Methods for the treatment and prevention of generalized pustular psoriasis (GPP)

Abstract

The present invention relates to the treatment of generalized pustular psoriasis (GPP) including the treatment and prevention of flare in adults and adolescents aged 12 years or older with a history of generalized pustular psoriasis, using an anti-IL-36 receptor antibody administered subcutaneously in an initial dose of 300 mg or 600 mg, followed by doses of 150 mg or 300 mg every 4 weeks or every 12 weeks. The use of microRNA 223-3p and 223-5p as biomarkers for monitoring the treatment.

Description

Technical Field

[0001] Sequence Listing This application includes a sequence listing, which is submitted in XML format via the Patent Center and is hereby incorporated by reference in its entirety. The XML copy was created on December 11, 2023, named 09-0745-US-2.XML, and is 139,264 bytes in size.

[0002] Technical Field of the Invention The present invention relates to the use of anti-IL-36 receptor antibodies in methods and compositions for the treatment of adults and adolescents 12 years of age and older having a history of generalized pustular psoriasis (GPP) and / or having a history of generalized pustular psoriasis as diagnosed by the criteria of the European Rare and Severe Psoriasis Expert Network (ERASPEN). More specifically, the present invention relates to the treatment of flares in a subject by administering to the subject a loading subcutaneous dose of 300 mg or 600 mg of an anti-IL-36 receptor antibody, followed by a maintenance dose of 150 mg or 300 mg of the anti-IL-36 receptor antibody administered subcutaneously at 4 or 12 week intervals, including the treatment and prevention of generalized pustular psoriasis (GPP).

[0003] Background Generalized pustular psoriasis is a rare, systemic autoinflammatory skin disease that manifests as recurrent episodes of severe flares affecting the skin and internal organs (Onoufriadis A, Simpson MA, Pink AE, et al. Mutations in IL36RN / IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. Am J Hum Genet 2011;89(3):432-437; Choon SE, Lai NM, Mohammad NA, Nanu NM, Tey KE, Chew SF. Clinical profile, morbidity, and outcome of adult-onset generalized pustular psoriasis: analysis of 102 cases seen in a tertiary hospital in Johor, Malaysia. Int J Dermatol. 2014;53(6):676-84), which can lead to life-threatening consequences. If left untreated, serious complications such as infection and sepsis can occur, potentially leading to hospitalization and, most commonly, even death due to septic shock or heart or kidney failure.

[0004] Acute flares of generalized pustular psoriasis (PUPTS) of varying severity occur in the majority of subjects and may be idiopathic or triggered by external stimuli such as infection, corticosteroid use or withdrawal, stress, or pregnancy. Moderate or severe flares of PUPTS cause significant morbidity and mortality due to tender, painful skin lesions, extreme fatigue, high fever, peripheral blood neutrophilia, and acute phase reactions, as well as sepsis. The acute phase is accompanied by an average hospital stay of 10 days (ranging from 3 to 44 days). The observed mortality rate of 7% reported in a retrospective study of 102 cases of PUPTS observed in tertiary care facilities in Johor, Malaysia, is likely an underestimation because not all subjects with PUPTS were included in the study. Mortality rates may also be underestimated due to failure to identify the cause of death as generalized pustular psoriasis, which is primarily caused by infectious complications and extracutaneous organ signs, such as renal failure, hepatic failure, respiratory failure, and heart failure.

[0005] It is estimated that up to 50% of subjects may suffer from chronic GPP, characterized by persistent erythema and desquamation (which may also include joint symptoms), after a response to treatment or after the spontaneous cessation of flare.

[0006] The classic symptoms of a GPP flare, as described by von Zumbusch, are strongly correlated with polymorphisms in the IL-36 receptor signaling pathway. Individuals with loss-of-function mutations in the IL36RN gene, which encodes the endogenous IL36 receptor antagonist (IL-36RN), have a dramatically higher incidence of GPP, suggesting that uncontrolled upregulation of IL36 signaling, resulting from a defect in IL36RN antagonism, leads to the inflammatory episodes observed in GPP. Genetic studies in humans have demonstrated the occurrence of GPP clusters in families with loss-of-function mutations in IL36RN that result in uncontrolled IL36 receptor signaling. Mutations in other genes associated with the IL36 pathway (e.g., CARD14) also lead to GPP. Recent gene expression studies have shown sustained activation of IL-1 and IL-36 in GPP, inducing neutrophil chemokine expression, infiltration, and pustule formation, suggesting that the IL-1 / IL-36 inflammatory axis is a powerful inducer of the disease pathogenesis in GPP. Furthermore, a recent meta-analysis investigated 233 published cases of GPP. It was found that 49 of these cases (21.0%) carried a recessive allele of IL36RN. These 49 recessive IL36RN alleles defined a GPP phenotype characterized by early onset of systemic inflammation and a high risk of these conditions.

[0007] The IL36 receptor is a cell surface receptor involved in inflammatory responses in the skin and intestines. It is a novel member of the IL1 receptor family, forming a heterodimeric complex with the IL1 receptor coprotein. The heterodimeric IL36 receptor system, including stimulant ligands (IL36α, IL36β, IL36γ) and inhibitory ligands (IL36Ra), shares many structural and functional similarities with other members of the IL1 / IL1 receptor family, such as IL1, IL18, and IL33 (R17-3602). All IL1 family members (IL1α, IL1β, IL18, IL36α, IL36β, IL36γ, and IL38) signal through their respective homologous receptor proteins, and upon ligand binding to the receptor, they recruit a common IL1RacP subunit, activating the NFκβ and MAP kinase pathways in receptor-positive cell types. In human skin tissue, the IL36 receptor is expressed in keratinocytes, cutaneous fibroblasts, and infiltrating myeloid cells. Activation of the IL36 receptor in skin tissue induces the production of inflammatory mediators (e.g., CCL20, MIP-1β, TNF-α, IL12, IL17, IL23, TGF-β) and modulates tissue remodeling genes (e.g., matrix metalloproteinases (MMPs), TGF-β). Therefore, the association between GPP and IL36RN mutations is somewhat similar to the well-established neonatal development of aseptic multiple osteomyelitis, periostitis, and pustulosis caused by the absence of an interleukin-1 receptor antagonist. In this case, the absence of a receptor antagonist allows for the unantagonism of interleukin-1, resulting in life-threatening systemic inflammation affecting the skin and bone. These clinical presentations responded to empirical treatment with the recombinant interleukin-1 receptor antagonist anakinra.

[0008] To properly manage GPP, both the acute and long-term chronic aspects of the disease must be addressed; that is, acute flares must be addressed as soon as they occur spontaneously, and maintenance therapy must be administered to prevent future flares. The treatment and prevention of GPP flares aim to control severe acute conditions by controlling systemic signs (C-reactive protein, fever, neutrophilia) and pustules (e.g., visible signs of inflammation), and further, to prevent infection and other complications that could make the event life-threatening. However, long-term maintenance therapy is important for sustained control of the signs and symptoms of GPP flares, as well as for preventing the occurrence of flares.

[0009] The European Network of Specialists in Rare and Severe Psoriasis (ERASPEN) common criteria for acute GPP include the presence of primary, sterile, macroscopically visible pustules on non-peripheral skin, with or without systemic inflammation, with or without plaque psoriasis, and being recurrent (more than one episode) or persistent (more than three months) (excluding cases where the pustules are limited to plaque psoriasis) (website: eraspen.eu / home / rfp / diagnostic-criteria.html (accessed May 9, 2018); European Network of Specialists in Rare and Severe Psoriasis (ERASPEN); 2018).

[0010] Chronic GPP describes the inter-flare state between disease flares, which can be characterized by the persistence of residual skin symptoms such as erythema, desquamation, and pustules. The clinical findings of GPP are of an episodic nature, which may include seemingly normal skin during the chronic period between very acute and severe disease flares.

[0011] While approved treatments for GPP flares are available, an unmet need for the treatment and prevention of GPP flares still exists (Choon, et al. 2014, ibid.). Prevention of GPP flares with safe and effective treatments would satisfy the high unmet need for access to proven treatments for subjects experiencing frequent relapses of this devastating condition, which is associated with high morbidity and mortality. Furthermore, due to the burden and severity of its symptoms, associated comorbidities, and the lack of tailored treatment, GPP can have a deeper impact on human health-related quality of life than other chronic skin conditions such as plaque psoriasis (psoriasis vulgaris, PV) (Lebwohl M, Medeiros RA, Mackey RH, et al. The Disease Burden of Generalized Pustular Psoriasis: Real-World Evidence From CorEvitas' Psoriasis Registry. Journal of Psoriasis and Psoriatic Arthritis 2022; 7(2): 71-8). Therefore, there is a need in the art for novel targeted therapies for the treatment and / or prevention of GPP.

[0012] Summary of the Invention The present invention addresses the above need by providing a biopharmaceutical, particularly an antibody, that binds to the IL-36 receptor, and provides therapeutic and maintenance treatments for generalized pustular psoriasis (GPP), including the treatment and prevention of flares, by preventing the onset and / or frequency of GPP flares and other accompanying signs and symptoms of GPP flares.

[0013] In a first embodiment, the present invention relates to the treatment of generalized pustular psoriasis (GPP), including the treatment and prevention of flares, in adults and adolescents aged 12 years or older who have a history of generalized pustular psoriasis and / or a history of generalized pustular psoriasis as diagnosed by the European Network of Rare and Severe Psoriasis Specialists (ERASPEN), comprising the steps of administering or having administered a therapeutically effective amount of an anti-IL-36 receptor antibody or its antigen-binding fragment to an adult or adolescent. In a preferred embodiment, the present invention relates to the treatment of GPP in adults and adolescents aged 12 years or older when flares are not occurring. In one embodiment related to this aspect, the anti-IL-36 receptor antibody is spesolimab.

[0014] In a second aspect, the present invention relates to a method for reducing or alleviating the signs and symptoms of generalized pustular psoriasis (GPP) in adults and adolescents aged 12 years or older who have a history of generalized pustular psoriasis and / or a history of generalized pustular psoriasis as diagnosed by the European Network of Rare and Severe Psoriasis Specialists (ERASPEN), the method comprising administering or having administered a therapeutically effective amount of an anti-IL-36 receptor antibody or its antigen-binding fragment to an adult or adolescent. In one embodiment related to this aspect, the present invention is a method for reducing or alleviating the number, prevalence, severity, and / or recurrence of flares in an adult or adolescent having GPP, the method comprising administering or having administered a therapeutically effective amount of an anti-IL-36 receptor antibody or its antigen-binding fragment to the subject. In one embodiment related to this aspect, the anti-IL-36 receptor antibody is spesolimab.

[0015] In a third aspect, the present invention relates to a method for reducing the occurrence and / or frequency of acute flares of generalized pustular psoriasis (GPP) in adults and adolescents aged 12 years or older who have a history of generalized pustular psoriasis and / or a history of generalized pustular psoriasis as diagnosed by the European Network of Rare and Severe Psoriasis Specialists (ERASPEN), the method comprising administering or having administered a therapeutically effective amount of the anti-IL-36 receptor antibody or its antigen-binding fragment to an adult or adolescent. In one embodiment related to this aspect, the anti-IL-36 receptor antibody is spesolimab.

[0016] In one embodiment relating to aspects 1 to 3, the anti-IL-36 receptor antibody or its antigen-binding fragment comprises a) a light chain variable region containing the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 35, 102, 103, 104, 105, 106, or 140 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, or 111 (H-CDR2); and the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

[0017] In further embodiments relating to aspects 1 to 3, the anti-IL-36 receptor antibody or its antigen-binding fragment is: ia) Light chain variable region containing the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 102 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3), II.a) Light chain variable region containing the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 103 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3), III.a) Light chain variable region containing the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 104 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3), IV.a) Light chain variable region containing the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 105 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3), Va) Light chain variable region containing the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 106 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3), VI.a) Light chain variable region containing the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 140 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3), Includes.

[0018] In further embodiments relating to aspects 1 to 3, the anti-IL-36 receptor antibody or its antigen-binding fragment is: (i) Light chain variable region containing the amino acid sequence of SEQ ID NO: 77; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 87; or, (ii) A light chain variable region containing the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 88; or, (iii) Light chain variable region containing the amino acid sequence of SEQ ID NO: 77; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 89; or, (iv) A light chain variable region containing the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 87; or, (v) Light chain variable region containing the amino acid sequence of SEQ ID NO: 80; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 88; or, (vi) Light chain variable region containing the amino acid sequence of SEQ ID NO: 80; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 89; or, (vii) Light chain variable region containing the amino acid sequence of SEQ ID NO: 85; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 100; or, (viii) Light chain variable region containing the amino acid sequence of SEQ ID NO: 85; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 101; or, (ix) Light chain variable region containing the amino acid sequence of SEQ ID NO: 86; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 100; or (x) Light chain variable region containing the amino acid sequence of SEQ ID NO: 86; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 101 Includes.

[0019] In further embodiments relating to aspects 1 to 3, the anti-IL-36 receptor antibody or its antigen-binding fragment is: i. A light chain containing the amino acid sequence of SEQ ID NO: 115; and a heavy chain containing the amino acid sequence of SEQ ID NO: 125; or ii. A light chain comprising the amino acid sequence of SEQ ID NO: 115; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 126; or iii. A light chain comprising the amino acid sequence of SEQ ID NO: 115; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 127; or iv. A light chain comprising the amino acid sequence of SEQ ID NO: 118; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 125; or v. A light chain comprising the amino acid sequence of SEQ ID NO: 118; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 126; or vi. A light chain comprising the amino acid sequence of SEQ ID NO: 118; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 127; or vii. A light chain comprising the amino acid sequence of SEQ ID NO: 123; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 138; or viii. A light chain comprising the amino acid sequence of SEQ ID NO: 123; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 139; or ix. A light chain comprising the amino acid sequence of SEQ ID NO: 124; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 138 is included.

[0020] In one embodiment related to any of the above groups of embodiments or groups of implementations, the anti-IL-36 receptor antibody is spesolimab.

[0021] In one embodiment related to any of Embodiments 1 to 3, the second therapeutic agent is administered to the subject before, after, or simultaneously with the anti-IL-36 receptor antibody or an antigen-binding fragment thereof. In related embodiments, the second therapeutic agent is selected from the group consisting of an antibacterial agent, an antiviral agent, an antifungal agent, another IL-36 receptor antagonist, an anti-PDE (phosphodiesterase) 4 antibody, an IL-17 antagonist, an IL-12 / IL-23 antagonist, an IL-23 antagonist, and an IL-1 antagonist, an IgE inhibitor, a corticosteroid, a non-steroidal anti-inflammatory drug, an IL-4 receptor antagonist, a tumor necrosis factor (TNF)-α inhibitor, and interferon γ.

[0022] Another embodiment of the present invention relates to the treatment of generalized pustular psoriasis (GPP), including the treatment and prevention of flares, in subjects with a history of symptoms of generalized pustular psoriasis (GPP) and / or a history (diagnosis) of generalized pustular psoriasis confirmed on the common diagnostic criteria defined by the ERASPEN diagnostic criteria, by administering to the subject a loading dose of 600 mg of anti-IL-36 receptor antibody or its antigen-binding fragment at week 0 or 1; followed by a maintenance dose containing 600 mg of the anti-IL-36 receptor antibody administered to the subject at intervals of 2, 4, 5, 6, 7, 8, 10, or 12 weeks. In a preferred embodiment, the present invention relates to the loading dose and maintenance dose, administered subcutaneously for the treatment of GPP in adults and adolescents aged 12 years or older when flares are not occurring. In an exemplary embodiment, a subcutaneous loading dose of 600 mg (four 150 mg injections) is administered, followed by another 600 mg (four 150 mg injections) subcutaneously four weeks later, and then every four weeks thereafter.

[0023] Another embodiment of the present invention relates to the treatment of generalized pustular psoriasis (GPP), including the treatment and prevention of flares, in subjects with a history of symptoms of generalized pustular psoriasis (GPP) and / or a history (diagnosis) of generalized pustular psoriasis confirmed on the common diagnostic criteria defined by the ERASPEN diagnostic criteria, by administering a loading dose of 600 mg of anti-IL-36 receptor antibody or its antigen-binding fragment at week 0 or 1; followed by a maintenance dose containing 300 mg of the anti-IL-36 receptor antibody administered to the subject at intervals of 2, 4, 5, 6, 7, 8, 10, or 12 weeks. In a preferred embodiment, the present invention relates to the loading dose and maintenance dose, administered subcutaneously for the treatment of GPP in adults and adolescents aged 12 years or older when flares are not occurring. In an exemplary embodiment, a subcutaneous loading dose of 600 mg (four 150 mg injections) is administered subcutaneously, followed by 300 mg (two 150 mg injections) four weeks later, and then every four weeks thereafter.

[0024] In another embodiment, the present invention relates to the treatment of generalized pustular psoriasis (GPP), including the treatment and prevention of flares, in subjects with a history of symptoms of generalized pustular psoriasis (GPP) and / or a history (diagnosis) of generalized pustular psoriasis confirmed on the common diagnostic criteria defined by the ERASPEN diagnostic criteria, by administering a loading dose of 600 mg of anti-IL-36 receptor antibody or its antigen-binding fragment at week 0 or 1, followed by a maintenance dose of 150 mg of the anti-IL-36 receptor antibody administered to the subject at intervals of 2, 4, 5, 6, 7, 8, 10, or 12 weeks. In a preferred embodiment, the present invention relates to the loading dose and maintenance dose, administered subcutaneously for the treatment of GPP in adults and adolescents aged 12 years or older, when flares are not occurring. In an exemplary embodiment, a subcutaneous loading dose of 600 mg (four 150 mg injections) is administered, followed by 150 mg (one 150 mg injection) subcutaneously four weeks later, and thereafter every four weeks.

[0025] In another embodiment, the present invention relates to the treatment of generalized pustular psoriasis (GPP), including the treatment and prevention of flares, in subjects with a history of symptoms of generalized pustular psoriasis (GPP) and / or a history (diagnosis) of generalized pustular psoriasis confirmed on the common diagnostic criteria defined by the ERASPEN diagnostic criteria, by administering a loading dose of 300 mg of anti-IL-36 receptor antibody or its antigen-binding fragment at week 0 or 1, followed by maintenance doses containing 300 mg of the anti-IL-36 receptor antibody administered at intervals of 2, 4, 5, 6, 7, 8, 10, or 12 weeks. In a preferred embodiment, the present invention relates to the loading dose and maintenance dose, administered subcutaneously for the treatment of GPP in adults and adolescents aged 12 years or older, when flares are not occurring. In an exemplary embodiment, a subcutaneous loading dose of 300 mg (two 150 mg injections) is administered, followed by another 300 mg (two 150 mg injections) subcutaneously after 4 weeks, and thereafter every 4 weeks.

[0026] In another embodiment, the present invention relates to the treatment of generalized pustular psoriasis (GPP), including the treatment and prevention of flares, in subjects with a history of symptoms of generalized pustular psoriasis (GPP) and / or a history (diagnosis) of generalized pustular psoriasis confirmed on the common diagnostic criteria defined by the ERASPEN diagnostic criteria, by administering a loading dose of 300 mg of anti-IL-36 receptor antibody or its antigen-binding fragment at week 0 or 1, followed by a maintenance dose of 150 mg of the anti-IL-36 receptor antibody administered at intervals of 2, 4, 5, 6, 7, 8, 10, or 12 weeks. In a preferred embodiment, the present invention relates to the loading dose and maintenance dose, administered subcutaneously for the treatment of GPP in adults and adolescents aged 12 years or older, when flares are not occurring. In an exemplary embodiment, a subcutaneous loading dose of 300 mg (two 150 mg injections) is administered, followed by 150 mg (one 150 mg injection) subcutaneously after 12 weeks, and thereafter every 12 weeks.

[0027] In aspects of the present invention relating to any of the above embodiments, the loading dose and / or maintenance dose(s) are administered parenterally, for example, intravenously and / or subcutaneously.

[0028] In one embodiment relating to any of the above sets of embodiments and embodiments, the anti-IL-36 receptor antibody is administered in one or more subcutaneous doses, where the total loading dose of the anti-IL-36 receptor antibody or its antigen-binding fragment is at least 300 mg to 600 mg of the anti-IL-36 receptor antibody, followed by a maintenance dose of 150 mg to 600 mg of the anti-IL-36 receptor antibody, administered subcutaneously to the subject at intervals of 4 weeks (q4w) to 12 weeks (q12w). In one embodiment, the total loading dose of 300 mg of the anti-IL-36 receptor antibody or its antigen-binding fragment is delivered subcutaneously at week 0 or 1, followed by a maintenance dose of 150 mg of the anti-IL-36 receptor antibody, administered subcutaneously to the subject at intervals of 12 weeks (q12w). In another embodiment, a loading dose of 600 mg of the anti-IL-36 receptor antibody is delivered subcutaneously at week 0 or 1, followed by a maintenance dose of 600 mg of the anti-IL-36 receptor antibody administered subcutaneously to the subject at 12-week (q12w) intervals. In another embodiment, a loading dose of 600 mg of the anti-IL-36 receptor antibody is delivered subcutaneously at week 0 or 1, followed by a maintenance dose of 300 mg of the anti-IL-36 receptor antibody administered subcutaneously to the subject at 12-week (q12w) intervals. In yet another embodiment, a loading dose of 600 mg of the anti-IL-36 receptor antibody is delivered subcutaneously at week 0 or 1, followed by a maintenance dose of 600 mg of the anti-IL-36 receptor antibody administered subcutaneously to the subject at 4-week (q4w) intervals. In a preferred embodiment, a total loading dose of 600 mg of the anti-IL-36 receptor antibody (e.g., four 150 mg injections) is delivered subcutaneously at week 0 or 1, followed by a maintenance dose containing 300 mg (e.g., two 150 mg injections) of the anti-IL-36 receptor antibody, which is subcutaneously administered to the subject four weeks after the last loading dose and thereafter every four weeks (q4w).

[0029] In one embodiment, the present invention relates to a method for treating the occurrence of a GPP flare in a subject receiving maintenance treatment with an anti-IL-36 antibody or its antigen-binding fragment as described in any of the prior embodiments, the method comprising administering to the subject at least one intravenous (iv) dose of 900 mg of anti-IL-36 receptor antibody. In the relevant embodiment, treatment of a GPP flare is at any point during the maintenance treatment period in a subject diagnosed with a flare, where a GPP flare is defined as the total score of two or more generalized pustular psoriasis generalized assessments (GPPGA) and two or more GPPGA pustule subscores. In the relevant embodiment, if symptoms of a GPP flare persist, an additional 900 mg dose may be administered one week after the initial dose.

[0030] In one embodiment, the present invention relates to a method for improving the quality of life by at least 10% in a subject having a history of symptoms of generalized pustular psoriasis and / or a history (diagnosis) of generalized pustular psoriasis confirmed based on the common diagnostic criteria defined by the ERASPEN diagnostic criteria (website:eraspen.eu / home / rfp / diagnostic-criteria.html (accessed May 9, 2018); European Network of Specialists in Rare and Severe Psoriasis (ERASPEN); 2018), the method comprising the steps of administering to the subject a loading dose of 600 mg of anti-IL-36 receptor antibody or its antigen-binding fragment in the first week; followed by a maintenance dose of 300 mg of the anti-IL-36 receptor antibody administered to the subject at intervals of 2, 4, 5, 6, 7, 8, 10 or 12 weeks. In related embodiments, the method includes administering to the subject a loading dose of 600 mg of the anti-IL-36 receptor antibody in week 0 or 1, followed by a maintenance dose of 600 mg of the anti-IL-36 receptor antibody administered at 12-week (q12w) intervals. In related embodiments, the method includes administering to the subject a loading dose of 600 mg of the anti-IL-36 receptor antibody in week 0 or 1, followed by a maintenance dose of 300 mg of the anti-IL-36 receptor antibody administered at 12-week (q12w) intervals. In related embodiments, the method includes administering to the subject a loading dose of 600 mg of the anti-IL-36 receptor antibody in week 0 or 1, followed by a maintenance dose of 600 mg of the anti-IL-36 receptor antibody administered at 4-week (q4w) intervals. In related embodiments, the method includes administering to a subject a loading dose of 600 mg of the anti-IL-36 receptor antibody in week 0 or 1, followed by a maintenance dose of 300 mg of the anti-IL-36 receptor antibody administered to the subject at 4-week (q4w) intervals.

[0031] In one embodiment, the present invention relates to a method for improving the quality of life by at least 10% in a subject having a history of symptoms of generalized pustular psoriasis and / or a history (diagnosis) of generalized pustular psoriasis confirmed based on common diagnostic criteria defined by the ERASPEN diagnostic criteria, the method comprising administering to the subject a loading dose of 300 mg of the anti-IL-36 receptor antibody or its antigen-binding fragment at week 0 or 1, followed by a maintenance dose of 150 mg of the anti-IL-36 receptor antibody administered to the subject at intervals of 2, 4, 5, 6, 7, 8, 10, or 12 weeks. In a related embodiment, the method comprises administering to the subject a loading dose of 300 mg of the anti-IL-36 receptor antibody at week 0 or 1, followed by a maintenance dose of 150 mg of the anti-IL-36 receptor antibody administered to the subject at intervals of 12 weeks (q12w).

[0032] In one embodiment relating to any of the above aspects, subjects having a history of symptoms of generalized pustular psoriasis and / or a history (diagnosis) of generalized pustular psoriasis confirmed based on common diagnostic criteria defined by the ERASPEN diagnostic criteria demonstrate a reduction in the occurrence of at least one GPP flare, as measured by the proportion of patients who experienced at least one flare event, where a GPP flare is defined as an increase of 2 or more in the total score of the Physician's Global Assessment for Generalized Pustular Psoriasis (GPPGA) from baseline to 48 weeks after the start of treatment, and 2 or more GPPGA pustule subscores.

[0033] In one embodiment relating to any of the above aspects, subjects with a history of symptoms of generalized pustular psoriasis and / or a history (diagnosis) of generalized pustular psoriasis confirmed based on common diagnostic criteria defined by the ERASPEN diagnostic criteria show a reduced risk of developing a GPP flare, where a GPP flare is defined as an increase of 2 or more in the total score of the Physician's Global Assessment for Generalized Pustular Psoriasis (GPPGA) from baseline to 48 weeks after the start of treatment, and 2 or more GPPGA pustule subscores.

[0034] In one embodiment relating to any of the above aspects, a subject having a history of symptoms of generalized pustular psoriasis and / or a history (diagnosis) of generalized pustular psoriasis confirmed based on common diagnostic criteria defined by the ERASPEN diagnostic criteria has a total physician's assessment (GPPGA) score of 1 or less and a GPPGA pustule subscore of 1 or less prior to administration of the initial loading dose of anti-IL-36 receptor antibody.

[0035] In one embodiment relating to any of the above aspects, a subject having a history of symptoms of generalized pustular psoriasis and / or a history (diagnosis) of generalized pustular psoriasis confirmed based on common diagnostic criteria defined by the ERASPEN diagnostic criteria has a total physician's global assessment (GPPGA) score of 1 or less and a GPPGA pustule subscore of 1 or less after administration of an initial loading dose of 300 mg or 600 mg of anti-IL-36 receptor antibody or its antigen-binding fragment subcutaneously at week 0 or 1, followed by at least one maintenance dose of 150, 300 mg or 600 mg of the anti-IL-36 receptor antibody administered to the subject at intervals of 2, 4, 5, 6, 7, 8, 10, or 12 weeks. In related embodiments, the subject has a total physician's global assessment (GPPGA) score of 1 or less for generalized pustular psoriasis and a GPPGA pustule subscore of 1 or less, at least 48 weeks after the initial loading dose, following administration of the loading and maintenance doses of the anti-IL-36 receptor antibody.

[0036] In one embodiment relating to any of the above aspects, a subject having a history of symptoms of generalized pustular psoriasis and / or a history (diagnosis) of generalized pustular psoriasis confirmed based on common diagnostic criteria defined by the ERASPEN diagnostic criteria has a total physician's global assessment (GPPGA) score of 1 or less and a GPPGA pustule subscore of 1 or less before and after administration of the initial loading dose of the anti-IL-36 receptor antibody or its antigen-binding fragment. In a related embodiment, a subject having a history of GPP flare has a total physician's global assessment (GPPGA) score of 1 or less and a GPPGA pustule subscore of 1 or less from before and after administration of the initial loading dose of the anti-IL-36 receptor antibody to at least 48 weeks after the initial loading dose.

[0037] In one embodiment, the present invention relates to a method for treating generalized pustular psoriasis (GPP), including the treatment and prevention of flares in a subject having a history of symptoms of generalized pustular psoriasis (GPP) and / or a history (diagnosis) of generalized pustular psoriasis confirmed based on common diagnostic criteria defined by the ERASPEN diagnostic criteria, and / or having a GPPGA pustule subscore of 1 or less, wherein the method (a) administers to the subject a loading dose of 600 mg of anti-IL-36 receptor antibody or its antigen-binding fragment at week 0 to week 1, followed by administration at intervals of 2, 4, 5, 6, 7, 8, 10 or 12 weeks. (b) a step of administering a maintenance dose containing 600 mg of the anti-IL-36 receptor antibody (the loading dose and / or maintenance dose of the anti-IL-36 receptor antibody is delivered subcutaneously); and (b) a step of evaluating the subject's total score of the Physician's Global Assessment of GPP (GPPGA) and / or GPPGA pustule subscores for at least 48 weeks after the initial loading dose (where the time to the first GPP flare up to 48 weeks after the start of treatment is defined by an increase of 2 or more GPPGA pustule subscores and an increase of 2 or more GPPGA total score from baseline).In another embodiment, the present invention relates to a method for treating generalized pustular psoriasis (GPP), including the treatment and prevention of flares in a subject having a history of symptoms of generalized pustular psoriasis (GPP) and / or a history (diagnosis) of generalized pustular psoriasis confirmed based on common diagnostic criteria defined by the ERASPEN diagnostic criteria, and / or having a GPPGA pustule subscore of 1 or less, wherein the method (a) administers to the subject a loading dose of 600 mg of anti-IL-36 receptor antibody or its antigen-binding fragment at week 0 to week 1, followed by administration at intervals of 2, 4, 5, 6, 7, 8, 10 or 12 weeks. (b) a step of administering a maintenance dose containing 300 mg of the anti-IL-36 receptor antibody (the loading dose and / or maintenance dose of the anti-IL-36 receptor antibody is delivered subcutaneously); and (b) a step of evaluating the subject's total score of the Physician's Global Assessment of GPP (GPPGA) and / or GPPGA pustule subscores for at least 48 weeks after the initial loading dose (where the time to the first GPP flare up to 48 weeks after the start of treatment is defined by an increase of 2 or more GPPGA pustule subscores and an increase of 2 or more GPPGA total score from baseline). In a related embodiment, step a) of the method includes administering to the subject a loading dose of 600 mg of anti-IL-36 receptor antibody or its antigen-binding fragment during weeks 0 to 1, followed by a maintenance dose containing 600 mg of the anti-IL-36 receptor antibody administered to the subject at 12-week intervals (the loading dose and / or maintenance dose of the anti-IL-36 receptor antibody is delivered subcutaneously). In a related embodiment, step a) of the method includes administering to the subject a loading dose of 600 mg of anti-IL-36 receptor antibody or its antigen-binding fragment during weeks 0 to 1, followed by a maintenance dose containing 300 mg of the anti-IL-36 receptor antibody administered to the subject at 12-week intervals (the loading dose and / or maintenance dose of the anti-IL-36 receptor antibody is delivered subcutaneously).In a related embodiment, step a) of the method includes administering to the subject a loading dose of 600 mg of anti-IL-36 receptor antibody from week 0 to week 1, followed by a maintenance dose containing 600 mg of the anti-IL-36 receptor antibody administered to the subject at 4-week intervals (the loading dose and / or maintenance dose of the anti-IL-36 receptor antibody is delivered subcutaneously). In a related embodiment, step a) of the method includes administering to the subject a loading dose of 600 mg of the anti-IL-36 receptor antibody from week 0 to week 1, followed by a maintenance dose containing 300 mg of the anti-IL-36 receptor antibody administered to the subject at 4-week intervals (the loading dose and / or maintenance dose of the anti-IL-36 receptor antibody is delivered subcutaneously).

[0038] In one embodiment, the present invention relates to a method for treating and preventing flares in a subject having a history of symptoms of generalized pustular psoriasis (GPP) and / or a history (diagnosis) of generalized pustular psoriasis confirmed based on common diagnostic criteria defined by the ERASPEN diagnostic criteria, and / or a GPPGA pustule subscore of 1 or less, wherein the method comprises (a) administering to the subject a loading dose of 300 mg of anti-IL-36 receptor antibody or its antigen-binding fragment at week 0 or week 1, followed by administration to the subject at intervals of 2, 4, 5, 6, 7, 8, 10 or 12 weeks. (b) a step of administering a maintenance dose containing 150 mg of the anti-IL-36 receptor antibody in one dose (the loading dose and / or maintenance dose of the anti-IL-36 receptor antibody is delivered intravenously and / or subcutaneously); and (b) evaluating the subject's total score of the Physician's Global Assessment of GPP (GPPGA) and / or GPPGA pustule subscore from after the initial loading dose up to at least 48 weeks (where the time from the initial GPP flare to 48 weeks is defined by an increase of 2 or more GPPGA pustule subscores and an increase of 2 or more GPPGA total score from baseline). In the related embodiments, (a) of the method includes administering to the subject a loading dose of 300 mg of the anti-IL-36 receptor antibody between weeks 0 and 1, followed by a maintenance dose of 150 mg of the anti-IL-36 receptor antibody administered to the subject at 12-week intervals (the loading dose and / or maintenance dose of the anti-IL-36 receptor antibody is delivered subcutaneously). In the related embodiments, the total score of the Physician's Global Assessment for GPP (GPPGA) and / or the GPPGA pustule subscore are measured at weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 after the start of treatment, and / or 16 weeks after the last dose.

[0039] In one embodiment relating to any of the above aspects, the present invention relates to a treatment for generalized pustular psoriasis (GPP), including the treatment and prevention of flares in a subject having a history of symptoms of GPP and / or a history (diagnosis) of generalized pustular psoriasis confirmed based on common diagnostic criteria defined by the ERASPEN diagnostic criteria, wherein clinical improvement is defined as a reduction in the risk of GPP flares and / or a reduction in the risk of worsening of the Psoriasis Symptom Rating Scale (PSS) up to 48 weeks after the start of treatment, defined as a 4-point increase in the total score from baseline. In related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of GPP subjects treated with the anti-IL-36 receptor antibody show a reduced risk of exacerbation of the Psoriasis Symptom Rating Scale (PSS) after the start of treatment, at weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, and / or 48 of treatment.

[0040] In one embodiment relating to any of the above aspects, the present invention relates to a treatment method for generalized pustular psoriasis (GPP), including the treatment and prevention of flares in subjects having a history of symptoms of generalized pustular psoriasis (GPP) and / or a history (diagnosis) of generalized pustular psoriasis confirmed based on common diagnostic criteria defined by the ERASPEN diagnostic criteria, wherein clinical improvement is defined as a reduction in the risk of worsening of the Quality of Life Indicator of Skin Disease (DLQI) up to 48 weeks after the start of treatment (where worsening is defined as an increase of 4 points in the total score from baseline). In the relevant embodiment, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of GPP subjects treated with the anti-IL-36 receptor antibody show a reduction in the risk of worsening of the Quality of Life Indicator of Skin Disease (DLQI) at weeks 4, 8, 12, 24, 36, and / or 48 of treatment.

[0041] In one embodiment relating to any of the above sets of embodiments or embodiments, administration of an anti-IL-36 receptor antibody or its antigen-binding fragment to a subject having a history of symptoms of generalized pustular psoriasis and / or a history (diagnosis) of generalized pustular psoriasis confirmed based on the common diagnostic criteria defined by the ERASPEN diagnostic criteria achieves one or more of the following results: (a) After administration of the anti-IL-36 receptor antibody, without the use of treatment for GPP flare or standard treatment (SoC) prescribed by the principal investigator, at all visits up to week 48, the subject is generalized. (b) Maintaining a global assessment (GPPGA) pustule subscore of 0 for pustular psoriasis; and / or (b) Maintaining a GPPGA total score of 0 or 1 after administration of the anti-IL-36 receptor antibody, after the initial loading dose, up to week 48; or (c) Experiencing sustained remission as defined for a subject treated with the anti-IL-36 receptor antibody, maintaining a GPPGA score of 0 or 1 (clear or nearly clear) at all visits up to week 48 without treatment for GPP flares or standard of care (SoC) prescribed by the principal investigator.

[0042] One embodiment of the present invention relating to any of the above aspects concerns the proportion of subjects with a history of symptoms of generalized pustular psoriasis and / or a history (diagnosis) of generalized pustular psoriasis confirmed based on common diagnostic criteria defined by the ERASPEN diagnostic criteria, who achieved any of the above results, greater than that of placebo-treated subjects, for any of the listed evaluation items by administration of an anti-IL-36 receptor antibody.

[0043] In another aspect, the present invention relates to a method for treating generalized pustular psoriasis (GPP), including the treatment and prevention of flares in a subject having a history of symptoms of generalized pustular psoriasis and / or a history (diagnosis) of generalized pustular psoriasis confirmed on the common diagnostic criteria defined by the ERASPEN diagnostic criteria, the method comprising (a) obtaining a biological sample from the subject (the biological sample here obtained from a source including a skin lesion or whole blood); (b) determining the gene expression profile of one or more genes; and (c) administering to the subject an effective amount of anti-IL-36 receptor antibody as described in any embodiment relating to any of the above aspects. In related embodiments, one or more of the profiled genes are IL12B, IL1B, IL6, CXCL1, IL23A, TNF, IL17C, IL24, or IL1B in skin lesions, and IL1B, S100A9, S100A12, S100A8, MMP25, MMP9, or CD177 in whole blood.

[0044] In another aspect, the present invention relates to a method for detecting the presence or absence of a beneficial response in GPP patients after administration of an anti-interleukin-36 receptor antibody (anti-IL-36R antibody), comprising the steps of (a) obtaining biological samples from patients before treatment and after treatment with an anti-IL-36 receptor antibody; (b) measuring the levels of one or more biomarkers in each sample before and after treatment, or the expression levels of one or more biomarkers in each sample; (c) comparing the pre-treatment level of a biomarker with the post-treatment level; and (d) determining the difference between the levels of the pre-treatment sample and the post-treatment sample to reflect a beneficial response in the patient (wherein one or more biomarkers include microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p, where post-treatment downregulation or upregulation compared to the pre-treatment baseline indicates a beneficial response). In exemplary embodiments, the biological sample is a skin biopsy material, blood, plasma, or serum sample. In preferred embodiments, one or more microRNAs are miR-223-5p or miR-223-3 in the skin lesion or serum.

[0045] In another embodiment, the present invention relates to a method for detecting the presence or absence of a beneficial response in GPP patients after administration of an anti-interleukin-36 receptor antibody (anti-IL-36R antibody), comprising the steps of: a) preparing biological samples from patients before treatment and after treatment with an anti-IL-36R antibody; b) measuring the level of one or more biomarkers in each of the pre-treatment and post-treatment samples, or the expression level of one or more biomarkers in each sample, ex vivo; c) comparing the pre-treatment level of the biomarker with the post-treatment level; and d) determining the difference between the levels of the pre-treatment sample and the post-treatment sample to reflect a beneficial response in the patient (wherein one or more biomarkers include microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p, where post-treatment downregulation or upregulation compared to the pre-treatment baseline indicates a beneficial response). In exemplary embodiments, the biological sample is a skin biopsy specimen, blood, plasma, or serum sample. In preferred embodiments, one or more microRNAs are miR-223-5p or miR-223-3 in the skin lesion or serum.

[0046] In another embodiment, the present invention provides a step of a) preparing biological samples from a patient before treatment and after treatment with an anti-IL-36R antibody; b) measuring the level of one or more biomarkers in each of the pre-treatment and post-treatment samples, or the expression level of one or more biomarkers in each sample (e.g., ex vivo); c) comparing the pre-treatment level of a biomarker with the post-treatment level; and d) determining the difference between the levels of the pre-treatment sample and the post-treatment sample to reflect a beneficial response in the patient (here, one or more biomarkers) The maker relates to the use of an anti-interleukin-36 receptor antibody (anti-IL-36R antibody) in a method for detecting the presence or absence of a beneficial response in GPP patients after administration of the anti-interleukin-36 receptor antibody, comprising a microRNA selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p, wherein post-treatment downregulation or upregulation compared to the baseline before treatment indicates a beneficial response. In exemplary embodiments, the biological sample is a skin biopsy material, blood, plasma, or serum sample. In preferred embodiments, one or more microRNAs are miR-223-5p or miR-223-3 in the skin lesion or serum.

[0047] In another aspect, the present invention relates to a method for detecting the presence or absence of a beneficial response in GPP patients after administration of an anti-interleukin-36 receptor antibody (anti-IL-36R antibody), wherein one or more levels of the microRNAs miR-223-5p and miR-223-3 in skin lesions or serum correlate with the GPPASI and / or GPPGA scores, and wherein treatment or prevention of flare in subjects with a history of GPP symptoms is measured as the achievement of one or more of the following results: (a) Maintenance of a pustule subscore of 0 or 1 on the Global Assessment for Generalized Pustular Psoriasis (GPPGA) and maintenance or reduction of miR-223-5p and / or miR-223-3 levels from the initial loading dose to 48 weeks after administration of the anti-IL-36R antibody; (b) Maintenance of a total GPPGA score of 0 or 1, and maintenance or reduction of miR-223-5p and / or miR-223-3 levels, from the initial loading dose to 48 weeks after administration of the anti-IL-36R antibody; (c) Sustained remission of GPP symptoms, and maintenance or reduction of miR-223-5p and / or miR-223-3 levels, defined as subjects treated with the anti-IL-36R antibody, maintaining a GPPGA score of 0 or 1 (clear or nearly clear) at all visits up to week 48, without the use of drug therapy for GPP flare or standard treatment (SoC) prescribed by the principal investigator; (d) A reduction in the incidence of GPP flares from baseline to 48 weeks, and maintenance or reduction in the levels of miR-223-5p and / or miR-223-3 (wherein GPP flare is defined as an increase of 2 or more in the total score of the Physician's General Assessment for Generalized Pustular Psoriasis (GPPGA) and 2 or more GPPGA pustule subscores); or (e) An increase in the time to the first GPP flare, as measured by the time from baseline to the onset of the first GPP flare, up to 48 weeks from baseline (wherein a GPP flare is defined as an increase of 2 or more in the total score of the Physician's General Assessment (GPPGA) for generalized pustular psoriasis, and 2 or more GPPGA pustule subscores), and an increase in the levels of miR-223-5p and / or miR-223-3.

[0048] In another aspect, the present invention relates to a method for detecting the presence or absence of a beneficial response in GPP patients after administration of an anti-interleukin-36 receptor antibody (anti-IL-36R antibody), wherein one or more levels of the microRNAs miR-223-5p and miR-223-3 in the skin lesion or serum correlate with the GPPASI and / or GPPGA scores, wherein the one or more levels of the microRNAs are determined or determined ex vivo in the sample, and wherein the treatment or prevention of flare in subjects with a history of GPP symptoms is measured as the achievement of one or more of the following results: (a) Maintenance of a pustule subscore of 0 or 1 on the Global Assessment for Generalized Pustular Psoriasis (GPPGA) and maintenance or reduction of miR-223-5p and / or miR-223-3 levels, following administration of the anti-IL-36R antibody up to 48 weeks after the initial loading dose; (b) Maintenance of a total GPPGA score of 0 or 1, and maintenance or reduction of miR-223-5p and / or miR-223-3 levels, following administration of the anti-IL-36R antibody up to 48 weeks after the initial loading dose; (c) Sustained remission of GPP symptoms, and maintenance or reduction of miR-223-5p and / or miR-223-3 levels, defined as subjects treated with the anti-IL-36R antibody, maintaining a GPPGA score of 0 or 1 (clear or nearly clear) at all visits up to week 48, without the use of drug therapy for GPP flare or standard treatment (SoC) prescribed by the principal investigator; (d) A reduction in the incidence of GPP flares from baseline to 48 weeks, and maintenance or reduction in the levels of miR-223-5p and / or miR-223-3 (wherein GPP flare is defined as an increase of 2 or more in the total score of the Physician's General Assessment for Generalized Pustular Psoriasis (GPPGA) and 2 or more GPPGA pustule subscores); or (e) An increase in the time to the first GPP flare, as measured by the time from baseline to the onset of the first GPP flare, up to 48 weeks from baseline (wherein a GPP flare is defined as an increase of 2 or more in the total score of the Physician's General Assessment for Generalized Pustular Psoriasis (GPPGA) and 2 or more GPPGA pustule subscores), and an increase in the levels of miR-223-5p and / or miR-223-3.

[0049] In another aspect, the present invention relates to the use of an anti-interleukin-36 receptor antibody (anti-IL-36R antibody) in a method for detecting the presence or absence of a beneficial response in GPP patients after administration of the antibody, wherein one or more levels of the microRNAs miR-223-5p or miR-223-3 in skin lesions or serum correlate with the GPPASI and / or GPPGA scores, wherein the treatment or prevention of flare in subjects with a history of GPP symptoms is measured as the achievement of one or more of the following results: (a) Maintenance of a pustule subscore of 0 or 1 on the Global Assessment for Generalized Pustular Psoriasis (GPPGA) and maintenance or reduction of miR-223-5p and / or miR-223-3 levels, following administration of the anti-IL-36R antibody up to 48 weeks after the initial loading dose; (b) Maintenance of a total GPPGA score of 0 or 1, and maintenance or reduction of miR-223-5p and / or miR-223-3 levels, following administration of the anti-IL-36R antibody up to 48 weeks after the initial loading dose; (c) Sustained remission of GPP symptoms, and maintenance or reduction of miR-223-5p and / or miR-223-3 levels, defined as subjects treated with the anti-IL-36R antibody, maintaining a GPPGA score of 0 or 1 (clear or nearly clear) at all visits up to week 48, without the use of drug therapy for GPP flare or standard treatment (SoC) prescribed by the principal investigator; (d) A reduction in the incidence of GPP flares from baseline to 48 weeks, and maintenance or reduction in the levels of miR-223-5p and / or miR-223-3 (wherein GPP flare is defined as an increase of 2 or more in the total score of the Physician's General Assessment for Generalized Pustular Psoriasis (GPPGA) and 2 or more GPPGA pustule subscores); or (e) An extension of the time to the first GPP flare, as measured by the time from baseline to the onset of the first GPP flare, up to 48 weeks from baseline (where a GPP flare is defined as an increase of 2 or more in the total score of the Physician's General Assessment for Generalized Pustular Psoriasis (GPPGA) and 2 or more GPPGA pustule subscores), and an increase in the levels of miR-223-5p and / or miR-223-3.

[0050] In one embodiment related to any of the above, the present invention relates to a method for determining the level of a biomarber by small RNA sequencing, quantitative PCR, or ELISA and histoimmunochemistry.

[0051] In another embodiment, the present invention relates to a method for detecting the presence or absence of a beneficial response in a GPP patient after administration of an anti-IL-36R antibody, further comprising the step of continuing administration of the anti-IL-36R antibody to the patient if the difference in levels between a pre-treatment sample and a post-treatment sample reflects a beneficial response in the patient.

[0052] In another aspect, the present invention relates to the use of an anti-interleukin-36 receptor antibody (anti-IL-36R antibody) in a method for detecting the presence or absence of a beneficial response in a GPP patient after administration of the anti-IL-36R antibody, further comprising the step of continuing administration of the anti-IL-36R antibody to the patient if the difference in levels between a pre-treatment sample and a post-treatment sample reflects a beneficial response in the patient.

[0053] In another embodiment, the present invention is (a) The step of obtaining a first biological sample from a GPP patient before flare and / or before treatment with a candidate therapeutic agent; (b) The process of treating GPP patients with candidate therapeutic agents; (c) The process of obtaining a second biological sample from a GPP patient after treatment with a candidate therapeutic agent; (d) A step of measuring the expression level of one or more biomarkers in the first and second samples; and (e) A step of comparing the biomarker level in the second sample with the level in the first sample. (Here, a change in biomarker levels (e.g., lower or higher) in the second sample compared to the first sample indicates that the candidate therapeutic agent is effective, and further, one or more biomarkers here include microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p.) This relates to a method for determining whether a candidate therapeutic agent is effective in the treatment and prevention of GPP.

[0054] In another embodiment, the present invention is (a) The step of preparing a first biological sample from a GPP patient before flare and / or before treatment with a candidate therapeutic agent; (b) The process of treating GPP patients with candidate therapeutic agents; (c) The process of preparing a second biological sample from a GPP patient after treatment with a candidate therapeutic agent; (d) a step of measuring the expression level of one or more biomarkers in the first and second samples ex vivo; and (e) A step of comparing the biomarker level in the second sample with the level in the first sample. (Here, a change in biomarker levels (e.g., lower or higher) in the second sample compared to the first sample indicates that the candidate therapeutic agent is effective, and further, one or more biomarkers here include microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p.) This relates to a method for determining whether a candidate therapeutic agent, including [specific agent name], is effective in the treatment and prevention of GPP.

[0055] In another embodiment, the present invention is (a) The step of preparing a first biological sample from a GPP patient before flare and / or before treatment with a candidate therapeutic agent; (b) The process of treating GPP patients with candidate therapeutic agents; (c) The process of preparing a second biological sample from a GPP patient after treatment with a candidate therapeutic agent; (d) the step of measuring the expression level of one or more biomarkers in the first and second samples (for example, ex vivo); and (e) A step of comparing the biomarker level in the second sample with the level in the first sample. (Here, a change in biomarker levels (e.g., lower or higher) in the second sample compared to the first sample indicates that the candidate therapeutic agent is effective, and further, one or more biomarkers here include microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p.) The present invention relates to the use of anti-interleukin-36 receptor antibodies (anti-IL-36R antibodies) in a method for determining whether a candidate therapeutic agent is effective in the treatment and prevention of GPP.

[0056] In related embodiments, the present invention relates to a method in which a change in biomarker levels (e.g., lower or higher) in a second sample compared to a first sample correlates with an improvement in a measure of clinical efficacy. Further embodiments relate to continuing treatment of a patient if the biomarker levels in the second sample have changed (e.g., higher or lower) compared to the first sample.

[0057] In a related embodiment, the present invention relates to a method for treating generalized pustular psoriasis (GPP) in a subject with a history of GPP when not experiencing a flare, which includes a) determining whether to initiate treatment for the subject, modify the treatment dose, modify the medication interval, or discontinue treatment, based on any of the prior embodiments; and b) modifying the treatment regimen based on the determination.

[0058] In a related embodiment, the present invention relates to the use of an anti-interleukin-36 receptor antibody (anti-IL-36R antibody) in a treatment method for generalized pustular psoriasis (GPP) in a subject with a history of GPP in a non-flaring state, which includes a) determining whether to initiate treatment for the subject, modify the treatment dose, modify the medication interval, or discontinue treatment, based on any of the prior embodiments; and b) modifying the treatment regimen based on the determination.

[0059] In another embodiment, the present invention is (a) The process of obtaining a first biological sample from the patient; (b) a step of measuring the level of one or more biomarkers in the first biological sample (wherein the one or more biomarkers include microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p); (c) The step of administering the treatment compound to the patient; (d) the step of obtaining a second biological sample from the patient; (e) the step of measuring the level of one or more biomarkers in the second biological sample; and (f) A step of comparing the levels of one or more biomarkers obtained from the first and second biological samples. (Here, post-treatment upregulation or downregulation, compared to the baseline before treatment, indicates a valid response.) This relates to methods for monitoring patient responses to GPP treatment, including [specific methods].

[0060] In another embodiment, the present invention is (g) the step of obtaining a first biological sample from the patient; (h) a step of measuring the level of one or more biomarkers in the first biological sample (wherein the one or more biomarkers include microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p); (i) The step of administering the treatment compound to the patient; (j) The step of obtaining a second biological sample from the patient; (k) a step of measuring the level of one or more biomarkers in the second biological sample; and (l) A step of comparing the levels of one or more biomarkers obtained from the first and second biological samples. (Here, post-treatment upregulation or downregulation, compared to the baseline before treatment, indicates a valid response.) This relates to methods for monitoring patient responses to GPP treatment, including [specific methods].

[0061] In another embodiment, the present invention is (m) The step of preparing a first biological sample from the patient; (n) the step of measuring the level of one or more biomarkers in the first biological sample (for example, ex vivo) (wherein the one or more biomarkers include microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p); (o) The step of administering the treatment compound to the patient; (p) The process of preparing a second biological sample from the patient; (q) the step of measuring the level of one or more of the biomarkers in the second biological sample (for example, ex vivo); and (r) A step of comparing the levels of one or more biomarkers provided from the first and second biological samples. (Here, post-treatment upregulation or downregulation, compared to the baseline before treatment, indicates a valid response.) This relates to the use of anti-interleukin-36 receptor antibodies (anti-IL-36R antibodies) in methods for monitoring patient responses to GPP treatment, including the use of anti-interleukin-36 receptor antibodies (anti-IL-36R antibodies).

[0062] In another embodiment, the present invention is (a) the step of obtaining a first biological sample from the patient; (b) a step of measuring the level of one or more biomarkers in the first biological sample (wherein the one or more biomarkers include microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p); (c) The step of administering the treatment compound to the patient; (d) the step of obtaining a second biological sample from the patient; (e) the step of measuring the level of one or more biomarkers in the second biological sample; and (f) A step of comparing the levels of one or more biomarkers obtained from the first and second biological samples. (Here, post-treatment upregulation or downregulation, compared to the baseline before treatment, indicates the patient's adherence to the drug treatment protocol.) This relates to methods for monitoring patient adherence to drug treatment protocols for the treatment and prevention of GPP flares, including the following.

[0063] In another embodiment, the present invention is (g) The process of preparing a first biological sample from the patient; (h) measuring the level of one or more biomarkers in the first biological sample ex vivo (wherein the one or more biomarkers include microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p); (i) The step of administering the treatment compound to the patient; (j) The process of preparing a second biological sample from the patient; (k) the step of measuring the level of one or more biomarkers in the second biological sample ex vivo; and (l) A step of comparing the levels of one or more biomarkers obtained from the first and second biological samples. (Here, post-treatment upregulation or downregulation, compared to the baseline before treatment, indicates the patient's adherence to the drug treatment protocol.) This relates to methods for monitoring patient adherence to drug treatment protocols for the treatment and prevention of GPP flares, including the following.

[0064] In another embodiment, the present invention is (m) The process of preparing the first biological sample from the patient; (n) the step of measuring the level of one or more biomarkers in the first biological sample (for example, ex vivo) (wherein the one or more biomarkers include microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p); (o) The step of administering the treatment compound to the patient; (p) The process of preparing a second biological sample from the patient; (q) the step of measuring the level of one or more of the biomarkers in the second biological sample (for example, ex vivo); and (r) A step of comparing the levels of one or more biomarkers obtained from the first and second biological samples. (Here, post-treatment upregulation or downregulation, compared to the baseline before treatment, indicates the patient's adherence to the drug treatment protocol.) This relates to the use of anti-interleukin-36 receptor antibodies (anti-IL-36R antibodies) in a method for monitoring patient adherence to drug treatment protocols for the treatment and prevention of GPP flares, including the use of anti-interleukin-36 receptor antibodies (anti-IL-36R antibodies).

[0065] In another aspect described above, the present invention relates to a method for monitoring a patient's response to GPP treatment, wherein the level of one or more biomarkers in a second biological sample is reduced by at least about 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% or more compared to the level in a first biological sample.

[0066] In exemplary embodiments related to the above, the present invention relates to any of the above methods, wherein the biological sample is a sample of skin biopsy material, blood, plasma, or serum.

[0067] In yet another embodiment related to the above, the present invention relates to a method in which the treatment compound is an anti-IL-36R antibody.

[0068] In related embodiments, the present invention relates to any of the above methods, wherein the level of a biomarker is determined by small RNA sequencing or ELISA and immunohistochemistry.

[0069] Any method, administration scheme and / or dose regimen disclosed herein will be understood to be equally applicable to the use of any disclosed anti-IL-36R antibody to such methods, administration schemes and / or dose regimens and any combination thereof: for example, for the use of an anti-IL-36R antibody such as that disclosed herein in the treatment, prevention, reduction and / or remission of any disclosed disease and / or condition. In other words, the present invention also provides the use of an anti-IL-36R antibody such as that disclosed herein for the manufacture of a pharmaceutical product for the treatment, prevention, reduction and / or remission of any disclosed disease and / or condition. Or, an anti-IL-36R antibody such as that disclosed herein for use in the treatment, prevention, reduction and / or remission of any disclosed disease and / or condition, said use further comprises any of the methods, administration schemes and / or dose regimens disclosed herein.

[0070] Additional features and advantages of the present invention are set forth in the following description, some of which are evident from the specification or can be learned through practice of the subject art. It should be understood that both the above general description and the following detailed description are illustrative and descriptive, and are intended to provide a further description of the claimed invention.

[0071] The accompanying drawings, included to provide a further understanding of the present invention and incorporated herein and constituting part thereof, illustrate aspects of the subject art and, together with the text, illustrate the principles of the present invention. [Brief explanation of the drawing]

[0072] [Figure 1] Phase IIb Clinical Trial Design: A proof-of-concept clinical trial aimed at exploring the efficacy of spesolimab for the prevention of acute GPP flares in subjects with a history of GPP symptoms. Overall trial design including a loading treatment group and a maintenance treatment group, as well as management of GPP flares during the randomized maintenance treatment period. *GPP flare is defined as an increase of 2 or more GPPGA total score from baseline, and 2 or more pustular elements of GPPGA. [Figure 2] Figures 2A-C. Time from the first GPP flare to week 48. (A) Table showing formal trial results for primary and key secondary endpoints. (B) Kaplan-Meier plots showing the estimated probability of the first GPP flare over 48 weeks for all treatment groups. Use of intravenous open-label spesolimab therapy or other investigator-prescribed therapy was considered a GPP flare. (C) Bar graph showing the proportion of patients who experienced one or more GPP flares by week 48. Multiple imputation was used for binary endpoints, including monotonic missing assessments, using permutation logistic regression analysis. Stratified Cochrane-Mantel-Henzel tests were performed for each dose level of spesolimab, stratified by the use of systemic GPP therapy at randomization compared to placebo. [Figure 3] Subgroup analysis of time to first GPP flare up to week 48 for high-dose spesolimab compared to placebo. [Figure 4] Figures 4A-C (A) Table showing formal examination results for other secondary endpoints: worsening of PSS (Psoriasis Symptom Rating Scale) and DLQI (Disease-Related Quality of Life Index) up to week 48. For both scores, worsening was defined as a 4-point increase in the total score from baseline. (B, C) Kaplan-Meier plots showing the estimated probability of the first worsening of PSS and DLQI scores, respectively. Use of open-label spesolimab therapy or therapy prescribed by another investigator was considered an event. †Nominal P-value; statistical significance was not achieved in previous families by hierarchical statistical testing. CI, confidence interval; DLQI, quality of life index for skin disease; GPP, generalized pustular psoriasis; IV, intravenous; nc, not calculable; OL, open-label; P10, estimated probability of first GPP flare = 0.1; P25, estimated probability of first GPP flare = 0.25; PSS, psoriasis symptom rating scale; SC, subcutaneous. [Figure 5] Figures 5A-E. (A) Graph showing model predicted concentration-time profiles for intravenous delivery of 300 mg versus subcutaneous delivery of 300 mg over a 12-week period. (B) Graph showing model predicted concentration-time profiles for 900 mg (intravenous) versus 600 mg (subcutaneous) spesorimab. (C) Graph showing model predicted concentration-time profiles for two doses of 900 mg (intravenous) spesorimab versus two doses of 600 mg (subcutaneous) spesorimab. (D) Graph showing model predicted concentration-time profiles for 900 mg (intravenous) spesorimab versus 2250 mg (subcutaneous) spesorimab. (E) Summary of exposure measurements after a single intravenous or subcutaneous administration in GPP patients. [Figure 6]Figures 6A-B. (A) Histopathological analysis of selected neutrophil proteins in representative patients; Patient A and Patient B. Representative Patient A was IL36RN mutation-positive, presented with pustules and desquamation, and had been treated with cyclosporine prior to participation in the spesorimab trial. Patient A was randomized to receive high doses of spesorimab and did not relapse throughout the entire trial. In contrast, representative Patient B did not have IL36RN mutations, had a high neutrophil count, and had been treated with acitretin prior to participation. Patient B was randomized to receive placebo and continued to receive spesorimab rescue treatment for flare during the trial. (B) Figures illustrating the patient treatment scenarios in the Effisayil2 trial, as well as the clinical morphology of patient A at baseline and VOL, i.e., open-label visits (patient A) and at VR1, i.e., the first emergency visit; and at VR6, i.e., the sixth emergency visit (patient B), showing reduced expression of neutrophil markers (neutrophil elastase, lipocalin [LCN]), IL-36 receptor markers, and inflammatory markers (S100A7, human β-defensin 2 [hBD2]), indicating reduced inflammation and neutrophil pustule formation. [Figure 7] Figures 7A-B. Changes in microRNA (miRNA) expression in GPP lesions compared to healthy controls (HC). (A) Principal component analysis plots including confidence ellipses for each group (healthy controls (HC), lesion-free skin (nL), and lesioned skin (L)). (B) Volcano plot showing increased expression of 173 miRNAs and decreased expression of 160 miRNAs in the skin of GPP patients compared to healthy controls. Horizontal lines indicate corrected p-values ​​of 0.05. Vertical lines indicate change multipliers of +1.5 and -1.5. Differences in miRNA expression are shown in the upper left and upper right quadrants within the box, indicating the top miRNAs that were deregulated. [Figure 8]Figures 8A-B. Changes in miRNA expression in GPP lesions after treatment with spesorimab. (A) Principal component analysis plots including confidence ellipses for each group (healthy control (HC), skin lesions before and after spesorimab treatment (L), and lesion-free skin before spesorimab administration (nL)). (B) Volcano plots show deregulated miRNAs in skin lesions (n=12) after spesorimab administration compared to the baseline (n=9). Horizontal lines indicate p-values ​​of 0.05. Vertical lines indicate change magnifications of +1.5 and -1.5. miRNAs with differing expression after spesorimab treatment are shown in the upper left and upper right quadrants of the box. [Figure 9] Figures 9A-B. Changes in miRNA expression in serum obtained from GPP patients compared to healthy controls (HC). (A) Principal component analysis plots including confidence ellipses for each group (healthy controls (HC), GPP patients before spesorimab administration). (B) Volcano plot showing increased expression of 69 miRNAs and decreased expression of 45 miRNAs in the serum of GPP patients compared to healthy controls. Horizontal lines indicate corrected p-values ​​of 0.05. Vertical lines indicate change multipliers of +1.5 and -1.5. MiRNAs with regulatory differences are shown in the upper left and upper right quadrants of the box, where representative miRNAs with the strongest expression changes are shown. [Figure 10] Figures 10A-B. Changes in the transcriptome of GPP serum after treatment with spesorimab. (A) Venn diagram. Confidence ellipses are shown for each group. (B) Volcano plot shows deregulated miRNAs (n=11) in GPP lesions after spesorimab administration, compared to the baseline (n=12). Horizontal lines indicate p-values ​​of 0.05. Vertical lines indicate change magnifications of +1.5 and -1.5. miRNAs showing difference in expression after spesorimab treatment are shown in red. [Figure 11]Figures 11A-B. Overlap of miRNAs with differential expression in skin lesions and serum from GPP patients compared with healthy controls and treatment with spesolimab. Number of miRNAs with differential expression in GPP lesions (n=9) and serum (n=12) from GPP patients compared with healthy controls (skin n=10, serum n=20). (A) Venn diagram shows the overlap of miRNAs with differential expression in GPP lesions and serum from GPP patients compared with healthy controls and after treatment with spesolimab. (B) Change metric and corresponding P-value for pairwise comparison of 5 selected miRNAs. [Figure 12] Figures 12A-B. Expression levels of selected miRNAs in the skin were determined by reverse transcription quantitative PCR: (A) Confirmation of miRNA expression in the skin of GPP patients (n=9) at baseline compared with healthy controls (HC; n=10). (B) Deregulation in the skin after spesorimab treatment (n=12) compared with baseline (before spesorimab administration). Each sample is indicated by a black dot, and the box plot shows the median of the principal component analysis (ratio to control). Statistical analysis was performed by the non-parametric Mann-Whitney U test; ****P≦0.0001, ***P≦0.001, **P≦0.01, *P<0.05. [Figure 13] Figures 13A-B. Expression levels of selected miRNAs in serum were determined by reverse transcription quantitative PCR: (A) Confirmation of miRNA expression in the serum of GPP patients (n=12) at baseline compared with healthy controls (HC; n=20). (B) Deregulation in the serum after spesorimab treatment (n=11) compared with baseline (before spesorimab administration). (D) Each sample is indicated by a black dot, and the box plot shows the median of the principal component analysis (ratio to control). Statistical analysis was performed by the non-parametric Mann-Whitney U test; ****P≦0.0001, ***P≦0.001, **P≦0.01, *P<0.05. [Figure 14]Figures 14A-C. Correlation between miRNAs exhibiting differential expression in skin and serum and clinical parameters measured by GPPASI and GPPGA scores. (A) Correlation between the expression levels of miR-223-3p and miR-233-5p collected from the skin [log2CPM (counts per million)] and the GPPASI score. (B) Correlation between the expression levels of miR-223-3p and miR-233-5p collected from the skin [log2CPM (counts per million)] and the GPPGA score. (C) Correlation between the expression levels of miR-223-3p and miR-233-5p collected from serum [log2CPM (counts per million)] and the GPPGA score. Black circles indicate GPP lesions at the baseline, while black dots indicate GPP lesions after treatment with spesorimab. The Spearman correlation coefficient Rsg is shown within each plot. ****P≦0.0001, **P≦0.01, *P≦0.05.

[0073] Detailed description of the invention In the following detailed description, numerous specific details are provided to give a complete understanding of the invention. However, it will be apparent to those skilled in the art that the technology in question can be practiced without using some of these specific details. In other cases, well-known structures and techniques are not described in detail for the sake of clarity of the invention.

[0074] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this invention pertains.

[0075] The inventors have found that, in particular, in subjects with a history of generalized pustular psoriasis and / or a confirmed diagnosis of generalized pustular psoriasis based on the common diagnostic criteria defined by the ERASPEN diagnostic criteria, inhibiting the interleukin-36 pathway with the humanized anti-interleukin-36 receptor (anti-IL-36R) monoclonal antibody of the present invention can prevent and / or significantly alleviate the signs and symptoms of GPP by prolonging the time interval between flares and / or reducing the duration or severity of flares. Furthermore, maintenance treatment with the humanized anti-interleukin-36 receptor (anti-IL-36R) monoclonal antibody of the present invention resulted in sustained remission in GPP subjects up to 48 weeks after the administration of the initial loading dose, with no clinical symptoms of acute generalized pustular psoriasis and no recurrence of GPP flares.

[0076] Therefore, the present invention relates to compositions and methods for the treatment of generalized pustular psoriasis (GPP), including the treatment and prevention of flares in subjects. More specifically, the present invention relates to compositions and methods for the treatment and prevention of GPP, acute GPP, chronic GPP, and / or GPP flares in mammals, using the anti-IL-36R antibody or its antigen-binding fragment of the present invention. The compositions and methods include administering a therapeutically effective amount of the anti-IL-36R antibody or its antigen-binding fragment to a mammal before the onset of flares in a patient with a history of GPP, wherein the anti-IL-36R antibody is administered as a dose regimen comprising a loading dose of 300 mg to 600 mg delivered subcutaneously at week 0 or 1, followed by at least one maintenance dose, more preferably a series of maintenance doses of 150 mg to 600 mg delivered subcutaneously at intervals of 2, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks, thereby preventing the onset of GPP flares or the frequency of GPP symptoms. In exemplary embodiments of the present invention, the anti-IL-36R antibody is administered as a loading dose of 600 mg followed by a maintenance dose of 300 mg delivered at 4-week intervals; or as a loading dose of 600 mg followed by a maintenance dose of 300 mg delivered at 12-week intervals; or as a loading dose of 300 mg followed by a maintenance dose of 150 mg delivered at 12-week intervals.

[0077] [Table 1]

[0078] While we do not wish to dwell on theory, it is believed that anti-IL-36R antibodies or their antigen-binding fragments bind to human anti-IL-36R and thus interfere with the binding of IL-36 agonists, thereby at least partially blocking the signaling cascade from IL-36R to inflammatory mediators. The anti-IL-36R antibodies of the present invention are disclosed in U.S. Patent No. 9,023,995 or International Publication No. 2013 / 074569, the entire contents of which are incorporated herein by reference.

[0079] I. Definition The term "approximately" generally refers to the degree of acceptable error or deviation of a measured quantity, taking into account the nature or accuracy of the measurement. Typical exemplary degrees of error or deviation are within 5%, 3%, or 1% of a given number or range of numbers. For example, the expression "approximately 100" includes 105 and 95, or 103 and 97, or 101 and 99, and all numbers in between (e.g., 95.1, 95.2, etc. for the range of 95-105; or 97.1 or 97.2, etc. for the range of 97-103; or 99.1, 99.2, etc. for the range of 99-101). Unless otherwise specified, quantities shown herein are approximate, meaning that the term "approximately" can be inferred unless explicitly stated.

[0080] The phrases "one aspect" and similar phrases do not imply that such aspects are essential to the invention or that such aspects apply to all configurations of the subject technology. A disclosure relating to one aspect may apply to all configurations or one or more configurations. One aspect may provide one or more examples of the disclosure. The phrases "one aspect" and similar phrases may refer to one or more aspects, and vice versa. The phrases "one embodiment" and similar phrases do not imply that such embodiments are essential to the subject technology or that such embodiments apply to all configurations of the subject technology. A disclosure relating to one embodiment may apply to all embodiments or one or more embodiments. A single embodiment may provide one or more examples of the disclosure.

[0081] II. The antibody of the present invention The anti-IL-36R antibody of the present invention is disclosed in U.S. Patent No. 9,023,995 or International Publication No. 2013 / 074569, the entire contents of which are incorporated herein by reference.

[0082] The terms “antibody,” “anti-IL-36R antibody,” “humanized anti-IL-36R antibody,” “humanized anti-IL-36R epitope antibody,” and “mutant humanized anti-IL-36R epitope antibody” specifically include monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), antibodies with minor modifications such as N-terminal and / or C-terminal truncation, as well as antibody fragments, such as variable domains, and other parts of the antibody that exhibit desired biological activity, such as binding to IL-36R.

[0083] The term “monoclonal antibody” (mAb) refers to an antibody that is highly specific and directed toward a single antigenic determinant, i.e., an “epitope.” Therefore, the modifier “monoclonal” indicates an antibody that is directed toward the same epitope and is not expected to require antibody production by any particular method. Monoclonal antibodies should be understood to be produced by any technique or method known in the art, including, for example, the hybridoma method (Kohler et al., 1975, Nature 256:495) or recombinant DNA methods known in the art (see, for example, U.S. Patent No. 4,816,567), or methods for isolating recombinantly produced monoclonal antibodies using a phage antibody library, using techniques described in Clackson et al., 1991, Nature 352: 624-628 and Marks et al., 1991, J. Mol. Biol. 222: 581-597.

[0084] The term "monomer" refers to a homogeneous antibody. For example, in the case of a full-length antibody, a monomer refers to a monomeric antibody that has two identical heavy chains and two identical light chains.

[0085] A chimeric antibody consists of variable regions of the heavy and light chains of an antibody derived from one species (e.g., a non-human mammal, e.g., mouse) and constant regions of the heavy and light chains of an antibody from another species (e.g., human), which can be obtained by ligating the DNA sequence encoding the variable region of the antibody from the first species (e.g., mouse) to the DNA sequence of the constant region of the antibody from the second species (e.g., human), and then transforming the host using an expression vector containing the ligated sequence, thereby enabling it to produce a chimeric antibody. Alternatively, a chimeric antibody may also be an antibody in which one or more regions or domains of the heavy and / or light chains are identical, homologous, or variant thereof to the corresponding sequence in a monoclonal antibody derived from another class or isotype of immunoglobulin, or from a common sequence or germline sequence. Chimeric antibodies may contain fragments of such antibodies, where the antibody fragment exhibits the desired biological activity of the parent antibody, for example, binding to the same epitope (see, e.g., U.S. Patent No. 4,816,567; and Morrison et al., 1984, Proc. Natl. Acad. Sci. USA 81: 6851-6855).

[0086] In one embodiment, this specification describes and discloses anti-IL-36R antibodies, particularly humanized anti-IL-36R antibodies, and compositions and products comprising one or more anti-IL-36R antibodies, particularly one or more of the humanized anti-IL-36R antibodies of the present invention. Also described are conjugates comprising antigen-binding fragments of anti-IL-36R antibodies, particularly humanized anti-IL-36R antibodies.

[0087] According to certain embodiments, the antibody used in the method of the present invention specifically binds to IL-36R. Terms such as "specifically bind" mean that the antibody or its antigen-binding fragment forms a complex with an antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis and surface plasmon resonance. For example, an antibody that "specifically binds" to IL-36R, as used in the context of the present invention, has a K content of less than approximately 1000 nM, less than approximately 500 nM, less than approximately 300 nM, less than approximately 200 nM, less than approximately 100 nM, less than approximately 90 nM, less than approximately 80 nM, less than approximately 70 nM, less than approximately 60 nM, less than approximately 50 nM, less than approximately 40 nM, less than approximately 30 nM, less than approximately 20 nM, less than approximately 10 nM, less than approximately 5 nM, less than approximately 4 nM, less than approximately 3 nM, less than approximately 2 nM, less than approximately 1 nM, or less than approximately 0.5 nM when measured by surface plasmon resonance assay. D This includes antibodies that bind to human IL-36R antibodies. However, isolated antibodies that specifically bind to human IL-36R antibodies may cross-react to other antigens, such as IL-36R molecules derived from other (non-human) species.

[0088] In certain exemplary embodiments relating to any aspect of the present invention, an anti-IL-36R antibody or its antigen-binding fragment that can be used in the context of the method of the present invention comprises: a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 35, 102, 103, 104, 105, 106, or 140 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 or 141 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, 111, or 142 (H-CDR2); and the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

[0089] According to a particular embodiment, an anti-IL-36R antibody or its antigen-binding fragment is ia) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 102 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3); or II.a) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 103 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3); or III.a) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 104 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3); or IV.a) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 105 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3); or Va) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 106 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3); or VI.a) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 140 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3); or VII.a) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 104 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 141 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110, 111 or 142 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3). Includes.

[0090] According to a particular embodiment, an anti-IL-36R antibody or its antigen-binding fragment is (i) Light chain variable region containing the amino acid sequence of SEQ ID NO: 77; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 87; or (ii) Light chain variable region containing the amino acid sequence of SEQ ID NO: 77; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 88; or (iii) Light chain variable region containing the amino acid sequence of SEQ ID NO: 77; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 89; or (iv) Light chain variable region containing the amino acid sequence of SEQ ID NO: 80; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 87; or (v) Light chain variable region containing the amino acid sequence of SEQ ID NO: 80; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 88; or (vi) Light chain variable region containing the amino acid sequence of SEQ ID NO: 80; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 89; or (vii) Light chain variable region containing the amino acid sequence of SEQ ID NO: 85; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 100; or (viii) Light chain variable region containing the amino acid sequence of SEQ ID NO: 85; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 101; or (ix) Light chain variable region containing the amino acid sequence of SEQ ID NO: 86; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 100; or (x) Light chain variable region containing the amino acid sequence of SEQ ID NO: 86; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 101 Includes.

[0091] According to a particular embodiment, an anti-IL-36R antibody or its antigen-binding fragment is (i) a light chain containing the amino acid sequence of SEQ ID NO: 115; and a heavy chain containing the amino acid sequence of SEQ ID NO: 125; or (ii) A light chain containing the amino acid sequence of SEQ ID NO: 115; and a heavy chain containing the amino acid sequence of SEQ ID NO: 126; or (iii) A light chain containing the amino acid sequence of SEQ ID NO: 115; and a heavy chain containing the amino acid sequence of SEQ ID NO: 127; or (iv) A light chain containing the amino acid sequence of SEQ ID NO: 118; and a heavy chain containing the amino acid sequence of SEQ ID NO: 125; or (v) A light chain containing the amino acid sequence of SEQ ID NO: 118; and a heavy chain containing the amino acid sequence of SEQ ID NO: 126; or (vi) A light chain containing the amino acid sequence of SEQ ID NO: 118; and a heavy chain containing the amino acid sequence of SEQ ID NO: 127; or (vii) A light chain containing the amino acid sequence of SEQ ID NO: 123; and a heavy chain containing the amino acid sequence of SEQ ID NO: 138; or (viii) A light chain containing the amino acid sequence of SEQ ID NO: 123; and a heavy chain containing the amino acid sequence of SEQ ID NO: 139; or (ix) Light chain containing the amino acid sequence of SEQ ID NO: 124; and heavy chain containing the amino acid sequence of SEQ ID NO: 138 Includes.

[0092] In one embodiment, what is described and disclosed herein are anti-IL-36R antibodies, in particular humanized anti-IL-36R antibodies, and compositions and products comprising one or more anti-IL-36R antibodies, in particular one or more humanized anti-IL-36R antibodies of the present invention. Also described are antigen-binding fragments of anti-IL-36R antibodies, in particular binding substances comprising humanized anti-IL-36R antibodies.

[0093] In one embodiment, the anti-IL-36R antibody described and disclosed herein is a spesolimab.

[0094] III. Pharmaceutical compositions, formulations, dosages, and administration In this context, "pharmaceutical composition" refers to a dosage form in which the biological activity of the active ingredient(s) is clearly effective, and which contains no additional ingredients that are significantly toxic to the subject to whom the composition is to be administered, whether liquid or powder. Such compositions are sterile. "Powder" refers to a freeze-dried or spray-dried pharmaceutical composition for parenteral use. Powders are typically reconstituted or dissolved in water. Freeze-drying is a low-temperature dehydration process that involves freezing the product, reducing the pressure, and then removing the ice by sublimation. Freeze-drying results in a high-quality product due to the low temperatures used in the process. In well-developed freeze-dried formulations, the shape and appearance of the product are maintained over time, and the quality of the rehydrated product is excellent. Spray-drying is another method of producing a dry powder from a liquid or slurry by rapidly drying it using high-temperature gas with the aim of achieving a consistent particle size distribution.

[0095] "Pharmaceutical formulation" or "formulation" refers to the process of producing a final pharmaceutical product or drug by combining an active drug or active substance with a chemical substance, but it also refers to the product of the process. Therefore, the final formulation refers to a pharmaceutical product such as a liquid, powder, or composition. Thus, in one embodiment, a pharmaceutical formulation is a pharmaceutical composition.

[0096] The antibodies of the present invention can be incorporated into pharmaceutical compositions suitable for administration to a subject. The compounds of the present invention can be administered alone or in combination with pharmaceutically acceptable carriers, diluents and / or excipients, in single or multiple doses. The pharmaceutical compositions for administration are designed to suit the selected mode of administration and may use pharmaceutically acceptable diluents, carriers and / or excipients as appropriate, such as dispersants, buffers, surfactants, preservatives, solubilizers, isotonic agents, stabilizers, etc. The compositions are designed in accordance with prior art, such as Remington, The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA 1995, which provides an overview of formulation techniques generally known to those skilled in the art.

[0097] The pharmaceutical composition comprising the anti-IL-36R monoclonal antibody of the present invention may be administered to subjects with a history of generalized pustular psoriasis and / or a history (diagnosis) of generalized pustular psoriasis confirmed based on the common diagnostic criteria defined by the ERASPEN diagnostic criteria (website: eraspen.eu / home / rfp / diagnostic-criteria.html (accessed May 9, 2018); European Network of Specialists in Rare and Severe Psoriasis (ERASPEN); 2018) using standard administration techniques, including oral, intravenous, intraperitoneal, subcutaneous, intrapulmonary, transdermal, intramuscular, intranasal, buccal, sublingual, or suppository administration.

[0098] The antibody of the present invention may be administered orally, parenterally, by inhalation, or topically. Preferably, the antibody of the present invention can be incorporated into a pharmaceutical composition suitable for parenteral administration. As used herein, the term parenteral includes intravenous, intramuscular, subcutaneous, rectal, vaginal, or intraperitoneal administration. Peripheral systemic delivery by intravenous, intraperitoneal, or subcutaneous injection is preferred. Vehicles suitable for such injections are known in the art.

[0099] Pharmaceutical compositions typically must be sterile and stable under the conditions of manufacture and storage within the provided container, including, for example, sealed vials or syringes (e.g., for containing unit dose formulations). Therefore, pharmaceutical compositions may be sterile filtered after formulation or otherwise made microbiologically acceptable. Typical compositions for intravenous infusion may have a large volume of liquid, such as 250–1000 ml, e.g., sterile Ringer's solution, physiological saline, dextrose solution, and Hank's solution, and an antibody concentration of a therapeutically effective dose (e.g., 1–100 mg / mL or higher). The dose may be modified depending on the type and severity of the disease. As is well known in the medical field, the dose for any one subject depends on many factors, including the subject's physique, body surface area, age, the specific compound to be administered, sex, time and route of administration, overall health condition, and other drugs administered concurrently. A typical dose may be, for example, in the range of 0.001 to 1000 mg, however, doses below or above this exemplary range are also possible, especially considering the factors mentioned above.

[0100] In one embodiment, the present invention provides a pharmaceutical composition formulated in a unit dose dosage form, wherein such a single dose dosage form comprises at least 150 mg, 300 mg, 450 mg, 600 mg, or 900 mg of the anti-IL-36R antibody. In a related embodiment, the unit dose dosage form is used in the preparation of a pharmaceutical for the treatment of a subject having generalized pustular psoriasis (GPP). In a related embodiment, the unit dose dosage form is a parenteral (e.g., intravenous or subcutaneous) dose dosage form.

[0101] In related embodiments, the present invention provides a drug preparation (or "product" as described herein hereafter) comprising one, two, three, or four unit dose formulations containing 150 mg of the anti-IL-36R antibody; one, two, three, or four unit dose formulations containing 300 mg of the anti-IL-36R antibody; one, two, three, or four unit dose formulations containing 450 mg of the anti-IL-36R antibody; or one, two, three, or four unit dose formulations containing 600 mg of the anti-IL-36R antibody; or one, two, three, or four unit dose formulations containing 900 mg of the anti-IL-36R antibody; or any combination thereof that reaches an effective dose.

[0102] In related embodiments, one, two, three, or four of the unit dose formulations (e.g., in a drug preparation) are administered at intervals of once a week (qw), once every two weeks (q2w), once every four weeks (q4w), or once every 12 weeks (q12w). Preferably, if the unit dose formulation contains 150 mg, 300 mg, 450 mg, 600 mg, or 900 mg of the anti-IL-36R antibody, then one, two, three, or four of the unit dose formulations are administered as a loading dose and / or subcutaneous maintenance dose at intervals of once a week (qw), once every two weeks (q2w), once every four weeks (q4w), or once every 12 weeks (q12w).

[0103] In one embodiment, the present invention relates to the use of an anti-IL-36R antibody or its antigen-binding fragment (as disclosed herein) in the preparation of a pharmaceutical product for treating, preventing, or relieving GPP. In one embodiment related to this aspect, the anti-IL-36R antibody is spesolimab.

[0104] As used herein, the term "dose" refers to the amount of anti-IL-36R antibody or its antigen-binding fragment administered to a subject.

[0105] As used herein, the term “medication” refers to the administration of an anti-IL-36R antibody or its antigen-binding fragment to achieve a therapeutic objective (e.g., treatment of a subject with a history of GPP). In preferred embodiments, the dose is delivered by parenteral administration, for example, intravenously and subcutaneously.

[0106] "Dose regimen" refers to a treatment plan for an anti-IL-36R antibody or its antigen-binding fragment, for example, a treatment plan extending over an extended period or over the entire duration of a maintenance treatment course. For example, in an unrestrictive embodiment, the treatment plan includes an initial loading dose of the anti-IL-36R antibody or its antigen-binding fragment at week 0 or 1, followed by maintenance doses of the anti-IL-36R antibody or its antigen-binding fragment at least once, but preferably second, third, fourth, or more doses during the maintenance treatment period, wherein the doses are delivered at intervals of 2, 4, 5, 6, 7, 8, 10, or 12 weeks, and the loading dose and / or maintenance doses are administered parenterally, for example, intravenously and / or intravenously.

[0107] As used herein, the terms “intravenous dose” (iv) and “subcutaneous dose” (sc) refer to the temporal sequence of administration of anti-IL-36R antibody, in addition to their usual meanings. Treatment with anti-IL-36R antibody may be initiated as a subcutaneous injection to prevent GPP flares or with an intravenous dose of anti-IL-36R antibody to treat GPP flares. In a preferred embodiment, a dose prescription plan for the treatment of generalized pustular psoriasis (GPP), including the treatment and prevention of flares in adults and adolescents 12 years of age or older, includes a subcutaneous loading dose of 600 mg, including four 150 mg injections, followed by a maintenance dose of 300 mg (including two 150 mg injections) administered subcutaneously every four weeks. If a subject develops a GPP flare while receiving subcutaneous maintenance treatment with the anti-IL-36R antibody, the GPP flare may be treated with intravenous anti-IL-36R antibody, after which the maintenance treatment may be resumed. Maintenance therapy may be resumed four weeks after the completion of flare treatment with intravenous anti-IL-36R antibody, and this maintenance therapy includes a dose of 300 mg (two 150 mg injections) administered every four weeks; subcutaneous loading doses are not required.

[0108] Therefore, in one embodiment, the “loading dose” is the dose typically administered at the start of the treatment regimen (also referred to as the “baseline dose”); it may also be referred to as the “initial dose” or “induction dose.” The “maintenance doses” are doses or dose groups administered after the initial loading dose, which may also be referred to as “subsequent doses,” and which are part of the “maintenance treatment.” The loading dose and maintenance dose may all contain the same amount of anti-IL-36R antibody or its antigen-binding fragment, but may generally differ from each other in terms of the amount of antibody administered or the frequency of administration. In one embodiment, the loading dose is equal to or greater than the maintenance dose. The “loading dose” may be a single dose or, alternatively, a set of doses. The loading dose may be administered intravenously or subcutaneously, and each dose may be a single dose or, alternatively, a set of doses, but is preferably a subcutaneous dose.

[0109] The terms “maintenance dose” or “treatment dose” refer to the amount of anti-IL-36R antibody or its antigen-binding moiety ingested by a subject to maintain or continue a desired therapeutic effect. The maintenance dose is administered during the treatment or maintenance period of the treatment. In one embodiment, the maintenance dose(s) are smaller than the loading dose(s) and may be equal in amount to each other if administered consecutively. In one embodiment, the present invention provides a maintenance dose of 150 mg or 300 mg of anti-IL-36R antibody or its antigen-binding moiety administered subcutaneously to a subject at intervals of 2, 4, 5, 6, 7, 8, 10, or 12 weeks, wherein the loading dose and / or maintenance dose are delivered subcutaneously. In one embodiment, the maintenance dose is initiated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks after the last loading dose and administered every 4 weeks. In one embodiment, the maintenance dose is administered approximately 4 weeks after the initial loading dose, and thereafter at intervals of 4 weeks (q4w). In another embodiment, the maintenance dose is initiated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 weeks after the last loading dose, and administered every 12 weeks. In yet another embodiment, the maintenance dose is administered approximately 12 weeks after the initial loading dose, and thereafter at intervals of 12 weeks (q12w).

[0110] The terms "intravenous" or "intravenous infusion" refer to the delivery of a drug into the veins of an animal or human subject over a period of approximately 15 minutes or more, typically ranging from 30 to 90 minutes.

[0111] The term "subcutaneous administration" refers to the delivery of a drug from a drug container to the subcutaneous tissue of an animal or human subject, preferably into a pocket between the skin and the underlying tissue, by relatively slow and continuous delivery. A pocket can be created by pinching the skin and lifting it away from the underlying tissue.

[0112] As used herein, terms such as “treatment” and “therapy” include therapeutic and preventive or inhibitory measures for a disease or disorder that result in any clinically desirable or “beneficial effect” or “beneficial response,” including but not limited to the reduction or alleviation of one or more symptoms, or the regression, slowing, or cessation of the progression of the disease or disorder. Therefore, for example, the term “treatment” includes the administration of a drug before or after the onset of symptoms or groups of symptoms of a GPP disease, for example, before a flare occurs, thereby preventing or eliminating one or more signs of the disease or disorder. Beneficial responses may also be exemplified by sustained remission of GPP symptoms, a reduction in the occurrence of GPP flares, an extension of the time to the first GPP flare, as measured by the time from baseline to the first GPP flare, or a change in biomarker levels (miR-223-5p and / or miR-223-3 of microRNAs present in the skin or serum), defined as subjects treated with the anti-IL-36R antibody maintaining a pustule subscore of the General Assessment for Generalized Pustular Psoriasis (GPPGA), a GPPGA total score of 0 or 1, or a GPPGA score of 0 or 1 (clear or nearly clear), or a change in biomarker levels (miR-223-5p and / or miR-223-3 of microRNAs present in the skin or serum). Another example of the term includes combating the symptoms of the disease by administering a drug after the clinical signs of GPP. Furthermore, the administration of a drug after the onset and after the occurrence of clinical symptoms (where the administration affects clinical parameters of the disease or disorder, such as the degree of tissue damage, regardless of whether the treatment results in remission of the disease) is included in the term "treatment" or "therapy" as used herein. Furthermore, the composition of the present invention, either alone or in combination with another therapeutic agent, should be considered an effective treatment of the underlying disease, insofar as it reduces or remits at least one symptom of the treated GPP compared to the symptoms without the use of the humanized anti-IL-36R antibody composition, regardless of whether all symptoms of the disorder are reduced.

[0113] The term “effective prophylactic dose” is used to refer to the dose and duration effective in achieving the desired prophylactic outcome, e.g., the dose and duration required to treat and prevent flares in a subject. Typically, a prophylactic dose is used to prevent or suppress the onset of acute flares by being administered to subjects with a history of generalized pustular psoriasis (GPP) and / or a history of generalized pustular psoriasis as diagnosed by the European Network of Rare and Severe Psoriasis Specialists (ERASPEN) criteria, prior to the onset of GPP flares and / or the onset of symptoms of GPP (which may be moderate or severe). Subjects without GPP flares have a total physician's assessment (GPPGA) score of 1 or less for generalized pustular psoriasis and a GPPGA pustule subscore of 1 or less. In one embodiment, the maintenance dose as conceived herein is a prophylactic dose used after a loading dose in subjects who have a history of moderate to severe GPP symptoms and / or a confirmed history (diagnosis) of GPP based on common diagnostic criteria as defined by the ERASPEN diagnostic criteria, in order to prevent a recurrence of a GPP flare or exacerbation of the disease that may occur in the subject.

[0114] As used herein, “buffer solution” refers to a buffered solution that can withstand changes in pH due to the action of its acid-base conjugated components. As used herein, “pH” refers to the acidity or alkalinity of the composition at room temperature. Standard methods for measuring the pH of a composition are known to those skilled in the art. Typically, pH measurement involves calibrating an instrument, placing an electrode in a well-mixed sample, and then directly decoding the pH from a pH meter. Exemplary buffer solutions of the present invention include acetates, citrates, histidines, succinates, phosphates, and Tris.

[0115] As used herein, the terms “isotonic agent” or “isotonic substance” refer to a substance that provides an osmotic pressure equivalent to that of serum in the body, and include salts (e.g., sodium chloride, potassium chloride, magnesium chloride) or sugars (e.g., sucrose, trehalose, sorbitol, magnesium sulfate (MgSO4), glycerol, mannitol, or dextrose). Furthermore, sugars present in solution act as cryoprotectants for proteins, allowing the drug to be frozen without damage. This enables shipment in frozen form and long-term storage of the drug before filling. Exemplary isotonic agents of the present invention include sodium chloride, potassium chloride, magnesium chloride (salts) and / or sucrose, trehalose, sorbitol, magnesium sulfate (MgSO4), glycerol, mannitol, or dextrose (sugars).

[0116] As used herein, the terms “stabilizer” or “stabilizer” refer to substances that contribute to the stability of the active ingredient in a pharmaceutical formulation. Examples of stabilizers of the present invention include arginine, histidine, glycine, cysteine, proline, methionine, lysine, or pharmaceutically acceptable salts thereof.

[0117] As used herein, the term “surfactant” refers to a substance that tends to reduce the surface tension of the liquid in which it is dissolved. Exemplary surfactants of the present invention include poloxamer 188, polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80.

[0118] In one embodiment relating to any of the above aspects, an anti-IL-36R antibody or its antigen-binding fragment (disclosed herein) is present in a stable pharmaceutical formulation for administration to a mammal or subject (as described in concurrently pending U.S. Patent Application No. 16 / 809,606, filed on March 5, 2020, the entire content of which is incorporated herein by reference) in accordance with any one aspect of the present invention.

[0119] In one embodiment, the treatment method described in any of the embodiments described herein comprises about 20 mg / mL to about 150 mg / mL of anti-IL-36R antibody (disclosed herein), about 20 mM to about 80 mM of a pharmaceutically acceptable buffer (e.g., acetate buffer), about 100 mM to about 250 mM of a pharmaceutically acceptable isotonic agent (e.g., sucrose), about 0 mM to about 80 mM of a pharmaceutically acceptable stabilizer (e.g., arginine) or a pharmaceutically acceptable salt thereof, about 0 to about 150 mM of a pharmaceutically acceptable salt (e.g., sodium chloride), and about 0 g / L to about 1.5 g / L of a pharmaceutically acceptable surfactant ( The process includes administering a therapeutic dose of a stable pharmaceutical formulation, for example, containing polysorbate 20), to a mammal or subject, wherein subjects with a history of GPP symptoms and / or a confirmed history (diagnosis) of GPP based on common diagnostic criteria defined by the ERASPEN diagnostic criteria are treated, and / or acute GPP symptoms are prevented or resolved, or GPP-associated skin disorders in the subject are treated, or GPP-associated skin inflammation and / or flare in the subject is reduced or mitigated, or complete resolution of GPP symptoms in the subject is achieved. In the relevant embodiments, the stable pharmaceutical formulation is an aqueous pharmaceutical formulation. In the relevant embodiments, the pH of the aqueous pharmaceutical formulation is approximately 5 to approximately 7. In the relevant embodiments, the pharmaceutical formulation is for intravenous administration to a mammal or subject. In the relevant embodiments, the pharmaceutical formulation is for subcutaneous administration to a mammal or subject. In the relevant embodiments, the pharmaceutical formulation for intravenous administration contains approximately 60 mg / mL of anti-IL-36R antibody, with one vial containing 450 mg. In the relevant embodiments, the pharmaceutical formulation for subcutaneous administration contains approximately 150 mg / mL of anti-IL-36R antibody, with one pre-filled syringe containing 300 mg of antibody for subcutaneous injection.

[0120] Various delivery systems are known and can be used to administer IL-36R-conjugated substances. Methods of delivery include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. IL-36R-conjugated substances can be administered, for example, by infusion, bolus, or injection, and may be administered together with other bioactive substances, such as chemotherapeutic agents. Administration may be systemic or topical. In preferred embodiments, administration is by subcutaneous injection. Such injectable formulations may be prepared, for example, in a filled syringe, which may be administered every other week.

[0121] In one embodiment, the present invention provides a product comprising a subcutaneous administration device for delivering a fixed dose of the antibody of the present invention to a patient. In some embodiments, the subcutaneous administration device is a pre-filled syringe, an auto-injector, or a high-volume injector. For example, Roche's MyDose® product, a disposable injector that enables subcutaneous administration of large volumes of liquid drugs, can be used as the administration device. Numerous reusable pen-type and auto-injector delivery devices are applicable to the subcutaneous delivery of the pharmaceutical composition of the present invention. Examples include, but are not limited to, AutoPen (trademark) (Owen Mumford Ltd., Woodstock, UK), Disetronic Pen (trademark) (Disetronic Medical Systems Ltd., Burgdorf, Switzerland), Humalog Mix 75 / 25 Pen, Humalog Pen, Humulin 70 / 30 Pen (Eli Lilly Ltd., Indianapolis, Indiana), Novopen I, II and III (Novo Nordisk Ltd., Copenhagen, Denmark), Novopen Junior (trademark) (Novo Nordisk Ltd., Copenhagen, Denmark), BD Pen (Becton Dickinson Ltd., Franklin Lakes, New Jersey), OptiPen (trademark), OptiPen Pro (trademark), OptiPen Starlet (trademark), and OptiClick (trademark) (Sanofi-Aventis Ltd., Frankfurt, Germany). Examples of disposable pen-type delivery devices applicable to the subcutaneous delivery of the pharmaceutical composition of the present invention include, but are not limited to, Solostar® Pen (Sanofi-Aventis), FlexPen® (Novo Nordisk), and QuickPen® (Eli Lilly), Superclick® Autoinjector (Amgen, Thousand Oaks, California), Penlet® (Haselmeyer, Stuttgart, Germany), EpiPen (Dey, LP), and Humira® Pen (Abbott Laboratories, Abbott Park III), YPSOMATE®, YPSOMATE 2.25®, and VAIROJECT® (Ipsmed, Burgdorf, Switzerland).Additional information regarding exemplary delivery devices that may be used with the antibody of the present invention can be found, for example, in publications CH705992A2, WO2009 / 040602, WO2016 / 169748, and WO2016 / 179713.

[0122] In specific embodiments, the IL-36R conjugate composition is administered by injection, via a catheter, via a suppository, or via an implant, the implant being a porous, non-porous, or gel-like material, such as a membrane, e.g., a silastic membrane, or a fiber. Typically, when the composition is administered, an anti-IL-36R antibody or a material that is not absorbed by the substance is used.

[0123] In other embodiments, the anti-IL-36R antibody or substance is delivered by a release control system. In one embodiment, a pump may be used (see, for example, Langer, 1990, Science 249:1527-1533; Sefton, 1989, CRC Crit. Ref. Biomed. Eng. 14:201; Buchwald et al., 1980, Surgery 88:507; Saudek et al., 1989, N. Engl. J. Med. 321:574). In other embodiments, polymer materials may be used (see, for example, Medical Applications of Controlled Release (Langer and Wise eds., CRC Press, Boca Raton, Fla., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds., Wiley, New York, 1984); Ranger and Peppas, 1983, Macromol. Sci. Rev. Macromol. Chem. 23:61). See also Levy et al., 1985, Science 228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105. Other release control systems are also discussed above, for example, by Langer.

[0124] For the purposes of the treatment, the term “subject” or “patient” refers to any animal classified as a mammal (including humans), domesticated animals and agricultural animals, and animals for zoos, sports, or pets, such as dogs, horses, cats, and so on. Preferably, mammals are humans. Human subjects suitable for the treatment are adult and adolescent subjects who have a history of GPP as diagnosed by the ERASPEN criteria, regardless of IL36RN mutation status, and who have previously experienced at least two GPP flares of moderate to severe intensity, regardless of IL36RN mutation status. Subjects also have a GPPGA total score of 0 or 1 prior to initiation of prophylactic treatment with the anti-IL-36R antibody of the present invention. “History of GPP” may also include a history of subjects experiencing flares during concomitant GPP treatment, or a history of flares at dose reduction or discontinuation of concomitant drug therapy, the latter of which includes other known systemic and / or topical treatments for GPP.

[0125] The terms “maintenance therapy” or “maintenance dose regimen” refer to a treatment plan for a subject who has a history of GPP, and / or a history (diagnosis) of GPP, which may be moderate to severe, as confirmed by the common diagnostic criteria defined by the ERASPEN diagnostic criteria, that enables the subject to maintain health in a given state, for example, with a reduced frequency or occurrence of GPP symptoms (including moderate to severe symptoms) and acute GPP flares, or to achieve a clinical response. In one embodiment, the maintenance therapy of the present invention is used for subjects who have a history of GPP, and / or a history (diagnosis) of GPP, as confirmed by the common diagnostic criteria defined by the ERASPEN diagnostic criteria, to enable the subject to maintain health in a state of complete symptom-free status or with reduced symptoms associated with the disease. In one embodiment, the maintenance therapy of the present invention is used for subjects who have a history of GPP and / or a history (diagnosis) of GPP confirmed based on common diagnostic criteria defined by the ERASPEN diagnostic criteria, in order to enable them to maintain health in a state substantially free from symptoms associated with the disease. In one embodiment, the maintenance therapy of the present invention is used for subjects who have a history of GPP, in order to maintain health in a state in which symptoms associated with the disease are significantly reduced.

[0126] As used herein, the terms “treatment” or “maintenance treatment” refer to a treatment period that includes the administration of an anti-IL-36R antibody or its antigen-binding moiety to a subject in order to maintain a desired therapeutic effect, for example, acute GPP and / or improved symptoms associated with GPP.

[0127] In one embodiment of the present invention, maintenance treatment may be performed after the onset of a GPP flare or after the exacerbation of the GPP disease. Maintenance treatment would be initiated once the subject's GPP flare has been treated and the acute flare has been clinically stabilized.

[0128] "Treatment of GPP flare" is defined as treatment for the occurrence of GPP exacerbation in subjects using a 900 mg intravenous dose of spesolimab to treat the first GPP flare during the randomized maintenance treatment period. Criteria for receiving treatment of GPP flare with an open-label 900 mg intravenous dose of anti-IL-36R antibody were subjects with a GPPGA score of 3 or higher and 2 or more GPPGA pustular elements at R1 (the time of the first intravenous treatment for flare). Alternatively, treatment was indicated for subjects with a GPPGA score of 2 and 2 or more GPPGA pustular elements at R1, where 2 or more GPPGA pustular elements were present on R3 / day 8 (D8). Following treatment of GPP flares with a 900 mg intravenous dose of anti-IL-36R antibody (at R1 / D1, or at R1 / D1 and R3 / D8), respondents were subjects who showed no symptoms of moderate / severe flares, with a GPPGA score of less than 3 and a pustule element score of less than 2. Furthermore, subjects experienced a decrease of 1 or more in their GPPGA score from R1 / D1. Partial response to GPP flare treatment is defined as an observation of a decrease in the GPPGA score (less than 3) or GPPGA pustule subscore (less than 2) after treatment with a 900 mg intravenous dose of anti-IL-36R antibody, although the GPPGA score did not reach 0 or 1. Subjects may also receive more frequent subcutaneous maintenance doses, for example, increasing the frequency from a maintenance dose of 300 mg of anti-IL36R antibody every 12 weeks (q12w) to a maintenance dose of 300 mg every 4 weeks (q4w).

[0129] "Gravitational worsening of GPP disease" is defined as a deterioration of the clinical condition or, in the opinion of the principal investigator, skin and systemic symptoms of GPP that require treatment intervention.

[0130] A "GPP flare" is clinically defined as an increase of 2 or more GPPGA scores from the baseline, and 2 or more pustular elements in GPPGA. The baseline value for efficacy measurements was the last value measured before administration of the initial dose of anti-IL-36R antibody, e.g., spesolimab, at the second visit (V2).

[0131] V. Treatment evaluation items: Embodiments of the present invention provide means for the treatment of generalized pustular psoriasis (GPP), including the treatment and prevention of flares, in subjects having a history of GPP symptoms and / or a confirmed history (diagnosis) of GPP based on common diagnostic criteria defined by the ERASPEN diagnostic criteria, up to 48 weeks after the start of treatment.

[0132] In other embodiments, the present invention provides treatment methods including methods for reducing disease in subjects with a history of GPP and improving the quality of life for subjects with GPP.

[0133] In other embodiments, the present invention provides methods for treating specific subgroups of subjects, such as subjects who have failed or shown no response to previous treatment, or subjects who have shown an inadequate response to, intolerance to, or contraindication to, standard treatment. In certain embodiments, the present invention is used to treat subjects with a history of GPP who show an inadequate response to, intolerance to, or contraindication to, tumor necrosis factor α inhibitors.

[0134] The methods and uses described herein provide means for determining the efficacy of an anti-IL-36R antibody or its antigen-binding moiety for treating subjects having a history of symptoms of GPP and / or a history (diagnosis) of GPP confirmed based on the common diagnostic criteria defined by the ERASPEN diagnostic criteria, and the use of such an anti-IL-36R antibody for the treatment of generalized pustular psoriasis (GPP), including the treatment and prevention of flares in the subject. The efficacy of the treatment of GPP is determined by any of the measures described herein, or any measure known to those skilled in the art, e.g.: (a) A greater reduction in the risk of at least one GPP flare (defined as an increase of 2 or more GPPGA scores from baseline and 2 or more pustular elements of GPPGA) by week 48 compared to the placebo group. (b) Reduced risk of worsening of the Psoriasis Symptom Rating Scale (PSS), defined as a greater increase of 4 points from baseline in the Psoriasis Symptom Rating Scale than the placebo group by week 48. (c) By week 48, compared to the placebo group, there was a reduced risk of worsening of the DLQI (Disease-Limited Quality of Life Index), defined as a 4-point increase in the total score from baseline. This can be determined using

[0135] In the embodiments described above or in other embodiments related to any of the above aspects, administration of an anti-IL-36R antibody or its antigen-binding moiety yields one or more of the following efficacy endpoints, which are measured by the difference among GPP subjects receiving the treatment compared to a placebo group. (a) Percentage of subjects who did not experience a GPP flare by week 48; (b) Without receiving rescue drug therapy or standard treatment (SoC) prescribed by the principal investigator, a subscore on the Psoriasis Symptom Rating Scale remains below 1 at least 75% of visits up to week 48; (c) A DLQI score of 0 or 1 at all visits up to week 48 without receiving rescue drug therapy or standard care (SoC) prescribed by the principal investigator; (d) WPAI (Work Productivity and Activity Impairment Questionnaire) scores over time up to week 48; (e) GPPGA scores over time up to week 48; (f) GPPASI scores over time up to week 48; (g) SF-36 scores over time up to week 48; (h) Visual Analog Scale (VAS) scores for pain over time up to week 48; (i) EQ-5D-5L scores over time up to week 48; (j) Time-series JDA (Japanese Dermatological Association) GPP severity score up to week 48; (k) Temporal TPSS (Target Plaque Severity Score) up to week 48; (l) PGI-S (severity based on the patient's overall impression) over time up to week 48; (m) Time-series PGI-C (overall patient impression change) up to week 48; (n) Modified sustained remission, defined as a subject having a total GPPGA score of 0 or 1 and each GPPGA subscore of 2 or less at all visits up to week 48, without the use of rescue drug therapy or standard of care (SoC) prescribed by the principal investigator (added via TSAP (Plan for Study Statistical Analysis)); (o) Modified sustained remission, defined as a subject having a total GPPGA score of 0 or 1 and each GPPGA subscore of 2 or less at all visits up to week 48, without the use of rescue drug therapy or standard of care (SoC) prescribed by the principal investigator (added via TSAP (Plan for Study Statistical Analysis)).

[0136] In the above-described set of embodiments or other embodiments related to the above-described set of embodiments, the proportion of subjects responding to administration of anti-IL-36R antibody or its antigen-binding moiety is statistically significant compared to placebo subjects for one or more of the evaluation items (a) to (c) and / or (a) to (o).

[0137] In one embodiment related to the above embodiments, the present invention provides a method for the treatment of generalized pustular psoriasis (GPP), including the treatment and prevention of flares, in subjects with a history of GPP and / or a confirmed history (diagnosis) of GPP based on common diagnostic criteria defined by the ERASPEN diagnostic criteria, such as being evaluated using a physician's global assessment (GPPGA) for generalized pustular psoriasis. The GPPGA relies on a clinical evaluation of the skin symptoms of a GPP subject. It is a modified PGA (Physician's Global Assessment for Psoriasis), i.e., a physician's assessment of psoriatic lesions, which is applied to the evaluation of GPP subjects (Langley RG, Feldman SR, Nyirady J, et al. The 5-point Investigator's Global Assessment (IGA) Scale: A modified tool for evaluating plaque psoriasis severity in clinical trials. J Dermatol Treat 2015;26(1):23-31). The principal investigator scores all GPP lesions on a scale of 0 to 4 for erythema, pustules, and desquamation. Each element is graded separately, the mean is calculated, and the final GPPGA is determined from this composite score. Lower scores indicate lower severity, with 0 being clear and 1 being nearly clear. GPPGA was measured at weeks 0, 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48, as noted in the study, as well as 16 weeks after the last dose (see the flowchart of study activities in the example below).

[0138] In one embodiment related to the above embodiments, the present invention provides treatment for generalized pustular psoriasis (GPP), including treatment and prevention of flares, in subjects with a history of GPP and / or a confirmed history (diagnosis) of GPP based on common diagnostic criteria defined by the ERASPEN diagnostic criteria, as assessed using the Generalized Pustular Psoriasis Severity Index (GPPASI). GPPASI is an adaptation for GPP subjects of the PASI (Psoriasis Area Severity Index), an established measure of the severity and area of ​​psoriasis lesions in psoriasis subjects (Fredriksson T, Pettersson U. Severe psoriasis-oral therapy with a new retinoid. Dermatologica 1978; 157:238-244). In GPPASI, the induration element is replaced by the pustular element. It is a tool that provides a numerical score on the range of 0 to 72 for the subject's overall GPP disease status. It is a linear combination of the percentage of skin surface area affected by erythema, pustules, and desquamation across four regions of the body, and the severity of erythema, pustules, and desquamation (peeling). GPPASI was measured at weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48, as noted in the study, and 16 weeks after the last dose (see the flowchart of study activities in the examples below).

[0139] In one embodiment related to the above embodiments, the present invention provides a method for treating generalized pustular psoriasis (GPP), including treatment and prevention of flares, in subjects with a history of GPP and / or a confirmed history (diagnosis) of GPP, as assessed using the EQ-5DL questionnaire, up to 48 weeks after the start of treatment. The EQ-5D-5L self-report questionnaire is a standardized assessment scale developed by the European Quality of Life Group (EuroQol Group) for use as a measure of health outcomes (EuroQol G. EuroQol-a new facility for the measurement of health-related quality of life. Health Policy 1990; 16:199-208; Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011; 20:1727-1736). It includes five questions about various aspects of health (e.g., mobility, self-care) and one visual analog scale about current health. The response options include a five-point ordinal scale for reporting five health status items and a visual analog scale for reporting the subject's self-assessed health status as a number from 0 to 100.The minimum clinically important difference (MCID) for the 5-item portion and the visual analog scale was estimated to be 0.074 and 7 points, respectively (Walters SJ, Brazier JE. Comparison of the minimally important difference for two health state utility measures: EQ-5D and SF-6D. Qual Life Res 2005; 14:1523-1532; Pickard AS, Neary MP, Cella D. Estimation of minimally important differences in EQ-5D utility and VAS scores in cancer. Health Qual Life Outcomes 2007; 5:70). All questions refer to current health status ("today"). The EQ-5D-5L questionnaire was administered at weeks 1, 4, 8, 12, 24, 36, and 48 as noted in the study (see the flowchart of study activities in the example below).

[0140] In one embodiment related to the above embodiments, the present invention provides a treatment method for generalized pustular psoriasis (GPP), including the treatment and prevention of flares, in subjects with a history of GPP and / or a confirmed history (diagnosis) of GPP based on common diagnostic criteria defined by the ERASPEN diagnostic criteria, as assessed using the SF-36 questionnaire as a measure of the subject's quality of life before, during, and / or after treatment. The SF-36 is a widely used assessment scale to measure health-related quality of life among healthy subjects and subjects with acute and chronic conditions. It consists of 36 questions (Ware JE, editor. SF-36 Health Survey: Manual and Interpretation Guide. Boston: The Health Institute, New England Medical Center; 1993). SF-36 scores can be compared between various subject populations and healthy subjects. The answer choices vary, but it is usually a 5-item or 3-item assessment scale. Sub-rating scales (physical functioning, role functioning (physical), bodily pain, overall health, vitality, social functioning, role functioning (mental), and mental health) were reported individually and summarized as a physical quality of life summary score (PCS) and a mental quality of life summary score (MCS) (range: 0-100, a score of 50±10 was deemed to reflect US standards (Ware JE. SF-36 health survey update. Spine 2000;25(24):3130-3139)). A difference of 3 points is recommended as the MCID (minimum clinically significant difference) threshold for comparing PCS and MCS between groups (Frendl DM, Ware JE. Subject-reported functional health and well-being outcomes with drug therapy: a systematic review of randomized trials using the SF-36 health survey. Med Care 2014;52(5):439-445). An acute version of SF-36 with a one-week recall period was used.SF-36 was measured at weeks 1, 12, 24, 36, and 48 (see the flowchart of research activities in the example below).

[0141] In one embodiment related to the above embodiments, the present invention provides a treatment for generalized pustular psoriasis (GPP), including treatment and prevention of flares, in subjects having a history of GPP symptoms as assessed using the PSS (Psoriasis Symptom Rating Scale) and / or a confirmed history (diagnosis) of GPP based on common diagnostic criteria defined by the ERASPEN diagnostic criteria, where the effectiveness of the subject's response to treatment with an anti-IL-36R antibody or its antigen-binding moiety is measured as a reduction in the risk of symptom exacerbation, as assessed by the PSS by week 48, compared to the placebo group. The PSS (Psoriasis Symptom Rating Scale) is a four-item subject-reported outcome (PRO) rating scale developed to assess the severity of psoriasis symptoms in subjects with psoriasis (Rentz AM, Skalicky AM, Burslem K, et al. The content validity of the PSS in subjects with plaque psoriasis. J Patient Rep Outcomes 2017; 1:4). When completing this questionnaire, patients report the symptoms arising from their generalized pustular psoriasis. These symptoms include pain, redness, itching, and burning. The severity of current symptoms is assessed using a five-point scale ranging from 0 (none) to 4 (very severe). Symptom scores are added to an unweighted total score (range: 0-16). The PSS (Psoriasis Symptom Rating Scale) scale was measured at weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48, as noted in the study (see the study activity flowchart in the example below).

[0142] In one embodiment related to the above embodiments, the present invention provides a treatment method for generalized pustular psoriasis (GPP), including treatment and prevention of flare, in subjects having a history of GPP symptoms and / or a confirmed history (diagnosis) of GPP based on common diagnostic criteria defined by the ERASPEN diagnostic criteria, wherein the effectiveness of the subject's response to treatment with an anti-IL-36R antibody or its antigen-binding moiety is measured using the WPAI-GPP (Work Productivity and Activity Impairment Questionnaire, GPP-specific version). The WPAI-GPP is a frequently used questionnaire, GPP-specific version, consisting of six questions that assess social functioning in relation to absence from work due to illness, working while unwell, and impairment of daily activities. The answer choices include actual hours worked and hours absent (due to GPP and due to unrelated reasons), and a numerical rating scale (0-10) that assesses impairment of work and daily activities due to GPP. The recall period is 7 days. The WPAI-GPP rating scale was measured at weeks 1, 12, 36, and 48, as noted in the study (see flowchart of study activities in the example below).

[0143] In one embodiment related to the above embodiments, the present invention provides a method for treating generalized pustular psoriasis (GPP), including treatment and prevention of flares, in subjects having a history of GPP symptoms and / or a history (diagnosis) of GPP confirmed based on common diagnostic criteria defined by the ERASPEN diagnostic criteria, wherein the effectiveness of the subject's response to treatment with an anti-IL-36R antibody or its antigen-binding moiety is measured using a visual analog rating scale for pain (VAS for pain). The VAS for pain is a one-dimensional measure of pain intensity (Hawker GA, Mian S, Kendzerska T, et al. Measures of adult pain: Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP Arthritis Care Res (Hoboken) 2011;63(Suppl). 11): S240-S252). It is a continuous rating scale consisting of horizontal or vertical lines, usually 10 cm (100 mm) long, with reference points fixed at each end by words indicating the degree of symptoms ("no pain," "very severe pain"). The VAS for pain was completed by the respondent themselves. Respondents were asked to draw vertical (|) marks on the horizontal lines to indicate the severity of their pain. Using a ruler, the distance (mm) between the "no pain" anchor on the 10 cm line and the patient's mark was measured, and a score ranging from 0 to 100 was determined. A higher score indicated a greater intensity of pain.Pain VAS was measured at weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48, as noted in the study (see flowchart of study activities in the example below).

[0144] In another embodiment related to the embodiments described above, the present invention provides a method for treating generalized pustular psoriasis (GPP), including treatment and prevention of flares, in subjects having a history of GPP symptoms and / or a confirmed history (diagnosis) of GPP based on common diagnostic criteria defined by the ERASPEN diagnostic criteria, wherein the effectiveness of the subject's response to treatment with an anti-IL-36R antibody or its antigen-binding moiety is measured as a reduction in the risk of deterioration of the subject's Skin Disease Quality of Life Index (DLQI) score (here, a high score (i.e., impaired quality of life) and a lower score (i.e., no or minimal impact on quality of life)). A reduced risk means that the DLQI score is maintained at the baseline level at the start of treatment and / or decreases from a higher score to a lower score, defined as a 4-point increase in the total score from the baseline by 48 weeks after the start of treatment. The DLQI is a 10-item quality of life questionnaire administered to patients, covering six domains (symptoms and emotions, daily life, leisure, work and school, relationships, and treatment) (Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) - a simple practical measure for routine clinical use. Joint Ann Mtg of the British Association of Dermatologists and the Canadian Dermatology Association, Oxford, 6 - 10 Jul 1993. Clin Exp Dermatol 1994; 19:210-216). The DLQI has a one-week recall period. The response categories include "not applicable" (score 0), "not at all" (score 0), "somewhat" (score 1), "quite" (score 2), and "very much" (score 3). Question 7 is a "yes / no" question, where "yes" is scored as 3. The DLQI total score is calculated by summing the scores for each question, resulting in a score ranging from 0 to 30. The higher the score, the more the quality of life is impaired.The DLQI assessment scale was measured at weeks 1, 4, 8, 12, 24, 36, and 48, as noted in the study (see flowchart of study activities in the example below).

[0145] In another embodiment related to the above embodiments, the present invention provides a method for treating generalized pustular psoriasis (GPP), including treatment and prevention of flares, in subjects having a history of GPP symptoms and / or a confirmed history (diagnosis) of GPP based on common diagnostic criteria defined by the ERASPEN diagnostic criteria, wherein the effectiveness of the subject's response to treatment with an anti-IL-36R antibody or its antigen-binding moiety is measured by the JDA (Japanese Dermatological Association) GPP severity score. The JDA GPP severity score was established by the Japanese Dermatological Association (JDA) and consists of an evaluation of skin symptoms and an evaluation of systemic symptoms / laboratory findings. Each item of skin symptoms (overall erythema area, erythema area with pustules, and edema area) was graded from 0 to 3, and the evaluation of systemic symptoms / clinical findings (fever, white blood cell count, C-reactive protein, and serum albumin) was graded from 0 to 2 (Cosentyx 150 mg subcutaneous injection syringe, 150 mg subcutaneous injection (secukinumab) (Novartis), physician prescription only: review report (November 12, 2015), website: pmda.go.jp / files / 000216877.pdf (accessed May 9, 2018); Pharmaceuticals and Medical Devices Agency (PMDA); 2015). The total score of the Japanese Dermatological Association's severity index for GPP is assigned to a score of 0-17 (0 = best, 17 = worst), and clinical improvement here is defined as an increase in the total score from baseline, and is defined as a reduction in the risk of worsening of the JDA severity index for GPP score from the start of treatment to week 48. The JDP GPP severity score was measured at weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48, as noted in the study, and 16 weeks after the last dose (see flowchart of study activities in the example below).

[0146] In another embodiment related to the above embodiments, the present invention provides a method for treating generalized pustular psoriasis (GPP), including treatment and prevention of flares, in subjects having a history of GPP symptoms and / or a confirmed history (diagnosis) of GPP based on common diagnostic criteria defined by the ERASPEN diagnostic criteria, wherein the effectiveness of the subject's response to treatment with an anti-IL-36R antibody or its antigen-binding moiety is measured by the degree of improvement in Clinical Global Impression (CGI) according to the JDA Severity Index. The Clinical Global Impression Improvement (CGI-I) is an observer-grade rating scale that measures the overall improvement of the condition (CGI-I, according to the JDA Severity Index Guidelines) (ibid.). It was classified as “worsening,” “no change,” “slight improvement,” “moderate improvement,” or “marked improvement.” Clinical overall impression-improvement tests were conducted at weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48, as noted in the test, and 16 weeks after the last dose (see flowchart of test activities in the example below).

[0147] In another embodiment related to the above embodiments, the present invention provides a method for treating generalized pustular psoriasis (GPP), including treatment and prevention of flares, in subjects having a history of GPP symptoms and / or a history (diagnosis) of GPP confirmed based on common diagnostic criteria defined by the ERASPEN diagnostic criteria, wherein the effectiveness of the subject's response to treatment with an anti-IL-36R antibody or its antigen-binding moiety is measured by a Targeted Plaque Severity Score (TPSS). The Targeted Plaque Severity Score (TPSS) is measured in patients with concomitant psoriasis vulgaris when a corresponding target lesion area is identified and the severity threshold is met as described below: a TPSS of 5 or higher and an induration subscore of 2 or higher for at least 9 cm 2The target lesion was selected by the principal investigator at baseline. The severity of erythema, desquamation, and induration (plaque thickness) of this selected target lesion was assessed by the principal investigator at baseline and at subsequent visits using a 5-point rating scale ranging from 0=none to 4=very prominent. The TPSS was measured at weeks 1, 4, 16, 20, 24, and 48, as noted in the study (see flowchart of study activities in the example below).

[0148] In another embodiment related to the embodiments described above, the present invention provides a treatment method for generalized pustular psoriasis (GPP), including treatment and prevention of flares, in subjects having a history of GPP symptoms and / or a confirmed history (diagnosis) of GPP based on common diagnostic criteria defined by the ERASPEN diagnostic criteria, where the effectiveness of the subject's response to treatment with an anti-IL-36R antibody or its antigen-binding moiety is measured by the PGI-S (Patient's Overall Impression Severity). The PGI-S is a single-item self-assessment of the severity of the present disease. Patients were asked to grade the severity of their generalized pustular psoriasis (GPP) on a five-point scale ranging from "normal" to "very severe". The PGI-S was measured at weeks 1, 4, 8, 12, 24, 36 and 48, as noted in the study (see flowchart of study activities in the following examples).

[0149] In another embodiment related to the embodiments described above, the present invention provides a treatment method for generalized pustular psoriasis (GPP), including treatment and prevention of flares, in subjects having a history of GPP symptoms and / or a confirmed history (diagnosis) of GPP based on common diagnostic criteria defined by the ERASPEN diagnostic criteria, where the effectiveness of the subject's response to treatment with an anti-IL-36R antibody or its antigen-binding moiety is measured by PGI-C (Patient General Impression Change). PGI-C is a single-item self-assessment of how the patient feels their generalized pustular psoriasis (GPP) has changed since the start of the study. Patients were asked to grade the perceived change on a seven-point rating scale ranging from "very good" to "very bad". PGI-C was measured at weeks 1, 4, 8, 12, 24, 36 and 48, as noted in the study (see flowchart of study activities in the following examples).

[0150] In another embodiment related to the above embodiment, the proportion of subjects responding to administration of anti-IL-36R antibody is significantly different for one or more endpoints compared to subjects treated with placebo.

[0151] In one embodiment, the present invention relates to a method for extending the time to the first GPP flare by 48 weeks in a subject with a history of generalized pustular psoriasis (GPP) and / or a history of GPP as diagnosed by the European Network of Rare and Severe Psoriasis Specialists (ERASPEN) criteria, wherein a GPP flare is defined in a subject with a history of GPP as diagnosed by the ERASPEN criteria by an increase of more than 2 in the GPPGA pustule subscore and an increase of 2 or more in the GPPGA total score from baseline, and the method comprises administering to the subject one or more doses of the anti-IL-36R antibody described in any embodiment of the above embodiments. In one embodiment, the method comprises administering to the subject one or more effective doses of anti-IL-36R antibody in subcutaneous doses, delivered as an initial loading dose of 300 mg to 600 mg of anti-IL-36R antibody, followed by a maintenance dose of 150 mg to 600 mg of anti-IL-36R antibody.

[0152] In one embodiment, the present invention relates to a method for achieving prevention of moderate to severe GPP flares in subjects with a history of GPP as diagnosed by ERASPEN criteria after treatment with an anti-IL-36R antibody as described in any embodiment of the above embodiments; wherein the symptoms of GPP include inflammatory lesions, abscesses, GPP-related inflammation (erythema, induration, open ulcers) and / or GPP-related pain.

[0153] In one embodiment or group of embodiments relating to any of the above embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of subjects exhibit clinical improvement (defined by a GPPGA pustule subscore of more than 2 and an increase of 2 or more GPPGA total score from baseline) at weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 of treatment, as measured by time to GPP flare.

[0154] In one embodiment or group of embodiments relating to any of the above embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of subjects show improvement, expressed as a reduction in the occurrence of at least one GPP flare, at weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 of the treatment.

[0155] In one embodiment or group of embodiments relating to any of the above embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of subjects show improvement (defined as a 4-point increase in the total score from baseline), as measured by the time to the first worsening of the PSS, at weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 of treatment.

[0156] In one embodiment or group of embodiments relating to any of the above embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of subjects show improvement, as measured by the time to the first worsening of the Quality of Life Index (DLQI) (defined as an increase of 4 points in the total score from baseline), at weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 of treatment.

[0157] In one embodiment or group of embodiments relating to any of the above embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of subjects achieve complete remission at weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 of treatment.

[0158] Embodiments of the present invention relating to any of the above aspects include the evaluation of biomarkers for assessing pre- and post-treatment changes in generalized pustular psoriasis (GPP), including treatment and prevention of flares, in subjects having a history of GPP symptoms and / or a confirmed history (diagnosis) of GPP based on common diagnostic criteria defined by the ERASPEN diagnostic criteria. Serum and skin biopsy materials were collected at the time points shown in the flowchart(s) for biomarker analysis.

[0159] In embodiments of the present invention, skin biopsy material was collected before administration of the test drug and during maintenance treatment to evaluate changes in gene and protein levels before and after treatment with spesorimab. Histological evaluation of skin thickness, epidermal and dermal appearance were assessed before and after treatment, and summarized with an overall histopathological score for each subject at each time point. Markers evaluated by immunohistochemistry included, but were not limited to, K16, Ki67, S100A7, lipocalin 2, β-defensin 2, CD3-positive T lymphocytes, CD11-positive dendritic cells, IL-17C, IL8, NFκβ, tumor necrosis factor α, IL36γ, IL36 receptor, and neutrophil elastase. The expression of some of these markers was evaluated in dermal and epidermal tissue. In related embodiments, serum was collected to evaluate changes in selected IL-36 pathway protein levels and GPP disease-specific markers before and after treatment with spesorimab. The assay analysis of the sample using biomarkers is performed using a stepwise approach.

[0160] In embodiments of the present invention, skin biopsy materials were collected before administration of the test drug and during maintenance treatment to evaluate changes in microRNA expression levels before and after treatment with spesorimab. MicroRNAs (miRNAs) are small, non-coding RNA molecules capable of post-transcriptional regulation of gene expression. MicroRNAs evaluated by small RNA sequencing included, but were not limited to, miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p, and the post-treatment downregulation or upregulation compared to pre-treatment is associated with a beneficial response to the treatment. MicroRNA analysis of lesion-free skin and skin lesion samples, as well as serum samples, collected from GPP patients before and after treatment with spesorimab is also associated with clinical outcomes such as GPPASI and GPPGA scores.

[0161] In embodiments of the present invention, blood samples are used to evaluate genes for known GPP mutations that cause GPP, such as IL36RN, CARD14, and AP1S3. Subsequently, the potential impact of these mutations on disease activity and / or drug efficacy within the context of clinical trials is evaluated.

[0162] VI. Mechanism of Action The anti-IL-36R antibody of the present invention is an antagonistic, humanized monoclonal IgG1 antibody that blocks signaling at the human IL-36 receptor. Binding of the anti-IL-36 receptor antibody, spesolimab, to the IL-36 receptor prevents subsequent activation of the IL-36 receptor by its homologous ligands (IL-36α, β, and γ), as well as the activation of downstream pro-inflammatory and pro-fibrotic pathways. IL-36 receptor signaling is distinguished from the inhibitory pathways of tumor necrosis factor α, integrins, and IL-23 by directly and simultaneously blocking both inflammatory and pro-fibrotic pathways. Human genetic studies have established a strong link between IL-36 receptor signaling and skin inflammation. The IL-36 receptor is also known as IL-1RL2 and IL-1Rrp2. Agonist-type IL-36 ligands (α, β, or γ) bind to the IL-36 receptor and subsequently initiate the signaling cascade by forming heterodimers with the IL-1 receptor co-protein (IL-1RAcP). IL-36 antagonist ligands (IL-36RA / IL1F5, IL-38 / ILF10) inhibit the signaling cascade.

[0163] The anti-IL-36R antibody of the present invention, as provided herein, has been evaluated and found to be effective in treating subjects with acute generalized pustular psoriasis (GPP), a severe inflammatory skin disease driven by uncontrolled IL36 activity. The randomized, double-blind, placebo-controlled clinical trial in EFFISAYIL®-1 demonstrated the clinical efficacy and safety of the anti-IL-36R antibody, Spevigo®, in adult patients experiencing a flare of generalized pustular psoriasis (GPP) as diagnosed by the European Network of Rare and Severe Psoriasis Specialists (ERASPEN) criteria. At week 1, there was a statistically significant difference in the proportion of patients achieving a GPPGA pustule subscore of 0 (indicating no visible pustules) and a GPPGA total score of 0 or 1 (clear or nearly clear skin) in the Spevigo® treatment group compared to placebo. The results of the clinical trials EFFISAYIL®-1 (NCT03782792) and EFFISAYIL®-ON (NCT03886246) (open-label extension studies) are incorporated herein by reference in their entirety.

[0164] VII.Product In another embodiment, the product includes a material useful for treating the above-mentioned disorder. The product includes a container and a label. Suitable containers include, for example, bottles, vials, syringes, and test tubes (for example, for holding unit dose dosage forms). The container may be made of a variety of materials, such as glass or plastic. The container may hold a composition useful for treating the condition and may have a sterile access port. For example, the container may be an infusion bag or a vial with a stopper that can be pierced by a subcutaneous needle. The container for the composition may hold a composition that is effective for treating the condition and may have a sterile access port. The active substance in the composition is a humanized anti-IL-36R antibody. A label on or attached to the container indicates that the composition is used for treating a selected condition. The product may further include a second container containing a pharmaceutically acceptable buffer, such as phosphate-buffered saline, Ringer's solution, and dextrose solution. It may also include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and accompanying documentation, including instructions for use.

[0165] The term "package insert" is used to refer to instructions that are customarily included on the commercial packaging of a therapeutic product, containing information regarding indications, usage, administration, contraindications, and / or warnings relating to the use of such therapeutic product.

[0166] The present invention is further described in the following embodiments, which are not intended to limit the scope of the invention. Those skilled in the art will recognize or be able to identify numerous equivalents to the specific substances and procedures described herein.

[0167] In one embodiment, the present invention provides a pharmaceutical composition formulated in a unit dose dosage form, wherein such a single-dose dosage form contains at least 150 mg, 300 mg, 450 mg, or 600 mg of the anti-IL-36R antibody. In a related embodiment, the unit dose dosage form is used in the preparation of a pharmaceutical for the treatment of subjects having generalized pustular psoriasis (GPP), including the treatment and prevention of flares in subjects having a history of symptoms of GPP and / or a history (diagnosis) of generalized pustular psoriasis confirmed based on common diagnostic criteria defined by the ERASPEN diagnostic criteria. In a related embodiment, the unit dose dosage form is used in the preparation of a pharmaceutical for the treatment of subjects having GPP, in subjects with a history of generalized pustular psoriasis (GPP) when they are not experiencing flares. In related embodiments, the unit dose formulation is used to prepare a pharmaceutical product for reducing the onset, recurrence, and / or frequency of flares of generalized pustular psoriasis (GPP) in subjects having a history of symptoms of GPP and / or a history (diagnosis) of generalized pustular psoriasis confirmed based on common diagnostic criteria defined by the ERASPEN diagnostic criteria.

[0168] In embodiments relating to any of the above embodiments, the unit dose dosage form is a parenteral (e.g., intravenous or subcutaneous) dose dosage form, preferably a subcutaneous dose dosage form.

[0169] In related embodiments, the present invention provides a drug preparation (or "product" as described herein hereafter) comprising one, two, three, or four unit dose formulations containing 150 mg of the anti-IL-36R antibody; one, two, three, or four unit dose formulations containing 300 mg of the anti-IL-36R antibody; one, two, three, or four unit dose formulations containing 450 mg of the anti-IL-36R antibody; or one, two, three, or four unit dose formulations containing 600 mg of the anti-IL-36R antibody; or any combination thereof that reaches an effective dose.

[0170] In related embodiments, 1, 2, 3, or 4 of the unit dose formulations (e.g., in a drug preparation) are administered as an initial loading dose of 300 mg to 600 mg of anti-IL-36 receptor antibody; thereafter, maintenance doses of 150 mg to 600 mg of the anti-IL-36 receptor antibody are administered to the subject at 4-week intervals (q4w) or 12-week intervals (q12w) for 8 to 48 weeks after the last maintenance dose.

[0171] Examples Standard treatment guidelines for GPP often follow those for plaque psoriasis, despite limited evidence regarding the effectiveness of antipsoriasis drugs, including biological agents, in GPP (Gooderham MJ, Van Voorhees AS, Lebwohl MG. An update on generalized pustular psoriasis. Expert Rev Clin Immunol. 2019;15(9):907-19).In Japan, Taiwan, and Thailand, several biologics targeting pro-inflammatory pathways associated with GPP have been approved for patient use. However, the rarity of the disease means that their approval is based on a limited number of open-label clinical trials involving small numbers of participants. (Fujita H, Terui T, Hayama K, et al. Japanese guidelines for the management and treatment of generalized pustular psoriasis: the new pathogenesis and treatment of GPP. J Dermatol. 2018;45(11):1235-70; Takeichi T, Akiyama M. Generalized pustular psoriasis: clinical management and update on 358 Dermatol Ther (Heidelb) (2023) 13:347-359 autoinflammatory aspects. Am J Clin Dermatol. 2020;21(2):227-36; Thailand Food and Drug Administration. LUMICEF Summary of Product Characteristics 2019; Taiwan Center for Drug Evaluation. Lumicef subcutaneous injection) 210 mg syringe 201; Morita A, Kotowsky N, Gao R, Shimizu R, Okubo Y. Patient characteristics and burden of disease in Japanese patients with generalized pustular psoriasis: results from the Medical Data Vision claims database. J Dermatol. 2021;48(10):1463-73).

[0172] In an open-label proof-of-concept trial (NCT02978690), patients with a history of GPP flare experienced complete or near-complete GPP resolution by 4 weeks after treatment with one dose of spesorimab (humanized anti-interleukin-36 receptor monoclonal antibody) (Bachelez H, Choon SE, Marrakchi S, Burden AD, Tsai TF, Morita A, et al. Inhibition of the interleukin-36 pathway for the treatment of generalized pustular psoriasis. N Engl J Med. 2019;380(10): 981-3). Subsequently, the Effisayil™ 1 trial (NCT03782792), the first randomized clinical trial to investigate a treatment targeted to GPP, showed that adult patients with GPP flares treated with spesolimab achieved rapid resolution of pustules and skin symptoms (Bachelez H, Choon SE, Marrakchi S, Burden AD, Tsai TF, Morita A, et al. Trial of spesolimab for generalized pustular psoriasis. N Engl J Med. 2021;385(26):2431-40). These results were essential for the U.S. Food and Drug Administration's approval of spesolimab as a first-line treatment for GPP flares.Recurrent GPP (persistent disease with recurrent flares or intermittent flares) highlights the need to develop preventive measures for flares (Navarini AA, Burden AD, Capon F, Mrowietz U, Puig L, Köks S, et al. European consensus statement on phenotypes of pustular psoriasis. J Eur Acad Dermatol Venereol. 2017;31(11):1792-9), and a recent survey found that 67% of dermatologists whose patients experienced frequent flares felt that currently available treatments were insufficient to adequately prevent new flares (Strober B, Kotowsky N, et al. Unmet medical needs in the treatment and management of generalized pustular psoriasis flares: evidence from a survey of Corrona Registry Dermatologists. Dermatol Ther (Heidelb). 2021;11(2):529-41).

[0173] Example 1: Study Design: Effisayil® 2 was a multicenter, randomized, parallel-group, double-blind, placebo-controlled Phase IIb dose-finding study that evaluated the efficacy and safety of spesorimab compared to placebo in preventing flare of generalized pustular psoriasis (GPP) in subjects with a history of generalized pustular psoriasis (GPP). Effisayil® 2 was the first study to investigate the use of an antibody against the interleukin-36 receptor for the prevention of GPP flare, and was a key step in evaluating the efficacy of spesorimab in a disease that recurs intermittently and repeatedly, and in determining the optimal dose regimen for subcutaneous maintenance treatment with spesorimab.

[0174] Objective: EFFISAYIL® 2 (NCT04399837) was evaluated for the efficacy and safety of subcutaneous spesolimab in adult and adolescent subjects with a history of GPP diagnosed by ERASPEN criteria, regardless of IL36RN mutation status, and who had previously experienced at least two moderate to severe GPP flares. Subjects were required to discontinue systemic and topical therapies for GPP before or at randomization. These subjects had a history of flares during concomitant GPP treatment or at the time of dose reduction or discontinuation of these concomitant therapies.

[0175] The primary objective was to demonstrate a non-flat curve for the primary endpoint—time to the first GPP flare up to week 48—in subjects with a history of GPP (according to the ERASPEN criteria) who presented with a GPPGA score of 1 or 1 (clear or nearly clear) (at screening and randomization), and to characterize the dose-response relationship of three subcutaneous dose prescription plans for spesorimab (each prescription plan included a single loading dose and separate maintenance subcutaneous dose prescription plans vs. placebo).

[0176] The primary endpoint of the study was time to the first GPP flare (defined as a GPPGA pustule subscore greater than 2 and an increase of 2 or more points in the GPPGA total score from baseline) by week 48. The key secondary endpoint of the study was the occurrence of at least one GPP flare by week 48, i.e., how long it took for a subject to experience a GPP flare while receiving spesorimab or placebo. An additional secondary endpoint at week 48 was time to the first worsening of the Psoriasis Symptom Rating Scale (PSS) and the Quality of Life Indicator of Skin Disease (DLQI), defined as a 4-point increase in the total score from baseline.

[0177] Overall design: A randomized, multicenter, parallel-group, double-blind, placebo-controlled Phase IIb trial included three effective doses compared to placebo in adolescents aged 12 to under 18 years with a history of GPP and a current GPPGA score of 0 or 1 (clear or nearly clear); the effective treatment group consisted of an effective loading dose and an effective maintenance treatment.

[0178] A total of 123 eligible subjects with generalized pustular psoriasis (GPP) were randomized in a 1:1:1:1 ratio to receive placebo, a low-dose treatment, a medium-dose treatment, or a high-dose treatment (Figure 1).

[0179] [Table 2]

[0180] All subjects received their initial dose of the study drug on day 1. Each randomized subject received four injections (loading dose) on week 1 / day 1, followed by two more injections (maintenance treatment) at subsequent visits until week 44, provided no flare occurred. The maintenance treatment period ended at week 48.

[0181] A primary statistical analysis of the trial was performed once all randomized subjects had either completed the 48-week maintenance period or discontinued early.

[0182] Inclusion Criteria: The primary diagnosis for participation in the study was that individuals aged 12 to 75 years had a history (diagnosis) of GPP confirmed based on the common diagnostic criteria defined by ERASPEN, and such subjects had to have prior evidence (of past GPP flares) of any of the following: fever and / or asthenia, and / or myalgia, and / or elevated C-reactive protein, and / or leukocytosis (above the upper limit of normal) with peripheral blood neutrophilia. The ERASPEN diagnostic criteria were primary, sterile, macroscopic pustules on non-peripheral skin (excluding cases where the pustules were limited to plaque psoriasis) that were either i) with or without systemic inflammation; ii) with or without plaque psoriasis; and iii) recurrent (more than one episode) or persistent (more than 3 months).

[0183] Each participant met all of the following selection criteria to be included in the study: Subjects with a history and medical record of GPP according to the ERASPEN criteria (regardless of IL36RN mutation status), including at least two GPP flares accompanied by new pustules (newly appearing or worsening). • Subjects whose GPPGA score is 0 or 1 at the time of screening and randomization. At the time of randomization (second visit), subjects who were not receiving concomitant GPP treatment had to have experienced at least two GPP flares in the past year, with at least one of those flares having evidence of fever and / or elevated C-reactive protein and / or elevated white blood cell count and / or asthenia and / or myalgia. • Subjects who were not receiving concomitant GPP treatment at the time of randomization (second visit) but who were receiving concomitant GPP treatment immediately prior to randomization (within 12 weeks prior to randomization) must have a history of flare during concomitant GPP treatment or when the dose of such concomitant medication was reduced or discontinued. • Subjects receiving concomitant treatment regimens with retinoids and / or methotrexate and / or cyclosporine must discontinue these regimens on the day of randomization (second visit). These subjects must have a history of flare during concomitant GPP treatment or upon dose reduction or discontinuation of such concomitant medications. • Male or female subjects aged 12-75 years at the time of screening. All subjects were required to weigh at least 40 kg. Prior to authorization for the trial, signed and dated written informed consent and informed assent must be obtained in accordance with ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use)-GCP (Good Clinical Practice) and local regulations. • Women of childbearing potential (WOCBP)1 can rapidly use highly effective contraception methods according to ICH M3(R2) with an annual failure rate of less than 1% when used consistently and correctly. A list of contraceptives meeting these criteria was provided in the CTP (Clinical Trial Protocol) and in the information of the subjects, parents (or legal guardians) of the subjects.

[0184] Exclusion criteria: Subjects with SAPHO (synovitis-acne-pustulosis-osteoproliferative disorder-osteitis) syndrome. • Subjects with primary erythrodermic psoriasis vulgaris. Severe, progressive, or uncontrolled liver disease, defined as an increase of more than three times the upper limit of normal (ULN) in AST (aspartate aminotransferase), ALT (alanine aminotransferase), or alkaline phosphatase, or an increase of more than two times the upper limit of normal in total bilirubin. a. Any limited drug therapies as specifically noted in the CTP (Clinical Trial Protocol), or any drugs that may interfere with the safe conduct of the trial as assessed by the principal investigator. b. Any prior exposure to spesorimab or other IL36 receptor inhibitor biologics. • Increased risk of infectious complications as assessed by the principal investigator (e.g., recent suppurative infection, any congenital or acquired immunodeficiency (e.g., human immunodeficiency virus), previous organ or stem cell transplantation). • At the time of randomization, the presence of a related chronic or acute infection, including active tuberculosis, human immunodeficiency virus (HIV) infection, or viral hepatitis. Subjects may be rescreened if they have been treated and recovered from an acute infection. Active tuberculosis or latent tuberculosis. • A history of allergy / hypersensitivity to the investigational drug or its excipients administered systemically. • Any recorded active malignancy or suspected malignancy, or a history of malignancy, within the five years prior to screening, except for appropriately treated basal cell carcinoma, squamous cell carcinoma of the skin, or cervical intraepithelial neoplasia. • Currently participating in a trial of another investigational medical device or drug, or have completed a trial(s) of another investigational medical device or drug less than 30 days ago, or are receiving another investigational treatment(s). Exception: Subjects of trial 1368-0013 who are in the screening period and were not randomized to trial 1368-0013, or who were not eligible to be randomized to trial 1368-0013, because the trial met its target number of randomized subjects, may participate in trial 1368-0027 if they meet all inclusion / exclusion criteria. • Women who are pregnant, breastfeeding, or planning to become pregnant during the clinical trial. Women who stop breastfeeding before administration of the investigational drug are not excluded from participation; however, they should refrain from breastfeeding for 16 weeks after the last dose of the investigational drug. • Major surgical procedures (as assessed by the principal investigator) performed within 12 weeks prior to receiving the first dose of the investigational drug, or planned during the trial, such as total hip replacement, aneurysm removal, or gastric ligation, as assessed by the principal investigator. • Current or past illnesses, medical conditions other than GPP (including chronic alcoholism or substance abuse or congestive heart disease or any condition), surgical procedures, psychiatric or social problems, findings from health examinations (including vital signs and electrocardiogram (ECG)), or evidence of clinical laboratory values ​​outside the reference range that, in the opinion of the principal investigator, would cause the participant to be unreliable in adhering to the protocol, complying with all consultations / procedures for the trial, or completing the trial. Subjects with SAPHO (synovitis-acne-pustulosis-osteoproliferative disorder-osteitis) syndrome. • Subjects with primary erythrodermic psoriasis vulgaris. Severe, progressive, or uncontrolled liver disease, defined as a more than three-fold increase in AST, ALT, or alkaline phosphatase above the upper limit of normal (ULN), or a more than two-fold increase in total bilirubin above the upper limit of normal. a. Any limited drug therapies as specified in the CTP (Clinical Trial Protocol), or any drugs that may interfere with the safe conduct of the trial as assessed by the principal investigator. b. Any prior exposure to spesorimab or other IL36 receptor inhibitor biologics.

[0185] Example 2: Treatment administered The spesorimab molecule is a heterodimer anti-human IL-36 receptor monoclonal antibody with a molecular weight of approximately 146 kDa. Spesorimab injection (subcutaneous administration) is formulated at 150 mg / mL as indicated in 1 mL pre-filled syringes (150 mg / syringe). Spesorimab injection (intravenous administration) is formulated at 60 mg / mL as indicated in 10 mL vials containing a nominal filling volume of 7.5 mL (450 mg).

[0186] [Table 3]

[0187] Dosage and dosage regimen: The objective of the current clinical trial Effisayil® 2 was to provide dose-ranging data for three subcutaneous dose regimens of spesorimab: a proposed 300 mg subcutaneous dose every 4 weeks, followed by a 600 mg loading dose, followed by a 300 mg subcutaneous dose every 12 weeks, and a 300 mg loading dose followed by a 150 mg subcutaneous dose every 12 weeks. These regimens were selected to assess a wide range of exposures in order to thoroughly evaluate the exposure-response relationship of spesorimab in GPP subjects.

[0188] If a subject experienced a GPP flare (an increase of 2 or more GPPGA scores from baseline and 2 or more pustular elements of GPPGA) during the randomization maintenance period, an open-label intravenous treatment for the GPP flare with 900 mg of spesorimab was administered on day 1 (R1 / D1). Subjects who met the criteria specified in the protocol were eligible for another open-label intravenous dose of 900 mg of spesorimab on day 8 (R3 / D3). The 900 mg intravenous dose of spesorimab was selected based on positive results from previous clinical trials in subjects and healthy volunteers, demonstrating that spesorimab is safe, tolerable, and within safe limits even in subjects with lower body weight.

[0189] To maintain blinding of the treatment, all subjects received the blinded treatment every four weeks.

[0190] [Table 4] TIFF2026521240000005.tif79170

[0191] Example 3: [Table 5] TIFF2026521240000007.tif193170 TIFF2026521240000008.tif197170 TIFF2026521240000009.tif206170

[0192] Example 4: Demographic information of subjects and efficacy parameters at relevant baselines The trial population consisted of 38.2% males and 61.8% females. The mean age was 40.4 years (range: 14–75 years), with 8 subjects (6.5%) being adolescents (2 per treatment group); 64.2% of subjects were Asian and 35.8% were Caucasian (Table 6). Subjects included in the trial had a GPPGA pustule subscore of 1 (28.5%) or 0 (71.5%), and subjects had a GPPGA total score of 1 (86.2%) or 0 (13.8%). At randomization, 74.8% of subjects were treated with systemic therapy for GPP, which was discontinued at the start of the randomization trial treatment.

[0193] Considering the genetic, ethnic, and geographical heterogeneity in the prevalence and severity of GPP, the effectiveness of treatments in specific patient populations was investigated. For example, a higher prevalence of interleukin-36 mutations in the Asian population had previously been associated with higher overall disease severity. A post-hoc analysis of the Effisayil® 2 trial showed that the effect of spesolimab in preventing flare was similar between the Asian population and the overall population.

[0194] [Table 6] TIFF2026521240000011.tif235170

[0195] As required by the selection criteria, all subjects had a GPPGA total score of 0 (clear; 13.8%) or 1 (nearly clear; 86.2%) at baseline. All subjects had a GPPGA pustule subscore of 0 (71.5%) or 1 (28.5%). At baseline, the mean (standard deviation) was 4.2 (3.4) for the Psoriasis Symptom Rating Scale (PSS) total score, 8.1 (6.4) for the Skin Disease Quality of Life (DLQI) total score, and 3.29 (3.74) for the GPPASI total score. Variables relating to efficacy at baseline were generally comparable between treatment groups. However, there were some signs of a higher disease burden in subjects in the high-dose spesorimab group compared to the placebo group. The mean (standard deviation) total score on the Psoriasis Symptom Rating Scale (PSS) was 5.3 (3.8) in the high-dose spesorimab group and 3.6 (2.9) in the placebo group; the total score on the Quality of Life with Skin Disease (DLQI) was 11.1 (6.9) in the high-dose spesorimab group and 7.2 (5.6) in the placebo group; and the total score on the GPPASI was 3.92 (4.42) in the high-dose spesorimab group and 3.11 (2.81) in the placebo group.

[0196] [Table 7] TIFF2026521240000013.tif46170

[0197] In this study, DNA sequencing of the IL-36RN, CARD14, and AP1S3 genes was performed. Potentially pathogenic IL-36RN mutations (containing amino acid substitutions) were reported in 22.8% of all subjects, lower in the placebo group (12.9%) than in the spesorimab group (low dose 22.6%, medium dose 32.3%, high dose 23.3%). Otherwise, gene mutations were generally similar between the treatment groups.

[0198] Most subjects received their initial GPP diagnosis more than five years prior to randomization. Clinical examination is the most common diagnostic method, after skin biopsy and histopathological examination. The median annual flare count (Q1 (first quartile), Q3 (third quartile)) was 2.0 (1.0, 3.0), with a maximum of 21. These data were generally comparable between treatment groups (see Table 8 below).

[0199] [Table 8]

[0200] Current or past occurrences of psoriasis were reported in 80 subjects (65.0%), arthritis in 10 subjects (8.1%), and ongoing chronic plaque-type psoriasis in 34 subjects (27.6%). Overall, 74.0% of all subjects had at least one baseline condition / medical history. The most common dictionary terms were hypertension, psoriasis, and obesity.

[0201] Overall, 93.5% of subjects had a history of taking at least one previous medication for GPP (i.e., drug therapy for GPP discontinued before screening). The most frequently used previous medications at the preferred name level were acitretin, methotrexate, and cyclosporine. The most common systemic drug therapies for GPP at randomization were acitretin, cyclosporine, and methotrexate. These therapies were used within four weeks prior to randomization or at the time of randomization and discontinued before the start of the randomization trial treatment.

[0202] All 123 subjects randomized to this trial received at least one dose of the investigational drug. The mean (standard deviation) duration of exposure during the randomization maintenance period was higher in the spesorimab dose groups (low dose: 33.9 [18.2] weeks, medium dose: 31.9 [18.5] weeks, high dose: 33.1 [18.2] weeks) than in the placebo group (25.4 [20.8] weeks). A total of 32 subjects received intravenous spesorimab for the treatment of flare; of these subjects, 22 subjects (68.8%) received a single intravenous dose of 900 mg, and 10 subjects (31.3%) received two intravenous doses of 900 mg (two doses). Among the 20 subjects who continued open-label (OL) maintenance subcutaneous treatment with spesorimab after flare treatment, 11 subjects (55.0%) continued on a 300 mg (subcutaneous) dose regimen every 12 weeks, and 9 subjects (45.0%) were gradually increased to a 300 mg (subcutaneous) dose regimen every 4 weeks. The mean (standard deviation) duration of exposure over the entire study period was 39.3 (11.2) weeks for subjects initially randomized to placebo, 37.1 (15.0) weeks for subjects initially randomized to low-dose spesorimab, 38.3 (12.9) weeks for subjects initially randomized to medium-dose spesorimab, and 34.6 (17.1) weeks for subjects initially randomized to high-dose spesorimab.

[0203] Example 5: Effectiveness: Primary objective and important secondary objective summary: Regarding the primary objective, a non-flat dose-response relationship was demonstrated. Subsequently, a confirmatory trial for the secondary objective was conducted. High-dose spesolimab demonstrated statistically significant efficacy compared to placebo, based on the primary endpoint and an important secondary endpoint.

[0204] First objective: By week 48 of the trial, a total of 35 patients had a GPP flare; fewer patients had a GPP flare in the low-dose (7 patients, 22.6%), medium-dose (9 patients, 29.0%), and high-dose (3 patients, 10.0%) spesolimab groups compared to the placebo group (16 patients, 51.6%; Figure 2A). A non-flat dose-response relationship for spesolimab compared to placebo was established using a statistically significant P-value for each of the predefined models (P = 0.002 for the linear models in Trials 1 and 2; P = 0.003 for the exponential model); therefore, the first trial objective was met.

[0205]

Table 9

[0206] Second objective: Fewer subjects had a GPP flare by week 48 in all spesolimab groups compared to the placebo group. The prescription regimens of low-dose, medium-dose, and high-dose spesolimab numerically decreased the risk of GPP flare over 48 weeks at hazard ratios of 0.35 (95% confidence interval, 0.14 - 0.86; nominal P-value = 0.0057), 0.47 (95% confidence interval, 0.21 - 1.06; P-value = 0.027), and 0.16 (95% confidence interval, 0.05 - 0.54; P = 0.0005), respectively (Figure 2A). High-dose spesolimab was statistically significant in reducing the risk of GPP flare with a hazard ratio of 0.157 (95% confidence interval, 0.046, 0.541; p = 0.0005) compared to placebo.

[0207] The separation of the estimated probability of the first GPP flare between the spesolimab group and the placebo group began during the first 4 weeks after randomization and was maintained until week 48 (Figure 2B). After 4 weeks, no flares were reported for the high-dose group. Analysis of the key secondary endpoints revealed risk differences of -0.31 (95% confidence interval, -0.54 to -0.08; nominal P-value = 0.0068), -0.23 (95% confidence interval, -0.46 to 0.01; nominal P-value = 0.036), and -0.39 (95% confidence interval, -0.62 to -0.16; P = 0.0013) for low-dose, medium-dose, and high-dose spesolimab, respectively, compared with placebo for the occurrence of GPP flares over 48 weeks (Figures 2A and C). Using an α level of 0.00625 in a one-sided test (adjusted for multiplicity), the prescription regimen of high-dose spesolimab achieved a statistically significant improvement over placebo for the key secondary endpoints (P = 0.0013).

[0208] The primary analysis of high-dose spesolimab compared with placebo for time to first GPP flare by week 48 was generally consistent across subgroups (see Figure 3).

[0209] Example 6: Key Outcomes Regarding Efficacy: The trial endpoints were selected to establish the efficacy and safety of spesolimab for the prevention of GPP flares with maximum statistical power. Systemic aspects of GPP flares were assessed using a scale that includes elements of the Japanese Dermatological Association's GPP severity score, which was developed for the Ministry of Health, Labour and Welfare as a diagnostic tool for measuring the severity of GPP during its onset (Fujita H, Terui T, Hayama K, Akiyama M, Ikeda S, Mabuchi T, et al. Japanese guidelines for the management and treatment of generalized pustular psoriasis: the new pathogenesis and treatment of GPP. J Dermatol. 2018;45(11):1235-70). A series of patient-reported outcomes (PROs) were measured, providing unique insights into the impact of GPP and the trial intervention from the patient's perspective. PROs are considered by dermatologists to be important factors in making treatment decisions for psoriasis patients (Mercieca-Bebber R, King MT, Calvert MJ, Stockler MR, Friedlander M. The importance of patient-reported outcomes in clinical trials and strategies for future optimization. Patient Relat Outcome Meas. 2018; 9:353-67; Feldman SR, Regnier SA, Chirilov A, Hey F, Gilloteau I, Cella D).Some of these PROs (Psoriasis Symptom Rating Scale, Pain Visual Analog Rating Scale, and Quality of Life for Skin Disease) were successfully used in the Effisayil® 1 trial (Bachelez H, Choon SE, Marrakchi S, Burden AD, Tsai TF, Morita A, et al. Trial of spesolimab for generalized pustular psoriasis. N Engl J Med. 2021;385(26):2431-40), and were also used in the Effisayil® 2 trial to assess participants' health-related quality of life, ability to participate in daily activities, and pain experience.

[0210] [Table 10] TIFF2026521240000018.tif190170

[0211] Primary analysis of effectiveness: The effectiveness of the treatment was measured as the time to the first flare of generalized pustular psoriasis (GPP) up to week 48 (defined as an increase of two or more physician's global assessment (GPPGA) scores for generalized pustular psoriasis from baseline and two or more pustular elements in the GPPGA).

[0212] By week 48, a total of 35 patients experienced a GPP flare, of which 32 met the criteria for a GPP flare. All of these patients received open-label intravenous spesorimab treatment, and three patients did not meet the criteria for a GPP flare but received standard treatment prescribed by the principal investigator for the treatment of GPP exacerbation. Fewer patients experienced flares in the low-dose (7 patients), medium-dose (9 patients), and high-dose (3 patients) spesorimab groups compared to the placebo group (16 patients).

[0213] Regarding the primary objective, the adjusted p-values ​​for each predefined model (0.002 for the linear models of Trial 1 and Trial 2; 0.003 for the exponential model) were statistically significant, thus demonstrating a non-flat dose-response relationship with spesolimab compared to placebo for the primary endpoint.

[0214] Regarding the second objective, high-dose spesorimab was statistically significant compared to placebo in the primary analysis for reducing the risk of GPP flare, with a hazard ratio (95% confidence interval, 0.046, 0.541; p=0.0005) of 0.157. The hazard ratio was 0.350 (95% confidence interval, 0.143, 0.857; nominal p=0.0057) for low-dose and 0.468 (95% confidence interval, 0.206, 1.064; p=0.0269) for medium-dose. Since the medium-dose did not reach statistical significance, the important secondary endpoint was further evaluated only for the high-dose group. Separation of the estimated probability of the first GPP flare between the spesorimab and placebo groups began in the first four weeks after randomization and was maintained until week 48. After 4 weeks, no flare was reported in the high-dose group (see Figure 2).

[0215] Sensitivity analyses using alternative sensing methods, or patient analyses set under the primary estimator, and additional analyses under different estimators were consistent with the primary analysis. The primary analysis of time to the first GPP flare up to week 48 for high-dose spesolimab versus placebo was generally consistent across subgroups.

[0216] [Table 11] TIFF2026521240000020.tif63170

[0217] Secondary endpoints for effectiveness: A. At least one GPP flare occurring by week 48. The proportion of patients experiencing at least one GPP flare (defined as an increase of 2 or more GPPGA scores from baseline and 2 or more pustular elements) by week 48 was lower in all spesorimab groups than in the placebo group. High-dose spesorimab was statistically significant compared to placebo in reducing the incidence of GPP flare, with an adjusted risk difference of -0.390 (95% confidence interval, -0.621, -0.159; p=0.0013). The difference between medium-dose spesorimab and placebo was not statistically significant (-0.225; 95% confidence interval, -0.462, 0.013; nominal p=0.0358). The incidence of GPP flare was lower with low-dose spesorimab compared to placebo (-0.308; 95% confidence interval, -0.535, -0.081; nominal p-value = 0.0068).

[0218] [Table 12]

[0219] Landmark analysis showed that the proportion of patients experiencing flare was lower in the high-dose spesorimab group than in the placebo group, which was evident at week 12 and continued until week 48 (Figure 4). The primary analysis of high-dose spesorimab versus placebo for the occurrence of at least one GPP flare up to week 48 was generally consistent across subgroups (Figure 5). Subgroup results with point estimates of risk differences that were not within the 95% confidence interval of the overall analysis were based on a small number of patients and very few endpoint events (Figure 5).

[0220] B. Time to first exacerbation of the Psoriasis Symptom Rating Scale (PSS) up to week 48. Time to first exacerbation of the Psoriasis Symptom Rating Scale (PSS) by week 48, defined as a 4-point increase in the total score from baseline. Ingestion of rescue drug therapy or standard treatment prescribed by the principal investigator was considered the onset of exacerbation.

[0221] As demonstrated by hazard ratios of 0.46 (95% confidence interval, 0.22–0.95; nominal P-value = 0.0079), 0.56 (95% confidence interval, 0.28–1.10; nominal P-value = 0.052), and 0.42 (95% confidence interval, 0.20–0.91; P = 0.013) for the low, medium, and high dose prescription regimens, respectively, spesolimab reduced the risk of PSS worsening over 48 weeks compared to placebo (Figure 4A). A lower proportion of patients reported worsening of their PSS score in the low (12 / 31, 38.7%), medium (13 / 31, 45.2%), and high (10 / 30, 33.3%) dose spesolimab groups compared to the placebo group (20 / 31, 64.5%) (Figure 4B). The confirmatory trial was stopped because the required significance level of 0.00625 was not reached at the high dose. However, the separation of the estimated probability of PSS worsening between the spesolimab group and placebo began during the first 8 weeks after randomization and was maintained through week 48. Data from the Effisayil™ ON trial, a non-blind extension trial for patients in the Effisayil™ 1 trial who received one or two intravenous doses of 900 mg of spesolimab, support the need for dosing at 300 mg once every 4 weeks compared to once every 12 weeks when initiating preventive treatment for GPP flares. One-third (33.3% [36 / 108]) of the participants who initiated dosing once every 12 weeks in the Effisayil™ ON trial either escalated to a once every 4-week prescription regimen (n = 4) or had a flare (n = 12).

[0222] In summary, the results of Effisayil™ 2 and Effisayil™ ON suggest that a loading dose of spesolimab 600 mg / (subcutaneous) 300 mg once every 4 weeks is the optimal dosing regimen for the prevention of GPP flares.

[0223]

Table 13

[0224] C. Time to first worsening of quality of life (DLQI) due to skin disease by week 48: Time to the first exacerbation of the quality of life (DLQI) of skin disease by week 48, defined as a 4-point increase in the total score from baseline. Ingestion of rescue drug therapy or standard treatment prescribed by the principal investigator was considered the onset of exacerbation.

[0225] By week 48, a total of 59 patients had shown worsening of their DLQI. Approximately half (31 patients) met the criteria for worsening DLQI (a 4-point increase in the total score from baseline), and only a small number of these patients (5 patients) received intravenous spesorimab for flare; to treat worsening of GPP that did not meet the criteria for worsening DLQI, 27 patients received intravenous spesorimab, and one patient received standard treatment prescribed by the principal investigator.

[0226] Regarding the time to first DLQI worsening by week 48, fewer patients in the low-dose (16 patients), medium-dose (16 patients), and high-dose (7 patients) spesorimab groups experienced worsening compared to the placebo group (20 patients). The hazard ratios were 0.580 (95% confidence interval, 0.296, 1.136; nominal p-value = 0.0429) for the low-dose group, 0.601 (95% confidence interval, 0.309, 1.168; nominal p-value = 0.0476) for the medium-dose group, and 0.259 (95% confidence interval, 0.109, 0.620; nominal p-value = 0.0010) for the high-dose group (see Table 14 below).

[0227] The separation of estimated probabilities of DLQI worsening between the spesorimab group and placebo began in the first 8 weeks after randomization. The separation between high-dose and placebo was maintained until week 48, and no worsening events were reported in the high-dose group after week 8. Fewer patients in all spesorimab groups reported DLQI worsening by week 48 than in the placebo group (Figure 4C).

[0228] [Table 14] TIFF2026521240000025.tif98170

[0229] D. Sustained remission up to week 48 Sustained remission was defined as a patient having a GPPGA score of 0 or 1 (clear or nearly clear) at all visits up to week 48, without the use of drug therapy for the treatment of GPP flares or standard treatment prescribed by the principal investigator.

[0230] The proportion of patients showing sustained remission was numerically higher in the spesorimab group: 0.516 for low-dose spesorimab, 0.452 for medium-dose spesorimab, and 0.633 for high-dose spesorimab, compared to 0.290 for placebo. The risk difference compared to placebo was 0.246 (95% confidence interval, 0.013, 0.478) for low-dose spesorimab, 0.166 (95% confidence interval, -0.069, 0.401) for medium-dose spesorimab, and 0.345 (95% confidence interval, 0.099, 0.591) for high-dose spesorimab. Results using stricter criteria were similar for high-dose spesorimab vs. placebo (Table 15 below).

[0231] [Table 15]

[0232] Landmark analysis showed that the high-dose spesolimab group had a lower proportion of patients with sustained remission decline compared to the placebo group, which was evident at week 12 and continued until week 48 (data not shown).

[0233] Example 7. Further evaluation items A. Modified Sustained Remission: Other definitions of sustained remission were analyzed as additional endpoints ("Modified Sustained Remission"), with sustained pustule clearance (pustule subscore of 0) and sustained completely clear skin (GPPGA total score of 0 starting at week 8) being analyzed as post-hoc tests. "Modified Sustained Remission" is defined as a subject having a GPPGA total score of 0 or 1, and each GPPGA subscore of 2 or less, at all visits up to week 48, without the use of rescue drug therapy or standard treatment prescribed by the principal investigator (added via TSAP (Plan for Study Statistical Analysis)).

[0234] The results (Table 16) show that the proportion of patients with other definitions of sustained remission was numerically higher in the higher-dose spesolimab group than in the placebo group.

[0235] [Table 16]

[0236] B.0 GPPGA pustule subscore: Two post-hoc analyses supported sustained remission. The first analysis measured the proportion of patients with a GPPGA pustule subscore of 0 at all visits from week 4 to week 48 (see the third section of Table 16). For sustained remission up to week 48, the proportion of patients showing sustained remission by this scale was numerically higher in the spesorimab groups (0.484 for low dose, 0.452 for medium dose, and 0.636 for high dose) than in the placebo group (0.258). The risk difference compared to placebo was 0.241 (95% confidence interval, 0.0101, 0.472) for low-dose spesorimab, 0.196 (95% confidence interval, 0.036, 0.429) for medium dose, and 0.379 (95% confidence interval, 0.138, 0.619) for high dose. Therefore, using a stricter definition, the results were comparable in high-dose spesolimab versus placebo.

[0237] C.0's GPPGA total score: The second analysis measured the proportion of patients with a GPPGA score of 0 at all visits from week 8 to week 48 (see the second section of Table 16). The proportion of patients showing sustained remission by this scale was numerically higher in the medium-dose and high-dose spesorimab groups (0.129 for medium-dose and 0.210 for high-dose) than in the placebo group (0.032). The risk difference compared to placebo was 0.096 (95% confidence interval, 0.038, 0.230) for the medium-dose group and 0.176 (95% confidence interval, 0.009, 0.343) for the high-dose group.

[0238] D. At all visits up to week 48, without the use of rescue drug therapy or standard treatment prescribed by the principal investigator, a DLQI of 0 or 1 was observed. The proportion of patients who first achieved this endpoint was higher in the high-dose spesorimab group compared to the placebo group. There was only a small difference between the low-dose spesorimab group, the medium-dose spesorimab group, and the placebo group (Table 17).

[0239] [Table 17]

[0240] Summary: In a further analysis using a DLQI of 0 or 1 at all visits during the randomized maintenance period up to 48 weeks, the proportion of patients whose quality of life was not affected by the disease was higher in the higher-dose spesorimab group than in the placebo group.

[0241] Based on the time to the first GPP flare, PSS worsening, and DLQI worsening, the effects of the two spesorimab loading doses (300 mg and 600 mg) during the first four weeks of the randomized maintenance period were similar to each other and better than placebo.

[0242] The geometric mean values ​​for spesorimab indicate that plasma concentrations of spesorimab were dose-related. Following treatment with any spesorimab (subcutaneous or intravenous), the proportion of patients positive for anti-drug antibodies in this study was 45%, 68%, and 41% in patients initially randomized to low-dose, medium-dose, and high-dose spesorimab, respectively. The proportion of patients positive for neutralizing antibodies (all positive for anti-drug antibodies) after treatment with any spesorimab was 45%, 68%, and 34% at low-dose, medium-dose, and high-dose levels. The median onset of anti-drug antibodies ranged from 8.0 to 10.6 weeks, and the time to peak titer ranged from 17.1 to 22.6 weeks. No clear correlation was observed between the development of anti-drug or neutralizing antibodies and the efficacy of spesorimab treatment, in terms of GPP flare occurrence, flare onset time, or sustained remission, during the maintenance randomization period (data not shown).

[0243] In 32 patients who received an open-label intravenous dose of 900 mg of spesorimab to treat flare, the probability of response at 1 week was 0.554 (95% confidence interval, 0.388, 0.734). Within 2 weeks, 9 patients (0.594, 95% confidence interval, 0.423, 0.745) achieved a response. In patients (20 patients) who participated following an open-label maintenance period with 300 mg of spesorimab (subcutaneous), their condition appeared stable during the analysis period; 9 patients strengthened their dosing interval from once every 12 weeks to once every 4 weeks.

[0244] Patients who did not experience flare and received subcutaneous spesorimab or placebo showed stable levels of C-reactive protein, neutrophils, and white blood cells over time, which remained within the normal range during the randomization treatment period. Albumin levels remained within the normal range throughout the study. After flare and open-label intravenous spesorimab treatment, elevated C-reactive protein, neutrophils, and white blood cell counts rapidly decreased over time after intravenous flare treatment with spesorimab, reaching normal levels by week 2, and this level persisted thereafter.

[0245] Example 8: Occurrence of adverse events under experimental treatment: Safety was assessed based on analysis of adverse events (AEs, including serious adverse events (SAEs) and particularly noteworthy adverse events (AESIs)), health examinations, vital signs recording, clinical laboratory tests, and 12-lead electrocardiograms (clinically relevant findings were to be recorded as adverse events).

[0246] [Table 18] TIFF2026521240000030.tif186170

[0247] The proportion and incidence of any adverse events, as well as severe, serious, and investigator-defined drug-related adverse events, were comparable across all dose groups during the randomization maintenance period (Table 16). No fatal adverse events occurred in this study. The adverse events leading to discontinuation of spesorimab were pustular psoriasis (2 patients, 2.2%); psoriasis, psoriatic arthritis, and breast cancer (1 patient, 1.1% for each adverse event).

[0248] Similar proportions of patients receiving spesorimab (90.3%) and placebo (86.7%) experienced adverse events; the incidence of adverse events was similar between the spesorimab dose groups and did not follow a dose-dependent pattern (Table). Patients receiving spesorimab (all doses) and placebo showed similar incidences of serious adverse events (19.4% vs. 23.3%, respectively) and investigator-defined drug-related adverse events (39.8% vs. 33.3%, respectively). There were no fatal adverse events; the majority of adverse events were not serious or severe. The most common adverse events were pustular psoriasis, psoriasis, and injection site erythema (24.7%, 14.0%, and 14.0%, respectively, in patients receiving spesorimab, compared to 53.3%, 10.0%, and 3.3%, respectively, in patients receiving placebo). Infection rates were balanced across treatment groups. A higher proportion of patients receiving spesorimab experienced serious adverse events (SAEs) compared to the placebo group (9.7% vs. 3.3%); serious adverse events did not follow a dose-dependent pattern with spesorimab. Serious adverse events reported in the high-dose spesorimab group were pustular psoriasis, breast cancer, and cholelithiasis (one patient each). Overall, the safety profile of spesorimab was favorable; infection rates were similar across treatment groups with no indication of increased proportions at higher doses. There were no fatal adverse events and no hypersensitivity events leading to discontinuation of treatment.

[0249] Example 9: Exposure to spesolimab in plasma after intravenous and subcutaneous administration in GPP patients. Three dose regimens were selected in the Effisayil™ 2 trial to test a broad range of exposures, enabling a thorough evaluation of the exposure-response relationship of spesorimab in GPP patients. Where other prescribing plans were discontinued, loading doses of 600 or 300 mg were included to assess whether exposure was effective in preventing GPP flares. Dosing intervals of once every 12 weeks vs. once every 4 weeks were selected to assess whether flare prevention could be achieved with a dose administered every 3 months or whether monthly dosing was necessary. The placebo prescribing plan was important in this trial because the incidence of flares in the untreated population was unknown, and a high incidence of the disease was essential to demonstrate the patient benefit from prophylactic treatment. No effective control group was included in the trial because there are currently no approved drugs for the prevention of GPP flares. In the Effisayil® 2 trial, the treatment was administered subcutaneously because patients have clear or nearly clear skin at the time of randomization, which means that a different spesorimab exposure than that required for treating flares was expected. Furthermore, subcutaneous administration is often preferable for patients and may improve participant adherence. In the Effisayil® 1 trial, a 900 mg intravenous dose of spesorimab was shown to be effective in treating GPP flares with an acceptable safety profile, and was therefore selected as the dose for administration if a patient experienced a GPP flare during the Effisayil® 2 trial and used as a comparative dose for exposure studies.

[0250] To simulate the pharmacokinetics of intravenous or subcutaneous doses of spesolimab, compare drug exposure profiles in GPP patients, and support medication recommendations, a population pharmacokinetic model was developed using individual pharmacokinetic, anti-drug antibody, and covariate data from 18 trials in which subjects received intravenous or subcutaneous administration of spesolimab.

[0251] Mathematical models quantified the pharmacokinetics of spesolimab after intravenous and subcutaneous administration, including the effects of patient-specific factors (e.g., body weight, disease status, anti-drug antibody titer) on pharmacokinetics. The resulting population pharmacokinetic models were used to simulate the concentration-time profiles over 12 weeks (84 days) for various intravenous and subcutaneous doses (300 mg and 900 mg of spesolimab administered intravenously over 90 minutes as one dose, or 900 mg as two doses (with a one-week interval), and 300 mg, 600 mg, 900 mg, and approximately 2250 mg of spesolimab administered subcutaneously as one or two doses (with a one-week interval)). For each dose, Cmax, Tmax, and AUC were summarized over 14 and 84 days.

[0252] Pharmacokinetic data from this simulation in GPP patients demonstrate that intravenous and subcutaneous administration of spesorimab may result in differences in drug exposure in clinical practice. Significantly higher Cmax and faster Tmax were observed with intravenous spesorimab compared to subcutaneous spesorimab. Theoretically, a subcutaneous dose more than 2.5 times greater (2250 mg, equivalent to 15 pre-filled syringes of 150 mg subcutaneous injections) would be required to match the Cmax of a 900 mg intravenous dose. The immediate response and high bioavailability of intravenous spesorimab compared to subcutaneous spesorimab support the use of intravenous or subcutaneous spesorimab in drug administration strategies for the treatment or prevention of acute GPP flares, respectively.

[0253] The plasma spesorimab concentration-time course for various subcutaneous and intravenous doses was simulated using a pharmacokinetic model of a typical GPP subject, assuming a reference value for body weight (75 kg), negative for anti-drug antibodies, subcutaneous injection into the abdomen, and all other covariates. The simulations are presented in Figures 5A–E. Figure 5A is a graph of the concentration-time profiles predicted by the model over a 12-week period for 300 mg delivered intravenously versus 300 mg delivered subcutaneously. The simulated Cmax was approximately 2.5 times higher with 300 mg (intravenous) spesorimab compared with 300 mg (subcutaneous). Tmax was approximately one week after administration for subcutaneous spesorimab, compared to the end of the 90-minute infusion for intravenous spesorimab. Figure 5B is a graph of the concentration-time profiles predicted by the model for 900 mg (intravenous) spesorimab compared to 600 mg (subcutaneous) spesorimab. The simulated Cmax was 3.7 times higher for 900 mg (intravenous) than for 600 mg (subcutaneous). Tmax occurred approximately one week after administration for subcutaneous spesorimab, compared to the end of the 90-minute infusion for intravenous spesorimab. Figure 5C is a graph of the concentration-time profiles predicted by the model for two doses of 900 mg (intravenous) spesorimab versus two doses of 600 mg (subcutaneous) spesorimab. When administered as a two-dose prescription plan, exposure increased due to accumulation. However, Cmax was still 3 times higher for intravenous administration compared to subcutaneous administration after the second dose. Similarly, Tmax occurred approximately one week after each subcutaneous dose compared to immediately after the completion of each 90-minute intravenous infusion. Figure 5D is a graph of the concentration-time profiles predicted by the model for 900 mg (intravenous) spesorimab versus 2250 mg (subcutaneous) spesorimab. A subcutaneous dose of 2250 mg was required to reach the target Cmax, which is equivalent to 900 mg of spesorimab (intravenous). With the subcutaneous dose, Tmax was delayed by one week, and the AUC was almost doubled; most importantly, a subcutaneous injection of this size is not clinically viable (equivalent to 15 subcutaneous injections of 150 mg pre-filled syringes).Figure 5E outlines the exposure measurement methods after single-dose intravenous or subcutaneous administration in GPP patients. Simulated spesolimab exposure demonstrated that the Cmax and AUC for the single-dose 900 mg intravenous administration route consistently exceeded all viable single-dose spesolimab subcutaneous administrations. Similar trends were observed for two-dose intravenous and subcutaneous administration prescription plans. Slow absorption was expected with the subcutaneous formulation, with Tmax reached approximately one week after subcutaneous injection compared to immediately after 90 minutes of infusion for the single-dose intravenous administration.

[0254] Example 10: Treatment with spesolimab controls the disease characteristics of GPP in both the acute and chronic phases: Treatment with a 600 mg loading dose followed by 300 mg of spesorimab every four weeks was superior to placebo in preventing flares and reducing the risk of flares by 84% over 48 weeks (p=0.0005). Skin biopsy specimens (5 mm samples) were collected at the second (baseline) and fourteenth (week 48) visits during the maintenance treatment period; and at the first, sixth (four weeks after flare) and fourteenth (open-label) emergency visits during rescue treatment. Baseline skin biopsy specimens (n=15) were obtained for use in half for RNA sequencing and half for immunohistochemical analysis.

[0255] Treatment with spesorimab resulted in clinical improvement and reduced expression of pathogenic genes associated with GPP flare in patients' skin biopsy materials. Ten patients in the substudy of this biomarker underwent multiple biopsies. Six patients had received cyclosporine prior to randomization; all had gene expression patterns suggestive of low-grade inflammation at baseline. In the four patients who experienced flare (randomized to placebo [n=1], low-dose [150 mg subcutaneously every 12 weeks] [n=1], and medium-dose [300 mg subcutaneously every 12 weeks] [n=2] spesorimab), pathogenic genes associated with GPP flare and / or IL-36 signaling were further upregulated from baseline. Intravenous treatment of flare with 900 mg of spesorimab reduced the expression of these pathogenic genes in three out of four patients. In five patients who received high-dose subcutaneous spesorimab, no new flares occurred, and between baseline and week 48, GPP flare / IL-36-related gene expression decreased (or remained low). Histopathological analysis of selected neutrophil proteins confirmed low-grade inflammation at baseline, reflecting changes in disease activity and clinical improvement.

[0256] Figures 6A and 6B show exemplary outcomes for two patients who had received prior treatment for GPP, demonstrating that GPP patients can successfully transition from background immunosuppressive therapy to maintenance or rescue therapy with spesolimab.

[0257] Histopathological analysis of selected neutrophil proteins is shown in Figure 6A. Representative patient A, shown here, was IL36RN mutation-positive, presented with pustules and desquamation, and had received cyclosporine treatment prior to participation in the spesorimab trial. Patient A was randomized to receive high doses of spesorimab and did not experience flare throughout the trial. Representative patient B did not have IL36RN mutations, had a high neutrophil count, and had been treated with acitretin prior to participation. Patient B was randomized to receive placebo and continued to receive spesorimab rescue treatment for flare during the trial.

[0258] Pathogenic genes associated with GPP flares and the IL-36 pathway (including IL17C, CXCL6, IL19, IL20, CXCL8, NCF1, IL36G, and DEFB4A) showed differing expression levels from baseline visits to visits for initial rescue procedures (VR1) (unadjusted p<0.05). Skin biopsy specimens from patients prone to recurrent flares showed higher expression levels of IL-36 pathway genes and GPP flare-related genes (IL36G, DEFB4A, CXCL8, CXCL6, IL19, IL20, IL17C, and NCF1) at change levels ranging from 1.4 to 5.2 (unadjusted p<0.05) compared to patients with more stable disease. Figure 6A shows reduced expression of neutrophil markers (neutrophil elastase, lipocalin [LCN]), IL-36 receptor markers, and inflammatory markers (S100A7, human β-defensin 2 [hBD2]), indicating a reduction in inflammation and neutrophil pustule formation after treatment with spesolimab.

[0259] Furthermore, as shown in Figure 6B, the clinical morphology reflected histopathological changes in both patients A and B, demonstrating that the spesorimab rescue treatment almost completely resolved the skin symptoms of GPP flare. Moreover, the spesorimab treatment prevented GPP flare through the suppression of disease activity. Overall, the results suggest that spesorimab is more effective than current immunosuppressive therapies in managing GPP.

[0260] Example 11: MicroRNA 223-3p and 223-5p as biomarkers to monitor the effects in skin and serum in generalized pustular psoriasis after treatment with spesolimab. Background: Previous studies have shown that GPP lesions, compared to lesion-free skin, are associated with elevated expression of IL-36-related transcripts (IL-36α, IL-37β, IL-36γ), neutrophil-recruiting cytokines (CXCL1, CXCL8), pro-inflammatory cytokines (IL-6, IL-19, IL-20), and skin inflammation markers (DEFB4A, S100A7, S100A8, S100A9), which were significantly downregulated by using one dose of spesorimab (Baum et al., 2021; Farag et al., confidential data, 2024). However, the mechanisms leading to changes in the expression of specific mRNAs in GPP are not well understood.

[0261] MicroRNAs (miRNAs) are small, non-coding RNA molecules that can post-transcribe gene expression and contribute to the development or regulation of several diseases, including skin inflammation (Guo et al. 2010). While only a few studies have attempted to explain the miRNA expression profile in the skin of atopic dermatitis patients (Carreras-Badosa et al., 2022), several studies have been conducted for psoriasis and / or psoriatic arthritis (Hawkes et al., 2016; Liu et al., 2017; Delic et al., 2020). In addition to tissues, miRNAs are also found in bodily fluids such as serum or plasma, where they have demonstrated significant value as minimally invasive circulating disease markers. Ganguly et al. identified a set of overlapping miRNAs between skin and serum samples, correlated them with the severity of psoriasis, and used miR-147b, miR-3614-5p, and miR-125a-5p to differentiate between patients with low-severity and high-severity psoriasis (Ganguly et al., 2024). Previous studies have reported that the expression levels of circulating miR-146a-5p, miR-206, miR338-3p, miR-338-5p, miR-Let 7a, miR-24-1-5p, and miR26a-5p in patients with hidradenitis suppurativa were significantly different compared to healthy controls (De Felice et al., 2022). To date, there is no information whatsoever regarding the role of miRNAs in both skin and blood samples from GPP patients.

[0262] Methods: MicroRNAs in the skin and serum of GPP patients were identified as biomarkers for GPP. MicroRNA expression profiles were measured using small RNA sequencing, and candidate miRNAs were confirmed to be significant using quantitative PCR and associated with clinical outcomes.

[0263] A total of 25 skin biopsy samples were obtained for analysis from a population of GPP patients treated with spesorimab in the Effisayil1 trial. Skin punch biopsy samples (5 mm) were collected from lesional skin (L; n=9) and non-lesional skin (nL; n=4) at baseline on day 1 / pre-drug administration (pre-spesorimab administration). Lesionary skin biopsy samples were also collected on day 8 after drug administration (n=7) and at 8 weeks after an additional open-label dose (n=5). Due to the limited number of samples available after treatment, lesional samples collected on day 8 and at 8 weeks post-treatment were combined for analysis (=post-spesorimab administration). Skin biopsy samples from 10 healthy controls (50% male; age: 41.9 ± 14.0 years) were obtained from Discovery Life Sciences (Kyiv, Ukraine).

[0264] Serum samples stored in the biobank were obtained from a group of 12 GPP patients participating in the EFFISAYIL® 1 trial. A total of 25 serum samples were available, collected on day 1 / baseline (n=12) and at 12 weeks post-treatment (n=11). The placebo group was not included in further analysis due to its limited sample size (n=2).

[0265] EFFISAYIL® 2 was used as a confirmatory test. Forty-one skin biopsy samples were collected from the following groups: Patients with flare: 5 at baseline, 5 at flare, 6 at 4 weeks post-treatment, and 7 at 52 weeks post-treatment; Patients without flare: 10 at baseline and 7 at 52 weeks post-treatment.

[0266] Total RNA Isolation: Skin biopsy material was collected in RNA-later® tissue protection tubes (Qiagen, Germany, Hilden) and stored at -20°C until use. Total RNA (including miRNA enrichment) derived from human skin tissue was extracted using the RNeasy fibrous tissue mini-kit (Qiagen, Germany, Hilden). miRNA-enriched total RNA was isolated from serum samples using the miRNeasy serum / plasma advanced kit (Qiagen, Germany, Hilden) according to the manufacturer's protocol. RNA purity and quantity were assessed using the Imprene NanoPhotometer® N120 (Imprene, Germany, Munich).

[0267] Preparation and sequencing of small RNA libraries: Sequencing libraries derived from skin and serum RNA samples were prepared using the QIAseq® miRNA UDI Library Kit (96) (Qiagen, Germany, Hilden) and the QIAseq miRNA 96 Index Kit UDI AH (Qiagen, Germany, Hilden) according to the manufacturer's protocol. Sequencing was performed using the NovaSeq® 6000 S4 Reagent Kit Version 1.5 (200 cycles) (Illumina, San Diego, USA) on a NovaSeq® 6000 sequencing system (Illumina) according to the manufacturer's instructions.

[0268] MicroRNA Quantitative Real-Time PCR: Using the TaqMan® Advanced miRNA-cDNA Synthesis Kit (Applied Biosystems, Inc., Waltham, Massachusetts), miRNAs from skin and serum were reverse transcribed and pre-amplified according to the manufacturer's protocol. Reverse transcription quantitative PCR was performed using the TaqMan® Fast Advanced Master Mix (Applied Biosystems, Inc., Waltham, Massachusetts) and the TaqMan Advanced miRNA Assay (Applied Biosystems, Inc., Waltham, Massachusetts), with cDNA pre-amplified according to the manufacturer's instructions. Reverse transcription quantitative PCR was performed in duplex mode on the QuantStudio7Flex Real-Time PCR System® (Applied Biosystems, Inc., Waltham, Massachusetts) according to the cycling parameters recommended by the manufacturer. The following assays were used: hsa-miR-223-3p (Assay ID: 477983_mir), hsa-miR-223-5p (Assay ID: 477984_mir), hsa-miR-1304-3p (Assay ID: 479574_mir), has-miR-337-5p (Assay ID: 478036_mir), hsa-miR-485-5p (Assay ID: 478126_mir), and hsa-miR-361-5p (Assay ID: 478056_mir). hsa-miR-361-5p was selected as the endogenous control miRNA for standardization after stable expression and low variability were confirmed using the NormFinder tool, and next-generation sequencing data were selected based on evaluation using "NormFinder_0953" and vendor recommendations. The cycle threshold (Ct) was determined using QuantStudio® 6 and 7Flex real-time PCR system software version 1.7.2. Relative change in gene expression was analyzed according to the 2-ΔΔCt method.

[0269] Results: MicroRNA analysis was performed on lesion-free skin and skin lesion samples from GPP patients before and after treatment with spesorimab, and the results were correlated with clinical outcomes in two independent populations. By further correlating findings in skin biopsy materials with patient-concordant samples recovered from serum, it was determined whether miRNAs isolated from serum were soluble "liquid biopsy" biomarker candidates that reflect events occurring both in the skin and systemically.

[0270] We explored differences in the miRNA expression profiles of GPP patient-derived skin compared to healthy controls by performing a difference in miRNA expression analysis between GPP skin lesions and lesion-free skin compared to healthy controls. Overall, 333 miRNAs were significantly deregulated (absolute change ≥ 1.5, corrected P-value ≤ 0.05) in skin lesions compared to healthy skin. The expression levels of 173 miRNAs were significantly increased, while 160 miRNAs showed significantly lower expression levels in GPP lesions (Figure 7B).

[0271] The most potent upregulations were observed in miR-142-5p, miR-451a, and miR-3613-5p, with change ratios ranging from 61 to 107 times. Furthermore, among the top 10 upregulated miRNAs, miR-144-3p, miR-944, miR-590-3p, miR-7-5p, miR-142-3p, miR-223-3p, and miR-223-5p showed significant increases of 36 to 56 times in GPP skin lesions compared to healthy controls (Figure 7B). The most potent downregulations were observed in miR-483-3p, miR-4446, and miR-204-3, with expression decreases of 27 to 40 times in GPP patient skin lesions compared to healthy controls.

[0272] Some of the miRNAs that were significantly deregulated in GPP skin lesions compared to healthy controls were also deregulated in GPP skin lesions, but to a lesser degree, compared to lesion-free skin (Denis Delic, et al.; unpublished data not shown).

[0273] MiRNAs exhibiting differential expression in GPP skin lesions after spesorimab treatment compared to healthy controls: To investigate the effects of spesorimab treatment on skin lesions derived from GPP patients and to identify potential biomarker candidates, small RNA sequencing was performed on 12 GPP lesion samples after spesorimab treatment. Principal component analysis revealed that the skin miRNA profile separated GPP lesion biopsy materials from subjects treated with spesorimab from healthy controls. While the skin miRNA profile did not completely separate GPP lesion biopsy materials after spesorimab treatment from baseline biopsy materials, a shift towards GPP in the direction of non-lesion biopsy materials was identified (Figure 8A).

[0274] Differential expression analysis (absolute value of change ≥ 1.5, P ≤ 0.05) identified 34 deregulated miRNAs in the GPP lesion after spesorimab treatment relative to the baseline. A total of 14 miRNAs showed lower gene expression levels, while 20 miRNAs were increased in the GPP lesion after spesorimab treatment (Figure 8B). The strongest decreases were observed in miR-223-3p, miR-223-5p, and miR-4455, with expression levels 3.3 to 5.2 times lower. Among the set of upregulated miRNAs, miR-483-5p, miR-493-5p, and miR-485-5p showed the strongest effects, with expression increasing 1.8 to 2.1 times after spesorimab treatment. The overall effect of spesorimab on miRNAs with differential expression is summarized in Table 19 below.

[0275] [Table 19]

[0276] MiRNAs exhibiting differential expression in GPP serum compared to healthy controls: By examining minimally invasive / non-invasive serum miRNA biomarkers, we determined whether changes observed in the skin had spread to surrounding areas. Small RNA sequencing was performed on serum samples obtained from 12 GPP patients and 20 healthy controls. Principal component analysis of serum miRNA expression profiles clearly separated GPP patients from healthy study volunteers, demonstrating substantial differences in the systemic miRNA profiles of GPP patients (Figure 9A).

[0277] Compared to healthy trial volunteers, a total of 114 serum miRNAs were significantly deregulated (absolute change ≥ 1.5, corrected P ≤ 0.05) in GPP patients. Of these, 69 miRNAs showed upregulated miRNA expression levels, while 45 miRNAs showed downregulated expression levels (Figure 9B). Compared to healthy serum, the top deregulated miRNAs in GPP patients included miR-12136, miR-4286, and miR-29c-5p, which increased 4.6 to 6.3 times, and miR-144-3p, miR-299-3p, and miR-375-3p, which decreased 4.7 to 7.6 times.

[0278] miRNAs exhibiting differential expression in serum after spesorimab treatment of GPP: By examining the effect of treatment on the serum miRNA profile, we evaluated whether the effects of treatment observed in the skin are also reflected in the serum, and whether serum miRNAs can serve as minimally invasive / non-invasive biomarker candidates for monitoring treatment in GPP patients (including, but not limited to, detecting the presence or absence of a beneficial response in GPP patients after administration of anti-interleukin-36 receptor antibodies), determining whether a candidate therapeutic agent is effective in the treatment and prevention of GPP, determining whether to initiate treatment in a subject, modify the treatment dose, modify the dosing interval, or discontinue treatment, and monitoring patient response to treatment and patient adherence to the treatment protocol. Small RNA sequencing was performed on 11 serum samples derived from GPP patients treated with spesorimab.

[0279] Principal component analysis of miRNA expression profiles in sieved serum showed that samples from GPP patients treated with spesolimab formed clusters between the baseline and healthy control samples (Figure 10A).

[0280] Differential miRNA expression analysis revealed that 50 miRNAs showed altered expression (1.5 times; P<0.05) compared to baseline (including 21 upregulated miRNAs and 29 downregulated miRNAs) (see Figure 20). The most strongly deregulated serum miRNAs (including miR-376b-3p, miR-337-5p, and miR-5189-3p) showed a 2.7 to 2.8-fold increase in serum levels after spesorimab treatment compared to baseline, while miR-16-5p, miR-8060, and miR-8085 showed a 2.7 to 2.9-fold decrease (Figure 10B).

[0281] [Table 20] TIFF2026521240000033.tif70170

[0282] Identification of a core set of miRNAs and analysis of the target mRNA pathways of the incorporated miRNAs: Comparison of skin lesion biopsy materials and serum from GPP patients with healthy controls and after treatment with spesorimab identified a set of five core miRNAs that demonstrated consistent deregulation and modulation of GPP upon treatment with spesorimab. This set of miRNAs included miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, and miR-337-5p (Figure 11A), and the effect on deregulation after spesorimab in skin and serum is summarized in Figure 11B.

[0283] To further elucidate the mechanisms underlying the identified set of miRNA biomarkers, target prediction analyses of candidate miRNAs were performed using MirTarBase. Target mRNAs were selected from differential gene expression analysis in skin obtained from patient data matched in EFFISAYIL® 1 (Farag et al., 2024), and pathway analysis was performed using reactionome and Hallmark datasets obtained from MSigDB (Molecular Sign Database). Significant enrichment of pathways was observed in miR-223-3p, which includes important signaling pathways in the inflammatory process (confidential data).

[0284] Confirmation of selected miRNA candidates and correlation with clinical parameters in GPP: Small RNA sequencing results were confirmed by reverse transcription quantitative PCR to confirm the set of miRNA biomarker candidates identified in skin and serum. Pairwise comparisons of data prepared by reverse transcription quantitative PCR confirmed significant deregulation (P<0.0001) of biomarker candidates in the skin of GPP lesions compared to healthy controls for all miRNAs except miR-1304-3p. Strong upregulation of miR-223-3p and miR-223-5p in GPP lesions was confirmed by reverse transcription quantitative PCR, indicated by a median point of content (POC) of over 1,500% to over 9,800% compared to control, and downregulation in GPP patients was confirmed for miR-485-5p, indicated by a median POC of 14% to 32% (Figure 12A). Treatment with spesorimab significantly reduced the expression of miR-223-3p and miR-223-5p by 76% to 84% (P<0.001), which was consistent with small RNA sequencing data. However, no significant effect on miR-485-5p levels was detected after spesorimab treatment (Figure 12B).

[0285] Reverse transcription quantitative PCR analysis of serum confirmed significant (P<0.05) upregulation of miR-223-5p at a median POC of 174%, while miR-223-3p showed a trend toward 134% upregulation in baseline serum compared to healthy controls (P<0.09). Significant downregulation in baseline serum was observed for miR-485-5p (P<0.05), indicated by a median POC ranging from 23% to 48% (Figure 13A). Treatment with spesorimab significantly reduced the expression of miR-223-5p (32%) in the serum of GPP patients, while the expression levels of miR-223-3p followed a similar trend (P=0.17). In short, miR-223-3p and miR-223-5p proved to be the most promising miRNA candidates for monitoring disease progression and treatment effectiveness.

[0286] To investigate whether differential miRNA expression changes in the skin could be used to monitor disease progression and response to treatment, pre- and post-spesoriumab treatment with miRNA levels in the skin were correlated with GPPASI and GPPGA scores. Correlation analysis demonstrated a very significant (P<0.0001) positive correlation between changes in GPPASI and GPPGA scores after spesoriumab treatment and the skin expression levels of miR-223-3p (Rs_GPPASI=0.91; Rs_GPPGA=0.84) and miR-223-5p (Rs_GPPASI=0.86; Rs_GPPGA=0.83) (Figure 14A, B). Correlation analysis between serum miRNA levels and GPPGA scores revealed significant correlations for miR-223-5p (Rs_GPPGA=0.7; P<0.001) and miR-223-3p (Rs_GPPGA=0.59; P<0.01) (Figure 14C).

[0287] Summary: In skin and serum samples derived from GPP patients, the inventors identified five miRNAs, miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, and miR-337-5p, which were increased in GPP patients compared to healthy controls and decreased after treatment with spesorimab. Specifically, three miRNAs (including miR-223-3p, miR-223-5p, and miR-1304-3p) were upregulated in skin lesions and serum of GPP patients and downregulated after treatment with spesorimab. Conversely, two miRNAs (including miR-485-5p and miR-337-5p) were downregulated in GPP patients and upregulated after treatment with spesorimab. Integrated miRNA-mRNA analysis identified that miRNAs, particularly miR-223-3p, are involved as upstream regulators of their target mRNAs in multiple pathways contributing to the pathophysiology of GPP.

[0288] MiR-223 has previously been reported to show elevated expression levels in various inflammatory disorders, including plaque-type psoriasis, asthma, chronic obstructive pulmonary disease, and inflammatory bowel disease (Lovendorf et al., 2014; Roffel et al., 2020, Yarani et al., 2022). This study demonstrated the involvement of both miR-223, miR-223-3p, and miR-223-5p in the deregulated molecular mechanisms of GPP. While I don't want to get bogged down in theory, upregulation of miR-223 in GPP patients may mediate anti-inflammatory effects through negative modulation of the NF-κβ signaling cascade, targeting CXCL2 and CCL3 chemokines (Roffel et al., 2020) (both known to recruit immune cells, including neutrophils) (Filippo et al., 2013; Reichel et al., 2009). Therefore, increased miR-223 may exhibit an antagonistic mechanism that mitigates the excessive inflammatory response and neutrophil recruitment observed in GPP.

[0289] This study using quantitative PCR confirmed findings for miR-223-3p and miR-223-5p and demonstrated significant correlations with GPPASI and GPPGA, suggesting that miR-223-3p and miR-223-5p can be used as minimally invasive / non-invasive biomarkers to monitor the progression of GPP disease and the treatment response induced by spesorimab.

Claims

1. A method for treating and preventing flares of generalized pustular psoriasis (GPP) in a subject having a history of symptoms of GPP and / or a history (diagnosis) of generalized pustular psoriasis confirmed on common diagnostic criteria defined by ERASPEN (European Network of Specialists in Rare and Severe Psoriasis) diagnostic criteria, comprising the steps of administering to the subject an initial loading dose of 300 mg to 600 mg of an anti-IL-36 receptor antibody, and subsequently administering to the subject a maintenance dose of 150 mg to 600 mg of the anti-IL-36 receptor antibody at 4-week intervals (q4w) or 12-week intervals (q12w) for 8 to 48 weeks after the final maintenance dose, wherein the loading dose and maintenance dose are delivered parenterally.

2. The method of claim 1, wherein the total loading dose comprises 300 mg of anti-IL-36 receptor antibody delivered subcutaneously in week 0 or week 1, followed by a maintenance dose of 150 mg of the anti-IL-36 receptor antibody administered subcutaneously at 12-week (q12w) intervals.

3. The method of claim 1, wherein the total loading dose comprises 600 mg of anti-IL-36 receptor antibody delivered subcutaneously in week 0 or week 1, followed by a maintenance dose of 300 mg of the anti-IL-36 receptor antibody administered subcutaneously at 12-week (q12w) intervals.

4. The method of claim 1, wherein the total loading dose comprises 600 mg of anti-IL-36 receptor antibody delivered subcutaneously in week 0 or week 1, followed by a maintenance dose of 300 mg of the anti-IL-36 receptor antibody administered subcutaneously at 4-week (q4w) intervals.

5. A method for treating generalized pustular psoriasis (GPP) in a subject with a history of GPP and who is not experiencing a flare, comprising the steps of: administering to the subject an initial loading dose of 300 mg to 600 mg of an anti-IL-36 receptor antibody; and subsequently administering to the subject a maintenance dose of 150 mg to 600 mg of the anti-IL-36 receptor antibody at 4-week intervals (q4w) or 12-week intervals (q12w) for 8 to 48 weeks after the final maintenance dose, wherein the loading dose and maintenance dose are delivered parenterally.

6. The method of claim 5, wherein the total loading dose comprises 300 mg of anti-IL-36 receptor antibody delivered subcutaneously in week 0 or week 1, followed by a maintenance dose of 150 mg of the anti-IL-36 receptor antibody administered subcutaneously at 12-week (q12w) intervals.

7. The method of claim 5, wherein the total loading dose comprises a maintenance dose consisting of 600 mg of anti-IL-36 receptor antibody delivered subcutaneously in week 0 or week 1, followed by 300 mg of the anti-IL-36 receptor antibody administered subcutaneously at 12-week (q12w) intervals.

8. The method of claim 5, wherein the total loading dose comprises 600 mg of anti-IL-36 receptor antibody delivered subcutaneously in week 0 or week 1, followed by a maintenance dose of 300 mg of the anti-IL-36 receptor antibody administered subcutaneously at 4-week (q4w) intervals.

9. A method for reducing the onset, recurrence, and / or frequency of flares of generalized pustular psoriasis (GPP) in a subject having a history of symptoms of GPP and / or a history (diagnosis) of generalized pustular psoriasis confirmed based on common diagnostic criteria defined by the ERASPEN diagnostic criteria, comprising the steps of administering to the subject an initial loading dose of 300 mg to 600 mg of an anti-IL-36 receptor antibody, and subsequently administering to the subject a maintenance dose of 150 mg to 600 mg of the anti-IL-36 receptor antibody at 4-week intervals (q4w) or 12-week intervals (q12w) for 8 to 48 weeks after the final maintenance dose, wherein the loading dose and maintenance dose are delivered parenterally.

10. The method of claim 9, wherein the total loading dose comprises a maintenance dose consisting of 300 mg of anti-IL-36 receptor antibody delivered subcutaneously in week 0 or week 1, followed by 150 mg of the anti-IL-36 receptor antibody administered subcutaneously at 12-week (q12w) intervals.

11. The method of claim 9, wherein the total loading dose comprises 600 mg of anti-IL-36 receptor antibody delivered subcutaneously in week 0 or week 1, followed by a maintenance dose of 300 mg of the anti-IL-36 receptor antibody administered subcutaneously at 12-week (q12w) intervals.

12. The method of claim 9, wherein the total loading dose comprises 600 mg of anti-IL-36 receptor antibody delivered subcutaneously in week 0 or week 1, followed by a maintenance dose of 300 mg of the anti-IL-36 receptor antibody administered subcutaneously at 4-week (q4w) intervals.

13. The method of claim 5, wherein the total loading dose comprises 600 mg of anti-IL-36 receptor antibody delivered subcutaneously in week 0 or week 1, followed by a maintenance dose of 300 mg of the anti-IL-36 receptor antibody administered subcutaneously at 4-week (q4w) intervals.

14. The method according to any one of claims 1 to 13, wherein the subject has a total physician's global assessment (GPPGA) score of 1 or less for generalized pustular psoriasis at the start of treatment.

15. The method according to any one of claims 1 to 13, wherein the subject has a total physician's overall assessment (GPPGA) score of 1 or less for generalized pustular psoriasis and a GPPGA pustule subscore of 1 or less at the start of treatment and / or before administration of the initial loading dose of anti-IL-36 receptor antibody.

16. The method according to any one of claims 1 to 13, wherein the subject has a total physician's global assessment (GPPGA) score of 1 or less and a GPPGA pustule subscore of 1 or less after administration of at least one maintenance dose of 150 or 300 mg of anti-IL-36 receptor antibody for at least 48 weeks after an initial loading dose of 300 mg or 600 mg of anti-IL-36 receptor antibody.

17. The method according to any one of claims 1 to 13, wherein the subject has a total physician's global assessment (GPPGA) score of 1 or less for generalized pustular psoriasis and a GPPGA pustule subscore of 1 or less before and after administration of at least one maintenance dose of 150 or 300 mg of anti-IL-36 receptor antibody for at least 48 weeks after an initial loading dose of 300 mg or 600 mg of anti-IL-36 receptor antibody.

18. Administration of anti-IL-36 receptor antibodies to subjects with a history of symptoms of generalized pustular psoriasis and / or a history (diagnosis) of generalized pustular psoriasis confirmed based on common diagnostic criteria defined by the ERASPEN diagnostic criteria results in one or more of the following outcomes: (a) Maintenance of a global assessment (GPPGA) pustule subscore of 0 or 1 for generalized pustular psoriasis after administration of the anti-IL-36 receptor antibody up to 48 weeks following the initial loading dose; (b) Maintaining a GPPGA total score of 0 or 1 after administration of the anti-IL-36 receptor antibody for up to 48 weeks following the initial loading dose; (c) Sustained remission of GPP symptoms, defined as a subject treated with the anti-IL-36 receptor antibody, maintaining a GPPGA score of 0 or 1 (clear or nearly clear) at all visits up to week 48, without taking any drug therapy for GPP flares or using any standard of care (SoC) prescribed by the principal investigator after administration of the anti-IL-36 receptor antibody; (d) Reduction in the occurrence of GPP (flare) from baseline to 48 weeks after administration of the anti-IL-36 receptor antibody (wherein a GPP flare is defined as an increase of 2 or more in the total score of the Physician's General Assessment for Generalized Pustular Psoriasis (GPPGA) and 2 or more GPPGA pustule subscores); or (e) An extension of the time to the first GPP flare, as measured by the time from baseline to the onset of the first GPP flare, up to 48 weeks after administration of the anti-IL-36 receptor antibody (wherein a GPP flare is defined as an increase of 2 or more in the total score of the Physician's Global Assessment for Generalized Pustular Psoriasis (GPPGA) and 2 or more GPPGA pustule subscores). A method according to any one of claims 1 to 13 that achieves the objective.

19. The method according to any one of claims 1 to 13, wherein the subject has a reduced risk of worsening of his Psoriasis Symptom Rating Scale (PSS) score up to 48 weeks after receiving maintenance treatment with anti-IL-36R antibody, where worsening is defined as an increase of 4 points in the total score compared to the subject's baseline PSS score before administration.

20. The method according to any one of claims 1 to 13, wherein the subject has a reduced risk of worsening of the quality of life index (DLQI) of skin disease up to 48 weeks after receiving maintenance treatment with anti-IL-36R antibody, wherein worsening is defined as an increase of 4 points in the total score compared to the subject's baseline DLQI score before administration.

21. A treatment method for generalized pustular psoriasis (GPP), including treatment and prevention of flares in a subject having a history of symptoms of GPP and / or a history (diagnosis) of generalized pustular psoriasis confirmed based on common diagnostic criteria defined by the ERASPEN diagnostic criteria, wherein the subject has a GPPGA total score of 1 or less and a GPPGA pustule subscore of 1 or less prior to the start of treatment, and the method is: (a) administering to the subject a loading dose of 600 mg of anti-IL-36 receptor antibody from week 0 to week 1, followed by a maintenance dose of 300 mg of anti-IL-36 receptor antibody administered to the subject at 4-week intervals (the loading dose and maintenance dose of anti-IL-36 receptor antibody are delivered subcutaneously); and (b) After the initial loading dose, evaluate the subject's total score of the physician's overall assessment of GPP (GPPGA) and / or GPPGA pustule subscores for at least 48 weeks (where the time to the first GPP flare up to 48 weeks after the start of treatment is defined by an increase of 2 or more GPPGA pustule subscores and an increase of 2 or more GPPGA total score from baseline). The treatment method, including the treatment method.

22. A treatment method for generalized pustular psoriasis (GPP), including treatment and prevention of flares in a subject having a history of symptoms of GPP and / or a history (diagnosis) of generalized pustular psoriasis confirmed based on common diagnostic criteria defined by the ERASPEN diagnostic criteria, wherein the subject has a GPPGA total score of 1 or less and a GPPGA pustule subscore of 1 or less prior to the start of treatment, and the method is: (a) administering to the subject a loading dose of 600 mg of anti-IL-36 receptor antibody from week 0 to week 1, followed by a maintenance dose of 300 mg of anti-IL-36 receptor antibody administered to the subject at 12-week intervals (the loading dose and maintenance dose of anti-IL-36 receptor antibody are delivered subcutaneously); and (b) After the initial loading dose, evaluate the subject's total score of the physician's overall assessment of GPP (GPPGA) and / or GPPGA pustule subscores for at least 48 weeks (where the time to the first GPP flare up to 48 weeks after the start of treatment is defined by an increase of 2 or more GPPGA pustule subscores and an increase of 2 or more GPPGA total score from baseline). The treatment method, including the treatment method.

23. A treatment method for generalized pustular psoriasis (GPP), including treatment and prevention of flares in a subject having a history of symptoms of GPP and / or a history (diagnosis) of generalized pustular psoriasis confirmed based on common diagnostic criteria defined by the ERASPEN diagnostic criteria, wherein the subject has a GPPGA total score of 1 or less and a GPPGA pustule subscore of 1 or less prior to the start of treatment, and the method (a) administering to the subject a loading dose of 300 mg of anti-IL-36 receptor antibody from week 0 to week 1, followed by a maintenance dose of 150 mg of anti-IL-36 receptor antibody administered to the subject at 12-week intervals (the loading dose and maintenance dose of anti-IL-36 receptor antibody are delivered subcutaneously); and (b) After the initial loading dose, evaluate the subject's total score of the physician's overall assessment of GPP (GPPGA) and / or GPPGA pustule subscores for at least 48 weeks (where the time to the first GPP flare up to 48 weeks after the start of treatment is defined by an increase of 2 or more GPPGA pustule subscores and an increase of 2 or more GPPGA total score from baseline). The treatment method, including the treatment method.

24. The method according to any one of claims 1 to 13 and 21 to 23, wherein the anti-IL-36 receptor antibody comprises a) a light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 35, 102, 103, 104, 105, 106, or 140 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, or 111 (H-CDR2); and the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

25. The aforementioned anti-IL-36 receptor antibody, I. a) Light chain variable region containing the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 102 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3). II. a) Light chain variable region containing the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 103 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3), III. a) Light chain variable region containing the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 104 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3), IV. a) Light chain variable region containing the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 105 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3), V. a) Light chain variable region containing the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 106 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3), VI. a) Light chain variable region containing the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 140 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequences of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3), A method according to any one of claims 1 to 13 and 21 to 23, including the method described above.

26. The aforementioned anti-IL-36 receptor antibody, i. A light chain variable region containing the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 87; or, ii. A light chain variable region containing the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 88; or, iii. A light chain variable region containing the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 89; or, iv. A light chain variable region containing the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 87; or, v. A light chain variable region containing the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 88; or, vi. A light chain variable region containing the amino acid sequence of SEQ ID NO: 88; and a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 89; or, vii. A light chain variable region containing the amino acid sequence of SEQ ID NO: 85; and a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 100; or, viiii. A light chain variable region containing the amino acid sequence of SEQ ID NO: 85; and a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 101; or, ix. A light chain variable region containing the amino acid sequence of SEQ ID NO: 86; and a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 100; or x. Light chain variable region containing the amino acid sequence of SEQ ID NO: 86; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 101 A method according to any one of claims 1 to 13 and 21 to 23, including the method described above.

27. The aforementioned anti-IL-36 receptor antibody, i. Light chains containing the amino acid sequence of SEQ ID NO: 115; and ii. A light chain containing the amino acid sequence of SEQ ID NO: 115; and a heavy chain containing the amino acid sequence of SEQ ID NO: 126; or iii. A light chain containing the amino acid sequence of SEQ ID NO: 115; and a heavy chain containing the amino acid sequence of SEQ ID NO: 127; or iv. A light chain containing the amino acid sequence of SEQ ID NO: 118; and a heavy chain containing the amino acid sequence of SEQ ID NO: 125; or v. A light chain containing the amino acid sequence of SEQ ID NO: 118; and a heavy chain containing the amino acid sequence of SEQ ID NO: 126; or vi. A light chain containing the amino acid sequence of SEQ ID NO: 118; and a heavy chain containing the amino acid sequence of SEQ ID NO: 127; or vii. A light chain containing the amino acid sequence of SEQ ID NO: 123; and a heavy chain containing the amino acid sequence of SEQ ID NO: 138; or viiii. A light chain containing the amino acid sequence of SEQ ID NO: 123; and a heavy chain containing the amino acid sequence of SEQ ID NO: 139; or ix. A light chain containing the amino acid sequence of SEQ ID NO: 124; and a heavy chain containing the amino acid sequence of SEQ ID NO:

138. A method according to any one of claims 1 to 13 and 21 to 23, including the method described above.

28. The method according to claims 1 to 13 and 21 to 23, wherein the anti-IL-36 receptor antibody is spesolimab.

29. (a) A step of obtaining biological samples from patients before treatment and after treatment with administration of anti-IL-36 receptor antibodies; (b) A step of measuring the level of one or more biomarkers in each sample before and after treatment, or the expression level of one or more biomarkers in each sample; c) A step of comparing the pre-treatment level of a biomarker with the post-treatment level; and, d) A step of determining the difference between the levels of the sample before treatment and the levels of the sample after treatment to reflect a beneficial response in the patient (wherein one or more biomarkers include microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p, where post-treatment downregulation or upregulation compared to the pre-treatment baseline indicates a beneficial response). A method for detecting the presence or absence of a beneficial response in GPP patients after administration of an anti-interleukin-36 receptor antibody (anti-IL-36R antibody), including the above.

30. The method of claim 29, wherein the biological sample is a skin biopsy material, blood, plasma, or serum sample.

31. The method according to claims 29 to 30, wherein one or more microRNAs are miR-223-5p or miR-223-3 in the skin lesion or serum.

32. One or more levels of microRNAs (miR-223-5p and miR-223-3) in skin lesions or serum correlate with GPPASI and / or GPPGA scores, where treatment or prevention of GPP symptoms in subjects with a history of GPP symptoms leads to one or more of the following outcomes: (a) Maintenance of a global assessment (GPPGA) pustule subscore of 0 or 1 for generalized pustular psoriasis, and maintenance or reduction of miR-223-5p and / or miR-223-3 levels, from the initial loading dose to 48 weeks after administration of the anti-IL-36 receptor antibody; (b) Maintaining a GPPGA total score of 0 or 1, and maintaining or reducing the levels of miR-223-5p and / or miR-223-3, from the initial loading dose to 48 weeks after administration of the anti-IL-36 receptor antibody; (c) Sustained remission of GPP symptoms, and maintenance or reduction of miR-223-5p and / or miR-223-3 levels, as defined by a subject treated with the anti-IL-36R antibody, maintaining a GPPGA score of 0 or 1 (clear or nearly clear) at all visits up to week 48, without taking any drug therapy for GPP flare or using standard care (SoC) prescribed by the principal investigator; (d) A reduction in the incidence of GPP flares from baseline to 48 weeks, and maintenance or reduction of miR-223-5p and / or miR-223-3 levels (wherein GPP flares are defined as an increase of 2 or more in the total score of the Physician's Global Assessment for Generalized Pustular Psoriasis (GPPGA) and 2 or more GPPGA pustule subscores); or (e) An increase in the time to the first GPP flare, as measured by the time from baseline to the onset of the first GPP flare, up to 48 weeks from baseline (wherein a GPP flare is defined as an increase of 2 or more in the total score of the Physician's Global Assessment for Generalized Pustular Psoriasis (GPPGA) and 2 or more GPPGA pustule subscores), and an increase in the levels of miR-223-5p and / or miR-223-3. The method of claim 31, which is measured as having achieved the objective.

33. The method according to claims 29 to 32, wherein the level of the biomarker is determined by small RNA sequencing, quantitative PCR, or ELISA and immunohistochemistry.

34. The method according to any one of claims 29 to 33, further comprising the step of continuing administration of a maintenance dose of anti-IL-36 receptor antibody to the patient if the level difference between a sample before treatment and a sample after treatment reflects a beneficial response in the patient.

35. (a) The step of obtaining a first biological sample from a GPP patient before flare and / or before treatment with a candidate therapeutic agent; (b) A step of treating GPP patients with a candidate therapeutic agent; (c) A step of obtaining a second biological sample from a GPP patient after treatment with a candidate therapeutic agent; (d) A step of measuring the expression level of one or more biomarkers in the first sample and the second sample; and (e) A step of comparing the biomarker level in the second sample with the level in the first sample. (Here, a change in biomarker levels (e.g., lower or higher) in the second sample compared to the first sample indicates that the candidate therapeutic agent is effective, and further, one or more biomarkers here include microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p.) A method for determining whether a candidate therapeutic agent is effective in the treatment and prevention of GPP, including [specific example].

36. The method according to claim 35, wherein a change (e.g., lower or higher) in the biomarker level in the second sample compared to the first sample correlates with an improvement in a measure of clinical efficacy.

37. The method according to claim 35, further comprising the step of continuing treatment of the patient if the biomarker level in the second sample has changed (e.g., higher or lower) compared to the first sample.

38. a) A step of determining whether to start treatment for a subject, modify the dosage of treatment, modify the interval between doses, or discontinue treatment, based on any of the methods of prior claims 29 to 37; and b) The process of modifying the treatment regimen based on the decision. Treatment methods for generalized pustular psoriasis (GPP) in subjects with a history of GPP who have not experienced flare-ups.

39. (a) The process of obtaining a first biological sample from the patient; (b) A step of measuring the level of one or more biomarkers in the first biological sample (wherein the one or more biomarkers include microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p); (c) The step of administering the treatment compound to the patient; (d) the step of obtaining a second biological sample from the patient; (e) the step of measuring the level of one or more biomarkers in the second biological sample; and (f) A step of comparing the levels of one or more biomarkers obtained from the first and second biological samples. (Here, post-treatment upregulation or downregulation, compared to the baseline before treatment, indicates a valid response.) A method for monitoring a patient's response to GPP treatment, including [details omitted].

40. (a) The process of obtaining a first biological sample from the patient; (b) A step of measuring the level of one or more biomarkers in the first biological sample (wherein the one or more biomarkers include microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p); (c) The step of administering the treatment compound to the patient; (d) the step of obtaining a second biological sample from the patient; (e) the step of measuring the level of one or more biomarkers in the second biological sample; and (f) A step of comparing the levels of one or more biomarkers obtained from the first and second biological samples. (Here, post-treatment upregulation or downregulation, compared to the baseline before treatment, indicates the patient's adherence to the drug treatment protocol.) A method for monitoring patient adherence to drug treatment protocols for the treatment and prevention of GPP flare, including the following.

41. The method of claim 39, wherein the level of one or more biomarkers in the second biological sample is reduced by at least about 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% or more compared to the level in the first biological sample.

42. The method of claim 39, wherein the biological sample is a sample of skin biopsy material, blood, plasma, or serum.

43. The method of claim 39, wherein the level of the biomarker is determined by small RNA sequencing or ELISA and immunohistochemistry.

44. The method of claim 39, wherein the treatment compound is an anti-IL-36 receptor antibody.

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