows a change in weekly average of daily sleep disturbance-NRS score after one or more doses of said anti-OX40 antibody have been administered, as compared to a baseline.

[0114] E81 . The method of any one of E52-E79, wherein said subject shows a reduction in weekly average of daily sleep disturbance-NRS score of 4 points or more after one or more doses of said anti-OX40 antibody have been administered, as compared to a baseline.

[0115] E82. The method of E80 and E71 , wherein said baseline is the subject’s weekly average of daily sleep disturbance-NRS score before the first dose of the anti-OX40 antibody is administered, or is a predetermined baseline value.

[0116] E83. The method of any one of E52-E82, wherein said subject shows a change in Hospital Anxiety and Depression Scale (HADS) score after one or more doses of said 0X40 or OX40L inhibitor have been administered, as compared to baseline.

[0117] E84. The method of E83, wherein said baseline is the subject’s Hospital Anxiety and Depression Scale (HADS) score before the first dose of the anti-OX40 antibody is administered, or is a pre-determined baseline value.

[0118] E84a. The method of E83 and E84, wherein said baseline is the subject’s HADS anxiety subscale score or HADS depression subscale score before the first dose of the 0X40 or OX40L inhibitor is administered, or is a pre-determined baseline value.

[0119] E84b. The method of any one of E52-E84a, wherein said subject shows any one of the following after one or more doses of said 0X40 or OX40L inhibitor have been administered: (1 ) a reduction in weekly average of daily prurigo nodularis skin pain NRS score of 4 points or more as compared to a baseline; (2) a weekly average of daily Wl NRS score less than 2, preferably at week 24 or earlier; (3) a weekly average of daily Wl NRS score of 0 or 1 ; (4) a weekly average of daily Wl NRS score of 0, 1 , or 2; or (5) a combination thereof.

[0120] E84c. The method of E84b, wherein said baseline is the subject’s weekly average of daily prurigo nodularis skin pain NRS score before the first dose of the 0X40 or OX40L inhibitor is administered, or is a pre-determined baseline value.

[0121] E84d. The method of any one of E1 -E84c, wherein said subject shows a change in EQ-5D visual analog scale (VAS) score after one or more doses of said 0X40 or OX40L inhibitor have been administered, as compared to baseline.

[0122] E84e. The method of E84d, wherein said baseline is the subject’s EQ-5D visual analog scale (VAS) score before the first dose of the 0X40 or OX40L inhibitor is administered, or is a pre-determined baseline value.

[0123] E84f. The method of any one of E52-E84e, wherein said subject shows a change number of lesions in a representative area, as determined from PAS, after one or more doses of said 0X40 or OX40L inhibitor have been administered, as compared to baseline.

[0124] E84g. The method of E84f , wherein the subject achieves 76% or more healed lesions, as determined from PAS.

[0125] E84h. The method of E84f or E84g, wherein said baseline is the subject’s number of lesions in a representative area, determined from PAS, before the first dose of the 0X40 or OX40L inhibitor is administered, or is a pre-determined baseline value.

[0126] E85. The method of E83, or E84a-E84h, wherein said subject shows a change in HADS anxiety subscale score or in HADS depression subscale score after one or more doses of said 0X40 or OX40L inhibitor have been administered, as compared to a baseline.

[0127] E86. The method of E85, wherein said baseline is the subject’s HADS anxiety subscale score or HADS depression subscale score before the first dose of the anti-OX40 antibody is administered, or is a predetermined baseline value.

[0128] E87. The method of any one of E51 -E84, wherein the anti-OX40 antibody is administered subcutaneously or intravenously.

[0129] E88. The method of any one of E52-E87, wherein said subject further receives topical treatment, such as a topical calcineurin inhibitor (TCI) or a topical corticosteroid (TCS). E89. The method of E88, wherein said subject further receives one or more of the following treatments: an antihistamine, topical capsaicin, an intralesional glucocorticosteroid, cryotherapy, phototherapy, a gabapentinoid, an antidepressant, an immunosuppressants (such as cyclosporine or methotrexate), a neurokinin-1 receptor antagonist, an l-opioid receptor antagonist, and dupilumab.

[0130] E90. A method for treating prurigo nodularis (PN), comprising: during a first phase, administering to a subject in need thereof an anti-QX40 antibody at a dose of 150 mg, once every 4 weeks (Q4W), and an additional loading dose of anti-OX40 antibody at a dose of 150 mg at week 2 (W2); and during a second phase, administering to said subject the anti-OX40 antibody at a dose of 150 mg once every 8 weeks (Q8W), once every 12 weeks (Q12W), or once every 16 weeks (Q16W); wherein said anti-OX40 antibody comprises: i) (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 31 ; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 32; or ii) (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:33, 37, 38, or a combination thereof; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 34.

[0131] E91 . A method for treating prurigo nodularis (PN), comprising: during a first phase, administering to a subject in need thereof an anti-QX40 antibody at a dose of 200 mg, once every 4 weeks (Q4W), and an additional loading dose of anti-QX40 antibody at a dose of 200 mg at week 2 (W2); and during a second phase, administering to said subject the anti-QX40 antibody at a dose of 200 mg once every 8 weeks (Q8W), once every 12 weeks (Q12W), or once every 16 weeks (Q16W); wherein said anti-QX40 antibody comprises: i) (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 31 ; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 32; or ii) (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:33, 37, 38, or a combination thereof; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 34.

[0132] E92. A method for treating prurigo nodularis (PN), comprising: during a first phase, administering to a subject in need thereof an anti-QX40 antibody at a dose of 250 mg, once every 4 weeks (Q4W), and an additional loading dose of anti-QX40 antibody at a dose of 250 mg at week 2 (W2); and during a second phase, administering to said subject the anti-QX40 antibody at a dose of 250 mg once every 8 weeks (Q8W), once every 12 weeks (Q12W), or once every 16 weeks (Q16W); wherein said anti-OX40 antibody comprises: i) (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 31 ; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 32; or ii) (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:33, 37, 38, or a combination thereof; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 34.

[0133] E93. A method for treating prurigo nodularis (PN), comprising: during a first phase, administering to a subject in need thereof an anti-OX40 antibody at a dose of 300 mg, once every 4 weeks (Q4W), and an additional loading dose of anti-OX40 antibody at a dose of 300 mg at week 2 (W2); and during a second phase, administering to said subject the anti-OX40 antibody at a dose of 300 mg once every 8 weeks (Q8W), once every 12 weeks (Q12W), or once every 16 weeks (Q16W); wherein said anti-OX40 antibody comprises: i) (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 31 ; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 32; or ii) (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:33, 37, 38, or a combination thereof; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 34.

[0134] E94. The method of any one of E90-E93, wherein the first phase is at least 12 weeks long.

[0135] E95. The method of any one of E90-E93, wherein the first phase is at least 16 weeks long.

[0136] E96. The method of any one of E90-E93, wherein the first phase is at least 20 weeks long.

[0137] E97. The method of any one of E90-E93, wherein the first phase is at least 24 weeks long.

[0138] E98. The method of any one of E90-E93, wherein the first phase is at least 28 weeks long.

[0139] E99. The method of any one of E90-E93, wherein the first phase is at least 32 weeks long.

[0140] E100. The method of any one of E90-E93, wherein the first phase is at least 36 weeks long.

[0141] E101 . The method of any one of E90-E93, wherein the first phase is at least 40 weeks long.

[0142] E102. The method of any one of E90-E93, wherein the first phase is at least 44 weeks long.

[0143] E103. The method of any one of E90-E93, wherein the first phase is at least 48 weeks long.

[0144] E104. The method of any one of E90-E93, wherein the first phase is at least 52 weeks long. E105. The method of any one of E90-E104 , wherein transition from the first phase to second phase occurs when the subject shows a change in weekly average of daily Worst Itch Numeric Rating Scale (WI-NRS) score after one or more doses of said anti-OX40 antibody have been administered, as compared to a baseline.

[0145] E106. The method of any one of E90-E104, wherein said subject’s weekly average of daily Worst Itch Numeric Rating Scale (WI-NRS) score is reduced by 4 points or more after one or more doses of said anti-OX40 antibody have been administered, as compared to a baseline.

[0146] E107. The method of E105 or E106, wherein said baseline is the subject’s weekly average of daily WI-NRS score before the first dose of the anti-OX40 antibody is administered, or is a pre-determined baseline value.

[0147] E108. The method of any one of E90-E107, wherein said subject shows a change in Investigator's Global Assessment for Chronic Nodular Prurigo-Stage (IGA CNPG-S) score after one or more doses of said anti-OX40 antibody have been administered, as compared to a baseline.

[0148] E109. The method of E108, wherein said baseline is the subject’s IGA CNPG-S score before the first dose of the anti-OX40 antibody is administered, or is a pre-determined baseline value.

[0149] E110. The method of any one of E90-E107, wherein said subject’s IGA CNPG-S score is 0 (clear) or 1 (almost clear) (IGA CNPG-S 0 / 1 ) after one or more doses of said anti-OX40 antibody have been administered.

[0150] E11 1 . The method of any one of E90-E110, wherein said subject shows a reduction in weekly average of daily WI-NRS score of 4 points or more, as compared to a baseline; and an IGA CNPG-S score of 0 (clear) or 1 (almost clear) (IGA CNPG-S 0 / 1 ), after one or more doses of said anti-OX40 antibody have been administered.

[0151] E112. The method of E1 1 1 , wherein said baseline is the subject’s weekly average of daily WI-NRS score before the first dose of the anti-OX40 antibody is administered, or is a pre-determined baseline value.

[0152] E113. The method of any one of E90-E112 wherein said subject shows a change in Dermatology Life Quality Index (DLQI) score after one or more doses of said anti-OX40 antibody have been administered, as compared to a baseline.

[0153] E114. The method of any one of E90-E112, wherein said subject shows a reduction in DLQI score of 4 points or more after one or more doses of said anti-QX40 antibody have been administered, as compared to a baseline. E115. The method of E113 and E114, wherein said baseline is the subject’s DLQI score before the first dose of the anti-OX40 antibody is administered, or is a pre-determined baseline value.

[0154] E116. The method of any one of E90-E115, wherein said subject shows a change in weekly average of daily prurigo nodularis skin pain NRS score after one or more doses of said anti-OX40 antibody have been administered, as compared to a baseline.

[0155] E117. The method of any one of E90-E115, wherein said subject shows a reduction in weekly average of daily prurigo nodularis skin pain NRS score of 4 points or more after one or more doses of said anti- 0X40 antibody have been administered, as compared to a baseline.

[0156] E118. The method of E116 and E117, wherein said baseline is the subject’s weekly average of daily prurigo nodularis skin pain NRS score before the first dose of the anti-OX40 antibody is administered, or is a pre-determined baseline value.

[0157] E119. The method of any one of E90-E118, wherein said subject shows a change in weekly average of daily sleep disturbance-NRS score after one or more doses of said anti-OX40 antibody have been administered, as compared to a baseline.

[0158] E120. The method of any one of E90-E118, wherein said subject shows a reduction in weekly average of daily sleep disturbance-NRS score of 4 points or more after one or more doses of said anti-OX40 antibody have been administered, as compared to a baseline.

[0159] E121 . The method of E1 19 and E120, wherein said baseline is the subject’s weekly average of daily sleep disturbance-NRS score before the first dose of the anti-OX40 antibody is administered, or is a predetermined baseline value.

[0160] E122. The method of any one of E90-E121 , wherein said subject shows a change in Hospital Anxiety and Depression Scale (HADS) score after one or more doses of said anti-OX40 antibody have been administered, as compared to baseline.

[0161] E123. The method of E122, wherein said baseline is the subject’s Hospital Anxiety and Depression Scale (HADS) score before the first dose of the anti-OX40 antibody is administered, or is a predetermined baseline value.

[0162] E124. The method of E122 or E123, wherein said subject shows a change in HADS anxiety subscale score or in HADS depression subscale score after one or more doses of said anti-OX40 antibody have been administered, as compared to a baseline. E125. The method of E124, wherein said baseline is the subject’s HADS anxiety subscale score or HADS depression subscale score before the first dose of the anti-OX40 antibody is administered, or is a pre-determined baseline value.

[0163] E126. The method of any one of E90-E125, wherein the anti-OX40 antibody is administered subcutaneously or intravenously.

[0164] E127. The method of any one of E90-E126, wherein said subject further receives topical treatment such as a topical calcineurin inhibitor (TCI) or a topical corticosteroid (TCS).

[0165] E128. The method of E127, wherein said subject further receives one or more of the following treatments: an antihistamine, topical capsaicin, an intralesional glucocorticosteroid, cryotherapy, phototherapy, a gabapentinoid, an antidepressant, an immunosuppressants (such as cyclosporine or methotrexate), a neurokinin-1 receptor antagonist, an l-opioid receptor antagonist, and dupilumab.

[0166] E129. The method of any one of E52-E128, wherein said subject is a human.

[0167] E130. An 0X40 inhibitor or OX40L inhibitor for use in a method as set forth in any one of E1 -E129.

[0168] E131 . Use of an 0X40 inhibitor or OX40L inhibitor as set forth in E130 in the preparation of a medicament for the treatment of Prurigo Nodularis.

[0169] E132. An article of manufacture comprising:

[0170] (a) a container comprising an 0X40 inhibitor or an OX40L inhibitor; and

[0171] (b) a package insert with instructions for treating prurigo nodularis in a subject according to any one of E1 -E129.

[0172] E133. An article of manufacture comprising:

[0173] (1 ) a container comprising an 0X40 antibody, wherein said antibody comprises: i) (a) a heavy chain comprising the amino acid sequence of SEO ID NO:33, 37, 38, or a combination thereof; and (b) a light chain comprising the amino acid sequence of SEO ID NO: 34; or

[0174] II) (a) a heavy chain variable region comprising the amino acid sequence of SEO ID NO: 31 ; and (b) a light chain variable comprising the amino acid sequence of SEO ID NO: 32; and

[0175] (2) a package insert with instructions for treating prurigo nodularis in a subject according to any one of E1 -E129. BRIEF DESCRIPTION OF THE DRAWINGS

[0176] [8] FIG. 1 is a schematic illustration of dose levels and treatment scheme for the prurigo nodularis clinical study as shown in the Examples. IGA CNPG-S = Investigator’s Global Assessment for Chronic Nodular Prurigo Stage; SC = Subcutaneous, Q4W = every 4 weeks; W = week; WI-NRS = Worst Itch Numeric Rating Scale; WI-NRS > 3p improvement = Worst Itch-Numeric Rating Scale greater or equal than 3-point improvement compared to day 1 .aAt week 24, subjects meeting the W24 assessment criteria at each arm will continue with their original treatment arms.

[0177] DETAILED DESCRIPTION

[0178] 1. Prurigo nodularis

[0179] [9] Prurigo nodularis presents as intensely itchy, excoriated nodules on the extensor surfaces of the arms and legs and on the trunk. Palms, soles, and face are spared. Lesions vary in size from a few millimeters to 2 to 3 cm in diameter, and range in number from a few to hundreds. The hallmark of prurigo nodularis is unrelenting itch, which is greater in intensity, frequency, and effect on quality of life than itch associated with other chronic, pruritic skin diseases such as atopic dermatitis (AD) and psoriasis. This intense itch can cause patients to scratch themselves to the point of bleeding and pain. As a result, the patients have markedly impaired quality of life, often with sleep deprivation, and a high incidence of anxiety and depression.

[0180]

[0010] Prurigo nodularis can coexist with the symptoms of AD. A survey where subjects reported they have current or past medical history of prurigo nodularis showed that the full atopic triad (AD, asthma, and seasonal allergies) is commonly reported in adult patients with prurigo nodularis, with one study finding 50% of patients with prurigo nodularis also having AD, 31 % having asthma, and 71 % having allergic rhinitis (Aggarwal et al, Clinical characteristics and disease burden in prurigo nodularis. Clin Exp Dermatol. 2021 Oct;46(7):1277-1284).

[0181]

[0011] The pathogenesis of prurigo nodularis is multifactorial and thought to be related to underlying neuroimmune dysregulation mediated by a complex interplay between inflammatory cells, pro- inflammatory cytokines, neuropeptides, and sensitization of cutaneous neurons.

[0182]

[0012] A variety of immune cells, including T cells, eosinophils, neutrophils, macrophages, and mast cells, have been found infiltrating lesional skin of prurigo nodularis. An increase of diverse inflammatory cytokines such as IL-4, IL-17, IL-22, and IL-31 in the skin lesions of prurigo nodularis has been reported (Park et al, Increased expression of mRNAs for IL-4, IL-17, IL-22 and IL-31 in skin lesions of subacute and chronic forms of prurigo. Eur J Dermatol. 201 1 Jan-Feb;21 (1 ):135-6). Given that the full atopic triad is commonly reported in adult patients with prurigo nodularis, this suggests that T helper 2 (Th2) pathway deregulation is an underlying part of prurigo nodularis pathophysiology (Aggarwal et al, 2021 ). T helper 2 (Th2) cytokines such as IL-4, IL-5, IL 10, and IL 13 are increased in the lesional dermis of prurigo nodularis patients without concurrent atopy, indicating the involvement of Th2 cells in the pathogenesis of prurigo nodularis beyond those with underlying atopy (Fukushi et al, Nuclear localization of activated STAT6 and STAT3 in epidermis of prurigo nodularis. Br J Dermatol. 2011 Nov;165(5):990-6). Several studies have identified a role for Th2 and Th22 immune dysregulation in both the blood and skin (Belzberg et al, Prurigo Nodularis Is Characterized by Systemic and Cutaneous T Helper 22 Immune Polarization. J Invest Dermatol. 2021 Sep;141 (9):2208-2218.e14). In addition, prurigo nodularis lesions have significantly increased expression of Th1 / Th2 / Th17 / Th22-associated genes, suggesting multiple T- cell pathway deregulation contributes to disease pathogenesis.

[0183]

[0013] Prurigo nodularis has a broader pathophysiology beyond the Th2 pathways. Belzberg et al (2021 ) reported significant expression of Th22 / IL 22 associated genes in lesional prurigo nodularis skin. Moreover, the itch severity has been shown to correlate with the degree of Th22 related gene dysregulation. Further to this, Th17-cell infiltration is also increased, and Belzberg et al (2021 ) revealed increased Th17 / IL 17 induced genes in lesional skin of prurigo nodularis.

[0184]

[0014] The neural architecture in patients with prurigo nodularis is disrupted: lesional skin shows thickening, increased number of dermal nerves, and reduced density of intraepidermal nerve fibers. Imbalanced expression of neuropeptides and neuroinflammatory mediators have been shown to have a pathogenic role in prurigo nodularis.

[0185]

[0015] Peripherally increased excitability of sensory neurons can be attributed to hyperinnervation or the loss of innervation as well as increased expression, sensitivity, and / or responsiveness of pruriceptors. A subset of sensory neurons co-express neuropeptides and receptors for type 2 cytokines, including interleukin 4 receptor alpha (IL-4Ra) and interleukin 31 receptor A (IL-31 RA). Both IL-4 and IL-31 are implicated in the transmission of the pruritic sensation.

[0186]

[0016] In summary, T cell driven inflammation occurs across multiple pathways in patients with prurigo nodularis.

[0187]

[0017] For prurigo nodularis, first-line treatments include topical corticosteroids, topical calcineurin inhibitors, and antihistamines. Nearly all adult patients have treatment failure with topical glucocorticoids. Prurigo nodularis is a nonhistaminergic itch condition, and therapy with antihistaminergic agents is generally ineffective aside from its sedative properties and not recommended unless a comorbid histamine-mediated condition is associated (Zeidler et al, Investigator's Global Assessment of Chronic Prurigo: A New Instrument for Use in Clinical Trials. Acta Derm Venereol. 2021 Feb 17;101 (2):adv00401 ).

[0018] Second-line treatments may include topical capsaicin, intralesional glucocorticosteroids, cryotherapy, and phototherapy. Third-line treatments include systemic treatments such as gabapentinoids, antidepressants, and immunosuppressants such as cyclosporine or methotrexate. Fourth-line treatments include neurokinin-1 receptor antagonists, l-opioid receptor antagonists, and targeted treatments. Dupilumab is currently the only US FDA-approved targeted therapy for the treatment of prurigo nodularis (DUPIXENT US Prescribing Information [USPI], January 2024) and the only EMA- approved targeted therapy in the European Union for the treatment of adults with moderate-to-severe prurigo nodularis which are candidates for systemic therapy (DUPIXENT summary of product characteristics [SmPC], October 2023). However, around 61% to 68% of patients do not respond sufficiently to dupilumab in both reduction in itch and lesions after 24 weeks of treatment (Yosipovitch et al, 2023).

[0188] 2. 0X40 and OX40L Inhibitors

[0189]

[0019] 0X40 (also called ACT35, CD134, TXGP1 L or TNFRSF4), belonging to the TNFR superfamily, is a type 1 transmembrane mature protein containing 249 amino acids with a 49 amino acids in cytoplasmic tail and a 186 amino acids in extracellular region. 0X40 protein was first recognized on activated rat CD4+ T cells in 1987, and has the amino acid sequence set out in sequence database accession number P3489 (Swiss-Prot). Subsequently, 0X40 expression was also found expressed in mice and humans. 0X40 is mainly expressed on activated CD4+ T cells and CD8+ T cells, whereas its expression level is relatively low on NK cells and NKT cells. 0X40 sometimes is also referred to as “0X40 receptor.”

[0190]

[0020] OX40L (also named as CD252, TNFSF4, TXGP1 , CD134L or gp34), the ligand of 0X40, is a type

[0191] II glycoprotein with a 23 amino acids cytoplasmic tail and a 133 amino acids extracellular domain. OX40L has the amino acid sequence set out in sequence database accession number P23510 (Swiss-Prot). As a member of the TNF superfamily, it is expressed as a trimer. OX40L was initially identified as gp34 protein on human T-cell leukemia virus transformed cells in 1985. Later, it was found that OX40L is mainly expressed on antigen presenting cells, such as B cells and dendritic cells.

[0192]

[0021] As a pair of costimulatory molecules, OX40 / OX40L is required for T cell activation especially in the later phase of the immune response. OX40 / OX40L plays important roles in enhancing the function of effector T cells, maintaining their survival and inhibiting their apoptosis. OX40 / OX40L pathway has been reported to be involved in autoimmune diseases such as SLE, RA, and Graves’ disease.

[0193]

[0022] One example of an OX40L inhibitor is an anti-OX40L antibody, such as Amlitelimab. Amlitelimab is a fully human non-T cell depleting monoclonal antibody that blocks OX40L. It is being investigated for treating moderate-to-severe atopic dermatitis, asthma, hidradenitis suppurativa, scleroderma, celiac disease, and alopecia.

[0023] Another example of an 0X40 inhibitor is an anti-OX40 antibody, such as rocatinlimab or telazorlimab. Tolazorlimab is a humanized anti-OX4 monoclonal antibody. Rocatinlimab is a fully human afucosylated IgG 1 monoclonal antibody specific for inhibiting OX40 / OX40L interaction. Rocatinlimab can reduce activated T cells to and is being investigated for treating autoimmune diseases such as atopic dermatitis. The sequence of rocatinlimab is provided below in Table A.

[0194] Table A: Rocatinlimab Sequences

[0195]

[0024] In Table B, exemplary “Complementarity Determining Regions" (CDRs) sequences of rocatinlimab are shown. As used herein, “Complementarity Determining Regions" (CDRs) can be identified according to the definitions of the Kabat, Chothia, the accumulation of both Kabat and Chothia, AbM, contact, North, and / or conformational definitions or any method of CDR determination well known in the art. See, e.g., Kabat et al., 1991 , Sequences of Proteins of Immunological Interest, 5th ed. (hypervariable regions); Chothia & Lesk, 1987, J Mol Biol., 196:901 -917 (structural loop structures). The identity of the amino acid residues in a particular antibody that make up a CDR can be determined using methods well known in the art. AbM definition of CDRs is a compromise between Kabat and Chothia and uses Oxford Molecular’s AbM antibody modeling software (Accelrys®). The “contact” definition of CDRs is based on observed antigen contacts, set forth in MacCallum et al., 1996, J. Mol. Biol., 262:732-745. The “conformational” definition of CDRs is based on residues that make enthalpic contributions to antigen binding (see, e.g., Makabe et al., 2008, J. Biol. Chem., 283:1 156-1 166). North has identified canonical CDR conformations using a different preferred set of CDR definitions (North et al., 2011 , J. Mol. Biol. 406: 228-256). In another approach, referred to herein as the “conformational definition” of CDRs, the positions of the CDRs may be identified as the residues that make enthalpic contributions to antigen binding (Makabe et al., 2008, J Biol. Chem. 283:1 156-1 166). Martin definition (also called enhanced Chothia definition) combines the Kabat and Chothia definitions and differs from them only in the heavy chain, where CDR- H1 includes all residues of Kabat and Chothia while CDR-H2 is seven residues shorter than that defined by Kabat (Martin, Bioinformatics tools for antibody engineering. Handbook of Therapeutic Antibodies. Weinheim: Wiley-VCH Verlag GmbH; (2008). p. 95-1 17; see also the database maintained by the Institute of Structural and Molecular Biology at the University College London, http: / / www.bioinf.org.Uk / abs / #cdrid). Still other CDR boundary definitions may not strictly follow one of the above approaches, but will nonetheless overlap with at least a portion of the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding. For example, “combined” CDRs may also be used. Therefore, a CDR may refer to CDRs defined by any approach known in the art, including combinations of approaches. For any given embodiment containing more than one CDR, the CDRs (or other residue of the antibody) may be defined in accordance with any of Kabat, Chothia, North, AbM, Contact, IMGT, Martin, combined Kabat and Chothia, and / or conformational definitions.

[0196]

[0025] For example, Table B shows a few alterative definition of CDR.

[0197] Table B: CDR sequences of rocatinlimab.

[0198]

[0026] In certain embodiments, the 0X40 inhibitor is an anti-OX40 antibody that comprises: (a) a heavy chain variable region (VH) that comprises: (i) a VH complementarity determining region one (CDR-H1 ) comprising the amino acid sequence of any one of SEQ ID NOs:1 -5; (ii) a CDR-H2 comprising the amino acid sequence of any one of SEQ ID NOs:6-10; and (iii) a CDR-H3 comprising the amino acid sequence of any one of SEQ ID NOs:11 -15; and (b) a light chain variable region (VL) that comprises: (i) a VL complementarity determining region one (CDR-L1 ) comprising the amino acid sequence of any one of SEQ ID NQs:16-20; (ii) a CDR-L2 comprising the amino acid sequence of any one of SEQ ID NOs:21 -25; and (iii) a CDR-L3 comprising the amino acid sequence of any one of SEQ ID NQs:26-30.

[0199]

[0027] In certain embodiments, the 0X40 inhibitor is an anti-QX40 antibody that comprises: (a) a heavy chain variable region (VH) that comprises the CDR-H1 , CDR-H2, and CDR-H3 of SEQ ID NO:31 ; and (b) a light chain variable region (VH) that comprises the CDR-L1 , CDR-L2, and CDR-L3 of SEQ ID NO:32. The CDRs of SEQ ID NO:7 and SEQ ID NO:8 can be defined according to any art-recognized definitions.

[0200]

[0028] In certain embodiments, the anti-QX40 antibody comprises:

[0201] (a) a VH that comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:1 , a CDR-H2 comprising the amino acid sequence of SEQ ID NO:6, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:11 ; and a VL that comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:21 , and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:26;

[0202] (b) a VH that comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:2, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:7, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:12; and a VL that comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:17, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:22, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:27;

[0203] (c) a VH that comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:3, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:8, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:13; and a VL that comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:18, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:28;

[0204] (d) a VH that comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:4, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:9, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:14; and a VL that comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:19, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:24, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:29; or

[0205] (e) a VH that comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:5, a CDR-H2 comprising the amino acid sequence of SEQ ID NQ:10, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:15; and a VL that comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:20, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:25, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:30.

[0206]

[0029] In certain embodiments, the anti-OX 40 antibody comprises: a VH that comprises the amino acid sequence of SEQ ID NO:31 , and a VL that comprises the amino acid sequence of SEQ ID NO:32.

[0207]

[0030] The anti-QX40 antibody may further comprise a constant domain. In general, immunoglobulin heavy chain constant domain includes a CH1 domain and a Fc domain (CH2-CH3). Constant domains can be derived human IgG 1 , a human lgG2, a human lgG3, or a human lgG4.

[0208]

[0031] In some embodiments, the Fc domain comprises one or more mutations resulting in altered biological activity, such as to improve half-life / stability or to render the antibody more suitable for expression / manufacturability. For example, mutations may be introduced into the Fc domain to reduce the effector activity (e.g., WO 2005 / 063815; which is incorporated by reference herein), and / or to increase the homogeneity during the production of the recombinant protein.

[0209]

[0032] C-terminal lysine clipping is a common phenomenon occurring during the bioproduction of monoclonal antibodies. Often, the lysine residue is removed via carboxypeptidase D (CpD), which results in generation of a mixture of antibody isoforms bearing zero or one C-terminal lysine residues on each heavy chain. Further, following C-terminal lysine cleavage, peptidylglycine a-amidating monooxygenase (PAM) catalyzes the hydroxylation of glycine and removal of the glyoxylate from the glycine residue, leaving an amidated C-terminal proline. Therefore, during recombinant production of a monoclonal antibody, the product is often a mixture of C-terminal processing variants, with heavy chain C-terminus ends at (amidated) proline, glycine, or lysine. Sometimes, it may be desirable to delete the C-terminal lysine of the Fc domain to increase the homogeneity during the production of the recombinant protein.

[0210]

[0033] In some embodiments, the terminal lysine may be absent; in some embodiments, the terminal lysine may be present; in some embodiments, the terminal glycine-lysine may be absent; in some embodiments, the terminal glycine-lysine may be present. It will be appreciated that in some embodiments, a pharmaceutically suitable composition may comprise a mixture of species that do and do not comprise the terminal lysine and / or glycine-lysine.

[0211]

[0034] In some embodiments, the heavy chain constant domain comprises a sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 90%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 35.

[0035] The anti-OX40 antibody described herein may also comprise a kappa or lambda light chain constant domain. In some embodiments, the kappa light chain constant domain comprises a sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 36.

[0212]

[0036] In some embodiments, the anti-OX 40 antibody comprises: a heavy chain that comprises a sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:33, 37, 38, or a combination thereof, and a light chain that comprises a sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:34. SEQ ID NO:33 refers to full length heavy chain without terminal clipping; SEQ ID NO:37 refers to the heavy chain where C-terminal lysine has been clipped during post-translation modification; and SEQ ID NO:38 refers to the heavy chain where both terminal G and K residues are clipped during post- translational modification. For SEQ ID NO:38, the terminal proline may be amidated. As described in detail above, the antibody composition for administration often comprises a mixture of C-terminal processing variants, with heavy chain C-terminus ends at (amidated) proline, glycine, or lysine.

[0213]

[0037] In some embodiments, the anti-OX 40 antibody comprises: a heavy chain that comprises the amino acid sequence of SEQ ID NO:33, 37, 38, or a combination thereof, and a light chain that comprises the amino acid sequence of SEQ ID NO:34.

[0214] 3. Administration of 0X40 or OX40L Inhibitors

[0215]

[0038] The treatment method disclosed herein relates to a method for treating prurigo nodularis (PN). Preferred treatment scheme comprises administering to a subject in need thereof an 0X40 or OX40L inhibitor, at a dose of from about 150 mg to about 300 mg, once every 4 weeks (Q4W), with an additional loading dose at week 2 (W2). A preferred 0X40 inhibitor is rocatinlimab as described herein.

[0216]

[0039] Also contemplated is a treatment scheme comprising administering to a subject in need thereof an 0X40 or OX40L inhibitor, at a dose of from about 150 mg to about 300 mg, once every 2 weeks (Q2W). Also contemplated is a treatment scheme comprising administering to a subject in need thereof an 0X40 or OX40L inhibitor, at a dose of from about 150 mg to about 300 mg, once every 3 weeks (Q3W), with an additional loading dose at week 2 (W2). Also contemplated is a treatment scheme comprising administering to a subject in need thereof an 0X40 or OX40L inhibitor, at a dose of from about 150 mg to about 300 mg, once every 6 weeks (Q6W), with an additional loading dose at week 2 (W2). Also contemplated is a treatment scheme comprising administering to a subject in need thereof an 0X40 or OX40L inhibitor, at a dose of from about 150 mg to about 300 mg, once every 8 weeks (Q8W), with an additional loading dose at week 2 (W2). A preferred 0X40 inhibitor is rocatinlimab as described herein.

[0217]

[0040] Loading doses are generally a means to quickly achieve therapeutic drug concentrations or prompt an immediate clinical response. The disclosed methods of treating PN are contemplated to comprise administration of a loading does at or during week 2 (W2). A loading dose at W2 is chosen here with a goal to reach target steady-state early on and to improve the therapeutic outcome. The time it takes for a therapeutic drug to reach steady-state is a function of the elimination half-life of the drug. In general, it takes approximately 5-7 half-lives of the drug to achieve steady-state. For drugs with rapid elimination and short half-life values, this is usually not a problem; however drugs with slow elimination could require days or weeks to achieve steady-state. It is believed that if therapeutic effects are needed quickly, and the drug has a long half-life, one can use a loading dose to achieve therapeutic levels on the first dose. The loading dose can help rapidly achieve the therapeutic response, and subsequent doses help maintain the response.

[0218]

[0041] In certain embodiments, the 0X40 or OX40L inhibitor is an anti-OX40 antibody, such as rocatinlimab, which is administered at a dose of about 150 mg once every 4 weeks for at least 3 administrations (12 weeks), with an additional loading dose of about 150 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about

[0219] 150 mg once every 4 weeks for at least 4 administrations (16 weeks), with an additional loading dose of about 150 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 150 mg once every 4 weeks for at least 5 administrations (20 weeks), with an additional loading dose of about 150 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 150 mg once every 4 weeks for at least 6 administrations (24 weeks), with an additional loading dose of about 150 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 150 mg once every 4 weeks for at least 7 administrations (28 weeks), with an additional loading dose of about 150 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 150 mg once every 4 weeks for at least 8 administrations (32 weeks), with an additional loading dose of about 150 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 150 mg once every 4 weeks for at least 9 administrations (36 weeks), with an additional loading dose of about 150 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 150 mg once every 4 weeks for at least 10 administrations (40 weeks), with an additional loading dose of about 150 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 150 mg once every 4 weeks for at least 1 1 administrations (44 weeks), with an additional loading dose of about 150 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 150 mg once every 4 weeks for at least 12 administrations (48 weeks), with an additional loading dose of about 150 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 150 mg once every 4 weeks for at least 13 administrations (52 weeks), with an additional loading dose of about 150 mg administered at week 2.

[0220]

[0042] In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 200 mg once every 4 weeks for at least 3 administrations (12 weeks), with an additional loading dose of about 200 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 200 mg once every 4 weeks for at least 4 administrations (16 weeks), with an additional loading dose of about 200 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 200 mg once every 4 weeks for at least 5 administrations (20 weeks), with an additional loading dose of about 200 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 200 mg once every 4 weeks for at least 6 administrations (24 weeks), with an additional loading dose of about 200 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 200 mg once every 4 weeks for at least 7 administrations (28 weeks), with an additional loading dose of about 200 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 200 mg once every 4 weeks for at least 8 administrations (32 weeks), with an additional loading dose of about 200 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 200 mg once every 4 weeks for at least 9 administrations (36 weeks), with an additional loading dose of about 200 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 200 mg once every 4 weeks for at least 10 administrations (40 weeks), with an additional loading dose of about 200 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 200 mg once every 4 weeks for at least 11 administrations (44 weeks), with an additional loading dose of about 200 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 200 mg once every 4 weeks for at least 12 administrations (48 weeks), with an additional loading dose of about 200 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 200 mg once every 4 weeks for at least 13 administrations (52 weeks), with an additional loading dose of about 200 mg administered at week 2.

[0221]

[0043] In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 250 mg once every 4 weeks for at least 3 administrations (12 weeks), with an additional loading dose of about 250 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 250 mg once every 4 weeks for at least 4 administrations (16 weeks), with an additional loading dose of about 250 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 250 mg once every 4 weeks for at least 5 administrations (20 weeks), with an additional loading dose of about 250 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 250 mg once every 4 weeks for at least 6 administrations (24 weeks), with an additional loading dose of about 250 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 250 mg once every 4 weeks for at least 7 administrations (28 weeks), with an additional loading dose of about 250 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 250 mg once every 4 weeks for at least 8 administrations (32 weeks), with an additional loading dose of about 250 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 250 mg once every 4 weeks for at least 9 administrations (36 weeks), with an additional loading dose of about 250 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 250 mg once every 4 weeks for at least 10 administrations (40 weeks), with an additional loading dose of about 250 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 250 mg once every 4 weeks for at least 11 administrations (44 weeks), with an additional loading dose of about 250 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 250 mg once every 4 weeks for at least 12 administrations (48 weeks), with an additional loading dose of about 250 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 250 mg once every 4 weeks for at least 13 administrations (52 weeks), with an additional loading dose of about 250 mg administered at week 2.

[0222]

[0044] In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 300 mg once every 4 weeks for at least 3 administrations (12 weeks), with an additional loading dose of about 300 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 300 mg once every 4 weeks for at least 4 administrations (16 weeks), with an additional loading dose of about 300 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 300 mg once every 4 weeks for at least 5 administrations (20 weeks), with an additional loading dose of about 300 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 300 mg once every 4 weeks for at least 6 administrations (24 weeks), with an additional loading dose of about 300 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 300 mg once every 4 weeks for at least 7 administrations (28 weeks), with an additional loading dose of about 300 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 300 mg once every 4 weeks for at least 8 administrations (32 weeks), with an additional loading dose of about 300 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 300 mg once every 4 weeks for at least 9 administrations (36 weeks), with an additional loading dose of about 300 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 300 mg once every 4 weeks for at least 10 administrations (40 weeks), with an additional loading dose of about 300 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 300 mg once every 4 weeks for at least 11 administrations (44 weeks), with an additional loading dose of about 300 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 300 mg once every 4 weeks for at least 12 administrations (48 weeks), with an additional loading dose of about 300 mg administered at week 2. In certain embodiments, the anti-OX40 antibody, such as rocatinlimab, is administered at a dose of about 300 mg once every 4 weeks for at least 13 administrations (52 weeks), with an additional loading dose of about 300 mg administered at week 2.

[0223]

[0045] Sometimes, the treatment may comprise two phases: a treatment phase and a maintenance phase. During the treatment phase, the 0X40 inhibitor may be administered at a higher dose, or at a higher frequency to achieve a desired result; then, during the maintenance phase, the 0X40 inhibitor may be administered at a lower dose, or at a lower frequency to “maintain” the results achieve from the treatment phase. For example, during the treatment phase, the anti-OX40 antibody, such as rocatinlimab, may be administered at a dose of from about 150 mg to about 300 mg once every 4 weeks for at least 3 administrations (12 weeks), with an additional loading dose of from about 150 mg to about 300 mg administered at week 2; then the subject may be switched to maintenance phase, where the anti-OX40 antibody, such as rocatinlimab, may be administered at a dose of from about 150 mg to about 300 mg once every 8 weeks (Q8W), once every 12 weeks (Q12W), or once every 16 weeks (Q16W).

[0224]

[0046] Accordingly, in some embodiments, the treatment may comprise a first phase and a second phase, wherein the 0X40 inhibitor is administered at a lower dose or a lower frequency during the second phase as compared to the first phase. In certain embodiments, during the first phase, an anti-OX40 antibody, such as rocatinlimab, can be administered according to any of the dosing regimen described in detail above, such as 150 mg Q4W (with a loading dose at W2), 200 mg Q4W (with a loading dose at W2), 250 mg Q4W (with a loading dose at W2), or 300 mg Q4W (with a loading dose at W2). During the second phase, an anti-OX40 antibody, such as rocatinlimab, can be administered at a dose of about 150 mg once every 8 weeks, once every 12 weeks, or once every 16 weeks. Alternatively, during the second phase, an anti-OX40 antibody, such as rocatinlimab, can be administered at a dose of about 200 mg once every 8 weeks, once every 12 weeks, or once every 16 weeks. Alternatively, during the second phase, an anti-OX40 antibody, such as rocatinlimab, can be administered at a dose of about 250 mg once every 8 weeks, once every 12 weeks, or once every 16 weeks. Alternatively, during the second phase, an anti-OX40 antibody, such as rocatinlimab, can be administered at a dose of about 300 mg once every 8 weeks, once every 12 weeks, or once every 16 weeks.

[0225]

[0047] In certain embodiments, the 0X40 or OX40L inhibitor is an anti-OX40L antibody, such as amlitelimab, which is administered at a dose of about 150 mg once every 4 weeks (Q4W) or once every 12 weeks (Q12W) for at least 3 administrations, with an optional loading dose of about 150 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 150 mg once every 4 weeks (Q4W) or once every 12 weeks (Q12W) for at least 4 administrations, with an optional loading dose of about 150 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about

[0226] 150 mg once every 4 weeks (Q4W) or once every 12 weeks (Q12W) for at least 5 administrations, with an optional loading dose of about 150 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 150 mg once every 4 weeks (Q4W) or once every 12 weeks (Q12W) for at least 6 administrations, with an optional loading dose of about 150 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 150 mg once every 4 weeks (Q4W) or once every 12 weeks (Q12W) for at least 7 administrations, with an optional loading dose of about 150 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 150 mg once every 4 weeks(Q4W) or once every 12 weeks (Q12W) for at least 8 administrations, with an optional loading dose of about 150 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 150 mg once every 4 weeks(Q4W) or once every 12 weeks (Q12W) for at least 9 administrations, with an optional loading dose of about 150 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 150 mg once every 4 weeks(Q4W) or once every 12 weeks (Q12W) for at least 10 administrations, with an optional loading dose of about 150 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 150 mg once every 4 weeks(Q4W) or once every 12 weeks (Q12W) for at least 1 1 administrations, with an optional loading dose of about 150 mg administered at week 2. In certain embodiments, the anti- OX40L antibody, such as amlitelimab, is administered at a dose of about 150 mg once every 4 weeks (Q4W) or once every 12 weeks (Q12W) for at least 12 administrations, with an optional loading dose of about 150 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 150 mg once every 4 weeks(Q4W) or once every 12 weeks (Q12W) for at least 13 administrations, with an optional loading dose of about 150 mg administered at week 2.

[0227]

[0048] In certain embodiments, the 0X40 or OX40L inhibitor is an anti-OX40L antibody, such as amlitelimab, which is administered at a dose of about 200 mg once every 4 weeks (Q4W) or once every 12 weeks (Q12W) for at least 3 administrations, with an optional loading dose of about 200 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 200 mg once every 4 weeks (Q4W) or once every 12 weeks (Q12W) for at least 4 administrations, with an optional loading dose of about 200 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 200 mg once every 4 weeks (Q4W) or once every 12 weeks (Q12W) for at least 5 administrations, with an optional loading dose of about 200 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 200 mg once every 4 weeks (Q4W) or once every 12 weeks (Q12W) for at least 6 administrations, with an optional loading dose of about 200 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 200 mg once every 4 weeks (Q4W) or once every 12 weeks (Q12W) for at least 7 administrations, with an optional loading dose of about 200 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 200 mg once every 4 weeks(Q4W) or once every 12 weeks (Q12W) for at least 8 administrations, with an optional loading dose of about 200 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 200 mg once every 4 weeks(Q4W) or once every 12 weeks (Q12W) for at least 9 administrations, with an optional loading dose of about 200 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 200 mg once every 4 weeks(Q4W) or once every 12 weeks (Q12W) for at least 10 administrations, with an optional loading dose of about 200 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 200 mg once every 4 weeks(Q4W) or once every 12 weeks (Q12W) for at least 1 1 administrations, with an optional loading dose of about 200 mg administered at week 2. In certain embodiments, the anti- OX40L antibody, such as amlitelimab, is administered at a dose of about 200 mg once every 4 weeks (Q4W) or once every 12 weeks (Q12W) for at least 12 administrations, with an optional loading dose of about 200 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 200 mg once every 4 weeks(Q4W) or once every 12 weeks (Q12W) for at least 13 administrations, with an optional loading dose of about 200 mg administered at week 2.

[0228]

[0049] In certain embodiments, the 0X40 or OX40L inhibitor is an anti-OX40L antibody, such as amlitelimab, which is administered at a dose of about 250 mg once every 4 weeks (Q4W) or once every 12 weeks (Q12W) for at least 3 administrations, with an optional loading dose of about 250 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 250 mg once every 4 weeks (Q4W) or once every 12 weeks (Q12W) for at least 4 administrations, with an optional loading dose of about 250 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 250 mg once every 4 weeks (Q4W) or once every 12 weeks (Q12W) for at least 5 administrations, with an optional loading dose of about 250 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 250 mg once every 4 weeks (Q4W) or once every 12 weeks (Q12W) for at least 6 administrations, with an optional loading dose of about 250 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 250 mg once every 4 weeks (Q4W) or once every 12 weeks (Q12W) for at least 7 administrations, with an optional loading dose of about 250 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 250 mg once every 4 weeks(Q4W) or once every 12 weeks (Q12W) for at least 8 administrations, with an optional loading dose of about 250 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 250 mg once every 4 weeks (Q4W) or once every 12 weeks (Q12W) for at least 9 administrations, with an optional loading dose of about 250 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 250 mg once every 4 weeks(Q4W) or once every 12 weeks (Q12W) for at least 10 administrations, with an optional loading dose of about 250 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 250 mg once every 4 weeks(Q4W) or once every 12 weeks (Q12W) for at least 1 1 administrations, with an optional loading dose of about 250 mg administered at week 2. In certain embodiments, the anti- OX40L antibody, such as amlitelimab, is administered at a dose of about 250 mg once every 4 weeks (Q4W) or once every 12 weeks (Q12W) for at least 12 administrations, with an optional loading dose of about 250 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 250 mg once every 4 weeks(Q4W) or once every 12 weeks (Q12W) for at least 13 administrations, with an optional loading dose of about 250 mg administered at week 2.

[0229]

[0050] In certain embodiments, the 0X40 or OX40L inhibitor is an anti-OX40L antibody, such as amlitelimab, which is administered at a dose of about 300 mg once every 4 weeks (Q4W) or once every 12 weeks (Q12W) for at least 3 administrations, with an optional loading dose of about 300 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 300 mg once every 4 weeks (Q4W) or once every 12 weeks (Q12W) for at least 4 administrations, with an optional loading dose of about 300 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 300 mg once every 4 weeks (Q4W) or once every 12 weeks (Q12W) for at least 5 administrations, with an optional loading dose of about 300 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 300 mg once every 4 weeks (Q4W) or once every 12 weeks (Q12W) for at least 6 administrations, with an optional loading dose of about 300 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 300 mg once every 4 weeks (Q4W) or once every 12 weeks (Q12W) for at least 7 administrations, with an optional loading dose of about 300 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 300 mg once every 4 weeks(Q4W) or once every 12 weeks (Q12W) for at least 8 administrations, with an optional loading dose of about 300 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 300 mg once every 4 weeks(Q4W) or once every 12 weeks (Q12W) for at least 9 administrations, with an optional loading dose of about 300 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 300 mg once every 4 weeks(Q4W) or once every 12 weeks (Q12W) for at least 10 administrations, with an optional loading dose of about 300 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 300 mg once every 4 weeks(Q4W) or once every 12 weeks (Q12W) for at least 1 1 administrations, with an optional loading dose of about 300 mg administered at week 2. In certain embodiments, the anti- OX40L antibody, such as amlitelimab, is administered at a dose of about 300 mg once every 4 weeks (Q4W) or once every 12 weeks (Q12W) for at least 12 administrations, with an optional loading dose of about 300 mg administered at week 2. In certain embodiments, the anti-OX40L antibody, such as amlitelimab, is administered at a dose of about 300 mg once every 4 weeks(Q4W) or once every 12 weeks (Q12W) for at least 13 administrations, with an optional loading dose of about 300 mg administered at week 2.

[0230]

[0051] Dosing frequency is conventionally marked as weekly (QW), for example, once every 2 weeks (Q2W), once every 3 weeks (Q3W), or once every 4 weeks (Q4W). Sometimes it is also marked as days. For Q4W, a subject may be administered on day 1 , day 29 + 4 days, day 57 ± 7 days, day 85 ±7 days, day 1 13 ± 7 days, day 141 + 7 days, day 169 ± 7 days, day 197 ± 7 days, day 225 + 7 days, day 253 ± 7 days, day 281 ± 7 days, day 309 + 7 days, day 337 ± 7 days, etc. The loading dose may be administered on day 15± 4 days.

[0231]

[0052] Combination therapies are also contemplated. In addition to the OX-40 or OX40L inhibitor, the subject may receive additional treatments, sequentially or concurrently. For example, the subject may receive a topical treatment, such as a topical calcineurin inhibitor (TCI) or a topical corticosteroid (TCS). The FDA has approved two TCIs for eczema: Protopic® ointment (tacrolimus) for treating moderate to severe eczema, and Elidel® cream (pimecrolimus) for mild to moderate eczema. TCSs are available in several different forms and strength, such as clobetasone, hydrocortisone, beclometasone, betamethasone, clobetasol, fluticasone, and mometasone. The subject may also be treated with an antihistamine.

[0232]

[0053] The subject may also be treated with topical capsaicin, an intralesional glucocorticosteroid, cryotherapy, and / or phototherapy. The subject may also receive a systemic treatment, such as a gabapentinoid, an antidepressant, and / or an immunosuppressants (such as cyclosporine or methotrexate), The subject may also be treated with a neurokinin-1 receptor antagonist, and / or an l-opioid receptor antagonist. The subject may also receive a targeted therapy, such as dupilumab.

[0233] 4. Patient Selection and Efficacy Assessment

[0234]

[0054] Prurigo Nodularis is characterized by numerous excoriated firm nodules, the majority of which are situated symmetrically on the extremities (with a predilection for the anterior surfaces of limbs, trunk, and other easy-to-reach areas).

[0235]

[0055] Assessment tools for documenting the clinical presentation in patients with chronic prurigo have been developed. For example, the Prurigo Activity and Severity (PAS) score is a multi-item scale in which lesion type, number of lesions, affected body sites and scratch signs are assessed. In addition, Investigator’s Global Assessment (IGA) scales were developed in order to document the activity and stage of chronic prurigo. The IGA-CPG-activity scale documents the proportion of pruriginous lesions with scratch signs such as excoriations or crusts on top of the lesions, representing disease-related scratching activity. To assess the severity of chronic prurigo, IGA-scales for the stage of disease were developed for chronic prurigo (IGA-CPG-stage) and for the subtype chronic nodular prurigo (IGA-CNPG-stage; IGA CNPG-S). The former takes the number of all pruriginous lesions into account, while the latter scales only consider nodular lesions. Increasing severity of chronic nodular prurigo are measured by the physician IGA scales: 0: clear; 1 : almost clear; 2: mild; 3: moderate; 4: severe.

[0236]

[0056] Exemplary assessment tools are described in detail below.

[0237]

[0057] Worst Itch Numeric Rating Scale. The WI-NRS is a patient reported outcome (PRO) comprised of a single item rated on an 11 -point scale from 0 (“No itch”) to 10 (“Worst imaginable itch”). Worst-itch numerical rating scale (WI-NRS) asks subjects to report the severity of their worst itch in the past 24 hours.

[0238]

[0058] Prurigo Nodularis Skin Pain Numeric Rating Scale. The prurigo nodularis Skin Pain NRS is a single-item scale that assesses the severity of worst skin pain each day on an 11 -point scale between 0 and 10, with higher scores indicating worse skin pain.

[0239]

[0059] Sleep Disturbance Numeric Rating Scale. The sleep disturbance NRS is a single-item scale that assesses the severity of sleep disturbance on an 1 1 -point scale between 0 and 10, with higher scores indicating greater sleep disturbance.

[0240]

[0060] Dermatology Life Quality Index. The Dermatology Life Quality Index (DLQI) is a 10-item, selfadministered questionnaire, and is designed to measure the health-related quality of life of adult subjects suffering from skin disease. The DLQI measures subjects' perception of the impact of skin diseases on different aspects of their health-related quality of life over the last week. The DLQI is the most frequently used patient reported outcome measure in randomized controlled trials in dermatology.

[0241]

[0061] EuroQol-5 Dimension-5 Level. The EuroQol-5 Dimension-5 Level (EQ-5D-5L) questionnaire is a 2- page, standardized instrument for use as a measure of health outcome developed by the EuroQol group (Rabin et al., EQ-5D: a measure of health status from the EuroQol Group, Ann Med. 2001 Jul;33(5):337- 43). It is comprised of a 5-dimension health status measure and a visual analog scale (VAS). The 5- dimension health status measure evaluates: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression based on a 5-level scale: no problems, slight problems, moderate problems, severe problems, extreme problems. The visual analogue scale (VAS) records the subject's self-rated health on a vertical, VAS where the endpoints are labelled 'Best imaginable health state' and 'Worst imaginable health state'.

[0242]

[0062] Work Productivity and Activity Impairment for Prurigo Nodularis. The Work Productivity and Activity Impairment (WPAI) for Prurigo Nodularis questionnaire is an instrument to measure impairments in both paid work and unpaid work. It measures absenteeism, presenteeism as well as the impairments in unpaid activity because of health problems during the past 7 days.

[0243]

[0063] Patient Global Impression of Severity. The Patient Global Impression of Severity (PGI-S) is designed to capture the subject’s perception of change in symptom severity at the time of completion on a categorical response scale. There are 3 PGI-S items: worst itch, prurigo nodularis skin pain, and sleep disturbance.

[0244]

[0064] Patient Global Impression of Change. The Patient Global Impression of Change (PGI-C) is designed to capture the subject’s perception of change in symptom severity since starting study treatment at the time of completion. The assessment uses a 7-point rating scale, very much better to very much worse. There are 3 PGI-C items: worst itch, prurigo nodularis skin pain, and sleep disturbance.

[0245]

[0065] Assessments Completed by Investigator. Clinical evaluations of prurigo nodularis can be performed by an experienced and qualified dermatologist.

[0246]

[0066] Investigator’s Global Assessment for Prurigo Nodularis Stage. The IGA CNPG S is a validated assessment instrument used in clinical studies to rate the stage of the disease using a 5-point scale from 0 (clear) to 4 (severe) (Zeidler et al, Investigator's Global Assessment of Chronic Prurigo: A New Instrument for Use in Clinical Trials. Acta Derm Venereol. 2021 Feb 17;101 (2):adv00401 ).

[0247]

[0067] Investigator’s Global Assessment for Prurigo Nodularis Activity. The Investigator’s Global Assessment for Prurigo Nodularis Activity (IGA CNPG A) is a validated assessment instrument used in clinical studies to rate the activity of the disease using a 5-point scale from 0 (clear) to 4 (severe) (Zeidler et al. 2021 ).

[0068] Prurigo Activity Score. The Prurigo Activity Score (PAS) is a clinician reported outcome measurement. The original PAS questionnaire Version 0.9 consists of 7 items, developed by expert clinicians in prurigo nodularis (Polking et al, Prurigo Activity Score (PAS): validity and reliability of a new instrument to monitor chronic prurigo; J Eur Acad Dermatol Venereol., 2018 Oct;32(10):1754-1760).

[0248]

[0069] The Hospital Anxiety and Depression Scale. The Hospital Anxiety and Depression Scale (HADS) has been developed (Zigmond et. al., The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand 1983;67:361-370) to measure anxiety and depression in a general medical population of patients. HADS focuses on non-physical symptoms so that it can be used to diagnose depression in people with significant physical ill-health. The questionnaire comprises seven questions for anxiety and seven questions for depression. Although the anxiety and depression questions are interspersed within the questionnaire, they are in general scored separately. Cut-off scores are available for quantification, for example a score of 8 or more for anxiety has a specificity of 0.78 and a sensitivity of 0.9, and for depression a specificity of 0.79 and a sensitivity of 0.83. In general, for both cases, scores of less than 7 indicate non-cases, 8-10 indicate mild cases, 1 1 -14 indicate moderate cases, and 15-21 indicate severe cases.

[0249]

[0070] The disclosed methods are carried out on subjects in need. For example, subjects in need of the 0X40 or OX40L inhibitor treatment or any of the disclosed methods may be those who report average Worst-Itch NRS > 7 based on electronic daily diary assessment the last 7 days prior to treatment. The subjects in need may also be those who have a history inadequate response to TCS of medium or higher potency for prurigo nodularis (with or without TCI as appropriate) or for whom TCS is otherwise medically inadvisable. Inadequate response may be defined as inability to achieve and / or maintain a low disease state (comparable to IGA CNPG-S score of < 2) despite treatment with a daily regimen of medium-to-super potent TCS (± TCI as appropriate) applied for at least 14 days (or for the maximum duration recommended by the product prescribing information or local guidelines, whichever is shorter). Subjects with any previous systemic treatment for prurigo nodularis or phototherapy for prurigo nodularis, independent of response, are also considered as inadequate responders to topical treatments and are also considered subject in need for 0X40 or OX40L inhibitor treatment or any of the disclosed methods.

[0250]

[0071] In certain embodiments, the 0X40 or OX40L inhibitor treatment or any of the methods disclosed herein results in a change in weekly average of daily Worst Itch Numeric Rating Scale (WI-NRS), as compared to a baseline in the subject in need. Preferably, the treatment results in a reduction of 1 point or more, 2 points or more, 3 points or more, or 4 points or more in the subject’s weekly average of daily WI-NRS score. The baseline may be the subject’s weekly average of daily WI-NRS score before treatment, or a pre-determined baseline value.

[0072] In certain embodiments, the 0X40 or OX40L inhibitor treatment or any of the methods disclosed herein results in a change in Investigator's Global Assessment for Chronic Nodular Prurigo-Stage (IGA CNPG-S) score, as compared to a baseline in the subject in need. The baseline may be the subject’s IGA CNPG-S score before treatment, or a pre-determined baseline value. Preferably, the treatment results in a subject’s IGA CNPG-S score being 0 (clear) or 1 (almost clear) (IGA CNPG-S 0 / 1 ).

[0251]

[0073] In certain embodiments, the 0X40 or OX40L inhibitor treatment or any of the methods disclosed herein results in a reduction in weekly average of daily WI-NRS score of 4 points or more, as compared to a baseline in the subject in need; and an IGA CNPG-S score of 0 (clear) or 1 (almost clear) (IGA CNPG-S 0 / 1 ). The baseline may be the subject’s weekly average of daily WI-NRS score before treatment, or a predetermined baseline value.

[0252]

[0074] In certain embodiments, the 0X40 or OX40L inhibitor treatment or any of the methods disclosed herein results in a change in Dermatology Life Quality Index (DLQI) score, as compared to a baseline. Preferably, the treatment results in a reduction in DLQI score of 1 point or more, 2 points or more, 3 points or more, or 4 points or more, as compared to a baseline in the subject in need. The baseline may be the subject’s DLQI score before treatment, or a pre-determined baseline value.

[0253]

[0075] In certain embodiments, the 0X40 or OX40L inhibitor treatment or any method disclosed herein results in a change in weekly average of daily prurigo nodularis skin pain NRS score, as compared to a baseline in a subject in need. Preferably, the treatment results in a reduction in weekly average of daily prurigo nodularis skin pain NRS score of 1 point or more, 2 points or more, 3 points or more, or 4 points or more, as compared to a baseline. The baseline may be the subject’s weekly average of daily prurigo nodularis skin pain NRS score before treatment, or a pre-determined baseline value.

[0254]

[0076] In certain embodiments, the 0X40 of OX40L inhibitor treatment or any method disclosed herein results in a change in weekly average of daily sleep disturbance-NRS score, as compared to a baseline in the subject in need. Preferably, the treatment results in a reduction in weekly average of daily sleep disturbance-NRS score of 1 point or more, 2 points or more, 3 points or more, or 4 points or more, as compared to a baseline. The baseline may be the subject’s in weekly average of daily prurigo nodularis skin pain NRS score before treatment, or a pre-determined baseline value.

[0255]

[0077] In certain embodiments, the 0X40 or OX40L inhibitor treatment or any of the methods disclosed herein results in a change in Investigator's Global Assessment for Chronic Nodular Prurigo-Activity (IGA CNPG-A) score, as compared to a baseline in the subject in need. The baseline may be the subject’s IGA CNPG-A score before treatment, or a pre-determined baseline value. Preferably, the treatment results in a subject’s IGA CNPG-A score being 0 (clear) or 1 (almost clear) (IGA CNPG-A 0 / 1 ).

[0078] In certain embodiments, the 0X40 or OX40L inhibitor treatment or any of the methods disclosed herein results in a change in Hospital Anxiety and Depression Scale (HADS) score, as compared to baseline in the subject in need. The baseline may be the subject’s Hospital Anxiety and Depression Scale (HADS) score before treatment, or is a pre-determined baseline value. In certain embodiments, the 0X40 or OX40L inhibitor treatment or any of the methods disclosed herein results in shows a change in HADS anxiety subscale score or in HADS depression subscale score, as compared to a baseline, in the subject in need. The baseline may be the subject’s HADS anxiety subscale score or HADS depression subscale score before treatment, or is a pre-determined baseline value.

[0256] 5. Articles of Manufacture

[0257]

[0079] Disclosed herein are articles of manufacture comprising: (a) a container comprising an 0X40 inhibitor or an OX40L inhibitor; and (b) a package insert with instructions for treating prurigo nodularis in a subject, as described in detail above. The instructions may specify the dosing regimen disclosed herein, including administering a dose of from about 150 mg to about 300 mg, once every 4 weeks (Q4W), with an additional loading dose of from about 150 mg to about 300 mg at week 2 (W2).

[0258] 6. Definitions

[0259]

[0080] The terms “treat” or “treatment” include prophylactic and / or therapeutic treatments. If it is administered prior to clinical manifestation of a condition, the treatment is considered prophylactic. Therapeutic treatment includes, e.g., ameliorating or reducing the severity of a disease, or shortening the length of the disease.

[0260]

[0081] “About” or “approximately,” when used in connection with a measurable numerical variable, refers to the indicated value of the variable and to all values of the variable that are within the experimental error of the indicated value (e.g. within the 95% confidence interval for the mean) or +10% of the indicated value, whichever is greater. Numeric ranges are inclusive of the numbers defining the range.

[0261]

[0082] As used herein, the singular forms “a,” “an,” and “the" designate both the singular and the plural, unless expressly stated to designate the singular only.

[0262] EXAMPLES

[0263] EXAMPLE 1. INTRODUCTION

[0264]

[0083] To date, there are only two United States Food and Drug Administration (US FDA), or European Medicines Agency (EMA) approved targeted therapy indicated for the treatment of prurigo nodularis (Dupilumab and Nemolizumab). However, around 61 % to 68% of patients do not respond sufficiently to dupilumab in both reduction in itch and lesions after 24 weeks of treatment. Therefore, there is still a large unmet need for novel biologic therapies with different mechanism of action and with improved safety profile for this population.

[0265]

[0084] Rocatinlimab is a recombinant, afucosylated, human immunoglobulin G subclass 1 (IgGt ) with kappa light chains, monoclonal antibody-targeting human 0X40 expressed on activated T cells.

[0266]

[0085] In a phase 2 multicenter, randomized, double-blind study in patients with Atopic dermatitis (AD) (Study 4083-006, consisting of an 18-week placebo-controlled treatment period, an 18 week treatment period, and a 20-week follow-up period, Guttman-Yassky et al., An anti-OX40 antibody to treat moderate- to-severe atopic dermatitis: a multicentre, double-blind, placebo controlled Phase 2b Study. Lancet. 2022 Dec 9:S0140-6736(22)02037-2), rocatinlimab decreased serum thymus and activation regulated chemokine, serum total immunoglobulin E (IgE), serum total interleukin 22 (IL 22), eosinophil, and lactate dehydrogenase (LDH) concentrations during the 36 week treatment period. Significant least-squares mean percent reductions in Eczema Area and Severity Index score at week 16 were observed in all rocatinlimab groups (rocatinlimab 150 mg every 4 weeks (Q4W) 48.3 [ 62.2 to 34.0], p = 0.0003; rocatinlimab 600 mg Q4W 49.7 [64.3 to 35.2], p = 0.0002; rocatinlimab 300 mg every 2 weeks (Q2W) 61.1 [ 75.2 to 47.0], p < 0.0001 ; and rocatinlimab 600 mg Q2W 57.4 [ 71 .3 to 43.4], p < 0.0001 ) vs placebo group ( 15.0 [95% Cl -28.6 to 1 .4]).

[0267]

[0086] Based on rocatinlimab mechanism of action of antagonizing OX40 / OX40L signaling, it can block and reduce the number of pathogenic activated T cells and decrease downstream production of several inflammatory cytokines and thereby, rocatinlimab has the potential to provide a therapeutic benefit for prurigo nodularis.

[0268] EXAMPLE 2. STUDY DESIGN

[0269]

[0087] This is a phase 3, 52-week, multicenter, randomized, placebo-controlled, double-blind study, designed to evaluate the efficacy, safety, and tolerability of rocatinlimab in adult subjects with prurigo nodularis, with > 20 prurigo nodularis nodules, who have not been controlled adequately with topical treatment, or who are not eligible for topical therapies. Treatment with previous systemic biologies or targeted small molecules is allowed with an adequate washout period. Subjects on stable use of TCS and / or TCI (TCS / TCI) may be able to continue the TCS / TCI application if they meet eligibility criteria and conditions of use.

[0270]

[0088] The maximum study duration for a single subject in the current study are approximately 68 weeks, including a screening period of up to approximately 4 weeks, a 52-week treatment period, and a 16-week safety follow-up (SFU) period after the last dose of investigational product at week 48.

[0089] Only the SC route of administration is used, which limits the risk of adverse effects associated with IV infusion. Overall, SC administration is associated with a lower incidence of systemic reactions and / or lower severity of acute reactions that tend to be local.

[0271]

[0090] Subjects who meet all eligibility criteria confirmed at the initial screening visit are assigned an electronic diary (eDiary) device where they are expected to complete daily questionnaires throughout the screening and treatment periods of the study. At the day 1 prerandomization visit, subjects who meet all eligibility criteria are randomized. Baseline randomization are stratified by baseline disease severity Investigator’s Global Assessment for Chronic Nodular Prurigo Stage (IGA CNPG-S score < 3 versus IGA CNPG-S score = 4) score, geographic region (Japan versus non-Japan Asian countries versus rest of world), and baseline stable use of TCS / TCI (yes or no), with block randomization strategy.

[0272]

[0091] Based on use of TCS / TCI assessed at screening visit, subjects are categorized into 1 of the

[0273] 2 groups. (1 ) Stable use of TCS / TCI: defined as stable TCS / TCI application, as measured by consistent frequency and potency usage for a minimum of 14 days without changes prior to initial screening visit, as assessed by the investigator. If subjects are on stable use of high potency or super-high potency TCS prior to initial screening visit, subjects should decrease potency to medium potency TCS minimum 7 days prior to day 1 and continue to apply per the same regimen until week 52. (2) Not on stable use of TCS / TCI: defined as absence of or ‘as needed’ usage of TCS / TCI during the 14 days prior to initial screening visit.

[0274] 1. Treatment Periods

[0275]

[0092] The 52 week treatment period includes: blinded treatment period A, blinded treatment period B, and an open label treatment period.

[0276] Blinded Treatment Period A (week 0 to week 24)

[0277]

[0093] Approximately 460 eligible subjects are randomized in a 2:2:1 ratio to 3 treatment groups for a duration of 24 weeks as follows:

[0278] • rocatinlimab 300 mg subcutaneous (SC) Q4W with a 300 mg loading dose at week 2;

[0279] • rocatinlimab 150 mg SC Q4W with a 150 mg loading dose at week 2;

[0280] • placebo SC Q4W with a placebo loading dose at week 2.

[0281] Blinded Treatment Period B (week 24 to week 52)

[0282] • At the week 24 visit, subjects continue their original treatment arms and enter the blinded treatment period B, if they meet either of following:

[0283] • subject achieves weekly average of daily Wl NRS > 3 point improvement compared to day 1 without worsening of IGA CNPG-S compared to day 1 ; • subject achieves IGA CNPG-S 0 / 1 without worsening of weekly average of daily Wl NRS compared to day 1 .

[0284] These subjects continue their original treatment arms as follows:

[0285] • rocatinlimab 300 mg SC;

[0286] • rocatinlimab 150 mg SC Q4W;

[0287] • placebo SC Q4W.

[0288] Open label Treatment Period (week 24 to week 52)

[0289]

[0094] At the week 24 visit, subjects in any of the 3 initial treatment groups are assigned to receive open label rocatinlimab 300 mg Q4W, if they do not qualify for continuation of the blinded treatments based on the above criteria.

[0290] 2. Optional Substudies

[0291]

[0095] Subjects from selected sites have the option to participate in a Biomarker Substudy, and / or Photography Substudy.

[0292] 3. Rescue Therapies for Prurigo Nodularis

[0293]

[0096] Allowed rescue therapies for prurigo nodularis are defined as those approved for treatment of prurigo nodularis as well as local standard of care. In the event of worsening and / or intolerable symptoms of prurigo nodularis, rescue therapies for prurigo nodularis may be given if deemed necessary by the investigator with limitations.

[0294] 4. Discontinuation of Study Treatment and Subject Discontinuation

[0295]

[0097] Subjects who permanently discontinue investigational product for any reason during the study are encouraged to complete all remaining visits and procedures with the exception of investigational product administration and post-dose monitoring procedures through week 52 for the evaluation of endpoints.

[0296]

[0098] Subjects who permanently discontinue investigational product and do not complete the remaining study visits through week 52 should complete an end of treatment (EOT) visit at the next scheduled visit following the last dose of the investigational product.

[0297] 5. Safety Follow up

[0298]

[0099] A SFU visit is required 16 weeks after the last dose of investigational product.

[0299] 6. Number of Subjects

[0300]

[0100] Approximately 460 subjects are to be enrolled in the study. 7. Objectives and Endpoints

[0301]

[0101] Objectives and Endpoints are summarized in Table 1 , and Exploratory endpoints are summarized in Table 2.

[0302] Table 1

[0303] Table 2

[0304] 8. Justification for Dose

[0305]

[0102] This study is to investigate rocatinlimab 150 mg Q4W for 52 weeks with an additional 150 mg dose on week 2 and 300 mg Q4W for 52 weeks with an additional 300 mg dose on week 2. Doses were selected based on exposure-response modeling to extrapolate from the observed pruritus Numerical Rating Score (NRS) score in AD to prurigo nodularis.

[0306]

[0103] A phase 2b dose ranging study was conducted in the Atopic Dermatitis (AD) indication. In Study 4083-006 (described above in Example 1 ), 3 dose levels and 2 dosing frequencies (150 mg Q4W, 600 mg Q4W, 300 mg every 2 weeks [Q2W], and 600 mg Q2W) were tested for induction. Both change and percent change from baseline to week 16 in pruritus NRS score were numerically greater in all 4 dose groups of rocatinlimab compared to the placebo group. The 150 mg Q4W (p <0.05) and doses above 300 mg Q2W (p < 0.001 ) were statistically superior to placebo for the percentage of subjects with a pruritus NRS score reduction from baseline of > 4-points.

[0307]

[0104] A pharmacokinetic / pharmacodynamic (PK / PD) model was developed using the exposure-pruritus NRS relationship observed in the phase 2 AD study (Study 4083-006) to predict > 4-point reduction in pruritus NRS score.

[0308]

[0105] The modeling predicts that 300 mg Q4W results in a clinically significant meaningful proportion of subjects with a > 4-point reduction in pruritus NRS score. Doses higher than 300 mg Q4W are expected to provide a similar pruritus NRS score response. The 150 mg Q4W is predicted to provide a numerically lower median response pruritus NRS score than the 300 mg Q4W dosing regimen. A single additional dose of the same strength (150 mg for the 150 mg Q4W regimen or 300 mg for the 300 mg Q4W regimen) administered at week 2 is planned to reduce the time to attain steady state concentrations and enhance the pharmacodynamic effect during the first month of treatment. Therefore, based on modeling and simulations, 300 mg Q4W with a 300 mg loading dose at week 2 and 150 mg Q4W with a 150 mg loading dose at week 2 are the selected doses for this phase 3 prurigo nodularis trial.

[0309] 9. Inclusion Criteria

[0310]

[0106] Subjects are eligible to be included in the study only if all the following criteria apply:

[0311] • Subject or the subject's legally authorized representative (if allowed, depending on the country concerned) has provided informed consent before initiation of any study-specific activities / procedures.

[0312] • Age > 18 years (or > legal age within the country if it is older than 18 years).

[0313] • A clinical diagnosis of prurigo nodularis (as defined by core symptoms according to the United States expert panel consensus (Elmariah et al, Practical approaches for diagnosis and management of prurigo nodularis: United States expert panel consensus. J Am Acad Dermatol. 2021 Mar;84(3):747-760), that has been present for at least 3 months before signing of informed consent. The prurigo nodularis defined core symptoms include pruritus for more than 6 weeks, evidence of chronic scratching, and presence of multiple pruriginous lesions and excoriated nodules.

[0314] • Patient-reported average Worst-Itch NRS > 7 based on electronic daily diary assessment the last 7 days prior to day 1 , at day 1 prerandomization.

[0315] • Has > 20 prurigo nodularis nodules in total with bilateral distribution on both legs, and / or both arms and / or trunk at initial screening and at day 1 prerandomization.

[0316] • Prior to informed consent, history of inadequate response to TCS of medium or higher potency for prurigo nodularis (with or without TCI as appropriate) or for whom TCS is otherwise medically inadvisable (eg, because of important side effects or safety risks). a. Inadequate response is defined as inability to achieve and / or maintain a low disease state (comparable to IGA CNPG-S score of < 2) despite treatment with a daily regimen of medium-to-super potent TCS (± TCI as appropriate), applied for at least 14 days (or for the maximum duration recommended by the product prescribing information or local guidelines, whichever is shorter). b. Subjects with any previous systemic treatment for prurigo nodularis or phototherapy for prurigo nodularis, independent of response, are also considered as inadequate responders to topical treatments and are potentially eligible to be included in the study after appropriate washout.

[0317]

[0107] Subject must have completed at least 4 days of daily diary entries within the 7 days preceding and including day 1 prerandomization.

[0318] 10. Exclusion Criteria

[0319]

[0108] Subjects are excluded from the study if any of the following criteria apply:

[0320] 10.1 Disease Related

[0321]

[0109] Skin or systemic morbidities, other than prurigo nodularis, that have been active or requiring treatment within the last 3 months, that interfere with the assessment of study outcomes, including but not limited to:

[0322] • atopic dermatitis (signs or symptoms other than dry skin or requiring treatment is not allowed; use of emollients and / or history of AD is allowed)

[0323] • a-1 antitrypsin deficiency

[0324] • bullous autoimmune disease

[0325] • coeliac disease

[0326] • cholestatic liver disease (eg, primary biliary cirrhosis)

[0327] • contact dermatitis

[0328] • folliculitis

[0329] • habitual picking / excoriation disorder

[0330] • hidradenitis suppurativa

[0331] • insect bites

[0332] • iron deficiency anemia

[0333] • lichen planus

[0334] • lichen simplex chronicus

[0335] • obstructive biliary disease

[0336] • psoriasis

[0337] • scabies

[0338] • uncontrolled thyroid disease

[0339] • venous stasis

[0110] Prurigo nodularis secondary to medications

[0340]

[0111] Prurigo nodularis secondary to neurologic or psychiatric medical conditions (e.g., notalgia paresthetica, brachioradial pruritus, neurotic excoriations, obsessive compulsive disorder, delusional parasitosis).

[0341] 10.2 Other Medical Conditions

[0342]

[0112] Active malignancy; multiple myeloma; myeloproliferative or lymphoproliferative disorder; or a history of any of these conditions within 5 years prior to informed consent (except curatively treated in situ cervical carcinoma, cutaneous basal cell carcinoma, or cutaneous squamous cell carcinoma).

[0343]

[0113] History of major immunologic reaction (e.g., serum sickness, anaphylaxis, or anaphylactic reaction) to any other biologic product or any excipient of rocatinlimab.

[0344]

[0114] Known sensitivity to any of the products or components to be administered during dosing.

[0345]

[0115] Diagnosis of a helminth parasitic infection within 6 months prior to day 1 prerandomization that had not been treated with or had failed to respond to standard of care therapy.

[0346]

[0116] Evidence of human immunodeficiency virus (HIV) infection or positive for HIV antibodies at initial screening or current acquired, common variable or inherited, primary or secondary immunodeficiency.

[0347]

[0117] Positive for hepatitis C virus (HCV) antibody at initial screening with confirmed positive HCV RNA.

[0348]

[0118] Active and non-virally suppressed hepatitis B infection at initial screening, defined as detectable hepatitis B DNA polymerase chain reaction (PCR) test in a subject with detectable hepatitis B Surface Antigen (HBsAg) and / or antibodies to hepatitis B core (anti-HBc). Subjects with detectable HBsAg are required to be viral ly suppressed with an approved hepatitis B antiviral therapy during the study (For sites and subjects participating in the European Economic Area [EEA],

[0349]

[0119] Positive or indeterminate QuantiFERON GOLD from central laboratory at initial screening

[0350] • Exception: A positive or indeterminate QuantiFERON test is allowed if ALL of the following are present at day 1 prerandomization per Screening Tuberculosis (TB) Risk Assessment Questionnaire provided by Amgen: no symptoms of TB

[0351] - documented history of a completed course of adequate prophylaxis (completed treatment for latent TB per local standard of care prior to start of investigational product)

[0352] - no known exposure to a case of active TB after most recent prophylaxis - no evidence of active TB on chest radiograph (chest X-ray or computer tomography) obtained within 3 months prior to day 1 prerandomization

[0353]

[0120] Active chronic or acute infection requiring treatment with systemic antibiotics, antiviral, antiparasitic, antiprotozoal, or antifungals within 4 weeks before day 1 prerandomization.

[0354]

[0121] Superficial skin infection within 2 weeks before day 1 prerandomization.

[0355]

[0122] Major psychiatric illness, (such as, but not limited to, major depressive disorder, schizophrenia, or bipolar disorder) within 1 year before day 1 prerandomization.

[0356]

[0123] Inpatient psychiatric admission within 1 year before day 1 prerandomization.

[0357]

[0124] Change in psychiatric medication for a psychiatric illness within 8 weeks before day 1 prerandomization.

[0358]

[0125] Anticipated need to change psychiatric medication for a psychiatric illness during the study.

[0359]

[0126] History of suicide attempts or suicidal ideation evidenced by endorsing items 4 or 5 of the electronic Columbia-Suicide Severity Scale (eC-SSRS) Findings Report within the last 6 months assessed at initial screening.

[0360]

[0127] Recent suicide attempt or suicidal ideation as evidenced by endorsing items 4 or 5 on the Since Last Contact eC-SSRS Findings Report assessed at day 1 prerandomization.

[0361]

[0128] History of alcohol or substance abuse within 6 months prior to initial screening.

[0362]

[0129] Any of the following laboratory abnormalities at initial screening:

[0363] • estimated glomerular filtration rate (eGFR) < 30 mL / min / 1 .73 m2

[0364] • aspartate aminotransaminase (AST) or alanine aminotransaminase (ALT):32.5 times the upper limit of normal (ULN)

[0365] • neutrophil count: < 1 .5 x 103 / pL (Exception: neutrophil count: < 1 .0 x 103 / pL in cases of documentation of a combined diagnosis of Benign Ethnic Neutropenia [BEN])

[0366]

[0130] History of New York Heart Association class lll / IV heart failure; diagnosis of uncontrolled hypertension (systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg) at initial screening; or inadequately treated cardiovascular conditions at initial screening including: cardiomyopathy, major congenital heart disease, or second or third-degree atrioventricular block.

[0367]

[0131] Recent cardiovascular events including cerebrovascular accident, myocardial infarction, coronary stenting, or unstable angina within 6 months of day 1 prerandomization.

[0132] A QT interval corrected by Fridericia's correction (QTcF) of > 450 msec in males or > 470 msec in females at initial screening as assessed by the investigator, or history of long QT syndrome.

[0368]

[0133] Subjects with the following signs or symptoms of Gl disease during the screening period: chronic diarrhea, bloody stool, bowel urgency, chronic or recurrent abdominal pain, unless evaluated by a gastroenterologist to exclude factors that may increase the risk of Gl ulceration or perforation (e.g,

[0369] H pylori infection, evidence of active IBD, previously undiagnosed chronic gastritis).

[0370]

[0134] Subjects with IBD, including those secondary to Crohn’s disease or ulcerative colitis, unless confirmed to be in a state of quiescence by a gastroenterologist prior to day 1 (pre-randomization).

[0371]

[0135] Subjects with any history of Gl tract ulcers, beyond the oral mucosa (for IBD, Crohn’s disease, and / or ulcerative colitis).

[0372]

[0136] History or evidence of any other clinically significant disorder, condition, or disease that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety, or interfere with the study evaluation, procedures or completion.

[0373] 10.3 Prior / Concomitant Therapy

[0374]

[0137] Subjects on prior stable use of TCS / TCI at screening visit are excluded if either of the following 2 criteria are met: a. Initiate treatment with high or super-high potency or increase to high or super-high potency of TCS during the screening period as compared with the stable use. b. Failure to decrease potency to medium potency TCS, at the screening visit, in participants who are on stable use of high potency or super-high potency TCS prior to screening. c. Change in the frequency of application of TCS / TCI during the screening period as compared with the stable use. d. Failure to have a minimum of 14 consecutive days of consistent frequency and potency usage without changes immediately prior to screening visit for each TCS / TCI medication.

[0375]

[0138] Subjects not on stable use of TCS or TCI at the screening visit are excluded if they use any treatment with TCS (any potency) or TCI during the screening period.

[0376]

[0139] Treatment with any systemic biologic immunosuppressive or systemic biologic immunomodulatory therapy for prurigo nodularis or any other autoimmune, inflammatory, or allergic disease within 12 weeks or 5 half-lives, whichever is longer, prior to day 1 prerandomization.

[0140] Any cell depletion therapy within 12 months from initial screening or until cell count returns to normal before screening, whichever is longer.

[0377]

[0141] Treatment with any of the following medications or therapies within 4 weeks or 5 half-lives, whichever is longer, prior to day 1 prerandomization:

[0378] • systemic or intralesional corticosteroids (inhaled corticosteroids, intra-articular local [i.e., bursa, tendons, and ligaments] corticosteroid injection for non-atopic dermatitis related conditions, eye, ear, or nasal drops containing corticosteroids are allowed), while suppositories, or enemas containing corticosteroids are not allowed

[0379] • systemic treatment with methotrexate, mycophenolate, mycophenolic acid, cyclosporine, calcineurin inhibitors, azathioprine, sulfasalazine, hydroxychloroquine, dapsone, colchicine, thalidomide, or other non-biologic, non-targeted systemic immunosuppressants and immunomodulatory therapies

[0380] • systemic treatment with opioid antagonist (e.g., naltrexone, naloxone), opioid partial / mixed agonists (e.g., nalbuphine, butorphanol), or opioid agonist (except when used for short term / acute pain); NK1 receptor antagonist (e.g., aprepitant, serlopitant)

[0381] • systemic treatment with gabapentin, pregabalin, and thalidomide

[0382] • phototherapy, including tanning beds

[0383] • oral or topical targeted immunomodulators (e.g., janus kinase [JAK] inhibitor)

[0384] • cryotherapy for prurigo nodularis

[0385] • laser therapy for prurigo nodularis

[0386]

[0142] Having initiated treatment with any of the following treatments for prurigo nodularis or changed the dose of the following treatments for prurigo nodularis within 3 months before the screening visit or expecting the dose of the following treatments to be changed throughout the study:

[0387] • paroxetine, fluvoxamine, or other selective serotonin reuptake inhibitors (SSRIs)

[0388] • serotonin and norepinephrine reuptake inhibitors (SNRIs)

[0389] • amitriptyline or other tricyclic or tetracyclic antidepressants

[0390] • pregabalin, gabapentin, and other gabapentinoids

[0391]

[0143] Treatment with any of the following agents within 1 week before day 1 prerandomization:

[0392] • topical anesthetics

[0393] • topical calcipotriene

[0394] • topical capsaicin

[0395] • topical phosphodiesterase inhibitors

[0396] • other topical immunosuppressive

[0397] • combination agents including any of the above

[0144] Treatment with live virus including live attenuated vaccination 12 weeks prior to day 1 prerandomization. Inactivated vaccination (eg, nonlive or nonreplicating agent) including COVID-19 vaccination, is allowed.

[0398] 10.4 Prior / Concurrent Clinical Study Experience

[0399]

[0145] Currently receiving treatment in another investigational device or drug study, or less than 30 days (16 weeks for Japan) or 5 half-lives, whichever is longer, since ending treatment on another investigational device or drug study(ies) prior to day 1 prerandomization.

[0400]

[0146] Ongoing investigational procedures or participation in observational research studies at screening visit or day 1 prererandomization, or planned such procedures or participation during the participation in this study.

[0401]

[0147] Previous participation in a study including rocatinlimab or any therapy selectively targeting OX40 / OX40L and receipt of active investigational product

[0402] 10.5 Other Exclusions

[0403]

[0148] Female subjects of childbearing potential unwilling to use protocol-specified method of contraception during treatment and for an additional 16 weeks after the last dose of investigational product.

[0404]

[0149] Female subjects who are breastfeeding or who plan to breastfeed while on study through 16 weeks after the last dose of investigational product.

[0405]

[0150] Female subjects planning to become pregnant while on study through 16 weeks after the last dose of investigational product.

[0406]

[0151] Female subjects of childbearing potential with a positive pregnancy test assessed at screening or day 1 prerandomization by a highly sensitive urine or serum pregnancy test.

[0407]

[0152] Subject likely to not be available to complete all protocol-required study visits or procedures, and / or to comply with all required study procedures (e.g., illiterate or partially sighted / blind and unable to complete Clinical Outcome Assessments (COAs)] to the best of the subject and investigator’s knowledge).

[0408]

[0153] Subjects falling under the vulnerable population definition (prisoners, institutionalized individuals, adult subjects under legal protection measures [judicial protection or guardianship measures] or others who may be considered vulnerable).

[0154] Subjects planning to donate eggs while on study through 16 weeks after the last dose of investigational product.

[0409] EXAMPLE 3. EFFICACY ASSESSMENTS

[0410]

[0155] Efficacy assessments should be collected on an electronic device and completed at scheduled visits at the time points indicated in the Schedule of Activities.

[0411]

[0156] The following assessments are to be completed:

[0412]

[0157] Worst Itch Numeric Rating Scale. The WI-NRS is a patient reported outcome (PRO) comprised of a single item rated on an 11 -point scale from 0 (“No itch”) to 10 (“Worst imaginable itch"). The WI-NRS is completed daily as part of the electronic daily diary assessment.

[0413]

[0158] Prurigo Nodularis Skin Pain Numeric Rating Scale. In the electronic daily diary assessment, subjects report the severity of prurigo nodularis skin pain over the past 24 hours.

[0414]

[0159] Sleep Disturbance Numeric Rating Scale. In the electronic daily diary assessment, subjects report the quality of their sleep over the past 24 hours.

[0415]

[0160] Dermatology Life Quality Index. The Dermatology Life Quality Index (DLQI) is a 10-item, selfadministered questionnaire, and is designed to measure the health-related quality of life of adult subjects suffering from skin disease. The DLQI measures subjects' perception of the impact of skin diseases on different aspects of their health-related quality of life over the last week.

[0416]

[0161] EuroQol-5 Dimension-5 Level. The EuroQol-5 Dimension-5 Level (EQ-5D-5L) questionnaire is a 2- page, standardized instrument for use as a measure of health outcome developed by the EuroQol group (Rabin et al., 2001 ). The visual analogue scale (VAS) records the subject's self-rated health on a vertical, VAS where the endpoints are labelled 'Best imaginable health state' and 'Worst imaginable health state'.

[0417]

[0162] Work Productivity and Activity Impairment for Prurigo Nodularis. The Work Productivity and Activity Impairment (WPAI): Prurigo Nodularis questionnaire is an instrument to measure impairments in both paid work and unpaid work. It measures absenteeism, presenteeism as well as the impairments in unpaid activity because of health problems during the past 7 days.

[0418]

[0163] Patient Global Impression of Severity. The Patient Global Impression of Severity (PGI-S) is designed to capture the subject’s perception of change in symptom severity at the time of completion on a categorical response scale. There are 3 PGI-S items: worst itch, prurigo nodularis skin pain, and sleep disturbance.

[0164] Patient Global Impression of Change. The Patient Global Impression of Change (PGI-C) is designed to capture the subject’s perception of change in symptom severity since starting study treatment at the time of completion. The assessment uses a 7-point rating scale, very much better to very much worse. There are 3 PGI-C items: worst itch, prurigo nodularis skin pain, and sleep disturbance.

[0419]

[0165] Assessments Completed by Investigator. Clinical evaluations of prurigo nodularis should be performed by an experienced and qualified dermatologist (board certified or equivalent) with experience in the conduct of clinical trials, or by an experienced and qualified medical professional with experience in the conduct of prurigo nodularis clinical trials when designated by the primary site investigator. The evaluator must receive and document protocol specific and applicable efficacy assessment scales training prior to performing these evaluations. To assure consistency and reduce variability, the same evaluator must assess all dermatological clinical evaluations for any individual subject throughout the study whenever possible; a back-up experienced and qualified, protocol-trained evaluator will only be allowed and documented in case of emergency or special situations when the designated evaluator is unable to perform the evaluation.

[0420]

[0166] Investigator’s Global Assessment for Prurigo Nodularis Stage. The IGA CNPG S is a validated assessment instrument used in clinical studies to rate the stage of the disease using a 5-point scale from 0 (clear) to 4 (severe) (Zeidler et al., 2021 ).

[0421]

[0167] Investigator’s Global Assessment for Prurigo Nodularis Activity. The Investigator’s Global Assessment for Prurigo Nodularis Activity (IGA CNPG A) is a validated assessment instrument used in clinical studies to rate the activity of the disease using a 5-point scale from 0 (clear) to 4 (severe) (Zeidler et al., 2021 ).

[0422]

[0168] Prurigo Activity and Severity Score. The Prurigo Activity and Severity Score (PAS) is a clinician reported outcome measurement. The original PAS questionnaire Version 0.9 consists of 7 items, developed by expert clinicians in prurigo nodularis (Polking et al, Prurigo Activity Score (PAS): validity and reliability of a new instrument to monitor chronic prurigo; J Eur Acad Dermatol Venereol., 2018 Oct;32(10):1754-1760). A 5-item simplified version of the PAS are used in the this study. In particular, Item 3 (lesion distribution) and Item 6 (lesion monitoring) of the original PAS were removed, and the response options slightly modified and refined.

[0423] EXAMPLE 4. STATISTICAL CONSIDERATIONS

[0424]

[0169] The primary hypothesis is that either rocatinlimab 300 mg or 150 mg is superior to placebo as treatment in adult subjects with prurigo nodularis who are inadequately controlled on topical therapies or not eligible for topical therapies, as assessed by the primary endpoint of achieving > 4-point reduction from baseline in weekly average of daily WI-NRS score at week 24. This primary endpoint needs to achieve statistical significance for either rocatinlimab dose to declare study success.

[0170] Approximately 460 subjects will be randomized in 2:2:1 ratio to 3 treatment groups as follows:

[0425] • rocatinlimab 300 mg Q4W with a 300 mg loading dose at week 2 (N = 184)

[0426] • rocatinlimab 150 mg Q4W with a 150 mg loading dose at week 2 (N = 184)

[0427] • placebo Q4W with a placebo loading dose at week 2 (N = 92)

[0428]

[0171] Assuming an even split of family wise alpha 0.01 between the 2 doses, approximately 460 subjects with 2:2:1 randomization ratio will provide around 90% power to detect a treatment difference of approximately 24.5%, assuming placebo response rate at 20%, for achieving > 4 point reduction from baseline in weekly average of daily Wl NRS score at week 24. The same sample size also provides around 90% power to detect a treatment difference of approximately 21 .5% for achieving > 4 point reduction from baseline in weekly average of daily Wl NRS score and achieving an IGA CNPG S 0 / 1 at week 24 with placebo response rate assumed at 10%.

[0429]

[0172] The specification is most thoroughly understood in light of the teachings of the references cited within the specification. The embodiments within the specification provide an illustration of embodiments of the invention and should not be construed to limit the scope of the invention. The skilled artisan readily recognizes that many other embodiments are encompassed by the invention. All publications, patents, and sequences cited in this disclosure are incorporated by reference in their entirety. To the extent the material incorporated by reference contradicts or is inconsistent with this specification, the specification will supersede any such material. The citation of any references herein is not an admission that such references are prior art to the present invention.

[0430]

[0173] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following embodiments.

Claims

CLAIMS1 . A method for treating prurigo nodularis (PN), comprising administering to a subject in need thereof an anti-OX40 antibody at a dose of 150 mg to 300 mg, once every 4 weeks (Q4W) for at least 12 weeks, and an additional loading dose of the anti-OX40 antibody at a dose of 150 mg to 300 mg at week 2 (W2); wherein said anti-OX40 antibody comprises: (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 31 ; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 32.

2. A method for treating prurigo nodularis (PN), comprising administering to a subject in need thereof an anti-OX40 antibody at a dose of 150 mg to 300 mg, once every 4 weeks (Q4W) for at least 12 weeks, and an additional loading dose of the anti-OX40 antibody at a dose of 150 mg to 300 mg at week 2 (W2); wherein said anti-OX40 antibody comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:33, 37, 38, or a combination thereof; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 34.

3. A method for treating prurigo nodularis (PN), comprising: during a first phase, administering to a subject in need thereof an anti-QX40 antibody at a dose of 150 mg to 300 mg, once every 4 weeks (Q4W), and an additional loading dose of anti-QX40 antibody at a dose of 150 mg to 300 mg at week 2 (W2); and during a second phase, administering to said subject the anti-QX40 antibody at a dose of 150 mg to 300 mg once every 8 weeks (Q8W), once every 12 weeks (Q12W), or once every 16 weeks (Q16W); wherein said anti-QX40 antibody comprises: i) (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 31 ; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 32; or ii) (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:33, 37, 38, or a combination thereof; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 34.

4. The method of any one of claims 1 -3, wherein said anti-QX40 antibody is administered at a dose of 150 mg once every 4 weeks (Q4W) for at least 12 weeks, with an additional loading dose of 150 mg at week 2 (W2).5.. The method of any one of claims 1 -3, wherein said anti-QX40 antibody is administered at a dose of 200 mg once every 4 weeks (Q4W) for at least 12 weeks, with an additional loading dose of 200 mg at week 2 (W2).

6. The method of any one of claims 1 -3, wherein said anti-OX40 antibody is administered at a dose of 250 mg once every 4 weeks (Q4W) for at least 12 weeks, with and an additional loading dose of 250 mg at week 2 (W2).

7. The method of any one of claims 1 -3, wherein said anti-OX40 antibody is administered at a dose of 300 mg once every 4 weeks (Q4W) for at least 12 weeks, with an additional loading dose of 300 mg at week 2 (W2).

8. The method of any one of claims 1 -7, wherein said anti-OX40 antibody is administered for at least 24 weeks.

9. The method of any one of claims 1 -8, wherein said anti-OX40 antibody is administered subcutaneously.

10. The method of any one of claims 1 -9, wherein said subject shows a change in weekly average of daily Worst Itch Numeric Rating Scale (WI-NRS) score after one or more doses of said anti-OX40 antibody have been administered, as compared to a baseline.1 1 . The method of claim 10, wherein said subject’s weekly average of daily Worst Itch Numeric Rating Scale (WI-NRS) score is reduced by 4 points or more after one or more doses of said anti-OX40 antibody have been administered, as compared to a baseline.

12. The method of any one of claims 1 -1 1 , wherein said subject shows a change in Investigator's Global Assessment for Chronic Nodular Prurigo-Stage (IGA CNPG-S) score after one or more doses of said anti-OX40 antibody have been administered, as compared to a baseline.

13. The method of claim 12, wherein said subject’s IGA CNPG-S score is 0 (clear) or 1 (almost clear) (IGA CNPG-S 0 / 1 ) after one or more doses of said anti-OX40 antibody have been administered.

14. The method of any one of claims 1 -13, wherein said subject shows a change in Dermatology Life Quality Index (DLQI) score after one or more doses of said anti-OX40 antibody have been administered, as compared to a baseline.

15. The method of claim 14, wherein said subject shows a reduction in DLQI score of 4 points or more after one or more doses of said anti-QX40 antibody have been administered, as compared to a baseline.

16. The method of any one of claims 1 -15, wherein said subject shows a change in weekly average of daily prurigo nodularis skin pain NRS score after one or more doses of said anti-QX40 antibody have been administered, as compared to a baseline.

17. The method of claim 16, wherein said subject shows a reduction in weekly average of daily prurigo nodularis skin pain NRS score of 4 points or more after one or more doses of said anti-OX40 antibody have been administered, as compared to a baseline.

18. The method of any one of claims 1 -17, wherein said subject shows a change in weekly average of daily sleep disturbance-NRS score after one or more doses of said anti-OX40 antibody have been administered, as compared to a baseline.

19. The method of claim 18, wherein said subject shows a reduction in weekly average of daily sleep disturbance-NRS score of 4 points or more after one or more doses of said anti-OX40 antibody have been administered, as compared to a baseline.

20. The method of any one of 1 -19, wherein said subject shows a change in Hospital Anxiety and Depression Scale (HADS) score after one or more doses of said anti-OX40 antibody have been administered, as compared to baseline.21 . The method of 20, wherein said subject shows a change in HADS anxiety subscale score or in HADS depression subscale score after one or more doses of said anti-OX40 antibody have been administered, as compared to a baseline.

22. An article of manufacture comprising:(1 ) a container comprising an anti-OX40 antibody that comprises: i) (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:33, 37, 38, or a combination thereof; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 34; orII) (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 31 ; and (b) a light chain variable comprising the amino acid sequence of SEQ ID NO: 32; and(2) a package insert with instructions for treating prurigo nodularis in a subject in need thereof, comprising administering to a subject in need thereof an anti-QX40 antibody at a dose of 150 mg to 300 mg, once every 4 weeks (Q4W) for at least 12 weeks, and an additional loading dose of150 mg to 300 mg at week 2 (W2).

Images