Methods for treating and preventing GPP

Abstract

The present invention relates to a method for the treatment of systemic pustular psoriasis, in particular to a method for the treatment of systemic pustular psoriasis; the present invention relates to anti-IL36R antibodies for general pustular psoriasis (GPP), including the treatment and prevention of flare in adults and teenagers having a general pustular psoriasis (GPP) medical history, and more than 12 years old, with a first dose of 300 mg or 600 mg followed by subcutaneous administration with a dose of 150 mg or 300 mg q4w or q12w. The microRNA RNAs 223-3p and 223-5p are used as biomarkers to monitor the treatment.

Description

[Reference to sequence list]

[0001] This application contains a sequence list that has been filed with the Patent Centre in XML format, and the entire text of that sequence list is hereby incorporated by reference. The XML copy was created on December 11, 2023, named 09-0745-US-2.XML, and is 139,264 bytes in size. Technical Field

[0002] This invention relates to the use of anti-IL-36R antibodies in methods and compositions for treating adults and adolescents aged 12 years and older with a history of generalized pustular psoriasis (GPP) and / or diagnosed according to the guidelines of the European Rare and Severe Psoriasis Expert Network (ERASPEN). More specifically, this invention relates to the treatment of generalized pustular psoriasis (GPP) comprising treating and preventing flare in subjects by administering a subcutaneous loading dose of 300 or 600 mg of anti-IL-36R antibody to the subject, followed by a maintenance dose of 150 or 300 mg of anti-IL-36R antibody administered subcutaneously at 4 or 12-week intervals. Background Technology

[0003] GPP is a rare, systemic, autoinflammatory skin disease characterized by recurrent episodes of severe, red, and irritating heat 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 JDermatol. 2014;53(6):676-84), and can have potentially life-threatening consequences. If left untreated, serious complications such as infection and sepsis may occur, leading to hospitalization or even death. The most common causes of death are septic shock or heart or kidney failure.

[0004] Most participants experience acute GPP fever-redness attacks of varying severity, which can be idiopathic or induced by external stimuli such as infection, corticosteroid use or discontinuation, stress, or pregnancy. Moderate to severe GPP fever-redness attacks can lead to high morbidity and mortality due to tenderness, painful skin lesions, extreme fatigue, high fever, peripheral blood neutrophilia, acute phase reactions, and sepsis. The acute phase is associated with a mean hospital stay of 10 days (range 3 to 44 days). In a retrospective study of 102 GPP cases seen in a tertiary hospital in Johor, Malaysia, the reported observed mortality rate was 7%, which may be underestimated because not all GPP participants were included in the study. Mortality may also be underestimated because the cause of death was not identified as GPP, and is largely due to infectious complications and extracutaneous organ manifestations such as renal, hepatic, respiratory, and cardiac failure.

[0005] After a response to treatment or cessation of spontaneous hot flashes, it is estimated that up to 50% of subjects may develop chronic GPP, which is characterized by persistent erythema and desquamation, and may also include joint symptoms.

[0006] The typical presentation of inflammatory flare-ups in geysersis (GPP) as described by von Zumbusch is strongly associated with polymorphisms in the IL36-R signaling pathway. Individuals with loss-of-function mutations in the IL36RN gene (IL-36RN), which encodes an endogenous IL36R antagonist, have a significantly higher incidence of GPP, indicating that uncontrolled upregulation of IL36 signaling due to defective IL36RN antagonism leads to the inflammatory flare-ups observed in GPP. Human genetic studies have confirmed that GPP occurs in clusters within families of IL36RN containing loss-of-function mutations leading to uncontrolled IL36R signaling. Mutations in other genes associated with the IL36 pathway, such as CARD14, also cause GPP. Recent published gene expression studies indicate 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 driver of the disease pathology in GPP. Furthermore, a recent meta-analysis of 233 publicly reported cases of GPP revealed that 49 (21.0%) of these cases carried the recessive IL36RN allele. These 49 recessive IL36RN alleles defined a GPP phenotype characterized by early onset and a high risk of systemic inflammation.

[0007] IL36R is a cell surface receptor involved in inflammatory responses in the skin and gut. It is a new member of the IL1R family, forming a heterodimeric complex with IL1R accessory proteins. The heterodimeric IL36R system, possessing stimulatory ligands (IL36α, IL36β, IL36γ) and an inhibitory ligand (IL36Ra), shares various structural and functional similarities with other members of the IL1 / IL1R family (such as IL1, IL18, and IL33 (R17-3602)). All IL1 family members (IL1α, IL1β, IL18, IL36α, IL36β, IL36γ, and IL38) transduce signals through unique homologous receptor proteins that, upon ligand binding, recruit a common IL1RacP subunit and activate the NF-κB and MAP kinase pathways in receptor-positive cell types. In human skin tissue, IL36R is expressed in keratinocytes, dermal fibroblasts, and infiltrative bone marrow cells. Activation of IL36R in skin tissue drives the production of inflammatory mediators (e.g., CCL20, MIP-1β, TNF-α, IL12, IL17, IL23, TGF-β) and regulates the expression of tissue remodeling genes (e.g., MMP, TGF-β). Therefore, the link between GPP and mutations in IL36RN is somewhat analogous to the recognized neonatal aseptic multifocal osteomyelitis, periostitis, and pustular lesions caused by the absence of an interleukin-1 receptor antagonist. In this case, the absence of the receptor antagonist allows the uninhibited action of interleukin-1, leading to life-threatening systemic inflammation involving the skin and bone. These clinical features respond to empirical treatment with the recombinant interleukin-1 receptor antagonist anakinra.

[0008] To adequately treat GPP, both the acute phase and the long-term chronic condition need to be addressed simultaneously. Acute febrile seizures must be resolved immediately upon their spontaneous occurrence, and maintenance therapy must be administered to prevent future recurrences. Treatment and prevention of GPP febrile seizures aim to control the severe acute condition by managing systemic symptoms (CRP, fever, neutrophils) and pustules (e.g., visible signs of inflammation), and further prevent infection and other life-threatening complications. However, long-term maintenance therapy is crucial for the sustained control of the signs and symptoms of GPP febrile seizures and for preventing their recurrence.

[0009] The European Network of Experts on Rare and Severe Psoriasis (ERASPEN) consensus guidelines include the following criteria as key diagnostic criteria for acute GPP: primary, sterile, macroscopically visible pustules on non-acral skin (excluding cases where pustules are confined to psoriatic plaques), with or without systemic inflammation, with or without plaque psoriasis, and recurrent (>1 episode) or persistent (>3 months) psoriasis (website: eraspen.eu / home / rfp / diagnostic-criteria.html (accessed May 9, 2018); European Network of Experts on Rare and Severe Psoriasis (ERASPEN); 2018).

[0010] Chronic GPP describes the state between acute and severe acute flare-up attacks of the disease, characterized by the persistence of residual skin symptoms such as erythema, desquamation, and pustules. The clinical presentation of GPP is intermittent, and may include a chronic phase in which the skin appears normal between acute and severe acute flare-up attacks.

[0011] Despite the existence of approved treatments for GPP hot red flare-ups, there remains an unmet need for both treatment and prevention of GPP hot red flare-ups (Choon et al., 2014, Id). Preventing GPP hot red flare-ups with a safe and effective treatment would address a significant unmet need for proven treatment in subjects with this devastating condition that is prone to relapse and has high morbidity and associated mortality. Furthermore, due to the distressing and severity of symptoms, associated comorbidities, and the scarcity of customized treatments, GPP may have a greater impact on an individual's health-related quality of life than other chronic skin conditions, such as plaque psoriasis (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, novel targeted therapies for the treatment and / or prevention of GPP are needed in this field. Summary of the Invention

[0012] This invention addresses the above needs by providing biological therapeutic agents, particularly antibodies, which bind to IL-36R and provide therapeutic and maintenance treatment for generalized pustular psoriasis (GPP) by preventing the occurrence and / or frequency of GPP hot red flare attacks and other related signs and symptoms of GPP hot red flare attacks, including treatment and prevention of hot red flare attacks.

[0013] In a first aspect, the present invention relates to the treatment of generalized pustular psoriasis (GPP), including the treatment and prevention of hot flashes in adults and adolescents aged 12 years and older with a history of generalized pustular psoriasis (GPP) and / or diagnosed according to the European Network of Experts on Rare and Severe Psoriasis (ERASPEN) guidelines, comprising administering, or having administered, a therapeutically effective amount of an anti-IL-36R antibody or its antigen-binding fragment to said adults and / or adolescents. In a preferred embodiment, the present invention relates to the treatment of GPP in adults and adolescents aged 12 years and older who have not experienced hot flashes. In an embodiment related to this aspect, the anti-IL-36R antibody is pesolimab.

[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 and older with a history of GPP and / or diagnosed according to the European Network of Experts on Rare and Severe Psoriasis (ERASPEN) guidelines, the method comprising administering, or having already administered, a therapeutically effective amount of an anti-IL-36R antibody or an antigen-binding fragment thereof to the adult or adolescent. In a related embodiment, the invention is a method for reducing or alleviating the number, incidence, severity, and / or recurrence of hot flashes in adults or adolescents with GPP, the method comprising administering, or having already administered, a therapeutically effective amount of an anti-IL-36R antibody or an antigen-binding fragment thereof to the subject. In a related embodiment, the anti-IL-36R antibody is pexolizumab.

[0015] In a third aspect, the present invention relates to a method for reducing the incidence and / or frequency of acute GPP hot flashes in adults and adolescents aged 12 years and older with a history of generalized pustular psoriasis (GPP) and / or diagnosed according to the European Network of Experts on Rare and Severe Psoriasis (ERASPEN) guidelines, the method comprising administering, or having already administered, a therapeutically effective amount of the anti-IL-36R antibody of the present invention or its antigen-binding fragment. In one embodiment related to this aspect, the anti-IL-36R antibody is pexolizumab.

[0016] In one embodiment related to aspects one through three, the anti-IL-36R antibody or its antigen-binding fragment 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 (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 another embodiment related to aspects one through three, the anti-IL-36R antibody or its antigen-binding fragment comprises: I. 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: 102 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region comprising 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). II. 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: 103 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region comprising 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). III. 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: 104 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region comprising 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). IV. 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: 105 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region comprising 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). V. a) The light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 106 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) the heavy chain variable region comprising 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). VI. 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: 140 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region comprising 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).

[0018] In another embodiment related to aspects one through three, the anti-IL-36R antibody or its antigen-binding fragment comprises: (i) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or (ii) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or (iii) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or (iv) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or (v) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or (vi) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or (vii) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 85; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100; or (viii) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 85; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 101; or (ix) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 86; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100; or (x) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 86; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 101.

[0019] In one embodiment related to aspects one through three, the anti-IL-36R antibody or its antigen-binding fragment comprises: 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. 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.

[0020] In one embodiment relating to any of the above aspects or embodiments, the anti-IL-36R antibody is pexolimab.

[0021] In one embodiment relating to any of aspects one through three, the second therapeutic agent is administered to the subject before, after, or simultaneously with the anti-IL-36R antibody or its antigen-binding fragment. In one relevant embodiment, the second therapeutic agent is selected from the group consisting of: antibacterial agents, antiviral agents, antifungal agents, another IL-36R antagonist, anti-PDE4, IL-17 antagonist, IL-12 / IL-23 antagonist, IL-23 antagonist and IL-1 antagonist, IgE inhibitor, corticosteroid, NSAID, IL-4R antagonist, TNF-α inhibitor, and IFNγ.

[0022] Another embodiment of the invention relates to the treatment of generalized pustular psoriasis (GPP), including the treatment and prevention of hot flashes in subjects with a history of GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria, achieved by administering a loading dose of 600 mg of anti-IL-36R antibody or its antigen-binding fragment to the subject at week 0 or week 1; followed by maintenance doses of the anti-IL-36R antibody comprising 600 mg at intervals of 2, 4, 5, 6, 7, 8, 10, or 12 weeks. In a preferred embodiment, the invention relates to the subcutaneous loading and maintenance doses for the treatment of adults and adolescents aged 12 years and older with GPP in the absence of hot flashes. In an exemplary embodiment, the subcutaneous loading dose is 600 mg (four 150 mg injections), followed by subcutaneous injections of 600 mg (four 150 mg injections) after 4 weeks, and thereafter every 4 weeks.

[0023] Another embodiment of the invention relates to the treatment of generalized pustular psoriasis (GPP), including the treatment and prevention of hot flashes in subjects with a history of GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria, achieved by administering a loading dose of 600 mg of anti-IL-36R antibody or its antigen-binding fragment to the subject at week 0 or week 1; followed by maintenance doses of 300 mg of said anti-IL-36R antibody administered to the subject at intervals of 2, 4, 5, 6, 7, 8, 10, or 12 weeks. In a preferred embodiment, the invention relates to the subcutaneous loading and maintenance doses for the treatment of adults and adolescents aged 12 years and older with GPP in the absence of hot flashes. In an exemplary embodiment, the subcutaneous loading dose is 600 mg (four 150 mg injections), followed by a subcutaneous injection of 300 mg (two 150 mg injections) after 4 weeks, and thereafter every 4 weeks.

[0024] In another aspect, the present invention relates to the treatment of generalized pustular psoriasis (GPP), including the treatment and prevention of hot flashes in subjects with a history of GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria. This is achieved by administering a loading dose of 600 mg of anti-IL-36R antibody or its antigen-binding fragment to the subject at week 0 or week 1, followed by maintenance doses of 150 mg of the anti-IL-36R 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 subcutaneous administration of the loading and maintenance doses for the treatment of adults and adolescents aged 12 years and older with GPP in the absence of hot flashes. In an exemplary embodiment, the subcutaneous loading dose is 600 mg (four 150 mg injections), followed by a subcutaneous injection of 150 mg (one 150 mg injection) after 4 weeks, and thereafter every 4 weeks.

[0025] In another aspect, the present invention relates to the treatment of generalized pustular psoriasis (GPP), including the treatment and prevention of hot flashes in subjects with a history of GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria. This is achieved by administering a loading dose of 300 mg of anti-IL-36R antibody or its antigen-binding fragment to the subject at week 0 or week 1, followed by maintenance doses containing 300 mg of the anti-IL-36R antibody at intervals of 2, 4, 5, 6, 7, 8, 10, or 12 weeks. In a preferred embodiment, the present invention relates to the subcutaneous loading and maintenance doses for the treatment of adults and adolescents aged 12 years and older with GPP in the absence of hot flashes. In an exemplary embodiment, the subcutaneous loading dose is 300 mg (two 150 mg injections), followed by a subcutaneous injection of 300 mg (two 150 mg injections) after 4 weeks, and thereafter every 4 weeks.

[0026] In another aspect, the present invention relates to the treatment of generalized pustular psoriasis (GPP), including the treatment and prevention of hot flashes in subjects with a history of GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria. This is achieved by administering a loading dose of 300 mg of anti-IL-36R antibody or its antigen-binding fragment to the subject at week 0 or week 1, followed by maintenance doses of 150 mg of the anti-IL-36R antibody at intervals of 2, 4, 5, 6, 7, 8, 10, or 12 weeks. In a preferred embodiment, the present invention relates to the subcutaneous loading and maintenance doses for the treatment of adults and adolescents aged 12 years and older with GPP in the absence of hot flashes. In an exemplary embodiment, the subcutaneous loading dose is 300 mg (two 150 mg injections), followed by a subcutaneous injection of 150 mg (one 150 mg injection) after 12 weeks, and thereafter every 12 weeks.

[0027] In aspects of the invention relating to any of the above embodiments, loading and maintenance doses are administered non-enterically, such as intravenously and / or subcutaneously.

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

[0029] In one aspect, the present invention relates to a method for treating the occurrence of GPP hot red attacks in a subject undergoing maintenance therapy with an anti-IL36 antibody or its antigen-binding fragment as described in any of the foregoing embodiments, the method comprising administering to the subject at least one 900 mg intravenous (iv) dose of an anti-IL-36R antibody. In a related embodiment, treatment for GPP hot red attacks is performed at any time during the maintenance therapy period of a subject diagnosed with experiencing a hot red attack, wherein a GPP hot red attack is defined as an increase of ≥2 in the GPP Physician Global Assessment (GPPGA) total score and ≥2 in the GPPGA pustulation subscore. In a related embodiment, if symptoms of GPP hot red attacks persist, an additional 900 mg dose may be administered one week after the initial dose.

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

[0031] In one aspect, the present invention relates to a method for improving the quality of life by at least 10% in subjects with a history of GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria, the method comprising administering a loading dose of 300 mg of an anti-IL-36R antibody or an antigen-binding fragment thereof to the subject in week 0 or week 1, followed by administering a maintenance dose of 150 mg of the anti-IL-36R antibody to the subject at intervals of 2, 4, 5, 6, 7, 8, 10, or 12 weeks. In a related embodiment, the method comprises administering a loading dose of 300 mg of the anti-IL-36R antibody to the subject in week 0 or week 1, followed by administering a maintenance dose of 150 mg of the anti-IL-36R antibody to the subject at intervals of 12 weeks (q12w).

[0032] In one embodiment relating to any of the above aspects, the incidence of at least one GPP hot flash event is reduced in subjects with a history of GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria, as measured by the proportion of patients experiencing at least one hot flash event, wherein a GPP hot flash event is defined as an increase of ≥2 in the total GPP Physician Global Assessment (GPPGA) score relative to baseline and a GPPGA pustular sub-score of ≥2 up to week 48 after the start of treatment.

[0033] In one embodiment relating to any of the above aspects, subjects with a history of GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria have a reduced risk of developing a GPP hot red attack, wherein a GPP hot red attack is defined as an increase of ≥2 in the total GPP Physician Global Assessment (GPPGA) score relative to baseline and a GPPGA pustular sub-score of ≥2 from the start of treatment up to week 48.

[0034] In one embodiment relating to any of the above aspects, prior to administration of the first loading dose of the anti-IL-36R antibody, subjects with a history of GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria have a total GPPGA score ≤1 and a GPPGA pustule sub-score ≤1.

[0035] In one embodiment related to any of the foregoing aspects, after an initial loading dose of 300 mg or 600 mg of the anti-IL-36R antibody or its antigen-binding fragment is administered subcutaneously at week 0 or week 1, followed by maintenance doses of at least 150, 300 mg, or 600 mg of the anti-IL-36R antibody administered to the subject at intervals of 2, 4, 5, 6, 7, 8, 10, or 12 weeks, subjects with a history of GPP symptoms and / or a history of GPP (diagnosis) as determined by consensus diagnostic criteria defined by the ERASPEN diagnostic criteria have a GPP Physician Global Assessment (GPPGA) total score ≤1 and a GPPGA pustule sub-score ≤1. In a related embodiment, after administration of such loading and maintenance doses of the anti-IL-36R antibody, the subject's GPP Physician Global Assessment (GPPGA) total score ≤1 and GPPGA pustule sub-score ≤1 persist for at least 48 weeks after the initial loading dose.

[0036] In one embodiment relating to any of the foregoing aspects, subjects with a history of GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria as defined by the ERASPEN diagnostic criteria, before and after administration of the first loading dose of the anti-IL-36R antibody or its antigen-binding fragment, have a GPP Physician Global Assessment (GPPGA) total score ≤1 and a GPPGA pustule sub-score ≤1. In a related embodiment, subjects with a history of GPP hot flashes, before and after administration of the first loading dose of the anti-IL-36R antibody, have a GPP Physician Global Assessment (GPPGA) total score ≤1 and a GPPGA pustule sub-score ≤1, continuing for at least 48 weeks after the initial loading dose.

[0037] In one aspect, the present invention relates to a treatment for a subject with generalized pustular psoriasis (GPP), including methods for treating and preventing hot red flare-ups, the subject having a history of GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria, and / or a GPPGA pustular subscale score ≤1, the method comprising the steps of: (a) administering a loading dose of 600 mg of anti-IL-36R antibody or its antigen-binding fragment to the subject from week 0 to week 1, followed by administering the subject a loading dose of 600 mg of anti-IL-36R antibody or its antigen-binding fragment at intervals of 2 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 10 weeks, or 12 weeks. (a) a maintenance dose of mg of anti-IL-36R antibody, wherein the loading dose and / or maintenance dose of the anti-IL-36R antibody are administered subcutaneously, and; (b) assessing the subject’s GPP Physician Global Assessment (GPPGA) total score and / or GPPGA pustular sub-score at least 48 weeks after the initial loading dose, wherein the time to the first GPP hot red flare up after the start of treatment up to 48 weeks is defined as a GPPGA pustular sub-score ≥2 and an increase of ≥2 in the GPPGA total score relative to baseline. In another aspect, the present invention relates to a treatment for a subject with generalized pustular psoriasis (GPP), including a method for treating and preventing hot red flare-ups, the subject having a history of GPP symptoms, and / or a history of GPP diagnosis (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria, and / or a GPPGA pustular subscale score ≤1, the method comprising the steps of: (a) administering a loading dose of 600 mg of anti-IL-36R antibody or its antigen-binding fragment to the subject from week 0 to week 1, followed by administering a loading dose of 300 mg of anti-IL-36R antibody or its antigen-binding fragment to the subject at intervals of 2 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 10 weeks, or 12 weeks. (a) administering a loading dose of 600 mg of anti-IL-36R antibody, wherein the loading dose and / or maintenance dose of the anti-IL-36R antibody are administered subcutaneously; and (b) assessing the subject's GPP Physician Global Assessment (GPPGA) total score and / or GPPGA pustular sub-score at least 48 weeks after the initial loading dose, wherein the time to the first GPP hot flashes up to week 48 after the start of treatment is defined as a GPPGA pustular sub-score ≥2 and an increase of ≥2 in the GPPGA total score relative to baseline. In a related embodiment, step a) of the method comprises administering a loading dose of 600 mg of anti-IL-36R antibody or its antigen-binding fragment to the subject from week 0 to week 1, followed by administering a maintenance dose of 600 mg of the anti-IL-36R antibody to the subject at 12-week intervals, wherein the loading dose and / or maintenance dose of the anti-IL-36R antibody are administered subcutaneously.In one related embodiment, step a) of the method includes administering a loading dose of 600 mg of anti-IL-36R antibody or its antigen-binding fragment to the subject during week 0 to week 1, followed by administering a maintenance dose of 300 mg of the anti-IL-36R antibody to the subject at 12-week intervals, wherein the loading dose and / or maintenance dose of the anti-IL-36R antibody are administered subcutaneously. In another related embodiment, step a) of the method includes administering a loading dose of 600 mg of the anti-IL-36R antibody to the subject during week 0 to week 1, followed by administering a maintenance dose of 600 mg of the anti-IL-36R antibody to the subject at 4-week intervals, wherein the loading dose and / or maintenance dose of the anti-IL-36R antibody are administered subcutaneously. In one relevant embodiment, step a) of the method includes administering a loading dose of 600 mg of the anti-IL-36R antibody to the subject during week 0 to week 1, followed by administering a maintenance dose of 300 mg of the anti-IL-36R antibody to the subject at 4-week intervals, wherein the loading dose and / or maintenance dose of the anti-IL-36R antibody are administered subcutaneously.

[0038] In one aspect, the present invention relates to a treatment for a subject with generalized pustular psoriasis (GPP), including methods for treating and preventing hot red flare-ups, the subject having a history of GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria, and / or a GPPGA pustular subscale score ≤1, the method comprising the steps of: (a) administering a loading dose of 300 mg of anti-IL-36R antibody or its antigen-binding fragment to the subject at week 0 or week 1, followed by administering at intervals of 2 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 10 weeks, or 12 weeks of a loading dose of 150 mg of anti-IL-36R antibody or its antigen-binding fragment. (a) a maintenance dose of at least one dose of the anti-IL-36R antibody, wherein the loading dose and / or maintenance dose of the anti-IL-36R antibody are administered intravenously and / or subcutaneously; and (b) assessing the subject's GPP Physician Global Assessment (GPPGA) total score and / or GPPGA pustule sub-score at least 48 weeks after the initial loading dose, wherein the time to the first GPP hot red flare up by week 48 is defined as a GPPGA pustule sub-score ≥2 and an increase of ≥2 in the GPPGA total score relative to baseline. In a related embodiment, step a) of the method comprises administering a loading dose of 300 mg of the anti-IL-36R antibody to the subject from week 0 to week 1, followed by administering maintenance doses of 150 mg of the anti-IL-36R antibody to the subject at 12-week intervals, wherein the loading dose and / or maintenance dose of the anti-IL-36R antibody are administered subcutaneously. In one relevant embodiment, the GPP Physician Overall Assessment (GPPGA) total score and / or GPPGA pustular sub-score were measured at weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 after the start of treatment, and / or at week 16 after the last dose.

[0039] In one embodiment related to any of the foregoing aspects, the present invention relates to a treatment for a subject with generalized pustular psoriasis (GPP), including methods for treating and preventing hot red flare-ups, the subject having a history of GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria, wherein clinical improvement is defined as a reduced risk of GPP hot red flare-ups and / or a reduced risk of worsening of the Psoriasis Symptom Scale (PSS) up to week 48 after initiation of treatment, the worsening being defined as an increase of 4 points in the total score relative to baseline. In a related embodiment, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of GPP subjects treated with the anti-IL-36R antibody showed a reduced risk of worsening of the Psoriasis Symptom Scale (PSS) at weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, and / or 48 after initiation of treatment.

[0040] In one embodiment related to any of the foregoing aspects, the present invention relates to a treatment for a subject with generalized pustular psoriasis (GPP), including methods for treating and preventing hot flashes, the subject having a history of GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria, wherein clinical improvement is defined as a reduced risk of worsening of the Dermatology Quality of Life Index (DLQI) from the start of treatment up to week 48 (a worsening is defined as an increase of 4 points in the total score relative to baseline). In a related embodiment, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of GPP subjects treated with the anti-IL-36R antibody showed a reduced risk of worsening of the Dermatology Quality of Life Index (DLQI) at weeks 4, 8, 12, 24, 36, and / or 48 of treatment.

[0041] In one embodiment relating to any of the above aspects or embodiments, administering an anti-IL-36R antibody or its antigen-binding fragment to a subject with a history of GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria to achieve one or more of the following outcomes: (a) maintaining a Generalized Pustular Psoriasis Global Assessment (GPPGA) pustular subscale score of 0 throughout all consultations up to week 48 after administration of the anti-IL-36R antibody, without treatment for GPP hot flashes or administration of investigator-specified standard of care (SoC); and / or (b) After administration of this anti-IL-36R antibody, maintain a GPPGA total score of 0 or 1 until week 48 after the initial loading dose; or (c) Experiencing sustained remission, defined as a subject treated with the anti-IL-36R antibody maintaining a GPPGA score of 0 or 1 (clean or nearly clean) throughout all consultations up to week 48, without requiring treatment for GPP hot red episodes or receiving investigator-specified standard care (SoC).

[0042] An embodiment of the invention relating to any of the foregoing aspects relates to the proportion of subjects with a history of GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria, who achieve any of the above results by administration of anti-IL-36R antibody, and whose administration effect is greater than that of subjects receiving placebo for any of the listed endpoints.

[0043] In another aspect, the present invention relates to a treatment for a subject with generalized pustular psoriasis (GPP), including methods for treating and preventing hot flashes, the subject having a history of GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria, the method comprising (a) obtaining a biological sample from the subject, wherein the biological sample is obtained from a source including lesion skin or whole blood; (b) determining the gene expression profile of one or more genes; and (c) administering to the subject an effective amount of an anti-IL-36R antibody as described in any embodiment associated with any of the foregoing aspects. In a relevant embodiment, one or more of the genes analyzed are IL12B, IL1B, IL6, CXCL1, IL23A, TNF, IL17C, IL24, or IL1B in lesion skin, 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), the method comprising: a) obtaining biological samples from the patient before and after treatment with the anti-IL-36R antibody; b) measuring the levels of one or more biomarkers, or the expression levels of one or more biomarkers, in each sample before and after treatment; c) comparing the pre-treatment levels of the biomarkers with the post-treatment levels; and d) determining the difference in levels between the pre-treatment and post-treatment samples, reflecting a beneficial response in the patient, wherein the one or more biomarkers comprise microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p, wherein downregulation or upregulation after treatment, compared to a pre-treatment baseline, indicates a beneficial response. In an exemplary embodiment, the biological sample is a skin biopsy, blood, plasma, or serum sample. In a preferred embodiment, one or more microRNAs are miR-223-5p or miR-223-3 from diseased skin or serum.

[0045] 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), the method comprising: a) providing biological samples from the patient before and after treatment with the anti-IL-36R antibody; b) measuring in vitro the levels of one or more biomarkers, or the expression levels of one or more biomarkers in each sample before and after treatment; c) comparing the pre-treatment levels of the biomarkers with the post-treatment levels; and d) determining the difference in levels between the pre-treatment and post-treatment samples, reflecting a beneficial response in the patient, wherein the one or more biomarkers comprise microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p, wherein downregulation or upregulation after treatment compared to a pre-treatment baseline indicates a beneficial response. In an exemplary embodiment, the biological sample is a skin biopsy, blood, plasma, or serum sample. In a preferred embodiment, one or more microRNAs are miR-223-5p or miR-223-3 from diseased skin or serum.

[0046] 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 anti-interleukin-36 receptor antibody, the method comprising: a) providing biological samples from the patient before and after treatment with the anti-IL-36R antibody; b) measuring (e.g., in vitro) 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 levels of the biomarkers with the post-treatment levels; and d) determining the difference in levels between the pre-treatment and post-treatment samples, reflecting a beneficial response in the patient, wherein the one or more biomarkers comprise microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p, wherein downregulation or upregulation after treatment compared to a pre-treatment baseline indicates a beneficial response. In one exemplary embodiment, the biological sample is a skin biopsy, blood, plasma, or serum sample. In a preferred embodiment, one or more microRNAs are miR-223-5p or miR-223-3 from diseased skin 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 the anti-interleukin-36 receptor antibody (anti-IL-36R antibody), wherein the levels of one or more microRNAs miR-223-5p and miR-223-3 in the affected skin or serum are correlated with GPPASI and / or GPPGA scores, wherein the treatment or prevention of hot flashes in subjects with a history of GPP symptoms is measured to achieve one or more of the following outcomes: (a) After administration of the anti-IL-36R antibody, maintain a Generalized Assessment of Pustules (GPPGA) score of 0 or 1 for the pustular sub-item and maintain or reduce the levels of miR-223-5p and / or miR-223-3 until week 48 after the initial loading dose; (b) After administration of the anti-IL-36R antibody, maintain a GPPGA total score of 0 or 1 and maintain or reduce the levels of miR-223-5p and / or miR-223-3 until week 48 after the initial loading dose; (c) Persistent remission of GPP symptoms, defined as the maintenance of a GPPGA score of 0 or 1 (clean or nearly clean) and maintenance or reduction of miR-223-5p and / or miR-223-3 levels in all outpatient visits up to week 48 in subjects treated with this anti-IL-36R antibody, without receiving GPP hot red attack medication or investigator-specified standard care (SoC). (d) Until week 48, the incidence of GPP hot red flare decreased and the levels of miR-223-5p and / or miR-223-3 were maintained or decreased, where GPP hot red flare was defined as an increase of ≥2 in the GPP Physician Global Assessment (GPPGA) total score relative to baseline and a GPPGA pustular sub-score of ≥2; or (e) By week 48, the time to the first GPP red eruption was prolonged, as measured from baseline to the onset of the first GPP red eruption, where a GPP red eruption was defined as an increase of ≥2 in the GPP Physician Global Assessment (GPPGA) total score relative to baseline, a GPPGA pustular sub-score of ≥2, and an increase in miR-223-5p and / or miR-223-3 levels.

[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 the anti-interleukin-36 receptor antibody (anti-IL-36R antibody), wherein the levels of one or more microRNAs miR-223-5p and miR-223-3 in the affected skin or serum are correlated with GPPASI and / or GPPGA scores, wherein the levels of one or more microRNAs are determined in vitro in a sample or have been determined in vitro in a sample, wherein the treatment or prevention of hot flashes in subjects with a history of GPP symptoms is measured to achieve one or more of the following results: (a) After administration of the anti-IL-36R antibody, maintain a Generalized Assessment of Pustules (GPPGA) score of 0 or 1 for the pustular sub-item and maintain or reduce the levels of miR-223-5p and / or miR-223-3 until week 48 after the initial loading dose; (b) After administration of the anti-IL-36R antibody, maintain a GPPGA total score of 0 or 1 and maintain or reduce the levels of miR-223-5p and / or miR-223-3 until week 48 after the initial loading dose; (c) Persistent remission of GPP symptoms, defined as the maintenance of a GPPGA score of 0 or 1 (clean or nearly clean) and maintenance or reduction of miR-223-5p and / or miR-223-3 levels or serotypes in subjects treated with the anti-IL-36R antibody without receiving GPP hot red attack medication or investigator-specified standard care (SoC) throughout all consultations up to week 48. (d) Until week 48, the incidence of GPP hot red flare decreased and the levels of miR-223-5p and / or miR-223-3 were maintained or decreased, where GPP hot red flare was defined as an increase of ≥2 in the GPP Physician Global Assessment (GPPGA) total score relative to baseline and a GPPGA pustular sub-score of ≥2; or (e) By week 48, the time to the first GPP red eruption was prolonged, as measured from baseline to the first GPP red eruption, where a GPP red eruption was defined as an increase of ≥2 in the GPP Physician Global Assessment (GPPGA) total score relative to baseline, a GPPGA pustular sub-score of ≥2, and an increase in miR-223-5p and / or miR-223-3 levels.

[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 anti-interleukin-36 receptor antibody, wherein the levels of one or more microRNAs miR-223-5p and miR-223-3 in the affected skin or serum are correlated with GPPASI and / or GPPGA scores, wherein the treatment or prevention of hot flashes in subjects with a history of GPP symptoms is measured to achieve one or more of the following outcomes: (a) After administration of the anti-IL-36R antibody, maintain a Generalized Assessment of Pustules (GPPGA) score of 0 or 1 for the pustular sub-item and maintain or reduce the levels of miR-223-5p and / or miR-223-3 until week 48 after the initial loading dose; (b) After administration of the anti-IL-36R antibody, maintain a GPPGA total score of 0 or 1 and maintain or reduce the levels of miR-223-5p and / or miR-223-3 until week 48 after the initial loading dose; (c) Persistent remission of GPP symptoms, defined as the maintenance of a GPPGA score of 0 or 1 (clean or nearly clean) and maintenance or reduction of miR-223-5p and / or miR-223-3 levels in all outpatient visits up to week 48 in subjects treated with this anti-IL-36R antibody, without receiving GPP hot red attack medication or investigator-specified standard care (SoC). (d) Until week 48, the incidence of GPP hot red flare decreased and the levels of miR-223-5p and / or miR-223-3 were maintained or decreased, where GPP hot red flare was defined as an increase of ≥2 in the GPP Physician Global Assessment (GPPGA) total score relative to baseline and a GPPGA pustular sub-score of ≥2; or (e) By week 48, the time to the first GPP red eruption was prolonged, as measured from baseline to the first GPP red eruption, where a GPP red eruption was defined as an increase of ≥2 in the GPP Physician Global Assessment (GPPGA) total score relative to baseline, a GPPGA pustular sub-score of ≥2, and an increase in miR-223-5p and / or miR-223-3 levels.

[0050] In one embodiment associated with any of the above, the present invention relates to a method wherein the level of a biomarker is determined by small RNA sequencing, qPCR, or ELISA and IHC.

[0051] In another aspect, 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, the method further comprising continuing to administer multiple doses of the anti-IL-36R antibody to the patient if the difference in levels between pre-treatment and post-treatment samples 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, the method further comprising continuing to administer multiple doses of the anti-IL-36R antibody to the patient if the difference in level or concentration between a pre-treatment sample and a post-treatment sample reflects a beneficial response in the patient.

[0053] In another aspect, the present invention relates to a method for determining whether a potential therapeutic agent is effective in treating and preventing GPP, the method comprising: (a) Obtain the first biological sample from the GPP patient before the onset of hot red and / or before treatment with a potential therapeutic agent; (b) Treating GPP patients with potential therapeutic agents; (c) Obtaining a second biological sample from a GPP patient after treatment with a potential therapeutic agent; (d) Measuring the expression levels of one or more biomarkers in the first and second samples; and (e) Compare the levels of biomarkers in the second sample with those in the first sample. The change in biomarker levels (e.g., lower or higher) in the second sample compared to the biomarker in the first sample indicates the effectiveness of the potential therapeutic agent, and in addition, one or more of the biomarkers contain microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p.

[0054] In another aspect, the present invention relates to a method for determining whether a potential therapeutic agent is effective in treating and preventing GPP, the method comprising: (a) Provide a first biological sample from a GPP patient before the onset of hot red and / or before treatment with a potential therapeutic agent; (b) Treating GPP patients with potential therapeutic agents; (c) Provide a second biological sample from a GPP patient following treatment with a potential therapeutic agent; (d) In vitro measurement of the expression levels of one or more biomarkers in the first and second samples; and (e) Compare the levels of biomarkers in the second sample with those in the first sample. The change in biomarker levels (e.g., lower or higher) in the second sample compared to the biomarker levels in the first sample indicates the effectiveness of the potential therapeutic agent, and in addition, one or more of the biomarkers contain microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p.

[0055] 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 determining whether a potential therapeutic agent is effective in treating and preventing GPP, the method comprising: (a) Provide a first biological sample from a GPP patient before the onset of hot red and / or before treatment with a potential therapeutic agent; (b) Treating GPP patients with potential therapeutic agents; (c) Provide a second biological sample from a GPP patient following treatment with a potential therapeutic agent; (d) Measuring (e.g., in vitro) the expression levels of one or more biomarkers in the first and second samples; and (e) Compare the levels of biomarkers in the second sample with those in the first sample. The change in biomarker levels (e.g., lower or higher) in the second sample compared to the biomarker levels in the first sample indicates the effectiveness of the potential therapeutic agent, and in addition, one or more of the biomarkers contain microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p.

[0056] In one related aspect, the invention relates to a method in which a change (e.g., lower or higher) in the level of a biomarker in a second sample compared to a first sample is correlated with an improvement in a measure of clinical efficacy. Another embodiment involves continuing treatment of a patient if the level of the biomarker in the second sample changes (e.g., lower or higher) compared to the first sample.

[0057] In one related aspect, the present invention relates to a method for treating a subject with a history of GPP in a non-flare-up state of generalized pustular psoriasis (GPP), the method comprising: a) determining, according to any of the foregoing embodiments, whether to initiate treatment of the subject, modify the treatment dose, modify the dosing interval, or discontinue treatment; and b) modifying the treatment regimen based on the result of the determination.

[0058] In one related aspect, the present invention relates to the use of an anti-interleukin-36 receptor antibody (anti-IL-36R antibody) in a method for treating a subject with a history of GPP in a non-flare-up generalized pustular psoriasis (GPP), the method comprising: a) determining, according to any of the foregoing embodiments, whether to initiate treatment of the subject, modify the treatment dose, modify the dosing interval, or discontinue treatment; and b) modifying the treatment regimen based on the result of the determination.

[0059] In another aspect, the present invention relates to a method for monitoring a patient's response to GPP treatment, the method comprising: (a) Obtaining the first biological sample from the patient; (b) Measure the level of one or more biomarkers in the first biological sample, wherein the one or more biomarkers comprise microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p; (c) Administering therapeutic compounds to the patient; (d) Obtain a second biological sample from the patient; (e) Measuring the level of one or more biomarkers in the second biological sample; and (f) Comparing the levels of one or more biomarkers obtained from the first and second biological samples; Upregulation or downregulation after treatment, compared to baseline before treatment, indicates an effective response.

[0060] In another aspect, the present invention relates to a method for monitoring a patient's response to GPP treatment, the method comprising: (g) Obtain the first biological sample from the patient; (h) Measure the level of one or more biomarkers in the first biological sample, wherein the one or more biomarkers comprise microRNAs selected from the group consisting of: miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p; (i) Administering therapeutic compounds to the patient; (j) Obtaining a second biological sample from the patient; (k) Measure the level of one or more biomarkers in the second biological sample; and (l) Compare the levels of one or more biomarkers obtained from the first and second biological samples; Upregulation or downregulation after treatment, compared to baseline before treatment, indicates an effective response.

[0061] 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 monitoring a patient's response to GPP treatment, the method comprising: (m) Provide the first biological sample from the patient; (n) Measuring (e.g., in vitro) the level of one or more biomarkers in the first biological sample, wherein the one or more biomarkers comprise microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p; (o) Administering therapeutic compounds to the patient; (p) Provide a second biological sample from the patient; (q) Measuring (e.g., in vitro) the level of one or more biomarkers in the second biological sample; and (r) Compare the levels of one or more biomarkers provided by the first and second biological samples; Upregulation or downregulation after treatment, compared to baseline before treatment, indicates an effective response.

[0062] In another aspect, the present invention relates to a method for monitoring patient compliance with a drug treatment regimen for the treatment and prevention of GPP hot red attacks, the method comprising: (a) Obtaining the first biological sample from the patient; (b) Measure the level of one or more biomarkers in the first biological sample, wherein the one or more biomarkers comprise microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p; (c) Administering therapeutic compounds to the patient; (d) Obtain a second biological sample from the patient; (e) Measuring the levels of one or more biomarkers in the second biological sample; and (f) Comparing the levels of one or more biomarkers obtained from the first and second biological samples; Compared to the baseline before treatment, an up- or down-adjustment after treatment indicates patient compliance with the drug treatment regimen.

[0063] In another aspect, the present invention relates to a method for monitoring patient compliance with a drug treatment regimen for the treatment and prevention of GPP hot red attacks, the method comprising: (g) Provide the first biological sample from the patient; (h) Measure the level of one or more biomarkers in the first biological sample in vitro, wherein the one or more biomarkers comprise microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p; (i) Administering therapeutic compounds to the patient; (j) Provide a second biological sample from the patient; (k) In vitro measurement of the levels of one or more biomarkers in the second biological sample; and (l) Compare the levels of one or more biomarkers obtained from the first and second biological samples; Compared to the baseline before treatment, an up- or down-adjustment after treatment indicates patient compliance with the drug treatment regimen.

[0064] 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 monitoring patient compliance with a drug treatment regimen for the treatment and prevention of GPP hot red attacks, the method comprising: (m) Provide the first biological sample from the patient; (n) Measuring (e.g., in vitro) the level of one or more biomarkers in the first biological sample, wherein the one or more biomarkers comprise microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p; (o) Administering therapeutic compounds to the patient; (p) Provide a second biological sample from the patient; (q) Measuring (e.g., in vitro) the level of one or more biomarkers in the second biological sample; and (r) Compare the levels of one or more biomarkers obtained from the first and second biological samples; Compared to the baseline before treatment, an up- or down-adjustment after treatment indicates patient compliance with the drug treatment regimen.

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

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

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

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

[0069] It should be understood that any of the methods, administration procedures, and / or dosing regimens disclosed herein are equally applicable to the use of any of the anti-IL-36R antibodies disclosed in such methods, administration procedures, and / or dosing regimens: for example, the anti-IL-36R antibody disclosed herein, for the treatment, prevention, reduction, and / or improvement of any of the disclosed diseases and / or conditions. In other words, the present invention also provides the use of the anti-IL-36R antibody disclosed herein for the manufacture of a pharmaceutical agent for the treatment, prevention, reduction, and / or improvement of any of the disclosed diseases and / or conditions. Alternatively, the anti-IL-36R antibody disclosed herein may be used for the treatment, prevention, reduction, and / or improvement of any of the disclosed diseases and / or conditions, and this use further includes any of the methods, administration procedures, and / or dosing regimens disclosed herein.

[0070] Other features and advantages of the invention will be set forth in the description below, and will be apparent to some extent from this description, or may be learned by practice of the invention. It should be understood that both the foregoing general description and the following detailed description are exemplary and explanatory, and are intended to provide further explanation of the invention as claimed. Attached Figure Description

[0071] The accompanying drawings are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification. They illustrate aspects of the invention and, together with this specification, explain the principles of the invention.

[0072] Figure 1 shows the design of the Phase IIb clinical trial: This proof-of-concept study aimed to investigate the role of pesolizumab in preventing acute GPP hot red attacks in subjects with a history of GPP symptoms. The overall study design included loading and maintenance therapy groups, with GPP hot red attacks treated during the randomized maintenance therapy period. *GPP hot red attack was defined as an increase of ≥2 in the total GPPGA score relative to baseline and ≥2 in the pustular component of the GPPGA.

[0073] Figures 2A through 2C show the time to first GPP hot red episode up to week 48. (A) is a table showing the results of formal tests for the primary and key secondary endpoints. (B) is a Kaplan-Meier plot showing the estimated probability of first GPP hot red episode in all treatment groups within 48 weeks. Use of drugs containing IV OL pesolimumab or other investigator-specified drugs was considered a GPP hot red episode. (C) is a bar graph showing the proportion of patients with ≥1 GPP hot red episode up to week 48. Multiple imputation was performed on binary endpoints with monotonic missing assessments using sequential logistic regression. The Cochran-Mantel-Haenszel test was used to stratify pesolimumab versus placebo at each dose level, stratified by the use of systemic GPP drugs at randomization.

[0074] Figure 3 shows a subgroup analysis of the time to first GPP hot red episode in patients receiving high-dose pesolimumab versus placebo up to week 48.

[0075] Figures 4A through 4C (A) are tables showing the results of formal tests for other secondary endpoints: worsening of PSS and DLQI up to week 48. For both scores, worsening was defined as an increase of 4 points in the total score relative to baseline. (B, C) are Kaplan-Mail plots showing the estimated probability of the first worsening of PSS and DLQI scores, respectively. Use of IV OL pesolimumab or other investigator-prescribed medications was considered an event. †Nominal P-value; no statistical significance was achieved for previous families at the level of statistical test. CI, confidence interval; DLQI, Dermatology Quality of Life Index; GPP, Generalized Pustular Psoriasis; IV, Intravenous; nc, Not calculable; OL, Open Label; P10, Estimated probability of first GPP hot red flare = 0.1; P25, Estimated probability of first GPP hot red flare = 0.25; PSS, Psoriasis Symptom Scale; SC, Subcutaneous.

[0076] Figures 5A to 5E: (A) Graphical representation of model-predicted concentration-time profiles for 300 mg IV versus 300 mg subcutaneously over a 12-week period. (B) Graphical representation of model-predicted concentration-time profiles for 900 mg IV versus 600 mg SC pesolimumab. (C) Graphical representation of model-predicted concentration-time profiles for 900 mg IV × 2 versus 600 mg SC × 2 pesolimumab. (D) Graphical representation of model-predicted concentration-time profiles for 900 mg IV versus 2250 mg SC pesolimumab. (E) Overview of exposure quantification in GPP patients following a single IV or SC dose.

[0077] Figures 6A to 6B (A) show the histopathological analysis of selected neutrophils 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 recruitment to the pesolimumab trial. Patient A was randomized to receive a high dose of pesolimumab and did not experience a hot flash during the study. In contrast, representative Patient B was IL36RN mutation unpositive, had a high neutrophil count, and had been treated with acitretin prior to recruitment. Patient B was randomized to receive placebo and continued emergency pesolimumab treatment during the study due to a hot flash. Decreased expression of neutrophils (neutrophil elastase, lipocalin [LCN]), IL-36R, and inflammatory markers (S100A7, human β-defensin 2 [hBD2]) was observed at baseline and at VOL, open-label consultation (Patient A), or VR1, first emergency consultation; and VR6, sixth emergency consultation (Patient B), indicating reduced inflammation and neutrophilic pustule formation. (B) is a schematic diagram of the treatment scenario of patients in the Effisayil 2 trial, the clinical morphology of Patient A at baseline and at week 48, and the emergency pesolimumab treatment in Patient B who showed remission of GPP hot erythema skin symptoms within 4 weeks.

[0078] Figures 7A and 7B show the changes in miRNA expression in GPP lesions compared to healthy controls (HC). (A) is a PCA plot, which includes confidence ellipses / groups (HC, unaffected (nL), and affected (L) skin). (B) is a 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 an adjusted p-value of 0.05. Vertical lines indicate FC values ​​of +1.5 and -1.5. Differentially expressed miRNAs are shown in the upper left and upper right quadrants of the box, with the dysregulated miRNAs indicated at the top.

[0079] Figures 8A and 8B show the changes in miRNA expression in GPP lesions after pesolimumab treatment. (A) is a PCA plot, which includes confidence ellipses / groups (healthy controls (HC), lesion (L) skin before and after pesolimumab treatment, and unlesioned (nL) skin before pesolimumab treatment). (B) is a volcano plot showing the dysregulated miRNAs in lesion skin after pesolimumab treatment (n = 12) compared to baseline (n = 9). Horizontal lines indicate p-values ​​of 0.05. Vertical lines indicate folded FC values ​​of +1.5 and -1.5. Differentially expressed miRNAs after pesolimumab treatment are shown in the upper left and upper right quadrants of the box.

[0080] Figures 9A and 9B show the changes in miRNA expression in serum obtained from GPP patients compared to healthy controls (HC). (A) is a PCA plot, which includes confidence ellipses / groups (healthy controls (HC), GPP patients before pexolizumab). (B) is a 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 an adjusted p-value of 0.05. Vertical lines indicate FC values ​​of +1.5 and -1.5. Differentially regulated miRNAs are located in the upper left and upper right quadrants of the box, with the most strongly expressed miRNAs indicated.

[0081] Figures 10A and 10B show the transcriptomic changes in serum GPP following pesolimumab treatment. (A) is a Venn diagram showing confidence ellipses / groups. (B) is a volcano plot illustrating dysregulated miRNAs in diseased GPPs after pesolimumab treatment (n=11) compared to baseline (n=12). Horizontal lines indicate p-values ​​of 0.05. Vertical lines indicate folded FC values ​​of +1.5 and -1.5. Differentially expressed miRNAs after pesolimumab treatment are shown in red.

[0082] Figures 11A and 11B show the overlap of differentially expressed miRNAs in the lesioned skin and serum of GPP patients compared to healthy controls and those treated with pesolimumab. The numbers of differentially expressed miRNAs in the lesioned GPPs (n = 9) and serum (n = 12) of GPP patients compared to healthy controls (skin n = 10, serum n = 20). (A) is a Venn diagram illustrating the overlap of differentially expressed miRNAs in the lesioned GPPs and serum of GPP patients compared to healthy controls and after pesolimumab treatment. (B) shows the fold change and corresponding p-values ​​for pairwise comparisons of the five selected miRNAs.

[0083] Figures 12A and 12B show the expression levels of selected miRNAs in the skin, determined by RT-qPCR: (A) confirms miRNA expression in the skin of GPP patients at baseline (n = 9) compared to healthy controls (HC; n = 10). (B) shows dysregulation in the skin after pexolimab treatment (n = 12) compared to baseline (before pexolimab). Samples are indicated by black dots, and box plots indicate the median POC (percentage of controls). Statistical analysis was performed using the nonparametric Mann-Whitney test; **** P ≤ 0.0001, *** P ≤ 0.001, ** P ≤ 0.01, * P < 0.05.

[0084] Figures 13A and 13B show the expression levels of selected miRNAs in serum, determined by RT-qPCR: (A) Confirmation of miRNA expression in the serum of GPP patients at baseline (n = 12) compared to healthy controls (HC; n = 20). (B) Dysregulation in serum after pesolimumab treatment (n = 11) compared to baseline (before pesolimumab). (D) Samples are indicated by black dots, and box plots indicate the median POC (percentage of control). Statistical analysis was performed using the nonparametric Mann-Whitney test; ****P ≤ 0.0001, ***P ≤ 0.001, **P ≤ 0.01, *P < 0.05.

[0085] Figures 14A to 14C show the correlation between differentially expressed miRNAs in skin and serum and clinical parameters measured by GPPASI and GPPGA scores. (A) Correlation between the expression levels [log2 CPM] of miR-223-3p and miR-233-5p obtained from skin and GPPASI score. (B) Correlation between the expression levels [log2 CPM] of miR-223-3p and miR-233-5p obtained from skin and GPPGA score. (C) Correlation between the expression levels [log2 CPM] of miR-223-3p and miR-233-5p obtained from serum and GPPGA score. Black circles represent diseased GPPs at baseline, while black dots represent diseased GPPs after pesolimumab treatment. Individual Spearman correlation coefficients (Rs) are shown in the figures. **** P ≤ 0.0001, ** P ≤ 0.01, * P ≤ 0.05. Detailed Implementation

[0086] In the following detailed description, numerous specific details are set forth to provide a full understanding of the invention. However, it will be apparent to those skilled in the art that the invention can be practiced without some of these specific details. In other instances, well-known structures and techniques have not been shown in detail so as not to obscure the invention.

[0087] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0088] The inventors have discovered that by inhibiting the interleukin-36 pathway with the humanized anti-interleukin-36R (anti-IL-36R) monoclonal antibody of the present invention, the signs and symptoms of GPP can be prevented and / or significantly alleviated in subjects with a history of GPP and / or a history of GPP (diagnosis) determined according to the consensus diagnostic criteria defined by the ERASPEN diagnostic criteria, by increasing the time between hot red attacks and / or reducing the duration or severity of hot red attacks. Furthermore, maintenance therapy with the humanized anti-interleukin-36R (anti-IL-36R) monoclonal antibody of the present invention induced sustained remission in GPP subjects who did not exhibit clinical symptoms of acute generalized pustular psoriasis and did not experience GPP hot red relapses for 48 weeks after administration of the first loading dose.

[0089] Therefore, this invention relates to the treatment of generalized pustular psoriasis (GPP) in subjects, including compositions and methods for treating and preventing hot red flare-ups. More specifically, this invention relates to compositions and methods for treating and / or preventing GPP, acute GPP, chronic GPP, and / or hot red flare-ups in mammals using the anti-IL36R antibody or its antigen-binding fragment of the present invention. The compositions and methods comprise administering a therapeutically effective amount of an anti-IL-36R antibody or its antigen-binding fragment to a mammal prior to the occurrence of a hot red flare-up in a patient with a history of GPP, wherein the anti-IL-36R antibody is administered as a dosing regimen comprising a loading dose of 300 mg to 600 mg subcutaneously delivered in week 0 or week 1, followed by at least one maintenance dose, more preferably a series of maintenance doses of 150 mg to 600 mg subcutaneously delivered at intervals of 2, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks, thereby preventing the occurrence of hot red flare-ups of GPP or the appearance of GPP symptoms. In an exemplary embodiment of the present invention, the anti-IL-36R antibody is administered as follows: a loading dose of 600 mg followed by a maintenance dose of 300 mg delivered at 4-week intervals; or a loading dose of 600 mg followed by a maintenance dose of 300 mg delivered at 12-week intervals; or a loading dose of 300 mg followed by a maintenance dose of 150 mg delivered at 12-week intervals.

[0090] Table 1: Treatment Groups in the Effisayil 2 Clinical Trial

[0091] Without being bound by theory, it is assumed that anti-IL-36R antibodies or their antigen-binding fragments bind to human anti-IL-36R, thereby interfering with the binding of IL-36 agonists, and thus at least partially blocking the signaling cascade of IL-36R with inflammatory mediators. The anti-IL-36R antibody of the present invention is disclosed in U.S. Patent No. 9,023,995 or WO2013 / 074569, the entire contents of which are incorporated herein by reference. I. Definition

[0092] The term “about” generally refers to the acceptable degree of error or deviation of a measured quantity given the nature or precision of the measured value. Typically, exemplary degrees of error or deviation are within 5%, 3%, or 1% of a given value or range of values. For example, the expression “about 100” includes 105 and 95, or 103 and 97, or 101 and 99, and all values ​​in between (e.g., 95.1, 95.2, etc. for the range of 95 to 105; or 97.1, 97.2, etc. for the range of 97 to 103; and 99.1, 99.2, etc. for the range of 99 to 101). Unless otherwise stated, the numerical quantities given herein are approximate and are meant to be inferred when not explicitly stated.

[0093] Phrases such as "one aspect" do not imply that such an aspect is essential to the invention or that such an aspect is applicable to all configurations of the invention. The disclosure relating to an aspect is applicable to all configurations, or one or more configurations. An aspect may provide one or more instances of this disclosure. Phrases such as "one aspect" may refer to one or more aspects, and vice versa. Phrases such as "an embodiment" do not imply that such an embodiment is essential to the invention or that such an embodiment is applicable to all configurations of the invention. The disclosure relating to an embodiment is applicable to all embodiments, or one or more embodiments. An embodiment may provide one or more instances of this disclosure. II. The antibody of the present invention

[0094] The anti-IL36R antibody of the present invention is disclosed in U.S. Patent No. 9,023,995 or WO2013 / 074569, the entire contents of which are incorporated herein by reference.

[0095] The terms “antibody,” “anti-IL-36R antibody,” “humanized anti-IL-36R antibody,” “humanized anti-IL-36R epitope antibody,” and “variant humanized anti-IL-36R epitope antibody” specifically encompass 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), and other portions of antibodies such as variable domain antibody fragments and antibodies exhibiting the desired biological activity (e.g., IL-36R binding).

[0096] The term "monoclonal antibody" (mAb) refers to an antibody that has high specificity against a single antigenic determinant "epitope". Therefore, the modifier "monoclonal" indicates an antibody against the same epitope and should not be construed as requiring the antibody to be produced by any particular method. It should be understood that monoclonal antibodies can be prepared by any technique or method known in the art; including, for example, hybridoma methods (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 using phage antibody libraries to isolate monoclonal isolates generated in a recombinant manner, as described in Clackson et al., 1991, Nature 352:624-628 and Marks et al., 1991, J. Mol. Biol. 222:581-597.

[0097] The term "monomer" refers to the homogeneous form of an antibody. For example, for a full-length antibody, a monomer means a monomeric antibody having two identical heavy chains and two identical light chains.

[0098] Chimeric antibodies consist of variable regions of the heavy and light chains of an antibody from one species (e.g., a non-human mammal, such as a mouse) and constant regions of the heavy and light chains of an antibody from another species (e.g., a human), and can be obtained by linking a DNA sequence encoding the variable region of an antibody from the first species (e.g., a mouse) to a DNA sequence encoding the constant region of an antibody from the second species (e.g., a human), and transforming a host with an expression vector containing the linked sequence to produce the chimeric antibody. Alternatively, a chimeric antibody may also be an antibody in which one or more regions or domains of the heavy chain and / or light chain are identical, homologous, or variants of corresponding sequences from another immunoglobulin class or type or from common or germline sequences in a monoclonal antibody. Chimeric antibodies may include fragments of such antibodies, limited to the antibody fragment exhibiting the desired biological activity of its parent antibody, such as binding to the same epitope (see, for example, U.S. Patent No. 4,816,567; and Morrison et al., 1984, Proc. Natl. Acad. Sci. USA 81: 6851-6855).

[0099] In one aspect, this document describes and discloses anti-IL-36R antibodies, particularly humanized anti-IL-36R antibodies, and compositions and articles comprising one or more anti-IL-36R antibodies, particularly one or more humanized anti-IL-36R antibodies of the present invention. Binding agents comprising antigen-binding fragments of anti-IL-36 antibodies, particularly humanized anti-IL-36R antibodies, are also described.

[0100] According to certain embodiments, antibodies used in the methods of the present invention specifically bind to IL-36R. The term "specific binding" or similar terms mean that an 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, surface plasmon resonance, and similar methods. For example, antibodies that "specifically bind" IL-36R as used in the context of the present invention include antibodies that bind IL-36R or a portion thereof, wherein K D The values ​​are below approximately 1000 nM, below approximately 500 nM, below approximately 300 nM, below approximately 200 nM, below approximately 100 nM, below approximately 90 nM, below approximately 80 nM, below approximately 70 nM, below approximately 60 nM, below approximately 50 nM, below approximately 40 nM, below approximately 30 nM, below approximately 20 nM, below approximately 10 nM, below approximately 5 nM, below approximately 4 nM, below approximately 3 nM, below approximately 2 nM, below approximately 1 nM, or below approximately 0.5 nM, as measured in surface plasmon resonance analysis. However, isolated antibodies that specifically bind to human IL-36R may exhibit cross-reactivity with other antigens, such as IL-36R molecules from other (non-human) species.

[0101] In certain exemplary embodiments relating to any aspect of the invention, an anti-IL-36R antibody or an antigen-binding fragment thereof that may be used in the context of the methods of the 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).

[0102] According to some embodiments, the anti-IL-36R antibody or its antigen-binding fragment comprises: Ia) 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: 102 (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 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3); or II.a) The light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 103 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) the heavy chain variable region comprising 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); the amino acid sequence of SEQ ID NO: 72 (H-CDR3); or III.a) The light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 104 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) the heavy chain variable region comprising 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); the amino acid sequence of SEQ ID NO: 72 (H-CDR3); or IV.a) The light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 105 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) the heavy chain variable region comprising 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); the amino acid sequence of SEQ ID NO: 72 (H-CDR3); or 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: 106 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) heavy chain variable region comprising 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); the amino acid sequence of SEQ ID NO: 72 (H-CDR3) or VI.a) The light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 140 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) the heavy chain variable region comprising 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); the amino acid sequence of SEQ ID NO: 72 (H-CDR3); or VII. 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: 104 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 141 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, 111 or 142 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

[0103] According to some embodiments, the anti-IL-36R antibody or its antigen-binding fragment comprises: (i) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or (iii) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or (iv) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or (v) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or (vi) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or (vii) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 85; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100; or (viii) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 85; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 101; or (ix) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 86; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100; or (x) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 86; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 101.

[0104] According to some embodiments, the anti-IL-36R antibody or its antigen-binding fragment comprises: (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) 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.

[0105] In one aspect, this document describes and discloses anti-IL-36R antibodies, particularly humanized anti-IL-36R antibodies, and compositions and articles comprising one or more anti-IL-36R antibodies, particularly one or more humanized anti-IL-36R antibodies of the present invention. Binding agents comprising antigen-binding fragments of anti-IL-36 antibodies, particularly humanized anti-IL-36R antibodies, are also described.

[0106] In one respect, the anti-IL-36R antibody described and disclosed herein is pesolimab. III. Pharmaceutical Compositions, Formulations, Dosage and Administration

[0107] In this context, "pharmaceutical composition" refers to a liquid or powder formulation in such form as to permit the proven bioactivity of the active ingredient and which contains no additional components that would be significantly toxic to the subject to whom the composition will be administered. Such compositions are sterile. "Powder" refers to a lyophilized, freeze-dried, or spray-dried pharmaceutical composition intended for non-enteric use. Powders are typically reconstituted or dissolved in water. Lyophilization is a low-temperature dehydration process involving freezing the product, reducing pressure, and subsequently removing the ice by sublimation. Lyophilization produces high-quality products because of the low temperatures used in the processing. For well-developed lyophilized formulations, the shape and appearance of the product remain unchanged over time, and the quality of the rehydrated product is excellent. Spray drying is another method for producing dry powders by rapidly drying a liquid or slurry with hot air, with the goal of achieving a constant particle size distribution.

[0108] "Pharmaceutical formulation" or "formulation" refers to the process and process products in which an active pharmaceutical ingredient or agent is combined with chemical substances to produce a final pharmaceutical product or drug product. The final formulation therefore refers to a pharmaceutical product such as a liquid, powder, or composition. Thus, in one embodiment, the pharmaceutical formulation is a pharmaceutical composition.

[0109] The antibodies of the present invention can be incorporated into pharmaceutical compositions suitable for administration to subjects. The compounds of the present invention can be administered alone or in combination with pharmaceutically acceptable carriers, diluents, and / or excipients in a single or multiple dose. Pharmaceutical compositions for administration are designed to suit a chosen mode of administration and, where appropriate, use pharmaceutically acceptable diluents, carriers, and / or excipients, such as dispersants, buffers, surfactants, preservatives, solubilizers, isotonics, stabilizers, and the like. The compositions are designed according to conventional techniques, for example, those outlined in Remington, *The Science and Practice of Pharmacy*, 19th edition, edited by Gennaro, Mack Publishing Co., Easton, PA 1995, which provides an overview of formulation techniques generally known to practitioners.

[0110] Pharmaceutical compositions comprising the anti-IL-36R monoclonal antibody of the present invention may be administered to subjects with a history of GPP and / or a confirmed history of GPP (diagnosis) according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria (website: eraspen.eu / home / rfp / diagnostic-criteria.html (accessed May 9, 2018); European Network of Experts on Rare and Severe Psoriasis (ERASPEN); 2018), using standard administration techniques described herein, including oral, intravenous, intraperitoneal, subcutaneous, transpulmonary, transdermal, intramuscular, intranasal, buccal, sublingual, or suppository administration.

[0111] The antibodies of the present invention can be administered orally, via inhalation, or topically. Preferably, the antibodies of the present invention can be incorporated into pharmaceutical compositions suitable for non-enteric administration. As used herein, the term non-enteric includes intravenous, intramuscular, subcutaneous, rectal, vaginal, or intraperitoneal administration. Peripheral systemic delivery via intravenous, intraperitoneal, or subcutaneous injection is preferred. Suitable media for such injections are known in the art.

[0112] Pharmaceutical compositions must generally be sterile and stable under manufacturing and storage conditions in the provided container, including, for example, a sealed vial or syringe (e.g., to contain a unit dosage form). Therefore, after preparation of the formulation, the pharmaceutical composition is sterilely filtered or otherwise made microbiologically acceptable. Typical compositions for intravenous infusion may have a volume of up to 250 to 1000 ml of fluid, such as sterile Ringer's solution, normal saline, dextran solution, and Hank's solution, and a therapeutically effective dose (e.g., 1 to 100 mg / mL or more) of antibody concentration. Dosage can vary depending on the type and severity of the disease. As is well known in the medical field, for any given subject, the dose depends on many factors, including the subject's physique, body surface area, age, the specific compound administered, sex, time and route of administration, general health condition, and any other medications administered concurrently. Typical doses may range, for example, from 0.001 to 1000 mg; however, doses below or above this exemplary range are contemplated, especially considering the foregoing factors.

[0113] In one embodiment, the present invention provides a pharmaceutical composition formulated in a unit dose form, wherein such a single dose 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 form is used to prepare a medicament for treating a subject suffering from generalized pustular psoriasis (GPP). In a related embodiment, the unit dose form is a non-enteric (e.g., intravenous or subcutaneous) dose form.

[0114] In one relevant embodiment, the present invention provides a pharmaceutical formulation (or the “article” described below) comprising: one, two, three, or four of the said unit dose forms containing 150 mg of the anti-IL-36R antibody; one, two, three, or four of the said unit dose forms containing 300 mg of the anti-IL-36R antibody; one, two, three, or four of the said unit dose forms containing 450 mg of the anti-IL-36R antibody; or one, two, three, or four of the said unit dose forms containing 600 mg of the anti-IL-36R antibody; or one, two, three, or four of the said unit dose forms containing 900 mg of the anti-IL-36R antibody; or any combination thereof, to achieve an effective dose.

[0115] In one relevant embodiment, one, two, three, or four of the unit dose forms (e.g., in a pharmaceutical formulation) are administered at intervals of 1 week (qw), 2 weeks (q2w), 4 weeks (q4w), and 12 weeks (q12w). Preferably, when the unit dose form comprises 150 mg, 300 mg, 450 mg, 600 mg, or 900 mg of the anti-IL-36R antibody, one, two, three, or four unit dose forms are administered at intervals of 1 week (qw), 2 weeks (q2w), 4 weeks (q4w), or 12 weeks (q12w) as a loading and / or subcutaneous maintenance dose.

[0116] In one aspect, the present invention relates to the use of an anti-IL-36R antibody or an antigen-binding fragment thereof (as disclosed herein) in the preparation of a medicament for treating, preventing, or improving GPP. In one embodiment related to this aspect, the anti-IL-36R antibody is pexolimab.

[0117] As used herein, the term “dosage” refers to the amount of anti-IL-36R antibody or its antigen-binding moiety administered to a subject.

[0118] As used herein, the term "administration" refers to the administration of an anti-IL-36R antibody or its antigen-binding portion to achieve a therapeutic objective (e.g., treating a subject with a history of GPP). In preferred embodiments, the dose is delivered non-enterically, such as intravenously or subcutaneously.

[0119] The “dosing regimen” describes the duration of treatment with the anti-IL-36R antibody or its antigen-binding portion, such as over an extended period or throughout maintenance therapy. For example, in a non-limiting embodiment, the regimen includes a first loading dose of the anti-IL-36R antibody or its antigen-binding portion at week 0 or week 1, followed by at least one maintenance dose of the anti-IL-36R antibody or its antigen-binding portion, but preferably a second, third, fourth or more doses during the maintenance therapy period, wherein the doses are delivered at intervals of 2 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 10 weeks or 12 weeks, and wherein the loading dose and / or maintenance dose are administered non-enterically, such as intravenously and / or intravenously.

[0120] As used herein, the terms “intravenous dose” (iv) and “subcutaneous dose” (sc) refer, in addition to their general meaning, to the timing of administration of anti-IL-36R antibody. Anti-IL-36R antibody therapy may be initiated subcutaneously to prevent GPP hot flashes, or with an intravenous dose of anti-IL-36R antibody to treat GPP hot flashes. In a preferred embodiment, for the treatment of generalized pustular psoriasis (GPP), including the treatment and prevention of hot flashes in adults and adolescents aged 12 years and older, the dosing regimen comprises a subcutaneous loading dose of 600 mg (comprising four 150 mg injections), followed by a maintenance dose of 300 mg subcutaneously every 4 weeks (comprising two 150 mg injections). If a subject experiences a GPP hot flash while receiving subcutaneous maintenance therapy with the anti-IL36R antibody, the GPP hot flash can be treated with intravenous anti-IL36R antibody, after which maintenance therapy can be restarted. Maintenance therapy can be restarted four weeks after treatment with intravenous anti-IL-36R for hot red attacks. Maintenance therapy consists of a dose of 300 mg every 4 weeks (two 150 mg injections) and does not require a subcutaneous loading dose.

[0121] Therefore, in one embodiment, the “loading dose” is the dose 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”. “One or more maintenance doses” are one or more doses administered after the initial loading dose, which may also be referred to as “one or more subsequent doses” as part of “maintenance therapy”. Both the loading and maintenance doses may contain the same amount of anti-IL-36R antibody or its antigen-binding fragment, but may generally differ from each other in the amount or frequency of antibody 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 subcutaneous doses are preferred.

[0122] The terms "maintenance dose" or "treatment dose" refer to the amount of anti-IL-36R antibody or its antigen-binding portion administered to a subject to maintain or continue the desired therapeutic effect. The maintenance dose is administered during the treatment or maintenance phase of the therapy. In one embodiment, the maintenance dose is less than the loading dose and may be equal to each other when administered sequentially. In one embodiment, the invention provides a maintenance dose of 150 mg or 300 mg of anti-IL-36R antibody or its antigen-binding portion 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 administered subcutaneously. In one embodiment, the maintenance dose is administered every four weeks starting at weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 following the last loading dose. In one embodiment, the maintenance dose is administered approximately 4 weeks after the initial loading dose, and thereafter at 4-week (q4w) intervals. In one embodiment, the maintenance dose is administered every twelve weeks, beginning at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 weeks after the last loading dose. In another embodiment, the maintenance dose is administered approximately 12 weeks after the initial loading dose and thereafter at 12-week (q12w) intervals.

[0123] The term “intravenous” or “intravenous infusion” refers to the introduction of a drug into a vein in an animal or human subject over a period of time exceeding approximately 15 minutes, typically between approximately 30 and 90 minutes.

[0124] The term "subcutaneous administration" refers to the introduction of a drug agent under the skin of an animal or human subject via a relatively slow, continuous delivery from a drug container, preferably into a depression between the skin and subcutaneous tissue. A depression can be created by pinching or pulling the skin away from the subcutaneous tissue.

[0125] As used herein, the terms “treatment,” “therapeutic,” “prevention,” and similar terms mean the treatment of a disease or condition, as well as preventive or suppressive measures, thereby producing any clinically necessary or “beneficial effect” or “beneficial response,” including but not limited to the reduction or relief of one or more symptoms, the resolution of the disease or condition, or the slowing or halting of its progression. Thus, for example, the term “treatment” includes administering an agent before or after the onset of one or more symptoms of a GPP disease, such as before a heat rash, thereby preventing or removing one or more symptoms of the disease or condition. Beneficial responses can also be exemplified by: maintaining the pustular subscale score on the Generalized Petechial Psoriasis Assessment (GPPGA); maintaining a GPPGA total score of 0 or 1; sustained remission of GPP symptoms (defined as maintaining a GPPGA score of 0 or 1 (clean or nearly clean) in subjects treated with the anti-IL-36R antibody); a reduced incidence of GPP hot red flare-ups; prolonged time to the onset of the first GPP hot red flare-up (measured from baseline to the first GPP hot red flare-up); or changes in the levels of biomarkers such as the microRNAs miR-223-5p and / or miR-223-3 present in the skin or serum. As another example, the term includes administering medication to combat the symptoms of the disease following the clinical presentation of GPP. Furthermore, in cases of administration of medication that affects clinical parameters of the disease or condition (such as the extent of tissue damage), regardless of whether the treatment results in disease improvement, administration of medication after an flare-up and after the onset of clinical symptoms includes the use of "treatment" or "therapeutic approach" as used herein. Furthermore, the result should be considered an effective treatment of the underlying condition as long as the composition of the present invention, alone or in combination with another therapeutic agent, reduces or improves at least one symptom of the treated GPP compared to the symptoms in the absence of the humanized anti-IL-36R antibody composition, regardless of whether all symptoms of the condition are reduced.

[0126] The term "preventative effective dose" refers to the amount that effectively achieves the desired preventative outcome (e.g., treatment and prevention of red flare-ups in the subject) within the necessary dose and timeframe. Typically, the preventative dose is administered before a red flare-up of GPP and / or before the onset of GPP symptoms (which may be moderate or severe) in subjects with a history of generalized pustular psoriasis (GPP) and / or diagnosed according to the European Network of Experts on Rare and Severe Psoriasis (ERASPEN) guidelines, to prevent or suppress the occurrence of acute red flare-ups. Subjects who have not experienced a red flare-up of GPP have a GPP Physician Global Assessment (GPPGA) total score ≤1 and a GPPGA pustular sub-score ≤1. In one embodiment, the maintenance dose as covered herein is the preventative dose, administered after a loading dose to subjects with a history of moderate to severe GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic guidelines, to prevent possible recurrence of red flare-ups of GPP or disease exacerbation.

[0127] As used herein, “buffer solution” refers to a buffer solution that resists pH changes through the action of an acid-base conjugate component. “pH” herein 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 the instrument, placing the electrode in a well-mixed sample, and then reading the pH directly from a pH meter. Exemplary buffer solutions of the present invention include acetate, citrate, histidine, succinate, phosphate, and Tris.

[0128] As used herein, the terms "tonicifying agent," "tonicity agent," or "tonicifer" refer to substances that provide an osmotic pressure equivalent to that of serum in vivo, including salts (e.g., sodium chloride, potassium chloride, magnesium chloride) or sugars (e.g., sucrose, trehalose, sorbitol, magnesium sulfate (MgSO4), glycerol, mannitol, or dextrose). Additionally, sugars present in solution act as cryoprotectants for proteins, allowing the active pharmaceutical ingredient to be frozen without damage. This permits shipment in frozen form and long-term storage of the active pharmaceutical ingredient prior to injection. Exemplary tonicifying 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).

[0129] As used herein, the term "stabilizer" or "stabilizing agent" refers to a substance that contributes to the stability of an active ingredient in a pharmaceutical formulation. Exemplary stabilizers of the present invention include arginine, histidine, glycine, cysteine, proline, methionine, lysine, or pharmaceutically acceptable salts thereof.

[0130] As used herein, the term "surfactant" refers to a substance that tends to reduce the surface tension of a liquid to which it is dissolved. Exemplary surfactants of the present invention include poloxamer 188, polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80.

[0131] In one embodiment relating to any of the foregoing aspects, an anti-IL-36R antibody or an antigen-binding fragment thereof (disclosed herein) is present in a stable pharmaceutical formulation (as described in U.S. Application No. 16 / 809,606, filed March 5, 2020, the entire contents of which are incorporated herein by reference) for administration to a mammal or a subject according to any aspect of the invention.

[0132] In one embodiment, a treatment method according to any of the aspects described herein includes administering a therapeutic amount of a stable pharmaceutical formulation to a mammal or subject, the stable pharmaceutical formulation comprising about 20 mg / mL to about 150 mg / mL of an 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 tonic modulator (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 at a concentration of about 0 g / L to about 1.5 g / L. A pharmaceutically acceptable surfactant (e.g., polysorbate 20) in g / L is used to treat subjects with a history of GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria, and / or to prevent or improve symptoms of acute GPP, or to treat subjects with GPP-related skin conditions, or to reduce or alleviate subjects with GPP-related skin inflammation and / or hot flashes, or to achieve complete resolution of subjects' GPP symptoms. In one relevant embodiment, the stable pharmaceutical formulation is an aqueous pharmaceutical formulation. In one relevant embodiment, the pH of the aqueous pharmaceutical formulation is from about 5 to about 7. In one relevant embodiment, the pharmaceutical formulation is intended for intravenous administration to a mammal or subject. In one relevant embodiment, the pharmaceutical formulation is intended for subcutaneous administration to a mammal or subject. In one relevant embodiment, the pharmaceutical formulation for intravenous administration contains an anti-IL-36R antibody in an amount of about 60 mg / mL, with one vial containing 450 mg. In one related embodiment, the drug formulation for subcutaneous administration contains an anti-IL-36R antibody in an amount of about 150 mg / mL, and one pre-filled syringe contains 300 mg of the antibody for subcutaneous injection.

[0133] Various delivery systems are known and can be used to administer the IL-36R binder. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The IL-36R binder can be administered, for example, by infusion, bolus, or injection, and can be administered in combination with other bioactive agents such as chemotherapeutic agents. Administration can be systemic or local. In preferred embodiments, administration is by intravenous or subcutaneous injection. Formulations for such injections can be prepared in pre-filled syringes, for example, for administration once weekly.

[0134] In one aspect, the present invention provides an article of manufacture comprising a subcutaneous administration device for delivering a fixed dose of the antibody of the present invention to a subject. In some embodiments, the subcutaneous administration device is a pre-filled syringe, an autoinjector, or a high-volume infusion device. For example, the MyDose™ product from Roche (a single-use infusion device capable of subcutaneously administering large volumes of liquid medication) can be used as an administration device. Many reusable pen-type and autoinjector delivery devices can be used for the subcutaneous delivery of the pharmaceutical compositions of the present invention. To name just a few, examples include, but are not limited to, AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25™ pen, HUMALOG™ pen, HUMALIN 70 / 30™ pen (Eli Lillyand Co., Indianapolis, Ind.), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™ and OPTICLIK™ (Sanofi-Aventis, Frankfurt, Germany). To name just a few, examples of disposable pen delivery devices used for subcutaneous delivery of the pharmaceutical compositions of the present invention include, but are not limited to, the SOLOSTAR™ pen (Sanofi-Aventis), FLEXPEN™ (Novo Nordisk) and KWIKPEN™ (Eli Lilly), SURECLICK™ autoinjector (Amgen, Thousand Oaks, Calif.), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP) and HUMIRA™ pen (Abbott Labs, Abbott Park, Ill.), YPSOMATE™, YPSOMATE 2.25™, and VAIROJECT™ (Ypsomed AG, Burgdorf, Switzerland).Further information relating to exemplary delivery devices that can be used with the antibodies of the present invention can be found, for example, in CH705992A2, WO2009 / 040602, WO2016 / 169748, and WO2016 / 179713.

[0135] In certain embodiments, the IL-36R binding composition is administered by injection, via catheter, via suppository, or via an implant, which is a porous, non-porous, or gel-like material, including membranes such as silicone rubber membranes, or fibers. Typically, when administering the composition, a material in which the anti-IL-36R antibody or drug is not absorbed is used.

[0136] In other embodiments, the anti-IL-36R antibody or agent is delivered in a controlled release 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 another embodiment, a polymeric material 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 controlled release systems are discussed, for example, by Ranger, as above. IV. Treatment of subjects with generalized pustular psoriasis (GPP), including treatment and prevention of hot red flare-ups:

[0137] For therapeutic purposes, as used herein, the terms “subject” or “patient” refer to any animal classified as a mammal, including humans, domesticated and farm animals, as well as zoo, sporting, or pet animals such as dogs, horses, cats, dairy cows, and similar animals. Preferably, the mammal is human. Human subjects suitable for treatment are adult and adolescent subjects with a history of GPP diagnosed according to the ERASPEN criteria (regardless of IL36RN mutation status) and having experienced at least two moderate to severe GPP hot flashes (regardless of IL36RN mutation status). Prior to initiating prophylactic treatment with the anti-IL36R antibody of the present invention, the subject's total GPPGA score is also 0 or 1. “History of GPP” may also include a history of hot flashes occurring while receiving concomitant treatment for GPP or after dose reduction or discontinuation of concomitant medications; examples of the latter include other known systemic and / or local therapies for treating GPP.

[0138] The term "maintenance therapy" or "maintenance dosing regimen" refers to a treatment course for subjects with a history of GPP (which may be moderate to severe) and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria as defined by the ERASPEN diagnostic criteria, in order to enable them to maintain their health in a given state, such as a reduction in the number or incidence of GPP symptoms (including moderate to severe symptoms and acute GPP hot flashes) or the achievement of a clinical response. In one embodiment, the maintenance therapy of the present invention is used for subjects with a history of GPP and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria as defined by the ERASPEN diagnostic criteria, in order to enable them to maintain their health in a state of complete asymptomatic or reduced disease-related symptoms. In one embodiment, the maintenance therapy of the present invention is used for one or more subjects with a history of GPP and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria as defined by the ERASPEN diagnostic criteria, in order to enable them to maintain their health in a state of substantially no disease-related symptoms. In one embodiment, the maintenance therapy of the present invention is used on one or more subjects with a history of GPP, so that they can maintain their health with a significant reduction in disease-related symptoms.

[0139] As used herein, the terms “treatment” or “maintenance treatment” refer to a period of treatment in which the subject is given an anti-IL-36R antibody or its antigen-binding moiety to maintain the desired therapeutic effect, such as improvement of symptoms associated with acute and / or GPP.

[0140] In embodiments of the invention, maintenance therapy may be initiated after a GPP hot red attack or a worsening of the GPP disease. Maintenance therapy is initiated in subjects after treatment for a GPP hot red attack and after clinical stabilization of an acute hot red attack.

[0141] "Treatment for GPP hot red attacks" is defined as treatment of a first GPP hot red attack with a 900 mg intravenous dose of pesolimumab during a randomized maintenance therapy period in subjects experiencing GPP exacerbations. Criteria for treatment of GPP hot red attacks with a 900 mg open-label (OL) intravenous dose of anti-IL36R antibody are a GPPGA score ≥3 and a pustular component of GPPGA ≥2 at R1 (the time of the first IV treatment for hot red attacks). Alternatively, treatment may be indicated if a GPPGA score of 2 and a pustular component of GPPGA ≥2 are indicated at R1, with a pustular component of GPPGA ≥2 at R3 / D8. Response to treatment of GPP hot red attacks with a 900 mg intravenous dose of anti-IL36R antibody (at R1 / D1 or at both R1 / D1 and R3 / D8) is defined as a subject who does not exhibit moderate / severe hot red attack symptoms and has a GPPGA score <3 and a pustular component score <2. Additionally, a reduction of ≥1 in the GPPGA score from R1 / D1 subjects was considered a partial response to treatment for GPP hot flashes. A GPPGA score of 0 or 1 was defined as a reduction in the GPPGA score (to <3) or a reduction in the GPPGA pustular subscale score (to <2) observed after treatment with a 900 mg intravenous dose of anti-IL36R antibody. Subjects may also receive subcutaneous maintenance doses at higher frequencies, for example, increasing the frequency from a 300 mg maintenance dose of anti-IL36R at 12-week (q12w) intervals to a 300 mg maintenance dose at 4-week (q4w) intervals.

[0142] “GPP disease exacerbation” is defined as a worsening of the clinical condition or skin and systemic symptoms of GPP in the researcher’s view that requires treatment intervention.

[0143] Clinically, “GPP hot red attack” is defined as an increase of ≥2 in the GPPGA score relative to baseline and ≥2 in the pustular component of the GPPGA. The baseline value for efficacy measurement is the last value measured at the second consultation (V2) before the first dose of anti-IL36R antibody (e.g., pexolimab). V. Therapeutic endpoint:

[0144] Embodiments of the present invention provide a method for treating generalized pustular psoriasis (GPP) in a subject, including methods for treating and preventing hot red flare-ups, the subject having a history of GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria up to week 48 after the initiation of treatment.

[0145] In other embodiments, the present invention provides a treatment method including a method for reducing the disease in subjects with a history of GPP and improving the quality of life of GPP subjects.

[0146] In other embodiments, the present invention provides a method for treating certain subject subgroups, including, for example, subjects who have failed previous therapies or have poor treatment responses, and subjects who, for example, have an inadequate or intolerable response to standard care or have contraindications. In some embodiments, the present invention is used to treat subjects with a history of GPP who have an inadequate or intolerable response to TNF-α inhibitors or have contraindications.

[0147] The methods and uses described herein provide a means of determining the efficacy of anti-IL-36R antibodies or their antigen-binding moiety in treating subjects with a history of GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria, and the use of such anti-IL-36R antibodies in treating subjects with generalized pustular psoriasis (GPP), including the treatment and prevention of hot red flare-ups. The efficacy of GPP treatment may be determined using any of the measures described herein, or any measures known in the art, such as: (a) Up to week 48, the risk of at least one GPP hot red episode (defined as a ≥2 increase in GPPGA score relative to baseline and a ≥2 pustular component of GPPGA) was reduced, and was greater in the placebo group. (b) Up to week 48, the risk of worsening of the Psoriasis Symptom Scale (PSS) (defined as an increase of 4 points in total score relative to baseline) was reduced, and greater than in the placebo group. (c) Up to week 48, the risk of worsening of the Dermatology Quality of Life Index (DLQI) was reduced compared to the placebo group, with worsening defined as an increase of 4 points in the total score relative to baseline.

[0148] In another embodiment related to any of the above embodiments or aspects, administration of the anti-IL-36R antibody or its antigen-binding portion causes one or more of the following efficacy endpoints, which are measured by the difference between treated GPP subjects and those in the placebo group: (a) The proportion of subjects who did not experience a GPP hot flash up to week 48. (b) Without receiving emergency medication or investigator-prescribed standard care (SoC), up to week 48, ≥75% of the consultations had no PSS sub-score >1; (c) In the absence of emergency medication or investigator-prescribed SoC, the DLQI score was 0 or 1 in all consultations up to week 48; (d) WPAI ratings as of week 48 (e) GPPGA score as of week 48 (f) GPPASI score as of week 48 (g) SF-36 score as of week 48 (h) Visual Analog Scale (VAS) score for pain as of week 48. (i) EQ-5D-5L scores as of week 48 (j) JDA GPP severity score as of week 48 (k) TPSS as of week 48 (l) PGI-S as of week 48 (m) PGI-C as of week 48 (n) Improved sustained remission, defined as a total GPPGA score of 0 or 1 across all consultations up to week 48, with each GPPGA sub-score less than or equal to 2, without the use of emergency medications or investigator-specified SoC (added via TSAP). (o) Improved sustained remission is defined as a total GPPGA score of 0 or 1 and each GPPGA sub-score less than or equal to 2 in all consultations up to week 48, without the subject receiving emergency medication or investigator-specified SoC (added via TSAP).

[0149] In another embodiment related to the above embodiments or aspects, for one or more of endpoints (a) to (c) and / or (a) to (o), the proportion of subjects responding to administration of the anti-IL-36R antibody or its antigen-binding portion was statistically significantly different from that of subjects receiving placebo.

[0150] In one embodiment related to the above embodiments, the present invention provides a method for treating generalized pustular psoriasis (GPP) in a subject, including methods for treating and preventing hot flashes, the subject having a history of GPP and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria, such as as assessed using the Generalized Pustular Psoriasis Physician Global Assessment (GPPGA). The GPPGA relies on a clinical assessment of the skin presentation of the GPP subject. It is a modified PGA (a physician assessment of psoriatic lesions) and has been adapted for assessing GPP subjects (Langley RG, Feldman SR, Nyirady J et al., The 5-point Investigator's Global Assessment (IGA) Scale: Amodified tool for evaluating plaque psoriasis severity in clinical trials. JDermatol Treat 2015;26(1):23-31). Researchers scored all GPP lesions (erythema, pustules, and desquamation) from 0 to 4. Each component was graded separately, and the average value was calculated. The final GPPGA was determined based on this composite score. Lower scores indicated less severity, with 0 indicating complete clearance and 1 indicating near-complete clearance. As mentioned in the study, GPPGA was measured at weeks 0, 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48, and at 16 weeks after the last dose (see flowchart of the study activities in the example below).

[0151] In one embodiment related to the above embodiments, the present invention provides a treatment for generalized pustular psoriasis (GPP), including treatment and prevention of hot flashes in subjects with a history of GPP and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria, as assessed using the Generalized Pustular Psoriasis Area and Severity Index (GPPASI). GPPASI is an adaptation of PASI for GPP subjects, which is an established measure of the severity and area of ​​psoriatic lesions in subjects with psoriasis (Fredriksson T, Pettersson U. Severepsoriasis-oral therapy with a new retinoid. Dermatologica 1978; 157:238-244). In GPPASI, the induration component has been replaced by the pustular component. It provides a numerical score ranging from 0 to 72 for the overall GPP disease symptoms of the subject. It is a linear combination of the percentage of skin surface area affected by erythema, pustules, and peeling and the severity of erythema, pustules, and peeling (scaly skin) in four body regions. As mentioned in the study, GPPASI was measured at weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48, and at week 16 after the last dose (see flowchart of study activities in the example below).

[0152] In one embodiment related to the above embodiments, the present invention provides a treatment for a subject with generalized pustular psoriasis (GPP), including methods for treating and preventing hot flashes, the subject having a history of GPP and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria, as assessed using the EQ-5D-5L self-report questionnaire at most 48 weeks after the initiation of treatment. The EQ-5D-5L self-report questionnaire was developed by the European Quality of Life Group (EuroQol Group) and is a standardized tool for measuring 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 contains five questions on different health dimensions (e.g., mobility, self-care) and a visual analog scale (VAS) on current health status. Response options include a five-point ranking scale reporting on the five health dimensions and a VAS scale where the subject reports their self-rated health status as a number between 0 and 100. The MCIDs for the five dimensions and the VAS scale have been estimated at 0.074 and 7, respectively (Walters SJ, Brazier JE. Comparison of the minimally important difference for two healthstate 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”).As mentioned in the study, the EQ-5D-5L questionnaire was measured at weeks 1, 4, 8, 12, 24, 36, and 48 (see flowchart of the study activities in the example below).

[0153] In one embodiment related to the above embodiments, the present invention provides a method for treating generalized pustular psoriasis (GPP) in a subject, including methods for treating and preventing hot flashes, the subject having a history of GPP and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria, as assessed before, during, and / or after treatment using the SF-36 questionnaire as a measure of the subject's quality of life. The SF-36 is a widely used tool for measuring the health-related quality of life of healthy subjects and subjects with acute and chronic conditions. It consists of 36 questions (Ware JE, SF-36 Health Survey: Manual and Interpretation Guide. Boston: The Health Institute, New England Medical Center; 1993). SF-36 scores can be compared among different subject groups and healthy subjects. Response options vary, but most are 5-item or 3-item scales. Subscales (physical function, physical limitations, bodily pain, general health, vitality, social function, emotional limitations, and mental health) were reported separately and summarized as Physical Component Summary (PCS) and Mental Component Summary (MCS) scores (range: 0 to 100, with scores of 50 ± 10 considered to reflect US standards) (Ware JE. SF-36 health survey update. Spine 2000;25(24):3130-3139). A difference of 3 points was recommended as the MCID cutoff for intergroup comparisons of PCS and MCS (Frendl DM, Ware JE. Subject-reported functional health and well-being outcomes with drugtherapy: a systematic review of randomized trials using the SF-36 health survey. Med Care 2014;52(5):439-445). An acute version of the SF-36 with a 1-week recall period was used. SF-36 was measured at weeks 1, 12, 24, 36, and 48 (see flowchart of study activities in the example below).

[0154] In one embodiment related to the above embodiments, the present invention provides a treatment for generalized pustular psoriasis (GPP), including treatment and prevention of red flare-ups in subjects with a history of GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria, such as assessment using the Psoriasis Symptom Scale (PSS), wherein the efficacy of the subject's response to treatment with anti-IL-36R antibody or its antigen-binding moiety is measured relative to the placebo group, up to week 48, with a reduced risk of symptom exacerbation as assessed by the PSS. The PSS is a four-subject-reported outcome (PRO) tool developed to assess the severity of psoriasis symptoms in subjects with psoriasis (Rentz AM, Skalicky AM, Burslem K et al., The contentvalidity of the PSS in subjects with plaque psoriasis. J Patient Rep Outcomes 2017; 1:4). When completing this questionnaire, patients report the symptoms they have experienced from generalized pustular psoriasis. The included symptoms are pain, redness, itching, and burning. Assess the current severity of symptoms using a 5-point scale ranging from 0 (none) to 4 (extremely severe). Add the symptom score to the unweighted total score (range: 0 to 16). Measure the PSS tool at weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48, as mentioned in the study (see flowchart of the study activities in the example below).

[0155] In one embodiment related to the above embodiments, the present invention provides a method for treating generalized pustular psoriasis (GPP) in a subject, including methods for treating and preventing hot flashes, the subject having a history of GPP symptoms and / or a history of GPP diagnosis determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria, wherein the Work Productivity and Activity Impairment Questionnaire (WPAI-GPP, a GPP-specific version) is used to measure the efficacy of the subject's response to treatment with anti-IL-36R antibody or its antigen-binding moiety. WPAI-GPP is a GPP-specific version of a frequently used questionnaire in which six questions assess social functioning regarding absence, attendance disorder, and impairment of daily activities. Response options include hours of work and absence (due to GPP and due to unrelated reasons) and a numerical rating scale (0 to 10) assessing impairment of work and daily activities caused by GPP. The recall period is 7 days. As mentioned in the study, the WPAI-GPP tool was measured at weeks 1, 12, 36, and 48 (see flowchart of the study activities in the examples below).

[0156] In one embodiment related to the above embodiments, the present invention provides a method for treating a subject with generalized pustular psoriasis (GPP), including methods for treating and preventing hot flashes, the subject having a history of GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria, wherein the efficacy of the subject's response to treatment with anti-IL-36R antibody or its antigen-binding moiety is measured using a Visual Analog Scale for Pain (VAS). VAS 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 ArthritisCare Res (Hoboken) 2011;63(Supplement 11):S240-S252). It is a continuous scale containing horizontal or vertical lines, typically 10 cm (100) long. The pain VAS (Various Anxiety Scale) was anchored by a descriptive phrase ('no pain', 'extreme pain') at each end. The pain VAS was self-assessed by the responder. The responder was asked to place a vertical (|) marker on a horizontal line to indicate the severity of pain. Using a ruler, the score was determined by measuring the distance (mm) between the "no pain" anchor and the patient's marker on a 10-cm line, providing a score range of 0 to 100. Higher scores indicate greater pain intensity. The pain VAS was measured at weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48, as mentioned in the study (see flowchart of the study activities in the example below).

[0157] In another embodiment related to the above embodiments, the present invention provides a treatment for a subject with generalized pustular psoriasis (GPP), including methods for treating and preventing hot flashes, the subject having a history of GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria, wherein the efficacy of the subject's response to treatment with anti-IL-36R antibody or its antigen-binding portion is measured as a reduced risk of worsening of the subject's Dermatology Quality of Life Index (DLQI) score, wherein a high score (i.e., impaired quality of life) and (more) low scores (i.e., no or minimal impairment of quality of life). The risk reduction results in the DLQI score remaining at baseline at the start of treatment and / or decreasing from a higher score to a lower score after the start of treatment up to week 48, defined as an increase of 4 points in the total score relative to baseline. The Dermatology Life Quality Index (DLQI) is a ten-question quality of life questionnaire administered to patients, covering six domains: symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment (Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) - a simple practical measure for routine clinical use. Joint Ann Mtgof the British Association of Dermatologists and the Canadian Dermatology Association, Oxford, July 6–10, 1993. Clin Exp Dermatol 1994; 19:210–216). The DLQI has a one-week recall period. Response categories include “not relevant” (score 0), “not at all” (score 0), “a little” (score 1), “a lot” (score 2), and “very much” (score 3). Question 7 is a yes / no question, with “yes” scored as 3. The total DLQI score is calculated by summing the scores of all questions that generate a score ranging from 0 to 30. The higher the score, the more severe the impairment of quality of life. As mentioned in the study, the DLQI tool was measured at weeks 1, 4, 8, 12, 24, 36, and 48 (see flowchart of the study activities in the example below).

[0158] In another embodiment related to the above embodiments, the present invention provides a method for treating generalized pustular psoriasis (GPP) in a subject, including methods for treating and preventing hot flashes, the subject having a history of GPP symptoms and / or a history of GPP diagnosis determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria, wherein the efficacy of the subject's response to treatment with anti-IL-36R antibody or its antigen-binding moiety is measured by the JDA GPP severity score. The JDA GPP severity score is established by the Japanese Dermatological Association (JDA) and consists of an assessment / testing of skin symptoms and systemic symptoms. Skin symptoms (total area of ​​erythema, area of ​​erythema with pustules, and area of ​​edema) were rated from 0 to 3, and systemic symptoms / laboratory results (fever, WBC count, CRP, and serum albumin) were rated from 0 to 2 (Cosentyx subcutaneous injection 150 mg, subcutaneous injection 150 mg (secukinumab) (Novartis), Rx 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 JDA severity index for GPP was designated as a score from 0 to 17 (0 = best, 17 = worst), where clinical improvement was defined as a decrease in the risk of worsening of the total JDA severity index of the GPP score from the start of treatment up to week 48, defined as an increase in the total score relative to baseline. As mentioned in the study, JDA GPP severity scores were measured at weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48, and at 16 weeks after the last dose (see flowchart of study activities in the example below).

[0159] In another embodiment related to the above embodiments, the present invention provides a method for treating generalized pustular psoriasis (GPP) in a subject, including methods for treating and preventing hot flashes, the subject having a history of GPP symptoms and / or a history of GPP diagnosis determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria, wherein the efficacy of the subject's response to treatment with an anti-IL-36R antibody or its antigen-binding moiety is measured by CGI-I improvement according to the JDA Severity Index (ibid.). CGI-I is an observer-rated scale that measures overall disease improvement (CGI-I - according to the JDA Severity Index guidelines) (ibid.). It is categorized as “worsening,” “no change,” “minimal improvement,” “significant improvement,” or “very significant improvement.” As mentioned in the study, CGI-I testing was performed at weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48, and at week 16 after the last dose (see flowchart of study activities in the examples below).

[0160] In another embodiment related to the above embodiments, the present invention provides a method for treating generalized pustular psoriasis (GPP) in a subject, including methods for treating and preventing hot flashes, the subject having a history of GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria, wherein the efficacy of the subject's response to treatment with anti-IL-36R antibody or its antigen-binding fraction is measured by a Target Plaque Severity Score (TPSS). The Target Plaque Severity Score (TPSS) is measured in patients with concurrent plaque psoriasis if a corresponding target lesion area is identified and meets the severity thresholds described below. At baseline, the investigator selects a target lesion of at least 9 cm² with a TPSS ≥5 and an induration subscale score ≥2. At baseline and subsequent consultations, the investigator assesses the severity of erythema, desquamation, and induration (plaque thickness) of this selected target lesion on a 5-point scale ranging from 0 = none to 4 = very pronounced. As mentioned in the study, TPSS was measured at weeks 1, 4, 16, 20, 24, and 48 (see flowchart of the study activities in the example below).

[0161] In another embodiment related to the above embodiments, the present invention provides a method for treating generalized pustular psoriasis (GPP) in a subject, including methods for treating and preventing hot flashes, the subject having a history of GPP symptoms and / or a history of GPP diagnosis determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria, wherein the efficacy of the subject's response to treatment with anti-IL-36R antibody or its antigen-binding moiety is measured by Patient Global Impression of Severity (PGI-S). PGI-S is a single self-assessment of the current severity of the disease. Patients are asked to rate the severity of their generalized pustular psoriasis (GPP) on a 5-point scale ranging from “normal” to “extremely severe”. As mentioned in the study, PGI-S was measured at weeks 1, 4, 8, 12, 24, 36, and 48 (see flowchart of study activities in the examples below).

[0162] In another embodiment related to the above embodiments, the present invention provides a method for treating generalized pustular psoriasis (GPP) in a subject, including methods for treating and preventing hot flashes, the subject having a history of GPP symptoms and / or a history of GPP diagnosis determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria, wherein the efficacy of the subject's response to treatment with anti-IL-36R antibody or its antigen-binding moiety is measured by Patient Global Impression of Change (PGI-C). PGI-C is a single self-assessment of how the patient feels their generalized pustular psoriasis (GPP) has changed since the start of the trial. Patients are asked to rate their perceived changes on a 7-point scale ranging from “significantly improved” to “significantly worsened.” As mentioned in the study, PGI-C was measured at weeks 1, 4, 8, 12, 24, 36, and 48 (see flowchart of the study activities in the examples below).

[0163] In another embodiment related to the above embodiments, for one or more endpoints, the proportion of subjects responding to anti-IL36R administration was significantly different compared to subjects treated with placebo.

[0164] In one aspect, the present invention relates to a method for prolonging the time to the onset of the first GPP hot red flare in a subject with a history of generalized pustular psoriasis (GPP) and / or diagnosed according to the European Network of Experts on Rare and Severe Psoriasis (ERASPEN) guidelines up to week 48, wherein a GPP hot red flare is defined as a GPPGA pustular subscale score >2 and an increase of ≥2 in the total GPPGA score relative to baseline in a subject with a history of GPP diagnosed according to ERASPEN guidelines, the method comprising administering to the subject one or more doses of an anti-IL-36R antibody as described in any of the aspects of the above embodiments. In one embodiment, the method comprises administering to the subject an effective amount of an anti-IL-36R antibody in one or more subcutaneous doses, which is delivered as a first loading dose of 300 mg to 600 mg of the anti-IL-36R antibody, followed by a maintenance dose of 150 mg to 600 mg of the anti-IL-36R antibody.

[0165] In one aspect, the present invention relates to a method for preventing moderate to severe GPP flare-ups in subjects with a history of GPP diagnosed according to the ERASPEN criteria, following treatment with an anti-IL-36R antibody as described in any of the above embodiments; wherein GPP symptoms include inflammatory lesions, abscesses, GPP-related inflammation (erythema, induration, open ulcers), and / or GPP-related pain.

[0166] In one embodiment relating to any of the above aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of subjects showed clinical improvement at weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 of treatment, as measured by the time to occurrence of a GPP hot red flare (defined as a GPPGA pustular subscore >2 and an increase of ≥2 in the total GPPGA score relative to baseline).

[0167] In one embodiment related to any of the above aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of subjects showed an improvement in the incidence of at least one GPP hot flash at weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 of treatment.

[0168] In one embodiment relating to any of the above aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of subjects showed improvement at weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 of treatment, as measured by the time of the first PSS deterioration (defined as an increase of 4 points in total score relative to baseline).

[0169] In one embodiment related to any of the above aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of subjects showed improvement at weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 of treatment, as measured by the time of the first deterioration in the Dermatology Quality of Life Index (DLQI) (defined as an increase of 4 points in the total score relative to baseline).

[0170] In one embodiment related to any of the above aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of the subjects showed complete remission at weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 of treatment.

[0171] Embodiments of the invention relating to any of the foregoing aspects include evaluating biomarkers to assess changes in generalized pustular psoriasis (GPP) before and after treatment, including a history of treatment and prevention of GPP symptoms, and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria. Serum and skin biopsies are collected at time points indicated in the flowchart for biomarker analysis.

[0172] In embodiments of the invention, skin biopsies were collected before administration of the study drug and at time points during maintenance therapy to assess changes in gene and protein expression levels before and after pesolimumab treatment. Histological assessments of skin thickness, epidermal and dermal appearance were performed before and after treatment and summarized in the overall histopathological score for each subject / time point. Markers assessed by immunohistochemistry included, but were not limited to, K16, Ki67, S100A7, lipocalin 2, β-defensin 2, CD3+ T lymphocytes, CD11+ dendritic cells, IL-17C, IL8, NFκβ, TNFα, IL36γ, IL36R, and neutrophil elastase. The expression of several of these markers was assessed in skin and epidermal tissue. In a related embodiment, serum was collected to assess changes in protein levels of selected IL-36 pathway and GPP disease-specific markers before and after pesolimumab treatment. Biomarker assays of the samples were performed using a segmented approach.

[0173] In embodiments of the invention, skin biopsies were collected at time points before administration of the study drug and during maintenance therapy to assess changes in microRNA expression levels before and after pesolimumab treatment. MicroRNAs (miRNAs) are small non-coding RNA molecules capable of regulating gene expression post-transcriptionally. MicroRNAs assessed by microRNA sequencing include, but are not limited to, miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p, wherein downregulation or upregulation after treatment compared to pre-treatment is associated with a beneficial response to treatment. MicroRNA analysis results from samples of unaffected and diseased skin, as well as serum obtained from GPP patients before and after pesolimumab treatment, were also correlated with clinical outcomes such as GPPASI and GPPGA scores.

[0174] In embodiments of the invention, blood samples are used to assess known GPP mutations, such as IL36RN, CARD14, and AP1S3 genes, caused by GPP. Subsequently, their potential impact on disease activity and / or drug efficacy in the above-mentioned scenarios of clinical trials is evaluated. VI. Mode of Action

[0175] The anti-IL-36R antibody of this invention is a humanized antagonistic monoclonal IgG1 antibody that blocks human IL-36R signaling. The binding of the anti-IL-36R antibody (pesolizumab) to IL-36R prevents subsequent activation of IL-36R via its homologous ligands (IL-36 α, β, and γ) and downstream activation of pro-inflammatory and pro-fibrotic pathways. IL-36R signaling differentiates from the TNF-α, integrin, and IL-23 inhibitory pathways by directly and simultaneously blocking both inflammatory and pro-fibrotic pathways. Human genetic studies have established a close link between IL-36R signaling and skin inflammation. IL-36R is also known as IL-1RL2 and IL-1Rrp2. It has been reported that agonistic IL-36 ligands (α, β, or γ) initiate a signaling cascade by binding to the IL-36 receptor, which subsequently forms a heterodimer with the IL-1 receptor accessory protein (IL-1RAcP). IL-36 antagonist ligands (IL-36RA / IL1F5, IL-38 / ILF10) inhibit signal transduction cascades.

[0176] As described herein, the anti-IL-36R antibody of the present invention has been evaluated and demonstrated to be effective in treating subjects with acute generalized pustular psoriasis (GPP), a severe inflammatory skin disease driven by uncontrolled IL36 activity. In the EFFISAYIL™-1, a randomized, double-blind, placebo-controlled clinical trial demonstrated the efficacy and safety of the anti-IL36R antibody SPEVIGO® in adult patients with red flare-like episodes of generalized pustular psoriasis (GPP) diagnosed according to the European Rare and Severe Psoriasis Specialists Network (ERASPEN) guidelines. At week 1, compared with placebo, there was a statistically significant difference in the proportion of patients achieving a GPGA pustular subscale score of 0 (indicating no visible pustules) and a GPPGA total score of 0 or 1 (cleared or nearly cleared skin) in the SPEVIGO® treatment group. The results of the clinical trials EFFISAYIL™-1 (NCT03782792) and EFFISAYIL™-ON (NCT03886246) (open-label extension) are incorporated herein by reference in full. VII. Products

[0177] In another aspect, this includes articles containing substances suitable for treating the conditions described above. The articles include containers and labels. Suitable containers include, for example, bottles, vials, syringes, and test tubes (e.g., to contain unit dosage forms). Containers can be formed from various materials, such as glass or plastic. The container holds the composition effectively treating the condition and may have a sterile dispensing port. For example, the container may be an intravenous solution bag or vial with a stopper that can be punctured by a subcutaneous needle. The active agent in the composition is a humanized anti-IL-36R antibody. A label on or associated with the container indicates that the composition is used to treat the selected condition. The articles may further include a second container containing pharmaceutically acceptable buffers, such as phosphate-buffered saline, Ringer's solution, and dextran solution. The articles may further include other substances desirable from a commercial and user's point of view, including other buffers, diluents, filters, needles, syringes, and instructions for use.

[0178] The term "packaging insert" refers to the instruction leaflet typically included in the commercial packaging of a therapeutic product, which contains information about indications, usage, application, contraindications, and / or warnings about the use of such therapeutic products.

[0179] The present invention is further described in the following examples, which are not intended to limit the scope of the invention. Those skilled in the art will recognize or be able to identify many equivalents of the particular substances and procedures described herein.

[0180] In one embodiment, the present invention provides a pharmaceutical composition formulated in unit dose form, wherein such single dose form comprises at least 150 mg, 300 mg, 450 mg, or 600 mg of the anti-IL-36R antibody. In a related embodiment, the unit dose form is used to prepare a medicament for treating subjects with generalized pustular psoriasis (GPP), including treating and preventing hot flashes in subjects with a history of GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria. In a related embodiment, the unit dose form is used to prepare an agent for treating subjects with generalized pustular psoriasis (GPP) who have a history of GPP but have not experienced hot flashes. In a related embodiment, the unit dose form is used to prepare a medicament for reducing the occurrence, recurrence, and / or frequency of hot flashes of generalized pustular psoriasis (GPP) in subjects with a history of GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria.

[0181] In one embodiment associated with any of the foregoing embodiments, the unit dose is in a non-enteric (e.g., intravenous or subcutaneous) dose form, preferably in a subcutaneous dose form.

[0182] In one relevant embodiment, the present invention provides a pharmaceutical formulation (or the “article” described below) comprising: one, two, three, or four of the said unit dose forms containing 150 mg of the anti-IL-36R antibody; one, two, three, or four of the said unit dose forms containing 300 mg of the anti-IL-36R antibody; or one, two, three, or four of the said unit dose forms containing 450 mg of the anti-IL-36R antibody; or one, two, three, or four of the said unit dose forms containing 600 mg of the anti-IL-36R antibody; or any combination thereof, to achieve an effective dose.

[0183] In one relevant embodiment, one, two, three, or four of the unit dose forms (e.g., in a pharmaceutical formulation) are administered as a first loading dose of 300 mg to 600 mg of the anti-IL-36R antibody; subsequently, after the last maintenance dose, a maintenance dose of 150 mg to 600 mg of the anti-IL-36R antibody is administered to the subject at intervals of 4 weeks (q4w) or 12 weeks (q12w) for 8 to 48 weeks. Example

[0184] Standard treatment guidelines for GPP generally follow those for plaque psoriasis, although there is limited evidence demonstrating the efficacy of anti-psoriatic drugs, including biologics, in GPP (Gooderham MJ, Van Voorhees AS, Lebwohl MG. An update on generalized pustular psoriasis. Expert Rev ClinImmunol. 2019;15(9):907-19).In Japan and Thailand, several biologics targeting pro-inflammatory pathways associated with GPP have been approved for patient use. In Taiwan, several biologics targeting pro-inflammatory pathways associated with GPP have also 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 with a small number 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. AmJ Clin Dermatol. 2020;21(2):227-36; Thailand Food and Drug Administration. LUMICEF Summary of Product Characteristics). 2019; Taiwan Center for DrugEvaluation (CHINA). Lumicef subcutaneous injection 210 mg syringe 201; MoritaA, 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).

[0185] In an open-label, proof-of-concept study (NCT02978690), patients experiencing GPP hot red attacks achieved complete or near-complete clearance by week 4 following a single dose of pesolizumab (a 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 study (NCT03782792) was the first randomized clinical trial to investigate targeted therapy for GPP, and pesolimab was reported to achieve rapid pustule and skin clearance in adult patients with GPP hot red flare-ups (Bachelez H, Choon SE, Marrakchi S, Burden AD, Tsai TF, Morita A et al., Trialof spesolimab for generalized pustular psoriasis. N Engl J Med. 2021;385(26):2431-40). The results of this study are an important part of the FDA-approved pesolimab as a first-line treatment option for GPP hot red flare-ups.The recurrent nature of GPP (recurrent pustular psoriasis flares or persistent disease with intermittent pustular psoriasis flares) highlights the need to develop treatments to prevent pustular psoriasis flares (Navarini AA, Burden AD, Capon F, Mrowietz U, Puig L, Ko¨ks S et al., European consensus statement on phenotypes of pustular psoriasis. J Eur Acad Dermatol Venereol. 2017;31(11):1792-9), in which a recent survey revealed that among dermatologists whose patients frequently experience pustular psoriasis flares, 67% felt that currently available treatments were insufficient to prevent new pustular psoriasis 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).

[0186] 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 pexolimab in preventing red flare-ups of generalized pustular psoriasis (GPP) in subjects with a history of GPP compared to placebo. Effisayil™ 2 was the first study to explore the use of an antibody targeting the interleukin-36 receptor for the prevention of red flare-ups in GPP. This was a key step in evaluating the efficacy of pexolimab in intermittent, recurrent red flare-ups and determined the optimal dosing regimen for pexolimab maintenance therapy.

[0187] TargetEFFASIYL™-2 (NCT04399837) evaluates the efficacy and safety of subcutaneous administration of pexolimab in adult and adolescent subjects with a history of GPP diagnosed according to the ERASPEN criteria (regardless of IL36RN mutation status) and at least two previous moderate to severe GPP hot flashes. Subjects were required to discontinue systemic and local GPP therapy before or at the time of randomization. These subjects had a history of hot flashes during or after receiving concomitant therapy for GPP.

[0188] The primary objective was to confirm non-uniform curves characterizing the dose-response relationship of three subcutaneous dosing regimens of pesolizumab (each regimen including a single loading dose and a separate maintenance subcutaneous dosing regimen) compared to placebo in subjects with a history of GPP (according to the ERASPEN criteria) and a GPPGA score (at screening and randomization) of 0 or 1 (clean or nearly clean). The primary endpoint was the time to the first GPP hot red episode up to week 48.

[0189] The primary endpoint of the study was the time to the first GPP hot red episode by week 48 (defined as a GPPGA pustular subscale score >2 and a total GPPGA score increase of ≥2 from baseline). The key secondary endpoint was the incidence of at least one GPP hot red episode by week 48, i.e., how long it took for a subject to experience a GPP hot red episode while receiving pesolimumab or placebo. Other secondary endpoints at week 48 included the time to the first worsening of the PSS and Dermatology Quality of Life Index (DLQI), defined as a total score increase of 4 points from baseline.

[0190] Overall Design A randomized, multicenter, parallel-group, double-blind, placebo-controlled phase IIb study included three effective doses compared to placebo in adolescents and adults aged 12 years and older to under 18 years of age with a history of GPP and currently presenting a GPPGA score of 0 or 1 (clean or nearly clean) at screening and randomization. The effective treatment group consisted of an effective loading dose and effective maintenance therapy.

[0191] A total of 123 eligible participants with generalized pustular psoriasis (GPP) were randomly assigned in a 1:1:1:1 ratio to either placebo, low, moderate, or high treatment groups. (Figure 1) Table 2 Treatment groups of EFFASIYL™ 2

[0192] All subjects received the first dose of the study drug on day 1. Subjects in each randomized group received four injections (loading dose) on week 1 / day 1, followed by two injections (maintenance therapy) at subsequent follow-up visits until week 44 (if no hot flashes occurred). Maintenance therapy ended at week 48.

[0193] Preliminary statistical analysis of the trial was conducted immediately after all randomized subjects had completed or prematurely discontinued the 48-week maintenance therapy period.

[0194] Inclusion criteria: The primary diagnosis for inclusion in the trial included individuals aged ≥12 years and ≤75 years with a history of GPP (diagnosis) as defined by the consensus diagnostic criteria of ERASPEN, and subjects must have previously presented with fever, and / or fatigue, and / or myalgia, and / or elevated C-reactive protein, and / or signs of peripheral blood leukocytosis (above ULN) with neutrophilia (for past GPP hot red episodes). The ERASPEN diagnostic criteria were: primary, sterile, macroscopically visible pustules on non-acral skin (excluding cases where the pustules are confined to psoriatic plaques), i) with or without systemic inflammation; ii) with or without plaque psoriasis; and iii) recurrent (>1 episode) or persistent (>3 months).

[0195] Each participant met all of the following inclusion criteria for inclusion in the trial: • Subjects must have a known and documented history of GPP according to the ERASPEN criteria (regardless of IL36RN mutation status) and have presented with at least two previous episodes of GPP hot red with fresh pustules (new or worsening). • Subjects had a GPPGA score of 0 or 1 during screening and randomization. • Subjects who were not receiving concomitant GPP therapy at randomization (V2) must have presented with at least two GPP hot red episodes in the past year, at least one of which was accompanied by fever and / or elevated CRP and / or elevated WBC, and / or signs of weakness and / or myalgia. • Subjects who did not receive concomitant GPP therapy at randomization (V2) but received concomitant GPP therapy shortly before randomization (≤12 weeks prior to randomization) must have had a history of hot flashes when receiving concomitant GPP therapy or when their concomitant medication was reduced or discontinued. • Subjects receiving concomitant therapy regimens with retinoids and / or methotrexate and / or cyclosporine must discontinue these regimens on the day of randomization (V2). These subjects must have a history of hot flashes when receiving concomitant therapy with GPP or when these concomitant medications are reduced or discontinued. • Male or female participants were aged 12 to 75 years at the time of screening. All participants were required to have a minimum weight of 40 kg. • Before being allowed to participate in the trial, a written informed consent form must be signed and dated in accordance with ICH-GCP and local regulations. • Women of childbearing potential (WOCBP)1 must be prepared and able to use a highly effective method of contraception according to ICH M3 (R2) that results in a low failure rate of less than 1% per year when used consistently and appropriately. A list of contraceptive methods that meet these guidelines is provided in the CTP and in the information of the subject, parents (or legal guardians) of the subject.

[0196] Exclusion criteria: • The subject had synovitis acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome. • The subject had primary erythrodermic psoriasis vulgaris. • Severe, progressive, or uncontrolled liver disease, defined as an increase of more than 3 times the upper limit of normal (ULN) for AST, ALT, or alkaline phosphatase, or an increase of more than 2 times the ULN for total bilirubin. • Treatment with the following: a. Any restricted medications as specified in the CTP, or any medications that the investigator assesses may interfere with the safe execution of the study. b. Any prior exposure to pesolimumab or another IL36R biological inhibitor. • As assessed by researchers, there is an increased risk of infectious complications (e.g., recent purulent infections, any congenital or acquired immunodeficiency (e.g., HIV), or past organ or stem cell transplants). • Subjects had a relevant chronic or acute infection at the time of randomization, including active tuberculosis, HIV infection, or viral hepatitis. Subjects may be re-screened if they received treatment for and recovered from an acute infection. • Active or latent TB. • A history of allergy / hypersensitivity to the test drug or its excipients administered systemically. • Any documented history of active or suspected malignant disease or malignant disease within 5 years prior to screening, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been appropriately treated. • Currently recruited to another investigational device or drug study, or having completed less than 30 days of another investigational device or drug study, or currently receiving other investigational treatments. Exception: Subjects who are in the screening phase of study 1368-0013, or who were not randomized in trial 1368-0013 due to reaching the target number of randomized subjects in that study, or who do not meet the criteria for randomization to study 1368-0013, may be recruited to study 1368-0027. • Women who are pregnant, breastfeeding, or planning to become pregnant during the trial. Women who stopped breastfeeding before the administration of the study drug do not need to be excluded from the participation; they should avoid breastfeeding for 16 weeks after the last administration of the study drug. • Major surgery performed or planned during the study, as assessed by the investigator, such as hip replacement, aneurysm removal, or gastric ligation, within 12 weeks prior to receiving the first dose of the study drug. • Current or prior medical conditions other than GPP (including chronic alcohol or drug abuse or congestive heart disease or any condition), surgical procedures, psychiatric or social problems, medical findings (including vital signs and electrocardiogram (ECG)), or evidence of laboratory values ​​outside the reference range at the time of screening that are clinically significant in the researchers' view and would prevent study participants from reliably following the protocol, adhering to all study consultations / procedures, or completing the trial, or that the subject has SAPHO (synovitis, acne, pustular, osteophyte, osteitis) syndrome. • The subject had primary erythrodermic psoriasis vulgaris. • Severe, progressive, or uncontrolled liver disease, defined as an increase of more than 3 times the upper limit of normal (ULN) for AST, ALT, or alkaline phosphatase, or an increase of more than 2 times the ULN for total bilirubin. • Treatment with the following: a. Any restricted medications as specified in the CTP, or any medications that the investigator assesses may interfere with the safe execution of the study. b. Any prior exposure to pesolimumab or another IL36R biological inhibitor.

[0197] Example 2: The treatment applied

[0198] Pesolimab is a heterodimer of a monoclonal antibody against the human IL-36 receptor with a molecular weight of approximately 146 kDa. Pesolimab solution for injection (subcutaneous administration) is prepared at 150 mg / mL and presented in a 1 mL pre-filled syringe (150 mg / syringe). Pesolimab solution for infusion (intravenous administration) is prepared at 60 mg / mL and presented in a 10 mL vial (450 mg) with a nominal fill volume of 7.5 mL. Table 3: Test Product: Spesolimab Dosage and administration regimen:

[0199] The current objective of the Effisayil™ 2 trial is to provide dose range data for three subcutaneous dosing regimens of pesolimumab, with proposed doses of 300 mg subcutaneously every 4 weeks and 12 weeks after a 600 mg loading dose, and 150 mg every 12 weeks after a 300 mg loading dose. These regimens were selected to assess a broad range of exposures to adequately evaluate the exposure-response relationship of pesolimumab in GPP subjects.

[0200] If a subject experiences a GPP hot red attack (a ≥2 increase in GPPGA score relative to baseline and a ≥2 pustular component of GPPGA) during the randomization maintenance therapy period, a 900 mg intravenous open-label dose of pesolimumab is administered on day 1 (R1 / D1) for GPP hot red attack treatment. If the criteria specified in the protocol are met, the subject is eligible to receive another 900 mg intravenous open-label dose of pesolimumab on day 8 (R3 / D8). The 900 mg intravenous dose of pesolimumab is selected based on positive results from previous trials in subjects and healthy volunteers, indicating that pesolimumab is safe and tolerable, and within the safety limits for subjects with lower body weight.

[0201] To maintain the blinded treatment, all subjects received blinded treatment once every 4 weeks. Table 4: Loading dose and maintenance therapy of anti-IL36R antibody pesolimumab

[0202] Example 3:

[0203] Table 5: Flowchart of Research-Related Activities ADA, Anti-drug Antibody; C, Comprehensive Physical Examination; CGI-I, Clinical Global Impression - Improvement; d, Day; DLQI, Dermatology Quality of Life Index; ECG, Electrocardiogram; EoS, Study End; EQ-5D-5L, EuroQoL 5 Dimensions 5 Levels; GPPASI, Generalized Pustular Psoriasis Area and Severity Index; GPPGA, Generalized Pustular Psoriasis Physician Global Assessment; HCRU, Healthcare Resource Utilization; IHC, Immunohistocompatibility Complex; IRT, Interactive Response Technology; JDA, Japanese Society of Dermatology; Nab, Neutralizing Antibody; PGI-C, Changes in Patient Global Impression; PGI-S, Severity of Patient Global Impression; PK, Pharmacokinetics; OLE, Open Label Expansion; PRO, Patient Reported Outcome; PSS, Psoriasis Symptom Scale; RNASeq, RNA Sequencing; S, Serum; T, Targeted Physical Examination; TPSS, Targeted Plaque Severity Score; U, Urine; V, Medical History; VAS, Visual Analogue Scale; 1 a) Infection testing includes assessments for tuberculosis, hepatitis B, hepatitis C, and HIV. For patients who signed informed consent ≥4 weeks prior to V2, repeat infection testing should have been conducted 2 to 4 weeks prior to V2. 2 If available, obtain the IL36RN mutation status from the patient's historical data. 3 Physical examination: C = comprehensive, T = specific. 4 Vital signs: a) On non-study drug administration days, vital signs should be assessed before blood sampling; b) On study drug administration days, vital signs should be assessed before administration (before blood sampling), 10 minutes after administration, and at the second and third consultations, with additional measurements taken approximately 60 minutes after administration (i.e., 60 minutes after the last injection). 5 Only applicable to women of childbearing potential. S - Serum pregnancy test (performed at screening). U - Urine pregnancy test performed at all other designated consultations. A urine pregnancy test should have been performed before administration of the study drug. The study drug is administered only if the test result is negative. In the case of a positive urine pregnancy test, a serum pregnancy (S) test is performed (via a central laboratory) and administration of the study drug is postponed until a negative serum pregnancy test result is available. 6 ECG measurements should always be performed before blood sampling and medication administration. 7Collection of samples for the DNA biobank is optional. Participating patients are required to provide informed consent specifically for the biobank. Only one blood sample is required for the DNA biobank, preferably at the second consultation (randomized). However, collection at a later consultation is permitted as long as the biobank's informed consent remains valid. 8 Safety laboratory tests include clinical chemistry, hematology, coagulation, and urinalysis, and are conducted in a concentrated manner. 9 Before performing a skin biopsy and administering investigational drugs, photographs of the skin / skin lesions should be taken. 10 Collecting serum biobank samples is optional. Participating patients are required to provide informed consent specifically for the biobank. Samples will be stored at the biobank facility for future research. 11 a) Patients should complete these measurements independently without any assistance or interpretation from others. If a patient is too ill to complete the questionnaire independently but is able to respond verbally, a member of the research team should read the instructions, questions, and response options aloud to the patient in the most neutral and unbiased manner possible and collect the patient's verbal responses. If this is not feasible, the questionnaire cannot be completed. The recommended order of completion for PROs is as follows: PSS; DLQI; Pain VAS; EQ-5D-5L; WPAI-GPP; SF-36; PGI-S and PGI-C. b) DLQI, EQ-5D-5L, PGI-S, and PGI-C should only be completed during consultations at V2, V3, V4, V5, V8, V11, and V14 / EoS1. c) SF-36 and WPAI-GPP should only be completed during consultations at V2, V5, V8, V11, and V14 / EoS1. d) For PROs performed by adolescent patients, please refer to section 6.2 for further guidance and details (see CTP, Appendix 16.1.1). 12 HCRU (Health Care Resource Utilization) data reports include the number of hospitalizations and length of stay, as well as the number of outpatient and emergency room visits (if applicable). Data should have been collected for the period since the most recent visit. 13 Local tolerability at the application site of pesolimumab / placebo (subcutaneous) should be assessed retrospectively since the most recent medical visit during study drug administration and during adverse event (AE) assessment. Any observed local tolerability reactions, such as swelling, induration, fever, redness, pain, and other findings, should be reported as adverse events. 14V14 records the study exit interview (i.e., EoS1) for patients who met the eligibility criteria and agreed to enroll in the OLE trial (1368-0025). V14 records the study exit interview (EoS1) for patients who discontinued their last treatment dose early up to day 232 and agreed to complete all remaining study interviews from randomization up to week 48. Because these patients discontinued their treatment early, they were ineligible to enroll in the OLE trial. 15 EoS2 consultation is for patients who are ineligible or do not agree to participate in the OLE trial at week 48 (1368-0025). EoS2 is also for patients who discontinued their last treatment dose after day 232. These patients are ineligible for participation in the OLE trial because of their early discontinuation. 16 Skin biopsies should be performed as needed and only in patients who have consented to the procedure. V2 and V14 skin biopsies (optional): One 5 mm puncture skin biopsy (split in half for IHC and RNASeq) should be collected prior to administration of the study drug. 17 Only applicable to patients with concurrent plaque psoriasis, capturing the Target Plaque Severity Score (TPSS). 18 This applies only if an infection test was not performed during a V14 / EoS1 consultation. 19 The vital signs of patients who were discharged early from day 232 on day V14 and who agreed to further contact but did not agree to a physical consultation were collected. 20 The vital signs of patients who discontinued their last treatment dose early after day 232 and agreed to further contact but did not agree to a physical consultation were collected at V15. 21 Patients are expected to register for IRT once at the end of the study (where appropriate).

[0204] Example 4: Subject demographics and relevant baseline efficacy parameters

[0205] The study population consisted of 38.2% males and 61.8% females. The mean age was 40.4 years (range: 14–75) years, including 8 (6.5%) adolescent subjects (2 per treatment group); 64.2% of the subjects were Asian and 35.8% were Caucasian (Table 6). The GPPGA pustular subscale score of the subjects included in the study was 1 (28.5%) or 0 (71.5%), and the total GPPGA score of the subjects was 1 (86.2%) or 0 (13.8%). At randomization, 74.8% of the subjects were treated with systemic GPP therapy, which was discontinued at the start of treatment in the randomization study.

[0206] Given the genetic, ethnic, and geographic heterogeneity in the incidence and severity of GPP, it is important to investigate the efficacy of treatment in specific patient populations. For example, a higher incidence of interleukin-36 mutations in Asian populations has previously been found to be associated with higher overall disease severity. A post-hoc analysis from the Effisayil® 2 study showed that pexolimab had a similar effect in preventing heat-related attacks between Asian and general populations. Table 6. Current demographic data and baseline characteristics of heatstroke. Results categorized as “Unspecified,” “Unknown,” or “Missing” are provided in the source table. BMI: Body Mass Index; ESRD: End-Stage Renal Disease. 1 Renal function is classified based on the estimated CLCR calculated using the CKD-EPI formula: normal renal function; (Stage 1) ≥90 mL / min / 1.73 m2, mildly decreased GFR; (Stage 2) = 60 to 89 mL / min / 1.73 m2, moderately decreased GFR; (Stage 3) = 30 to 59 mL / min / 1.73 m2, severely decreased GFR; (Stage 4) = 15 to 29 mL / min / 1.73 m2, end-stage renal disease; (Stage 5) = <15 mL / min / 1.73 m2, not receiving dialysis or requiring dialysis. For adolescents, the Bedside Schwartz Equation is used. 2 Defined as an international normalized ratio ≥2.2 and total serum bilirubin >51.3 μmol / L; see TSAP 3 Concurrent plaque psoriasis means that the subject had plaque psoriasis during the previous year and the condition persisted at baseline.

[0207] In accordance with the inclusion criteria, all subjects had a baseline GPPGA total score of 0 (complete clearance; 13.8%) or 1 (nearly complete clearance; 86.2%). All subjects had a GPPGA pustular subscale score of 0 (71.5%) or 1 (28.5%). At baseline, the mean (SD) of the PSS total score was 4.2 (3.4), the DLQI total score was 8.1 (6.4), and the GPPASI total score was 3.29 (3.74). Baseline efficacy variables were generally similar between treatment groups. However, there were indications that subjects in the high-dose pesoribumab group had a higher disease burden compared to the placebo group. The mean total PSS score (SD) in the high-dose pesolimab group was 5.3 (3.8) and in the placebo group was 3.6 (2.9); the total DLQI score in the high-dose pesolimab group was 11.1 (6.9) and in the placebo group was 7.2 (5.6); the total GPPASI score in the high-dose pesolimab group was 3.92 (4.42) and in the placebo group was 3.11 (2.81). Table 7: Baseline GPPGA, GPPASI, PS and DLQI scores and JDA GPP severity index. Patients under the age of 16 (i.e., 12 to 15 years old) do not need to complete the DLQI questionnaire.

[0208] In this trial, DNA sequencing of the IL-36RN, CARD14, and AP1S3 genes was performed. It was reported that 22.8% of the participants had potentially pathogenic IL36RN variants (with amino acid substitutions), and this was lower in the placebo group (12.9%) than in the pesolimumab group (low 22.6%, moderate 32.3%, high 23.3%). Otherwise, gene mutations were generally similar between the treatment groups.

[0209] Most participants received their first GPP diagnosis more than 5 years prior to randomization. Clinical examination was the most common method of diagnosis, followed by skin biopsy and histopathological confirmation. The median number of heat-related episodes per year (Q1, Q3) was 2.0 (1.0, 3.0), with a maximum of 12. These data were generally similar between treatment groups (Table 8 below). Table 8: Medical History of GPP

[0210] Eighty participants (65.0%) reported a current or past history of psoriasis, and ten participants (8.1%) reported arthritis; 34 participants (27.6%) reported persistent chronic plaque psoriasis. Overall, 74.0% of all participants had at least one baseline condition / history. The most common dictionary-derived terms were hypertension, psoriasis, and obesity.

[0211] Overall, 93.5% of participants had a history of using at least one GPP medication (i.e., had discontinued a GPP medication prior to screening). The most commonly used historical medications under the preferred nomenclature level were atratine, methotrexate, and cyclosporine. The most common systemic GPP medications at randomization were atratine, cyclosporine, and methotrexate. These medications were used within 4 weeks prior to randomization or at the time of randomization and were discontinued before the start of treatment in the randomized study.

[0212] In this trial, all 123 subjects who were randomized received at least one dose of the study drug. The mean duration of exposure (SD) during the maintenance therapy period was greater in the pesolimumab dose groups (low dose: 33.9 [18.2] weeks, intermediate dose: 31.9 [18.5] weeks, high dose: 33.1 [18.2] weeks) compared to the placebo group (25.4 [20.8] weeks). A total of 32 subjects received intravenous pesolimumab for the treatment of hot flashes; of these subjects, 22 (68.8%) received a single 900 mg intravenous dose and 10 (31.3%) received two 900 mg intravenous pesolimumab doses (double dose). Of the 20 subjects who continued open-label (OL) maintenance therapy with pesolimumab subcutaneously after treatment for heat rash, 11 subjects (55.0%) remained on the 300 mg subcutaneous q12w dosing regimen and 9 subjects (45.0%) were escalated to the 300 mg subcutaneous q4w dosing regimen. Throughout the study, the mean (SD) duration of exposure was 39.3 (11.2) weeks for subjects initially randomized to placebo, 37.1 (15.0) weeks for subjects initially randomized to low-dose pesolimumab, 38.3 (12.9) weeks for subjects initially randomized to intermediate-dose pesolimumab, and 34.6 (17.1) weeks for subjects initially randomized to high-dose pesolimumab.

[0213] Example 5: Efficacy: Primary and secondary objectives

[0214] Overview:

[0215] For the primary objective, a non-fixed dose-response relationship was confirmed. Subsequently, confirmatory tests were performed for secondary objectives. Based on the primary endpoint and key secondary endpoints, high-dose pesolimumab demonstrated statistically significant efficacy compared to placebo.

[0216] Main objectives: By week 48 of the trial, a total of 35 patients experienced GPP hot red attacks; fewer patients experienced GPP hot red attacks in the low-dose (7, 22.6%), intermediate-dose (9, 29.0%), and high-dose (3, 10.0%) pesolimumab groups compared to the placebo group (16, 51.6%; Figure 2A). A non-fixed dose-response relationship between pesolimumab and placebo was established, with statistically significant p-values ​​for each predefined model (P = 0.002 for linear, emax1, and emax2 models; P = 0.003 for exponential models); thus, the primary trial objective was achieved. Table 9. Time to first GPP hot red episode up to 48 weeks and incidence of GPP hot red episodes GPP hot red episode criteria: An increase of ≥2 in the GPPGA score relative to baseline and a ≥2 in the GPPGA pustular sub-score up to week 48. Treatment with intravenous pesolimumab as an emergency medication or investigator-prescribed standard of care (SoC) to treat GPP exacerbations is considered a GPP hot red episode. nc, cannot be calculated KM estimate of the time when the endpoint event occurs in 110% of patients 3. Cox regression model for stratification of systemic GPP drugs during randomization 3. Log-rank test for stratification of systemic GPP drugs during randomization

[0217] Secondary objectives Up to week 48, the number of GPP hot red attacks was lower in all subjects in the pesolimab groups compared to the placebo group. Low, intermediate, and high-dose pesolimab regimens numerically reduced the risk of GPP hot red attacks at week 48, with hazard ratios of 0.35 (95% CI, 0.14 to 0.86; nominal P = 0.0057), 0.47 (95% CI, 0.21 to 1.06; P = 0.027), and 0.16 (95% CI, 0.05 to 0.54; P = 0.0005), respectively (Figure 2A). The high-dose pesolimab regimen was statistically significant in reducing the risk of GPP hot red attacks compared to placebo, with an HR of 0.157 (95% CI 0.046, 0.541; p = 0.0005).

[0218] The estimated probability of the first GPP hot red episode between the pexolimab group and placebo was separated starting 4 weeks after randomization and maintained until week 48 (Figure 2B). No hot red episodes were reported in the high-dose group after 4 weeks. Analysis of key secondary endpoints revealed that the risk differences for GPP hot red episodes at 48 weeks between low, intermediate, and high doses of pexolimab and placebo were -0.31 (95% CI, -0.54 to -0.08; nominal P = 0.0068), -0.23 (95% CI, -0.46 to 0.01; nominal P = 0.036), and -0.39 (95% CI, -0.62 to -0.16; P = 0.0013), respectively (Figures 2A and 2C). Using a one-sided α of 0.00625 (adjusted for multiplicity), the high-dose pesolimumab regimen achieved a statistically significant improvement compared to placebo on the key secondary endpoint (P=0.0013).

[0219] Up to week 48, preliminary analysis of the time to first GPP hot flashes in high-dose pesolizumab versus placebo showed overall consistency across subgroups (see Figure 3).

[0220] Example 6: Main efficacy results:

[0221] The purpose of selecting the study endpoint was to determine the efficacy and safety of pesoribumab in preventing GPP flare-ups with maximum statistical power. The systemic aspects of GPP flare-ups were assessed using a metric that included components of the Japanese Society for Dermatology GPP Severity Score, a diagnostic tool developed by the Japanese Ministry of Health to measure the severity of GPP at the time of presentation (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). Measuring a range of patient-reported outcomes (PROs) can provide unique insights into the impact of GPP and trial interventions from the patient's perspective, and PROs are an important factor that dermatologists consider when making treatment decisions for patients with psoriasis (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 OutcomeMeas. 2018; 9:353-67; . Feldman SR, Regnier SA, Chirilov A, Hey F, Gilloteau I, Cella D).Some of these PROs (Psoriasis Symptom Scale, Pain Visual Analogue Scale, Dermatology Quality of Life Index) have been successfully used in the Effisayil™ 1 study (Bachelez H, Choon SE, Marrakchi S, Burden AD, Tsai TF, Morita A et al., Trial of spesolimab for generalized pustularpsoriasis. N Engl J Med. 2021;385(26):2431-40), and also in the Effisayil™ 2 study to assess participants’ health-related quality of life, ability to participate in daily activities, and experience of pain. Table 10: Overview of efficacy endpoints during the maintenance period up to week 48 in randomized groups If a GPP hot flash attack is suspected to occur between scheduled consultations as specified in the protocol, the patient should undergo an unscheduled clinical consultation.

[0222] Main efficacy analysis:

[0223] Treatment efficacy was measured up to week 48, the time to the first flare of generalized pustular psoriasis (GPP) (defined as an increase of ≥2 in the Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score relative to baseline and ≥2 in the pustular component of the GPPGA).

[0224] By week 48, a total of 35 patients experienced GPP hot red attacks. Of these, 32 patients met the GPP hot red attack criteria and all received intravenous olecranon pesolizumab, while 3 patients did not meet the GPP hot red attack criteria but received investigator-specified SoC to treat GPP exacerbations. Compared with the placebo group (16 patients), the number of patients experiencing hot red attacks was lower in the low-dose (7 patients), intermediate-dose (9 patients), and high-dose (3 patients) pesolizumab groups.

[0225] For the primary endpoint, the adjusted p-values ​​for each predefined model (linear, emax1, and emax2 were 0.002; exponential was 0.003) were statistically significant, thus confirming that pesolimumab had a non-fixed dose-response relationship compared to placebo for the primary endpoint.

[0226] For secondary endpoints, in the preliminary analysis, the high dose of pesolizumab was statistically significant compared with placebo in reducing the risk of GPP hot red attacks, with a HR of 0.157 (95% CI 0.046, 0.541; p = 0.0005). The HR for the low dose was 0.350 (95% CI 0.143, 0.857; nominal p = 0.0057) and for the intermediate dose it was 0.468 (95% CI 0.206, 1.064; p = 0.0269). The intermediate dose did not reach statistical significance, and further evaluation was conducted only for the key secondary endpoint of the high dose. The estimated probability of the first GPP hot red attack between the pesolizumab group and the placebo group was separated starting at the first 4 weeks after randomization and maintained until week 48. After 4 weeks, no hot red attacks were reported in the high-dose group (see Figure 2).

[0227] Sensitivity analyses of alternative testing methods or patient analysis sets under the primary estimate, and additional analyses under different estimate outcomes, were consistent with the preliminary analysis. Preliminary analyses of the time to first GPP hot flashes between high-dose pesolizumab and placebo up to week 48 were generally consistent across subgroups.

[0228] Table 11: Time until the first GPP hot red attack occurs up to week 48 and the incidence of GPP hot red attacks GPP hot red onset criteria: An increase of ≥2 in the GPPGA score relative to baseline and a ≥2 in the GPPGA pustular sub-score up to week 48. GPP exacerbation is defined as treatment with intravenous pesolimumab as a GPP hot red onset agent or investigator-prescribed standard of care (SoC). nc, cannot be calculated 1. KM estimate of the time when 10% of the participants experience the endpoint event. 2. Cox regression model for stratification of systemic GPP drugs during randomization 3. Log-rank test for stratification of systemic GPP drugs during randomization

[0229] Secondary efficacy endpoint:

[0230] A. Incidence of at least one GPP hot flash up to week 48:

[0231] Up to week 48, the proportion of patients experiencing at least one GPP hot red episode (defined as a ≥2 increase in GPPGA score relative to baseline and ≥2 pustular components of GPPGA) was lower in all pesolimab groups than in the placebo group. The high-dose pesolimab was statistically significant in reducing the incidence of GPP hot red episodes compared to placebo, with an adjusted risk difference of -0.390 (95% CI -0.621, -0.159; p = 0.0013). The difference between the intermediate-dose pesolimab and placebo did not reach statistical significance (-0.225; 95% CI -0.462, 0.013; nominal p = 0.0358). The low-dose pesolimab had a lower incidence of GPP hot red episodes compared to placebo (-0.308; 95% CI -0.535, -0.081; nominal p = 0.0068). Table 12: Proportion of patients who experienced at least one GPP hot flash up to week 48 Treatment with intravenous pesolimumab as an emergency medication or investigator-prescribed SoC therapy for worsening GPP is considered an attack of GPP hot red. 1 The Cochrane-Mantel-Hensell test was performed after multiple imputation, stratified by systemic GPP medication during randomization.

[0232] The marker analysis showed a lower proportion of patients experiencing hot flashes in the high-dose pesolizumab group compared to placebo, which was evident at week 12 and persisted until week 48 (Figure 4). Preliminary analysis of at least one GPP hot flash in the high-dose pesolizumab group versus placebo group up to week 48 was generally consistent across subgroups (Figure 5). Subgroup outcomes where the risk difference score estimate was not within the 95% CI of the overall analysis were based on a small number of patients and very few endpoint events (Figure 5).

[0233] B. The time until the first worsening of the Psoriasis Symptom Scale (PSS) at week 48:

[0234] The time until the first exacerbation of the Psoriasis Symptom Scale (PSS) at week 48 is defined as an increase of 4 points in the total score relative to baseline. Ingestion of emergency medications or administration of investigator-prescribed SoCs are considered exacerbations.

[0235] Compared with placebo, pesolimumab reduced the risk of PSS progression within 48 weeks, as demonstrated by hazard ratios of 0.46 (95% CI, 0.22 to 0.95; nominal P = 0.0079), 0.56 (95% CI, 0.28 to 1.10; nominal P = 0.052), and 0.42 (95% CI, 0.20 to 0.91; P = 0.013) for the low-, medium-, and high-dose regimens, respectively (Figure 4A). The proportion of patients reporting PSS progression was lower in the low-dose (12 / 31, 38.7%), medium-dose (14 / 31, 45.2%), and high-dose (10 / 30, 33.3%) pesolimumab groups compared to the placebo group (20 / 31, 64.5%) (Figure 4B). The confirmatory test was discontinued because the high-dose regimen did not reach the required significance level of 0.00625. However, the estimated probability of PSS worsening between the pesolimumab group and placebo was separated at the first 8 weeks after randomization and maintained until week 48. Data from the Effisayil™ ON study, an open-label extension of pesolimumab from the Effisayil™ 1 study that received one or two doses of 900 mg intravenously, supports the need for 300 mg q4w administration compared to q12w administration as initial treatment for the prevention of GPP hot red attacks. One-third (33.3% [36 / 108]) of participants who started q12w administration in Effisayil® ON progressed to a q4w regimen (n=24) or experienced a hot red attack (n=12).

[0236] In summary, the results of Effisayil® 2 and Effisayil® ON indicate that pesolizumab LD 600 mg / SC 300 mg q4w is the optimal dosing regimen for the prevention of GPP hot red attacks. Table 13: Time until the first deterioration of PSS in week 48: PSS worsening criteria: An increase of 4 points in the total score relative to baseline up to week 48. GPP worsening is defined as an episode of PSS worsening treated with intravenous pesolimumab as a treatment for GPP hot red episodes or with investigator-prescribed SoC therapy. Patients with missing baseline values ​​on day 1 (one patient in the high-dose pesolimumab group) or scores higher than 12 (maximum score possibly 16; one patient each in the low-dose and high-dose pesolimumab groups) were included. 1 KM estimate of the time when the endpoint event occurs in 25% of patients 2 Cox regression model for stratification of systemic GPP drugs during randomization. 3 Log-rank test for stratification of systemic GPP drugs during randomization.

[0237] C. The time until the first worsening of the Dermatology Quality of Life Index (DLQI) at week 48:

[0238] The time until the first deterioration of the Dermatology Quality of Life Index (DLQI) at week 48 was defined as an increase of 4 points in the total score relative to baseline. Ingestion of emergency medication or administration of investigator-prescribed System of Daily Occurrence (SoC) was considered a deterioration.

[0239] By week 48, a total of 59 patients experienced DLQI worsening. Approximately half (31 patients) met the DLQI worsening criteria (an increase of 4 points from baseline in total score), and only a small number (5 patients) received intravenous pesolimumab for hot red episodes; 27 patients received intravenous pesolimumab, and 1 patient received investigator-specified SoC for GPP worsening despite not meeting the DLQI worsening criteria.

[0240] Regarding the time to the first DLQI exacerbation up to week 48, the number of patients experiencing exacerbations was lower in the low-dose (16 patients), intermediate-dose (16 patients), and high-dose (7 patients) pesolizumab groups than in the placebo group (20 patients). The HR for the low-dose group was 0.580 (95% CI 0.296, 1.136; nominal p = 0.0429), for the intermediate-dose group it was 0.601 (95% CI 0.309, 1.168; nominal p = 0.0476), and for the high-dose group it was 0.259 (95% CI 0.109, 0.620; nominal p = 0.0010) (see Table 14 below).

[0241] The estimated probability of DLQI worsening between the pesolimumab group and placebo was separated starting in the first 8 weeks after randomization. The separation between the high-dose and placebo groups was maintained until week 48, during which no worsening events were reported in the high-dose group after 8 weeks. The number of patients reporting DLQI worsening in all pesolimumab groups was lower than that in the placebo group until week 48 (Figure 4C). Table 14: Time until the first worsening of DLQI in week 48 DLQI worsening criteria: An increase of 4 points in the total score relative to baseline up to week 48. GPP worsening is defined as an episode of DLQI worsening when treated with intravenous pesolimumab as a treatment for GPP hot red episodes or with investigator-prescribed SoC therapy. Patients aged 16 years or younger (i.e., 12 to 15 years); one patient each from the low-dose and high-dose pesolizumab groups were exempt from completing the DLQI questionnaire and were examined on day 1. No other patients had missing baseline values ​​or scores higher than 26 (maximum score may be 30). 1 KM estimates of the time when 25% of patients experience endpoint events. 2 Cox regression model for stratification of systemic GPP drugs during randomization. 3 Log-rank determination of systemic GPP drug stratification during randomization.

[0242] D. Continued remission until week 48:

[0243] Sustained remission was defined as a GPPGA score of 0 or 1 (clear or nearly clear) on all visits up to week 48, in patients who were not receiving GPP hot red attack treatment or investigator-specified SoC. The proportion of patients with sustained remission was numerically higher in the pesolimumab group compared to placebo (0.290): 0.516 for low-dose, 0.452 for intermediate-dose, and 0.633 for high-dose. The risk differences compared to placebo were 0.246 (95% CI 0.013, 0.478) for low-dose, 0.166 (95% CI -0.069, 0.401) for intermediate-dose, and 0.345 (95% CI 0.099, 0.591) for high-dose. Similar results were observed with more strictly defined use of pesolimumab compared to placebo (Table 15 below).

[0244] Table 15: Proportion of patients with sustained remission up to week 48

[0245] Marker analysis showed that, compared with placebo, the proportion of patients with sustained loss of response was lower in the high-dose pesolimumab group, which was evident at week 12 and persisted until week 48. (Data not shown).

[0246] Example 7. Other endpoints

[0247] A. Improved Persistent Response: Other definitions of persistent response were analyzed as an additional endpoint (“Improved Persistent Response”), with post-hoc analyses of persistent pustule clearance (pustule sub-score of 0) and persistent completely cleared skin (GPPGA total score of 0 from week 8 onwards). “Improved Persistent Response” was defined as a total GPPGA score of 0 or 1 across all consultations up to week 48, with each GPPGA sub-score less than or equal to 2, without the use of emergency medications or investigator-prescribed SoC (added via TSAP).

[0248] The results (Table 16) showed that, compared with placebo, the proportion of patients with other definitions of sustained response at high doses of pesolimumab was numerically higher. Table 16: Proportion of patients with other definitions of sustained remission up to week 48. 1. Other endpoint: "improved sustained remission". 2. Post-event analysis

[0249] B. GPPGA pustule sub-score is 0:

[0250] Two post-hoc analyses supported sustained remission. The proportion of patients with a GPPGA pustular subscale score of 0 was measured for the first time in all consultations from week 4 to week 48 (see block 3 in Table 16). For sustained remission up to week 48, the proportion of patients with sustained remission according to this measure was numerically higher in the pesolimab group (0.484 for low dose, 0.452 for intermediate dose, and 0.636 for high dose) than in the placebo group (0.258). The risk differences for low-dose pesolimab compared to placebo were 0.241 (95% CI 0.0101, 0.472), 0.196 (95% CI -0.036, 0.429) for intermediate dose, and 0.379 (95% CI 0.138, 0.619) for high dose. Therefore, the results of more rigorously defined use of high-dose pesolimab were similar compared to placebo.

[0251] C. GPPGA overall score: 0:

[0252] In all consultations from week 8 to week 48, the proportion of patients with a GPPGA score of 0 was measured in the second analysis (see block 2 in Table 16). The proportion of patients with sustained response according to this measure was numerically higher in the pesolizumab intermediate- and high-dose groups (0.129 for intermediate-dose and 0.210 for high-dose) than in the placebo group (0.032). The risk difference compared to placebo was 0.096 (95% CI -0.038, 0.230) for intermediate-dose and 0.176 (95% CI 0.009, 0.343) for high-dose.

[0253] D. Without receiving emergency medication or investigator-prescribed SoC, a DLQI score of 0 or 1 in all consultations up to week 48.

[0254] Compared to the placebo group, a higher proportion of patients in the high-dose pesolimumab group achieved this endpoint for the first time. Only minor differences were observed between the low-dose and intermediate-dose pesolimumab groups and placebo (Table 17). Table 17: Percentage of patients with a DLQI of 0 or 1 in all consultations up to week 48 without receiving emergency medication or investigator-prescribed SoC.

[0255] Overview: Further analysis of the randomized maintenance period up to week 48 using DLQI of 0 or 1 in all consultations showed that the high-dose pesolimumab group had a higher proportion of patients whose quality of life was not affected by the disease compared to placebo.

[0256] Based on the timing of the first GPP hot red episode, PSS worsening, and DLQI worsening, the effects of the two pesolimab loading doses (300 mg and 600 mg) were similar and better than placebo during the first 4 weeks of the randomized maintenance period.

[0257] The geometric mean of pesolimumab indicates that pesolimumab plasma concentrations are dose-related. Following any pesolimumab treatment (subcutaneous or intravenous), the percentages of ADA-positive patients in this trial were 45%, 68%, and 41% for patients initially randomized to low, intermediate, and high doses of pesolimumab, respectively. Following any pesolimumab treatment, the percentages of NAb-positive patients (all ADA-positive) at low, intermediate, and high doses were 45%, 68%, and 34%, respectively. The median time to ADA onset ranged from 8.0 to 10.6 weeks, and the time to maximum potency ranged from 17.1 to 22.6 weeks. No significant correlation was observed between the presence of ADA or NAb and the therapeutic effect of pesolimumab during the randomization maintenance period in terms of the incidence, number of NAb attacks, or duration of response in GPP (data not shown).

[0258] For 32 patients who received pesolimumab OL 900 mg intravenously to treat their hot flashes, the probability of response after one week was 0.554 (95% CI 0.388, 0.734). Within 2 weeks, 9 patients (0.594, 95% CI 0.423, 0.745) achieved a response. Among these patients (20 patients) who subsequently entered the maintenance phase with pesolimumab OL 300 mg subcutaneously, their status appeared stable during the analyzed period; 9 patients increased the dosing interval from q12w to q4w.

[0259] Patients who did not experience a heat rash and received either subcutaneous pesolimumab or placebo showed stable CRP, neutrophil, and white blood cell counts over time, remaining within the normal range during the randomization period. Albumin levels remained within the normal range throughout the trial. Following heat rash and intravenous pesolimumab treatment in the OL (oral lobe), elevated CRP, neutrophil, and white blood cell counts decreased rapidly over time after intravenous pesolimumab treatment for heat rash, reaching normal levels by week 2 and remaining constant thereafter.

[0260] Example 8: Occurrence of adverse events caused by treatment:

[0261] Safety is assessed based on the analysis of adverse events (AEs, including serious AEs (SAEs) and adverse events of concern (AESIs)), physical examination, vital sign recording, laboratory tests, and 12-lead electrocardiograms (clinically relevant findings should be recorded as AEs). Table 18. Overview of adverse events during the randomization period up to the first administration of OL pesolimumab. *Patients who were randomly assigned to the placebo group and who unexpectedly received a single dose of pesolimumab 150 mg on day 1 were assigned to the low-dose pesolimumab group for analysis of exposure and safety. †Per 100 patients per year. Serious adverse events (AEs) in patients receiving pesolimab included hypertensive encephalopathy, viral encephalitis, pneumonia, bacterial skin infection, angioedema, drug rash, palpitations, breast cancer, cholelithiasis, and pustular psoriasis. Notably, hypertensive encephalopathy was a differential diagnosis of viral encephalitis within the same patient. One patient receiving placebo had multiple sclerosis. § According to the preferred term, the most common adverse events (AEs) are those that occur in ≥10% of patients in any trial group. AE, Adverse Events; OL, Open Label; RCTC, Rheumatology Common Toxicity Criteria; SC, Subcutaneous

[0262] During the randomized maintenance therapy period, the proportion and incidence of any adverse events (AEs), as well as severe, serious, and investigator-defined drug-related AEs, were similar across all dose groups (Table 16). No fatal AEs occurred in this trial. AEs leading to pesolimumab discontinuation were pustular psoriasis (2 patients, 2.2%); psoriasis, psoriatic arthritis, and breast cancer (1 patient, 1.1% for each AE).

[0263] A similar proportion of patients receiving pesolimumab (90.3%) and placebo (86.7%) experienced adverse events (AEs); the incidence of AEs was similar across the pesolimumab dose groups and did not follow a dose-dependent pattern (Table). Patients receiving pesolimumab (total of all doses) and placebo had similar rates of severe AEs (19.4% vs. 23.3%, respectively) and investigator-defined drug-related AEs (39.8% vs. 33.3%, respectively). There were no fatal AEs; the majority of AEs were non-severe and non-major. The most common AEs were pustular psoriasis, psoriasis, and injection site erythema (24.7%, 14.0%, and 14.0% in patients receiving pesolimumab, compared to 53.3%, 10.0%, and 3.3% in patients receiving placebo, respectively). Infection rates were balanced across the treatment groups. Compared to the placebo group, a higher proportion of patients receiving pesolimumab experienced serious adverse events (SAEs) (9.7% vs. 3.3%); SAEs did not follow a dose-dependent pattern as with pesolimumab. SAEs reported in the high-dose pesolimumab group included pustular psoriasis, breast cancer, and gallstones (one patient each). Overall, the safety profile of pesolimumab was favorable; infection rates were similar across treatment groups, and there was no indication that higher doses increased infection rates. There were no fatal AEs or hypersensitivity events leading to treatment discontinuation.

[0264] Example 9: Pesolimab plasma exposure in GPP patients after IV and SC administration:

[0265] Three dosing regimens were selected in the Effisayil™ 2 study to test a broad range of exposures, allowing for a thorough assessment of the exposure-response relationship of pexolimab in patients with GPP. Loading doses of 600 or 300 mg were included to assess whether either exposure was effective in preventing GPP hot flashes if other regimens were discontinued. A q12w vs. q4w dosing interval was chosen to assess whether hot flash prevention with every 3 months of administration was sufficient, or whether monthly dosing was necessary. The placebo regimen was crucial for this study because the incidence of hot flashes in the untreated population was unknown, and a high incidence was essential to demonstrating that patients benefited from prophylactic treatment. An active control group was not included in the study because there are currently no approved drugs for the prevention of GPP hot flashes. Subcutaneous administration was used in the Effisayil™ 2 study because patients had clean or nearly clean skin at randomization, implying a different expected pexolimab exposure compared to the exposure required for treating hot flashes. Additionally, subcutaneous administration had the potential to improve participant compliance, as patients typically prefer SC dosing. In the Effisayil™ 1 study, 900 mg IV dose of pesolimumab was demonstrated to be effective in treating GPP hot red attacks with an acceptable safety profile, and therefore was selected as the dose to be administered and used as a comparative dose in exposure studies if patients experienced GPP hot red attacks during the Effisayil™ 2 study.

[0266] To simulate the pharmacokinetic profile of IV versus SC doses of pesolimumab to compare drug exposure profiles and support dosing recommendations for GPP patients, a population pharmacokinetic model was developed using subject-level pharmacokinetic, ADA, and covariate data from 18 studies in which subjects were treated with either IV or SC pesolimumab.

[0267] Mathematical models quantified the pharmacokinetic (PK) of pesolimumab after IV and SC administration, including the effects of patient-specific factors (e.g., weight, disease symptoms, ADA potency) on PK. The resulting population PK models were used to simulate the concentration-time profiles of various IV and SC doses over 12 weeks (84 days): administration of pesolimumab IV at a single dose of 300 mg and 900 mg over 90 minutes, or two doses of 900 mg (1 week apart), and injection of pesolimumab SC at single or two doses (1 week apart) of 300 mg, 600 mg, 900 mg, and approximately 2250 mg. For each dose, Cmax, Tmax, and AUC were summarized at 14 and 84 days.

[0268] This simulated PK data from GPP patients confirms that treatment with IV and SC pesolimumab can lead to differences in drug exposure in clinical practice. Significantly higher Cmax and a faster Tmax were observed for IV versus SC doses of pesolimumab. To match the Cmax of a 900 mg IV dose, a theoretical SC dose greater than 2.5 times (2250 mg, equivalent to 15 injections of a 150 mg SC pre-filled syringe) would be required. The immediate and high bioavailability of IV pesolimumab compared to SC pesolimumab supports the use of either IV or SC pesolimumab in treatment or prophylactic dosing strategies for acute GPP febrile seizures.

[0269] A pharmacokinetic (PK) model was used to simulate the plasma concentration-time profile of pesolimab at different SC and IV doses in typical GPP subjects, assuming a body weight of 75 kg, ADA negativity, SC administration to the abdomen, and all other covariates as reference values. The simulations are presented in Figures 5A through 5E. Figure 5A is a graphical representation of the model-predicted concentration-time profiles for 300 mg IV versus 300 mg subcutaneously delivered pesolimab over a 12-week period. The simulated Cmax of 300 mg IV pesolimab is approximately 2.5 times greater than that of 300 mg SC pesolimab. For IV pesolimab, Tmax is at the end of the 90-minute infusion, while for SC pesolimab it is approximately 1 week after administration. Figure 5B is a graphical representation of the model-predicted concentration-time profiles for 900 mg IV versus 600 mg SC pesolimab. The simulated Cmax of 900 mg IV is 3.7 times greater than that of 600 mg SC. For IV pesolimumab, Tmax occurred at the end of a 90-minute infusion, while for SC pesolimumab it occurred approximately one week after administration. Figure 5C is a graphical representation of the model-predicted concentration-time profiles for 900 mg IV × 2 versus 600 mg SC × 2 pesolimumab. When administered in a two-dose regimen, exposure increases due to accumulation. However, even after the second dose, the Cmax of the IV administration was still 3 times greater than that of the SC administration. Similarly, Tmax occurred approximately one week after each SC dose, compared to immediately following each 90-minute IV infusion. Figure 5D is a graphical representation of the model-predicted concentration-time profiles for 900 mg IV versus 2250 mg SC pesolimumab. A 2250 mg SC dose is required to achieve the target Cmax equivalent to 900 mg IV pesolimumab. At the SC dose, Tmax is delayed by 1 week, and AUC is almost twice as large; most importantly, this size of SC injection is not clinically feasible (equivalent to 15 injections of a 150 mg SC pre-filled syringe). Figure 5E provides an overview of exposure quantifications in GPP patients following a single IV or SC dose. Simulated pesolimumab exposure showed that Cmax and AUC of a single 900 mg IV administration route consistently exceeded those of all feasible single-dose pesolimumab SC doses. Similar trends were observed with both IV and SC two-dose regimens. Slow absorption of the SC formulation is expected, with Tmax reached immediately 90 minutes after a single IV infusion, compared to approximately 1 week after SC injection.

[0270] Example 10: Pesolizumab treatment for controlling GPP disease characteristics in both acute and chronic phases:

[0271] Treatment with a 600 mg loading dose, followed by 300 mg subcutaneous pesolimumab every 4 weeks, was superior to placebo in the prevention of heat-red attacks, reducing the risk of heat-red attacks by 84% over 48 weeks (p=0.0005). Skin biopsies (5 mm samples) were collected at the following times: the second consultation (baseline) and the 14th consultation (week 48) during maintenance therapy; and the first, sixth, and 14th emergency consultations (4 weeks after heat-red attack) and the 14th emergency consultation (OL) during emergency treatment. Skin biopsies at baseline (n=15) were obtained so that half would be used for RNA sequencing and half for immunohistochemical analysis.

[0272] Pesolizumab treatment resulted in clinical improvement and reduced expression of pathogenic genes associated with GPP hot flashes in patients' skin biopsies. Ten patients included in this biomarker sub-study underwent multiple biopsies. Six patients received cyclosporine prior to randomization; gene expression patterns in all patients indicated low-grade inflammation at baseline. In the four patients who developed hot flashes (randomized to placebo [n=1], low-dose [150 mg subcutaneously q12w] [n=1], and intermediate-dose [300 mg subcutaneously q12w] [n=2] pesolizumab), pathogenic genes associated with GPP hot flashes and / or IL-36 signaling were further upregulated relative to baseline. Treatment with 900 mg IV pesolizumab for hot flashes reduced the expression of these pathogenic genes in three-quarters of the patients. In the five patients receiving high-dose SC pesolimumab, no new hot red attacks occurred, and the expression of the GPP hot red attack / IL-36-related gene decreased (or remained low) between baseline and week 48. Histopathological analysis of selected neutrophil proteins confirmed low-grade inflammation at baseline and reflected changes in disease activity and clinical improvement.

[0273] Figures 6A and 6B present exemplary results from two patients who had received prior therapy for GPP, demonstrating that GPP patients can successfully transition from background immunosuppressive therapy to maintenance or emergency treatment with pesolimumab.

[0274] Histopathological analysis of selected neutrophil proteins is shown in Figure 6A. Representative patient A was IL36RN mutation positive, presenting with pustules and desquamation, and had been treated with cyclosporine prior to recruitment to the pesolimumab trial. Patient A was randomized to receive a high dose of pesolimumab and did not experience a heat rash throughout the study. Representative patient B was IL36RN mutation-free, had a high neutrophil count, and had been treated with atratin prior to recruitment. Patient B was randomized to receive placebo and continued emergency pesolimumab treatment during the study due to a heat rash.

[0275] Pathogenic genes and IL-36 pathway genes associated with GPP hot red attacks were differentially expressed between baseline and first emergency care (VR1) consultations (uncorrected p < 0.05). These genes included IL17C, CXCL6, IL19, IL20, CXCL8, NCF1, IL36G, and DEFB4A. Skin biopsies from patients with a tendency for recurrent hot red attacks showed higher expression of IL-36 pathway genes and GPP hot red attack-associated genes (IL36G, DEFB4A, CXCL8, CXCL6, IL19, IL20, IL17C, and NCF1) compared to patients with more stable disease (uncorrected p < 0.05), with fold changes ranging from 1.4 to 5.2. Figure 6A shows that patients experienced decreased expression of neutrophils (neutrophil elastase, lipid carrier protein [LCN]), IL-36R, and inflammatory markers (S100A7, human β-defensin 2 [hBD2]), indicating that inflammation and neutrophil pustule formation were reduced after pesolimumab treatment.

[0276] Furthermore, as shown in Figure 6B, the clinical morphology reflects the histopathological changes in patients A and B, indicating that emergency pesolimumab treatment almost completely resolved the skin symptoms of GPP febrile red attacks. In addition, pesolimumab treatment prevents GPP febrile red attacks by inhibiting disease activity. Overall, the results suggest that pesolimumab is more effective in controlling GPP compared to current immunosuppressive therapies.

[0277] Example 11: MicroRNAs 223-3p and 223-5p as biomarkers to monitor the effects of pesolimumab treatment on the skin and serum of patients with generalized pustular psoriasis.

[0278] Background: Previous studies have demonstrated that GPP lesions are associated with increased expression of IL-36-related transcripts (IL-36a, IL-36b, IL-36g), neutrophil recruitment (CXCL1, CXCL8), pro-inflammatory cytokines (IL-6, IL-19, IL-20), and skin inflammatory markers (DEFB4A, S100A7, S100A8, S100A9) compared to non-lesion skin, which are significantly downregulated by a single dose of pesolimumab (Baum et al., 2021; Farag et al., Unpublished Data, 2024). However, the mechanisms underlying these alterations in specific mRNA expression in GPP remain poorly understood.

[0279] MicroRNAs (miRNAs) are small non-coding RNA molecules that can regulate gene expression post-transcriptionally and contribute to the development or regulation of several diseases, including skin inflammation (Guo et al., 2010). Only a few studies have aimed to characterize miRNA expression in the skin of patients with atopic dermatitis (Carreras-Badosa et al., 2022), while numerous studies have been conducted on psoriasis and / or psoriatic arthritis (Hawkes et al., 2016; Liu et al., 2017; Delic et al., 2020). In addition to tissues, miRNAs have been found in body fluids (such as serum or plasma), demonstrating significant value as minimally invasive circulating markers of disease in these fluids. Ganguly et al. identified a group of miRNAs that overlapped between skin and serum samples and correlated with disease severity in psoriasis, with miR-147b, miR-3614-5p, and miR-125a-5p used to differentiate between low- and high-severity psoriasis patients (Ganguly et al., 2024). Previous studies have reported significantly different circulating levels of 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 (GPP) compared to healthy controls (De Felice et al., 2022). To date, no information exists regarding the role of miRNAs in skin and blood samples from GPP patients.

[0280] Methods: To identify microRNAs from the skin and serum of GPP patients as biomarkers in GPP, small RNA sequencing was used to measure microRNA expression profiles, and qPCR was used to significantly confirm candidate miRNAs and correlate them with clinical outcomes.

[0281] In the Effisayil 1 study, a total of 25 skin biopsies were available for analysis in the cohort of GPP patients treated with pesolimab. Skin biopsies (5 mm) were collected from lesion (L; n=9) and non-lesion (nL; n=4) skin on day 1 / baseline before drug administration (=pesolimab administration). Lesion skin biopsies were also collected on day 8 (n=7) after drug administration and at week 8 after administration of an additional open-label dose (n=5). Due to the limited number of samples available post-treatment, lesion samples collected on day 8 and week 8 post-treatment were pooled for analysis (=pesolimab administration). Skin biopsies were obtained from 10 healthy controls (50% male; age: 41.9 + / - 14.0 years) from Discovery LifeSciences (Kiev, Ukraine).

[0282] Serum samples were obtained from the biobank of 12 GPP patients participating in the EFFISAYIL® 1 study. A total of 25 serum samples were available, collected on day 1 / baseline (n = 12) and at week 12 post-treatment (n = 11). Due to sample size limitations (n ​​= 2), the placebo group was not included in further analysis.

[0283] EFFISAYIL® 2 was used for confirmatory studies. Forty-one skin biopsy samples were collected from the following groups: patients who experienced heat rash: 5 at baseline, 5 at the onset of heat rash, 6 at week 4 post-treatment, and 7 at week 52 post-treatment; patients who did not experience heat rash: 10 at baseline and 7 at week 52 post-treatment.

[0284] Total RNA isolation: Skin biopsies were collected in RNA-later® tissue preservation tubes (Qiagen, Hilden, Germany) and stored at -20°C until use. Total RNA, including miRNA enrichment, was extracted from human skin tissue using the RNeasy fibrous tissue mini kit (Qiagen, Hilden, Germany). Total RNA enriched with miRNAs was isolated from serum samples using the miRNeasy serum / plasma advanced kit (Qiagen, Hilden, Germany) according to the manufacturer's protocol. RNA purity and quantity were assessed using an Implen NanoPhotometer® N120 (Implen, Munich, Germany).

[0285] Small RNA library preparation and sequencing: Sequencing libraries from skin and serum RNA samples were prepared using the QIAseq® miRNA UDI Library Kit (96) (Qiagen, Hilden, Germany) and the QIAseq miRNA 96 Index Kit UDI AH (Qiagen, Hilden, Germany) according to the manufacturer's instructions. Sequencing was performed on a NovaSeq™ 6000 sequencing system (Illumina) using the NovaSeq 6000S4 Reagent Kit v1.5 (200 cycles) (Illumina, San Diego, USA) according to the manufacturer's instructions.

[0286] Quantitative Real-Time PCR of MicroRNAs: Following the manufacturer's protocol, the TaqMan™ Advanced miRNA cDNA Synthesis Kit (Applied Biosystems, Waltham, MA) was used for reverse transcription and pre-amplification of skin and serum miRNAs. RT-qPCR and pre-amplification of cDNA were performed using TaqMan™ Rapid Advanced Premix (Applied Biosystems, Waltham, MA) and TaqMan Advanced miRNA Assay (Applied Biosystems, Waltham, MA) according to the manufacturer's instructions. RT-qPCR was performed in duplicate on a QuantStudio 7 Flex Real-Time-PCR-System™ (AppliedBiosystems, Waltham, MA) according to the manufacturer's recommended cycling parameters. The following analyses were used: hsa-miR-223-3p (analysis ID: 477983_mir), hsa-miR-223-5p (analysis ID: 477984_mir), hsa-miR-1304-3p (analysis ID: 479574_mir), has-miR-337-5p (analysis ID: 478036_mir), hsa-miR-485-5p (analysis ID: 478126_mir), and hsa-miR-361-5p (analysis ID: 478056_mir). After confirming stable expression and low variability using the NormFinder tool, hsa-miR-361-5p was selected as the endogenous control miRNA for normalization, and NGS data were selected based on the assessment using "NormFinder_0953" and the supplier's recommendations. Cyclic cutoff values ​​(Ct) were determined using QuantStudio™ 6 and 7 FlexReal-Time PCR system software version 1.7.2. Relative fold changes in gene expression were analyzed using the 2-ΔΔCt method.

[0287] Results: MicroRNA analysis was performed on non-lesion and lesion skin samples from GPP patients before and after pesolimumab treatment, and the results were correlated with clinical outcomes in two independent cohorts. Skin biopsy results were further correlated with patient-matched samples collected from serum to determine whether serum-isolated miRNAs were potential soluble 'liquid biopsy' biomarkers reflecting skin and systemic conditions.

[0288] Differentially expressed miRNAs in lesions and non-lesions of GPP compared to healthy controls: Differential miRNA expression analysis was performed to investigate the differences in skin miRNA expression profiles between GPP patients and healthy controls. Overall, 333 miRNAs were significantly dysregulated in lesioned skin compared to healthy skin (absolute value FC ≥ 1.5, adjusted P ≤ 0.05). The expression levels of 173 miRNAs were significantly increased, while 160 miRNAs showed significantly lower expression levels in GPP lesions (Figure 7B).

[0289] The strongest upregulation of miR-142-5p, miR-451a, and miR-3613-5p was observed, with fold changes ranging from 61 to 107-fold. 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 a significant increase of 36-fold to 56-fold in the skin of patients with GPP compared to healthy controls (Figure 7B). The strongest downregulation of miR-483-3p, miR-4446, and miR-204-3p was observed, with expression reduced by 27-fold to 40-fold in the lesions of GPP patients compared to healthy controls.

[0290] Compared with healthy controls, several significantly dysregulated miRNAs in diseased GPP skin were also dysregulated in both diseased and non-diseased GPP skin, but to a lesser extent (Denis Delić et al., unpublished data not shown).

[0291] Differentially expressed miRNAs in lesioned skin of GPP patients compared to healthy controls and after pesolimumab treatment: To investigate the effect of pesolimumab treatment on lesioned skin from GPP patients and to identify potential biomarker candidates, small RNA sequencing was performed on 12 lesioned GPP samples after pesolimumab treatment. PCA revealed that skin miRNA profiling separated lesioned GPP biopsies from healthy controls derived from subjects treated with pesolimumab. Skin miRNA profiling did not completely separate lesioned GPP biopsies after pesolimumab treatment from baseline biopsies, but it identified transitions to non-lesioned GPP biopsies (Figure 8A).

[0292] Differential expression analysis (absolute value FC ≥ 1.5, P ≤ 0.05) identified 34 dysregulated miRNAs in the diseased GPP after pesolimumab treatment compared to baseline. A total of 14 miRNAs showed lower gene expression in the diseased GPP after pesolimumab treatment, while 20 miRNAs showed increased expression (Figure 8B). The most significant decreases were observed in miR-223-3p, miR-223-5p, and miR-4455, with expression levels decreasing by 3.3 to 5.2-fold. Among the upregulated miRNAs, miR-483-5p, miR-493-5p, and miR-485-5p showed the strongest effects, with expression increasing by 1.8 to 2.1-fold after pesolimumab treatment. The overall effects of pesolimumab on differentially expressed miRNAs are summarized in Table 19 below. Table 19: Induction of miRNA expression in skin by pesolimumab (>1.5-fold change; P<0.05)

[0293] Differentially expressed miRNAs in serum of GPP patients compared to healthy controls: This study investigated minimal / non-invasive serum miRNA biomarkers to determine whether changes observed in the skin also translated to the periphery. Small RNA sequencing was performed on serum samples obtained from 12 GPP patients and 20 healthy controls. PCA of serum miRNA expression profiles definitively separated GPP patients from healthy volunteers, indicating a significant difference in systemic miRNA profiles among GPP patients (Figure 9A).

[0294] Compared with healthy volunteers, a total of 114 serum miRNAs were significantly dysregulated in GPP patients (absolute value FC ≥ 1.5, adjusted P ≤ 0.05). Among them, 69 miRNAs showed upregulated expression levels and 45 miRNAs showed downregulated expression levels in GPP patients (Figure 9B). The most severely dysregulated miRNAs in GPP patients compared with healthy serum included miR-12136, miR-4286, and miR-29c-5p (increased by 4.6 to 6.3 times), and miR-144-3p, miR-299-3p, and miR-375-3p (decreased by 4.7 to 7.6 times).

[0295] Differentially expressed miRNAs in serum of GPP patients after pesolimab treatment: This study investigated the impact of treatment on serum miRNA profiles to assess whether treatment efficacy observed in the skin is also reflected in serum, and whether serum miRNAs can serve as candidates for very small / non-invasive biomarkers 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 the effectiveness of potential therapeutic agents in treating and preventing GPP, determining whether to initiate treatment in subjects, modify treatment doses, modify dosing intervals, or discontinue treatment, monitoring patient response to GPP treatment, and patient adherence to the treatment regimen. Small RNA sequencing was performed on 11 serum samples from GPP patients treated with pesolimab.

[0296] PCA analysis of filtered serum miRNA expression profiles showed that samples from GPP patients after pesolimumab treatment clustered between baseline and healthy control samples (Figure 10A).

[0297] Differential miRNA expression analysis revealed altered expression of 50 miRNAs compared to baseline (1.5-fold; P<0.05), including 21 upregulated and 29 downregulated miRNAs (see Table 20). The most strongly dysregulated serum miRNAs after pesoribumab treatment, including miR-376b-3p, miR-337-5p, and miR-5189-3p, showed a 2.7- to 2.8-fold increase compared to baseline, while miR-16-5p, miR-8060, and miR-8085 showed a 2.7- to 2.9-fold decrease in serum levels (Figure 10B). Table 20: Induction of serum miRNA expression by pesolimumab (>1.5-fold change; P<0.05)

[0298] Identification of the core miRNA group and analysis of integrated miRNA target mRNA pathways: Diseased skin biopsies and serum from GPP patients were compared with healthy controls and those treated with pexolizumab. A group of five core miRNAs was identified, showing consistent dysregulation in GPP and regulation following pexolizumab treatment. This group of miRNAs included miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, and miR-337-5p (Figure 11A), and the effects of pexolizumab on dysregulation in skin and serum are summarized in Figure 11B.

[0299] To further understand the mechanisms underlying the miRNA biomarkers identified in this study, target prediction analysis of candidate miRNAs was performed using MirTarBase. Target mRNAs were selected through differential gene expression analysis in skin obtained from patient data matched from EFFISAYIL® 1 (Farag et al., 2024), and pathway analysis was performed using the REACTOME and HALLMARK datasets obtained from MSigDB. Significant enrichment of the miR-223-3p pathway was observed, including key signaling pathways in the inflammatory process (data not publicly available).

[0300] Validation of selected miRNA candidates in GPP and their correlation with clinical parameters: To validate a group of miRNA biomarker candidates identified in skin and serum, RT-qPCR was used to confirm small RNA sequencing results. Pairwise comparisons of the data generated by RT-qPCR confirmed that, compared with healthy controls, all miRNA biomarker candidates in diseased GPP skin, except miR-1304-3p, were significantly dysregulated (P < 0.0001). RT-qPCR confirmed strong upregulation of miR-223-3p and miR-223-5p in GPP lesions, expressed as median percentage of control (POC) values ​​ranging from >1,500% to 9,800%, and downregulation of miR-485-5p in GPP patients, indicated by median POC values ​​between 14% and 32% (Figure 12A). Pesolizumab treatment significantly reduced the expression of miR-223-3p and miR-223-5p by 76% to 84% (P < 0.001), consistent with small RNA sequencing data, while no significant effect on miR-485-5p levels was detected after pesolizumab treatment (Figure 12B).

[0301] In serum, RT-qPCR analysis confirmed significant upregulation of miRNA-223-5p (P < 0.05) with a median POC of 174%, while miR-223-3p showed a trend of 134% upregulation in serum at baseline compared to healthy controls (P < 0.09). miR-485-5p was confirmed to be significantly downregulated in serum at baseline (P < 0.05), indicated by a median POC ranging from 23% to 48% (Figure 13A). Pesolizumab treatment significantly reduced the expression of miR-223-5p in the serum of GPP patients (32%), while the expression level of miR-223-3p followed the same trend (P = 0.17). In conclusion, miR-223-3p and miR-223-5p are promising miRNA candidates for monitoring disease progression and therapeutic efficacy.

[0302] To investigate whether changes in skin miRNA expression of differentially expressed miRNAs could be used to monitor disease progression and treatment response, skin miRNA levels before and after pesolimumab treatment were correlated with GPPASI and GPPGA scores. Correlation analysis showed that after pesolimumab treatment, changes in GPPASI and GPPGA scores were highly significant (P<0.0001) positively correlated with changes in 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) (Figures 14A and 14B). Correlation analysis between serum miRNA levels and GPPGA scores revealed a significant correlation between miR-223-5p (Rs_GPPGA = 0.7; P<0.001) and miR-223-3p (Rs_GPPGA = 0.59; P<0.01) (Figure 14C).

[0303] Overview: Five miRNAs—miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, and miR-337-5p—were identified in skin and serum samples from GPP patients. These miRNAs were increased in GPP patients and decreased after pexolimab treatment compared to healthy controls. Specifically, three miRNAs, including miR-223-3p, miR-223-5p, and miR-1304-3p, were upregulated in the diseased skin and serum of GPP patients and downregulated after pexolimab treatment. Conversely, two miRNAs, including miR-485-5p and miR-337-5p, were downregulated in GPP patients and upregulated after pexolimab treatment. Integrated miRNA-mRNA analysis identified miR-223-3p miRNA, in particular, as an upstream regulator of its target mRNA, participating in multiple pathways contributing to GPP pathophysiology.

[0304] Previous studies have reported increased expression levels of miR-223 in various inflammatory conditions, such as plaque psoriasis, asthma, chronic obstructive pulmonary disease, and inflammatory bowel disease (Lovendorf et al., 2014; Roffel et al., 2020; Yarani et al., 2022). This study confirms that two groups of miR-223, miR-223-3p, and miR-223-5p are involved in the molecular mechanisms of GPP dysregulation. Without being bound by theoretical constraints, the upregulation of miR-223 in GPP patients may mediate anti-inflammatory effects through negative regulation of the NF-κB signaling cascade, targeting chemokines CXCL2 and CCL3 (Roffel et al., 2020), which are known to recruit immune cells, including neutrophils (Filippo et al., 2013; Reichel et al., 2009). Therefore, the increase in miR-223 may represent a counter-regulatory mechanism to alleviate the excessive inflammatory response and neutrophil recruitment observed in GPP.

[0305] This study used qPCR to confirm the results of miR-223-3p and miR-223-5p, and confirmed their significant correlation with GPPASI and GPPGA, indicating that miR-223-3p and miR-223-5p can be used as minimal / non-invasive biomarkers to monitor GPP disease progression and pesolimumab-induced therapeutic effects.

Claims

1. A method for treating a subject with generalized pustular psoriasis (GPP), including a method for treating and preventing flare, the subject having a history of GPP symptoms and / or a history of GPP (diagnosis) as defined by consensus diagnostic criteria as defined by the ERASPEN diagnostic criteria, the method comprising administering to the subject a first loading dose of 300 mg to 600 mg of an anti-IL-36R antibody; followed by, after a final maintenance dose, administering to the subject a maintenance dose of 150 mg to 600 mg of the anti-IL-36R antibody at 4-week (q4w) or 12-week (q12w) intervals for 8 to 48 weeks, wherein the loading and maintenance doses are delivered non-enterically.

2. The method of claim 1, wherein the total loading dose comprises 300 mg of anti-IL-36R antibody delivered subcutaneously in week 0 or week 1, followed by a maintenance dose of 150 mg of the anti-IL-36R 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-36R antibody delivered subcutaneously in week 0 or week 1, followed by a maintenance dose of 300 mg of the anti-IL-36R 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-36R antibody delivered subcutaneously in week 0 or week 1, followed by a maintenance dose of 300 mg of the anti-IL-36R antibody administered subcutaneously at 4-week (q4w) intervals.

5. A method for treating a subject with a history of GPP for generalized pustular psoriasis (GPP) without experiencing a hot flash flare, comprising administering to the subject a first loading dose of 300 mg to 600 mg of an anti-IL-36R antibody; followed by, after a final maintenance dose, administering to the subject a maintenance dose of 150 mg to 600 mg of the anti-IL-36R antibody at 4-week (q4w) or 12-week (q12w) intervals for 8 to 48 weeks, wherein the loading and maintenance doses are delivered non-enterically.

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

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

9. A method for reducing the incidence, recurrence, and / or frequency of hot flashes in generalized pustular psoriasis (GPP) in a subject with a history of GPP symptoms and / or a history of GPP (diagnosis) as defined by consensus diagnostic criteria as defined by the ERASPEN diagnostic criteria, the method comprising administering a first loading dose of 300 mg to 600 mg of an anti-IL-36R antibody to the subject; followed by, after a final maintenance dose, administering a maintenance dose of 150 mg to 600 mg of the anti-IL-36R antibody to the subject at 4-week (q4w) or 12-week (q12w) intervals for 8 to 48 weeks, wherein the loading and maintenance doses are delivered non-enterically.

10. The method of claim 9, wherein the total loading dose comprises 300 mg of anti-IL-36R antibody delivered subcutaneously in week 0 or week 1, followed by a maintenance dose comprising 150 mg of the anti-IL-36R 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-36R antibody delivered subcutaneously in week 0 or week 1, followed by a maintenance dose of 300 mg of the anti-IL-36R 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-36R antibody delivered subcutaneously in week 0 or week 1, followed by a maintenance dose of 300 mg of the anti-IL-36R 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-36R antibody delivered subcutaneously in week 0 or week 1, followed by a maintenance dose of 300 mg of the anti-IL-36R antibody administered subcutaneously at 4-week (q4w) intervals.

14. The method as described in any one of claims 1 to 13, wherein at the start of treatment, the subject's total GPP Physician Global Assessment (GPPGA) score is ≤1.

15. The method of any one of claims 1 to 13, wherein at the start of treatment and / or before the administration of the first loading dose of the anti-IL-36R antibody, the subject's total GPPGA score is ≤1 and the GPPGA pustule sub-score is ≤1.

16. The method of any one of claims 1 to 13, wherein after administration of at least a maintenance dose of 150 or 300 mg of anti-IL-36R antibody, the subject’s total GPPGA score is ≤1 and the GPPGA pustule score is ≤1, for at least 48 weeks after the initial loading dose of 300 mg or 600 mg of anti-IL-36R antibody.

17. The method of any one of claims 1 to 13, wherein the subject’s total GPP General Assessment (GPPGA) score is ≤1 and the GPPGA pustule score is ≤1 before and after administration of at least a maintenance dose of 150 or 300 mg of anti-IL-36R antibody, for at least 48 weeks after the initial loading dose of 300 mg or 600 mg of anti-IL-36R antibody.

18. The method of any one of claims 1 to 13, wherein administration of anti-IL-36R antibody to a subject with a history of GPP symptoms and / or a history of GPP (diagnosis) determined according to consensus diagnostic criteria defined by the ERASPEN diagnostic criteria achieves one or more of the following results: (a) After administration of the anti-IL-36R antibody, maintain a Generalized Pectus Psoriasis Global Assessment (GPPGA) score of 0 or 1 for the pustular sub-score until at least 48 weeks after the initial loading dose; (b) After administration of the anti-IL-36R antibody, maintain a GPPGA total score of 0 or 1 until week 48 after the initial loading dose; (c) GPP symptoms remain relieved after administration of the anti-IL-36R antibody, defined as a GPPGA score of 0 or 1 (clear or nearly clear) maintained in all outpatient visits up to week 48 in subjects treated with the anti-IL-36R antibody without receiving GPP hot red attack medication or investigator-specified standard care (SoC). (d) A reduced incidence of GPP hot red flare up to week 48 following administration of the anti-IL-36R antibody, where a GPP hot red flare is defined as an increase of ≥2 in the GPP Physician Global Assessment (GPPGA) total score relative to baseline and a GPPGA pustular sub-score of ≥2; or (e) The time to the first GPP hot red attack is prolonged after administration of the anti-IL-36R antibody up to week 48, as measured by the time from baseline to the first GPP hot red attack, wherein a GPP hot red attack is defined as an increase of ≥2 in the total GPP Physician Global Assessment (GPPGA) score relative to baseline and an increase of ≥2 in the GPPGA pustular sub-score.

19. The method of any one of claims 1 to 13, wherein after receiving maintenance therapy with the anti-IL-36R antibody, the risk of the subject experiencing a worsening of the Psoriasis Symptom Scale (PSS) score is reduced until week 48, wherein a 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 of any one of claims 1 to 13, wherein after receiving maintenance therapy with the anti-IL-36R antibody, the risk of the subject experiencing a deterioration in the Dermatology Quality of Life Index (DLQI) is reduced until week 48, wherein a deterioration is defined as an increase of 4 points in the total score compared to the subject's baseline DQLI score before administration.

21. A method for treating generalized pustular psoriasis (GPP) in a subject, comprising methods for treating and preventing hot red flare-ups, the subject having a history of GPP symptoms and / or a history of GPP diagnosis as defined by consensus diagnostic criteria as defined by the ERASPEN diagnostic criteria, wherein the subject has a total GPPGA score ≤1 and a GPPGA pustular sub-score ≤1 prior to initiation of treatment, the method comprising the following steps: (a) The subject was administered a loading dose of 600 mg of anti-IL-36R antibody during week 0 to week 1, followed by maintenance doses of 300 mg of anti-IL-36R antibody at 4-week intervals, wherein the loading and maintenance doses of the anti-IL-36R antibody were administered subcutaneously; and (b) Assess the subject’s GPP Physician Global Assessment (GPPGA) total score and / or GPPGA pustular sub-score until at least 48 weeks after the initial loading dose, wherein the time to the first GPP hot red episode after the start of treatment up to 48 weeks is defined as a GPPGA pustular sub-score ≥2 and an increase of ≥2 in the GPPGA total score relative to baseline.

22. A method for treating generalized pustular psoriasis (GPP) in a subject, comprising methods for treating and preventing hot red flare-ups, the subject having a history of GPP symptoms and / or a history of GPP diagnosis as defined by consensus diagnostic criteria according to the ERASPEN diagnostic criteria, wherein the subject has a total GPPGA score ≤1 and a GPPGA pustular sub-score ≤1 prior to initiation of treatment, the method comprising the following steps: (a) The subject was administered a loading dose of 600 mg of anti-IL-36R antibody during week 0 to week 1, followed by maintenance doses of 300 mg of anti-IL-36R antibody at 12-week intervals, wherein the loading and maintenance doses of the anti-IL-36R antibody were administered subcutaneously; and (b) Assess the subject’s GPP Physician Global Assessment (GPPGA) total score and / or GPPGA pustular sub-score until at least 48 weeks after the initial loading dose, wherein the time to the first GPP hot red episode after the start of treatment up to 48 weeks is defined as a GPPGA pustular sub-score ≥2 and an increase of ≥2 in the GPPGA total score relative to baseline.

23. A method for treating generalized pustular psoriasis (GPP) in a subject, comprising methods for treating and preventing hot red flare-ups, the subject having a history of GPP symptoms and / or a history of GPP diagnosis as defined by consensus diagnostic criteria according to the ERASPEN diagnostic criteria, wherein the subject has a total GPPGA score ≤1 and a GPPGA pustular sub-score ≤1 prior to initiation of treatment, the method comprising the following steps: (a) The subject was administered a loading dose of 300 mg of anti-IL-36R antibody during week 0 to week 1, followed by maintenance doses of 150 mg of anti-IL-36R antibody at 12-week intervals, wherein the loading and maintenance doses of the anti-IL-36R antibody were administered subcutaneously; and (b) Assess the subject’s GPP Physician Global Assessment (GPPGA) total score and / or GPPGA pustular sub-score until at least 48 weeks after the initial loading dose, wherein the time to the first GPP hot red episode after the start of treatment up to 48 weeks is defined as a GPPGA pustular sub-score ≥2 and an increase of ≥2 in the GPPGA total score relative to baseline.

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

26. The method of any one of claims 1 to 13 and 21 to 23, wherein the anti-IL-36R antibody comprises: i. A light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or ii. A light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or iii. A light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or iv. A light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or v. A light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or vi. A light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or vii. The light chain variable region comprising the amino acid sequence of SEQ ID NO: 85; and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100; or viii. A light chain variable region comprising the amino acid sequence of SEQ ID NO: 85; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 101; or ix. A light chain variable region comprising the amino acid sequence of SEQ ID NO: 86; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100; or x. A light chain variable region comprising the amino acid sequence of SEQ ID NO: 86; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:

101.

27. The method of any one of claims 1 to 13 and 21 to 23, wherein the anti-IL-36R antibody comprises: i. A light chain 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 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. 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.

28. The method of claims 1 to 13 and 21 to 23, wherein the anti-IL-36R antibody is pesolimab.

29. 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) according to the method of claims 1 to 28, the method comprising: (a) Obtaining biological samples from the patient before treatment, after administration of the anti-IL-36R antibody, and after treatment; (b) Measure 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 and post-treatment levels of the biomarkers; and (d) Determining the difference in levels between the pre-treatment and post-treatment samples, reflecting a beneficial response in the patient, wherein the one or more biomarkers comprise microRNAs selected from the group consisting of: miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p. Downregulation or upregulation after treatment, compared to baseline before treatment, indicates a beneficial response.

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

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

32. The method of claim 31, wherein the levels of one or more microRNAs miR-223-5p and miR-223-3 in the affected skin or serum are correlated with GPPASI and / or GPPGA scores, wherein measuring one or more of the following outcomes achieved by the treatment or prevention of hot flashes in subjects with a history of GPP symptoms: (a) After administration of the anti-IL-36R antibody, maintain a Generalized Assessment of Pustules (GPPGA) score of 0 or 1 for the pustular sub-item and maintain or reduce the levels of miR-223-5p and / or miR-223-3 until week 48 after the initial loading dose; (b) After administration of the anti-IL-36R antibody, maintain a GPPGA total score of 0 or 1 and maintain or reduce the levels of miR-223-5p and / or miR-223-3 until week 48 after the initial loading dose; (c) Persistent remission of GPP symptoms, defined as the subject treated with the anti-IL-36R antibody maintaining a GPPGA score of 0 or 1 (clean or nearly clean) and maintaining or reducing levels of miR-223-5p and / or miR-223-3 in all outpatient visits up to week 48 without receiving GPP hot red attack medication or investigator-specified standard care (SoC); (d) Until week 48, the incidence of GPP hot red flare decreased and the levels of miR-223-5p and / or miR-223-3 were maintained or decreased, where GPP hot red flare was defined as an increase of ≥2 in the GPP Physician Global Assessment (GPPGA) total score relative to baseline and a GPPGA pustular sub-score of ≥2; or (e) By week 48, the time to the first GPP hot red episode was prolonged, as measured by the time from baseline to the first GPP hot red episode, wherein a GPP hot red episode was defined as an increase of ≥2 in the GPP Physician Global Assessment (GPPGA) total score relative to baseline, and a GPPGA pustular sub-score of ≥2, and an increase in the levels of miR-223-5p and / or miR-223-3.

33. The method of claims 29 to 32, wherein the level of the biomarker is determined by small RNA sequencing, qPCR, or ELISA and IHC.

34. The method of any one of claims 29 to 33, further comprising continuing to administer a maintenance dose of the anti-IL-36R antibody to the patient if the difference in levels between the pre-treatment sample and the post-treatment sample reflects a beneficial response in the patient.

35. A method for determining whether a potential therapeutic agent is effective in treating and preventing GPP, the method comprising: (a) Obtain a first biological sample from a GPP patient before the onset of hot red and / or before treatment with the potential therapeutic agent; (b) Treat the GPP patient with the potential therapeutic agent; (c) Obtain a second biological sample from the GPP patient after treatment with the potential therapeutic agent; (d) Measuring the expression levels of one or more biomarkers in the first and second samples; and (e) Compare the levels of biomarkers in the second sample with those in the first sample. The change in the level of the biomarker in the second sample (e.g., lower or higher) compared to the level of the biomarker in the first sample indicates that the potential therapeutic agent is effective, and furthermore, the one or more biomarkers comprise microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p.

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

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

38. A method for treating generalized pustular psoriasis (GPP) in a subject with a history of GPP without experiencing a hot flash flare, the method comprising: a) Determining whether to initiate treatment for the subject, modify the treatment dose, modify the dosing interval, or discontinue treatment according to the method of any one of claims 29 to 37; and b) Modify the treatment plan based on the determined results.

39. A method for monitoring a patient's response to GPP treatment, the method comprising: (a) Obtaining the first biological sample from the patient; (b) Measure the level of one or more biomarkers in the first biological sample, wherein the one or more biomarkers comprise microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p; (c) Administering the treatment compound to the patient; (d) Obtain a second biological sample from the patient; (e) Measuring the levels of one or more biomarkers in the second biological sample; and (f) Compare the levels of one or more biomarkers obtained from the first and second biological samples; Upregulation or downregulation after treatment, compared to baseline before treatment, indicates an effective response.

40. A method for monitoring patient compliance with a drug regimen used to treat and prevent GPP hot red attacks, the method comprising: (a) Obtaining the first biological sample from the patient; (b) Measure the level of one or more biomarkers in the first biological sample, wherein the one or more biomarkers comprise microRNAs selected from the group consisting of miR-223-3p, miR-223-5p, miR-1304-3p, miR-485-5p, or miR-337-5p; (c) Administering the treatment compound to the patient; (d) Obtain a second biological sample from the patient; (e) Measuring the levels of one or more biomarkers in the second biological sample; and (f) Compare the levels of one or more biomarkers obtained from the first and second biological samples; Compared to the baseline before treatment, an up- or down-adjustment after treatment indicates patient compliance with the drug treatment regimen.

41. The method of claim 39, wherein the level of the one or more biomarkers in the second biological sample is reduced by at least about 20%, 30%, 40%, 50%, 55%, 60%, 65%, 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 skin biopsy, blood, plasma, or serum sample.

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

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

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