Methods of treating psoriasis

Abstract

The present invention relates generally to a dosage regimen for psoriasis treatment with antibodies that bind to the p19 subunit of human IL-23, in particular for treatment of this disease.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201980056973.8, the filing date of the original application is September 5, 2019, and the title is "Methods for Treating Psoriasis".

[0002] The present invention generally relates to methods of treating inflammatory diseases (such as psoriasis) with antibodies that bind to the p19 subunit of human IL-23.

[0003] Psoriasis is a chronic, immune-mediated inflammatory skin disease with a global incidence of approximately 2%, a high incidence, and can have a significant psychosocial impact on the quality of life and health of patients. Plaque psoriasis is the most common form, affecting approximately 80-90% of patients, presenting as raised plaques on the skin; the disease usually begins in late adolescence and early adulthood and may persist into adulthood. The extent of the affected body surface area (BSA) and the degree of skin manifestations (including erythema, induration, and scale) define the severity of psoriasis, and approximately 20-30% of patients have moderate to severe psoriasis.

[0004] Histologically, psoriasis is characterized by inflammatory infiltrates and hyperproliferative keratinocytes that retain intact nuclei (parakeratosis), elongated rete ridges, and excessive coiling of the vascular system in the papillary dermis. The infiltrates in the dermis include prominent T cells, dendritic cells (DCs), and neutrophils. Dysregulation of the immune system, particularly the activation of pathogenic T cells, has been shown to play an important role in the development of psoriasis.

[0005] Psoriasis is a prototypical organ-specific T cell-driven inflammatory disease that has been considered a T helper (Th)1-type skin disease for decades until the identification of the new Th17 population (Steinman L, Nat Med., 13(2), pp139-145, 2007). A large number of clinical and laboratory findings have shown that the interleukin (IL)-23 / Th17 axis is essential in the pathogenesis of psoriasis (Di Cesare et al., J Invest Dermatol., 129(6), pp1339-1350, 2009). IL-23, a member of the IL-12 cytokine family, is a heterodimeric protein composed of two subunits; the p40 subunit is shared with IL-12, and the p19 subunit is thought to be specific for IL-23. IL-23 is produced by antigen-presenting cells such as dendritic cells (DCs) and macrophages and plays an important role in the maintenance and expansion of Th17 cells (Lee et al., J Exp Med., 199(1), pp125-130, 2004). In addition, the levels of Th17 cells and their downstream effector molecules, including IL-17A, IL-17F, IL-21, IL-22, and tumor necrosis factor α (TNF-α), are elevated in human psoriatic skin lesions and circulation (Boniface et al., Clin Exp Immunol., 150(3), pp407-415, 2007; Kagami et al., J Invest Dermatol., 130(5), pp1373-1383, 2010).

[0006] Treatment of psoriasis with biologic therapies, particularly drugs targeting the IL-23 / Th17 axis, has been shown to have clinical activity in psoriasis patients (Crow JM, Nature, 492(7429), S58-S59, 2012). Agents specifically targeting the IL-23 p19 subunit have shown clinical activity in psoriasis (Kopp et al., Nature,, 14175, 2015).

[0007] Treatment options for psoriasis need to produce favorable outcomes in patients, such as in terms of treatment efficacy, safety, and / or tolerability.

[0008] The present invention addresses the above needs and provides methods for treating inflammatory diseases, particularly methods comprising administering an anti-IL-23 p19 antibody to a patient in a certain amount and / or at certain intervals. In one aspect, the present invention provides a method for treating psoriasis, which comprises administering mirikizumab to a patient, the method comprising: a) administering to the patient at least one induction dose of mirikizumab, wherein the induction dose comprises 20 mg - 600 mg of mirikizumab; and

[0009] b) Administering to the patient at least one maintenance dose of mirikizumab after the last induction dose, wherein the maintenance dose comprises 20 mg - 600 mg of mirikizumab.

[0010] In an embodiment of the present invention, the psoriasis is moderate to severe plaque psoriasis.

[0011] In another embodiment of the present invention, the psoriasis is scalp psoriasis.

[0012] In another embodiment of the present invention, the patient has not received biotherapy. In an alternative embodiment of the method of the present invention, the patient has received biotherapy.

[0013] In yet another embodiment of the present invention, the at least one induction dose comprises 20 mg, 30 mg, 60 mg, 100 mg, 120 mg, 125 mg, 250 mg, 300 mg, 350 mg, 400 mg or 600 mg of mirikizumab.

[0014] Preferably, the at least one induction dose comprises 250 mg of mirikizumab.

[0015] In yet another embodiment of the present invention, one, two, three or four induction doses are administered to the patient.

[0016] Preferably, two induction doses are administered to the patient every 8 weeks.

[0017] Alternatively, preferably, three induction doses are administered to the patient every 4 weeks.

[0018] More preferably, four induction doses are administered to the patient every 4 weeks.

[0019] In yet another embodiment of the present invention, the at least one induction dose is administered subcutaneously.

[0020] In yet another embodiment of the present invention, the at least one maintenance dose comprises 20 mg, 30 mg, 100 mg, 120 mg, 125 mg, 250 mg, 300 mg, 350 mg, 400 mg or 600 mg of mirikizumab.

[0021] Preferably, the at least one maintenance dose comprises 125 mg or 250 mg of mirikizumab.

[0022] In yet another embodiment of the present invention, at least one maintenance dose is administered 2 - 16 weeks after the last induction dose.

[0023] In yet another embodiment of the present invention, at least one maintenance dose is administered 2, 3, 4, 5, 6, 7, 8, 12, or 16 weeks after the last induction dose.

[0024] Preferably, at least one maintenance dose is administered 4 weeks after the last induction dose.

[0025] Alternatively preferably, at least one maintenance dose is administered 8 weeks after the last induction dose.

[0026] Further optionally preferably, at least one maintenance dose is administered 12 weeks after the last induction dose.

[0027] Even more preferably, at least one maintenance dose is administered 16 weeks after the last induction dose.

[0028] In yet another embodiment of the present invention, multiple maintenance doses are administered to a patient, and a first maintenance dose is administered 2 - 16 weeks after the last induction dose.

[0029] In yet another embodiment of the present invention, a first maintenance dose is administered 2, 3, 4, 5, 6, 7, 8, 12, or 16 weeks after the last induction dose.

[0030] Preferably, a first maintenance dose is administered 4 weeks after the last induction dose.

[0031] Alternatively, preferably, a first maintenance dose is administered 8 weeks after the last induction dose.

[0032] Further optionally preferably, a first maintenance dose is administered 12 weeks after the last induction dose.

[0033] Even more preferably, a first maintenance dose is administered 16 weeks after the last induction dose.

[0034] In yet another embodiment of the present invention, one or more further maintenance doses are administered every 4, 8, or 12 weeks after the first maintenance dose.

[0035] Preferably, one or more further maintenance doses are administered every 4 weeks.

[0036] Alternatively preferably, one or more further maintenance doses are administered every 8 weeks.

[0037] Further optionally preferably, one or more further maintenance doses are administered every 12 weeks.

[0038] In yet another embodiment of the present invention, the maintenance dose is administered by subcutaneous injection.

[0039] In a preferred embodiment of the present invention, the method for treating psoriasis comprises:

[0040] a) administering to the patient by subcutaneous injection (i) two, three or four induction doses of mirikizumab, wherein each induction dose comprises 250 mg of mirikizumab; and

[0041] b) administering to the patient by subcutaneous injection at least one maintenance dose of mirikizumab every 4 weeks or 8 weeks, wherein the first maintenance dose is administered 4 weeks or 8 weeks after the last induction dose, and wherein each maintenance dose comprises 125 mg or 250 mg of mirikizumab,

[0042] wherein the psoriasis is moderate to severe plaque psoriasis.

[0043] Preferably, two induction doses of mirikizumab are administered 8 weeks apart, and the first maintenance dose is administered 8 weeks after the last induction dose.

[0044] Alternatively preferably, three induction doses of mirikizumab are administered every 4 weeks, and the first maintenance dose is administered 4 weeks after the last induction dose.

[0045] Further alternatively preferably, four induction doses of mirikizumab are administered every 4 weeks, and the first maintenance dose is administered 4 weeks after the last induction dose.

[0046] Further preferably, each maintenance dose comprises 250 mg of mirikizumab.

[0047] Alternatively preferably, each maintenance dose comprises 125 mg of mirikizumab.

[0048] On the other hand, the present invention provides a method for treating psoriasis, which comprises administering mirikizumab to a patient, and the method comprises:

[0049] a) administering to the patient one or more induction doses of mirikizumab during an induction period, wherein each dose of the one or more induction doses comprises 20 mg - 600 mg of mirikizumab;

[0050] b) determining the disease activity level of the patient at the end of the induction period, and

[0051] i) administering to a patient who does not achieve a high level of clinical response at the end of the induction period one or more maintenance doses, wherein each dose of the one or more maintenance doses comprises 20 mg - 600 mg of mirikizumab; and

[0052] ii) For patients who achieve a high-level clinical response after the induction period, continuously evaluate the level of their disease activity. If the patient's disease activity level drops below the high-level clinical response, administer one or more maintenance doses to the patient, where the one or more maintenance doses are administered until the patient regains a high-level clinical response, and each dose of the one or more maintenance doses contains 20 mg - 600 mg of mirikizumab.

[0053] In one embodiment of the present invention, a high-level clinical response is a disease activity level ≥ PASI 90 or ≥ sPGA (0, 1).

[0054] This treatment regimen enables patients who do not achieve a high-level clinical response at the end of the induction period to continue treatment with one or more maintenance doses in order to continue progressing towards a high-level clinical response. Those patients who achieve a high-level clinical response at the end of the induction period receive treatment on demand (PRN). That is, if the patient's disease activity level is below the high-level clinical response, the patient is treated with one or more maintenance doses until the patient again achieves a high-level clinical response.

[0055] In another embodiment of the present invention, psoriasis is moderate to severe plaque psoriasis.

[0056] In yet another embodiment of the present invention, psoriasis is scalp psoriasis.

[0057] In yet another embodiment of the present invention, the patient has not received biologic therapy. In an alternative embodiment of the present invention, the patient has received biologic therapy.

[0058] In yet another embodiment of the present invention, each dose of the one or more induction doses contains 20 mg, 30 mg, 100 mg, 120 mg, 125 mg, 250 mg, 300 mg, 350 mg, 400 mg or 600 mg of mirikizumab.

[0059] Preferably, each dose of the one or more induction doses contains 250 mg of mirikizumab.

[0060] In yet another embodiment of the present invention, one, two, three or four induction doses are administered to the patient.

[0061] In yet another embodiment of the present invention, the induction period is 12 weeks or 16 weeks.

[0062] Preferably, the induction period is 16 weeks, and two induction doses are administered to the patient every 8 weeks.

[0063] Or preferably, the induction period is 12 weeks, and three induction doses are administered to the patient every 4 weeks.

[0064] Alternatively or additionally, the induction period is 16 weeks, and four induction doses are administered to the patient every 4 weeks.

[0065] In yet another embodiment of the invention, the at least one induction dose is administered subcutaneously.

[0066] In yet another embodiment of the invention, each dose of the one or more maintenance doses comprises 20 mg, 30 mg, 100 mg, 120 mg, 125 mg, 250 mg, 300 mg, 350 mg, 400 mg or 600 mg of milizumab.

[0067] Preferably, each dose of the one or more maintenance doses comprises 125 mg or 250 mg of milizumab.

[0068] In yet another embodiment of the invention, the one or more maintenance doses are administered subcutaneously.

[0069] In yet another embodiment of the invention, if the patient does not achieve a high level of clinical response at the end of the induction period, the first maintenance dose is administered 2 - 16 weeks after the last induction dose.

[0070] In yet another embodiment of the invention, if the patient does not achieve a high level of clinical response at the end of the induction period, the first maintenance dose is administered 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 12 weeks or 16 weeks after the last induction dose.

[0071] Preferably, the first maintenance dose is administered 4 weeks after the last induction dose.

[0072] Alternatively preferably, the first maintenance dose is administered 8 weeks after the last induction dose.

[0073] Further optionally preferably, the first maintenance dose is administered 12 weeks after the last induction dose.

[0074] Even further optionally preferably, the first maintenance dose is administered 12 weeks after the last induction dose.

[0075] In yet another embodiment of the invention, one or more further maintenance doses are administered every 4, 8 or 12 weeks after the first maintenance dose.

[0076] Preferably, one or more further maintenance doses are administered every 4 weeks.

[0077] Alternatively preferably, one or more further maintenance doses are administered every 8 weeks.

[0078] In yet another embodiment of the present invention, if the patient has achieved a high level of clinical response at the end of the induction period and the disease activity level of the patient has subsequently dropped below the high level of clinical response:

[0079] i) Administer a first maintenance dose to the patient;

[0080] ii) After administering the first maintenance dose, evaluate the disease activity level every 4 weeks, 8 weeks, or 12 weeks; and

[0081] iii) If the patient has not achieved a high level of clinical response, administer a further maintenance dose after each evaluation of the disease activity level until the patient again achieves a high level of clinical response.

[0082] Those patients who achieve a high level of clinical response at the end of the induction period are treated as needed (PRN). If the disease activity level of the patient is below the high level of clinical response, the patient is administered a first maintenance dose. The disease activity level of the patient is evaluated 4 weeks (or 8 weeks or 12 weeks) after administering the first maintenance dose. If the patient does not again achieve a high level of clinical response after administering the first maintenance dose, a further maintenance dose is administered. This evaluation / treatment cycle will continue until the patient regains a high level of clinical response. Thereafter, the patient is treated again as needed, i.e., the treatment with further maintenance doses is suspended until the disease level of the patient again drops below the high level of clinical response.

[0083] In yet another embodiment of the present invention, the disease activity is evaluated every 4 weeks after administering the first maintenance dose, and a further maintenance dose is administered after each evaluation until the patient regains a high level of clinical response.

[0084] In yet another alternative embodiment of the present invention, the disease activity is evaluated every 8 weeks after administering the first maintenance dose, and a further maintenance dose is administered after each evaluation until the patient regains a high level of clinical response.

[0085] In yet another embodiment of the present invention, one or more maintenance doses are administered by subcutaneous injection.

[0086] On the other hand, the present invention provides a method for treating psoriasis, which comprises administering mirikizumab to a patient, and the method comprises:

[0087] i) Administering one or more induction doses of mirikizumab until the patient achieves clinical remission, wherein each dose of the one or more induction doses comprises 20 mg - 600 mg of mirikizumab; and

[0088] ii) Monitor the disease activity level of the patient, and if the disease activity of the patient is below clinical remission, administer one or more maintenance doses of mirikizumab until the patient reaches clinical remission again, and wherein each of the one or more maintenance doses contains 20 mg - 600 mg of mirikizumab.

[0089] In an embodiment of the present invention, clinical remission is a disease activity level of PASI 100 or sPGA(0).

[0090] This treatment regimen involves treating the patient until he / she reaches clinical remission, and then treating the patient as needed (PRN).

[0091] In another embodiment of the present invention, psoriasis is moderate to severe plaque psoriasis.

[0092] In yet another embodiment of the present invention, the patient has not received biologic therapy. In an alternative embodiment, the patient has received biologic therapy.

[0093] In yet another embodiment of the present invention, the disease activity is evaluated every 4 weeks, 8 weeks, or 12 weeks after the first induction dose is administered, and if the patient has not reached clinical remission, a further induction dose is administered after the disease activity level is evaluated.

[0094] The disease activity level of the patient is evaluated 4 weeks (or 8 weeks or 12 weeks) after the first induction dose is administered. If the patient has not reached clinical remission after the first induction dose is administered, another induction dose is administered. This evaluation / treatment cycle continues until the patient reaches clinical remission.

[0095] In yet another embodiment of the present invention, each of the one or more induction doses contains 20 mg, 30 mg, 100 mg, 120 mg, 125 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 600 mg of mirikizumab.

[0096] Preferably, each of the one or more induction doses contains 250 mg of mirikizumab.

[0097] In yet another embodiment of the present invention, if the disease activity level of the patient drops below clinical remission:

[0098] i) Administer the first maintenance dose of mirikizumab to the patient;

[0099] ii) After the first maintenance dose is administered, evaluate the disease activity every 4 weeks, 8 weeks, or 12 weeks; and

[0100] iii) If the patient does not reach clinical remission again, administer a further maintenance dose after each disease activity level evaluation.

[0101] If the disease activity level of a patient is lower than the clinical remission level, the patient is administered a first maintenance dose. The disease activity level of the patient is evaluated 4 weeks (or 8 weeks or 12 weeks) after administration of the first maintenance dose. If the patient has not reached clinical remission again after administration of the first maintenance dose, another maintenance dose is administered. This evaluation / treatment cycle continues until the patient reaches clinical remission again. Thereafter, the patient is treated again as needed, i.e., treatment with further maintenance doses is suspended until the patient's disease level drops below clinical remission again.

[0102] In another embodiment of the present invention, each of the one or more maintenance doses comprises 20 mg, 30 mg, 100 mg, 120 mg, 125 mg, 250 mg, 300 mg, 350 mg, 400 mg or 600 mg of mirikizumab.

[0103] Preferably, each of the one or more maintenance doses comprises 125 mg or 250 mg of mirikizumab.

[0104] The method of the present invention provides the advantage of enabling a patient to experience clinical improvement while receiving fewer administrations of mirikizumab.

[0105] On the other hand, the present invention provides mirikizumab for the treatment of psoriasis, wherein the treatment comprises:

[0106] a) administering at least one induction dose of mirikizumab, wherein the induction dose comprises 20 mg - 600 mg of mirikizumab; and

[0107] b) administering at least one maintenance dose of mirikizumab after administration of the last induction dose, wherein the maintenance dose comprises 20 mg - 600 mg of mirikizumab.

[0108] In an embodiment of the present invention, the psoriasis is moderate to severe plaque psoriasis.

[0109] In another embodiment of the present invention, the psoriasis is scalp psoriasis.

[0110] In yet another embodiment of the present invention, the patient has not received biologic therapy. In an alternative embodiment of the method of the present invention, the patient has received biologic therapy.

[0111] In yet another embodiment of the present invention, the at least one induction dose comprises 20 mg, 30 mg, 100 mg, 120 mg, 250 mg, 300 mg, 350 mg, 400 mg or 600 mg of mirikizumab.

[0112] Preferably, the at least one induction dose comprises 250 mg of mirikizumab.

[0113] In a further embodiment of the invention, one, two, three or four induction doses are administered to the patient.

[0114] Preferably, two induction doses are administered to the patient every 8 weeks.

[0115] Alternatively preferably, three induction doses are administered to the patient every 4 weeks.

[0116] Alternatively preferably, four induction doses are administered to the patient every 4 weeks.

[0117] In a further embodiment of the invention, the at least one inducer is administered subcutaneously.

[0118] In a further embodiment of the invention, the at least one maintenance dose comprises 20 mg, 30 mg, 100 mg, 120 mg, 125 mg, 250 mg, 300 mg, 350 mg, 400 mg or 600 mg of mirikizumab.

[0119] Preferably, the at least one maintenance dose comprises 125 mg or 250 mg of mirikizumab.

[0120] In a further embodiment of the invention, the at least one maintenance dose is administered 2 - 16 weeks after the last induction dose.

[0121] In a further embodiment of the invention, the at least one maintenance dose is administered 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 12 weeks or 16 weeks after the last induction dose.

[0122] Preferably, the at least one maintenance dose is administered 4 weeks after the last induction dose.

[0123] Alternatively preferably, the at least one maintenance dose is administered 8 weeks after the last induction dose.

[0124] Further optionally preferably, the at least one maintenance dose is administered 12 weeks after the last induction dose.

[0125] Even further optionally preferably, the at least one maintenance dose is administered 16 weeks after the last induction dose.

[0126] In a further embodiment of the invention, multiple maintenance doses are administered to the patient, and the first maintenance dose is administered 2 to 16 weeks after the last induction dose.

[0127] In yet another embodiment of the present invention, the first maintenance dose is administered 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 12 weeks or 16 weeks after the last induction dose.

[0128] Preferably, the first maintenance dose is administered 4 weeks after the last induction dose.

[0129] Alternatively preferably, the first maintenance dose is administered 8 weeks after the last induction dose.

[0130] Further optionally preferably, the first maintenance dose is administered 12 weeks after the last induction dose.

[0131] Even further optionally preferably, the first maintenance dose is administered 16 weeks after the last induction dose.

[0132] In yet another embodiment of the present invention, one or more further maintenance doses are administered every 4, 8 or 12 weeks after the first maintenance dose.

[0133] Preferably, one or more further maintenance doses are administered every 4 weeks.

[0134] Alternatively preferably, one or more further maintenance doses are administered every 8 weeks.

[0135] Further optionally preferably, one or more further maintenance doses are administered every 12 weeks.

[0136] In yet another embodiment of the method of the present invention, the maintenance dose is administered by subcutaneous injection.

[0137] In a preferred embodiment of the present invention, the treatment comprises:

[0138] a) administering to a patient by subcutaneous injection (i) two, three or four induction doses of mirikizumab, wherein each induction dose comprises 250 mg of mirikizumab; and

[0139] b) administering to the patient by subcutaneous injection at least one maintenance dose of mirikizumab every 4 weeks or 8 weeks, wherein the first maintenance dose is administered 4 weeks or 8 weeks after the last induction dose, and wherein each maintenance dose comprises 125 mg or 250 mg of mirikizumab,

[0140] wherein the psoriasis is moderate to severe plaque psoriasis.

[0141] Preferably, two induction doses of mirikizumab are administered every 8 weeks, and the first maintenance dose is administered 8 weeks after the last induction dose.

[0142] Alternatively, preferably, three induction doses of mirikizumab are administered every 4 weeks, and the first maintenance dose is administered 4 weeks after the last induction dose is administered.

[0143] Further optionally preferably, four induction doses of mirikizumab are administered every 4 weeks, and the first maintenance dose is administered 4 weeks after the last induction dose is administered.

[0144] Further preferably, each maintenance dose comprises 250 mg of mirikizumab.

[0145] Alternatively, preferably, each maintenance dose comprises 125 mg of mirikizumab.

[0146] In one aspect of the present invention, there is provided the use of mirikizumab for the treatment of psoriasis, said treatment comprising:

[0147] a) administering to a patient one or more induction doses of mirikizumab during an induction period, wherein each of said one or more induction doses comprises 20 mg - 600 mg of mirikizumab;

[0148] b) determining the disease activity level of the patient at the end of the induction period, and

[0149] i) administering to a patient who does not achieve a high level of clinical response at the end of the induction period one or more maintenance doses, wherein each of said one or more maintenance doses comprises 20 mg - 600 mg of mirikizumab;

[0150] ii) continuously assessing the disease activity level of a patient who achieves a high level of clinical response after the induction period, and if the disease activity level of said patient is lower than the high level of clinical response, administering to said patient one or more maintenance doses until said patient regains the high level of clinical response, and wherein each of said one or more maintenance doses comprises 20 mg - 600 mg of mirikizumab.

[0151] In one embodiment of the present invention, a high level of clinical response is a disease activity level of ≥PASI 90 or ≥sPGA(0,1).

[0152] In another embodiment of the present invention, the psoriasis is moderate to severe plaque psoriasis.

[0153] In yet another embodiment of the present invention, the psoriasis is scalp psoriasis.

[0154] In yet another embodiment of the present invention, the patient has not received biologic therapy. In an alternative embodiment of the present invention, the patient has received biologic therapy.

[0155] In yet another embodiment of the present invention, each of the one or more induction doses comprises 20 mg, 30 mg, 100 mg, 120 mg, 125 mg, 250 mg, 300 mg, 350 mg, 400 mg or 600 mg of mirikizumab.

[0156] Preferably, each of the one or more induction doses comprises 250 mg of mirikizumab.

[0157] In yet another embodiment of the present invention, one, two, three or four induction doses are administered to the patient.

[0158] In yet another embodiment of the present invention, the induction period is 12 weeks or 16 weeks.

[0159] Preferably, the induction period is 16 weeks, and two induction doses are administered to the patient every 8 weeks.

[0160] Alternatively preferably, the induction period is 12 weeks, and three induction doses are administered to the patient every 4 weeks.

[0161] Additionally, the induction period is 16 weeks, and four induction doses are administered to the patient every 4 weeks.

[0162] In yet another embodiment of the present invention, the one or more induction doses are administered subcutaneously.

[0163] In yet another embodiment of the present invention, each of the one or more maintenance doses comprises 20 mg, 30 mg, 100 mg, 120 mg, 125 mg, 250 mg, 300 mg, 350 mg, 400 mg or 600 mg of mirikizumab.

[0164] Preferably, each of the one or more maintenance doses comprises 125 mg or 250 mg of mirikizumab.

[0165] In yet another embodiment of the present invention, the one or more maintenance doses are administered by subcutaneous injection.

[0166] In yet another embodiment of the present invention, if the patient does not achieve a high level of clinical response at the end of the induction period, the first maintenance dose is administered 2 to 16 weeks after the last induction dose.

[0167] In yet another embodiment of the present invention, if the patient does not achieve a high level of clinical response at the end of the induction period, the first maintenance dose is administered 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 12 weeks or 16 weeks after the last induction dose.

[0168] Preferably, the first maintenance dose is administered 4 weeks after the last induction dose.

[0169] Alternatively, preferably, the first maintenance dose is administered 8 weeks after the last induction dose.

[0170] Further alternatively, preferably, the first maintenance dose is administered 12 weeks after the last induction dose.

[0171] Even further alternatively, preferably, the first maintenance dose is administered 12 weeks after the last induction dose.

[0172] In yet another embodiment of the present invention, one or more further maintenance doses are administered every 4, 8, or 12 weeks after the first maintenance dose.

[0173] Preferably, one or more further maintenance doses are administered every 4 weeks.

[0174] Alternatively, preferably, one or more further maintenance doses are administered every 8 weeks.

[0175] In yet another embodiment of the present invention, if the patient has achieved a high level of clinical response at the end of the induction period and the disease activity level of the patient has subsequently dropped below the high level of clinical response:

[0176] i) Administer the first maintenance dose to the patient;

[0177] ii) After the first maintenance dose is administered, evaluate the disease activity level every 4 weeks, 8 weeks, or 12 weeks; and

[0178] iii) If the patient has not achieved a high level of clinical response, administer a further maintenance dose after each evaluation of the disease activity level until the patient again achieves a high level of clinical response.

[0179] In yet another embodiment of the present invention, the disease activity is evaluated every 4 weeks after the first maintenance dose is administered, and a further maintenance dose is administered after each evaluation until the patient regains a high level of clinical response.

[0180] In yet another alternative embodiment of the present invention, the disease activity is evaluated every 8 weeks after the first maintenance dose is administered, and a further maintenance dose is administered after each evaluation until the patient regains a high level of clinical response.

[0181] In yet another embodiment of the present invention, one or more maintenance doses are administered by subcutaneous injection.

[0182] On the other hand, the present invention provides the use of mirikizumab for the treatment of psoriasis, the treatment comprising:

[0183] i) Administer one or more induction doses of mirikizumab until the patient achieves clinical remission, wherein each of the one or more induction doses comprises 20 mg to 600 mg of mirikizumab; and

[0184] ii) Monitor the disease activity level of the patient and, if the patient's disease activity is below clinical remission, administer one or more maintenance doses of mirikizumab until the patient again achieves clinical remission, wherein each of the one or more maintenance doses comprises 20 mg - 600 mg of mirikizumab.

[0185] In an embodiment of the present invention, clinical remission is a disease activity level of PASI 100 or sPGA(0).

[0186] In another embodiment of the present invention, the psoriasis is moderate to severe plaque psoriasis.

[0187] In yet another embodiment of the present invention, the patient has not received biologic therapy. In an alternative embodiment, the patient has received biologic therapy.

[0188] In yet another embodiment of the present invention, disease activity is evaluated every 4 weeks, 8 weeks, or 12 weeks after the first induction dose is administered, and if the patient has not achieved clinical remission, a further induction dose is administered after the disease activity level is evaluated.

[0189] In yet another embodiment of the present invention, each of the one or more induction doses comprises 20 mg, 30 mg, 100 mg, 120 mg, 125 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 600 mg of mirikizumab.

[0190] Preferably, each of the one or more induction doses comprises 250 mg of mirikizumab.

[0191] In yet another embodiment of the present invention, if the patient's disease activity level drops below clinical remission:

[0192] i) Administer the first maintenance dose of mirikizumab to the patient;

[0193] ii) Evaluate disease activity every 4 weeks, 8 weeks, or 12 weeks after the first maintenance dose is administered; and

[0194] vi) If the patient does not again achieve clinical remission, administer a further maintenance dose after each disease activity level evaluation.

[0195] In yet another embodiment of the present invention, each of the one or more maintenance doses comprises 20 mg, 30 mg, 100 mg, 120 mg, 125 mg, 250 mg, 300 mg, 350 mg, 400 mg or 600 mg of milizumab.

[0196] Preferably, the one or more maintenance doses comprise 125 mg or 250 mg of milizumab.

[0197] In yet another embodiment, the one or more maintenance doses are administered by subcutaneous injection.

[0198] Drawings

[0199] Figure 1 Shows the percentage of PASI 90 responders in placebo subjects and subjects treated with milizumab, where the subjects treated with milizumab had <PASI 90 at week 16 and received 300 mg of milizumab SC Q8W during the 16 - 52 week maintenance period.

[0200] Figure 2 Shows the percentage of PASI 100 responders in placebo subjects and subjects treated with milizumab, where the subjects treated with milizumab had <PASI 90 at week 16 and received 300 mg of milizumab SC Q8W during the 16 - 52 week maintenance period.

[0201] Figure 3a , 3b And 3c example shows the PASI 75, PASI90 and PASI 1000 scores at week 52 in never - exposed patient groups and previously - exposed patient groups, where the patients had moderate - to - severe plaque psoriasis and did not achieve PASI90 at week 16. Detailed Description of the Invention

[0203] Psoriasis is a chronic skin inflammatory disease characterized by dysregulated and hyperproliferative keratinocyte differentiation and a marked accumulation of inflammatory T cells and dendritic cells. For example, immune diseases include plaque psoriasis, such as chronic plaque psoriasis, such as moderate - to - severe chronic plaque psoriasis, such as in patients who are candidates for systemic or phototherapy.

[0204] There are various methods for measuring the level of disease activity.

[0205] The severity of psoriasis can be characterized by the body surface area (BSA), with <5% considered mild, 5 - 10% moderate, and >10% severe. The BSA percentage is evaluated as the percentage of the BSA affected by psoriasis for each patient and is a continuous rating system from 0% (unaffected) to 100% (fully affected). One percent corresponds to the size of the patient's hand area (including the palm, fingers, and thumb) (National Psoriasis Foundation 2009).

[0206] In some cases, the disease state is measured using the Psoriasis Area and Severity Index (PASI). PASI is the recognized primary efficacy measure in the development of psoriasis treatment. PASI combines an assessment of the extent of body surface involvement in four anatomical regions (head, trunk, arms, and legs), as well as the severity of scaling, erythema, and plaque induration / infiltration (thickness) in each region, resulting in a total score of 0 for no psoriasis and a maximum score of 72 for the most severe disease (Fredriksson and Pettersson, Dermatologica, 157(4), pp238 - 244, 1978). PASI is the most commonly used endpoint and measure of psoriasis severity in clinical trials (Menter et al., J Am Acad Dermatol., 58(5), pp826 - 850, 2008). A clinically meaningful response is PASI 75, which represents at least a 75% reduction (improvement) from the baseline PASI score. Higher levels of clearance of psoriasis (PASI 90) and complete remission (PASI 100) have become additional endpoints as there is increasing recognition of the association between higher clearance rates and higher health - related quality of life (HRQoL). The percentage of patients achieving PASI 75 (PASI 75), with a score at a specific time (e.g., at week 12 or week 16) that is 75% lower than the baseline, can be used as the primary endpoint in psoriasis treatment trials, for example. Or, the percentage of patients achieving PASI 90 (PASI 90), with a score at a specific time (e.g., at week 12 or week 16) that is 90% lower than the baseline, is used as the primary endpoint in psoriasis treatment trials, for example. Additionally, the percentage of patients achieving PASI 100 (PASI 100), with a score at a specific time (e.g., at week 12 or week 16) that is 100% lower than the baseline, is used as the primary endpoint in psoriasis treatment trials, for example.

[0207] In some cases, disease status is measured using Static Physician's Global Assessment (sPGA). The sPGA is the doctor's overall assessment of the patient's psoriasis lesions at a given point in time (EMA 2004). As shown in Table 1, the plaques are evaluated for sclerosis, erythema, and desquamation.

[0208] Table 1: Static Physician's Global Assessment (sPGA) Scale

[0209]

[0210]

[0211] For the analysis of response rates, the sPGA score is rounded to the nearest integer, and the patient's psoriasis is evaluated as clear (0), minimal (1), mild (2), moderate (3), severe (4), or very severe (5).

[0212] The Itch NRS is a patient-administered, 11-point scale anchored at 0 and 10, where 0 represents "no itch" and 10 represents "the worst itch imaginable". The overall severity of a patient's itch is represented by the number circled, which most appropriately describes the worst itch experienced in the past 24 hours.

[0213] The Nail Psoriasis Severity Index (NAPSI) is used to assess the severity of nail bed psoriasis and nail matrix psoriasis, based on the area of nail unit involvement. In this study, only nail involvement was evaluated. The nail is divided into four quadrants using imaginary horizontal and vertical lines. Each nail bed psoriasis (0 to 4 points) and nail matrix psoriasis (0 to 4 points) is scored based on the presence (1 point) or absence (0 points) of any features of nail bed and nail matrix psoriasis in each quadrant. The NAPSI score for a nail is the sum of the nail bed and nail matrix scores for each quadrant (up to 8 points). Each nail is evaluated, and the sum of all nails is the total NAPSI score (range from 0 to 80).

[0214] The Psoriasis Scalp Severity Index (PSSI) measures the area of scalp involvement and the severity of clinical symptoms. The PSSI is a composite score obtained by multiplying the sum of the scores for erythema, induration, and desquamation by the score for the extent of scalp involvement (range 0 to 72). Higher scores indicate worse severity ( et al., J Eur Acad Dermatol Venerol., 29(2), pp. 353 - 360, 2015)).

[0215] The Palmoplantar Psoriasis Area and Severity Index (PPASI) is a composite score obtained by multiplying the scores for erythema, induration, and desquamation by the score for the extent of palm and sole involvement (range 0 to 72).

[0216] The Dermatology Life Quality Index (DLQI) is a validated, dermatology-specific, patient-reported measure of patients' HRQoL. This questionnaire consists of 10 items divided into 6 domains, namely symptoms and sensations, daily activities, leisure, work and school, relationships and treatment. The recall period for this scale is more than 'last week'. Response categories include 'not at all', 'a little', 'a lot' and'very much' with corresponding scores of 0, 1, 2 and 3 respectively, and non-responses ('not relevant') are scored '0'. The total score ranges from 0 to 30 (least to most impairment) (Finlay and Khan, Clin Exp Dermatol., 19(3), pp. 210 - 216, 1994; Basra et al., Br J Dermatol., 159(5), pp. 997 - 1035, 2008). A DLQI total score of 0 to 1 is considered to have no impact on the patient's HRQoL, and a 5-point change compared to baseline is considered the minimum clinically important difference (MCID) threshold (Khilji et al., Br J Dermatol., 147 (Suppl 62), p. 50, 2002; Hongbo et al., J Invest Dermatol., 125(4), pp. 659 - 664, 2005).

[0217] The Psoriasis Symptoms Scale (PSS) is an assessment of four symptoms (itching, pain, stinging and burning); three signs (erythema, desquamation and fissuring); and discomfort associated with symptoms / signs in patients. Responders are asked to answer questions based on their psoriasis symptoms. The overall severity of each symptom / sign in psoriasis patients is represented by selecting a number from a numeric rating scale (NRS) from 0 to 10 that best describes the worst level of each symptom / sign in the past 24 hours, where 0 indicates no symptom / sign and 10 indicates the worst imaginable symptom / sign. The symptom severity score ranges from 0 to 10 and is the value of the selected number indicated by the patient on an instrument-level scale. Each of the 8 independent items will receive a score from 0 to 10 and will be reported as the item score for itching, pain, stinging, burning, erythema, desquamation, fissuring and discomfort. In addition, symptom scores from 0 (no symptoms) to 40 (worst imaginable symptoms) and symptom scores from 0 (no symptoms) to 30 (worst imaginable symptoms) will be reported.

[0218] The Patient's Global Assessment of Psoriasis (PatGA) is a patient-reported single-item scale that asks the patient to rank the severity of their psoriasis 'today' by selecting a number from a 0 - 5 NRS, where 0 (clear / no psoriasis) to 5 (severe).

[0219] As used herein, the terms "treating," "treat," or "treatment" refer to inhibiting, slowing down, alleviating, reducing, or reversing the progression or severity of existing symptoms, disorders, conditions, or diseases, or improving the clinical symptoms and / or signs of a condition. Beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms, diminishment of the degree of a disease or disorder, stabilization of a disease or disorder (i.e., the disease or disorder does not get worse), delay or slowing of the progression of a disease or disorder, improvement or remission of a disease or disorder, and remission (whether partial or complete) of a disease or disorder, whether or not detectable. Persons in need of treatment include those who are already suffering from a disease.

[0220] As used herein, "clinical remission" refers to the attainment of a disease activity level of PASI 100, sPGA(0), or an equivalent thereof in other measures of the disease activity level of psoriasis.

[0221] As used herein, "clinically meaningful response" refers to the attainment of a disease activity level of PASI 75, sPGA(2), or an equivalent thereof in other measures of the disease activity level of psoriasis.

[0222] As used herein, "high level of clinical response" refers to the attainment of a disease activity level of PASI 90, sPGA(0,1), or an equivalent thereof in other measures of the disease activity level of psoriasis.

[0223] As used herein, "induction period" refers to the period of treatment of a patient, including administration to the patient of an antibody that binds to the p19 subunit of human IL-23, particularly mirikizumab, to achieve a desired treatment effect or to achieve progress toward a desired treatment effect, the desired treatment effect being induction of clinical remission (as described above) and / or a clinically meaningful response (as described above), and / or a high level of clinical response (as described above). The "induction period" can be 4, 8, 12, or 16 weeks of induction.

[0224] As used herein, "induction dose" refers to the first dose of an antibody that binds to the p19 subunit of human IL-23, particularly mirikizumab, administered to a patient to achieve a desired treatment effect or to achieve progress toward a desired treatment effect, the desired treatment effect being induction of clinical remission (as described above) and / or a clinically meaningful response (as described above) and / or a high level of clinical response (as described above). The "induction dose" can be a single dose or a set of doses. The "induction dose" is administered during the induction period.

[0225] As used herein, "maintenance phase" refers to a treatment period that includes administering an antibody that binds to the p19 subunit of human IL-23 (particularly milizumab) to a patient to maintain the desired therapeutic effect and / or continue progress toward achieving the desired therapeutic effect, which is a clinical remission (as described above) and / or a clinically meaningful response (as described above), and / or a high level of clinical response (as described above). The "maintenance phase" follows the induction phase and is therefore initiated once the desired therapeutic effect and / or progress toward achieving the desired therapeutic effect is achieved.

[0226] As used herein, a "maintenance dose" refers to a subsequent dose of an antibody that binds to the p19 subunit of human IL-23, specifically miliguzumab, administered to a patient to maintain or continue progress toward a desired therapeutic effect, i.e., clinical remission (as defined above) and / or a clinically significant response and / or a high level of clinical response (as defined above). A "maintenance dose" is administered after an induction dose. A "maintenance dose" can be a single dose, or it can be a set of doses. A "maintenance dose" is administered during the maintenance phase of treatment.

[0227] As used herein, the term "antibody" is further intended to include antibodies, digestion fragments, specified portions and variants thereof, including antibody mimetics or antibody portions that mimic the structure and / or function of an antibody or specified fragment or portion thereof, including single-chain antibodies and fragments thereof. Functional fragments include antigen-binding fragments that bind to human IL-23. For example, antibody fragments that can bind to IL-12 / 23 or portions thereof, including but not limited to Fab (e.g., by papain digestion), Fab' (e.g., by pepsin digestion and partial reduction) and F(ab')2 (e.g., by pepsin digestion), facb (e.g., by plasmin digestion), pFc' (e.g., by pepsin or plasmin digestion), Fd (e.g., by pepsin digestion, partial reduction and reaggregation), Fv or scFv (e.g., by molecular biology techniques) fragments are all included in the present invention (see, e.g., Colligan et al., Current Protocols in Immunology, John Wiley & Sons, NY, NY, (1994-2001)).

[0228] Such fragments can be produced by enzyme cutting, synthesis or recombinant techniques known in the art and / or described herein. Antibodies can also be produced in various truncated forms using one or more stop codons introduced into antibody genes upstream of the natural termination site. For example, a combination gene encoding a F(ab')2 heavy chain portion can be designed to include a DNA sequence encoding the CH1 domain and / or hinge region of the heavy chain. The different parts of the antibody can be chemically linked together by conventional techniques, or can be prepared as a continuous protein using genetic engineering techniques.

[0229] As used herein, an "antibody that binds to the p19 subunit of human IL-23" refers to an antibody that binds to the p19 subunit of human IL-23 but does not bind to the p40 subunit of human IL-23. An "antibody that binds to the p19 subunit of human IL-23" thus binds to human IL-23 but does not bind to human IL-12.

[0230] Mirikizumab, CAS Registry Number 1884201-71-1, is an engineered IgG4-K monoclonal antibody that targets the p19 subunit of human IL-23. The antibody and its method of preparation are described in U.S. Patent No. 9,023,358.

[0231] An antibody that binds to the p19 subunit of human IL-23 or a pharmaceutical composition comprising the antibody can be administered by a parenteral route (e.g., subcutaneous, intravenous, intraperitoneal, intramuscular, or transdermal).

[0232] The term "intravenous infusion" refers to the introduction of a drug into the vein of an animal or human patient over a period of more than about 15 minutes, typically between about 30 and 90 minutes.

[0233] The term "subcutaneous injection" refers to the introduction of a drug under the skin of an animal or human patient, preferably into a pocket between the skin and the subcutaneous tissue, by relatively slow, continuous delivery from a drug container. A pocket can be formed by pinching or pulling the skin upward away from the underlying tissue.

[0234] A pharmaceutical composition comprising an anti-IL-23p19 antibody for use in the methods of the present invention can be prepared by methods well known in the art (e.g., Remington: the Science and Practice of Pharmacy, 19th Edition (1995), (a. Gennaro et al., Mack Publishing Co.)), and comprises an antibody as disclosed herein, as well as one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0235] In one aspect, the present invention provides a method for the treatment of psoriasis, which comprises administering mirikizumab to a patient, the method comprising:

[0236] a) administering to the patient at least one induction dose of mirikizumab, wherein the induction dose comprises 20 mg - 600 mg of mirikizumab; and

[0237] b) administering to the patient at least one maintenance dose of mirikizumab after the last induction dose, wherein the maintenance dose comprises 20 mg - 600 mg of mirikizumab.

[0238] In another aspect, the present invention provides a method for treating psoriasis, which comprises administering mirikizumab to a patient, and the method comprises:

[0239] a) Administering to the patient one or more induction doses of mirikizumab during an induction period, wherein the induction dose comprises 20 - 600 mg of mirikizumab;

[0240] c) Determining the disease activity level of the patient at the end of the induction period, and

[0241] i) Administering to a patient who does not achieve a high - level clinical response at the end of the induction period one or more maintenance doses, wherein each of the one or more maintenance doses comprises 20 mg to 600 mg of mirikizumab; and

[0242] ii) Continuously assessing the disease activity level of a patient who achieves a high - level clinical response after the induction period, and if the disease activity level of the patient is lower than the high - level clinical response, administering to the patient one or more maintenance doses until the patient regains the high - level clinical response, and wherein each of the one or more maintenance doses comprises 20 mg - 600 mg of mirikizumab.

[0243] In yet another aspect, the present invention provides a method for treating psoriasis, which comprises administering mirikizumab to a patient, and the method comprises:

[0244] i) Administering one or more induction doses of mirikizumab until the patient achieves clinical remission, wherein each of the one or more induction doses comprises 20 mg - 600 mg of mirikizumab; and

[0245] ii) Monitoring the disease activity level of the patient, and if the disease activity of the patient is lower than clinical remission, administering one or more maintenance doses of mirikizumab until the patient reaches clinical remission again, and wherein each of the one or more maintenance doses comprises 20 mg - 600 mg of mirikizumab.

[0246] The preferred embodiments of the present invention have been described above. Representative examples of the doses and dosage regimens according to the present invention are described in Table 2.

[0247] Table 2: Doses and Dosage Regimens

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257] Example

[0258] Example 1: Clinical Study

[0259] Overview

[0260] This study was a multicenter, randomized, parallel-group, placebo-controlled Phase II study in subjects with moderate to severe plaque psoriasis. The purpose of this study was to determine whether subcutaneous administration of mirikizumab is safe and effective in subjects with moderate to severe plaque psoriasis. The study included a screening period of up to 28 days, a 16-week double-blind SC treatment period, an 88-week SC treatment for responders and non-responders at Week 16, and a 16-week follow-up period.

[0261] Objective

[0262] The primary objective of this study was to test the hypothesis that mirikizumab treatment is superior to placebo in inducing a PASI 90 response at Week 16 in subjects with moderate to severe plaque psoriasis. Secondary objectives included:

[0263] · Evaluating the safety and tolerability of mirikizumab treatment;

[0264] · Evaluating the efficacy of mirikizumab in inducing PASI 100 and PASI 75 at Week 16 compared to placebo;

[0265] · Evaluating the efficacy of mirikizumab treatment in inducing sPGA 0 (clear) and sPGA 0 / 1 at Week 16 compared to placebo;

[0266] · Characterizing the long-term efficacy of mirikizumab in PASI 100, PASI 90, and PASI 75 responses at Weeks 52, 104, and 120; and

[0267] · Characterizing the PK of mirikizumab.

[0268] The endpoints of the study included:

[0269] · The proportion of subjects who achieved PASI 90 at Week 16;

[0270] · Adverse events and discontinuation rates;

[0271] · Proportion of subjects achieving PASI 100 and PASI 75 at Week 16;

[0272] · Proportion of subjects achieving sPGA 0 and sPGA 0 / 1 at Week 16;

[0273] · Proportion of subjects achieving PASI 100, PASI 90, and PASI 75 at Weeks 52, 104, and 120; and

[0274] · Clearance rate and volume of distribution.

[0275] Adverse events were coded according to the Medical Dictionary for Regulatory Activities (MedDRA), version 19.1, and summarized by system organ class, preferred term, severity, and relationship to the investigational drug. Treatment-emergent adverse events (TEAEs) were defined as events occurring for the first time or worsening in severity after baseline. The Columbia-Suicide Severity Rating Scale (C-SSRS; Columbia University Medical Center [WWW]) was used to record the incidence, severity, and frequency of suicide-related thoughts and behaviors.

[0276] Methods

[0277] The study included a screening period, and patients who achieved PASI 90 at Week 16 had two treatment periods (a 16-week double-blind SC induction treatment period and an 88-week SC maintenance treatment period), while patients who did not achieve PASI 90 at Week 16 had two treatment periods (a 16-week double-blind SC induction treatment period and an 88-week SC maintenance treatment period). After the maintenance period, there was a 16-week follow-up period to evaluate the safety of the subjects and the efficacy of the investigational drug.

[0278] Among the patients randomly assigned to receive the investigational treatment, approximately 40% had received at least one biologic treatment (anti-TNF biologic or anti-IL-17 targeted biologic), and approximately 60% of the patients had not received biologic treatment.

[0279] a) Screening period

[0280] Subjects were evaluated for study eligibility ≤28 days before the baseline visit. At the baseline visit, eligible subjects were randomly assigned to one of 4 induction treatment groups.

[0281] The inclusion criteria for this study included adult patients (18 - 75 years old), with a confirmed diagnosis of chronic plaque psoriasis vulgaris by the investigator at least 6 months before baseline. Patients must have had ≥10% of their body surface area (BSA) involved at screening and baseline, an absolute PASI score ≥12, a static physician global assessment (sPGA) score ≥3, and they must have been considered eligible for biologic therapy for psoriasis. Use of anti - tumor necrosis factor (Anti - TNF) or anti - IL - 17 biologics within 8 weeks after baseline examination was not permitted. Prior exposure to any biotherapy targeting IL - 23 was also not permitted, except for briakinumab. Throughout the study, patients should maintain a stable dose of their routine medication regimen to treat concomitant conditions or diseases, unless these medications were specifically excluded in the protocol or if treatment of adverse events (AE) required a change. Topical steroids could be used as needed, but only on the face, axilla, and / or genitalia, except within 24 hours before a study visit.

[0282] b) Induction period

[0283] A double - blind 16 - week induction period was designed to determine the efficacy and safety of administering mirikizumab at Week 0 and Week 8. At Week 0 (baseline), patients were enrolled into one of four induction treatment groups (placebo, 30 mg mirikizumab SC, 100 mg mirikizumab SC, and 300 mg mirikizumab SC) to fully evaluate the study endpoints. Patients enrolled in the trial were stratified into treatment groups based on their previous receipt of biologic therapy for psoriasis. A blinded study drug (mirikizumab or placebo) was administered at Week 0 and Week 8.

[0284] c) Maintenance period

[0285] The maintenance period included 88 weeks of treatment. At the end of the induction period (Week 16), subjects were in one of two treatment groups and continued maintenance treatment until Week 104. All placebo subjects and subjects receiving mirikizumab treatment with <PASI 90 at Week 16 received 300 mg mirikizumab SC Q8W throughout the maintenance period. Subjects with ≥PASI 90 at Week 16 (PRN dosing group) were assigned to a mirikizumab dosing frequency not exceeding QSW at the baseline dose level when the disease activity level <PASI 90, and this treatment continued until ≥PASI 90 was regained.

[0286] Subjects in the maintenance PRN dose group, if they did not regain PASI ≥90 after 3 consecutive retreatments, or any subject with <PASI 50 after one retreatment dose, could receive a blinded rescue treatment of 300 mg Q8W.

[0287] d) Follow-up period

[0288] The follow-up period included visits every 4 weeks for 16 weeks after week 104 to evaluate the safety of the subjects and the efficacy of the study drug.

[0289] Statistical analysis

[0290] Assuming that mirikizumab and placebo have PASI 90 response rates of 60% and 3% respectively at 16 weeks, the two-sided Fisher's exact test with a significance level of 0.05 has a test power of more than 99% for pairwise comparison with placebo and is not adjusted for multiple comparisons. All randomized patients were analyzed according to the dose group to which they were assigned (intention to treat). Safety analysis was performed on all patients who received at least one dose of the study drug.

[0291] Logistic regression analysis was used, including treatment, geographical region (US / Outside the US [US / OUS]), and previous biologic therapy (yes / no), to compare the categorical binary efficacy and health outcome variables for each mirikizumab dose regimen (300 mg, 100 mg, 30 mg) and placebo.

[0292] Results: Study population

[0293] Among the 251 patients screened, 205 patients were randomly assigned to placebo (N = 52), mirikizumab Q8W 30 mg (N = 51), mirikizumab Q8W 100 mg (N = 51), and mirikizumab Q8W 300 mg (N = 51). 97% of the patients completed the initial 16 weeks of this study ( Figure 2 ). Patients in each treatment group generally had similar baseline characteristics. The mean age of the patients was 47 years, the weight was 89 kg, and psoriasis had been diagnosed for 19 years. There were more male patients in all treatment groups, and approximately 41% of the patients had received biologic therapy. On average, the baseline PASI score of the patients was 20, and the BSA affected by psoriasis was 25%.

[0294] Results: Efficacy

[0295] At week 16, compared with the placebo group (0%), the proportions of patients achieving a PASI 90 response (primary outcome) in the 30 mg (29.4%, p = 0.009), 100 mg (58.8%, p < 0.001), and 300 mg (66.7%, p < 0.001) mirikizumab groups were significantly higher statistically (Table 3).

[0296] In addition, compared with 3.8% and 1.9% in the placebo group, at week 16, the PASI 75 and sPGA 0 / 1 response rates in each milizumab dose group were 52.9% and 37.3% in the 30 mg group, 78.4% and 70.6% in the 100 mg group, and 74.5% and 68.6% in the 300 mg group (p<0.001 for each milizumab vs placebo). At week 16, the PASI 100 and sPGA 0 response rates were the same, 15.7% in the 30 mg milizumab group, 31.4% in the 100 mg group, and 31.4% in the 300 mg group, while 0% in the placebo group (p = 0.039 for the 30 mg group vs placebo group; p = 0.007 for the high-dose groups vs placebo group) for complete clearance of psoriasis (Table 3). The complete clearance rate of scalp psoriasis measured by PSSI = 0 was 43.1% in the 30 mg group, 74.5% in the 100 mg group, 51.0% in the 300 mg group, while 5.8% in the placebo group (p<0.001 for each dose group compared with the placebo group) (Table 2). Among all the week 16 results presented here, the responses in the 100 mg and 300 mg milizumab treatment groups were the highest.

[0297] Similarly high response rates were observed for absolute PASI thresholds. Among patients treated with 100 mg or 300 mg of milizumab, at least 80% of the patients had a PASI score of 5 or lower at week 16, and at least 70% of the patients had a PASI score of 3 or lower. More than 50% of the patients treated with 300 mg of milizumab had an absolute PASI score of 1 or lower. In addition, more than 50% of the patients treated with 100 mg or 300 mg of milizumab had a psoriasis coverage of no more than 1% of the BSA at week 16 (Table 3).

[0298] At week 16, the proportion of patients reporting no symptoms of itching, pain, burning, or stinging (PSS symptom domain score = 0) and no impact of psoriasis on their quality of life (DLQI 0 / 1) was significantly higher in each milizumab treatment group than in the placebo group, with the highest response rates noted in the 100 mg and 300 mg treatment groups (Table 3).

[0299] Among those who had not received biotherapy and those who had received biotherapy previously, the response rates of PASI 90 were increased for 100 mg (66.7%, 47.6%; p = 0.001), 300 mg (69.0%, 63.6%; p = 0.001) and 30 mg (38.7%, 15.0%; p = 0.013) compared with placebo (0%). Similarly, compared with the placebo group (0%), the response rates of PASI 100 were improved in both groups of people after 100 mg (36.7%, 23.8%; p = 0.016), 300 mg (31.0%, 31.8%; p = 0.025) and 30 mg (22.6%, 5.0%, p = 0.050). In addition, compared with placebo, the response rates of PASI 75 for taking 100 mg Q8W and 300 mg Q8W were significantly higher in naïve (80.0% vs 6.5% and 72.4% vs 6.5%; p < 0.001) and previously treated (76.2% vs 0% and 77.3% vs 0%; p < 0.001) patient populations. The results of 30 mg Q8W and placebo were similar in the two patient populations (naïve: 61.3% vs 6.5%; previously treated: 40.0% vs 0%; p < 0.001). In the naïve patient population, compared with placebo (3.2%), the sPGA (0, 1) response rates for 100 mg Q8W (80.6%), 300 mg Q8W (69.0%) and 30 mg Q8W (48.4%) were significantly increased (p < 0.001). In the patient population that had received biotherapy previously, the sPGA (0, 1) response rates of the 100 mg Q8W group (55.0%; p < 0.001), 300 mg Q8W group (68.2%; p < 0.001) and 30 mg Q8W group (20.0%; p < 0.05) were also significantly higher than those of the placebo group (0%).

[0300] Table 3: Research results at week 16

[0301]

[0302]

[0303] ＊ p < 0.05; ＊＊ p < 0.01; ＊＊＊ p < 0.001 vs. placebo.

[0304] BMI = Body Mass Index; NRI = Non-Responder Imputation; PASI = Psoriasis Area and Severity Index; PASI 75 = 75% reduction in Psoriasis Area and Severity Index; PASI 90 = 90% improvement in Psoriasis Area and Severity Index; PASI100 = 100% improvement in Psoriasis Area and Severity Index; sPGA = Static Physician's Global Assessment; BSA = Body Surface Area; PSSI = Psoriasis Scalp Severity Index; PSS = Psoriasis Symptom Scale; DLQI = Dermatology Life Quality Index.

[0305] All placebo subjects and subjects who received less than PASI 90 of mirikizumab treatment at Week 16 received 300 mg of mirikizumab SC Q8W throughout the maintenance period.

[0306] At Week 52, after 36 weeks of receiving the maintenance dose of 300 mg of mirikizumab, 82.0% (n = 41) and 64.0% (n = 32) of the patients in the placebo / 300 mg group achieved PASI 90 and 100, respectively.

[0307] Among the patients who did not achieve PASI 90 at Week 16 and entered the study maintenance period, 76.5% (n = 26), 76.2% (n = 16), and 60.0% (n = 9) of the patients in the 30 mg / 300 mg (n = 34), 100 mg / 300 mg (n = 21), and 300 mg / 300 mg (n = 15) groups achieved PASI 90 at Week 52 ( Figure 1 ).

[0308] At Week 52, 47.1% (n = 16), 38.1% (n = 8), and 33.3% (n = 5) of the patients in the mirikizumab 30 mg / 300 mg, 100 mg / 300 mg, and 300 mg / 300 mg groups achieved PASI 100 ( Figure 2 ).

[0309] When the disease activity level was < PASI 90, subjects who were ≥ PASI 90 at Week 16 (PRN dosing group) received mirikizumab at the assigned baseline dose level with a dosing frequency not exceeding Q8W, and this treatment continued until ≥ PASI 90 was restored.

[0310] After week 16, the median time to loss of PASI 90 response for mirikizumab 30 mg, 100 mg, and 300 mg was 15.7 weeks, 11.8 weeks, and 16.3 weeks, respectively. The median time to loss of PASI 100 response was 14.1 weeks in the mirikizumab 30 mg group, 8.1 weeks in the 100 mg group, and 12.1 weeks in the 300 mg group. After four additional weeks of retreatment, 78.6% of patients in the mirikizumab 30 mg group, 65.4% of the 100 mg group, and 80.0% of the 300 mg group regained PASI 90, and 0% of patients in the mirikizumab 30 mg group, 12.5% of the 100 mg group, and 35.7% of the 300 mg group regained PASI 100. After eight additional weeks of retreatment, 92.9% of patients in the mirikizumab 30 mg group, 88.5% of the 100 mg group, and 96.7% of the 300 mg group regained PASI 90.

[0311] Subcutaneous injection of 100 mg or 300 mg of mirikizumab every 8 weeks resulted in most patients achieving clear or nearly clear skin after 16 weeks of induction therapy and 32 weeks of maintenance therapy. The response rates for all efficacy outcomes in all mirikizumab treatment groups were statistically significantly higher than those in the placebo group, and the response rates were highest in the mirikizumab 100 mg and mirikizumab 300 mg treatment groups. Although almost all patients in this trial had scalp psoriasis at baseline, more than 50% of patients in the mirikizumab 300 mg group and nearly 75% of patients in the mirikizumab 100 mg treatment group had no visible scalp psoriasis at week 16.

[0312] Long-term treatment with mirikizumab (weeks 16 - 52) significantly improved disease activity in patients with moderate-to-severe plaque psoriasis who did not achieve PASI 90 at week 16, both in those who were naïve and those who had prior exposure to biologic therapy (see Figure 3a 、 3b and 3c). The results showed that mirikizumab was effective in achieving high PASI 90 responses in patients who had received biologic therapy.

[0313] Results: Safety

[0314] During the first 16 weeks of this study, the percentage of patients reporting at least one TEAE was comparable across treatment groups. Specific events of hypertension were reported in the 100 mg (3 patients) and 300 mg (2 patients) dose groups, but not in the placebo or 30 mg groups. All of these patients had elevated or borderline elevated blood pressure at screening or baseline; two of them already had hypertension and were receiving treatment. None of these events were serious and none led to discontinuation of treatment. The incidence of infections was also comparable among patients in all treatment groups (Table 4). The most common adverse events included viral upper respiratory and other respiratory infections, injection site pain, hypertension, and diarrhea.

[0315] During the first 16 weeks of the trial, there were no death reports, nor were there any major adverse cardiac events or malignancies. During the initial 16-week period of the trial, 3 patients reported serious adverse events (SAEs). One patient in each of the mirikizumab group and the placebo group had an SAE of suicidal ideation. In both of these cases, each patient had a history of mental illness. Despite improvement in psychiatric treatment, both patients discontinued the study. The third patient who reported an SAE was hospitalized at a study visit due to elevated alanine aminotransferase and aspartate aminotransferase. The results of both tests were >10x ULN (upper limit of normal). The patient had a history of hypercholesterolemia and heavy alcohol use several years before starting the study. Other clinical chemistry parameters were within the normal range (bilirubin and alkaline phosphatase), and the serological results for active or acute hepatitis A, B, or C infection were negative. The patient was completely asymptomatic and denied alcohol use. After receiving oral phospholipid medications, the patient's liver enzymes returned to normal; however, the researchers decided to discontinue the patient's study. After discontinuation, the patient was reported to have resumed heavy alcohol use, and the liver enzymes were elevated again at follow-up.

[0316] Table 4: Adverse Events

[0317]

[0318] *Commonly defined as at least 3 people (≥5%) in any treatment group

[0319] TEAE = treatment-emergent adverse event; SAE = serious adverse event; URTI = upper respiratory tract infection.

[0320] During the maintenance period (weeks 16 - 52) of this study, among the patients who did not achieve PASI 90 at week 16, the most common (≥5%) treatment-emergent adverse events (AEs) included nasopharyngitis (n = 25; 20.8%), upper respiratory tract infection (n = 12; 10.0%), urinary tract infection (n = 6; 5.0%), arthralgia (n = 8; 6.7%), back pain (n = 6; 5.0%), headache (n = 6; 5.0%), injection site pain (n = 7; 5.8%), and hypertension. During the 16 - 52 week period, 4 (3.3%) patients in this group had SAE events, and 6 (5.0%) patients discontinued the study due to AEs.

[0321] During the maintenance period (weeks 16 - 52) of this study, among patients who achieved PASI 90 at week 16, treatment-emergent adverse events (AEs) occurred in 67% of the mirikizumab 30 mg cohort, 53% of the mirikizumab 100 mg cohort, and 62% of the mirikizumab 300 mg group. Two patients reported serious AEs, and three patients discontinued due to AEs (n = 1, 30 mg mirikizumab; n = 2, 100 mg mirikizumab). In all mirikizumab groups, the most common AEs were nasopharyngitis (10.1%), upper respiratory tract infection (5.1%), and hypertension (5.1%).

[0322] Results: Pharmacokinetics (PK) and exposure / response modeling

[0323] Overview of exposure-response model analysis

[0324] Q8W SC administered at doses of 30 mg, 100 mg, and 300 mg provided significant efficacy compared to placebo, with 100 mg and 300 mg showing superior efficacy to 30 mg at week 16. The 300 mg dose provided the highest efficacy for the primary endpoint (PASI 90) at week 16 and showed a trend of providing higher PASI 90 and PASI 100 rates at earlier time points. After week 16, the 300 mg dose also provided a more sustained response. Thus, the study results suggest that the highest dose (300 mg) provides the greatest efficacy.

[0325] The study results also suggest that additional dosing during the induction period may result in improved efficacy at week 16. This recommendation is based on the incremental benefit observed when non-responders at week 16 were administered a third dose and evaluated within 4 to 8 weeks after the administration of that dose. Model-based analysis and simulations suggest that administering 250 mg (total 1000 mg) at weeks 0, 4, 8, and 12 would maximize efficacy at the end of the 16-week induction period.

[0326] The dosing regimen of 250 mg SC Q8W during the maintenance period is expected to maintain or further increase the efficacy achieved at the end of the induction period. The 250 mg dose is expected to achieve exposures and efficacy indistinguishable from those observed with the 300 mg dose. A second maintenance dosing regimen of 125 mg Q8W SC can maintain efficacy at a lower dosing regimen. The second dosing regimen is expected to have minimal overlap in mirikizumab concentrations in individual subjects with the 250 mg mirikizumab Q8W SC regimen.

Claims

1. The use of mirikizumab for the preparation of a medicament for the treatment of moderate to severe plaque psoriasis, said treatment comprising: a) subcutaneously administering to the patient at least one induction dose of mirikizumab, wherein the induction dose comprises 20 mg - 600 mg of mirikizumab; and b) subcutaneously administering to the patient at least one maintenance dose of mirikizumab after the last induction dose, wherein the maintenance dose comprises 20 mg - 600 mg of mirikizumab.

2. The use according to claim 1, wherein the psoriasis is moderate to severe plaque psoriasis.

3. The use according to claim 1 or claim 2, wherein the patient has not received a biologic.

4. The use according to claim 1 or claim 2, wherein the patient has received a biologic.

5. The use according to any one of claims 1 - 4, wherein the at least one induction dose comprises 20 mg, 30 mg, 100 mg, 120 mg, 250 mg, 300 mg, 350 mg, 400 mg or 600 mg of mirikizumab.

6. The use according to any one of claims 1 - 5, wherein one, two, three or four induction doses are administered to the patient.

7. The use according to any one of claims 1 - 6, wherein the at least one maintenance dose comprises 20 mg, 30 mg, 100 mg, 120 mg, 125 mg, 250 mg, 300 mg, 350 mg or 600 mg of mirikizumab.

8. The use according to any one of claims 1 - 7, wherein the at least one maintenance dose is administered 2, 3, 4, 5, 6, 7, 8, 12 or 16 weeks after the last induction dose.

9. The use according to any one of claims 1 - 8, wherein multiple maintenance doses are administered to the patient, and wherein the first maintenance dose is administered 2 to 16 weeks after the last induction dose.

10. The use according to any one of claims 7 - 9, wherein one or more further maintenance doses are administered every 4, 8 or 12 weeks after the first maintenance dose.

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